Side Effects of Drugs Annual 32
HONORARY EDITOR Prof. M.N.G. Dukes, Oslo, Norway
ADVISORY EDITORIAL BOARD Prof. F. Bochner, Adelaide, Australia Prof. I.R. Edwards, Uppsala, Sweden Prof. G.P. Velo, Verona, Italy
SIDE EFFECTS OF DRUGS ANNUAL 32 A worldwide yearly survey of new data and trends in adverse drug reactions and interactions EDITOR
J.K. ARONSON MA, DPhil, MBChB, FRCP, FBPharmacolS, FFPM (Hon) Reader in Clinical Pharmacology University Department of Primary Health Care Old Road Campus, Headington, Oxford OX3 7LF, UK
Amsterdam – Boston – Heidelberg – London – New York – Oxford Paris – San Diego – San Francisco – Singapore – Sydney – Tokyo
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Contributors
SARAH ABBAS Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK M.C. ALLWOOD, BPHARM, PHD Pharmacy Academic Practice Unit, School of Biological, Forensic and Pharmaceutical Sciences, University of Derby, Mickleover, Derby, UK. E-mail:
[email protected] BRIAN J. ANGUS, MD John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. E-mail:
[email protected] J.K. ARONSON, MA, MBCHB, DPHIL, FRCP, FBPHARMACOLS, FFPM (HON) University Department of Primary Health Care, Old Road Campus, Headington, Oxford OX3 7LF, UK. E-mail:
[email protected] V.V. BANU REKHA Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600031, India. E-mail:
[email protected] MATTHIAS BEHREND, MD, PHD Klinik für Viszeral-, Gefäß-, Thorax- und Kinderchirurgie, Klinikum Deggendorf, Perlasberger Str. 41, D-94469 Deggendorf, Germany. E-mail:
[email protected] KRISTIEN BOELAERT, MD, PHD, MRCP MRC Clinician Scientist and Honorary Consultant Endocrinologist, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, IBR Building 2nd floor, University of Birmingham, Birmingham B15 2TT, UK. E-mail:
[email protected] FELIX BRAUN, MD, PHD Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Zentrum Chirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail:
[email protected] DIETER C. BROERING, MD, PHD Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Zentrum Chirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail:
[email protected] TEHREEM F. BUTT, MBCHB, MRCP (UK) Department of Clinical Pharmacology, College of Medical and Dental Sciences, Univer sity of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail:
[email protected] v
vi
Contributors
ANDREW BYRNE, BA, MB, BCH, BAO, MRCPSYCH, MMEDSCI Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield, WF1 3SP, UK. E-mail:
[email protected] ALFONSO CARVAJAL, MD, PHD Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail:
[email protected] K. CHAN, PHD, DSC, FSB, FCP, FRPHARMS, FRSM Herbal Medicines Research and Education Centre (HMREC) Faculty of Pharmacy, The University of Sydney, NSW2006; and CompleMED, College of Science & Health, University of Western Sydney, NSW2560, Australia. E-mail:
[email protected] N.H. CHOULIS, MD, PHD LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania, Attika, Greece. E-mail:
[email protected] JAMIE J. COLEMAN, MBCHB, MA(MED ED), MD, MRCP(UK) Department of Clinical Pharmacology, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail:
[email protected] NATASCIA CORTI, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail:
[email protected] J. COSTA, MD Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Ctra. de Canyet s/n, 08916 Badalona, Spain. E-mail:
[email protected] STEPHEN CURRAN, BSC, MBCHB, MMEDSC, MRCPSYCH, PHD Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield, WF1 3SP, UK. E-mail:
[email protected] H.R. DALTON, BSC, DPHIL, FRCP, DIPMEDED Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall, TR1 3LJ, UK. E-mail:
[email protected] GWYNETH A. DAVIES, MD, MRCP Senior Clinical Lecturer, Asthma & Allergy, School of Medicine, Swansea University, Swansea, Wales, UK. E-mail:
[email protected] JANE DEMOCRATIS Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK S. DITTMANN, MD, DSCMED 19 Hatzenporter Weg, 12681 Berlin, Germany. E-mail:
[email protected] Contributors
vii
IDA DUARTE Santa Casa de São Paulo Medical School, Sao Paulo, Brazil. E-mail:
[email protected] M.N.G. DUKES, MD, MA, LLM Trosterudveien 19, 0778 Oslo, Norway. E-mail:
[email protected] RIF S. EL-MALLAKH, MD Director, Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, MedCenter One, 501 E Broadway, Suite 340, Louisville, KY 40202, USA. E-mail:
[email protected] M. FARRÉ, MD Unitat de Farmacologia, Institut Municipal d’Investigació Mèdica (IMIM)-Hospital del Mar, Universitat Autònoma de Barcelona, Doctor Aiguader 88, 08003 Barcelona, Spain. E-mail:
[email protected] M.G. FRANZOSI, PHD Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea 62, 20157 Milan, Italy. E-mail:
[email protected] S. GALEA, MD, MRCPSYCH, MSC (ADDICTIVE BEHAVIOUR), DIP (FORENSIC MENTAL HEALTH), ASSOCIATE FELLOW, ICDP Centre for Addiction Studies, St George’s Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17 0RE, UK. E-mail:
[email protected] YONGLIN GAO, MD Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, MedCenter One, 501 E Broadway, Suite 340, Louisville, KY 40202, USA. E-mail:
[email protected] A.H. GHODSE, MD, PHD, FRCP, FRCPSYCH Centre for Addiction Studies, St George’s Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17 0RE, UK. E-mail:
[email protected] FREYA A. GOUMAS, MD Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Zentrum Chirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail:
[email protected] ANDREAS H. GROLL, MD Infectious Disease Research Program, Center for Bone Marrow Transplantation and Depart ment of Hematology/Oncology, University Children’s Hospital, Albert-Schweitzer-Strasse 33, 48129 Muenster, Germany. E-mail:
[email protected] PETER M. HADDAD, BSC, MBCHB, FRCPSYCH, MD Greater Manchester West Mental Health NHS Foundation Trust, Cromwell House, 32 Cromwell Road, Eccles, Salford M30 0GT, UK. E-mail:
[email protected] A. HALL, BSC, MBCHB, FRCA School of Clinical Science, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. E-mail:
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Contributors
ALEXANDER IMHOF, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail:
[email protected] NATALIA JIMENO, MD, PHD Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail:
[email protected] OLIVER KOCH Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. E-mail:
[email protected] SARAH LANGENFELD, MD University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, USA. E-mail:
[email protected] R. LATINI, MD Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea 62, 20157 Milan, Italy. E-mail:
[email protected] ROSANA LAZZARINI Santa Casa de São Paulo Medical School, São Paulo, Brazil. E-mail:
[email protected] MARTIN LEUWER, MD University Department of Anaesthesia, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. E-mail:
[email protected] KEIR E. LEWIS, MD, MRCP Senior Clinical Lecturer, School of Medicine, Swansea, Wales, UK. E-mail:
[email protected] Z.X. LIN, BSC, PHD School of Chinese Medicine, Faculty of Science, The Chinese University of Hong Kong, 1/F, Sino Building, CUHK, Shatin, N.T., Hong Kong SAR, PR China. E-mail:
[email protected] PAM MAGEE, BSC, MSC, MRPHARMS Director of Pharmaceutical Services, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UK. E-mail:
[email protected] LUIS H. MARTÍN ARIAS, MD, PHD Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail:
[email protected] R.H.B. MEYBOOM, MD, PHD Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands. E-mail:
[email protected] Contributors
ix
MARK MIDDLETON, PHD, FRCP University of Oxford, Department of Medical Oncology, Churchill Hospital, Oxford OX3 7LJ, UK. E-mail:
[email protected] TORE MIDTVEDT, MD, PHD Department of Microbiology, Tumor and Cell Biology (MTC), Von Eulers v. 5, Karolinska Institutet, Box 60 400, S-171 77 Stockholm, Sweden. E-mail:
[email protected] SHABIR MUSA, MBCHB, MRCPSYCH Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield, WF1 3SP, UK. E-mail:
[email protected] R.C.L. PAGE, MD, FRCP, MA (ED) Endocrine Unit, Dundee House, City Hospital, Hucknall Road, Nottingham NG5 1PB. E-mail:
[email protected] JAYENDRA K. PATEL, MD University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, USA. E-mail:
[email protected] CH. P. PESCOTT, MD Sanquin Blood Supply Foundation, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail:
[email protected] HARI KRSHNAN, MBBS, FANZCA MMED Department of Anaesthesia & Intensive Care, Kuala Lumpur General Hospital, Jalan Pahang, 50160 Kuala Lumpur, Malaysia. E-mail:
[email protected] R. RAMNARACE, MBBS, MRCP Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall, TR1 3LJ, UK. E-mail:
[email protected] NADJA RIFAIE Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Zentrum Chirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail:
[email protected] RONA J. ROBERTS, MD Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, MedCenter One, 501 E Broadway, Suite 340, Louisville, KY 40202, USA. E-mail:
[email protected] ANITA ROTTER Clinic of Dermatology, Santa Casa de São Paulo, São Paulo, Brazil. E-mail:
[email protected] AMI SABHARWAL University of Oxford, Department of Medical Oncology, Churchill Hospital, Oxford OX3 7LJ, UK. E-mail:
[email protected] x
Contributors
CATHERINE SARGENT Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. E-mail:
[email protected] MICHAEL SCHACHTER, MD Department of Clinical Pharmacology, National Heart and Lung Institute, Imperial College, St Mary’s Hospital, London W2 1NY, UK. E-mail:
[email protected] JURGEN SCHIEFERMUELLER Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK J.S.A.G. SCHOUTEN, MD Department of Ophthalmology, Maastricht University Hospital, PO Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail:
[email protected] DOMINIK SCHREY Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Hematology/Oncology, University Children’s Hospital, Albert-SchweitzerStrasse 33, 48129 Muenster, Germany. E-mail:
[email protected] STEPHAN A. SCHUG, MD, FANZCA, FFPMANZCA Level 2, MRF Building G Block, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. E-mail:
[email protected] REGINALD P. SEQUEIRA, PHD, FCP Department of Pharmacology & Therapeutics, College of Medicine & Medical Sciences, Arabian Gulf University, PO Box 22979, Manama, Bahrain. E-mail:
[email protected] SUSANNE SHEEHY Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. E-mail:
[email protected] DOMENIC A. SICA, MD Section of Clinical Pharmacology and Hypertension, Division of Nephrology, Medical College of Virginia of Virginia Commonwealth University, Box 980160 MCV Station, Richmond, VA 23298-0160, USA. E-mail:
[email protected] OSCAR OZMUND SIMOOYA, BSC, MBCHB, MSC The Copper belt University, Health Services Division, PO Box 21692, Kitwe, Zambia, Central Africa. E-mail:
[email protected];
[email protected] S. STRAUBE, BM, BCH, MA, DPHIL Department of Occupational and Social Medicine, University of Göttingen, Waldweg 37 B, D-37073 Göttingen, Germany. E-mail:
[email protected] P.F.W. STRENGERS, MD Sanquin Blood Supply Foundation, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail:
[email protected] Contributors
xi
SOUMYA SWAMINATHAN, MD Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600031, India. E-mail:
[email protected] GIJSBERT B. VAN DER VOET, PHD, ERT Health Council of The Netherlands, Parnassusplein 5, 2511 VX The Hague, The Netherlands. E-mail:
[email protected] P.J.J. VAN GENDEREN, MD, PHD Havenziekenhuis and Institute of Tropical Diseases, Department of Internal Medicine, Harbour Hospital, Haringvliet 2, 3011 TD Rotterdam, The Netherlands. E-mail:
[email protected] R. VERHAEGHE, MD Center for Vascular Diseases, University of Leuven, Herestraat, 49, 3000 Leuven, Belgium. E-mail:
[email protected] P. VERHAMME, MD Center for Vascular Diseases, University of Leuven, Herestraat, 49, 3000 Leuven, Belgium. E-mail:
[email protected] GARRY M. WALSH, MSC, PHD School of Medicine, Institute of Medical Sciences Building, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. E-mail:
[email protected] THOMAS J. WALSH, MD Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. E-mail:
[email protected] CHRISTA WENGER, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: christa.
[email protected] C. WILLIAMS, BSC, MBCHB, FRCA Department of Anaesthesia, 12th Floor, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK. E-mail:
[email protected] EILEEN WONG, MD Harvard Medical School, Massachusetts Mental Health Center, Department of Psychiatry, Jamaica Plain, MA 02130, USA. E-mail:
[email protected] GAETANO ZACCARA, MD U.O. Neurologia, Ospedale S Giovanni di Dio, Via Torregalli, 50100 Firenze. E-mail:
[email protected] Special reviews
Antidepressants and emergent suicidality Adverse effects of antidepressants in pregnancy SSRIs and gastrointestinal bleeding Lithium in neuroprotection Ecstasy and neurocognition Deaths associated with antipsychotic drug treatment Serious skin reactions to carbamazepine Overdose of valproate and its management Frequency of adverse reactions to opioid analgesics Levacetylmethadol (levo-a-acetylmethadol, LAAM) Oxymorphone Pholcodine An update on cardiovascular and gastrointestinal adverse effects
of non-selective NSAIDs and coxibs Stereoisomers of arylpropionic acids Adrenal suppression from etomidate Management of adverse drug reactions to local anesthetics with lipid emulsion Sugammadex Tolcapone Dimethyl fumarate Inhaled glucocorticoids and the risk of pneumonia Inhaled glucocorticoids: update on skeletal adverse effects Indacaterol The cardiovascular risks of anticholinergic drugs Zileuton Mortality during treatment of atrial fibrillation with digoxin Dyspnea and bronchospasm associated with adenosine Enhanced eryptosis as a possible mechanism of action of amiodarone Pilsicainide Quality of life and adherence to antihypertensive drugs ACE inhibitors and angioedema Thiamine deficiency due to diuretics Resistance to antibacterial drugs Intrapartum antibiotics for mothers with group B streptococcal colonization:
to treat or not to treat? Drug-drug interactions with antifungal azoles The use of pyrimethamine þ sulfadoxine in intermittent preventive regimens in malaria Hepatotoxicity of antituberculosis drugs Dosages of antituberculosis drugs in children Antituberculosis drug treatment in transplant recipients Pharmacovigilance of antihelminthic drugs in developing countries Adverse effects of vaccine adjuvants The benefit to harm balance of drotrecogin alfa (activated) Tetrahydrobiopterin and sapropterin
xvi
29
31
33
41
63
89
129
157
183
193
203
206
225
229
249
261
275
289
295
311
312
317
318
322
333
337
339
348
375
380
401
445
446
497
523
555
557
559
571
577
591
609
Special reviews
xvii
Heparin-induced thrombocytopenia type II in different populations of patients Danaparoid sodium Withdrawal of aprotinin TGN1412 Hormone replacement therapy and ovarian cancer Long-term medical and social consequences of androgenic anabolic steroid abuse Reduced bone density and risk of fracture due to thiazolidinediones Peroxisome proliferator-activated dual receptor agonists Torcetrapib Monofunctional alkylating agents Photodynamic therapy in the treatment of cancers Sialadenitis due to iodinated contrast media Contrast medium-induced nephrotoxicity Systemic fibrosis due to gadolinium-based contrast agents Injectable formulations of Chinese medicines
626
631
642
691
740
751
779
782
816
827
832
845
846
852
880
Cumulative indexes of special reviews, Annuals 12–31 1. Index of drugs Note: the format 31.352 refers to SEDA-31, p. 352. Abetimus, drug development, 29.460 ACE inhibitors acetylsalicylic acid, interaction, 28.124 angioedema, 22.225, 29.207, 31.352 cough, 19.211 indications, 24.233 Acetaminophen, see Paracetamol Acetylsalicylic acid, 21.100 ACE inhibitors, interaction, 28.124 antithrombotic effectiveness, 12.74 benefit to harm balance in preventing strokes and heart attacks, 27.109
co-medication, 26.423
gastrointestinal effects, 17.95, 18.90
Reye's syndrome, 11.79, 15.85
rhinosinusitis/asthma, 17.94
respiratory disease, 31.193
sensitivity, 12.75
Acupuncture incidence of adverse effects, 29.589 traumatic effects, 29.590 Adrenaline, myocardial infarction and vasospasm, 31.259 Aerosols, delivery, 27.172 Albumin, human, anaphylaxis, 14.296 Alcohol, 31.757 vitamin A, beta-carotene, interaction, 24.442 Aldosterone antagonists, in heart failure, 24.246 Alkylating drugs, 31.721 Aluminium in albumin solutions, 23.359
toxicity in children, 12.185
tumorigenicity, 31.383
Aminoglycoside antibiotics, 17.304 contact dermatitis, 13.225 dosage regimens, 20.234, 21.265, 23.264 nephrotoxicity, 15.268, 17.305 ototoxicity, 14.222, 18.268 and ribostamycin, 15.270
xviii
Amiodarone, dysrhythmias, 25.211 respiratory toxicity, 15.168 thyroid disease, 27.192, 31.327 Amphetamines, 29.3 Amphotericin, liposomal, 17.319 nephrotoxicity, 13. 231, 14.229, 27.276 Anabolic steroids, abuse in sport, 29.508 Analgesics agranulocytosis and aplastic anemia, 11.87 choice of drug and dose, 12.63 headache, 21.95 headaches in children, 23.114 nephropathy, 21.98 Androgens, in women, 24.477 Anesthesia, dental, safety of, 16.122 Anesthetics halogenated, renal damage, 20.106
local, combinations, 20.121
local, lipid rescue, 31.231
local, neurotoxicity, 21.129, 25.152
ocular, 17.542
Angiotensin II receptor antagonists, angioedema 30.238 Anisoylated plasminogen-streptokinase activator complex (APSAC), 12.313 Anorectic drugs cardiac valvulopathy 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Anthracyclines, 25.533 Antiallergic drugs, ocular treatment, 11.420 Antibacterial drugs, resistance, 31.413 Anticancer antimetabolites, 29.531 Anticholinergic drugs, 22.507, 31.273 Anticoagulants, oral, skin necrosis, 29.358 Anticonvulsants, see Antiepileptic drugs Antidepressants, see also individual agents during and after pregnancy, 21.17
mania, 29.18
overdose, 28.14
relative risks, 11.16
Cumulative indexes of special reviews, Annuals 12–31 Antidysrhythmic drugs in atrial fibrillation, 24.197 prodysrhythmic effects, 17.218, 23.196 Antiepileptic drugs bone loss, 27.74 comparison, 25.78 death, 23.83 overdosage, 22.84 psychiatric effects, 22.82, 27.72 Antiestrogens, genotoxicity and tumorigenicity, 27.429 Antifungal drugs drug interactions (azoles), 24.318, 28.299, 29.282, 30.320, 31.459 Pneumocystis jiroveci (carinii) pneumonia, 18.289 Antihelminthic drugs, Mazzotti reaction, 31.507 Antihistamines cardiovascular adverse effects, 17.196, 22.176, 25.183, 26.180 drowsiness/sedation, 21.170, 23.171, 26.182 Antihypertensive drugs, 19.209 in diabetes mellitus, 28.226 fixed-dose combinations, 22.224 individualizing therapy, 17.246 Antimalarial drugs, 14.237, 17.325, 20.257 adjunctive treatments, 24.330 prophylaxis, 13.239, 23.304 Antimicrobial drugs, see also different types allergic reactions, 23.251 coagulation disorders, 18.258 colitis, 12.216, 17.303 intestinal motility, 13.220 male fertility, 16.262 new, 13.210 new, with adjuvants, 17.296 the pill and pregnancy, 24, 274 policies and politics, 16.273 pregnancy, 11.231 prescribing, 15.254 preterm infants, 21.258 prudent use, 25.279 , 27.242, 28. 265 resistance, 12.206, 13.210, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273, 29.244, 31.413
seizures, 18.261
side chains, 16.264
Antioxidant vitamins, 20.363 Antiprotozoal drugs African trypanosomiasis, 18.293 toxoplasmosis, 20.262 Antipsychotic drugs comparisons of different types 25.53, 27.50 diabetes mellitus, 28.60 use in conditions other than schizophrenia, 27.49 use in elderly patients, 30.59 weight gain, 26.56 Antiretroviral drugs, metabolic complications, 28.329
xix
Antischistosomal drugs, 12.261 Antithyroid drugs, pregnancy, 13.377 Antituberculosis drugs, 16.341, 31.500 genetic susceptibility, 28.342 hepatotoxicity, 25.363, 26.339, 31.495 Mycobacterium avium–complex infection, 20.278 Appetite suppressants cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Aripiprazole, 31.70 Aspirin, see Acetylsalicylic acid Asthma medications, exacerbation of asthma, 20.165 Atovaquone, 19.266 Avoparcin lessons from, 27.242 resistance, 29.244 Azathioprine, see Thiopurines Azoles, see Antifungal drugs Baclofen, withdrawal syndrome, 26.152 Bambuterol, cardiac failure, 23.181 Benzodiazepines brain damage, 14.36
dependence, 12.41
depression, 17.43
medicolegal aspects, 13.33
Beta2-adrenoceptor agonists, 18.159 asthma, 19.178, 21.179 asthma deaths, 17.164 long-acting, respiratory adverse effects, 30.198, 31.309
long-acting, genetic susceptibility factors,
30.199, 31.310
Beta-adrenoceptor antagonists arthralgia, 11.164 sexual function, 15.188 Beta-carotene, see also Vitamin A alcohol, vitamin A, interaction, 24.442 tumorigenicity, 25.454 Beta-lactam antibiotics effects on eukaryotic cells, 13.212 immediate hypersensitivity reactions, 14.211 pregnancy, 25.280 Blood, see Transfusions Botulinum toxin A, use in primary axillary hyperhidrosis, 27.161 Budesonide, children, susceptibility factors, 30.194 Calcium antagonists, long-term safety, 20.185, 21.208, 22.214 Carnitine, 13.269 Carotenoids, tumorigenicity, 25.454 Ceftriaxone, 15.258 nephrolithiasis, 29.246
xx Cephalosporins immunological reactions, 28.267 hypersensitivity reactions, cross-reactivity with penicillins, 30.280 and vitamin K, 12.210 Charcoal, activated, in digitalis overdose, 24.201 Chloramphenicol, children, 15.267 Chloroquine, 15.286 Chondroprotective agents, 14.439 Chymopapain, 11.279, 14.264 Ciclesonide, 30.196 Ciclosporin, urinary system, 19.348 Clozapine, 15.50 agranulocytosis, 22.1359 Cocaine cardiovascular effects, 18.5 fetotoxicity, 29.41, 30.35 prenatal exposure and perinatal effects, 27.1 second-generation effects, 20.24 Cocamidopropylbetaine, allergy, 19.151 Complementary and alternative therapies, indirect risks, 27.521 esophagus, adverse effects on, 14.442 Contrast media adverse effects, 13.431, 24.525 anaphylactoid and allergic reactions, 20.422 delayed reactions, 26.513 in magnetic resonance imaging, 20.419 nephrotoxicity, 27.500, 28.556, 29.575, 31.731, 31.735 Codeine, breast feeding, 31.154 Corticosteroids, see Glucocorticoids Cosmetics adverse effects, 13/117
contact allergy, 11.142, 16.150, 19.151
ingredient labeling 22.159
Co-trimoxazole, hypersensitivity reactions, 20.264 COX-2 inhibitors, 24.115, 25.126, 26.116 vascular disease, 29.116 Daptomycin, muscle damage, 30.309 Deferiprone, cardiac siderosis, 29.235 Deferoxamine, 16.247 bone dysplasia, 23.241
cardiac siderosis, 29.235
bone dysplasia, 23.241
cardiac siderosis, 29.235
yersiniosis, 11.215
Diamorphine, progressive spongiform leukoencephalopathy, 24.40 Diclofenac, liver damage, 20.91 Diethylstilbestrol, transgenerational effects, 31.657 Digitalis, in atrial fibrillation, 24.197 Digoxin, compared with other drugs in heart failure in sinus rhythm, 14.141 compared with other drugs in chronic uncomplicated atrial fibrillation, 14.144
Cumulative indexes of special reviews, Annuals 12–31
in heart failure in sinus rhythm, 18.196
Dipeptidyl peptidase IV inhibitors, 30.498
Diuretics
diabetes mellitus, electrolyte abnormalities, and the ALLHAT trial, 27.219
hyponatremia, 29.219
interactions with NSAIDs, 12.80
renal cell carcinoma, 23.225
renal insufficiency, 25.250
DNA alkylating drugs, 31.721
Dofetilide, 26.208
Dopamine receptor agonists
pathological gambling, 30.174
sleep disorders, 26.160, 27.149
Doxylamine, overdose and rhabdomyolysis,
31.298 Ecstasy, see MDMA
EDTA, pseudothrombocytopenia, 21.250
Endothelin receptor antagonists, in
hypertension, 26.233 Enzyme inhibitors, 15.337 Epinephrine, see Adrenaline Erythromycin, versus the new macrolides, 21.269 Erythropoietin, pure red cell aplasia, 27.348 status and safety, 16.400
Ethambutol, optic neuropathy, 30.358
Ethylene oxide, dialyser hypersensitivity,
11.219
Etoposide, 27.477
Etretinate, ossification, 12.127
Euxyl K 400, contact allergy, 16.150
Fat emulsions, priapism, 11.313 Felbamate
aplastic anemia, 19.68, 22.86
risk/benefit ratio, 23.86
Fenfluramine cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Fenoterol, safety in severe asthma, 23.182 Fentanyl, buccal and transdermal administration, 20.77 Fertility drugs
malignant melanoma, 26.434
ovarian cancer, 24.474
Finasteride, 30.480
Fish oil, 13.460
Flecainide, in supraventricular dysrhythmias,
21.200
Fluoroquinolones, 12.250, 18.271
Fluorouracil, adverse effects, 23.476
Folic acid, dietary supplementation, 19.369
safety aspects, 27.407
Formoterol, tolerance, 24.187
Fragrances, contact allergy, 20.149
Cumulative indexes of special reviews, Annuals 12–31 Gadolinium salts, nephrotoxicity, 28.561, 31.735 General anesthetics, see Anesthetics Germanium, 16.545 Glucocorticoids bone, 16.447, 22.182, 25.195 contact allergy, 15.139, 21.158 effective dose and therapeutic ratio, 23.175 and eyes, 29.481 and growth, 14.335 inhaled, children, risks in, 27.174 inhaled, effects on mouth and throat, 29.168 inhaled, effects on skin, 29.169 inhaled, fracture risk, 31.307 inhaled, growth inhibition, 26.186 inhaled, hypothalamic–pituitary–adrenal gland function, 31.305 inhaled, systemic availability, 24.185, 26.187 musculoskeletal adverse effects, 21.417 osteoporosis and osteonecrosis, 16.447, 19.377, 20.374, 21.417, 22.182, 28.473 preterm infants, 17.445 Glucose solutions, hypophosphatemia, 11.312 Grapefruit juice, drug interactions 23.519 Growth hormone adults, 16.501
Creutzfeldt-Jakob disease, 11.371
insulin resistance, 24.504
malignancy, 23.468
Heparin low-molecular-weight, 12.311 thrombocytopenia, 30.404 Hepatitis B vaccine, demyelinating diseases, 21.331, 22.346, 24.374 Herbal medicines, warfarin, interactions, 30.400 Heroin, see Diamorphine Histamine (H2) receptor antagonists, 13.330, 15.393 HIV-protease inhibitors insulin resistance, 22.317 lipodystrophy, 22.317 HMG Co-A reductase inhibitors, interactions, 25.530, 30.517 Hormone replacement therapy, cardiovascular effects, 31.659 Hormones, sex breast cancer 11.346 tumors, 22.465 HRT, see Hormone replacement therapy 5-HT, see Serotonin Hydrochlorothiazide, non-cardiogenic pulmonary edema, 31.373 Hypnotics, 20.30 avoiding adverse effects, 21.37 Hypoglycemic drugs, combinations of, 27.458, 28.521
xxi
Immunization adverse effects, 24.364 and autoimmune disease, 27.336 bioterrorism, 25.378, 26.354 multiple, 27.334 surveillance after, 15.340, 22.333, 23.335, 24.364, 25.376, 26.353, 27.334 Immunotherapy, in leishmaniasis, 15.299 Incretin mimetics, 29.528 Indometacin, fetal and neonatal complications, 18.102 Influenza vaccine, 29.332 Inhalations, 11.151 Insulin edema, 11.364
human, and hypoglycemia, 15.452
inhalation, 30.495
modes of administration, 26.464
resistance, and growth hormone, 24.504
synthetic analogues, 24.489
Interferon þ ribavirin, 30.344
Interferons, psychological and psychiatric effects,
29.384 Interleukin-2, 14.325 Ipecacuanha, myopathy, 11.422 Irinotecan, 27.477 Iodine, radioactive, 11.358 Iron chelators, combinations, 31.399 Isoniazid genetic susceptibility factors, 12.257
prophylactic, toxicity, 24.352
Kathon® CG, 31.134 Kava kava liver damage, 27.518 adverse effects, 28.579 Ketoconazole, hepatotoxicity, 12.229 Ketorolac, risk of adverse effects, 17.110 Khat, 30.43 Lamotrigine, skin rashes, 20.62, 24.88 Latex, allergy, 31.761 Laxatives, abuse, 13.336 Leflunomide, 29.435 Leukotriene receptor antagonists, Churg–Strauss syndrome, 24.183, 27.177, 29.174 Levodopa, and malignant melanoma, 31.267 Lipid-lowering drugs, 13.402, 15.479 Lithium adverse effects, prevention and treatment, 13.17, 17.28 beneficial uses other than in bipolar disorder, 27.19 efficacy, comparisons with other agents, 30.23 interactions, 16.13, 18.30 intoxication, prevention and treatment, 17.29 monitoring therapy, 11.24, 18.25
xxii Lithium (cont) mortality, 19.14 urinary system, 14.18, 19.16 thyroid, 12.26 Local anesthetics, see Anesthetics Loop diuretics, see Diuretics Lorenzo's oil, 27.475 Lyme disease vaccine, autoimmune disease, 24.366 Macrolides, drug interactions, 14.220 intestinal motility, 18.269 Malaria vaccines, 22.306 Mannitol, 28.236 MAO inhibitors, see Monoamine oxidase inhibitors MDMA (ecstasy) cognitive effects, 26.32 deaths, 24.32 epidemiology of use, 30.37 Measles immunization see also MMR autism, 23.350 Crohn’s disease, 23.350 neurological adverse effects, 23.348 subacute sclerosing panencephalitis, 29.335 Mebendazole, hypersensitivity reactions, 12.263 Melatonin, 25.523 Mercaptopurine, see Thiopurines Metamfetamine, 29.3 Metformin contraindications, 28.515 lactic acidosis, 23.459, 29.526 Methyldibromoglutaronitrile, contact allergy, 16.150, 19.151 Methylphenidate, effects at different ages, 31.6 Methylthiotetrazole, 11.226 Mibefradil, drug interactions, 23.210 Midazolam, 15.112 Midodrine, 26.159 Milrinone, intravenous, acute heart failure, 21.196 MMR immunization autism, 23.350, 25.387, 28.363 Crohn’s disease, 23.350, 25.387 Mometasone furoate, 30.197 Monoamine oxidase inhibitors, 12.8, 13.6, 17.361 Morphine, managing adverse effects, 26.98 Muscle relaxants emergency medicine, 20.133
eyes, 21.145
hypersensitivity reactions, 27.138
intensive care, 19.140
Neuromuscular blocking agents, anaphylaxis, 29.145 non-depolarizing neuromuscular blockers, 15.127
recovery in intensive care, 12.114
Cumulative indexes of special reviews, Annuals 12–31
residual paralysis, 27.139
Niacin, extended-release, 16.440
N-Lost derivatives, 31.721
Nomifensine, 11.15
NSAIDs, see also COX-2 inhibitors
acute renal insufficiency, 28.122 blood pressure, 19.92, 27.102 children, 19.96 current controversies, 17.102 COX-2 inhibitors, 24.115, 25.126, 26.116 dyspepsia, 28.120 gastrointestinal adverse effects, 14.79, 17.95, 18.90, 18.99, 20.86, 21.96, 22.108, 23.114 gastrointestinal damage, role of Helicobacter pylori, 27.105 gastrointestinal damage, reducing, 30.125 gastrointestinal toxicity, prevention, 19.93 inflammatory bowel disease, 25.131 inhibiting cardioprotective effects of acetylsalicylic acid, 28.118 interactions with diuretics, 12.80 intracerebral hemorrhage, 28.119 necrotizing fasciitis, 28.121 nephrotoxicity, 11.82, 18.100, 20.89, 24.120, 26.111
osteoarthritis, 11.87
skin reactions, 13.72
topical, 18.163
Ocular drugs
allergic reactions, 21.486
geriatric patients, 16.542
risk factors for adverse effects, 22.507
Omeprazole, tumors, 16.423 Opioids
abuse, 29. 44
adverse effects, prevention, 24.100
death, 25.37
obstetric use, 24.102
routes of administration, 30.106
tolerance in neonates, 23.97
Oral contraceptives
antimicrobial drugs, and pregnancy, 24.274
and breast cancer, 15.426
formulations, 24.472
third-generation, 25.484, 26.442
venous thromboembolism, 23.442
Orlistat, 30.429 Paclitaxel, adverse effects, 21.463
Pancreatic enzyme supplements, fibrosing
colonopathy, 20.322
Paracetamol
asthma, 30.129
hepatotoxicity in alcoholism, 12.76
liver damage, 17.98, 18.94
overdose, 13.68, 23.117
Cumulative indexes of special reviews, Annuals 12–31 Parenteral nutrition bone effects, 22.378 cholestasis, 22.376 infections 22.379 Penicillins acute desensitization, 23.252 hypersensitivity reactions, cross-reactivity with cephalosporins, 30.280 immunological reactions, 28.267 Peritoneal dialysis fluids, effects on peritoneum, 22.381 Pertussis vaccine, 11.284, 11.285 Phentermine, cardiac valvulopathies, 24.4 Phytoestrogens, in foodstuffs, 31.655 Piroxicam gastrointestinal effects, 11.97, 12.91 Pivalic acid, and carnitine, 12.209 Platinum compounds, 26.490 Polio vaccine, AIDS, 23.352 Polyaspartic acid, protective against nephrotoxicity, 17.305 Polyethylene glycol, electrolyte, mineral, metal, and fluid balance, 29.376 Polystyrene sulfonates, 25.271 Polyvinylpyrrolidone, storage disease, 22.522 Pregabalin, 30.86 Propofol infusion syndrome, 26.135 prevention of pain, 30.143 Propolis, allergy, 17.181 Proton pump inhibitors, tumors, 23.383 Psilocybin, 31.49 PUVA, malignant melanoma, 22.166 Pyrazinamide, in latent pulmonary tuberculosis, 27.323 Quinidine, versus quinine, 15.295 Quinine, versus quinidine, 15.295 Rasagiline, 31.270 Rasburicase, 31.203 Renin inhibitors, 30.242 Rhesus anti-D, prophylaxis, 13.297 Ribavirin þ interferon, 30.344 Ribostamycin, and aminoglycosides, 15.270 Rocuronium, allergic reactions, 26.150 and pholcodine, 31.249 Rotashield, intussusception, 23.354 Rotavirus vaccine, Kawasaki disease, 31.522 Rubella vaccine, joints, 11.295 Salbutamol, adrenoceptor genotypes, 29.173 Salmeterol, tolerance, 24.187 Sedatives, 29.128 Sex hormones, tumors, 22.465 Serotonin receptor antagonists, 15.391
xxiii
selective serotonin reuptake inhibitors, drug interactions, 22.13 selective serotonin reuptake inhibitors, suicidal behavior, 29.19, 31.18 Smallpox vaccination, 27.339 Somatostatin, 15.468 Spinal manipulation, adverse effects, 29.591 SSRIs, see Serotonin Statins, see HMG Co-A reductase inhibitors Steroids, see Glucocorticoids Stimulants, in ADHD, 31.4 Sulfonamide derivatives, hypersensitivity reactions, 30.252 Sumatriptan, 17.171 Suprofen, nephrotoxicity, 12.88 Suramin, patients with prostate cancer, 20.283 Surgam, gastric effects, 12.89 Suxamethonium, postoperative myalgia, 28.155 Tamoxifen, versus aromatase inhibitors, 30.475 Teniposide, 27.477 Tetracyclines adverse effects, 12.212, 26.268
chemically modified, 31.419
comparative toxicity, 22.268
and metalloproteinases, 26.266
non-antimicrobial properties, 30.288
in pregnancy, 25.280
in rheumatology, 23.255
therapeutic effects, 24.278
Theophylline, asthma, 17.2, 18.1, 18.2 Thiazides, see Diuretics Thiazolidinediones cardiovascular effects, 31.697 peripheral edema, 29.531 Thiomersal, in vaccines, 28.357 Thiopurines, genetic susceptibility, 31.634 Thyroid hormones, 29.464 Thyroxine, drug interactions, 24.484 Tiaprofenic acid, cystitis, 18.106 TNF, see tumor necrosis factor Topiramate, cognitive effects, 26.81 Topoisomerase inhibitors, 27.477 Topotecan, 27.477 Transfusions AIDS, 12.298 complications, 12.300 Tretinoin, topical, teratogenicity, 18.164 Triazolam, 16.33 Tricyclic antidepressants endocrine effects, 11.12 mania, 13.8 L-tryptophan, eosinophilia-myalgia syndrome, 15.514 Tumor necrosis factor antagonists, infection risk, 29.395, 31.594 Tyrosine kinase inhibitors, 30.520
xxiv
Cumulative indexes of special reviews, Annuals 12–31
Vaccines, see also individual agents autism, 31.516 combinations, 29.327, 30.369 Guillain–Barré syndrome, 31.515 HIV-infected individuals, 12.269 Kawasaki disease, 31.522 national compensation systems, 12.271 poliomyelitis, 22.352 thiomersal in, 28.357 Valproate, polycystic ovary syndrome, 26.81 Vancomycin lessons from, 27.242 resistance, 29.244 Vigabatrin psychosis and abnormal behavior, 18.71 visual field defects, 21.78, 24.95, 25.98, 26.82 Vinca alkaloids, 28.538
Vitamin A, 17.436
alcohol, beta-carotene, interaction, 24.442
hypervitaminosis, 15.411
in pregnancy, 21.405
and prostate cancer, 13.346
Vitamin B6, debate, 23.420
Vitamin E, co-medication, 26.423
Vitamin K
cancer, 23.424
skin reactions, 25.461
Vitamins, in old age, 22.431
2. Index of adverse effects
asthma deaths, beta2-adrenoceptor agonists, 17.164 asthma exacerbation, asthma medications, 20.165 beta2-adrenoceptor agonists, long-acting, 30.198 bronchoconstriction, paradoxical, nebulizer solutions, 13.134 Churg–Strauss syndrome, leukotriene receptor antagonists, 24.183, 27.177, 29.174 cough, ACE inhibitors, 19.211 long-acting beta2-adrenoeceptor agonists, 31.309 primary pulmonary hypertension, appetite suppressants, 18.7, 21.2, 23.2, 25.5 pulmonary edema, non-cardiogenic, hydrochlorothiazide, 31.373 rhinosinusitis, acetylsalicylic acid, 17.94 Ear, nose, throat glucocorticoids, inhaled, 29.168 Nervous system anticholinergic effects, 31.273 brain damage, benzodiazepines, 14.36 Creutzfeldt–Jakob disease, growth hormone, 11.371 demyelinating diseases, hepatitis B vaccine, 21.331, 22.346, 24.374 drowsiness/sedation, antihistamines, 21.170, 23.171, 26.182 Guillain–Barré syndrome, vaccines 31.515 headache, analgesics, 21.95, 23.114 intracerebral hemorrhage, NSAIDs, 28.119 neuroleptic malignant syndrome, 11.47, 20.41 neurotoxicity, anesthetics, local, 21.129 neurotoxicity, measles immunization, 23.348 overdosage, antiepileptic drugs, 22.84 pain, propofol, 30.143 poliomyelitis, vaccines, 22.352 progressive spongiform leukoencephalopathy, diamorphine, 24.40
Cardiovascular atrial fibrillation, antidysrhythmic drugs, 24.197 atrial fibrillation, digitalis, 24.197 cardiac failure, aldosterone antagonists, 24.246 cardiac failure, bambuterol, 23.181 cardiac siderosis, deferoxamine/deferiprone, 29.235 cardiotoxicity, antihistamines, 17.196, 25.183, 26.180 cardiotoxicity, calcium antagonists, 20.185 cardiotoxicity, cocaine, 18.5 cardiotoxicity, coxibs, 29.116 cardiotoxicity, hormone replacement therapy, 31.659 cardiotoxicity, propofol, 26.135 cardiotoxicity, thiazolidinediones, 31.697 dysrhythmias, antihistamines, 22.176 dysrhythmias, amiodarone, 25.211 hypertension, NSAIDs, 19.92, 27.102 myocardial infarction, acetylsalicylic acid, 27.109 myocardial infarction, adrenaline, 31.259 prodysrhythmic effects, antidysrhythmic drugs, 17.218, 23.196 QT interval prolongation, 24.54 valvulopathies, fenfluramine, 22.3, 23.2, 24.4, 25.5 valvulopathies, phentermine, 24.4, 25.5 vasospasm, adrenaline, 31.259 venous thromboembolism, oral contraceptives, 23.442 Respiratory amiodarone, 15.168
asthma, acetylsalicylic acid, 17.94, 31.193
asthma, fenoterol, 23.182
asthma, paracetamol, 30.129
asthma, in pregnancy, 28.186
Warfarin, herbal medicines, interactions, 30.400 Ximelagatran, hepatotoxicity, 30.411 Zidovudine, 13.246
Cumulative indexes of special reviews, Annuals 12–31 seizures, antimicrobial drugs, 18.261 sleep disorders, dopamine receptor agonists, 26.160, 27.149 strokes, acetylsalicylic acid, 27.109 strokes, risperidone, 28.76 subacute sclerosing panencephalitis, measles vaccine, 29.335 tardive dyskinesia, 14.47, 20.38 tardive syndromes, 17.54 transient symptoms, intrathecal anesthetics, 25.152 Neuromuscular residual paralysis, neuromuscular blocking drugs, 27.139 Sensory systems eye effects, drug abuse, 12.33 eye effects, glucocorticoids, 29. 481 eye effects, muscle relaxants, 21.145 optic neuropathy, ethambutol, 30.358 ototoxicity, aminoglycosides, 14.222, 18.268 visual field defects, vigabatrin, 21.78, 24.95, 25.98, 26.82 Psychological cognitive effects, MDMA, 26.32 cognitive effects, metamfetamine, 29.3 cognitive effects, topiramate, 26.78 gambling, dopamine receptor agonists, 30.174 interferons, 29.384 Psychiatric antiepileptic drugs, 22.82, 27.72 autism, MMR/measles immunization, 23.350, 25.387, 28.363, 31.516 depression, benzodiazepines, 17.43 mania, antidepressants, 13.8, 29.18 interferons, 29.384 psychosis and abnormal behavior, vigabatrin, 18.71
suicidal behavior, SSRIs, 29.19, 31.18
Endocrine diabetes mellitus, antihypertensive drugs, 28.226 diabetes mellitus, antipsychotic drugs, 28.60 diabetes mellitus, diuretics, 27.219 hypothalamic–pituitary–adrenal gland function, inhaled glucocorticoids, 31.305 insulin resistance, growth hormone, 24.504 insulin resistance, HIV-protease inhibitors, 22.317
ovarian hyperstimulation syndrome,
valproate, 26.477 polycystic ovary syndrome, valproate, 26.81 thyroid disease, amiodarone, 27.192, 31.310 thyroid disease, lithium, 12.26 tricyclic antidepressants, 11.12 Metabolism antiretroviral drugs, 28.329
hyperlactatemia, 29.302
xxv
hypoglycemia, insulin, 15.452 lactic acidosis, metformin, 23.459, 29.526 lipoatrophy, 29.302 lipodystrophy, HIV-protease inhibitors, 22.317 metabolic acidosis, propofol, 26.135 mitochondrial toxicity, 29.302 polyvinylpyrrolidone storage disease, 22.522 weight gain, antipsychotic drugs, 26.56 Electroyte balance electrolyte abnormalities, diuretics, 27.219, 29.219
polyethylene glycol, 29.376
Mineral balance hypophosphatemia, glucose solutions, 11.312 polyethylene glycol, 29.376 Metal balance polyethylene glycol, 29.376 Fluid balance edema, insulin, 11.364
edema, thiazolidinediones, 29.531
polyethylene glycol, 29.376
Hematologic agranulocytosis, analegsics, 11.89 agranulocytosis, clozapine, 22.59 aplastic anemia, analegsics, 11.89 aplastic anemia, felbamate, 19.68, 22.86 coagulation disorders, beta-lactam antibiotics, 18.258 eosinophilia-myalgia syndrome, tryptophan, 15.514 hemolytic disease of the newborn, anti-D prophylaxis, 12.293 hemostasis, cephalosporins, 12.210 pseudothrombocytopenia, EDTA, 21.250 pure red cell aplasia, erythropoietin, 27.348 thrombocytopenia, heparin, 30.404 Mouth Glucocoricoids, inhaled, 29.168 Gastrointestinal bleeding, acetylsalicylic acid, 17.95, 18.90 cholestasis, total parenteral nutrition, 22.376 colitis, antimicrobial drugs, 12.216, 17.303 Crohn's disease, MMR/measles immunization, 23.350, 25.387 dyspepsia, NSAIDs, 28.120 fibrosing colonopathy, pancreatic enzyme supplements, 20.322 inflammatory bowel disease, NSAIDs, 25.131 intestinal motility, antimicrobial drugs, 13.220 intestinal motility, macrolides, 18.269 intussusception, Rotashield, 23.354 piroxicam, 12.91 Surgam, 12.89 ulceration, bleeding and perforation, NSAIDs, 11.97, 14.79, 16.103, 17.95, 18.90, 18.99, 19.93, 20.86, 21.96, 22.108, 23.114, 27.105, 30.125
xxvi Liver hepatotoxicity, alcohol/vitamin A/beta carotene, 24.442 hepatotoxicity, antituberculosis drugs, 25.363, 26.339, 31.495 hepatotoxicity, diclofenac, 20.91 hepatotoxicity, kava kava, 27.518 hepatotoxicity, ketoconazole, 12.229 hepatotoxicity, paracetamol, 12.76, 17.98, 18.94 hepatotoxicity, ximelagatran, 30.411 Reye's syndrome, acetylsalicylic acid, 11.79, 15.85 Urinary tract acute renal insufficiency, NSAIDs, 28.122 cystitis, tiaprofenic acid, 18.106 nephrolithiasis, ceftriaxone, 29.246 nephrotoxicity, aminoglycosides, 15.268, 17.305 nephrotoxicity, amphotericin, 13.231, 14.229, 27.276
nephrotoxicity, analgesics, 21.98
nephrotoxicity, anesthetics, halogenated,
20.106 nephrotoxicity, ciclosporin, 19.348 nephrotoxicity, contrast media, 27.500, 28.556, 29.575, 31.731, 31.735 nephrotoxicity, gadolinium salts, 28.561 nephrotoxicity, lithium, 14.18, 19.16 nephrotoxicity, NSAIDs, 11.82, 18.100, 20.89, 24.120, 26.111
nephrotoxicity, suprofen, 12.88
renal cell carcinoma, diuretics, 23.225
renal insufficiency, diuretics, 25.250
Skin contact allergy, 23.160 contact allergy, glucocorticoids, 15.139 contact dermatitis, aminoglycosides, 13.225 cutaneous reactions, NSAIDs, 13.72 glucocorticoids, inhaled, 29.169 necrosis, oral anticoagulation, 29.358 rashes, lamotrigine, 20.62, 24.88 vitamin K1, 25.461 Serosae peritoneum, peritoneal dialysis, 22.381
pleurodesis, 25.189
Musculoskeletal arthralgia, beta-adrenoceptor antagonists, 11.164 arthralgia, rubella vaccination, 11.295 bone, total parenteral nutrition, 22.378 bone dysplasia, deferoxamine, 23.241 bone loss, antiepileptic drugs, 27.74 bone mineral density, glucocorticoids, 25.195 eosinophilia-myalgia syndrome, tryptophan, 15.514
fractures, inhaled glucocorticoids, 31.307
Cumulative indexes of special reviews, Annuals 12–31
growth in children, inhaled glucocorticoids, 26.186 growth in children, oral glucocorticoids, 14.335 growth in children, stimulants, 31.4 muscle damage, daptomycin, 30.309 myopathy, ipecacuanha, 11.422 ossification, etretinate, 12.127 osteoarthritis, NSAIDs, 1187 osteoporosis and osteonecrosis, glucocorticoids, 16.447, 19.377, 20.374, 21.417, 22.182, 28.473 rhabdomyolysis, doxylamine overdose, 31.298 rhabdomyolysis, propofol, 26.135 postoperative myalgia, suxamethonium, 28.155 Sexual function beta-adrenoceptor antagonists, 15.188 priapism, fat emulsions, 11.313 Immunologic allergic reactions, antimicrobial drugs, 23.251 allergic reactions, contact allergy, cosmetics, 11.142 allergic reactions, contact allergy, Kathon® CG, 11.134 allergic reactions, latex, 31.761 allergic reactions, rocuronium, 26.150 allergy testing, chymopapain, 11.279 anaphylaxis, human albumin, 14.296 anaphylaxis, neuromuscular blocking agents, 29.145 angioedema, ACE inhibitors, 22.225, 29.207 aspirin sensitivity, 12.75 autoimmune disease, immunizations, 27.336 autoimmune disease, Lyme disease vaccine, 24.366
cocamidopropylbetaine, 19.151
contrast agents, 20.422
cosmetics, 16.150, 19.151
co-trimoxazole, 20.264
desensitization, penicillin, 23.252
Euxyl K 400, 16.150
fragrances, 20.149
glucocorticoids, 21.158
hypersensitivity reactions, beta-lactam
antibiotics, 14.211, 30.280 hypersensitivity reactions, ethylene oxide, 11.219 hypersensitivity reactions, muscle relaxants, 27.138
hypersensitivity reactions, mebendazole,
12.263 hypersensitivity reactions, rocuronium, 31.249 hypersensitivity reactions, sulfonamide derivatives, 30.252 immune reconstitution disease, 29.315 Kawasaki disease, rotavirus vaccine, 31.522 Mazzotti reaction, antihelminthic drugs, 31.507 methyldibromoglutaronitrile, 16.150, 19.151
Cumulative indexes of special reviews, Annuals 12–31 ocular drugs, 21.486
propolis, 17.181
red man syndrome, 17.312
Autacoids angioedema, angiotensin converting enzyme inhibitors, 31.352 angioedema, angiotensin II receptor antagonists, 30.238 Infection risk AIDS, polio vaccine, 23.352 AIDS, transfusions, 12.298 necrotizing fasciitis, NSAIDs, 28.121 total parenteral nutrition, 22.379 tumor necrosis factor antagonists, 29.395, 31.594
yersiniosis, deferoxamine, 11.215
Body temperature malignant hyperthermia, 18.112 Trauma acupuncture, 29.590 Death antiepileptic drugs, 23.83
calcium antagonists, 22.214
ecstasy, 24.32
lithium, 19.14
opiates, 25.37, 29.44
Drug abuse anabolic steroids in sport, 29.508 Drug tolerance antimicrobial drug resistance, 11.223,
12.208, 19.237, 20.228, 21.257,
22.265, 23.250, 24.273, 25.279,
29.244, 31.413
opioids in neonates, 23.97 Drug dependence benzodiazepines, 12.41 Drug withdrawal baclofen, 26.152 Genotoxicity antiestrogens, 27.429 Tumorigenicity alcohol/vitamin A/beta-carotene, 24.442 aluminium, 31.383 antiestrogens, 27.429 beta-carotene, 25.454 carotenoids, 25.454 fertility drugs, 24.474, 26.434 growth hormone, 23.468 levodopa, 31.267 omeprazole, 16.423 oral contraceptives, 11.346, 15.426 proton pump inhibitors, 23.383 PUVA, malignant melanoma, 22.166 sex hormones, 22.465 vitamin K, 23.424 Fertility fertility, male, antimicrobial drugs, 16.262
xxvii
Pregnancy affective disorders in, 21.17
antibiotics, 11.231
antimicrobial drugs and the pill, 24.274
antithyroid drugs, 13.377
asthma, 28.186
beta-lactams, 25.280
cocaine, 27.1
opioids, 24.102
tetracyclines, 25.280
vitamin A, 21.405
Teratogenicity antibiotics, 11.231
tretinoin, topical, 18.164
Fetotoxicity cocaine, 20.24, 27.1, 29.41, 30.35 diethylstilbestrol, transgenerational effects, 31.657
indometacin, 18.102
Lactation cocaine, 31.154 Susceptibility factors age, methylphenidate, 31.6 children, aluminum, 12.185 children, budesonide, 30.194 children, inhaled glucocorticoids 27.174 children, NSAIDs, 19.96 elderly patients, antipsychotic drugs, 30.59 genetic susceptibility, antituberculosis drugs, 28.342 genetic susceptibility, beta-adrenoceptor agonists, 29.173, 30.199, 31.310 genetic susceptibility, isoniazid, 12.257 genetic susceptibility, thiopurine toxicity, 31.634 HIV infection, immunization, 12.269 intensive care, muscle relaxants, 19.140 neonatal complications, indometacin, 18.102 ocular drugs, 22.507 old age, vitamins, 22.431 preterm infants, beta-lactam antibiotics, 21.258 Drug administration delivery of aerosols, 27.172 dosage regimens, aminoglycosides, 23.264 errors, 28.587, 29.596 formulations, oral contraceptives, 24.472 inhaled glucocorticoids, systemic availability, 24.185 inhaled insulin, 30.495 intravitreal and parabulbar injection, 29.581 labeling problems, cosmetics, 22.159 opioids, 30.106 Drug overdose antidepressants, 28.14
digitalis, charcoal, 24.201
paracetamol, 23.117
xxviii Drug formulations enantiomers and racemates, 13.442 Drug–drug interactions acetylsalicylic acid/ACE inhibitor, 28.124
acetylsalicylic acid/NSAIDs, 28.118
alcohol/vitamin A/beta-carotene, 24.442
antimicrobial drugs/the pill, 24.274
antifungal azoles, 24.318, 28.299, 29.282,
30.320, 31.459 diuretics/NSAIDs, 12.80 grapefruit juice, 23.519 herbal medicines/warfarin, 30.400 HMG Co-A reductase inhibitors, 25.530, 30.517 lithium, 16.13 lithium/selective serotonin reuptake inhibitors, 18.30
macrolides, 14.220
Cumulative indexes of special reviews, Annuals 12–31
mibefradil, 23.210 monoamine oxidase inhibitors/foods, 13.6 NSAIDs/ACE inhibitors, 28.122 paracetamol, 13.68 selective serotonin reuptake inhibitors, 22.13 thyroxine, 24.484 Methods ethnopharmacology, 14.429
eukaryotic cells, effects of beta-lactams,
13.212 hemolytic disease of the newborn, prophylaxis, 13.297 lithium, monitoring, 11.24 local anesthetic toxicity, lipid rescue, 31.231 onchocerciasis, treatment, 14.261 post-marketing surveillance, 14.210, 15.266, 24.274
Table of Essays, Annuals 1–31
SEDA
Author
Country
Title
1 2 3
M.N.G. Dukes K.H. Kimbel L. Lasagna
The Netherlands Germany USA
4 5
The Netherlands UK Hungary Canada Denmark UK Denmark Denmark Switzerland UK Denmark
Science vs practice and/or practice vs science Adverse reactions: some pitfalls and postulates The seven pillars of foolishness Let’s get our act together Integrated medicine, safer medicine and “AIDS” Hark, hark, the fictitious dogs do bark Both sides of the fence On our side of the fence The great cholesterol carousel
15
M.N.G. Dukes J.P. Griffin, P.F. D’Arcy I. Bayer E. Napke M.N.G. Dukes W.H.W. Inman S. Van Hauen M.N.G. Dukes M.C. Cone C. Medawar M.N.G. Dukes, E. Helsing P. Tyrer
The moments of truth Drug monitoring: why care? Wanted and unwanted drug effects: the need for perspective The van der Kroef syndrome Adverse reactions to drugs – the information lag
UK
16 17 18
M.N.G. Dukes M.N.G. Dukes R.D. Mann
Denmark Denmark UK
19
A. Herxheimer
UK
20
E. Ernst
UK
21
H. Jick
USA
22
UK
24
J.K. Aronson, R.E. Ferner K.Y. Hartigan-Go, J.Q. Wong I. Palmlund
UK
25 26
L. Marks D.J. Finney
UK UK
26 27 27 28 29
L.L. Iversen J.K. Aronson H. Jick J.K. Aronson M. Hauben, A. Bate J.K. Aronson J. Harrison, P. Mozzicato
UK UK USA UK USA/Sweden
The nocebo effect – poorly known but getting stronger Good enough for Iganga? The mists of tomorrow Databases, privacy, and confidentiality – the effect of proposed legislation on pharmacoepidemiology and drug safety monitoring Side effects: freedom of information and the communication of doubt Complementary/alternative medicine: what should we do about it? Thirty years of the Boston Collaborative Drug Surveillance Program in relation to principles and methods of drug safety research Errors in prescribing, preparing, and giving medicines: definition, classification, and prevention Inclusion of therapeutic failures as adverse drug reactions Secrecy hiding harm: case histories from the past that inform the future The pill: untangling the adverse effects of a drug From thalidomide to pharmacovigilance: a personal account How safe is cannabis? Louis Lewin – Meyler’s predecessor The General Practice Research Database Classifying adverse drug reactions in the 21st century Data mining in drug safety
UK USA
Drug withdrawals because of adverse effects MedDRA®: the tale of a terminology
6 7 8 9 10 11 12 13 14
23
30 31
Philippines
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Classifications of adverse drug reactions Adverse drug reactions are classified in SEDA using two complementary systems, EIDOS and DoTS (1–3). These two systems are illustrated in Figures 1 and 2.
1. EIDOS The EIDOS mechanistic classification of adverse drug effects has five elements: • • • • •
the Extrinsic species that initiates the effect (Table 1); the Intrinsic species that it affects; the Distribution of these species in the body; the (physiological or pathological) Outcome (Table 2); the Sequela, which is the adverse effect.
Extrinsic species This can be the parent compound, an excipient, a contaminant or adulterant, a degradation product or a derivative of any of these (e.g. a metabolite) (for examples see Table 1). Intrinsic species This is usually the endogenous molecule with which the extrinsic species interacts; this can be a nucleic acid, an enzyme, a receptor, an ion channel or transporter or some other protein. Distribution A drug will not produce an adverse effect if it is not distributed to the same site as the target species that mediates the adverse effect. Thus, the pharmacokinetics of the extrinsic species can affect the occurrence of adverse effects. Outcome Interactions between extrinsic and intrinsic species in the production of an adverse effect can result in physiological or pathological changes (for examples see Table 2). Physiological changes can involve either increased actions (e.g. clotting due to tranexamic acid) or decreased actions (e.g. bradycardia due to beta-adrenoceptor antago nists). Pathological changes can involve cellular adaptations (atrophy, hypertrophy, hyper plasia, metaplasia and neoplasia), altered cell function (e.g. mast cell degranulation in IgE-mediated anaphylactic reactions) or cell damage (e.g. cell lysis, necrosis or apoptosis). Sequela The sequela of the changes induced by a drug describes the clinically recogniz able adverse drug reaction, of which there may be more than one. Sequelae can be classified using the DoTS system.
xxx
Classifications of adverse drug reactions
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1. EIDOS: a mechanistic classification
2. DoTS: a clinical classification
Drug
Dose-relatedness
Drug Extrinsic
Intrinsic Patient
Outcome Adverse reaction
Patient Susceptibility factors
Adverse reaction Time course
Fig. 1. Classifying adverse drug reactions – two complementary systems. Note that the triad of drug–patient– adverse reaction appears outside the triangle in EIDOS and inside the triangle in DoTS.
Fig. 2. Classifying adverse drug reactions – two complementary systems. Here the two triangles in Figure 1 are superimposed, to show the relation between the two classification systems. An adverse reaction occurs when a drug is given to a patient (Gothic letters). Adverse reactions can be classified mechanistically (EIDOS; sans-serif letters) by noting that the extrinsic (drug) species, when co distributed with an intrinsic (patient) species, has a pharmacological or other effect (the outcome), producing the adverse effect (the sequela). The sequela can be further classified (DoTS; serif letters) by considering the three main features of the adverse reaction – its dose-relatedness, its time-course, and individual susceptibility.
Classifications of adverse drug reactions
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Table 1. The EIDOS mechanistic classification of adverse drug effects Feature
Varieties
Examples
E. Extrinsic species
1. The parent compound 2. An excipient 3. A contaminant
Insulin Polyoxyl 35 castor oil 1,1-Ethylidenebis [L-tryptophan] Lead in herbal medicines Outdated tetracycline
4. An adulterant 5. A degradation product formed before the drug enters the body 6. A derivative of any of these (e.g. a metabolite) I. The intrinsic species and the nature of its interaction with the extrinsic species: (a) Molecular
1. Nucleic acids • DNA • RNA 2. Enzymes • Reversible effect • Irreversible effect 3. Receptors • Reversible effect • Irreversible effect 4. Ion channels/transporters 5. Other proteins • Immunological proteins • Tissue proteins
(b) Extracellular
(c) Physical or
physicochemical
D. Distribution
O. Outcome (physiological or pathological change) S. Sequela
1. Water 2. Hydrogen ions (pH) 3. Other ions 1. Direct tissue damage 2. Altered physicochemical nature of the extrinsic species 1. Where in the body the extrinsic and intrinsic species occur (affected by pharmacokinetics) The adverse effect (See Table 2) The adverse reaction (Dose, Time, Susceptibility [DoTS] classification)
Acrolein (from cyclophosphamide)
Melphalan Mitoxantrone Edrophonium Malathion Prazosin Phenoxybenzamine Calcium channel blockers; digoxin and Na+/K+-ATPase Penicilloyl residue hapten N-acetyl-p-benzoquinone imine (paracetamol [acetaminophen]) Dextrose 5% Sodium bicarbonate Sodium ticarcillin Intrathecal vincristine Sulindac precipitation Antihistamines cause drowsiness only if they affect histamine H1 receptors in the brain – –
Classifications of adverse drug reactions
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Table 2. Examples of physiological and pathological changes in adverse drug reactions (some categories can be broken down further) Type of change 1. Physiological changes (a) Increased actions (b) Decreased actions
Examples
Hypertension (monoamine oxidase inhibitors); clotting (tranexamic acid) Bradycardia (beta-adrenoceptor antagonists); QT interval prolongation (antiarrhythmic drugs)
2. Cellular adaptations (a) Atrophy Lipoatrophy (subcutaneous insulin); glucocorticosteroid-induced myopathy (b) Hypertrophy Gynecomastia (spironolactone) (c) Hyperplasia Pulmonary fibrosis (busulfan); retroperitoneal fibrosis (methysergide) (d) Metaplasia Lacrimal canalicular squamous metaplasia (fluorouracil) (e) Neoplasia • Benign Hepatoma (anabolic steroids) • Malignant – Hormonal Vaginal adenocarcinoma (diethylstilbestrol) – Genotoxic Transitional cell carcinoma of bladder (cyclophosphamide) – Immune Lymphoproliferative tumors (ciclosporin)
suppression
3. Altered cell function IgE-mediated mast cell degranulation (class I immunological reactions) 4. Cell damage (a) Acute reversible damage • Chemical damage Periodontitis (local application of methylenedioxymetamfetamine [MDMA, ‘ecstasy’]) • Immunological Class III immunological reactions
reactions
(b) Irreversible injury • Cell lysis Class II immunological reactions • Necrosis Class IV immunological reactions; hepatotoxicity (paracetamol, after apoptosis) • Apoptosis Liver damage (troglitazone) 5. Intracellular accumulations (a) Calcification Milk-alkali syndrome (b) Drug deposition Crystal-storing histiocytosis (clofazimine); skin pigmentation (amiodarone)
2. DOTS In the DoTS system (SEDA-28, xxvii–xxxiii) adverse reactions are classified according to the Dose at which they usually occur, the Time-course over which they occur and the Susceptibility factors that make them more likely, as follows: • Relation to dose – Toxic reactions (reactions that occur at supratherapeutic doses) – Collateral reactions (reactions that occur at standard therapeutic doses) – Hypersusceptibility reactions (reactions that occur at subtherapeutic doses in susceptible individuals) • Time course – Time-independent reactions (reactions that occur at any time during a course of therapy) – Time-dependent reactions * Immediate or rapid reactions (reactions that occur only when a drug is administered too rapidly)
Classifications of adverse drug reactions
xxxiv *
First-dose reactions (reactions that occur after the first dose of a course of treatment and not necessarily thereafter) * Early reactions (reactions that occur early in treatment then either abate with continuing treatment, owing to tolerance or persist) * Intermediate reactions (reactions that occur after some delay but with less risk during longer term therapy, owing to the ‘healthy survivor’ effect) * Late reactions (reactions in which the risk increases with continued or repeated exposure) * Withdrawal reactions (reactions that occur when, after prolonged treatment, a drug is withdrawn or its effective dose is reduced) * Delayed reactions (reactions that occur some time after exposure, even if the drug is withdrawn before the reaction appears) • Susceptibility factors – Genetic – Age – Sex – Physiological variation (e.g. weight, pregnancy) – Exogenous factors (e.g. the effects of other drugs, devices, surgical procedures, food, smoking) – Diseases The following reactions have been classified in previous issues of SEDA using the DoTS system; in the italicized references to SEDA-31, the EIDOS and DoTS systems have both been used: ACE inhibitors: angioedema Adrenaline: hypertension Adrenaline: myocardial infarction Angiotensin II receptor antagonists: angioedema Anticoagulants, oral: skin necrosis Antipsychotic drugs: diabetes mellitus Antituberculosis drugs: hepatotoxicity Bisphosphonates: osteonecrosis of the jaw Cocaine: myocardial infarction Contrast media: nephrotoxicity Diuretics, loop and thiazide: hyponatremia Dopamine receptor agonists: pathological gambling Dopamine receptor agonists: sleep attacks Ephedrine: vasospasm Ergot-derived dopamine receptor agonists: fibrotic reactions Ethambutol: optic neuropathy Exenatide: nausea Fluvastatin: hepatitis and cholestatic hepatitis Gadolinium salts: nephrogenic systemic fibrosis Glucocorticoids: osteoporosis Heparin: type II thrombocytopenia Nitrofurantoin: lung disease Pseudoephedrine: toxic epidermal necrolysis SSRIs: suicidal behaviour Statins: acute pancreatitis Statins: myopathy and rhabdomyolysis Thionamides: agranulocytosis Vigabatrin: visual field loss Ximelagatran: liver damage
29.207 30.170 31.259 30.238 29.358 28.60 31.495 30.562 29.38 29.575, 30.535, 31.732 29.219 30.174, 31.269 28.162 30.171 30.176, 31.268 30.358 30.499 31.717 28.561, 31.735 28.185, 31.306 30.404, 31.439 30.303 30.172 29.19 31.715 30.516, 31.716 29.520, 30.490, 31.685 28.101, 29.99, 30.98, 31.137 30.411
Classifications of adverse drug reactions
xxxv
References 1. Aronson JK, Ferner RE. Joining the DoTS. New approach to classifying adverse drug reactions. BMJ 2003;327:1222–5. 2. Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf 2005;28(10):851–70. 3. Ferner RE, Aronson JK. EIDOS: A mechanistic classification of adverse drug effects. Drug Saf 2010;33(1):13–23.
How to use this book THE SCOPE OF THE ANNUAL Volumes in the Side Effects of Drugs Annual (SEDA) series have been published since 1977. The series is designed to provide a critical account of new information relating to adverse drug reactions and interactions from the clinician’s point of view. It complements the standard encyclopedic work in this field, Meyler’s Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions, the 15th edition of which was published in 2006.
PERIOD COVERED The present Annual reviews all reports that presented significant new information on adverse reactions to drugs during 2007 and the first half of 2008; the next volume (SEDA-33) will cover the second half of 2008 and all of 2009. During the production of this Annual, some more recent papers have also been included; older literature has also been cited when it is relevant. Special reviews (see below) often cover a much wider range of literature.
SELECTION OF MATERIAL In compiling the Side Effects of Drugs Annual particular attention is devoted to publications that provide essentially new information or throw a new light on problems already recognized. Some confirmatory reports are also described. In addition, some authoritative new reviews are listed. Publications that do not meet these criteria are omitted. Readers anxious to trace all references on a particular topic, including those that duplicate earlier work, or to cross-check an electronic search, are advised to consult Adverse Reactions Titles, a monthly bibliography of titles from about 3400 biomedical journals published throughout the world, compiled by the Excerpta Medica Interna tional Abstracting Service.
Special reviews The special reviews deal in more detail with selected topics, often interpreting conflicting evidence, providing the reader with clear guidance. They are identified by the traditional prescription symbol and are printed in italics. This volume includes a Cumulative Index of the Special Reviews that were published in SEDA-11 to SEDA-31 and a list of the Special Reviews that appear in the current Annual.
CLASSIFICATION OF DRUGS Drugs are classified according to their main field of use or the properties for which they are most generally recognized. In some cases a drug is included in more than one chapter (e.g. lidocaine is mentioned in Chapter 11 as a local anesthetic and in Chapter 17 as an antidysrhythmic drug). Fixed combinations of drugs are dealt with according to their most characteristic component or as a combination product.
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How to use this book
xxxvii
DRUG NAMES Drugs are usually called by their recommended or proposed International Non-proprietary Names (rINN or pINN); when these are not available, chemical names have been used. If a fixed combination has a generic combination name (e.g. co-trimoxazole for trimethoprim + sulfamethox azole) then that name has been used; in some cases brand names have been used instead.
SYSTEM OF TAGGING REFERENCES References in the text are tagged using the following system, which was introduced in SEDA-24: M A R r C c H E S
A meta-analysis or other form of systematic review;
An anecdote or set of anecdotes (i.e. case histories);
A major review, including non-systematic statistical analyses of published studies;
A brief commentary (e.g. an editorial or a letter);
A major randomized controlled trial or observational study;
A minor randomized controlled trial or observational study or a non-randomized study;
A hypothesis article;
An experimental study (animal or in vitro);
Official (e.g. Governmental, WHO) statements.
The various editions of Meyler’s Side Effects of Drugs are cited in the text as SED-l4, SED-15, etc.; the Side Effects of Drugs Annuals 1–31 are cited as SEDA-1, SEDA-2, etc.
INDEXES Index of drugs: this index provides a complete listing of all references to a drug for which adverse effects and/or drug interactions are described. Index of adverse effects: this index is necessarily selective, since a particular adverse effect may be caused by very large numbers of compounds; the index is therefore mainly directed to adverse effects that are particularly serious or frequent, or are discussed in special detail; before assuming that a given drug does not have a particular adverse effect, consult the relevant chapters. For indexing purposes American spelling has been used, for example anemia, estrogen rather than anaemia, oestrogen.
Kelvin Chan1 SIDE EFFECTS OF DRUGS ESSAY
Regulating complementary and alternative medicines Over the past decade, the increasing popularity of complementary and alterna tive medicines (CAM) and over-the counter (OTC) health foods and supple ments, nutraceuticals and medicinal pro ducts from plants or other natural sources (inclusively known as botanicals, includ ing herbal medicines, or phytomedicines) has also brought concerns about the pro fessionalism of practitioners, and about the quality, efficacy, and safety of their treatment methods and the available pro ducts that are derived from herbal and natural sources (1R). These OTC products may contain excessive or banned pesticides, microbial contaminants, chemical toxins and other contaminants or adulterants, such as heavy metals, and pharmaceuticals. Con taminants can come from locations where the plants are grown, collected, or pro cessed. Toxins can come from poor storage conditions. The presence of pharmaceuti cals may be illogically claimed to be due to accidental contamination during produc tion; however, such products are also 1
The author of this year’s Side Effects of Drugs Essay is Kelvin Chan PhD, DSc, FSB, FCP, FRPharmS, FRSM. Professor Chan is Joint Chair Professor in Traditional Chinese Medicine at Faculty of Pharmacy, University of Sydney, NSW2006, and at the College of Health and Science, University of Western Sydney, NSW2560, Australia.
xxxviii
manufactured unprofessionally and are deliberately adulterated (2R). Environment-related factors can be con trolled by implementing standard operat ing procedures (SOP), leading to Good Agricultural and Collection Practice (GACP), Good Laboratory Practice (GLP), Good Supply Practice (GSP), and Good Manufacturing Practice (GMP) for producing these medicinal products, before Good Clinical Trial Practice (GCTP) for evaluation of efficacy. There fore, regulatory policies should be set up to oversee the quality and safety of these products before they are made available to the public as OTC medicines, or for prescription. The public’s faith in herbal and natural products, which they believe (often incorrectly) to be safer than syn thetic pharmaceutical medicines, can only be rewarded by instituting regulatory con trols on these products, which demand that they should provide traceability of their sources and manufacture, using good codes of practice. Some national govern ment authorities have set up regulatory controls over the starting materials that are supplied to herbal companies for the manufacture of herbal products in order to safeguard the interests of the public. In this essay I focus on the progress of regulatory standards (3S–5S). Some aca demic and professional bodies have also taken initiatives to build reliable and repu table databases for monitoring the adverse
Regulating complementary and alternative medicines
effects of CAM, and we shall summarize the key reviews that have been published (6R, 7R).
Australia and New Zealand (3 S) In Australia and New Zealand comple mentary medicines, including herbal, minerals, nutritional/dietary supplements, aromatherapy oils and homeopathic med icines, are regulated under therapeutic goods/products legislation. The Thera peutic Goods Administration (TGA), a division of the Commonwealth Depart ment of Health and Ageing, is responsi ble for administering the provisions of the legislation in Australia. The New Zealand Medicines and Medical Devices Safety Authority (Medsafe) administers the provision of legislation in New Zealand. In December 2003 the Australian and New Zealand governments signed a treaty to establish a single, binational agency to regulate therapeutic products, including medical devices prescription, OTC medicines and complementary medicines. The single agency has replaced Medsafe in New Zealand and the TGA in Australia. The role of this agency is to safeguard public health through regulation of the quality, safety and efficacy or performance of therapeutic products in both countries. The major activities of the new joint A ustralia New Zealand Therapeutic Pro ducts Agency are in product licensing, specifying labelling standards and setting advertising schemes, as well as determin ing the risk classes of medicines and creating an expanded list of ingredients permitted in Class I medicines. A new, expanded definition of comple mentary medicines has been proposed, and this definition is currently under con sultation. Related Australian and New Zealand legislation is being developed to
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implement the joint scheme. Once this leg islation is passed, the Treaty will come into force and the new joint regulatory scheme will begin. The agency was originally expected to commence operation no later than 1 July 2006 and to result in a single agency to regulate CAM. However, con sultation continues. In Australia, there has been an initiative to introduce nationwide registration of traditional Chinese medi cine (TCM) practitioners by 2012.
China (4S) China’s National Center for Adverse Drug Reaction (ADR) Monitoring was estab lished in 1989, before China joined the World Health Organization’s Programme for International Drug Monitoring in 1998. In March 2004, China formally promul gated the final version of the Regulations on Adverse Drug Reaction Reporting and Monitoring. This modern system supple ments an informal reporting system in scholarly publications. Procedurally, the formal Chinese mon itoring system requires pharmaceutical companies and health-care professionals to report most adverse events quarterly. However, new, uncommon, serious or ‘group’ adverse events are required to be reported within a shorter period. Reports are made to local centres, which then analyse and transmit them to a national ADR centre operated by China’s State Food and Drug Administra tion (SFDA). The national authority is then empowered to authorize further stu dies, publish formal warning announce ments or prohibit the use of a product. TCM products are also regulated as drugs in China. Because the use of TCM products is increasing worldwide, Chinese adverse reactions monitoring is particu larly, if not uniquely, useful in reporting
xl
Regulating complementary and alternative medicines
of TCM-related adverse drug reactions. A survey of Chinese ADR alerts and findings regarding TCMs and other sub stances is included, providing an overview of the breadth and timeliness of the infor mation available from China’s increasing pharmacovigilance activity. Overall, the system shows considerable progress and promise, especially if awareness of the procedures for reporting suspected ADRs continues to grow among China’s healthcare professionals and public.
take part in experimental and research work in setting standard guidelines and monographic standards for the quality and safety of Chinese medicinal materials (CMM) available in Hong Kong and Mainland China. The standard criteria include chromato graphic fingerprints and assay values of markers of Chinese medicinal materials, together with all the required monographic data in established pharmacopoeias, such as the British, Chinese, European, Japanese, and US Pharmacopeias. Generation of these data is overseen and advised by an International Advisory Board of renowned experts from various countries and regions in Australia, Canada, China, Germany, Japan, Thailand, the UK, and the USA. A recent ‘Commentary article’ has given an overview of the encouragement of a global agreement on harmonizing pharmacopeia monographic standards of
Hong Kong Chinese Materia Medica Standards (HKCMMS) (5S) The Department of Health (DOH) in Hong Kong’s SAR Government initiated the HKCMMS project in 2003 and com missioned experts available in the local universities and research institutes to
Table 1. Pharmacopoeia or standards of various countries or regions that have monographic standards for
Chinese medicinal materials (modified from reference 6)
Pharmacopoeia or monograph
Authority
Status and remarks
WHO Monographs on Selected Medicinal Plants Pharmacopoeia of the People’s Republic of China (CP) Australian Regulatory Guidelines for Complementary Medicines European Pharmacopoeia
World Health Organization, Geneva
Four volumes; unofficial
State Food and Drug Administration (SFDA), PR China Therapeutic Goods Administration (TGA), Australia European Directorate for the Quality Medicines & Healthcare (EDQM) Department of Health, Hong Kong SAR, PR China The Pharmaceutical Affairs Thai Food and Drug Administration, Ministry of Public Health British Pharmacopoeia Commission, MHRA, UK Dietary Supplements Health and Education Act (DSHEA) decides that botanicals are treated as food supplements Kotzting/Bayer. Wald, Germany
Official
Hong Kong Chinese Materia Medica Standards Japan Pharmacopoeia Thai Herbal Pharmacopoeia British Pharmacopoeia American Herbal Pharmacopeia (AHP); contains some monographs on Chinese medicinal materials Chinese Drug Monographs and Analysis
TGA, Official Official Official Official Official Official Unofficial
Verlag f€ ur Ganzheitliche Medizin – Dr Erich Wuhr GmbH; unofficial
Regulating complementary and alternative medicines
Chinese medicinal materials, such that the quality of these starting herbal ingre dients can be assured for the practice of TCM and the manufacture of Chinese medicinal products (6R). Table 1 summarizes the major stan dards in various countries and regions for reference.
Initiative on International Standards for Data Collection (7R) Research on morbidity from TCM is an emerging field. Currently, not much is known and there is a lack of international standards for data collection and reporting. Based on the experience of developing a computerized system for patient data collection by colleagues at the University of Technology Sydney (UTS) Acupunc ture Clinic and reporting results from that database, a start can be made towards developing guidelines for reporting simi lar results from TCM clinical audits. This study has reported data relating to 5735 patients who had undergone 29 697 courses of treatment. Patient information is collected by a computerized database recording the International Classification of Primary Care (ICPC), reason for encounter (RFE) and symptom for encounter (SFE) data, and TCM tongue, pulse, diagnostic, and treatment data. Data coding is automated, and systems for reliability testing and error reporting
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have been developed. The UTS database has a 2.7% error rate and is within inter national standards of 5% error. Musculoskeletal disorders are the most common presentation (41%) of all RFE, followed by general disorders (13%) and digestive disorders (8.1%). International standards must be set for TCM morbidity data collection methods and reporting. It is hoped that the meth ods described and reported in this paper are an initial step in the setting of such standards and that they will be adopted by other researchers. In particular, meth ods for testing and reporting data relia bility must be adopted if TCM morbidity studies are to maintain any credibility.
Conclusion Differences among national or regional regulations on the import and export of medicinal plants can affect the quality control of herbal products. The same med icinal plant products may be classified as foods, food supplements, functional foods, nutriceuticals, or prescribed herbal medi cines in different countries or regions. A harmonized regulatory system in phar macopeial standards of herbal materials generated from medicinal plants would improve the quality of herbal materials, thereby ensuring the safety of manufac tured herbal products and assisting herbal practitioners.
References 1. Chan K. Chinese medicinal materials and their interface with western medical concepts. J Ethnopharmacol 2005;96:1–18. 2. Chan K. Some aspects of toxic contaminants in herbal medicines. Chemosphere 2003; 52:1361–71.
3. Ghosh D, Skinner M, Ferguson LR. The role of the Therapeutic Goods Administration and the Medicine and Medical Devices Safety Authority in evaluating complementary and alternative medicines in Australia and New Zealand Toxicology. Toxicology 2006; 221:88–94.
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4. Zhou Y-B, Miller V, Hogan M, Callahan L. An overview of adverse drug reaction moni toring in china. Int J Pharmaceut Med 2006;20(2):79–85. 5. Hong Kong Chinese Materia Medica Stan dards (HKCMMS) Chinese Medicine Divi sion of the Department of Health Hong Kong SAR China Government. http://www. dh.gov.hk/english/main/main_cm/main_cm_ hkcmms.html.
6. Chan K, Leung KSY, Zhao SS. Harmoniza tion of monographic standards is needed to ensure the quality of Chinese medicinal mate rials. BioMed Central: Chin Med 2009;4:18. http://www.cmjournal.org/content/4/1/18. 7. Meier P, Rogers C. Reporting traditional Chinese medicine morbidity – a University of Technology, Sydney, project with an emphasis on developing standards for testing and report ing data. J Alt Compl Med 2006;12(6): 529–34.
Reginald P. Sequeira
1
Central nervous system stimulants and drugs that suppress appetite
(SED-15, 180;
SEDA-29, 1; SEDA-30, 1; SEDA-31, 1)
AMPHETAMINES
Note on spelling: In International Nonpro prietary Names (INNs), the digraph -ph- is usually replaced by -f-, although usage is not consistent, and -ph- is used at the beginnings of some drug names (e.g. compare fenflura mine and phentermine) or when a name that begins with a ph- is modified by a prefix (e.g. chlorphentermine). For the amphetamines the spellings that are used in SEDA are as follows: amfetamine, benzfetamine, dex amfetamine, metamfetamine (methylampheta mine) and methylenedioxymetamfetamine (ecstasy); however, for the general term for the group of drugs the more common spelling ‘amphetamines’ is used.
segment depression. Her troponin concentration was raised at 7 ng/ml. An echocardiogram showed an ejection fraction of 20% with basal akinesia and moderate mitral and tricuspid regurgitation. She responded well to diuretic therapy. Ventriculography showed reverse apical ballooning with a hyperdynamic apex and akinetic basal walls. Angiography showed normal coronary arteries. She was discharged taking an angiotensin converting enzyme (ACE) inhibitor and metoprolol, and an electrocardiogram 2 weeks later showed complete recovery of left ventricular function.
• A 25-year-old woman developed shortness of breath shortly after inhaling amfetamine. She had a sinus tachycardia (140/minute), a raised blood pressure (160/90 mmHg) and pulmonary edema. An electrocardiogram showed ST
Transient left ventricular apical ballooning syndrome was first described in Japan as ‘Takotsubo cardiomyopathy’. Many varia tions of this syndrome have been reported, but the reverse type of this syndrome, with a hyperdynamic apex and complete akinesia of the base (as opposed to classical apical ballooning), is rare. The term ‘stress cardio myopathy’ is now commonly used to describe all varieties of this condition, defined as reversible left ventricular systolic dysfunction triggered by an acute stressful event without significant coronary artery disease. This syndrome can involve any segment of the left ventricular wall and has been classified into four types. The authors postulated that amfetamine-induced tachycardia and hypertension triggered reverse Takotsubo cardiomyopathy in this patient.
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32001-0 2010 Elsevier B.V. All rights reserved.
Drug abuse Adderall (see also Drug formulations below), a treatment that has been approved by the FDA for attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) in the
Amfetamine (SEDA-29, 2; SEDA-30, 1) Cardiovascular A rare case of reverse left ventricular apical ballooning syndrome has been attributed to amphetamines (1A).
1
2
USA, consists of a mixture of the neutral sulfate salts of dexamfetamine and amfeta mine, with the dextrorotatory isomer of amfetamine saccharate and d-levo amfetamine aspartate monohydrate. Of all calls related to Adderall received by several poison control centers in Texas during 1998–2004, 12% involved drug abuse (2c). There were 5140 calls about Adderall, including 3152 (61%) human exposures, 221 (4.3%) animal exposures, 1220 (24%) drug identification calls, and 547 (11%) requests for other information. Of the 3152 human exposures, 391 (12%) involved abuse. The number of calls received per year increased during the first half of this period but then fell. Most of the patients were male and the most frequently reported adverse effects were neurological, followed by cardiovascu lar and gastrointestinal. Adderall abuse exposures were more likely to involve almost all of the categories of adverse clin ical effects, and in particular the adverse effects of chest pain, hypertension, tachy cardia, nausea, dizziness, numbness, and tremor. When compared with non-abuse exposures, Adderall abuse exposures were more likely to (a) involve children under 13 years of age; (b) occur at others’ residences, schools and public areas; (c) be managed at health-care facilities; (d) involve more ser ious medical outcomes; (e) involve adverse clinical effects. This suggests that reported abuse exposures are more severe than reported after non-abuse exposures. This might be because of the use of higher doses of Adderall by abusers. Alternatively, Adderall abuse exposures might reflect reluctance for instances of abuse to be reported to poison control centers, unless thought to be severe. Lactation Dexamfetamine readily passes into human breast milk. In four women taking dexamfetamine the relative infant dose was 25%, although there was no clinically significant pro longation of the mean QT interval. About 2.5% of the subjects had two consecutive sys tolic blood pressures (SBPs) or diastolic blood pressures (DBPs) > 95th percentile for age, sex, and height, and in 3.6% the pulse rate rose by 25–110/minute. There were no serious cardiovascular adverse events. In general, 151 subjects (5.1%) had a treatment-related adverse event that resulted in withdrawal of MAS-XR; of these, seven (0.2%) had cardio vascular events, including hypertension, bouts of palpitation, and tachycardia. Nine subjects reported treatment-related
Central nervous system stimulants and drugs that suppress appetite
cardiovascular adverse events of moderate to severe intensity. The cardiovascular events reported by five of these nine subjects were deemed to be possibly or probably related to treatment with MAS-XR. There were no deaths. The product labelling of MAS-XR was revised in August 2004 to include a warn ing that sudden death had occurred in asso ciation with amfetamine treatment in children with structural cardiac abnormal ities. In February 2005, Health Canada reviewed the safety data and suspended the sale of MAS-XR in Canada. Subse quently, the FDA re-evaluated the data on sudden deaths in patients taking MAS XR, based on about 30 million prescrip tions ordered between 1999 and 2003 (7S). The incidence rate of sudden death in chil dren and adolescents was on average 3.3/ 100 000 per year, and more than half of these deaths were linked to hereditary con duction and cardiac structural abnormal ities. In August 2005, Health Canada reinstated the marketing authorization of MAS-XR. Given the minor cardiovascular effects of ADHD treatment with MAS-XR, patients should undergo routine cardiac monitoring. MAS-XR should not be used in patients with structural cardiac abnormalities. It should be used only after thorough exami nation in patients with a history of unexplained syncope, shortness of breath, a history of unexplained seizure or a history of chest pain on exertion (8S). Taken together, these results (6c–8S) support those previously published (9C, 10C) and further demonstrate that the cardiovascular profile of MAS-XR is associated with small divergences from age-specific population norms that pose very limited risks in otherwise healthy patients with ADHD.
Ecstasy (3,4-methylenedioxymet amfetamine, MDMA) See Chapter 4.
Chapter 1
3
Metamfetamine (SEDA-29, 3; SEDA-30, 2; SEDA-31, 1) Metamfetamine hydrochloride, or ‘crystal meth’ or ‘ice’, is a potent and addictive form of amphetamine. Smoking metamfeta mine is associated with a rapid high similar to other sympathomimetic stimulant drugs. In a retrospective study of enquiries to two poisons centers and the UK National Poi sons Information Service relating to all recreational drugs, metamfetamine, and ecstasy, there was a small increase in the number of metamfetamine-related calls from 0.1% of all recreational drugs cases in 2000 to 1.23% in 2006; however, it was still uncommon compared with ecstasy (17–43% of all recreational drugs cases) (11C). In 2005–2006, there were 12 enqui ries related to metamfetamine compared with 455 for ecstasy (0.014% and 0.52% of all enquiries respectively). There were five presentations at emergency departments over 15 months compared with 171 for ecstasy. Of 254 440 urine samples screened at the workplace from 2000 to 2006, three were positive for metamfetamine and 147 for ecstasy. Observational studies Intranasal metam fetamine produced predictable effects on multiple behavioral and physiological mea sures before peak plasma concentrations were observed (12c). In 11 non-treatment seeking metamfetamine abusers, placebo or one of three doses of metamfetamine (12, 25, and 50 mg/70 kg) was administered double-blind, and metamfetamine plasma concentrations, cardiovascular subjective effects and psychomotor/cognitive perfor mance effects, were assessed. Metamfeta mine increased cardiovascular measures and positive subjective effects, with peaks at 5–15 minutes after drug insufflation, when plasma concentrations were still ris ing. Cognitive performance on less compli cated tasks improved with all doses of metamfetamine, whereas performance on more complicated tasks improved only by 12 and 25 mg doses.The dissociation between metamfetamine plasma concentra tions with cardiovascular measures and
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positive subjective effects has important implications for potential toxicity after repeated doses. Cardiovascular Metamfetamine has been associated with cardiomyopathy in young patients in a case–control study based on chart review of discharges between 2001 and 2004 from a tertiary care facility, in which 107 cases and 114 controls were iden tified (13R). Metamfetamine users had 3.7 times increased odds ratio (95% confidence interval (CI) = 1.8, 7.8) for cardiomyopathy adjusted for age, body mass index, and renal failure; 4 of 10 patients with cardiomyopathy and aged 45 years or over had used metam fetamine. This study suggested that young patients who use metamfetamine are not only at a greater risk of cardiomyopathy but also of a more severe form of cardio myopathy, confirming the findings of a case series from Honolulu (14c). Because a his tory of drug use is inconsistently documen ted in medical records, a control group with a random selection of patients from medical records alone would underestimate the pre valence of drug use. Since fewer cases than controls (38% versus 55%, P = 0.02) had urine tested for toxicology at admission, the results probably underestimate the true effect size for metamfetamine. It is concei vable that hospitalized metamfetamine users with cardiomyopathy represent patients with more severe disease. If so, it would suggest that there is a larger propor tion of non-hospitalized metamfetamine users with subclinical cardiomyopathy. The findings of this study are applicable only to the smoked form of metamfetamine, as this was the more common method of abuse. Obtaining a detailed history of substance abuse, especially of metamfetamine, and toxicology screening in young patients with cardiomyopathy or heart failure is recommended. Nervous system It has been suggested that a history of chronic metamfetamine abuse is associated with motor neuron disease (15c). Among 61 patients with motor neuron disease seen over a period of 30 months in Arkansas, 6 admitted to metamfetamine
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abuse. The age at onset was 31–41 years, mostly men, with bulbar onset. The sole woman abuser had progressive bulbar palsy; the other five had definite (n = 3) or probable (n = 2) progressive amyotrophic lateral sclerosis. None was HIV positive. Abusers smoked or snorted metamfeta mine; the most extensive abuser had used it daily for 10 years. Four patients devel oped symptoms while still abusing the drug; one of them had been abstinent for 1 year and one for 6 years when symptoms began. One had abused solely metamfetamine, three had also smoked marijuana, and two had abused multiple substances. Whether metamfetamine per se or a contaminant is the actual culprit remains to be determined. Physicians caring for patients with motor neuron disease should obtain a detailed his tory of substance abuse and environmental toxin exposure to shed further light on the mechanism of the underlying motor neuron disease. In a study of abstinent metamfetamine abusers (n = 32) and healthy controls (n = 30) in Korea, the metamfetamine abusers had disrupted integrities in frontal white matter associated with clinical manifestations, including impairment of frontal executive function (16c). Furthermore, disrupted fron tal white matter integrities were found only in male metamfetamine abusers, suggesting that men are more vulnerable to metamfeta mine-induced effects on frontal white mat ter. The estimated cumulative intravenous metamfetamine dose was in excess of 50 g. Considering the small sample size, the sex difference observed in this study should not be taken to imply that metamfetamine abuse does not harm women of reproductive age. The confounding effects of age and the higher prevalence of current smoking among metamfetamine abusers also need to be addressed. Moreover, the metamfetamine abusers in the study may not have been representative of ‘typical’ metamfetamine abusers, as a number of metamfetamine abusers commonly have co-morbid psychia tric disorders. These criticisms limit general ization of the findings of this study. Metamfetamine-related abnormalities may, in part, recover with abstinence, in
Central nervous system stimulants and drugs that suppress appetite
grey matter, but not in white matter (17c). In 30 abstinent metamfetamine abusers and 20 healthy subjects, proton magnetic resonance spectroscopy was used to deter mine the concentrations of brain metabo lites, such as N-acetylaspartate and myoinositol, which are markers for neuro toxicity. The total cumulative lifetime dose of metamfetamine was estimated at around 100 g and the duration of abstinence at about 6 months. The self-reported nature of drug use and a lack of information regarding metamfetamine purity are caveats for interpreting the findings of this study. Another limitation of this study is that participants were not screened for HIV, and HIV infection in metamfetamine abusers has been reported to have additive effects on metabolic abnormalities in the brain (18c). Psychological The neural substrate dysfunc tions and disrupted cognitive, affective, and experiential processes observed in metam fetamine- and cocaine-dependent indivi duals have been reviewed (19R). Stimulant dependence is characterized by attenuated anterior and posterior cingulate activation, reduced inferior frontal and dorsolateral prefrontal cortex activation, and altered posterior parietal activation, suggesting inadequate demand-specific processing of information. Processes that have been most consistently reported to be deficient in functional neuroimaging studies include inhibitory control, executive functioning, and decision making. The authors con cluded that an emerging theme is that stimulant-dependent individuals show spe cific, rather than generic, brain activation differences, i.e. instead of showing more or less brain activation regardless of task, they have process-related brain activation differ ences that are consistent with a shift from context-specific, effortful processing to a more stereotyped habitual response generation. Fetotoxicity Prenatal metamfetamine expo sure has been associated with neuro behavioral patterns of reduced arousal, increased stress, and poor quality of move ment in neonates. In the Infant
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Development, Environment and Lifestyle (IDEAL) study, 13 808 subjects were screened and 1632 were eligible and con sented; 166 (of whom 74 had been exposed) were followed up (20c). Exposure was determined by detection in the meconium and self-reporting. The NICU Network Neurobehavioral Scale (NNNS) was admi nistered in the first 5 days of life. In heavy users of metamfetamine, there was lower arousal, more lethargy, and increased phy siological stress. First trimester use was related to increased stress abstinence and third trimester to poorer quality of move ment. Higher concentrations of ampheta mine metabolites in the meconium were associated with increased nervous system stress. It is unclear whether the observed neurobehavioral effects in neonates repre sented adverse effects of metamfetamine or acute withdrawal-like effects. The subtle effects observed in children exposed to pre natal metamfetamine have both short-term and potentially long-term implications. However, because of limitations, caution needs to be exercised when interpreting these preliminary results of the IDEAL study, and a ‘rush to judgement’ regarding the long-term outcomes of these children should be avoided (21c). Periventricular leukomalacia has been reported in a preterm infant with no other known susceptibility factors after in utero exposure to metamfetamine (22A). Longterm follow up at 24 months showed severe developmental delay, with spastic quadri plegic cerebral palsy that required baclofen. It is unclear whether other unknown con founding prenatal factors, including contami nants in the metamfetamine, contributed to this effect. The authors’ recommendation that premature infants exposed prenatally to metamfetamine should be screened for periventricular leukomalacia is justified. Susceptibility factors Genetic A family his tory of psychiatric illness may further increase the risk of recurrent psychotic symptoms associated with metamfetamine abuse. There was a positive correlation between the frequency of metamfetamine-related psy chotic episodes and scores on the Wender
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Utah Rating Scale, a scale that retrospec tively measures childhood behaviors relevant to ADHD. These findings were based on a study of behavioral characteristics in 39 drug-abstinent metamfetamine-dependent subjects who experienced psychotic symp toms associated with metamfetamine abuse (23c). However, the correlational patterns reported do not necessarily imply causality. A PICK1 (protein interacting with C kinase) gene has been implicated in the pathophysiology of metamfetamine psycho sis (24C). PICK1 plays a role in the targeting and localization of synaptic membrane pro teins, such as the dopamine transporter, and also interacts with alpha amino-3-hydroxy 5-methyl-4-isoxazole propionate (AMPA) receptors and metabotropic glutamate receptors, which have been implicated in the pathophysiology of substance abuse as well as schizophrenia. The association between PICK1 gene polymorphisms and metamfetamine abuse has been explored in 208 Japanese metamfetamine abusers and 218 healthy subjects. The effects of four highly frequent single nucleotide poly morphisms (SNPs), rs737622 (–332 C/G) and rs3026682 (–205 G/A) in the promoter region, rs713729 (T/A) in intron 3, and rs2076369 (T/G) in intron 4, were studied. Of these SNPs, rs713729 was significantly associated with metamfetamine abuse in gen eral and rs713729 and rs2076369 were signif icantly associated with spontaneous relapse of psychosis. The specific haplotypes of these SNPs were associated with metamfeta mine abuse. A gene reporter assay showed that the two SNPs in the promoter region significantly altered transcriptional activity. Sex Sex differences in susceptibility to metamfetamine neurotoxicity have been reported (25E, 26E), and estrogens may have played a neuroprotective role. Drug overdose Metamfetamine body packing can be fatal. Three Nigerian men were found to have concealed packages of metamfetamine HCl in their stomach, in quantities ranging from 73 to 498 g (27A). One died with acute poisoning from an estimated 20 g of metamfe tamine that had leaked into the stomach. His
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plasma concentration was 8.6 µg/ml when he was hospitalized, 17 hours before he died. An autopsy showed extreme pulmonary conges tion and edema, moderate hepatic edema, and petechiae. Analysis by GC/MS showed extre mely high concentrations of metamfetamine and its metabolite amfetamine in cardiac blood, urine, gastric contents, and all other autopsy samples. Impurity-profiling analysis of the seized metamfetamine showed that the metamfetamine smuggled by the three suspects originated from the same batch. Metamfetamine plasma concentrations in the other two suspects, who survived, were 8.6 and 7.8 µg/ml. In another study, a shift towards the use of alternative precursors for illicit manufacture of metamfetamine in Korea between 1997 and 2005 has been shown by determining the enantiomer ratio in the samples. This finding has considerable implications for profiling international trafficking of metam fetamine (28H). As a consequence of regula tory restrictions, clandestine laboratories have difficulties in obtaining pure ephedrine, and alternative precursors are increasingly being used. Accidental exposure With increasing preva lence of metamfetamine use and clandestine production at home, children are at risk of injuries resulting from living in a drugendangered environment. Chemicals used for clandestine metamfetamine production (such as precursors, solvents, reducing agents, bases, and acids) can be responsible. In homes where metamfetamine was being produced, two young children suffered che mical burns after ingesting commercial clea ners containing sulfuric acid (29A). In both cases metamfetamine and amfetamine were detected, confirming exposure. Several find ings led medical personnel to suspect a drugendangered environment. • A 5-year-old girl was found gasping and vomiting in the kitchen near an open bottle of Liquid Fire, a commercial cleaner containing sulfuric acid used as a drain opener. Her lips, tongue, and oropharynx were severely burned and there were partial-thickness burns on her hands. She had multiple healed marks on her chest, abdomen, left flank, and back. Arterial
Central nervous system stimulants and drugs that suppress appetite blood gas analysis showed a metabolic acidosis. Flexible esophagogastroscopy showed significant edema of the anterior and posterior oropharynx with esophagitis and gastritis. Microlaryngoscopy and bronchoscopy showed extensive burns on the uvula, tonsils, epiglottis, vallecula, vocal cords, and arytenoids. Her hair tested positive for metamfetamine and amfetamine. • A 2-year-old child ingested Liquid Lightening, which contained sulfuric acid used as a drain opener, and developed drooling, stridor, and skin blistering on the neck, chest, and abdomen. There were partial-thickness burns on the neck, chest, abdomen, lips, and anterior oral cavity. The child had a metabolic acidosis. Urine toxicology was positive for metamfetamine and amfetamine.
These children had suffered severe caustic ingestion in homes where metamfetamine was being produced. Although ingestion of household cleaners is usually accidental and not a result of illicit drug use or production, medical providers need to be aware of the chemicals associated with illicit drug pro duction to identify patients harmed in this environment.
Fenfluramines
(SED-15, 1333; SEDA-29, 11; SEDA-30, 7)
Cardiovascular Seven years after fenflura mines were withdrawn, reports of mitral and aortic valvular disease continue to appear (30A). • When a 39-year-old woman developed pneumonia, her systolic and diastolic murmurs, which had been previously detected, were re-evaluated. Echocardiography showed grade III mitral regurgitation and grade II/III aortic regurgitation. The valves were pearly white and retractile, with no commissural symphysis or calcification. From the age of 19 years she had taken intermittent treatment with anorectics for 10 years (cumulative total of 34 months of fenfluramine 60 mg/day and 3 months of dexfenfluramine 45 mg/day). The murmurs were first detected at the age of 25 years, 6 years after she had started taking anorectics. Histological examination of the resected valves showed proliferation of myofibroblasts expressing smooth muscle a-actin.
This case suggests that severe valvular re gurgitation associated with fenfluramines can
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occur late. Long-term health surveillance of anorectic exposed subjects may be necessary. The evidence implicating ion channels in pulmonary artery smooth muscle vaso constriction, proliferation, and/or reduced apoptosis has been reviewed (31R). Pulmonary arterial hypertension may be considered as a form of vascular channelo pathy. Experiments performed on cloned, voltage-activated potassium channels (Kv channels) in expression systems have con firmed that dexfenfluramine inhibits cloned Kv2.1 channels expressed in Xeno pus laevis oocytes (32E); a number of anor ecticdrugs, including aminorex, dexfenfluramine, phentermine, and sibu tramine, inhibit Kv1.5 channels expressed in CHO cells (33E). To reduce the risk of future epidemics of pulmonary arterial hypertension, it has been suggested that potential appetite-suppressant molecules should be screened in heterologous Kv channel expression systems. Nervous system Direct evidence of fenflur amine neurotoxicity in humans has emerged (34c). Using quantitative positron emission tomography (PET) with (14C)McN5652, a serotonin transporter ligand, global, and regional distribution volumes of the ligand were compared in 15 subjects who had pre viously used fenfluramine for weight loss and 17 age-matched controls. There was a significant reduction in ligand binding in 14 of the 15 brain regions of interest, more than 4 years after drug withdrawal. How ever, the study only showed an association between fenfluramine use and reduction in brain 5HT transporter density and did not prove that fenfluramine had caused this reduction. The fenfluramine-exposed group were mostly women, whereas the controls were men, leaving the possibility that sex differences might have played a part. Most of the subjects in the fenflura mine group had also been exposed to phen termine as part of a ‘Fen/Phen’ combination for weight loss for variable periods (average duration 8.3 months). Whether these changes are reversible cannot be deduced from this study, because the time since the last use of fenfluramine varied. Given the
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important role of 5HT neurons in various brain functions, reductions in 5HT transpor ter binding density associated with fenflur amine might be anticipated to predispose an individual to behavioral disturbances.
Atomoxetine Systematic reviews The efficacy and safety of atomoxetine in children and adolescents have been evaluated in a systematic review of nine randomized placebo-controlled trials (35M). Atomoxetine (n = 1150) was superior to placebo (n = 678) in reducing ADHD symptoms. The NNTB values for treatment response and relapse prevention were 3.43 (95% CI = 2.79, 4.45) and 10.3 (95% CI = 5.89, 40.62), respectively. The most common adverse events were gastro intestinal (reduced appetite, NNTH = 9; abdominal pain, NNTH = 22; vomiting, NNTH = 30; dyspepsia, NNTH = 49) and somnolence (NNTH = 19). Young age and high baseline hyperactive/impulsive symp toms were associated with more adverse events, and ADHD inattentive subtype was associated with fewer adverse events. Cardiovascular Since atomoxetine is a selec tive noradrenaline transport blocker, it could cause increased blood pressure by increasing noradrenaline concentrations in peripheral sympathetic neurons, an effect that could be masked in healthy subjects by central sympatholytic mechanisms. The pressor effect of atomoxetine (18 mg) has been studied in 21 patients with impaired central (n = 10) and peripheral (n = 11) autonomic nervous system functions in a randomized, crossover, placebo-controlled study (36C). Atomoxetine acutely increased sitting and standing SBPs in patients with central autonomic impairment by 54 and 45 mmHg respectively, compared with pla cebo. However, in those with peripheral autonomic impairment, atomoxetine had no pressor effect. The authors proposed that this suggests that a functional central sympatholytic pathway is essential to avoid hypertension in patients taking
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atomoxetine. They suggested caution when atomoxetine is used in patients with auto nomic impairment. Nervous system Seizures and seizurerelated symptoms have been studied using two of the manufacturers’ databases: the atomoxetine clinical trials database and the atomoxetine post-marketing spontaneous adverse event database (37c). The crude incidence rates of seizure adverse events with atomoxetine, methylphenidate, and placebo did not differ. In two children with ADHD, aged 6 and 8 years, relatively low doses of atomoxetine exacerbated and precipitated tics, which improved after withdrawal (38A). A 13 year-old boy was similarly affected (39A). Two cases of neurological complications requiring hospitalization occurred when atomoxetine was added to other psycho active drugs (40A). A 9-year-old taking cloni dine and dexamfetamine developed a psychosis, abnormal involuntary movements, and insomnia. An 18-year-old who took venlafaxine developed facial tics, tremors, and speech disturbance. The acute symptoms did not respond to diphenhydramine in either case, but resolved after atomoxetine and other medications were withdrawn. The possible explanations proposed by the authors included atypical atomoxetine effects, excess atomoxetine or metabolites due to poor CYP2D6 metabolizer status, drug–drug interactions leading to raised drug concentrations, or excess synaptic nora drenaline or dopamine concentrations. They suggested that there may be a risk of dyski nesias when atomoxetine is combined with dopaminergic, noradrenergic or serotonergic medications. Psychological Potential aggression and hostility have been studied in a meta-analysis of 14 acute clinical trials of atomoxetine for ADHD in children (atomoxetine, n = 1308; placebo, n = 806), active compara tor databases in children (atomoxetine, n = 566; methylphenidate, n = 472), and pla cebo-controlled studies in adults (atomoxe tine, n = 541; placebo, n = 405) (41M). In the placebo-controlled database, 21 patients
Central nervous system stimulants and drugs that suppress appetite
taking atomoxetine and 9 taking placebo had aggression/hostility events. In the active comparator database, there were seven events in patients taking atomoxetine and four in patients taking methylphenidate. In the adult database, there was one event in a patient taking placebo. The authors con cluded that events related to aggression or hostility occurred in less than 2% of patients and were not significantly more frequent in patients taking atomoxetine or methyl phenidate compared with placebo. Psychiatric Suicide-related events in 14 acute, double-blind, and placebo- or active comparator-controlled trials with atomoxe tine in children have been reviewed (42M). There were no completed suicides. The fre quency of suicidal ideation was 0.37% (5/1357) with atomoxetine versus 0% (0/851) with placebo (RR = 2.92; 95% CI = 0.63, 13). Frequencies of suicide-related events did not differ between methylphenidate and atomoxetine. The NNTH for an additional suicide-related event was 227 compared with the NNTB of 5 to achieve remission of ADHD symptoms. Electrolyte balance Hyponatremia has been attributed to atomoxetine (43A). Salivary glands Salivary stones have been associated with atomoxetine (44A). Gastrointestinal Atomoxetine has been given to 13 individuals who were seeking treatment for marijuana dependence in an 11-week open study; 8 completed the trial. Atomoxetine was associated with a large number of gastrointestinal adverse events: 10 of 13 subjects had mild to moderate adverse events, including nausea, vomiting, dyspepsia, and loose stools (45c). Liver Case reports that mentioned potential hepatobiliary events have been identified by a computerized search of the manufac turers’ spontaneous adverse events and clin ical trials databases (46c). Of 7961 children and adults who received atomoxetine in clinical trials, 41 had hepatobiliary events requiring additional analysis. Most were
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slight increases in transaminase activities. None progressed to liver failure. During the 4 years after marketing, 351 sponta neous reports of adverse events were related to the liver, of which 69 had other explanations unrelated to atomoxetine. Of the other 282 cases, 133 had possible con founding factors and were thought to be possibly related and 146 included too little information to assess. Three implicated ato moxetine as a probable cause of liver damage, one of whom had a positive rechal lenge; all three recovered after drug with drawal. The authors concluded that atomoxetine should be withheld in patients with jaundice or laboratory evidence of liver damage and should not be restarted. • An 8-year-old girl with ADHD was given atomoxetine hydrochloride. She complained of increased abdominal pain and occasional vomiting. Her transaminase activities and bilirubin concentration were markedly raised. Atomoxetine was withdrawn and a liver biopsy showed hepatitis with moderate piecemeal necrosis. She improved over 13 days.
The authors rated this as a probable adverse effect of atomoxetine (47A). Musculoskeletal The effects of atomoxetine on growth during long-term treatment for ADHD have been studied in 1312 patients, aged 6–17 years, of whom 61 were studied for 5 years (48C). The patients were slightly shorter than expected after 12 months and reached a maximum shortfall at 18 months; however, they returned to expected height by 24 months. Susceptibility factors The effects of CYP2D6 on the efficacy, safety, and tolerability of atomoxetine has been studied in children and adolescents using pooled data from atomoxetine clinical trials (49M). Poor meta bolizers had markedly greater reductions in mean symptom severity scores than exten sive metabolizers. Poor metabolizers had greater increases in heart rate and diastolic blood pressure and smaller increases in weight than extensive metabolizers. Several adverse events, including reduced appetite
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and tremor, were more frequent in poor metabolizers. Drug overdose Pediatric cases of atomoxe tine ingestion reported to Texan poison control centers during 2003–2005 have been analysed (50c). There were higher rates of serious outcomes at a maximum dose of > 2.8 mg/kg or > 200 mg or more than four tablets. Serious outcomes were also more common if the exposure involved intentional self-harm. • A 17-year-old girl took 2840 mg of atomoxetine in an attempt to kill herself, and about 3 hours later she had a tonic–clonic seizure lasting 1 minute (51A). The serum atomoxetine concentration was 1995 µg/l and the serum naproxen concentration was 12 µg/l. • A 16-year-old girl with ADHD took 15 tablets of Concerta (modified-release tablets of methylphenidate 54 mg each), 5–10 tablets of Ritalin (methylphenidate 10 mg each) and 8 tablets of Strattera (atomoxetine 40 mg each) (52A). About 2 hours later she was awake and oriented but with a fluctuating level of consciousness. She complained of dizziness and had periodic jerks in the lower limbs and tremor in both hands. The serum atomoxetine concentration about 6 hours after intake was 6410 µg/l (usual target range 13–204). In a second blood sample taken about 21 hours after intake, the serum concentration was 2902 µg/l. Methylphenidate concentrations were 174 and 9 µg/l (usual target range at tmax 2–17 µg/l). She recovered with supportive therapy. Her CYP2D6 genotype was *4/*5; the *4 polymorphism is a splice-site mutation that yields inactive enzyme, and *5 is a gene deletion.
The authors of the second case concluded that intoxication with atomoxetine can take a benign course, even in CYP2D6 poor metabolizers.
Methylphenidate (SED-15, 2307; SEDA-29, 10; SEDA-30, 4; SEDA-31, 3) Two reviews have comprehensively addressed the adverse effects of drugs used in the treatment of ADHD (53R, 54R). Observational studies The effects of methyl phenidate have been studied in 303 children
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aged 3–5.5 years with ADHD. Methyl phenidate was effective in preschool children with ADHD, but was associated with a high rate of adverse events (55C). The strengths of the study included a meticulous diagnostic process, participation of all parents in an intensive behavioral management programme before considering medication, randomization to different doses of medica tion (1.25, 2.5, 5.0, and 7.5 mg immediaterelease methylphenidate tds) and long-term follow-up to assess safety. The diagnosis of ADHD remains a chal lenge, because the core symptoms – hyper activity, impulsivity, and inattentiveness – are consistent with developmental variations in preschool children. Clinicians must decide which of these children fall outside expected behavioral norms and should weigh the potential benefits of methylphenidate against the relatively high rate of adverse events (56r). Comparative studies Immediate-release methylphenidate versus modified-release methylphenidate Based on a chart review, switching from immediate-release methyl phenidate to OROS methylphenidate in adults with ADHD was associated with improved treatment adherence and effec tiveness. There were no differences between the two formulations in terms of tolerability (57c). The most common adverse events with immediate-release and OROS methylphenidate were headache (21% versus 26%), reduced appetite (24% versus 20%), tachycardia (13% versus 31%), and insomnia (21% versus 18%). Although the reports of tachycardia and mood instability were more common in patients taking OROS methylphenidate, they were not significantly so. This study had limita tions, particularly (a) potential reporter bias due to non-blind design and (b) adherence assessment based on self-reporting without objective measures such as methylphenidate serum concentrations. Modified-release methylphenidate versus atomoxetine A modified-release formula tion of methylphenidate has been compared with atomoxetine in a large randomized,
Central nervous system stimulants and drugs that suppress appetite
controlled trial in children and adolescents with ADHD (58C). The study incorporated many desirable features, including rando mized design, a placebo arm, a large num ber of subjects, and optimal formulations and dosing strategies. The results suggested that while both drugs were better than pla cebo, methylphenidate was more effective in reducing the symptoms of ADHD than atomoxetine. Methylphenidate had a large effect size with a highly favorable NNTB of 3. Atomoxetine had a medium effect size and a less favorable, but still acceptable, NNTB of 5. Sleep difficulties were more frequent with methylphenidate, and somno lence with atomoxetine. Both drugs caused reduced appetite, but weight loss was greater with methylphenidate. Both increased diastolic blood pressure, but atomoxetine increased heart rate as well. The short dura tion of treatment (6 weeks) was adequate for detecting acute effects but was too short for measuring the effects on level of func tioning or on long-term adverse effects, such as growth suppression. A potential bias was introduced by including responders to previous methylphenidate treatment, while excluding patients who had not responded or could not tolerate it. Other limitations were the asymmetrical crossover after the initial 6-week trial, as only the methylphenidate group was switched to ato moxetine, and the lack of placebo control during this phase of the study. However, these data confirm that stimulants and ato moxetine, consistent with adrenergic activ ity, cause cardiovascular changes, which are on average small but whose long-term impact is unknown (59r). Methylphenidate versus clonidine Cloni dine, used alone or in combination with methylphenidate, has been evaluated in ADHD in a 16-week, randomized, doubleblind, placebo-controlled trial in 122 children aged 7–12 years with any type of ADHD (60C). The primary outcome was measured using Conners Teachers Abbreviated Symp tom Questionnaire (CTASQ) and the sec ondary outcome with Conners Abbreviated Symptom Questionnaire for Parents and the Children’s Global Assessment Scale
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(CASQPCGAS). On the CTASQ, clonidine did not improve the symptoms of ADHD, whereas methylphenidate gave significant improvement. On the CASQPCGAS score, clonidine not only improved the symptoms, but also caused more sedation, which never theless abated after 8 weeks, suggesting that it is more an acute than a long-term problem. In general, these findings should be viewed cautiously in the light of the differential rates of attrition across groups. The rate of attri tion was high in the placebo group, owing to lack of perceived efficacy or parental request or loss to follow-up. The findings were also limited by the exclusion of children with cer tain co-morbidities, such as mood and anxi ety disorders. Given that all of the subjects participated in psychoeducational and beha vioral interventions as part of the protocol, these results may be limited to settings in which these behavioral interventions are used. A further comparison of groups in terms of adverse events and changes from base line to week 16 showed that there were more instances of bradycardia (defined as a heart rate under 60/minute) in those who took clonidine (18% versus 3.4%), but no other significant group differences regard ing electrocardiography and other cardio vascular outcomes. Moderate and severe adverse events were more common in those taking clonidine (79% versus 49%) but not associated with higher rates of early withdrawal from the study. Drowsi ness was more common with clonidine, but generally resolved by 6–8 weeks. It is pru dent to monitor bradycardia and advise patients about the high likelihood of initial drowsiness. However, the safety of clonidine alone or with methylphenidate in children with ADHD and cardiac problems is not established. It is important to note that rare but important adverse events, either cardio vascular or psychiatric, may only be captured in a much larger sample. Should bradycardia or other intolerable adverse effects occur, clinicians can try lowering the dose of cloni dine gradually to see whether they resolve, but should avoid abrupt withdrawal of clo nidine, especially when patients are taking higher doses, to avoid rebound.
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Cardiovascular In a retrospective cohort analysis 10 years (1994–2004) of Florida Medicaid, claims data were cross-linked to the Vital Statistics Death Registry data (61cr). The cohort included subjects aged 3–20 years. During 124 932 person-years of observation (n = 55 383), 73 youths died, 5 from cardiac causes. No cardiac death occurred during 42 612 person-years of sti mulant use. Hospital admissions from car diac causes occurred in 27 children (8 due to stimulant use, 11 during 35 671 person-years of former use, and 8 during 46 649 personyears of non-use); and 1091 children visited the emergency department for cardiac causes (8.7 per 1000 person-years). Current stimulant use was associated with a 20% increase in the hazard for emergency department visits compared with non-use. There was no increased risk for periods of former use compared with non-use. Two important findings emerged from this study. First, the use of stimulants was asso ciated with an increased incidence of car diac symptoms. Second, the incidence of fatal and serious events from circulatory causes was low and seemed to be similar to national background rates. Although multivariate analysis showed that cardiac risk factors were adjusted, unmeasured con founders may have been missed. This could have included concomitant use of other medications with cardiac adverse effects that were not reimbursed by Medicaid, such as oral decongestants or appetite sup pressants, or the presence of undiagnosed congenital heart disease. Thus, a direct comparison between non-use and current use periods may be biased. However, addi tional analysis of former use mitigated such bias, because the hazard rates of periods of former use and of non-use were almost identical. It is important to note that ato moxetine was not included in this analysis. Nervous system Acute and transient dys kinesia occurred within hours of taking modified-release methylphenidate in a stimu lant-naïve 7-year-old boy who had recently stopped taking risperidone; rechallenge resulted in recurrence of the dyskinesia (62A). An interaction between supersensitive
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dopamine receptors and acute exposure to an indirect dopamine receptor agonist could have caused this adverse reaction. The authors suggested slow neuroleptic drug withdrawal followed by an extended wash out period before starting a psychostimulant in a low dose, with immediate withdrawal of the psychostimulant if dyskinesia should occur. Psychiatric An acute psychosis has been attributed to methylphenidate (63A). • A 10-year-old boy with ADHD and a chronic pattern of somatization developed somatic hallucinations after an increase in the dose of methylphenidate. He had a history of prenatal exposure to cannabis and cocaine, leading to foster placements before adoption. He had been taking OROS methylphenidate 36 mg/ day for 2 years but, because of disruptive behavior, was switched to regular-release methylphenidate 10 mg bd and then titrated to 15 mg bd Within 2 days after dose titration, his somatic symptoms intensified and became overtly hallucinatory, incorporating new themes and bodily functions. He believed that his genitalia were deformed and that urine was constantly trickling down his legs. Over the next several days he developed delusional parasitosis – tactile hallucinations of bugs crawling beneath his skin. His treatment was switched to clonidine and he had no somatic complaints at follow-up 1 year later.
Methylphenidate has been known to pro duce psychotic symptoms, in particular tac tile hallucinations (64A), at therapeutic doses. These are rare and usually of acute onset, and they may occur in the context of underlying psychotic disorder or substance abuse (65A). • A 7-year-old girl with ADHD and mild mental retardation displayed excessive masturbation and hypersexual behavior during After methylphenidate therapy (66A). withdrawal of methylphenidate, her ADHD symptoms increased as expected, but her sexual behavior improved rapidly and disappeared completely in 1 week.
Hypersexuality and masturbation were deemed to have been direct effects of methylphenidate, on the grounds that there was no history of such behavior before methylphenidate and that it increased in
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proportion with the increase in methylpheni date dose. In addition, the behaviors abated during drug holidays and completely disap peared shortly after drug withdrawal. Liver Hepatitis has been attributed to methylphenidate after liver transplantation (67A). • A 57-year-old Caucasian man, who had had an orthotopic liver transplantation 4 years before for chronic hepatitis C infection, developed liver function abnormalities. He had been maintained on cyclosporin, venlafaxine, omeprazole, hydrochlorothiazide, fosinopril, and a multivitamin formulation during the previous year. He denied using any herbal medications. In the months before presentation his liver function had been stable. His doctor had given him a long-acting formulation of methylphenidate 1 month earlier for impaired concentration and depressive symptoms refractory to venlafaxine. He had a raised antinuclear antibody titre (1:80) with a nucleolar pattern and anti-smooth-muscle antibodies (1:40). A liver biopsy showed a lobular and periportal necro-inflammatory infiltrate with predominant lymphocytes, plasma cells, and eosinophils, consistent with autoimmune hepatitis. On withdrawal of methylphenidate his liver function improved. He continued to take his previous medications plus prednisone 10 mg/day. His liver function normalized after a few months and the prednisone was withdrawn. He was also given a dexamfetamine/amfetamine combination. A liver biopsy 1 year after the acute episode of hepatitis showed marked improvement in the inflammatory infiltration.
Hematologic Hematological changes over the course of a 2-year trial of once-daily OROS methylphenidate in otherwise healthy children, aged 6–13 years, with ADHD, have been investigated (68C). Of 407 subjects, 289 completed 12 months and 229 completed 21 months. There were no clinically significant changes from baseline. These data suggest that long-term therapy with OROS methylphenidate has no clini cally relevant hematological effects, chal lenging the practice of routine hematological monitoring in otherwise healthy children with ADHD. Although rare cases of thrombocytopenia and easy bruisability, epistaxis, gingival bleeding, leucopenia, anemia, and
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eosinophilia have been reported in patients taking methylphenidate, a causal relation with the drug has not been established. Drug abuse The abuse potential of a single dose of OROS methylphenidate has been compared with that of immediate-release methylphenidate and placebo in healthy subjects with a history of recreational stimu lant use. Although requiring epidemiologi cal confirmation, the results suggested that OROS methylphenidate, with its character istic slow-ascending plasma concentration profile, may have less abuse potential. This conclusion was supported by fewer subjec tive responses during early hours compared with the immediate-release formulation, with its rapid drug delivery and accompany ing greater subjective effects (69C). This study did not pretest if the subjects could reliably report the effects of stimulants. This would have contributed to increased overall intersubject variation in subjective effects and a reduction in study power. Genotoxicity A threefold increase in geno mic damage in 12 children after 3 months of therapy with methylphenidate (70c) could not be replicated in a later study (71C). In a prospective study, genomic damage was studied in 38 children with ADHD before and after 1 month (n = 30), 3 months (n = 21), and 6 months (n = 8) after starting methylphenidate treatment. The measure of genomic damage was the frequency of micronuclei, a subset of chromosomal aber ration in peripheral lymphocytes. There were no changes in the number of micronucleated cells after methylphenidate treat ment at any time. The reasons for the discrepancies in the results of these studies have not been adequately addressed. The lack of supporting data should mitigate con cerns about the risk of cancer (72c, 73cr). Drug–drug interactions Disulfiram A possi ble drug–drug interaction of methylpheni date with disulfiram has been reported (74A). • A 33-year-old man with alcohol abuse and ADHD was given disulfiram 400 mg/day
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It is important to have a washout period in patients taking disulfiram before starting methylphenidate. Risperidone Three children developed severe hyperactivity, agitation, and irritabil ity on taking methylphenidate after with drawal of risperidone. These adverse reactions resolved on withdrawal of methyl phenidate; rechallenge with methylpheni date in two of these patients did not produce adverse effects after a risperidone free interval (75A). As atypical antipsycho tic drugs are being increasingly used in the treatment of childhood behavioral disor ders, either alone or in combination, their safety needs to be established. Functional adaptations in receptors during risperidone treatment may lead to altered behavioral responses on switching to methylphenidate. Tapering the dosage of the antipsychotic drug and a drug-free interval are recom mended.
Reginald P. Sequeira
nearly sleepless. Modafinil was withdrawn, and the hallucinations resolved within 1 week.
According to the Naranjo Scale, modafi nil was possibly the cause of this patient’s hallucinations. There have been two other case reports of the potential of modafinil to trigger or exacerbate psychotic symptoms in a schizophrenic patient receiving clozapine (77A) and in a healthy man who partici pated in a research project (78A). Drug–drug interactions Monoamine oxidase inhibitors Although a case report has suggested that modafinil combined with tranylcypromine is safe (79A), another report has illustrated the need for a study on the safety of combining modafinil with non-selective monoamine oxidase inhibitors. • A 34-year-old Caucasian woman developed chorea and confusion. She had a 15-year history of depression, stable with tranyl cypromine 80 mg/day. Three days before admission she had started to take modafinil 200 mg/day to improve wakefulness. She became restless and had tics, severe choreiform movement of all limbs, lip smacking and rhythmic rapid tongue protrusions. Her neck was in opisthotonus with rhythmic bilateral rotations. She was treated with cyproheptadine for presumed serotonin syndrome. The symptoms resolved in 48 hours (80A).
Overdose Combined overdose with methyl phenidate and atomoxetine has been reported (see above, under Atomoxetine).
METHYLXANTHINES (SEDA-29, 1; SEDA-30, 5; SEDA-31, 8)
Modafinil
(SED-15, 2369; SEDA-29, 10; SEDA-30, 6; SEDA-31, 7) Nervous system Hallucinations have been attributed to modafinil (76A).
• A 53-year-old man with a 10-year history of unipolar major depression without psychotic symptoms or substance abuse took venlafaxine 225 mg/day for 3 months. Modafinil was added, titrated up to 200 mg/ day. Three weeks later, he developed severe visual and coenesthetic primary hallucinations and became increasingly fearful, agitated, and
Caffeine
(SED-15, 588; SEDA-29, 1; SEDA-30, 5; SEDA-31, 8)
Fetotoxicity The premature neonate of an Argentinian mother who reported drinking yerba maté (the traditional name for the Ilex paraguariensis shrub, family Aquifolia ceae) during pregnancy developed jitteri ness and irritability, a high pitched cry, hypertonia in the limbs and brisk tendon reflexes, consistent with a neonatal with drawal syndrome (81A). There were high
Central nervous system stimulants and drugs that suppress appetite
concentrations of caffeine and theobromine in the placenta, cord blood, neonatal urine, maternal and neonatal hair, meconium, and breast milk, demonstrating both acute and chronic prenatal and postnatal exposure to methylxanthines, present in high amounts in home-brewed maté. The symptoms gradu ally resolved at 84 hours of age, although residual irritability persisted at 24 days of age. Plant extracts containing caffeine and other methylxanthines have become popu lar in North America and Europe as com ponents of ‘energy dietary supplements’. The authors noted that because of migration, doctors are seeing increasing number of South American pregnant women who consume yerba maté during pregnancy in Europe. Furthermore, highly variable amounts of methylxanthines in plants (because of differ ent methods of preparation) make it difficult to recommend intake limits for popular herbbased drinks. It has been suggested that there is an association between maté drinking dur ing pregnancy and a risk of preterm and smallfor-gestational-age birth (82A). Drug–drug interactions Regadenoson Rega denoson is a selective adenosine A2A receptor agonist. Regadenoson-induced coronary blood flow reserve was not significantly affected by prior caffeine ingestion 200 mg in the majority of 41 subjects studied in a phase II, double-blind, randomized, placebo-controlled, crossover study (83C). Caffeine blunted the coronary vasodilatory effect of adenosine but had a limited effect on regadenoson. How ever, it attenuated the severity of adverse effects and improved the tolerability of rega denoson. Moderate coffee consumption does not seem to interfere with regadenoson stress myocardial perfusion imaging. Synephrine Dietary supplements promoted to enhance athletic performance often con tain herbal sympathomimetics, such as Citrus aurantium (synephrine) and caffeine. In a three-arm, double-blind, placebo-controlled, crossover study, 10 healthy adults aged 20–31 years took one dose of a dietary supplement (Ripped Fuel Extreme Cut®), containing synephrine 21 mg and caffeine 304 mg (84c). There were significant increases in post
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exercise diastolic blood pressure and post prandial plasma glucose concentrations. Peak plasma concentrations of synephrine after a single oral dose averaged 10 mmHg/bpm were observed in 4.7 and 3.5% of subjects, respectively. Fifteen subjects died; 10 deaths were attributed to a cardiovascular cause, equivalent to 1.2 and 0.8 deaths per 100 years of exposure respectively. A further analysis of a subgroup in this trial showed that despite an initial lower body weight, older women with cardio vascular disease and diabetes mellitus appear to lose as much weight as men. The adverse effects profile of sibutramine in this older at-risk population was similar to that pre viously observed in younger patients (101C). The SCOUT trial is a double-blind, ran domized, placebo-controlled, parallel group trial conducted at 300 centers in 16 coun tries, predominantly in Europe. The overall dropout rate due to adverse events was 6.8% during the lead-in phase. Cardiac dis orders (0.6%) and blood pressure increases (0.2%) caused a minority of withdrawals, whereas others were due to previously reported and well-known adverse effects of sibutramine. All these numbers are much lower than anticipated. The benefit to-harm balance needs to be assessed, since many patients with manifest cardiovas cular disease, and in particular those at high risk (i.e. diabetics with metabolic syndrome), actually have the problem of obesity (102r). Sibutramine had comparable effects in men and women, as well as in those taking or not taking b-blocker. Although the authors of SCOUT study highlighted the potential of b-blockers to protect against disadvantageous changes in blood pressure and heart rate, there are no ambulatory blood pressure data to support this claim. Identifying the subgroups that would parti cularly benefit from sibutramine might emerge when the complete trial results are available. The concomitant use of sibutramine and b-blockers raises two conflicting problems. The Hypertension–Obesity–Sibutramine (HOS) study has shown the effects of
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Reginald P. Sequeira
different antihypertensive regimens (felodi pine þ ramipril versus trandolapril þ vera pamil versus metoprolol þ hydrochloro thiazide). Although the antihypertensive effects were not significantly different, those who took metoprolol þ hydrochlor othiazide had the greatest falls in blood pressure. More importantly, metoprolol þ hydrochlorothiazide attenuated the effect of sibutramine on weight loss and waist cir cumference. This treatment abrogated the improvement in glucose tolerance, as assessed by an oral glucose tolerance test, suggesting that this combination of antihy pertensive drugs was associated with wor sening of the metabolic syndrome (103C). Weight gain associated with b-blockers, mostly due to an increase in body fat (104c), is a disadvantage for combining them with sibutramine in patients with the metabolic syndrome and coronary artery disease. Thus, a prognostic benefit of com bining sibutramine with a b-blocker has yet to be confirmed. Two women developed myocardial infarctions with acute ST segment elevation associated with the use of sibutramine and phentermine (105A). The absence of cardio vascular risk factors and the negative results of other investigations suggested that the use of appetite suppressants may have been responsible. Respiratory In an open study in 87 middleaged men with obesity (BMI = 34 kg/m2) and symptomatic obstructive sleep apnea, moderate weight loss (~10%) with sibutra mine and a weight loss programme improved the severity of sleep apnea with out increasing the blood pressure (106c). However, there was a small increase in rest ing heart rate. Given the high prevalence of hypertension in patients with sleep apnoea, it is important first to establish whether con cerns about the risks of using sibutramine are justified. Paradoxically, there was a ten dency for the SBP to fall during sibutramine therapy and then revert to baseline after drug washout. This finding is in keeping with the inhibitory clonidine-like effect of sibutramine on the central nervous system (107c).
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Psychiatric Two reports have described another three cases of psychosis probably induced by sibutramine that responded to antipsychotic drugs (108A, 109A). Although causality is not yet established, sibutramine could be a susceptibility factor for people who are vulnerable to psychosis (110H). Drug–drug interactions Lorazepam Con current use of sibutramine 10 mg and loraz epam 2 mg resulted in hypoglycemic coma after less than 12 hours of fasting (111A). There was no other attributable cause, such as medication errors, ethanol ingestion, neoplasms, or liver disease.
Rimonabant The most frequent adverse effects of this endocannabinoid receptor antagonist are nausea, dizziness, diarrhea, and insomnia, each 1–9% more often than with placebo. Adverse effects leading to drug withdrawal occurred in 13–16% of patients taking the 20-mg dose (112C–115C). In the RIO-Europe, RIO-North America, and RIO Lipids clinical trials, drug withdrawal due to depression occurred in 6–7% of those tak ing rimonabant and an absolute increase of 2–5% over placebo. Because patients with mental illnesses were excluded from the RIO programme, these estimates of the potential of psychiatric adverse effects of this drug are conservative (116R, 117M).
DRUGS USED IN ALZHEIMER’S DISEASE (SEDA-29, 12; SEDA-30, 8; SEDA-31, 10)
Donepezil
(SED-15, 1179; SEDA-29, 12; SEDA-30, 8; SEDA-31, 10) Placebo-controlled studies In a multi national, double-blind, placebo-controlled trial at 98 sites, donepezil preserved
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cognition and global function in patients with severe Alzheimer’s disease (118C). Adverse events were consistent with the known cholinergic effects of donepezil, similar to those encountered in patients with mild to moderate Alzheimer’s disease. Furthermore, the Swedish Alzheimer Treat ment Study (SATS) has shown that 3-year treatment with donepezil had positive global and cognitive outcomes in the routine clin ical setting (119C). Since this study enrolled patients with concomitant diseases and medications, the 3-year-completion rate was 38%, comparable with earlier studies. Treatment with donepezil for 12 weeks has no significant advantage for donepezil over placebo in the treatment of clinically signifi cant agitation in patients with Alzheimer’s disease (120C). Sensory systems Intraoperative floppy-iris syndrome associated with long-term donepezil has been reported (121A). • A 75-year-old white man, who had taken donepezil for 8 years, had phacoemulsification under general anesthesia. Mydriasis was achieved preoperatively with topical cyclo pentolate, phenylephrine, and diclofenac. During surgery, the features of floppy-iris syndrome developed, such as billowing of the iris, which also prolapsed through the phaco and side-port incisions with progressive miosis. Phacoemulsion was continued with a low vacuum, a low flow rate and injection of 2.3% sodium hyaluronate to achieve good mechanical pupil dilatation and keep the iris away from the incision. The surgery was uneventful, and the patient had a visual acuity of 6/6.
Identifying drugs that can influence the out come of cataract surgery is crucial, and the authors stressed the importance of thor oughly evaluating a patient’s medication history preoperatively. Drug–drug interactions Atracurium Don epezil can prevent neuromuscular blockade due to atracurium during general anesthe sia. The authors recommended withdrawal of cholinesterase inhibitors 3–4 weeks before anesthesia in patients with Alzhei mer’s disease (122A).
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Memantine
(SED-15, 2250)
Systematic reviews There is considerable interest in assessing drugs used in the treat ment of Alzheimer’s disease for other types of dementias. Cholinesterase inhibitors and memantine do not have regulatory approval in most countries for treating vascular dementia. The available evidence has been examined in a systematic review (123M). The authors concluded that cholinesterase inhibi tors and memantine produce little benefit on cognition in patients with mild to moderate vascular dementia. Three donepezil, two galantamine, one rivastigmine, and two memantine clinical trials, comprising 3093 patients receiving drug therapy and 2090 patients on placebo, were included in this analysis. Compared with placebo, there were more dropouts and adverse effects, such as anorexia, nausea, vomiting, diarrhea, and insomnia, with cholinesterase inhibitors but not with memantine. The trials included in this meta-analysis lasted 6 months and were designed specifi cally to assess symptomatic rather than neuroprotective effects. Although the risk of adverse events with memantine seemed to be less than with cholinesterase inhibi tors, reporting was more limited, precluding full assessment. The clinical heterogeneity of patients with vascular dementia limits generalizability of the trial’s outcomes, because the effect of treatment on specific patients or subgroups cannot be defined.
Rivastigmine (SED-15, 3072; SEDA-30, 10; SEDA-31, 11) Observational studies There were no signif icant benefits of rivastigmine on the pro gression rate of mild cognitive impairment to Alzheimer’s disease or on cognitive func tion over a span of 4 years in patients with mild cognitive impairment (124C). Rivastigmine was not associated with any significant safety concerns. Placebo-controlled studies In the IDEAL (Investigation of Trans-Dermal Exelon in
Reginald P. Sequeira
Alzheimer’s disease) study, rivastigmine transdermal patches were compared with rivastigmine capsules and placebo in a 24 week double-blind, double-dummy, pla cebo- and active-controlled trial (125C). Patients with Alzheimer’s disease were ran domized to placebo or one of three active treatments: a 10-cm2 rivastigmine patch (delivering 9.5 mg/day), a 20-cm2 rivastig mine patch (17.4 mg/day) or rivastigmine capsules 6 mg bd A total of 1195 patients participated. The 10-cm2 patch showed similar efficacy to the capsules, with about two-thirds fewer reports of nausea (7.2% versus 23%) and vomiting (6.2% versus 17%), incidences that were not statistically different from placebo (5.0 and 3.3% for nausea and vomiting respectively). The 20-cm2 patch produced earlier improve ment and numerically superior scores com pared with the 10-cm2 patch and similar tolerability to the capsules. There was excel lent adhesion of the patch, even in tropical countries, where sweating is expected at the site of application of the patch. There was no skin irritation. Cardiovascular Complete heart block has been attributed to rivastigmine (126A). • A 67-year-old Turkish woman with Alzheimer’s disease developed dizziness and syncope. She had taken amlodipine 5 mg/day for hypertension and nateglinide 120 mg/day for diabetes mellitus for over 5 years and oral rivastigmine 6 mg/day for 5 months. She had had dizziness since she had started to take rivastigmine. Her blood pressure was 90/ 60 mmHg and her pulse rate 34/minute. An electrocardiogram showed complete atrio ventricular (AV) block. Echocardiography, serum electrolytes, cardiac biochemical markers and the coronary arteries were normal. A temporary transvenous pacemaker was implanted, and amlodipine and rivastigmine were withdrawn. Two days later, the AV block reverted spontaneously to sinus rhythm. Complete AV block recurred after rivastigmine 6 mg/day was restarted and she required a permanent pacemaker.
According to the Naranjo Scale, there was a probable association between rivas tigmine therapy and complete AV block. Other cholinesterase inhibitors used for
Central nervous system stimulants and drugs that suppress appetite
treating Alzheimer’s disease can also cause AV block in susceptible individuals. Nervous system Therapy with rivastigmine in patients with mild Alzheimer’s disease induces remodelling of the cholinergic and related neuronal networks in the brain, which is clinically manifested by reduced progression of the disease. Changes in 11 C-nicotine binding have been assessed by dual-tracer PET scanning in 10 patients with mild Alzheimer’s disease (127c). The main cognitive domain associated with nico tinic receptors after treatment was the attention domain. Drug formulations The pharmacokinetics of rivastigmine from a transdermal patch cor related with inhibition of plasma butyrylcholinesterase enzyme activity in 51 patients. Average exposure with a 10-cm2 patch was comparable with rivastigmine capsules 6 mg bd. In those who used the 10-cm2 patch, nausea and vomiting occurred in 8 and 4% of patients respectively. In those who used capsules 12 mg/day, nausea and vomiting occurred in 28 and 17% respectively. In total, 16 patients withdrew because of adverse events, mainly gastrointestinal. Drug administration route The regional variation in transdermal availability of rivas tigmine has been explored (128c). Taking the upper back as the reference site, the relative availability of rivastigmine from the other anatomical sites was 100% for the chest, 92% for the upper arm, 80% for the abdo men and 71% for the thigh. From all body sites, rivastigmine was detectable in less than an hour after application of the patch. Drug–drug interactions Memantine Conco mitant administration of memantine did not alter the extent of systemic exposure to riv astigmine and its metabolite NAP226-90 at steady state in an open single-center study in patients with mild to moderate Alz heimer’s disease (129c). The combination was well tolerated when a gradual step-up approach was used to increase the dose of
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memantine in patients already stabilized on rivastigmine.
Tacrine
(SED-15, 3279; SEDA-27, 7)
Susceptibility factors Genetic In 69 patients of Caucasian origin taking tacrine for Alz heimer’s disease, 241 SNPs in 19 candidate genes potentially related to hepatotoxicity have been genotyped (130c). The data sug gested, but did not prove, an association between tacrine-induced transaminase rises and genetic variants in ABCB4, which encodes the phosphatidylcholine transpor ter multidrug resistance protein 3 (MDR3). Tacrine, however, does not seem to be either a substrate or an inhibitor of MDR3. The mechanisms by which tacrine interacts with MDR3, phosphatidylcholine transport, and possibly membrane fluidity, requires further investigation. This study has also highlighted the limitations of genetic studies of rare adverse events, since genotyping strategies that evaluate multiple genes or whole genomes will have limited statistical power. Hepatic gene expression has been deter mined using microarray in rats treated with single dose of tacrine (131Ec]. The interleukin 6 gene was identified as a potential candidate for susceptibility to changes in transaminases. In the same study, 69 patients with Alzhei mer’s disease taking tacrine, with or without altered transaminases, were genotyped for 17 interleukin-6 gene polymorphisms. The results suggested that the interleukin-6 geno type may be a susceptibility factor. An obvious limitation of this study was the small number of patients and the large number of SNPs investigated, raising the possibility of false-positive associations. Moreover, one cannot exclude the possibility that the associa tion with interleukin-6 is due to linkage dis equilibrium with a neighboring gene on chromosome 7. Given that tacrine is no longer used in clinical practice, further investigations will be of limited value. However, the role of acute dosing in rats in identifying candidate genes associated with drug-induced liver damage in humans merits further study.
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exposure presenting as caustic ingestions in children. Ann Emerg Med 2007;49:341–3. 30. Greffe G, Chalabreysse L, Mouly-Bertin C, Lantelme P, Thivolet F, Aulagner G, Obai dia J-F. Valvular heart disease associated with fenfluramine detected 7 years after dis continuation of treatment. Ann Thorac Surg 2007;83:1541–3. 31. Guibert C, Marthan R, Savineau J-P. Modulation of ion channels in pulmonary arterial hypertension. Curr Pharm Des 2007;13:2443–55. 32. Patel AJ, Lazdunski M, Honore E. Kv9.3, a novel ATP-dependent delayed rectifier Kþ channel in oxygen-sensitive pulmonary artery myocytes. EMBO J 1997;16:6615–25. 33. Perchenet L, Hilfiger L, Mizrahi J, ClementChomienne O. Effects of anorexigen agents on cloned voltage-gated (Kþ) channel hKv1.5. J Pharmacol Exp Ther 2001;298:1108–19. 34. McCann UD, Szabo Z, Vranesic M, Seckin E, Wand G, DuVal A, Dannals RF, Ricaurte GA. Quantitative positron emission tomo graphy studies of the serotonin transporter in humans previously treated with the appe tite suppressants fenfluramine or dexfenflur amine. Mol Imaging Biol 2007;9:151–7. 35. Cheng JY, Chen RY, Ko JS, Ng EM. Efficacy and safety of atomoxetine for attention-deficit/hyperactivity disorder in children and adolescents – meta-analysis and meta-regression analysis. Psychophar macology (Berl) 2007;194:197–209. 36. Shibao C, Raj SR, Gamboa A, Diedrich A, Choi L, Black BK, Robertson D, Biaggioni I. Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function. Hypertension 2007;50:47–53. 37. Wernicke JF, Holdridge KC, Jin L, Edison T, Zhang S, Bangs ME, Allen AJ, Ball S, Dunn D. Seizure risk in patients with attention-deficit– hyperactivity disorder treated with atomoxetine. Dev Med Child Neurol 2007;49:498–502. 38. Pa´ rraga HC, Pa´rraga MI, Harris DK. Tic exacerbation and precipitation during ato moxetine treatment in two children with attention-deficit/hyperactivity disorder. Int J Psychiatry Med 2007;37:415–24. 39. Sears J, Patel NC. Development of tics in a thirteen-year-old male following atomoxetine use. CNS Spectr 2008;13:301–3.
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72. Suter W, Martus HJ, Elhajouji A. Methyl phenidate is not clastogenic in cultured human lymphocytes and in the mouse bone marrow micronucleus test. Mutat Res 2006;607:153–9. 73. Jacobson-Kram D, Mattison D, Shelby M, Slikker W, Tice R, Witt K. Methylpheni date and chromosome damage. Cancer Lett 2008;260:216–8. 74. Caci H, Bayle F. A case of disulfiram–methyl phenidate interaction: implications for treat ment. Am J Psychiatry 1759;2007:164. 75. Sabuncuoglu O. Risperidone-to-methyl phenidates witch reaction in children: three cases. J Psychopharmacol 2007;21:216–9. 76. Oulis P, Kouzoupis AV, Kontoangelos K, Pachou E, Masdrakis VG, Soldatos CR. Visual and coenesthetic hallucinations asso ciated with modafinil. J Clin Psychopharma col 2008;28:251–2. 77. Narendran R, Young CM, Valenti AM, Nickolova MK, Pristach CA. Is psychosis exacerbated by modafinil? Arch Gen Psy chiatry 2002;59:292–3. 78. Mariani JJ, Hart CL. Psychosis associated with modafinil and shift work. Am J Psy chiatry 1983;2005:162. 79. Clemons WE, Makela E, Young J. Conco mitantuse of modafinil and tranylcypromine in patient with narcolepsy: a case report. Sleep Med 2004;5:509–11. 80. Vytopil M, Mani R, Adlakha A, Zhu J-J. Acute chorea and hyperthermia after con current use of modafinil and tranylcypro mine. Am J Psychiatry 2007;164:684. 81. Martin I, Lopez-Vilchez MA, Mur A, Garcia-Algar O, Rossi S, Marchei E, Pichini S. Nenonatal withdrawal syndrome after chronic maternal drinking of mate. Ther Drug Monit 2007;29:127–9. 82. Santos IS, Matijasevich A, Valle CJ. Mate drinking during pregnancy and risk of preterm and small for gestational age birth. J Nutr 2005;135:1120–3. 83. Gaemperli O, Schepis T, Koefli P, Siegrist PT, Fleischman S, Nguyen P, Olmsted A, Wang W, Lieu H, Kaufmann PA. Interaction of caffeine with regadenoson-induced hyperemic myocardial blood flow as measured by posi tron emission tomography. A randomized, double-blind, placebo-controlled crossover trial. J Am Coll Cardiol 2008;51:328–9.
26 84. Haller CA, Duan M, Jacob III P, Benowitz N. Human pharmacology of a performanceenhancing dietary supplement under resting and exercise conditions. Br J Clin Pharma col 2008;65:833–40. 85. McGuffin M. Effecton heart rate of bitter orange, caffeine and exercise. Am J Med 2007;120:e19. 86. Haller CA, Benowitz NL. Effect on heart rate of bitter orange, caffeine, and exercise. Am J Med 2007;120:e21. 87. Rogers PJ, Smith JE, Heatherley SV, PleydellPearce CW. Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. Psychopharmacology 2008;195:596–77. 88. Haskel CF, Kennedy DO, Milne AL, Wesnes KA, Scholey AB. The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychiatry 2008;77:113–22. 89. Cysneiros RM, Farkas D, Harmatz JS, von Moltke LL, Greenblatt DJ. Pharmacoki netic and pharmacodynamic interactions between zolpidem and caffeine. Clin Phar macol Ther 2007;82:54–62. 90. Korematsu S, Miyahara H, Nagakura T, Suenobu S, Izumi T. Theophylline-asso ciated seizure and their clinical characteri zations. Pediatr Int 2008;50(1):95–8. 91. Bowton DI, Stump DA, Anderson R. Effect of chronic theophylline therapy on brain blood flow and function in adult asthmatics. Am J Respir Crit Care Med 1994;150:1002–5. 92. Ryu JY, Song IS, Sunwoo YE, Schon JH, Liu KH, Cha IJ, Shin JG. Development of the ‘Inje cocktail’ for high-throughput evaluation of five human cytochrome P450 isoforms in vivo. Clin Pharmacol Ther 2007;82:531–40. 93. Streetman DS, Bleakley JF, Kim JS, Nafzi ger AN, Leeder JS, Gaedigk A, Gotschall R, Kearns GL, Bertino Jr. JS. Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyl transferase-2 and xanthine oxidase with the ‘Cooperstown cocktail’. Clin Pharmacol Ther 2000;68:375–83. 94. Christensen M, Anderson K, Dalen P, Mir ghani RA, Muirhead GJ, Nordmark A, Tybring G, Wahlberg A, Yasar U, Bertilsson L. The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin Pharmacol Ther 2003;73:517–28.
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95. Horvath K, Jeitler K, Siering U, Stich AK, Skipka G, Gratzer TW, Siebenhofer A. Long term effects of weight reducing inter ventions in hypertensive patients. Arch Intern Med 2008;168:571–9. 96. Fleming RM, Boyd LB. The longitudinal effects of fenfluramine–phentermine use. Angiology 2007;58:353–9. 97. Anonymous. Weight loss pills. Warning about serious health risks. WHO Newslett 2009;1:7. 98. Anonymous. Dietary supplements contain ing undeclared drug. WHO Newslett 2009;2:7. 99. SwissMedic. Swiss Agency for Therapeutic Products. Dangerous side effects of the ille gal slimming product ‘Zhen de Shou’. http:// www.swissmedic.ch/aktuell/00003/00687/ index.html?lang=en. 100. Torp-Pedersen C, Caterson I, Coutinho W, Finer N, Van Gaal L, Maggioni A, Sharma A, Brisco W, Deaton R, Shepherd G, James P, SCOUT Investigators Cardiovascular responses to weight management and sibu tramine in high-risk subjects: an analysis from the SCOUT trial. Eur Heart J 2007;28:2915–23. 101. Coutinho WF. The obese older female patient: CV risk and the SCOUT study. Int J Obesity 2007;31:S26–30. 102. von Haehling S, Lainscak M, Anker SD. Sibutramine in cardiovascular disease: is SCOUT the new STORM on the horizon? Eur Heart J 2007;28:2830–1. 103. Scholze J, Grimm E, Herrmann D, Unger T, Kintscher U. Optimal treatment of obesityrelated hypertension. The Hypertension– Obesity–Sibutramine (HOS) study. Circulation 2007;115:1991–8. 104. Lainsack M, Keber I, Anker SD. Body composition changes in patients with systo lic heart failure treated with beta blockers: a pilot study. Intl J Cardiol 2006;106:319–22. 105. Azarisman SM, Magdi YA, Noorfaizan S, Oteh M. Myocardial infarction induced by appetite suppressants in Malaysia. N Engl J Med 2007;357:1873–4. 106. Yee BJ, Phillips CL, Banerjee D, Caterson I, Hedner JA, Grunstein RR. The effect of sibutramine-assisted weight loss in men with obstructive sleep apnea. Int J Obesity 2007;31:161–8.
Central nervous system stimulants and drugs that suppress appetite 107. Birkenfeld AL, Schroeder C, Pischon T, Tank J, Luft FC, Sharma AM, Jordan J. Paradoxical effect of sibutramine on auto nomic cardiovascular regulation in obese hypertensive patient. Clin Autonom Res 2005;15:200–6. 108. Rosenbohm A, Bux CJ, Connemann BJ. Psychosis with sibutramine. J Clin Psycho pharmacol 2007;27:315–7. 109. Litvan L, Alcoverro-Fortuny O. Sibutra mine and psychosis. J Clin Psychopharma col 2007;27:726. 110. Fern´andez P, Peiró AM. A sibutramineinduced delusional disorder relapse. J Neu ropsychiatry Clin Neursosci 2007;19:88–9. 111. Lin Y-Y, Hsu C-W, Chu S-J, Tsai S-H. Another dangerous combination for hypogly cemic coma: Concurrent use of sibutramine and lorazepam. Q J Med 2008;101:243–4. 112. Després JP, Golay A, Sj¨ostrom ¨ L, Rimonabant in Obesity–Lipids Study Group. Effects of rimonabant on metabolic risk fac tors in overweight patients with dyslipide mia. N Engl J Med 2005;353:2121–4. 113. Van Gaal LF, Rissanen AM, Sheen AJ, Ziegler R, Rossner S, for the RIO–Europe Study Group. Effects of cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1 year experience from the RIO–Europe study. Lancet 2005;365:1389–97. 114. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. RIO–North Amer ica Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in over weight or obese patients. J Am Med Assoc 2006;295:761–5. 115. Scheen AJ, Finer N, Hollander P, Jensen MD, van Gaal LF, RIO–Diabetes Study Group. Group efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes. Lancet 2006;368:1160–72. 116. Padwal RS, Majumdar SR. Drug treatments for obesity: orlistat, sibutramine, and rimo nabant. Lancet 2007;369:71–7. 117. Curioni C, Andre C. Rimonabant for over weight or obesity. Cochrane Database Syst Rev 2006;18:CD 006162(4). 118. Black SE, Doody R, Li H, McRae T, Jambor KM, Xu Y, Sun Y, Perdomo CA,
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Richardson S. Donepezil preserves cognition and global function in patients with severe Alzheimer’s disease. Neurology 2007;69:459–69. Wallin AK, Andreasen N, Eriksson S, Bats man S, Nasman B, Ekdahl A, Kilander L, Grut M, Ryden M, Wallin A, Jonsson M, Olofsson H, Londos E, Wattmo C, Jonhagen ME, Minthon L, Swedish Alzheimer Treat ment Study Group. Donepezil in Alzheimer’s disease: what to expect after 3 years of treat ment in a routine clinical setting. Dementia Geriatr Cognitive Disord 2007;23:150–60. Howard RJ, Juszczak E, Ballard CG, Ben tham P, Brown RG, Bullock R, Burns AS, Holmes C, Jacoby R, Johnson T, Knapp M, Lindesay J, O’Brien JT, Wilcock G, Katona C, Jones RW, DeCesare J, Rodger M, CALMAD Trial Group. Donepezil for the treatment of agitation in Alzheimer’s dis ease. N Engl J Med 2007;357:1382–92. Papadopoulos R, Bachariou A. Intraopera tive floppy-iris syndrome associated with chronic intake of donepezil. J Cataract Refract Surg 2007;33:1997–8. Baruah J, Easby J, Kessel G. Effects of acetylcholinesterase inhibitor therapy for Alzheimer’s disease on neuromuscular block. Br J Anaesth 2008;100:420. Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomized controlled trials. Lancet Neurol 2007;6:782–92. Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, Tekin S, Burns A, Cummings J, der Ser T, Inzitari D, Orgo gozo JM, Sauer H, Scheltens P, Scarpini E, Herrmann N, Farlow M, Potkin S, Charles HC, Fox NC, Lane R. Effect of rivastigmine on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment: the InDDEx study. Lancet Neurol 2007;6:473–5. Winblad B, Grossberg G, Frolich L, Farlow M, Zechner S, Nagel J, Lane R. IDEAL A, 6-month, double-blind, placebo controlled study of the first skin patch for Alzheimer’s disease. Neurology 2007;69:S14–2. Kayrak M, Yazici M, Ayhan SS, Koc F, Ulgen MS. Complete atrioventricular block associated with rivastigmine therapy. Am J Health-Syst Pharm 2008;65:1051–3.
28 127. Kadir A, Darreh-Shori T, Almkvist O, Wall A, Langstrom B, Nordberg A. Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer’s disease following rivastigmine treatment as assessed by PET. Psychopharmacology 2007;191:1005–14. 128. Lefevre G, Sedek G, Huang HA, Saltzman M, Rosenberg M, Kiese B, Fordham P. Pharmacokinetics of a rivastigmine trans dermal patch formulation in healthy volun teers: relative effects of body site application. J Clin Pharmacol 2007;47:471–8. 129. Shua-Haim J, Smith J, Picard F, Sedek G, Athalye S, Pommier F, Lefevre G. Steadystate pharmacokinetics of rivastigmine in patients with mild to moderate Alzheimer’s
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disease not affected by co-administration of memantine. An open label, cross-over, sin gle-center study. Clin Drug Invest 2008;28:361–74. 130. Alfirevic A, Mills T, Carr D, Barratt BJ, Jawaid A, Sherwood J, Smith JC, Tugwood JD, Hartkoorn R, Owen A, Park KB, Pir mohamed M. Tacrine-induced liver damage: an analysis of 19 candidate genes. Pharmacogenet Genomics 2007;17:1091–9. 131. Carr D, Alfirevic A, Tugwood JD, Barratt BJ, Sherwood J, Smith J, Pirmohamed M, Park BK. Molecular and genetic association of interleukin-6 in tacrine-induced hepato toxicity. Pharmacogenet Genomics 2007; 17:961–72.
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Antidepressant drugs
GENERAL Antidepressants and emergent suicidality Before reviewing recent publications in this controversial area, it will be helpful to review the background briefly. The term ‘emergent suicidality’ refers to suicidal thoughts or behaviors that occur soon after an anti depressant is introduced. Emergent suicidality may be a symptom of the underlying psy chiatric illness, e.g. depression, that led to use of the antidepressant, but the possibility that antidepressants may paradoxically cause or increase suicidality in some individuals has been periodically raised for decades. This most recently came to attention in 2005 when the US Food and Drug Administration (FDA) issued a black-box warning that all antidepressants increase the risk of suicidal thinking and behavior in children and ado lescents. The warning was based on a meta analysis of randomized placebo-controlled trials that showed that in younger people suicidal thinking and behavior occurred twice as often in those taking an antidepres sant as it did in those taking placebo; however, within this data set there were no completed suicides in either group (1M). Sub sequent analyses of suicidality in placebocontrolled antidepressant trials in adults have shown that the risk of both suicidal behaviour (completed suicide, attempted suicide, or preparatory acts) and suicidal ideation are age dependent (2M). Compared Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32002-2 � 2010 Elsevier B.V. All rights reserved.
with placebo, antidepressant use is associated with an increased risk of suicidal behavior and ideation among those under the age of 25 years (i.e. children, adolescents, younger adults). Among those aged 25–64 years, there is a neutral effect on suicidal behavior and possibly a protective effect on suicidal ideation. Among those aged 65 years and older, antidepressants are associated with a reduced risk of suicidal behavior and idea tion compared with placebo (2M). An updated meta-analysis conducted by Lilly, the manufacturers of fluoxetine, assessed suicidality in a database that brought together results from 18 double-blind, placebo-controlled fluoxetine trials in adults (fluoxetine, n = 2200; placebo, n = 1551) (3M). Fluoxetine treatment led to greater improve ment and faster resolution of suicidal idea tion than placebo. Of course, this result does not exclude the possibility that there may be individual patients in whom the opposite occurs, i.e. the result is still compatible with there being adults in whom fluoxetine leads to increased suicidal ideation. In a secondary analysis of data from an open 12-week trial of fluoxetine 20 mg/day in out-patients with an episode of non-psychotic major depression, 59 of 414 subjects (14%) without suicidal ideation at baseline reported suicidal ideation on at least one subsequent visit (4c). Independent factors associated with suicidal ideation included emergence of acti vation, worsening of depression, female sex, younger age, and having thoughts that life was not worth living before treatment. Emer gent suicidal ideation was associated with treatment resistance, i.e. depression that was more difficult to treat. The authors concluded that emergence of suicidal ideation was rela tively common, at least in this trial of fluox etine, and was associated with the emergence
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of activation and overall symptomatic wor sening. The lack of a placebo group means that one cannot determine to what extent the emergence of suicidal ideation in this study reflected the natural history of the underlying depressive illness, an effect of fluoxetine treat ment or both. However, the association of suicidal ideation with symptomatic worsening strongly suggests that suicidal ideation was a symptom of the underlying depressive illness. Elderly patients with major depression who took either paroxetine or nortriptyline were divided into four groups: those with no suici dal ideation, those with emergent suicidal ideation, those with persistent suicidal idea tion, and those who had resolved suicidal ideation (5c). The rates of emergent, persistent, and resolved suicidality were 7.8, 13, and 16%, respectively. The rates of emergent suicidal ideation were the same in those who took paroxetine or nortriptyline. Patients with emergent suicidality had lower selfesteem than non-suicidal patients at the start of treatment, were more likely to maintain higher depression scores, and had higher levels of anxiety and agitation during treat ment than patients with resolved suicidality. Emergent suicidal ideation was not asso ciated with akathisia. Emergent suicidal idea tion was associated with treatment resistance, i.e. depression that was more difficult to treat. In a retrospective cohort study using the UK General Practice Research Database, the risk of completed suicide and suicide attempts in adults aged 18–89 years taking venlafaxine was compared with the risk associated with citalopram, fluoxetine, and dothiepin (6c). Venlafaxine was associated with an increased unadjusted risk of completed suicide and attempted suicide. However, compared with patients taking other antidepressants, those who took venlafaxine were more likely to have susceptibility factors for suicide, includ ing a prior suicide attempt, and markers for severe or treatment-resistant depression. After adjustment for these confounders, the risks of both completed and attempted suicide with venlafaxine were substantially reduced. In summary, the increased risk of attempted and completed suicide in patients taking ven lafaxine compared with other antidepressants appears to be largely due to the increased
Chapter 2
Peter M. Haddad
likelihood that it will be prescribed for patients at higher risk of suicide rather than an increased likelihood that it causes suicidality. Liver A detailed review of antidepressantmediated liver damage has highlighted that the mechanisms are not understood (7R). In some reports it was not possible to estab lish causality, because of underlying liver damage or the concurrent use of other drugs. Among selective serotonin re-uptake inhibitors (SSRIs) there were more cases of hepatotoxicity with paroxetine than with other SSRIs. The most serious cases of hepa tic damage were seen with nefazodone, a serotonin–noradrenaline re-uptake inhibitor (SNRI), which led to its withdrawal in 2003 and 2004. Reports of hepatotoxicity were also noted with monoamine oxidase inhibi tors (MAOIs) and tricyclic antidepressants. The authors concluded that most anti depressant agents can produce hepatic damage. The key to management is prompt recognition followed by withdrawal of the causal antidepressant. Musculoskeletal The association between the risk of a fracture and the use of three classes of psychiatric drugs – anxiolytics and sedatives (including benzodiazepines), anti psychotic drugs, and antidepressants – has been investigated in a case–control study (8C). Both anxiolytics/sedatives and anti psychotic drugs were associated with a small increase in the overall risk of fracture, but there was no dose–response relationship, throwing some doubt on the findings. By contrast, antidepressants showed a dose–response relationship for the risk of fracture. The risk of fracture was higher with SSRIs than with tricyclic antidepressants. Whether the increased risk of fracture seen with the three medication groups represents a causal relationship with drug use is unclear. For example, impaired attention and concen tration, a common symptom of many psychia tric disorders, could lead to an increased risk of falls and fractures. Conversely, there are several mechanisms whereby psychiatric medications could increase the risk of frac ture. For example, sedation may increase the
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risk of falls and some antipsychotic drugs can cause hyperprolactinemia, which when marked can cause secondary hypogonadism, which in turn can lead to reduced bone mineral density and an increased risk of fracture when a fall occurs (9R). The existence of a dose–response relationship with anti depressants and fracture-risk in this study suggests that the relationship may be causal, but this requires further investigation. Drug withdrawal Withdrawal symptoms can occur with all the major antidepressant classes. These symptoms are usually mild and self-lim iting and resolve within a few days without treatment; however, occasionally they are severe, disabling, and of longer duration (10R). In an attempt to minimize or prevent their occurrence, most guidelines for antide pressant drug treatment recommend that if an antidepressant drug is withdrawn when a patient is well, it should be withdrawn gradu ally over several weeks rather than stopped abruptly. Whether or not dosage tapering is needed when switching between antidepres sants will depend on the pharmacological pro files of the two antidepressants, the one that is being stopped and the one that is being started. Abrupt switching is generally safe when switching between antidepressants with simi lar pharmacological actions. Although one would intuitively expect tapering to reduce the incidence of withdrawal symptoms, few studies have assessed whether that is the case. In a small study, patients taking SSRIs or venlafaxine who were still currently depressed were randomized to a 3-day (short) or 14-day (longer) antidepressant taper and openly assessed after a drug-free washout period for 5–7 days (11c). The patients were assessed for a third time after 7 days of treatment with a new antidepressant of the clinician’s choice. This is currently the only published rando mized study to have assessed the effect of taper length on the incidence of antidepres sant withdrawal symptoms. There was a ‘dis continuation syndrome’ (three or more new symptoms on the Discontinuation Emergent Signs and Symptoms checklist) in 46% of patients, with similar frequencies in those who had had the short or longer taper. Anti depressant withdrawal symptoms included
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worsening depression and increased suicida lity. In keeping with the results of other stu dies, patients who were initially treated with a short half-life antidepressant had significantly greater increases in withdrawal and depres sive symptoms than those who stopped taking fluoxetine (a long half-life antidepressant). The results support the importance of halflife in the etiology of withdrawal symptoms and suggest that there is no advantage to a 2 week taper over a 3-day taper when switching or stopping antidepressants. Drug overdose The effect of a single dose of activated charcoal on the risk of QT interval prolongation after citalopram over dose has been studied in a retrospective case-note review (12c). Data from eight emergency departments were combined to yield two groups of patients who presented with citalopram overdose, those who were treated with activated charcoal and those who were not. The two groups were similar in terms of age, sex, citalopram dose, and co-ingested cardiotoxic drugs. No patient in either group developed torsade de pointes. The relative risk of QT prolongation was significantly less in the charcoal group than in those who did not receive charcoal. The authors concluded that a single dose of activated charcoal may be effective in reducing the risk of QT interval prolonga tion in patients after citalopram overdose.
Adverse effects of antidepressants in pregnancy When a mother develops a depressive illness during pregnancy, the decision of whether to prescribe an antidepressant requires a bal ancing of the risks that the antidepressant will harm the fetus and the mother against the risks to both mother and child from an untreated depressive illness, both during pregnancy and after delivery. A similar question applies when a woman taking a maintenance antidepressant becomes pregnant – do the benefits of medica tion in terms of reducing the risk of a depres sive recurrence outweigh the potential adverse effects of the medication?
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Teratogenicity A study from UnitedHealth care (www.uhc.com), a large US insurer, has shown that first-trimester exposure to paroxe tine was associated with an increased risk of congenital malformations compared with other antidepressants (13c). A population reg ister study from Quebec showed that neither paroxetine nor other SSRIs were associated with an increased risk of congenital cardiac malformations compared with non-SSRI antidepressants (14c). However, when the effect of dose was investigated, first-trimester use of paroxetine in doses over 25 mg/day was associated with an increased risk of major congenital malformations and major cardiac malformations. This study highlights the fact that drug dosage is an important variable that needs to be considered when assessing potential teratogenic risk. A meta-analysis concluded that first-trimester exposure to paroxetine was associated with an increased risk of cardiac malformations (15M). An increased risk of cardiovascular defects following exposure to bupropion during pregnancy has been reported in the GlaxoSmithKline Bupropion Pregnancy Registry. A further study using data from UnitedHealthcare compared the prevalence of congenital malfor mations in infants with first-trimester exposure to bupropion to that seen with (i) other anti depressants in the first trimester and (ii) bupro pion outside the first trimester (16c). The rate of all congenital malformations, and also that of cardiovascular malformations, did not differ significantly between the three groups. In sum mary, this study did not find evidence that firsttrimester bupropion exposure was teratogenic. Fetotoxicity An increased rate of symptoms has been reported in neonates whose mothers had taken antidepressants up to delivery com pared with the offspring of mothers who had not taken antidepressants. There has been a debate whether the underlying mechanism represents an antidepressant withdrawal syn drome, serotonin toxicity, or a combination of the two (17R). Previous reports have high lighted the fact that these neonatal symptoms are self-limiting and resolve, usually within a few days, without treatment. These findings have been confirmed in a retrospective cohort that compared mothers who had taken SSRIs or venlafaxine during the third trimester and
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mothers who had not been given an anti depressant or any psychotropic agent at the time of delivery (18c). Data from 76 mothers taking antidepressants and 90 untreated mothers and their neonates were analysed. Signs involving the central nervous and the respiratory systems were more frequent in the antidepressant-exposed infants (63% versus 41%). In the antidepressant-exposed group signs appeared within 24 hours of delivery, had a median duration of 3 days, and were more common in those who were premature than in those born at full term. This last result suggests that premature infants may be more vulnerable than full-term infants to the effects of exposure to SSRIs and venlafaxine during the third trimester. There was recurrent hypothermia until day 10 of life in concordant monozygotic twins born to a mother who had taken mir tazapine during pregnancy (19A). The twins were born at 35 weeks’ gestation with birth weights of 2426 and 2355 g. Other causes were excluded. The authors suggested that hypothermia had been due to adrenergic and serotonergic receptor antagonism.
MONOAMINE OXIDASE INHIBITORS (SED-15, 2371; SEDA-29, 19) Drug overdose Drug-induced myocarditis is a rare adverse effect that has been asso ciated with various drugs, including amitripty line (20A), clozapine (21R), and cocaine (22R). The Scottish Poisons Information Bureau has suggested that myocarditis may also be a complication of phenelzine overdose (23A). • A 23-year-old woman, previously physically healthy and with no history of cardiovascular disease, took a very large overdose of phenelzine (2760 mg) plus olanzapine 50 mg, two glasses of beer, and a glass of wine. In addition to the recognized clinical features of overdosage with phenelzine (impaired consciousness, tachycardia, seizures), she developed severe hypotension and reduced left ventricular function and died after a few days. Post-mortem toxicology showed
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a high serum phenelzine concentration (4.1 mg/l) and histology showed the characteristic features of drug-induced myocarditis.
SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SED-15, 3109; SEDA-29, 19; SEDA-30, 16; SEDA-31, 18) Nervous system Given the association of SSRIs with an increased risk of gastrointes tinal bleeding, the risk of hemorrhagic stroke in users of SSRIs has been studied in the USA (24c). The use of SSRIs was not associated with an increased risk of either intracerebral hemorrhage (n = 500) or sub arachnoid hemorrhage (n = 416). This is in keeping with the results of a previous study (25C). However, owing to limited power and the association between the use of SSRIs and bleeding at other sites, it is important that larger population studies be conducted to confirm or refute this finding. Endocrine The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a rare but well-recognized complication of many drugs, including antidepressants (26R). With antidepressants it usually occurs in the first weeks after starting treatment and is more common in elderly patients. A case of SIADH involving citalopram has been reported (27A). • A 54-year-old woman with hypertension took diuretics and a salt-restricted diet. After starting to take citalopram, she became drowsy and developed paresthesia, fatigue, nausea, vomiting, and visual hallucinations. She had hyponatremia (97 mmol/l) and hypokalemia (2.3 mmol/l). Her symptoms resolved after withdrawal of citalopram and fluid restriction, and the serum sodium and potassium concentrations increased to 137 and 5.2 mmol/l respectively.
The authors suggested that salt restriction may have increased her susceptibility to SIADH due to citalopram.
33 • A 58-year-old man with schizophrenia and a long history of excessive water intake developed nausea, fatigue and irregular fluctuating pyrexia soon after starting to take fluoxetine (28A). His symptoms improved after fluid restriction and withdrawal of fluoxetine.
It is possible that long-standing psychogenic polydipsia made this patient more vulner able to fluoxetine-induced SIADH.
SSRIs and gastrointestinal bleeding Reports have linked SSRIs to bleeding at sev eral body sites (29AR). Reported reactions range from mild spontaneous bleeding, includ ing bruising and nose bleeds, to serious events, including gastrointestinal bleeding, genito urinary bleeding and in one study an increased risk of bleeding and subsequent need for blood transfusion during orthopedic surgery (30c). In population-based cohort studies, SSRI users have been shown to be more likely to have upper gastrointestinal bleeding than non-users (31C, 32C), and in one study the risk of lower gastrointestinal bleeds was also increased (33c). The increased risk of bleeding is thought to reflect inhibition of the serotonin re-uptake transporter in platelet plasma membranes. The transporter allows the uptake of sero tonin into platelets, which cannot themselves synthesize it. Platelets release serotonin in response to vascular injury. The serotonin is responsible for vasoconstriction and a change in platelet shape, which, in the presence of other agents, such as collagen or adrenaline, leads to aggregation and clot formation. By depleting platelets of serotonin, SSRIs impair clot formation and so increase the risk of bleeding from pre-existing lesions, particu larly in the gastrointestinal tract, or from a new injury. This mechanism is supported by various studies, including a cohort study, in which the increased risk of abnormal bleeding was strongly associated with the degree of serotonin re-uptake inhibition (34C). There is no evidence that SSRIs cause direct injury to the gastrointestinal mucosa.
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A meta-analysis, using data from four observational studies involving 153 000 patients, has shown that SSRIs increase the risk of upper gastrointestinal hemorrhage and that the risk is further increased if the SSRI is used in combination with a non-steroidal anti inflammatory drug (NSAID) (35M). The odds ratio for an association of SSRIs with upper gastrointestinal hemorrhage was 2.36 (95% CI = 1.44, 3.85); for an SSRI co-prescribed with an NSAID the odds ratio was 6.33 (95% CI = 3.40, 12). In patients aged over 50 years, with no risk factors for upper gastrointestinal hemorrhage, the NNTH per year was 411 for SSRIs alone and 106 for SSRIs co-prescribed with an NSAID. A further study using the General Practice Research Database (GPRD) confirmed that SSRIs were associated with an increased risk of upper gastrointestinal hemorrhage (36C). However, unlike several earlier studies, the authors controlled for the confounding effect of heavy alcohol consumption. The excess risk of upper gastrointestinal hemorrhage with SSRIs was smaller than previously reported (rate ratio, RR = 1.3; 95% CI = 1.1, 1.6). There was no increase in the estimated risk of upper gastrointestinal hemorrhage with tricyclic antidepressants, but the risk with venlafaxine was the highest of the three antidepressant groups assessed. In summary, this study showed that SSRIs increase the risk of upper gastrointestinal hemorrhage but sug gested that earlier studies may have overesti mated the risk by failing to account for the confounding effect of heavy alcohol intake. Although there is some controversy about the magnitude of the risk, the association of SSRIs with an increased risk of upper gastro intestinal hemorrhage is a consistent finding across studies. The risk is increased in patients who also take NSAIDs, including aspirin. This is an important interaction, given the widespread use of NSAIDs and SSRIs and the seriousness of upper gastrointestinal hemorrhage. There are several clinical impli cations. SSRIs should be used with caution in patients with a history of bleeding disorders or risk factors for bleeding, e.g. cirrhosis. When possible, the combination of an SSRI and an NSAID should be avoided. Paraceta mol is a safer alternative if regular analgesia
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is required. If the combination of an SSRI and an NSAID is required, the patient should be informed of the risks and asked to report any bleeding; the prescription of a gastro protective agent such as ranitidine or omepra zole should also be considered. However, it should be noted that no studies have inves tigated whether this approach reduces the risk of bleeding with SSRIs. Skin Mild skin reactions are well recognized with antidepressants, but serious skin reac tions are rare. Toxic epidermal necrolysis probably reflects cell-mediated hypersensi tivity and can occur with many drugs, includ ing antibiotics and anticonvulsants (37R). It is characterized by extensive cutaneous lesions, and the diagnosis is made when more than 30% of the epidermis is affected. The mucous membranes are often involved, systemic signs can occur and there can be multiple complications. Not surprisingly, mortality is high. A case of toxic epidermal necrolysis has been reported in a 34-year-old patient in association with fluoxetine (38A).
SEROTONIN AND NORADRENALINE RE-UPTAKE INHIBITORS (SNRIs) Duloxetine Cardiovascular Pre-existing heart failure worsened after the introduction of duloxetine in a 68-year-old man (39A). The resulting tachycardia remitted after drug withdrawal. Duloxetine is an SNRI, and increased con centrations of noradrenaline may be the underlying mechanism for the worsened heart failure. The authors recommended that SNRIs be avoided or used with caution and regular monitoring in patients with heart failure. Drug–drug interactions Interactions involving CYP2D6 The relative effects of escitalo pram 20 mg/day, duloxetine 60 mg/day, and
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sertraline 100 mg/day on the activity of CYP2D6 have been studied in young healthy adults by measuring changes in the pharmacokinetics of metoprolol, a substrate of CYP2D6 (40C). All three antidepressants produced statistically significant changes in metoprolol pharmacokinetics, but the size of the effect was greatest with duloxetine and least with sertraline. The change seen with duloxetine was significantly greater than with sertraline. The changes produced by escitalopram and sertraline were similar. The study confirms that dulox etine is a moderate inhibitor of CYP2D6 and that caution is needed when duloxetine is co-prescribed with drugs that are predominantly metabolized by CYP2D6 (e.g. risperidone, tricyclic antidepressants), particularly if they have a narrow thera peutic index.
Venlafaxine
(SED-15, 3614; SEDA-29, 24; SEDA-30, 19; SEDA-31, 22)
Cardiovascular Venlafaxine is associated with increased blood pressure. By contrast, hypotension associated with venlafaxine is much rarer. A physically healthy woman, taking no other medication, developed hypo tension with venlafaxine (41A). There was a temporal and a dose–response relation between the hypotension and the use of ven lafaxine, supporting a causal association. Pre-existing heart failure worsened after the introduction of venlafaxine in a 39-year-old woman (39A). The resulting tachycardia remitted after drug withdrawal. Venlafaxine is an SNRI, and increased concentrations of noradrenaline may be the underlying mechanism for the worsened heart failure. The authors recommended that SNRIs be avoided or used with caution and regular monitoring in patients with heart failure. Drug overdose The features of venlafaxine toxicity in overdose have been investigated in a retrospective case-note review of 235 patients admitted to a Scottish hospital after venlafaxine overdose between January 2000 and June 2006 (42c). Seizures occurred
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in 8.9%. Patients who had seizures had taken significantly larger amounts of venla faxine than those who did not develop sei zures: median (interquartile range) 2800 (2006–4350) mg versus 1500 (900–2700) mg. There was a positive correlation between the amount of venlafaxine ingested and creatine kinase activity both across the whole group and in those without seizures, suggesting that venlafaxine overdose is associated with acute muscle damage irrespective of the occurrence of seizures.
OTHER ANTIDEPRESSANTS Bupropion (amfebutamone)
(SED
15, 108; SEDA-29, 24; SEDA-30, 20; SEDA-31, 22) Liver There have been rare reports of severe but non-fatal hepatotoxicity associated with bupropion, and in one case an auto immune mechanism appeared to be involved (43A). Fatal hepatotoxicity related to bupro pion has been reported (44A). This appeared to involve an autoimmune mechanism. • A 55-year-old man developed jaundice and severe hepatic damage about 6 months after starting to use bupropion for smoking cessation. Laboratory investigations showed a mixed picture of hepatocellular injury and cholestasis and were positive for autoimmune markers. Liver biopsy was consistent with drug-induced severe hepatic injury. Steroid treatment led to an initial improvement in his clinical condition, but he subsequently died of infectious complications.
Bupropion should be added to the list of drugs that can cause hepatocellular jaundice. Teratogenicity
See Special review above.
Drug–drug interactions Lopinavir þ rito navir The potential interaction of a single 100 mg dose of modified-release bupropion with the combination of lopinavir þ ritona vir 100 mg bd has been studied in 12 healthy volunteers (45C). Lopinavir þ ritonavir significantly reduced the Cmax of bupropion by 57% and the area under the curve (AUC)
36
infinity. The Cmax and AUC infinity of the active metabolite hydroxybupropion were also reduced. The proposed mechan ism is induction of CYP2D6 and UDP-glucuronosyltransferase. The authors suggested that the interaction may require as much as a doubling of the dose of bupropion in patients who are concur rently taking lopinavir þ ritonavir.
Reboxetine
(SED-15, 3028; SEDA-30, 21; SEDA-31, 22)
Endocrine Pseudopheochromocytoma has been attributed to reboxetine (46A).
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mirtazapine had no beneficial effect (48C). There were frequent withdrawals because of lethargy (2 in the first study, 15 in the second). Weight gain was significantly greater with mirtazapine than with placebo in both trials. Nervous system Worsening of seizures has been attributed to mirtazapine in a patient stabilized on phenytoin (49A). • A 50-year-old woman with simple partial seizures and secondarily generalized tonic– clonic seizures, occasionally precipitated by fever, took phenytoin 200 mg/day for 11 years and was seizure free. She then developed a low mood, anhedonia, pessimistic views about the future, anergia, and insomnia and was given mirtazapine 7.5 mg/day. After taking one dose of mirtazapine, she had two partial motor seizures with secondarily generalized tonic– clonic seizures while asleep. The following night, after a second dose she had another similar episode. Mirtazapine was withdrawn and she was given escitalopram. Her seizures did not recur.
• A 47-year-old man, who was taking colchicine for familial Mediterranean fever, developed major depression and was given reboxetine 8 mg/day, fluoxetine 20 mg/day, and clonazepam 2 mg/day. After 1 year, he developed episodic dizziness and syncope with asymptomatic runs of sinus tachycardia (118/minute) lasting up to 4 minutes. He was given metoprolol 50 mg/day but continued to have symptoms. His lying blood pressure was 148/85 mmHg, with a marked fall to 100/50 on standing, when his heart rate rose from 84 to 114/minute. Pheochromocytoma was suspected, and urinary collections for catecholamines and their metabolites showed very high concentrations. Reboxetine and fluoxetine were withdrawn and the urinary catecholamines and metabolites became normal. He was free of symptoms 2 years later.
The mechanism of this effect is unclear. Mirtazapine does not alter the metabolism of phenytoin, and in any case the event occurred too quickly to be explained kinetically. The seizures may have reflected the epileptogenic action of mirtazapine, though the existing literature suggests it has a very low seizureinducing potential. Alternatively a pharma codynamic interaction of mirtazapine with phenytoin could have been responsible.
Sexual function Erectile dysfunction and seminal emission and ejaculation during defecation and micturition have been attrib uted to reboxetine (47A).
Psychiatric Adding mirtazapine to a sero tonin re-uptake inhibitor may increase its antidepressant effects and is more likely to cause a switch to a manic phase.
• A 44-year-old man with depression but without any sexual dysfunction was given venlafaxine, but because of delayed ejaculation and occasional episodes of absent ejaculation he was switched to reboxetine. After 2 weeks he reported erectile dysfunction and premature ejaculation; seminal emission and ejaculation during defecation and micturition occurred after 8 weeks. He was given sertraline 50 mg/day instead, and his sexual dysfunction resolved after 2 weeks.
• A 66-year-old woman with type II diabetes mellitus, hypertension, hyperlipidemia, chronic renal insufficiency, unstable angina, and osteoporosis, but no history of mania, hypomania, or major depression, became depressed, irritable, and agitated and was given fluoxetine 20 mg/day. Her feelings persisted and she was switched to mirtazapine 30 mg/day, without a period of tapering off, washout, or cross-titration. Three days later, her selfesteem was inflated and her irritability, agitation, and argumentativeness worsened. She slept less but was energetic and talkative. After 6 days she developed vivid grandiose delusions with religious content. Her mood was elated and labile. After 8 days she had become violent and uncooperative. She asserted that she was free from all physical illnesses and could save her country and help all people
Mirtazapine Placebo-controlled studies In two rando mized, double-blind, placebo-controlled trials of mirtazapine (7.5, 15, 30, or 45 mg) for obstructive sleep apnea in 20 and 65 patients,
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rise to higher levels, spiritually and materially. Her speech was pressured and she was elated. Mirtazapine was withdrawn and valproate and low-dose risperidone begun. Her manic symptoms subsided gradually during the next 2 weeks.
The authors suggested that because of its long half-life fluoxetine might have persisted in the body after withdrawal and inhibited the metabolism of mirtazapine or produced a pharmacodynamic interaction (50A). Electrolyte balance A 61-year-old man and a 79-year-old woman developed profound hyponatremia (sodium 112 and 113 mmol/l) 7 and 10 days after starting to take mirtaza pine for depression (51Ar). Investigations excluded other causes, and withdrawal of mirtazapine led to recovery of sodium con centrations to at least 132 mmol/l after 7 and 10 days respectively. The authors graded the likelihood that mirtazapine had caused hypo natremia in these cases as ‘probable’ accord ing to the Naranjo criteria. A review of published cases showed that mirtazapine associated hyponatremia occurs in patients aged over 60 years, after a mean of 6.5 days, and with doses as low as 7.5 mg/day. The sodium concentration fell to a mean of 117 mmol/l, and after withdrawal of mirtaza pine the mean time to recovery was 11 days. Liver Mirtazapine has been associated with dose-related asymptomatic rises in hepatic enzymes (52c). Pancreas Pancreatitis is a rare complica tion of many drugs. Recurrent pancreatitis, thought to be due to mirtazapine, has been reported (53A). Fetotoxicity
See special review above.
Lactation The transfer of mirtazapine and desmethylmirtazapine into breast milk has been investigated in eight breast-feeding women who were taking a median dose of 38 mg/day and in four of their infants (54c). The mean infant doses of mirtazapine and desmethylmirtazapine were 1.5 and 0.4%, respectively. The mean milk-to-plasma ratios (AUC) were 1.1 for mirtazapine and 0.6 for desmethylmirtazapine. There were no adverse effects. Mirtazapine was detected in only one of the four infants tested (1.5 µg/l).
37
The authors concluded that it is probably safe for lactating women to use mirtazapine. Susceptibility factors Genetic Mirtazapine is given as a racemic mixture of Sþ and R– mirtazapine (55c). It is absorbed from the gut with a rate constant of 0.2/minute (half life 3.5 minutes) for the Sþ isomer and 0.08/ minute (half-life 9 minutes) for the R– isomer. The kinetics of R– mirtazapine are not related to CYP2D6 genotype, but the total clearance of the Sþ enantiomer is 1.3, 2.3, and 3.4 l/minute in poor, extensive, and ultrarapid metabolizers of CYP2D6 respec tively; there was substantial first-pass meta bolism in rapid and ultrarapid metabolizers. The effects of mirtazapine on heart rate and blood pressure correlated better with R– than Sþ concentrations, but sedation corre lated equally with the two enantiomers. Drug overdose In a retrospective chart review of 71 patients who took an overdose of mirtazapine reported to a poison centre during 2004, 33 isolated exposures were reviewed (56c). The average age was 27 (range 6–82) years. The mean dose ingested was 343 (range 15–1500) mg. The most common neu rological symptom was drowsiness, which occurred in eight patients; one became agi tated and 14 had no abnormal neurological findings. There were cardiovascular effects in four patients: three had tachycardia and one had bradycardia and hypotension. There were no deaths. In another retrospective case analysis of overdoses over a 5-year period, there were 117 cases (57c). The median (interquartile range) dose ingested was 450 (240–785) mg. Consciousness was impaired in 27% and there was a higher incidence of tachycardia (30%) than predicted. There were no other significant clinical, laboratory or electro cardiographic abnormalities. These reports suggest that mirtazapine is relatively safe in overdose and are consis tent with earlier reports (58R). Declaration of potential conflicts of interest In the past 3 years PMH has received fees for lecturing and/or consultancy from the manufacturers of various antide pressants, including Eli-Lilly and Servier.
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pregnancy. Can J Clin Pharmacol 2008;15(2): e188–90. 20. Ansari A, Maron BJ, Berntson DG. Druginduced toxic myocarditis. Tex Heart Inst J 2003;30(1):76–9. 21. Haas SJ, Hill R, Krum H, Liew D, Tonkin A, Demos L, Stephan K, McNeil J. Clozapine associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993– 2003. Drug Saf 2007;30(1):47–57. 22. Phillips K, Luk A, Soor GS, Abraham JR, Leong S, Butany J. Cocaine cardiotoxicity: a review of the pathophysiology, pathology, and treatment options. Am J Cardiovasc Drugs 2009;9(3):177–96. 23. Waring WS, Wallace WA. Acute myocarditis after massive phenelzine overdose. Eur J Clin Pharmacol 2007;63(11):1007–9. 24. Kharofa J, Sekar P, Haverbusch M, Moomaw C, Flaherty M, Kissela B, Broderick J, Woo D. Selective serotonin reuptake inhibitors and risk of hemorrha gic stroke. Stroke 2007;38(11):3049–51. 25. Bak S, Tsiropoulos I, Kjaersgaard JO, Andersen M, Mellerup E, Hallas J, García Rodríguez LA, Christensen K, Gaist D. Selective serotonin reuptake inhibitors and the risk of stroke: a population-based casecontrol study. Stroke 2002;33(6):1465–73. 26. Strickland P. Syndrome of inappropriate secretion of antidiuretic hormone. In: Haddad P, Dursun S, Deakin B, editors. Adverse syn dromes and psychiatric drugs: a clinical guide. Oxford: Oxford University Press, 2004:261–9. 27. Bez Y, Aktolga S, Balci M, Nurmedov S, Topçuoglu V. Citalopram-induced SIADH in a hypertensive patient on salt-restricted diet. J Psychopharmacol 2007;21(6):665–7. 28. Ozturk S, Ozsenel EB, Kazancioglu R, Turk men A. A case of fluoxetine-induced syndrome of inappropriate antidiuretic hormone secre tion. Nat Clin Pract Nephrol 2008;4(5):278–82. 29. Nelva A, Guy C, Tardy-Poncet B, Beyens MN, Ratrema M, Benedetti C, Ollagnier M. Hemor rhagic syndromes related to selective serotonin reuptake inhibitor (SSRI) antidepressants: seven case reports and review of the literature. Rev Med Interne 2000;21:152–60. 30. Movig KL, Janssen MW, de Waal Malefijt J, Kabel PJ, Leufkens HG, Egberts AC. Rela tionship of serotonergic antidepressants and
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effects on cytochrome P450 2D6 function in healthy volunteers. J Clin Psychopharmacol 2007;27(1):28–34. Alexandrino-Silva C, Nadalini Maua´ FH, de Andrade AG, de Toledo Ferraz Alves TC. Hypotension caused by therapeutic doses of venlafaxine: case report and proposed patho physiological mechanisms. J Psychopharma col 2008;22(2):214–6. Wilson AD, Howell C, Waring WS. Venla faxine ingestion is associated with rhabdo myolysis in adults: a case series. J Toxicol Sci 2007;32(1):97–101. Alvaro D, Onetti-Muda A, Moscatelli R, Atili AF. Acute cholestatic hepatitis induced by bupropion prescribed as pharmacological support to stop smoking. A case report. Dig Liver Dis 2001;33(8):703–6. Humayun F, Shehab TM, Tworek JA, Fontana RJ. A fatal case of bupropion (Zyban) hepatotoxicity with autoimmune features: Case report. J Med Case Reports 2007;18(1):88. Hogeland GW, Swindells S, McNabb JC, Kashuba AD, Yee GC, Lindley CM. Lopi navir/ritonavir reduces bupropion plasma concentrations in healthy subjects. Clin Phar macol Ther 2007;81(1):69–75. Zornitzki T, Knobler H, Schattner A. Rebox etine treatment and pseudopheochromo cytoma. QJM 2007;100(1):61–2. Sivrioglu EY, Topaloglu VC, Sarandol A, Akkaya C, Eker SS, Kirli S. Reboxetine induced erectile dysfunction and sponta neous ejaculation during defecation and mic turition. Prog Neuropsychopharmacol Biol Psychiatry 2007;31(2):548–50. Marshall NS, Yee BJ, Desai AV, Buchanan PR, Wong KK, Crompton R, Melehan KL, Zack N, Rao SG, Gendreau RM, Kranzler J, Grunstein RR. Two randomized placebocontrolled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea. Sleep 2008;31 (6):824–31.
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49. Zia UI, Haq M, Prakash R, Akhtar S. Mirta zapine precipitated seizures: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2008;32(4):1076–8. 50. Liu CC, Liang KY, Liao SC. Antidepressantassociated mania: soon after switch from fluox etine to mirtazapine in an elderly woman with mixed depressive features. J Psychopharmacol 2009;23(2):220–2. 51. Cheah CY, Ladhams B, Fegan PG. Mirtaza pine associated with profound hyponatremia: two case reports. Am J Geriatr Pharmac other 2008;6(2):91–5. 52. Adetunji B, Basil B, Mathews M, Osinowo T. Mirtazapine-associated dose-dependent and asymptomatic elevation of hepatic enzymes. Ann Pharmacother 2007;41 (2):359. 53. Hussain A, Burke J. Mirtazapine associated with recurrent pancreatitis – a case report. J Psychopharmacol 2008;22(3):336–7. 54. Kristensen JH, Ilett KF, Rampono J, Kohan R, Hackett LP. Transfer of the antidepres sant mirtazapine into breast milk. Br J Clin Pharmacol 2007;63(3):322–7. 55. Brockmo¨ ller J, Meineke I, Kirchheiner J. Pharmacokinetics of mirtazapine: enantio selective effects of the CYP2D6 ultra rapid metabolizer genotype and correlation with adverse effects. Clin Pharmacol Ther 2007;81(5):699–707. 56. LoVecchio F, Riley B, Pizon A, Brown M. Out comes after isolated mirtazapine (Remeron) supratherapeutic ingestions. J Emerg Med 2008;34(1):77–8. 57. Waring WS, Good AM, Bateman DN. Lack of significant toxicity after mirtazapine over dose: a five-year review of cases admitted to a regional toxicology unit. Clin Toxicol (Phila) 2007;45(1):45–50. 58. Kelly CA, Dhaun N, Laing WJ, Strachan FE, Good AM, Bateman DN. Comparative toxi city of citalopram and the newer antidepres sants after overdose. J Toxicol Clin Toxicol 2004;42(1):67–71.
Rif S. El-Mallakh, Rona J. Roberts, and Yonglin Gao
3 Uses The therapeutic use of lithium appears to be declining. In a study of in patient prescribing practices in 63 German, Austrian, and Swiss hospitals over a 10-year period from 1994 to 2004, the use of lithium for acute mania declined significantly from 43 to 35% (1M). This decline was more than offset by an increase in the use of both anticonvulsants (from 40 to 61%) and sec ond-generation antipsychotic drugs (from 19 to 44%). In the USA the use of lithium in outpatient Medicaid populations (n = 26 133) in the early 2000s was 13–25% of bipo lar subjects (2M, 3M). Yet when the entire weight of evidence is taken into account, lithium appears to be both underused and underappreciated (4r). Thus, it is not sur prising that in some areas (e.g. Spain), lithium use has actually increased, while in others (e.g. England), it is still commonly used (5r).
Lithium in neuroprotection Several animal and in vitro studies have demon strated a neuroprotective effect of lithium against a wide array of toxic insults (6E, 7E). Several magnetic resonance imaging (MRI) studies in patients have found increases in hippocampal volume. In humans, grey matter density was greater in 20 lithium-treated patients compared with 8 patients not taking lithium and 29 matched healthy controls, Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32003-4 2010 Elsevier B.V. All rights reserved.
Lithium particularly in the right anterior cingulate (8c). In 12 bipolar patients who took lithium for 2–4 years there was improvement in verbal memory performance and increased volume of the hippocampus (9E). Similarly, in 33 bi polar patients (12 unmedicated and 21 taking lithium) and 62 matched healthy controls, the total hippocampal volume was 10% larger in the lithium-treated patients and 14% larger than in unmedicated bipolar patients (10E). In a third study, of 12 patients who had taken lithium for 1–8 years (mean age 16 years, 7 male), 9 unmedicated and medica tion naïve patients (14 years, 3 male), 7 bipo lar subjects receiving anticonvulsants (26 years, 3 male), and 30 healthy controls (25 years, 14 male), the authors reported that both the hippocampal head and tail were increased in those taking lithium compared with all the other groups (11E). The authors were surprised that a neuroplastic change occurred so quickly. While collectively these studies might suggest a neurotrophic effect, none of the studies corrected for the effect of lithium on water. Lithium has the highest energy of hydration of all the alkali metals, and is consequently surrounded by a large amount of water, so as to make its hydrated size equivalent to that of calcium (12R). Con sequently, when rats are given lithium, the frontal cortical grey matter experiences an increase of 3.1% water (13E). However, lithium does induce synaptic plasticity in rats (14E). Lithium may have a neurotrophic effect by several mechanisms. Lithium treatment is asso ciated with elaboration of a variety of growth factors. It attenuates the reduction that is observed in bipolar subjects in the receptors for insulin-like growth factors in the prefrontal cortex (15E); lithium prevents the reduction in vascular endothelial growth factor (VEGF)
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that is normally seen in stressed rats (16E); it increases expression of brain-derived neuro trophic factor (BDNF) in cultured rat neurons (17E); and finally, it reduces the activity of proapoptotic glycogen synthase kinase-3 (GSK3) (17E, 18E). Furthermore, lithium reduced basal ganglia glutamate/glutamine concentrations, as measured by magnetic reso nance spectroscopy in eight healthy controls who took lithium for 2 weeks (19c). Addition ally, lithium increased dorsomedial frontal cortical glucose utilization as measured with fluorodeoxyglucose positron emission tomo graphy in 20 healthy volunteers who took lithium for 4 weeks (20c). Finally, lithium may have an antioxidant effect. It reduced superoxide dismutase activity, catalase activity, and thiobarbituric acid reactive substances in 15 bipolar patients (21c, 22c). Lithium reduced total plasma antioxidant activity in 15 subjects who took it alone (for 6 months) or in combination with olanzapine (for an additional 6 months) (23c). Thus, it is not sur prising that lithium protected cognitive function in irradiated mice (24E) and reduced ischemic damage in a gerbil model of stroke (25E). In 66 elderly euthymic patients with bipolar illness, lithium was associated with a reduc tion in the risk of dementia compared with 48 similar patients not taking lithium (26C). The overall prevalence of dementia was 19% in the bipolar patients compared with only 7% in an age-matched general population; how ever, dementia was diagnosed in 5% of the lithium-treated patients compared with 33% in the non-lithium-treated sample. Several studies have attempted to correlate lithium activity with specific genes (27E–29E), but given that 1027 of 4474 genes tested chan ged significantly with lithium treatment (30E), it would be difficult to accept any single obser vation as being particularly important. Adherence to treatment Adherence to treatment recommendations reduces the risk of both mood relapse and toxicity. In a Veterans Administration study of 44 637 patients with bipolar disorder, 54% of the bipolar patients were fully adherent to mood stabilizer treatment (defined as a medication possession ratio of > 0.80), 25% were
Rif S. El-Mallakh, Rona J. Roberts, and Yonglin Gao
partially adherent (a medication possession ratio > 0.50 and 300 mg/day) were 400 ms (A/A), 426 ms (A/C) and 427 ms (C/C). The QT interval in children taking psy chotropic drugs has been extensively reviewed in the light of the increased use of these medications and reports of several cases of sudden death in children (13R). It is recommended that before prescribing a psy chotropic drug a detailed past medical and family history should be taken, looking spe cifically for a family history of sudden death, a personal or family history of unex plained syncope or seizures, a history of congenital heart disease, deafness or disor ders involving electrolyte imbalance, and use of medications that can cause electro lyte imbalance, interfere with the metabo lism of other drugs, or cause QT interval prolongation themselves. In a retrospective case-control study, in which the records of 700 patients receiving in-hospital care between 1995 and 2003 were analysed, haloperidol was associated with car diac arrest (adjusted OR = 3.8; 95% CI = 1.6, 9.2) (14C). Cardiac arrest was defined as cir culatory arrest in patients for whom interven tion of the advanced life support resuscitation team was requested (n = 140). Nervous system Sedation and mental clouding may be implicated in social with drawal, but their severity may be under estimated by psychiatrists. Accordingly, consultations with consenting patients were taped and transcribed to explore these adverse effects in relation to antipsychotic drugs (15c). These problems were raised as topics in 39 of 92 consultations, more often by patients than by doctors. The authors suggested that presentation of this material sheds light on why patients often complain about not being told enough about adverse drug effects. The risk of extrapyramidal symptoms in schizophrenic patients taking antipsychotic
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drugs has been studied using a populationbased claim database detailing a total of 98 320 hospitalizations in 40 561 patients with a diagnosis of schizophrenia (male 59%; mean age 36 years) between 1999 and 2003 in Taiwan (16C). Antiparkinsonian drugs, an indirect indicator of extrapyramidal symptoms, were frequently co-prescribed, but fell over the years, with a 15% reduction during the study period. The adjusted relative risk of antiparkinsonian drug prescribing in those taking typical antipsychotic drugs was 1.8 (95% CI = 1.7, 1.8) compared with those taking atypical antipsychotic drugs; hospitalizations that involved a higher-than-recommended dose (prescribed daily dose > defined daily dose) were also associated with more use of antiparkinsonian drugs (RR = 1.8, 95% CI = 1.8, 1.9). The ranking of the crude co-prescribing rate of antiparkinsonian drugs after adjustment for covariates, in increasing order, was clozapine (31%), quetiapine (33%), olanzapine (36%), thioridazine (66%), chlorpromazine (69%), zotepine (72%), risperidone (75%), clotia pine (82%), sulpiride (83%), flupentixol (91%), haloperidol (94%), zuclopenthixol (95%), loxapine (96%) and trifluoperazine (97%). The evolution of antipsychotic druginduced extrapyramidal symptoms during long-term treatment has also been studied twice: in 1975 in in-patients taking regular typical antipsychotic drugs and/or clozapine (n = 200; mean age, 42 years; mean duration of illness, 16 years) with regard to the presence of extrapyramidal effects and again in 2003/2004 (n = 83); the respective prevalences were 17 and 29% for parkin sonism, 14 and 14% for akathisia, and 24 and 13% for tardive dyskinesia (17c). In a multivariate analysis, there was a tendency for the long-term evolution of tardive dys kinesia to depend on illness duration as the only variable; considering the category of uncertain dyskinesia, there was worsening of the syndrome in 11 patients and improve ment in 22; thus, the authors stated that tardive dyskinesia is not always persistent or irreversible. As the type of antipsychotic drug or combination used changed during the study, and since there might have been a
survival bias, it is difficult to draw firm con clusions from these results. Rabbit syndrome Rabbit syndrome is a movement disorder that is associated with long-term exposure to neuroleptic drugs. In a search carried out in MEDLINE and PubMed (1972–2006), 34 cases of rabbit syndrome associated with different typical antipsychotic drugs and 11 cases with atypi cal drugs have been identified (18M); of the latter, all but three were associated with risperidone. It is said that, unlike tardive dyskinesia, rabbit syndrome responds favourably to anticholinergic agents, such as benzatropine, biperiden, procyclidine and trihexyphenidyl. Tardive dyskinesia Tardive dyskinesia is a hyperkinetic movement disorder induced by dopamine receptor antagonists. It not only typically presents with stereotypy or dysto nia, but can also cause akathisia, myoclonus or tremor. However, there have been no detailed reports of gait abnormalities. Three patients exposed to dopamine receptor antagonists for long periods developed ‘tard ive gait’; one, a 73-year-old woman, had a dancing gait – a repetitive pattern of several short steps on her toes, followed by a long step; the other two, 58- and 78-year-old women, had a ‘duck-like’ gait – a short stride length and initial contact with the ground by the toes instead of the heels at the end of the swing phase (19Ar). There was no association with DRD1 and DRD2 polymorphisms and extrapyramidal adverse effects in two studies in 130 out patients in stable remission who met the DSM-IV criteria for schizophrenia spectrum disorders and were receiving long-term main tenance therapy with haloperidol, fluphena zine, zuclopenthixol or risperidone (20c) and in 47 in-patients receiving perphenazine (21c). However, in the latter study, the 102C allele of HTR2A and the –697C and 23Ser alleles of HTR2C were more frequent among patients with extrapyramidal symptoms (n = 25) than in patients without these symp toms (n = 22) (OR = 3.2, 95% CI = 1.1, 8.7; and OR = 4.3, 95% CI = 1.4, 13.0 for the two alleles, respectively); the difference remained
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significant after multiple model analyses, including age, sex and duration of anti psychotic drug treatment as covariates. Psychological Working memory is a multi faceted cognitive construct that includes the internal maintenance, manipulation and sequencing of information; the oculomotor delayed response task is a translational paradigm that is used to examine the main tenance of spatial location information of working memory. In 14 antipsychotic drugnaïve patients with schizophrenia, an oculo motor delayed response task was performed before and 6 weeks after antipsychotic drug treatment (risperidone n = 11; olanzapine n = 3); they were compared with 15 matched healthy individuals (22c). The pre-treatment deficit in accurately remem bering spatial locations was exacerbated by antipsychotic drug treatment; however, this occurred only when covert attention was directed away from remembered locations during delay periods. The authors stated that disruption in the allocation of covert attention might contribute to patients’ decline in spatial working memory after antipsychotic drug treatment, which they explained as alterations in prefrontal dopa minergic systems or reduced thalamocorti cal drive. Blockade of dopamine D2 receptors, which is thought to mediate antipsychotic drug efficacy, has also been implicated in adverse subjective experiences. The relation ship between striatal and extrastriatal dopa mine D2 receptor binding potential and occupancy and adverse subjective experi ences has been examined in a double-blind controlled study (23c). Patients with recentonset psychoses (n = 12) were randomly assigned to olanzapine 2.5 or 15 mg/day or risperidone 1 or 4 mg/day. Subjective experi ences, motor adverse effects and striatal and extrastriatal dopamine D2 receptor numbers (respectively determined by [11C]raclopride and [11C]FLB 457 PET scans) were evalu ated after 2 weeks of continuous antipsycho tic drug treatment. D2 occupancy was 50–91% in the striatum and 4–95% in the different extrastriatal regions. There was a
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significant association between striatal block ade and mental functioning; higher dopa mine D2 receptor occupancy in the striatal, temporal and insular regions was negatively associated with subjective experiences when patients were receiving stable doses of anti psychotic drugs. Endocrine Autoimmune thyroiditis was observed in a study in 74 consecutive, clini cally stable out-patients with schizophrenia who had received stable doses of different antipsychotic drugs for at least 3 months (mean age 40 years) and had no history of overt thyroid disease. Mean serum prolactin concentrations were significantly higher in patients with thyroid autoantibodies (n = 11; mean age 37 years) compared with patients without (n = 63; mean age 40 years) (24c). Metabolic Weight gain and diabetes mellitus due to antipsychotic drugs EIDOS classification: Extrinsic moiety: Antipsychotic drugs Intrinsic moiety: 5HT2C receptors Distribution: Adipocytes and other cells Outcome: Altered physiology (leptin secretion, insulin resistance, impaired glucose tolerance) Sequela: Weight gain and diabetes mellitus due to antipsychotic drugs DoTS classification: Dose relation: Collateral reaction Time course: Intermediate Susceptibility factors: Genetic (African American origin); sex (male) In an observational study, 98 out-patients with newly diagnosed first-episode psy choses receiving antipsychotic drugs gained significantly more weight during 1 year than 30 healthy controls and seven untreated patients (25C). BMI increased by 2.2 in the treated patients (mean age 27 years), by 0.4 in the healthy controls (mean age 21 years) and by 0.5 in the untreated patients (age not stated); olanzapine, risperidone, haloperi dol and perphenazine were associated with BMI gains of 5.5 (n = 11), 2.5 (n = 43),
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1.4 (n = 24) and 0.5 (n = 13) respectively. There was more weight gain in younger patients and in those with more negative symptoms at baseline; higher individual total co-medication counts and antidepressant co-prescriptions were also associated with weight gain independent of antipsychotic drug therapy. The authors stated that beha vioral treatments have been successful at con trolling weight in chronic schizophrenia patients and may also be appropriate interven tions in patients with first-episode psychoses. In 99 patients with first-episode schizo phrenia (mean age 26 years) and 51 healthy matched controls (mean age 28 years), fol lowed up for 6 weeks to explore the predictors of antipsychotic drug-induced weight gain, there were significant changes in waist circum ference, weight and BMI between baseline and end-point, influenced by the presence of the disease (versus healthy controls) (26C). There were significant negative correlations between weight at baseline and both waist circumference changes and BMI. The BMI at baseline influenced clinically significant weight gain (>7% above baseline); patients with lower BMI scores of below 18.5 gained more weight (71%, n = 38) than those between 18.5 and 23 (45%, n = 51) and those between 23 and 27 (50%, n = 10). Among the antipsychotic drugs, more of the patients who were taking olanzapine had significant weight gain (77%, n = 35) than those who were tak ing risperidone (64%, n = 33) or haloperidol (23%, n = 31). Weight gain over time has been also compared in 32 boys with tics taking tetra benazine (mean age 13 years) and an agematched group of 41 patients (33 boys) with tics taking only antipsychotic drugs (mean age 12 years) (27c). Weight gain with tetra benazine was 0.36 kg/month (mean follow-up duration 25 months) and with antipsychotic drugs 0.75 kg/month (mean follow-up dura tion 19 months). In patients with severe mental disorders who were on monotherapy with olanzapine or clozapine (n = 80), monotherapy with other antipsychotic drugs (n = 80) or un medicated (n = 82), and despite similar BMIs, dyslipidemia (high triglycerides and low high-density lipoprotein (HDL)
cholesterol) was significantly more prevalent in those who received antipsychotic drugs than in unmedicated subjects (28c). There were no significant intergroup differences in the prevalence of metabolic syndrome, obe sity, hypertension or hyperglycemia. After adjusting for age and body mass, olanzapine and clozapine-treated patients had signifi cantly higher prevalence of dyslipidemia than unmedicated patients; they also had sig nificantly higher mean triglyceride concentra tions and lower mean HDL cholesterol concentrations; patients taking other antipsy chotic drugs had intermediate values. Although the cross-sectional design of this study precluded conclusions about causality, the authors stated that these results suggest a primary effect of some antipsychotic drugs on lipid regulation that may be important in the development of cardiovascular disease. Compared with patients receiving conven tional antipsychotic drugs, the risk of newonset diabetes was greatest among patients taking risperidone (HR = 3.8; 95% CI = 2.7, 5.3), olanzapine (HR = 3.7; 95% CI = 2.5, 5.3) and quetiapine (HR = 2.5; 95% CI = 1.4, 4.3) in a retrospective nested case-control study in which cases were patients with diabetes (n = 283) who were matched by age, sex and index date with 1134 controls (29C). The cases and controls had bipolar disorder and all had been exposed for at least 3 months to either conventional or atypical antipsychotic drugs or three filled prescriptions for treatment disorders. The relationship between drug-induced weight gain and the risk of diabetes has been reviewed (30R). The degree of adipos ity during antipsychotic drug treatment was strongly related to insulin in a study, in which 63 non-diabetic patients with schizo phrenia taking different antipsychotic drugs were compared with 14 age- and BMImatched controls (31c). BMI and waist cir cumference explained on average 33–34% of the variance in insulin sensitivity, with possible additional contributions from geno type and degree of fitness. Gastrointestinal Dysphagia has been attri buted to antipsychotic drugs (32A).
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• A 53-year-old man with paranoid schizophrenia was treated with haloperidol 15 mg/day, diazepam 15 mg/day and levomepromazine 150 mg/day and 14 days later complained of disturbed swallowing and food getting stuck in the throat. He was given biperiden 4 mg/day, without improvement. His antipsychotic medication was changed to risperidone 6 mg/day, but he became agitated and aggressive, and had paranoid delusions 1 week later. He was given fluphenazine 10 mg/day and diazepam and levomepromazine were continued. His psychotic symptoms disappeared and the dysphagia improved.
Liver Antipsychotic drugs commonly cause asymptomatic increases in liver enzymes and serum bilirubin concentrations. In a retrospective study, the charts of 110 psychiatric patients (age range 12–65 years) were reviewed to evaluate the effect of the atypical antipsychotic drugs olanzapine (n = 33), risperidone (n = 29) and quetiapine (n = 48) on liver enzymes and serum biliru bin concentrations after 1 and 6 months (33c). Of the 110 patients, 31 had asympto matic increases in transaminases, gamma glutamyltranspeptidase activity, and serum bilirubin concentrations in the first month of the study; after 6 months there were abnormalities in liver function tests in 27 patients; there were no significant differ ences among the three groups. Two of the 110 patients had high increases and stopped treatment. Musculoskeletal Bone mineral density can be negatively influenced by hyper prolactinemia (34A). • A 52-year-old woman had a spontaneous rib fracture after taking antipsychotic drugs for several years (mainly risperidone 2 mg/day), antidepressants (mainly sertraline 50 mg/day) and anxiolytics (mainly lorazepam 2.5 mg/ day). At the time of the fracture, there was severe osteoporosis (T score at L2–L4 = –3.35) and a markedly increased plasma prolactin concentration (117 ng/ml; reference range 3–24 ng/ml). The latter normalized 2 months after withdrawal of sertraline and risperidone.
In young women maintained on either prolactin-raising antipsychotic drugs (e.g. risperidone, amisulpride; n = 20) or olanzapine,
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a prolactin-sparing drug (n = 12), there was an overall gain in lumbar bone mineral den sity over 1 year in the latter compared with overall loss in the former (35c).
Deaths associated with antipsychotic drug treatment Both atypical and conventional antipsycho tic drugs are associated with an increased risk of cerebrovascular adverse events when used in elderly people with dementia (36S). Furthermore, atypical antipsychotic drugs are associated with increased mortality in this population (SEDA-30, 60). There has been growing concern that physicians may switch patients to conventional antipsychotic drugs, based on absence of evidence of risk rather than evidence of absence of risk. A number of observational studies have been conducted in an attempt to determine whether or not conventional antipsychotic drugs, like atypical antipsychotic drugs, are associated with increased mortality when used in elderly people with dementia. For instance, short-term mortality among elderly people who received conventional and atypi cal antipsychotic drugs has been assessed in a large population-based cohort (37C). Linked health-care utilization data of all British Columbia (Canada) residents were used to identify a cohort of people aged 65 years and older who began taking antipsy chotic drugs between January 1996 and December 2004 and had no cancers. The 180-day all-cause mortality rates among resi dents taking conventional antipsychotic drugs (n = 12 882) and those taking atypical antipsychotic drugs (n = 24 359) were com pared; 1822 patients (14%) in the conven tional drug group died, compared with 2337 (9.6%) in the atypical drug group (adjusted mortality ratio = 1.3, 95% CI = 1.2, 1.4). Compared with risperidone, haloperidol was associated with the greatest increase in mortality (mortality ratio = 2.1; 95% CI = 1.9, 2.4) and loxapine with the lowest (mortality ratio = 1.3; 95% CI = 1.2, 1.4). The greatest increase in mortality occurred among those who were taking higher (above
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median) doses of conventional antipsychotic drugs (mortality ratio = 1.7; 95% CI = 1.5, 1.9) and during the first 40 days after the start of drug therapy (mortality ratio = 1.6, 95% CI = 1.4, 1.8). In another population-based, retrospective cohort study carried out in other province of Canada, older adults with dementia were fol lowed up between 1 April 1997 and 31 March 2003 (38C). A total of 27 259 matched pairs were identified. New use of atypical antipsy chotic drugs was associated with a statistically significant increase in the risk of death at 30 days compared with non-use in both the com munity-dwelling cohort (adjusted hazard ratio = 1.3; 95% CI = 1.0, 1.7) and the longterm care cohort (adjusted hazard ratio = 1.5; 95% CI = 1.1, 2.1). The excess risk persisted to 180 days, but unequal rates of censoring over time may have affected these results. Relative to atypical antipsychotic drug use, conventional antipsychotic drug use was asso ciated with a higher risk of death at all times. A sensitivity analysis showed that unmea sured confounders that increase the risk of death could reduce or eliminate the observed associations. In this regard, there is a state ment from the European Medicines Agency (EMA) (39S). By contrast, neither atypical nor conven tional antipsychotic drugs increased mortal ity or hospital admissions in a sample of 254 very frail patients with dementia (mean age 86 years) (40C). Medical records were exam ined to provide information on the use of daily antipsychotic drugs, and central regis ters confirmed mortality for up to 2 years. Nearly a half (48%) of the patients used antipsychotic drugs (typical antipsychotic drugs, n = 95; atypical drugs, n = 28). The mean number of hospital admissions was higher among the non-users than among the users of conventional or atypical antipsycho tic drugs. Of the users of atypical antipsycho tic drugs (risperidone, olanzapine), 32% died within 2 years; the respective figures for users of conventional neuroleptic drugs were 45%, and for non-users 50%. In the Cox proportional hazard model, only a high number of medications and the use of physical restraint predicted higher mortality at 2 years. Furthermore, other data did not
show an increased mortality risk from anti psychotic drugs in adults with schizophrenia. Mortality rates have also been assessed in adults with schizophrenia, by reviewing safety data from clinical trials conducted from approximately 1982 to 2002 (41M). These trials involved 16 791 adults with schizophre nia (DSM-III or DSM-IV criteria) in the FDA’s Summary Basis of Approval reports for six antipsychotic drugs. The mortality rate for patients assigned to placebo was signifi cantly higher than for either the investiga tional antipsychotic drug (OR = 0.2; 95% CI = 0.1, 0.4) or the active control group (OR = 0.2; 95% CI = 0.1, 0.4).
Fetotoxicity In an analysis of 22 843 cases carried out by the Hungarian Case-Control Surveillance of Congenital Abnormalities during 1980–1996, 25 congenital abnormal ities were identified; 3648 (16%) were born to mothers treated orally with promethazine during pregnancy (42C). Of 38 151 matched population controls without congenital abnormalities, 6025 (16%) had mothers who had taken promethazine during pregnancy. There were higher rates of cleft lip ± cleft palate (adjusted OR = 1.5; 95% CI = 1.1, 2.0) and poly/syndactyly (adjusted OR = 1.3; 95% CI = 1.0, 1.8) after promethazine treat ment during the 2nd and 3rd months of gesta tion. Since these associations were not confirmed after evaluation of only medically recorded uses of promethazine, these risks were explained by recall bias. Susceptibility factors Genetic The effects of CYP2D6 genotypes on the occurrence of neuroleptic malignant syndrome have been tested in 53 patients who had experienced the condition and 112 healthy individuals (43c). There was a higher prevalence of the CYP2D6*5 allele in the group of patients with neuroleptic malignant syndrome, although the difference was not statistically significant (10% versus 5.4%; OR = 2.0, 95% CI = 0.9, 4.8). However, the preva lence of the CYP2D6*5 allele in the 29 patients who developed neuroleptic
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malignant syndrome as a result of having taken CYP2D6 substrates was significantly higher than in the controls (16% versus 5.4%; OR = 3.2, 95% CI = 1.3, 8.1). The CYP2D6 genotype contributed to the development of acute extrapyramidal symptoms in 79 patients receiving anti psychotic drugs in hospital compared with 188 controls (44c). There was a significant association between the risk of antipsychotic drug-induced acute extrapyramidal symp toms and the homozygous CYP2D6*4 polymorphism (OR = 4.1; 95% CI = 1.0, 16.0) and the heterozygous CYP2D6*6 poly morphism (OR = 5.4; 95% CI = 1.1, 18.0). Age The efficacy and tolerability of antipsy chotic drugs in children and adolescents with psychoses have been reviewed (45R–47R). There are few comparative data on whether there are differences among the different antipsychotic drugs in clinical effectiveness; the available data from short-term studies suggest that young subjects might be more likely than adults to develop antipsychotic drug-related adverse effects (e.g. extrapyra midal adverse effects, sedation, raised prolac tin, weight gain). In addition, preliminary data suggest that atypical antipsychotics can lead to the development of diabetes in some young subjects. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population. A few results from one study favoured clozapine over haloperidol in treating treatment-resistant childhood-onset schizophrenia (n = 21, WMD Bunney–Hamburg Psychosis Rating Scale –3.6, 95% CI –6.6, –0.6). However, those who took clozapine were more likely to have drowsiness (n = 21; RR = 3.3, 95% CI = 1.2, 8.8; NNTH = 2, 95% CI = 2, 17) and half of the children who took clozapine had neutropenia (n = 21; RR = 12, 95% CI = 0.7, 193). Drug overdose The impact of legislative changes on patterns of antipsychotic drug prescribing and self-poisoning in Scotland during 2000–2006 has been analysed (48c).
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During that period, regulatory authorities in the UK restricted the use of thioridazine because of cardiotoxicity (SEDA-24, 55). The prescribing pattern then changed; there was a fall in the use of typical anti psychotic drugs, whereas the use of atypical antipsychotic drugs increased. In general, the number of hospital admissions associated with atypical antipsychotic drug overdose was low, representing 1.5 (95% CI = 1.3, 1.7) admissions per 1000 prescriptions during that period; admissions after typical antipsychotic drug ingestion were significantly higher, representing 3.4 (95% CI = 2.7, 4.0) per 1000 prescriptions. Management of adverse drug reactions Dyskinesias Tetrabenazine inhibits vesi cular monoamine transporter 2, leading to depletion of dopamine and other monoa mines in the central nervous system. In a retrospective chart review, 448 patients who had used tetrabenazine between 1997 and 2004 (mean age at onset of the movement disorder, 43 years; 42% men) were treated for a variety of hyperkinesias, including tardive dyskinesia (n = 149), dystonia (n = 132), chorea (n = 98), tics (n = 92) and myoclonus (n = 19) (49c). They were treated for a mean of 2.3 years and efficacy was sustained in most cases. Common adverse effects included drowsiness (25%), parkinsonism (15%), depression (7.6%) and akathisia (7.6%). Although it has repeatedly been observed that tetrabena zine alleviates hyperkinetic movements, it can worsen parkinsonism (50R). Weight gain In a 12-week double-blind, placebo-controlled, randomized trial of sibu tramine on clozapine-associated weight gain, there were no significant differences in changes in weight, BMI, abdominal and waist circumferences, glycated hemoglobin (HbA1), fasting glucose or cholesterol con centrations between sibutramine (n = 11) and placebo (n = 10) (51c). Other specific interventions for weight gain associated with olanzapine have been proposed, including reboxetine (52c) and metformin (53c).
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• A 49-year-old African American woman with a schizoaffective disorder, hypertension, type II diabetes, stress incontinence and obesity was given topiramate to treat weight gain over three distinct trials, followed by a 4-week washout before starting acetazolamide (54A). The weight changes with topiramate in the successive trials were 1.9 kg (3 months), 0.2 kg (4 months), 6.7 kg (12 months) and for acetazolamide 5.0 kg (2 months).
The authors suggested that acetazolamide was as effective as topiramate in reversing weight gain due to antipsychotic drugs; however, they stated that, since there are no clearly effective treatments, cognitive behavioral programmes should be recom mended for motivated patients.
INDIVIDUAL DRUGS Amisulpride
(SED-15, 173; SEDA-29, 65; SEDA-31, 69)
Observational studies Of 106 consecutive out-patients with cancers and depressive symptoms in a prospective 4-week study with low doses of amisulpride 50 mg/day, two withdrew owing to an adverse event (weight gain and excessive activation, one each) (55c). Scores on the Montgomery– Asberg Rating Scale for depression improved significantly from baseline to endpoint, includ ing both emotional and physical aspects.
Comparative studies In an open study, patients with stable schizophrenia and a major or minor depressive episode taking risperidone were randomized into a risperi done continuation group (n = 45; mean age 38 years) or an amisulpride switch group (n = 42; mean age 33 years) (56c). The main outcome measures were changes from base line on the Calgary Depression Scale for Schi zophrenia and the Beck Depression Inventory. The mean dose at 12 weeks was 4.2 mg/day for risperidone and 458 mg/day for amisulpride. Improvements were significantly greater in the amisulpride switch group than
in the risperidone continuation group at weeks 8 and 12. Mean changes in body weight did not differ significantly between groups (þ0.2 kg for amisulpride and –0.6 kg for risperidone); mean serum prolactin concentrations increased with amisulpride (71–83 ng/ml) and fell slightly with risperi done (71–67 ng/ml). Extrapyramidal symp toms did not significantly differ between groups from baseline to endpoint; akathisia (n = 18 versus n = 15), tremor (n = 8 versus n = 7). Other effects were oligomenorrhea (n = 6 and n = 5; one new case in each group); somnolence (n = 5 in both groups) and lassitude (n = 6 versus n = 3). Nervous system Extrapyramidal symp toms in patients taking amisulpride have been reported (SEDA-29, 65). These symp toms were associated with higher amisul pride plasma concentrations in a drug monitoring survey in 378 schizophrenia patients, supported by Sanofi-Aventis (57c). Patients taking amisulpride (dosage range 100–1550 mg/day) who experienced extra pyramidal symptoms (15%) had signifi cantly mean higher amisulpride plasma concentrations (377 ng/ml) than patients without extrapyramidal symptoms (305 ng/ml), despite similar doses (595 mg/day versus 594 mg/day). Mean amisulpride daily doses (594 mg/day) and plasma concentrations (315 ng/ml) were significantly correlated. Tardive dyskinesia has been associated with amisulpride (58A). • A 37-year-old woman with schizophrenia tak ing haloperidol developed acute extrapyrami dal symptoms, including muscle rigidity and tremor. Amisulpride monotherapy was started, increasing up to 800 mg/day, and her symptoms improved. After 6 months she developed involuntary movements periorally and in the left upper limb. Amisulpride was maintained at the same dose and the intensity and fre quency of the abnormal movements increased; she also developed periodic involuntary oral– buccal–lingual movements and choreoathetoid movements in her left arm, wrist and fingers. The symptoms gradually remitted throughout the next 3 months after amisulpride was with drawn and treatment was given with quetiapine 300 mg/day, clonazepam, amantadine hydro chloride and vitamins E and B6.
Antipsychotic drugs
Aripiprazole
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(SEDA-30, 61;
SEDA-31, 70) Drug combination studies A fixed dose of aripiprazole 15 mg/day added to previous clozapine (mean dose 478 mg/day) resulted in significant improvement on PANSS scores in 27 clinically stabilized patients with chronic schizophrenia (22 men; mean age 42 years) in a 16-week open uncon trolled study (59c). There were no signifi cant changes from baseline to end-point in extrapyramidal symptoms, body weight or prolactin concentrations; none of the four dropouts was due to adverse events. Placebo-controlled studies Aripiprazole (15 mg/day, n = 19) has been compared with methylphenidate (54 mg/day, n = 17) and placebo (n = 17) in patients with amphetamine dependence in a randomized 20-week study (60c). The study was termi nated prematurely owing to unexpected results of an interim analysis; patients allo cated to aripiprazole had significantly more amphetamine-positive urine samples than patients in the placebo group (OR = 3.8, 95% CI = 1.5, 9.2), whereas patients who were taking methylphenidate had signifi cantly fewer (OR = 0.5, 95% CI = 0.3, 0.8). Nervous system Although aripiprazole seems to produce fewer extrapyramidal symptoms than other antipsychotic drugs, symptoms have occasionally been associated with it (SEDA-30, 61; SEDA-31, 75). New cases have appeared (61A, 62A). • A 54-year-old woman with bipolar disorder who had taken lithium for 25 years and olanzapine for 1 year was changed to lithium and amisulpride up to 200 mg/day because of increased appetite and weight gain. Since the weight gain persisted, amisulpride was replaced by aripiprazole (up to 10 mg/day). She suddenly developed an akinetic hypertonic parkinsonian syndrome, with shaking of the upper limbs and stiffness of all four limbs, impeding her usual daily movements; she later developed facial, oral and axial dystonia, as well as recurrent psychotic symptoms. Aripiprazole was then withdrawn and she was given trihexyphenidyl
93 15 mg/day, olanzapine 5 mg/day and lithium. After 3 months, her motor and psychotic symptoms disappeared and her appetite returned. • A 54-year-old woman with a history of breast cancer, who had taken tamoxifen for 4 years and olanzapine for 5 years for a schizoaffective disorder, developed weight gain. The olanzapine was replaced by aripiprazole (up to 20 mg/day). Ten months later, she developed ‘tongue heaviness’, a lisp, lip smacking, tongue protrusion and lingual writhing movements. Aripiprazole was withdrawn and the dyskinetic movements resolved completely within 1 month. She was successfully maintained on quetiapine without recurrence of dyskinesias for 1 year.
Surprisingly, aripiprazole has been reported to improve haloperidol-induced dyskinesia (SEDA-31, 75) and has also been reported to improve tics associated with risperidone in a 31-year-old man (63A). Endocrine In a randomized, double-blind study, 56 patients with hyperprolactinemia taking haloperidol monotherapy were assigned to either haloperidol þ aripiprazole (n = 26; 11 men; mean age 38 years) or halo peridol þ placebo (n = 28; 11 men; mean age 41 years) (64C). There were no significant differences in haloperidol mean doses; ari piprazole was prescribed in a fixed dose of 15 mg/day during weeks 1–4 and 30 mg/day during weeks 5–8. Baseline prolactin concen trations were not significantly different between the two groups; prolactin concen trations in the aripiprazole group, compared with placebo, were significantly lower during the study, with a significant time effect. Reductions in prolactin concentrations in the aripiprazole-treated patients were 77 and 84% from baseline at weeks 4 and 8 respectively. At week 8 in the aripiprazole group 89% of patients had normal prolactin concentrations compared with 3.6% of patients receiving placebo; the change in prolactin concentrations from baseline to end-point was not significantly different between men and women. Plasma concen trations of haloperidol were not significantly altered. Furthermore, of the 11 women with menstrual disturbances randomly assigned to aripiprazole, seven regained menstruation during the study, whereas none receiving
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placebo did. The mean prolactin concentra tions in patients randomly assigned to ari piprazole who regained menstruation were 94 ng/ml at baseline, 32 ng/ml at week 4, and 19 ng/ml at week 8. Five women had galac torrhea at baseline; two were randomly assigned to aripiprazole and three to pla cebo. At week 8, one of the two patients taking aripiprazole no longer complained of signs or symptoms of galactorrhea, whereas all three who were taking placebo continued to experience it. No patients had gynecomas tia during the study. Cumulative adverse effects in the study in patients randomly assigned to aripiprazole were: insomnia (42%), dry mouth (31%), headache (23%), sedation (12%) and weakness (8%). In the placebo group, the adverse events were dry mouth (21%), sedation (18%) and insomnia (18%). Insomnia, dry mouth and sedation occurred more often during treatment with aripiprazole 15 mg/day compared with the last 4 weeks of the study, when the dose was 30 mg/day. Insomnia (42%), dry mouth (31%), headache (23%), sedation (12%) and weakness (8%) were also reported in patients taking aripiprazole, and dry mouth (21%), sedation (18%), and insomnia (18%) in those taking placebo.
Metabolism Hyperglycemia has been described in a 7-year-old child with a family history of diabetes mellitus while taking aripiprazole (65A). • An overweight 7-year-old boy (34.7 kg, BMI 21 kg/m2, 98th percentile) with attention deficit hyperactivity disorder, mood disorders and a family history of type II diabetes mellitus, had been treated with methylphenidate up to 54 mg/day. Because of worsening mood lability and aggression, methylphenidate was replaced by aripiprazole 2.5 mg/day. Four weeks later, he developed polydipsia, polyuria and poly phagia; his blood glucose concentration was 37 mmol/l (reference range 3.9–5.8 mmol/l) (659 mg/dl; 70–105 mg/dl), triglycerides 2.88 mmol/l (0.84–2.25 mmol/l) (255 mg/dl; 74–199 mg/dl) and mild ketonuria (150 mg/l). Aripiprazole was withdrawn and insulin was started; 4 weeks later, the blood sugar had normalized and insulin was withdrawn, but 6 months later he developed insulin-dependent diabetes.
Susceptibility factors Genetic An unusual aripiprazole blood concentration has been reported in a patient with genetic suscep tibility factors (66A). • A 51-year-old woman with schizophrenia taking aripiprazole 15 mg/day was changed to 30 mg per day because of lack of efficacy. Within 2 weeks, she developed progressive symptoms of lethargy and memory loss. The serum aripipra zole concentration was 2990 ng/ml, about seven times the expected plasma concentration at a dosage of 30 mg/day. She had a genetic polymorphism in the CYP2D6 gene, consisting in substitution of G1934!A on both alleles (homozygote CYP2D6*4/*4), and correspond ing to poor metabolism.
Clozapine
(SED-15, 823; SEDA-29, 66; SEDA-30, 61; SEDA-31, 78)
Observational studies The prescription patterns of clozapine use in China (Hong Kong and Beijing) have been investigated in a randomly selected group of 398 patients taking antipsychotic drugs (67c). Clozapine was prescribed for 16% of patients. On multi ple logistic regression analysis, the number of hospitalizations, place (Hong Kong versus Beijing), use of typical antipsychotic drugs, polypharmacy and co-prescription with antic holinergic drugs were significantly associated with the prescription of clozapine. There were no significant differences between the cloza pine and non-clozapine groups with regard to any of the quality-of-life domains. The patterns of clozapine use in New Zealand have been studied in 2796 patients with schizophrenia, of whom 917 (33%) were given clozapine, at a mean dosage of 372 mg/day and an average duration of ill ness of 9.7 years before starting clozapine (68c). Patients who had started treatment after clozapine was funded by the govern ment (n = 1658; 59%) and had received a median of three antipsychotic drugs before starting clozapine; most of the treatment regimens included one second-generation antipsychotic drug (91%). Clozapine-treated patients were less likely to have another anti psychotic drug co-prescribed compared with non-clozapine-treated patients (11.7% versus 17.6%). Both the clozapine and non
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clozapine treated groups had fewer psycho tropic medications prescribed (median 2); for clozapine-treated patients, the second drug was most probably for the treatment of hypersalivation. The case notes of 17 consecutive patients with schizophrenia given compulsory treat ment with clozapine have been retrospec tively rated (69C). At the last observation, 10 of the 11 patients still taking clozapine were classified as being much to very much improved; the degree of custodial restriction at the last observation was improved in 11 patients and there was no change in six. There were no serious adverse events; sialorrhea was reported in two patients, and somnolence and speech disorder in one. Two patients taking 150 and 225 mg/day devel oped local swellings and one had backflow of clozapine solution at the injection site. Transient leukopenia in one patient led to withdrawal of clozapine. Comparative studies The effectiveness and safety of clozapine versus high-dose olanzapine (up to 30 mg/day) have been evaluated in treatment-refractory adoles cents with schizophrenia aged 10–18 years (70C). They were randomized to 12 weeks of double-blind, flexibly dosed treatment with clozapine (n = 18) or olanzapine (n = 21). Significantly more clozapine-treated adolescents (66%) than olanzapine-treated subjects (33%) met the response criteria. Clozapine was superior to olanzapine in terms of reduced psychosis and negative symptoms from baseline to end-point. Both treatments were associated with sig nificant weight gain and related metabolic abnormalities; five of 39 participants (three clozapine, two olanzapine) gained > 7% of their baseline body weight by the end of the study. One olanzapine-treated patient developed neutropenia, as did four cloza pine-treated patients. Systematic reviews A meta-analysis of randomized, placebo-controlled trials of clozapine augmentation with another anti psychotic drug in patients with schizophrenia
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who partially responded to clozapine has been performed (71M). The four identified studies (n = 166) had clinically important heterogeneity. The two studies lasting 10 weeks or more gave an odds ratio of response to treatment of 4.4 (95% CI = 1.4, 14). The same pattern of response was seen in eight open studies. The main treatment-related adverse effects were extrapyramidal adverse effects and raised serum prolactin. Cardiovascular Cardiomyopathy has been associated with clozapine; an incidence of 0.2% in the first month has been estimated (SED-15, 824). • A 33-year-old woman without cardiac history or other susceptibility factors developed heart failure after taking clozapine and olanzapine for 6 weeks (72A). After withdrawal of the two drugs, her heart function improved significantly. • Atypical clozapine-induced cardiomyopathy occurred in a 28-year-old man who presented with a panic attack (73A). • A 34-year-old man developed hypokinetic cardiomyopathy while taking clozapine and was successfully treated with carvedilol and captopril (74A).
The authors of the last case suggested that beta-blockers and angiotensin-converting enzyme (ACE) inhibitors may allow resump tion of clozapine in refractory schizophrenia in which it has been withdrawn because of cardiotoxicity. Myocarditis has been estimated to occur in 0.01–0.19% of patients taking clozapine (SEDA-31, 79). • A 32-year-old man developed myocarditis, documented by late gadolinium enhancement cardiovascular MRI, after taking clozapine for 1 week (75A). The condition gradually resolved 5 weeks after withdrawal of clozapine.
Pericardial effusion accompanied by pleural effusion has been associated with clozapine (SEDA-29, 67). • A 33-year-old man developed pericarditis and a pericardial effusion after taking clozapine 200 mg bd for 10 weeks (76A). The symptoms disappeared within 1 week after withdrawal of clozapine.
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• A 47-year-old man developed an effuso constrictive pericarditis associated with clozapine; his symptoms improved after drug withdrawal (77A). • A 60-year-old woman developed polyserositis with a pericardial effusion and bilateral pleural effusions after taking clozapine for 13 months (78A). • A 43-year-old woman developed clozapine associated polyserositis (pleuritis and serositis) and hepatitis, although an electrocardiogram and a transthoracic echocardiogram were normal (79A).
Nervous system It is believed that cloza pine causes less tardive dyskinesia than haloperidol and may even improve the pre-existing dyskinesia; however, isolated cases have been associated with clozapine (SEDA-31, 79). Dystonia in a 34-year-old man associated with clozapine satisfied the criteria for antipsychotic drug-induced tardive dyskinesia (80A), and there has been another report of blepharospasm, a type of focal tardive dystonia that is usually considered to be a variant of tardive dys kinesia, in a 46-year-old woman (81A). On the other hand, an antidyskinetic effect of zotepine on clozapine-associated tardive dyskinesia has been reported (82c). The low prevalence of akathisia in patients taking clozapine has led to a pro posal that clozapine should be used in patients with antipsychotic drug-induced chronic akathisia (SED-15, 826). However, a case of acute nocturnal akathisia has been reported in a 43-year-old man taking cloza pine who was successfully treated with betablockers (83A). Restless legs syndrome is a neurological disorder characterized by irresistible move ments and dysesthetic sensations in the legs. A case associated with clozapine has been described, supposedly for the first time (84A). • A 26-year-old man developed severe extrapyramidal symptoms characterized by tremor, bradykinesia and sialorrhea while taking haloperidol 20 mg/day and valproate 1400 mg/day. Haloperidol was replaced by clozapine 50 mg/day and valproate was continued. After 3 days he started to have unpleasant sensations in his calves and burning sensations over his feet.
Several cases of stuttering have been associated with clozapine and it can occur before a generalized epileptic seizure (SEDA-27, 56). A further report has now been published, describing two patients who developed stuttering while taking clozapine (85A). Two additional cases of stuttering have emerged; the first, in a 40-year-old man started to stutter when his clozapine dosage was increased from 400 mg/day; it was also associated with a marked increase in seizure activity (86A). The other case was in a 44-year-old man whose clozapine-induced speech dys fluency disappeared when clozapine was withdrawn (87A). Electroencephalographic abnormalities and stuttering may be harbingers of seizures and clozapine is thought to increase the risk of this (SEDA-27, 56). Two cases have been reported in a 74-year-old man and a 56 year-old man, both with non-epileptic clo zapine-induced drop attacks, bouts of sud den collapse without loss of consciousness, and symptoms of posterior circulation dis ruption (88A). Cataplexy, an abnormal state character ized by atonia and believed to represent dis sociated rapid eye movement (REM) sleep phenomena that intrude into wakefulness, has been reported in a 29-year-old woman taking clozapine (89A). Psychiatric Eating disorders can be induced or aggravated by clozapine. Food craving and binge eating have been studied in patients who were randomized to cloza pine (n = 15) or olanzapine (n = 15) (90c). There were no differences in improvement in clinical symptoms and severity of illness. Adverse effects occurred significantly less often with olanzapine than with clozapine. The likelihood of food craving at any time during drug treatment tended to be higher with olanzapine (49%) than with clozapine (23%), and the likelihood of binge eating at any time during drug treatment was higher, but not significantly so, with olanzapine (17%) than with clozapine (9%). In another open observational study, patients taking clozapine (n = 33) or
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olanzapine (n = 31) were screened to iden tify subjects with prior eating disorders (91c). The authors concluded that both drugs might induce recurrence or deteriora tion of binge eating or full-blown eating disorders in those who had the conditions before the start of treatment. Metabolism Weight gain is a common and well-known adverse effect of clozapine (SEDA-29, 67; SEDA-30, 62; SEDA-31, 79). The possible variables associated with weight gain have been analysed in 50 treatment-refractory patients with schizo phrenia who were randomized to clozapine 100, 300 or 600 mg/day in a 16-week, doubleblind study (92C). Weight gain varied across three baseline body mass index (BMI) cate gories: normal weight (þ4.1 kg), overweight (þ2.6 kg), and obese (þ0.4 kg), and accord ing to dosing: 600 mg (þ4.4 kg), 300 mg (þ2.6 kg) and 100 mg (þ1.3 kg). Sex had no effect after controlling for baseline BMI and dose, but African American ethnicity had a strong significant effect, despite the small number included in the sample (n = 6). Plasma norclozapine concentration was not significantly correlated with weight gain. Hematologic Agranulocytosis, leucopenia and neutropenia associated with clozapine have been extensively studied and discussed (SED-15, 829; SEDA-31, 80). Severe neutro penia can occur unexpectedly and suddenly during a quiet laboratory monitoring period, as illustrated by the case of a 36-year-old man who developed sudden, unpredictable, lateonset, clozapine-related, life-threatening agranulocytosis, with a nadir of 14 106/l polymorphonuclear cells (93A). Rates of leukopenia and agranulocytosis as reasons for withdrawal of clozapine have been examined retrospectively in 1875 patients who took clozapine between 1989 and 1999 (94c). No African American patient developed agranulocytosis, whereas eight Caucasian patients (0.62%) did; how ever, 5.3% of the African American cohort versus 2.4% of the Caucasian cohort had to
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stop taking clozapine treatment because of leukopenia. The authors suggested that it is likely that the African American patients had clozapine withdrawn unnecessarily because of benign ethnic neutropenia, within a lower reference range for white blood cell count. Patients with neutropenia secondary to clozapine are supposed to be at high risk of recurrent neutropenia and, which is more important, agranulocytosis if re-exposed. Nevertheless, cases of negative or positive rechallenge in patients with neutropenia with prior agranulocytosis have appeared (SED-15, 830; SEDA-30, 63; SEDA-31, 80). • A 40-year-old woman with clozapine-induced neutropenia prolonged by subsequent use of olanzapine was successfully rechallenged with both olanzapine and then clozapine (95A).
Patients with leukopenia associated with clozapine have been successfully treated with lithium carbonate (SEDA-29, 68), and another case has been reported in a 55-year old man (96A). Salivary glands Sialorrhea has commonly been associated with clozapine, and var ious drugs, such as antimuscarinic agents, adrenoceptor antagonists, and adrenocep tor agonists, have been used to treat it, although no drug has been found to be superior (SED-15, 831; SEDA-29, 68; SEDA-30, 63; SEDA-31, 80). The effec tiveness of glycopyrrolate 4 mg day, an anticholinergic drug that is structurally related to atropine, has been reported, sup posedly for the first time, in a 40-year-old man with clozapine-induced sialorrhea (97A). Glycopyrrolate 4–8 mg has also been successfully used in three adolescent girls (aged 13–16 years) who developed sialorrhea secondary to clozapine (98A). Glycopyrrolate was generally well toler ated; however, one patient reported con stipation and another reported dry mouth. Gastrointestinal A case of clozapine induced microscopic colitis, a condition that can occasionally be life-threatening,
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has been reported, supposedly for the first time (99A). • A 37-year-old man taking clozapine up to 500 mg/day, with no other medications, devel oped intermittent severe watery diarrhea after 3 months. Microscopic colitis was diagnosed by colonic biopsy. Clozapine was withdrawn and he gradually improved; multiple colonic biopsies taken 7 days later were normal.
Sexual function The frequency and course of sexual disturbances associated with cloza pine have previously been studied (SED-15, 832). Priapism has occasionally been described (SEDA-19, 54). Recurrent priap ism requiring surgical intervention has also been reported in a 33-year-old man taking clozapine 300 mg/day and lithium carbonate 1800 mg, and also while he was taking quetia pine or haloperidol (100A). The authors speculated that some individuals are more susceptible for unknown reasons. Teratogenicity and fetotoxicity Neuro developmental disorders, particularly delayed speech, have been described in a baby, whose mother, a 30-year-old woman with schizophrenia, took clozapine treat ment throughout her 9 months of pregnancy and during lactation (101A). Susceptibility factors Sex Only sex signifi cantly affected clozapine concentrations in a retrospective study in Chinese patients with schizophrenia, in which dosages and plasma clozapine concentrations in 116 men and 77 women, younger ( 40 years, n = 111) and cur rent male smokers (n = 50) and non-smokers (n = 66) were analysed (102c). Women had significantly higher concentrations than men. Drug overdose Fatal and non-fatal cases of clozapine overdose have been reported (SED-15, 833; SEDA-30, 63). The notes of 47 patients who attempted suicide by ingest ing large amounts of clozapine have been analysed retrospectively (103c). Of the 20 unconscious patients with plasma clozapine
concentrations of more than 2000 ng/ml, 14 were given a combination of hemoperfusion and symptomatic treatment, whereas the other six and the remaining 27 patients received only symptomatic treatment. One patient died of pulmonary edema and subse quent heart failure, but the others recovered without any sequelae. Patients who received hemoperfusion regained consciousness signif icantly faster than their counterparts with the same clozapine plasma concentration who did not receive hemoperfusion. Fatal poisoning has been reported in a neo nate in the final stage of gestational life. His mother, when 9 months pregnant, took a toxic dose of clozapine intending to commit suicide (104A). Analysis of post-mortem blood speci mens collected from the neonate showed clo zapine and its two metabolites, norclozapine and clozapine-N-oxide. The woman was also severely poisoned, but her life was saved. Drug–drug interactions Aluminium hydroxide An interaction of clozapine with aluminium hydroxide has been reported, supposedly for the first time (105A). • A 26-year-old man almost doubled his plasma clozapine concentration after he stopped tak ing aluminium hydroxide. The clozapine serum concentration had been previously stable at 382 ng/ml. A few weeks later, he became sleepier and was drooling a lot more than before; the plasma clozapine concentra tion was 739 ng/ml.
Chemotherapy Seven references report ing no synergistic effect of clozapine and chemotherapy on blood counts have been reviewed (106r). A 39-year-old man was successfully restarted on clozapine while receiving ablation chemotherapy and an autologous stem cell transplant for Hodg kin’s lymphoma (107A). Ciprofloxacin Another case of an inter action of clozapine with ciprofloxacin has been reported (108A). CYP inhibitors A series of five case of drug–drug interactions involving clozapine, each of which illustrates a different
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mechanism by which the metabolism of cloza pine can be altered, has been reported (109A). Four were with fluoxetine, ciprofloxacin, ethinylestradiol and cimetidine, and one was with smoking. Fluoxetine can reasonably be considered a CYP pan-inhibitor, much like cimetidine; thus, the addition of fluoxetine led to moderate inhibition of CYP1A2, CYP2C9/19, CYP2D6 and CYP3A4, causing increased clozapine and norclozapine concen trations. Similarly, ethinylestradiol inhibits both CYP1A2 and CYP2C19. Levomepromazine Two cases of suspected interaction between levomepromazine and clozapine, with lack of therapeutic efficacy of clozapine, have been reported (110A). Rifampicin Rifampicin and clozapine may interact, as illustrated by the case of a 30-year-old man with pulmonary tuberculosis, whose psychiatric symptoms worsened after introduction and improved after withdrawal of rifampicin (111A). Rifampicin induces sev eral CYP isoforms, which would have caused a reduction in clozapine serum concentration. Drug–smoking interactions It is generally believed that plasma concentrations of clo zapine are lower in smokers than in non smokers (SEDA-31, 81). • A 27-year-old man with schizophrenia failed trials of haloperidol, tiotixene, olanzapine, ari piprazole and quetiapine, and was given cloza pine, which was titrated to 500 mg/day, giving a clozapine concentration of 417 ng/ml (109A). Over the next several weeks, he improved and was discharged from hospital. He then started smoking again (2 packs/day), and 3 weeks later his paranoia and hallucinations returned. The clozapine concentration was only 192 ng/ml, even though he was said to be consistently compliant with his medication. The dosage of clozapine was increased to 900 mg/day and his clozapine concentration rose to 392 ng/ml.
The authors attributed this effect to induction of CYP1A2, and noted that chew ing-tobacco, nicotine patches and nicotine inhalers do not do this. Monitoring therapy Prediction of response to clozapine by measurement of peripheral
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biochemical markers, such as plasma serotonin, platelet serotonin and platelet monoamine oxidase (MAO) activity, has been examined in 20 patients taking clozapine and 20 healthy controls matched for age, sex and smoking (112c). After 8 weeks, plasma serotonin and platelet MAO increased significantly in those taking clozapine; platelet serotonin concentrations fell significantly. Baseline platelet MAO explained 22% of the variance in the Clinical Global Impression Improvement Scale and in improvement in attention, whereas baseline platelet serotonin predicted 23% of the variance in the improvement in positive symptoms. The authors concluded that clozapine might reverse or compensate for a pre-existing alteration in serotonin neurotransmission in schizophrenic patients.
Olanzapine (SED-15, 2598; SEDA-29, 70; SEDA-30, 64; SEDA-31, 81) Observational studies In a 12-month uncontrolled study in different Asian coun tries, olanzapine (mean dose at baseline 8.4 mg/day, at end-point 9.3 mg/day) was given to refractory outpatients with schizo phrenia (n = 1267, mean age 33 years, 53% men) (113C). A total of 954 patients (75%) completed the study and 87% of them responded to treatment as assessed by at least a 30% reduction in the Brief Psychiatric Rating Scale. Concomitant medications from baseline to end-point changed from 10 to 4.5% for other antipsychotic drugs and from 49 to 27% for other drugs. Only seven patients dropped out because of adverse events. Across the study period, mean scores in the Abnormal Involuntary Movement Scale fell markedly and mean weight increased signifi cantly from 62 to 65 kg; 39% of subjects (ran ging from 32% in Korea to 43% in China) gained 7% of body weight or more. Comparative studies Olanzapine and haloperidol In a study in which patients were randomized to either intramuscular olanzapine or haloperidol þ promethazine
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(n = 150 in each group), both drugs were effective for rapid sedation or sleep induc tion at 15 and 240 minutes in patients with agitated or violent behavior (7C). Adverse events included akathisia (one patient tak ing olanzapine) and dehydration (one patient taking haloperidol); after 2 weeks, one patient taking olanzapine who had been switched to clozapine developed intestinal obstruction. Olanzapine and lithium Chinese patients with bipolar acute mania were randomized to olanzapine (n = 69, mean dose 18, range 5–20 mg/day) or lithium carbonate (n = 71, mean dose 1110, range 600– 1800 mg/day) in a 4-week, multi-center, double-blind, randomized study (114C). The study was completed by 91% of patients taking olanzapine and 79% of those taking lithium; there was a signifi cantly greater mean change in patients taking olanzapine as measured by differ ent scales. Adverse events occurred in 55 and 42% of the patients respectively. The most common events with olanzapine were constipation (13%), nausea (7.2%) and somnolence (7.2%); with lithium, there were nausea (13%) and nasophar yngitis (5.6%), and one patient dropped out because of abnormal hepatic function. Mean weight gain was 1.85 kg with olan zapine and 0.73 kg with lithium; 16% of those taking olanzapine and 2.9% of those taking lithium had significant weight gain ( 7% of baseline). A high blood glucose concentration was reported in one patient taking olanzapine and high total cholesterol concentrations in four patients (three taking olanzapine). Olanzapine and quetiapine In a prospec tive 12-month study, adults with schizophre nia previously treated with first-generation antipsychotic drugs were randomized to olanzapine (n = 42; mean dose 17 mg/day) or quetiapine (n = 43; mean dose 613 mg/ day) (115c). Clinical improvements were similar in the two groups. Cognitive assess ment with the computer-assisted test bat tery COGLAB showed a significantly better performance in attention tasks only
in patients taking quetiapine. Neurological adverse effects abated in both groups from baseline to end-point according to scores in the scales UKU-SR, SAS and AIMS; mean weight increases were 7.2 kg in patients tak ing olanzapine and 2.8 kg in those taking quetiapine; olanzapine caused dysglycemia, defined as a fasting plasma glucose of at least 5.6 mmol/l (one case at baseline and 13 at end-point) but quetiapine did not (three and four cases respectively). Olanzapine, quetiapine and risperidone Subjects with schizophrenia who had been randomly assigned to and then discontinued perphenazine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study (SEDA-30, 59) were randomly reas signed to double-blind treatment with olan zapine 7.5–30 mg/day (n = 38); quetiapine 200–800 mg/day (n = 38) or risperidone 1.5–6.0 mg/day (n = 38) (116C). Time to discontinuation was longer in those taking olanzapine (7.1 months) and quetiapine (9.9 months) than in those taking risperidone (3.6 months); discontinuation rates were 58% for quetiapine, 61% for olanzapine and 84% for risperidone. There were no significant differences in reasons for drop out, including lack of efficacy, intolerability or patient decision. There were no notable differences in total scores on the Positive and Negative Syndrome Scale (PANSS) among the treatment groups at any time, nor in CGI global severity at 6 or 12 months. Adverse events, detected by systematic inquiry, ranged from 42% of those taking risperidone (n = 16) to 69% of those taking olanzapine (n = 27); the most frequent were anticholinergic effects (n = 13) and hypersomnia (n = 10) with olanzapine; hypersomnia (n = 16), insomnia, sexual dysfunction and orthostatic faintness (n = 18 for each event) with quetiapine, and anticholinergic effects (n = 24), hypersomnia (n = 6), and insomnia (n = 6) with risperidone; rashes were reported by three, one and four patients respectively. Mean body weight gains across the study were higher for olanzapine (4.1 kg, range –3 to 33) than for risperidone (3.6 kg, range –16 to 22)
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and quetiapine (0.9 kg, range –32 to 33); rates of weight change were þ0.7 kg/month for olanzapine, þ0.2 kg/month for risperidone and –0.2 kg/month for quetiapine. Choles terol and triglyceride concentrations increased significantly in patients taking olanzapine and moderately in those on risperidone and quetiapine. Olanzapine, quetiapine and risperidone have also been compared in a doubleblind, multi-center study in patients with schizophrenia and other psychoses (mean age 25 years, 63% men), who were randomi zed to olanzapine (n = 133), quetiapine (n = 134) or risperidone (n = 133) (mean modal doses 12, 506 and 2.4 mg/day respec tively) (117C). At week 52, discontinuation rates were 68% for olanzapine, 71% for quetiapine and 71% for risperidone; med ian times to discontinuation (25–27 weeks) did not differ significantly. The three groups had reduced scores in total PANSS. Adverse effects accounted for 40 dropouts (olanzapine, n = 14; quetiapine and risperidone, n = 13 each); patient deci sion was also a reason for withdrawal (n = 57, 52 and 57 respectively). There were 18 serious adverse events during the 52-week follow-up, four with olanzapine and seven each with quetiapine and risper idone; these events included two suicide attempts and one alleged homicide in those taking olanzapine, two completed suicides and one case of suicidal ideation in those taking quetiapine, and one suicide attempt in those taking risperidone. As expected, olanzapine was associated with a higher proportion of patients with a weight gain of at least 7%; at week 52 this increase was apparent in 80% of patients taking olanzapine compared with 50% of those taking quetiapine and 58% of those taking risperidone. In women, ris peridone was significantly associated with greater increases in weight and BMI than quetiapine. Quetiapine and olanzapine were associated with greater rises in fasting concentrations of triglycerides and cholesterol than risperidone. Prolactin concentrations rose with risperidone. Extrapyramidal symptoms were infrequent and did not differ significantly across the
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groups; nevertheless, these data should be interpreted cautiously, because of the final reduced group sample sizes at week 52: 37 for olanzapine and risperidone each and 44 for quetiapine. In an 8-week study, 75 patients with schizophrenia were randomized to olanza pine, quetiapine or risperidone (25 in each group; mean doses at end-point 15, 590 and 5.1 mg/day, respectively) (118c). There were no significant differences in efficacy among the three drugs, as measured by the PANSS scale. Risperidone was associated with significantly worse scores on the Simp son–Angus Scale for extrapyramidal symp toms at week 3. Weight gains of at least 7% from baseline were more frequent in patients taking olanzapine (29%) than in those taking quetiapine or risperidone (8% each). Olanzapine, quetiapine, risperidone and haloperidol In 101 patients with psy choses allocated to olanzapine, risperi done, quetiapine or haloperidol for acute agitation, aggressive behaviour, as mea sured by the Modified Overt Aggression Scale and the Hostility-suspiciousness factor derived from the Brief Psychiatric Rating Scale, improved significantly in all groups, with no significant between-group differences (119c). Extrapyramidal symp toms were more common in those who took haloperidol; somnolence was the most common adverse event in the other three groups.
Olanzapine and risperidone done below.
See Risperi
Drug combination studies Patients with schizophrenia stabilized on olanzapine were randomized to dehydroepiandroster one or placebo (n = 20 in each group) for 12 weeks in a double-blind study (120c). Negative symptoms improved in those who took dehydroepiandrosterone, even when baseline scores were controlled as a co-variate, and there was some improvement
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in parkinsonism and akathisia compared with baseline. Body weight did not change signifi cantly in either group. Placebo-controlled studies In a 3-week, multi center, double-blind study, adoles cents of both sexes with bipolar mania were randomized to olanzapine (n = 107, mean modal dose 11 mg/day) or placebo (n = 54) (121C). The mean change from baseline to end-point in the Young Mania Rating Scale total score was significantly greater in patients who took olanzapine. Olanzapine caused significant weight gain and increases in the serum concentrations of prolactin, fasting glucose, fasting total cholesterol and uric acid. Olanzapine was not effective in video poker pathological gamblers (n = 9) com pared with placebo (n = 12) (122c). Two subjects stopped taking olanzapine because of sedation. Cardiovascular Pulmonary thrombo embolism has been associated with olanza pine and risperidone (123A); 5HT2 receptor antagonism may be the mechanism. • A 25-year-old man with schizoaffective disor der, otherwise healthy, and not overweight, but a smoker (1 pack/day) and without a personal or familial history of venous thromboembolism, was given olanzapine 20 mg/day, paroxetine 20 mg/day and valproate 2000 mg/day; 12 weeks later he developed sud den back pain radiating to the thorax with dyspnea and hemoptysis. A CT scan showed bilateral pulmonary embolism, and he was given anticoagulants. Olanzapine was withdrawn, but he was then given risperidone. A second episode of thromboembolism was attributed to non-adherence to anticoagulant treatment, but after a third event risperidone was changed to amisulpride, which does not affect 5HT2 receptors.
Nervous system Although it is unusual, somnambulism has been associated with olanzapine (124A). • A 52-year-old man with bipolar disorder, who had taken valproic acid and lithium for years, had his doses increased to 1000 mg/day and
900 mg/day respectively, because of a manic episode; olanzapine was also titrated up to 20 mg/day. Six days later he developed episodes of somnambulism with subsequent amnesia; dosage reduction of olanzapine to 15 mg/day caused a reduction in the number of episodes.
The authors suggested that this had hap pened because of an interaction of olanza pine with both valproate and lithium.
Endocrine Hyperprolactinemia and amen orrhea associated with olanzapine have been reported (SEDA-29, 73) and a new case has appeared (125A). • A 35-year-old woman with psychotic depres sion was given olanzapine up to 30 mg/day and citalopram 40 mg/day. After 4 weeks she developed amenorrhea and her serum prolactin was 253 ng/ml (reference range, 2.8–29 ng/ml). The plasma olanzapine concen tration was 78 ng/ml (usual target range, 20–80 ng/ml). After the addition of aripipra zole 15 mg, her menstrual pattern and prolac tin concentrations normalized; 5 weeks later the improvement persisted.
Metabolism Insulin sensitivity fell signifi cantly from 5.7 to 4.7 ml/hour/kg in 14 healthy subjects taking olanzapine 10 mg/ day for 10 days, but not in a comparison group taking ziprasidone 80 mg/day (n = 15) (126c). Furthermore, hyperglycemia asso ciated with olanzapine 5 mg/day has been reported after 3 weeks in a 27-year-old patient with anorexia nervosa (127A). Finally, a case of hyperglycemia and diabetic ketoacidosis has been described in a 35-year old-woman with a urinary tract infection who had taken olanzapine 10 mg/day for 2 weeks (128A). Weight gain in relation to antipsychotic drugs, particularly olanzapine, has been addressed previously (SEDA-26, 56; SEDA-29, 74; SEDA-30, 66; SEDA-31, 81). However, weight loss has been observed in an open 12-month study, in which 26 patients with schizophrenia taking olanzapine standard oral tablets were switched to an orally disintegrating formu lation (129c). Mean weight loss was –2.5 kg
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at 3 months, –2.9 kg at 6 months, and –3.4 kg at 12 months; body mass index fell by 1.0 kg/m2 overall. In another study, there was a significantly smaller increase in weight after 6 weeks in patients taking orally disintegrating olanza pine (mean weight increase 3.3 kg) com pared with those taking standard tablets (mean weight increase 6.3 kg) (130c). In a prospective comparison of weight gain in children and adolescents taking clo zapine (n = 15), olanzapine (n = 15) or ris peridone (n = 15), average weight gain was significantly higher with olanzapine (þ4.6 kg) than with risperidone (þ2.8 kg) or clozapine (þ2.5 kg) at 6 weeks (131c). Olanzapine and risperidone, but not cloza pine, caused disproportionately greater weight gain in children and adolescents than in adults. Fluid balance Edema is unusual in patients taking olanzapine; a case with posi tive rechallenge has been described (132A). • A 34-year-old woman with bipolar disorder took olanzapine 10 mg/day for 4 months and developed bilateral pedal edema, which disap peared with slow withdrawal of olanzapine but recurred with reintroduction at 5 mg/day.
Urinary tract Acute urinary retention occurred in two elderly patients with previous benign prostatic hyperplasia when they took olanzapine (133A). Skin Skin reactions are not common in patients taking olanzapine; however, a gen eralized lichenoid eruption affecting the thighs, arms, hands, nails, feet and tongue affected a 73-year-old woman taking olan zapine 15 mg/day and escitalopram 20 mg/ day; the eruption disappeared after 3 weeks when olanzapine was replaced by risperi done (134A). Nails A 47-year-old woman developed photo-onycholysis 1 month after switching from chlorpromazine to olanzapine (135A).
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A change to aripiprazole further worsened the illness, which resolved after 4 months with avoidance of fingernail sun exposure. Musculoskeletal Treatment with olanza pine 15 mg/day and topiramate 40 mg/day for 8 weeks is suspected to have caused hyperthermia of 42.2°C and rhabdomyolysis in a 14-year-old girl who had exercised at high temperatures and became unrespon sive, with increases in creatine kinase (peak 11007 U/l), urine myoglobin (up to 5930 pg/l) and serum iron (1.53 ng/l); after withdrawal of both drugs, olanzapine was restarted for symptom recurrence, and was well tolerated for 2 weeks after discharge (136c). Fetotoxicity Cardiac and musculoskeletal abnormalities occurred in a neonate whose mother had been exposed to olanzapine (137A). • A 25-year-old primigravida took olanzapine 10 mg/day for schizophrenia and gave birth to a baby with an atrioventricular canal defect and unilateral clubfoot; the baby’s karyotype was 46XY and there were no other identifiable sources of teratogenicity. The baby recovered fully with a plaster cast and open heart surgery at 6 months.
Susceptibility factors Genetic Some genetic polymorphisms have been suggested as susceptibility factors for olanzapine associated weight gain, including genes for apolipoprotein E and apolipoprotein A4 (138c), an S promoter (SERTPR), a serotonin transporter variant (139c), an AG –2548 polymorphism in the leptin gene in Korean patients (140c), a G allele of the –1548 polymorphism in the leptin gene (141c) and the G allele of the prome lanin hormone gene (142c). Drug formulations Intramuscular olanza pine (mean dose 10 mg) was effective in severely agitated patients with bipolar mania (n = 22) or schizophrenia (n = 52) in
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a 1-week observational study (143c). Most of the patients (93%) received only one dose; antipsychotic drugs were the most fre quent concomitant medications (94%). Insomnia (9.5%), arthralgia (7.9%) and headache (6.3%) were the most commonly reported adverse events; there were no sig nificant changes in sitting pulse rate or blood pressure 1 day after the first injection. Drug overdose Olanzapine overdose in 37 patients was associated with tachycardia (73%), central nervous system depression (43%), miosis (39%) and delirium (54%) (144c). Delirium increased the length of hospital stay and the rate of admission to an intensive care unit. Drug–drug interactions Concomitant use of carbamazepine or lamotrigine signifi cantly altered plasma olanzapine concentra tions in 163 adults (145c). Drug–smoking interactions In a study in 163 adults, plasma olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine compared with non smokers not taking lamotrigine (145c).
Perphenazine (SED-15, 2783; SEDA-29, 75) Drug–drug interactions Midodrine A 53 year-old woman who had been receiving perphenazine 4 mg/day for 4 years for major depression was given midodrine 7.5 mg/day for orthostatic hypotension (146A). After 3 days later she developed acute bilateral, unpredictable, repetitive involuntary movements of the perioral muscles and continuous tonic neck muscle contraction with head deviation to the right. Midodrine was immediately withdrawn and the dys tonic movements disappeared after 1 day. Midodrine is metabolized by CYP2D6 and inhibits it; it may therefore increase the concentrations of substances metabolized by CYP2D6, such as perphenazine.
Quetiapine (SED-15, 2995; SEDA-29, 75; SEDA-30, 67; SEDA-31, 87) A violation by AstraZeneca, consisting of oral and written promotion of quetiapine for major depressive disorder, an un approved use, has been denounced (147S). Observational studies The safety of que tiapine in general practice in England has been examined in a Prescription Event Mon itoring study in 1728 patients (median age 39 years, 53% women) (148C). Drowsiness/ sedation was the most frequently reported event during the first month of treatment (n = 47, 3% of the cohort) and the most common reason for stopping quetiapine (n = 51). There were low incidences of extra pyramidal symptoms (n = 21) and hyperpro lactinemia (n = 3). There was new-onset diabetes mellitus in three cases. There were six pregnancies and four live births, with no reported congenital abnormalities. From the 56 deaths reported during this study, the most frequently reported causes were cardi ovascular (n = 18) and respiratory (n = 15). There was a high discontinuation rate in an open study (68%, mean duration 18 weeks) in patients with rapid-cycling bipolar disorder who received quetiapine either as monother apy (n = 19) or as add-on therapy (n = 22) for up to 1 year (mean dose 196.6 mg/day, range 25–900 mg/day) (149c). Mean body weight fell from 91 kg at baseline to 86 kg at end point with quetiapine monotherapy but did not change in the whole sample. Placebo-controlled studies Up to four different re-analyses of the same four double-blind, placebo-controlled studies of quetiapine in mania (150c), agitation, and aggression in bipolar mania (151c), efficacy across a broad range of symptoms (152c) and target dose for efficacious treatment (153c) have been published; all were sup ported by AstraZeneca, the Marketing Authorization holder. Quetiapine was claimed to be well tolerated. In a 2-week, multi center, randomized, open study funded by AstraZeneca,
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patients with acute schizophrenia or schizoaffective disorder received quetiapine either rapidly (200 mg on day 1, 400 mg on day 2, 600 mg on day 3 and 800 mg on day 4; n = 139) or in a conventional regimen (50 mg on day 1, 100 mg on day 2, 200 mg on day 3, and 400 mg on day 4; n = 130) (154C). In both cases, treatment was followed by a flexible dosage of 400–800 mg/day (mean maximal dosages 786 mg/day and 508 mg/day respec tively). During week 1, the rates of patients who had at least one adverse event were 39% with the rapid regimen and 25% with the conventional regimen. The most com mon adverse events associated with quetia pine (somnolence, dizziness and orthostatic hypotension) occurred in 10 and 5.4% of patients in the rapid conventional regimens, respectively. The most common adverse events overall were hypotension (14% with the rapid regimen versus 7.7% with standard therapy), tachycardia (9.4% versus 10%), somnolence (6.5% versus 3.8%) and seda tion (5.8% versus 5.3%). There were no sig nificant differences in withdrawal rates due to adverse events (rapid regimen, n = 3, 2.1%; conventional regimen, n = 4, 3.1%). The only serious adverse event was agitation in the rapid initiation group. Comparative studies Quetiapine and lithium Quetiapine was more efficacious than lithium in Chinese bipolar patients in a 4-week, multi center, double-blind study supported by AstraZeneca, in which patients with acute mania were randomized to either quetiapine (n = 77, mean dose 648 mg/day, maximum 800 mg/day) or lithium (n = 77, mean serum concentration 0.80 mmol/l, maximum 2000 mg/day) (155C). The authors reported a significantly higher response rate, defined as a 50% reduction from baseline to day 28 in the YMRS total score, with quetiapine (78% versus 60% with lithium) and a higher remission rate. The most frequent adverse events with que tiapine were constipation (35%), dizziness (15%), diarrhea (10%), rises in alanine ami notransferase (9.0%) and palpitation (9.0%); in those taking lithium, they were nausea (17%), constipation (13%), vomiting
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(13%) and nasopharyngitis (12%). Adverse events led to withdrawal in three patients taking lithium. Extrapyramidal symptoms were similarly in the two groups (5.1% and 6.5%). Weight gain was 1.5 kg in patients taking quetiapine and 0.3 kg in those taking lithium. Quetiapine and risperidone Quetiapine and risperidone have been compared in patients with schizophrenia in a 12-week double-blind study supported by AstraZeneca (156c). Quetiapine (n = 19, mean final dose 569 mg/day) produced signifi cantly fewer extrapyramidal effects accord ing to the Simpson–Angus Scale than risperidone (n = 15, mean final dose 5.1 mg/day). Conversely, in a randomized study in patients with dementia, Simpson–Angus Scale scores did not change significantly from baseline after 8 weeks, in patients taking quetiapine (n = 38) or risperidone (n = 34); mean end-point dosages were 77 mg/day and 0.9 mg/day respectively (157c). There were no significant changes in blood pressure or body weight. Three patients taking quetiapine and one taking risperidone had a serious adverse events (quetiapine: thigh fracture, n = 2, a fall with contusions, n = 1; risperidone: halluci nations, n = 1); the most common adverse events were sedation (11%) and fatigue (7.9%) in patients taking quetiapine, and diarrhea and muscle rigidity (15% each) in those taking risperidone. Quetiapine, risperidone, chlorpromazine and haloperidol Data from 4956 patients with schizophrenia or related disorders in randomized, double-blind, controlled studies in the AstraZeneca clinical trials database have been re-analysed (158c). These data allowed comparison of quetiapine (mean doses 357–496 mg/day) with placebo, risper idone (5.5 mg/day), haloperidol (10 mg/day) or chlorpromazine (552 mg/day). When que tiapine (n = 536, median dose 419 mg/day) was compared with risperidone (n = 541, median dose 5.9 mg/day), the most common adverse events were headache (12% versus 15%) and sedation (13% versus 9.6%); the
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incidences of serious adverse events were similar in both groups (4.9 and 3.7% respec tively), as were the rates of withdrawal due to adverse events (8.6 and 8.7% respec tively). As expected, extrapyramidal symp toms were significantly less common (quetiapine 12.5%; risperidone 24.8%; OR = 0.4, 95% CI = 0.3, 0.6). In the compar ison of quetiapine (n = 347, median dose 552 mg/day) and chlorpromazine (n = 348, median dose 553 mg/day), insomnia (15% versus 13%) and agitation (12% versus 10%) were the most common adverse events; extrapyramidal symptoms consisted mainly of akathisia and tremor. In the com parison of quetiapine (n = 1177, median dose 321 mg/day) and haloperidol (n = 752, med ian dose 9.9 mg/day), insomnia (15% versus 18%) and headache (14% versus 11%) were the most common adverse events; akathisia (22% versus 5.3%) and tremor (18% versus 3.8%) were significantly more common with haloperidol than with quetiapine. Drug combination studies Quetiapine (mean dosage 182 mg/day) has been added to SSRIs or venlafaxine in an 8-week, dou ble-blind, placebo-controlled study in 58 patients with major depressive disorder (159c). Eight out of eleven dropouts in the quetiapine group were because of adverse effects (sedation/somnolence/lethargy, n = 6; weight gain and fatigue, n = 1; increased appetite, irritability and somnolence, n = 1; total dropouts, n = 11); two patients withdrew from the placebo group (sedation/ somnolence/lethargy, n = 1; increased irrit ability, n = 1). Quetiapine has been added to antidepres sants in elderly patients (n = 9, mean age 73 years) with major depressive disorder and cerebrovascular damage (160c), although it is not approved for this indication. Placebo-controlled studies Quetiapine (n = 963, median dose 300 mg/day) and placebo (n = 292) for patients with schizo phrenia have been compared in trials that have been re-analysed (158c). Headache was the most common adverse event in both
groups (18% versus 20%), followed by sedation, which was significantly more com mon with quetiapine (15% versus 6.2%; OR = 2.7, 95% CI = 1.6, 4.5); somnolence and orthostatic hypotension were also sig nificantly more common with quetiapine. The frequency of extrapyramidal symptoms was similar in the two groups (9.6 and 11% respectively). There was no clinical improvement accord ing to the Neuropsychiatric Inventory and the Clinical Global Impression of Change in elderly patients with Alzheimer’s disease and behavioral and psychological symptoms when they were randomized to quetiapine (n = 20, median dose 200 mg/day) or placebo (n = 20) in a 6-week double-blind trial (161c). Extrapyramidal effects did not differ signifi cantly between the groups. Nervous system Quetiapine reportedly caused generalized tonic–clonic seizures in a 16-year-old girl with ornithine transcarbamy lase deficiency and mental retardation and in a 7-year-old boy with autism (162A). Quetiapine might modulate human motor cortex excitability (163c). There was significant prolongation of the cortical silent period in 15 healthy subjects, using transcranial magnetic stimulation, after a single 100-mg dose of quetiapine compared with placebo; however, the difference did not remain significant during treatment with quetiapine 100 mg/day for 5 days. Endocrine Galactorrhea has been des cribed in a patient taking quetiapine (164A). • A 31-year-old woman with a personality disorder taking divalproex sodium 1250 mg/ day, gabapentin 900 mg/day and venlafaxine 150 mg/day was given quetiapine 100 mg/day. Ten days later she complained of heaviness in her breasts and galactorrhea; the symptoms disappeared when quetiapine was stopped and at 2 months’ follow-up.
Metabolism A patient with refractory schizophrenia and a fasting glucose concen tration of 6.8 mmol/l (123 mg/dl) at baseline developed diabetes mellitus during a
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12-week open study while taking quetiapine 1400 mg/day (165c). Haematologic Quetiapine has been asso ciated with leukopenia and thrombocytope nia (166A). • A 45-year-old man taking sodium valproate 1500 mg/day, zuclopenthixol depot 150 mg every 2 weeks, and quetiapine up to 600 mg/ day developed a white cell count of 2.7 109/l and a platelet count of 146 109/l after 7 weeks of treatment. The counts normalized after drug withdrawal.
Hair Alopecia has been associated with que tiapine, supposedly for the first time (167A). • A 34-year-old woman took citalopram 20 mg/ day and quetiapine up to 100 mg/day for 6 weeks and developed hair loss, which resolved when quetiapine was withdrawn.
Drug abuse Possible abuse of quetiapine has been previously reported (SEDA-30, 68), and two further cases have been pub lished (168A, 169A). • A 39-year-old male prisoner with hepatitis C and a history of opiate abuse was treated for generalized anxiety with quetiapine 800 mg/ day and clonidine 0.9 mg at bedtime. The psychiatrist was concerned about the risks of prescribing an antipsychotic drug for a patient with hepatitis without a serious mental disorder. The patient refused to discuss other treatment alternatives, stating, ‘I need my Seroquel’. Efforts to enlist his cooperation for a quetiapine taper were unsuccessful. He abruptly left a treatment team meeting and informed staff that he would purchase quetiapine illegally from other inmates, as he had done before. • A 33-year-old man with a history of polysubstance dependence, including alcohol, heroin and cocaine, regularly diverted quetiapine from his wife’s prescription and took 400–800 mg/day by crushing the tablets, mixing them with cocaine and water and injecting the mixture intravenously.
Drug overdose In a 5-year retrospective study using the California Poison Control System database, 945 cases of quetiapine
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acute ingestion were identified (median age 35 years; range 18–84 years; 45% men) (170C). Intentional ingestion accounted for 87% of cases. The clinical manifestations included drowsiness (76%), coma (10%), seizures (2%), tachycardia (56%), hypo tension (18%) and respiratory depression (5%). There were three deaths; all had coma, tachycardia and respiratory depres sion requiring ventilatory support. Com pared with overdose with all other antipsychotic agents as a group, quetiapine was more likely to cause hypotension (OR = 2.0, 95% CI = 1.5, 2.8), coma (OR = 2.2, 95% CI = 1.5, 3.2), respiratory depression (OR = 2.5, 95% CI = 1.4, 4.4) and a need for tracheal intubation (OR = 1.9; 95% CI = 1.4, 2.6); deaths and major medical outcomes were also more common (OR = 2.6; 95% CI = 1.8, 3.8).
Risperidone (SED-15, 3052; SEDA-29, 76; SEDA-30, 69; SEDA-31, 90) In June 2008, the US Food and Drug Administration approved the first generic versions of risperidone tablets (171S). It issued an amendment to the existing warn ing, based on increased mortality in elderly patients with dementia-related psychosis, stating that elderly patients with dementiarelated psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, showed that the risk of death in drug-trea ted patients was 1.6–1.7 times the risk of death in placebo-treated patients (172S). Over the course of a typical 10-week con trolled trial, the death rate in drug-treated patients was about 4.5%, compared with about 2.6% with placebo. Although the causes of death were varied, most appeared to be either cardiovascular (e.g. heart fail ure, sudden death) or infective (e.g. pneu monia). Observational studies have suggested that, similar to atypical antipsy chotic drugs, treatment with conventional antipsychotic drugs may increase mortality.
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The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Risperidone is not approved for patients with dementia-related psychosis. For a review of antipsychotic drugs in elderly patients see SEDA-30, 59. Observational studies Of 54 children with epilepsy and behavioural disorders (age range 2–18 years; 70% boys) treated with risperidone for 3 months (mean dose, 0.038 mg/kg/day) five withdrew because of adverse events (increased seizure fre quency, n = 2; agitation, n = 2; somnolence, n = 1) (173c). Risperidone and haloperidol In a retro spective study using medical reports in Japanese patients with delirium who were treated with risperidone (n = 39), oral halo peridol and intravenous or intramuscular haloperidol (n = 61) deaths during delirium were significantly more common with intra venous or intramuscular haloperidol (13%) than with oral haloperidol (2.1%) or risper idone (3.2%) (174c). Risperidone and olanzapine In a multi center, open, 53-week, two-phase study, patients were randomized either to longacting injectable risperidone (n = 318, initially 25 or 50 mg every 2 weeks) or olanzapine (n = 300, 5–20 mg/day) (175C). Long-acting risperidone was at least as effec tive as oral olanzapine. Adverse events resulted in treatment withdrawal in 3% of patients who took long-acting risperidone and 4% of those who took olanzapine. Ser ious adverse events were reported by 23% of the patients who took long-acting risperi done group and 21% of those who took olanzapine; the most frequent adverse events included psychosis (29 and 25%, respectively), insomnia (22 and 24%), depression (20 and 14%), anxiety (14 and 16%), agitation (10 and 5%) and headache (8 and 5%). Eight patients died during the study, two taking risperidone and six taking olanzapine. Mild extrapyramidal symptoms
were reported by 25% of those who took long-acting risperidone and 15% of those who took olanzapine. New tardive dyskine sia occurred in two patients in each group. Other relevant adverse events were nonpuerperal lactation (five and two respec tively), impotence (two in each group), diabetes mellitus (one in each group) and hyperglycemia (four in each group). Mean body weight increased by 1.7 kg in those who took long-acting risperidone group and by 4.0 kg in those who took olanzapine; there was weight gain of 7% or more in 20% of those who took long-acting risperidone and 36% of those who took olanzapine; there were reductions of 7% in 6% of patients in both groups. Risperidone, olanzapine and haloperidol In an open randomized trial, 145 patients had a first episode of psychosis and were assigned to haloperidol (n = 40, 4.2 mg/day), olanzapine (n = 41, 13 mg/day), or risperi done (n = 47, 3.6 mg/day) (176C). A total of 128 patients (88%) completed the 12-week study. There was significant weight gain with all three drugs. Mean increases were haloperidol 3.8 kg, olanzapine 7.5 kg and risperidone 5.6 kg. All three drugs caused significant increases in total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations but only olanzapine caused a significant increase in triglyceride concentra tion. There were no significant changes in parameters involving glucose metabolism. Placebo-controlled studies Augmentation therapy with risperidone has been investi gated in a multi center, double-blind, rando mized, placebo-controlled trial to determine whether it reduces symptoms and increases responses to antidepressant therapy and remission of depression in adults (177C). After a 4-week run-in period to ensure a response to standard antidepressants, 274 adults with major depressive disorder that was suboptimally responsive to antidepres sant therapy were randomly assigned to ris peridone 1 mg/day or placebo for 6 weeks; after 4 weeks, the dosage of risperidone was increased to 2 mg/day in some cases. Of the
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intention-to-treat population (268 patients), 81% (111 of 137) who took risperidone and 88% (115 of 131) who received placebo com pleted 6 weeks of double-blind treatment. Mean Hamilton Rating Scale for Depression scores improved significantly more with ris peridone augmentation than with placebo (13 versus 16). Significantly more risperidone recipients had remission of depression (25% versus 11%) and had a response (46% versus 30%). Headache (8.8% of risperidone recipi ents versus 15% of placebo recipients), som nolence (5.1% versus 1.5%) and dry mouth (5.1% versus 0.8%) were the most frequent adverse events. In an 8-week double-blind study, 55 autis tic children were randomized to either risper idone (mean dosage 1.37 mg/day; n = 27) or placebo (n = 28) (178c). Patients who took risperidone had significantly improved scores in the Aberrant Behavior Checklist Irritabil ity subscale (–13.4 versus –7.2). There was somnolence in 74% versus 7%; it was usually mild and resolved spontaneously. Adverse events were reported in all those who took risperidone and in 71% of those who took placebo; other events were upper respiratory infections (41% versus 18%), rhinitis (26% versus 7%) and fever (26% versus 18%). Weight increase was reported in two patients taking risperidone and none taking placebo; movement disorders, including extrapyrami dal symptoms, dyskinesia, hypokinesia and involuntary muscle contractions (n = 1 each), and hyperkinesia and tremor (n = 2 each) were also reported in patients taking risperidone; there were no changes in chem istry values or electrocardiography. Systematic review A meta-analysis of four randomized placebo-controlled trials in aged patients with dementia has been per formed (mean age 83 years; mostly women) (179M). The patients taking risperidone (n = 515) had significantly improved scores in the different scales compared with pla cebo (n = 380). Somnolence and extrapyra midal symptoms were significantly more common with risperidone than with placebo (18% versus 8% and 12% versus 5.8%, respectively). Death occurred in 16 patients
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(3.1%) taking risperidone and seven taking placebo (1.8%). Cerebrovascular disorder occurred in 1.6% versus 0.8%, respectively. In a Cochrane review of the use of risper idone and olanzapine in the treatment of schizophrenia, there were no significant dif ferences in efficacy (180M). Adverse events occurred in 75% of those who were given either drug, including anticholinergic symp toms in 20%. Both groups experienced insomnia, although this was more frequent with risperidone (n = 1588; five RCTs; RR = 1.4, 95% CI = 1.1, 1.7); about 30% experienced sleepiness (n = 1713; six RCTs; RR = 0.9, 95% CI = 0.8, 1.1). People given either drug often had some extrapyr amidal symptoms and 25% of those using risperidone required medication to alleviate these symptoms (n = 419; two RCTs; RR = 1.8, 95% CI = 1.2, 2.5; NNTH = 8, 95% CI = 4, 25). People allocated to risper idone were less likely to gain weight than those given olanzapine, and the weight gain was often considerable and of quick onset (n = 984; two RCTs; weight gain 7% in the short term, RR = 0.5, 95% CI = 0.4, 0.6; NNTH = 7, 95% CI = 6, 10). Patients taking risperidone were more likely to have abnor mal ejaculation (n = 370; two RCTs; RR = 4.4, 95% CI = 1.4, 14; NNTH = 20, 95% CI = 6, 176). Both drugs were asso ciated with high attrition rates; in the long term, consistent 66% of those allocated to risperidone left the study early compared with 56% given olanzapine (n = 1440; five RCTs; RR = 1.2, 95% CI = 1.1, 1.3; NNTH = 11, 95% CI = 7, 23). Randomized comparisons of risperidone and olanzapine for schizophrenia have also been reviewed (181M). Both drugs were commonly associated with adverse events and high attrition rates. Cardiovascular Acquired long QT syn drome associated with risperidone has again been reported (182A). • An 83-year-old woman with senile dementia and psychosis, who had taken risperidone 1.5 mg/day for the past 2 years and was also taking diltiazem 120 mg/day and torasemide 5 mg/day, developed a slow pulse. An electrocardiogram showed a
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phase 2 polymorphous ventricular tachycardia associated with torsade de pointes. Her family refused a pacemaker and she died.
Nervous system Risperidone-induced move ment disorders in children with disruptive behaviour and sub average intellectual func tioning have been retrospectively analysed using data from three 1-year, open studies (patients’ age range 4–14 years; 82% men; n = 668) (183C). About 70% of the patients completed the studies (mean risperidone dosage 1.6 mg/day). There were movement disorders in 23% of patients, although mean Extrapyramidal Symptom Rating Scale scores remained low; 4.3% required antiparkinsonian drugs. Fifty patients with drew owing to adverse events, 13 had a movement disorder; in five cases this was the only reported adverse event: dyskinesia, dyskinesia plus tardive dyskinesia, tardive dyskinesia, an extrapyramidal disorder plus hypertonia and hyperkinesia, and an extra pyramidal disorder. One subject met prede fined criteria for tardive dyskinesia after a dosage reduction; the symptoms persisted for 4 weeks and resolved with continued treatment and no further dosage change. Two other subjects were considered to have tardive dyskinesia, including a 7-year-old boy who had occasional mild movements of his lips after taking risperidone for 133 days; 7 days after a dosage reduction, he devel oped marked lip movements and recovered fully when risperidone was withdrawal. A re-analysis sponsored by Janssen showed that treatment with low-dose risperidone in children with disruptive behaviours disorder is associated with a low rate of tardive dyskinesia and other movement disorders. Salivary glands Sialorrhea or hyper saliva tion is an uncomfortable adverse effect that develops during treatment with antipsycho tic medications, especially clozapine (SEDA-29, 68). Sialorrhea associated with risperidone has been reported (184A). • An 18-year-old woman with schizophrenia who was taking risperidone 2 mg/day and lorazepam 1 mg/day gradually increased the
dosage of risperidone to 6 mg/day over 3 days. On day 4, her psychomotor agitation improved but she developed hypersalivation, associated mild speech impairment and mildly impaired postural reflexes. She responded to intramuscular biperiden.
Sexual function Sexual adverse effects of quetiapine and risperidone have been com pared in a 6-week, randomized, doubleblind trial in men with schizophrenia who had previously had risperidone-associated sexual dysfunction and were randomized to risperidone continuation (n = 12, mean dose = 4.3 mg/day) or quetiapine switch (n = 10, mean dose = 300 mg/day) (185c). There was a significant positive relationship between serum prolactin concentration and impairment of sexual function according to the Arizona Sexual Experience Scale total score only in those who took risperidone.
Sertindole (SED-15, 3120; SEDA-30, 72) Psychological In a 12-week trial, patients with schizophrenia were randomized to ser tindole (n = 17) or haloperidol (n = 17) (186c). Cognitive sub processes were inves tigated with the Reaction Time Decomposi tion method and the Wisconsin Card Sorting Test, at baseline and weeks 4 and 12. Sertindole reversed cognitive deficits significantly more than haloperidol; cogni tive processing improved independently of motor function. Death Sertindole has been associated with a prolonged QT interval in clinical trials; it was suspended because of an excessive rela tive reporting rate of sudden deaths in 1998 and then re-introduced in 2001 in Europe under certain restrictions (SEDA-26, 66). The European Sertindole Safety and Exposure Survey was a follow-up study of patients treated with sertindole in Germany, Austria, Belgium, Hungary, the Netherlands and the UK, aimed at identify ing deaths and their causes in those patients (187C); a nested case-control study of potential susceptibility factors was
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conducted within that study comparing patients with cardiac or unexplained deaths with randomly selected survivors matched for age and sex. A total of 8608 patients were identified as having taken sertindole, for 3819 person-years; 35 had died (all cause mortality rate, 0.9 per 100 personyears exposed. Eight deaths were suicides and 11 were cardiac deaths. On average, patients who died because of cardiac disor ders were older and patients who com mitted suicide were younger than the other patients who died; patients who had taken sertindole were at a higher risk of prema ture cardiac or unexplained death if they had hypertension or other cardiovascular disorders associated with diabetes or meta bolic disorder. The authors stated that the mortality rate was not higher than in clinical trials that had led to market authorization; in Belgium, where the drug was not mar keted and there was an exhaustive register of all patients treated, the all-cause death rate was 0.8.
Ziprasidone (SED-15, 3721; SEDA-29,
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In an open 12-week observational study of 276 patients with schizophrenia and schizoaffective disorder who took flexible of ziprasidone (40–160 mg/day) a high pro portion of patients withdrew (60%), most of them within the first 4 weeks (189c). This was explained by invoking initial and over all under-dosing; in those who completed the study, ziprasidone was associated with improvements in different scales. One treatment-emergent adverse event was experienced by 217 patients; in 30 patients (14%) the adverse event was severe. The most common severe event was re-emer gence or deterioration of psychotic symp toms (‘schizophrenic reactions’ and ‘psychoses’); other events were agitation, depression, insomnia, gastrointestinal syn dromes, dizziness, urticaria and intentional overdose. The incidence of extrapyramidal symptoms was 6%. Body weight fell on average by 1.3 kg. There was a non-signifi cant prolongation of the average QTc inter val from a mean of 392 ms at baseline to 395 ms; the maximum was 461 ms; there were no cases of torsade de pointes or other severe dysrhythmias.
81; SEDA-30, 72; SEDA-31, 94) Observational studies Several open stu dies, all promoted by Pfizer, have emerged; two deserve some attention because of the large numbers of patients included, allowing the identification of adverse reactions of very low frequency. In a multi center, 6-month, uncontrolled observational study, 1266 patients taking ziprasidone were enrolled (188c). Of those analysed at the end of the study (n = 1022), 47% had at least a 30% reduction in PANSS total score. In total, 453 patients (36%) withdrew; ziprasidone doses greater than 120 mg/day were asso ciated with a lower risk of withdrawal for any cause (OR = 0.5; 95% CI = 0.3, 0.6). About one-third (n = 374) of the 1260 patients evaluable for safety reported at least one adverse event. There were serious adverse events in 19 patients (1.5%), includ ing five deaths (three suicides, one sudden death, and one brain abscess). Adverse reac tions were elicited using an open-ended ques tionnaire, which can lead to under-reporting.
Nervous system Ziprasidone-induced extrapyramidal symptoms have previously been reported (SEDA-29, 81; SEDA-31, 95). Four new cases of dystonia associated with ziprasidone have now been published (190-2A); two of the patients used cocaine, which could have been a susceptibility factor. • A 31-year-old woman with schizophrenia, who had previously had acute dystonia with haloperidol and mild extrapyramidal symptoms with risperidone, took ziprasidone 120 mg bd, increased from 160 mg/day. Within 2 days of the dosage increase, she developed transient tongue dystonia, general body stiffness, and conjugate eye deviation on two separate occasions. She continued to take the increased dose and on day 4 had a severe acute dystonic reaction, including an oculogyric crisis, lockjaw, tongue protrusion, severe generalized body stiffness and respiratory difficulty. Her symptoms resolved with intravenous diphenhydramine 50 mg. • A 20-year-old man with a schizoaffective disorder and cocaine dependence was given
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divalproex sodium 500 mg/day, ziprasidone 60 mg/day and trazodone 100 mg at bedtime. On day 2, the dose of divalproex sodium was increased to 1000 mg/day and ziprasidone to 60 mg bd Two hours after the second dose of ziprasidone, he developed lateral flexion of the trunk towards the right side with slight rotation (Pisa syndrome), dysphonia and dysphagia. Benzatropine 1 mg intramuscularly produced rapid complete resolution. • An 18-year-old man with paranoid schizophrenia was given ziprasidone 20 mg bd, increasing to 40 mg bd on day 2 and 60 mg bd on day 3. He then started choking and had difficulty in speaking. His symptoms completely resolved within 15 minutes of a dose of benzatropine 1 mg intramuscularly. • A 37-year-old man with a psychotic disorder who had snorted cocaine intermittently for about 6 months was given three doses of ziprasidone 40 mg/day; 5 hours after the third dose he developed trismus, which resolved with benzatropine 1 mg intramuscularly.
Psychiatric Antipsychotic drugs have been associated with depression. Depression has been attributed to ziprasidone in three patients with schizophrenia (193A). How ever, since depression in patients with schi zophrenia is multi factorial, it is difficult to establish a causal relationship.
Endocrine Hyperprolactinemia has been attributed to ziprasidone (194A). • A 22-year-old woman took ziprasidone 60 mg/day and lithium 1500 mg/day for bipolar affective disorder, and after 40 days developed galactorrhea and breast pain. The plasma prolactin concentration was 135 ng/ml (reference range 3.4–24 ng/ml); after withdrawal of ziprasidone it fell to 18 ng/ml within 2 weeks.
Zuclopenthixol (SED-15, 3722) Placebo-controlled studies The effects of zuclopenthixol on aggressive behaviour in patients with intellectual disabilities have been investigated (195A). Of 49 patients who responded to zuclopenthixol during 6 weeks of open treatment, 39 took part in a 12-week randomized withdrawal trial. The placebo subgroup (n = 20) had significantly more aggressive behaviour, as indicated by outcomes observed by external raters on the Modified Overt Aggression Scale. The number of adverse events and possible symptoms of withdrawal, such as nausea, insomnia and diarrhea, did not differ between the groups.
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147. Food and Drug Administration. Quetia pine, indications. http://www.fda.gov/ downloads/Drugs/GuidanceComplianceR egulatoryInformation/EnforcementActivi tiesbyFDA/WarningLettersandNoticeofVio lationLetterstoPharmaceuticalCompanies/ ucm053948.pdf 148. Twaites BR, Wilton LV, Shakir SA. The safety of quetiapine: results of a post-market ing surveillance study on 1728 patients in Eng land. J Psychopharmacol 2007;21:392–9. 149. Goldberg JF, Kelley ME, Rosenquist KJ, Hsu DJ, Filkowski MM, Nassir Ghaemi S. Effectiveness of quetiapine in rapid cycling bipolar disorder: a preliminary study. J Affect Disord 2008;105:305–10. 150. Adler CM, Fleck DE, Brecher M, Stra kowski SM. Safety and tolerability of que tiapine in the treatment of acute mania in bipolar disorder. J Affect Disord 2007; 100(Suppl 1):S15–S22. 151. Buckley PF, Paulsson B, Brecher M. Treat ment of agitation and aggression in bipolar mania: efficacy of quetiapine. J Affect Dis ord 2007;100(Suppl 1):S33–43. 152. McIntyre RS, Konarski JZ, Jones M, Pauls son B. Quetiapine in the treatment of acute bipolar mania: efficacy across a broad range of symptoms. J Affect Disord 2007;100 (Suppl 1):S5–14. 153. Vieta E, Goldberg JF, Mullen J, Vågerö M, Paulsson B. Quetiapine in the treatment of acute mania: target dose for efficacious treatment. J Affect Disord 2007;100(Suppl 1): S23–31. 154. Boidi G, Ferro M. Rapid dose initiation of quetiapine for the treatment of acute schi zophrenia and schizoaffective disorder: a randomised, multicentre, parallel-group, open study. Hum Psychopharmacol 2007;22:299–306. 155. Li H, Ma C, Wang G, Zhu X, Peng M, Gu N. Response and remission rates in Chinese patients with bipolar mania treated for 4 weeks with either quetiapine or lithium: a randomized and double-blind study. Curr Med Res Opin 2008;24:1–10. 156. Riedel M, Spellmann I, Strassnig M, Douhet A, Dehning S, Opgen-Rhein M, Valdevit R, Engel RR, Kleindienst N, M€ uller N, Möller HJ. Effects of risperidone and quetiapine on cognition in patients with schizophrenia and
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predominantly negative symptoms. Eur Arch Psychiatry Clin Neurosci 2007;257:360–70. Rainer M, Haushofer M, Pfolz H, Struhal C, Wick W. Quetiapine versus risperidone in elderly patients with behavioural and psy chological symptoms of dementia: efficacy, safety and cognitive function. Eur Psychia try 2007;22:395–403. Timdahl K, Carlsson A, Stening G. An ana lysis of safety and tolerability data from controlled, comparative studies of quetia pine in patients with schizophrenia, focus ing on extrapyramidal symptoms. Hum Psychopharmacol 2007;22: 315–25. McIntyre A, Gendron A, McIntyre A. Que tiapine adjunct to selective serotonin reup take inhibitors or venlafaxine in patients with major depression, comorbid anxiety, and residual depressive symptoms: a rando mized, placebo-controlled pilot study. Depress Anxiety 2007;24:487–94. Carta MG, Zairo F, Mellino G, Hardoy MC. Add-on quetiapine in the treatment of major depressive disorder in elderly patients with cerebrovascular damage. Clin Pract Epidemiol Ment Health 2007;3:28. Paleacu D, Barak Y, Mirecky I, Mazeh D. Quetiapine treatment for behavioural and psychological symptoms of dementia in Alz heimer’s disease patients: a 6-week, doubleblind, placebo-controlled study. J Geriatr Psychiatry 2008;23(4):393–400. Yalug I, Tufan AE, Kayaalp L. Quetiapine may be associated with new-onset seizures in patients with seizurogenic conditions. J Neu ropsychiatry Clin Neurosci 2007;19:341–2. Langguth B, Eichhammer P, Spranz C, Landgrebe M, Frick U, Sand P, Hajak G. Modulation of human motor cortex excit ability by quetiapine. Psychopharmacology 2008;196:623–9. Gupta M. Low dose quetiapine induced galactorrhoea: a case report. Clin Pract Epi demiol Ment Health 2007;3:12. Boggs DL, Kelly DL, Feldman S, McMa hon RP, Nelson MW, Yu Y, Conley RR. Quetiapine at high doses for the treatment of refractory schizophrenia. Schizophr Res 2008;101:347–8. Shankar BR. Quetiapine-induced leucope nia and thrombocytopenia. Psychosomatics 2007;48:530–1.
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167. McLean RM, Harrison-Woolrych M. Alopecia associated with quetiapine. Int Clin Psychopharmacol 2007;22:117–9. 168. Pinta ER, Taylor RE. Quetiapine addic tion? Am J Psychiatry 2007;164:174–5. 169. Waters BM, Joshi KG. Intravenous quetia pine–cocaine use (‘Q-ball’). Am J Psychia try 2007;164:173–4. 170. Ngo A, Ciranni M, Olson KR. Acute quetia pine overdose in adults: a 5-year retrospective case series. Ann Emerg Med 2008;52:541–7. 171. Medical News Today. FDA approves first generic risperidone to treat psychiatric con ditions. http://www.medicalnewstoday.com/ articles/113701.php 172. US Food and Drug Administration. Risper dal (risperidone) Tablets, August 2008. http:/www.fda.gov/Safety/MedWatch/Safety Information/Safety-RelatedDrugLabeling Changes/ucm123246.htm 173. Holzhausen SP, Guerreiro MM, Baccin CE, Montenegro MA. Use of risperidone in children with epilepsy. Epilepsy Behav 2007;10:412–6. 174. Miyaji S, Yamamoto K, Hoshino S, Yama moto H, Sakai Y, Miyaoka H. Comparison of the risk of adverse events between risper idone and haloperidol in delirium patients. Psychiatry Clin Neurosci 2007;61:275–82. 175. Keks NA, Ingham M, Khan A, Karcher K. Long-acting injectable risperidone v. olan zapine tablets for schizophrenia or schizoaf fective disorder. Randomised, controlled, open-label study. Br J Psychiatry 2007; 191:131–9. 176. Perez-Iglesias R, Crespo-Facorro B, Amado JA, Garcia-Unzueta MT, RamirezBonilla ML, Gonzalez-Blanch C, MartinezGarcia O, Vazquez-Barquero JL. A 12 week randomized clinical trial to evaluate metabolic changes in drug-naive, first-epi sode psychosis patients treated with halo peridol, olanzapine, or risperidone. J Clin Psychiatry 2007;68:1733–40. 177. Mahmoud RA, Pandina GJ, Turkoz I, Kosik-Gonzalez C, Canuso CM, Kujawa MJ, Gharabawi-Garibaldi GM. Risperi done for treatment-refractory major depressive disorder: a randomized trial. Ann Intern Med 2007;147:593–602. 178. Pandina GJ, Bossie CA, Youssef E, Zhu Y, Dunbar F. Risperidone improves beha vioral symptoms in children with autism in
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a randomized, double-blind, placebo-con trolled trial. J Autism Dev Disord 2007;37:367–73. Katz I, de Deyn PP, Mintzer J, Greenspan A, Zhu Y, Brodaty H.The efficacy and safety of risperidone in the treatment of psychosis of Alzheimer’s disease and mixed dementia: a meta-analysis of 4 pla cebo-controlled clinical trials. Int J Geriatr Psychiatry 2007;22:475–84. Jayaram MB, Hosalli P, Stroup TS. Risper idone versus olanzapine for schizophrenia. Cochrane Database Syst Rev 2006;1: CD005237. Jayaram MB, Hosalli PM, Stroup TS. Risper idone versus olanzapine for treatment of schi zophrenia. Schizophr Bull 2007;33:1274–6. Raviña T, Raviña P, Gutierrez J. Acquired long QT syndrome: risperidone-facilitated triggered activity and torsades de pointes during complete AV blockI. Int J Cardiol 2007;116:416–20. Pandina GJ, Bossie CA, Zhu Y, Gharabawi GM. Evaluating movement disorders in pediatric patients receiving risperidone: a comparison of spontaneous reports and research criteria for TD. Child Adolesc Psy chiatry Ment Health 2007;1:3. Panagiotidis PT, Fountoulakis KN, Sia mouli M, Magiria S, Iacovides A, Kaprinis G. Risperidone-induced sialorrhea respon sive to biperiden treatment. Schizophr Res 2007;93:410–1. Nakonezny PA, Byerly MJ, Rush AJ. The relationship between serum prolactin level and sexual functioning among male outpa tients with schizophrenia or schizoaffective disorder: a randomized double-blind trial of risperidone vs. quetiapine. J Sex Marital Ther 2007;33:203–16. Gallhofer B, Jaanson P, Mittoux A, TanghÏj P, Lis S, Krieger S. Course of recovery of cognitive impairment in patients with schi zophrenia: a randomized double-blind study comparing sertindole and haloperi dol. Pharmacopsychiatry 2007;40:275–86. Peuskens J, Moore N, Azorin JM, Toumi M, Cochran J. The European Sertindole Safety and Exposure Survey: a follow-up study of 8600 patients. Pharmacoepidemiol Drug Saf 2007;16:804–11. Arango C, Gómez-Beneyto M, Brenlla J, Gastó C, Sarramea-Crespo F, Chamorro L,
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Masramon X, Díez T. On behalf of the ZIS Study Group. A 6-month prospective, observational, naturalistic, uncontrolled study to evaluate the effectiveness and tol erability of oral ziprasidone in patients with schizophrenia. Eur Neuropsychopharmacol 2007;17:456–63. 189. Kudla D, Lambert M, Domin S, Kasper S, Naber D. Effectiveness, tolerability, and safety of ziprasidone in patients with schizophrenia or schizoaffective disorder: results of a multi-centre observational trial. Eur Psychiatry 2007;22:195–202. 190. Rosenfield PJ, Girgis RR, Gil R. High-dose ziprasidone-induced acute dystonia. Prg Neuro-Psycopharmacol Biol Psychiatry 2007;31:546–7. 191. Duggal HS. Acute Pisa syndrome and pharingolaryngeal dystonia due to
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ziprasidone. J Neuropsychiatry Clin Neurosci 2008;20:108–9. Duggal HS. Ziprasidone-induced acute laryngeal dystonia. Prog Neuro-Psycho pharmacol Biol Psychiatry 2007;31:970. Kaptsan A, Dwolatzky T, Lerner V. Zipra sidone-associated depressive state in schizo phrenic patients. Clin Neuropharmacol 2007;30:357–61. Citil DY, Secuk E, Karlida R. Ziprasidone induced hyperprolactinemia: a case report. Prog Neuro-Psychopharmacol Biol Psychia try 2008;32:905–6. Haessler F, Glaser T, Beneke M, Pap AF, Bodenschatz R, Reis O. Zuclopenthixol Disruptive Behaviour Study Group. Zuclo penthixol in adults with intellectual disabili ties and aggressive behaviours: discontinua tion study. Br J Psychiatry 2007; 190:447–8.
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Antiepileptic drugs
GENERAL Hypersusceptibility adverse reactions to antiepileptic drugs have been reviewed, and their mechanisms of action and risk factors have been described (1R). These reactions include (1) immune-mediated hypersensitiv ity reactions, (2) reactions involving unusual non-immune-mediated individual hypersus ceptibility, often related to abnormal produc tion or defective detoxification of reactive cytotoxic metabolites, and (3) so-called ‘off target’ pharmacology, whereby a drug inter acts directly with a system other than that for which it is intended (reactions that are classified as collateral adverse reactions in the DoTS framework (2H). Comparative studies The long-term efficacy and tolerability of antiepileptic drugs in patients with newly diagnosed epilepsy need to be evaluated in comparative studies. Two randomized, unblinded, long-term studies have been published. In the first study carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate were compared in 1721 patients with epilepsy for whom carbamazepine was deemed to be standard treatment (patients with partial epilepsies) (3C). In the second study, 716 patients for whom valproate was considered to be standard treatment were randomized to valproate, lamotrigine, or topiramate (4C). One of two primary outcomes was time to
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32007-1 � 2010 Elsevier B.V. All rights reserved.
treatment failure, which is a mixed measure of efficacy and tolerability. In the first study, time to treatment fail ure was significantly better for lamotrigine than for carbamazepine (HR = 0.78; 95% CI = 0.63, 0.97), gabapentin (0.65; 0.52, 0.80), and topiramate (0.64; 0.52, 0.79), and there was a non-significant advantage com pared with oxcarbazepine (1.15; 0.86, 1.54). Adverse events occurred in 45–53% (lamo trigine 45%, topiramate 53%). The most common adverse effect associated with treatment failure was rash (7% of patients taking carbamazepine, 6% of those taking oxcarbazepine and 3% of those taking lamotrigine). In the second study valproate was signifi cantly better than topiramate (HR = 1.57; 95% CI = 1.19, 2.08), but there was no sig nificant difference between valproate and lamotrigine (1.25; 0.94, 1.68). The adverse events associated with treatment failure were most commonly psychiatric symptoms, cognitive symptoms, tiredness, and fatigue, all of which were more common with topira mate. For lamotrigine, rash was the most common symptom associated with treat ment failure (4% of patients randomized), whereas for valproate weight gain was the most common symptom (4% of patients randomized).
Systematic reviews In a meta-analysis of the most frequent treatment-related central nervous system adverse effects of new antiepileptic drugs from double-blind, addon, placebo-controlled studies in adults with epilepsy 36 suitable studies were identified (5M). No meta-analysis was possible for oxcarbazepine and tiagabine. Gabapentin was significantly associated with somnolence
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and dizziness; lamotrigine with dizziness, ataxia, and diplopia; levetiracetam with somnolence; pregabalin with somnolence, dizziness, ataxia, and fatigue; topiramate with somnolence, dizziness, cognitive impairment, and fatigue; zonisamide with somnolence, and dizziness. Psychological Clinically important cognitive effects of anticonvulsants have been investigated in a double-blind, parallel group, randomized, placebo-controlled study of anticonvulsant drug withdrawal in subjects with completely controlled seizures taking a single anticonvulsant (6c). Drug withdrawal was associated with significant improvement in performance on the Controlled Oral Word Association Test and the Stroop ColourWord Interference Test. Psychiatric The association of Alzheimer’s disease and all types of dementia with epilepsy and the use of antiepileptic drugs has been investigated in 5376 elderly people (aged 65 years or older) with no prior evidence of dementia, defined as a Modified Mini-Mental State score of at least 78 (7C). Those who took antiepileptic drugs had a significantly higher risk of developing dementia but not Alzheimer’s disease. The association remained significant in those who took only phenytoin. Further investigation is warranted to determine whether it is indeed antiepileptic drug therapy or some underlying confounding pathology that is associated with the development of dementia in these patients. The adverse effects of antiepileptic drugs on mood have been reviewed (8RH). The barbiturates, vigabatrin, and topiramate are more likely than other antiepileptic drugs to be associated with depressive symptoms, which are present in up to 10% of patients taking these drugs. Tiagabine, levetiracetam, and felbamate present an intermediate risk, with a prevalence of depression of about 4% or less. For zonisamide, the data are less clear, but it seems that mood disorders may occur in up to 7% of patients, even though in most cases slow titration can significantly
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reduce the risk. Phenytoin, ethosuximide, carbamazepine, oxcarbazepine, gabapentin, sodium valproate, pregabalin, and lamotri gine are all associated with low risks of depression ( 14), car bamazepine, phenobarbital, and phenytoin. In general, the risk was restricted to the first few weeks of drug exposure. Musculoskeletal The prevalence of abnormal bone mineral density, measured using dual X-ray absorptiometry, in an urban population has been investigated in a cross-sectional study of 130 consecutive patients with epilepsy (18C). There were T scores of –1 or worse (the criterion for
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osteopenia in postmenopausal women) in 55% of patients and scores below –2.0 in 15%, more than six times the number expected in the general population. Older age, menopause in women, longer duration of therapy, and a history of using phenytoin or phenobarbital were markers for reduced bone mineral density. Teratogenicity The incidence of congenital malformations and other pregnancy outcomes as a function of in utero antiepileptic drug exposure has been studied in a systematic review of 59 published studies involving 65 533 pregnancies in women with epilepsy and 1817024 in healthy women (19M). The calculated incidence of births with congenital malformations in women with epilepsy (7.1%) was significantly higher than that in healthy women (2.3%). The incidence was highest for antiepileptic drug polytherapy (16.8%), mainly when the combination included phenobarbital, phenytoin or valproate. Valproate was associated with the highest incidence (10%). The first results derived from analysis of the Australian register of antiepileptic drugs in pregnancy have been published (20C). The data were collected between 1999 and December 2006 and contained data on 1002 pregnancies in women with epilepsy. There was a significant dose-related increased risk of fetal malformations associated with valproate; a tendency towards lower birth weights in live-born malformed offspring and a substantially reduced risk of seizures in pregnancies in which there had been free dom from seizures for 1 year. It has been hypothesized that fetal genetic variations in the expression and activity of some transport proteins may influence fetal exposure to antiepileptic drugs and thus the risk of teratogenicity (21RH). Fetal exposure to antiepileptic drugs may be influenced by drug transporting proteins in the placenta, including P-glycoprotein, multidrug resis tance protein 1, and breast cancer resistance protein. The location of these proteins in the syncytiotrophoblast plasma membrane (the interface of the maternal and fetal circula tions) allows these transport proteins to
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efflux xenobiotics back to the mother and offers the fetus protection from medications taken during pregnancy. Two of four pregnant women who took valproic acid and had offspring with neural tube defects had reduced phosphopyridoxal concentrations compared with controls (22c). The woman with the greatest reduction in plasma phosphopyridoxal took periconcep tional pyridoxine with folic acid in a second pregnancy, which had a normal outcome. The authors suggested that other vitamins, such as vitamin B6, in addition to folate, may be involved in neural tube defects in patients taking antiepileptic drugs. Drug formulations The advantages and disadvantages of extended-release formulations of antiepileptic drugs have been discussed (23R). Such formulations are usually designed to reduce dosage frequency and maintain relatively constant or flat plasma drug concentrations. Flat plasma concentrations of an antiepileptic drug may improve efficacy and minimize concentrationrelated adverse effects. Furthermore, consistent plasma concentrations may simplify the management of antiepileptic drug therapy. However, while the possibility of taking a drug once or twice a day might be more convenient, it will not necessarily improve therapeutic coverage. In fact, the effect of a missed dose in this case is larger and the risk of breakthrough seizures higher during once-daily administration than twicedaily administration.
Carbamazepine (SED-15, 627; SEDA 29, 88; SEDA-30, 78; SEDA-31, 107) Comparative studies The cognitive effects of carbamazepine and topiramate have been compared in patients with epilepsy in an open, observer-blinded, parallel-group, randomized trial in children with benign rolandic epilepsy (24c). Topiramate was introduced at a dose of 12.5 mg/day, with a minimum target dose of 50 mg/day over 4 weeks. Carbamazepine was started at a dose
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of 10 mg/kg/day, with a minimum target dose of 20 mg/kg/day. Changes in neuropsychological tests performed at baseline and after 28 weeks of treatment showed that topiramate had slightly worse effects than carbamazepine. There were no differences in behavioral adverse effects between carbamazepine and phenobarbital in a randomized, controlled trial in 108 children with generalized tonic– clonic or partial and secondarily generalized seizures in Bangladesh (25c). Placebo-controlled studies The efficacy of carbamazepine in 89 subjects with unipolar depression who had never received antidepressants has been evaluated in a double-blind, randomized, placebo-controlled study (26C). The patients had had at least two major depressive episodes but had never had mania or hypomania. They were random ized to immediate-release carbamazepine 300–800 mg/day (n = 51) or placebo (n = 38) for 12 weeks. There was mild leukopenia in 14/46 of those taking the active drug and 2/37 of those taking placebo. There were rashes in 11% of those taking carbamazepine and in none of those taking placebo. Nausea, headache, tremor, blurred vision, and somnolence almost exclusively occurred in those taking carbamazepine. Dizziness occurred in similar percentages (13% and 16% respectively). Cardiovascular Complete atrioventricular block has been attributed to carbamazepine (27A). Carbamazepine-induced dysrhythmias have two distinct forms: sinus tachycardia in the setting of massive carbamazepine overdose (mainly seen in young adults) and bradydysrhythmias or atrioventricular block, which are almost exclusively seen in elderly women and at carbamazepine con centrations in the usual target range. Psychological The absolute effect of antiepileptic drugs on cognition can only be observed in healthy volunteers. The neuropsychological and neurophysiological
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effects of carbamazepine and levetiracetam have been compared in a double-blind, two-period, crossover, randomized study in 28 healthy adults (28C). Evaluations were conducted at times of screening, baseline pre-drug treatment, the end of each maintenance phase (4 weeks), and the end of each washout period. The dosage of carbamazepine was adjusted to achieve midtarget range concentrations. The dosage of levetiracetam was titrated to 2000 mg/day. An overall composite score showed significantly worse effects of carbamazepine compared with levetiracetam and for both drugs compared with non-drug treatment. Furthermore, carbamazepine was worse than levetiracetam in 15 of 34 variables and none favored carbamazepine. These results suggest that carbamazepine has more negative cognitive effects than levetiracetam at commonly used dosages and that these differences may be clinically significant in some individuals. Up to now, there has been no conclusive evidence in patients with epilepsy of a sig nificant difference between two different antiepileptic drugs, with some exceptions. The cognitive effects of carbamazepine and remacemide hydrochloride have been compared in a double-blind, parallel-group study in patients with newly diagnosed epilepsy, who were randomized to either carbamazepine 200 mg/day (n = 282) or remacemide 200 mg/day (n = 288) for 2 weeks and slowly titrated to a target dose of 600 mg/day of both drugs (29C). After the 6-week titration period, the patients entered a maintenance phase, with possible upward or downward dosage adjustments of 200 mg/day. Repeated assessments of neuro psychological function and mood were carried out using computerized and conven tional measures. The trial ended after 20 months, following the second interim analysis, which showed inferiority of rema cemide compared with carbamazepine in preventing seizure recurrence. The patients who took carbamazepine had consistently worse performances than those who took remacemide on measures of information pro cessing, psychomotor speed, and attention. The authors suggested that the observed
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differences may have been due to direct pharmacological effects of the treatments themselves and did not seem to be influenced by aspects such as seizure control and adverse events profiles. Sensory systems Conjunctival metaplasia has been associated with carbamazepine in a 22-year-old man (30A). Endocrine Carbamazepine affects the serum concentrations of thyroid hormones, typically reducing concentrations of circulating thyroxine, both total and free, with variable effects on triiodothyronine. In patients with no underlying thyroid pathology this is only exceptionally clinically important. However, in hypothyroid patients such changes may be significant. Thyrotropin, total thyroxine, and free thyroxine serum concentrations have been studied in 29 hypothyroid patients taking levothyroxine and in 19 patients with no thyroid disorders who were taking levothyroxine for other reasons; measurements were made before carbamazepine therapy and then weekly for 7 weeks (31c). In the first group, total thyroxine fell significantly by 15–25%, starting from the first week; the fall in free thyroxine was smaller (10–15%) and delayed. In contrast, thyrotropin concentrations increased only slightly and stayed within the reference range. In the second group there were similar falls in total and free thyroxine, but followed by a significant increase in thyrotropin. Hence, in patients with no thyroid pathology there was a compensatory reaction, leading to a new steady state. In patients who were taking levothyroxine for hypothyroidism, increased metabolic clearance of thyroid hormones may lead to worsening of hypothyroidism. Metabolism The possible association between the effects of carbamazepine on thyroid function and lipid profile has been studied in 18 children with epilepsy (32c). During carbamazepine monotherapy there was a significant association between serum
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low-density lipoprotein (LDL) cholesterol and thyrotropin concentrations at 6 and 12 months. These results suggest that the increase in LDL cholesterol concentrations that occur in patients taking carbamazepine may be the consequence of altered thyroid function. Hematologic A young patient with a bipolar disorder started carbamazepine and developed pure red cell aplasia (33A). Carbamazepine can cause pseudolymphoma, and there have also been iso lated reports of true lymphomas. • A 73-year-old patient with erythroderma had an anaplastic large cell lymphoma; he had started to take carbamazepine for diabetic neuropathy 3 months before the development of skin lesions (34A).
However, the time course in this case was very short, suggesting that carbamazepine was not implicated. In a 5-year-old boy intravascular hemoly tic anemia with erythroblastopenia was con sidered probably due to carbamazepine (35A). Subsequently reduced erythrocyte activity of the enzyme glutathione peroxi dase was found in the boy and his mother. The authors speculated that reduced activ ity of this enzyme confers a high risk of carbamazepine-induced hemolysis. Gastrointestinal Drug rash with eosinophilia and systemic symptoms (DRESS), also known as anticonvulsant hypersensitivity syndrome, is typically characterized by multiorgan involvement (blood dyscrasias, hepatitis, nephritis, myocarditis, thyroiditis, interstitial pneumonitis, and encephalitis). Carbamazepine is often implicated. Two cases of carbamazepine-induced eosinophilic esophagitis in the contest of DRESS have been reported (36A). The involvement of the esophagus in this contest had probably never been noted before. Urinary tract Urinary retention has been attributed to carbamazepine (37A).
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• A 38-year-old woman with a 2-year history of epilepsy taking carbamazepine 200 mg bd started to have urgency and dribbling of urine and 3 days later developed acute urinary retention. Mechanical obstruction and all other causes of urinary retention were ruled out. Carbamazepine was the only medication with anticholinergic properties that she was taking. It was withdrawn and replaced by valproic acid. Her symptoms did not recur.
Although similar cases have previously been described, this case was unique because there was no evidence of underly ing disease, such as long-standing diabetes mellitus with severe peripheral neuropathy or Fabry’s disease with autonomic dysfunc tion. Carbamazepine has anticholinergic effects which may explain this complication. Skin A 52-year-old woman took carba mazepine 600 mg/day for 2 months and developed a psoriasiform eruption on her palms and soles followed 1 month later by alopecia (38A).
Serious skin reactions to carbamazepine Drug reaction with eosinophilia and systemic symptoms (DRESS) Several cases of carbamazepine-induced DRESS have been reported (39A–43A). A 16-year-old girl with Bourneville tuberous sclerosis took carbamazepine monotherapy for 5 weeks and developed DRESS. The unique characteristic of this case is that the complication recurred 3 weeks after treatment with valproic acid, which was substituted for carbamazepine (44A). After an immunological reaction to carbamazepine, valproate, which has a non-aromatic structure, is often used instead. In this case cross-sensitivity between these two drugs has been considered as possible. Stevens–Johnson syndrome and toxic epidermal necrolysis Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are now considered to be the same disease presenting with differences
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in severity. SJS is less extensive and affects less than 10% of body surface area, whereas TEN involves more than 30% of body surface area. The association between mood stabilizers and other medications used in patients with a bipolar disorder and severe cutaneous reac tions, such as erythema multiforme, SJS, and TEN has been evaluated epidemiologically (45C). In a database of more than 12 000 patients with bipolar disorders, 72 patients had had a serious skin reaction; 288 patients matched for sex and age, who had not had a serious skin disease during the same time, were also selected. The use of carbama zepine and valproate significantly predicted erythema multiforme, SJS, and TEN. Other significant predictors were other anticonvul sants (phenytoin, phenobarbital, and lamo trigine) and other concurrent drugs. The combination of carbamazepine and parace tamol (acetaminophen) further increased the risk. Re-administration of a drug that previously caused SJS may lead to TEN, which has a very high mortality rate (46A). • A 26-year-old man with schizophrenia and a history of carbamazepine-induced SJS 5 years before was again given carbamazepine. After 3 days he developed TEN (body surface area >90%). Despite appropriate treatment, he died 5 days later due to multiple organ failure.
In the West the overall estimated risk of SJS/TEN associated with carbamazepine is fairly low at about 1–6 per 10 000 new users (47C,48C). In some Asian countries, the risk is about 10 times higher than in Caucasian populations. In a case–control study in Tai wan, 59 of 60 patients with SJS/TEN asso ciated with carbamazepine were positive for HLA-B*1502, far higher than the 4% incidence of HLA-B*1502 in carbamaze pine-tolerant controls (49C). These findings suggest an initial estimate of a 5% absolute risk of SJS/TEN in HLA-B*1502 positive patients exposed to carbamazepine. Further more, in a case series of European patients with SJS/TEN associated with carbamaze pine, patients with Asian ancestry were over-represented. Of 12 patients, 4 were of
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Asian ancestry and all were positive for HLA-B*1502 (50C). In a further study in Hong Kong all of four cases of SJS/TEN associated with carbamazepine occurred in patients positive for HLA-B*1502 (51C). On the other hand, HLA-B*1502 is largely absent in individuals not of Asian origin, and it has therefore not been found to be a susceptibility factor for SJS/TEN in Cauca sians (52C). HLA-B*1502, an inherited allelic variant of the HLA-B gene, is found almost exclu sively in some individuals across broad areas of Asia, including South-Asian Indians. However, the prevalence of HLA-B*1502 has not been studied in many regions of Asia. It has been roughly calculated that 10–15% of people living in some parts of China, Thailand, Malaysia, Indonesia, the Philippines, and Taiwan carry the allele (53S). Since tests for HLA-B*1502 are already used to check for compatibility before tissue transplantation, the FDA has recommended that patients with ancestry from areas in which HLA-B*1502 is prevalent should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine. If they test positive, carbamazepine should not be used, unless the expected benefit clearly outweighs the increased risk of serious skin reactions. On the other hand, since over 90% of carbamazepine-treated patients who will experience SJS/TEN have this reaction within the first few months of treatment, patients of any ethnicity or genotype (includ ing HLA-B*1502 positive) who have been taking carbamazepine for more than a few months are at low risk of SJS/TEN from carbamazepine.
Musculoskeletal Bone mineral density has been measured in 21 patients taking carbamazepine monotherapy and 21 patients taking valproate; the former had an increased frequency of lower bone density (54c). Enthesitis and Staphylococcus aureus tendon sheath abscess occurred as complica tions of severe carbamazepine hypersensi tivity in a 10-year-old girl (55A).
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Immunologic Recurrent Herpes simplex virus encephalitis has been attributed to carbamazepine-induced hypogammaglobu linemia (56A). • A 40-year-old man developed rigors, nausea, vomiting, photophobia, visual hallucinations, and behavioral changes followed by a tonic– clonic seizure. Cerebrospinal Fluid (CSF) analysis showed a lymphocytosis and the presence of Herpes simplex virus DNA type 1. Serum immunoglobulin concentrations were normal. He completed 3 weeks of intravenous aciclovir therapy and was discharged taking carbamazepine. Seven months later he had another tonic–clonic seizure and became agitated, confused and febrile. The CSF, an MRI scan, and electroencephalography were consistent with viral encephalitis. He had profound hypogammaglobulinemia and Herpes simplex virus DNA type 1 in the CSF.
Secondary bronchiolitis obliterans organiz ing pneumonia with repeated respiratory infections has also been associated with carbamazepine-induced hypogammaglobu linemia (57A). Drug formulations Cmax and AUC, which reflect the extent of availability, are not sufficiently sensitive parameters for distinguishing between formulations of carbamazepine in terms of tolerability, since the speed of availability is crucial (see below). In a reanalysis of the results of a bioequivalence study, using a mixed-effects pharmacokinetic–pharmacodynamic model to describe the dependence of adverse events on carbamazepine concentration, there was rapid tolerance to most neurological adverse effects (58R). The authors proposed the use of alternative, more sensitive methods for measuring bioequivalence between generic and branded formulations of antiepileptic drugs. Drug dosage regimens Slow titration of the dose of carbamazepine reduces the frequency and intensity of some of its nervous system adverse effects. It is therefore of interest to study what happens when it is given in a loading dose. The safety and efficacy of carbamazepine have been evaluated after the administration of a oral loading dose
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of 8 mg/kg in 36 patients (42 oral loads) (59c). The mean plasma carbamazepine concentration 3 hours after administration was 6.5 mg/l. There were adverse effects in about 60% of patients. The most common were drowsiness (26%) and nausea (23%) and others included dizziness, nystagmus, abdominal pain, vomiting, ataxia, and double vision. This confirms the low tolerability of carbamazepine when it is given in therapeutic doses without titration. It should be noted that the peak plasma concentrations were at the lower end of the usual target range. Drug overdose In 62 cases of carbamazepine overdose there was a statistically significant relationship between the serum carbamazepine concentration at time of admission and the Glasgow Coma Scale (60c). Seizures occurred exclusively in patients with epilepsy and a serum carbamazepine concentration over 25 mg/l. The authors proposed a classification into three neurological severity ranks (minimal, moderate, and important). Treatment of carbamazepine overdose consists mainly of supportive measures, the administration of activated charcoal, and gas tric lavage. In patients poisoned with modified-release formulations, multiple doses of activated charcoal are recommended, to enhance the elimination of carbamazepine. Whole bowel irrigation has been suggested to be beneficial but is not yet accepted as routine treatment because of limited human data. Gastrointestinal decontamination has been reported to be of limited efficacy in a case of severe overdose with slow-release carbamazepine (61A). Three cases of carbamazepine overdose in adolescents were managed with standard low-flux hemodialysis in two cases and char coal hemoperfusion in one. The authors concluded that hemodialysis is a cheaper and easier alternative, with fewer adverse effects than hemoperfusion (62A).
Gabapentin
(SED-15, 1465; SEDA-29, 89; SEDA-30, 80; SEDA-31, 110)
Observational studies When gabapentin was used to chronic irritability and recurrent
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pain in 9 neurologically impaired children, care-givers reported marked improvement; one child developed nystagmus and withdrawal was required (63c). Of eight patients who were refractory to first-line treatment in whom gabapentin was used as second-line treatment for chronic cluster headache in a prospective study, six responded; one had transient drowsiness at high doses and one had sexual dysfunc tion (64c). Gabapentin (initially 900 mg/day, increas ing up to a maximum of 2400 mg/day) has been evaluated in 55 patients with lumbar spinal stenosis (65c). Gabapentin increased walking distance and improved pain scores. The most frequent adverse effects were drow siness and dizziness and two patients had transient ataxia. There were no withdrawals. Comparative studies The hypothesis that both amitriptyline and gabapentin are more effective in relieving neuropathic pain than diphenhydramine has been tested in a randomized, double-blind, triple crossover, 8-week trial in 38 adults with spinal cord injuries (66c). Maximum daily doses were 2600 mg for gabapentin and 150 mg for amitriptyline. Amitriptyline was more efficacious in relieving neuropathic pain than diphenhydramine. Withdrawal because of possible adverse effects occurred five times during gabapentin treatment: (1) shortness of breath; (2) dizziness, fatigue, and nausea; (3) increased spasticity and pain; (4) fatigue, drowsiness, constipation, and dry mouth, and (5) severe itching. The four most frequent adverse events were dry mouth, drowsiness, fatigue, and constipation, which were all more common with amitriptyline. Placebo-controlled studies The efficacy and safety of gabapentin in doses up to 2400 mg/day for neuropathic pain caused by traumatic or postsurgical peripheral nerve injury have been investigated in a doubleblind, crossover, randomized, placebocontrolled study in 120 patients (67C). There was no statistically significant difference in the primary outcome of efficacy, although
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gabapentin provided significantly better pain relief than placebo. In 11 patients treatment was withdrawn because of adverse events. During gabapentin run-in, one patient had diplopia, ataxia, amnesia, and dysarthria, one had nausea and vomiting, one dizziness and vertigo, and one erythema. During gabapentin maintenance treatment, one patient was withdrawn because of cough and another because of vertigo. The most commonly reported adverse events during the gabapentin period were dizziness and vertigo, reported by 33% of the patients, and malaise and tiredness (26%), compared with 7.5% and 14% during placebo treatment respectively. Gabapentin (1200–2400 mg/day) and pla cebo have been compared in a 12-week, dou ble-blind, randomized study in 150 patients with pain associated with fibromyalgia (68C). Gabapentin produced greater improvement in average pain severity scores. Adverse events necessitated withdrawal in 12 patients taking gabapentin and 7 taking placebo. Gabapentin was associated with significantly more dizziness (19 versus 7 patients), seda tion (18 versus 3), light-headedness (11 versus 1), and weight gain (6 versus 0). Gabapentin (300 mg/day initially, increas ing to a maximum of 4200 mg/day) and pla cebo have been compared in a 12-week randomized, placebo-controlled trial in 50 patients with chronic masticatory myalgia (69c). Gabapentin was better than placebo in reducing pain and masticatory muscle hyperalgesia. The most frequent adverse effects were dizziness (in seven patients taking gabapentin and two patients taking placebo), drowsiness (n = 7 and 5 respec tively), impairment of memory and cogni tion (4 and 1), dry mouth (3 and 1), and fatigue (3 and 2). The effects of gabapentin 800 mg and dexamethasone 20 mg on postoperative pain, given together or separately 1 hour before the start of varicocele surgery, have been investigated in a randomized, doubleblind, placebo-controlled trial in 60 patients (70c). Gabapentin þ dexamethasone improved postoperative analgesia and pre vented postoperative nausea and vomiting better than either drug alone. The most
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frequent adverse effects were vomiting, nau sea, and dry mouth, which were significantly more common with placebo. Headache and pruritus occurred with similar frequencies in all four groups. The effects of gabapentin 1200 mg alone and gabapentin 1200 mg þ paracetamol 20 mg/kg, 1 hour before surgery, on post operative pain and morphine consumption in patients undergoing abdominal hyster ectomy have been compared in a three-arm, double-blind, placebo-controlled study in 75 patients (71c). Gabapentin alone and in combination with paracetamol reduced opioid requirements and increased patients’ satisfaction postoperatively. There were no significant differences between the groups in terms of adverse effects. The analgesic effect of gabapentin 1.2 g before the operation has been studied in patients undergoing elective hand surgery with intravenous regional anesthesia in a double-blind, placebo-controlled study (72c). Gabapentin was significantly superior to placebo in several measures of efficacy. Two of those who were given gabapentin and three of those who were given placebo had nausea that required antiemetic drugs and two of those who were given gabapentin complained of dizziness. Another postopera tive complaint was dry mouth in four patients given gabapentin and two given placebo. None reported being excessively drowsy after surgery. Gabapentin 600 mg has been assessed in the prevention of high-altitude headache in a placebo-controlled randomized study at an altitude of 3500 m in 202 unacclimatized hotel guests aged 15–65 years (73c). The total incidence of headaches was not signi ficantly affected by gabapentin, but there was a reduction in the incidence of moder ate/severe high-altitude headache. Somno lence was the most common adverse effect and was more common among gabapentin users. Dizziness, fatigue, and gastrointestinal adverse effects were not significantly differ ent between the groups. Gabapentin 2400 mg/day and tiagabine 24 mg/day in reducing cocaine use have been evaluated in a three-arm, 10-week, double-blind, placebo-controlled study in
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76 cocaine-dependent methadone-treated patients (74c). Treatment retention was sig nificantly reduced by gabapentin, but it was ineffective in reducing cocaine use. Adverse effects were not reported. Gabapentin up to 1200 mg/day for 8 days has been evaluated as an alternative to benzodiazepines in the treatment of alco hol withdrawal in 35 non-treatment-seek ing alcoholic subjects in a double-blind placebo-controlled study (75c). Gabapentin had no overall effect on drinking or crav ing. However, no adverse effects of the combination of gabapentin with alcohol were reported. The effects of memantine 10–40 mg/day and gabapentin up to 2400 mg/day on con genital nystagmus have been studied in 48 patients in a randomized, three-arm, doublemasked, placebo-controlled study over 56 days (76c). Both drugs improved visual acuity and reduced the intensity of nystag mus. In 16 patients given gabapentin 9 had adverse effects: each felt dizzy, or tired, or sleepless, or light-headed, nauseated, forget ful, and shaky, had headaches or was depressed; two had to reduce the dosage. Of 15 subjects who took placebo, 5 had adverse effects (dizziness, tiredness, light headedness, nausea, and headaches). Nervous system Life-threatening myoclonic status has been attributed to gabapentin (77A). • A 57-year-old man who had hand tremors and jerks involving the upper limbs was given gabapentin 900 mg/day and after 3 days developed continuous, fast-frequency, highamplitude jerking of the trunk and extremities, which severely impaired his normal activities. Progressive confusion, agitation, and disorientation developed soon after. Five days later he was admitted to the hospital. He was afebrile and had high-frequency, continuous, erratic, multifocal myoclonus, which was asynchronous in different parts of the body. Electroencephalography showed diffuse theta slowing and multifocal spikes. The diagnosis was cortical tremor. He was given thiopental after intubation and ventilation. Gabapentin was withdrawn. Genetic studies showed that he had a haplotype that co-segregates with benign adult familial myoclonic epilepsy. He was treated with levetiracetam 1000 mg/day, which controlled his symptoms.
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There have been several reports of gaba pentin-induced chorea. A patient with Parkinson’s disease developed new-onset dyskinesia (choreoathetosis involving both upper and lower limbs) when gabapentin was introduced, with full resolution when it was withdrawn (78A). Three further cases of chorea have been reported in patients without extrapyramidal disorders taking gabapentin. • A 46-year-old woman developed chorea in her neck, trunk and limbs soon after taking gabapentin for complex regional pain syndrome in her left arm (79A). The chorea lasted for 1 year and resolved completely within 2 weeks of withdrawal of gabapentin. • A 68-year-old hypertensive woman, who reported lumbar pain radiated to the legs associated with paresthesia, developed chorea 30 days after starting to take gabapentin; it resolved 1 week after drug withdrawal (80A). • A 41-year-old man with a thoracic cord lesion and subsequent severe neuropathic pain had right-sided hemichorea after taking gabapentin; it abated gradually after drug withdrawal (81A). An MRI scan was normal but functional imaging of regional cerebral blood flow showed hypoperfusion of the left basal ganglia, especially the left caudate.
A 57-year-old woman with diabetes melli tus and uremia on regular hemodialysis, who had bilateral leg dysesthesia, developed severe dizziness and lethargy after a single dose of gabapentin 75 mg; she recovered rapidly after one session of hemodialysis (82A). Hematologic Leukopenia has attributed to gabapentin (83A).
been
• A 35-year-old woman who had taken gabapentin 300 mg/day for 2 months for a trapped nerve, developed leukopenia and bilateral cervical lymphadenopathy, which resolved within 2 days after drug withdrawal. An infective cause was excluded and the authors concluded that the illness had been caused by gabapentin.
Musculoskeletal A severe myopathy has been attributed to gabapentin (84A). • An 85-year-old woman with diabetes mellitus, severe pain in her legs and difficulty in walking
134 took gabapentin 150 mg tds On the first day she developed psychomotor agitation and gastric pain, which were treated with haloperidol 10 mg and lansoprazole 30 mg. During the next few hours, the muscle pain became more severe and she developed a myopathy with acute renal failure (CK 459 U/l, myoglobin 11 437 ng/ml, creatinine 406 µmol/l), which worsened despite withdrawal of haloperidol and lansoprazole. Gabapentin was then withdrawn and her condition rapidly improved with complete recovery within 10 days.
Severe myotonia and dystonia after general anesthesia has been attributed to gabapentin (85A). This is the first report to suggest that anesthesia may precipitate this rare gabapen tin-induced adverse effect. • A 55-year-old woman who had undergone uneventful general anesthesia on numerous previous occasions took gabapentin for neuropathic pain. Subsequently she developed severe movement disorders on emerging from general anesthesia, unrelated to the choice of anesthetic or antiemetic. The last and most important episode was observed after anesthesia that lasted for 20 minutes, in which sevoflurane 1.8–2.2%, oxygen, dexamethasone 8 mg, and fentanyl 0.1 mg were used. On emerging she developed violent dystonic movements affecting her torso and limbs, and nearly fell off the trolley. The dystonia came in episodes lasting 1–5 minutes, with myoclonic jerks of the arms, and then subsided for the same period. She was given benzodiazepines and the movement disorder gradually abated over 5 days. Before discharge, she reported that she had experienced ‘twitchiness’ on occasions after starting to take gabapentin, which was withdrawn.
Drug withdrawal In two cases abrupt withdrawal of gabapentin after long-term treatment with high doses resulted in withdrawal symptoms, characterized by confusion, tremors, agitation, hallucinations, and vegetative symptoms (tachycardia and fever) (86A). The symptoms promptly resolved after gabapentin was reintroduced.
Lamotrigine
(SED-15, 1990; SEDA-29, 90; SEDA-30, 80; SEDA-31, 113)
Comparative studies In about 100 patients with bipolar II disorder, randomized to
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lamotrigine or lithium, both drugs were effective, but lamotrigine had a better profile of tolerability (87A). In a similar study in 34 patients with unipolar depression, there were no differences in tolerability between lamotrigine and lithium (88c). In a small, open, randomized comparison of lamotrigine and sustained-release carba mazepine for the treatment of newly diag nosed symptomatic seizures after stroke in elderly people, lamotrigine was significantly better tolerated (89c). Lamotrigine and sustained-release carbamazepine have been compared in a double-blind, parallel-group study in patients over 65 years old with newly diag nosed epilepsy who had had at least two unprovoked seizures (90C). The trial lasted 40 weeks, with a 4-week dose escalation phase, during which doses were adjusted up to 500 mg/day for lamotrigine and 2000 mg/day for carbamazepine. The pri mary end-point was retention in the trial, which is a mixed measure of efficacy and tolerability; 68/93 (73%) and 61/92 (67%) of patients randomized to lamotrigine or carbamazepine respectively completed the study. There was a non-significant trend to higher seizure-free rates for carbamazepine and better tolerability for lamotrigine. Pre vious comparative studies in the same populations of elderly patients had shown significant findings in favour of better toler ability of lamotrigine. The explanation for this partial discrepancy may be that because a sustained-release formulation of carbama zepine was used initial target dosages were lower and carbamazepine titration was slower. In a double-blind comparison of lamotri gine 100 mg bd and amitriptyline 50 mg/day in 53 patients with diabetic neuropathy, the two drugs had equal efficacy and favourable tolerability (91c). Placebo-controlled studies There were positive effects on cognitive function and no adverse effects in a double-blind, placebocontrolled study in a small population of patients with schizophrenia in which lamotrigine was added to clozapine (92c).
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Systematic reviews In an analysis of five double-blind, randomized, placebocontrolled trials in the acute treatment of bipolar depression, lamotrigine monotherapy was not effective (93M). The incidences of mania, hypomania, or mixed episodes were low and did not differ between lamotrigine and placebo. Lamotrigine did not precipitate or worsen manic symptoms. The potential role of lamotrigine in patients with schizophrenia resistant to atypical antipsychotic drugs has been evalu ated in several studies. In an analysis of two multicenter, double-blind, placebocontrolled, parallel-group studies of a flexible dose of lamotrigine 100–400 mg/day as add-on treatment in more than 400 patients with schizophrenia and stable residual psychotic symptoms there were similar percentages of adverse effects in the two groups (94M). Serious adverse events were reported by 3 patients who took placebo and 11 who took lamotrigine; they mainly concerned worsening of psychiatric symptoms. Only one serious adverse event, a suicide attempt, was considered to be possibly related to lamotrigine.
135 • A 17-year-old boy with a long history of intractable secondarily generalized tonic– clonic seizures and a normal MRI scan took lamotrigine 25 mg/day initially and gradually increased the dose to 200 mg/day. His epileptic seizures were significantly improved. After 5 days he developed involuntary, continuous, jerky movements of all four limbs, gradually worsening to the point of causing excoriation and bruising of the legs and impaired walking. The disorder, which was thought to be consistent with bilateral ballismus, disappeared about 10 days after withdrawal of lamotrigine.
Two cases of aseptic meningitis have been attributed to lamotrigine (97A). In the first case it had been prescribed for prevention of seizures in an HIV-positive patient. In the second, it had been substituted for valproic acid in a pregnant woman with epilepsy. Myoclonus provoked by lamotrigine has been described in a patient with bipolar affective disorder (98A).
• A 4-year-old boy with cerebral palsy and epilepsy was treated with primidone 375 mg/day and valproic acid 500 mg/day. Since his seizures were not controlled, lamotrigine 250 mg/day (16 mg/kg) was added, and 3 weeks later he developed an intermittent fever and a rash. He became comatose and had generalized tonic–clonic seizures with marked hepatosplenomegaly. He had a low white blood cell count (2.1 109/l), a low hemoglobin concentration, and a low platelet count. Liver function and renal function were abnormal. A bone marrow biopsy showed hemophagocytosis. He was given intravenous immunoglobulin and glucocorticoids, and his liver function, renal function, and pancytopenia resolved within 2 weeks.
Psychiatric Of about 1400 patients with epilepsy taking lamotrigine, 6 developed a psychotic disorder, mainly, but not exclusively, consisting of paranoid– hallucinatory (schizophrenia-like) symptoms (99c). A clear cause and effect relationship could not be determined because of the retrospective nature of the data, even though there was rapid remission of the psychotic symptoms after dosage reduction or withdrawal. Lack of a history of previous psychotic episodes in all cases but one made the author consider that these disorders were de novo psychoses. Lamotrigine can cause positive psychotic symptoms in patients with epilepsy or bi polar disorder, and can exacerbate positive psychotic symptoms in patients with schizoaffective disorder. In two cases positive symptoms in paranoid schizophrenia were exacerbated (100A). There have been sporadic cases of delir ium, hallucinations, and mania in patients taking lamotrigine for various psychiatric conditions (101A–104A).
Nervous system Ballismus has been associated with lamotrigine in a patient with epilepsy (96A).
Mouth Mouth ulcers occurred in two patients taking lamotrigine in whom oxcarbazepine had been withdrawn some weeks before the
Cardiovascular A hemophagocytic synd rome has been attributed to lamotrigine in a high initial dose (95A).
136
observation of the supposed adverse effect (105A). The authors speculated that deinduction may have contributed to the pathogenesis of this adverse effect. Liver Lamotrigine-induced hepatitis has previously been described, is considered to be immune-mediated and is often part of an anticonvulsant hypersensitivity syndrome. A patient with a history of schizophrenia taking lamotrigine 200 mg/day and aripiprazole 15 mg/day developed acute hepatitis, which, according to the Naranjo Probability Scale for adverse drug reactions, was considered probably due to lamotrigine (106A). Other cases have been described (107A–109A). Skin Lamotrigine-induced skin reactions vary from mild urticarial/maculopapular eruptions to potentially life-threatening reactions. In 44 patients the rash recurred after rechallenge in only five cases (110M). The authors concluded that patients who develop a benign rash with lamotrigine can be rechallenged, often without adverse consequences. A patient developed lamotrigine-induced SJS after withdrawal of interferon and riba virin (111A). The authors hypothesized that withdrawal of the immunosuppressive medi cations may have triggered the complication. Musculoskeletal Bone mineral densities in 13 children who were taking lamotrigine monotherapy and who had never been exposed to other medications have been compared with measurements in 36 nonepileptic subjects and 40 epileptic patients who had taken polytherapy (112c). The Z scores of bone mineral density for lamotrigine and control subjects were similar and higher than in those taking polytherapy. These results suggest that lamotrigine does not interfere with bone metabolism. Death Four cases of sudden unexpected death in epilepsy (SUDEP) have been reported in non-hospitalized patients who
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were taking lamotrigine monotherapy (113A). All were women with generalized tonic–clonic seizures. Three had generalized forms of epilepsy and the fourth had an idiopathic localization-related form. Two were seizure free, one had monthly simple partial seizures, and the fourth had had two seizures during the previous week. In the three cases in which post-mortem lamotrigine blood concentrations were measured, the plasma concentrations were low in two and absent in the third. The authors speculated that certain patients with epilepsy may be at increased risk of torsade de pointes and sudden unexpected death when taking lamotrigine, and that the risk may be higher in women. Experimental studies have shown that lamotrigine and other antiepileptic drugs inhibit the cardiac rapid delayed rectifier potassium ion current (Ikr), and drugs with this effect may increase the risk of cardiac dysrhythmias and sudden unexpected death (114E). However, this hypothesis has been questioned, since not all drugs that inhibit potassium channels prolong the QT interval, in particular those that are also active at sodium channels (115H). Teratogenicity Following the publication of data from the UK pregnancy registry, which showed an increased risk of major birth defects in patients who had been exposed to daily doses of lamotrigine over 200 mg/ day, data from the International Lamotrigine Pregnancy registry were analysed to examine the effect of a maximal first trimester maternal dose of lamotrigine monotherapy on the risk of major birth defects (116C). Among 802 exposures, the frequency of these effects was 2.7% and the distribution of dose did not differ between infants with and without major birth defects up to a dose of 400 mg/day. Antiepileptic drugs increase the risk of birth defects by two to six times, and studies of individual drugs have been enabled by the establishment of drug registries. Two reports have yielded contradictory findings on the risk of orofacial clefts after in utero exposure to lamotrigine. The North American Antiepileptic Pregnancy Registry showed no
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overall risk of major malformations in 684 infants exposed to lamotrigine monotherapy, but an increased risk of orofacial clefts (7.3/1000) (117C). This was an 11-fold increased risk compared with a control group of 221 746 unexposed infants. In the same study, data from five registries showed that the risk of orofacial clefts was increased (2.5/1000) in 1623 infants exposed to lamo trigine monotherapy compared with the above-mentioned control group. However, this finding was not confirmed by the EUROCAT congenital anomaly reg ister, which covered 3.9 million births from 19 registries in Europe (118M). Among 72 lamotrigine-exposed births (40 monother apy and 32 polytherapy) the numbers of cases of orofacial clefts were not signifi cantly different between patients who had taken lamotrigine in the first trimester and non-epileptic, non-antiepileptic drug users. This disparity can be explained by the small numbers of children with cleft defects in the lamotrigine group or by bias of some sort. Further information is necessary to clarify the question (119H). Drug formulations A new formulation of lamotrigine (extended-release; XR), administered once daily, has been evaluated in a double-blind, parallel-group, placebocontrolled study in 239 drug-resistant patients with epilepsy (120C). This formulation was effective and particularly well tolerated. The most common adverse events were headache (lamotrigine XR 17%, placebo 15%) and dizziness (lamotrigine XR 18%, placebo 5%). Drug overdose Lamotrigine overdose is not often reported. Most patients present with varying degrees of lethargy, disorientation, ataxia, and stupor (121A). Seizures and status epilepticus can occur (122A–125A). • A 42-year-old woman developed a seizure disorder at the age of 7 years and took carbamazepine and subsequently lamotrigine. After a pregnancy ended in a spontaneous abortion, she took lamotrigine 4.1 g (41 tablets of 100 mg) in a suicide attempt. About 1–2 hours later she had a series of secondarily generalized
137 tonic–clonic seizures over 3 hours without full recovery of consciousness between seizures. The serum lamotrigine concentration was 47 µg/ml.
Drug–drug interactions Aripiprazole Stevens–Johnson syndrome occurred in two patients taking lamotrigine and aripiprazole for schizophrenia (126A). The authors suggested that the risk of a lamotrigine induced severe skin reaction was increased by an interaction between these two drugs. Management of adverse drug reactions Toxic epidermal necrolysis is difficult to treat. Several options have been tried, including systemic corticosteroids, thalidomide, pentoxifylline, ciclosporin, cyclophosphamide, and intravenous immunoglobulin, with different and controversial results (127Ar). One of the most important problems is to reduce the degree of exudation from denudated areas. In one case of TEN due to lamotrigine the application of amniotic membranes on areas of skin detachment reduced exudation and pain (128A).
Levetiracetam
(SED-15, 2035; SEDA 29, 91; SEDA-30, 82; SEDA-31, 116)
Observational studies In 2007 and the first half of 2008 more than 30 observational studies of levetiracetam in different populations of patients with epilepsy or other neurological and psychiatric diseases were published. In a prospective, 16-week, open study, levetiracetam was given as add-on therapy to 1541 adults with treatment-resistant partial seizures (129C). More than 80% (1346 subjects) completed the study, and 7.5% reported adverse events as the most important reason for withdrawing. The more common adverse effects were somnolence (19%), fatigue (14%), dizziness (8%), and headache (10%). There were serious adverse events attributed to levetiracetam in 1%. In a retrospective study of 301 patients who had taken levetiracetam since its intro duction, 138 (46%) stopped taking it during the 24-month follow-up period; adverse
138
events were responsible for 6% of cases of withdrawal (130c). The most commonly reported adverse effects at the time of with drawal were mood disorders, both activat ing (14%) and deactivating (13%), tiredness (14%), and sleepiness (8.5%). Behavioral adverse events were more common in patients with mental handicap. In a prospective, open study, levetirace tam was given as add-on therapy to adults with treatment-resistant partial seizures (131c). The dose was 500 mg bd initially, increasing to 1500 mg bd in a 4-week titra tion period, and followed by a 12-week maintenance period. Of 100 patients 92 com pleted the study and 4 withdrew because of adverse effects, the most common of which were somnolence (36%), dizziness (12%), and headache (8%). Of 379 critically ill patients studied retro spectively, 124 (35%) received levetiracetam 500–4000 mg/day, either orally or via a feed ing tube (132C). The adverse effects profile of levetiracetam was better than with other antiepileptic drugs, particularly phenytoin. For example, encephalopathy occurred in 40 patients (24%) who received phenytoin and in none who received levetiracetam. In a retrospective multicenter 4-year study of levetiracetam 8–100 mg/kg/day (mean 39 mg/kg) in 200 children with refractory epilepsies the retention rate was 49% at 1 year (133C). Adverse events were reported in 24% of the children and in no case were they serious. Emotional lability (7.5%), aggression (6%), depression (3%), and som nolence (2.5%) were the most frequently reported. There were pre-existing behavioral problems in 8%, and less than half of these children had relevant behavioral abnormal ities during follow-up. In a prospective, open, add-on, 26-week study in 33 children aged 4–16 years with refractory epilepsies, levetiracetam was given in an initial dose of 10 mg/kg/day and increased at 2-week intervals up to a maxi mum of 60 mg/kg/day (134c). The retention rate was 70%. Two children stopped taking levetiracetam because of aggressive behavior. All reported at least one behavioral, sleeprelated, cognitive, or physical problem in a standardized adverse effects questionnaire.
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The most common complaints were hyper activity (49%), somnolence (36%), irritability (33%), and aggressive behavior (27%). In a retrospective study in 81 children aged under 4 years with refractory epilep sies, levetiracetam was added to previous therapy in an initial dose of 10 mg/day and increased every week up to a maximum of 62 mg/kg/day (134c). There was at least one adverse event in 34%, most commonly drowsiness (45%), nervousness (36%), cog nitive disturbances (29%), loss of appetite (14%), and sleep disturbances (7%). There were no life-threatening adverse effects. In 129 children and adolescents with refractory epilepsy in a prospective, open, long-term study the retention rate among responders after 3 years was 23% (135c). The rate of adverse effects, which was similar in patients taking monotherapy or polytherapy, was 40% in all patients. The most frequent adverse effects during the first 6 months were fatigue (13%), gastrointestinal disorders (13%), and aggressiveness (7.8%). During long-term treatment no new adverse effects were mentioned by the parents or their care-givers. In a retrospective analysis of 122 children aged under 4 years, followed for at least 6 months, levetiracetam produced seizure remission in 70 (136c). Adverse effects occurred in 34% but required withdrawal in only 16%. The most frequent adverse effects were irritability or other behavioral disturbances (22%), somnolence (5%), diffi culty in sleeping (4%), increased seizure frequency (3.3%), and dizziness (2.5%). In a retrospective study, eight patients with non-convulsive status epilepticus were given levetiracetam, mostly via nasogastric tube, and titrated from a starting dose of 500/1000 mg bd up to a maximum dose of 2000 mg/day within 2 days (137c). The authors stressed the excellent tolerability of this drug compared with standard antiepileptic drugs in a similar population of 11 subjects treated with conventional intra venous medications. In a prospective study of 25 patients with advanced Alzheimer’s disease and new-onset epileptic seizures, levetiracetam was given in a dosage of 1000–1500 mg/day (138c). About
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70% were seizure free for at least 1 year. Four stopped taking levetiracetam because of adverse events. In two small open studies of the use of leve tiracetam for psychiatric diseases in elderly people there were excellent tolerability pro files (139c,140c). Comparative studies See also Topiramate. In a multicenter, double-blind, noninferiority, parallel-group comparison of levetiracetam and controlled-release carba mazepine as first treatments in newly diag nosed epilepsy, adults with at least two partial or generalized tonic–clonic seizures were randomly assigned to levetiracetam 500 mg bd (n = 288) or carbamazepine 200 mg bd (n = 291) (141C). The dosages were increased incrementally to maxima of levetiracetam 1500 mg bd and carbamaze pine 600 mg bd Similar percentages of patients were free of seizures at 6 and 12 months and retention at 12 months was similar in the two groups. Similar propor tions of patients in the groups had at least one adverse effect. However, fewer patients taking levetiracetam group (41/288; 14%) stopping taking therapy because of adverse effects than those assigned to carbamaze pine controlled release (56/291; 19%), although this difference was not significant. Placebo-controlled studies In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, adults and children with generalized epilepsies, who had tonic– clonic seizures despite stable doses of one or two antiepileptic drugs, were randomized to levetiracetam (target dose 3000 mg/ day for adults; 60 mg/kg/day for children; n = 80) or placebo (n = 84), and a 4-week titration period was followed by a 20-week evaluation period (142C). Levetiracetam produced a significantly greater reduction in seizure frequency. Adverse events caused withdrawal of therapy in 1.3% of patients compared with 4.8% on placebo, but the proportion of patients who had adverse effects was similar in the two groups (72% with levetiracetam and 68%
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with placebo). Psychiatric disorders were the most common drug-related adverse effects, in about 23% of patients treated with levetiracetam and 14% with placebo. Fatigue (10% levetiracetam versus 6.0% placebo), somnolence (5.1% versus 4.8%), headache (5.1%, versus 3.6%), and irritability (5.1% versus 1.2%) were reported in more than 5% of patients. Adolescents and adults with idiopathic generalized epilepsy, who had myoclonic seizures (juvenile myoclonic epilepsy or juvenile absence epilepsy) despite antiepi leptic drug monotherapy, were randomized to levetiracetam 3000 mg/day (n = 60) or placebo (n = 60) in a multicenter, doubleblind, placebo-controlled trial (143C). Two patients taking levetiracetam and one patient taking placebo withdrew because of adverse events and similar numbers of patients in each groups had at least one adverse event. Somnolence was reported in those taking levetiracetam during up-titration. In 22 children with tics, levetiracetam (max imum dose 30 mg/kg/day) or placebo were given for 4 weeks in a crossover, doubleblind, randomized, placebo-controlled trial with a 2-week washout period between treat ments (144c). Adverse effects observed during treatment with levetiracetam included irrit ability, hyperkinesia (only during the escala tion phase), insomnia, sadness, tiredness, verbal aggression, reduced school participa tion, anxiousness, and headache. Cardiovascular In a randomized, placeboand active-controlled, four-way crossover study in 52 healthy adult subjects there were no clinically important changes in the QTc interval after a single dose of levetiracetam 1000 or 5000 mg (145C). Nervous system A 28-year-old man with idiopathic epilepsy and generalized seizures developed an encephalopathy characterized by a slowing of electroencephalographic background activity, increased seizure fre quency, and worsening of neuropsychologi cal findings after starting treatment with
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levetiracetam 3000 mg/day, which had been added to valproate 2000 mg/day (146A). The effects resolved after levetiracetam withdrawal. A 5-year-old girl, with a drug-resistant symptomatic focal epilepsy developed status gelasticus after levetiracetam was added to oxcarbazepine and diazepam (147A). Psychological The effects of lamotrigine 400 mg/day and levetiracetam 2000 mg/day on anger/hostility and mood in patients with epilepsy have been compared in a randomized, double-blind, 8-week, parallelgroup study in 268 adults with drug-resistant partial seizures (148C). There were no significant differences in their effects on seizures and their overall tolerability profiles were similar. However, there were significant differences between the change from baseline to the end of the 12-week maintenance phase in the Anger–Hostility subscale score of the Profile of Mood States in favour of lamotrigine. Psychiatric Levetiracetam-induced halluci nations in the absence of underlying neurological or psychiatric disease have been reported (149A). In another case there was agitation, anxiety, and sleeplessness during treatment with valproate and levetiracetam (150A). Respiratory Interstitial pneumonitis has been attributed to a low dose of levetiracetam in a 9-year-old girl who had a history of epilepsy, cerebral palsy, mental retardation, asthma and repeated hospitalizations for presumed aspiration pneumonia (151A). Metabolism Significant weight loss associ ated with levetiracetam 500–2000 mg/day has been reported in 19 patients (152c). The authors hypothesized that significant weight loss may be a complication of treatment with levetiracetam but that it is probably limited to a small population of susceptible individuals, who remain to be characterized.
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Electrolyte balance A 76-year-old man with complex partial seizures developed asymptomatic hyponatremia after two levetiracetam challenges (153A). Hematologic In a review of studies conducted in healthy men to evaluate the effect of levetiracetam on bleeding time the authors concluded that levetiracetam does not produce clinically significant increases in bleeding time (154R). Thrombocytopenia has been attributed to levetiracetam (155A). • A 64-year-old patient with symptomatic epilepsy taking levetiracetam and valproate developed thrombocytopenia; it did not improve after valproate withdrawal but did after levetiracetam withdrawal.
Drug formulations In 2006, an intravenous formulation of levetiracetam was approved for patients with epileptic seizures who are unable to take oral medications. When intravenous infusions of levetirace tam (100 ml of a solution of 5–15 mg/ml bd over 15 minutes) were given instead of oral doses for 4 days in 25 patients with epilepsy drug-related adverse effects were dizziness, blurred vision, ear pain, dysuria, and reduced diastolic blood pressure in one case each (156c). Intravenous levetiracetam has been retro spectively assessed in 50 critically ill patients for seizure prophylaxis or treatment of seizures or status epilepticus (157c). There were no major adverse effects. Two patients without hematological disorders developed mild transient thrombocytopenia. In 18 episodes of benzodiazepine-refractory focal status epilepticus in 16 patients treated with intravenous levetiracetam (mean dose 944 mg usually given within 30 minutes) there were no severe adverse effects (158c). The use of further antiepi leptic drugs after intravenous levetiracetam was necessary in only two episodes. In two retrospective studies of the effects of intravenous levetiracetam 0–40 mg/kg/ every 8 hours for infants and every 12 hours for older children in small populations
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intravenous levetiracetam was not withdrawn because of adverse effects (159c,160c). In one study, minor adverse reactions in the days after the infusion were considered potentially related to the intravenous formulation. Most were behavioral adverse effects and in three cases there were small falls in white cell count. Drug dosage regimens In an observational study of the effects of an oral loading dose of levetiracetam 1500 mg in 37 adults with epilepsy, followed by a maintenance dose of 500–1000 mg bd starting 12 hours later, there were no spontaneous complaints of adverse effects (161c). On questioning, only four patients reported transient irritability, imbalance, tiredness, or light-headedness. Levetiracetam concentrations, performed in only some cases, were around 30 mg/l after 1–2 hours and 12 mg/l after 12 hours. Drug overdose In two children who acci dentally received doses 4 and 10 times hig her than the usual therapeutic dose of levetiracetam, there were no remarkable a dverse effects; levetiracetam was restarted after a few days with no adverse consequen ces (162A). Drug–drug interactions Antiepileptic drugs The effects of age and co-medications on levetiracetam pharmacokinetics have been retrospectively studied in 629 adult out-patients (163C). Older adults had lower clearances than younger adults and required a mean 40% lower dose to achieve the same serum concentration. Co-medication with enzyme-inducing antiepileptic drugs increased levetiracetam clearance by 24–37%. There were intolerable adverse events in about 32% of the younger patients and about 41% of the older. The most common adverse effects were drowsiness (12% versus 25%), psychiatric effects (depression, anxiety, behavioural changes) (10% versus 14%), cognitive effects (4.1% versus 7.7%), imbalance (1.2% versus 6.9%), dizziness (1.9% versus 4.4%), and headache (3.2% versus 1.9%).
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In a study of the pharmacokinetics of levetiracetam in children with epilepsy who were also taking carbamazepine or valproate, levetiracetam clearance was 7–13% faster and AUC was 15–24% less in those taking carbamazepine compared with valproate (164c). However, these small differences were not considered clinically important. Ciclosporin Lack of interaction between levetiracetam and ciclosporin has been described in a 14-year-old girl who underwent orthotopic heart transplantation, followed by antirejection therapy including ciclosporin (165A).
Oxcarbazepine (SED-15, 2646; SEDA 29, 93; SEDA-30, 83; SEDA-31, 118) Observational studies Oxcarbazepine monotherapy was given for at least 12 weeks to 35 patients with idiopathic trigeminal neuralgia unresponsive to carbamazepine (166c). There was a significant reduction in pain frequency and improved patient satisfaction, but 14 patients reported adverse effects, the most common of which were vomiting (19%), dizziness (17%), nausea (17%), and somnolence (15%). Four patients withdrew because of adverse effects. There was hyponatremia in 10 patients, but none had a sodium concentration below 125 mmol/l. Of 147 epileptic patients taking oxcarba zepine monotherapy for a median of 18 (range 14–36) months, about 60% were sei zure free for at least 12 months and under 40% were unresponsive (167c). There were intolerable adverse effects leading to drug withdrawal in about 9% of patients: Stevens– Johnson syndrome (n = 2); fatigue and drow siness (n = 2); dizziness, nausea and vomiting with normal laboratory tests (n = 2); hypona tremia (12 years). Group I com prised participants treated with vigabatrin for at least 6 months; group II participants had previously taken vigabatrin for at least 6 months and had stopped taking it for at least 6 months; group III had never taken it. Visual field loss attributable to vigabatrin was associated with duration of therapy (OR = 14; 95% CI = 5.0, 41); mean dose (OR = 8.5; 95% CI = 2.2, 33) and male sex (OR = 2.1; 95% CI = 1.2, 3.7). The relation between vigabatrin-induced visual field loss and maximum daily dose, cumulative dose and duration of dose has been investigated in 34 patients, who under went standard automated static visual field examination of the central visual field. A regression model suggested that the maxi mum dose was the only factor significantly
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correlated with individual eye severity and symmetry of visual field defect (344c). Eight patients with epilepsy and visual field loss attributed to vigabatrin had their retinal nerve fibre layer evaluated by scan ning laser polarimetry (345A). With this tech nique it is possible to perform objective measurement of the thickness of the retinal nerve fibre layer. The thickness of the retinal nerve was significantly reduced in all patients. However, this finding did not correlate with cumulative dose or time on treatment. The authors suggested that scanning laser polarimetry can be used to screen patients taking vigabatrin, especially those who may not tolerate formal field testing well. Drug withdrawal Four patients with focal cortical dysplasia and asymmetric spasms that were easily controlled by first-line vigabatrin therapy benefited from normal development. Vigabatrin was withdrawn after 1–5 years but the spasms recurred in all cases, were refractory to vigabatrin, and led to severe mental retardation (346A).
Zonisamide
(SED-15, 3728; SEDA-29, 100; SEDA-30, 99; SEDA-31, 137)
Observational studies Zonisamide as long-term adjunctive therapy in Lennox– Gastaut syndrome has been evaluated in 62 children (347c). Two had somnolence and one had anorexia and weight loss. Zonisamide in a dosage of at least 6 mg/kg/day has been assessed for 16 weeks in 30 patients with refractory pro gressive myoclonic epilepsies, more than one-third of whom had at least a 50% reduction in myoclonic seizure frequency (348c). Five patients stopped taking zonisa mide because of adverse events, the most common of which were reduced appetite, somnolence, and weakness. Zonisamide 130 mg/day has been assessed for a mean of 27 weeks in 35 out patients with bipolar disorder (349c). The most common adverse effects were nausea (19%) and sedation (25%). Treatment was
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withdrawn in six patients owing to adverse effects (nausea in two cases, abdominal pain, pulmonary embolism, diarrhea and dizziness in one each). Seven patients, five of whom withdrew early, had worsening of manic symptoms. In an open study of zonisamide as adjunctive therapy in 24 mentally retarded and multiply handicapped patients with severe childhood-onset epilepsy, 10 were still taking it after 18 months and one became completely seizure free (350c). The most common adverse event was reduced appetite in five cases. Three patients had fatigue, one reported constipa tion, one nausea, and one behavioral change. Two stopped taking zonisamide because of loss of appetite. Placebo-controlled studies In a 16-week, randomized, double-blind, placebocontrolled, flexible-dose (100–600 mg/day) trial, 60 patients with binge eating disorders and obesity took zonisamide (n = 30) or placebo (n = 30) (351c). Zonisamide was associated with a significantly greater rate of reduction in binge eating, body weight and other outcomes. There was no statistically significant difference between the treatment groups in the incidence of any particular adverse event. The most frequent were dry mouth (13 versus 10 with placebo), somnolence (12 versus 7), headache (11 versus 9), nausea (11 versus 5), and nervousness (8 versus 3). In a double-blind, randomized, placebocontrolled study of zonisamide in 20 patients with essential tremor the initial dose was 100 mg/day, increasing to 200 mg at day 14 (352c). Tremor amplitude improved signifi cantly with zonisamide. Three patients taking zonisamide 100 mg/day withdrew because of adverse effects (headache and nausea, fatigue, diarrhea, and headache). Three others taking zonisamide 200 mg/ day developed adverse effects (fatigue in one patient on day 15, mild sleepiness and headache in one patient on day 22, and paresthesia and fatigue in one patient on day 22), but none withdrew.
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In a 12-week, multicenter, double-blind, parallel-treatment, placebo-controlled study, 347 patients with Parkinson’s disease were randomized to zonisamide 25 mg/day (n = 84), 50 mg/day (n = 87), 100 mg/day (n = 87), or placebo (n = 89) as adjunctive treatment (353c). There was significant improvement in the primary end-point with 25 and 50 mg/day versus placebo. There was no significant difference in the incidence of adverse events between 25 and 50 mg/day compared with placebo, but the incidence was significantly higher with 100 mg/day. Adverse events for which the incidence was greater in the total group of patients treated with zonisamide than in the placebo group were somnolence (11%), apathy (8.5%), weight loss (6.9%), and con stipation (6.5%). Respiratory It has been suspected that co-administration of zonisamide and valproate for epileptic spasms might have exacerbated interstitial pneumonitis in a 6 month-old girl (354A). Nervous system Restless legs syndrome has been associated with zonisamide and attributed by the authors to a dopaminergic effect of the drug (355A). Dopamine receptor agonists can cause neuroleptic malignant syndrome when they are withdrawn. A patient with epi lepsy, mental retardation, and aggressive behavior taking zonisamide and carbama zepine developed a neuroleptic malignantlike syndrome after abrupt withdrawal of zonisamide (356A). The authors suggested that abrupt withdrawal of zonisamide may have caused an imbalance in dopaminergic activity, resulting in the described symptoms. Psychological In a randomized open investi gation of the long-term effects of zonisamide monotherapy on cognition and mood in 43 patients with epilepsy the final doses were 100, 200, 300, and 400 mg/day (357A). Nine patients withdrew before the follow-up
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neuropsychological test. After 1 year, 16 patients complained of cognitive deficits and 5 had mood changes. Neuropsychological tests showed that zonisamide had several negative effects on cognition. Psychiatric A patient developed psychotic symptoms after starting to take zonisamide; they improved only after zonisamide was withdrawn and antipsychotic drugs were given (358A). Metabolism Zonisamide effectiveness and tolerability has been assessed for the treatment of obesity in euthymic bipolar disorder patients (359c). Weight change in 25 patients was assessed prospectively for a maximal duration of 6 months. The mean final dose of zonisamide was 375 mg/ day (range 75–800). Mean weight loss was 1.2 BMI points. Eleven patients withdrew because of altered mood (eight with depression, two with mania, and one with subsyndromal mixed symptoms). Urinary tract The prevalence of renal calculi in patients taking zonisamide has been studied by reviewing all reports of renal calculi from four double-blind, placebo-controlled trials, their long-term open extension phases, and the US/ European zonisamide clinical trial program (360C). Pooled safety data from all clinical trials identified 15/1296 (1.2%) patients with symptomatic renal calculi during treatment for up to 8.7 years. Postmarketing surveillance revealed 9 cases from 59 667 patient-years of exposure in the USA, and 14 from 709 294 patientyears of exposure in Japan. No cases of renal calculi were reported among 59 patients taking concomitant topiramate in the clinical trial population. In the postmarketing safety surveillance database, only one patient of 25 taking zonisamide and topiramate had a renal calculus. The authors concluded that the risk of renal calculi during zonisamide treatment is low and that data are still insufficient to
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determine whether concomitant treatment with topiramate increases this risk. Skin Xerosis and pityriasis associated with zonisamide treatment have been described (361A). • A 5-year-old child developed generalized dryness and asymptomatic hypopigmented macules on her face and trunk, some with minimal erythema, after taking zonisamide for 2 months for West’s syndrome. She was managed with emollients and zonisamide was withdrawn. Both the dryness and the skin lesions improved.
The authors suggested that hypohidrosis, due to zonisamide-induced inhibition of car bonic anhydrase, may have contributed to the sudden development of xerosis and pityriasis alba-like changes. Several reports have described a close relation between HHV-6 reactivation and drug rash with eosinophilia and systemic symptoms (DRESS). Toxic epidermal necrolysis associated with HHV-6 reactiva tion has been described in a patient taking zonisamide (362A). • A 71-year-old man developed a fever and a rash over his entire body. He had been taking zonisamide 300 mg/day, added to valproate, for 23 days for epilepsy. Zonisamide was withdrawn but his condition worsened and a diagnosis of toxic epidermal necrolysis was made clinically and histopathologically. Intravenous immuno globulin 5 g/day was given for 3 days and the progression of skin lesions appeared to slow. However, 9 days after the onset, the eruption recurred, accompanied by a high fever. HHV-6 IgG antibody titers and HHV-6 DNA concentration greatly increased between day 4 and day 22. Three weeks after the onset, the condition resolved.
Drug–drug interactions Antiepileptic drugs Zonisamide is mainly metabolized by CYP3A4. Relevant drug–drug interaction studies have been reviewed (363R). Zonisamide has no effect on the steady-state pharmacokinetics of carbamazepine, phenytoin, sodium valproate, or lamotrigine. However, enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and
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phenobarbital) increase its clearance and this interaction may necessitate a dosage increase. Lamotrigine Neither zonisamide nor lamotrigine concentrations are likely to be influenced by co-administration. Topiramate Zonisamide and topiramate are both weak inhibitors of carbonic
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anhydrase and may independently increase the risk of renal calculi. When they are co-administered, there is a theoretical poten tial for an adverse pharmacodynamic interaction. Valproic acid Valproic acid, which is an enzyme inhibitor, may marginally increase zonisamide concentrations without clinically significant effects.
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A.H. Ghodse and S. Galea
8
Opioid analgesics and narcotic antagonists
Note on receptor nomenclature: Opioid receptors, originally called , and µ recep tors, then OP1, OP2 and OP3 receptors, have also been called DOR, KOR and MOR respectively.
GENERAL The World Health Organization (WHO) guidelines for pain relief recommend a three-step analgesic ladder depending on persistent or increasing pain (1S). The effect of extending the WHO guidelines to include evaluation of adverse effects of opioids has been explored prospectively (2C). Patients may report lack of response to opioids not only because of poor analgesic efficacy but also because of intolerable adverse effects. The authors propose a five-step analgesic and adverse effects ladder, with opioid switching recommended if less than 30% pain relief from morphine has been achieved or if a patient has marked confu sion or hallucinations, marked drowsiness or a significantly dry mouth. Prescribing opioids, even in the longer term, for appropriate clinical indications is clinically appropriate and should be accom panied by adequate clinical inquiry and doc umentation (3R). However, physicians may be reluctant to prescribe opioids because of Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32008-3 2010 Elsevier B.V. All rights reserved.
fear of having to deal with inappropriate demands from patients, fear of monitoring by authorities, the risk of diversion and the risk of serious direct adverse events, such as respiratory depression and death. Continu ous opioid therapy is not indicated for the treatment of chronic headache. The role of anesthesiologists in facilitat ing recovery and reducing hospital stay has been reviewed (4R). Attention to minimiz ing the adverse effects of opioids, while ensuring adequate pain relief, is one aspect linked to improved patient care. The quality of pain management with opioids has been explored in 59 patients with cancer and the frequency of adverse effects described (5c). The most frequent adverse effects were constipation, nausea, vomiting, xerostomia, sweating, confusion, cognitive dysfunction, and sedation. Of these, only nausea, vomiting and constipation were treated, highlighting the potential for improv ing patients’ experiences of treatment.
Frequency of adverse reactions to opioid analgesics The prevalence of adverse consequences to continuous opioid administration has been reviewed (6R). The most common adverse effects in patients taking prescribed opioids for chronic non-malignant pain are nausea, vomiting, constipation, dry mouth, dry skin, pruritus, and drowsiness or dizzi ness. Longer-term adverse effects include cardiac problems, opioid-induced hyperalge sia, cognitive dysfunction, hypogonadism, immunosuppression, and drug dependence.
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Adverse effects tend to be experienced by about 50% of those taking the prescribed medication and about 20% stop treatment as a result. Those who take opioids conti nuously tend to have more adverse effects than those who take them intermittently (7R). In another review article a higher pre valence has been reported in 59% of those who have taken opioids for less than 3 months and 73–90% of those who have taken them for more than 3 months (3R). Opioid-induced adverse events affect the length of hospital stay and health-care costs. Among patients admitted for surgery, 1.8% had adverse events, causing 7.4% higher overall hospital costs and 10% longer hospi tal stays (8C). Rates of adverse effects vary with the opioid used (9C). In 5684 subjects taking long-acting opioid analgesics, including extended-release oxycodone, methadone, extended-release morphine, and transdermal fentanyl, those who took extended-release oxycodone were 33% less likely to require emergency treatment for adverse effects than those who took extended-release morphine and 23% less likely to require hospitaliza tion; they had a 41% lower risk of constipa tion and a 29% lower risk of death. Fentanyl was associated with higher requirements for emergency opioid-related treatment. Metha done was associated with a higher risk of overdose than extended-release morphine. Constipation occurs in 52–65% of those taking opioids and tolerance does not develop (3R). Those aged over 65 years are 7.33 times more likely to develop constipation if they take modified-release oxycodone rather than transdermal fentanyl (10R). There was a clear link between the use of opioids, in particular naturally occur ring opium alkaloids, and the risk of post operative paralytic ileus in a case-control study in 180 279 subjects (11C). The risk increased from 1 in 500 to 1 in 185 in patients using opioids during their hospital admission. Nausea occurs in 50–54% of patients, and tolerance develops after several days (3R). Vomiting occurs in 26–29% of patients (3R). Dizziness occurs in 24–25%. Tolerance to the sedating effects tends to develop
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within a week of starting treatment (3R). The use of morphine and other opiates is associated with a risk of fractures, due to falls related to dizziness (12R). The use of opioids in relation to the risk of fractures has been reviewed (10R). There are conflict ing views; one study reported a reduced risk of falls and fractures with opioids but another provided odds ratios that suggested an increased risk (morphine 1.47, fentanyl 2.23, methadone 1.39, oxycodone 1.36, tra madol 1.54, codeine 1.16, and buprenor phine 0.86). The most commonly abused opioids are oxycodone, hydrocodone, hydromorphone, methadone, and morphine. The prevalence of addiction in those treated with opioids for pain control is reported to be the same as in the general population (6–10%); how ever, the risk of diversion remains signifi cant, especially with some opioids, such as oxycodone (3R). Sustained-release oxycodone is reported to have the highest opioid attractiveness and fentanyl patches the lowest (7R). Oxytrex, a combination of oxycodone and naltrexone, minimized the potential for physical dependence (12R). Characteris tics associated with increased risk for abuse in chronic non-malignant pain include male sex, young age, a history of alcohol or cocaine abuse, associated mental health problems, multiple pain regions and pain from motor vehicle accidents (7R). Other vulnerable groups include anesthetists. In this group, second-hand exposure was offered as an explanation for the increased incidence of fentanyl abuse (12R).
Cardiovascular Cardiac problems associ ated with opioid use include QT interval prolongation, especially with methadone, and cardiac wall motion abnormalities and reduced left ventricular ejection fraction, which have been reported after abrupt withdrawal of oxycontin. QT interval prolongation has also been reported with buprenorphine and naloxone when combined with antiretroviral drugs in HIVnegative and opioid-dependent subjects (7R, 12R). The active metabolite of
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dextropropoxyphene, norpropoxyphene, causes prolongation of the QRS interval and ventricular dysrhythmias, including ventricular fibrillation. These effects of norpropoxyphene, combined with the respiratory depressant effects of dextro propoxyphene, increase the risk of death from overdose (13R). Respiratory Respiratory depression and drug-related deaths are linked to the amount of opioid ingested, the speed of absorption, the route of administration, the degree of tolerance of the individual and other modulating factors, such as sex and greater respiratory depressant effects being observed in women (13R, 14R). Other respiratory depressants, such as propofol, sevoflurane, midazolam, and ethanol, have synergistic effects on respiratory depression when they are combined with opioids (14R). Other conditions increase the risk of respiratory depression, including sleep apnea, pulmonary disease, and other serious medical conditions (3R). Naloxoneinsensitive respiratory depression can occur with high doses of buprenorphine, especially when it is combined with a benzodiazepine (12R). Tramadol has less respiratory depressant potential than equianalgesic doses of pethidine or oxycodone; however, tramadol-induced respiratory depression has been reported in patients with renal insufficiency (14R). Opioid toxicity and respiratory depres sion can occur in individuals who illegally carry drugs in packets inserted in the mouth, rectum and vagina (body packers). In one case 81 packets containing opium were inserted abdominally and required surgical removal; the individual had respiratory distress and loss of conscious ness (15A).
Nervous system Opioid-induced hyper algesia, generally attributed to morphine, can also be associated with other opioids, especially short-acting opioids, such as remifentanil. Opioids can cause hyperalgesia, even after short-term use,
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through triggering of a sensitization process that can last several days (10R, 16R). • A 54-year-old man with hepatocellular carcinoma was initially given oral oxycodone modified-release 800 mg 8-hourly with hourly rescue doses of 200 mg, switched to oral methadone 225 mg 8-hourly with buccal fentanyl 800 micrograms hourly as required and then switched to intravenous methadone 30 mg/hour with an additional 10 mg every 15 minutes as required; he developed opioidinduced hyperalgesia (17A).
The presence and nature of opioid-induced hyperalgesia has been studied in 110 patients (58 men and 52 women) with either cancerrelated or non-cancer-related pain (18C). There was no evidence of opioid-induced hyperalgesia in cold pain measures, but there was significantly less diffuse noxious inhibitory control in those who received opioids compared with those who did not. This difference was sex-specific and was sig nificant in men but not women. Psychological Opioid-treated individuals have impaired reaction times, psychomotor speed, and working memory (7R). However, such changes are generally modest. In one study there was modest impairment in digit span test and clock drawing test in 14 patients with cancers treated with opioids, indicating impaired attention, concentration, working memory, and executive abilities (19c). Such impairments could influence treatment comprehension and compliance. Despite modest changes, the differences were not significant, possibly because the sample was small. Impaired ability to drive has social and legal implications; however, most studies of opioids have failed to show impaired driv ing ability (3R). Psychiatric The association between opioid use and delirium, especially in patients with cancer, warrants recognition. In one study 114 hospitalized cancer patients had a 40% higher risk of delirium when receiving high doses of opioids (over 90 mg morphine equivalents/day)
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compared with lower doses. There were 667 delirium events (six per patient) (20C). Gastrointestinal Opioid-induced bowel dysfunction results in a range of symptoms, including constipation, bloating, abdominal cramps, delayed and reduced gastric emptying and formation of hard stools. It has been suggested that clinicians should encourage patients to discuss such adverse effects, to facilitate optimal management, pain control and medication compliance (21R). Sexual function Hypogonadism has been attributed to opioids, especially with intrathecal administration (7R, 10R, 22R). Reduced libido in both men and women, impotence in men and amenorrhea or irregular menstrual cycles have been reported. Sexual dysfunction is a recognized com plication in the treatment of opiate depen dence. The incidence of sexual dysfunction in those dependent on heroin has been com pared with that in those on methadone or buprenorphine treatment for opiate depen dence (23C). Those who used heroin (n = 30) and those who used methadone (n = 33) reported significantly higher levels of sexual dysfunction than those who used buprenorphine (n = 28). Forms of sexual dysfunction that occurred with statistically significant differences between buprenor phine, heroin, and methadone included loss of sexual desire (57% heroin, 58% methadone, 7.1% buprenorphine); loss of sexual fantasies (33% heroin, 15% metha done, 7.1% buprenorphine); erectile impo tence (33% heroin, 24% methadone, none with buprenorphine); premature ejaculation (57% heroin, 42% methadone, 21% bupre norphine); loss of penis angulation (50% heroin, 70% methadone, 21% buprenor phine); and loss of morning erection (47% heroin, 24% methadone, 11% buprenor phine). Other forms of dysfunction that did not differ across the drugs included loss of dream erection, inability to ejaculate and ejaculation with a soft penis.
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Immunologic Codeine, fentanyl, metha done, morphine, and remifentanil have the most immunosuppressive potential of all opioids, whereas hydromorphone, oxycodone and tramadol are less immuno suppressive and buprenorphine has no immunosuppressive effects (7R, 10R). Drug abuse The abuse of prescription drugs is on the increase. It is suggested that physicians set up systems that support safe prescribing, including measures such as use of tamper-proof prescription pads, monitoring and addiction screening to identify patients at risk of dependence (24r). In veterans taking opioids for chronic non-cancer pain, a history of nonopioid substance abuse is an uncommon but strong susceptibility factor for opioid abuse, whereas a history of mental health problems is common but presents only a moderate risk of opioid abuse (25C). Drug tolerance and dependence In most patients using prescribed opioids, dose escalation is needed because of tolerance, especially in younger patients with nociceptive pain, but does not tend to be a major problem (7R). Drug withdrawal Common symptoms of withdrawal in patients receiving opioids include deep bone pain, increased pain, and muscle aches (7R).
Susceptibility factors Diseases The manage ment of pain by individuals with cognitive impairment, such as dementia, is complicated by the fact that such individuals generally find it difficult to communicate clearly; in addition, adverse effects tend to be more prevalent in individuals with dementia (26R). Opioid-related adverse effects that tend to be more prevalent in this population include worsening of cognitive impairment, sedation, problems with balance and constipation. Pethidine has been associated with delirium, and
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propoxyphene with ataxia and dizziness. Such opioids should be avoided or prescribed with caution. Attention should also be paid to other associated problems, such as renal impairment, which could result in increased serum concentrations of opioids. Opioid rotation has been suggested as one way of mitigating adverse effects. Constipation tends to be a common problem and so the administration of prophylactic bowel regimens is recommended.
Drug overdose Chronic morphine pre treatment reduces the potential for morphine-induced, but not heroin-induced, death after overdose. Prescribing naloxone for injecting heroin-users as a public health measure has been reported to be associated with reduced heroin-related deaths. There was a positive correlation between methadone-related deaths and positive urine testing for tricyclic anti depressants and benzodiazepines (12R). In an epidemiological study on acute poi soning among the indigenous population of Tehran, opium (74%) was the most com mon cause of acute poisoning (27C). This prevalence is significantly higher than other causal agents such as hypnosedatives (33%), psychotropic drugs (27%), methanol (65%), and ethanol (35%). Other opioids included heroin (15%), morphine (3.4%), codeine (3.1%), methadone (2.3%) and pethidine (2.3%). The overall death rate was 1.3%.
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When alfentanil was used there was oxygen desaturation in 11, and 9 required supplementary oxygen, compared with 3 when ketamine was used. Drug–drug interactions Propofol The combination of propofol (2 mg/kg) and alfentanil (10 micrograms/kg), used as anesthesia in a 10-year-old child undergoing ambulatory laser therapy, was associated with bradycardia and cardiac arrest (29A). The child was taking long-term methylphenidate for attention deficit hyperactivity disorder. The authors postulated that chronic methylphenidate use depleted stored noradrenaline and dopamine, resulting in a blunted sympathetic response, which, in the presence of propofol and alfentanil, could have serious consequences.
Codeine
(SED-15, 880; SEDA-31, 156)
Drug formulations Tylenol No. 3, which contains paracetamol (acetaminophen), codeine and caffeine, has been compared with paracetamol and ibuprofen in the management of pain after outpatient general surgical procedures. Of those who received Tylenol No. 3 (n = 74), more had more adverse effects (58% versus 41%), mostly resulting from a higher incidence of nausea (16% versus 7%), and more withdrew because of adverse effects (11% versus 3%) (30C).
Dextromethorphan (SED-15, 1088; SEDA-29, 105; SEDA-30, 109; SEDA-31, 158) OPIOID RECEPTOR AGONISTS Alfentanil
(SED-15, 72; SEDA-31, 153)
Respiratory Alfentanil (20 micrograms/kg) and propofol (2 mg/kg) have been compared with propofol (2 mg/kg) and ketamine (1 mg/kg) in a prospective crossover study in 20 patients aged 2–15 years undergoing lumbar puncture (28c).
Psychiatric Dextromethorphan-induced psychosis has been described in a 66-year-old man with no previous history of psychiatric disorders who was a poor CYP2D6 metabolizer (31A). He developed auditory hallucinations associated with near fatal suicidal behavior, after taking excessive amounts of a cough syrup containing dextromethorphan (1575 mg/day, gradually increasing to up to 3150 mg/day). Cough syrup should be recommended with
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caution in elderly patients, who may be more susceptible to adverse effects. Drug overdose Dextromethorphan toxicity was reported in a 20-year-old man after free-basing of dextromethorphan using the ‘Agent Lemon’ technique (1 g of liquid free-base dextromethorphan) (32A). He became unresponsive shortly after ingestion and developed hypotension and shallow respiration, which did not respond to naloxone and flumazenil. He then developed flushing, axillary sweating, hypoactive bowel sounds and dilated pupils with a sluggish response to light. He became agitated and tremulous and had myoclonic jerks, hypertension and tachycardia. His symptoms abated after 13 hours.
Interference with diagnostic tests Dextro methorphan and its metabolites gave a false-positive result for phencyclidine using the ‘instant-view multi-test’ in a urine sample from a 24-month-old girl with ataxia and generalized seizures who had acciden tally ingested dextromethorphan; the urine concentration of dextromethorphan was 5.1 mg/l (33A).
Diamorphine (heroin) (SED-15, 1096; SEDA-28, 106; SEDA-29, 106; SEDA-30, 110; SEDA-31, 158) Cardiovascular Cardiomyopathy has been attributed to heroin. • A 23-year-old man developed generalized weakness and edema in both legs after using heroin. Over the next 24 hours he had reduced urine output and respiratory distress, which required intubation and mechanical ventilation. A chest X-ray showed pulmonary edema. Electrocardiography showed T wave inversion in leads V3–6. He had raised activities of AsT (1337 U/l), AlT (1732 U/l), LDH (5280 U/l), creatine kinase (72 500 U/l) and creatine kinase MB isoenzyme (2225 U/l), and raised serum concentrations of creatinine (600 µmol/l) and urea (27 mmol/l). An echocardiogram showed severe global systolic left ventricular dysfunction with
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an ejection fraction of 15%. Cardiac catheterization showed pulmonary edema. He was given intravenous dobutamine and continuous venovenous hemofiltration. His cardiac output gradually improved. On day 8 he developed abdominal pain and a fall in hematocrit. A large retroperitoneal hematoma was found on an abdominal computed tomography (CT) scan. Angiography showed multiple small aneurysms in the upper of the two left renal arteries. Embolization of the vessel was successful and he improved gradually. Four months later, he still had a reduced left ventricular ejection fraction of 45%.
Nervous system Neurotoxicity resulting from chronic heroin use has been explored in 15 heroin-dependent patients (34c). These patients had reduced concentrations of nerve growth factor and brain-derived neurotrophic factor, both of which are postulated to influence the survival of neurons, suggesting that they may have a role in neurotoxicity associated with heroin use. • A 45-year-old man developed a generalized dyskinetic syndrome, impaired vision and severe parkinsonism 24 hours after snorting heroin (35A). Brain imaging showed grey matter lesions in the basal ganglia and cerebral cortex. It is unclear whether these lesions were caused by the heroin itself or by additives.
Skin Necrolytic migratory erythema has been reported in a heroin smoker (36A). • An 18-year-old woman developed a rash similar to recurrent seborrheic dermatitis, with well-demarcated erythema, pustules, and hair loss over the scalp. Topical steroids, systemic antibiotics, antifungal agents and descaling measures produced some improvement. During the next 12 months, she had erythematous, scaly, weepy rashes, which waxed and waned in the axillae and toe webs. Skin scrapings were repeatedly negative for fungi. Two years later, she again developed the rash in the groins and perineal area as well. She admitted to smoking heroin, underwent detoxification, and enrolled in a methadone programme. Blood tests for hepatitis and HIV were negative. The rash persisted. Six months later, she developed septicemia secondary to cutaneous Herpes simplex and staphylococcal infection in the groin and had recurrent viral and bacterial infections. A biopsy from the groin area showed psoriasiform features and vacuolar
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changes. The methadone was slowly withdrawn and 4 months later the rash had cleared and her hair had completely re-grown. When she was re-challenged with methadone twice, the rash returned.
The role of opiates in the development of necrolytic migratory erythema is unclear; however, the association is important to recognize.
Musculoskeletal Rhabdomyolysis has been attributed to heroin in 3.6% of 181 patients (37c). • A 23-year-old man inhaled heroin and developed rhabdomyolysis and cardiogenic pulmonary edema, complicated by spontaneous rupture of a renal artery aneurysm, resulting in retroperitoneal hemorrhage (38A).
Infection risk Infection due to Clostridium botulinum following subcutaneous or intramuscular injection of heroin (‘skin popping’) by opiate-abusers has been described in 12 patients (39c). In 58% cranial nerves were affected, resulting in mydriasis, diplopia, dysarthria, and dysphagia, followed by paralysis of proximal muscles and respiratory muscles, requiring mechanical ventilation for a mean duration of 27 days. Five were given trivalent equine antitoxin. The authors speculated that contamination had probably occurred during the preparation of the heroin. Drug withdrawal Protracted abstinence syndrome following withdrawal of heroin, consisting of craving, negative mood, and physiological changes, has been investigated in 70 former heroin-users (40C). Some were using short-term methadone, others long-term methadone; some were in the 15–45-day period of being opiate-free after methadone-assisted detoxification and some were 5–6 months after methadone-assisted detoxification. The symptoms of protracted abstinence were worse in those within the 15–45 day period and best (especially mood) in those using long-term methadone.
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Fetotoxicity The use of heroin and methadone during pregnancy is associated with an increased risk of sudden infant death syndrome. In a study of 563 HIVinfected mothers over a 13-year period there were 24 infant deaths. Of these, 10 were associated with maternal opiate use during pregnancy and another 4 with use before pregnancy. The relative risk of sudden infant death syndrome was 69 in those with intra-uterine exposure, compared with the general population incidence of 0.82/1000 (41C). Diamorphine as a single dose of 7.5 mg intramuscularly during labor in 100 women was associated with low Apgar scores and resuscitation in neonates (42C). There were low Apgar scores in 20 neonates, and 14 needed resuscitation. The interval between the administration of diamorphine and deliv ery influenced adverse events. Susceptibility factors Genetic In 281 Spanish methadone-maintained heroindependent patients, there was an association with heroin dependence in the A1–A1 genotype, regardless of sex, and in the A1 allele in men (43C). Drug contamination Heroin intoxication causes a classical syndrome of respiratory and central nervous system depression with pupillary constriction. However, modification of the street drug with other substances can result in unusual or atypical presentations. Adulteration is the intentional addition of a pharmacologically active substance in an attempt to use less of the active drug without the user being aware. Aluminium The use of illicit heroin has been associated with aluminium (44c). Current (n = 27) and past (n = 23) users of illicit heroin had significantly higher concentrations of urinary aluminium than controls. This was believed to be due to drug contamination and volatilization, which facilitates passage of heroin into the blood.
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Clenbuterol Clenbuterol adulteration of heroin has been recognized as a public health problem in the USA (45c, 46A, 47r). Clenbuterol is a long-acting beta2 adrenoceptor agonist used to treat asthma and illegally by body-builders because of its anabolic properties. Exposure to clenbuterol-containing heroin can cause nausea, chest pain, palpitation, shortness of breath, and tremor. Physical findings include tachycardia and hypotension. Significant laboratory effects include hyperglycemia, hypokalemia, and lactic acidosis. The adverse effects of adulteration of her oin with clenbuterol in the context of heroin abuse have been reported in 34 probable cases of clenbuterol contamination (48c). Sympathomimetic effects, metabolic acidosis, and myocardial injury were described. Expo sure was confirmed in 13 patients, with clenbuterol concentrations of 2.4–26 µg/l in the blood and 9–13 µg/l in the urine. This study highlights the importance of a public health approach to identification of trends. In six cases there was evidence of myocardial damage from increased troponin concentra tions. In 10 cases beta-adrenoceptor antago nists caused resolution of symptoms. Fentanyl Substitution of fentanyl for heroin has resulted in morbidity and mortality (47r). During 12 months in 2006–2007, the Philadelphia County Medical Examiner’s office records included over 250 overdose deaths associated with fentanyl exposure. In this case, apparent heroin overdose is naloxone-resistant. Drug overdose Although heroin is responsible for most illicit drug-related deaths, the leading cause of death being accidental overdose, only 2–4% or about 1 in 20 overdoses end in death. Among the heroin-using population, serious clinical outcomes include bronchopneumonia, pulmonary edema, rhabdomyolysis, renal failure, cognitive loss and trauma. In a study in Australia, the pattern of non-fatal overdose and the effect on subsequent
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overdoses in heroin-users was investigated (49C). About 387 heroin-users, who were recruited for the Australian Treatment Outcome Study (ATOS), a study of treatment for heroin dependence, were interviewed at 12, 24, and 36 months. Before the ATOS, 55% had had a heroin overdose, 36% had had multiple overdoses and 40% had been given naloxone. Heroinusers not receiving treatment were also recruited. ATOS recruits were from programmes that provided methadone/ buprenorphine maintenance treatment, drug-free residential rehabilitation or detoxification. At 36 months, 52% continue to be enrolled in a treatment programme. Compared with the entry year, the rates of heroin overdose were substantially lower in the subsequent 3 years. In the first 12 months, rates of heroin use, overdose, and naloxone administration fell and then became stable. During follow-up, 19% reported a heroin overdose and 12% reported having received naloxone; 10 took more than one overdose. A history of an overdose in the previous year was the strongest predictor of a subsequent overdose. The authors suggested that the data and trends in overdose frequency justify screening heroin-users for histories of recent overdose for clinical management and prognosis. Diagnosis of adverse drug reactions A 39-year-old man with a 2-year history of regular heroin use died 6 days after heroin overdose. His bile contained morphine 21 mg/l and his hair 4.8 µg/g, but morphine was absent from blood, urine and the liver. These findings suggest that enterohepatic recycling does not play a role until about 144 hours after the last dose of heroin and that the gall bladder acts as a storage depot, in which high concentrations of morphine suggest regular use of heroin (50A).
Dihydrocodeine
(SED-15, 1125)
Comparative studies Dihydrocodeine has been compared with nabilone, a synthetic cannabinoid, in the treatment of chronic
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neuropathic pain (51C). Dihydrocodeine provided better pain relief and was associated with fewer adverse effects. Only tiredness and nightmares were more frequent with dihydrocodeine. Sexual function A 42-year-old woman with a 2-year history of dihydrocodeine abuse (600–750 mg/day with peak ingestion 1350 mg/day) developed secondary amenor rhea and serum gonadotrophin concentra tions consistent with hypogonadotrophic hypogonadism (52A). All other investigations were normal. Her menses returned sponta neously 3 months after dosage reduction.
Fentanyl
(SED-15, 1346; SEDA-29, 106; SEDA-30, 110; SEDA-31, 159)
Observational studies The addition of transdermal fentanyl in 226 patients with severe pain from rheumatoid arthritis improved pain relief, function, sleep, well-being, and patient satisfaction (53C). Adverse events were experienced by 39 patients (17%) and 10% stopped taking the treatment. The most frequent adverse events were nausea and vomiting; others included dizziness, sedation, and constipation. Combinations of varying doses of fen tanyl with bupivacaine have been com pared with bupivacaine alone in 58 infants undergoing lower abdominal and urologi cal surgery (54c). The treatments were 0.5% hyperbaric bupivacaine alone and bupivacaine þ fentanyl 0.25, 0.5 or 1 µg/kg. There was no significant difference in adverse effects across the groups. There was pruritus in three infants who received fentanyl. The safety and efficacy of patientcontrolled analgesia (PCA) using fentanyl 1 microgram/kg plus continuous intrave nous infusion of midazolam 2 micrograms/ kg/minute have been explored in 16 chil dren with moderate to severe postoperative pain (55c). Minor adverse effects occurred in 25%. Two had pruritus, one a
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maculopapular rash, and one vomiting. There were no problems related to PCA. In a similar study on PCA, fentanyl 1 microgram/kg/hour þ booster doses of intravenous fentanyl 1 microgram/kg were given to 18 children with moderate to severe pain (56c). Adverse effects were reported by 39% and included pruritus (17%), vomiting (11%) and rashes (11%); there were no major adverse effects. In a prospective open trial in 81 patients with moderate to severe osteoarthritis, transdermal fentanyl 25 micrograms/hour was associated with mild to moderate adverse effects (57c). Treatment was with drawn in 32 patients because of nausea, vomiting, or dizziness. Systematic reviews Transdermal ionto phoretic fentanyl was as effective as morphine PCA in the management of acute postoperative pain, but was associated with fewer treatment failures related to adverse events, less pruritus and less somnolence (58M). Cardiovascular Midazolam (median dose 0.11 mg/kg) and fentanyl (median dose 2.77 micrograms/kg) were given intravenously to 1226 children, mean age 9 years, undergoing endoscopy; there were mild to moderate cardiovascular events, mainly hypertension and hypotension, in 10% (59C). Patient-controlled epidural analgesia consisting of 0.16% ropivacaine þ 3.5 micro grams/ml fentanyl (n = 25) has been com pared with epidural boluses of 0.1% methadone 4–6 mg 8-hourly (n = 24), in con trolling acute post-thoracotomy pain (60c). Fentanyl þ ropivacaine caused more hypo tension during the first postoperative hour. Respiratory The combination of midazolam þ fentanyl in 100 children caused adverse events in 25%, with respiratory events in 9% (59C). Most of the respiratory events were mild to moderate, and apnea occurred in two patients.
192 • Severe respiratory depression simulating a stroke occurred in a 78-year-old woman on PCA with fentanyl after routine surgery for endoluminal graft repair for abdominal aortic aneurysm (61A). The fentanyl analgesia was programmed at 20-micrograms doses with 5 minutes lockout, resulting in administration of 600 micrograms of fentanyl 16 hours after the operation. She had a slightly impaired renal function (creatinine 167 µmol/l) and a history of obstructive sleep apnea, which together with the fentanyl contributed to the development of respiratory depression.
Intravenous fentanyl is often associated with a reflex cough. In 300 adults under going elective surgery, intravenous fentanyl 2 micrograms/kg in 2 seconds was followed by cough in 39%. Perioperative administra tion of clonidine 2 micrograms/kg reduced the incidence of cough to 17% (62C). Low-dose intravenous ketamine (0.15 mg/kg) reduced fentanyl-induced cough and the time of onset of cough in a placebocontrolled study in 360 patients undergoing elective surgery who received fentanyl 1.5 micrograms/kg in 5 seconds (63C). Nervous system Serotonin syndrome occurred in a 25-year-old man who was given intrathecal fentanyl (64A). The authors suggested that the combination of fentanyl with dihydroergotamine, which the patient was taking for migraine, precipitated the serotonin syndrome and that his illicit use of 3,4-methylenedioxymetamfetamine and ephedrine exaggerated the clinical symptoms. In a comparison of propofol þ ketamine and propofol þ fentanyl for analgesia in children aged 5–60 months, both regimens produced sedation and analgesia, but there was more restlessness (in seven patients) among those who received propofol þ fentanyl (65c). Drug abuse Oral/transmucosal abuse of transdermal fentanyl patches has been reported and can be fatal. In seven cases of fentanyl-related deaths after oral administration of fentanyl patches, blood fentanyl concentrations were 7–97 µg/l
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(66c). Fentanyl alone was considered responsible for two of the deaths, and the combination of fentanyl, ethanol, other substances, and medical causes was causative in the others. Fetotoxicity Fentanyl can cause impaired infant feeding after birth (67R). Drug administration route A novel fenta nyl transdermal matrix patch 12.5 micro grams/hour has been studied in 87 patients with cancer pain; there was no increase in the incidence of adverse events (68c). Fentanyl buccal tablets using OraVescent® technology have improved the systemic availability and speed of drug delivery (69R). Adverse effects include local irritation, erythema, pain, and oral ulcers. Systemic adverse effects include nausea and dizziness. Accidental overdose can cause loss of consciousness. It is easy to swallow the tablet accidentally, and prescribing should be accompanied by appropriate education. The administration of bupivacaine þ fentanyl epidural analgesia during labor and Cesarean section precipitated transi ent Horner’s syndrome in a 29-year-old woman at 39 weeks gestation, perhaps because of upward spread of the anesthetic within the epidural space (70A). Drug overdose A 1-year-old girl died from fentanyl intoxication after accidental ingestion of a transdermal patch containing fentanyl 4.2 mg; the blood concentration of fentanyl was 5.6 µg/l and norfentanyl 5.9 µg/l (71A). Drug–drug interactions Antifungal azoles The interaction between fentanyl and the triazole antifungal drugs voricona zole and fluconazole has been explored in a randomized study in healthy volunteers (72c). Voriconazole reduced the clearance of intravenous fentanyl 5 micrograms/kg by 23% and fluconazole by 16%. This suggests that that continuous use of fentanyl could
Opioid analgesics and narcotic antagonists
Chapter 8
have resulted in 100% increase in fentanyl concentrations, potentially causing severe respiratory distress. Midazolam Midazolam and fentanyl are frequently co-administered to induce sedation in children undergoing gastrointes tinal endoscopy. In a prospective analysis of 1226 patients, respiratory adverse events were more likely in children under 6 years of age (73C). Within the whole sample, vomiting occurred in 5%, agitation in 1%, rashes in 0.7%, apnea in 0.2%, desaturation below 92% for more than 20 seconds in 0.7%, and desaturation below 92% for less than 20 seconds in 9%.
Hydromorphone (SED-15, 1703; SEDA-28, 47; SEDA-29, 107; SEDA-31, 162) Comparative studies Hydromorphone 10 micrograms/kg (n = 20) as caudal blockade has been compared with clonidine 2 micrograms/kg (n = 20) and morphine 50 micrograms/kg (n = 20) in children aged 6 months to 6 years undergoing ureteral reimplantation (74C). Those who were given hydromorphone and morphine had significantly more nausea and vomiting (90 and 80% respectively, compared with 50%) and pruritus (70 and 75% compared with 30%) than those who were given clonidine. Endocrine Secondary adrenocortical insufficiency and secondary amenorrhea due to hypogonadotrophic hypogonadism have been attributed to hydromorphone. • A 32-year-old woman taking hydromorphone 32 mg bd and up to 2.6 mg qds as required developed fatigue, weakness, dizziness, postural hypotension, loss of weight, and amenorrhea (75A). Abnormal investigations included low plasma adrenocorticotropic hormone (ACTH), reduced serum cortisol, reduced urinary cortisol excretion, and reduced estradiol. When she was given tramadol instead, the abnormal results and symptoms resolved.
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Drug formulations Once-daily hydromor phone OROS® was well tolerated by 336 patients with chronic non-malignant pain when they were switched to OROS® from other opioids (76c). The adverse effects were those expected from opioid treatment; they were mild to moderate and occurred in 79% of patients. The most common were nausea, vomiting, constipation, headache, dizziness, and somnolence. There were severe events in 4%, but most were not considered to be related to the treatment. Drug administration route Different routes of administration of hydromorphone for postoperative analgesia in patients undergoing transabdominal gynecological surgery have been compared: hydromor phone PCA 0.2 mg every 8 minutes (n = 37), scheduled intravenous hydro morphone every 3 hours (n = 48) or scheduled subcutaneous hydromorphone every 3 hours (n = 37) (77c). More morphine was used in the PCA group, more time was spent in treatment and there were higher rates of pruritus.
Levacetylmethadol (levo-a-acetylmethadol, LAAM) Levacetylmethadol, an MOR agonist, is a congener of methadone with a longer halflife. It was developed as an alternative to methadone for the management of opioid withdrawal (78R). However, it was removed from the market throughout the European Union in 2001 because of reports of prolon gation of the QT interval and 10 cases of life-threatening cardiac disorders, including torsade de pointes (79S). At the same time, in the USA, the Food and Drug Adminis tration (FDA) required the addition of a black box warning to the drug labelling in 2001. Electrocardiographic monitoring before and periodically during therapy was made compulsory and there was a conse quent marked drop in the use of the drug. The manufacturers therefore decided to stop marketing the drug in the USA in 2003,
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although it is still approved by the FDA (80r, 81r). During levacetylmethadol induction there is a delay in opioid activity as the long-acting metabolites are formed; withdrawal medica tion must therefore usually be given during the first 96 hours of treatment to suppress opioid withdrawal symptoms adequately and prevent self-administration by the patient. Comparative studies In a randomized comparison of levacetylmethadol three doses per week and daily methadone maintenance therapy for 26 weeks in 315 patients, those taking levacetylmethadol were less likely to test positive for opioid use, both during treatment and at 26 weeks (40% versus 60%) (82C). There were no adverse events, cardiological or otherwise. In a randomized, crossover trial, 62 patients stable on methadone received lev acetylmethadol on alternate days and daily methadone for 3 months each, followed by a further 6 months during which they were free to choose between the two drugs (83C). Levacetylmethadol mainte nance was associated with a lower rate of heroin use than methadone maintenance. Most of the subjects preferred levacetyl methadol rather than methadone (27 versus 12). Their main reasons were that it pro duced less withdrawal, fewer adverse effects and less craving for heroin, and entailed fewer pick-up days. Systematic reviews In a meta-analysis of 18 comparisons of levacetylmethadol and methadone (15 randomized controlled trials and 3 controlled prospective studies), 3 were excluded because of lack of data on retention, heroin use or mortality (84M). Opioid withdrawal (11 studies, 1473 participants) was better with levacetylmethadol (RR = 1.36; 95% CI = 1.07, 1.73; NNTB = 8). Non-abstinence was less with levacetylmethadol (5 studies, 983 participants; RR = 0.81, 95% CI = 0.72, 0.91; NNTB = 9). In 10 studies (1441 participants) there were 6 deaths from a range of causes, 5 in participants assigned
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A.H. Ghodse and S. Galea
to levacetylmethadol CI = 0.59, 8.9).
(RR = 2.28;
95%
Cardiovascular Reports of torsade de pointes attributed to levacetylmethadol started to appear in 2001 (85A). • A patient whose heroin dependency was being managed with high doses of levacetylmethadol developed a prolonged QT interval and polymorphic QRS complexes consistent with torsade de pointes. The patient was taking other drugs that prolong the QT interval (fluoxetine and intravenous cocaine), and others that inhibit the P450 enzymes that metabolize levacetylmethadol and its active metabolite (fluoxetine, cocaine, and marijuana).
In a 17-week randomized, controlled trial of equally effective doses of levacetylmethadol, methadone and buprenorphine in 154 opioid-addicted subjects with normal baseline QTc intervals, 12-lead electrocardiograms were collected at baseline and every 4 weeks (86C). Levacetylmethadol and methadone were significantly more likely to prolong the QTc interval to over 470 or 490 ms or to increase the QTc interval from baseline by more than 60 ms. In a randomized, controlled comparison of levacetylmethadol with racemic metha done in 53 patients, electrocardiographic recordings were made during a run-in period when all the patients were taking methadone and 24 weeks after randomization to metha done or levacetylmethadol (87C). After 24 weeks, the patients taking levacetylmethadol had a significant increase in QT interval (409 ms versus 418 ms), whereas there were no significant changes in patients taking methadone. The effects of levacetylmethadol on the cloned human cardiac potassium channels human ether-a-go-go-related gene (HERG), KvLQT1/mink, and Kv4.3 have been studied using patch clamp electrophysiology (88E). Levacetylmethadol inhibited HERG channel currents in a voltage-dependent manner, with an IC50 value of 3 µmol/l. Its major active metabolite, noracetylmethadol, inhibited HERG channels with an estimated IC50 of 12 µmol/l. Levacetylmethadol had little or no effect on Kv4.3 or KvLQT1/minK channel
Opioid analgesics and narcotic antagonists
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currents at concentrations up to 10 µmol/l. The authors concluded that the pro dysrhythmic effects of levacetylmethadol are due to block ade of the HERG cardiac potassium channel and suggested that noracetylmethadol might be a safer alternative in the treatment of opioid addiction. Respiratory Five occasional opioid-users took once weekly doses of either placebo, levacetylmethadol or methadone (15, 30, or 60 mg/70 kg) and then received naloxone (1.0 mg/70 kg intramuscularly) 24, 72, and 144 hours after agonist exposure (89c). Three were withdrawn because of greater than anticipated and clinically relevant respiratory depression after levacetylmethadol 60 mg. Naloxone did not fully reverse the pupillary constriction produced by levacetylmethadol 60 mg. Psychiatric Of 28 heroin addicts who received levacetylmethadol instead of methadone over 6 weeks in an out-patient detoxification programme, 9 withdrew early and crossed over to methadone (90c). They had a variety of complaints, ranging from anxiety about possibly receiving an experimental drug to withdrawal symptoms and dysphoria, which they had not experienced while taking methadone. Endocrine In nine male heroin addicts who took levacetylmethadol for 5 months there was no change in plasma concentrations of testosterone and luteinizing hormone 72 hours after a dose and during 2 weeks after abrupt withdrawal of levacetylmethadol (91c). Liver In 959 opioid addicts treated with levacetylmethadol for up to 36 months, there was no evidence of long-term hepatic toxicity or tumor formation as studied by liver function studies and liver–spleen imaging (92c). Genotoxicity Levacetylmethadol was genotoxic in the ad-3 forward-mutation test
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in Neurospora crassa and weakly mutagenic in the mouse lymphoma forward-mutation assay (93E). Analysis of the ad-3 mutants showed that they were the result of a parasexual phenomenon rather than forward mutation. There was one confirmed trans location carrier in the heritable translocation study, which by conservative interpretation might imply some germ-cell risk associated with exposure to LAAM. Drug dosage regimens In a randomized, double-blind trial, 180 male and female opioid-dependent patients were assigned to one of three doses of levacetylmethadol. Low-dose induction (25 mg) was constant from the start of treatment (n = 62), medium-dose induction (50 mg) lasted 7 days (n = 59) and high-dose induction (100 mg) lasted 17 days (n = 59) (94C). There were more agonist-related adverse effects in the high-dose group. All those who dropped out because of levacetylmethadol-related adverse effects were in the high-dose group (five women and three men). The adverse effects reported included anorexia, feeling over medicated, sedated/drowsy, nausea, and vomiting. The 31 patients who dropped out averaged 14 days in treatment and had a mean dose of 53 mg. One woman in the high-dose group died during the second week of treatment and toxicological analysis showed the presence of multiple drugs, although the concentrations of levacetylmethadol, norlevacetylmethadol, and dinorlevacetylmethadol were within the expected ranges. Drug–drug interactions Levacetylmetha dol is metabolized by CYP3A4-mediated N-demethylation and CYP3A-mediated inacti vation. Its metabolites are norleva cetylmethadol and dinorlevacetylmethadol. Patients who take CYP3A4 inducers (for example, rifampicin) are susceptible to increased metabolism, reduced plasma concentrations, and withdrawal. Those taking CYP3A inhibitors (for example, troleando mycin) are susceptible to reduced metabolism,
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increased plasma concentrations and toxicity (95R). However, unexpectedly, CYP3A induction reduced and inhibition increased the concentrations and clinical effects of the active metabolites, which suggests that there is a CYP3A-mediated metabolic pathway that leads to inactive metabolites, which predominates over CYP3A-dependent conversion to the active metabolites. Antiretroviral drugs In a study in 40 patients taking methadone or levacetyl methadol, delavirdine significantly reduced methadone clearance and increased metha done half-life, with a resultant increase in the area under curve (AUC) of 19% and Cmin of 29% (96C). Delavirdine significantly increased the AUC of the total concentration of levacetylmethadol and its active metabolites, norlevacetylmethadol and dinorlevacetylmethadol, by 43%, the Cmax by 30% and the Cmin by 59%, and reduced the tmax. There were no changes in cognitive function over the 7-day study period, measured by the Mini-Mental State Examination, no opioid withdrawal symptoms, measured by the Objective Opioid Withdrawal Scale and no complaints of adverse symptoms. Neither methadone nor levacetylmethadol altered delavirdine concentrations.
Ketoconazole In vivo inhibition of CYP3A by ketoconazole altered the pharmacokinetics and pharmacodynamics of levacetylmethadol 5 mg/70 kg in a singleblind, crossover, randomized study in 13 opioid-naive subjects (6 women and 7 men) (97C). Co-administration of ketoconazole resulted in 3.22-fold and 5.29-fold increases in the Cmax and AUC of levacetylmethadol. The tmax of norlevacetylmethadol and dinorlevacetyl methadol increased 2.43 and 11.6 times, respectively, and their Cmax values were reduced to 77 and 55%. The AUCs of norleva cetylmethadol and dinorlevacetylmethadol were increased 2.25 and 1.21 times respectively. Pupil diameter was significantly reduced by levacetylmethadol after both placebo and
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ketoconazole pretreatment; ketoconazole increased the tmax for miosis 2.92 times.
Methadone (SED-15, 2270; SEDA, 107; SEDA-30, 112; SEDA-31, 163) Cardiovascular Methadone-induced long QT syndrome associated with torsade de pointes can be effectively managed by the use of implantable cardioverter defibrillators, as has been shown in eight patients on methadone maintenance (98c). • In a 40-year-old woman, torsade de pointes after an increase in daily methadone dose to 135 mg for heroin addiction was treated with cardioversion and infusions of magnesium sulfate and lidocaine (99A). • In a 52-year-old HIV-positive woman, QT interval prolongation and torsade de pointes were associated with high-dose methadone (145 mg/day) (100A). Pulseless polymorphic ventricular tachycardia was reversed by car diopulmonary resuscitation. The QT interval shortened with eventual normalization when the dosage of methadone was reduced to 80 mg/day. She was not taking other medica tions that would have increased the serum methadone concentration. • A 53-year-old HIV-positive woman stopped taking lopinavir þ ritonavir and developed QT interval prolongation and torsade de pointes (101A).
In the last case, the authors suggested that withdrawal of the protease inhibitors had led to de-induction of metabolism of methadone and increased its blood concentration. In a cross-sectional study in heroin addicts, there was an association between methadone dosage and QT interval (102C). There was QT interval prolongation in 28% of the men and 32% of the women taking methadone, associated with a higher inci dence of syncope; a 50 mg higher dose of methadone increased the odds for syncope by 1.2 times. There was no association between buprenorphine treatment and QT interval. QT interval prolongation was also found in a neonate born to a mother taking metha done (103A). Bradycardia, tachycardia, or an irregular heart rate in neonates should
Opioid analgesics and narcotic antagonists
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increase the suspicion of the possibility of QT interval prolongation.
Respiratory The relation between metha done concentrations and respiratory effects has been highlighted by the case of a 44-year old man who took 240 mg of methadone, after which he became comatose, developed respiratory depression and had pinpoint pupils. The plasma concentration of R,S-methadone was 1204 µg/l. Concentrations of R- and S-methadone fell log-linearly over time (104A). Pulmonary edema secondary to non-fatal overdose of oral methadone has been described (105A). Methadone caused severe respiratory failure and non-cardiogenic pulmonary edema. Naloxone reversed the central nervous system and respiratory depression but did not reverse the pulmon ary edema.
Nervous system Methadone ingestion by children can have serious consequences (106A). • A 3-year-old girl took methadone and developed acute atypical severe cerebellitis. She was unresponsive, had labored breathing, and was hypothermic. CT and magnetic resonance imaging (MRI) scans showed cerebellar pathology with hypoxic-ischemic injuries in a watershed distribution.
Opioid-dependent patients (n = 23) had abnormal heat and pain perception for months after successful detoxification from methadone (107C) compared with 27 patients in remission. Stable opiate-dependent individuals (10 on methadone, 14 on buprenorphine) have been compared with healthy volun teers in investigation of dysfunction of the dorsal anterior cingulated cortex asso ciated with opiate addiction (108c). The opiate-dependent patients had more taskrelated activation of the frontal, parietal and cerebellar regions and reduced concentrations of N-acetylaspartate and
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glutamate/glutamine in the dorsal anterior cingulate cortex. The abnormalities were believed to have contributed to poor inhi bitory control, which is characteristic of addictive behavior. Fluid balance A 45-year-old woman with chronic back pain was given methadone 5 mg tds plus etodolac and gabapentin (109A). After 1 week she complained of feeling ‘drunk’, had leg swelling, and felt bloated. Etodolac and gabapentin were withdrawn and the dose of methadone was increased. The edema continued to worsen. Methadone was eventually withdrawn, resulting in resolution of the edema and bloatedness. Sexual function In men taking methadone maintenance treatment (n = 84) and buprenorphine maintenance treatment (n = 19), 53% of those taking methadone had erectile dysfunction, which was moderate to severe in 26% (110C). A similarly high prevalence of erectile dysfunction has been reported in another study (111C), with an overall prevalence of 58% in 201 men (85 taking methadone maintenance and 116 taking buprenor phine). There was severe erectile dysfunc tion in 19%, moderate dysfunction in 4.7%, mild to moderate dysfunction in 7.1% and mild dysfunction in 20% of those taking methadone. About half of those taking methadone did not have erectile dysfunc tion. Those taking buprenorphine had fewer problems with erectile dysfunction (severe in 18%, moderate in 1.8%, mild to moderate in 3.5%, mild in 13%); 64% had no problem at all. Death Methadone is a potent drug with potential lethal consequences (112r), and deaths due to methadone ingestion in children are steadily increasing in frequency, as in the case of a 22-month-old child who developed fatal posterior ischemic cerebral and cerebellar changes after methadone ingestion (113A).
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Drug tolerance Eight patients maintained on methadone had cross-tolerance to remifentanil (114c). They were given intravenous remifentanil in seven increasing doses of 0.5–3.5 micrograms/kg/minute 20 hours after their last dose of methadone (range 50–110 mg/day). Antinociception was achieved, but substantially higher doses than usual of remifentanil were required. The respiratory rate fell in a dose-related manner with remifentanil infusion and returned to baseline 25 minutes after the end of the infusion. There were opiate withdrawal effects after the end of the infusion.
maternal vagal reactivity (118C). There was no association with a history of maternal substance abuse, methadone maintenance, or psychotropic drug exposure. The severity and treatment require ments in neonatal abstinence syndrome was investigated in neonates born to opioid-maintained mothers, of whom 22 were on methadone maintenance, 17 on modified-release oral morphine, and 14 on buprenorphine (119C). Treatment was required by 32 neonates (60%), most being related to methadone maintenance (n = 15) and morphine maintenance (n = 14).
Drug withdrawal Opiate-dependent patients (n = 48) admitted to a specialist in-patient drug treatment service were withdrawn from opiates using a 10-day methadone reduction schedule (115c). Patients withdrawn from higher doses of methadone reported more severe withdrawal symptoms, but the effect was not strong.
Drug–drug interactions Aspirin A 42-year old man taking long-term methadone developed chest pain due to an acute myocardial infarction after taking aspirin 330 mg/day for 3 days (120A). The underlying mechanism was unclear but could have been due to paradoxical activation of major platelet receptors during chronic methadone exposure after exposure to aspirin.
Teratogenicity Horizontal nystagmus occurred in 12 infants who had been exposed to opiates (mainly methadone and heroin) in utero (116c). Fetotoxicity Fetal exposure to methadone (n = 35) has been compared with buprenorphine (n = 47) during treatment for opiate dependence in pregnancy (117C). Exposure to methadone was associated with a higher incidence of neonatal abstinence syndrome (78% compared with 40%) and more infants required treatment for withdrawal (53% compared with 15%). It was also associated with a low birth weight and a small birth height; buprenorphine exposure was not associated with abnormal birth weight. In another study of neonatal abstinence syndrome related to intra-uterine exposure to methadone, male infants had more pro found symptoms requiring pharmacother apy and neonatal abstinence was related to
Diazepam The interaction of diazepam 0–40 mg with methadone (mean dose 69 mg) has been explored in four patients (121c). The combination resulted in increased sedation and impaired reaction times, attention and psychomotor skills. These effects peaked within the first 2 hours of administration. Oxygen saturation was also reduced when higher doses of methadone (150% of the usual dose) were used in combination. Nevirapine Nevirapine altered the pharmacokinetics of methadone in 10 HIV-positive patients (122c). Nevirapine is a potent inducer of CYP3A4, resulting in significantly reduced plasma methadone concentrations and consequent opioid withdrawal symptoms, requiring an increase in methadone dose. Nevirapine 200 mg daily and 400 mg daily produced similar effects.
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Quetiapine The plasma concentration of (R)-methadone was increased by co-administration with quetiapine in 14 patients, probably because of an interaction with CYP2D6 or P glycoprotein (123c). Voriconazole Voriconazole 200 mg bd reduced the metabolism of (S)-methadone and (R)-methadone, with a larger effect on (S)-methadone in 23 patients (124c). Voriconazole should be prescribed with caution in patients taking methadone, and dose reduction should be given consideration.
Morphine
(SED-15, 2386; SEDA-29, 107; SEDA-30, 113; SEDA-31, 164)
Observational studies Lumbar plexus blockade reduced the dosage requirements of PCA morphine and produced improved analgesia, increased patient satisfaction and decreased nausea and vomiting compared with PCA morphine alone in 17 patients undergoing hip arthroplasty (125c). The incidence of adverse effects correlated with dose. One patient developed respiratory depression. Low doses (4–5 micrograms/kg) of intrathecal morphine for postoperative pain in 187 children were generally well tolerated, and there was no severe respira tory depression (126C). There was nausea and vomiting in 32%, pruritus in 37%, and urinary retention in 6%. The addition of small doses of ketamine to morphine in PCA reduces the amount of morphine required and improves respira tory function, reducing the potential for respiratory depression. In 50 patients undergoing lobectomy, intravenous mor phine 1 mg/ml was compared with intra venous morphine 1 mg/ml þ ketamine 1 mg/ml as PCA for postoperative analgesia (127C). The addition of ketamine resulted in a significant reduction in cumulative mor phine consumption and improved respira tory function.
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Alfentanil þ morphine has been com pared with morphine alone in the treat ment of postoperative pain in 453 patients (128C). The combination provided better and earlier patient comfort without increasing the incidence of adverse effects.
Systematic reviews In a systematic review of morphine regimens in children with postoperative pain, the most common adverse effects after intravenous administra tion were nausea, vomiting, and sedation; there was no relation to morphine dosage (129M).
Respiratory Morphine can be used as an alternative to general anesthesia in infants. In a retrospective study, 109 infants undergoing laser treatment for retinopathy of prematurity were given infusions of morphine (maximum rate 40 micrograms/ kg/hour) (130C). Mechanical ventilation for morphine-induced apnea was required in only three cases. There were minor alterations in oxygen saturation ( G p. D70G and c.1615G> A p. A539T (4c). Homozygotes for the for mer (i.e. atypical or A) are the only indi viduals whose butyrylcholinesterase activity could lead to adverse reactions to suxamethonium.
NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-15,
C. Williams and M. Leuwer
concluded that suxamethonium creates excellent intubation conditions more reliably than rocuronium and should still be used as a first-line muscle relaxant for rapidsequence induction intubation. If an alternative agent is required, rocuronium can be used to create acceptable intubation conditions, but it should only be used as a second-line treatment. However, only a few studies used a dose of 1.2 mg/kg, which significantly shortens onset time compared with 0.6 mg/kg. The ability of sugammadex to reverse deep neuromuscular blockade under rocuronium may alter the benefit to harm balance in comparison with suxamethonium, which was not considered in the review.
2489; SEDA-28, 155; SEDA-31, 248)
Mivacurium
(SED-15, 2363;
SEDA-28, 155) Susceptibility factors Genetic Prolonged postoperative paralysis after anesthesia with mivacurium was successfully treated with transfusion of fresh frozen plasma, with reversal of the respiratory paralysis and complete recovery (5A). There was reduced cholinesterase activity because of a homozygous atypical and heterozygous K variant of the cholinesterase gene. Fresh frozen plasma is rarely indicated in such cases, because of the risks of transmitting infection.
Rocuronium
(SED-15, 3073;
SEDA-31, 248) Systematic reviews Because of its fast onset of action, rocuronium is a potential alternative to suxamethonium for rapidsequence intubation in patients with an increased risk of aspiration. The Cochrane review of rocuronium versus suxamethonium for rapid-sequence intubation has been updated with the inclusion of 11 additional studies (6M). When rocuronium was used, the relative risk for excellent intubating conditions was 0.86, with a NNTH of 8. The authors
Neuromuscular Prolonged paralysis has been reported after a single intubating dose of rocuronium, highlighting the clinical impact of interindividual variations in pharmacokinetics and pharmacodynamics (7A). • An 84-year-old woman, with no known co-morbidities, who was not taking any regular medications, received rocuronium 0.6 mg/kg for induction of anesthesia to facilitate endotracheal intubation. After 2 hours there was no twitch response to train of-four stimulation of the ulnar nerve, but the post-tetanic count was 8. After 193 minutes one twitch response to train-of-four stimulation was recorded, and after 215 minutes a second twitch response appeared. At this time, neostigmine 0.05 mg/ kg was given for reversal, and 8 minutes later a train-of-four ratio >0.9 was observed. She was extubated without signs of residual paralysis.
The authors suggested that the unusually long duration of action of rocuronium in this case had been caused by a combination of factors, including genetically increased sensitivity to rocuronium, advanced age, reduced liver function, female sex, and the use of sevoflurane. However the extent of prolonged paralysis after rocuronium in this patient was far outside the normal range and was not easily explained by the combination of factors listed by the authors. Muscle disease, such as mitochon drial myopathies, can cause pronounced
Neuromuscular blocking agents and skeletal muscle relaxants
sensitivity to non-depolarizing neuromus cular agents and all cases of extreme sensi tivity to muscle relaxants in apparently healthy individuals warrant further investigation.
Sugammadex Sugammadex is a modified -cyclodextrin designed to reverse the effects of rocuro nium selectively by encapsulating the aminosteroid within its lipophilic core. It is the first selective agent for binding a muscle relaxant. Sugammadex forms a stable com plex in plasma, resulting in a rapid reduc tion in effector site concentration at the neuromuscular junction. This is in contrast to conventional anticholinesterase reversal agents, such as neostigmine, which prolong the action of acetylcholine at the neuro muscular junction. Its pharmacology has been reviewed (8R–10R). Sugammadex was licensed for clinical use in the European Union in 2008. Observational studies The first exposure of sugammadex (then Org 25969) in 29 healthy volunteers produced nine adverse events (11c). All those related to sugammadex were reported to be of limited duration and mild intensity, except for a period of paresthesia of moderate intensity at the intravenous cannula site. In a phase II, dose-finding trial involving 80 ASA I and ASA II adults four adverse effects were attributed to sugammadex: one instance each of short-lived moderate tachycardia, delayed awakening by 5 minutes, erythema, and abdominal discomfort (12c). There were no serious adverse reactions. The investigators did not comment on the biological plausibility of the adverse reactions reported. Delayed awakening from anesthesia by 5 minutes would be within the variation seen in clinical practice. In a phase II dose-finding and safety study in 45ASA I–II adults there were two adverse events (diarrhea and light
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anesthesia) associated with sugammadex (13c). Light anesthesia maybe related to rapid reversal of neuromuscular block by sugammadex. In a phase I safety trial of the effect of sugammadex on the QT interval in 16 healthy volunteers there were 23 adverse events, none of which was serious (14c). All were mild or moderate in intensity and all resolved by the end of the study. Comparative studies The speed of reversal of rocuronium by sugammadex has been compared with reversal of cis-atracurium by neostigmine in 84 ASA I–III adults (15c). Four patients who were given sugammadex group (nausea in one, shivering in one, increased urinary N-acetyl glucosaminidase in two, and altered facial sensation in one patient) and one given neostigmine group (nausea) had at least one adverse reaction that the investigators attributed to the study drugs. Most of the adverse events were not considered to be related to the study drugs. Nausea and shivering after anesthesia are common adverse events. The authors did not explain their rationale for attributing nausea and shivering to sugammadex. Postoperative urinary N-acetyl glucosaminidase was raised in seven of those who received sugammadex and one of those who received neostigmine. No inferential analysis was performed on these data. Endocrine Sugammadex could encapsulate other steroidal drugs and endogenous steroids. However, the clinical relevance of this is likely to be small, as the affinity of sugammadex for these substances is up to 700 times less than for rocuronium (16E).
Susceptibility factors In a study of the safety and efficacy of sugammadex in 15 patients with end-stage renal failure (creatinine clearance less than 30 ml/minute) and 15 control patients with normal renal function there were no serious adverse effects (17c). Currently, sugammadex is not recommended for use in patients with
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significant renal impairment and further safety studies are warranted.
toxicity after accumulation of the drug secondary to acute renal insufficiency (23A).
Drug overdose A healthy volunteer who received an accidental overdose of sugammadex 40 mg/kg had no adverse effects in the 7 days after the event (18A).
Botulinum toxins
SKELETAL MUSCLE RELAXANTS Baclofen
(SED-15, 408; SEDA-30, 164; SEDA-31, 250) Observational studies In a trial of baclofen in suppressing alcohol consumption in 148 alcohol-dependent subjects with alcoholic liver cirrhosis it was well tolerated (19c).
Cardiovascular system Extreme bradycardia and hypotension has been reported in a tetraplegic patient given oral baclofen (20A). Another dose resulted in the same complications. However, this patient had a history of autonomic dysreflexia. Nervous system Recurrent transient global amnesia has been reported in a middle-aged woman after intrathecal baclofen (21A). The episodes were reduced by fludrocortisone and terminated by sublingual glyceryl trinitrate. This association has not previously been reported. Baclofen reduced hot and cold tempera ture perception in patients with spinal cord injuries (22c), consistent with experimental data in animals. This suggests a role for baclofen in the treatment of neuropathic pain. The authors did not comment on any potential adverse effects of reduced tem perature perception. Drug overdose Bicarbonate hemodialysis cleared baclofen in a patient who developed
(SED-15, 551; SEDA-29, 156; SEDA-30, 165; SEDA-31, 252) Uses The authors of a literature review of the safety and efficacy of botulinum toxin in movement disorders concluded that it should be offered as a treatment of cervical dystonia, may be offered as a treatment for blepharospasm, focal upper extremity dystonia, adductor laryngeal dystonia, and upper extremity essential tremor, and may be considered for hemifacial spasm, focal lower limb dystonia, and motor tics (24R). In a study of the role of botulinum toxin in autonomic disorders and pain the authors concluded that botulinum toxin should be offered for the treatment of axillary hyper hidrosis and detrusor overactivity (25R).
Observational studies The FDA has issued an early communication about its review of botulinum toxin A (Botox and Botox Cosmetic) and botolinum toxin B (Myobloc) (26S). The Agency says that it has received reports of adverse reactions associated with the use of these products, including respiratory compromise and death, suggestive of botulism. Most of the reported cases involved children who had received the drugs for limb spasticity in cerebral palsy, a condition for which botulinum toxins are not approved in the USA in children under 12 years. The FDA’s Adverse Event Reporting Sys tem database and the medical literature con tain reports of iatrogenic botulism in patients aged under 16 years, with serious outcomes, including hospitalization and death. No deaths were reported among adults. In cases of botulism the dose of botulinum toxin A was 6.25–32 U/kg in children and 10–700 U/kg in adults, and the doses of botu linum toxin B were 388–625 U/kg in children and 10 000–20 000 U/kg in adults.
Neuromuscular blocking agents and skeletal muscle relaxants
The Australian Adverse Drug Reaction Advisory Committee has emphasized the importance of adherence to the indications and dosing instructions in the use of botulinum toxin-containing products (27S). Botulinum toxin type A (Botox, 100 U/vial) is used for treatment of strabismus, blepharospasm, facial nerve disorders, spasmodic torticollis, various spasticity disorders, spasmodic dysphonia, axillary hyperhidrosis, and brow furrow lines. A hemagglutinating complexed form of botu linum toxin A has similar but more limited indications. Since 1994, the Therapeutic Goods Administration in Australia has received 45 reports in connection with the use of botulinum toxin, none of which have described a fatal outcome. The reactions reported are most commonly of muscle weak ness (n = 16) at sites adjacent to or distant from the injected area, including dysphagia (n = 8), respiratory failure or dyspnea (n = 3), and generalized muscle weakness (n = 7). Other reactions have included rashes or other allergic reactions, diplopia, and fatigue. Seven reports cited off-label use and 17 cited use for cosmetic reasons, but the others cited use according to approved indications. Nervous system In a double-blind, randomized, placebo-controlled trial of botulinum toxin type A injections for 12 weeks in 40 patients with writer’s cramp, the reported adverse effects were hand weakness, which was mostly mild and always transient, and pain at the injection site (28C). Despite weakness in the hand, most of the patients preferred to continue treatment. Infection risk Fournier’s gangrene has been reported in an elderly diabetic patient after an injection of botulinum toxin into the anal sphincter (29A). Diabetes mellitus in this patient probably increased the risk of this complication. Chlorzoxazone (SED-15, 735; SEDA-31, 253) Liver Chlorzoxazone has been used as a centrally acting muscle relaxant for several
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decades. However, it can cause liver damage, as highlighted by a report of severe liver necrosis requiring liver transplant (30Ar). • A 38-year-old woman developed nausea, vomiting, scleral icterus, confusion, and lethargy after taking chlorzoxazone 500 mg for 6 weeks. Serum alanine and aspartate transaminases and bilirubin were markedly raised and a transjugular liver biopsy showed acute hepatitis with bridging necrosis, severe hepatocyte ballooning degeneration, and a mixed inflammatory cell infiltrate, suggestive of drug-induced injury. As her condition did not improve, she underwent orthotopic liver transplantation. Extensive exploration revealed no other causes of liver damage.
The authors reviewed chlorzoxazone-asso ciated liver damage. So far, few cases have been reported, but some have been severe, including fulminant liver failure and death, with no obvious relation to dose. Surveil lance studies did not identify hepatotoxicity as a problem and there were no recommen dations for routine monitoring of liver enzymes.
Tetrabenazine Nervous system Tetrabenazine inhibits vesicular monoamine transporter 2, leading to depletion of dopamine and other monoamines in the central nervous system. In a retrospective chart review, 448 patients who had used tetrabenazine between 1997 and 2004 (mean age at onset of the movement disorder, 43 years; 42% men) were treated for a variety of hyperkinesias, including tardive dyskinesia (n = 149), dystonia (n = 132), chorea (n = 98), tics (n = 92), and myoclonus (n = 19) (31c). They took treatment for a mean of 2.3 years and efficacy was sustained in most cases. Common adverse effects included drowsiness (25%), parkinsonism (15%), depression (7.6%), and akathisia (7.6%). Although it has repeatedly been observed that tetrabenazine alleviates hyperkinetic movements, it can worsen parkinsonism (32R).
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Metabolism Weight gain over time has been compared in 32 boys with tics taking tetrabenazine (mean age 13 years) and an age-matched group of 41 patients (33 boys) with tics taking only antipsychotic drugs (mean age 12 years) (33c). Weight gain with tetrabenazine was 0.36 kg/month (mean follow-up duration 25 months) and with antipsychotic drugs 0.75 kg/month (mean follow-up duration 19 months).
drug safety, and effectiveness in healthy subjects and patients have been reviewed (34R). There is evidence that the relation between plasma concentrations of tizanidine and dose is linear and that the most common adverse events are related to drug concentration. A low therapeutic index and wide interpatient variability in plasma concentrations make it necessary to individualize therapy.
Tizanidine
Susceptibility factors Liver disease Tizanidine is a substrate of hepatic CYP1A2 and caused hypotension in a patient with liver cirrhosis (35A). Serum concentrations of the drug were raised.
(SED-15, 3436; SEDA-28, 157; SEDA-29, 146) Pharmacokinetics Tizanidine hydrochlor ide dose relationships to pharmacokinetics,
References 1. Holak EJ, Connelly JF, Pagel PS. Suxametho nium-induced hyperkalemia 6 weeks after chemoradiotherapy in a patient with rectal carcinoma. Br J Anaesth 2007;98(6):766–8. 2. Piotrowski AJ, Fendler WM. Hyperkalemia and cardiac arrest following succinylcholine administration in a 16-year-old boy with acute nonlymphoblastic leukemia and sepsis. Pediatr Crit Care Med 2007;8(2):183–5. 3. Guttormsen AB, Johansson SGO, Öman H, Wilhelmsen V, Nopp A. No consumption of IgE antibody in serum during allergic drug anaphylaxis. Allergy 2007;62(11):1326–30. 4. Zelinski T, Coghlan G, Mauthe J, TriggsRaine B. Molecular basis of succinylcholine sensitivity in a prairie Hutterite kindred and genetic characterization of the region con taining the BCHE gene. Mol Genet Metab 2007;90(2):210–6. 5. van Gammeren AJ, Cobbaert CM, Schrau wen CJ, Voets MA, Ermens AA. Fresh frozen plasma transfusion for reversal of pro longed post-anesthesia apnea. Transfus Med 2008;18(2):134–6. 6. Perry JJ, Lee JS, Sillberg VA, Wells GA. Rocuronium versus succinylcholine for rapid
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sequence induction intubation. Cochrane Database Syst Rev 2008;16(2):CD002788. Claudius C, Karacan H, Viby-Mogensen J. Prolonged residual paralysis after a single intubating dose of rocuronium. Br J Anaesth 2007;99:514–7. Hunter JM, Flockton EA. The doughnut and the hole: a new pharmacological concept for anesthetists. Br J Anaesth 2006;97(2):123–6. Naguib M. Sugammadex: another milestone in clinical neuromuscular pharmacology. Anesth Analg 2007;104:575–81. Bom A, Hope F, Rutherford S, Thomson K. Preclinical pharmacology of sugammadex. J Crit Care 2009;24:29–35. Gijsenbergh F, Ramael S, Houwing N, van Iersel T. First human exposure of Org 25969, a novel agent to reverse the action of rocur onium bromide. Anesthesiology 2005;103 (4):695–703. Suy K, Morias K, Cammu G, Hans P, van Duijnhoven WG, Heeringa M, Demeyer I. Effective reversal of moderate rocuronium or vecuronium-induced neuromuscular block with sugammadex, a selective relaxant bind ing agent. Anesthesiology 2007;106(2):283–8.
Neuromuscular blocking agents and skeletal muscle relaxants 13. de Boer HD, Driessen JJ, Marcos MAE, Kerkkamp H, Heeringa M, Klimek M. Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugamma dex: a multicenter, dose-finding and safety study. Anesthesiology 2007;107(2):239–44. 14. Cammu G, De Kam PJ, Demeyer I, Decoop man M, Peeters PAM, Smeets JMW, Fou bert L. Safety and tolerability of single intravenous doses of sugammadex adminis tered simultaneously with rocuronium or vecuronium in healthy volunteers. Br J Anaesth 2008;100(3):373–9. 15. Flockton EA, Mastronardi P, Hunter JM, Gomar C, Mirakhur RK, Aguilera L, Giunta FG, Meistelman C, Prins ME. Reversal of rocuronium-induced neuromuscular block with sugammadex is faster than reversal of cisatracurium-induced block with neostig mine. Br J Anaesth 2008;100(5):622–30. 16. Zhang MQ. Drug-specific cyclodextrins: the future of rapid neuromuscular block rever sal? Drugs Future 2003;28(4):347–54. 17. Staals LM, Snoeck MM, Driessen JJ, Flockton EA, Heeringa M, Hunter JM. Multicen tre, parallel-group, comparative trial evaluating the efficacy and safety of sugam madex in patients with end-stage renal fail ure or normal renal function. Br J Anaesth 2008;101(4):492–7. 18. Molina AL, de Boer HD, Klimek M, Heeringa M, Klein J. Reversal of rocuro nium-induced (1.2 mg kg–1) profound neuro muscular block by accidental high dose of sugammadex (40 mg kg–1). Br J Anaesth 2007;98(5):624–7. 19. Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A Abenavoli L, D’Angelo C, Caputo F, Zambon A, Haber PS, Gasbarrini G. Effectiveness and safety of baclofen for maintenance of alcohol absti nence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind con trolled study. Lancet 2007;370(9603):1915–22. 20. Smit CAJ, Slim EJ. Heart conduction pro blems in a tetraplegic patient caused by a single therapeutic dosage of Baclofen. Spinal Cord 2008;46(4):317–8. 21. Grande LA, Loeser JD, Samii A. Recurrent transient global amnesia with intrathecal baclofen. Anesth Analg 2008;106(4):1284–7.
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22. Oliviero A, Rubio-Esteban M, Foffani G, Aguilar J, Lopez-Dolado E, Arzoz-Lezaun T, Godino-Duran JA, Gómez-Arg€ uelles JM, Pérez-Borrego Y, Sebastia´n de la Cruz F, Di Lazzaro V. Effects of baclofen on tem perature perception in humans. Neurosci Res 2007;59:89–92. 23. Brvar M, Vrtovec M, Kovač D, Kozelj G, Pezdir T, Bunc M. Haemodialysis clearance of baclofen. Eur J Clin Pharmacol 2007;63 (12):1143–6. 24. Simpson DM, Blitzer A, Brashear A, Comella C, Dubinsky R, Hallett M, Jankovic J, Karp B, Ludlow CL, Miyasaki JM, Naumann M, So Y. Botulinum neurotoxin for the treatment of movement dis orders (an evidence-based review). Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008;70(19):1699–706. 25. Helmstaedter V, Wittekindt C, Huttenbrink K-B, Guntinas-Lichius O. Safety and efficacy of botulinum toxin therapy in otorhinolaryn gology: experience from 1,000 treatments. Laryngoscope 2008;118(5):790–6. 26. Anonymous. Botulinum toxins. Report of systemic adverse reactions. WHO Newslett 2008;2:7. 27. Anonymous. Botulinum toxin type A. Adverse reactions such as muscle weakness. WHO Newslett 2009;2:2. 28. Kruisdijk JJ, Koelman JH, Ongerboer de Visser BW, de Haan RJ, Speelman JD. Botu linum toxin for writer’s cramp: a randomised, placebo-controlled trial and 1-year followup. J Neurol Neurosurg Psychiatry 2007;78 (3):264–70. 29. Mallo-Gonzalez N, Lopez-Rodriguez R, Fentes DP, Campos-Franco J, Lado FL, Alende-Sixto MR. Fournier’s gangrene fol lowing botulinum toxin injection. Scand J Urol Nephrol 2008;42(3):301–3. 30. Jackson J, Anania FA. Chlorzoxazone as a cause of acute liver failure requiring liver transplantation. Dig Dis Sci 2007;52:3389–91. 31. Kenney C, Hunter C, Davidson A, Jankovic J. Short-term effects of tetrabena zine on chorea associated with Huntington’s disease. Mov Disord 2007;22:10–3. 32. Morgan JC, Sethi KD. Drug-induced tre mors. Lancet Neurol 2005;4:866–76.
280 33. Ondo W, Jong D, Davis A. Comparison of weight gain in treatments for Tourette syn drome: tetrabenazine versus neuroleptic drugs. J Child Neurol 2008;23:435–7. 34. Henney III HR, Runyan JD. A clinically relevant review of tizanidine hydrochloride dose relationships to pharmacokinetics, drug
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safety and effectiveness in healthy subjects and patients. Int J Clin Pract 2008;62 (2):314–24. 35. Momo K, Homma M, Abei M, Hyodo I, Kohda Y. Tizanidine-induced hypotension in patients with liver cirrhosis. Eur J Clin Pharmacol 2008;64(6):6478.
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Drugs that affect autonomic functions or the extrapyramidal system
DRUGS THAT STIMULATE BOTH ALPHA- AND BETA-ADRENOCEPTORS (SEDA-27, 145; SEDA-29, 148; SEDA 30, 170; SEDA-31, 259)
Adrenaline (epinephrine) (SED-15, 41; SEDA-29, 148; SEDA-30, 170; SEDA 31, 259) Cardiovascular Ischemic heart disease EIDOS classification: Extrinsic moiety: Adrenaline Intrinsic moiety: Alpha-adrenoceptors Distribution: Myocardial blood vessels Outcome: Vasospasm Sequela: Ischemic heart disease due to adrenaline DoTS classification: Dose-relation: Toxic Time-course: Time-independent Susceptibility factors: Diseases (pre existing ischemic heart disease) In 54 patients with coronary artery dis ease undergoing dental extraction under local anesthesia, who were randomized to two groups with and without adrenaline Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32013-7 � 2010 Elsevier B.V. All rights reserved.
1:100 000, three had ST-segment depression after administration of adrenaline and two others had increased CK-MB activity (1c). Surprisingly, the authors concluded that dental extraction performed under local anesthesia with 1:100 000 adrenaline does not imply additional ischemic risks. Hypotension Local administration of adrenaline can cause serious problems. For instance, a solution containing lidocaine þ adrenaline is widely used for scalp infiltration before craniotomy. A group in China have compared the hemodynamic effects of scalp infiltration of 1% lidocaine (16 ml) combined with adrenaline 40, 80, or 160 micrograms, or no adrenaline at all (n = 40 in each group) (2C). In each of the adrenaline-treated groups there was a similar and significant fall in mean arterial pressure of 17–19 mmHg at 1.5 minutes after administration, with full recovery by 3 minutes. Heart rate increased by about 12/minute over the same time. It is important that clinicians are aware that this is likely to happen and do not attempt to treat a self-limiting response, although in some patients even this brief period of hypotension can be hazardous. Drug administration route The use of intravenous adrenaline should be considered very carefully even in emergencies, as a case report from Korea shows (3A). • A 36-year-old man, with no previous history of allergy, became hypotensive (80/50 mmHg) after multiple bee stings and did not respond
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282 to subcutaneous adrenaline 0.3 mg. He was then given a further 1 mg of adrenaline by intravenous infusion, in a total volume of 2200 ml. He improved and was discharged, but was readmitted unconscious after 27 hours, shortly after complaining of a severe headache and having a tonic–clonic seizure. His blood pressure was 180/80 mmHg, which was lowered by unspecified medication to 90/60 mmHg. A CT scan showed subarachnoid and intraventricular hemorrhages. He was ventilated but did not regain consciousness and died 7 days later.
Although the authors argued that this event was caused by a specific interaction between the bee stings and adrenaline, it is more likely that the adrenaline itself caused a hyperten sive crisis, leading to rupture of a pre-existing aneurysm, and that it would have been better not to have given the drug intra venously, or at least not in such a high dose.
Noradrenaline (norepinephrine) (SED-15, 2582) Comparative studies In a multicenter, double-blind study in 778 patients who were given noradrenaline 5–15 micro grams/minute or low-dose vasopressin 0.0 1–0.03 U/minute in addition to open vasopressors, there was no significant difference between the two groups in 28 day mortality (39 and 35% respectively) or in 90-day mortality (50 and 44%) (4C). There were no significant differences in the overall rates of serious adverse events (Table 1).
Ephedra and ephedrine (SED-15, 1221; SEDA-29, 148; SEDA-30, 171; SEDA-31, 262) Cardiovascular Myocardial infarction EIDOS classification: Extrinsic moiety: Ephedrine Intrinsic moiety: Alpha-adrenoceptors Distribution: Myocardial blood vessels Outcome: Vasospasm Sequela: Ischemic heart disease due to ephedrine
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DoTS classification: Dose-relation: Toxic Time-course: Time-independent Susceptibility factors: Diseases (pre existing ischemic heart disease) Acute myocardial infarction in a young athlete who had used ephedrine over the previous 5 years to improve physical perfor mance was associated with an intracoronary thrombus in the left anterior descending cor onary artery; after removal of the thrombus, only an intact non-obstructive atherosclero tic plaque was found (5Ar). The authors suggested that in this case there was a patho genetic link between non-obstructive coron ary atherosclerosis, focal vasoconstriction and obstructive thrombosis. Drug overdose Intractable ventricular fibrillation, requiring frequent defibrillation, has been reported in a patient who took an overdose of a dietary supplement containing Ephedra and caffeine (6A).
Pseudoephedrine (SED-15, 1221; SEDA-29, 149; SEDA-30, 171; SEDA-31, 263) Urinary tract Acute urinary retention has been attributed to pseudoephedrine in a 3-year-old boy (7A). Skin Acute generalized exanthematous pus tulosis has been attributed to pseudo ephedrine (8A). Death The Office of the Philadelphia Medical Examiners has reported 15 deaths between February 1999 and June 2005 of infants and toddlers aged 16 months and younger in which 10 different drugs commonly found in over-the-counter cold remedies were detected: pseudoephedrine, dextromethorphan, paracetamol, bromphe niramine, carbinoxamine, chlorphenamine, ethanol, doxylamine, phenobarbital, and phenytoin (9c). Pseudoephedrine was detec ted in all cases, with blood concentrations of
Drugs that affect autonomic functions or the extrapyramidal system
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Table 1. Numbers (%) of serious adverse events in patients with septic shock (4C)
Event
Noradrenaline (n = 382)
Vasopressin (n = 396)
At least one serious adverse event Acute myocardial infarction or ischemia Cardiac arrest Life-threatening dysrhythmia Acute mesenteric ischemia Digital ischemia Hyponatremia Stroke
40 (11) 7 (1.8) 8 (2.1) 6 (1.6) 13 (3.4) 2 1 1
41 (10) 8 (2.0) 3 (0.8) 8 (2.0) 9 (2.3) 8 1 1
0.10–17.0 (mean 3.34) mg/l; it was the only drug detected in three cases. A 31-year-old woman took over-the-coun ter pseudoephedrine, had a hypertensive cri sis with congestive heart failure, and died of a cardiac dysrhythmia and shock (10A). At autopsy a right adrenal pheochromocytoma was found and there was evidence of congestive heart failure and catecholamineinduced cardiomyopathy. The authors sug gested that her death was linked to the use of pseudoephedrine in the presence of an undiagnosed pheochromocytoma. They also suggested that over-the-counter packaging should include a warning about the dangers of using pseudoephedrine in those with a pheochromocytoma or a family history. Drug–drug interactions Selegiline In 25 healthy volunteers transdermal selegiline had no effects on the pharmacokinetics or pharmacodynamics of pseudoephedrine or phenylpropanolamine (11c).
DRUGS THAT PREDOMINANTLY STIMULATE ALPHA1 ADRENOCEPTORS (SEDA-27, 147; SEDA-29, 150; SEDA-30, 172; SEDA-31, 264)
Dopamine In low doses the effects of dopamine are generally limited to dopamine receptors; at
higher doses it also has beta-adrenoceptor agonist effects, and at higher doses still is an alpha-adrenoceptor agonist. A report from Bulgaria suggests that the last of these actions can nevertheless occur at relatively low doses (12A). • A 64-year-old man with diabetes mellitus developed septicemia and toxic shock second ary to gangrene in the right leg. Because of p oor renal function he was given an infusion of dopamine, initially 1.25 micrograms/kg/minute, increasing to 2.5 micrograms/kg/minute beca use of a poor response. There was a good di uretic response, but after 36 hours all the fingers of both hands, except the thumbs, had become ischemic, as had the previously normal left leg. In fact the right leg was amputated, possibly because of dopamine-exacerbated is chemia but this was unclear. Dry gangrene also developed in the affected fingers, although it is also unclear whether they were saved.
This was clearly an alpha-adrenergic effect of dopamine, though as the authors here point out this is seldom seen at doses below 5 micrograms/kg/minute.
Phenylephrine (SED-15, 2808; SEDA 30, 172; SEDA-31, 264) Cardiovascular The selective alpha-adreno ceptor agonist phenylephrine is used in some clinical settings to reverse hypotension. An example is spinal anesthesia for cesarean sections, as described in a report of cardiac dysrhythmias (13A). • A 31-year-old woman who required emer gency cesarean section after failure to progress during labor was given phenylephrine
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284 200 micrograms by infusion immediately after intrathecal injection of bupivacaine and dia morphine; the dose was repeated whenever the blood pressure fell below baseline. Within seconds of starting the infusion she developed ventricular bigeminy at a rate of 94/minute, which persisted until delivery, sinus rhythm returned without treatment. The blood pres sure was between 122/76 and 143/80 mmHg.
The mechanism of this effect was unclear. The authors suggested that there may have been increased after-load, leading to increased ven tricular stretch, but this was speculative. The rise in blood pressure that phenyl ephrine causes may itself be hazardous, even if it is not given systemically, or at least not intentionally (14A). • A 23-year-old African American man devel oped ischemic priapism as a result of sickle cell disease. After intracavernosal injection of phe nylephrine 500 micrograms he complained of very severe headache and a CT scan showed subarachnoid hemorrhage. His blood pressure was 180/100 mmHg, compared to his baseline reading of 130/88 mmHg. He was given enalapril (dose not stated) and his blood pressure fell. Fortunately, he had no neurological symptoms then or later.
The authors very reasonably suggested reducing the standard dose to be injected in these circumstances to 200 micrograms, to be repeated if necessary. Skin Local phenylephrine as an insert caused an acute blepharoconjunctivitis with eyelid eczema (15A), confirmed by patch testing. Generalized eczema can develop when phenylephrine is given intravenously.
Michael Schachter
extensive. They included 940 patients with hemorrhagic stroke that occurred between October 2002 and March 2004 and 1880 matched controls. Of those who had had a stroke, 16 (1.7%) had been exposed to phenylpropanolamine in the preceding 2 weeks, compared with 14 (0.74%) of the controls. There were no significant differen ces in the men (50% of each group), but in the women there was an increased risk of stroke associated with exposure to phenyl propanolamine, and this was graded accord ing to dose, more recent date of exposure and longer duration. The overall odds ratios were about 2 for exposure versus no expo sure; over 5 for an exposure within 3 days; over 3 for an exposure of greater than 3 days; and over 2 for a dose of greater than 75 mg/day. The risk was much greater in women. In a previous study the risk of stroke associated with phenylpropanolamine was significant only in women, but only women reported using appetite suppressants con taining phenylpropanolamine (17C). How ever, the ABBA study suggested that the more evident risk in women cannot be attributed to a difference in the exposure rate between the sexes.
DRUGS THAT STIMULATE BETA 1-ADRENOCEPTORS (SEDA-29, 150; SEDA-30, 173; SEDA-31, 265)
Dobutamine Phenylpropanolamine
(SED-15, 2811; SEDA-29, 150; SEDA-30, 173; SEDA-31, 264)
Nervous system Korean authors have analysed the risk of hemorrhagic stroke in individuals taking phenylpropanolamine as a cold remedy (16M). This drug has been withdrawn nearly everywhere in the world largely for this reason, although the previous data were less systematic and less
(SED-15, 1169; SEDA-29, 150; SEDA-30, 173; SEDA-31, 265) Cardiovascular Dobutamine stress testing is widely used in cardiology, but it is timeconsuming and efforts continue to produce new protocols that are quicker but retain diagnostic utility while being at least as safe as the standard procedure. An accelerated protocol has been described, in which the starting dose of dobutamine was 20 micrograms/kg/ml, escalating in one step to 40 micrograms/kg/ml after 3 minutes, with
Drugs that affect autonomic functions or the extrapyramidal system
administration of atropine after 1 minute if the target heart rate was not reached at the higher dose of dobutamine (18C). In contrast, the standard protocol started at a dose of 10 micrograms/kg/ml, with 10 micrograms/kg/ml increments every 3 minutes, usually to 40 but sometimes to 50 micrograms/kg/ml, with atropine given towards the end of this process. In all, 164 patients were allocated alternately to one of the protocols. The total test time was reduced in the new protocol from over 19 minutes to about 12 minutes, while the average duration of symptoms was just over 3 minutes rather nearly 6 minutes. In both protocols women had shorter test times than men. The incidence of dysrhythmias of all types was about 50% with both protocols. Cardiologists from Rio de Janeiro have described another approach to this problem (19C). They used the same standard proto col for comparison, while the accelerated version differed in that atropine was given after the lowest dose of dobutamine (10 micrograms/kg/ml). In all, 168 patients were allocated alternately to the two proce dures. As expected, the total test time was shorter with the new protocol (about 16 minutes versus 20 minutes). There were considerably fewer adverse effects, mainly dysrhythmias, in patients who received the accelerated protocol (35 versus 55). There were no sex differences. These reports, taken together, support the case for accelerated protocols, which are as useful as the standard one, with equal or even superior safety and tolerability.
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Levodopa
had had the disease for at least 5 years. Five, of whom two were women, had had abnormal involuntary eye movements for 7–18 years; two were also taking dopamine receptor agonists. The abnormal move ments all occurred during the ‘on’ phase of therapy and had a common pattern. They consisted of stereotyped and repetitive move ments, upwards, sideways, or both. Some were phasic and others more sustained and tonic; in both cases they were usually (4/5) towards the side of the body more affected by the disease. The authors commented that this should be recognized as a particular type of dyskinesia, and one that may have a negative effect on postural stability. Although it seems intuitively likely that the dosage of levodopa will have a signifi cant effect on the incidence of dyskinesias, this topic has received surprisingly little attention. At the same time there is evi dence that patients in whom ropinirole or pramipexole are used initially are less likely to develop dyskinesias. Neurologists from England and France have used data from two comparisons of levodopa and ropinirole (056 and REAL-PET) in 430 patients (21C). These trials confirmed the much higher risk of dyskinesias in patients who started on levodopa rather than ropinirole – 35% of patients taking levodopa developed dyski nesia in 2–5 years compared with 5% of those taking ropinirole. Among those tak ing only levodopa there was a highly signif icant difference in dosage between those who developed dyskinesia and those who did not: 9.2 mg/kg versus 6.9 mg/kg. Logistic regression analysis showed that the only variables associated with the emergence of dyskinesia were age and levodopa dosage per kilogram.
Nervous system Levodopa-induced dys kinesia is very common. Neurologists from Geneva have examined the frequency and characteristics of a subtype of dyskinesia, abnormal involuntary eye movements (20C). They studied 32 patients with advanced Par kinson’s disease, all of whom had moderate to severe symptoms and dyskinesias, and
Drug dosage regimens Long-term levodopa therapy often causes complications, which can occasion great distress and diffi culty for patients. Some of these problems may arise from the intermittent nature of the therapy in most circumstances. How ever, John Nutt has reviewed this hypoth esis and on balance argued against it, noting that it does not avoid the problems of
(SED-15, 2039; SEDA-28, 162; SEDA-29, 151; SEDA-30, 174; SEDA 31, 266)
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hypersensitization and tolerance, that it encourages 24-hour attempts at treating th e motor effects of Parkinson’s disease and its therapies, and that it may therefore enc ourage excessive medication (22H). Never theless, he favours rigorous randomized clinical trials to test the hypothesis.
Dopamine receptor agonists
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about 1800 patients were included (25M). There was evidence of superior efficacy for pramipexole as well as greater tolerability. Specifically, the odds ratios for nausea, vomiting, and dizziness were significantly lower for pramipexole (0.37, 0.21, and 0.47 respec tively). Whether a direct comparison is likely to be carried out is doubtful, although not out of the question, as both drugs are or soon will be generic in most countries.
Neurologists from Pisa have briefly outlined the uses and role of dopamine receptor ago nists in the treatment of Parkinson’s disease and their major adverse effects, both periph eral and central; in the former category they discuss orthostatic hypotension, peripheral edema, and pleuropulmonary fibrosis (23R). However, they give a far more detailed analysis of fibrotic heart valve dis ease, though arguably their verdict on the ergoline derivatives is rather optimistic. The central adverse effects that they discuss include motor complications, but in much greater depth the problem of somnolence and sleep attacks. Pathological impulse dis orders, especially pathological gambling, are also discussed in detail.
Cardiovascular Fibrotic reactions
Observational studies Researchers from 11 countries have performed a 52-week open study of ropinirole 0.25–4 (mean 1.9) mg/day in 310 patients (24C). Although over 91% of the participants reported at least one adverse event, these led to drug withdrawal in only 8.7%. Nausea was by far the most common adverse effect (in over 55%), and vomiting, dizziness, fatigue, and somnolence had frequencies of 6–8%; somnolence was severe enough to lead to drug withdrawal in only two patients. Sleep attacks as such were not described or even specifically enquired about.
In the last few years the most important influence on dopaminergic drug prescribing has been the recognition that ergot-derived dopamine agonists are associated with cardiac valvulopathies. Two Japanese physicians have reviewed the evidence for the patho genetic mechanism and have agreed with the consensus view that stimulation of serotonin 5HT2B receptors is most probably responsible (26R). However, they have pointed out that ropinirole and pramipexole, which have little or no affinity for 5HT2B receptors, can very rarely cause fibrosis in other organs. They do not go as far as to advise the complete cessa tion of prescribing of the ergot derivatives, particularly if the doses used are low. In a Danish cross-sectional study of the association of ergot-derived dopamine ago nists with valvulopathy in Parkinson’s dis ease and the value of different screening approaches for this pathology 138 patients, median age 64 years, 62% men, were
Systematic reviews In a meta-analysis of the comparative efficacy and tolerability of ropinirole and pramipexole in restless legs syndrome, there were no direct headto-head comparisons, and only 14 studies of which 10 involved ropinirole were identified;
EIDOS classification: Extrinsic moiety: Dopamine receptor
agonists (especially pergolide and
cabergoline)
Intrinsic moiety: 5HT2B receptors Distribution: Serosae, cardiac valves Outcome: Hyperplasia (fibrosis) Sequela: Fibrotic reactions due to some ergot-derived dopamine receptor agonists DoTS classification: Dose-relation: Collateral Time-course: Late Susceptibility factors: Unknown
Drugs that affect autonomic functions or the extrapyramidal system
recruited (27C). All had taken dopamine receptor agonists for at least 6 months, either ergot-derived drugs (n = 85) or other dopaminergic agents (n = 53). They were screened for valvulopathy clinically and by assessor-blinded echocardiography. The main outcome was valvular regurgita tion as confirmed by the latter. Among those taking ergot derivatives, 22 had moder ate to severe regurgitation affecting the aor tic, mitral or tricuspid valves; the five severe cases all involved the aortic valve. Two of the patients taking other dopamine agonists had moderate valvular regurgitation. The authors calculated that the risk of at least moderate valvular regurgitation was 7.2% among those taking ergot-derived drugs. They concluded that clinical screening, including natriuretic peptide assays, have only about 62% sensi tivity and even lower specificity. Therefore, patients who take ergot derivatives should be followed up with echocardiography as well as clinical assessment. In a smaller series from Texas, echocardiography was used to study 36 patients with Parkinson’s disease taking pergolide 0.375–6 mg/day and a matched group taking ropinirole and pramipexole (28c). The authors calculated severity scores for regur gitation ranging from 1 (trace) to 4 (severe) for the aortic, mitral and tricuspid valves, with the following comparisons for ergot versus non-ergot drugs: aortic 0.83 versus 0.19; mitral 1.42 versus 0.39; tricuspid 1.43 versus 0.19. All these differences were highly significant and overall exposure to dopaminergic medication was similar in the two groups. These results clearly re inforce recommendations to avoid or with draw pergolide if at all possible, and similar considerations apply to cabergoline. Hypotension Apomorphine has a long history of parenteral usage in the treatment of severe Parkinson’s disease. It is being increasingly used, often in the patient’s home, for the treatment of acute ‘off’ episodes. In a multicenter study in the USA the efficacy and safety of apomorphine has been examined in 62 patients, half of whom were randomized to placebo and half to active drug (29C). They had all been using
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intermittent apomorphine for at least 3 months, at least twice daily, and the effect of a single dose was assessed. There was a significant improvement in motor function after 20 minutes. Apomorphine also reduced both heart rate and blood pressure, but the changes were smaller than with placebo. Orthostasis occurred in similar numbers of patients, 11 for apomorphine and 8 for placebo. Of course, baseline dopamine replacement therapy will itself produce postural hypotension. Nervous system Sleep attacks EIDOS classification: Extrinsic moiety: Dopamine receptor agonists Intrinsic moiety: Dopamine (?D2) receptors Distribution: Brain Outcome: Altered cell function (nature unknown) Sequela: Sleep attacks due to dopamine receptor agonists DoTS classification: Dose-relation: Collateral Time-course: Time-independent Susceptibility factors: Not known Dopamine receptor agonists are asso ciated with sleep attacks (30R). A 73-year old woman with Parkinson’s disease taking excessive doses of levodopa and pergolide had sleep attacks and her family noticed that each was heralded by slowness of speech (31A). In rats low doses of levodopa (1–5 mg/kg) and of the dopamine D2 recep tor agonists talipexole and quinpirole (0.1 mg/kg) caused delayed increases in delta and theta power on electroencephalo graphy (32E). Higher doses led to immedi ate stable reductions in alpha1, alpha2 and beta1 power, as reported with dopamine D1 receptor agonists. Administration of the D2 antagonist sulpiride 10–20 mg/kg resulted in increased alpha2 power. The authors sug gested that since delayed increases in delta and theta activity are thought to originate from heterosynaptic, presynaptic dopamine
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D2 receptors on cholinergic neurons, these effects could explain daytime tiredness or sudden sleep attacks in patients with Par kinson’s disease.
Psychiatric Pathological gambling EIDOS classification: Extrinsic moiety: Dopamine receptor
agonists
Intrinsic moiety: Dopamine (?D1/D3)
receptors Distribution: Brain Outcome: Altered cell function (nature unknown) Sequela: Pathological gambling due to
dopamine receptor agonists
(particularly pramipexole)
DoTS classification: Dose-relation: Collateral
Time-course: Intermediate
Susceptibility factors: Genetic
(dopamine D1 receptor gene allele DRD1-800 T/C); age (younger age of onset of Parkinson’s disease); sex (male); drugs (combined therapy with levodopa) An extraordinary range of behavioral adverse reactions have been associated with dopaminergic therapies. Pathological gam bling is well known and has previously been reviewed in SEDA (SEDA-30, 174). Neurol ogists and psychiatrists from the Mayo Clinic have studied 11 patients with Parkinson’s dis ease who developed excessive gambling behaviour and 37 patients matched for age, sex and duration of disease (33c). Combined therapy with levodopa and pramipexole did not increase the risk of gambling, but prami pexole itself was apparently associated with such an increase, with an odds ratio of 3.6, which approached but did not quite reach significance. This is largely in agreement with the literature, although the authors noted that the cause has not been established. Early in the history of levodopa therapy for Parkinson’s disease it was noted that
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hypersexuality was a complication, especially in younger patients, although it was not until the late 1980s that this was put in the wider context of compulsive behaviours. The use of dopaminergic drugs for restless legs syn drome is much more recent, and neurologists at the Mayo Clinic in Arizona have examined whether similar behaviours occur in this con text (34C). They sent questionnaires to 261 patients, of whom just over a third (97) replied: this relatively low rate may have introduced bias. On the 97 respondents, 77 were taking one or more dopaminergic medications; 3 reported an increase in sexual desire. Of the 70 patients who responded specifically to the gambling questions, 4 reported an increase in gambling activity after starting medication. One patient noted increases in both sexual desire and gambling behaviour. Although the numbers were small the authors concluded that the pattern of drug-induced behaviours in rest less legs syndrome resemble those in Parkin son’s disease. In an extraordinary case report from Gen eva, two patients are described, a man and a woman aged 70 and 71 years with advanced Parkinson’s disease who developed compul sive singing, each of one particular melody, while taking high-dose dopamine replace ment therapy (35A). The first was taking cabergoline 4 mg/day, levodopa/carbidopa 800/200 mg/day, and tolcapone 300 mg/day (high doses). The other was taking levo dopa/benserazide 1000/250 mg/day. Both were resistant to reductions in dosage. They can be regarded as suffering from dopamine dysregulation syndrome, a type of punding, that is to say repetitive stereotyped behaviors. Even so, the melodies were by Donizetti and Mozart, so not all discernment was lost.
DRUGS THAT STIMULATE BETA 2-ADRENOCEPTORS For the use of beta2-adrenoceptor agonists in respiratory disorders see Chapter 16.
Drugs that affect autonomic functions or the extrapyramidal system
Clenbuterol Respiratory Clenbuterol is used by body builders for its anabolic effects. A 33-year old man inhaled clenbuterol in powder form for unknown reasons (36A). He immediately complained of headache, chest pain, and palpitation, and vomited. His blood pressure was 116/27 mmHg with a regular pulse rate of 146/minute, in sinus rhythm. An electrocardiogram showed ST segment depression in the lateral leads and 6 hours later he developed acute respiratory failure, with oxygen saturation of 64% and pulmonary edema on chest X-ray. He required intubation for 4 days.
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Hematologic Ritodrine has rarely been associated with life-threatening maternal neutropenia and three such cases have been described in three primiparous women aged 23–36 years (39A). Intravenous ritodrine was given for 2–5 weeks in unspecified but presumably standard doses. In one patient there was agranulocytosis and in the two others very low neutrophil counts (50 and 500 106/l at their lowest). Ritodrine was withdrawn and recombinant granulocyte stimulating factor was given for 3–7 days. On average, neutrophils counts returned to normal within about 4 days. There were no infections or other complications and all the babies were normal.
Ritodrine Cardiovascular In a Turkish study of the echocardiographic findings in 30 women treated with intravenous ritodrine 50–300 micrograms for pre-term labour compared with 32 women with uncomplicated pregnancies, the results confirmed positive chronotropic and inotropic effects (37c). Heart rate rose from 76 to 106/minute and there was a modest but significant increase in fractional shortening form 40 to 41%. Systolic and diastolic blood pressures fell from 120/78 to 108/71 mmHg. The authors commented that changes in contractility and heart rate are likely to increase myocardial oxygen demand and they therefore recommended that ritodrine and similar drugs should be avoided in women with ischemic or structural heart disease. Respiratory In another Turkish study oral ritodrine 15 mg/day was given over months to prevent premature labour, but the patient was nevertheless hospitalized because of increasing uterine contractions, and the dose of ritodrine was increased to 80 mg/day (38A). On the 5th day she developed respiratory distress due to pulmonary edema, which responded to oxygen and furosemide. The authors noted that this is a very rare complication of ritodrine in any form, and that the mechanisms have not been defined.
OTHER DRUGS THAT INCREASE DOPAMINE ACTIVITY Catechol-O-methyl transferase inhibitors (SED-15, 1219; SEDA-29, 153)
Tolcapone The story of tolcapone is a fascinating one, not only in its own right but as a case history of assessment of the benefit to harm balance in therapeutics. Tolcapone is a selective inhibitor of catechol-O-methyl transferase (COMT), which catalyses a relatively minor pathway of dopamine metabolism. It there fore enhances the action of dopamine. Its introduction had a major impact on the man agement of Parkinson’s disease, and within months tens of thousands of patients throughout the world were taking it. Tolca pone was considered to be useful in prolong ing the half-life of levodopa, thereby allowing dosage reduction and possibly smoother therapeutic responses. In early studies the most frequent adverse effects of tolcapone were dyskinesias, nausea, sleep disorders, dystonia, orthostatic hypotension, diarrhea, dizziness, and
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hallucinations (40R). There was also a report of progressive vitiligo in a 50-year-old patient who took tolcapone 300 mg/day in combina tion with co-careldopa; the first depigmented lesions appeared a week after starting the drug, and the authors speculated that increased concentrations of dopamine may have interfered with melanin synthesis (41A). However, during clinical trials rises in liver enzyme were noted, and the health authorities withdrew tolcapone from most European countries following an EMEA rul ing in November 1998 (42R). Increases of more than three times the upper limits of the reference ranges for aminotransferase activ ities occurred in 1 and 3% of patients taking tolcapone 100 mg tds and 200 mg tds respec tively. Increases of more than three times the upper limits of the reference ranges for ami notransferase activities occurred in 0.3 and 1.7% of patients taking tolcapone 100 mg tds and 200 mg tds respectively. Subsequently there were three deaths from acute liver failure in patients taking tolcapone during a total exposure of 40 000 patient-years, leading to the complete withdrawal of the drug. An ear lier review, predating the withdrawal of tolca pone, had suggested that it could be safely used provided liver function was closely mon itored in the first 6 months of therapy (43R). Some neurologists believed that this course of action was reasonable because they regard tolcapone as being of superior efficacy to other COMT inhibitors and a useful addition to the therapeutic options in the management of Parkinson’s disease. In the USA the mar keting of tolcapone was severely restricted, and individual written consent and compul sory liver function monitoring was required for each patient. The background to these events was briefly reviewed soon after this happened (44R). Two American neurologists have commen ted on the events since then (45R). In more than 40 000 patient-years there have been only three cases of severe but reversible liver damage and no deaths. Another COMT inhibitor, entaca pone, was introduced after tolcapone was lar gely withdrawn, but the clinical consensus was that it had less efficacy than the older drug. As a result of the new data and of professional demand, tolcapone was marketed again, with
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strict guidelines regarding liver function mon itoring. This should be carried out every 2–4 weeks for the first 6 months of treatment and at the physician’s discretion thereafter. A multicenter, placebo-controlled trial from the late 1990s has been reported 10 years later (46C). It examined the tolerability and safety of tolcapone 100 mg tds in 677 patients with early Parkinson’s disease just starting levodopa therapy. Although it was originally intended to last 6 years, the trial was stopped after 15 months because of the safety problems mentioned above. There were increases in serum transaminase activ ities in 28% of the patients taking tolcapone but also in 20% of those taking placebo. There were increases of more than three times the upper limit of normal in only 1.2 and 1.8% of those taking placebo and tolca pone respectively. In 80% of those taking tolcapone liver enzymes returned to normal despite continuation of the drug. There were no cases of serious hepatotoxicity. Sympto matically the main problem with tolcapone therapy was diarrhea, which was reported in 29% of those taking tolcapone but only 11% of those taking placebo. This caused with drawal of treatment in 10% of the former, while overall 17% of patients stopped taking the drug for any reason: only 3% of those taking placebo stopped treatment.
DRUGS THAT AFFECT THE CHOLINERGIC SYSTEM (SEDA-29, 153; SEDA-30, 177; SEDA-31, 272)
Anticholinergic drugs
(SED-15, 264; SEDA-29, 153; SEDA-30, 153; SEDA-31, 273)
Observational studies In two large 12-week studies, from the USA and Germany, the adverse effects of extended-release formula tions of oxybutynin and tolterodine in patients with overactive bladder and urinary inconti nence were as expected from the pharmacolo gical actions of these drugs. The first study
Drugs that affect autonomic functions or the extrapyramidal system
involved 576 patients (94% women) and a parallel group of 399 patients taking extendedrelease tolterodine 4 mg/day (47C). The second study involved nearly 1700 patients (44% men) taking tolterodine 4 mg/day or placebo (48C). Dry mouth was by far the most common adve rse effect, although the prevalences were differ ent in the two series. In the German series it was 23% and in the US study 11%, about three times the rate in those taking placebo. The reason for this discrepancy was unclear. In bo th cases constipation was the next most com monly reported adverse event. No novel or unexpected problems emerged in either study. Urinary urgency and incontinence are fre quent problems, not only in older adults but also transiently in primary school-aged chil dren. There have been relatively few studies on the use of anticholinergic medications in this group, although there is general agree ment that they are efficacious. In a multina tional, 12-month, open study of extendedrelease tolterodine 2 mg/day in 318 children aged 5–11 years (54% boys), only 4 reported dry mouth and the most common adverse events were urinary tract infection (7%), nasopharyngitis (5%), and headache (5%) (49C). Whether the first two of these really were related to the treatment must be ques tionable. No fewer than 35% of the subjects withdrew from the study, mostly because of either symptomatic improvement or conver sely failure to respond; only 3% of the with drawals were due to adverse drug effects. Cardiovascular Although there have been no reports of a dysrhythmogenic effect of tolterodine, in vitro interactions with cardiac potassium channels have suggested that ventricular dysrhythmias could occur.
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Of 48 subjects recruited for a thorough study of the effect of tolterodine on the QT interval, 25 were men and 45% were poor metabolizers of tolterodine, largely because of low CYP2D6 activity; in a random sample of the population, only 7.5% of subjects would be in this category (50C). In a crossover design they were given tolterodine immediate-release 2 mg bd, a high dose of 4 mg bd, and as a positive control the qui nolone antibiotic moxifloxacin 400 mg/day, which is known to cause QT interval pro longation. The end-point was the Fridericia corrected QT interval on the fourth day of treatment at a time of peak drug expo sure. For moxifloxacin the mean prolonga tion of the QTc interval was 8.9 ms machineread and 19.3 ms manually. For the normal and high doses of tolterodine the readings were 1.2 and 5.6 ms machine-read, and 5.0 and 12 ms manually. None of the treatments came even close to the clinically relevant threshold of a 60 ms prolongation of QTc, reinforcing the clinical impression that tolterodine is safe even at high doses in poor metabolizers. Sensory systems Atropine 1% for topical use as an ointment is used to retard the development of myopia. Among 23 children (mean age 7.4 years) who used daily atropine for 1 year, one developed a mild allergic reaction, which resolved quickly after withdrawal (51c). In another study atropine was used to treat amblyopia and was compared with patching in patients aged 8–20 years (52c). Redness of the eye was observed more often in the atropine group. In one child the redness recurred after 6 months and the atropine was stopped and changed to patching on request of the parents.
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292 scalp with epinephrine-containing lidocaine solution. J Neurosurg Anesthesiol 2007; 19:31–7. 3. Kwon OY, Chung SP, Lee KR, Kim SW. Spontaneous subarachnoid hemorrhage after intravenous epinephrine use for multiple bee stings. Am J Emerg Med 2007;25:249–50. 4. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D, VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358 (9):877–87. 5. Kranjec I, Cerne A, Noc M. Ephedrineinduced acute myocardial infarction in a young athlete: a case of thrombus manage ment. Angiology 2009;60(2):254–8. 6. Takeuchi S, Homma M, Inoue J, Kato H, Murata K, Ogasawara T. Case of intractable ventricula fibrillation by a multicomponent dietary supplement containing ephedra and caffeine overdose. Chudoku Kenkyu 2007;20 (3):269–71. 7. Soyer T, Göl IH, Eroglu F, Cetin A. Acute urinary retention due to pseudoephedrine hydrochloride in a 3-year-old child. Turk J Pediatr 2008;50(1):98–100. 8. Ben Salem C, Slim R, Denguezli M, Sriha B, Hmouda H, Bouraoui K. Pseudoephedrineinduced acute generalized exanthematous pustulosis. Int J Dermatol 2008;47(4):418–9. 9. Wingert WE, Mundy LA, Collins GL, Chmara ES. Possible role of pseudoephe drine and other over-the-counter cold medi cations in the deaths of very young children. J Forensic Sci 2007;52(2):487–90. 10. Sizemore GW, Scrogin KE, Weisenberg ES, Weldon-Linne CM, Madoo OB. Hyperten sive crisis, catecholamine cardiomyopathy, and death associated with pseudoephedrine use in a patient with pheochromocytoma. Endocr Pract 2008;14(1):93–6. 11. Azzaro AJ, VanDenBerg CM, Ziemniak J, Kemper EM, Blob LF, Campbell BJ. Evalua tion of the potential for pharmacodynamic and pharmacokinetic drug interactions between selegiline transdermal system and two sym pathomimetic agents (pseudoephedrine and phenylpropanolamine) in healthy volunteers. J Clin Pharmacol 2007;47(8):978–90.
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12. Yovcheski P, Markov G, Kirov G, Boneva Z. Digital necrosis after low-dose dopamine treatment. NDT Plus 2008;3:186. 13. Lai FM, Jenkins JG. Ventricular bigeminy during phenylephrine infusion used to main tain normotension during caesarean section under spinal anaesthesia. Int J Obstet Anesth 2007;16:288–90. 14. Davila HH, Parker J, Webster JC, Lockhart JL, Carrion RE. Subarachnoid hemorrhage as com plication of phenylephrine injection for the treatment of ischemic priapism in a sickle cell disease patient. J Sex Med 2008;5:1025–8. 15. Dewachter P, Mouton-Faivre C. Anaesthe tists should be aware of delayed hypersensi tivity to phenylephrine. Acta Anaesthesiol Scand 2007;51:637–9. 16. Yoon BW, Bae HJ, Hong KS, Lee SM, Park BJ, Yu KH, Han MK, Lee YS, Chung DK, Park JM, Jeong SW, Lee BC, Cho KH, Kim JS, Lee SH, Yoo KM. Phenylpropanolamine con tained in cold remedies and risk of hemorrha gic stroke. Neurology 1007(68):146–9. 17. Kernan WN, Viscoli CM, Brass LM, Broderick JP, Brott T, Feldmann E, Morgen stern LB, Wilterdink JL, Horwitz RI. Phenyl propanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000;343:1826–32. 18. Pastorius CA, Knickelbine T, Schum K, Nelson TF, Harris KM. Tolerability and infusion time of an accelerated infusion dobutamine echocardiography protocol. Echocardiogra phy 2007;24:393–6. 19. de Souza LeãoLima R, de Lorenzo A, Issa A. Int J. Reduced adverse effects with an accel erated dobutamine stress protocol compared with the conventional protocol: a prospective, randomized myocardial perfusion scintigra phy study. Cardiovasc Imaging 2008;24:55–9. 20. Grötzsch H, Sztajzel R, Burkhard PR. Levo dopa-induced ocular dyskinesia in Parkin son’s disease. Eur J Neurol 2007;1124–8. 21. Sharma JC, Ross IN, Rascol O, Brooks D. Relationship between weight, levodopa and dyskinesia: the significance of levodopa dose per kilogram body weight. Eur J Neurol 2008;15:493–6. 22. Nutt JG. Continuous dopaminergic stimula tion: is it the answer to the motor complica tions of levodopa? Movement Disord 2007;22:1–9.
Drugs that affect autonomic functions or the extrapyramidal system 23. Bonuccelli U, Ceravolo R. The safety of dopamine agonists in the treatment of Par kinson’s disease. Expert Opin Drug Saf 2008;7:111–27. 24. Garcia-Borreguero D, Grunstein R, Sridhar G, Dreykluft T, Montagna P, Dom R, Lainey E, Moorat A, Roberts J. A 52-week open-label study of the long-term safety of ropinirole in patients with restless legs syndrome. Sleep Med 2007;8:742–52. 25. Quilici S, Abrams KR, Nicolas A, Martin M, Petit C, LLeu P-L, Finnern HW. Meta-ana lysis of the efficacy and tolerability of prami pexole versus ropinirole in the treatment of restless legs syndrome. Sleep Med 2008;9:715–26. 26. Yamamoto M, Uesugi T. Dopamine agonists and valvular heart disease in patients with Parkinson’s disease: evidence and mystery. J Neurol 2007;254(Suppl 5):74–8. 27. Rasmussen VG, Poulsen SH, Dupont E, Østergaard K, Safikhany G, Egeblad H. Heart valve disease associated with treat ment with ergot-derived dopamine agonists: a clinical and echocardiographic study of patients with Parkinson’s disease. J Intern Med 2008;263:90–8. 28. Dewey RB, Reimold SC, O’Suilleabhain PE. Cardiac valve regurgitation with pergolide compared with nonergot agonists in Parkin son’s disease. Arch Neurol 2007;64:377–80. 29. Pfeiffer RF, Gutmann L, Hull KL, Bottini PB, Sherry JH. Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson’s disease. Parkinson Rel Dis 2007;13:93–100. 30. Constantinescu R. Update on the use of pra mipexole in the treatment of Parkinson’s dis ease. Neuropsychiatr Dis Treat 2008;4 (2):337–52. 31. Hirayama M, Nakamura T, Hori N, Koike Y, Sobue G. The video images of sleep attacks in Parkinson’s disease. Mov Disord 2008;23 (2):288–90. 32. Dimpfel W. Pharmacological modulation of dopaminergic brain activity and its reflection in spectral frequencies of the rat electrophar macogram. Neuropsychobiology 2008;58 (3–4):178–86. 33. Imamura A, Geda YE, Slowinski J, Wszolek ZK, Brown LA, Uitti RJ. Medications used
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to treat Parkinson’s disease and the risk of gambling. Eur J Neurol 2008;15:350–4. 34. Driver-Dunckley ED, Nobel BN, Hentz JG, Evidente VGH, Caviness JN, Parish J, Krahn L, Adler CH. Gambling and increased sexual desire with dopaminergic medications in restless legs syndrome. Clin Neuropharmacol 2007;30:249–55. 35. Bonvin C, Horvath J, Christe B, Landis T, Burkhard PR. Compulsive singing: another aspect of punding in Parkinson’s disease. Ann Neurol 2007;62:525–8. 36. Schechter E, Hoffman RS, Stajic M, Tarabar A. Pulmonary edema and respiratory failure asso ciated with clenbuterol exposure. Am J Emerg Med 2007;25(735):e1–3. 37. Tulumbaci O, Onan MA, Turkoglu S, Kurdoglu M, Boyaci B, Tiras MB. Effects of ritodrine tocolysis on echocardiographic parameters. J Mat-Fet Neonat Med 2007; 20:751–5. 38. Findik S, Dirican A, Sengul B, Uzun O, Atici A, Erkan L. Acute pulmonary edema secondary to long-term use of oral ritodrine in a woman with triplet pregnancy. Int J Gynecol Obstet 2007;96:208–11. 39. Kikkawa M, Matsubara S, Takatoku M, Kuwata M, Ohkuchi A, Izumi A, Watanabe T, Suzuki M. Granulocyte-colony stimulating factor for the treatment of ritodrine-induced neutropenia. J Obstet Gynecol Res 2008;34:286–90. 40. Micek E. Tolcapone: a novel approach to Parkinson’s disease. Am J Health-Syst Pharm 1999;56(21):2195–205. 41. Sabaté M, Bosch A, Pedrós C, Figueras A. Vitiligo associated with tolcapone and levodopa in a patient with Parkinson’s disease. Ann Pharmacother 1999;33:1228–9. 42. Watkins P. COMT inhibitors and liver toxi city. Neurology 2000;55(Suppl 4):S51–2. 43. Olanow CW. Tolcapone and hepatotoxic effects. Arch Neurol 2000;57:263–7. 44. Colosimo C. The rise and fall of tolcapone. J Neurol 1999;246:880–2. 45. Olanow CW, Watkins PB. Tolcapone: an efficacy and safety review (2007). Clin Neu ropharmacol 2007;30:287–94. 46. Lees AJ, Ratziu V, Tolosa E, Oertel WH. Safety and tolerability of adjunctive tolca pone treatment in patients with early
294 Parkinson’s disease. J Neurol Neurosurg Psy chiatry 2007;78:944–8. 47. Armstrong RB, Dmochowski RR, Sand PK, MacDiarmid S. Safety and tolerability of extended-release oxybutynin once daily in urinary incontinence: combined results from two phase 4 controlled clinical trials. Int Urol Nephrol 2007;39:1069–77. 48. Dmochowski R, Abrams P, MarschallKehrel D, Wang JT, Guan Z. Efficacy and tolerability of tolterodine extended release in male and female patients with overactive bladder. Eur Urology 2007;51: 1054–64. 49. Nijman RJM, Borgstein NG, Ellsworth P, Siggaard C. Long-term tolerability of tolterodine extended release in children 5–11 years of age: results from a 12
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month, open-label study. Eur Urol 2007;52:1511–7. 50. Malhotra BK, Glue P, Sweeney K, Anziano R, Mancuso J, Thorough WP. QT study with recommended and supratherapeutic doses of tolterodine. Clin Pharmacol Ther 2007; 81:377–85. 51. Fan DSP, Lam DSC, Chan CKM, Fan AH, Cheung EYY, Rao SK. Topical atropine in retarding myopic progression and axial length growth in children with moderate to severe myopia: a pilot study. Jpn J Ophthal mol 2007;51:27–33. 52. Menon V, Shailesh G, Sharma P, Saxena R. Clinical trial of patching versus atropine penalization for the treatment of aniso metropic amblyopia in older children. J AAPOS 2008;12:493–7.
Ida Duarte, Rosana Lazzarini, and Anita Rotter
14
Dermatological drugs, topical agents, and cosmetics
Editor’s note: The adverse effects of many drugs that are used to treat some skin diseases are covered in other chapters, for example, monoclonal antibodies in Chapter 37 and non-topical corticosteroids in Chapter 39. Vitamin A (carotenoids) is covered in Chapter 34.
Dimethyl fumarate
sufficient to inhibit NF�B1–RelA binding to NF�B consensus oligonucleotides in DNAbinding assays (10E). It has also been used to treat disseminated granuloma annulare (11c), alopecia areata (12c), necrobiosis lipoidica (13c), pityriasis rubra pilaris (14c), multiple sclerosis (15C), and non-infectious uveitis (16c). Observational studies In a retrospective study of 58 patients (25 women, 33 men) who had received fumaric acid esters for severe psoriasis, adverse events were reported in 66% (17 c). They mainly consisted of abdominal pain (61%), diarrhea (55%), flushing (45%), nausea (21%) and malaise (15%). Withdrawal of treatment was required in 15 patients after a mean period of 4.7 months. Lymphocytopenia occurred in 57% of patients, all of whom had had a baseline value within the reference range, but in only one case was it considered severe enough to warrant withdrawal. Eosinophilia is also common (18C).
Dimethyl fumarate is a fumaric acid deriva tive that is used to treat psoriasis (1c, 2C, 3C). After oral administration it is quickly hydro lysed at alkaline pH in the blood to methyl hydrogen fumarate (4E), which stimulates polarization of granulocytes and elastase release (5E). In transformed keratinocytes, dimethyl fumarate releases calcium mainly from intracellular stores into the cytoplasm and inhibits cell proliferation (6E). It reduces cell adhesion by inhibition of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin expression (7E) and inhibits expres sion of HLA-DR (8E). It inhibits the secretion of interleukin-6 (IL-6), transforming growth factor (TGF) alpha and interferon gamma in psoriatic cells (9E). It inhibits nuclear factor kappa B1 (NF�B1) nuclear localization in normal human dermal fibroblasts proved
Gastrointestinal A patient who took Fumaderm® (dimethyl fumarate þ monoethyl fumarate) for chronic plaque psoriasis developed abdominal pain and cramps, diar rhea, nausea and bloating, symptoms that disguised the fact that there was a bowel cancer and partial bowel obstruction (19A).
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32014-9 � 2010 Elsevier B.V. All rights reserved.
Skin Fumaric acid derivatives are potent contact sensitizers (20E) and occupational contact dermatitis has been reported (21A). Cases related to newly acquired sofas and
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chairs have surpassed the news threshold in some countries and the cause of the Chinese sofa/chair dermatitis epidemic is likely to have been contact allergy to dimethyl fuma rate (22A). Five patients with contact derma titis related to newly purchased chairs or sofas were studied. The chairs contained up to 470 micrograms/kg of dimethyl fumarate. The patients had strongly positive patch tests to upholstery fabric samples and to dimethyl fumarate, down to a concentration of 1 ppm in the most severe case.
DYESTUFFS Hair dyes Tumorigenicity Previous studies have sug gested an association between the use of hair dyes and some cancers (SED-15, 1573; SEDA-30, 182, SEDA-31, 288). Several studies have found an association of non Hodgkin’s lymphoma with the use of hair dyes, particularly permanent dark colors and use before 1980, when hair dye formu lations changed. The risk of non-Hodgkin’s lymphoma has been examined in relation to reported hair dye use among 1321 cases and 1057 controls from a US population-based multicenter study. DNA was extracted from blood or buccal cells to identify genetic variations in N-acetyltransferase 1 (NAT1) and 2 (NAT2), which encode enzymes that metabolize aromatic amine compounds found in hair dyes. There was a increased risk of non-Hodgkin’s lymphoma among women who used dark colored or intensetone permanent hair dyes before 1980 (23C).
Henna The crushed leaves of henna are used as a cosmetic agent worldwide, particularly in the Middle East. It causes a red-brown col oration of the skin. Lawsone (2-hydroxy-1,4 naphthoquinone) is a chemical present in henna.
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Hematological Percutaneous application of henna can cause hemolysis in blood cells deficient in glucose-6-phosphate de hydrogenase (G6PD). Hemolysis has been reported after application of henna (24A). • A 7-day-old boy developed mild pallor and jaundice 29 hours after the application of henna for prevention of nappy rash and for traditional cosmetic purposes. He was hypoactive and very icteric. About 50% of the skin surface had the red-brown color typical of henna. Screening revealed G6PD deficiency. Urinalysis was positive for protein, bilirubin, and hemoglobin.
Hemolysis in neonates with G6PD defi ciency is usually secondary to certain trigger ing factors. In this case, other medications, nutriments and infection that could have caused hemolytic anemia in G6PD defi ciency were excluded. The relatively thin newborn skin and the large application area used in this child could have resulted in enhanced percutaneous absorption of henna. Drug contamination Cutaneous deposi tion of mercury has been reported after application of henna that contained a red pigment (25A). • A 13-year-old boy developed a painful cutaneous granuloma and an abscess on the lateral aspect of his swollen arm. He had had a henna dye tattoo 4 months previously. The cutaneous granuloma was incised and mercury droplets were seen embedded in the subcutaneous tissues. Microscopic evaluation of the tissues also revealed zinc salt deposits in the chorion, with reactive granulomatosis.
This illustrates an adverse effect caused by heavy metal contamination of henna.
Paraphenylenediamine Skin In recent years contact dermatitis after henna tattoos has been attributed to the sensitizer paraphenylenediamine, which is used as an antioxidant and favours a longlasting effect of the henna (26A). The use of paraphenylenediamine in henna is responsible for early sensitization to it in children, and in some cases local hypopigmentation occurs in the tattoo (27A).
Dermatological drugs, topical agents and cosmetics
Immunomodulators, topical Tumorigenicity Tacrolimus and pimecroli mus, calcineurin inhibitors, inhibit the dephosphorylation of nuclear factors of activated T cells, causing reduced produc tion of proinflammatory cytokines, such as IL-2. Systemic absorption of topical pime crolimus and tacrolimus is low but detect able in a minority of patients. Although the reported incidence of malignancies in users of these agents has not increased compared with the general population, experts have advised that they be used with caution because of lack of long-term safety data. Two cases of interdigitating dendritic cell tumor have been reported in patients exposed to topical tacrolimus (Protopic) or pimecrolimus (Elidel) (28A). The tumors occurred in the regional lymph nodes draining the areas where the drugs had been applied. Although conclusions cannot be drawn as to the relation between these events, these presentations warrant further clinical observation and investiga tion into the carcinogenic potential of topi cal calcineurin inhibitors.
Pimecrolimus Skin Allergic contact dermatitis from pimecrolimus in a patient with tacrolimus allergy has been described, showing the possibility of cross-reactions among topical immunomodulators (29A). • A 15-year-old man with previously documented allergic contact dermatitis from tacrolimus had an allergic reaction to pimecrolimus, demonstrated by double-blind, right-versus-left provocative testing with pimecrolimus cream 1% versus inactive vehicle. The patient was also patch-tested and was weakly positive (1þ) with pimecrolimus cream 1% and negative with the vehicle. Patch tests on 30 control patients with pimecrolimus cream 1% were negative.
Molluscum contagiosum on the preauri cular area associated with the topical use of pimecrolimus in pityriasis alba has been reported (30A). Although clinical trials have not shown an increased risk of
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cutaneous infections, viral infections such as eczema herpeticum and molluscum eczema can be observed during treatment with pimecrolimus and tacrolimus.
Minoxidil Cardiovascular There have been reports of hypotension and tachycardia after chronic scalp application of minoxidil, suggesting that topical minoxidil can be systemically absorbed. Three young patients with alope cia areata treated with topical minoxidil 2% had cardiovascular adverse effects (31A). • A 12-year-old boy with extensive alopecia areata developed a tachycardia after using minoxidil 1% for 1 month. When minoxidil was withdrawn the tachycardia resolved. • A 10-year-old girl with alopecia totalis developed bouts of palpitation and dizziness after using topical minoxidil 1% for 1 month. The symptoms resolved on withdrawal. • A 14-year-old girl with alopecia areata developed bouts of palpitation and dizziness after using topical minoxidil 1% for 20 days.
Skin Oral minoxidil for the treatment of uncontrolled hypertension was associated with Stevens–Johnson syndrome in a 50-year-old man with chronic renal insuffi ciency (32A).
PHOTOTHERAPY AND PHOTOCHEMOTHERAPY (SED-15, 2823; SEDA-28, 171; SEDA-29, 158)
Aminolevulinic acid Nervous system Pain is the main adverse effect of photodynamic therapy. Each lesion is generally treated twice, and clinical expe rience suggests that the second treatment causes more pain than the first and becomes a therapy-limiting factor. Intrapatient varia tion in the experience of pain, between the first and second treatments, has been
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investigated in 38 patients (33c). The pain score was higher after the second treatment in 21 patients, was unchanged in 6 and was reduced in 11. The pain experienced after the first course of treatment may predict pain after subsequent treatments.
Nervous system Isolated sixth nerve palsy is rarely associated with drug treatment. A man developed diplopia secondary to iso lated sixth nerve palsy after the use of aci tretin for non-melanoma skin cancer chemoprophylaxis (36A).
Skin Topical photodynamic therapy has been used to treat non-melanoma skin can cer. The procedure involves light activation of an endogenous photosensitizer after topi cal application. Allergic contact dermatitis to the prodrug, a rare effect, has again been reported (34A).
Sensory systems Eyes A 33-year-old man with psoriasis vulgaris took oral acitretin 30 mg/day (37A). After 60 days he devel oped watery eyes, erythema and edema near the eyes. There was an excess of gran ulation tissue on the palbebral conjunctivae bilaterally. Microscopic examination was consistent with granulation tissue, which was believed to be related to the therapy. Acitretin was withdrawn, and 40 days later the effects resolved spontaneously. The excess granulation tissue reported with reti noids usually appears after 3–12 weeks of therapy, but there have been reports of reactions after 6 months. The reaction may resolve spontaneously after withdrawal of therapy or after reduction of the dose.
• An old woman developed acute eczema a few days after a fourth course of photodynamic therapy for a basal cell carcinoma on her left leg; the eczema rapidly became generalized over much of her body. After 3 months she had patch tests with a standard series, a textile and lower leg series, disodium ethylenediamine tetraacetate (EDTA), and 1, 5, and 10% aminolevulinic acid methyl ester cream in white soft paraffin. There was a positive reaction to the cream. In order to exclude a false-positive irritant reaction, the cream was applied to 30 consecutive healthy controls; no positive reactions were seen.
There is also a possibility in this case that allergy may have occurred to an untested excipient.
VITAMIN A (RETINOIDS) (SED-15, 3653; SEDA-29, 158; SEDA-30, 185; SEDA-31, 291; for vitamin A carotenoids see Chapter 34 )
Acitretin Cardiovascular Capillary leak syndrome is a rare and potentially life-threatening condi tion caused by a shift of intravascular fluid and proteins to the interstitial space. A patient with pustular psoriasis developed capillary leak syndrome after the start of aci tretin therapy (35A). In such cases, immediate withdrawal of retinoic acid is necessary and glucocorticoid therapy should be considered.
Isotretinoin Cardiovascular Cardiovascular adverse effects have been infrequently reported, but several case reports have suggested that isotretinoin can cause cardiac dysrhyth mias. These cases include patients with atrial tachycardia and incomplete right bun dle branch block, right bundle branch block associated with sinus tachycardia and tran sient sinus tachycardia (38A). • A 22-year-old man with nodular acne developed bouts of palpitation in the third week of a third course of isotretinoin. He took alcohol socially and denied other drug use. An electrocardiogram showed atrial tachycardia at a rate of 127/minute. He was given adenosine 6 mg, his response to which confirmed the diagnosis of atrial tachycardia. Over time there was a gradual fall in heart rate and an eventual return to sinus rhythm, consistent with the long half-life of isotretinoin. After 9 months he was asymptomatic.
Nervous system Accumulating evidence over the past decade has suggested that
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synthetic retinoids may affect both growth and differentiation of nervous tissue. Neuro logical examination and electroneuromyo graphy in 18 patients with various skin diseases before, at 3 months and at the end of isotretinoin treatment suggested the pre sence of a typical distal, length-dependent, predominantly sensory polyneuropathy (39c). The authors suggested that electro neuromyographic investigations should be performed in all patients who report symp toms (e.g. paresthesia, numbness, sensory loss), before and during oral isotretinoin treatment. The precise clinical significance of the isotretinoin-induced neurophysiologi cal alterations reported in this study remains to be determined. Cerebellar demyelination has been attrib uted to isotretinoin (40A). • A demyelinating lesion located in the left cerebellar region developed after treatment with oral isotretinoin for 3 months. One year before, the patient had had endocrinological problems and a brain magnetic resonance imaging (MRI) scan had been normal. However, 3 months after starting to take isotretinoin she reported lack of appetite, faintness and tinnitus. A second MRI scan showed a cerebellar lesion and isotretinoin was withdrawn. One month later the lesion became less prominent and after 3 months it had disappeared.
It is difficult to be sure that there was a causal association between the demyelina tion and isotretinoin in this case. Cerebral ischemia has been associated with isotretinoin (41A). • A 30-year-old right-handed man developed a left-sided facial paralysis and dysarthria. He had taken oral isotretinoin 45 mg/day for 3 months for severe acne. A cerebral CT scan showed a hypodensity in the right middle cerebral territory, suggesting cerebral ischemia. He reported having had a similar episode 7 years before, after taking oral isotretinoin for 3 months. No susceptibility factors were identified. Isotretinoin was withdrawn and the disorder resolved.
Isotretinoin seems to act on the coagulation process by a still-unexplained mechanism. Sensory systems Eyes Ocular adverse effects are common in patients taking
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isotretinoin, and have been comprehen sively reviewed (42R). Most are short-lived and usually resolve entirely on drug with drawal. They include abnormal meibomian gland secretion, sicca syndrome, blepharo conjunctivitis, reduced tolerance to contact lenses, photophobia, and keratitis. However, more significant and potentially persistent abnormalities can occur, including corneal opacities and raised intracranial pressure. Reduced retinal function has been reported, but in most patients it appears to improve on withdrawal. Typical symptoms include blurred vision, reduced night vision, and glare. In many cases patients are asympto matic or unaware of visual adverse effects, despite objectively demonstrable electro physiological abnormalities. Night blindness after the use of low-dose isotretinoin for a very short period has been reported (43A). • A 21-year-old, 60 kg female student was given isotretinoin 20 mg/day and 2 weeks later developed severe deterioration of night vision. Her serum concentrations of vitamin A and retinol binding protein were normal (2.2 µmol/l: reference range 1.4–4.0; and 39 µmol/l: reference range 32–60). She was given vitamin A 5000 units/day and by 4 months after stopping isotretinoin her night vision had recovered.
This case highlights the need to encourage all patients to report changes in night vision promptly, even in the earliest stages of iso tretinoin treatment. Patients such as pilots and commercial drivers, for whom the con sequences of even small changes in night vision would be serious, should be consid ered for electroretinography before and early during the course of isotretinoin ther apy. Measurement of serum concentrations of vitamin A and retinol binding protein can be helpful in assessing patients with impaired night vision, and vitamin A, even with normal serum concentrations, can help to speed recovery. Since isotretinoin is a retinoid, the mechanism of impaired night vision is likely to be interference with the retinol pathway, essential to the function of photoreceptors. Myopia has been attributed to isotreti noin (44A).
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• A 29-year-old Caucasian woman took isotretinoin 40 mg/day for acne and after 20 days suddenly noticed a marked reduction in visual sharpness. An ophthalmologist confirmed binocular myopia of 1.5 and 0.5 dioptres. Isotretinoin was discontinued 6 weeks later, but 13 months later she still had the same defect of refraction.
recovered baseline salivary flow 2 months after the end of treatment.
The authors could conclude that there was a certain relation between myopia and iso tretinoin, because it did not resolve after drug withdrawal. However, sudden onset of myopia in an adult without any previous ocular problem is remarkable.
• A 31-year-old African-Caribbean man was given oral isotretinoin 40 mg/day for dissecting cellulitis of the scalp and 4 weeks later developed sudden, sharp, right-sided chest pain, worse on deep inspiration. There was nothing abnormal on examinations and exhaustive hematological and biochemistry tests were normal, as was a chest X-ray. His chest pain lasted for 2 hours and resolved without pharmacological intervention. He stopped taking isotretinoin but started again 2 weeks later. After 1 week he had another episode of self-limiting right-sided pleuritic chest pain and stopped taking isotretinoin. An echocardiogram was normal. He later restarted isotretinoin and had a third admission with similar symptoms and negative investigations.
Hematologic Agranulocytosis has been attributed to isotretinoin (45A). • A 15-year-old girl with acne vulgaris developed a fever and odynophagia after taking isotreti noin 0.5 mg/kg for 5 weeks and then 1 mg/kg for 15 weeks. She had stopped taking isotretinoin 8 days before. Her hemoglobin was 13.7 g/dl, white blood cell count 1.2 109/l, and platelet count 145 109/l. There were no neutrophils. Bone marrow aspiration excluded malignancy. Antineutrophil antibodies were negative. Epstein–Barr virus, cytomegalovirus and human immunodeficiency virus (HIV) serologies were negative. Neutropenia was attributed to isotretinoin. She was given cefepime 150 mg/ kg/day and a single dose of recombinant human granulocyte colony stimulating factor (r-HuGCSF) subcutaneously. Her fever resolved and her white blood cell count rose to 7.7 109/l with a neutrophil count of 3.3 109/l. During the next year her neutrophil counts were normal.
Agranulocytosis is found in a variety of infectious diseases, but studies in this patient failed to reveal an infectious trigger. Teeth In a cohort study of the oral adverse effects of isotretinoin 0.5 mg/kg/ day salivary flow, the buffering capacity of the saliva, the number of pathogenic bac teria and the DMFT index (number of decayed, missing, and filled teeth) were assessed at each visit in 18 patients and 99 controls (46c). None of the measurements varied with time in the control group, whereas the DMFT index worsened signifi cantly in the treated group. Salivary flow gradually fell with time, but the patients
Serosae Non-musculoskeletal pleuritic chest pain has been associated with isotreti noin (47A).
The exact cause of the chest pain in this patient was undetermined, but the temporal association with isotretinoin on three occa sions and resolution of symptoms on with drawal suggests an association. Musculoskeletal Sacroiliitis and a sensori motor demyelinating polyneuropathy have been associated with isotretinoin (48A). • A 20-year-old otherwise healthy man developed bilateral hip pain. He had been using isotretinoin for acne for the previous 3 months (initial dose 30 mg/day for 2 months, increased to 40 mg/day for 1 month). The sacroiliac joints were very painful bilaterally and he had a Trendelenburg gait. His erythrocyte sedimentation rate was 50 mm/ hour (reference range 0–15); creatine kinase 1629 U/l (0–195), serum lead 160 µg/l (0–20), rheumatoid factor 22 IU/ml (0–15), and C-reactive protein 19 mg/l (0–5). He was HLA-B27 positive. An MRI scan of his sacroiliac joints showed bilaterally diffuse subarticular edema. Electromyography of the leg muscles showed a sensorimotor demyelinating polyneuropathy. Isotretinoin was withdrawn and he was given naproxen 500 mg/day. Within 4 weeks the laboratory results improved and the symptoms almost completely resolved. During 2 years of follow-up, the MRI findings fluctuated, showing presence and absence of sacroiliitis.
Dermatological drugs, topical agents and cosmetics Electromyography 2 years after the initial diagnosis showed mild improvement. A sural nerve biopsy showed demyelinating polyneuropathy with active regeneration.
Reproductive system Although there have been several reports of menstrual irre gularities related to isotretinoin, they were only mentioned as uncommon or trivial adverse effects. Of 40 women with acne patients who took isotretinoin 0.7–1.2 mg/ kg/day for 16 weeks or more, 8 had men strual irregularities during treatment (49c). They all denied previous menstrual irregula rities. Their hormone concentrations, including serum luteinizing hormone (LH), follicular stimulating hormone (FSH), thyroid-stimulating hormone (TSH), prolac tin, estradiol, and androgen, were within the reference ranges, and sonography showed no abnormalities. The progesterone withdrawal test using oral medroxyprogesterone 10 mg for 7 days resulted in bleeding. In all eight patients, menstruation regularity returned to normal after withdrawal of isotretinoin. The mechanism of menstrual irregularity induced by isotretinoin is unclear. Because this study examined women taking high doses of isotre tinoin (maintenance dose 1–1.2 mg/kg/day) for at least 16 weeks, it is difficult to draw a conclusion about the precise effect of treat ment duration and cumulative dose. How ever, normal hormone concentrations and a positive response to progesterone withdrawal in two patients suggested that the irregulari ties were caused by some disturbance in the pattern of pulsatile gonadotropin-releasing hormone (GnRH) secretion. Teratogenicity Of 8609 women aged 13–45 years with a first prescription for isotretinoin, 90 became pregnant, an annual incident preg nancy rate of 33 per 1000 person-years of treatment (95% CI = 27, 40) (50C). Of those 90 women, 76 had a termination, 3 had a spontaneous abortion (3%), 2 had trauma during delivery resulting in neonatal deaths (2%) and 9 had live births. Among the live births, only one had a congenital anomaly of the face and neck. Adjusting for potential confounders, predictors of becoming preg nant while taking isotretinoin were lower
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socio-economic class, one or more visits to the doctor or to the emergency department, or one or more episodes of hospitalization while taking isotretinoin; concomitant oral contraceptive use was preventive. This non interventional population-based study gener ated incidence rates of pregnancy while on isotretinoin four times greater than have been reported so far; elective abortion rates were also much higher.
Tretinoin (all-trans retinoic acid, ATRA) (SEDA-30, 186) In a multicenter, open evaluation of a gel formulation containing a crystalline suspen sion of clindamycin phosphate 1.2% þ tre tinoin 0.025% (called CLIN/RA) in 442 patients, the most frequent adverse events were acne (29/442; 7%, usually a flare), sun burn (12/442; 3%), hypersensitivity reactions (7/442; 2%), contact dermatitis (5/442; 1%), and desquamation at the site of application (3/442; 1%) (51r).
VITAMIN D ANALOGUES, TOPICAL (SED-15, 594; SEDA-29, 156; SEDA-31, 293; for oral vitamin D analogues see Chapter 34)
Tacalcitol Mineral metabolism Tacalcitol is a vitamin D analogue used as an ointment for psoriasis. It can cause hypercalcemia (52A). • A young man with severe psoriasis had an exacerbation of his skin disease (PASI = 68) and was given dithranol in alternation with tacalcitol (Curatoderm®). Tacalcitol was limited to 30% of body surface area once a day. On day 3 he developed severe abdominal pain and vomiting and admitted that he had already used tacalcitol for 3 months in a mean dosage of about 30 g/day. Thus, the cumulative dose was 2500–3000 g, exceeding the manufacturer’s guidelines by 8–10 times. He had severe hypercalcemia due to vitamin D intoxication, which was thought to have been responsible for acute pancreatitis.
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This patient had a very severe disease, in which scaling could have influenced drug absorption. However, he had also used a very high total dose, exceeding the manufac turer’s guidelines by 8–10 times and long-
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term exposure by 2–3 times. This is important, because the amount of drug absorption by the skin is often underestimated by patients and ointments are considered as relatively harmless compared with oral formulations.
References 1. Kolbach DN, Nieboer C. Fumaric acid ther apy in psoriasis: results and side effects of 2 years of treatment. J Am Acad Dermatol 1992;27(5 Pt 1):769–71. 2. Altmeyer PJ, Matthes U, Pawlak F, Hoffmann K, Frosch PJ, Ruppert P, Wassilew SW, Horn T, Kreysel HW, Lutz G Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter doubleblind study in 100 patients. J Am Acad Der matol 1994;30(6):977–81. 3. Mrowietz U, Christophers E, Altmeyer P. Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study. German Multicentre Study. Br J Der matol 1998;138(3):456–60. 4. Litjens NH, van Strijen E, van Gulpen C, Mattie H, van Dissel JT, Thio HB, Nibbering PH. In vitro pharmacokinetics of anti-psoriatic fumaric acid esters. BMC Pharmacol 2004;4:22. 5. Nibbering PH, Thio B, Zomerdijk TP, Beze mer AC, Beijersbergen RL, van Furth R. Effects of monomethylfumarate on human granulocytes. J Invest Dermatol 1993;101 (1):37–42. 6. Thio HB, Zomerdijk TP, Oudshoorn C, Kempenaar J, Nibbering PH, van der Schroeff JG, Ponec M. Fumaric acid deriva tives evoke a transient increase in intracel lular free calcium concentration and inhibit the proliferation of human keratinocytes. Br J Dermatol 1994;131(6):856–61. 7. Vandermeeren M, Janssens S, Borgers M, Geysen J. Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endo thelial cells. Biochem Biophys Res Com mun 1997;234(1):19–23. 8. Sebok B, Bonnekoh B, Vetter R, Schneider I, Gollnick H, Mahrle G. The antipsoriatic
dimethyl-fumarate suppresses interferon gamma-induced ICAM-1 and HLA-DR expression on hyperproliferative keratino cytes. Quantification by a culture platedirected APAAP–ELISA technique. Eur J Dermatol 1998;8(1):29–32. 9. Ockenfels HM, Schultewolter T, Ockenfels G, Funk R, Goos M. The antipsoriatic agent dimethylfumarate immunomodulates T-cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network. Br J Derma tol 1998;139(3):390–5. 10. Vandermeeren M, Janssens S, Wouters H, Borghmans I, Borgers M, Beyaert R, Geysen J. Dimethylfumarate is an inhibitor of cyto kine-induced nuclear translocation of NFkappa B1, but not RelA in normal human dermal fibroblast cells. J Invest Dermatol 2001;116(1):124–30. 11. Weber HO, Borelli C, Ro¨ cken M, Schaller M. Treatment of disseminated granuloma annu lare with low-dose fumaric acid. Acta Derm Venereol 2009;89(3):295–8. 12. Venten I, Hess N, Hirschm€ uller A, Altmeyer P, Brockmeyer N. Treatment of therapy-resistant alopecia areata with fumaric acid esters. Eur J Med Res 2006;11(7):300–5. 13. Kreuter A, Knierim C, St€ ucker M, Pawlak F, Rotterdam S, Altmeyer P, Gambichler T. Fumaric acid esters in necrobiosis lipoidica: results of a prospective noncontrolled study. Br J Dermatol 2005;153(4):802–7. 14. Coras B, Vogt TH, Ulrich H, Landthaler M, Hohenleutner U. Fumaric acid esters therapy: a new treatment modality in pityriasis rubra pilaris? Br J Dermatol 2005;152(2):388–9. 15. Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O’Neill GN,
Dermatological drugs, topical agents and cosmetics BG-12 Phase IIb Study Investigators. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebocontrolled phase IIb study. Lancet 2008;372 (9648):1463–72. 16. Heinz C, Heiligenhaus A. Improvement of noninfectious uveitis with fumaric acid esters: results of a pilot study. Arch Ophthal mol 2007;125(4):569–71. 17. Harries MJ, Chalmers RJ, Griffiths CE. Fumaric acid esters for severe psoriasis: a retrospective review of 58 cases. Br J Der matol 2005;153(3):549–51. 18. Nieboer C, de Hoop D, Langendijk PN, van Loenen AC, Gubbels J. Fumaric acid therapy in psoriasis: a double-blind com parison between fumaric acid compound ther apy and monotherapy with dimethylfumaric acid ester. Dermatologica 1990;181(1): 33–7. 19. Ng SY, Wilkinson J. A salutary case of Fuma derm potentially masking the symptoms of bowel cancer and partial bowel obstruction. Br J Dermatol 2007;157(4): 825–6. 20. de Haan P von Blomberg-van der Flier BM, de Groot J, Nieboer C, Bruynzeel DP. The risk of sensibilization and contact urticaria upon topical application of fumaric acid deri vatives. Dermatology 1994;188(2):126–30. 21. Foti C, Zambonin CG, Cassano N, Aresta A, Damascelli A, Ferrara F, Vena GA. Occupa tional allergic contact dermatitis associated with dimethyl fumarate in clothing. Contact Derm 2009;61(2):122–4. 22. Rantanen T. The cause of the Chinese sofa/ chair dermatitis epidemic is likely to be con tact allergy to dimethylfumarate, a novel potent contact sensitizer. Br J Dermatol 2008;159(1):218–21. 23. Morton LM, Bernstein L, Wang SS, Hein DW, Rothman N, Colt JS, Davis S, Cerhan JR, Severson RK, Welch R, Hartge P, Zahm SH. Hair dye use, genetic variation in N-acetyl transferase 1 (NAT1) and 2 (NAT2), and risk of non-Hodgkin lymphoma. Carcinogen esis 2007;28(12):1759–64. 24. Katar S, Devecioglu C, Ozbek MN, Ecer S. Henna causes life-threatening hyperbilirubi naemia in glucose-6-phosphate dehydrogenase deficiency. Clin Exp Dermatol 2006;32:235–6. 25. Mouzopoulos G, Tsouparopoulos V, Stamatakos M, Mihelarakis I, Pasparakis D,
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Agapitos E. Cutaneous mercury deposits after henna dye application in the arm. Br J Dermatol 2007;157(2):394–5. 26. Davies EEG, Grabczynska S. Para phenylenediamine allergy from a henna tat too. Arch Dis Child 2007;92(3):243. 27. Corrente S, Moschese V, Chianca M, Graziani S, Iannini R, La Rocca M, Chini L. Temporary henna tattoo is unsafe in atopic children. Acta Paediatr 2007;96(3):469–71. 28. Gordon MK, Kraus M, van Besien K. Inter digitating dendritic cell tumors in two patients exposed to topical calcineurin inhi bitors. Leuk Lymphoma 2007;48(4):816–8. 29. Shaw DW, Maibach HI, Eichenfield LF. Allergic contact dermatitis from pimecro limus in a patient with tacrolimus allergy. J Am Acad Dermatology 2007;56(2): 342–5. 30. Goksugur N, Ozbostanci B, Goksugur SB. Molluscum contagiosum infection associated with pimecrolimus use in pityriasis alba. Pediatr Dermatol 2007;24(5):63–5. 31. Georgala S, Befon A, Maniatopoulou E, Georgala C. Topical use of minoxidil in chil dren and systemic side effects. Dermatology 2007;214(1):101–2. 32. Callen EC, Church CO, Hernandez CL, Thompson ED. Stevens–Johnson syndrome associated with oral minoxidil: a case report. J Nephrol 2007;20(1):91–3. 33. Katrine EK, Lindeburg KEK, Brogaard HMV, Jemec GBE. Pain and photodynamic therapy (PDT). Dermatology 2007;215(3):206–8. 34. Harries MJ, Street G, Gilmour E, Rhodes LE, Beck MH. Allergic contact dermatitis to methyl aminolevulinate (Metvix) cream used in photodynamic therapy. Photoderma tol Photoimmunol Photomed 2007;23:35–6. 35. Vos LE, Vermeer MH, Pavel S. Acitretin induces capillary leak syndrome in a patient with pustular psoriasis. J Am Acad Dermatol 2007;56(2):339–42. 36. Arnault JP, Petitpain N, Granel-Brocard F, Cuny JF, Barbaud A, Schmutz JL. Acitretin and sixth nerve palsy. J Eur Acad Dermatol Venereol 2007;21(9):1258–9. 37. Bastos PR, Avelleira JCR, Cruz MA, de Oliveira NC, Azulay DR. Granulation tissue in palpebral conjunctivae associated with aci tretin therapy. J Am Acad Dermatol 2008;58 (2):S41–2.
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38. Dresden G. Atrial tachycardia associated with isotretinoin use. Arch Dermatol 2007;143(8):1084–5. 39. Aydogan K, Karli N. Effects of oral isotreti noin therapy on peripheral nerve functions: a preliminary study. Clin Exp Dermatol 2007;32(1):81–4. 40. Yaman M, Albayram S, Altintas A, Yeni SN, Karaagac N, Islak C. A cerebellar demyeli nating lesion following treatment of acne with isotretinoin. Clin Exp Dermatol 2008;33(2):118–21. 41. Laroche ML, Macian-Montoro F, Merle L, Vallat JM. Cerebral ischemia probably related to isotretinoin. Ann Pharmacother 2007;41(6):1073–6. 42. Taibjee SM, Charles-Holmes R. Pitfalls of pre scribing acne therapies including isotretinoin for pilots. Br J Dermatol 2008;158(3):653–5. 43. Halpagi P, Grigg J, Klistorner A, Damian DL. Night blindness following low-dose isotretinoin. J Eur Acad Dermatol Venereol 2008;22(7):893–4. 44. Martinez-Gonzalez MC, Garcia-Silva J, Sanchez MA, Castineiras I, Del Pozo J, Capdevila EF. Acute myopia while on oral isotretinoin treatment. J Eur Acad Dermatol Venereol 2007;21(7):977–8. 45. Ozdemir MA, Kose M, Karakukcu M, Ferahbas A, Patiroglu T, Koklu E. Isotretinoin induced agranulocytosis. Pediatr Dermatol 2007;24(4):425–6.
Ida Duarte, Rosana Lazzarini, and Anita Rotter
46. Lupi-Pegurier L, Muller-Bolla M, Fontas E, Ortonne JP. Reduced salivary flow induced by systemic isotretinoin may lead to dental decay. Dermatology 2007;214 (3):221–6. 47. Madan V, Muston HL, Marsland AM. Isotretinoin-induced pleuritic chest pain. Br J Dermatol 2007;157(2):385–6. 48. Eksioglu E, Oztekin F, Unlu E, Cakci A, Keyik B, Karadavut IK. Sacroiliitis and poly neuropathy during isotretinoin treatment. Clin Exp Dermatol 2008;33(2):122–4. 49. Kwon HJ, Lee JY, Cho BK, Park HJ. Menstrual irregularity during isotretinoin treatment. J Am Acad Dermatol 2007;21(4): 562–3. 50. Berard A, Azoulay L, Koren G, Blais L, Perreault S, Oraichi D. Isotretinoin pregnan cies, abortions and birth defects: a popula tion-based perspective. Br J Clin Pharmacol 2007;63(2):196–205. 51. Kircik LH, Peredo MI, Bucko AD, Loss Jr. RW, Fowler Jr. JF, Wortzman M, Neumaier GJ. Safety of a novel gel formulation of clindamycin phosphate 1.2%–tretinoin 0.025%: results from a 52 week open-label study. Cutis 2008;82(5): 358–66. 52. Knackstedt C, Winograd R, Koch A, Abuzahra F, Trautwein C, Wasmuth HE. Acute necrotic pancreatitis induced by severe hypercalcaemia due to tacalcitol ointment. Br J Dermatol 2007;156:575–612.
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15
Antihistamines (H1 receptor antagonists)
Histamine plays a prominent and diverse role in the pathophysiology of allergic disease, and therapeutic intervention is therefore typically focussed on blocking the effects of this biogenic amine. The histamine H1 recep tor is a heptahelical transmembrane molecule that transduces extracellular signals to intra cellular second messenger systems via G pro teins. Antihistamines act as inverse agonists that combine with H1 receptors, stabilizing them in the inactive form and shifting the equilibrium towards the inactive state (1R).
Brompheniramine
(SED-15, 562; see also dexbrompheniramine below)
Placebo-controlled studies Both sleepiness and hyperactivity were reported in children taking combinations of antihistamines þ decongestants (brompheniramine þ phenyl propanolamine and brompheniramine þ phenylephrine þ phenylpropanolamine) (2 C , 3 c ).
Cetirizine
(SED-15, 702; SEDA-29, 161; SEDA-30, 189; SEDA-31, 297) Cardiovascular The cardiotoxic effects of antihistamines are of concern in patients with long QT syndrome who also have allergies
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32015-0 � 2010 Elsevier B.V. All rights reserved.
(4R). In a randomized, single-blind study 15 asymptomatic patients with type 1 or type 2 long QT syndrome and 15 healthy volunteers were given placebo or cetirizine 10 mg (5A). Electrocardiography was performed at rest and after exercise. Cetirizine did not prolong the QT intervals either at rest or during exercise and recovery in either group. Thus, it may be safe in carriers of the gene mutations that cause long QT syndrome. Skin Fixed drug eruptions are the most frequent types of adverse cutaneous drug reaction; although fixed drug eruptions caused by systemic antihistamines are very rare, some have been previously reported with both cetirizine and levocetirizine (SEDA-31, 300), and another has been reported (6A). • A 45-year-old woman developed multiple, welldefined, round, erythematous, violaceous plaques, with central blisters on the trunk, forearms, and backs of the hands. She had taken oral cetirizine 10 mg for allergic rhinitis 4 hours before the lesions had appeared and reported three previous eruptions with the same morphology in the same sites, which had resolved spontaneously in 8–10 days, leaving only residual brown to grey hyperpigmentation, features typical of a fixed drug eruption. However, the previous episodes had not been associated with any medication. After an 8-day tapering regimen of methylprednisolone, starting with 32 mg/day, the lesions resolved. Six weeks later patch testing with cetirizine, levocetirizine, hydroxyzine, nimesulide, piroxicam, and vehicle controls produced positive reactions with cetirizine, levocetirizine, and hydroxyzine, but only on previously affected areas as defined by the residual hyperpigmented lesions. She was advised to avoid these three antihistamines and had no relapses.
305
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The authors concluded that cutaneous crossreactivity to cetirizine, levocetirizine, or hydroxyzine was due to the fact that they have the same chemical piperazine structure and similar pharmacological profiles. An urticarial reaction that was repro duced by challenge with cetirizine was not reproduced by levocetirizine (7A). • A 22-year-old man with chronic idiopathic urticaria, asthma and allergic rhinitis developed a severe exacerbation of generalized urticaria. He had previously taken cetirizine and hydroxyzine without aggravation of symptoms, and for the previous 3 months had taken only loratadine. He was given cetirizine and montelukast for nasal symptoms and asthma and 4 hours later developed severe generalized urticaria. Cetirizine and montelukast were withdrawn and the urticarial lesions disappeared spontaneously within 5 days. Subsequently, single-blind, placebo-controlled skin challenge tests were performed with cetirizine, levocetirizine, chlorphenamine, ebastine, fexofenadine, hydroxyzine, loratadine, montelukast, and placebo. Cetirizine and hydroxyzine reproduced the generalized urticaria after 3 and 4 hours respectively; levocetirizine and the other drugs and placebo had no effect. Drug-specific serum IgE was not found.
It is possible that dextrocetirizine, the dextrorotatory enantiomer of cetirizine, was the causative agent in this case, but this possibility was not directly tested.
Garry M. Walsh
urticaria (11C). Adverse events in those taking desloratadine were similar to events in those taking placebo. Because of a phenotypic polymorphism, about 6% of individuals have a reduced ability to metabolize desloratadine to the active metabolite 3-hydroxydesloratadine (12R). In one study three African American sub jects with normal liver function who were poor metabolizers of desloratadine had 2.6–6.5 times greater exposure to des loratadine than subjects with normal liver function and metabolism (13c). Adverse effects in those subjects were no more common than in those with nor mal metabolism.
Dexbrompheniramine
(SED-15, 1081; see also brompheniramine above) Placebo-controlled studies There were more cases of dizziness and dry mouth in patients taking dexbrompheniramine þ pseudephedrine (6 mg þ 120 mg bd for 7 days) (14c).
Dexchlorpheniramine (SED-15, 1081; SEDA-30, 162)
Teratogenicity In a prospective observa tional cohort study in 196 pregnant women exposed to cetirizine during the first trime ster and 1686 women who were not exposed to potential teratogens, cetirizine had no significant teratogenic effects (8C).
Desloratadine(SED-15, 1074; SEDA 29, 162; SEDA-30, 189; SEDA-31, 298; see also Loratadine below) Susceptibility factors Genetic Randomized trials have shown that desloratadine is effective and well tolerated in allergic rhinitis (9C, 10C) and chronic idiopathic
Nervous system First-generation sedating antihistamines such as dexchlorphenira mine and diphenhydramine readily cross the blood–brain barrier, resulting in block ade of histamine H1 receptors in the brain, which are responsible for maintaining a state of arousal, leading to drowsiness, fati gue, and psychomotor disturbances. The effect of first-generation antihistamines on a complex task such as car driving is well established. In a single-blind, placebocontrolled, crossover study the effect of oral dexchlorpheniramine 6 mg on regional cerebral blood flow responses, measured by positron emission tomography and (15O) H2O, was evaluated during a simulated car-driving task (15c). The numbers of lane
Antihistamines (H1 receptor antagonists)
Chapter 15
deviations were significantly increased by dexchlorpheniramine because of sup pression of visuospatial cognition and visuo motor coordination, rather than an effect on attention and motor functions. The authors reported no significant effect on subjective feelings of drowsiness, most probably because a modified-release formulation of dexchlorpheniramine (Repetab) was used in the study.
Diphenhydramine
(SED-15, 1134; SEDA-29, 163; SEDA-30, 189; SEDA-31, 298)
Drug overdose Diphenhydramine is inclu ded in many over-the-counter formulations for the treatment of allergic disease, insom nia, and symptoms of the common cold. Such medications are often used in chil dren, with the consequential risk of un intended diphenhydramine overdose. In a retrospective review of 25 012 cases of acute diphenhydramine overdose in young children, 926 met the following inclusion criteria: younger than 6 years, a single med ication ingested, a known quantity ingested, and a known clinical outcome (16c). The mean age was 30 months (range 1–72 months) and 49% were boys. The mean dose was 6.4 mg/kg (median 4.6). There were symptoms in 32%; most were minor (29%), 2.9 % had moderate symptoms, and 0.11% had severe symptoms. There was no relation between dose and symptom inten sity. A diphenhydramine dose of 7.5 mg/kg or more did not predict symptom severity; however, the authors concluded that patients who take a single dose greater than this should be referred to a healthcare facility. Overdosage in an adult has also been reported (17A). • A 47-year-old obese (110 kg) Caucasian man took 230 tablets of diphenhydramine (Benocten), giving a total dose of 10 mg/kg. He developed slight rotational nystagmus, opened his eyes only on command, and had no comprehensible speech. His Glasgow Coma Scale (GCS) score was 9. However, 3
307 hours after ingestion his cognitive state deteriorated to a GCS score of 5. He was intubated, sedated with propofol 100 mg/hour, and given activated charcoal 110 g over 6 hours through a nasogastric tube. After another 9 hours he awoke and remained asymptomatic thereafter.
The authors expressed surprise that a diphenhydramine plasma concentration above 15 µmol/l 8 hours after ingestion led to only a few hours of impaired conscious ness in this patient and no other symptoms. Severe symptoms, including coma, seizures, delirium, psychosis, agitation, and/or elec trocardiographic changes, are commonly expected with diphenhydramine doses above 1 g (18C).
Doxylamine
(SED-15, 1192;
SEDA-31, 298) Nervous system Giddiness and drowsiness were reported in adults taking Vicks Medi nite syrup (doxylamine þ dextromethor phan þ ephedrine þ paracetamol) (19c). Musculoskeletal Rhabdomyolysis is a potentially life-threatening complication of doxylamine overdose and in some cases leads to acute renal insufficiency, requiring dialysis. Most patients recover completely from rhabdomyolysis if it is recognized and treated promptly. Accordingly, early detec tion and management of patients at high risk of rhabdomyolysis after doxylamine overdose is important. In a prospective, observational study of 27 patients with doxylamine overdose, 16 developed rhabdomyolysis and 3 had acute renal insufficiency (20C). A dose of doxylamine greater than 20 mg/kg predicted rhabdomyolysis, with a sensitivity of 81%. As the authors acknowledged, the chief limitation of this study was the small number of subjects. However, they concluded that all patients with doxylamine overdose should be investigated for rhabdomyolysis and treated promptly to prevent progression to acute renal insufficiency.
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Levocetirizine (SED-15, 2038; SEDA-29, 163; SEDA-30, 190; SEDA-31, 300; see also Cetirizine above) Cardiovascular In a four-way, crossover, randomized, placebo- and positive-controlled trial of the effect of levocetirizine 5 and 30 mg/ day on the QT interval in 52 healthy men and women, levocetirizine had no significant effects on cardiac repolarization, in contrast to the effect of moxifloxacin (21C). Teratogenicity An analysis of safety data from the Early Prevention of Asthma in Atopic Children Study, in which 510 atopic children aged 12–24 months at entry received either levocetirizine 0.125 mg/kg bd or placebo for 18 months showed no significant adverse effects or treatment-associated drop outs associated with levocetirizine (22C). This comprehensive and well-constructed study confirms the long-term safety of levocetirizine in young atopic children.
Loratadine
(SED-15, 2162; SEDA-29, 164; see also Desloratadine above)
Garry M. Walsh
insomnia) were reported in 30% of those taking loratadine þ pseudoephedrine (5 mg 120 mg bd for 4 days) compared with 21% of those taking placebo (23C).
Rupatadine Rupatadine is a dual-acting compound that acts as both a histamine H1 receptor antago nist and a potent antagonist of the proinflammatory lipid mediator platelet activating factor (PAF). In randomized clin ical trials rupatadine has been effective and well tolerated in patients with allergic rhini tis (24C) and chronic idiopathic urticaria (25C, 26C). Placebo-controlled studies In a rando mized, double-blind, three-way, crossover study of the effect of rupatadine 10 mg on the actual driving performance of 20 healthy volunteers, it had no significant effect on lateral positioning, while the posi tive control hydroxyzine 50 mg significantly impaired it (27C).
Placebo-controlled studies Adverse events (including dry mouth, headache, and
References 1. Leurs R, Church MK, Taglialatela M. H1-antihistamines: inverse agonism, anti inflammatory actions and cardiac effects. Clin Exp Allergy 2002;32:489–98. 2. Clemens CJ, Taylor JA, Almquist JR, Quinn HC, Mehta A, Naylor GS. Is an antihistamine– decongestant combination effective in tem porarily relieving symptoms of the common cold in preschool children? J Pediatr 1997; 130(3):463–6. 3. Hutton N, Wilson MH, Mellits ED, Baumgardner R, Wissow LS, Bonuccelli C, Holtzman NA, DeAngelis C. Effectiveness of an antihistamine-decongestant combination for young children with the common cold: a
randomized, controlled clinical trial. J Pediatr 1991;118(1):125–30. 4. Yap YG, Camm AJ. Potential cardiac toxi city of H1-antihistamines. Clin Allergy Immunol 2002;17:389–419. 5. Hekkala AM, Swan H, Väänänen H, Viitasalo M, Toivonen L. The effect of antihistamine cetirizine on ventricular repo larization in congenital long QT syndrome. J Cardiovasc Electrophysiol 2007;18(7): 691–5. 6. Cravo M, Goncalo MFigueiredo A. Fixed drug eruption to cetirizine with positive lesional patch tests to the three piperazine derivatives. Int J Dermatol 2007;46:760–2.
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7. Chang YS, Kwon HS, Cho SH, Kim YY, Min KU. A case of urticaria induced by both hydroxyzine and cetirizine but not by levocetirizine. Allergy 2007;62(7):819–21. 8. Weber-Schoendorfer C, Schaefer C. The safety of cetirizine during pregnancy: a pro spective observational cohort study. Reprod Toxicol 2008;26(1):19–23. 9. Pradalier A, Neukirch C, Dreyfus I, Devillier P. Desloratadine improves quality of life and symptom severity in patients with allergic rhinitis. Allergy 2007;62:1331–4. 10. Lam HC, Tong MC, van Hasselt CA. Rhinitis symptoms and quality of life in patients with chronic perennial rhinitis treated with deslor atadine. J Laryngol Otol 2007;121:1151–5. 11. Ortonne JP, Grob JJ, Auquier P, Dreyfus I. Efficacy and safety of desloratadine in adults with chronic idiopathic urticaria: a rando mized, double-blind, placebo-controlled, multicenter trial. Am J Clin Dermatol 2007;8:37–42. 12. Prenner B, Kim K, Gupta S, Khalilieh S, Kantesaria B, Manitpisitkul P, Lorber R, Wang Z, Lutsky B. Adult and paediatric poor metabolisers of desloratadine: an assessment of pharmacokinetics and safety. Expert Opin Drug Saf 2006;5:211–23. 13. Gupta SK, Kantesaria B, Wang Z. Multipledose pharmacokinetics and safety of deslor atadine in subjects with moderate hepatic impairment. J Clin Pharmacol 2007; 47:1283–91. 14. Curley FJ, Irwin RS, Pratter MR, Stivers DH, Doern GV, Vernaglia PA, Larkin AB, Baker SP. Cough and the common cold. Am Rev Respir Dis 1988;138(2):305–11. 15. Tashiro M, Sakurada Y, Mochizuki H, Hor ikawa E, Maruyama M, Okamura N, Wata nuki S, Arai H, Itoh M, Yanai K. Effects of a sedative antihistamine, D-chlorpheniramine, on regional cerebral perfusion and perfor mance during simulated car driving. Hum Psychopharmacol 2008;23(2):139–50. 16. Stojanovski SD, Baker SD, Casavant MJ, Hayes JR, Robinson RF, Nahata MC. Impli cations of diphenhydramine single-dose unintended ingestions in young children. Pediatr Emerg Care 2007;23:465–8. 17. Frick S, Roos M, Fattinger K. How much is too much? Oligosymptomatic presentation
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after 11.5 g of diphenhydramine. Hum Exp Toxicol 2007;26:131–3. 18. Radovanovic D, Meier PJ, Guirguis M, Lorent JP, Kupferschmidt H. Dose-dependent toxicity of diphenhydramine overdose. Hum Exp Toxicol 2000;19:489–95. 19. Thackray P. A double-blind, crossover con trolled evaluation of a syrup for the night time relief of the symptoms of the common cold, containing paracetamol, dextromethor phan hydrobromide, doxylamine succinate and ephedrine sulphate. J Int Med Res 1978;6(2):161–5. 20. Jo YI, Song JO, Park JH, Koh SY, Lee SM, Seo TH, Lee JH. Risk factors for rhabdo myolysis following doxylamine overdose. Hum Exp Toxicol 2007;26:617–21. 21. Hulhoven R, Rosillon D, Letiexhe M, Meeus MA, Daoust A, Stockis A. Levocetir izine does not prolong the QT/QTc interval in healthy subjects: results from a thorough QT study. Eur J Clin Pharmacol 2007;63:1011–7. 22. Simons FE, Early Prevention of Asthma in Atopic Children (EPAAC) Study Group. Safety of levocetirizine treatment in young atopic children: an 18-month study. Pediatr Allergy Immunol 2007;6:535–42. 23. Berkowitz R, Connell J, Dietz A, Greenstein S, Tinkelman D. The effectiveness of the nonsedating antihistamine loratadine plus pseudoephedrine in the symptomatic man agement of the common cold. Ann Allergy 1989;63(4):336–9. 24. Fantin S, Maspero J, Bisbal C, Agache I, Donado E, Borja J, Mola O, Izquierdo I Inter national Rupatadine Study Group. A 12-week placebo-controlled study of rupatadine 10 mg once daily compared with cetirizine 10 mg once daily, in the treatment of persistent aller gic rhinitis. Allergy 2008;63(7):924–31. 25. Gimenez-Arnau A, Pujol RM, Ianosi S, Kaszuba A, Malbran A, Poop G, Donado E, Perez I, Izquierdo I, Arnaiz E, Rupata dine Urticaria Study Group. Rupatadine in the treatment of chronic idiopathic urticaria: a double-blind, randomized, placebocontrolled multicentre study. Allergy 2007;62:539–46. 26. Dubertret L, Zalupca L, Cristodoulo T, Benea V, Medina I, Fantin S, Lahfa M,
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310 Pérez I, Izquierdo I, Arnaiz E. Once-daily rupatadine improves the symptoms of chronic idiopathic urticaria: a randomised, double-blind, placebo-controlled study. Eur J Dermatol 2007;17:223–8.
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27. Vuurman E, Theunissen E, van Oers A, van Leeuwen C, Jolles J. Lack of effects between rupatadine 10 mg and placebo on actual driving performance of healthy volunteers. Hum Psychopharmacol 2007;22(5):289–97.
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Drugs that act on the respiratory tract
INHALED GLUCOCORTICOIDS (SEDA-29, 168; SEDA-30, 193; SEDA-31, 305)
Inhaled glucocorticoids and the risk of pneumonia
EIDOS classification:
Extrinsic species: Glucocorticoids
Intrinsic species: Not known
Distribution: Lungs
Outcome: Not known
Sequela: Pneumonia from inhaled
glucocorticoids in COPD
DoTS classification:
Dose-relation: Collateral reaction
Time-course: Early
Susceptibility factors: Age (over 55
years); physiological changes (low body mass index); diseases (severe COPD) A large cohort of patients with chronic obstructive pulmonary disease (COPD) using inhaled glucocorticoids has been stud ied in a retrospective, nested, case-control study (1c). Each subject who was hospita lized for pneumonia between 1988 and 2003 (n = 23 942) was age- and timematched with four control subjects (n = 95 768). After adjusting for co-morbidity and Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32016-2 � 2010 Elsevier B.V. All rights reserved.
severity of COPD, the rate ratio of hospita lization for pneumonia associated with cur rent use of inhaled glucocorticoids was 1.70 (95% CI = 1.63, 1.77); for hospitalization for pneumonia followed by death within 30 days the rate ratio was 1.53 (95% CI = 1.30, 1.80). The rate ratio of hospitalization for pneumo nia was greatest with the highest doses of inhaled glucocorticoids. For example, at a dosage equivalent to fluticasone 1 mg/day or more, the rate ratio was 2.25 (95% CI = 2.07, 2.44). All-cause mortality was similar for patients hospitalized for pneumo nia, whether or not they had used inhaled glucocorticoids (7.4 and 8.2%, respectively). The Towards a Revolution in COPD Health (TORCH) randomized controlled trial also reported that there was an excess of patients who developed pneumonia if they were using study medications containing inhaled glucocorticoids (either as monotherapy or in combination with a long-acting beta-adrenoceptor agonist) (2C). A post hoc analysis of their data showed that, after adjusting for time on treatment, there was a higher rate of pneumonia in those who used either fluticasone or salmeterol þ fluticasone (84 and 88 per 1000 treatment-years respec tively) compared with salmeterol only and pla cebo (52 and 52 per 1000 treatment-years respectively), despite a higher withdrawal rate in the placebo arm (3C). Susceptibility factors for pneumonia in those using inhaled glucocorticoids were age 55 years or more, more severe COPD with an FEV1 under 50% predicted, COPD exacerbations in the year before the study, worse Medical Research Council dyspnea scores and body mass index (BMI) under 25 kg/m2. There was no increase in pneumonia deaths
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with salmeterol þ fluticasone, but this could not be concluded for fluticasone alone. In a review of 18 randomized controlled trials involving 16 966 subjects with COPD, inhaled glucocorticoids were associated with a significantly increased risk of any pneumonia (RR= 1.60; 95% CI = 1.33, 1.92) and serious pneumonia (RR = 1.71; CI = 1.46, 1.99), but without a significantly increased risk of pneumonia-related mortality (RR = 1.27; CI = 0.80, 2.03) or overall mortality (RR = 0.96; CI = 0.86, 1.08) (4M). Moreover, inhaled glucocorticoids were associated with a significantly increased risk of serious pneu monia compared with placebo (RR = 1.81; CI = 1.44, 2.29) and also when the combination of inhaled glucocorticoids and long-acting beta-adrenoceptor agonists was compared with long-acting beta-adrenoceptor agonists alone (RR = 1.68; CI = 1.20, 2.34). In an analysis of pooled data from seven large trials comparing 3801 patients using inhaled budesonide (320–1280 micrograms/ day) with or without formoterol, with 5212 patient-years of exposure to treatment, versus 3241 patients in the control arms receiving placebo or formoterol alone, there was no significant difference in the occurrence of pneumonia (3% in both groups, adjusted HR = 1.05, 95% CI = 0.81, 1.37) or for time to pneumonia (log rank test = 0.94) (5M). The authors concluded that (in contrast to other inhaled glucocorticoids) budesonide used for 12 months did not increase the risk of pneumonia in patients with COPD. In summary, despite the benefits of inhaled glucocorticoids in the management of COPD, health-care providers should remain vigilant to the possibility of non-fatal pneumonia as a complication of inhaled glucocorticoids. Skin Cutaneous thinning and bruising have been reported in adults using inhaled glucocorticoids, but a double-blind, randomized, placebo-controlled trial of inhaled triamcinolone in COPD has provided more specific details on the exact prevalence of cutaneous adverse effects (6C). Bruising occurred in 11% of those who used inhaled glucocorticoids and 3.7% with placebo; delayed wound healing
Chapter 16
Keir E. Lewis and Gwyneth A. Davies
occurred in 2.4% and 0.5% respectively. These adverse effects were dose-related and increased with age.
Inhaled glucocorticoids: update on skeletal adverse effects The effects of inhaled glucocorticoids on osteoporosis and the risk of hip fracture were reviewed in SEDA-31 (p. 307), but more evidence is accruing about those who use inhaled glucocorticoids specifically for COPD. The dose–response relationship between inhaled glucocorticoids and the risk of frac ture in people with COPD, independent of confounders, has been investigated in a nested case-control study (7 c). Cases (people with a fracture identified from network data bases, n = 1235) were assigned up to four controls (n = 4598). The risk of fracture increased with increasing mean daily doses of inhaled glucocorticoids, and was most marked in those whose daily dose was at least 1.6 mg (OR = 1.80, 95% CI = 1.04, 3.11). This effect was virtually unchanged by adjustment for the degree of airflow obstruction and the annual prescription rate for oral glucocorticoids (adjusted OR for highest exposure = 1.74, 95% CI = 1.00, 3.01). The prevalence and progression of osteo porosis, specifically in patients taking inhaled glucocorticoids for COPD, was studied in a subset of 658 patients in the TORCH study (8C). This US subgroup had annual assess ments of bone mineral density. At baseline, 18% of the men and 30% of the women had osteoporosis and 42% of the men and 41% of the women had osteopenia. Annual changes in bone mineral density at the hip and lumbar spine over 3 years were small and there were no significant differences between treatment arms (adjusted mean percentage change from baseline at the hip was –3.1% for pla cebo, –1.7% for salmeterol only, –2.9% for fluticasone only, and –3.2% for the combina tion of salmeterol þ fluticasone; the respective changes at the lumbar spine were 0, 1.5, –0.3 and –0.3%). The incidence of fractures was low and similar with all treatments (5.1–6.3%). The authors concluded that
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osteoporosis is highly prevalent in patients with COPD, irrespective of sex, but there was no significant effect of standard doses of inhaled glucocorticoids on bone mineral density compared with placebo. In a case-control study of all patients with a fracture (n = 124 655), in the year 2000 in Denmark each with three age- and sexmatched controls randomly drawn from the general population (n = 373 962), COPD (OR = 1.19; CI = 1.13, 1.25), emphysema (OR = 1.31; CI = 1.16, 1.48), and other chronic lung diseases (OR = 1.20; CI = 1.00, 1.44) were associated with a higher relative risk of any fracture than asthma (OR = 1.06; CI = 1.01, 1.12) (9c). Oral glucocorticoids were associated with a dose-related increased risk of fractures. Apart from beta-adreno ceptor agonists (see below), other bronchodila tors and inhaled glucocorticoids at standard doses (up to 1 mg/day of beclometasone equiva lents) were not associated with a risk of fracture. From a sample of 10 941 adults who entered a Norwegian asthma study in 1995–1997, 2848 were interviewed, under went spirometry, and had their forearm bone mineral density assessed again in 2001; 528 had used inhaled glucocorticoids at both baseline and follow-up (10c). The yearly loss of adjusted forearm distal bone mineral density was higher in those who had used inhaled glucocorticoids at both baseline and follow-up compared with subjects with out respiratory symptoms. In women, the figures were 3.14 versus 2.26 mg/cm2, and in men they were 3.76 versus 1.92 mg/cm2. However, there was no significant associa tion between loss of bone mineral density and either daily dose or duration of use of inhaled glucocorticoids. Reduced lung func tion was an independent susceptibility factor for increased bone loss in both sexes, so residual confounding by disease severity could not be ruled out. Even if inhaled gluco corticoids did affect forearm bone mineral density in people with asthma, it should have minor clinical significance in most patients using low to moderate doses. In summary, there is growing evidence that inhaled glucocorticoids are associated with a small increase in the risk of fracture, but further reviews suggest that this occurs
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only at higher doses (11M), and such an effect has been confirmed by specific analysis in older adults, in whom the relative risk of non-vertebral fractures increases by about 12% for each 1 mg/day increase in the dose of beclometasone or equivalent (12M). The effect is stronger in COPD. Even then, the magnitude of this risk is considerably less than other common susceptibility factors for fracture in older adults.
Susceptibility factors Children The phar macokinetics, pharmacodynamics, efficacy, and adverse effects of different inhaled glucocorticoids in children with asthma have been reviewed (13R). Optimizing drug kinetics and metabolism is important in reducing adverse effects. An ideal inhaled glucocorticoid should have high pulmonary deposition; in this respect, des-ciclesonide is better than beclometasone with a hydrofluor oalkane (HFA) propellant. A longer lung residency time is also favorable, and this increases when both budesonide and des ciclesonide undergo reversible fatty acid ester ification. The clearance rate of des-ciclesonide is very high, increasing its safety profile. Fluti casone and mometasone have the highest receptor-binding affinity (18 and 22 times that of dexamethasone respectively), followed by budesonide (9.4; dexamethasone = 1). In low to medium doses, inhaled glucocorticoids hardly suppress the adrenal pituitary axis (see also SEDA-31, 305), but in high doses (e.g. 2 mg beclometasone equivalent), there is potential for significant adrenal suppression and adrenal crisis in children and adults. So, at the recommended doses, their effect on the adrenal glands is not clinically relevant, and the small change in cortisol concentrations that occurs reflects their presence in the blood. In several longitudinal studies in children, inhaled glucocorticoids have been con firmed to cause a small reduction in growth velocity (1–2 cm) during the first year of treatment. However, during follow-up of children who used budesonide for up to 10 years, there was no change in target adult height. Others have similarly concluded that growth velocity is slowed when inhaled
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glucocorticoids are used in younger chil dren, but this occurs only in the first months of treatment and is followed by a catch-up period and consistent data sup port the lack of a significant effect on final height (14R). However, close follow-up is warranted when doses of inhaled gluco corticoids higher than recommended are used.
BETA 2-ADRENOCEPTOR AGONISTS (SEDA-29, 171; SEDA-30, 198; SEDA-31, 308) Combination therapy Asthma guidelines recommend adding long-acting beta2 adrenoceptor agonists (LABAs) to inhaled glucocorticoids at step 3 in adults and adolescents before increasing the dose of beclometasone or other glucocor ticoids above 400 micrograms equivalents and certainly before increasing above 800 micrograms (15S, 16S). LABAs and combination therapy are licensed for chil dren over 5 years, but have not yet been adequately evaluated below this age. They should not be used in isolation in asthma but as add-on therapy to inhaled glucocor ticoids (17S). Comparative studies Arformoterol versus salmeterol Nebulized arformoterol (50 micrograms/day; n = 528) and salmeterol metered-dose inhaler (MDI; 42 micrograms bd n = 265) have been compared over 12 months in subjects with COPD (18C). There was no evidence of tolerance in either group – no increase in exacerbation rates or reduc tion in forced expiratory volume in 1 second (FEV1) response. Adverse events occurred in 91% with arformoterol and 88% with salmeterol. Tremor was more common with nebulized arformoterol (13%) than salme terol (1.1%). Formoterol versus salbutamol Formoterol (12 þ 12 micrograms via Aerolizer) has been compared with salbutamol (200 þ 200 þ
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200 micrograms via spacer) each at 20-minute intervals in 60 patients with acu te exacerbations of asthma in a doubleblind, randomized, placebo-controlled study (19C). Typical beta2-adrenoceptor mediated symptoms (reported as adverse events) occurred in 12 patients who used formoterol and 11 who used salbutamol. There was no significant difference in inci dence of adverse events between the two groups: dry mouth (38% versus 36%), dizziness (16% versus 7.1%), headache (9.4% versus 7.1%). The effects of formoterol Turbuhaler® (2 9 micrograms and 6 9 micrograms) and salbutamol Diskhaler® (3 400 micro grams and 9 400 micrograms) have been compared in 26 patients with asthma in a double-blind, crossover, randomized, pla cebo-controlled study (20C). Maximum heart rate and palpitation and tremor scores were statistically significant greater after sal butamol. Other systemic effects were com parable and the effects were brief. These findings need to be interpreted with caution, given the small size of the study. Adrenoceptor agonists versus glucocortic oids Combination therapy with salmeterol þ fluticasone propionate has been compared with increased doses of inhaled glucocor ticoids in patients with asthma in a meta analysis of 12 studies (5218 subjects) (21M). Combination therapy produced a statistically significant small improvement in lung function and symptoms but no significant reduction in exacerbations. Adverse events were less common with low-dose combination therapy (183/2522) than with increased doses of inhaled glu cocorticoids (263/2547) (OR = 0.85; n = 11; 95% CI = 0.76, 0.96). There were no sig nificant differences in hoarseness, oral can didiasis, upper respiratory tract infections or headache. Three previous systematic reviews (total n = 10 231) comparing LABAs þ inhaled glucocorticoids with different maintenance strategies using inhaled glucocorticoids in adults with asthma have been further combined (22M). The addition of a LABA
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to an inhaled glucocorticoid resulted in significantly better asthma control than maintenance inhaled glucocorticoids. The addition of a LABA to an inhaled gluco corticoid was associated with increased tre mor, which was both significant for initial therapy (NNTH = 21) and compared with higher doses of inhaled glucocorticoids (NNTH = 74). Headache and withdrawals caused by adverse events were similar. There were significantly fewer total withdrawals compared with a similar dose of an inhaled glucocorticoid alone (RR = 0.87; 95% CI = 0.77, 0.98). The authors concluded that the greatest benefit and least harm from using LABAs resulted from their addition to a similar dose of an inhaled glucocorticoid in adults with symptomatic asthma. Cardiovascular Concerns have been raised about the long-term safety of longacting beta2-adrenoceptor agonists; their overall adverse effects were reviewed in SEDA-30 (p. 198) and their respiratory adverse effects in SEDA-31 (p. 309). Subsequently, death from any cause was examined in the 3-year, multi center, rando mized, placebo-controlled TORCH trial in COPD, in which salmeterol þ fluticasone (50 and 500 micrograms bd) was compared with salmeterol alone, fluticasone alone, or placebo (n = 6184; 1542 in the salmeterol arm; mean age 65 years) (2C). All-cause mortality rates were 13% with the combina tion, 14% with salmeterol, 16% with fluti casone, and 15% with placebo. Although there was an 18% reduction in the risk of death with combination therapy compared with placebo, this did not quite reach statis tical significance (HR = 0.825; 95% CI = 0.681, 1.002). There was no significant difference in the cardiovascular causes of death (3% of patients) or in all-cause mortality between salmeterol and placebo. The incidence of cardiac disorders was not significantly increased by salmeterol (reported event rates per study year: 0.087 with combination therapy, 0.114 with salme terol alone, 0.102 with fluticasone, and 0.113 with placebo). Some have linked the use of
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beta2-adrenoceptor agonists to an increased risk of fractures, but the incidence of fractures was comparable across the groups. The risk of acute myocardial infarction in patients using beta2-adrenoceptor ago nists has been assessed in a nested casecontrol study (n = 2476) within a cohort of antihypertensive drug users in the Dutch PHARMO RLS database (23C). Current users had an increased risk of acute myo cardial infarction (crude OR = 1.36; 95% CI = 1.15, 1.61), but this risk was reduced after adjustment for the severity of asthma and COPD (adjusted OR = 1.18; 95% CI = 0.93, 1.49). Thus, only patients with ischemic heart disease with low cumulative exposure to beta2-adrenoceptor agonists had an increased risk of acute myocardial infarction (adjusted OR = 2.47; 95% CI = 1.60, 3.82). This excess risk was attributed to latent cardiovascular disease rather than to the direct effects of beta2 adrenoceptor agonists. Metabolism Lactic acidosis (peak serum concentration 5.2–13 mmol/l) has been described in a retrospective series of four children who were treated with nebulized beta2-adrenoceptor agonists for acute severe asthma (24A). However, it should be noted that a causal relationship was speculative; lactic acidosis may have been caused by mechanisms related to acute severe asthma. Musculoskeletal In a survey of all Danish patients who sustained fractures during 1 year (n = 124 655) compared with age- and sex-matched controls from the general population, the risk of fracture was assessed in patients with chronic lung diseases using bronchodilator drugs, inhaled glucocorticoids and oral glucocorticoids (9C). Inhaled short-acting beta2-adrenoceptor agonists (SABAs) were associated with an increased risk of fracture that was not dose-related: low doses were associated with an increased risk but higher doses were not. Inhaled LABAs (singly and in combination) and
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other bronchodilators were not associated with an increased risk. These results suggest that the increased risk of fracture may have been associated with the severity of the underlying lung disease rather than the drugs themselves. Susceptibility factors Genetic The effect of beta2-adrenoceptor gene (ADRB2) polymorphisms on the response to LABAs was reviewed in SEDA-31 (p. 310). There has since been a pharmacogenetic analysis of two randomized studies, to determine whether ADRB2 polymorphisms affect responses to LABAs in combination with inhaled corticosteroids (25M). In one 6-month, double-blind, randomized study (n = 2250), budesonide þ formoterol main tenance and reliever therapy, fixed-dose budesonide þ formoterol and fixed-dose fluticasone þ salmeterol were compared. Another study was of similar design (n = 405). In the first study, worsening asthma (the most common serious adverse event, n = 17) occurred at a comparable frequency across all the genotype groups. The Gly16Arg genotype did not influence adverse events or therapeutic responses in either study. In a double-blind, crossover, randomized, placebo-controlled study (n = 20), responses to subcutaneous terbutaline after treatment for 2 weeks with either terbutaline inhalation or placebo have been compared in patients with homozygous Arg16 or Gly16 in ADRB2 (26c). There were no genotypic dif ferences in the rise in FEV1 after subcuta neous terbutaline, whether or not it was preceded by terbutaline inhalation. For the Arg16 genotype only, subcutaneous terbuta line-induced hypokalemia was attenuated by pre-treatment with inhaled terbutaline (which resulted in an overall increase in baseline plasma potassium). However, it is difficult to extrapolate these differences to a general population, given the small size of this study. Prospective randomized con trolled trials are needed to clarify whether ADRB2 variance affects genetic susceptibil ity in relation to adverse events associated with beta2-adrenoceptor agonists.
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Age Adverse events relating to beta2 adrenoceptor agonists in older people (electrolyte disturbances, cardiac effects, tremor, tolerance, poor disease control, sudden life-threatening exacerbations, asth ma-related deaths, osteoporosis, nervous tension, headaches, sleep/behavior disturbance) have been reviewed (27R). Older people and those with co-morbidities were under-represented in drug trials, and caution must be exercised in interpreting these adverse events data.
Formoterol Placebo-controlled studies Racemic formo terol (6, 12, 24, and 48 micrograms) has been investigated over 5 days in 20 patients with COPD in a double-blind, crossover, randomized, placebo-controlled study (28C). There was a dose–response relationship with tremor, which increased with 24 and 48 micrograms. There was a statistically significant rise in mean heart rate after 48 micrograms but no dose–response rela tionship. The systemic effects at high doses were minimal. However, these findings should be interpreted with caution, given the small size of the study. Electrolyte balance High-dose therapy with 10 puffs of budesonide þ formoterol (100 þ 6 micrograms) or formoterol 6 micro grams during maintenance treatment with budesonide þ formoterol 2 puffs/day has been studied in 18 patients with asthma in a double-blind, three-way crossover, placebocontrolled study (29C). Formoterol was associated with a significantly greater reduc tion in serum potassium than budesonide þ formoterol or placebo (difference in mean minimum concentrations 0.11 and –0.15 mmol/l, respectively). There were no signifi cant differences in QTc interval, plasma lactate or vital signs. It should be emphasized that patients with asthma should not be treated with LABAs alone and that these should always be used as add-on therapy to inhaled corticosteroids (15S, 16S, 17S).
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Dosage regimens Once-daily versus twicedaily formoterol (total 24 micrograms/day) via Novolizer® have been compared over 12 weeks in 321 patients with moderate to severe COPD in a parallel-group, multi center, double-blind, randomized, active-controlled study (31C). The incidences of adverse events were comparable between groups and inclu ded tremor, confusional states, and insomnia. Over 96% of the patients and their physicians assessed tolerability as good or very good in both groups.
Indacaterol Indacaterol is a LABA. In contrast to sal meterol, which is a partial agonist with a duration of action of 12 hours, indacaterol is a full agonist with a duration of action of 24 hours (32RE, 33C, 34C). Comparative studies Indacaterol 200 or 1000 micrograms, salbutamol 200 or 1000 micrograms, salmeterol 50 or 2500 micro grams and placebo have been compared in 20 patients with persistent asthma, using single therapeutic and supra-therapeutic doses, in a randomized, open, crossover study (35c). There were few adverse events, and all were mild or moderate in intensity. The adrenoceptor agonists caused initial changes in glucose, potassium, heart rate, and QTc interval, but all values remained within the reference ranges. Placebo-controlled studies Indacaterol has been studied in 163 patients with moderate COPD in a 28-day, double-blind, randomized, placebo-controlled study (36C). They were randomized 2:2:1 to indacaterol 400 or 800 micrograms/day or placebo by singledose dry-powder inhaler, and 155 completed the study. There were no statistically significant differences between the groups in the overall incidence of adverse events (35%, 51% and 25%, respectively). Most of the adverse events were mild or moderate in intensity, and there were no drug-related
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serious adverse events. There were no statistically significant differences between indacaterol and placebo in mean pulse rate and QTc interval, and isolated statistically significant differences in mean blood pressure, blood glucose, and serum potassium. The effects of indacaterol 200, 400, or 600 micrograms have been assessed in 156 patients with asthma in a 28-day, multi cen ter, double-blind, randomized, placebo-con trolled study (37C). The most frequent adverse event was nasopharyngitis (15% with indacaterol 200 micrograms). Tremor was reported by two patients taking indaca terol 600 micrograms. There was a higher incidence of cough on treatment: four, seven and three patients using indacaterol 200, 400, and 600 micrograms, respectively, compared with one using placebo. There was no evidence of dose-related increases in the incidence of adverse events or of clinically significant hypokalemia or hyperglycemia. Mean changes in pulse rate were minor, with maximum changes from baseline at 1 hour of –3.7, –3.3, and –2.2/minute for indacaterol and –2.9/minute for placebo. Mean QTc interval was similar across the groups and there was a change from baseline of over 60 ms in only two patients. Indacaterol 400 and 800 micrograms/day via a single-dose dry powder inhaler has been investigated in 144 patients with persistent asthma in a 28-day, double-blind, parallelgroup, multi center, randomized, placebocontrolled study (38C); 135 completed the study. The incidences of adverse events were similar across the groups and when they occurred were mild or moderate in most cases. There was no dose-response relationship between indacaterol and the incidence of adverse events (400 micrograms 41%; 800 micrograms 37%; placebo 39%). There were small clinically unimportant differences between indacaterol and placebo in mean serum potassium and glucose. There was a trend to QTc interval prolongation with increas ing exposure (maximum mean change 8.9 ms). Indacaterol 50, 100, 200, or 400 micro grams via a multidose dry-powder inhaler (CertihalerTM), indacaterol 400 micrograms via a single-dose dry-powder inhaler and placebo have been compared in 436 patients
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with persistent asthma (39C). Most adverse events were mild to moderate and the most common were respiratory, thoracic, and mediastinal disorders. Cough was reported by 11–33% (1.4% of patients taking pla cebo) and was dose-related. Headache was reported by 0–7.9% of patients (2.8% of those taking placebo) and was not doserelated. One severe adverse event was con sidered to be related to indacaterol – severe palpitation, tachycardia, headache, vertigo, nausea, and insomnia in a patient taking 400 µg via the multi-dose inhaler. Another, taking indacaterol 100 micrograms/day, withdrew because of adverse events that were thought to be drug-related (erythema, anxiety, nausea, and tachycardia). There were no important differences between the groups in blood glucose, serum potassium, pulse rate, blood pressure or QTc interval and the incidences of other adverse events were comparable across the groups.
Ritodrine For the use of ritodrine in treating premature labor, see Chapter 13.
ANTICHOLINERGIC DRUGS (SEDA-29, 174; SEDA-30, 203; SEDA-31, 311)
The cardiovascular risks of anticholinergic drugs The Lung Health Study was the first randomi zed controlled trial to suggest that anti cholinergic drugs may increase the risk of adverse cardiovascular outcomes (40C). A subgroup analysis of hospitalizations and causes of death suggested that smokers randomized to inhaled ipratropium had a sig nificantly increased risk of cardiovascular death than smokers who used placebo (41C). However, the statistical tests used in this study were not adjusted for multiple tests and end
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points, no dose-effect relationship was estab lished and most of the cardiovascular deaths in the ipratropium group occurred in patients who were non-adherent. A later meta-analysis of 17 studies in a total of 13 645 patients, with follow-up dura tions of 6 weeks to 5 years, included systema tic reviews, regulatory authority studies, and randomized controlled trials of any inhaled anticholinergic drug for the treatment of COPD in which cardiovascular events were reported (42M). The primary outcome, a composite end point of cardiovascular deaths, myocardial infarction, or stroke, occurred in 134 of 6984 patients (1.9%) using inhaled anticholinergic drugs and 83 of 6661 patients (1.2%) using other therapies (RR = 1.60; CI = 1.22, 2.10). Among individual components of cardiovas cular risk, inhaled anticholinergic drugs signifi cantly increased the risk of myocardial infarction and cardiovascular deaths but not stroke. The secondary outcome of all-cause mortality was reported in 2.1% of the patients who used inhaled anticholinergic drugs and 1.6% of the controls (RR = 1.29; CI = 1.00, 1.65). A sensitivity analysis restricted to six long-term trials (lasting over 6 months) confirmed the significantly increased risk of cardiovascular death, myocardial infarction or stroke (RR = 1.73; CI =1.27, 2.35), suggest ing that inhaled anticholinergic drugs are associated with a significantly increased myocardial infarction risk among patients with COPD. Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT), the largest randomized con trolled trial of an anticholinergic drug, involved patients at least 40 years old with COPD (43C). It compared 4 years of therapy with either tiotropium (n= 2987) or placebo (n= 3006), and the patients were allowed to use all other respiratory medications (including combinations of long-acting beta agonists þ inhaled glucocorticoids), except inhaled anticholinergic drugs. In contrast to the pooled analyses, UPLIFT showed no difference in the rates of cardiovascular events but also no difference in the primary end point of rate of decline in lung function, despite other clinical improvements.
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A post-hoc, subgroup analysis of the UPLIFT data looked at the secondary end point of mortality in more detail during treatment and with follow-up of patients who withdrew (44C). An end-point commit tee adjudicated the causes of death. There were 792 deaths, with a lower risk in those who used tiotropium (HR = 0.84; 95% CI = 0.73, 0.97). There was a statistically significant difference in survival at the end of the protocol-defined treatment period, but not 30 days thereafter, possibly because of missing data. Adjustment by severity of lung function, sex, age, baseline smoking beha vior, and baseline respiratory medications did not alter the results. The HR for respira tory mortality was 0.86 (0.68, 1.09) and for cardiac mortality 0.86 (0.75, 0.99), suggest ing reduced risks. The most recent meta-analysis of cardio vascular adverse events in patients taking tiotropium concentrated only on large ran domized controlled trials, but noted short comings in all of them when evaluating cardiovascular risk, which none was designed specifically to do (45M). It is not certain why there is such a wide disparity in findings among the published studies in which the cardiovascular risks of inhaled anticholinergic drugs have been eval uated. The different findings may be explained by the use of composite end points in some but not all analyses, placebo controls being lumped together with active treatment controls in the comparator groups, and inac curate reporting of adverse events in reviews because of lack of access to source data; furthermore, differential dropout rates in the non-treatment arms could have resulted in shorter observational periods in these groups. Some have advocated caution in pre scribing anticholinergic drugs in patients with cardiovascular disease (46R), but nearly all agree that more prospective, adequately powered trials are needed to provide more evidence about the cardiovascular safety or otherwise of tiotropium and particularly ipratropium and to look for particular sus ceptibility factors associated with cardiovas cular events in people using anticholinergic drugs.
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Tiotropium bromide (SEDA-29, 174; SEDA-30, 203; SEDA-31, 311) Systematic reviews Following placebocontrolled studies and in ‘addition to stan dard treatment’ studies, ipratropium is increasingly being replaced by tiotropium, whose overall safety was reviewed in SEDA-31 (p. 311). Since then, there has been a pooled meta-analysis of adverse events data from 19 double-blind, rando mized, placebo-controlled trials in patients with obstructive lung disease treated with tio tropium (n = 4435) or placebo (n = 3384), contributing 2159 person-years of exposure to tiotropium and 1662 person-years of exposure to placebo (47M). There was a higher relative risk of dry mouth with tiotro pium (RR = 3.60; 95% CI = 2.56, 5.05), no difference in all-cause mortality (RR = 0.76; 0.50, 1.16), and no difference in either cardi ovascular mortality (RR = 0.57; 0.26, 1.26) or respiratory mortality (RR = 0.71; 0.29, 1.74). For urinary retention the RR was 11 (1.3, 95). This pooling of adverse events data from pre-approval and post-approval tiotro pium clinical trials increased the precision of effect estimates and suggested a relatively good safety profile of inhaled tiotropium. Post-marketing surveillance has since included rare case reports of possible asso ciations with photosensitivity reactions (48A) and acute angle-closure glaucoma (49A).
LEUKOTRIENE MODIFIERS (SEDA-29, 174; SEDA-30, 203; SEDA-31, 312)
Montelukast Comparative studies Montelukast 4 or 5 mg/ day has been compared with budesonide inhalation suspension 0.5 mg/day in 395 children aged 2–8 years with mild asthma or recurrent wheezing in a 12-month, multi center, randomized study (50C). There were similar increases in height from baseline to 12 months. The frequencies of adverse events
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were comparable, most being of mild to moderate intensity. In those who took montelukast (n = 198), there was one case each of headache, lower respiratory tract infection, and abnormal behavior, which were considered to be drug-related. Adverse events that were reported by at least 10% of patients using montelukast were upper respiratory tract infections (29%), pyrexia (23%), otitis media (17%), sinusitis (14%), nasopharyngitis (12%), headache (11%), and pharyngitis (10%). Five patients stopped taking montelukast because of adverse events, the commonest reasons for withdrawal being asthma or pneumonia. There were no deaths. Montelukast 5 mg/day and inhaled bude sonide 200 µg bd have been compared in a 3-week, crossover, randomized, placebocontrolled study in 71 children (aged 6–11 years) with mild asthma (51c). Montelukast did not significantly affect short-term lower leg growth rate, while budesonide was asso ciated with a reduced mean growth rate compared with placebo. Adverse events were comparable. No patients using monte lukast were thought to have had a drugrelated adverse event. Montelukast (10 mg/day) has been com pared with levocetirizine 5 mg/day for 2 consecutive days in 418 adults with ragweed-induced allergic rhinitis in a double-blind, parallel-group, randomized, placebo-controlled study (52C). Treat ment-related adverse events were more common with montelukast (18 of 156 patients) compared with placebo (8.6%) and levocetirizine (8.3%). Adverse events that were considered to be drug-related were more common with montelukast (5.8%) than levocetirizine (3.8%) or pla cebo (2.9%). There were no serious treat ment-related adverse events. Headache was the commonest adverse event with monte lukast (3.2%) and placebo (1.9%) but it was not reported in those taking levocetirizine. Somnolence was reported by one patient taking montelukast, two taking levocetiri zine, and none taking placebo.
glucocorticoids versus inhaled glucocorti coids alone or montelukast þ inhaled gluco corticoids versus active control þ inhaled glucocorticoids in adolescents and adults i ncluded 13 randomized controlled trials (duration at least 12 weeks) in a total of 2 746 331 patients (53M). Meta-analyses were performed where feasible. The addition of montelukast did not result in a greater overall rate of adverse events or increased withdrawal rates related to adverse events. When comparing montelukast with salmeterol as add–on therapy to inhaled glucocorticoids, the overall adverse event rates were comparable. However, separate meta-analyses of 12-week and 48-week trials suggested that montelukast was associated with a significantly lower rate of serious adverse events than salmeterol (RR = 0.68; 95% CI = 0.49, 0.94).
Systematic reviews A systematic review of comparisons of montelukast þ inhaled
Observational studies In a prescription event monitoring (PEM) study in 7976
Liver Hepatitis has been attributed to montelukast in a child with fatigue, nausea, vomiting and abdominal pain who had taken montelukast 5 mg/day for 2 years; resolution occurred within 2 weeks of drug withdrawal (54A). Susceptibility factors Age The single-dose pharmacokinetics of montelukast oral granules (4 mg and 8 mg/day) have been evaluated for 7 days in a placebo-controlled study in 12 infants aged 1–3 months with bronchiolitis or a history of bronchiolitis and asthma-like symptoms (55c). There was increased systemic exposure after a single dose of montelukast 4 mg compared with historical data: the population area under curve (AUC) estimate was 3.6 times higher than in infants aged 3–24 months. Three patients had transient drug-related increases in aspartate transaminase activity (montelukast 8 mg, n = 2; placebo, n = 1).
Zafirlukast
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patients for the period August 1998 to December 2000 (56c), general practitioners reported 152 adverse events in 120 patients (1.5%). The most frequent events were headache and nausea. Zafirlukast was withdrawn in 3148 patients (40%), the most frequent reason being that the drug was ineffective (2008 patients; 25%). Headache was the most common reason for withdrawal (82 patients; 1.0%). Exposure to zafirlukast during the first trimester was reported in 20 pregnancies, of which 9 live births with no recorded congenital abnormalities were reported. There was a total of 151 deaths (1.9%), 38% of which were related to the respiratory system (including COPD, asthma, and bronchopneumonia).
PHOSPHODIESTERASE
TYPE IV INHIBITORS (SEDA-29,
174; SEDA-30, 203; SEDA-31, 313)
Several strategies are currently being pur sued to improve the clinical efficacy and reduce adverse effects of phosphodiesterase type IV inhibitors, including delivery by inhalation, better understanding of the dis tinct tissue specificity of phosphodiesterase type IV isoforms and development of non-emetic inhibitors. New mixed inhibitors are reported to have an improved therapeu tic window, including tetomilast, oglemilast, and apremilast; clinical data on these are awaited.
Cilomilast
(SEDA-29, 174; SEDA-30, 203; SEDA-31, 313) Placebo-controlled studies A review of the efficacy and safety of cilomilast in five Phase III double-blind, parallel-group, randomized, placebo-controlled pivotal studies in over 6000 patients with COPD did not show any serious safety concerns, but neither there were consistent beneficial
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effects in a range of clinical and laboratory outcomes to replicate the promising early pre-clinical data (57R). These Phase III studies have led to termination of the development of cilomilast by its manufacturer.
Roflumilast (SEDA-29, 174; SEDA-30, 203; SEDA-31, 313) Placebo-controlled studies In two doubleblind, multi center, randomized, placebocontrolled studies in patients with moderate to severe COPD, oral roflumilast 500 micrograms/day alone or in addition to salmeterol, or placebo in addition to tiotropium, were compared (58M). Nausea, diarrhea, weight loss, and to a lesser extent headache were more frequent in patients who used roflumilast, but with no major difference between the studies using different comparator groups. In both trials, there was gradual weight loss with roflumilast (salmeterol þ roflumilast –2.0 kg, tiotropium þ roflumilast –1.8 kg) but little change in the placebo groups (salmeterol þ placebo þ 0.2 kg, tiotropium þ placebo þ 0.3 kg).
Systematic reviews A pooled analysis of two large randomized, controlled trials of patients with COPD, severe airflow limitation and exacerbations has suggested that those who used oral roflumilast 500 micrograms/day for 1 year in addition to long-acting beta agonists (n = 1537) had better lung function and less exacerbations than those who took placebo in addition to LABAs (n = 1554) (59M). Inhaled glucocorticoids and tiotropium were not allowed. Overall mortality was similar, with no differences in cardiovascular adverse events or dysrhythmias, pneumonia, or other pulmonary infections. Adverse events were more common with roflumilast (67%) than placebo (62%) and the probability of withdrawal was higher with roflumilast in the first 12 weeks;
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however, serious adverse events were similar (19% and 22%); 14% of the patients taking roflumilast and 12% of those taking placebo withdrew because of adverse events, diarrhea, nausea, and headache being the most common reasons. Vomiting was reported by 17 patients taking roflumilast and 11 taking placebo. Significantly more people taking roflumilast had weight loss (n = 8); the pooled analysis suggested a mean weight loss of 2.1 kg with roflumilast. The change in weight for roflumilast was the greatest in the first 6 months and was more likely to occur in those who reported diarrhea, nausea, vomiting, or headache. The largest absolute weight loss occurred in patients with a BMI of over 30 kg/m2. However, as many people with COPD are already underweight, this potential adverse effect needs careful investigation.
Zileuton
Keir E. Lewis and Gwyneth A. Davies
(FDA) approval, 2458 patients with asthma took zileuton 600 mg qds in addition to usual asthma care, and 489 patients received usual asthma care only (70C, 71C). Dyspep sia (17% versus 9.8%) and nausea (12% versus 5.7%) were more frequent with zileuton. Sinusitis was commoner in those receiving usual care and rates of infection were comparable. Withdrawals because of adverse events with zileuton comprised 20% compared with 2.2%. The commonest adverse events associated with withdrawal in the two groups were asthma exacerba tions (3.7 and 1%, respectively), raised levels of the liver enzyme Alanine transam minase (ALT) activity (2.7 and 0.2%), nau sea (2.4 and 0%), and dyspepsia (1.6 and 0%), Miscellaneous adverse events (not described) associated with withdrawal occurred in 9.3 and 1%. There were five deaths, which were considered unrelated to treatment and not associated with abnormal liver function. Changes in ALT activity in this study are discussed below.
(SEDA-15, 3717)
The 5-lipoxygenase pathway involves the metabolism of arachidonic acid and forma tion of leukotrienes, including leukotriene B4 (LTB4), 5-oxo-6E,8Z,11Z,14Z-eicosatetra noic acid, and the cysteinyl leukotrienes (LTC4, LTD4, and LTE4). It activates four leukotriene receptors: BLT1, BLT2, cysLT1, and cysLT2. Zileuton is an orally active specific inhibitor of 5-lipoxygenase and is the first of this class of medications to be used in the treatment of asthma in adults and children. It has bronchodilatory effects and attenuates induced bronchospasm. It can provide anti inflammatory or steroid-sparing effects with both single doses (800 mg) and during longterm treatment (400 and 600 mg qds) (60C, 61C, 62c, 63c, 64c). Pediatric data are currently limited. Adverse effects, including dyspepsia and raised liver enzymes, have been reported in about 3%. Zileuton has also been used to treat acne (65c), atopic dermatitis (66c, 67r), and the Sjo¨ gren–Larsson syndrome (68A, 69c). In a 12-month open study conducted before US Food and Drug Administration
Placebo-controlled studies Zileuton 800 mg bd or 600 mg qds has been studied in a 4-week, double-blind, parallel-group, randomized, pla cebo-controlled study in 139 patients with mild to moderate asthma (not using inhaled or oral glucocorticoids) (63c). The incidences of adverse events were comparable across the groups. Dyspepsia was reported by three patients taking zileuton 2.4 g/day and three taking 1.6 g/day, and in none taking placebo. There were no clinically significant changes in liver function. One patient developed urticaria and abnormal liver function tests after taking zileuton 1.6 g/day for 24 days, which resolved after drug withdrawal. Zileuton 400 or 600 mg qds has been studied in 401 patients with mild to moderate asthma (managed with inhaled beta2-adre noceptor agonists alone) in a 12-week, parallel-group, double-blind, randomized, placebo-controlled study (61C). Five patients taking zileuton 600 mg/day, three taking zileuton 400 mg/day, and none taking placebo developed abnormal liver function tests (over 3 times the upper limit of normal), which resolved after withdrawal (61C).
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Zileuton 400 or 600 mg qds has been studied in 373 patients with mild to moderate asthma (managed with inhaled beta2 adrenoceptor agonists alone) in a 24-week, multi center, parallel-group, double-blind, placebo-controlled study (60C). There were no dose-related adverse effects. The most common adverse events were acute exacer bation of asthma, infections, and headaches. Severe events occurred in 25 patients taking zileuton 600 mg/day, 23 taking 400 mg/day, and 10 taking placebo. Adverse events that occurred in 5% or more of the patients in any treatment group were worsening asthma, infections, headache, pharyngitis, flu-like syndromes, pain, sinusitis, back pain, dys pepsia, myalgia, nausea, weakness, diarrhea, rhinitis, bronchitis, accidental injury, and dizziness. These adverse events were not usually considered to be related to the study drug. Of 46 patients who left the study pre maturely, at least in part because of adverse events, 15 were taking zileuton 600 mg/day, 15 were taking zileuton 400 mg/day, and 16 were taking placebo. Rises in liver enzymes (to at least twice the upper limit of normal), including Aspartate transaminase (AST), glutamic–pyruvic transaminase, �-glutamyl transferase, and lactate dehydrogenase, or increases in total bilirubin occurred in 11 patients taking zileuton 600 mg/day, 9 taking zileuton 400 mg/day, and 12 taking placebo. There were mild rises in liver enzymes in 11 patients taking placebo (up to 2–3 times the upper limit of normal). Six patients taking zileuton 600 mg/day and five taking 400 mg/ day had either moderately or markedly increased enzyme activities (respectively 3–8 and over 8 times the upper limit of normal). There were no cases of jaundice or symptoms associated with these abnormal liver function tests, which resolved both during continuation or on withdrawal of the drug. Zileuton controlled-release 1200 mg bd added to usual care versus usual care alone has been studied in 926 patients with moder ate asthma in a multi center, double-blind, placebo-controlled study (72C). The ALT activity rose to over 3 times the upper limit of normal in 11 patients (1.8%) taking zileu ton and 2 patients (0.2%) taking placebo. These rises usually occurred in the first 3
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months of treatment and most resolved within 21 days of withdrawal. The incidence of gastrointestinal disorders was higher in the treatment group (31% versus 21%): nausea (9.2% versus 5.9%), diarrhea (5.3% versus 2.3%), and vomiting (5.0% versus 2.0%). Overall adverse events were comparable between the groups. Zileuton 600 mg qds has been studied in 40 patients with aspirin-intolerant asthma in a 6-week, crossover, double-blind, placebocontrolled study (73c). All the patients but one were using either medium-dose or highdose inhaled or oral glucocorticoids. Five had exacerbations of asthma during the pla cebo period and one while taking zileuton. There were no drug-related adverse effects. Unusually, liver function does not appear to have been monitored in this study. Comparative studies Zileuton versus beclometasone Zileuton 400 or 600 mg qds þ beclometasone dipropionate 200 micro grams bd has been compared with placebo þ beclometasone dipropionate 400 micrograms bd in 320 patients with persistent asthma in a 12-week, multi center, double-blind, randomized, active-control study (74C). The incidence and types of adverse events were similar in the three groups and included infections, exacerbation of asthma or eczema, headaches, rhinitis, flulike syndromes, dyspepsia, pharyngitis, and nausea. There were rises in ALT activity in two of those taking zileuton 2400 mg, two of those taking zileuton 1600 mg, and two of those taking beclometasone. Zileuton versus theophylline Zileuton has tended to have been studied in patients who require a daily inhaled beta2-adrenoceptor agonist; comparative studies are currently limited. Zileuton 400 or 600 mg qds has been compared with slow-release theophylline in 377 patients with chronic asthma in a 13-week, double-blind, multi center, randomized study (75C). One or more treatment-related adverse events were reported by comparable numbers in all the groups: zileuton 400 mg, 94%; zileuton
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600 mg, 94%; theophylline, 89%. Adverse events that were reported by at least 5% of patients were headache, infection, pharyngitis, flu-like syndromes, myalgia, dyspepsia, nausea, pain, back pain, sinusitis, and insomnia. One or more episodes of exacerbation of asthma were reported by about 75% of the patients across all treatment groups at some point in the 13-week double-blind phase. Of the 32 patients who left the study prematurely, 11 had adverse events that led to termination and were considered probably or possibly related to the study drug: three taking zileuton 400 mg/day (insomnia in one, raised liver enzyme activities in two), three taking zileuton 600 mg/day (dyspepsia in one, raised liver enzymes in two), and five taking theophylline. There were raised liver enzyme activities (to above twice the upper limit of normal) in 25 patients: eight taking zileuton 400 mg/day, nine taking 600 mg/day, and eight taking theophylline. Of those taking zileuton 400 mg/day, six had mild increases, one had a moderate increase, and one had a large increase. Of those taking zileuton 600 mg/day, the corresponding numbers were five, two, and two, and in those taking theophylline three, four, and one. No patient developed hepatotoxicity with jaundice. Hematologic In an in vitro study zileuton was associated with increased thromboxane B2 concentrations and platelet aggregation in 10 patients with asthma, with a theoretical thrombotic risk (76E). However, no thrombotic adverse effects have been reported. A study by the manufacturers of zileuton showed that there was no significant increase in thromboxane B2 concentrations when zileuton was given to healthy volunteers (77c). Liver In addition to all the studies quoted above, there have been reports of abnormal liver enzymes in patients taking zileuton. In 2947 patients at 233 centers in the USA randomly assigned in a 5:1 ratio to zileuton plus usual asthma care or usual asthma care alone, the patients who took zileuton had significantly fewer corticosteroid rescues,
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required less emergency care, had fewer hos pitalizations, and had greater increases in FEV1 (70C). They also had significantly greater improvements in asthma symptoms. There were increases in ALT activity to 3 times or more the upper limit of normal in 4.6% of patients taking zileuton and 1.1% of those receiving usual care; most of the increases occurred during the first 2–3 months. Hepatic damage was predominantly hepatocellular. Raised ALT activity was usually not associated with raised alkaline phosphatase and/or total bilirubin concen trations. Most of the liver enzyme abnormal ities in the treatment group (70%) occurred within the first 3 months. There was no cor relation between the time of onset and the height of the peak ALT activity. Women were more likely than men to have ALT activity over 8 times the upper limit of nor mal (1.8% versus 0.5%) and women aged over 65 years were at greater risk. Patients with ALT activity over 5 times the upper limit of normal continued treatment, and 53% successfully continued with resolution of ALT to below twice the upper limit of normal. For those who withdrew because of a raised ALT, the mean time to resolution was 4 weeks. Two developed mildly raised total bilirubin concentrations in association with raised ALT. There were no cases of jaundice, chronic liver disease, or liver fail ure. These data suggest that with appropriate monitoring the risk of irreversible liver injury appears to be low, but careful monitoring is indicated particularly in the first 3 months. Despite these changes in liver enzymes, jaundice is uncommon. There was a single reported case of jaundice among over 6000 patients taking zileuton (78R, 79R). The pattern of liver function abnormal ities suggests a mechanism relating to metabolic idiosyncrasy. In vitro and animal data suggest that hepatotoxicity is related to the biotransformation of zileuton to 2-acetylbenzothiophene (2-ABT) and further toxic metabolites (80E). 2-ABT is cytotoxic in a P450-dependent manner. Further in vitro work has implicated the reactive metabolite 2-ABT-S-oxide, which can cause irreversible alkylation of human serum albumin (81E).
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Pregnancy There are animal data of concern regarding the use of zileuton in pregnancy, and guidelines recommend that leukotriene modifiers should not be begun in pregnancy (30S). In general these drugs would not be recommended in pregnancy, although their use could be considered in those with poorly controlled asthma who have previously demonstrated significant benefit (82S). There are no adequate human data. Drug dosage regimens Zileuton 600 mg qds for 8 weeks has been compared with zileuton 600 or 800 mg tds for 16 weeks followed by twice-daily treatment for 8 weeks in 278 patients with chronic asthma, in a multi center randomized study (83C). The commonest treatment-related adverse effects were headaches (23%), infections (22%), pain (10%), pharyngitis (8.3%), rhinitis (7.9%), flu-like syndromes (7.2%), and nausea (7.2%). Adverse effects caused 41 patients to withdraw: 11 had adverse effects that were probably zileuton-related, of which 4 were severe, and 20 had adverse effects that were possibly zileuton-related, of which 2 were severe. The other 10 patients had events that were unrelated to zileuton, of which 2 were severe. Four patients developed raised ALT activity during the first 2 months of treatment. All cases resolved, in one case during continuation of treatment and in three cases after withdrawal. Drug–drug interactions Zileuton is mainly eliminated by metabolism to zileuton glucuronides, but it can also be metabolized by cytochrome P450 isoenzymes. Drug interaction studies have suggested that interactions of zileuton with other drugs are mediated by inhibition of CYP1A2 (84E, 85R). Propranolol Patients taking propranolol should be closely monitored and doses may need to be reduced because of reduced clearance (86E). Terfenadine Zileuton should not be co administered with terfenadine because of
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increases in the plasma terfenadine concentration, but without significant prolongation of the QTc interval (87c). Theophylline In 16 healthy adult men who were given theophylline (Slo-Phyllin) 200 mg qds for 5 days and either zileuton 800 mg bd or placebo in a randomized, crossover, placebo-controlled study (88c), zileuton increased mean peak theophylline concentrations from 12 to 21 mg/l and reduced the apparent plasma clearance from 3.74 to 1.91 l/hour. The tmax of theophylline was delayed by 0.5 hours and the half-life was significantly prolonged by 1.5 hours. There were 44 mild to moderate adverse events in 14 subjects, possibly related to co-administration of zileuton, compared with eight who reported such events while taking placebo. Three volunteers who took theophylline þ zileuton withdrew prematurely. The authors advised that if theophylline is co-administered with zileu ton, dosages may need to be halved and plasma theophylline concentrations will require close monitoring. Warfarin Patients taking warfarin should be closely monitored and doses may need to be reduced because of reduced clearance (demonstrated for R-warfarin but not S-warfarin, the more active stereoisomer) (89E). Other drugs No significant interactions have been demonstrated between zileuton and digoxin, phenytoin, sulfasalazine, or naproxen (85R).
MUCOLYTICS Mucolytics are being increasingly pre scribed for COPD and bronchiectasis. In a Chinese multi center, randomized, placebocontrolled trial, carbocisteine 500 mg tds significantly reduced COPD exacerbations over 1 year (90C). Withdrawals occurred in 14% and 12% of patients in the two groups.
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There were 57 adverse events in those tak ing carbocisteine and 56 in those taking pla cebo, the most common (5 or more events) being gastrointestinal upsets (14 versus 5) and cardiac events (9 versus 5). There were no deaths.
Non-prescription cough and cold medicines (SEDA-31, 314) FDA guidance on non-prescription cough medicines was reviewed in SEDA-31 (p. 314). In particular it was noted that adverse events were often dose-related and that these preparations should not be used in children under 2 years unless speci fically advised by a health-care professional. For the adverse effects of proprietary cough medicines containing antihistamines, see Chapter 15. Placebo-controlled studies In a placebocontrolled study of the anti-tussive moguisteine (total daily dose 600 mg) for 3.5 days in 108 adults, there was an increased incidence of adverse events in the treatment group (22% versus 8%) (91c). The most frequent adverse events were nausea, vomiting, and abdominal pain, with four withdrawals in the treatment group because of adverse events.
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The adverse effects of guaifenesin (an expectorant) included nausea and urticaria (92C). Systematic reviews The effects of oral non-prescription cough medicines in 25 trials (17 in adults, 8 in children; 2876 adults and 616 children) in acute cough have been reviewed (93M). The data were conflicting and the number of studies in each category of cough medicines was small. The authors concluded that there was currently insufficient evidence for or against the effectiveness of non prescription cough medicines. Many studies failed to report adverse events. Counterfeit medicines Vicks Kingo is a proprietary cough medicine that contains guaiphenesin and cetylpyridinium chloride. The Tanzania Food and Drugs Authority (TFDA) has released a statement about counterfeit Vicks Kingo circulating in the market. The agency has taken a tough line on the matter and has threatened legal action against traders (94S). The counterfeit Vicks Kingo tablets are white instead of cream-colored and they do not have the menthol smell of the genuine tablets. The TFDA has urged anyone in possession of the counterfeit product to return it to the suppliers and report it to the nearest district health office or local TFDA.
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44. Celli B, Decramer M, Kesten S, Liu D, Mehra S, Tashkin DP, UPLIFT Study Investigators. Mortality in the 4 year trial of tiotropium (UPLIFT) in patients with COPD. Am J Respir Crit Care Med 2009;180(10):948–55. 45. Hilleman DE, Malesker MA, Morrow LE, Schuller D. A systematic review of the cardi ovascular risk of inhaled anticholinergics in patients with COPD. Int J Chron Obstruct Pulmon Dis 2009;4(2):253–63. 46. Oba Y, Zaza T, Thameem DM. Safety, toler ability and risk benefit analysis of tiotropium in COPD. Int J Chron Obstruct Pulmon Dis 2008;3(4):575–84. 47. Kesten S, Jara M, Wentworth C, Lanes S. Pooled clinical trial analysis of tiotropium safety. Chest 2006;130(6):1695–703. 48. Pérez-Pérez L, Cabanillas M, Pereiro Fer reirós MM, Peteiro C, Toribio J. Photosensi tive lichenoid eruption and inhaled tiotropium bromide. Dermatology 2007;214(1):97–8. 49. Oksuz H, Tamer C, Akoglu S, Duru M. Acute angle-closure glaucoma precipitated by local tiotropium absorption. Pulm Phar macol Ther 2007;20(6):627–8. 50. Szefler SJ, Baker JW, Uryniak T, Goldman M, Silkoff PE. Comparative study of budeso nide inhalation suspension and montelukast in young children with mild persistent asthma. J Allergy Clin Immunol 2007;120 (5):1043–50. 51. Pedersen S, Agertoft L, Williams-Herman D, Kuznetsova O, Reiss TF, Knorr B, Dass SB, Wolthers OD. Placebo-controlled study of montelukast and budesonide on short-term growth in prepubertal asthmatic children. Pediatr Pulmonol 2007;42(9):838–43. 52. Day JH, Briscoe MP, Ratz JD. Efficacy of levocetirizine compared with montelukast in subjects with ragweed-induced seasonal aller gic rhinitis in the Environmental Exposure Unit. Allergy Asthma Proc 2008;29(3):304–12. 53. Joos S, Miksch A, Szecsenyi J, Wieseler B, Grouven U, Kaiser T, Schneider A. Montelu kast as add-on therapy to inhaled corticoster oids in the treatment of mild to moderate asthma: a systematic review. Thorax 2008;63 (5):453–62. 54. Incecik F, Onlen Y, Sangun O, Akoglu S. Probable montelukast-induced hepatotoxicity in a pediatric patient: case report. Ann Saudi Med 2007;27(6):462–3.
329 55. Kearns GL, Lu S, Maganti L, Li XS, Migoya E, Ahmed T, Knorr B, Reiss TF. Pharmacoki netics and safety of montelukast oral granules in children 1 to 3 months of age with bronch iolitis. J Clin Pharmacol 2008;48(4):502–11. 56. Twaites BR, Wilton LV, Shakir SA. Safety of zafirlukast: results of a postmarketing sur veillance study on 7976 patients in England. Drug Saf 2007;30(5):419–29. 57. Rennard S, Knobil K, Rabe KF, Morris A, Schachter N, Locantore N, Canonica WG, Zhu Y, Barnhart F. The efficacy and safety of cilomilast in COPD. Drugs 2008;68 (Suppl 2):3–57. 58. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease trea ted with long-acting bronchodilators: two randomised clinical trials. Lancet 2009;374 (9691):695–703. 59. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ, M2 124 and M2-125 Study Groups. Roflumilast in symptomatic chronic obstructive pulmon ary disease: two randomised clinical trials. Lancet 2009;374(9691):685–94. 60. Liu MC, Dubé LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group J Allergy Clin Immunol 1996;98(5 Pt 1):859–71. 61. Israel E, Cohn J, Dubé L, Drazen JM. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A rando mized controlled trial. Zileuton Clinical Trial Group. J Am Med Assoc 1996;275(12):931–6. 62. Kearns GL, Lu S, Maganti L, Li XS, Migoya E, Ahmed T, Knorr B, Reiss TF. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med 1993;119(11):1059–66. 63. Israel E, Rubin P, Kemp JP, Grossman J, Pierson W, Siegel SC, Tinkelman D, Murray JJ, Busse W, Segal AT, Fish J, Kaiser HB, Ledford D, Wenzel S, Rosenthal R, Cohn J, Lanni C, Pearlman H, Karahalios P, Drazen JM. The effect of inhibition of 5-lipoxygen ase by zileuton in mild-to-moderate asthma. Ann Intern Med 1993;119(11):1059–66. 64. Dahlén B, Nizankowska E, Szczeklik A, Zetterstro¨ m O, Bochenek G, Kumlin M,
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from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirinintolerant asthmatics. Am J Respir Crit Care Med 1998;157(4 Pt 1):1187–94. 74. O’Connor BJ, Lofdahl CG, Balter M, Szczek lik A, Boulet LP, Cairns CB. Zileuton added to low-dose inhaled beclomethasone for the treatment of moderate to severe persistent asthma. Respir Med 2007;101(6):1088–96. 75. Schwartz HJ, Petty T, Dubé LM, Swanson LJ, Lancaster JF. A randomized controlled trial comparing zileuton with theophylline in moderate asthma. The Zileuton Study Group Arch Intern Med 1998;158(2):141–8. 76. Wu X, Dev A, Leong AB. Zileuton, a 5-lipoxygenase inhibitor, increases produc tion of thromboxane A2 and platelet aggre gation in patients with asthma. Am J Hematol 2003;74(1):23–5. 77. Rubin P, Dubé L, Braeckman R, Swanson L, Hansen R, Albert D, Carter G. Pharmacokinetics, safety, and ability to diminish leukotriene synthesis by zileuton, an inhibi tor of 5-lipoxygenase. Agents Actions Suppl 1991;35:103–16. 78. Wenzel SE, Kamada AK. Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma. Ann Pharmacother 1996;30 (7–8):858–64. 79. Berger W, De Chandt MT, Cairns CB. Zileu ton: clinical implications of 5-lipoxygenase inhibition in severe airway disease. Int J Clin Pract 2007;61(4):663–76. 80. Joshi EM, Heasley BH, Chordia MD, Macdonald TL. In vitro metabolism of 2-acetylbenzothiophene: relevance to zileu ton hepatotoxicity. Chem Res Toxicol 2004;17(2):137–43. 81. Li F, Chordia MD, Woodling KA, Macdo nald TL. Irreversible alkylation of human serum albumin by zileuton metabolite 2-acet ylbenzothiophene-S-oxide: a potential model for hepatotoxicity. Chem Res Toxicol 2007;20(12):1854–61. 82. The use of newer asthma and allergy medica tions during pregnancy. The American College of Obstetricians and Gynecologists (ACOG) and The American College of Allergy, Asthma and Immunology (ACAAI). Ann Allergy Asthma Immunol 2000;84(5):475–80. 83. DuBuske LM, Grossman J, Dubé LM, Swan-
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zileuton in patients with moderate asthma: effect of reduced dosing frequency and amounts on pulmonary function and asthma symptoms. Zileuton Study Group Am J Manag Care 1997;3(4):633–40. 84. Machinist JM, Mayer MD, Shet MS, Ferrero JL, Rodrigues AD. Identification of the human liver cytochrome P450 enzymes involved in the metabolism of zileuton (ABT-077) and its N-dehydroxylated meta bolite, Abbott-66193. Drug Metab Dispos 1995;23(10):1163–74. 85. Dubé LM, Swanson LJ, Awni W. Zileuton, a leukotriene synthesis inhibitor in the man agement of chronic asthma. Clinical pharma cokinetics and safety. Clin Rev Allergy Immunol 1999;17(1–2):213–21. 86. Yoshimoto K, Echizen H, Chiba K, Tani M, Ishizaki T. Identification of human CYP iso forms involved in the metabolism of propra nolol enantiomers – N-desisopropylation is mediated mainly by CYP1A2. Br J Clin Pharmacol 1995;39(4):421–31. 87. Awni WM, Cavanaugh JH, Leese P, Kasier J, Cao G, Locke CS, Dubé LM. The pharma cokinetic and pharmacodynamic interaction between zileuton and terfenadine. Eur J Clin Pharmacol 1997;52(1):49–54. 88. Granneman GR, Braeckman RA, Locke CS, Cavanaugh JH, Dubé LM, Awni WM. Effect of zileuton on theophylline pharmacokinetics. Clin Pharmacokinet 1995;29(Suppl 2):77–83.
331 89. Awni WM, Hussein Z, Granneman GR, Patterson KJ, Dubé LM, Cavanaugh JH. Pharmacodynamic and stereoselective phar macokinetic interactions between zileuton and warfarin in humans. Clin Pharmacokinet 1995;29(Suppl 2):67–76. 90. Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L, Bai CX, Wang CZ, Wang C, Chen BY, Shi Y, Liu CT, Chen P, Li Q, Wang ZS, Huang YJ, Luo ZY, Chen FP, Yuan JZ, Yuan BT, Qian HP, Zhi RC, Zhong NS. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmon ary disease (PEACE study): a randomised placebo-controlled study. Lancet 2008;371 (9629):2013–8. 91. Adams R, Hosie J, James I, Khong T, Kohn H, Smith I. Antitussive activity and tolerability of moguisteine. Adv Ther 1993;10(6):263–71. 92. Robinson R, Cummings W, Deffenbaugh E. Effectiveness of guaifenesin as an expector ant: a cooperative double-blind study. Curr Ther Res 1977;22(2):284–96. 93. Smith SM, Schroeder K, Fahey T. Over the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev 2008;(1): CD001831. 94. Anonymous. Counterfeit medicines. Regula tor tackles incident of fake Vicks Kingo. WHO Newslett 2008;4:1.
J.K. Aronson
1 7 Positive inotropic drugs and drugs used in dysrhythmias CARDIAC GLYCOSIDES (SED-15, 648; SEDA-29, 182; SEDA-30, 209; SEDA-31, 321) Observational studies Hospital admissions because of digoxin toxicity became signifi cantly less common from 1991 to 2004 in the USA and the UK in the former this was associated with a reduction in the use of digoxin, but in the latter there was no such change. However, in both countries, the num ber of prescriptions written for a dose of at least 250 micrograms fell (1C). Of 2 987 580 hospital admissions in the Netherlands during 2001–2004 there were 1286 cases of digoxin intoxication (0.04%) (2C). The incidence rate for admission related to digoxin intoxication was 49 per 100 000 prescriptions (95% confidence interval [CI] = 46, 51), corresponding to 1.94 admissions per 1000 treatment-years. Women had a 1.4-fold higher risk of intox ication than men (95% CI = 1.3, 1.6). The age- and sex-adjusted relative risk of death in patients with digoxin intoxication com pared with those admitted for other reasons was 0.7 (95% CI = 0.5, 0.8). Cardiovascular Digoxin toxicity has again been briefly reviewed in the context of two cases, one associated with sinus bradycardia and ventricular bigemini and one with second-degree heart block (3Ar). Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32017-4 2010 Elsevier B.V. All rights reserved.
Gastrointestinal Non-occlusive mesenteric ischemia secondary to digitalis is rare but has again been reported, in a 76-year-old woman with digoxin intoxication (serum concentration 6.0 µg/l) (4A).
Mortality during treatment of atrial fibrillation with digoxin There have been several studies of the risk of death during treatment of atrial fibrillation with digoxin. In a post-hoc analysis of the results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study, the use of rhythm-control drugs was asso ciated with increased mortality after adjust ment for the other co-variates (hazard ratio [HR] = 1.49) and digoxin was associated with an increased risk of death (HR = 1.42; 95% CI = 1.09, 1.86) (5c). However, the authors suggested that that may have been caused by the use of digoxin in patients at a higher risk of death, such as those with heart failure, rather than by a deleterious effect of digoxin on survival. They also suggested that there may be other confounding factors in the reasons that physicians choose digoxin. Similarly, the survival of users and non users of digitalis has been investigated in a post-hoc analysis of data from the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III and V studies, in which 7329 patients with atrial fibril lation were randomized to warfarin or xime lagatran to prevent thromboembolism (6c). Users had a higher mortality than non-users
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(255/3911 versus 141/3418; 6.5% versus 4.1%; HR = 1.58; 95% CI = 1.29, 1.94). However, digitalis users also had more baseline risk fac tors, which would have confounded the results, even though after multivariate adjustment, the increased mortality persisted (HR = 1.53; 95% CI = 1.22, 1.92). The authors nevertheless sug gested that digitalis may increase mortality in patients with atrial fibrillation. Since both of these studies involved posthoc non-randomized analyses, they should be regarded as merely hypothesis generating. In a 1-year study using data from the Registry of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA), mortality was measured among 60 764 patients admitted to coronary care units with atrial fibrillation with or without congestive heart failure during 1995–2003 and adjusted for differences in background characteristics and other medications and treatments by propensity scoring (7c). Among those with atrial fibrillation without congestive heart failure there was a higher mortality rate in those who were discharged taking digoxin than in those who were not (adjusted RR = 1.42; 95% CI = 1.29, 1.56); there was no such difference among those who had con gestive heart failure with or without atrial fibrillation. The authors suggested that longterm therapy with digoxin may be an indepen dent susceptibility factor for death in patients with atrial fibrillation without congestive heart failure. However, as this study was based on registry data, confounding could have occurred. In 2824 patients with atrial fibrillation, who were studied prospectively for a mean of 4.6 years, information about medications was obtained from the local hospital registry and information about diagnoses, hospitali zations, and deaths from national registries (8c). Propensity score matching and Cox regression was used to account for con founding. Factors associated with the use of digoxin were permanent atrial fibrillation (HR = 3.2, CI = 2.7, 3.9), absence of a pace maker (HR = 2.3, CI = 1.6, 3.2), a history of heart failure (HR = 2.0, CI = 1.7, 2.5), treat ment in an internal medicine ward rather than a cardiology ward (HR = 1.6, CI = 1.3, 2.0), female sex (HR = 1.6, CI = 1.3, 1.9), and age 80 years or more (HR = 1.4, CI = 1.1, 1.7).
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Mortality was higher among those who used digoxin than among those who did not (51% versus 31%); however, after adjustment for co-variates there were no effects of digoxin on all-cause mortality, myocardial infarction, ischemic stroke, time to readmission to hospital, or days spent in hospital per year at risk. The authors concluded that the increased mortality associated with digoxin is attributable to its use in an elderly and frailer subset of patients with atrial fibrillation. Conclusion There is currently no good evi dence that the use of digoxin is associated with increased mortality in patients with atrial fibrillation, with or without concurrent congestive heart failure. A proper prospec tive randomized study would be necessary to confirm or refute this hypothesis. Susceptibility factors Sex In an analysis of adverse drug reactions in four German pharmacovigilance centres, which resulted in hospitalization of 3092 patients in 2000– 2004, 314 patients were admitted because of adverse effects associated with cardiac gly cosides. The incidence of adverse reactions was 1.9 (CI = 1.0, 3.3) per 1000 patients exposed to cardiac glycosides per 3 months exposure. More women were affected than men (244 versus 70) and oral digitoxin was involved in 296 (228 women). Women received significantly higher body weightrelated doses of digitoxin and had signifi cantly higher digitoxin plasma concentra tions than men. Doses were high (over 1 microgram/kg/day) in 71% of the women but in only 29% of the men. Those who had adverse reactions to cardiac glycosides had a significantly lower body weight and were significantly older than patients with other adverse drug reactions. Drug administration route In a retrospec tive analysis of 1795 pregnant women at 17–24 weeks’ gestation who received vary ing doses of digoxin by transabdominal intrafetal injection (up to 1.0 mg) or intraamniotic injection (up to 0.5 mg) to obtain fetal death in advance of elective termination in the second trimester, the overall failure
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rate was 6.6% (9c). There were no failures using an intrafetal dose of 1.0 mg, but fail ures occurred with lower doses. Failure rates were higher with intra-amniotic administration of 0.5 mg (8.3%) than intrafetal administration (3.6%). There were no adverse maternal events. Drug overdose The management of over dose with cardiac glycosides when there are serious complications involves the use of Fab fragments of digoxin-specific anti bodies. However, in patients with severe renal impairment, the clearance of Fab– digoxin complexes is reduced, and plasma pheresis has been used to remove them (10A, 11A), as illustrated by another report (12A). However, it should be remembered that although plasma exchange removes digoxin–Fab complexes and prevents rebound digoxin toxicity, it does not increase the clearance of digoxin, which has a large apparent volume of distribution. Non-fatal self-poisoning with Digitalis purpurea, whose main constituent is digi toxin, occurs occasionally (13A, 14A), and unintentional poisoning can occur when the leaves of the plant are mistaken for those of comfrey (Symphytum officinale) (15A, 16A). Fatal self-poisoning with D. pur purea has been reported (17Ar). • A 64-year-old man ate a whole D. purpurea plant. He became nauseated and developed a junctional rhythm, with concave up-sloping ST segment depression; he later developed a bradycardia and runs of second-degree atrioventricular block, which rapidly progressed to a sinus pause lasting 3.5 seconds, followed by sinus arrest. The serum potassium concentration was 4.3 mmol/l and the serum glycoside concentration, measured using a digoxin assay, was 36 µg/l. Despite repeated doses of activated charcoal and administration of digoxin-specific antibodies, he had a cardiac arrest and died. At post-mortem examination there were undigested and partially digested foxglove plant parts in the stomach.
The reference to van Gogh in the title of this report is misleading (18r, 19r). Drug–drug interactions Calcium salts Although it has been suggested that intra venous calcium should be used to treat the
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hyperkalemia that can occur in digitalis intoxication (20R), this suggestion has been challenged, on the grounds that calcium salts may increase the risk of cardiac dys rhythmias in such cases (21r). However, evi dence that that is so is anecdotal, and counterexamples have also been published (22A, 23A, 24r). This question has been reviewed in the light of a case in which intravenous calcium gluconate was benefi cial in a patient with hyperkalemia and digoxin intoxication (25AR). The authors concluded that digoxin toxicity should be treated with digoxin-specific antibodies, when they are available (as they were not in their case). However, for patients with life-threatening hyperkalemia with loss of P waves, and especially if there is QRS widening, they recommended intravenous calcium. They also recommended that while slow infusion of calcium may be desirable, the speed of infusion should be determined by the urgency of the problem. Proton pump inhibitors There are several ways in which proton pump inhibitors might interact with digoxin. Inhibition of gastric acid secretion prevents hydrolysis of digoxin in the stomach, increasing its sys temic availability (26C). In one study ome prazole increased the average Cmax and area under curve (AUC) of digoxin by about 10% and slightly shortened the tmax, although in a few patients the effect was larger (up to 30%); the half-life was not changed, suggesting a change in availability rather than clearance (27C). Proton pump inhibitors also cause a transepithelial paracellular leak in the gas tric mucosa, which allows molecules as large as 4 kDa to cross (28c), although the effect is specific for certain molecules, as it allows the passage of digoxin but not phenytoin (29E). Omeprazole also inhibits P glycoprotein (30E), inhibition of which in the transepithe lial transport of digoxin in the intestine and kidney would reduce its clearance. There has been a single report of digoxin toxicity attributed to an interaction with omeprazole (31A).
336 • A 65-year-old woman developed weakness, loss of balance, nausea, and xanthopsia. She had been taking digoxin 0.0625 mg/day for paroxysmal atrial fibrillation and her serum digoxin concentration had been 1.1 µg/l. Omeprazole 20 mg/day had been added for gastroesophageal reflux disease and her serum digoxin concentration was 3.9 µg/l; renal function was normal. She was given antidigoxin antibody Fab fragments and quickly recovered.
Rabeprazole may also increase the effects of digoxin (32c). However, a single oral of pantoprazole 40 mg had no effect on the pharmacokinetics of oral beta-acetyldigoxin 0.2 mg bd in 18 healthy volunteers or on the electrocardiographic effects of digoxin (33c). Quinine The interaction of digoxin with quinine has only occasionally been described (SED-15, 664). It seems to have the same basis as the interaction of digoxin with quini dine. Torsade de pointes has now been attributed to this interaction in a 76-year-old man who was taking digoxin 0.5 mg/day, qui nine sulfate 750 mg/day, aspirin 100 mg/day, candesartan 8 mg/day, and amlodipine 10 mg/ day; the plasma digoxin concentration was 5 µg/l (6.4 µmol/l) (34A). Vildagliptin In an open, randomized, three-period, crossover study in 18 healthy subjects during co-administration of vilda gliptin 100 mg/day and digoxin (0.5 mg, then 0.25 mg/day on days 2–7), there were no effects on the exposure to either drug, assessed by AUC0!24h and Cmax, or on half-life or clearance (35c). Management of adverse drug reactions In a retrospective review of the records of 838 patients with raised serum digitalis con centration (digoxin > 1.95 µg/l or digitoxin > 23 µg/l), only 67 (8%) had received Fab fragments of antidigoxin antibody (36c). The authors concluded that the antibodies are underused in patients with raised digitalis con centrations and especially in those with chronic digitalis intoxication, who had a higher mortality rate than those with acute poisoning. They proposed that there should be identical criteria for the use of antidigoxin antibody after both acute and chronic poisoning.
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Monitoring therapy The reasons for mon itoring the plasma digoxin concentration have again been reviewed in the context of a case report (37Ar). In summary: • measure the plasma digoxin concentration to monitor adherence to therapy; • measure it to diagnose toxicity, if indicated by the patient’s clinical state; • measure it to monitor for potential toxicity if renal function changes, or after a change in dosage, or after the addition of another drug that affects the pharmacokinetics of digoxin; • always measure the serum potassium concen tration at the same time as the plasma digoxin concentration, because potassium depletion makes the plasma digoxin concentration unin terpretable, and toxicity should be assumed in the presence of hypokalemia, whatever the plasma digoxin concentration; • measure the serum potassium and renal function indices at intervals, depending on the patient’s clinical state and other drugs taken; • samples for digoxin measurement should be taken at least 6–12 hours after the last dose (ideally 11 hours); note that steady state takes 8–10 days to reach after any change in dose if renal function is normal, and longer in renal impairment; • plasma concentration monitoring is not necessary in clinically and biochemically stable patients.
OTHER POSITIVE INOTROPIC DRUGS
(SED-15, 2822; SEDA-29, 183; SEDA-30, 212; SEDA-31, 323)
Milrinone (SED-15, 2346; SEDA-29, 183; SEDA-30, 212; SEDA-31, 323) Drug administration route Milrinone by inhalation reduces pulmonary artery pres sure and its use has been studied retrospec tively in high-risk patients, mean age 64 years, to evaluate their postoperative course (38c). Milrinone 5 mg was given administered before (n = 30) or after (n = 40) cardiopulmonary bypass, which lasted a mean of 145 minutes, with crossclamping for 91 minutes. Those who received inhaled milrinone before the start of cardiopulmonary bypass had a lower
Positive inotropic drugs and drugs used in dysrhythmias
pulmonary artery pressure after bypass and fewer needed emergency reinitiation of bypass after weaning (3% versus 23%). There were no detectable adverse effects.
ANTIDYSRHYTHMIC DRUGS Antidysrhythmic agents of class III have been reviewed, including the newer agents dofetilide, ambasilide, azimilide, chromanol 293B, dronedarone, ersentilide, ibutilide, sematilide, tedisamil, and trecitilide, as well as amiodarone, bretylium, and sotalol (39R).
ADENOSINE RECEPTOR AGONISTS (SED-15, 36; SEDA-29, 185; SEDA-30, 212; SEDA-31, 323)
Adenosine and analogues Cardiovascular In a retrospective review of 1948 adenosine stress myocardial perfusion studies, adenosine-induced atrial fibrillation occurred in eight (0.41%) cases 90–170 seconds after the infusion (40Ac). Three had a history of atrial fibrillation, two had a his tory of coronary artery disease, and seven had more than one risk factor for coronary artery disease. In three cases, the dysrhyth mia was preceded by bradycardia, adenosineinduced second-degree atrioventricular block, or sinus pauses. All converted spon taneously to sinus rhythm after 15 seconds to 6 hours. Pre-excited atrial fibrillation occurred in a 31-year-old woman with Wolff–Parkinson– White syndrome after the administration of adenosine (41A). The adverse effects of adenosine are usually transient, because it has a half-life of a few seconds. One patient developed a monomorphic ventricular tachycardia after termination of an atrioventricular nodal re-entrant tachycardia with intravenous
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adenosine 12 mg, which terminated sponta neously after 3 minutes (42A). Although not prolonged, this is longer than one would expect. Prolonged complete heart block requiring intubation and temporary pacing, after the administration of adenosine to a patient with an atrial flutter treated with metoprolol and diltiazem, has also been reported (43A). Accessory conduction pathways can be associated with dysrhythmias after the administration of adenosine. A 79-year-old man developed sustained second-degree atrioventricular block after adenosine infu sion for nuclear stress testing and required a permanent pacemaker (44A). In another case a non-sustained polymorphous ventri cular tachycardia occurred during adeno sine stress perfusion imaging in a patient with a pre-excitation electrocardiographic pattern (45A). Paradoxical coronary artery vasospasm with bursts of polymorphous tachycardia occurred after withdrawal of adenosine following a stress test in a patient with vasospastic angina (46A).
Dyspnea and bronchospasm associated with adenosine Asthma is a contraindication to the use of adenosine, which can cause bronchospasm in susceptible patients. In one case aden osine, 140 micrograms/kg/minute for 1 min ute, caused severe bronchospasm in a 78 year-old woman with pre-existing chronic obstructive pulmonary disease (COPD), but no evidence of reversible obstruction; it did not respond to repeated doses of inhaled salbutamol 100 micrograms but did respond to intravenous theophylline 50 mg (47A). However, the authors stressed that they did not want to discourage the use of adenosine in patients with COPD but no evidence of pre-existing reversible airway obstruction, as this adverse effect is rare in such patients. In another case, adenosine caused respiratory arrest in a patient with asthma (48A). In patients with a history of COPD or asthma, who were given adenosine
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140 mg/kg/minute for 4 minutes for stress myocardial perfusion scintigraphy, those with a history of asthma were given an inhaled bronchodilator before the administration of adenosine (49A). Most of the patients (24/46) did not have any dyspnea or chest pain during adenosine infusion. However, 14 had chest discomfort during adenosine and 9 complained of dyspnea. None required aminophylline or resuscitation. In a case-control study, patients with known or suspected mild asthma or COPD were pre treated with an inhaled beta2-adrenoceptor agonist and adenosine titrated up to a max imum of 140 micrograms/kg/minute over 6 minutes (50C). Of 1261 patients, 124 had known or suspected airway disease and 72 who were suitable for adenosine stress testing were compared with 72 controls. The most common adverse effects were dyspnea and chest pain; the former was significantly more common in those with asthma (38 versus 25 controls) but not the latter (14 versus 16 con trols); these effects were mostly mild and well tolerated. Bronchospasm occurred in five patients with asthma/COPD but resolved shortly after the end of the adenosine infusion; aminophylline was not required in any case. Because of the association of adenosine with bronchospasm, beta2-adrenoceptor agonist-induced supraventricular tachycardia in patients with asthma poses a therapeutic problem. In two boys with exacerbations of asthma and salbutamol-induced supraventri cular tachycardia, adenosine converted the rhythm without worsening the asthma (51A). This confirms previous reports that adenosine may be safe in such cases (52Ar, 53c). However, adenosine can cause dyspnea in the absence of bronchospasm, perhaps through stimulation of vagal C fibers in the airways and lungs. In 12 healthy subjects, mean age 32 years, intravenous adenosine 10 mg was given after inhalation of aerosoli zed lidocaine or placebo on two separate days (54C). After about 20 seconds, adenosine caused dyspnea, increased minute ventilation and caused transient bradycardia followed by tachycardia. The intensity of the dyspnea was markedly reduced by lidocaine, but the increased minute ventilation and heart rate responses were not affected.
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Of 54 patients, 7 of whom had mild COPD, 36 developed dyspnea during adenosine infu sion (55c). In those with mild COPD, respira tory resistance was significantly higher (0.48 versus 0.27 kPa/l/second), but neither those with nor those without COPD had a signi ficant increase in respiratory resistance during adenosine infusion. Respiratory resistance in those with dyspnea was insignificantly lower than in those without dyspnea. The authors concluded that bronchospasm had not been the cause of the dyspnea that their patients had suffered.
Adenosine receptor agonists (SEDA-30, 213; SEDA-31, 324) Observational studies In an open, rando mized, parallel-group, multicenter study in 133 adults who had completed diagnostic cardiac catheterization, the selective A2A adenosine receptor agonist binodenoson 0.3, 0.5 or 1 micrograms/kg/minute for 3 minutes or as a bolus injection of 1.5 or 3 micrograms/kg caused dose-related coron ary hyperemia within seconds (56c). All doses transiently caused reduced blood pressure, increased heart rate and an increased rate–pressure product. There were no adverse effects on the electrocardiogram. In an open dose-escalation study, the selective A2A adenosine receptor agonist regadenoson 10–500 micrograms by rapid intravenous bolus dose-relatedly increased peak intracoronary blood flow velocity in 34 subjects by up to 3.4 times (57c). Regade noson 400–500 micrograms increased heart rate by a mean of 21/minute and reduced systolic blood pressure by 5–24 mmHg and diastolic blood pressure by 8–15 mmHg. In another four subjects aminophylline 100 mg attenuated the increase in peak flow velocity but not the tachycardia caused by 400 micrograms of regadenoson. Adenosine and regadenoson in stress myocardial perfusion imaging have been compared in a database study of 2015 patients; regadenoson caused less chest pain, flushing, and throat, neck, or jaw
Positive inotropic drugs and drugs used in dysrhythmias
pain, but more headache and gastrointestinal discomfort (58c). Placebo-controlled studies In a crossover, randomized, double-blind, placebo-controlled trial, patients with asthma were challenged with adenosine monophosphate after rega denoson or placebo pretreatment (59C). The forced expiratory volume in 1 second (FEV1) was significantly higher at baseline at 10–60 minutes after treatment with regadenoson, but one patient had a 36% asymptomatic reduction in FEV1, which resolved spontaneously. The most common adverse events with regadenoson were tachy cardia (66%), dizziness (53%), headache (45%), and dyspnea (34%). Regadenoson increased the mean heart rate significantly (maximum 10/minute) compared with placebo. In a randomized, double-blind, placebocontrolled, crossover trial of regadenoson in 38 patients with moderate COPD and 11 patients with severe disease, there were no differences between regadenoson and pla cebo on multiple lung function parameters, including FEV1 and forced vital capacity, respiratory rate and oxygen saturation (60C). The mean maximum falls in FEV1 were 0.11 and 0.12 liters in patients who received regadenoson and placebo, respec tively, and there was new-onset wheezing in 6% and 12%. No patient required acute treatment with bronchodilators or oxygen.
Amiodarone
(SED-15, 148; SEDA-29, 185; SEDA-30, 213; SEDA-31, 324)
Enhanced eryptosis as a possible mechanism of action of amiodarone Eryptosis is a process of suicidal cell death undergone by erythrocytes, in which the pro cess known as scrambling of the cell mem brane occurs; erythrocyte shrinkage, exposure of membrane-bound phosphatidylserine, and annexin binding occur, mimicking features of
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apoptosis in nucleated cells (61R). The phos pholipids in erythrocyte plasma membranes are asymmetrically distributed; sphingo myelin and phosphatidylcholine are predomi nantly in the outer leaflet of the bilayer and phosphatidylserine and phosphatidylethano lamine in the inner leaflet. Alteration (‘scram bling’) of this asymmetry is an important feature of eryptosis. Eryptosis can be triggered by activation of calcium-permeable cation channels (62E–64E), with entry of calcium, which activates calcium-dependent potassium channels, leading to egress of potassium, chloride, and water, and thus to cell shrinkage (65E, 66E). These effects can be stimulated by the calcium ionophore iono mycin and by osmotic shock, oxidative stress, and glucose depletion. They are inhibited by inhibitors of the channels involved, such as amiloride and its analo gue ethylisopropylamiloride, charybdo toxin, chloride channel blockers such as niflumic acid, and antisense oligonucleo tides against the small-conductance cal cium-activated potassium channel isoform hSK4 (KCNN4); some of these effects are inhibited by phenylephrine, dobutamine, dopamine, catecholamines, and erythropoie tin. Calcium further triggers calcium-sensi tive scrambling of the cell membrane, causing breakdown of phosphatidylserine asymmetry, thought to result from activation of a so-called scramblase, which is sensitive to the intracellular concentration of free calcium (67E), with translocation of plasma membrane phospholipids and exposure of phosphatidylserine at the erythrocyte sur face. Cell membrane scrambling is also trig gered by ceramide (acylsphingosine) (68E). Erythrocytes in which membrane phosphati dylserine is exposed are rapidly eliminated from the blood, being engulfed by circulating macrophages (69E). Drugs that can stimulate eryptosis include chlorpromazine (70E), ciclosporin (71c), and paclitaxel (72c). Exposure of erythrocytes to lead (73E) and mercury (74E) does likewise. Several diseases are associated with acceler ated eryptosis, including sickle cell disease, thalassemia, and glucose-6-phosphate dehy drogenase deficiency (75c), hemolytic–uremic
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syndrome (76c), malaria (77E), in which it may contribute to accelerated removal of the erythrocytic form of the parasite (78E), sepsis (79c), phosphate depletion (80E), iron deficiency (81E), Wilson’s disease (82E), and amyloidosis (83E). When erythrocytes from healthy volun teers were exposed to amiodarone 1 µmol/l, the intracellular calcium concentration rose and annexin V binding was triggered (84E). However, amiodarone did not significantly affect ceramide formation, which is a feature of eryptosis. Amiodarone also increased annexin binding after hypertonic shock by the addition of sucrose 550 mmol/l but did not significantly alter the enhanced annexin binding after chloride removal by replace ment with gluconate. Thus, amiodarone appears to produce some of the effects that are associated with eryptosis and triggers phosphatidylserine exposure. However, it is not clear that the concentrations that produce this effect in vitro are relevant to in vivo therapy with amiodarone and specifically its adverse effects on the blood. Because eryptosis may be a mechanism whereby the clearance of Plasmodiuminfected erythrocytes are cleared, the effect of amiodarone on phosphatidylserine expo sure in Plasmodium-infected erythrocytes has been studied, in case it might affect the course of malaria (85E). Human erythro cytes were infected in vitro with Plasmodium falciparum, which increased annexin V bind ing, and this effect was significantly increased by amiodarone 10 µmol/l. Amiodarone also significantly reduced intraerythrocytic DNA/ RNA content and in vitro parasitemia. Fol lowing infection of mice with Plasmodium berghei, amiodarone 50 mg/kg significantly reduced the parasitemia and increased the survival of infected mice (from 0% to 70% 26 days after infection). Amiodarone also significantly increased the percentage of infected erythrocytes. Thus, amiodarone inhibited the intra-erythrocytic growth of Plasmodium falciparum, enhanced the suicidal death of infected erythrocytes, reduced parasitemia after Plasmodium bergheiinfection and supported host survival during malaria.
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Cardiovascular In the context of a case report it has been suggested that prolonga tion of the QT interval by amiodarone is the result of combined block of the rapid and slow components of the outward potassium current (IKr and IKs) in cardiac cells (86Ar). It has been proposed that activation of the IKs channel, for example with isoprenaline, could mitigate this adverse effect of amio darone (87A). The importance of susceptibility factors for cardiac dysrhythmias has been stressed in two cases. In one case intravenous amio darone unmasked congenital prolongation of the QT interval in a 62-year-old man with new-onset atrial fibrillation and no history of other dysrhythmias (88A). In another case torsade de pointes occurred in a 72-year old woman with pre-existing QT interval prolongation after the administration of amiodarone 300 mg/h for 3 hours (89A). Sinus bradycardia has been studied in 477 patients, mean age 49 years, taking amio darone, mean loading dose 809 mg/day, mean maintenance dosage 263 mg/day, mean duration of follow-up 21 months (90c). There was sinus bradycardia in 32% and 11% of patients during loading with amiodarone and maintenance treatment respectively. Phlebitis is a common complication when amiodarone is infused into a peripheral blood vessel, and although it may be possi ble to reduce the risk by using a low con centration (e.g. less than 2 mg/ml), the risk is still relatively high and has been esti mated at 14% (95% CI = 2.6, 25%) in a study in 273 patients, of whom 36 developed phlebitis (91c). When possible a large vein should be used for infusion of amiodarone. Respiratory Amiodarone-associated pneu monitis has again been reviewed in the context of case reports (92Ar, 93Ar). The hypothesis that aryl radical forma tion is involved in the adverse effects of amiodarone has been tested (94E). Photo lysis of anerobic aqueous solutions of amio darone and N-desethylamiodarone resulted in the formation of an aryl radical, as deter mined by spin-trapping and electron para magnetic resonance (EPR) spectroscopy.
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The non-iodinated analogue, didesiodo amiodarone, did not form aryl radicals under identical conditions. The cytotoxicity of these compounds was also studied in human lung epithelioid HPL1A cells. Desethylamiodarone had a more rapid and potent effect (LC50 8 µmol/l) than amio darone (LC50 146 µmol/l), and dides iodoamiodarone was intermediate (LC50 26 µmol/l), suggesting that the iodine atoms play a minor part. Incubation of human lung epithelial cells with the spintrapping nitrones alpha-phenyl-N-t-butyl nitrone 10 mmol/l and alpha-(4-pyridyl N-oxide)-N-t-butylnitrone 5.0 mmol/l did not significantly protect against cytotoxicity. Intratracheal administration of amiodarone to hamsters produced pulmonary fibrosis by day 21, which was not prevented by 4 days of treatment with the spin-trapping nitrones. The authors suggested that although amiodarone can generate an aryl radical photochemically, its in vivo forma tion may not be a major contributor to toxicity. The mechanisms of amiodarone-induced lung toxicity have been studied in relation to interferon gamma, which inhibits pul monary fibroblast proliferation, and inter leukin-4 (IL-4), which increases fibroblast growth and collagen production (95c). The ratio of interferon gamma to interleukin-4 produced by activated peripheral cluster of differentiation 4 (CD4) T cells increased during treatment with amiodarone in 26 patients, 6 of whom had lung toxicity. The serum concentration of desethylamiodar one was lower in those with lung damage and was inversely proportional to the ratio of interferon gamma to interleukin, which was the most powerful indicator of amiodar one lung toxicity in a multilogistic regression analysis. In an analysis of 237 cases of amiodarone associated pulmonary toxicity (described as interstitial lung disease, pulmonary fibrosis, pulmonary infiltrates, pleural effusion, alveolitis fibrosis, pneumonitis, bronchiolitis obliterans organizing pneumonia, or crypto genic organizing pneumonia), only age and duration of therapy significantly affected the risk (96c). The authors suggested that
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targeted monitoring of patients aged over 60 years and those who have taken amio darone for 6–12 months may minimize the risk of morbidity and mortality secondary to lung complications. In the context of three men, all smokers, aged 75, 93, and 85 years, who developed diffuse interstitial pneumonitis after taking amiodarone 200 mg/day for an average of 6.6 months, the authors suggested that old age and pre-existing lung abnormalities caused by smoking could be associated with amio darone-related pulmonary toxicity (97Ar). In a patient with peripheral edema and respiratory crackles on auscultation, a diag nosis of cardiac failure was made. However, there was platypnea rather than orthopnea, and a computed tomography (CT) scan showed an interstitial pneumonitis, which was attributed to amiodarone (98A). In 15 patients with raised serum globulin concentrations who were taking amiodar one the serum globulin concentrations nor malized after drug withdrawal; 11 of these patients had amiodarone toxicity according to the authors, and 9 had amiodarone-asso ciated pneumonitis (99c). A pleural effusion has been attributed to the combination of amiodarone and hypo albuminemia in a patient with severe burns (100A), but could have been due to the hypoalbuminemia alone. There have been rare reports of isolated lung masses attributed to amiodarone, and another case has been reported (101A). The mass contained myofibroblasts, aggregates of foamy macrophages containing multiple lamellar bodies (typical of amiodarone), and chronic interstitial inflammatory cells. The lesion resolved completely within 3 months of amiodarone withdrawal. Following reports that the adverse effects of amiodarone on the lungs can occur after relatively short-term therapy (SEDA-30, 214; SEDA-29, 186), a prospective study has been conducted in 102 patients, who were admitted to an intensive care unit (ICU) after cardiac surgery and who received short-term prophylactic amiodar one if they were thought to be at high risk of atrial fibrillation (102c). They were given 900 mg/day intravenously for the first 2 days
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and 600 mg/day thereafter. There were no significant effects of amiodarone on respira tory function. In contrast, a rapidly fatal case of lung damage has been reported in a man who was given intravenous amiodarone. • A 72-year-old man who developed atrial fibrillation after three-vessel coronary artery bypass grafting was given an intravenous loading dose of amiodarone 5 mg/kg over 20 minutes and then an infusion at a rate of 750 mg/day. Sinus rhythm was restored after 2 hours, but he became increasingly breathless, with an oxygen saturation of 85% on oximetry. His breath sounds were reduced at the lung bases and there were bibasilar râles. Arterial blood gases showed a respiratory acidosis. His erythrocyte sedimentation rate was 156/hour and the leukocyte count was 16.5 109/l. A chest X-ray showed bilateral alveolo interstitial infiltrates. A CT scan showed prominent bilateral densities, mainly at the perihilar space, radiating to the periphery, with a ground-glass appearance. He died after an episode of ventricular fibrillation. Post mortem examination showed a diffusely deranged lung parenchyma with foamy cells typical of amiodarone toxicity, interstitial and intra-alveolar edema, and hyaline membranes with diffuse dilatation of the airways and hyperplasia of the alveolar cells.
In 500 consecutive Japanese patients tak ing amiodarone who were retrospectively evaluated, the mean follow-up period was 48 months and the mean maintenance dosage was 141 mg/day (103c). The cumula tive incidences of lung damage at 1, 3, and 5 years were 4.2%, 7.8%, and 11% respec tively. Multivariate analysis showed that age at the start (HR = 1.48; 95% CI = 1.13, 1.93) was a significant pretreatment suscept ibility factor. Age (HR = 1.64; 95% CI =1.29, 2.09), maintenance dosage (HR = 1.90; 95% CI = 1.45, 2.49) and plasma monodesethylamiodarone concen tration (HR = 1.30; 95% CI = 1.08, 1.58) were susceptibility factors during treatment. The diagnostic sensitivity and specificity of percent predicted diffusion capacity of carbon monoxide were 68% and 69% for at least a 15% reduction and 59% and 74% for at least a 20% reduction. The diagnostic sensitivity and specificity of a serum KL-6 concentration of at least 500 U/ml were 25% and 91% respectively. The authors
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concluded that amiodarone can cause sub stantial pulmonary toxicity even at low doses, particularly in older patients. Nervous system Cerebellar ataxia, with a wide-based gait, bilateral dysdiadochokinesia, and bilateral nystagmus, has been reported in a 95-year-old woman who had taken amio darone 200 mg/day for 8 months (104A). Sensory systems Eyes In vivo confocal microscopy has been performed in 20 eyes of 10 patients (6 men and 4 women) at different stages of amiodarone-induced ker atopathy (105c). There were brilliant intra cellular inclusions with high reflectivity in the basal epithelium layer in all cases. Patients with stage 2 and 3 changes had all corneal layers affected. There was thinning and increased tortuosity of the corneal nerves in patients with stage 2 and 3 changes. The authors concluded that the basal epithelium was most affected at any stage of keratopathy; in stage 1 only the superficial and basal epithelium are affected, while in stages 2 and 3 all the corneal layers are affected. With advancing keratopathy the corneal nerves became thinner and tortuous. Rarely, keratopathy can affect the whole cornea (106A). Amiodarone can cause optic neuropa thies (107Ar). The question of whether it can cause a non-arteritic anterior ischemic optic neuropathy at all has been briefly discussed (108r, 109r), and ischemic optic neuropathy has again been reported (110A). In a prospective, double-masked, rando mized study of amiodarone (n = 837) or pla cebo (n = 832) with a median follow-up in survivors of 46 months, there were no cases of bilateral visual loss (111C). The authors calculated that the maximum possible annual incidences of bilateral visual loss in subjects taking amiodarone continuously for 4 to over 60 months in daily doses of > 2.0 mg/kg (n = 696), > 3.0 mg/kg (n = 559), or > 4.0 mg/kg (n = 219) were 0.23%, 0.29%, and 0.74% respectively. Smell Anosmia has been attributed to amiodarone in a 66-year-old man who took amiodarone 200 mg/day for 3 years;
Positive inotropic drugs and drugs used in dysrhythmias
the symptom abated when the dosage was reduced to 100 mg/day (112A). Endocrine Thyroid There are two types of amiodarone-induced thyrotoxicosis: type 1 occurs in those with latent disease and is due to the iodine that amiodarone contains; type 2 is due to a destructive thyroiditis in a previously normal gland. The incidence and predictability of amiodarone-induced thyrotoxicosis and hypothyroidism have been studied in 72 patients with cardiomyopathy during a median follow-up period of 8 months (113c). The prevalence of thyroid dysfunc tion before the start of amiodarone therapy was 38% (n = 27), with almost equal distri bution between hypothyroidism and hyperthyroidism (n = 14 and 13). After treatment with amiodarone, thyroid dys function was diagnosed in 25 of the 44 patients without pre-existing dysfunction. Of these, nine developed either subclinical or overt hypothyroidism and 16 developed either subclinical or overt hyperthyroidism. Factors such as 99mTc-pertechnetate scan uptake, thyroid autoimmunity, age, thyroid autonomy, or abnormal thyroid morpho logy were not significantly associated with the development of thyroid dysfunction The usefulness of thyroid scintigraphy has been assessed in 27 consecutive patients (mean age 65 years, 13 women) with amio darone-associated hyperthyroidism (114c). All underwent 99mTc-pertechnectate thyroid scintigraphy and were classified according to the qualitative estimation of radiotracer uptake. Type 1, defined by increased/normal uptake, occurred in nine patients, all of whom responded to antithyroid drugs or radioiodine, except one with subclinical hyperthyroidism, who received no therapy. Type 2, defined by very low or undetectable uptake, occurred in 13 patients, 11 of whom responded to withdrawal of amiodarone or prednisone therapy. Hyperthyroidism was resistant in two patients and required antithyroid drugs or potassium perchlorate. The authors concluded that thyroid scinti graphy can establish the correct therapeutic approach in most cases of amiodarone induced hyperthyroidism.
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The usefulness of Doppler scanning in differentiating the two types has been eval uated in 84 healthy subjects, 30 euthyroid patients taking amiodarone, 14 patients with type 1 thyrotoxicosis, and 9 with type 2 thyrotoxicosis (115c). The two types were classified by 131I uptake and the clinical out come. The authors suggested that systolic peak velocity in the thyroid arteries could differentiate the two types of thyrotoxicosis. In another study of the usefulness of colorflow Doppler sonography, amiodarone associated thyrotoxicosis was classified as type 1 if there was increased blood flow (n = 11) and as type 2 if there was low or no blood flow (n = 10). Ten of the 11 patients in the first group had a hypervascular nodular pattern and one had a hypervascular parenchymal pattern; the clinical diagnoses were toxic nodular goiter and Graves’ disease respectively. Of the 10 patients in the second group, 6 had a normal thyroid volume, 3 a small diffuse goiter, and one a small multinodular goiter (116c). In a retrospective analysis of the preva lence and relative proportions of type 1 and type 2 amiodarone-associated thyrotoxico sis in 215 patients seen over 27 years in an Italian centre, type 1 was more frequent (60%) at the start but became less frequent with time; the annual mean number of patients with type 1 thyrotoxicosis was 3.6 at the beginning of the study period and 2.5 during the later years (117c). In contrast, the mean annual number of new cases of type 2 thyrotoxicosis progressively increased from 2.4 to 13. Likewise, the proportion of cases of type 2 thyrotoxicosis increased linearly, and by the end of the study was accounting for 89% of the cases. Patients with type 2 thyrotoxicosis were preponderantly male, had a higher serum free T4/free T3 (FT4/ FT3) ratio and lower 3 hour and 24 hour thyroid radioactive iodine uptake, and had taken a higher cumulative dose of amiodarone. The long-term risk of amiodarone induced thyroid dysfunction has been studied in 612 men who had taken part in a prospective, randomized, placebocontrolled trial of amiodarone and sotalol for persistent atrial fibrillation (118C).
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Subclinical hypothyroidism, with thyroidstimulating hormone (TSH) concentrations of 4.5–10 mU/L, occurred in 26% of those taking amiodarone and only 6.6% of the controls, and overt hypothyroidism (TSH > 10 mU/l) in 5.0% versus 0.3%; 94% of the cases of overt hypothyroidism were detected by 6 months, suggesting an inter mediate time-course. There was a trend towards a greater frequency of hyperthyr oidism (TSH < 0.35 mU/l) in those who took amiodarone (5.3% versus 2.4%). The histopathology of amiodarone-asso ciated hypothyroidism in a 66-year-old Japanese woman has been reported (119A). Most of the thyroid follicles were enlarged with dense colloid substance and lined by flattened follicular cells (involuted follicles). A few damaged follicles were infiltrated by macrophages, which were immunopositive for HAM56. Sudan IV staining showed many lipid droplets in folli cular cells. Ultrastructurally, the follicular cells contained large residual bodies com posed of abundant electron-lucent lipid dro plets of variable sizes. The methods by which different endocrin ologists manage amiodarone-induced thyr oid disease vary (SEDA-29, 186). In a questionnaire study the methods used by North American specialists (n = 115) have been compared with those of European specialists from a previous study (n = 101) (120c). Amiodarone-induced hyperthyroid ism was less frequent than amiodarone induced hypothyroidism in North America (34% and 66% of all cases of amiodarone induced thyroid dysfunction respectively, versus 75% and 25% in Europe). When hyperthyroidism is suspected, in North America hormonal assessment is mostly based on serum free T4 and TSH measure ments, and serum FT3 determination is requested less often than in Europe; thyr oid autoimmunity is included in the initial assessment less often than in Europe. The most commonly used other diagnostic pro cedures include, as in Europe, thyroid color-flow Doppler sonography, and to a lesser extent radioactive iodine uptake and thyroid scanning. Withdrawal of amioda rone is more often considered unnecessary
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in North America (21% versus 10% in type 1 hyperthyroidism and 34% versus 20% in type 2). In type 1, thionamides are the treatment of choice by both groups, but they are used as monotherapy in North America in 65% of cases com pared with 51% in Europe, where potas sium perchlorate is more often considered as a useful addition (31% versus 15% in North America). Glucocorticoids are the treatment of choice for type 2 hyperthyr oidism, alone (62% versus 46% in Europe) or in association with thionamides (16% versus 25% in Europe). After restoration of euthyroidism, thyroid ablation in the absence of recurrent thyrotoxicosis is recommended in type 1 hyperthyroidism less often in North America. If amiodar one therapy needs to be reinstituted, pro phylactic thyroid ablation is advised by 76% in type 1 hyperthyroidism, while a wait-and-see strategy is adopted by 61% in type 2 hyperthyroidism, similar to the European approach. The effects of potassium perchlorate on thyroid function have been retrospectively studied in 10 patients with amiodarone induced thyrotoxicosis without underlying thyroid disease while they continued to take amiodarone (121c). Potassium perchlorate restored euthyroidism in all patients within 28 (range 15–45) days, but after it was with drawn all the patients became thyrotoxic again after 45 (range 30–60) days. One patient developed a mild leukopenia and one had a slight increase in serum creatinine, which normalized after withdrawal of potas sium perchlorate. The authors recommended that potassium perchlorate should not be used as a first-line treatment for thyrotoxi cosis if amiodarone needs to be continued. The use of radioactive iodine to cause thyroid ablation has been studied in four patients with type 2 amiodarone-induced thyrotoxicosis who either were poor candi dates for surgery or had refused it (122c). They had been initially treated with thion amides and glucocorticoids and all but one had become euthyroid. All four patients received one dose of radioactive iodine (range 29–80 mCi) and were followed up for 12 months. There were no exacerbations of
Positive inotropic drugs and drugs used in dysrhythmias
thyrotoxicosis, but hypothyroidism occurred in three patients in the first 6 months. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hyponatremia due to SIADH has again been attributed to amiodarone (123A, 124A). Hematologic Amiodarone-associated bone marrow granulomata have been reviewed in the light of two further cases, in an 81-year-old man who developed leukopenia, thrombo cytopenia, and hepatosplenomegaly after tak ing amiodarone for 2 years and an 80-year-old man who developed pancytopenia after 2.5 years; both patients had non-caseating granulomata in the bone marrow (125Ar). The authors reviewed eight other published cases, one of which also featured hepatic granulomata. Liver Intravenous amiodarone can rarely cause acute hepatitis, and further cases have been reported, associated with very high rises in serum transaminases (126A, 127A). It is not clear whether this effect is due to the amiodarone itself or to the vehicle in which it is formulated, polysorbate (Tween) 80. The PPAR-Iþ/- gene may be a susceptibility factor. Pancreas Pancreatitis, a rare adverse effect of amiodarone, has again been reported (128Ar). • A 66-year-old woman who had taken amiodar one 200 mg/day for 1 month developed epigas tric pain radiating to both flanks associated with a raised serum lipase but a normal serum amylase. Endoscopic ultrasonography suggested pancreatitis. There were no asso ciated causal factors, such as biliary stones, hypertriglyceridemia or excess alcohol con sumption. Amiodarone was withdrawn. Her symptoms quickly resolved and the serum lipase activity fell. Three months later the abdominal pain had not recurred.
Urinary tract Renal damage associated with amiodarone-induced phospholipidosis has been reported; a renal biopsy showed lamellar lipid inclusions typical of amiodar one and there were also corneal microdepo sits (129A).
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Skin The blue-grey skin pigmentation in sun-exposed areas associated with amiodarone has been presumed to be due to deposition of lipofuscin. However, electron microscopy and high-performance liquid chromatogra phy have shown deposits of amiodarone in a sample of skin from a patient with such pigmentation, and no lipofuscin (130A). The authors therefore suggested that amiodar one-related skin pigmentation should be considered a skin storage disease that is secondary to drug deposition, i.e. a betweenthe-eyes reaction of type 1 (131H). Sexual function Another case of epididy mitis, a rare adverse effect of amiodarone, has been reported (132Ar). Immunologic The immunomodulatory properties of amiodarone in the inflamma tory response induced by cardiac surgery with cardiopulmonary bypass have been investigated in a double-blind, placebocontrolled trial in 20 patients (133c). They were given amiodarone 600 mg/day for 7 days orally before surgery and 45 mg/hour intravenously for 48 hours postoperatively. Fibrinogen formation was significantly increased by amiodarone, and plasma fibri nogen concentrations more than doubled by 96 hours after the start of surgery. The secretion of monocyte chemoattractant protein 1 transiently increased 4 hours after the start of surgery but rapidly fell there after; it was not affected by amiodarone. The plasma concentrations of C-reactive protein (CRP), tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), and interleu kin-10 (IL-10) changed significantly, but were not altered by amiodarone. Although the authors suggested that amiodarone is associated with some proinflammatory actions, the data were not convincing. A hypersensitivity reaction to oral amio darone occurred in a patient who had had a previous urticarial reaction to an iodinated radiocontrast agent (134A). • A 55-year-old man developed facial urticaria after intra-arterial injection of iohexol during coronary angiography and was successfully treated with intravenous hydrocortisone and promethazine. Two subsequent episodes of
346 fast atrial fibrillation were treated with intravenous amiodarone, which was followed by oral therapy. Within 1 hour after the first oral dose of 400 mg, he developed lip swelling and tingling, which was treated with intravenous promethazine. Amiodarone was withdrawn. The Naranjo scale suggested a probable adverse reaction.
Death In a post-hoc analysis of the effects of amiodarone in 364 patients (155 of New York Heart Association [NHYA] class II and 209 of class III) from among 3029 patients with chronic heart failure who were randomized to carvedilol or metoprolol and followed for a median of 58 months, mortality was higher than in those who did not take amiodarone: 39% and 59% of those who used amiodarone in NYHA classes II and III þ IV died compared with 26% and 43% of those who did not use amiodarone (135c). This difference was maintained in a multivariate analysis (HR = 1.5; 95% CI = 1.2, 1.7). The difference was explained by an increased risk of death due to circula tory failure (HR = 2.4; CI = 1.9, 3.1). Sudden death was not different (HR = 1.07; CI = 0.8, 1.4). The authors concluded that amiodarone was associated with an increased risk of death from circulatory failure independent of functional class. However, analyses of this sort often prove to be wrong because of confounding factors. In another example of this type of posthoc analysis, an apparent association between the use of amiodarone and death has been reported in a study that was designed for a completely different purpose (136c). The study was a randomized com parison of valsartan, captopril, or both in patients with acute myocardial infarction with heart failure and/or left ventricular sys tolic dysfunction. In 825 patients who were taking amiodarone at randomization and 13 875 patients who were not, amiodarone was associated with a significant increase in mortality during three of the four study periods: HR = 1.5 (95% CI = 1.1, 2.0) for days 1–16; 2.1 (1.5, 2.9) for days 17–45; 1.1 (0.83, 1.46) for days 46–198; and 1.4 (1.2, 1.6) for days 199–1096. However, the patients who were treated with amiodarone were older, had higher Killip class, and were
Chapter 17
J.K. Aronson
more likely to have a history of diabetes mellitus and hypertension. Although the analysis was adjusted for baseline predictors of mortality, it is highly likely that other confounders were not allowed for. Only proper prospective randomized stu dies can be relied upon to answer the ques tions posed by these post-hoc analyses. Fetotoxicity Amiodarone can cause transi ent congenital hypothyroidism after gesta tional exposure, as has again been reported in two cases (137Ar). The neonatal TSH concentrations were 78 and 134 mU/l (reference range 100 nmol/l), which can only be achieved experimentally, or after particularly high doses (50–200 mg/day), the renal clearance of thiamine can approximate renal plasma flow. Tubular reabsorption of thiamine is an important aspect of its renal handling, and at plasma concentrations of 20–50 nmol/l, 2–5 times higher than are seen in healthy volunteers not taking supplements, it is only half maximal.
401
402
In 100 hospitalized patients with conges tive heart failure and 50 control subjects, the former had more thiamine deficiency (33 versus 6); 99 were taking furosemide, 28 spironolactone, and 15 metolazone (8c). Thiamine deficiency was related to urinary thiamine loss, non-use of thiamine-containing supplements, and preserved renal function. Increased urinary thiamine loss was the only significant positive predictor of thia mine status. The OR for furosemide use in thiamine depletion was 1.62, but the CI was wide (0.53, 4.91). Urinary thiamine losses with loop diure tics are not specific to their site of action. Urinary thiamine losses occur with virtually all diuretics (working at multiple nephron sites), including mannitol, acetazolamide, chlorothiazide, and amiloride (9E, 10c, 11c). Data on mannitol and amiloride in parti cular show that the major determinant of diuretic-related urinary thiamine loss is urine flow rate and not sodium excretion. These findings suggest that diuretic-induced thiamine depletion, when it occurs in the patients with heart failure, is not unique to loop diuretic therapy, but possibly occurs in patients who take long-term high-dose diure tic therapy for whatever indication. Patients with persistent polyuria, unrelated to diuretic therapy, are also candidates for thiamine deficiency. In addition to an effect on urinary excre tion, amiloride may also inhibit the absor ption of thiamine, because there is an amiloride-sensitive, pH-dependent, electro neutral, carrier-mediated mechanism for thiamine absorption in the jejunal brush-border membrane vesicles (12E, 13E). The effect of furosemide may be enhanced by an action on cardiac cells, because furo semide and digoxin reduce intracellular con centrations of thiamine pyrophosphate after in vitro exposure, with a half-life of 16–19 days; the effects of furosemide or digoxin are additive (14E). However, not all diuretics have this effect. In 11 patients with heart failure (New York Heart Association [NYHA] grades III or IV) taking furosemide, the addition of spir onolactone 25 mg/day significantly increased thiamine concentrations, determined by
Chapter 21
Domenic A. Sica
measuring erythrocyte transketolase activity, compared with 11 patients who were not given spironolactone and were taking the same daily dose of furosemide (15c). Susceptibility factors Some studies have not shown thiamine deficiency as a recognizable complication of furosemide therapy (16c). The absence of thiamine deficiency in certain patients taking diuretics may be coupled to the manner in which the body responds to diuretic therapy. The urine flow rate response to a diuretic is temporally linked to chronicity of dosing. A diuretic most reliably increases urine flow rate in the first few days of therapy; thereafter, a new steady state arises as a consequence of avid post-diuretic sodium and chloride absorption. Urine flow rate and sodium excretion therefore fall off, unless a high sodium intake is maintained; thus, if thiamine excretion were to follow urine flow rate faithfully, it would fall over time unless somehow a high urine flow rate were to persist with diuretic therapy. Nevertheless, patients who take diuretics and have a significant daily diuresis can become thiamine-depleted, particularly when intake or absorption is marginal. Age Elderly people may be more susceptible to thiamine deficiency if they take diuretics. In a random sample of 342 home-bound older adults, diuretic users were at increased risk of deficient dietary thiamine intake (17c). Surgery Prior gastrointestinal surgery can reduce thiamine intake and increase the risk of diuretic-induced deficiency (18A, 19A). • A 68-year-old Japanese man developed pretibial pitting edema, foot numbness, and a gait disturbance after taking furosemide 20 mg/day for 2 months. He had had a pancreaticoduodenectomy several years before for carcinoma of the ampulla of Vater. He had a polyneuropathy, peripheral edema, and a hyperkinetic heart. His plasma thiamine concentration was 14 µg/l (reference range 20–72). Oral thiamine supplementation (75 mg/day) was started for a presumed diagnosis of beriberi; he soon had a massive
Diuretics
Chapter 21
diuresis and his polyneuropathy began to improve. His plasma thiamine concentration rose to 78 µg/l. • A 66-year-old man, who had had a partial gastrectomy for cancer, developed severe pitting edema in the legs and was given loop diuretics, which relieved the edema at first, but did not resolve it completely. Levothyroxine for hypothyroidism produced further partial relief. However, he then developed an unsteady gait and worse edema. There was a stocking-and glove pattern of sensory disturbance and distal muscle weakness in the legs. The plasma thiamine concentration was low, and supplementation caused complete resolution of the edema in a few days, with improvement in the gait disturbance.
In these cases previous gastrointestinal sur gery with latent thiamine deficiency may have contributed to diuretic-induced deficiency. Patients with prior gastrointestinal surgery of a type that might interfere with nutrient absorption should be carefully observed for signs and symptoms of thiamine deficiency if loop diuretics are being considered. Management The effect of intravenous thiamine 200 mg/day has been studied in 30 patients with moderate to severe congestive heart failure who had taken long-term furosemide therapy in a 1-week, double-blind, placebo-controlled study, followed by oral thiamine 200 mg/day in all 30 patients for 6 weeks (20C). After intravenous thiamine, diuresis, sodium excretion, and left ventricular ejection fraction all increased.
CARBONIC ANHYDRASE INHIBITORS (SED-15, 643; SEDA-29, 220; SEDA-30, 254; SEDA-31, 371)
Brinzolamide Comparative studies Brinzolamide and brimonidine Brimonidine 0.15% (n = 79) and brinzolamide 1% (n = 84) added to travoprost have been compared in a 3-month, randomized, double-masked, parallel-group design (21C). The most
403
frequent adverse events were allergy, eye pain, headache, hyperemia, and taste disturbances. The incidences were not significantly different between the groups, but that does not mean that the two drugs are equivalent in terms of the incidences of adverse effects. Brinzolamide and levobetaxolol In chil dren aged under 6 with congenital glau coma, adverse events were evaluated in a randomized, double-masked study of brinzolamide (n = 32) and levobetaxolol (n = 46) with a follow-up of 12 weeks (22C). Reported adverse events judged to be related to the drugs were based on all 80 patients. They were hyperemia of the eyes, discharge, discomfort, tearing, foreign body sensations, hordeolum, pruritus of the eye, fatigue, and bradycardia. No concerns were identified with regard to visual acuity, the adnexae, anterior segment, posterior segment, vitreous, patient alertness, or cardiovascular parameters. Eight patients (five using brinzolamide and three using levobetaxolol) had an increase in corneal diameter of at least 1 mm in at least one eye. The adverse events in the overall population were predominately non-serious and were generally mild to moderate in intensity. No patient had a serious adverse event that was related to a study drug. There were no withdrawals because of adverse events. Sensory systems Tear film and the integrity of the ocular surface can be altered by long-term therapy with antiglaucoma agents, such as brinzolamide, dorzolamide, brimonidine, and timolol. In 21 patients who had used long-term antiglaucoma medications for a minimum of 8 months, there was significantly higher fluorescein and lisamine green staining and lower tear film break-up times, with marginal differences for ocular discomfort compared with age- and sexmatched controls not using ocular or systemic medications (23c). A finding in common with all of these medications was that the preservative benzalkonium
404
chloride was used; thus, the anti-glaucoma medications (or their preservatives) may cause a pro-inflammatory environment on the ocular surface. However, this process appears to be heterogeneous in its occurrence, not precisely related to duration of therapy, and in other studies was partially reversible with preservativefree eyedrops.
Dorzolamide Comparative studies Dorzolamide and latanoprost Dorzolamide 2% and timolol 0.5% alone (n = 70) or added to latanoprost (n = 280) have been compared in an open, non-randomized study (24c). There were 116 predominantly mild non-serious adverse events reported by 86 patients (25%). The most frequent were eye irritation (n = 42; 12%) and a bad taste in the mouth (n = 15; 4%). There were five treatment-related non-serious adverse events of severe intensity (eye irritation, diarrhea, nausea, gout, and headache). There were no serious adverse events. Sensory systems Eyes The integrity of the lacrimal drainage apparatus can be damaged by anti-glaucoma medications. In a prospective, controlled, blinded, observational case series, 130 eyes from 98 patients using topical anti-glaucoma medications were compared with 280 eyes from 178 patients matched with respect to age, sex, and associated systemic disorders (25c). The participants underwent external eye and slit lamp examinations, diagnostic probing, irrigation tests, and a dye disappearance test. There was significantly more lacrimal duct system obstruction in the cases than in the control, in both the upper and lower portions of the drainage system. The patients had typically been using various drug combinations for differing durations of time. Two drug combinations, in particular, timolol þ dorzolamide and timolol þ dorzolamide þ pilocarpine, were
Chapter 21
Domenic A. Sica
associated with lacrimal duct system obstruction. As the upper lacrimal drainage system is close to the conjunctiva and fornix, it would not be expected to be more affected than the lower lacrimal drainage system, as was the case in this series. Unlike the controls, in whom lacrimal duct system obstruction was related to age, in the cases there was no relationship to age, suggesting that the duct obstruction was related more to the antiglaucoma medications. The widespread use of anti-glaucoma medications necessitates awareness by physicians of such findings such that early recognition and treatment of this adverse effect might lessen the need for future advanced lacrimal drainage apparatus surgery. Topical dorzolamide has been associated with hypotony and choroidal detachment (26A). • A 60-year-old white woman underwent trabeculectomy on both eyes. Fluctuating intraocular pressures over several years resulted in the need for topical anti-glaucoma medication in the left but not the right eye. A subsequent increase in intraocular pressure to 32 mmHg in the right eye prompted treatment with timolol 5% þ dorzolamide 2%. She then gradually lost vision in the right eye over 3 months (20/60 versus a baseline of 20/30) and hypotony (an intraocular pressure less than 5 mmHg). Fundoscopy and a B-scan ultrasound confirmed a four-quadrant choroidal detachment. All intraocular medications were stopped and over 12 weeks the choroidal detachment resolved, with improvement in visual acuity to 20/40. Three months later the intraocular pressure had risen to 28 mmHg in the right eye and timolol þ dorzolamide was restarted. However, her visual acuity fell dramatically once again (to 20/200) and the hypotony recurred (intraocular pressure 2 mmHg). Once again, there was choroidal detachment in the right eye. All anti-glaucoma medications were withdrawn and within 2 months the choroidal detachment resolved.
Achieving very low intraocular pressures with any combination of anti-glaucoma medications can result in choroidal detach ment, which may be heralded by sudden reduction in visual acuity. In 13 patients with peri-orbital dermatitis, ectropion was presumed to have been due to one or more of the drugs that they were using – betaxolol, brimonidine,
Diuretics
Chapter 21
405
dorzolamide, latanoprost, timolol, or travo prost, or the preservatives in which they were formulated; the drugs were withdrawn and the patients were assessed again, with re-challenge after the last assessment (27c). The ectropion resolved partly or completely after the eyedrops had been withheld and there was recurrence after re-challenge. Dorzolamide (seven cases) was the most common offender, followed by brimonidine (three cases). Two patients successfully underwent surgical correction for ectropion after withdrawal of the eyedrops, but those who had a short course of a glucocorticoid did not need surgical correction. Smell Anosmia associated with dorzolamide resolved after withdrawal (28A). In a series of patient-blinded experiments with challenges and re-challenges with dor zolamide and latanoprost, the dysosmia only occurred with dorzolamide. In the nasal mucosa, the balanced ion concentra tion that is maintained by carbonic anhy drase is necessary for depolarization of the olfactory receptor neurons during olfactory transduction. This could have been influ enced by dorzolamide. Skin Topical dorzolamide associated with erythema (29A).
• An 80-year-old woman developed conjunctival inflammation and severe peri-orbital eczematous dermatitis of the right eye, which had been evolving for 6 months in association with a few round, patchy, eczematous lesions on the abdomen. For more than 2 years she had been using timolol þ dorzolamide (Cosopt®) exclusively in the right eye. The Cosopt® was withdrawn and within 1 month there was discrete improvement in the peri orbital skin findings. A repeated open application testing with Cosopt® and timolol maleate (Timoptol®), each applied to the volar surface of the forearm, was performed. The test was positive with Cosopt® only, and within 3 days there was an obvious recurrence of dermatitis in the right eye and reactivation of the fixed eczematous lesions on the abdomen. The test was repeated 1 month later with dorzolamide (Trusopt®) alone and once again right peri-ocular dermatitis and abdominal eczematous lesions developed rapidly.
Topical dorzolamide is associated with a number of local adverse effects of an irritant or allergic nature; however, its use is rarely associated with systemic symptoms. In this instance, topical dorzolamide clearly trig gered a systemic contact dermatitis when applied to the forearm in the course of allergy testing. This pattern mimicked what had occurred with dorzolamide eyedrops.
has been multiforme
• An 80-year-old Caucasian woman developed eruptions on her arms, lips and ears, with peri ocular and peri-oral hyperemia after taking timolol þ dorzolamide (Cosopt®) for primary open-angle glaucoma. The lesions were symmetrically distributed, with several classic target lesions on the forearms. She had previously been exposed to Cosopt® and had developed peri-ocular hyperemia and itching at that time. Prompt withdrawal of dorzolamide, together with topical glucocorticoids, led to rapid resolution of the skin lesions.
Erythema multiforme can rarely occur with topical sulfonamide derivatives, in par ticular dorzolamide. Patients should be monitored carefully for skin reactions when treated with topical dorzolamide. Topical dorzolamide has been associated with systemic contact dermatitis (30A).
THIAZIDE AND THIAZIDE LIKE DIURETICS (SED-15, 3375;
SEDA-29, 221; SEDA-30, 256;
SEDA-31, 372)
Tumorigenicity Diuretics are photo sensitizers. However, there is scant information about how they affect the risk of skin cancers. In a population-based casecontrol study in Denmark to determine whether the use of photosensitizing diuretics was associated with an increased risk of basal cell carcinoma, squamous cell carcinoma, or malignant melanoma, primary cases during 1989–2003 were identified from the Danish Cancer Registry (31C).
406
Four age- and sex-matched population controls for each case were selected from the Danish Civil Registration System. Prescriptions for photosensitizing diuretics before the diagnosis of cancer were ascertained from the country’s Prescription Database. Conditional logistic regression was used to compute an incidence rate ratio (IRR), controlling for chronic medical conditions and prior use of oral glucocorticoids. There was an increased risk of squamous cell carcinoma (IRR = 1.79; 95% CI = 1.45, 2.21) and malignant melanoma (IRR = 1.43; CI = 1.09, 1.88) in users of the combination of hydro chlorothiazide þ amiloride. There was also an increased risk of malignant melanoma (IRR = 3.30; CI = 1.34, 8.10) among users of indapamide. For each of these findings there was a trend of increasing risk with the amount of drug and length of time between prescriptions and diagnosis. Because of the low proportion of cases in the general population, the risk estimates had very limited statistical precision, which is a significant limitation of these studies. These data are probably most relevant to individuals with pre-existing squamous cell carcinoma or malignant melanoma, in whom starting or continuing therapy with photosensitizing diuretics should be given careful consideration.
Chapter 21
Domenic A. Sica
concentration of at least 7 mmol/l (126 mg/dl), or a random glucose of at least 11 mmol/l. The mediating variable was the change in serum potassium during year 1 of treatment. Of the 459 incident cases of diabetes during follow-up, 42% occurred during year 1. In year 1, the adjusted risk of diabetes (hazard ratio [HR]) with chlortalidone was 2.07 (95% CI = 1.51, 2.83). After adjustment for the change in serum potassium, the risk was significantly reduced (HR = 1.54; 95% CI = 1.09, 2.17). The extent of risk attenuation (41%; 95% CI = 34, 49) was consistent with an effect mediated by potassium. Each 0.5 mmol/l fall in serum potassium was independently associated with a 45% (95% CI = 24, 70) higher adjusted risk of diabetes. After year 1, use of chlortalidone was not associated with a noteworthy increased risk of diabetes. Those with a fasting glucose of 5.5 mmol/l or more, treatment with chlortalidone 12.5 mg/day or more and a fall in serum potassium of 0.5 mmol/l or more were at the greatest risk of developing diabetes. Potassium supplementation might prevent thiazideinduced diabetes, but this remains to be proved in a suitably designed randomized trial.
Hydrochlorothiazide
Chlortalidone
Sensory systems Hydrochlorothiazide has been associated with retinal phototoxicity after exposure to an ultraviolet tanning device (33A).
Endocrine Multiple mechanisms have been proposed for the association of thiazide-type diuretics with diabetes mellitus, including potassium depletion. To determine the strength of the relationship between thiazide-induced diabetes and changes in potassium, 3790 non-diabetic participants in the Systolic Hypertension in Elderly Program, a randomized clinical trial of isolated systolic hypertension in individuals aged 60 years and over taking chlortalidone or placebo, were evaluated in a post hoc analysis (32c). Incident diabetes was defined by self-report, the use of antidiabetic medications, a fasting glucose
• A 40-year-old woman with myopia complained of blurred vision and a superior central scotoma in her left eye. These symptoms appeared immediately after exposure to an ultraviolet (UV) light source from a tanning bed. During the tanning session she had always worn UV-protective eyewear, except for a few minutes when she took the protective goggles off to put her spectacles. She had taken a fixed-dose combination of lisinopril 21.8 mg and hydrochlorothiazide 12.5 mg once a day for 2 years. At baseline her visual acuity was 10/25 and 10/80 in her right and left eyes, respectively. Fundoscopy showed lesions in both retinae. More specific tests confirmed the presence of phototoxic macular damage. Hydrochlorothiazide was withdrawn and she was advised to wear UV
Diuretics
Chapter 21
filtering glasses. Over the next 12 months she slowly recovered visual acuity in both eyes.
The UV absorption peak for hydro chlorothiazide is in the wavelength range 277–294 nm, which is the range encountered during artificial tanning. Endocrine Among antihypertensive drugs, beta-blockers and thiazide diuretics have been reported to cause reduced insulin sensi tivity and increase the risk of diabetes mellitus. Conversely, angiotensin receptor antagonists and angiotensin-converting enzyme inhibitors are associated with a reduced risk. The diabe togenic effects of thiazide and thiazide-like diuretics have been attributed to increased hepatic glucose production, impaired periph eral glucose uptake and/or b-cell dysfunction mediated by potassium depletion. The effects of candesartan 16–32 mg/day, hydrochlor othiazide 25–50 mg/day and placebo on the actions and secretion of insulin and on body fat distribution have been explored in 22 non-diabetic, hypertensive patients with abdominal obesity in the Mechanisms for the Diabetes Preventing Effect of Candesartan Study (MEDICA), a three-way, 12-week, randomized, crossover trial (34C). Insulin sen sitivity was reduced by hydrochlorothiazide compared with both candesartan and placebo, liver fat content was higher, and the subcuta neous to visceral abdominal adipose tissue ratio was reduced. Glycated hemoglobin and high-sensitivity C-reactive protein concentra tions and alanine and aspartate transaminase activities were higher after hydrochlorothia zide. Visceral fat redistribution, liver fat accu mulation, and low-grade inflammation appear to be additional factors that may explain increased insulin resistance observed in patients taking thiazide diuretics. Redistribu tion of fat in these studies could have related to insulin resistance and not to a primary effect of hydrochlorothiazide on adipocyte production.
Indapamide Cardiovascular Indapamide has been associated with prolongation of the QT
407
interval and Brugada syndrome in the setting of severe hypokalemia and hyponatremia (35A). • A 64-year-old man developed generalized weakness and dizziness. He was taking indapamide 2.5 mg/day for hypertension. Electrocardiography showed coved ST segment elevation in V2 with deep T-wave inversion (type 1 Brugada pattern) and a prolonged QT interval of 508 ms. His serum potassium concentration was 1.7 mmol/l and serum sodium 111 mmol/l. He had a sudden cardiac arrest with a polymorphous ventricular tachycardia, which was successfully defibrillated. His QTc interval gradually normalized as his serum potassium returned to normal; however, his Brugada pattern did not correct until his serum sodium had normalized some 48 hours later.
Indapamide-induced acquired long QT syndrome has been previously reported. However, an association between indapa mide and Brugada syndrome has not been previously reported. The exact mechanism by which the indapamide-related electrolyte disturbances resulted in Brugada syndrome in this case was unclear. Indapamide, and for that matter any diuretic that produces significant hypokalemia and hyponatremia, should be used with caution in patients who are genetically predisposed to or at risk of developing acquired long QT or Brugada syndromes. Endocrine Indapamide has been associated with primary hyperparathyroidism (36A). • A 75-year-old man developed constipation and epigastric discomfort and had a raised serum calcium concentration of 2.84 mmol/l. He had been taking indapamide 2.5 mg/day for about 2 years and was also taking perindopril 2 mg/day and atenolol 100 mg/day. His serum calcium had been 2.38 mmol/l when indapamide was started. Indapamide was withdrawn and his serum calcium fell to 2.46 mmol/l and his parathyroid hormone concentration fell from 10.6 to 7.0 pmol/l (reference range 1.5–7.7). His serum calcium and parathormone concentrations remained normal for more than a year after indapamide withdrawal.
Various renal, endocrine, and bonerelated mechanisms have been proposed to account for the development of hyper calcemia during therapy with thiazide-like
408
diuretics, but primary hyperparathyroidism has rarely been reported. Measurement of parathormone concentrations should be an important consideration in the initial eva luation of patients with thiazide-like diure tic-related hypercalcemia. Electrolyte balance Hyponatremia and hypokalemia
EIDOS classification: Extrinsic moiety: Loop, thiazide, and
thiazide-like diuretics
Intrinsic moiety: Na/K/Cl co-transporters (loop diuretics) or Na/Cl co transporters (thiazides) Distribution: Nephrons: loop of Henle (loop diuretics) or distal convoluted tubule (thiazides) Outcome: Altered physiology (excess
natriuresis and kaliuresis)
Sequela: Hyponatremia and
hypokalemia
DoTS classification: Dose-relation: Collateral Time-course: Time independent, but
typically occurs within weeks of
starting therapy
Susceptibility factors: Age; sex (female); physiological factors (reduced solute intake)
Hyponatremia and hypokalemia have again been reported in a patient taking indapamide (37A). • An 83-year-old woman took indapamide 1 mg/ day for hypertension and 2 months later developed nausea, vomiting, and loss of appetite, and frequently fell down. She was hypotensive (90/54 mmHg) and somnolent and had severe hyponatremia (115 mmol/l) and hypokalemia (2.8 mmol/l). Indapamide was withdrawn and her level of consciousness and serum electrolytes rapidly normalized.
In another case concomitant acquired long QT syndrome and Brugada syndrome were associated with severe hypokalemia and hyponatremia after the use of indapa mide for hypertension (38A).
Chapter 21
Domenic A. Sica
Nails Indapamide has been associated with photo-onycholysis (39A). • A 75-year-old Caucasian woman with hypertension and osteoporosis developed yellowish-brown discoloration, onycholysis, and nail-fold erythema of all 10 fingernails; the toenails were not involved. She had taken indapamide, risedronate, vitamin D, atorvastatin, atenolol, aspirin, and famotidine for several years and had been using artificial acrylic nails that were removed and reapplied by her beautician about every 6 weeks without problems. She stopped taking indapamide and applied an opaque nail polish as a photoprotective agent. Her nails returned to normal within about 4 months.
There was delayed onset in this case, probably as the result of photoprotection afforded by the artificial nails. The photo sensitizing potential of indapamide was thought to arise from the chlorine substi tuents that it shares with thiazide diure tics, resulting in UV-induced dissociation of the chlorine substituent and free radi cal reactions with lipids, proteins, and DNA.
(SED-15, 567, 1454; SEDA-29, 222; SEDA-30, 258; SEDA-31, 375)
LOOP DIURETICS
Skin Papuloerythroderma has associated with furosemide (40A).
been
• A 79-year-old man with a 25-year history of mild eczema on the trunk and limbs developed heart failure and was given furosemide. After 4 months he developed an erythematous papular eruption, which quickly progressed. There was widespread erythroderma, with coalescent solid papules predominantly on the trunk and limbs; the face, axillae, and skin folds were spared. There was a normal leukocyte count but 13% eosinophils (678 106/l). A biopsy showed moderate perivascular infiltration with lymphocytes and eosinophils in the papillary dermis. A patch test with furosemide was negative, but a lymphocyte stimulation test was positive. Furosemide was withdrawn and he was treated with topical 0.05% betamethasone
Diuretics
Chapter 21
butyrate propionate once a day for 1 month, resulting in improvement. After oral challenge with furosemide the erythematous papular eruption recurred within 48 hours.
Prior sensitization to furosemide can lead to rapid development of such skin lesions on repeat exposure. Torasemide has been associated with the development of pseudoporphyria (41A). • A 64-year-old man with chronic renal insufficiency took torasemide for about 4 months followed by furosemide for about 2 months before developing blistering lesions, crusts, erosions, and hypopigmented scars on his scalp and the backs of his hands. Urinary porphyrin concentrations were normal.
Diuretic-induced pseudoporphyria has been described in relation to chlortalidone, bumetanide, and furosemide and to an interaction of hydrochlorothiazide with triamterene. The persistence of lesions after switching to furosemide and disap pearance of the cutaneous eruption after withdrawing it suggests cross-reactivity between torasemide and furosemide. Drug–drug interactions Warfarin Tora semide has been reported to potentiate the effects of warfarin (42A). • A 43-year-old Hispanic woman with heart failure, hypothyroidism, anemia, atrial fibrillation, and a mechanical mitral valve was anticoagulated with a target international normalized ratio (INR) of 2.5–3.5 on a warfarin regimen of 50–52.5 mg/week. One week after she started to take torasemide 40 mg in the morning and 20 mg in the afternoon, there was a marked increase in the INR to 6.2, requiring a reduction in the dose of warfarin. Subsequent titration of the dose of warfarin over 3 weeks was required to reach a target INR of 2.9–3.3, with a new weekly dose of 47.5 mg.
The basis of this interaction was probably competition for CYP2C9, by which both warfarin and torasemide are metabolized. Protein binding displacement of warfarin from albumin by torasemide is less likely, since that would have produced only a tran sient effect. Other potential causes of an increased INR, such as reduced absorption of vitamin K, were ruled out. Care should be taken when torasemide is added to
409
warfarin therapy. A similar interaction with furosemide and bumetanide has not been previously reported; neither of those loop diuretics is metabolized by CYP2C9.
ALDOSTERONE RECEPTOR ANTAGONISTS Spironolactone
(SED-15, 3176; SEDA 29, 222; SEDA-30, 259; SEDA-31, 375)
Gastrointestinal There have been two reports of an increased rate of gastrointestinal bleeding in patients taking spironolactone. In a population-based case-control study in Denmark in 3652 subjects with serious upper gastrointestinal bleeding and 36 502 age- and sex-matched controls, the adjusted OR for an effect of spironolactone was 2.7 (95% CI = 2.2, 3.2) (43C). The risk increased with higher doses of spironolactone (OR = 5.4; CI = 3.4, 8.6), but there was no trend with increasing cumulative doses. The strongest association was found among users aged 55–74 years (OR = 13; CI = 6.5, 26). Current use of loop diuretics was also associated with an increased risk of upper gastrointestinal bleeding (OR = 1.9; CI = 1.7, 2.1). In another study using pharmaceutical prescriptions from 2000 to 2006, a cohort of residents in Milan was identified with chronic exposure to spironolactone or other diuretics 44C. The main outcome was defined as hospital admissions for upper gastrointestinal bleeding or ulcers. To control for potential bias related to the use of spironolactone, propensity scores were estimated, and each patient taking spironolactone was randomly matched with one taking other diuretics and having the same propensity score using the caliper matching method. Proportional hazard models were fitted by computing HRs. Of 53 550 non-exposed subjects and 10 564 who had been exposed to spironolac tone, 174 (3.2%) and 51 (4.8%) respectively had been hospitalized for upper gastrointestinal bleeding (HR = 1.94; 95% CI = 1.42, 2.65). A sensitivity analysis
410
based on the matched design using the propensity score showed a statistically significant twofold increase in upper gastrointestinal bleeding only among sub jects who had been exposed to high doses of spironolactone (HR = 2.50; 95% CI = 1.08, 5.79). Both of these studies suggest that spiro nolactone increases the risk of upper
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Domenic A. Sica
gastrointestinal bleeding. This relationship has been hinted at in previous literature, but has not been shown with such clarity. These studies do not offer a mechanistic basis for this effect. Considering that many patients taking spironolactone are at high risk of upper gastrointestinal bleeding, confound ing by treatment indication may have played some part.
References 1. Rieck J, Halkin H, Almog S, Seligman H, Lubetsky A, Olchovsky D, Ezra D. Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab Clin Med 1999;134:238–43. 2. Seligmann M, Halkin H, Rauchfleisch S, Kaufmann N, Tal R, Motro M, Vered Z, Ezra D. Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study. Am J Med 1991;91:151–5. 3. Zenuk C, Healey J, Donnelly J, Vaillancourt R, Almalki Y, Smith S. Thiamine deficiency in congestive heart failure patients receiving long term furosemide therapy. Can J Clin Pharmacol 2003;10:184–8. 4. Suter PM, Haller J, Hany A, Vetter W. Diure tic use: a risk for subclinical thiamine defi ciency in elderly patients. J Nutr Health Aging 2000;4(2):69–71. 5. da Cunha S, Albanesi Filho FM, da Cunha Bastos VL, Antelo DS, Souza MM. Thiamin, selenium, and copper levels in patients with idiopathic dilated cardiomyopathy taking diuretics. Arq Bras Cardiol 2002;79 (5):454–65. 6. Härdig L, Daae C, Dellborg M, Kontny F, Bohmer T. Reduced thiamine phosphate, but not thiamine diphosphate, in erythrocytes in elderly patients with congestive heart failure treated with furosemide. J Intern Med 2000;247(5):597–600. 7. Sica DA. Loop diuretic therapy, thiamine bal ance, and heart failure. Congest Heart Fail 2007;13:244–7. 8. Hanninen SA, Darling PB, Sole MJ, Barr A, Keith ME. The prevalence of thiamin
deficiency in hospitalized patients with con gestive heart failure. J Am Coll Cardiol 2006;47(2):354–61. 9. Lubetsky A, Winaver J, Seligmann H, Olchovsky D, Almog S, Halkin H, Ezra D. Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load. J Lab Clin Med 1999;134(3):232–7. 10. Markkanen T. The effect of acetazolamide and mercaptomerin on the urinary excretion of thiamine, riboflavin and pantothenic acid. Z Vitam Horm Fermentforsch 1965;14 (1):72–6. 11. Kasper H, Der HI. Einfluss von Hydrochlor othiazid auf die Thiaminausscheidung im Urin. [Influence of hydrochlorothiazide on urine thiamine excretion.] Klin. Wochenschr. 1966;44(10):568–71. 12. Dudeja PK, Tyagi S, Kavilaveettil RJ, Gill R, Said HM. Mechanism of thiamine uptake by human jejunal brush-border membrane vesi cles. Am. J. Physiol Cell Physiol 2001;281(3): C786–92. 13. Dudeja PK, Tyagi S, Gill R, Said HM. Evi dence for a carrier-mediated mechanism for thiamine transport to human jejunal basolat eral membrane vesicles. Dig Dis Sci 2003;48 (1):109–15. 14. Zangen A, Botzer D, Zangen R, Shainberg A. Furosemide and digoxin inhibit thiamine uptake in cardiac cells. Eur J Pharmacol 1998;361(1):151–5. 15. Rocha RM, Silva GV, de Albuquerque DC, Tura BR, Albanesi Filho FM. Influence of spironolactone therapy on thiamine blood levels in patients with heart failure. Arq Bras Cardiol 2008;90(5):324–8.
Diuretics
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16. Yue QY, Beermann B, Lindstro¨ m B, Nyquist O. No difference in blood thiamine diphosphate levels between Swedish Caucasian patients with congestive heart failure treated with furosemide and patients without heart fail ure. J Intern Med 1997;242(6):491–5. 17. McCabe-Sellers BJ, Sharkey JR, Browne BA. Diuretic medication therapy use and low thia min intake in homebound older adults. J Nutr Elder 2005;24(4):57–71. 18. Tsujino T, Nakao S, Wakabayashi K, Lee M, Kimura T, Yoshikawa H, Sakoda T, Ohyanagi M, Masuyama T. Loop diuretic pre cipitated beriberi in a patient after pancreati coduodenectomy: a case report. Am J Med Sci 2007;334:407–9. 19. Akahori H, Tsujino T, Masutani M, Akagami T, Tanabe K, Masai M, Fujioka Y, Ohyanagi M, Masuyama T. [Postgastrect omy beriberi exaggerated by diuretic use: a case report.] J Cardiol 2007;49(1):49–53. 20. Shimon I, Almog S, Vered Z, Seligmann H, Shefi M, Peleg E, Rosenthal T, Motro M, Halkin H, Ezra D. Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiv ing long-term furosemide therapy. Am J Med 1995;98(5):485–90. 21. Feldman RM, Tanna AP, Gross RL, Chuang AZ, Baker L, Reynolds A, Prager TC. Com parison of the ocular hypotensive efficacy of adjunctive brimonidine 0.15% or brinzola mide 1% in combination with travoprost 0.004%. Ophthalmology 2007;114:1248.e2–54. 22. Whitson JT, Roarty JD, Vijaya L, Robin AL, Gross RD, Landry TA, Dickerson JE, Scheib SA, Scott H, Hua SY, Woodside AM, Bergamini MVW. Efficacy of brinzolamide and levobetaxolol in pediatric glaucomas: a randomized clinical trial. J AAPOS 2008;12:239.e3–46. 23. Baffa L, Ricardo JR, Dias AC, Modulo CM, Braz AM, de Paula JS, Rodriguez M, Rocha EM. Tear film and ocular surface alterations in chronic users of antiglaucoma medica tions. Arq Bras Oftalmol 2008;71:18–21. 24. Lesk MR, Koulis T, Sampalis F, Sampalis JS, Bastien NR. Effectiveness and safety of dor zolamide–timolol alone or combined with latanoprost in open-angle glaucoma or ocu lar hypertension. Ann Pharmacother 2008;42:498–504.
411 25. Sharma T, Salmon JF. Hypotony and choir oidal detachment as a complication of topical combined timolol and dorzolamde. J Ocul Pharmacol Ther 2007;23:202–4. 26. Kashkouli MB, Rezaee R, Nilforoushan N, Salimi S, Foroutan A, Naseripour M. Topical antiglaucoma medications and lacrimal drai nage system obstruction. Opht Plas Recons Surg 2008;24:172–5. 27. Hegde V, Robinson R, Dean F, Mulvihill HA, Ahluwalia H. Drug-induced ectropion. What is best practice? Ophthalmology 2007;114:362–6. 28. Turgut B, Turkcuoglu P, Guler M, Akyol N, Celiker U, Demir T. Anosmia as an adverse effect of dorzolamid. Acta OphthalmolScand 2007;85:228–9. 29. Munshi V, Ahluwalia H. Erythema multiforme after use of topical dorzolamide. J Ocul Pharmacol Ther 2008;24:91–3. 30. Kluger N, Guillot B, Raison-Peyron N. Sys temic contact dermatitis to dorzolamide eye drops. Contact Derm 2008;58:167–8. 31. Jensen AÃ, Thomsen HF, Engebjerg MC, Olesen AB, SÏrensen HT, Karagas MR. Use of photosensitising diuretics and risk of skin cancer: a population-based case-control study. Br J Cancer 2008;99:1522–8. 32. Shafi T, Appel LJ, Miller III ER, Klag MJ, Parekh RS. Changes in serum potassium mediate thiazide-induced diabetes. Hyper tension 2008;52:1022–9. 33. Costagliola C, Menzione M, Chiosi F, Romano MR, Della Corte M, Rinaldi M. Retinal phototoxicity induced by hydro chlorothiazide after exposure to a UV tanning device. Photochem Photobiol 2008;84:1294–7. 34. Eriksson JW, Jansson PA, Carlberg B, Hägg A, Kurland L, Svensson MK, Ahlstro¨ m H, Stro
¨ m C, Lo
¨ nn L, Ojbrandt K, Johansson L, Lind L. Hydrochlorothiazide, but not can desartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: The Mechanisms for the Diabetes Preventing Effect of Candesartan (MEDICA) study. Hypertension 2008;52(6):1030–7. 35. Mok NS, Tong CK, Yuen HC. Concomitantacquired long QT and Brugada syndromes associated with indapamide-induced hypo kalemia and hyponatremia. PACE 2008;31:772–5.
412 36. Debono M, Banerjee R. Indapamide induced hyperparathyroidism: a case report. Eur J Clin Pharmacol 2007;63:809–11. 37. Hamano T, Yamamoto T, Miyamori I, Kuriyama M. [Hyponatremia with somno lence due to indapamide.] Rinsho Shinkei gaku 2008;48(1):52–5. 38. Mok NS, Tong CK, Yuen HC. Concomitantacquired Long QT and Brugada syndromes associated with indapamide-induced hypo kalemia and hyponatremia. Pacing Clin Elec trophysiol 2008;31(6):772–5. 39. Rutherford T, Sinclair R. Photo-onycholysis due to indapamide. Australas J Dermatol 2007;48:35–6. 40. Sugita K, Kabashima K, Nakashima D, Tokura Y. Papuloerythroderma of Ofuji induced by furosemide. J Am Acad Derma tol 2008;58(2 Suppl):S54–5.
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41. Pérez-Bustillo A, Sa´nchez-Sambucety P, Sua´ rez-Amor O, Rodríiguez-Prieto MA. Torsemide-induced pseudoporphyria. Arch Dermatol 2008;144:812–3. 42. Bird J, Carmona C. Probable interaction between warfarin and torsemide. Ann Phar macother 2008;42:1893–8. 43. Gulmez SE, Lassen AT, Aalykke C, Dall M, Andries A, Andersen BS, Hansen JM, Andersen M, Hallas J. Spir onolactone use and the risk of upper gastrointestinal bleeding: a populationbased case-control study. Br J Clin Phar macol 2008;66:294–9. 44. Russo A, Autelitano M, Bisanti L. Spirono lactone and gastrointestinal bleeding: a population based study. Pharmacoepidemiol Drug Saf 2008;17:495–500.
Gijsbert B. van der Voet
22 Aluminium (SED-15, 97; SEDA-29, 225; SEDA-30, 262; SEDA-31, 383) The occupational, environmental and clini cal human health risks of aluminium, alumi nium oxide and aluminium hydroxide have been reviewed (1R). Nervous system There is epidemiological evidence of an association between alumi nium in drinking water and Alzheimer’s dis ease, and between aluminium in dialysate and dialysis dementia. The exact role of alu minium in the pathogenesis of these and other dementias is not clear. The acute effects of aluminium on cognitive function have been investigated in patients with Alzheimer’s disease and related dementias and in age-matched and younger volunteers with normal cognitive function (2M). Whether individuals with Alzheimer’s dis ease and/or the apolipoprotein E (ApoE) "4 genotype had enhanced gastrointestinal absorption of aluminium was determined, as was the relation between blood aluminium concentrations and acute cognitive effects. The subjects were randomized to a single dose of aluminium orally (Amphojel plus citrate) for 3 days, followed by washout for 3 weeks, and then 3 days of matched placebo, or vice versa. Serum aluminium concentra tions were measured and the daily dose of the drug was adjusted to a target aluminium concentration of 50–150 µg/l. There was large inter individual variation in serum aluminium
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32022-8 � 2010 Elsevier B.V. All rights reserved.
Metals
concentrations after the same initial dose. There were no significant differences in neu ropsychological test scores after aluminium in healthy volunteers or patients with cogni tive impairment. There was no association between the ApoE 4 genotype and alumi nium absorption. These results neither sup ported the hypothesis that aluminium in these doses has acute effects on cognition or adverse effects, nor did they show that patients with Alzheimer’s disease are more vulnerable to such outcomes. Sensory systems Ears Potential ototoxi city of aluminium on the specified neural organ of the inner ear and its relation to serum aluminium concentration has been investigated in 40 patients on hemodialysis and 40 age-matched healthy subjects without hearing complaints (3C). Highfrequency hearing impairment was the pre dominant auditory dysfunction in patients on hemodialysis, who had worse high-tone hearing on pure-tone audiometry and diminished amplitudes of distortion-product otoacoustic emissions compared with controls. Serum aluminium concentration correlated negatively with the amplitude of distortion-product otoacoustic emissions 2K, but not with emissions 3K or 4K, hear ing pure-tone audiometry or wave latencies on auditory brainstem responses. These results suggest that aluminium mainly affects cochlear rather than retrocochlear function. Drug–drug interactions Clozapine An interaction of aluminium hydroxide with clozapine has been described (4A). • A 26-year-old man with a non-specified psychotic disorder, violence, and alcohol
413
414 abuse was given clozapine 100 mg bd. The clozapine serum concentration was stable at 382 ng/ml. A few weeks later he became sleepier and was drooling more than before. The clozapine concentration was 739 ng/ml. There had been no changes in his other medications, except that he was taking less aluminium hydroxide. The dose of clozapine was adjusted and the signs of clozapine overdose disappeared.
Aluminium hydroxide can adsorb clozapine and reduce its gastrointestinal absorption.
Antimony
(SED-15, 316; SEDA-29, 226; SEDA-30, 263; SEDA-31, 384)
Drug resistance Pentavalent antimonial compounds, such as sodium stibogluconate and meglumine antimoniate, continue to be used in the first-line chemotherapy of leish maniasis (5R) and in oncology (6R). Atten tion has been paid to the molecular mechanisms of resistance to antimonials in leishmaniasis (7R).
Arsenic (SED-15, 339; SEDA-29, 227; SEDA-30, 263; SEDA-31, 385) Observational studies Organic arsenicals have been investigated for their potential as anticancer drugs (8R). The use of arsenic trioxide in acute promyelocytic anemia is gaining more attention, and its adverse effects have been reviewed (9R). During induction therapy, a leukocytosis can occa sionally occur, which can be associated with fluid accumulation, pulmonary infiltration, prolongation of the QT interval, and dysrhythmias. Skin Arsenic-induced hyperkeratosis has been reported (10A). • A 52-year-old black woman developed rough painful lesions of the palms of both hands and the legs; she had had the lesions for many years. She had grown up in an area where the only drinking water came from a well. There were thick, firm, punctuate, brown, keratotic papules on both palms, the soles, and the
Chapter 22
Gijsbert B. van der Voet
legs. A skin biopsy showed arsenic keratosis, with epidermal hyperplasia, hyperkeratosis, and a sparse, perivascular, predominantly lymphocytic infiltrate in the dermis. Topical keratolytics produced minimal relief of pain and slight improvement in the lesions.
Psychological The effects of arsenic expo sure on children’s intelligence and growth have been investigated in a study of 720, aged 8–12 years, in rural villages in China (11c). The children had been exposed to drinking water containing arsenic 142 µg/l (medium-dose group) or 190 µg/l (high dose group) and a control group had been exposed to low concentrations of arsenic (mean 2 µg/l). Mean IQ scores were 105 in the controls, 101 in the medium-dose group and 95 in the high-dose group.
Bismuth (SED-15, 518; SEDA-29, 227; SEDA-30, 264; SEDA-31, 385) Systematic reviews The safety of bismuth salts (ranitidine bismuth citrate, colloidal bis muth subcitrate, tripotassium dictratobis muthate, bismuth subsalicylate, and bismuth subnitrate) used in Helicobacter pylori eradi cation regimens has been investigated in a systematic review of 35 randomized con trolled trials in 4763 patients (12M). Abdom inal pain, diarrhea, dizziness, headache, metallic taste, nausea, and/or vomiting and dark stools were included as adverse events. There were no serious adverse events in patients taking bismuth. There was no statis tically significant difference in total adverse events (RR = 1.01; 95% CI = 0.87, 1.16), adverse events that led to withdrawal of therapy (RR = 0.86; CI = 0.54, 1.37), or specific individual adverse events, with the exception of dark stools (RR = 5.06; CI = 1.59, 16).
Chromium (SED-15, 737; SEDA-29, 228; SEDA-30, 264; SEDA-31, 386) Observational studies The potential human health effects of occupational exposure to
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415
cobalt and chromium contaminants with exposure from surgical devices such as ortho pedic joint replacements have been reviewed (13R). Both industrial and surgical exposure cause inflammatory and other immune reac tions in the directly exposed tissues. There is a well-established risk of lung cancer after longterm exposures to hexavalent chromium; however, sarcoma in the connective tissues adjacent to implants in response to metal particles is rare. Both types of exposure are associated with changes in the peripheral blood, including evidence of oxidative stress and altered numbers of circulating immune cells. There is dissemination of cobalt and chromium to sites distant to the orthopedic implant, but less is known about systemic dissemination of these metals away from the lung. There is increasing concern about the health effects (hypersensitivity, osteolysis, carcinogenicity) of metal-to-metal surgical implants. Long-term wear and dissolution of the material can lead to internal exposure. The blood concentrations of chromium and cobalt were followed at 3, 6, 12, and 24 months after a metal-on-metal surface replacement hip arthroplasty using a high-carbon-content chromium–cobalt alloy implant in 64 patients (14C). The blood concentrations of chromium and cobalt were significantly increased 3 months postoperatively but gradually fell. At 1 year, mean whole blood ion concentra tions were 1.61 µg/l (0.4–5.5) for chromium and 0.67 µg/l (0.23–2.09) for cobalt, both of which are above the reference ranges. The preoperative ion concentrations, compo nent size, female sex, and the inclination of the acetabular component were inversely pro portional to the chromium and/or cobalt ion concentrations at 1 year postoperatively. Other factors, such as age and activity, did not correlate with the metal ion concentra tions. The authors concluded that these concentrations may be specific to the hip resurfacing implant and have diagnostic value.
available evidence suggests that genotoxic effects are very unlikely to occur in humans exposed to nutritional or to moderate recommended supplementary concentra tions of chromium(III). Excessive supple mentation is not warranted. Thus, like other nutrients that have genotoxic effects at high concentrations in vitro, the nutri tional benefits appear to outweigh the theoretical risk of genotoxic effects in vivo at normal or modestly raised intakes. However, this observation has been con tradicted in another review (16R), in which it was stated that the same biochemical mechanism underlies the beneficial as well as the toxic effects of chromium(III). Chromium(III) is transformed into different chemical species, including (i) partial hydrolysis products and (ii) highly reactive chromium(VI/V/IV) species and organic radi cals. Low concentrations of these species are likely to cause alterations in cell signal ling (including enhancement of insulin sig nalling), through interactions with the active centers of regulatory enzymes in the cell membrane or in the cytoplasm, while higher concentrations are likely to produce genotoxic DNA lesions in the cell nucleus. These data suggest that the poten tial for genotoxic adverse effects of chro mium(III) complexes may outweigh their possible benefits as insulin enhancers, and that recommendations for their use as either nutritional supplements or antidiabetic drugs need to be reconsidered.
Genotoxicity The question of the geno toxic effects of chromium(III) nutritional supplements has been reviewed (15R). The
Uses Wilson’s disease (17R, 18R) and Menke’s disease (19R), including the role of copper, have again been reviewed.
Cobalt
(SED-15, 847; SEDA-30, 264; SEDA-31, 386) See ‘Chromium’ above.
Copper
(SED-15, 901; SEDA-29, 228; SEDA-30, 265; SEDA-31, 387)
416
Systematic reviews A meta-analysis of 35 randomized controlled studies of the effec tiveness and adverse effects of copper-con taining intra-uterine contraceptive devices (IUCDs) has been published (20M). There were 18 comparisons of 10 different IUCDs in about 48 000 women. TCu380A was more effective in preventing pregnancy than MLCu375 (RD = 1.70%; 95% CI = 0.07, 2.95%) after 4 years of use. TCu380A was also more effective than MLCu250, TCu220, and TCu200. There tended to be fewer pregnancies with TCu380S than with TCu380A after the first year of use, a difference that became statistically signifi cant in the fourth year (RD = �1.62%; 95% CI = �3.00, �0.24%). This occurred despite more expulsions with TCu380S (RD = 3.50%; 95% CI = 0.36, 6.63% at 4 years). MLCu375 was no more effective than TCu220 at 1 year of use or than MLCu250 and NovaT up to 3 years. Com pared with TCu380A or TCu380S, none of the IUCDs showed any benefits in terms of bleeding or pain, or any of the other reasons for early withdrawal. None of the trials that reported events at insertion found one IUCD easier to insert than another or less painful. There is no evidence that uterine perforation rates vary by type of device. The authors concluded that TCu380A or TCu380S is more effective than other IUCDs. No IUCD had consistently lower removal rates for bleeding and pain than any other. There is no evidence that any particular framed copper device is better suited to women who have not had children.
Gallium
(SED-15, 1477; SEDA-29, 228; SEDA-30, 265)
Drug resistance Resistance to gallium of different cancer cell types has been reviewed (21R). This is the trigger for specific research on resistance mechanisms and the develop ment of new antineoplastic agents. The cytotoxicity of gallium maltolate, a novel gallium compound, has been compared with gallium nitrate in lymphoma cell lines, including p53 variant and unique gallium
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Gijsbert B. van der Voet
nitrate-resistant cells (22E). Gallium malto late inhibited cell proliferation and induced apoptosis through the mitochondrial path way at lower concentrations and more rapidly than gallium nitrate did. Gallium mal tolate produced an increase in intracellular reactive oxygen species (ROS) within 2 hours of incubation; this effect was blocked by mitoquinone, a mitochondria-targeted antioxidant. The role of the transferrin recep tor in the action of gallium maltolate was examined using monoclonal antibody 42/6 to block transferrin receptor function. How ever, although it reduced gallium maltolate induced caspase-3 activity, it had only a minor effect on cell growth inhibition. Gal lium maltolate induced apoptosis in cells resistant to gallium nitrate, and, unlike gal lium nitrate, its cytotoxicity was not affected by cellular p53 status. Cellular gallium uptake was greater with gallium maltolate than with gallium nitrate. The authors con cluded that gallium maltolate inhibits cell proliferation and induces apoptosis more efficiently than gallium nitrate. Gallium mal tolate is incorporated into lymphoma cells to a greater extent than gallium nitrate via both transferrin receptor-independent and recep tor-dependent pathways. It has significant activity against gallium nitrate-resistant cells and acts independently of p53.
Gold and gold salts
(SED-15, 1520; SEDA-29, 228; SEDA-30, 265; SEDA-31, 387)
Uses The clinical pharmacology of gold compounds has been reviewed (23R). Aur anofin exhibits potential as an antimalarial agent (24R) and gold complexes are receiv ing attention as anticancer agents (25R). Skin Gold salts are used in the treatment of pemphigus, but have paradoxically been reported to cause paucilesional pemphigus vulgaris (26A). • A 44-year-old woman took an oral auranofin 3 mg bd for 6 months for seronegative rheumatoid arthritis. During the first 3 months
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Chapter 22
bullous lesions appeared in her left leg. Glucocorticoid treatment caused them to disappear, but 3 weeks later new bullous lesions appeared in her legs and ruptured leading to reddened erosions, which were large because of their tendency to spread at the periphery. The auranofin was withdrawn and she recovered.
Iron salts
(SED-15, 1911; SEDA-29, 229; SEDA-30, 265; SEDA-31, 387)
Comparative studies The adverse effects of two intravenous iron formulations, iron dextran and iron sucrose, have been studied in 60 patients with end-stage renal disease (27C) who were randomized to one of the two formulations. Standard test doses of 25 mg of low-molecular-weight iron dextran and iron sucrose were given over 15 minutes during the initial visit, monitoring very clo sely for adverse reactions. If this dose was well tolerated, 75 mg of iron diluted in 100 ml of isotonic saline was given over 30 minutes. The mean age of the patients was 52 (range 21–80) years. Of the 30 patients who received low-molecular-weight iron dextran, 11 had adverse reactions: pruritus, wheezing, chest pain, hypotension, swelling (n = 1 each), headache (n = 2), and nausea (n = 4). Of the 30 patients who received iron sucrose, 13 developed adverse effects: prur itus, wheezing, diarrhea, swelling (n = 1 each), hypotension (n = 2), headache (n = 3), and nausea (n = 4). Adverse events occurred with similar frequency in the two treatment groups. There were no serious reactions. The adverse effects of parenteral iron products have been reviewed (28R). The authors concluded that iron sucrose and ferric gluconate are safer than iron dextran, but this may be a premature conclusion. Tumorigenicity Intramuscular iron–car bohydrate is not very often required, but can cause calcification of the soft tissues. The suggestion that it can cause sarcoma formation has not been proven. Siderosis at the injection site has been described (29A).
417 • A 66-year-old woman who had received injections of iron polymaltose into her right buttock every month for 8 months for iron deficiency anemia developed a hard lump at the injection site, which eroded through the skin over the next few years. Imaging showed that the mass was limited to the subcutaneous tissues with no intramuscular extension. The area was excised and a vacuum-assisted closure dressing was applied and closed with a skin graft. Histology showed only siderosis and inflammatory change.
Lanthanum carbonate (SEDA-31, 389) Susceptibility factors Renal disease Lan thanum carbonate is an aluminium-free, calcium-free, phosphate-binding agent used to control phosphorus concentrations in patients with renal insufficiency (30R). However, there are concerns about lanthanum accumulation in tissues during long-term oral administration. Moreover, the rate of intestinal absorption of lanthanum is increased in chronic renal insufficiency. Drug–drug interactions Ciprofloxacin The effect of six doses of lanthanum 1 g tds on the systemic availability of a single oral dose of ciprofloxacin 750 mg has been inves tigated in a randomized crossover study in 12 patients (31C). Lanthanum reduced the mean ciprofloxacin AUC by 54% and the Cmax by 56%. The 24-hour urinary recovery of cipro floxacin was reduced by 52%. There were no significant changes in tmax, half-life or renal clearance. The authors concluded that lanthanum carbonate significantly reduces the systemic availability of oral ciprofloxacin and that concomitant administration should be avoided.
Magnesium salts
(SED-15, 2196; SEDA-30, 266; SEDA-31, 390)
Systematic reviews In a meta-analysis of the use of intravenous magnesium sulfate to treat atrial fibrillation in 515 patients in 10 studies, magnesium caused transient
418
minor symptoms (flushing, tingling, and dizziness) in 17% (32M). Although intra venous magnesium was less effective than either calcium channel blockers or amiodar one (21% versus 59%; OR = 0.19, 95% CI = 0.09, 0.44), it was also less likely to cause significant bradycardia or atrioventri cular block (0% versus 9.2%; OR = 0.13, 95% CI = 0.02, 0.76); there was significant hypotension in only six patients. Nervous system Hypermagnesemia causes impaired neuromuscular junction transmis sion, which has reportedly caused quadripar esis (33A). • A 32-year-old woman with end-stage renal disease developed progressively worse abdominal pain. She had chronic constipation and for 1 year had been taking magnesium oxide powder 3.0 g/day. She was alert and her vital signs were stable, but by day 8 she could not move her arms or legs and her muscle strength was symmetrically reduced to grade 1–2. Nerve conduction studies showed a severe polyneuropathy, with blocked nerve conduction. The magnesium-containing cath artics were withdrawn. Her serum magnesium concentration was 4.35 mmol/l (10.6 mg/dl). By day 28 the serum magnesium had fallen to 1.27 mmol/l and her weakness and quadriparesis had improved.
Musculoskeletal Hypermagnesemia can cause impaired normal bone mineralization and osteomalacia (34A). • A 42-year-old woman developed joint pains, spreading from the ankles, to the knees, hips, and shoulders, and had difficulty in walking. She had used magnesium hydroxide as a laxative for the previous 2 years (10–15 g/day). Her serum calcium, phosphorus, and vitamin D concentrations were all reduced, while magnesium, alkaline phosphatase, and para thormone were increased. The magnesium was withdrawn and the osteomalacia was treated with vitamin D and oral calcium. She improved within 2 months.
Manganese
(SED-15, 2200; SEDA-29, 230; SEDA-30, 267) Nervous system The literature on manga nese accumulation in the brain, as detected
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Gijsbert B. van der Voet
by symmetrical high-signal intensity in the globus pallidus on T1-weighted MR images without an abnormal signal on T2-weighted images, has been reviewed (35AR). Com mon causes of manganese accumulation in the brain are overload from total parenteral nutrition and manganese intoxication in welders. However, manganese accumula tion in the brain can be due to acquired or congenital liver disease, including hepatic cirrhosis with a portosystemic shunt, congenital biliary atresia, primary biliary cirrhosis, congenital intrahepatic portosys temic shunt without liver dysfunction, Rendu–Osler–Weber syndrome with diffuse intrahepatic portosystemic shunting, and patent ductus venosus. Metal metabolism Manganese is an essen tial trace element included in parenteral nutrition. However, long-term parenteral administration, which bypasses the normal alimentary tract regulatory mechanism, can cause hypermanganesemia. Manganese poi soning presents clinically with parkinsonian symptoms and psychological changes. Sei zures are rare but have been reported (36A). • A 10-year-old girl, who had received total parenteral nutrition for 3 months because of short bowel syndrome, had a tonic–clonic seizure with a reduced level of consciousness and a fever. Her serum electrolytes, glucose, and cerebrospinal fluid were normal. Blood cul tures grew Pantoea agglomerans. A magnetic resonance imaging (MRI) scan of the brain showed no evidence of infection, but there were symmetrical high-intensity signals on T1-weighted images in the basal ganglia, especially the globus pallidus. The whole blood manganese concentration was 37 µg/l (670 nmol/l), which was significantly higher than the reference range (4–14 µg/l, 70–250 nmol/l).
The presence of hypermanganesemia and the symptoms of manganese toxicity depend on dose, duration of use and the presence of significant liver disease, because manganese is predominantly eliminated by biliary excretion. In this case the presenta tion was probably multifactorial, since sep tic shock could have contributed. Unusual
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features included the fact that the patient was receiving a daily dose of manganese within the recommended range (about 8 micrograms/kg/day, 145 nmol/kg/day; recom mended dose 2–10 micrograms/kg/day) and was given parenteral nutrition for a relatively short time, as symptoms are not usually expected until after 1 year (37R). Because there was no evidence of hepatic dysfunction, the reasons for this reaction are unclear. However, the daily dose was close to the upper limit of the recommended adult range, which may have been excessive in this child. Daily recommended pediatric doses of parenteral managanese have a lower limit of 1 micrograms/kg/day (18 nmol) (38S).
Mercury and mercurial salts (SED-15, 2259; SEDA-29, 230; SEDA-30, 268; SEDA-31, 391) The Global Advisory Committee on Vac cine Safety (GACVS) has considered a pharmacokinetic study of mercury in premature and low-birth-weight infants who received a birth dose of hepatitis B vaccine containing thiomersal (39S). The results suggested that exposure to thio mersal-containing vaccines does not result in accumulation of mercury in blood and that the half-life of intramuscular ethyl mercury from thiomersal in vaccines in infants (2.9–4.1 days) is substantially shorter than that of oral methyl mercury in adults. The authors concluded that exposure guidelines based on oral methyl mercury may not be appropriate for use in assessing the risk of thiomersal in vac cines at dosages consistent with standard immunization regimens. Nervous system The relation between neurotoxicity and mercury in dental amal gams and between autism and mercury (thiomersal) in vaccines continues to be discussed, without definitive conclusions (40r, 41R). The GACVS has considered the results of an Italian study that examined
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neuropsychological performance 10 years after immunization in infancy with thiomersal containing vaccines (39S). Higher thiomersal exposure through vaccines administered in the first year of life was significantly associated with lower scores on two neuro psychological outcomes (motor function, measured using the finger-tapping test, and language, measured using the Boston naming test). The differences in mean scores were very small, detected only in girls, of doubtful clinical relevance, and not consistent with results from other studies of ethyl mercury. The observed associations may reflect the effect of chance. On the basis of these data, GACVS remains of the view that there is no evidence supporting any change in WHO’s recommendations for thiomersal containing vaccines and the immunization of low-birth-weight infants when indicated. Sensory systems Thiomersal (sodium ethylmercurithiosalicylate) has been com monly used as a preservative in eyedrops and contact lens disinfecting solutions. However, it is a known sensitizer (SEDA 21, 255) and cases of allergy have been reported after application to the eyes (SEDA-23, 248). Although thiomersal is increasingly being withdrawn from phar maceuticals because of toxicity, it is still used in some products. Unilateral total limbal stem failure and corneal opacifica tion, secondary to thiomersal exposure from a contact lens solution, has further confirmed the need for restrictions in the use of thiomersal in ophthalmic formula tions (42A).
Nickel
(SED-15, 2502; SEDA-29, 230; SEDA-30, 268; SEDA-31, 392) Immunologic Nickel is allergenic. The use of nickel in alloy-based implant materials combined with titanium is a new internal route of exposure to nickel, which is a con cern for patients undergoing orthopedic surgery (43S).
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Selenium
(SED-15, 3119; SEDA-29, 231; SEDA-30, 269; SEDA-31, 392)
Uses Selenium may be an effective chemo preventive and anticancer agent, with a broad spectrum against several human can cer cells (prostate, colon, bladder, lung, liver, ovarian, and leukemia cells). Apoptosis is one of the most plausible mechanisms for this activity and has been reviewed (44R). The use of selenium in intensive care medi cine as adjuvant therapy has also received attention (45r).
Silver salts and derivatives (SED-15, 3140; SEDA-29, 231; SEDA-30, 269; SEDA-31, 393) Skin Another case of argyria has been reported (46A). • A 23-year-old man with recessive dystrophic epidermolysis bullosa developed diffuse silvery-grey pigmentation over several months. Since birth he had had silver sulfadiazine (Silvadene®) cream applied to denuded areas regularly to prevent infections and had consistently used it on affected areas two or three times a day. The diffuse slate-grey pigmentation was particularly prominent on the face. The serum silver concentration was 130 µg/l (reference range below 5 µg/l). He was not bothered by his argyria. Despite being advised to stop using the silver-containing cream, he chose to continue using it, because he believed that it helped his skin heal faster and prevented infections.
Although silver can be removed from the bloodstream, it is very difficult to remove it from the skin. Sunscreens can prevent further darkening. They also will prevent further reduction by sunlight of the colorless silver compounds in the dermis to elemental silver in a process similar to film developing.
Strontium salts The UK Medicines and Healthcare products Regulatory Agency (MHRA) has advised that there is a risk of severe allergic reac tions, including drug rashes and eosinophilia
Gijsbert B. van der Voet
with systemic symptoms (DRESS), with strontium ranelate (47S). The liver, kidneys, and lungs can also be affected. The symp toms usually resolve when treatment is with drawn and with glucocorticoid therapy, but recovery is often slow and there is a risk of recurrence during recovery. Patients who develop a rash should stop taking strontium and should consult their physician immedi ately. Health-care professionals are advised not to restart strontium once treatment has been stopped.
Titanium
(SED-15, 3434; SEDA-29, 231; SEDA-30, 270; SEDA-31, 394) Immunologic Allergic reactions to tita nium alloy in artificial joints can interfere with the implant/restoration process (48A).
• A 64-year-old man underwent a total hip arthroplasty for severe osteoarthritis of his left hip following avascular osteonecrosis. An SEM3 type (Science et Médecine, Montrouge, France) cementless forged Ti-6Al-4V alloy, with femoral stem size 12, coated with hydroxyapatite on the proximal third, with a metallic head of a diameter 28 mm and an ultra-high-molecular-weight polyethylene (UHMWPE) insert (liner) with a metal acetabular cup (50 mm) was inserted. Four years after the operation, he developed severe pain in the left hip while walking, which showed an inability to bear weight. An X-ray showed a fracture of the femoral neck without bone loss in the proximal femur and he underwent a revision of the total hip arthroplasty. There was an extensive amount of bone adherent to the device, and the fractured implant was well fixed.
Zinc
(SED-15, 3717; SEDA-29, 232; SEDA-30, 270; SEDA-31, 394)
Respiratory Pulmonary embolism has been reported after the intravenous admin istration of talc and zinc oxide (49A). • A 74-year-old woman recovering from colonic surgery died immediately after receiving an intravenous infusion of about 1.5 ml of a
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white emulsion that was believed to contain 1% propofol. However, it was suspected that a zinc oxide shake lotion (containing 20% zinc oxide, 20% talc, 25% glycerol, and 35% water), intended for external treatment, had been mistaken for propofol. At autopsy, an anatomical cause of death could not be found. Propofol and other drugs that she had received were found in therapeutic or sub-therapeutic concentrations. However, the concentration of zinc in the lungs was about 200 times higher than that found in a control case, 10 times higher in cardiac blood and 3–4 times higher in kidney and liver tissues. There was no increase in venous blood. Histology showed a large pulmonary embolism containing birefingent sharp-edged crystals, which were identified as talc, and an amorphous component (zinc oxide). There were similar smaller emboli in the brain, heart, liver, pancreas, and kidneys.
chronically. The zinc concentration in the denture creams was investigated as a possible source of excess zinc ingestion; Fixodent and Poli-Grip denture creams contained zinc in concentrations ranging from about 17 000 to 34 000 µg/g. The patients were given copper supplements. Copper and zinc concentra tions were obtained after treatment at vary ing intervals. Serum zinc concentrations improved in three patients after they stopped using the denture cream and copper supple mentation resulted in mild neurological improvement in two. No alternative source of excess zinc ingestion or explanation for the hypocupremia was identified. Exacerbation of epileptic seizures has been attributed to oral zinc supplementation (51R).
Nervous system Denture adhesives are a source of zinc and can cause hyperzincemia and hypocupremia. In four patients with various neurological abnormalities, hypo cupremia and hyperzincemia were identified (50A). Each wore dentures and had used very large amounts of denture cream
• A 28-year-old man with seizures about twice a year, for which he took phenytoin 300 mg/day, took oral zinc gluconate 240 mg/day (elemental zinc 64 mg/day) and within 2 days had three complex partial seizures. After withdrawal of the zinc he had no further seizures. One month later he started taking zinc again in the same dosage and had another seven seizures over 3 days. Electroencephalography showed an epileptiform focus.
References 1. Krewski D, Yokel RA, Nieboer E, Borchelt D, Cohen J, Harry J, Kacew S, Lindsay J, Mah fouz AM, Rondeau V. Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health B Crit Rev 2007;10(Suppl 1):1–269. 2. Molloy DW, Standish TI, Nieboer E, Turnbull JD, Smith SD, Dubois S. Effects of acute exposure to aluminum on cognition in humans. J Toxicol Environ Health A 2007;70(23):2011–9. 3. Chu P-L, Wu C-C, Hsu C-J, Wang Y-T, Wu K-D. Potential ototoxicity of aluminum in hemodialysis patients. Laryngoscope 2007;117(1):137–41. 4. Allard M, Légaré N, Millaud F. A possible case of clozapine interaction with aluminium hydroxide. Scizophren Res 2008;101(1–3):346.
5. Mishra J, Saxena A, Singh S. Chemotherapy of leishmaniasis: past, present and future. Curr Med Chem 2007;14(10):1153–69. 6. Sharma P, Perez D, Cabrera A, Rosas N, Arias JL. Perspectives of antimony com pounds in oncology. Acta Pharmacol Sin 2008;29(8):881–90. 7. Ashutos SS, Goyal N. Molecular mechan isms of antimony resistance in Leishmania. J Med Microbiol 2007;56(Pt 2):143–53. 8. Dilda PJ, Hogg PJ. Arsenical-based can cer drugs. Cancer Treat Rev 2007;33(6):542–64. 9. Au WY, Kwong YL. Arsenic trioxide: safety issues and their management. Acta Pharma col Sin 2008;29(3):296–304. 10. Spohr K, Guavara D, Glick BP, Kerdel FA. Arsenic keratosis. J Am Osteol Coll Derma tol 2007;8(2):6–8.
422 11. Wang SX, Wang ZH, Chen XT, Li J, Sang ZP, Zhang XD, Han LL, Qiao XY, Wu ZM, Wang ZH. Arsenic and fluoride expose in drinking water: children’s IQ and growth in Shanyin Country, Shanxi Province, China. Envirom Health Perspect 2007;115(4):643–7. 12. Ford AC, Malfertheiner P, Giguère M, Santana J, Khan M, Moayyedi P. Adverse events with bismuth salts for Helicobacter pylori eradication: systematic review and meta-analysis. World J Gastroenterol 2008;14 (28):7361–70. 13. Keegan GM, Learmonth ID, Case CP. A systematic comparison of the actual, potential, and theoretical health effects of cobalt and chromium exposures from indus try and surgical implants. Crit Rev Toxicol 2008;38(8):645–74. 14. Vendittoli PA, Mottard S, Roy AG, Dupont C, Lavigne M. Chromium and cobalt ion release following the Durom high carbon content, forged metal-on-metal surface replacement of the hip. J Bone Joint Surg Br 2007;89–B(4): 441–8. 15. Eastmond DA, Macgregor JT, Slesinski RS. Trivalent chromium: assessing the genotoxic risk of an essential trace element and widely used human and animal nutritional supple ment. Crit Rev Toxicol 2008;38(3):173–90. 16. Levina A, Lay PA. Chemical properties and toxicity of chromium(III) nutritional supplements. Chem Res Toxicol 2008;21 (3):563–71. 17. Medici V, Rossaro L, Stumiolo GC. Wilson disease – a practical approach to diagnosis, treatment and follow up. Dig Liver Dis 2007;39(7):601–09. 18. Pfeiffer RF. Wilson’s disease. Semin Neurol 2007;27(2):123–32. 19. Bertini I, Rosato A. Menkes disease. Cell Mol Life Sci 2008;65(1):89–91. 20. Kulier R, O’Brien PA, Helmerhorst FM, Usher-Patel M, D’Arcangues C. Copper containing, framed intra-uterine devices for contraception. Cochrane Database Syst Rev 2007;(4):CD005347. 21. Heffeter P, Jungwirth U, Jakupec M, Hartinger C, Galanski M, Elbling L, Micksche M, Keppler B, Berger W. Resistance against novel anticancer metal compounds: differences and similarities. Drug Resist Updat 2008;11(1–2):1–16.
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22. Chitambar CR, Purpi DP, Woodliff J, Yang M, Wereley JP. Development of gallium com pounds for treatment of lymphoma: gallium maltolate, a novel hydroxypyrone gallium compound, induces apoptosis and circum vents lymphoma cell resistance to gallium nitrate. J Pharmacol Exp Ther 2007;322 (3):1228–36. 23. Kean WF, Kean IR. Clinical pharmacology of gold. Inflammopharmacology 2008;16 (3):112–25. 24. Sannella AR, Casini A, Gabbiani C, Messori L, Bilia AR, Vincieri FF, Majori G, Severini C. New uses of old drugs. Auranofin, a clinically established antiarthritic metallodrug, exhi bits potent antimalarial effects in vitro: mechanistic and pharmacological implica tions. FEBS Lett 2008;582(6):844–7. 25. Tiekink ER. Anti-cancer potential of gold complexes. Inflammopharmacology 2008;16 (3):138–42. 26. Lo Schiavo A, Sangiuliano S, Puca RV, Brunetti G, Rocco E, Cozzi R. Pemphigus and chrysotherapy: all that glitters is not gold! Int J Dermatol 2008;47(6):645–7. 27. Sav T, Tokgoz B, Sipahioglu MH. Is there a difference between the allergic potencies of the iron sucrose and low molecular weight iron dextran? Renal Fail 2007;29(4):423–6. 28. Auerbach M, Al Talib K. Low-molecular weight iron dextran and iron sucrose have similar comparative safety profiles in chronic kidney disease. Kidney Int 2008;73(5):528–30. 29. Maher R, Blake W, Brown T. Differential diagnosis of a soft tissue mass following long term parenteral iron injection. J Plast Reconstr Aesthet Surg 2008;61(5):582. 30. Dr€ ueke TB. Lanthanum carbonate as firstline phosphate binder: the ‘cons’. Semin Dial 2007;20(4):329–32. 31. How PP, Fischer JH, Arruda JA, Lau AH. Effects of lanthanum carbonate on the absorp tion and oral bioavailability of ciprofloxacin. Clin J Am Soc Nephrol 2007;2(6):1235–40. 32. Ho KM, Sheridan DJ, Paterson T. Use of intravenous magnesium to treat acute onset atrial fibrillation: a meta-analysis. Heart 2007;93(11):1433–40. 33. Jung GJ, Gil HW, Yang JO, Lee EY, Hong SY. Severe hypermagnesemia causing quad riparesis in a CAPD patient. Perit Dial Int 2008;28(2):206.
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34. Sivas F, G€ unesen O, Ozoran K, Alemdaroglu E. Osteomalacia from Mg-containing antacid: a case report of bilateral hip fracture. Rheumatol Int 2007;27(7):679–81. 35. Uchino A, Noguchi T, Nomiyama K, Takase Y, Nakazono T, Nojiri J, Kudo S. Manganese accumulation in the brain: MR imaging. Neuroradiology 2007;49(9):715–20. 36. Hsieh C-T, Liang J-S, Peng SS-F, Lee W-T. Seizure associated with total parenteral nutrition-related hypermanganesemia. Pediatr Neurol 2007;36(3):181–3. 37. Dickerson RN. Manganese intoxication and parenteral nutrition. Nutrition 2001;17(7–8):689–93. 38. Committee on Nutrition, American Acad emy of Pediatrics. Pediatrics Nutrition Hand book. 4th ed. Elk Grove Village, IL: American Academy of Pediatrics, 1998. 39. Global Advisory Committee on Vaccine Safety. Thiomersal. Meeting of Global Advisory Committee on Vaccine Safety, 18–19 June 2008. Wkly Epidemiol Rec 2008;83(32):287–92. 40. Anonymous. Silencing debate over autism. Nat Neurosci 2007;10(5):531. 41. Geier DA, Sykes LK, Geier MR. A review of thimerosal (merthiolate) and its ethylmer cury breakdown product: specific historical considerations regarding safety and effec tiveness. J Toxicol Environ Health B Crit Rev 2007;10(8):575–96. 42. Nguyen DQ, Srinivasan S, Hiscott P, Kaye SB. Thiomersal-induced limbal cell failure: report of a case and review of the literature. Eye Contact Lens 2007;33(4):196–8. 43. Thomas P, Schuh A, Ring J, Thomsen M. Orthopedic surgical implants and allergies. Joint statement by the Implant Allergy Working Group (AK 20) of the DGOOC (German Asssociation of Orthopedics and
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Orthopedic Surgery), DKG (German Con tact Dermatitis Research Group) and DGAKI (German Society for Allergology and Clinical Immunology). Haurartzt 2008;59(3):220–9. Sanmartín C, Plano D, Palop JA. Selenium compounds and apoptotic modulation: a new perspective in cancer therapy. Mini Rev Med Chem 2008;8(10):1020–31. Berger MM, Shenkin A. Selenium in inten sive care: probably not a magic bullet but an important adjuvant therapy. Crit Care Med 2007;35(1):306–7. Browning JC, Levy ML. Argyria attributed to silvadene application in a patient with dystrophic epidermolysis bullosa. Dermatol Online J 2008;14(4):9. Anonymous. Strontium ranelate. Risk of severe allergic reactions. WHO Pharmaceu ticals Newsletter 2008;1:9–10. Grivas TB, Savvidou OD, Psarakis SA, Bernard PF, Triantafyllopoulos G, Kovanis I, Alexandropoulos P. Neck fracture of a cementless forged titanium alloy femoral stem following total hip arthroplasty: a case report and review of the literature. J Med Case Rep 2007;1:174. Pragst F, Correns A, Priem F, Herre S, Martin H. A sudden death with lung embolism after inadvertent infusion of zinc oxide shave lotion. Forensic Sci Int 2007;170(2):207–12. Nations SP, Boyer PJ, Love LA, Burritt MF, Butz JA, Wolfe GI, Hynan LS, Reisch J, Trivedi JR. Denture cream: an unusual source of excess zinc, leading to hypocupre mia and neurologic disease. Neurology 2008;71(9):639–43. Green AL, Weaver DF. Potential proconvul sant effects of oral zinc supplementation: a case report. Neurotoxicology 2008;29 (3):476–7.
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Metal antagonists
IRON CHELATORS At the 16th International Conference on Chelation in 2006, it was emphasized that around the world the current regulations and practices for the development, approval, post-introduction safety evalua tion and pricing of new medicines are inap propriate and may disadvantage patients (1R). Drastic reforms are deemed neces sary, in particular with regard to diseases that are common in less affluent countries, such as thalassemia major. In the past few decades, thanks to the introduction of effective, tolerable, and last ing iron chelation regimens, the life expec tancy, in both duration and quality, of patients with thalassemia major has improved tremendously. In a medical records study in the Mazandaran Province of Iran, where thalassemia major is the most common genetic disease, morbidity and mortality among 1010 patients with tha lassemia have been reviewed (2CR). The complexity and seriousness of the secondary pathology in these patients demonstrates the devastating nature of the disease, in particu lar when supplies of iron chelators are lim ited and non-adherence is common. In other countries, myelodysplastic syndromes, aplastic anemia, Diamond– Blackfan anemia and other transfusiondependent anemia are more frequent indications for transfusion and can cause iron overload. Novel tests for measuring iron accumulation in the heart and liver, Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32023-X 2010 Elsevier B.V. All rights reserved.
such as superconducting quantum inference devices (SQUIDs) and magnetic resonance imaging (MRI), and new oral chelators enable even more sophisticated, effective, and tolerable treatment of thalassemia. In order to ensure that these new technologies are used to their best advantage, the Italian Society of Hematology has developed struc tured consensus clinical treatment guide lines, covering critical matters such as the level of iron storage requiring chelation therapy, when to start chelation, how to monitor chelation and switching to an alter native treatment (3R). There have been reviews of current knowledge about iron overload in myelo dysplastic syndromes, describing the com plexity of intra- and extracellular iron homeostasis and metabolism and the impor tance of the peptide hormone hepcidine produced by the liver and emphasizing the crucial role of non-transferrin-bound iron in damaging organs and the rationale of chela tion treatment (4R–6R). Until recently the use of deferoxamine for transfusional iron overload in myelodysplastic syndromes has been sparse, but the literature on the use of iron chelators in these patients is expanding (7R, 8R). A retrospective study in Japan has also confirmed that in these patients iron storage is a major cause of morbidity and mortality, in particular cardiac and hepatic dysfunction, underlining the fact that iron chelators should be started in time in these patients when the iron burden increases (e.g. when the serum ferritin concentration exceeds 1000 µg/l) (9CR). While awaiting further trials, it seems appropriate to offer, of the five general subtypes of myelodys plastic syndromes, iron chelation to at least patients with refractory anemia and refrac tory anemia with ringed sideroblasts.
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In the treatment of iron storage disease, the use of chelators aims at detoxifying and excreting surplus iron. Reactive oxygen spe cies should be scavenged as far as possible. Chelators containing ‘hard’ oxygen donor atoms stabilize the ferric state, resulting in redox-inactive complexes, and are suitable for the treatment of iron storage disease. The careful choice of ‘soft’ donor atoms, such as nitrogen or sulfur, on the other hand, results in redox-active iron complexes with high redox affinity and may be effective in oncolytic chemotherapy. Several series of such compounds are in development (10R): 2-pyridylcarboxaldehyde isonicotinoyl hydra zone series di-2-pyridylketone isonicotinoyl hydrazone series di-2-pyridylketone thiosemicarbazone series 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
Their toxicological properties differ consider ably from the classical iron chelators and they should receive more attention in future. Combination studies Deferoxamine + deferiprone The advantage of combining deferoxamine with deferiprone is that deferoxamine can be given less often and for a shorter duration, which may improve adherence. In a randomized, double-blind, controlled comparison of clinically equivalent doses of deferoxamine with deferiprone (n = 32) and deferoxamine with placebo (n = 33) in adults with thalassemia major, combination treat ment was superior in reducing myocardial iron and improving ventricular and endothelial functions (11cr). Mild gastrointestinal symp toms (nausea, vomiting, or abdominal pain) were the most common adverse events, in 38% of patients who received the combination and in 24% of those who received deferoxa mine monotherapy. Such events were more often recurrent in the combination group (19% versus only 3%). Pain and/or swelling of joints occurred in 9% of patients taking the combination and were more frequent in patients who only received deferoxamine, which is unexpected, since arthropathy typi cally occurs in connection with deferiprone.
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Because it is common in clinical practice to alternate treatment with deferiprone and deferoxamine, in a comparative study in Egypt alternating use of these drugs (n = 30) was compared with simultaneous use in combination (n = 30) (12cr). Alternat ing administration of deferiprone 75 mg/kg/ day orally for 4 days and deferoxamine 40 mg/kg/day by subcutaneous infusion for the next 2 days was safe and effective in patients with thalassemia major. Taste dis turbances (a metallic taste and inability to distinguish between bitter and sweet) occurred in two patients after the first month. Taste returned to normal sponta neously while treatment was continued. Oral deferiprone alone 75 mg/day (n = 12) has been compared with deferiprone þ defer oxamine 40–50 mg/kg twice weekly (n = 12) and with deferoxamine alone 40–50 mg/kg on 5 days/week (n = 12) (13cr). There was neutropenia in two patients taking deferi prone (one with deferiprone alone, one with the combination). In one patient two episodes of neutropenia (in weeks 4 and 10) were fol lowed by full-blown agranulocytosis (in week 11), which was treated with granulocyte sti mulating factor and recovered within 11 days. In no case was there progressive hepatic fibrosis, and only in the patients taking com bination therapy did the histology activity index and liver iron scores fall substantially. There was grade 2 arthralgia in one patient taking combination therapy. Aseptic meningi tis occurred in week 45 in one patient taking deferiprone alone, and in another taking deferiprone alone an acute and transient cer ebellar syndrome was observed, which was thought not to be drug-induced but to have followed an infection. A quality-of-life assess ment questionnaire showed improvement in 64% of those who took deferiprone and only in 20% of those who took deferoxamine.
Deferasirox (SEDA-29, 236; SEDA-30, 273; SEDA-31, 401) There is increasing knowledge of the pharma cology of deferasirox and interest in its ther apeutic use, in particular in non-hemolytic
Metal antagonists
Chapter 23
transfusion-dependent anemias (8CR, R R 14 –20 ). At the same time, post-marketing reports have raised concerns about the possi ble occurrence of serious adverse reactions, such as anaphylaxis, gastrointestinal ulceration and hemorrhage, neurosensory hearing loss, lenticular opacities, acute renal insufficiency, liver damage, agranulocytosis, and thrombo cytopenia (8R, 16r, 17r, 21R, 22S). However, detailed information is sparse, and there is an urgent need for clarification of the current uncertainty. It is possible that deferasirox can damage various organs, especially the kidneys, by increasing iron absorption and de-compartmentalizing chelated iron in these tissues (1R). Drug–drug interactions A large but incomplete list of drugs that are assumed to interact with deferasirox is available on the Internet (23S). Aluminium salts Deferasirox has affinity for aluminium and forms lipophilic complexes with it. It should not be combined with aluminium-containing antacids (22S). Theoretically, long-term use of deferasirox might increase the gastrointestinal absorption of aluminium and lead to accumulation in the brain and perhaps to dementia (1R). Cytochrome P450 (CYP) isoenzymes Deferasirox is involved in both enzyme inhi bition and enzyme induction and affects CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, and CYP2C19. In particular, its effects on CYP3A4 and CYP2C8 may be clinically important. Potentiation of ciclos porin, hormonal contraceptives, midazolam, paclitaxel, repaglinide, and simvastatin has been documented or is expected, and it may be necessary to adjust the dose of these drugs (22S). Midazolam In healthy volunteers co-administration of deferasirox with midazolam, a CYP3A4 substrate, resulted in a 23% reduction in the Cmax of midazolam and a 17% reduction in AUC (22S). This was presumably due to induction of CYP3A4 by deferasirox.
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Repaglinide In healthy volunteers con comitant administration of deferasirox 30 mg/kg/day for 4 days with the CYP2C8 probe substrate repaglinide in a single dose of 0.5 mg increased the AUC of repaglinide 2.3 times and the Cmax by 62% (22S). The manufacturers recommended reducing the dose of repaglinide and monitoring blood glucose concentrations if this combination is used. UDP glucuronyltransferase inducers Deferasirox is metabolized by uridine 50 diphospho- (UDP) glucuronyltransferase (UGT), and concomitant use of inducers of UGT, such as rifampicin, phenytoin, or phenobarbital, can therefore lead to lower concentrations of deferasirox; monitoring of serum ferritin is indicated.
Drug–food interactions The effect of a high-fat or standard breakfast on the phar macokinetics of deferasirox has been investigated in healthy volunteers and patients with transfusional hemosiderosis (24c). The type of food, its caloric content and the fat content of the meal affected the systemic availability of deferasirox, but not when it was taken at least 30 minutes before a meal, which is the preferred timing.
Deferiprone (SED-15, 1054; SEDA-29, 237; SEDA-30, 273; SEDA-31, 402) Observational studies In an open trial in 13 patients with Friedreich’s ataxia aged 14–23 years, deferiprone 20–30 mg/kg/day for 6 months removed accumulated iron from a specific brain area (detected using MRI scanning) and produced significant neurological improvement compared with age-matched controls (25cr). Four patients withdrew because of adverse events, two because of musculoskeletal pain, one because of Guillain–Barré syndrome, and one because of reversible agranulocytosis.
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Guillain–Barré syndrome is not an estab lished adverse effect of deferiprone. During the study there was a clear reduction in body iron, as shown by reductions in serum iron, ferritin, and hemoglobin con centrations. It is not clear for how long deferiprone can be continued safely in Friedreich’s ataxia and whether iron supple ments are beneficial. Hematologic An underlying susceptibility may have played a part in a case of fatal agranulocytosis that was probably caused by deferiprone (26AR). • A 10-year-old girl was given deferiprone 45 mg/kg/day for excess iron storage following erythrocyte transfusions for congenital Diamond–Blackfan anemia. A fall in white cell count during week 8 rapidly progressed to agranulocytosis in week 9 followed by Staphylococcus aureus sepsis and pneumonia. She was given antibiotics and filgrastim, followed by glucocorticoids and ciclosporin, because of persistent agranulocytosis. However, the neutrophil count remained low and she died.
While in Diamond–Blackfan anemia only red cell production is affected, bone marrow examination in this patient on day 23 showed variable cellularity, with lympho cytic infiltration and fibrosis. In areas of low cellularity, mainly macrophages and megakaryocytes were found. Granulopoi esis and erythropoiesis were scarce. The lymphoid infiltrates consisted mainly of a mixture of CD4þ and CD8þ9 cells (CD, cluster of differentiation). CD117 staining showed a diffuse increase in mast cells. Bone-marrow flow cytometry showed that 72% of the cells were in the lymphocyte region, of which 86% were T cells with signs of activation. This report also illus trates that, despite regular monitoring, agranulocytosis can occur unexpectedly and can progress rapidly. There is one more case on record of agranulocytosis (together with reversible thrombocytope nia) in a patient with Diamond–Blackfan anemia who received deferiprone (27A) and another of neutropenia that slowly
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progressed to aplastic anemia (28A). Patients with Diamond–Blackfan may be more susceptible to agranulocytosis from deferiprone than those with thalassemia. In vitro progenitor cell cultures, using venous blood samples from 16 patients with major thalassemia and normal blood counts, yielded unexpected findings (29CR). Nine patients (three with splenect omy) received subcutaneous deferoxamine 45 mg/kg/day on 5 days/week, 7 patients (four with splenectomy) took deferiprone 75 mg/kg/day and there were 10 healthy controls. Granulocyte–erythrocyte–monocyte– megakaryocyte colony-forming units were more common in those who received defer oxamine or deferiprone than in the controls. Granulocyte–macrophage colony-forming units were more common and macrophage colony-forming units less common with deferiprone than in the controls. Granulo cyte colony-forming units were more com mon with deferoxamine than in the controls. Addition of serum from patients taking deferiprone to cultures of cells from the controls resulted in maturation arrest of the granulocytic lineage. These findings sug gest that deferiprone can cause maturation arrest of granulocyte–macrophage colonyforming units, an effect that may play a role in the pathogenesis of deferiprone induced agranulocytosis. Immunologic Rare serious adverse drug reactions probably result often from a com bination of different susceptibility factors, both known and unknown. Henoch–Schönlein purpura, with renal and pulmonary involve ment and intestinal invagination, has been reported in temporal association with expo sure to deferiprone (30AR). • A 7-year-old splenectomized boy with b-thalassemia, who had been receiving erythrocyte transfusions and deferoxamine for most of his life for a Coombs-positive hemolytic anemia, was given low-dose prednisolone and cyclophosphamide. Because of non-adherence and a serum ferritin concentration of 11489 ng/ml, the deferoxamine was replaced by deferiprone 60 mg/kg/day. After 5 months he developed arthritis of the ankles and palpable purpuric
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lesions on the legs. There was no history of infection, and virus serology and bacterial cultures were negative. A renal biopsy showed diffuse Henoch–Scho¨ nlein nephritis with crescent formation and immunoglobulin A (IgA) deposition in the mesangium and glomerular basement membrane. Deferiprone was withdrawn. At follow-up 2 years later renal function was normal and there was no proteinuria. DNA analysis because of recurrent attacks of abdominal pain showed familial Mediterranean fever and a homozygous M694V mutation.
therapeutic index of less than 0.025 she remained asymptomatic, but whereas initi ally her fundi had been normal, she slowly developed a pigmentary retinopathy. At 33 years the dose of deferoxamine was increased to 49 mg/kg/day and the deficits in dark-adapted visual sensitivity and postreceptor retinal sensitivity relapsed. When the dose of deferoxamine was again reduced, the dark-adapted visual sensitivity recovered. Mild deficits in post-receptor sensitivity persisted, as did deficits in photo receptor sensitivity.
In this patient Henoch–Scho¨ nlein purpura was thought to have developed because of the co-occurrence of M694V homozyg osity (an established susceptibility factor), profound cellular and humoral immunolo gical disturbances secondary to thalasse mia, and perhaps treatment with deferiprone.
The recovery of post-receptor sensitivity suggests that ‘remodelling’ of the retina and its functional processes is the basis for recovery of visual sensitivity despite irreversible compromise of photoreceptor function, leaving the retina particularly vulnerable to new exposure to deferox amine. The relation between retinal injury resulting from iron storage and that secondary to chelation treatment with deferoxamine has been reviewed (32AR).
Deferoxamine (SED-15, 1058; SEDA-29, 237; SEDA-30, 274; SEDA-31, 402)
Special senses Eyes A detailed case study of a woman with major thalassemia, receiving long-term deferoxamine 50 mg/kg/ day, yielded valuable information on deferoxamine-related retinopathy (31AR). • A 28-year-old woman with previously nor mal visual and retinal responses found that her eyes did not adjust to the dark. Eight weeks before, heart failure and raised liver iron concentrations had prompted a dou bling of the dose of deferoxamine. Visual acuity was 20/200 in both eyes. There were dense central and paracentral scotomata, and dark-adapted visual sensitivity was 2 log units below normal. Scotopic electrore tinography showed deficits in rod photore ceptor and post-receptor sensitivity. Deferoxamine was withdrawn and her visual acuity and visual fields rapidly normalized, while her dark-adapted visual sensitivity gradually improved. Three weeks later deferoxamine was restarted in a dose of 12 mg/kg/day and gradually increased to 25 mg/kg/day. During follow-up dark-adapted visual sensitivity gradually became normal, as did post-receptor sensitivity, but deficits in rod photoreceptor sensitivity persisted (at less than half the baseline sensitivity). While receiving deferoxamine doses adjusted to a
Ears The physiological capacity for elimination of iron from intracranial spaces is limited. Chronic or recurrent subarachnoidal bleeding, a rare condition, can cause superficial hemosiderosis in the central nervous system (33CR). As the vestibulocochlear nerve runs through the pontine cistern and has a long glial segment, superficial hemosiderosis almost always has auditory effects and causes bilateral sensorineural hearing loss. MRI scanning is very sensitive to ironcontaining hemosiderin and typically shows a rim of hypointensity on T2-weighted images, predominantly affecting the surfaces of the brainstem and cerebellum, the cranial nerves and the spinal cord. Pure-tone audiometry is used in the early detection of deferoxamine ototoxi city but may be insufficiently sensitive. In 60 patients with thalassemia receiving sub cutaneous deferoxamine 40 mg/kg/day on 5 days/week, distortion-product otoacous tic emission was compared with pure-tone audiometry (34C). The former was more sensitive than the latter and as a screening
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tool has the advantage of being non invasive, objective, rapid, and easy to use. Urinary tract Deferoxamine is contraindi cated in patients with severe kidney disease, and in overdose acute renal failure can occur (SEDA-28, 256). However, deferoxamine is commonly used off-label to remove alumi nium and to prevent or treat aluminiumrelated bone disease in patients with chronic kidney disease stage 4 (GFR 15–30 ml/min ute). The clinical and pathological findings in deferoxamine-induced acute renal failure in a patient with a renal transplant have been described (35AR). • A 58-year-old man with a cadaveric kidney transplant for Goodpasture’s syndrome who was taking long-term oral ciclosporin (trough concentration 90 µg/l), prednisolone, candesar tan, carvedilol, furosemide, verapamil, panto prazole, benzbromarone, pravastatin, ezetimibe, and warfarin was given subcutaneous deferox amine 2 g/day for 3 weeks, and 1 day after the last infusion was found to have renal impair ment. The serum creatinine concentration had increased to 250 µmol/l, there was proteinuria 1.1 g/day and the creatinine clearance was 31 ml/minute. To exclude graft rejection, a renal biopsy was performed. There were no signs of acute humoural or cellular rejection. There was no isometric vacuolization or microcalcification, as signs of calcineurin inhibitor toxicity, although the arterioles had marked cuff-like hyalinosis, indicating chronic vascular ciclosporin toxicity. There was about 15% cor tical tubular atrophy, interstitial fibrosis in a non-striped pattern and a partially flattened epithelium with attenuated brush borders, indicating acute tubular damage in the remain ing cortical tubules. The acutely damaged cor tical tubular epithelial cells had degenerated mitochondria, with myelin-like figures and loss of cristae, but there was no swelling of mitochondria or endoplasmic reticulum.
The authors suggested that the underlying mechanism of renal tubular toxicity in this patient was removal of iron from the mito chondria and subsequent depletion of mito chondrial ATP. The mitochondrial changes in this patient were different from the pat tern commonly seen in acute tubular injury, and may be diagnostic of deferoxamine toxicity. It is advisable to monitor renal function in patients with renal disease who receive deferoxamine.
R.H.B. Meyboom
Infection risk Deferoxamine and changes in iron metabolism may increase the infec tivity of a variety of fungi and bacteria (SED-15, 1064; SEDA-29, 237). In a case of endocarditis due to Salmonella enterica subsp. arizonae, chelation therapy with deferoxamine was thought to have been a possible susceptibility factor (36Ar).
PENICILLAMINE AND RELATED DRUGS (SED-15, 2729; SEDA-29, 238; SEDA-30, 274; SEDA 31, 403)
Penicillamine Uses In children, penicillamine-stimulated urinary copper excretion is a reliable non invasive test for Wilson’s disease. In a liver biopsy-controlled study in 43 patients it was also reliable and safe in adults; patients with penicillamine-stimulated urinary copper excretion below 1057 µg/day are unlikely to have Wilson’s disease and are unlikely to benefit from liver biopsy (37cr). In patients with an acute Wilsonian crisis, prompt copper chelation plus plasmapher esis can be life-saving. In an 18-year-old girl with Wilson’s disease, acute hemolysis and impending liver failure, chelation with peni cillamine (dose unspecified) and plasma pheresis led to recovery (38A). Observational studies In a trial in 15 preterm neonates, daily enteral penicillamine (in a locally produced formulation, dose not specified) for 2 weeks after birth elimi nated stage I and II retinopathy of prema turity but not of laser surgery (39cr). There were no adverse effects in these babies. The finding that penicillamine in high doses, as used in Wilson’s disease, reduces total skin collagen has prompted a trial in diffuse cutaneous systemic sclerosis. In a retrospec tive analysis of 84 patients with recent onset progressive disease, penicillamine, median dose 750 mg/day for at least 3 months, caused
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Chapter 23
significant reduction in skin disease and improvement of renal, cardiac and pulmon ary involvement (40cr). At the last followup, 20% of the patients were still taking penicillamine, 30% had stopped because of disease improvement and 21% had stopped because of adverse effects, showing the familiar pattern of proteinuria (n = 7), rash (n = 4), neutropenia (n = 3), and pemphigus (n = 2). In addition, 23% had died, mainly from complications of the disease. Four patients were lost to follow-up. Systematic reviews Penicillamine 600– 1200 mg/day has been compared with pla cebo or no intervention in primary biliary cirrhosis, another disorder in which peni cillamine has been tried because of its effects on collagen, in a meta-analysis of seven randomized trials in 706 patients (41M). Although the treatment group had significantly reduced serum AlT activity, there were differences neither in other liver tests nor in pruritus, fatigue, liver complications, progression of liver histolo gical stage, liver transplantation, or mortality. Skin An eruption resembling elastoma perforans serpiginosa, with the typical lumpy-bumpy histological appearance and pruritic lesions of 5–7 cm, is a late complica tion of the use of high doses of penicilla mine, and was originally described by Gephart and Bardach (42AR).
OTHER CHELATORS Edetic acid (ethylenediaminetetraacetic acid, EDTA) (SED-15, 1300; SEDA-30, 276; SEDA-31 405)
Uses A newly identified inherited disorder in a 12-year-old girl, characterized by
431
manganese storage, dystonia, polycythemia, and liver injury, was successfully treated with monthly infusions of calcium disodium eden tate 40 mg/kg/day for 5 consecutive days (43A). Penicillamine had previously been ineffective. Urinary tract Lead compounds are nephrotoxic. In a placebo-controlled trial, the protective effect of lead chelation was studied in a follow-up study of 4 years duration in 58 Chinese patients with a high normal lead burden and non-diabetic chronic kidney disease (serum creatinine concentrations 133–345 µmol/l) (44cr). Compared with placebo there was a sub stantial reduction in the progression of renal insufficiency. Interference with diagnostic tests The use of EDTA as an anticoagulant in blood samples can cause pseudothrombo cytopenia in automated cell counts (SED 15, 1202), usually because of clumping of neutrophil leukocytes and only rarely lym phocytes. In vitro EDTA caused artifactual agglutination of lymphocytes in a patient with a large B-cell non-Hodgkin’s lym phoma (45A).
Trientine
(SED-15, 3508; SEDA-29, 239)
Comparative studies In patients with Wilson’s disease initial worsening of neu rological symptoms is a notorious compli cation of chelation therapy. In an 8-week double-blind trial, initial treatment with trientine 1 g/day and zinc 100 mg/day (salt not specified) was compared with tetrathiomolybdate 60 mg/day and zinc 100 mg/day, with special reference to the worsening of neuropsychiatric symptoms (46A). The adverse events are shown in Table 1. Of the 23 patients who received trien tine, 6 fulfilled the criteria for neurological deterioration, while of the 25 patients
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Table 1. Adverse events in a comparison of trientine and tetrathiomolybdate Adverse event
Trientine (n = 23)
Tetrathiomolybdate (n = 25)
Rise in aminotransferases Anemia and/or leukopenia Neurological deterioration Death
0 1 6 4
4 3 1 2
who received tetrathiomolybdate, dete rioration occurred in only 1, suggesting that tetrathiomolybdate is superior to tri entine in the initial treatment of neurolo gical Wilson’s disease. Four patients in the trientine arm died and two in the tetra thiomolybdate arm. With one exception of a case of fatal leukemia, all the patients who died had severe neurological impair ment. As four of the seven patients with neurological deterioration died, this event may forecast poor survival. Drug dosage regimens Trientine and zinc have become major tools in the manage ment of Wilson’s disease. Zinc (usually zinc acetate dehydrate 75–150 mg/day in three divided doses) inhibits the enteric absorption of copper by stimulating intest inal and hepatic metallothioneins. As a cop per chelator, trientine when taken with meals also reduces enteric copper absorp tion and promotes urinary copper excretion; the usual daily dose is 500–1500 mg/day, in two to four divided doses. However, non-adherence is a common problem. In a retrospective review of the clinical records of 22 children with Wilson’s disease, new increases in serum aminotransferase activities during long-term treatment (mostly with trientine and/or zinc) were commonly found to be secondary to non adherence (47CR). In a retrospective study in five patients, trientine 500–1000 mg/day as a single dose was effective in controlling Wilson’s dis ease (48c). Larger prospective trials are needed to confirm the efficacy of oncedaily trientine and to determine the required dose.
POLYSTYRENE SULFONATES (SED-15, 2894; SEDA-29, 239; SEDA-30, 275)
Treatments for non-oliguric hyperkalemia in preterm neonates, including ion exchange resins, have been reviewed (49M). Comparative studies In a comparison of rectal sodium polystyrene sulfonate 1 g/kg every 4 hours (n = 15) and salbutamol infu sion 4 micrograms/kg every 4 hours (n = 30) for non-oliguric hyperkalemia in preterm infants, there were no important adverse events in those who received salbutamol, but two cases of severe ventricular tachycar dia and one of intestinal obstruction in those who received the polystyrene sulfonate (50c). Gastrointestinal Perforated necrotizing enterocolitis requiring resection has been reported in a 27-week, 850 g infant after rectal administration of sorbitol-free sodium polystyrene sulfonate for life-threatening hyperkalemia due to progressive anuria (51A). Although sorbitol has previously been blamed for gastrointestinal damage after the administration of Kayexalate (SED-15, 2896), this case suggests that sodium polystyrene sulfonate can also cause such damage. Rectal stenosis due to sodium polystyrene sulfonate crystals, requiring colonic resec tion, has been reported in a 46-year-old man who was given sorbitol-free Kayexa late by a nasogastric tube (52A). Histology showed fibrosis of the submucosa with numerous basophilic polygonal crystals sur rounded by macrophages.
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Tetrathiomolybdate versus trientine in the initial treatment of neurologic Wilson’s dis ease. Prog Neurother Neuropsychopharma col 2008;3(1):153–65. Arnon R, Flores Calderon J, Schilsky M, Shneider ES, Benjamin L. Wilson disease in children: serum aminotransferases and urin ary copper on triethylene tetramine dihy drochloride (trientine) treatment. J Pediatr Gastroenterol Nutr 2007;44(5):596–602. Fox AN, Schilsky M. Once daily trientine for maintenance therapy of Wilson disease. Am J Gastroenterol 2008;103:494–5. Vemgal P, Ohlsson A. Interventions for non oliguric hyperkalaemia in preterm neonates. Cochrane Database Syst Rev 2007;(1): CD005257. Yaseen H, Khalaf M, Dana A, Yaseen N, Darwich M. Salbutamol versus cationexchange resin (kayexalate) for the treat ment of nonoliguric hyperkalemia in preterm infants. Am J Perinatol 2008;25(3):193–7. Rugolotto S, Gruber M, Solano PD, Chini L, Gobbo S, Pecori S. Necrotizing enterocolitis in a 850 gram infant receiving sorbitol-free sodium polystyrene sulfonate (Kayexalate): clinical and histopathologic findings. J Peri natol 2007;27(4):247–9. Chatelain D, Brevet M, Manaouil D, Yzet T, Regimbeau JM, Sevestre H. Rectal stenosis caused by foreign body reaction to sodium polystyrene sulfonate crystals (Kayexalate). Ann Diagn Pathol 2007;11(3):217–9.
Pam Magee
24
ALDEHYDES
Antiseptic drugs
and disinfectants
(SED-15, 1439, 1513;
SEDA-31, 409)
Formaldehyde Many countries have revised their regula tions and lowered their occupational expo sure limits (OELs) for formaldehyde. After a request from the Canadian Commission for Occupational Health and Safety, the impact on irritating effects (irritation of the eyes, nose and throat) of lowering the OELs for formaldehyde from 2 to 1, 0.75 or 0.3 ppm has been studied (1c). A concen tration of 0.75 ppm was considered to be safe, and the additional health gain was estimated to be negligible below this. Respiratory At low concentrations for maldehyde irritates the respiratory tract by a chemosensory effect, i.e. an interaction with local nerve endings. High occupational concentrations of inhaled formaldehyde increase the risks of impaired lung function and asthma (SEDA-20, 225; SEDA-31, 409). However, whether non-occupational exposure to formaldehyde is related to asthma is still subject to discussion. The effect of formaldehyde on the asthmatic response to inhaled allergen challenge has been investigated in a double-blind, cross over study in 12 subjects with intermittent
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32024-1 � 2010 Elsevier B.V. All rights reserved.
asthma and allergy to pollen. After expo sure to formaldehyde 500 mircrograms/m3, the higher end of a realistic environmental indoor formaldehyde concentration, there was no significant adverse effect on airway allergen responsiveness (2c). Sensory systems At low concentrations formaldehyde irritates the eyes by a chemosensory effect, i.e. an interaction with local nerve endings. In an examination of the occurrence of sensory irritation and subjective symptoms in volunteers exposed to formaldehyde concentrations relevant to the workplace, eye irritation was the most sensi tive parameter. There was minimal objective eye irritation at a concentration of 0.5 ppm. Subjective complaints of ocular and nasal irritation at lower concentrations were strongly influenced by personality and smell (3c). Although breathing air containing low concentrations of formaldehyde causes sensory irritation, it is not known if the symptoms of burning of the nose and throat, coughing and difficulty in breathing that can occur at higher concentrations, are associated with formaldehyde-specific immunoglobulin E (IgE) production. During long-term exposure of mice to gaseous formaldehyde, the threshold limit of formaldehyde 0.08 ppm did not cause ovalbumin-specific IgE inflammatory immune responses (4E). However, higher than threshold concentrations resulted in both enhanced allergen-specific IgE responses and natural killer (NK) cell activity in peripheral blood cells. Formaldehyde may therefore be involved in promoting allergic inflammatory effects in subjects primed with specific
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allergens by NK cell activation. This suggests that even threshold concentrations of formaldehyde may play a regulatory role in systemic cell-mediated immune responses. Occupational asthma from formaldehyde exposure is well documented, although it occurs sporadically. There is a latent period, which extends from weeks to years before symptoms begin. Pneumonitis and asthma, different from the occupational exposure data, have been reported, suggesting direct and indirect effects of formaldehyde in healthy human airways (5A). • A 54-year-old man accidentally ingested 10% formaldehyde and inhaled while vomiting. He developed a cough, dyspnea and wheezing, and there were bilateral infiltrates on a chest X-ray. His pulmonary symptoms and forced expiratory volume in 1 second (FEV1) responded well to systemic glucocorticoids and nebulized salbutamol, and the infiltrates cleared. Two weeks later he had massive hemoptysis, fever, a leukocytosis, bronchospasm, auscultatory crackles, and new infiltrates on a chest X-ray. After antibiotics and glucocorticoid therapy, his symptoms and crackles resolved and the radiographic infiltrates regressed. Delayed hypersensitivity to a formaldehyde patch test concurred with his late-onset symptoms.
Gastrointestinal Formalin is a 40% solution of formaldehyde in water. It has been used for many years in concentrations of 2–4% to treat radiationinduced hemorrhagic proctitis. Only a few minor complications have been reported after treatment – acute proctitis, worsening of radiation-induced strictures, worsening of incontinence, and severe pain (6c, 7c). In a retrospective review of 49 patients who received formalin for hemorrhagic radiation-induced proctitis, two sub sequently developed anorectal cancer. As pelvic irradiation increases the risk of a sec ond malignancy, it is not known what role, if any, formalin played in the development of these new cancers. However, continued sur veillance of patients exposed to formalin should be recommended (8A). Tumorigenicity Since 2004 formaldehyde has been classified as a human carcinogen,
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based on evidence of nasopharyngeal cancer (SEDA-31, 409). However, this classification is still debated. In a review of cohort and case-control studies of the association between occupational exposure to formaldehyde and nasopharyngeal cancer, the evidence failed to reach a convincing conclusion on carcinogenicity and could not be used to establish a possible dose-response relationship (9R). In a case-control study of excess naso pharyngeal cancer mortality among formal dehyde-exposed workers in Wallingford, Connecticut, the results suggested that the mortality excess may not have been due to formaldehyde exposure, but rather reflected the effect of external employment in the ferrous and non-ferrous metal indus tries in the local area (10C). However, a method has been established to integrate benchmark dose estimates with genomic data, using gene expression changes in rat nasal epithelium after acute formaldehyde exposure. This suggested that in rats the carcinogenic activity of formalde hyde is associated with cytotoxic/prolifera tive mechanisms (11E).
Glutaral (glutaraldehyde) Observational studies Glutaral-based pro ducts are typically used in hospitals and clinics as cold sterilizers, to disinfect and clean heat-sensitive medical devices. Glu taral is a potent sensitizer and respiratory irritant, and it has been implicated as a cause of asthma in health-care workers. This has led to a search for alterative disin fectants for instrumental sterilization (SEDA-20, 225). However, glutaral continues to be used as a disinfectant and sterilizer, particularly in developing countries. This requires occupa tional health monitoring and establishment of safe practices for its use. In a Canadian study to assess the effect of work practices and general ventilation sys tems on employees’ exposure to glutaral, air samples were taken in five hospitals (12c). The presence of local or general ventilation,
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air changes per hour, the quantity of glu taral used and work practices were recorded. Work practices constituted the most important factor affecting the degree of exposure to glutaral. In locations where ‘poor’ or ‘unsafe’ practices were employed, glutaral concentrations were much higher and there was an increased prevalence of headache and itchy eyes among employees.
BISBIGUANIDES Chlorhexidine
(SED-15, 714; SEDA-29, 241; SEDA-30, 278; SEDA-31, 410)
Observational studies Chlorhexidine inter ventions have been shown to have the potential to reduce maternal and neonatal mortality and morbidity significantly in lowresource settings, although data on safety were incomplete (SEDA-31, 410). A further review of the research available has shown that despite positive results the use of chlor hexidine to prevent perinatal mortality and morbidity has not been widely adopted (13R). In the transition from chlorhexidine research to public health implementation in developing countries, the authors suggested that high priority be given to evaluate whether further evidence is needed to demonstrate safety and effectiveness, and to determine how evidence should be obtained. Sensory systems Chlorhexidine has been associated with occasional reports of ulcera tive keratitis, cataract, and iris atrophy when it is used in the treatment of Acantha meba keratitis (SEDA-29, 242). In a retro spective study of 81 patients looking for the characteristics that are associated with cat aract during the treatment of Acanthameba keratitis, 9 had developed a densely white ipsilateral cataract (14c). Chlorhexidine was part of the multidrug treatment in all of these cases. It is generally considered that compounds such as chlorhexidine can dis rupt the surface of the lens, provoke lenti cular oxidative or osmotic stress and
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contribute to cataract formation by altering lipid membranes, damaging lens fibers and inducing electrolyte imbalance. A cornea that has been damaged by amebic infection may allow increased penetration of topi cally applied drugs that have intra-ocular adverse effects, and improved therapeutic alternatives are needed. Immunologic Chlorhexidine-induced ana phylaxis is well documented, although still rare (SEDA-31, 411). More often anaphylaxis occurs when chlorhexidine is applied to mucous membranes, although it does occur after non-mucosal topical application. Anaphylaxis, toxic epidermal necrolysis, and Stevens–Johnson syndrome after nonmucosal topical drug application have been evaluated in a systematic review of the Ger man pharmacovigilance authority’s Adverse Drug Reactions Database (15R). The data base included reports of chlorhexidine ana phylaxis, but no reports of toxic epidermal necrolysis or Stevens–Johnson syndrome. Application to skin wounds or skin with impaired barrier function was identified as a major susceptibility factor.
BORATES
(SED-15, 548)
Boric acid Boric acid was first used as a topical antisep tic by Lister in 1873. It has subsequently been used in eye washes, mouthwashes, skin powders and ointments. Boric acid has also been as an irrigant for body cavities, including the pleural space, vagina, and rec tum. The medical use of these solutions and irrigants has now been abandoned, because of toxicity and potential lethality. However, boric acid is used as a household disinfectant, and deaths due to accidental poisoning are still reported (16A). Comparative studies Boric acid is being investigated in pessary/suppository form for the treatment of vulvovaginal candidiasis. In
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a randomized open comparison of boric acid vaginal suppositories and oral fluconazole for the treatment of vulvovaginal candidiasis in 112 patients with diabetes mellitus, boric acid produced a higher mycological cure rate (17c). However, two of the patients who were given boric acid withdrew because of vaginal burning, which improved after withdrawal. In a review of conventional and non-con ventional methods of managing recurrent vulvovaginal candidiasis, boric acid pro duced a good response but with some skin irritation and a caution concerning systemic toxicity (18c).
CATIONIC SURFACTANTS Benzalkonium compounds (SED-15, 421; SEDA-28, 261) Comparative studies Benzalkonium chlor ide is widely used as a preservative in eyedrops; in higher concentrations it is used as an antiseptic and disinfectant. In a rando mized crossover study two concentrations of benzalkonium chloride, 0.1% and 0.4%, used as a sanitary wipe were compared with a 62% ethyl alcohol emollient gel for safety and acceptability in male genital antisepsis (19c). Of the 39 participants one reported dry skin with 0.1% benzalkonium and a gen ital ulcer was reported in one patient assigned to 0.4% benzalkonium. No adverse effects were observed during use of the etha nol gel, which was preferred by most men.
(SEDA-15, 1896; SEDA-29, 242; SEDA-30, 279; SEDA-31, 411)
IODOPHORS
Polyvinylpyrrolidone (povidone) and povidone–iodine Povidone–iodine is a stable chemical com plex of polyvinylpyrrolidone (povidone)
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and elemental iodine, which contains 9–12% iodine. Observational studies Povidone–iodine solution has been used as an effective broadspectrum antiseptic and disinfectant since the 1950s. In the early 1980s, a tumoricidal effect was reported. In colorectal operations, povidone–iodine has generally been used for the purpose of minimizing postoperative septic complications and reducing cancer recurrence, although there is little evidence to support its use. In a review of the literature on the use of povidone–iodine in colorectal surgery, few prospective randomized controlled trials were identified (20R). The authors found no conclusive evidence of benefits but were able to comment on adverse effects. Serious adverse effects of povidone–iodine were not common; metabolic acidosis, acute renal failure, hyperthyroidism and toxic reactions to iodine or iodide had been reported. The authors recommended that in general povidone–iodine should be avoided in patients with a history of allergic reactions to iodine-containing compounds, thyroid disease, renal insufficiency and established systemic sepsis. Endocrine Povidone–iodine for pleuro desis is safe and effective (SEDA-31, 411). However, topical administration can cause thyroid dysfunction (SEDA-25, 277; SEDA 28, 263; SEDA-30, 279; SEDA-31, 411). In a retrospective study of 12 patients who underwent povidone–iodine pleurodesis, in which thyroid hormone concentrations were routinely monitored, there were no signs or symptoms of hyper- or hypothyroidism (21c). Povidone–iodine is a widely used gargling preparation in Japan, where iodine-induced hypothyroidism has been reported. Usually, the hypothyroidism is mild and resolves spontaneously on cessation of gargling. However, in the case of a 63-year-old patient who developed overt hypothyroid ism due to habitual gargling with povidone– iodine for more than 10 years, thyroid func tion did not improve on discontinuing the gargling (22A).
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Skin Povidone–iodine is a very effective anti-infective agent in the treatment of infected and potentially infected wounds of various types and is widely used in the treatment of burns. Unfortunately, povidone–iodine formulations dessicate the wound surface. While a moist environment promotes epithelialization of superficial wounds, dessication of the wound surface can have a detrimental effect on wound healing. Immunologic Immediate allergic reactions to povidone–iodine are rare and often overlooked, as it is difficult to diagnose. Polyvinylpyrrolidone is thought to play a mechanistic role. The usefulness of the histamine release test for diagnosing polyvinylpyrrolidone allergy has been studied in a single case (23A). • A 9-year-old boy with eosinophilia (1500 � 106/l) and rasied total IgE (1376 IU/ml) was sus pected of having polyvinylpyrrolidone allergy, as he had anaphylactic reactions twice when he was exposed to povidone–iodine for impetigo contagiosum. Skin prick tests were performed with povidone–iodine solution, polyvinylpyr rolidone, gentamicin sulfate, and two other medicines containing polyvinylpyrrolidone. The histamine release test was assessed using peripheral blood basophils. Skin prick tests with povidone–iodine, polyvinylpyrrolidone and the other medicines were all negative. Polyvinyl pyrrolidone caused histamine release in the pre sence of autologous serum, but not in its absence.
These observations accorded with the clinical findings that anaphylaxis had devel oped only when his skin had been exposed to povidone–iodine solution so that baso phils could contact polyvinylpyrrolidone in
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the presence of serum, probably because of broken skin and vessels. Drug formulations A liposomal hydrogel of povidone–iodine, developed to combine the antimicrobial effects of povidone–iodine with the moisturizing effects of liposomal hydrogels, has been compared with a conven tional silver sulfadiazine cream in 43 patients with partial thickness burns (24c). The lipo somal povidone–iodine hydrogel produced significantly faster complete healing of the burn wounds than silver sulfadiazine. The cosmetic result was excellent in 37% of the wounds treated with liposomal povidone– iodine hydrogel compared with 13% of those treated with silver sulfadiazine cream.
PHENOLIC COMPOUNDS (SED-15, 2800, SEDA-28, 263) Nervous system Phenol indiscriminately damages motor and sensory nerves and intrathecal administration is used to relive spasticity in those who do not have any functional movement in their legs. A single injection often lasts many months and before administration a long-acting local anesthetic drug is given. In a retrospective review of the case notes of 40 patients who had been treated with intrathecal phenol over 10 years all had improvement in spasticity, rated as substantial or excellent in 34 (25c). Seven patients required repeat injections with similar outcomes. Seven had temporary adverse effects.
References 1. Noisel N, Bouchard M, Carrier G. Evaluation of the health impact of lowering the formaldehyde occupational exposure limit for Quebec work ers. Reg Toxicol Pharmacol 2007;48:118–27.
2. Ezratty V, Bonay M, Neukirch C, OrsetGuillossou G, Dehoux M, Koscielny S, Cabanes PA, Lambrozo J, Aubier M. Effect of formaldehyde on asthmatic response to
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inhaled allergen challenge. Environ Health Perspect 2007;115:210–4. Lang I, Bruckner T, Triebig G. Formalde hyde and chemosensory irritation in humans: a controlled human exposure study. Reg Toxicol Pharmacol 2007;50:23–6. Gu YH, Fujimiya Y, Kunugita N. Long-term exposure to gaseous formaldehyde promotes allergen-specific IgE-mediated immune responses in a murine model. Hum Exp Tox icol 2008;27:37–43. Baccioglu A, Kalpaklioglu AF. An unusual form of formaldehyde induced lung disease. Allergol Immunopathol 2007;35:110–2. Raman RR. Two percent formalin retention enemas for haemorrhagic radiation proctitis: a preliminary report. Dis Colon Rectum 2007;50:1032–9. Lee SI, Park YA, Sohn SK. Formalin appli cation for the treatment of radiation-induced haemorrhagic proctitis. Yonsei Med J 2007;48:97–100. Stern DR, Steinhagen RM. Anorectal cancer following topical formalin application for haemorrhagic radiation proctitis. Colorectal Dis 2007;9:275–8. Duhayon S, Hoet P, van Maele-Fabry G, Lison D. Carconogenic potential of formal dehyde in occupational settings: a critical assessment and possible impact on occupa tional exposure levels. Int Arch Occup Environ Health 2008;81:695–710. Marsh GM, Youk AO, Buchanich JM, Erdal S, Esmen NA. Work in the metal industry and nasopharyngeal cancer mortality among for maldehyde-exposed workers. Reg Toxicol Pharmacol 2007;48:308–19. Thomas RS, Allen BC, Nong A, Yang L, Bermudez E, Clewell HJ, Andersen ME. A method to integrate benchmark dose esti mates with genomic data to assess the func tional effects of chemical exposure. Toxicol Sci 2007;98:240–8. Nayebzadeh A. The effect of work practices on personal exposure to glutaraldehyde among health care workers. Ind Health 2007;45:289–95. McCkure EM, Goldenberg RL, Brandes N, Darmstadt GL, Wright LL, for the CHX working group. The use of chlorhex idine to reduce maternal and neonatal mortality and morbidity in low-resource
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settings. Int J Gynaecol Obstet 2007; 97:89–94. Herz NL, Matoba AY, Wilhelmus KR. Rapidly progressive cataract and iris atrophy during treatment of Acanthamoeba keratitis. Ophthalmology 2008;115(5):866–9. Sachs B, Fischer-Barth W, Erdmann S, Merk HF, Seebeck J. Anaphylaxis and toxic epidermal necrolysis or Stevens–Johnson syndrome after nonmucosal topical drug application: fact or fiction? Allergy 2007; 62:877–83. Hamilton RA, Wolf BC. Accidental boric acid poisoning following the ingestion of household pesticide. J Forensic Sci 2007;52:706–8. Ray D, Goswami R, Banerjee U, Dadwhal V, Goswami D, Mandal P, Sreenivas V, Kochupillai N. Prevalence of Candida glab rata and its response to boric acid vaginal suppositories in comparison with oral flucona zole in patients with diabetes and vulvovagi nal candidiasis. Diabetes Care 2007;30:312–7. Watson C, Calabretto H. Comprehensive review of conventional and non-conven tional methods of management of recurrent vulvovaginal candidiasis. Aust N Z J Obstet Gynaecol 2007;47:262–72. Bukusi EA, Steele M, Cohen CR, Nguti R, Maingi CW, Thomas KK, Holmes KK. Safety, acceptibility, and tolerability of 3 topical microbiocides among heterosexual Kenyan men. J Acquir Immun Defic Syndr 2007;44:423–8. Pattana-arun J, Wolff BG. Benefits of povi done–iodine solution in colorectal opera tions: science or legend? Dis Colon Rectum 2008;51:966–71. Yeginsu A, Karamustafaoglu A, Ozugurlu F, Eitkan I. Iodopovidine pleurodesis does not affect thyroid function in normal adults. Interact Cardiovasc Thorac Surg 2007;6 (4):563–4. Sato K, Ohmori T, Shiratori K, Yamazaki K, Yamada E, Kimura H, Takano K. Povidone iodine-induced overt hypothyroidism in a patient with prolonged habitual gargling; urinary excretion of iodine after gargling in normal subjects. Int Med 2007;46:391–5. Yoshida K, Sakurai Y, Kawahara S, Takeda T, Ishikawa T, Murakami T, Yoshioka A. Anaphylaxis to polyvinylpyrrolidone in povi done–iodine for impetigo contagiosum in a
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boy with atopic dermatitis. Int Arch Allergy Immunol 2008;146(2):169–73. 24. Homann H-H, Rosbach O, Moll W, Vogt PM, Germann G, Hopp M, Langer-Brauburger B, Reimer K, Steinau H-U. A liposome hydrogel with polyvinyl-pyrrolidone iodine
443 in the local treatment of partial- thickness burn wounds. Ann Plast Surg 2007;59: 423–7. 25. Pinder C, Bhakta B, Kodavali K. Intrathecal phenol: an old treatment revisited. Disabil Rehab 2008;30(5):381–6.
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Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Resistance to antibacterial drugs Emerging and increasing resistance to anti biotics continues to be a serious threat to public health worldwide. Thus, 70 years since their introduction, we are now facing the possibility of a future without effective antibiotics for several types of micro-organ isms that cause serious diseases. In 2001, the European Commission pre sented their strategy for combating this threat. Later in the same year, EU Health Ministers adopted a Council Recommenda tion (1S). The key point was surveillance. Since then, many working groups have worked hard in nearly all European coun tries and we have excellent overviews of high degrees of resistance in Southern Europe and considerably less in Northern Europe. How ever, a general trend has been an increase in both places. Surveillance is of importance, for the microbes are on the move. In short, the field of beta-lactamases exemplify what is happening. Alexander Fleming discovered that some strains of staphylococci could destroy penicillin because they produced penicillinases. It is now well recognized that the most effective resistance mechanism against beta-lactams is expression of beta lactamases. These enzymes hydrolyse the Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32025-3 � 2010 Published by Elsevier B.V.
beta-lactam ring, using either a serine residue (as in class A, C, and D beta-lactamases) or a zinc molecule (as in class B, also called metallo-beta-lactamases, MBLs) (2R). The spreading of metallo-beta-lactamases consti tutes an ever-increasing serious threat for human health, due to (i) their broad activity profiles that encompass most beta-lactam antibiotics, including the carbapenems; (ii) the potential for horizontal gene transfer; and (iii) the absence of clinically useful inhi bitors. The last of these points contrasts with serine beta-lactamases (3R), although sidero phore-containing monobactams show pro mising results in vitro and may be of clinical importance (4R). If these enzymes are becoming widespread among pathogenic bacteria, the end of the beta-lactam antibiotics is coming closer. Metallo-beta-lactamases are also present intracellularly in plants and animals, and the possibilities for interactions beyond these kingdoms are completely unknown. Thus, there is an increasing concern that surveillance might not be able to cope with the problem. There should be a focus on better guidelines for registration and use of antibiotics. In Europe this view brings into focus the European Medicines Agency (EMA), which is responsible for registering new antibiotics and general guidelines for their proper use. Without going into detail, it can briefly be mentioned that protocols for the approval of new antibiotics lack proper demands regard ing their environmental fate. It should be recognized that most chemicals, including
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drugs, can act on the environment. This is of specific concern for antibiotics, as microbes are everywhere. However, that view is not recognized in the current rules. Another area for improvement is regular post-marketing follow-up of the develop ment of resistance and cross-resistance. For example, if it became evident that the use of carbapenems triggered the spread of metallo beta-lactamases, their use would have to be restricted. On these – and other points – EMA and other agencies should act. Then pharmaceu tical companies should be challenged. For years they have been very active in produ cing sophisticated groups of antibiotics. The numbers of cephalosporins and fluoroquino lones on the market are overwhelming, and new ones, with very limited improvements, continue to appear. The time has come to change this, and some companies are already doing so. In relation to beta-lactam antibio tics, one can be mentioned. It has been shown that endogenous nitric oxide protects bacteria against a long list of cephalosporins, penicillins and moxalactam (5R). Cefotaxime kills nitric oxide-deficient Staphylococcus aureus far more efficiently than it kills wildtype bacteria. Moreover, pre-treatment with exogenous nitric oxide temporarily protects bacteria against cefotaxime toxicity.
Intrapartum antibiotics for mothers with group B streptococcal colonization: to treat or not to treat? Asymptomatic vaginal carriage of group B streptococci was described as early as in 1935 (6E). However, the first report of group B streptococcal sepsis in a neonate did not appear until 1964 (7c); since then, group B streptococci have been recognized as a com mon cause of neonatal infectious morbidity and mortality, maternal morbidity, asympto matic bacteriuria in pregnancy, and urinary tract and other infections in adults (8R). Over the years, it has been well established that the gastrointestinal tract, vagina, and
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urethra serve as reservoirs for group B strep tococci without causing disease. A systematic review of the prevalence has shown that the rate of vaginal colonization was 6.5–36%, and 10 of 31 studies showed a carrier rate above 20% (9M). In 1976, chemoprophylaxis was pro posed for reducing maternal colonization with group B streptococci, in order to reduce neonatal disease (10C). Since then many reports have appeared, and penicil lin and ampicillin have been the two most commonly used drugs. It is generally accepted that beta-lactams given during labor significantly reduce colonization with group B streptococci. However, severe allergic reactions to antibiotics have been reported (11C, 12A, 13c), besides an increased incidence of post-natal mater nal and neonatal yeast infections. Intra partum antibiotic prophylaxis may also increase exposure of neonates to ampicil lin-resistant Enterobacteriaceae (14C). This was the background to a recent Cochrane analysis (15M), in which it was stated that it is important to know if intra partum antibiotics do more good than harm in trying to reduce mortality and morbidity from neonatal group B streptococcal infec tions. Since most women colonized with group B streptococci are asymptomatic, screening is necessary if they are to be iden tified. However, of women in labor who have group B streptococci, very few will give birth to babies who are infected. Hence, giving intravenous antibiotics to all these women in labor will put many women and babies at unnecessary risk of adverse effects, includ ing potentially fatal anaphylaxis, and occa sion the emergence of drug-resistant organisms. The authors concluded that there is no evidence from well-designed and wellconducted studies that intrapartum antibiotics should be recommended in order to reduce early-onset neonatal infection. Ideally, the effectiveness of intrapartum antibiotics to reduce infection should be studied in ade quately sized, double-blind, controlled trials. They also stated that there is no information about whether intrapartum ampicillin is preferable to penicillin or about possible
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
changes in neonatal flora and the develop ment of resistance. It is not easy to be a doctor in the labor room, left alone with the question of whether to treat or not. The time has come for the regulatory authorities to come up with new guidelines. Unnecessary use of antibiotics should be reduced.
BETA-LACTAM ANTIBIOTICS (SED-15, 478; SEDA-29, 267; SEDA-30, 280; SEDA-31, 420) Immunologic Penicillin is the most com mon cause of drug-induced anaphylaxis (16S). Ever since the beta-lactam anti biotics came on the market, the incidence of cross-reactivity between penicillin and other groups of antimicrobial drugs has been a matter of concern. There are a confusingly large number of studies on this question and the conclusions have sometimes been contradictory. As a result, owing to a fear of serious crossreactivity, other beta-lactams are often avoided in patients with known penicillin allergy. This might result in increased health-care costs, a risk of bacterial resis tance, the use of alternative antibiotics with other potentially dangerous adverse affects (17R) and the use of inferior anti biotics, such as vancomycin for the treat ment of meticillin-susceptible S. aureus infections (18R). As reviews of cross-reactivity between penicillins and cephalosporins are common (19R–21R), only comments are made here on the possible allergic cross-reactivity of penicillins with carbapenems and mono bactams (22R). Penicillins versus carbapenems There is no current consensus on what the crosssensitivity is between penicillins and carbapenems, or how much allergy can be attributed to a coincidental total allergic
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reaction to the carbapenem that is not related to the fact that the patient is also allergic to penicillin. When studies that have verified penicillin allergy by accepted standards (i.e. skin tests with the major and minor penicillin determinants) and have tested for carbapenem allergy by administering a full therapeutic dose to carbapenem skin test-negative patients were examined, cross-reactivity between skin tests appeared to be 1%, with all carbapenem skin test-negative patients tolerating the challenge (23C–25C). The authors recommended that if a carbapenem skin test is negative in patient with penicillin allergy, carbapenem can be used safely. Penicillins versus monobactams Aztreonam is the only monobactam widely available for clinical use. Of 3360 patients who received multiple doses of aztreonam, 7 (0.2%) had type 1 reactions (26c). Reviews of the immu nological studies and evidence from clinical trials have not shown cross-reactivity between aztreonam and penicillins, except for sensitization reactions in patients with cystic fibrosis. In addition, some immunolo gical and clinical data suggest that there may be a degree of cross-reactivity between ceftazidime and aztreonam because of a similarity in the side chain. The authors emphasized that choosing antibiotics in penicillin-allergic patients is difficult. However, the risk of inducing an immunoglobulin E (IgE)-mediated-type reaction in these patients by choosing either a carbapenem or a monobactam is lower than many believe.
Teratogenicity Penicillins and cephalo sporins are generally thought to be safe in pregnancy. However, in a recent Ser bian study of 6099 women, congenital malformations were found in 7 babies born to 112 women who had taken a beta-lactam antibiotic during the first tri mester (27c). All except one (hypospa dias) were minor malformations. The
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results thus suggested a possible terato genic potential, even with antibacterial drugs that are considered to be safe. However, as those that occur are usually minor, they often pass unnoticed.
(SED-15, 638; SEDA-29, 246; SEDA-30, 246; SEDA-31, 420)
CARBAPENEMS
Drug–drug interactions Valproic acid (SEDA-30, 421) Carbapenems can reduce serum concentrations of valproic acid to one-third. Meropeneum seems to have the most pronounced lowering effect but the mechanism is unclear (28c). In a Japanese study on human, monkey, and rat liver cells, carbapenems inhibited valproic acid glucuronidases (29E).
Doripenem Nervous system The seizure-inducing potential of doripenem (SEDA-30, 421) has been reviewed (30R). In patients with nosocomial pneumonia, the incidence of seizures was 1.2% in patients taking doripe nem (6/485) and 3.8% in patients taking imipenem (10/263). For patients with condi tions that predispose to seizures, seizures occurred in 3 of 193 patients taking doripe nem (1.5%) and 6 of 116 taking imipenem (5.2%). These data suggest that doripenem has a lower seizure-inducing potential than imipenem.
Ertapenem Nervous system Seizures have been reported infrequently in patients receiving ertapenem (31R), but this might not reflect the real incidence. Of 30 patients taking ertapenem, 3 had seizures (32c). All had moderate renal insufficiency
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(creatinine clearances 44, 54, and 56 ml/min) and all had received intra venous ertapenem 1 g/day. All three patients had some kind of nervous system disorders, but only one previously had had seizures. Two were given prophylactic anti-epileptic drugs. Using Naranjo’s cri teria, the events were classified as prob able in one case and possible in the other two. Thus, like other carbapenems, erta penem may lower the convulsive thresh old in some patients.
(SED-15, 688; SEDA-29, 246; SEDA-30, 284; SEDA-31, 422)
CEPHALOSPORINS
Nutrition Pivoxil is used as a component of prodrugs for its ability to increase drug absorption from the gastrointestinal tract. However, it can cause carnitine depletion, as illustrated in a report from Japan where three different pivoxil-containing cephalo sporins are marketed (33A). • A 1-year-old boy was given pivoxil-containing cephalosporins for recurrent otitis media and upper respiratory tract inflammation. He developed a tremor in his hands and feet, which led to a generalized convulsion. His blood carnitine concentration of was about 1/10 of normal.
Cefdinir Gastrointestinal Passage of red stools after the use of cefdinir (SEDA-31, 422) continues to be reported and has been reviewed (34R). The red color is believed to be due to the formation in the gastro intestinal tract of a non-absorbable com plex between cefdinir or its breakdown products and iron (commonly found in infant formulae). Whether or not this influences the amount of cefdinir that is absorbed was not evaluated.
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Cefoperazone Gastrointestinal A 9-year-old boy with Meckel’s diverticulum who was taking cefo perazone had gastrointestinal bleeding on the fifth day after an operation (35A). This is a reminder that cefoperazone, like other cephalosporins that contain a methylthio tetrazole side chain, can cause hypopro thrombinemia and bleeding.
Cefotaxime Biliary tract Ceftriaxone can cause biliary sludge and cholelithiasis in children. Reports related to other cephalosporins, including cefotaxime, have been rare (36C). Cefotax ime has now been implicated (37A). • A 2-week-old girl developed fever, abdominal distension, jaundice, and pale stools. Electrolytes and aspartate transaminase and alkaline phosphatase activities were normal, but gamma glutamyltransferase activity and bilirubin were raised. Ultrasonography showed ascites, but the liver was normal and there was no intrahepatic or extrahepatic biliary ductal ectasia or biliary sludge. Blood cultures grew Aeromonas hydrophila and Klebsiella pneumoniae. She was given ampicillin and cefotaxime for 10 days and the jaundice disappeared. However, 1 week later, the jaundice and pale stools recurred. There was mild hepatomegaly, and bilirubin and gamma glutamyltransferase were raised. Ultrasonography showed cholestasis, dilatation of the intrahepatic and extrahepatic biliary ducts with a lot of sludge, and a large sludge ball in the gall bladder. She was given ursodeoxycholic acid and her stools became pigmented after 2 days. Subsequent ultrasonography showed reduced sludge in the biliary tree and gall bladder. By 6 months there was complete resolution.
Ceftobiprole The controversial classification of cephalo sporins into ‘generations’ is partly based upon when they arrived on the market and partly upon their spectrum of activity (38R). Continuing development of new cephalosporins may create ‘fifth-generation’
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cephalosporins. Ceftobiprole is the frontrun ner in this group. It is already on the market in Canada, Switzerland, and Ukraine and is currently under review by the FDA and EMA. It has been stated to be active against methicillin-resistant staphylococci as well as several Gram-negative organisms, including Pseudomonas aeruginosa (39R). However, it can be broken down by extended-spectrum beta-lactamases from Escherichia coli, Kleb siella spp., and others. Based on one report it has been claimed that its characteristics make significant drug–drug interactions less likely (40R). However, the mere fact that it has to be given as a carbamate prodrug, ceftobiprole medocaril, and depends on plasma esterases to activate it, makes such statements uncer tain. Its main adverse effects are similar to those of most other cephalosporins, with one exception – it causes more taste disturbances (41c, 42C); the mechanism is not known.
Ceftriaxone Liver The advantage of a long half-life, broad spectrum, and high tissue penetration make ceftriaxone a frequent choice in the treatment of childhood infections, in spite of its tendency to cause formation of biliary and urinary sludge. Hepatitis has also been reported (43A) • A 12-year-old boy developed weakness and fatigue after taking ceftriaxone 50 mg/day for 6 days for tonsillitis. Aspartate and alanine transaminases, gamma glutamyltransferase and alkaline phosphatase activities, and total bilirubin were all raised. Ultrasonography showed a minimally enlarged liver with a normal parenchyma. The gall bladder was normal. There was eosinophilia of 8%. Ceftriaxone was withdrawn and the boy was given pulse methylprednisolone. He recovered slowly over the next 10 weeks.
The first case of hepatitis associated with ceftriaxone was described in 1991 (44A). It has since been associated often with hemo lytic anemia, which can be fatal (45A). The underlying mechanisms are still not known.
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(SED-15, 2378; SEDA-29, 247; SEDA-30, 286; SEDA-31, 423)
reasonable to agree with the authors’ statement that early use of amoxicillin is one of the causative factors of molar inci sor hypomineralization.
Chemically modified monobactams and their non-antimicrobial properties
Co-amoxiclav and clavulanic acid
MONOBACTAMS
N-Methylated derivatives of the mono bactams can cause DNA damage, growth arrest, and apoptosis in mammalian cell cul tures (46E). Stereochemical modifications may produce more specifically targeted compounds (47E), leading to the develop ment of novel anticancer drugs. In a breast cancer xenograft mouse model using syn thetic N-thiolated monobactams, the com pound L-1 caused significant inhibition of tumor growth (48E).
PENICILLINS (SED-15, 2756; SEDA-30, 286; SEDA-31, 424) Amoxicillin Teeth The etiology of molar incisor hypomineralization is still unclear, but it has been suggested that use of antibiotics in early childhood may play a role (49c–51c). However, it is not clear whether the causative factor is the illness itself or the drugs used to treat it. The use of anti biotics in 141 schoolchildren and children under the age of 4 has been examined (52cE). Of 23 children with molar incisor hypomineralization, 12 had taken anti biotics during the first year, compared with 40 of the children without hypomineraliz ation. The number of courses of amoxicillin was significantly associated with hypomineralization. The authors also cultivated embryonic mouse teeth with and without amoxicillin, which increased enamel but not dentine formation. Thus, the use of amoxicillin gives an altered pattern of amelogenesis and interferes with the mineralization. Of course, amoxicillin may not be the sole cause, but it seems
The combination of amoxicillin þ clavulanic acid (co-amoxiclav) has been marketed in several formulations. In Europe, it is avail able in ratios of 2:1, 4:1, and 7:1; in the USA, a 14:1 ratio has been approved (53S). Liver Clavulanic acid can cause liver damage. The first case was described more than two decades ago (54A), since when more than 100 cases have been reported (55Ar). Reports of liver damage due to amoxicillin alone are considerably fewer. In two studies, amoxicillin alone was asso ciated with a sixfold lower incidence of liver injury than co-amoxiclav (56c) (57C). Among all antibiotics co-amoxiclav is the one most frequently associated with liver damage and the one that most often leads to hospitalization for drug-induced liver dis ease (58R). The onset liver damage due to co amoxiclav generally occurs at several days to weeks after starting therapy. A combination of advanced age and longterm therapy (more than 10 days) increases the risk (56c). Co-amoxiclav induced hepatitis is usually reversible after rapid drug withdrawal, but may per sist for weeks. However, in an analysis from a Spanish hepatotoxicity register, co-amoxiclav was the most common cause of chronic liver damage (59c). Moreover, in a prospective case series in 69 patients, there was an unfavorable out come (death, liver transplantation or per sistent liver damage) in 5 (60c). The mechanism underlying liver damage from co-amoxiclav is unclear. The com bined deficiency of alleles M1 and T1 in glutathione S-transferase genes plays a role in susceptibility (61C).
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Flucloxacillin Liver Flucloxacillin was the second most common beta-lactam to be associated with liver damage (58R). In 51 patients with flu cloxacillin-induced liver damage, a specific genotype, HLA-B*5701, was a major deter minant for this adverse effect (62c). This is the same phenotype that is associated with an increased risk of abacavir-induced hypersensitivity reactions (SEDA-31, 483). However, the authors stated that the overall clinical usefulness of such genotyping can be assessed accurately only by a prospective study of the risk of liver damage in subjects who take flucloxacillin and are positive or negative for the HLA B*5701 phenotype. Urinary tract Acute interstitial nephritis has been attributed to flucloxacillin in a report that included discussion of the treat ment of drug-induced acute nephritis (63Ar). Drug–drug interactions Warfarin Over the years, there have been a handful of reports saying that the effect of warfarin can be a reduction in patients taking either nafcillin or dicloxacillin (64Ar, 65A). A recent report has suggested that flucloxacillin might have a similar effect (66A).
TETRACYCLINES AND GLYCYLCYCLINES (SED-15, 3330; SEDA-29, 248; SEDA-30, 288; SEDA-31, 419)
Tetracyclines and glycylcyclines and their non-antimicrobial properties The matrix metalloproteinases (MMPs) form a family of nearly 30 enzymes that are intimately involved in tissue remo delling. Put simply, pathophysiological
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processes associated with the MMPs are related to imbalances between activation and inhibition of various MMPs, resulting in degradation of extracellular matrix. There are now about 25 000 reports on MMPs in Medline, covering a very large variety of diseases and experimental condi tions. Of the many groups of drugs that affect MMPs, the tetracyclines, including the glycylcyclines, have been the most pro mising. However, so far, only one drug (doxycycline) has been marketed for the treatment of one condition, periodontal dis ease. So far, most articles end by indicating in some way that there is hope that synthetic and natural matrix proteinase inhibitors will be useful in the prevention of . . . (67R).
Doxycycline Placebo-controlled studies Doxycycline 100 mg/day alone or in combination with diethylcarbamazine þ albendazole has been used in a 6-week, double-blind, random ized, placebo-controlled field trial in patients with Brugia malayi infection (68C). After 4 months of treatment with doxycycline (n = 119) or placebo (n = 42), the patients were given diethylcarbamazine 6 mg/kg þ albendazole 400 mg or a match ing placebo. The adverse effects of doxy cycline were mild and included myalgia (n = 6), nausea (n = 4), dizziness (n = 5), headache (n = 3), insomnia (n = 2), abdom inal pain (n = 2), itching (n = 2), diarrhea (n = 1), rash (n = 1), malaise (n = 1), and drowsiness (n = 1); none of the patients had to stop taking doxycycline because of adverse reactions. There were no reports of photosensitivity reactions. Adverse events in the placebo group (n = 42) were myalgia (n = 2), nausea (n = 1), dizziness (n = 2), insomnia (n = 1), and itching (n = 1). Adverse reactions were least common in those who took doxycycline þ placebo and most common in those who took placebo and diethylcarbamazine þ albendazole. There were significantly fewer patients with high fever and severe adverse reactions in those who took doxycycline and diethyl carbamazine þ albendazole.
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In a randomized, placebo-controlled trial in Ghana, 67 patients with onchocerciasis took doxycycline 200 mg/day for 4 or 6 weeks, followed by ivermectin 0.15 mg/kg after 6 months (69C). After 6, 20, and 27 months, efficacy was evaluated by onchocercoma histology, polymerase chain reaction (PCR), and determination of microfilariae. Doxycycline resulted in endobacteria depletion and female worm sterilization; the 6-week regimen was macrofilaricidal, and over 60% of the female worms were found dead, despite the presence of new Wolbachia-containing worms acquired after the administration of doxycycline. Doxycycline could be devel oped as a second-line drug for onchocercia sis, to be administered in areas without transmission, in foci with ivermectin resistance, and in areas with Loa loa co infections. Treatment with doxycycline was associated with bloody diarrhea in one patient; it resolved after withdrawal and treatment with metronidazole, although day 3 may have been too early for anti biotic-associated colitis. Other adverse events were mild, did not last longer than 3 days, and did not occur more often after administration of doxycycline. No serious adverse events were observed. Nervous system Pseudotumor cerebri, or benign intracranial hypertension, is a diag nosis of exclusion made by the following criteria: • signs and symptoms of increased intracranial pressure such as papilledema; • normal cerebral anatomy as shown on imaging; • increased intracranial pressure demonstrated on lumbar puncture; • normal cerebrospinal fluid (CSF) composition.
It can occur either as a primary condition or secondary to medications, and minocycline has long been known to cause it (70A, 71A). Doxycycline has rarely been implicated (72A, 73A), but another case has been reported (74A). • A 23-year-old woman took oral doxycycline 100 mg bd for acne and after 5–8 weeks developed worsening headaches associated
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with occasional nausea and blurred vision. Physical examination was normal except for bilateral papilledema. A lumbar puncture showed a mildly raised pressure with no CSF abnormalities. She felt substantially better soon after the lumbar puncture. A magnetic resonance imaging (MRI) scan of the brain was unremarkable and ruled out dural sinus thrombosis. Pseudotumor cerebri was suspected and doxycycline was withdrawn. Her headache, nausea, and blurred vision resolved after 1 week and the papilledema after 3 months.
Minocycline The French National Pharmacovigilance Committee has reported on the adverse effects of minocycline (75S). When sales fig ures were taken into account, reports were more frequent with minocycline than with doxycycline, and the proportion of severe adverse effects, including life-threatening hypersensitivity reactions and autoimmune adverse effects, were more common with minocycline than with doxycycline. Respiratory Acute eosinophilic pneumo nia has been attributed to minocycline in a 55-year-old woman who had taken mino cycline, paracetamol, theophylline, and pro caterol; the association with minocycline was confirmed by re-challenge, although a preceding lymphocyte stimulation test had suggested that paracetamol was to blame; re-challenge with paracetamol was unevent ful (76A). In another case, a 55-year-old man taking minocycline developed an acute eosinophilic pneumonia, and although a drug-induced lymphocyte stimulation test for minocycline was negative, the previous case suggests that minocycline may never theless have been to blame (77A). Pneumonitis has been attributed to mino cycline in a 51-year-old man who had taken minocycline for 11 days for a urinary tract infection (78A). A lymphocyte stimulation test for minocycline in the peripheral blood and pleural effusion was negative, but pro vocation with minocycline reproduced the original effects (fever, dry cough, and bilateral ground-glass opacities on the chest
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
X-ray). He recovered rapidly after gluco corticoid therapy. Sensory systems Blue sclerae and diffuse bilateral slate-grey pigmentation, particu larly in the interpalpebral fissures, devel oped in a 50-year-old man who had taken minocycline 100 mg/day for 10 years for acne (79A). He also had multiple superficial conjunctival cysts. Metabolism Lactic acidosis has been attributed to minocycline in an 18-year-old woman contributed to by a mitochondrial myopathy, with heteroplasmy for the G8363A mutation in tRNA(Lys), which was present in about 80% of her mitochon drial DNA (80A). Liver Fulminant hepatic failure requiring liver transplantation occurred in a 33-year old woman who had taken minocycline for 6 weeks (81Ar). Skin In a retrospective medical records review of 121 patients with rheumatoid arthritis who had taken at least one course of minocycline for 30 days or more, 44 (36%) developed hyperpigmentation, including 33 during the initial course over a median duration of 9 (range 2.2–78) months (82c). Hyperpigmentation was most commonly seen on the arms and legs and in the head and neck. Increasing age was the only significant susceptibility factor (hazard ratio [HR] = 1.04; 95% confidence interval [CI] = 1.00, 1.07). Hyperpigmentation in an 86-year-old woman taking warfarin was mistaken for bruising but was due to minocycline (83A). The affected areas showed blue-grey dis coloration with fading borders in a sym metric distribution over both forearms and hands, more on the ventral than the dorsal surfaces. They were darker during the day and lighter at night. The histology of minocycline pigmenta tion in the legs has been described in four
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cases with subcutaneous involvement (84c). There were brown/black pigment granules in macrophages clustered around vessels and eccrine coils in the reticular dermis. Similar pigmented macrophages were visi ble in fat septae and between lipocytes. There were macrophages laden with green-grey, flocculent, non-refractile glo bules in the subcutis in all cases, and two had lipid deposition associated with pigment. Hyperpigmentation attributed to mino cycline in a 23-year-old Hispanic man resolved after treatment with oral isotreti noin for acne vulgaris (85A). Nails Nail discoloration developed in a 73-year-old man and a 33-year-old woman after 8 weeks of therapy with minocycline 100 mg bd, without pigmentation elsewhere (86A). Musculoskeletal In a retrospective cohort study of patients, 27 developed rheumatolo gical symptoms while taking minocycline between 1996 and 2006 (87c). The mean age at onset was 17 years and the mean duration of minocycline use before diagno sis was 13 months. All presented with con stitutional symptoms: 22 had polyarthralgia and 17 had polyarthritis, mostly affecting hands and feet. Three types of syndrome were identified: transient, intermediate, and chronic. Seven patients developed chronic autoimmune disease that was still active a mean of 32 (13–48) months after onset. Six had an intermediate course, with resolution of symptoms within 12 months, and 14 had symptoms that resolved rapidly on withdrawal of minocycline. Immunologic Autoimmune hepatitis and idiopathic thrombocytopenic purpura have been attributed to minocycline in a 15 year-old girl who took it for 1 month for acne (88A). Minocycline-induced drug rash with eosinophilia and systemic symptoms (DRESS) has been studied in nine patients,
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seven of whom had skin phototypes V or VI (89c). The authors suggested that melanin in pigmented skin could promote the forma tion of a melanin–minocycline complex, which could explain the severe and pro longed skin manifestations of DRESS that occur in patients with dark skin, and espe cially in African and African-American patients. Lung involvement, with bilateral radiological alveolar opacities, has also been reported in a 19-year-old man with DRESS who had acute respiratory distress with a fever (40°C), lymph node enlarge ment, hepatomegaly, splenomegaly, and eosinophilia (1640 106/l) (90A). In a cross-sectional study in 252 patients with acne, 69% of whom had taken mino cycline at some time, there was no differ ence in the prevalence of positive antinuclear antibody (ANA) tests between patients who had been exposed or not exposed to minocycline, but high titers of ANA (1/160 or higher) were more common in the former (45% versus 12%). Antineu trophil cytoplasmic antibody (ANCA) titers were positive in 7% of the former and in none of the latter (91c). In 58% of cases, the ANCA was of the perinuclear pattern (pANCA) with myeloperoxidase specificity, and this was associated with symptoms in most cases. Two p-ANCA-positive patients were thought in retrospect to have devel oped a lupus-like syndrome. There have been a few reports of poly arteritis nodosa in patients taking mino cycline (92A), and a case of p-ANCA positive cutaneous polyarteritis nodosa has been reported (93Ar). • A 30-year-old Afro-Caribbean took mino cycline 100 mg/day for acne and after 1 year developed increasingly tender nodules with overlying brown pigmentation on her legs. Minocycline was withdrawn and a skin biopsy showed no evidence of minocycline pigmenta tion but a mixed inflammatory perivascular infiltrate throughout the dermis, with scattered nuclear dust and vasculitis involving a med ium-sized artery in the border between the reticular dermis and subcutis. There was focal and segmental fibrinoid necrosis in the vessel wall associated with nuclear debris and intimal thickening, all consistent with polyarteritis nodosa. pANCA was detected in a titer of 1/
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20, but myeloperoxidase ANCA and protei nase-3 ANCA were both negative, as was the antinuclear antibody. Within 3 months of min ocycline withdrawal, the nodules resolved with residual macular hyperpigmentation.
A lupus-like syndrome with severe myal gia and arthralgia occurred in a 15-year-old boy who had taken minocycline for 14 days (94A). Hyperthyroidism and lupus-like syndrome have been reported in a patient who took minocycline for acne (95A). Tumorigenicity Papillary thyroid carci noma surrounded by sarcoid granulomas developed in a 35-year-old woman who had taken minocycline 200 mg/day for 2.5 years; there was also dark brown pigment deposition typical of ‘black thyroid syndrome’ (96Ar). Previous reports have suggested that this syndrome can predis pose to thyroid carcinoma.
Tetracycline Urinary tract Renal damage following the use of tetracycline in a patient with pre existing renal disease has again been reported (97A). • A 42-year-old woman with polycystic kidney disease took tetracycline 250 mg qds after undergoing tooth extractions. She developed nausea, vomiting and diarrhea within days, and end-stage renal disease within 2 weeks. The tetracycline was withdrawn, but hemolysis was required to stabilize her condition.
Tigecycline Gastrointestinal Phase III studies have identified gastrointestinal effects, especially nausea and vomiting (20–45%), as the most common adverse effects of tigecycline (98C– 100C). Antiemetics are needed in 30% of cases and withdrawal in 4% (101R). Pancreas Pancreatitis has been attributed to tigecycline (102A).
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines • A 35-year-old man was given tigecycline 50 mg bd by intravenous infusion over 30–60 minutes for chronic osteomyelitis. Nausea and vomiting occurred from the start of therapy, and 13 days later he developed an acute abdominal ‘stab-like’ pain. His serum lipase activity was up 16 times the upper limit of the reference range and a computed tomography (CT) scan showed pancreatic edema without necrosis. Abdominal echotomography and biliary echoendoscopy excluded biliary stones. Tigecycline was withdrawn and he rapidly improved, including resolution of the abdominal pain and vomiting. The lipase
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activity gradually normalized 43 days after withdrawal.
An unpublished manufacturers’ Phase III study of tigecycline showed raised amylase activity in 9 of 292 patients (3%) (103S). The authors emphasized that the second Periodic Safety Update Report had pre sented a cumulative review of 24 cases of acute pancreatitis, including cases from pre clinical studies and spontaneous reports; two were fatal.
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Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines 37. Miloh T, Rosenberg HK, Kochin I, Kerkar N. Inspissated bile syndrome in a neonate treated with cefotaxime. J Ultrasound Med 2008;28:541–4. 38. El-Shaboury SR, Salch GA, Mohamed EA, Rageh AH. Analysis of cephalosporin antibiotics. J Pharm Biomed Anal 2007;45:1–19. 39. Schirmer PL, Deresinsinki SC. Ceftobi prole: a new cephalosporin for the treat ment of skin and skin structure infections. Anti Infect Ther 2009;7:777–91. 40. Murthy B, Schmitt-Hoffman A. Pharmaco kinetics and pharmacodynamics of ceftobi prole, an anti-MRSA cephalosporin with broad-spectrum activity. Clin Pharmaco kinet 2008;47:21–33. 41. Schmitt-Hoffmann A, Nyman L, Roos B, Schleimer M, Sauer J, Nashed N, Brown T, Man A, Weidekamm E. Multiple-dose pharmacokinetics and safety of a novel broad-spectrum cephalosporin (BAL5788) in healthy volunteers. Antimicrob Agents Chemother 2004;48(7):2576–80. 42. Noel GJ, Strauss RS, Amslet K, Heep M, Pypstra R, Solomkin JS. Results of a dou ble-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by gram-positive bacteria. Antimicrob Agents Chemother 2008;52:37–44. 43. Peker E, Cagan E, Dogan M. Ceftriaxone induced toxic hepatitis. World J Gastro enterol 2008;15:2669–71. 44. Nadelman RB, Arlin Z, Wormser GP. Lifethreatening complications of empiric cef triaxone therapy for ‘seronegative Lyme disease’. South Med J 1991;84(10):1263–5. 45. Bell M, Stockwell DC, Luban NL, Shirey RS, Shaak L, Ness PM, Wong ECC. Cetriaxone-induced hemolytic anemia and hepatitis in an adolescent with hemoglobin SC disease. Pediatr Crit Care Med 2005;6:363–6. 46. Kuhn DJ, Wang Y, Minic V, Coates C, Reddy GS, Daniel KG, Shim JY, Chen D, Lndis-Piwowar KR, Miller FR, Turos E, Dou QP. Structure–activity relationships of N-methylthiolated beta-lactam antibiotics with C3 substitutions and their selective induction of apoptosis in human cancer cells. Front Biosci 2005;10:1183–90.
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47. Frezza M, Garay J, Chen D, Cui C, Turos E, Dou QP. Induction of tumor cell apop tosis by a novel class of N-thiolated beta lactam antibiotics with structural modifica tions at N1 and C3 of the lactam ring. Int J Mol Med 2008;6:689–95. 48. Chen D, Falsetti SC, Frezza M, Milacic V, Kazi A, Cui QC, Long TE, Turos E, Dou QP. Anti-tumor activity of N-thiolated beta-lactam antibiotics. Cancer Lett 2008;268:63–9. 49. Jälevik B, Norén JG. Enamel hypominera lization of permanent first molars: a mor phological study and survey of possible aetiological factors. Int J Paediatr Dent 2000;10(4):278–89. 50. Jälevik B, Norén JG, Klingberg G, Barregård L. Etiological factors influen cing the prevalence of demarcated opaci ties in permanent first molars in a group of Swedish children. Eur J Oral Sci 2001;109(4):230–4. 51. Beentjes VE, Weerheijm KL, Groen HJ. Factors involved in the aetiology of molar– incisor hypomineraliation (MIH). Eur J Paediatr Dent 2002;3(1):9–13. 52. Laisi S, Ess A, Sahlberg P, Arvio P, Lukin maa PL, Alaluusua S. Amoxicillin may cause molar incisor hypomineralization. J Dent Res 2009;88:132–6. 53. GlaxoSmithKline. Prescribing information for Augmentin http:www.augmentin.com2. 54. van den Broek JW, Buennemeyer BL, Stricker BH. Cholestatische hepatitis door de combinatie amoxicilline en clavulaan zuur (Augmentin). [Cholestatic hepatitis due to amoxicillin and clavulanic acid (Aug mentin).] Ned Tijdschr Geneeskd 1988;132 (32):1495–7. 55. Cundiff J, Joe S. Amoxicillin–clavulanic acid-induced hepatitis. Am J Otolaryngol 2007;28(1):28–30. 56. Garcia Rodriguez LA, Stricker BH, Zim merman H. Risk of acute liver injury asso ciated with the combination of amoxicillin and clavulanic acid. Arch Intern Med 1996;156(12):1327–32. 57. De Abajo F, Montero D, Madurga M, García Rodríguez LA. Acute and clinically rele vant drug-induced liver injury: a population based case-control study. Br J Clin Pharma col 2004;58(1):71–80.
458 58. Salvo F, De Sarro A, Caputi AP, Polimeni G. Amoxicillin and amoxicillin plus clavula nate: a safety review. Expert Opin Drug Saf 2009;8(1):111–8. 59. Andrade RJ, Lucena MI, Kaplowitz N, García-Mun¸oz B, Borraz Y, Pachkoria K, García-Cortés M, Fernández MC, Pelaez G, Rodrigo L, Durán JA, Costa J, Planas R, Barriocanal A, Guarner C, Romero-Gomez M, Mun¸oz-Yag€ ue T, Salmerón J, Hidalgo R. Outcome of acute idiosyncratic druginduced liver injury: long-term follow-up in a hepatotoxicity registry. Hepatology 2006;44:1581–8. 60. Lucena MI, Andrade RJ, Fernández MC, Pachkoria K, Pelaez G, Durán JA, Villar M, Rodrigo L, Romero-Gomez M, Planas R, Barriocanal A, Costa J, Guarner C, Blanco S, Navarro JM, Pons F, Castiella A, Avila S, Spanish Group for the Study of DrugInduced Liver Disease (Grupo de Estudio para las Hepatopatías Asociadas a Medica mentos (GEHAM)). Determinants of the clinical expression of amoxicillin– clavulanate hepatotoxicity: a prospective ser ies from Spain. Hepatology 2008;44(4):850–6. 61. Lucena MI, Andrade RJ, Martínez C, Ulzurrun E, García-Martín E, Borraz Y, Fernández MC, Romero-Gomez M, Cas tiella A, Planas R, Costa J, Anzola S, Agún dez JA, Spanish Group for the Study of Drug-Induced Liver Disease. Glutathione S-transferase mM1 and T1 null genotypes increase susceptibility to idiosyncratic druginduced liver injury. Hepatology 2008;48 (2):588–96. Erratum in: 2009;49(3):1058. 62. Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe’er I, Floratos A, Daly MJ, Goldstein DB, John S, Nelson MR, Graham J, Park BK, Dillon JF, Bernal W, Cordell HJ, Pir mohamed M, Aithal GP, Day CP, DILIGEN Study, International SAE Consortium. HLA-B*5701 genotype is a major determi nant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41(7):816–9. 63. Xu B, Murray M. Flucloxacillin induced acute renal failure. Aust Fam Physician 2008;37:1009–11. 64. Kim Ky, Frey RJ, Epplen K, Furuhari F. Interaction between warfarin and nafcillin: case report and review of the literature. Pharmacotherapy 2007;27:1467–70.
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65. Lacey CS. Interaction of dicloxacillin with warfarin. Am Pharmacother 2004;38:898. 66. Alka G, Decreased MM. INR response sec ondary to warfarin–flucloxacillin inter action. Ann Pharmacother 2009;43:1374–5. 67. Lia NG, Shib ZH, Tang YP, Duan JA. Selective matrix metalloproteinase inhibi tors for cancer. Curr Med Chem 2009;16 (29):3805–27. 68. Supali T, Djuardi Y, Pfarr KM, Wibowo H, Taylor MJ, Hoerauf A, Houwing-Duistermaat JJ, Yazdanbakhsh M, Sartono E. Doxycycline treatment of Brugia malayi-infected persons reduces microfilaremia and adverse reactions after diethylcarbamazine and albendazole treatment. Clin Infect Dis 2008;46:1385–93. 69. Hoerauf A, Specht S, Buttner M, Pfarr K, Mand S, Fimmers R, Marfo-Debrekyei Y, Konadu P, Debrah AY, Bandi C, Brattig N, Albers A, Larbi J, Batsa L, Taylor MJ, Adjei O, Buttner DW. Wolbachia endo bacteria depletion by doxycycline as antfi larial therapy has macrofilaricidal activity in onchocerciasis: a randomised placebocontrolled study. Med Microbiol Immunol 2008;197:295–311. 70. Monaco F, Agnetti V, Mutani R. Benign intracranial hypertension after minocycline therapy. Eur Neurol 1988;144:218–20. 71. Ang ERG, Zimmerman C, Malkin E. Pseudotumor cerebri secondary to mino cycline intake. J Am Board Fam Pract 2002;15:229–33. 72. Lockhead J, Elston JS. Doxycycline induced intracranial hypertension. BMJ 2003; 326:641–2. 73. Friedman DI, Gordon IK, Egan RA, Jacob son DM, Pomeranz H, Harrison AR, Goldhammer Y. Doxycycline and intra cranial hypertension. Neurology 2004; 42:2297–9. 74. Tabibian JH, Gutierrez MA. Doxycyclineinduced pseudotomor cerebri. South Med J 2009;102:310–1. 75. French National Pharmacovigilance Com mittee. Fewer adverse effects with doxy cycline than with minocycline. Prescrire Int 2009;18(103):213. 76. Ono E, Miyazaki E, Matsuno O, Nureki S, Okubo T, Ando M, Kumamoto T. Mino cycline-induced acute eosinophilic pneumo nia: controversial results of lymphocyte
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stimulation test and re-challenge test. Intern Med 2007;46(9):593–5. Shimizu T, Shimizu N, Kinebuchi S, Toyama J. [Case of acute eosinophilic pneu monia probably induced by minocycline.] Nihon Kokyuki Gakkai Zasshi 2008;46 (2):136–40. Arai S, Shinohara Y, Kato Y, Hirano S, Yoshizawa A, Hojyo M, Kobayashi N, Sugiyama H, Kudo K. [Case of mino cycline-induced pneumonitis with bilateral pleural effusion.] Arerugi 2007;56(10): 1293–7. McAllum P, Slomovic A. Scleral and con junctival pigmentation following minocy cline therapy. Can J Ophthalmol 2007;42 (4):626–7. Zoraster RM, Rison RA. Severe lactic acidosis secondary to minocycline in a teen ager with infectious mononucleosis and mitochondrial myopathy. Clin Neurol Neurosurg 2008;110(6):627–30. Losanoff JE, Holder-Murray JM, Ahmed EB, Cochrane AB, Testa G, Millis JM. Minocycline toxicity requiring liver trans plant. Dig Dis Sci 2007;52(11):3242–4. Fay BT, Whiddon AP, Puumala S, Black NA, O’Dell JR, Mikuls TR. Minocycline induced hyperpigmentation in rheumatoid arthritis. J Clin Rheumatol 2008;14(1):17–20. Huq F, Durso SC. Spurious bruising in a patient taking warfarin: minocycline induced skin hyperpigmentation. J Am Geriatr Soc 2008;56(6):1156–7. Bowen AR, McCalmont TH. The histo pathology of subcutaneous minocycline pig mentation. J Am Acad Dermatol 2007;57 (5):836–9. Soung J, Cohen J, Phelps R, Cohen SR. Case reports: minocycline-induced hyper pigmentation resolves during oral isotreti noin therapy. J Drugs Dermatol 2007;6(12): 1232–6. Ban M, Kitajima Y. Nail discoloration occurring after 8 weeks of minocycline ther apy. J Dermatol 2007;34(10):699–701. El-Hallak M, Giani T, Yeniay BS, Jacobs KE, Kim S, Sundel RP, Dedeoglu F. Chronic minocycline-induced autoimmunity in chil dren. J Pediatr 2008;153(3):314–9. Egiguren L, Minondo L, Zapata E, Castiella A. Paciente con hepatitis autoinmunitaria y
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púrpura trombocitopénica idiopática tras un tratamiento con minociclina. [Patient with autoimmune hepatitis and idiopathic thrombocytopenic purpura after minocycline therapy.] Gastroenterol Hepatol 2007;30(9): 565–6. Maubec E, Wolkenstein P, Loriot MA, Wechsler J, Mulot C, Beaune P, Revuz J, Roujeau JC. Minocycline-induced DRESS: evidence for accumulation of the culprit drug. Dermatology 2008;216(3):200–4. Favrolt N, Bonniaud P, Collet E, Fayard M, Rabec C, Camus C, Bour JB, Camus P. Syndrome d’hypersensibilité médicamen teuse avec manifestations systémiques sévères après traitement par minocycline. [Severe drug rash with eosinophilia and sys temic symptoms after treatment with mino cycline.] Rev Mal Respir 2007;24(7):892–5. Marzo-Ortega H, Baxter K, Strauss RM, Drysdale S, Griffiths B, Misbah SA, Gough A, Cunliffe WJ, Emery P. Is mino cycline therapy in acne associated with antineutrophil cytoplasmic antibody positivity? A cross-sectional study. Br J Dermatol 2007;156(5):1005–9. Tehrani R, Nash-Goelitz A, Adams E, Dahiya M, Eilers D. Minocycline-induced cutaneous polyarteritis nodosa. J Clin Rheumatol 2007;13(3):146–9. Gait RC, Affleck AG, Leach IH, Varma S. Perinuclear antineutrophilic cytoplasmic antibody-positive polyarteritis nodosa sec ondary to minocycline treatment for acne vulgaris. J Am Acad Dermatol 2008; 58(5 Suppl 1):S123–4. Geddes R. Minocycline-induced lupus in adolescents: clinical implications for physi cal therapists. J Orthop Sports Phys Ther 2007;37(2):65–71. Benjamin RW, Calikoglu AS. Hyperthyroid ism and lupus-like syndrome in an adolescent treated with minocycline for acne vulgaris. Pediatr Dermatol 2007;24(3):246–9. Bruins NA, Oswald JE, Morreau H, Kievit J, Pavel S, Smelt AH. Papillary thyroid car cinoma in a patient with sarcoidosis treated with minocycline. Neth J Med 2007;65(5): 185–7. Miller CS, McGarity GJ. Tetracyclineinduced renal failure after dental treatment. J Am Dent Assoc 2009;140:56–60.
460 98. Sacchidanand S, Penn RL, Embil JM, Cam pos ME, Curcio D, Ellis-Grosse E, Loh E, Rose G. Efficacy and safety of tigecycline monotherapy compared with vancomycin plus aztreonam, in patients with compli cated skin and skin-structure infections: results from a Phase III randomized dou ble-blind trial. Int J Infect Dis 2005;9 (5):251–61. 99. Breedt J, Teras J, Gardovskis J, Maritz FJ, Vaasna T, Ross DP, Gioud-Paquet M, Dar tois N, Ellis-Grosse EJ, Loh E, Tigecycline 305 cSSSI Study Group. Safety and efficacy of tigecycline in treatment of skin and skin-structure infections: results of a double-blind Phase III comparison study with vancomycin–aztreonam. Antimicrob Agents Chemother 2005;49(11):4658–66. 100. Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E. The efficacy and safety of
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tigecycline in the treatment of skin and skin-structure infections: results of 2 dou ble-blind Phase III comparison studies with vancomycin–aztreonam. Clin Infect Dis 2005;4(Suppl 5):341–53. 101. Zhanel GG, Karlowsky JA, Rubinstein E, Hoban DJ. Tigecycline: a novel glycyl cycline antibiotic. Exp Rev Am Infect Dis 2006;4:9–25. 102. Gilson M, Moachon L, Jeanne L, Dumaine V, Eyrolle L, Morand P, Ben m’Rad MB, Salmon D. Acute pancreatitis related to tige cycline: case report and review of the litera ture. Scand J Infect Dis 2009;40(8):681–3. 103. Calvo G (rapporteur), Marcia MA, MartinSerrano G (pharmacovigilance assessors), Fenandez-Cortizo MJ (clinical assessor). Tygacyl. Second Periodic Safety Update Report – Preliminary Assessment Report, 15 Jan 2005 to 14 Dec 2006. 1 April 2007.
Natascia Corti, Alexander Imhof, and Christa Wenger
26
Miscellaneous antibacterial drugs
AMINOGLYCOSIDE ANTIBIOTICS (SED-15, 118; SEDA-29, 253; SEDA-30, 297; SEDA-31, 427) Sensory systems The use of aminoglyco sides in Ménière’s disease and the inci dence, mechanism, susceptibility factors, and prevention of ototoxicity have been reviewed, based on published literature from 1966 to 2004 (1R). Streptomycin and gentamicin primarily cause vestibular toxi city, whereas amikacin, neomycin, and kana mycin primarily cause cochlear toxicity. In a review of studies published between 1975 and January 2008 there was no corre lation of serum aminoglycoside concentra tions with vestibular toxicity but there was an effect of duration of therapy (2R). Ototoxicity was evaluated in 64 patients with tuberculosis, of whom 34 received amikacin, 26 kanamycin, and 4 capreo mycin, with a mean treatment duration of 20 months; 19% developed irreversible hearing loss and 6.3% had involvement of speech frequencies (3c). Urinary tract In a case–control study of 24 patients with cystic fibrosis, aminoglycoside therapy was associated with an increased risk of renal insufficiency, and gentamicin was more nephrotoxic than tobramycin (4c).
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32026-5 � 2010 Elsevier B.V. All rights reserved.
Amikacin
(SED-15, 111; SED A-29, 253; SEDA-31, 427)
Sensory systems Vestibular function has been evaluated by caloric testing and vestibular-evoked myogenic potentials (VEMPs) in 28 infants before and after treatment with systemic amikacin 15 mg/ kg/day over 10–14 days for respiratory tract infections or sepsis (5c). There were abnormal results in both VEMP (n = 4) and caloric testing (n = 6), without signs of hearing loss. Drug dosage regimens There was no significant difference in nephrotoxicity when amikacin 15 mg/kg/day or 12.5 mg/kg bd was given to 40 adults with hematolo gical malignancies (6c). However, because of differences in susceptibility factors between the groups these results must be interpreted cautiously.
Gentamicin
(SED-15, 1500; SEDA-29, 253; SEDA-30, 297; SEDA-31, 427)
Sensory systems Eyes The retinal toxicity of intravitreal gentamicin has been briefly reviewed (7r). A 75-year-old diabetic man developed retinal toxicity after subconjunc tival gentamicin injection following vitrect omy. The authors suggest that gentamicin should be avoided for this indication (8A). Ears Vincristine neurotoxicity on the medial olivocochlear bundle (MOCB) was not increased by adding different cumulative
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Chapter 26
doses of gentamicin in 12 children with acute lymphoblastic leukemia being treated with the BMF-95 protocol (vincristine, daunorubicin, asparaginase, cyclophosphamide þ mesna, cytarabine, mercaptopurine, prednisone, and methotrexate) (9c). Impaired evoked vestibulo-ocular reflexes (eVORs) in 12 patients with disequilibrium after gentamicin treatment compared with healthy volunteers suggested that vestibular hair cell function might act as a the marker of gentamicin vestibular toxicity (10c). In 40 patients receiving hemodialysis who were given either gentamicin alone or with N-acetylcysteine, significantly fewer of the latter had ototoxicity; the authors concluded that acetylcysteine might be oto protective, mainly in the high audiometric tone frequency range (11c). Mineral metabolism In a retrospective analysis of 1624 neonates, serum calcium concentrations were measured during genta micin therapy (12c). There was hypocalcemia ( 1000 cases). There were more than 20 cases of IgA linear dermatosis and maculo papular rash and single case reports of vancomycin-induced anaphylaxis, erythroderma, toxic epidermal necrolysis, and vasculitis. Skin reactions were reported significantly less often with teicoplanin. Cross-reactivity with vancomycin was postulated for most of
469
the skin reactions, apart from the ‘red man syndrome’ and IgA linear dermatosis. Hematologic Agranulocytosis occurred in a 57-year-old woman after 24 days of van comycin therapy (102A). It resolved within 4 days after switching to teicoplanin but recurred on day 11. Possible cross-reactivity with teicoplanin was postulated. Urinary tract Renal function has been monitored prospectively in two groups of 50 patients with neutropenia and persistent fever (103c). One group received teico planin combined with gentamicin and piper acillin þ tazobactam and the other received vancomycin combined with meropenem and levofloxacin. Vancomycin and con comitant treatment with amphotericin were independently associated with an increased risk of nephrotoxicity. Immunologic DRESS (Drug-induced rash with eosinophilia and systemic symptoms) occurred in a 52-year-old Japanese woman with a meticillin-resistant post-operative ear wound after treatment with teicoplanin for 2 weeks (104A). Vancomycin was substi tuted, and a few days later she developed a high fever with generalized lymphadeno pathy, facial edema, leukocytosis, eosino philia and hepatic and renal dysfunction. The reaction was associated with reactiva tion of human herpesvirus-6 (HHV-6). After withdrawal of the glycopeptides and treatment with glucocorticoids her symp toms improved.
Teicoplanin
(SED-15, 3305; SEDA-29, 260; SEDA-30, 301)
Skin A 54-year-old woman with a T-cell lymphoma developed a pruriginous maculopapular rash after taking teico planin and co-trimoxazole for 7 days (105A). Provocation tests were carried out: co-trimoxazole was negative but intra venous teicoplanin was positive. However, a controlled challenge with vancomycin was well tolerated.
Chapter 26
Natascia Corti, Alexander Imhof, and Christa Wenger
(SED-15, 3593; SEDA-29, 261; SEDA-30, 301)
an infected total knee arthroplasty with combined gentamicin- and vancomycinimpregnated cement (111A). Acute interstitial nephritis with a raised eosinophil count was associated with combined treatment with vancomycin and ceftriaxone in two cases (112A). Despite persistently normal serum creati nine concentrations and estimated glomer ular filtration rate (eGFR), inappropriate doses of vancomycin led to toxic concentra tions and initially unrecognized worsening of kidney function in an emaciated HIVinfected man (113A). The authors pointed out that serum creatinine and eGFR may be misleading when estimating renal function or nephrotoxicity in HIV-infected patients with low muscle mass. Nephrotoxicity has been investigated in five neonates receiving prolonged treat ment with aminoglycosides and vancomycin (114c). Although serum drug concentrations were maintained in the usual target ranges, there was renal tubular wasting of potas sium, phosphate, and calcium, along with hypokalemia in all five and a transient rise in serum creatinine in four. Nephrotoxicity from more aggressive vancomycin dosing has been evaluated in 94 patients with meticillin-resistant S. aureus pneumonia in a retrospective observational cohort study (115c). Vancomycin serum trough concentrations of over 15 mg/l were independently associated with renal toxicity (adjusted OR = 2.82) and with a larger change in creatinine clearance (–19 ml/minute) than vancomycin trough concentrations below 15 g/l (–7.6 ml/minute). In another study, increased vancomycin doses of more than 4 g/day in 26 patients were compared with doses of 4 g/day or less in 220 patients and with linezolid (116c). There was a significantly higher rate of nephrotoxicity in the high-dose group than in the low-dose group (35% versus 11%) and compared with linezolid (6.7%).
470
Vancomycin
Respiratory Acute non-cardiogenic pul monary edema developed in a 57-year-old man 4 hours after a first intravenous dose of vancomycin 1 g for cellulitis (106A). The edema resolved within 12 hours after treatment with furosemide, diphenhydra mine, and famotidine. Sensory systems In a review of intravitreal injections of antibiotics and antiviral drugs, vancomycin was considered to be safe if injected at doses of 1 g and at intervals of 48 hours (107R). Retinal toxicity can occur if doses of 10 g and over are injected. Hematologic In a prospective study in Japanese patients with MRSA nosocomial pneumonia, complicated skin and softtissue infections and sepsis were treated with either linezolid or vancomycin. Rever sible anemia and thrombocytopenia were reported more often in those who received linezolid, but significantly lower platelet counts were more common in those who received vancomycin (108c). Vancomycin-dependent, platelet-reactive antibodies of the IgG class, IgM class, or both were detected in 20% of blood samples from 34 patients in whom vanco mycin-induced thrombocytopenia was sus pected, whereas no IgG antibodies and one sample with IgM antibodies were detected in blood from 451 healthy donors and no antibodies were detected in 25 patients who received vancomycin without evidence of thrombocytopenia (109c). The authors concluded that testing for drug-dependent antibodies can be helpful in identifying vancomycin as a cause of thrombocytopenia. Vancomycin had to be withdrawn in a patient with left-sided endocarditis on day 36 because of neutropenia; the leukocyte count normalized after daptomycin was given instead (110A). Urinary tract A 61-year-old patient with diabetes mellitus and hypertension devel oped acute renal failure after treatment of
Skin A 63-year-old woman developed local skin necrosis during intravenous administration of vancomycin into the dorsum of the left foot for postoperative peritoneal infection (117A).
Miscellaneous antibacterial drugs
Chapter 26
The authors postulated leakage of the intra venous line or capillary leakage with drug extravasation causing necrosis. Two patients with vancomycin-associated, histopathologically confirmed linear IgA bullous dermatosis presented with a morbilli form eruption without blisters (118A). Immunologic A 16-year-old girl receiving vancomycin for endocarditis caused by viridans group streptococci developed a maculopapular rash after 18 hours, with an intermittent fever and progressive reduc tions in leukocyte and platelet counts (119A). She developed hypotension on day 8. She improved after withdrawal of vanco mycin and the use of glucocorticoids. Vancomycin-induced DRESS (drug rash with eosinophilia and systemic symptoms) has been reported (120A). • A 60 year diabetic woman with a wound infec tion with meticillin-resistant S. aureus devel oped a fever, a progressive maculopapular rash, eosinophilia and acute renal insufficiency after receiving vancomycin for 2 days. The syndrome resolved after withdrawal of vanco mycin and treatment with glucocorticoids.
KETOLIDES (SED-15, 1976; SEDA-29, 262; SEDA-30, 301; SEDA-31, 436) The ketolides are a subclass of macrolides, which were designed specifically to over come macrolide-resistant respiratory patho gens. Ketolides lack the cladinose sugar, which is replaced with a 3-ketone group. They bind to a secondary region on domain II of the 23S rRNA subunit. Telithromycin was the first ketolide to be approved by the Food and Drug Administration (FDA) in 2004 for community-acquired pneumonia, acute exacerbations of chronic bronchitis and sinusitis. However, after reports of ser ious hepatotoxicity, the FDA issued a public health advisory followed by a warning. In 2007 the indications for treatment of acute exacerbations of chronic bronchitis and sinusitis were removed from the label.
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Cethromycin (ABT-773) is the only other ketolide currently being developed.
Cethromycin Cethromycin is a once-daily ketolide that originated from research by Abbott Laboratories. It is effective against Strepto coccus pneumoniae, including multidrug resistant isolates, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila. There have been few studies of cethromycin so far. Data on adverse effects are limited and appear to be mainly gastrointestinal; there have been no reports of serious hepato toxicity (121R, 122r).
Telithromycin Cardiovascular Telithromycin can cause prolongation of the QT interval, and a warn ing has been issued against using it in patients who are already at increased risk, including those receiving class IA and class III antidysrhythmic agents (123r). Nervous system Telithromycin has been implicated in exacerbation or unmasking of myasthenia gravis (124r). Liver Telithromycin-related hepatotoxi city has been reported. In a case–control study of spontaneous reports of hepatotoxi city in telithromycin recipients using the FDA’s Adverse Event Reporting System, 2219 cases and 20 667 controls were identi fied (125C). The reporting odds ratio for hepatotoxicity associated with telithromycin compared with other agents was 1.82 (95% CI = 1.12, 2.96) after controlling for age and sex, approximating an 82% excess risk in users of telithromycin relative. A 25-year-old man taking telithromycin 400 mg/day developed acute hepatitis (126A). Skin Toxic epidermal necrolysis has been associated with telithromycin (127A).
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Immunologic A 54-year-old woman with hypertension developed an immediate hypersensitivity reaction to telithromycin shortly after a singe dose, with severe short ness of breath, wheezing, and angioedema (128A). Her allergic history included a maculopapular rash after sulfonamide anti biotics, but she had used erythromycin and azithromycin in the past without adverse effects. She was treated with adrenaline, diphenhydramine, and glucocorticoids and made a full recovery.
(SED-15, 2063; SEDA-29, 263; SEDA-30, 302; SEDA-31, 437)
LINCOSAMIDES
Clindamycin Observational studies In a retrospective review of the records of 50 consecutive patients with active toxoplasmic chorioreti nitis treated with clindamycin, five had gastrointestinal adverse events and six had rashes (129c) Nervous system A 14-year-old girl with autism developed hiccup-like movements after receiving clindamycin 300 mg bd and risperidone 5.5 mg/day for 1 day; 3 days after withdrawal of clindamycin the abnormal movements resolved (130A). Sensory systems Topical clindamycin has been associated with taste disorders. In the adverse drug reactions database of the Netherlands Pharmacovigilance Centre, seven patients were identified with taste disorders (131c). In five cases an oral for mulation was involved, in one intravenous administration and in one both formulations were used. Latency was less than 1 day after exposure and in one case taste disorders occurred repeatedly at 10 minutes after every intravenous dose. The adjusted report ing odds ratio was 7.0 (95% CI = 2.8, 17), supporting a causal relationship.
Natascia Corti, Alexander Imhof, and Christa Wenger
Liver Acute hepatotoxicity occurred in a 42-year-old woman after administration of clindamycin for a dental infection (132A). Skin Acute generalized exanthematous pustulosis (AGEP) is a rare skin eruption most commonly caused by medications. AGEP occurred in an 82-year-old Cauca sian woman after she had taken clindamycin for 2 days. She was treated with intravenous methylprednisolone, hydrocortisone cream 1%, hydroxyzine, doxepin, and paracetamol. The redness and pustulosis stopped spread ing in 1 day and resolved in 5 days (133A). Immunologic A 47-year-old woman devel oped acute febrile neutrophilic dermatosis (Sweet’s syndrome) after receiving oral and intravenous clindamycin for a tooth infection; after the clindamycin was withdrawn her symptoms resolved over several days (134A). Infection risk In 836 patients aged 65 years or older, clindamycin exposure was associated with the highest rate ratio of infection with C. difficile (RR = 32, 95% CI = 18, 58) (135r).
MACROLIDE ANTIBIOTICS (SED-15, 2183; SEDA-29, 263; SEDA-30, 302; SEDA-31, 437) Simvastatin A 78-year-old man taking simvastatin 80 mg/day developed rhabdo myolysis after completing a short course of macrolides (136A). The mechanism was probably inhibition of CYP3A4 and possi bly P glycoprotein.
Azithromycin
(SED-15, 389; SEDA-29, 264; SEDA-30, 302; SEDA-31, 437) Cardiovascular Significant prolongation of the QT interval leading to torsade de pointes has been reported within a few hours of a dose of azithromycin (137A).
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Nervous system A 55-year-old man took azithromycin 500 mg/day for pharyngitis and within 12 hours of the first dose he developed hiccups, which were persistent and very distressing (138A). They lasted for 3 days and resolved when azithromycin was withdrawn. Sensory systems Ears Azithromycin has been associated with mild-to-moderate, gra dual, reversible sensorineural hearing loss in the speech frequencies, as in a patient with otitis media who took low-dose oral azithro mycin (139A). Taste Dysgeusia after a course of azithro mycin has been described (140A). Gastrointestinal In a randomized investi gator-blinded, multicenter trial, azithro mycin 500 mg/day for 3 days was compared with moxifloxacin 400 mg/day for 5 days in out-patients with acute exacerbations of chronic bronchitis (141C). At least one treatment-related adverse event was asso ciated with azithromycin in 18.3%. The most common adverse events were diar rhea, nausea, and abdominal pain. In an open, non-comparative study in 52 teenagers taking oral azithromycin 500 mg thrice weekly for 8 weeks for acne vulgaris, only three had adverse events, including heartburn and nausea (142c). In a double-blind, randomized study 208 patients with cystic fibrosis were assigned to azithromycin either 250 mg/day (n = 103) or 1200 mg once a week (n = 105) for 6 months; gastrointestinal adverse effects were more common with weekly therapy (143C). Liver Azithromycin can cause cholestatic jaundice (144R). Skin Onychomadesis is total or partial loss of the nail plate as a result of separation starting in the proximal nail unit. A 10-year-old girl developed onychomadesis after taking azithromycin 500 mg/day for 6 days (145A). Her parents reported that peri ungual erythema and edema had developed
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in the index finger of right hand on day 5 and that loss of the nails had started after com pletion of the course of azithromycin.
Clarithromycin (SED-15, 799; SEDA-29, 265; SEDA-30, 302; SEDA-31, 438) Cardiovascular Torsade de pointes in asso ciation with prolongation of the QT interval after treatment with clarithromycin has been reported in two women aged 79 and 55 years (146A, 147A). Psychiatric Acute psychosis induced by clarithromycin is extremely uncommon, but delirium has been reported in a 63-year-old woman (148A) and an 87-year old man (149A). Hallucinations have also been described (150A). Gastrointestinal In a study of high-dose clarithromycin in 343 children over a period of 9 months, 78% received doses that exceeded the recommended dose of 15 mg/ kg/day and 26% received doses of at least 30 mg/kg/day (median 20 mg/kg/day); adverse reactions, mainly gastrointestinal in nature, were reported in 18% (151c). Liver Clarithromycin can cause cholestatic jaundice and cases of fatal acute hepatitis have also been described (144R). Skin Toxic epidermal necrolysis has been described in a 2-year-old girl who was given clarithromycin suspension (152A). Stevens–Johnson syndrome has been described in a 13-year-old boy after treat ment with clarithromycin (153A). Drug–drug interactions Carbamazepine Carbamazepine is extensively metabolized by cytochrome P450 enzymes, especially CYP34A, as is clarithromycin. In seven patients taking carbamazepine alone or in combination with other drugs, clarithro mycin led to transient toxicity (ataxia,
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dizziness, diplopia, nausea, vomiting, and drowsiness) (154c). Colchicine An interaction of clarithro mycin with colchicine resulted in an acute neuromyopathy in a 73-year-old man with chronic renal insufficiency (155A). Clari thromycin inhibits the metabolism of colchi cine via CYP3A4 and inhibition of P glycoprotein can alter its cellular transport. Pranlukast In an open, two-way crossover, randomized study in 16 healthy men, clari thromycin minimally affected the pharmaco kinetics of pranlukast (156A). Repaglinide An interaction of clarithro mycin 500 mg bd with repaglinide has been described in an 80-year-old man with endstage renal disease and well-controlled type 2 diabetes (157A). He had taken repaglinide 0.5 mg tds for 2 years, but within 48 hours of starting to take clarithromycin he developed severe hypoglycemia, which resolved with intravenous glucose. However, 48 hours later, he again had hypoglycemia and was unresponsive. Intravenous glucose was again effective. Repaglinide was withdrawn, and he had no further episodes of hypoglycemia. Sirolimus Concomitant administration of clarithromycin and sirolimus in a woman with a kidney transplant caused a large increase in sirolimus trough concentrations from 6.2 to 54 µg/l (158A). This increase was associated with acute impairment of renal function, which was almost completely resolved on withdrawal of both drugs. This interaction was probably due to inhibition of CYP3A4 and P glycoprotein.
Erythromycin (SED-15, 1237; SEDA-29, 265; SEDA-30, 302; SEDA-31, 438) Psychiatric A 64-year-old man developed hallucinations and tremors 24 hours after he started to take oral erythromycin 1 g bd and methylprednisolone 16 mg bd (159A).
Natascia Corti, Alexander Imhof, and Christa Wenger
Sensory systems Ears Loss of auditory acuity and tinnitus can occur during treat ment with erythromycin, even oral treat ment at standard doses (160r). Gastrointestinal In a review of studies of the use of erythromycin for gastrointestinal dysmotility in preterm infants, none of the randomized controlled trials reported any adverse effects, in particular hypertrophic pyloric stenosis (161c, 162C). However, hypertrophic pyloric stenosis has been described in monovular extremely preterm twins after the use of erythromycin (163A). Liver In a Spanish study, erythromycininduced hepatotoxicity has been estimated to occur in 3.6 per 100 000 users (144R). Mouth Black hairy tongue has been asso ciated with long-term oral erythromycin (164A). Immunologic An immediate IgE-depen dent hypersensitivity reaction has been reported in patients taking erythromycin; the mechanism is unknown and skin tests are negative in most cases (165r).
(SED-15, 2645; SEDA-29, 266; SEDA-30, 304; SEDA-31, 439)
OXAZOLIDINONES
Although only minor adverse effects were seen in phase III trials of linezolid, more serious effects were reported after its com mercial release, including cases of lactic acidosis, peripheral and optic neuropathy, and serotonin syndrome (166r). Peripheral and optic neuropathies usually occurred after several months of therapy (median 5 months), lactic acidosis after several weeks (median 6 weeks) and serotonin syndrome after several days (median 4 days). Death occurred in two of seven reported cases of lactic acidosis, and three of fifteen reported cases of serotonin syndrome. Improvement or complete recovery occurred in all cases
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of optic neuropathy, but no patient with peripheral neuropathy recovered. Linezolid should be withdrawn immediately in patients who have these adverse effects. Hematological toxicity due to inhibition of mitochondrial protein synthesis has also been reported (167c). Observational studies There were serious adverse events in 18 of 24 patients with mycobacterial infection treated with combi nations that included linezolid (168c). There was an optic and/or peripheral neuropathy in 11 cases and anemia in 10 cases. Nervous system Posterior reversible leuko encephalopathy has been described a 71-year-old woman after 5 days of intra venous linezolid therapy; she improved rapidly after withdrawal of linezolid (169A). Prolonged use of linezolid can cause a painful neuropathy (170A). • A 53-year-old woman developed a pure smallfiber painful neuropathy after taking linezolid for 6 months. Eight months after withdrawal of linezolid her skin became fully re-innervated, the neuropathic pain resolved and the warm threshold normalized.
This raises the possibility that small-dia meter sensory nerves in the skin, which are responsible for transmitting nociceptive information, might be affected by linezolid. Sensory systems Long-term use of linezo lid can be associated with severe peripheral and optic neuropathy (swollen or pale optic disc), symmetrical painless impairment of visual acuity and color vision, and bilateral visual field defects (171r). Of 51 consecutive adults taking linezolid, 1 developed a reversible optic and an irre versible peripheral neuropathy after 24 months (172c). Metabolism Lactic acidosis has been asso ciated with linezolid in an 80-year-old woman (173A) and in another patient after renal transplantation (174A). Hematologic Hematological disturbances are a major concern when linezolid is
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administered for prolonged periods of time. Thrombocytopenia and anemia occurred in 5 of 51 adults taking linezolid, necessitating withdrawal in 3 of them (172c). In contrast, in a retrospective chart review of the use of linezolid in 45 patients with marked baseline thrombocytopenia, although platelet counts fell in 35 patients during linezolid therapy, there was only one episode of non-life-threa tening bleeding, which could have been attri butable to coagulopathy from heparin therapy (175c). The effects of pyridoxine, rifampicin, and renal function on hematological adverse events induced by linezolid have been stu died in 52 patients (176c). Thrombocyto penia was defined as a reduction to less than 75% of the baseline platelet count and anaemia when the hemoglobin count fell by at least 0.2 g/dl from the baseline value. Linezolid alone was used in 24 patients and linezolid plus pyridoxine 200 mg/day in 28; pyridoxine did not prevent linezolid-related hematological adverse events (the cumu lative probabilities of thrombocytopenia and anemia). Hematological adverse events were less frequent in patients taking rifampi cin and were more frequent in patients with renal failure. Rifampicin was the only inde pendent predictor associated with a lower risk of thrombocytopenia (HR = 0.37; 95% CI = 0.14, 0.98). Sideroblastic anemia following prolonged linezolid therapy has been described in a patient with laryngeal cancer (177A). Pancytopenia has been reported in two organ-transplant patients after treatment with linezolid 600 mg bd for 3 and 5 weeks (178A). Urinary tract Linezolid-related acute renal insufficiency has been reported in a patient with a kidney transplant. • A 60-year-old man took linezolid for 8 days and developed acute renal failure (serum creatinine 221 µmol/l), associated with mild eosinophilia, anemia, and thrombocytopenia (179A). A biopsy of the transplanted kidney 7 days later showed interstitial nephritis and focal tubular atrophy. After withdrawal of linezolid and treatment with prednisolone 20 mg/day, the serum creatinine fell and was 166 and 159 µmol/l after 2 and 4 weeks respectively.
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Skin Black hairy tongue has been asso ciated with long-term oral linezolid (180A). Drug–drug interactions Pethidine Serotonin syndrome has been described in a 27-year-old man with acute leukemia who took linezolid and pethidine (181A). Selective serotonin re-uptake inhibitors Linezolid interacts with selective serotonin re-uptake inhibitors and other sympatho mimetic drugs, resulting in serotonin syndrome (182r). Drugs that have been impli cated include citalopram and escitalopram (183A), fluoxetine (184A), and venlafaxine (185A).
(SED-15, 2542; SEDA-29, 266; SEDA-30, 303; SEDA-31, 439)
NITROFURANTOIN
Nervous system A 16-year-old girl devel oped weakness and paresthesia after taking nitrofurantoin for several months for recur rent urinary tract infections; within 3 months of drug withdrawal the paresthesia improved and she partially recovered motor function (186A). Respiratory
Natascia Corti, Alexander Imhof, and Christa Wenger
Pulmonary fibrosis has been associated with prolonged use of nitrofurantoin for recurrent urinary tract infection in two patients, both of whom died because of respiratory failure (187A, 188A). In two patients nitrofurantoin-induced lung disease was reversible after withdrawal of the drug despite prolonged use (189A, 190A). Acute pneumonitis was presumed to have been caused by nitrofurantoin after 48 hours in a pregnant woman with a urinary tract infection; acute dyspnea, hemoptysis, and chest pain resolved completely 24 hours after withdrawal of the drug and treatment with glucocorticoids (191A). Nitrofurantoin-induced eosinophilic pneu monitis has been described in a 46-year-old patient with multiple sclerosis who devel oped fatigue a dry cough, and patchy pul monary infiltrates on a CT scan; her symptoms resolved after withdrawal of nitro furantoin (192A). Combined pulmonary symptoms with radiographic changes compatible with pneumonitis and concomitantly raised liver enzymes have been reported in two women who took nitrofurantoin for prevention of recurrent urinary tract infections; in both cases the symptoms resolved after with drawal of the drug (193A, 194A).
POLYMYXINS
(SED-15, 2891;
SEDA-31, 441) EIDOS classification: Extrinsic species: Nitrofurantoin Intrinsic species: Cells involved in
allergic reactions (lymphocytes,
eosinophils), fibroblasts,
pneumocytes
Distribution: Lungs Outcome: Fibrosis or inflammation Sequela: Nitrofurantoin-induced lung disease DoTS classification: Dose-relation: Hypersusceptibility reaction
Time-course: Late
Susceptibility factors: Female sex
Colistin Respiratory A 29-year-old woman with cys tic fibrosis developed fatal acute respiratory distress syndrome (ARDS) after treatment for chronic airway infection with P. aerugi nosa with inhaled colistimethate sodium, a pro-drug of colistin (195A). A 5-week-old pharmacy-compounded pre-mixed solution had been administered and excessive conver sion to biologically active colistin was postu lated to have caused airway or alveolar injury. The authors recommended reconsti tution of colistimethate sodium solution just before use, in order to avoid toxicity.
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Urinary tract Of 15 patients treated with colistin 3 millionIU 8-hourly for multidrug-resistant Acinetobacter bau manii ventilator-associated pneumonia, 5 developed nephrotoxicity compared with 2 of 13 patients treated with ampicillin þ sulbactam 9 g every 8 hours (196c). In a prospective open study in 78 patients treated with intravenous colistin 5 mg/kg/day divided into two doses com pared with 25 patients treated with other antibiotics for infections with A. baumanii or P. aeruginosa, there was reversible nephrotoxicity in 24 of the colistin-treated patients (197c). In a retrospective chart review of 14 chil dren treated with intravenous colistin mean dose 4.74 mg/kg/day in three or four divided doses over 3–42 days, two developed signif icant rises in serum creatinine. Neither required renal replacement therapy or developed neurological complications (198c). In another retrospective study in 120 patients with ventilator-associated pneumo nia who were given either intravenous colis tin 6 millionIU divided into three doses or imipenem 2 g/day, none developed renal insufficiency (199c). Musculoskeletal Severe rhabdomyolysis associated with intravenous colistin has been reported (200A).
SULFONAMIDES, TRIMETHOPRIM, AND CO-TRIMOXAZOLE (SED-15, 3216, 3510; SEDA-29, 270; SEDA-30, 308; SEDA-31, 442) Hematologic In two reviews of epidemio logical studies of drug-induced agranulocy tosis, co-trimoxazole and sulfasalazine were associated with a high risk of agranulocyto sis (OR > 5) (201R, 202R). In a combined analysis of three case–control studies the
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highest risk ratios were observed for sulfa salazine (OR = 207; 95% CI = 61, 708), antithyroid drugs, procainamide, and dipyrone.
Sulfadiazine Urinary tract An HIV-positive patient with toxoplasmic encephalitis developed acute renal failure after treatment with sulfa diazine; renal ultrasound showed echogenic areas presumed to be sulfonamide crystals (203A). Crystalluria occurs in 45% of patients taking sulfonamides and acute renal insuffi ciency in 0.4–29% (204R). Hydration and urinary alkalinization can prevent and resolve crystal formation.
Trimethoprim and co-trimoxazole Sensory systems Sulfa-based drugs like co-trimoxazole can cause acute angleclosure glaucoma by ciliary body edema with anterior rotation of the iris–lens diaphragm (205R). A 41-year-old woman who had taken tri methoprim for 2 days developed bilateral acute anterior uveitis with bilateral painful red eyes, chills, itching, arthralgia, and myalgia; subsequent rechallenge was posi tive (206A). Hematologic Thrombocytopenia with a platelet count of 4 109/l occurred in a 29-year-old man who had taken co-trimox azole for 7 days for a urinary tract infection. Platelet transfusion had little effect and a strong sulfamethoxazole-dependent, plateletreactive antibody was detected that and was still present after 5 years (207A). A Jehovah’s witness developed throm botic thrombocytopenic purpura within 48 hours of co-trimoxazole therapy (208A). Hemolysis triggered by co-trimoxazole occurred in two HIV-positive patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency (209c).
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A 44-year-old woman developed granulo cytic maturation arrest and a histiocytoid Sweet’s-like reaction after a course of co trimoxazole for sinusitis. She had a fever, agranulocytosis, and a hemorrhagic nodule on the left flank. The fever and agranulo cytosis resolved 2 days after withdrawal, and the nodule regressed 1 week later (210A). Liver A 30-year-old man with a urinary tract infection developed acute cholestatic hepatitis with fever and rash after taking co-trimoxazole for 15-day treatment; he improved after supportive therapy and pre dnisolone and recovered fully within a few months (211A). Skin In a retrospective analysis of 200 Indian patients with cutaneous eruptions, co-trimoxazole was the most common cau sative drug (n = 26), followed by ibuprofen (n = 20) (212c). Psoriasis in a 50-year-old man worsened dramatically after he had taken co-trimo xazole for 3 days after an insect bite (213A). There was erythroderma, fever, generalized malaise and severe edema of the legs. The symptoms resolved after withdrawal and administration of methylprednisolone. A 40-year-old woman developed Sweet’s syndrome with a neutrophilia after taking co-trimoxazole for 6 days for vaginitis (214A). Immunologic After receiving intravenous co-trimoxazole for 10 days for Pneumocystis jiroveci pneumonia after kidney transplan tation, a 48-year-old woman developed purpura associated with IgG/IgA-mixed cryoglobulinemia (type II); a skin biopsy confirmed hypersensitivity vasculitis (215A). Cross-sensitivity to celecoxib, a sulfacontaining drug, could not be demonstrated in five patients with confirmed sulfamethoxa zole allergy (216c). A 61-year-old patient with scleroderma developed a drug-induced hypersensitivity syndrome with a concomitant increase in mumps virus and parainfluenza virus type 2 antibody titers after taking co-trimoxazole for 3 weeks (217A).
Natascia Corti, Alexander Imhof, and Christa Wenger
Drug–drug interactions Coumarin anti coagulants In a retrospective cohort study in 52 102 users of acenocoumarol and 7885 users of phenprocoumon, co trimoxazole and other antibiotics were associated with an increased relative risk of bleeding of 3–5 (218C). Preventive reduc tion of the doses of coumarin anticoagulants has been evaluated; it produced a risk reduction but a prolonged duration of undercoagulation and the authors recom mended avoiding this combination (219c). Pioglitazone Trimethoprim increased the AUC of pioglitazone by 42% in a random ized crossover study in healthy volunteers (220c). Management of adverse reactions In three small clinical trials desensitization resulted in fewer treatment withdrawals and overall adverse reactions than co-trimoxazole rechallenge for prophylaxis of opportunistic infections in HIV-infected patients with a previous history of mild or moderate hyper sensitivity to co-trimoxazole (221c). In a 85-year-old woman with a nonallergic fixed drug eruption to co-trimoxazole, desensitization was successful after 10 days (222A).
OTHER ANTIMICROBIAL DRUGS Daptomycin
(SED-15, 1053; SEDA-29, 271; SEDA-30, 309; SEDA-31, 446)
Respiratory Because of known cephalo sporin sensitivity, a 60-year-old man was given intravenous daptomycin for S. aureus endocarditis and 2 weeks later developed a fever, rigors, profound sweating and raised C-reactive protein (CRP) concentrations. A CT scan of the lung showed diffuse patchy areas (223A). A transbronchial lung biopsy showed alveolar and interstitial eosinophils. Daptomycin was stopped for 8 days, but within 4 hours of reintroduction he spiked a fever, sweated profusely, and required
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intubation for respiratory failure. Daptomy cin was withdrawn and he was given intra venous methylprednisolone. There was significant improvement within 24 hours. Liver A 35-year-old man developed raised transaminases 5 weeks after starting treat ment with daptomycin for osteomyelitis; fol lowing withdrawal renal and hepatic function improved (224A). Musculoskeletal After three doses of daptomycin 5 mg/kg/day, a 68-year-old woman with recurrent postoperative cholangitis and fever developed profound muscle weakness and rhabdomyolysis with creatine kinase activity of 25 234 U/l and raised liver enzymes; daptomycin was with drawn and the enzymes normalized 10 days later (225A). In a retrospective record review of 29 patients receiving parenteral antibiotics as outpatients, two developed reversible myo toxicity (creatine kinase activity 2369 and
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5500 U/l) while receiving daptomycin 6 mg/ kg/day and one developed transient cuta neous and renal toxicity with concomitant clindamycin (226c). Interference with laboratory tests An interaction of daptomycin with recombinant thromboplastin reagents leads to false pro longation of the prothrombin time and INR (227E).
Fusidic acid (SED-15, 1460; SEDA-29, 259) Drug–drug interactions Statins Rhabdo myolysis occurred in two patients who took fusidic acid with atorvastatin or simvastatin (228A, 229A). The authors postulated inhibition of CYP3A4 by fusidic acid, with increased exposure to atorvastatin and simvastatin.
References 1. Selimoglu E Aminoglycoside-induced oto toxicity. Curr Pharm Des 2007;13(1):119–26. 2. Ariano E, Zelenitsky SA, Kassum DA. Aminoglycoside-induced vestibular injury: maintaining a sense of balance. Ann Phar macother 2008;42(9):1282–9. 3. Duggal P, Sarkar M. Audiologic monitoring of multi-drug resistant tuberculosis patients on aminoglycoside treatment with long term follow-up. BMC Ear Nose Throat Disord 2007;7:5. 4. Smyth A, Lewis S, Bertenshaw C, Choo nara I, McGaw J, Watson A. Case-control study of acute renal failure in patients with cystic fibrosis in the UK. Thorax 2008;63 (6):532–5. 5. Zagólski O. Vestibular system in infants after systemic therapy with amikacin. J Oto laryngol Head Neck Surg 2008;37(4):534–9. 6. Kiel PJ, Lo M, Stockwell D, Patel GP. An evaluation of amikacin nephrotoxicity in
the hematology/oncology population. Am J Ther 2008;15(2):131–6. 7. Dille B. Toxicity of intraocular gentamicin. Arch Ophthalmol2007;125(10):1442; author reply 1442–3. 8. Cardascia N, Boscia F, Furino C, Sborgia L. Gentamicin-induced macular infarction in transconjunctival sutureless 25-gauge vitrect omy. Int Ophthalmol 2008;28(5):383–5. 9. Riga M, Korres S, Varvutsi M, Kosmidis H, Douniadakis D, Psarommatis I, Yiotakis I, Ferekidis E. Long-term effects of chemo therapy for acute lymphoblastic leukemia on the medial olivocochlear bundle: effects of different cumulative doses of gentamicin. Int J Pediatr Otorhinolaryngol 2007;71(11): 1767–73. 10. Aw ST, Todd MJ, Aw GE, Weber KP, Hal magyi GM. Gentamicin vestibulotoxicity impairs human electrically evoked vestibulo ocular reflex. Neurology 2008;71(22):1776–82.
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pauta estandar de claritromicina. [Halluci nations by administration of a standard regimen of clarithromycin.] Farm Hosp 2007;31(5):321–3. 151. Kafetzis DA, Chantzi F, Tigani G, Skevaki CL. Safety and tolerability of clarithro mycin administered to children at higher than-recommended doses. Eur J Clin Microbiol Infect Dis 2007;26(2):99–103. 152. Clayton TH, Barry J, Fitzgerald D, Wat son R, Irvine AD. Clarithromycin suspen sion-associated toxic epidermal necrolysis in a 2-year-old girl. Clin Exp Dermatol 2007;32(6):755–6. 153. Chłystowska M, Pietruszka-Chmarra A, Szafran´ ski T, Michalak J. Zespol Ste vensa–Johnsona w swietle danych z pis miennictwa i badan wlasnych. [Stevens– Johnson syndrome in the literature and authors’ own studies.] Med Wieku Rozwoj 2008;12(3):799–803. 154. Gélisse P, Hillaire-Buys D, Halaili E, JeanPastor MJ, Vespignan H, Coubes P, Crespel A. Carbamazépine et clarithromycine: une interaction médicamenteuse cliniquement significative [Carbamazepine and clarithro mycin: a clinically relevant drug interac tion.] Rev Neurol (Paris) 2007;163(11): 1096–9. 155. van der Velden W, Huussen J, Ter Laak H, de Sévaux R. Colchicine-induced neuro myopathy in a patient with chronic renal failure: the role of clarithromycin. Neth J Med 2008;66(5):204–6. 156. Nakade S, Yamauchi A, Komaba J, Ohno T, Kitagawa J, Honda N, Hasegawa C, Yoneda K, Kodama Y, Yasuda K, Azuma J, Miyata Y. Effect of clarithromycin on the pharmacokinetics of pranlukast in healthy volunteers. Drug Metab Pharmacokinet 2008;23(6):428–33. 157. Khamaisi M, Leitersdorf E. Severe hypo glycemia from clarithromycin-repaglinide drug interaction. Pharmacotherapy 2008;28 (5):682–4. 158. Capone D, Palmiero G, Gentile A, Basile V, Federico S, Sabbatini M, Potenza M, Perfetti A, Pieri M, Tarantino G. A phar macokinetic interaction between clarithro mycin and sirolimus in kidney transplant recipient. Curr Drug Metab 2007;8 (4):379–81.
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159. Gallerani M, Boari B. Hallucinations and tremors due to oral therapeutic doses of erythromycin and methylprednisolone. Intern Emerg Med 2008;3(3):283–5. 160. Anonymous Reversible erythromycin oto toxicity. Prescrire Int 2007;16(87):20. 161. Ng PC. Use of oral erythromycin for the treatment of gastrointestinal dysmotility in preterm infants. Neonatology 2009;95 (2):97–104. 162. Aly H, Abdel-Hady H, Khashaba M, ElBadry N. Erythromycin and feeding intol erance in premature infants: a randomized trial. J Perinatol 2007;27(1):39–43. 163. Shoji H, Suganuma H, Daigo M, Shinohara K, Umezaki H, Shiga S, Shimizu T, Yama shiro Y. Hypertrophic pyloric stenosis in mono-ovular extremely preterm twins after use of erythromycin. Pediatr Int 2008;50 (5):701–2. 164. Pigatto PD, Spadari F, Meroni L, Guzzi G. Black hairy tongue associated with longterm oral erythromycin use. J Eur Acad Dermatol Venereol 2008;22(10):1269–70. 165. Araújo L, Demoly P. Macrolides allergy. Curr Pharm Des 2008;14(27):2840–62. 166. Narita M, Tsuji BT, Yu VL. Linezolid-asso ciated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy 2007;27(8):1189–97. 167. Beekmann SE, Gilbert DN, Polgreen PM. Toxicity of extended courses of linezolid: results of an Infectious Diseases Society of America Emerging Infections Network sur vey. Diagn Microbiol Infect Dis 2008;62 (4):407–10. 168. Ntziora F, Falagas ME. Linezolid for the treatment of patients with mycobacterial infections a systematic review. Int J Tuberc Lung Dis 2007;11(6):606–11. 169. Nagel S, Ko¨ hrmann M, Huttner HB, Storch-Hagenlocher B, Schwab S. Linezo lid-induced posterior reversible leuko encephalopathy syndrome. Arch Neurol 2007;64(5):746–8. 170. Chao CC, Sun HY, Chang YC, Hsieh ST. Painful neuropathy with skin denervation after prolonged use of linezolid. J Neurol Neurosurg Psychiatry 2008;79(1):97–9. 171. Li J, Tripathi RC, Tripathi BJ. Druginduced ocular disorders. Drug Saf 2008;31 (2):127–41.
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172. Rao N, Hamilton CW. Efficacy and safety of linezolid for Gram-positive orthopedic infections: a prospective case series. Diagn Microbiol Infect Dis 2007;59(2):173–9. 173. Wiener M, Guo Y, Patel G, Fries BC. Lac tic acidosis after treatment with linezolid. Infection 2007;35(4):278–81. 174. Lee YR, Powell N, Bonatti H, Sawyer RG, Barroso L, Pruett TL, Sifri CD, Volles D. Early development of lactic acidosis with short term linezolid treatment in a renal recipient. J Chemother 2008;20(6):766–7. 175. Grim SA, Rene L, Gupta S, Clark NM. Safety of linezolid in patients with baseline thrombocytopenia. J Antimicrob Chemo ther 2008;62(4):850–1. 176. Soriano A, Ortega M, Garcia S, Penarroja G, Bove A, Marcos M, Martinez JC, Marti nez JA, Mensa J. Comparative study of the effects of pyridoxine, rifampin, and renal function on hematological adverse events induced by linezolid. Antimicrob Agents Chemother 2007;51:2559–63. 177. Kakimoto T, Nakazato T, Miura R, Kurai H, Yamashita D, Sagara Y, Ishida A. [Sideroblastic anemia after prolonged line zolid therapy.] Rinsho Ketsueki 2008;49 (11):1566–8. 178. Faguer S, Kamar N, Fillola G, Guitard J, Rostaing L. Linezolid-related pancytopenia in organ-transplant patients: report of two cases. Infection 2007;35(4):275–7. 179. Esposito L, Kamar N, Guilbeau-Frugier C, Mehrenberger M, Modesto A, Rostaing L. Linezolid-induced interstitial nephritis in a kidney-transplant patient. Clin Nephrol 2007;68(5):327–9. 180. Refaat M, Hyle E, Malhotra R, Seidman D, Dey B. Linezolid-induced lingua villosa nigra. Am J Med 2008;121(6):e1. 181. Das PK, Warkentin DI, Hewko R, Forrest DL. Serotonin syndrome after concomitant treatment with linezolid and meperidine. Clin Infect Dis 2008;46(2):264–5. 182. Hernandez-Lorente E, Broto PL, Brumós LG, Simeón Aznar CP. Sindrome serotoni nergico desencadenado por linezolid. [Ser otonin syndrome associated with linezolid.] Med Clin (Barc) 2009;132(4):157–8. 183. Lorenz RA, Vandenberg AM, Canepa EA. Serotonergic antidepressants and linezolid: a retrospective chart review and presentation
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of cases. Int J Psychiatry Med 2008;38(1): 81–90. Steinberg M, Morin AK. Mild serotonin syndrome associated with concurrent linezolid and fluoxetine. Am J Health Syst Pharm 2007;64(1):59–62. Packer S, Berman SA. Serotonin syndrome precipitated by the monoamine oxidase inhibitor linezolid. Am J Psychiatry 2007;164(2):346–7. Sharafadinzadeh N, Moghtaderi A, AlaviNaini R. Nitrofurantoin-induced peripheral neuropathy: a lesson to be re-learnt. Neurol India 2008;56(1):94–6. Fux R, Morike K, Gleiter CH. Unerwunschte Arzneimittelwirkungen von Antibiotika – eine differenzialdiagnostische Herausforder ung. [Unwanted side effects of antibacterials – a diagnostic challenge.] Dtsch Med Wochenschr 2008;133(Suppl 0):F4. Goemaere NN, Grijm K, van Hal PT, den Bakker MA. Nitrofurantoin-induced pul monary fibrosis: a case report. J Med Case Reports 2008;2:169. Lin DC, Bhally H. Nitrofurantoin-induced interstitial lung disease. N Z Med J 2007;120 (1263):U2753. Bhullar S, Lele SM, Kraman S. Severe nitrofurantoin lung disease resolving with out the use of steroids. J Postgrad Med 2007;53(2):111–3. Mohamed A, Dresser GK, Mehta S. Acute respiratory failure during pregnancy: a case of nitrofurantoin-induced pneumonitis. CMAJ 2007;176(3):319–20. Schelhorn J, Ho¨ fer L, Syrbe G, Polzer U. Eosinophile Pneumonie als unerwunschte Arzneimittelwirkung. [Drug-induced eosi nophilic pneumonia.] Nervenarzt 2008;79(6):696–8. Koulaouzidis A, Bhat S, Moschos J, Tan C, De Ramon. Nitrofurantoin-induced lungand hepatotoxicity. Ann Hepatol 2007;6(2):119–21. Peall AF, Hodges A. Concomitant pulmon ary and hepatic toxicity secondary to nitro furantoin: a case report. J Med Case Reports 2007;1:59. McCoy KS. Compounded colistimethate as possible cause of fatal acute respiratory dis tress syndrome. N Engl J Med 2007;357 (22):2310–1.
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196. Betrosian AP, Frantzeskaki F, Xanthaki A, Douzinas EE. Efficacy and safety of highdose ampicillin/sulbactam vs. colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ven tilator-associated pneumonia. J Infect 2008;56(6):432–6. 197. Koomanachai P, Tiengrim S, Kiratisin P, Thamlikitkul V. Efficacy and safety of colis tin (colistimethate sodium) for therapy of infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii in Siriraj Hospital, Bangkok, Thailand. Int J Infect Dis 2007;11(5):402–6. 198. Goverman J, Weber JM, Keaney TJ, Sheridan RL. Intravenous colistin for the treatment of multi-drug resistant, Gramnegative infection in the pediatric burn population. J Burn Care Res 2007;28 (3):421–6. 199. Kallel H, Hergafi L, Bahloul M, Hakim A, Dammak H, Chelly H, Hamida CB, Chaari A, Rekik N, Bouaziz M. Safety and efficacy of colistin compared with imipenem in the treatment of ventilator-associated pneumo nia: a matched case-control study. Intensive Care Med 2007;33(7):1162–7. 200. Evagelopoulou P, Katsaros A, Myrianthefs P, Karatzas S, Boutzouka E, Fildissis G, Bal topoulos G. Colistin and rhabdomyolysis: a causative agent or an innocent bystander? Intensive Care Med 2007;33(3):556–7. 201. Andres E, Maloisel F. Idiosyncratic druginduced agranulocytosis or acute neutro penia. Curr Opin Hematol 2008;15 (1):015–21. 202. Garbe E. Non-chemotherapy drug-induced agranulocytosis. Expert Opin Drug Saf 2007;6(3):323–35. 203. de la Prada Alvarez FJ, Prados Gallardo AM, Tugores Vazquez A, Uriol Rivera M, Morey Molina A. Insuficiencia renal aguda por depósito de cristales de sulfadiacina. [Acute renal failure due to sulfadiazine crystalluria.] An Med Interna 2007;24 (5):235–8. 204. Yarlagadda SG, Perazella MA. Druginduced crystal nephropathy: an update. Expert Opin Drug Saf 2008;7(2):147–58. 205. Lachkar Y, Bouassida W. Drug-induced acute angle closure glaucoma. Curr Opin Ophthalmol 2007;18(2):129–33.
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206. Pathak S, Power B. Bilateral acute anterior uveitis as a side effect of trimethoprim. Eye (Lond) 2007;21(2):252–3. 207. Aster H, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med 2007;357(6):580–7. 208. Martin MG, Whitlatch NL, Shah B, Are pally GM. Thrombotic thrombocytopenic purpura induced by trimethoprim–sulfa methoxazole in a Jehovah’s witness. Am J Hematol 2007;82(7):679–81. 209. Tungsiripat M, Drechsler H, Sarlone C, Amyot K, Laffey E, Aberg J. Prevalence and significance of G6PD deficiency in patients of an urban HIV clinic. J Int Assoc Physicians AIDS Care (Chic Ill) 2008;7(2):88–90. 210. Wu J, Rodgers T, Fullen DR. Drug-asso ciated histiocytoid Sweet’s syndrome: a true neutrophilic maturation arrest variant. J Cutan Pathol 2008;35(2):220–4. 211. Kouklakis G, Mpoumponaris A, Zezos P, Moschos J, Koulaouzidis A, Nakos A, Peh livanidis A, Iosiphidis M, Molyvas E, Niko laidis N. Cholestatic hepatitis with severe systemic reactions induced by trimetho prim–sulfamethoxazole. Ann Hepatol 2007;6(1):63–5. 212. Raksha MP, Marfatia YS. Clinical study of cutaneous drug eruptions in 200 patients. Indian J Dermatol Venereol Leprol 2008;74(1):80. 213. Esposito M, Saraceno R, Schipani C, Di Marcantonio D, Bianchi L, Chimenti S. Trimethoprim–sulfamethoxazole induced erythrodermic psoriasis. J Infect 2008;57 (1):90–2. 214. Kluger N, Marque M, Stoebner PE, Dandurand M, Meunier L. Possible drug-induced Sweet’s syndrome due to trimethoprim–sulfamethoxazole. Acta Derm Venereol 2008;88(6):637–8. 215. Leclercq P, Frippiat F, Lambermont B. Cotrimoxazole induced mixed type II cryo globulinemia. Eur J Intern Med 2008;19 (4):303–4. 216. Figueroa J, Ortega N, Almeida L, Blanco C, Castillo R. Sulfonamide allergy without cross-reactivity to celecoxib. Allergy 2007;62(1):93. 217. Naniwa T, Naniwa T, Maeda S, Sawada H, Watanabe Y, Osawa T, Hayami Y, Banno
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218.
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222.
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S, Morita A, Ueda R. Drug-induced hyper sensitivity syndrome associated with a marked increase in anti-paramyxovirus antibody titers in a scleroderma patient. Allergol Int 2007;56(3):303–8. Penning-van Beest FJ, Koerselman J, Her ings M. Risk of major bleeding during con comitant use of antibiotic drugs and coumarin anticoagulants. J Thromb Hae most 2008;6(2):284–90. Schalekamp T, van Geest-Daalderop JH, Kramer MH, van Holten-Verzantvoort AT, de Boer A. Coumarin anticoagulants and co-trimoxazole: avoid the combination rather than manage the interaction. Eur J Clin Pharmacol 2007;63(4):335–43. Tornio A, Niemi M, Neuvonen PJ, Backman JT. Trimethoprim and the CYP2C8*3 allele have opposite effects on the pharma cokinetics of pioglitazone. Drug Metab Dis pos 2008;36(1):73–80. Lin D, Li WK, Rieder MJ. Cotrimoxazole for prophylaxis or treatment of opportunis tic infections of HIV/AIDS in patients with previous history of hypersensitivity to co trimoxazole. Cochrane Database Syst Rev 2007;(2):CD005646. Patriarca G, Schiavino D, Buonomo A, Aruanno A, Altomonte G, Nucera E. Desensitization to co-trimoxazole in a patient with fixed drug eruption. J Investig Allergol Clin Immunol 2008;18(4):309–11.
489 223. Hayes Jr. D, Anstead MI, Kuhn RJ. Eosinophilic pneumonia induced by dapto mycin. J Infect 2007;54(4):e211–3. 224. Abraham G, Finkelberg D, Spooner LM. Daptomycin-induced acute renal and hepa tic toxicity without rhabdomyolysis. Ann Pharmacother 2008;42(5):719–21. 225. Patel SJ, Samo TC, Suki WN. Early-onset rhabdomyolysis related to daptomycin use. Int J Antimicrob Agents 2007;30 (5):472–4. 226. Seaton RA, Macconnachie AA. Experience with daptomycin in an infectious diseases service over 1 year: utility in an outpatient parenteral antibiotic programme. Int J Antimicrob Agents 2008;31(5):492–7. 227. Webster PS, Oleson Jr. FB, Paterson DL, Arkin CF, Mangili A, Craven DE, Adcock DM, Lindfield KC, Knapp AG, Martone WJ. Interaction of daptomycin with two recombinant thromboplastin reagents leads to falsely prolonged patient prothrombin time/International Normalized Ratio results. Blood Coagul Fibrinolysis 2008;19 (1):32–8. 228. Burtenshaw AJ, Sellors G, Downing R. Presumed interaction of fusidic acid with simvastatin. Anaesthesia 2008;63(6):656–8. 229. O’Mahony C, Campbell VL, Al-Khayatt MS, Brull DJ. Rhabdomyolysis with ator vastatin and fusidic acid. Postgrad Med J 2008;84(992):325–7.
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27 (SEDA-29, 280; SEDA-30, 316; SEDA-31, 457)
ALLYLAMINES Terbinafine
(SED-15, 3316; SEDA-29, 280; SEDA-30, 316; SEDA-31, 457)
Liver Terbinafine can cause a wide range of types of liver damage, from mild hepato cellular or cholestatic effects to acute or subacute liver failure. Terbinafine-induced autoimmune hepatitis has been reported in a patient with chronic hepatitis B infection (1A). • A 57-year-old Taiwanese man with chronic hepatitis B virus (HBV) infection and normal liver enzymes took oral terbinafine 250 mg/day for toenail onychomycosis. After 12 weeks he developed malaise and anorexia followed by ascites and jaundice and abnormal liver function tests. He was taking no other medications or herbal supplements, did not drink alcohol, and did not have a flare of HBV infection. The diagnosis was supported by the presence of transient autoantibodies and a liver biopsy consistent with acute autoimmune drug injury. Terbinafine was withdrawn and after 3 weeks AsT (1282 IU/l), AlT (1044 IU/l), and bilirubin (100 µmol/l) peaked. He was treated with supportive care, including vitamin K, diuretics, and adefovir, to prevent hepatitis B exacerbation. The liver function tests began to normalize 6 weeks after terbinafine was withdrawn.
The pathogenesis of this drug-induced autoimmune hepatitis was speculative, but may have involved hapten–carrier com-
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32027-7 � 2010 Elsevier B.V. All rights reserved.
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plexes and CYP isoenzymes. Chronic HBV infection state may have predisposed to this autoimmune reaction. In one case terbinafine-induced liver dis ease resulted in liver transplantation (2A). • A 50-year-old African-American man with normal liver function took terbinafine for toenail onychomycosis and became progressively more jaundiced, with weight loss, anorexia, myalgia, and pruritus. After 3 months his AsT activity was 95 IU/l, AlT 149 IU/L, total bilirubin 496 µmol/l, and creatinine 124 µmol/l. Terbinafine was withdrawn. After 33 days his AsT was 228 IU/l, AlT 144 IU/l, alkaline phosphatase 497 IU/l, albumin 22 g/l, bilirubin 1173 µmol/l, blood urea nitrogen (BUN) 41 mmol/l, and creatinine 1251 µmol/l. Hepatitis A, B, and C were negative, as were antinuclear antibody, anti-smooth muscle antibody, antimitochondrial antibody, and human immunodeficiency virus (HIV). Paracetamol was not detected in plasma. The serum ceruloplasmin concentration was normal. Supportive care, including hemodialysis, was instituted, but his condition deteriorated with progressive subacute liver failure, and he underwent successful orthotopic liver transplantation. Histological examination of his explanted liver showed severe cholestasis, hepatocellular injury, and marked paucity of bile ducts.
Hematologic Of 12 patients with granulo cytopenia associated with terbinafine in Australia, mean age 64 (range 35–79) years, 10 were women (3c). The time to onset of was 4–5 weeks in most cases. Neutropenia was typically severe, with neutrophil counts below 300 106/l in eight patients. Terbinafine was with drawn in all cases. Five patients were hospitalized and one died of septic shock. Six received antibiotics and three were given granulocyte colony stimulating factor.
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Skin Cutaneous adverse effects reportedly occur in 1–3% of patients taking terbinafine. The overwhelming majority of these reactions consist of mild to moderate macular rashes. More serious skin disorders, such as erythema multiforme, toxic epidermal necrolysis, Stevens–Johnson syndrome, toxic erythema, cutaneous lupuslike syndrome, acrodermatitis continua of Hallopeau, and generalized pustular eruptions, continue to be reported but are rare (4A–7A). Of five patients with severe rashes during oral terbinafine therapy, four had been treated without mycological testing and two had cutaneous or fingernail candidiasis, for which terbinafine is not indicated (8c). Acute generalized exanthematous pustu losis (AGEP) can be caused by terbinafine. Characteristic features include suddenonset fever over 38°C, with a widespread erythematous eruption, rapidly progressing to a fine, non-follicular, micropustular rash. There is usually a leukocytosis, sometimes with eosinophilia. The illness usually resolves spontaneously within 15 days, sometimes followed by desquamation. Further cases of AGEP associated with oral terbinafine have been reported (9C, 10), including one with hepatic dysfunction (11A). Terbinafine can cause a systemic lupuslike syndrome (12c), and has also been asso ciated with the cutaneous variety. An ana lysis of in 27 cases cutaneous lupus was 6 times more common in women than in men. Skin lesions evolved on average after about 7 weeks of exposure. In 21 cases antinuclear antibody was detected, and there were Ro/SS-A antibodies in 23, La/SS-B anti bodies in 11 and anti-histone antibodies in only 8. In all cases terbinafine-induced lupus resolved after withdrawal. Systemic treatment with antimalarial drugs and/or glucocorticoids does not appear to be man datory (6A). Dermatomyositis, in which antibodies to the endothelium of the microvasculature of the skin, muscle, and lung are implicated, is characterized by photodistributed erythema, a heliotrope rash, Gottron’s
papules, muscle weakness, and interstitial pulmonary fibrosis. Endotheliotropic viruses and underlying neoplasia are among the inciting triggers, but drugs have also been implicated, including terbinafine (13Ar). • A 57-year-old man developed a photodistrib uted rash and muscle weakness after taking terbinafine. A skin biopsy confirmed the presence of endothelial cell injury with pro minent staining of C5b-9 along the dermal– epidermal junction and in the vasculature. Western blot studies showed strong seroreac tivity of the serum to an endothelial-based protein weighing 45 000kDa, a common target described in other forms of microvascular damage.
The mechanism of this reaction is unknown but may include enhanced endothelial cell apoptosis, with displacement of various cel lular antigens, resulting in a state of neo antigenicity and anti-endothelial cell antibody formation, or promotion of an interferon-rich T-helper-1-dominant cytokine milieu. Musculoskeletal Rhabdomyolysis has been reported in association with terbinafine 250 mg/day in an otherwise healthy 24-year-old man with a fungal skin infection (14A). During the second 14-day treatment cycle he developed general malaise, myalgia, and dark urine. Creatine kinase was 1120 U/l; renal function was normal. Withdrawal of terbinafine and hydration resulted in prompt resolution of all signs and symptoms within a few days.
Drug–drug interactions Carbamazepine Terbinafine is a potent competitive inhibitor of CYP2D6. An interaction of carbamazepine with terbinafine has been reported in a 50-year-old Caucasian man whose carbamazepine concentration rose after he started to take terbinafine 250 mg/ day for toenail onychomycosis, causing carbamazepine toxicity (gait ataxia, dizziness, and falls) (15A). Terbinafine and carbamazepine are both metabolized by
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Chapter 27
CYP3A4, CYP2C9, CYP1A2, CYP2C19 and CYP2C8, and terbinafine probably inhibited the metabolism of carbamazepine.
(SED-15, 192; SEDA-29, 280; SEDA-30, 317; SEDA-31, 458)
AMPHOTERICIN
Comparative studies Amphotericin and itraconazole have been compared in empiri cal antifungal drug treatment of febrile neu tropenia in an open, randomized study in 162 patients who received either intrave nous itraconazole followed by oral itra conazole suspension or intravenous amphotericin for a maximum of 28 days (16c). Itraconazole was associated with significantly fewer withdrawals because of any adverse event (22% versus 57%). The main reason was a rise in serum creati nine (1.2% versus 24%). Renal toxicity was significantly worse and there were more drug-related adverse events with amphotericin. Liver Amphotericin lipid formulations have been associated with abnormal liver function tests, but as such abnormalities are multifactorial in severely immunocompro mised patients, there is uncertainty about their clinical significance. Hepatic histo pathology at autopsy has been studied in 64 patients who had hematological malignancies and fungal infections and had received lipo somal amphotericin B (L-AmB) or ampho tericin B lipid complex (ABLC) for at least 7 days within 30 days before death (17c). Based on data from animal studies and in view of the lack of studies in humans, multifocal necrosis, fatty infiltration, macrophage vacuolation, and/or ‘foamy macrophage’ accumulation were all considered to be abnormalities asso ciated with the use of lipid formulations. There were no significant between-group differences in demographic factors, in the cumulative dose (6 and 7 g), the median
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daily dose (5 mg/kg) or the median duration of treatment (20 and 19 days). There were abnormal results (a greater than fivefold change from baseline) in 12 and 10 patients who received ABLC and L-AmB, respec tively, but these findings were thought to be associated with concomitant use of other hepatotoxic drugs. There were non specific abnormalities in 94% of patients. Thus, although abnormal liver function test results and histopathological changes in the liver were found in 94% of these debilitated patients with hematologic malignancies, there was no direct evidence of toxicity associated with lipid formula tions of amphotericin. Urinary tract Lipid-based formulations (amphotericin B colloidal dispersion [ABCD], ABLC and L-AmB) are less nephrotoxic than conventional amphotericin B deoxycholate (DAMB) (18R). In a pro spective cohort study of 418 consecutive adults who were treated with amphotericin in hematology and oncology wards in 20 hospitals in Europe, the patients initially received DAMB (62%), L-AmB (27%), or other lipid formulations of amphotericin (11%) (19C). Of the patients who were initi ally treated with DAMB, 36% had therapy switched to lipid formulations, primarily because of increased serum creatinine con centrations (46%) or other amphotericinattributed adverse events (41%). There was nephrotoxicity, defined as a 50% or more increase in serum creatinine concentration, in 57% of the patients who had normal kid ney function at baseline. Compared with patients without nephrotoxicity, patients with nephrotoxicity had a higher mortality rate (24%) and their mean length of stay in the hospital was prolonged by 8.6 days. Increases in serum creatinine concentration were associated with a significantly longer stay in the hospital. Severe nephro toxicity (a more than 200% increase in serum creatinine) was a significant predic tor of death, as were severe underlying medical conditions and documented fungal infections.
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Drug-dosage regimens Combinations of two different doses of amphotericin and flucytosine have been used in 64 HIVpositive patients with a first episode of cryptococcal meningitis (20C). They were randomized to either amphotericin 0.7 mg/ kg/day plus flucytosine 25 mg/kg qds or amphotericin 1 mg/kg/day plus flucytosine 25 mg/kg qds for 2 weeks, followed by oral fluconazole. The incidence of renal impairment was the same in the two groups. Anemia was associated with female sex. Renal impairment and anemia resolved when fluconazole was used.
Amphotericin B colloidal dispersion (ABCD) Drug-dosage regimens In an open, randomized trial in Bihar, India, a 6-day course of ABCD was investigated at three different total doses, 7.5, 10, and 15 mg/kg, each in 135 patients (21c). Although infusion-related fever and chills occurred in 56–68% of the patients in the three different dose groups, 401 of 405 patients completed the course. All 135 patients who were given 7.5 mg/kg completed treatment, and the final cure rate was 97%. Of those who received 15 mg/kg, severe backache, an unusual adverse effect, was observed in eight (5.9%). Serious adverse effects led to withdrawal of two patients (1.5%) each from those who received 10 and 15 mg/kg. The authors concluded that the high efficacy associated with short-term lowdose ABCD provided another alternative for the treatment of visceral leishmaniasis, especially in regions where the disease is refractory to antimonials.
Amphotericin B deoxycholate (DAMB) Cardiovascular Raynaud’s phenomenon after intravenous administration or inhalation of DAMB is rare and has been linked to spasm of peripheral vessels mediated by thromboxane A2 (22A).
Another case of acrocyanosis has been reported in a patient receiving DAMB; re-challenge with ABLC was well tolerated (23A). Liver A 53-year-old woman with an intraabdominal infection secondary to Candida albicans developed hyperbilirubinemia after receiving DAMB and ABLC (24A). While amphotericin can cause abnormal liver function tests, there have been only a few reports of hyperbilirubinemia, each with different patterns of abnormalities in other liver function tests. The unpredictable nature of this adverse effect warrants monitoring of liver function tests during amphotericin therapy. Drug overdose The adverse effects of DAMB have led to increased preference for lipid formulations with more favorable safety profiles. However, many hospital formularies list both lipid and non-lipid formulations. Fatal dispensing and administration errors can occur (SEDA-30, 319) and an error has again been reported (25A). • A 41-year-old woman with a history of proliferative glomerulonephritis developed cryptococcal meningitis and was scheduled to receive liposomal amphotericin 5 mg/kg/day; however, DAMB 5 mg/kg was inadvertently administered. The patient developed cardiac dysrhythmias, acute renal insufficiency, and anemia. The medication error was noticed after she had received two doses of DAMB, which was then withdrawn. Despite treatment in the intensive care unit (ICU), she died on day 6.
In overdose DAMB can cause significant cardiotoxicity in adults with pre-existing cardiac disease, with ventricular dysrhyth mias and bradycardia, and even when admi nistered at conventional dosages and infusion rates. Given the fulminant course of overdosage and lack of effective therapy, stringent safeguards against its improper administration should be in place, as has been emphasized by two further, non-fatal cases of DAMB overdose in infants due to administration errors (26A).
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Amphotericin B lipid complex (ABLC) Observational studies ABLC has shown promise in lung transplant recipients as a convenient means of delivering protective drug to the upper airways, avoiding systemic adverse effects (27c). Aerosolized ABLC in 40 subjects undergoing allogeneic hemopoietic stem cell transplantation has been prospectively investigated in an open, non-comparative study. ABLC was given once daily for 4 days, then once weekly for 13 weeks in addition to systemic fluconazole. Cough, nausea, taste disturbances, or vomiting occurred in 2.2% of 458 administrations of inhaled ABLC; 5.2% of administrations were associated with at least a 20% reduction in pulmonary function FEV1 or FVC), but none required treatment with bronchodilators or withdrawal from the study. Four mild adverse events were considered possibly or probably related to treatment; no deaths or withdrawals were attributed to treatment. Of three proven invasive fungal infections that occurred during the study, only one, a catheterrelated case of disseminated fusariosis, occurred while the subject was taking the study medication. Comparative studies The use of glucocorticoids is an important susceptibility factor for invasive fungal infections after allogeneic hemopoietic stem cell transplantation. In an open pilot study in which all patients received oral fluconazole or itraconazole 200–400 mg/day, those who were also taking prednisone in doses of at least 30 mg/day from day 30 onwards were switched to twice-weekly ABLC 4 mg/kg (28c). Those who were taking lower doses of prednisone continued to take fluconazole or itraconazole prophylaxis. Between 1999 and 2002, 100 patients were enrolled and followed for 1 year. Seven were given daily ABLC before day 30, and 30 did not need prophylactic ABLC; only one developed candidemia. ABLC prophylaxis was used for a median of 52 days (range: 1–289) in 63 patients, and there were seven
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breakthrough infections; there were no drug-related withdrawals.
Liposomal amphotericin (L-AmB) Observational studies Response rates and the adverse effects of treatment with L-AmB have been assessed in a Phase IV cohort study in 406 patients aged 1 day to 77 years, of whom 83% had malignancies and 66% had fever of unknown origin (29c). The mean duration of treatment was 20 days and the mean daily dose 2.3 mg/kg. There was either a complete or partial response in 314 patients (77%). There were drug-related adverse events in 94 patients (23%). Among these, hypokalemia (6.2%) and abnormal liver function tests (5.2%) were the most common; there was nephrotoxicity in 17 patients (4.2%). Weekly prophylactic high-dose L-AmB 7.5 mg/kg has been investigated in 21 adults receiving high-dose prednisone 2 mg/kg/day for acute graft-versus-host disease after allogeneic hemopoietic stem cell transplan tation (30c). Patients received a median of four (range: one to eight) infusions of L-AmB. Seven withdrew because of drugrelated adverse events, consisting of raised serum creatinine (> 1.5 times from baseline; n = 5), hypotension and pain (n = 1), and severe chest pain and dysrhythmias (n = 1). The overall frequency of infusion-related reactions was 29% (n = 6), but these reac tions were always transient and relieved by stopping the infusion. In an open, prospective pilot study in adults receiving chemotherapy for acute leukemia (n = 21) or allogeneic hemopoi etic stem cell transplantation (n = 8), the former received weekly infusions of L-AmB 10 mg/kg for 4 weeks and the latter 10 mg/kg for 8 weeks (31c). The most fre quent drug-related adverse events were infusion-related reactions, 12 of which (of a total of 76 infusions) led to increased infu sion duration for better tolerance. No adverse events led to withdrawal of prophy lactic treatment in the patients with acute leukemia. In those with hemopoietic stem cell transplants, eight adverse events (in six
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patients) were reported to be related to the study treatment and led to withdrawal.
hypokalemia below 3 mmol/l occurred in five patients in all.
Comparative studies In a double-blind, randomized, non-inferiority study, micafungin 100 mg/day (n = 264) was compared with L-AmB 3 mg/kg/day (n = 267) as first-line treatment of candidemia and invasive candidiasis (32C). Treatment was successful in 181/202 patients (90%) treated with micafungin and 170/190 patients (90%) treated with L-AmB. There were fewer treatmentrelated adverse events, including those that were serious or led to treatment withdrawal, with micafungin than with L-AmB. Aerosolized liposomal amphotericin and amphotericin B deoxycholate have been retrospectively compared in 38 consecutive lung transplant recipients (33c). In all, 1206 doses of DAMB and 1149 doses of L-AmB were administered; 18 patients received DAMB only, 11 received L-AmB only and 9 received the two medications sequentially. The total numbers of complaints were 1.0% of doses of DAMB and 1.2% of doses of L-AmB. There were no differences between the groups on lung biopsy specimens. Plasma amphotericin concentrations were 0.2–0.9 mg/l with DAMB and under 0.2 mg/l with L-AmB.
Cardiovascular A reversible cardiomyo pathy has been reported after treatment with liposomal amphotericin (5 mg/kg/day for 5 days) and flucytosine (100 mg/kg/day for 2 days) for cryptococcal laryngitis; either agent could have been responsible (35A).
Combination studies In an open pilot study, a combination of L-AmB 3 mg/kg/day and caspofungin at the standard dose or monotherapy was compared with high-dose L-AmB 10 mg/kg/day in 30 patients with invasive aspergillosis (34c). The median durations of treatment were 18 and 17 days respectively. There were significantly more favorable overall responses in the combination group (10 of 15 patients versus 4 of 15 patients). Survival rates at 12 weeks were similar. There were infusion-related reactions in three patients in the highdose monotherapy group. There was a twofold increase in serum creatinine in 4 of 17 patients who received highdose monotherapy and 1 of 15 patients who received combination therapy;
Drug-dosage regimens In a double-blind trial, patients with proven or probable invasive mould infection were randomized to L-AmB 3 or 10 mg/kg/day for 14 days followed by 3 mg/kg/day (36C). Of 201 patients with confirmed invasive mould infections, 107 received 3 mg/kg/day and 94 received 10 mg/kg/day. Invasive aspergillosis accounted for 97% of cases. There were favorable responses in 50% and 46% of patients given 3 and 10 mg/kg/ day, respectively; the respective survival rates at 12 weeks were 72% and 59%. However, there were significantly higher rates of nephrotoxicity and hypokalemia in the high-dose group. Thus, a regimen of 10 mg/kg/day had no advantage and higher rates of nephrotoxicity. Susceptibility factors Children In a pilot study of prophylactic L-AmB in preventing invasive fungal infections in hemopoietic stem cell transplant recipients, 51 patients (median age 6 years) were given L-AmB 3 mg/kg/day intravenously for 100 days. There were no breakthrough infections (37c). When used as secondary prophylaxis in 11 adolescents (aged 11–18 years) with acute leukemia and a history of antecedent invasive pulmonary aspergillosis, L-AmB 1 mg/kg/day from the start of the condition ing regimen until engraftment (median duration 30 days) was well tolerated and withdrawn early in only one patient (38c). In a pharmacokinetic pilot study of once-weekly high-dose L-AmB, 14 children (median age 37 months) undergoing hemo poietic stem cell transplantation received once-weekly intravenous L-AmB prophylaxis
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(10 mg/kg as a 2-hour infusion) (39c). L-AmB was well tolerated at this dose and achieved measurable amphotericin plasma concentrations 7 days after infusion. Interference with laboratory tests Acute increases in serum inorganic phosphate in the absence of hypocalcemia and tissue deposition of calcium phosphate have been seen in patients receiving L-AmB (40A, 41A). However, hyperphosphatemia was found only when the samples were measured by one of two analysers. There was a direct linear relation between the concentration of L-AmB in spiked samples and the analyser results, indicating an increase of 0.9 mmol/l inorganic phosphate for every 100 mg/l increase in L-AmB. Ultrafiltration normalized the results. Thus, serum inorganic phosphate may be falsely increased because of interference by L-AmB.
FLUCYTOSINE Cardiovascular A reversible cardio myopathy has been reported after treat ment with liposomal amphotericin (5 mg/ kg/day for 5 days) and flucytosine (100 mg/ kg/day for 2 days) for cryptococcal laryngi tis; either agent could have been responsi ble (35A).
ANTIFUNGAL AZOLES (SED 15, 301; SEDA-29, 282; SEDA-30, 320; SEDA-31, 459) Drug–drug interactions with antifungal azoles Ciclosporin The effect of steady-state ciclo sporin (trough whole blood concentrations 200–400 ng/ml) on the single-dose pharma
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cokinetics of itraconazole 200 mg as a 1-hour intravenous infusion has been investi gated in 10 patients with a hematological malignancy and an allogeneic stem cell transplant (42c). The AUC0!24 h of itraconazole was not significantly altered, but the AUC0!24 h of hydroxyitraconazole was significantly increased (median increase 49%), with significant pro-longation of the tmax (37%) and half-life (176%). These differences may have resulted from variability in the affinity of itraconazole, hydroxyitraconazole, and ciclosporin for the CYP3A4 and the occurrence of P glyco protein polymorphisms. Co-administration of ketoconazole with ciclosporin in children with idiopathic gluco corticoid-dependent nephrotic syndrome caused a significant reduction in ciclosporin cost and net cost savings, which is important in developing countries (43C). It also appeared to result in a significant improve ment in the response to ciclosporin and more successful glucocorticoid withdrawal as well as a reduction in the frequency of renal impairment. Liver function tests remained normal up to and including the final followup at a mean of 34 months. The effect of oral posaconazole on the pharmacokinetics of ciclosporin has been assessed in a single-center, open pharmaco kinetic study in four adult heart transplant recipients (44C). The patients had taken an established dose of ciclosporin three times a day for 6 weeks or longer and were given posaconazole 200 mg/day for 10 days. Co administration of posaconazole increased ciclosporin exposure and necessitated dosage reductions of 14–29% in three subjects. These findings suggest that the dosage of ciclosporin should be reduced when posaco nazole is started and that plasma ciclosporin concentrations should be monitored during posaconazole therapy and after withdrawal, so that dosages are adjusted accordingly. Cinitapride The pharmacokinetic and electrocardiographic interactions of the prokinetic drug cinitapride with ketoconazole have been investigated in a double-blind, crossover, placebo-controlled study in healthy men and women (45c). Cinitapride
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is rapidly absorbed after oral administration and is metabolized by CYP3A4 and CYP2C8. At steady state, co-administration with ketoconazole 200 mg bd increased its mean Cmax and AUC during a dosage interval by 1.63 and 1.98 times, respectively. There were small increases in the mean QTc interval and baseline-corrected QT interval on day 7, due to the effects of ketoconazole alone. Cyclophosphamide Fluconazole inhibits CYP2C9, which is involved in the activation of cyclophosphamide and may provide protection from cyclophosphamide-related adverse effects. Cyclophosphamide and metabolite data have been compared in patients who took fluconazole (n = 56) or not (n = 17) (46c). Fluconazole increased the cyclophosphamide AUC and reduced the Cmax of 4-hydroxycyclophosphamide. In a separate study, outcomes were analysed in patients taking cyclophosphamide who were randomized to either fluconazole (n = 152) or placebo (n = 147). Those who took fluconazole had less hepatic and renal toxicity and lower mortality; there was no difference in relapsed malignancy. Efavirenz An interaction of itraconazole with efavirenz has been reported in a patient with disseminated histoplasmosis and AIDS. The combination resulted in persistently raised urinary Histoplasma antigen concentrations and subtherapeutic plasma itraconazole concentrations (47A). Changing treatment from efavirenz to a protease inhibitor resolved the problem. In a one-sequence, two-period pharmaco kinetic interaction study in 12 HIV-positive subjects, pre-treatment with efavirenz signifi cantly increased the clearance of ketocona zole by 201%. Cmax was significantly reduced by 44%, AUC0!24 h by 72% and half-life by 58% (48c). Thus, efavirenz is a strong inducer of the metabolism of ketoconazole. The interactions of voriconazole with anti retroviral drugs are complex (49R). The inter action of voriconazole with efavirenz has been evaluated in a two-period, multiple-dose, randomized, placebo-controlled study in
34 healthy men (50C). They took voriconazole 200 mg bd after two loading doses of 400 mg (n = 17) or placebo (n = 17) for 3 days; then they took efavirenz 400 mg/day for 10 days followed by efavirenz co-administered with voriconazole 200 mg bd or placebo for 9 days. Efavirenz reduced the mean steadystate voriconazole AUC by 80% and Cmax by 66%. This was probably mainly due to induc tion of CYP2C19 and CYP2C9 by efavirenz. Voriconazole increased the mean steady-state AUC of efavirenz by 43% and Cmax by 37%. This was probably due to inhibition of CYP3A4 by voriconazole. The authors sug gested that co-administration of voriconazole with efavirenz should be contraindicated. Different dosage combinations of efavirenz and voriconazole have been assessed in an open, four-treatment, multiple-dose, fixedsequence study in 16 healthy men, with the goal of finding a dosage combination that pro vides systemic exposures similar to standarddose monotherapy with each drug (51C). Steady-state pharmacokinetics were assessed after two test treatments (voriconazole 300 mg bd þ efavirenz 300 mg/day and voriconazole 400 mg bd þ efavirenz 300 mg/ day) and compared with standard-dose monotherapy (voriconazole 200 mg b.d. and efavirenz 600 mg/day). Voriconazole 300 mg bd þ efavirenz 300 mg/day reduced voricona zole steady-state AUC by 55% and Cmax by 36% compared with monotherapy. Vorico nazole 400 mg bd þ efavirenz 300 mg/day reduced voriconazole steady-state AUC by 7% and increased Cmax by 23%, and increased efavirenz AUC by 17% without a change in Cmax when compared with monotherapy. Thus, the authors recommended that when voriconazole and efavirenz are co administered, the dosage of voriconazole should be increased to 400 mg bd and the dosage of efavirenz reduced to 300 mg/day in order to provide systemic exposures similar to standard-dose monotherapy. Fentanyl The potential interactions of fentanyl with fluconazole and voriconazole have been investigated in a randomized crossover study in three phases in 12 healthy volunteers (52C). They were given intravenous fentanyl 5 micrograms/kg without pre
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treatment, after oral fluconazole (400 mg once on the first day and 200 mg once on the second day) or after oral voriconazole (400 mg twice on the first day and 200 mg twice on the second day). Plasma concentrations of fentanyl, norfentanyl, fluconazole, and voriconazole were determined up to 24 hours. The mean plasma clearance of intravenous fentanyl was reduced by 16% by fluconazole and 23% by voriconazole. Voriconazole increased the AUC by 40%. Caution should be exercised, especially in patients who are given voriconazole or fluconazole during long-lasting fentanyl treatment, because insidiously elevated fentanyl concentration can cause respiratory depression. Care should be taken in patients who are given fluconazole or voriconazole during long-lasting fentanyl treatment, because insi diously raised fentanyl concentration can cause respiratory depression. This has been emphasized by a report of a fatal outcome that was attributed to an interaction of fen tanyl with fluconazole (53A). • A 46-year-old man weighing 80 kg, with tonsillar cancer, was given a fentanyl transdermal patch 100 micrograms/hour (Durogesic), which was increased to 150 micrograms/hour over a period of 1.5 months. He also took oral morphine 10 mg/day, diclofenac 50 mg tds, paracetamol 1 g tds, oxazepam 15 mg bd, zolpidem 5 mg before bedtime, nystatin 100 000 IU/ml 3–4 ml qds, lactulose 670 mg/ml 20 ml tds, lidocaine oral spray, and rectal metoclopramide 20 mg tds. He was then given oral fluconazole 50 mg/day for an oral fungal infection and after 3 days he died in his sleep. Forensic analysis of femoral blood showed a toxic concentration of fentanyl (0.017 µg/g), high concentrations of fluconazole (2.4 µg/g), lidocaine (1.6 µg/g), and metoclopramide (0.15 µg/g), and a therapeutic concentration of zolpidem (0.07 µg/g). Ethanol and drugs of abuse were not identified. Autopsy showed no pathological findings other than pulmonary congestion and brain edema.
The coroner concluded that the cause of death was respiratory depression and circulatory failure due to fentanyl intoxication; there was no indication of intentional overdose. Haloperidol The combined effects of the CYP3A4 inhibitor itraconazole and the CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of
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prolongation and haloperidol (QTc neurological adverse effects), a substrate of both CYP2D6 and CYP3A4, have been evaluated in 19 healthy volunteers in a randomized crossover study (54C). A single dose of haloperidol 5 mg was given after pre treatment with placebo or itraconazole 200 mg/ day for 10 days. Itraconazole increased the mean AUC of haloperidol by 55%; those with the CYP2D6*10/*10 genotype had 81% higher AUCs than those with the CYP2D6*1/ *1 genotype. The CYP2D6*10 genotype and itraconazole pre-treatment reduced the oral clearance of haloperidol by 24% and 25% respectively, but without statistical significance. Itraconazole in those with the CYP2D6*10 genotype significantly reduced the oral clearance of haloperidol to 42% of the value in subjects with the wild genotype after placebo pre-treatment. The Barnes Akathisia Rating Scale (BARS) after itraconazole pre-treatment in subjects with CYP2D6*10/*10 was significantly higher than in those with the CYP2D6*1/*1 genotype after placebo pre-treatment. No other pharmacodynamic measurements were significantly changed. Thus, the moderate effect of the CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol is augmented by itraconazole. Hormonal contraceptives The interaction of voriconazole with Ortho-Novum 1/35, an oral contraceptive containing norethindrone 1 mg and ethinylestradiol 35 micrograms, has been studied in 16 healthy women, who took voriconazole 400 mg bd on day 1 and 200 mg bd on days 2–4, Ortho-Novum on days 12–32, and the combination on days 40–60 in an open study (55c). OrthoNovum increased the steady-state AUC of voriconazole by 46% and the Cmax by 14%. Voriconazole increased the AUC of ethinylestradiol by 61% and the Cmax by 36% and the AUC of norethindrone by 53% and the Cmax by 15%. Adverse events were generally mild, although four subjects had severe adverse events. Ibuprofen The effects of fluconazole and voriconazole on the pharmacokinetics of S-(þ)- and R-(–)-ibuprofen have been
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investigated in 12 healthy men in a randomized study, in which they took a single oral dose of 400 mg racemic ibuprofen alone and after fluconazole or voriconazole 400 mg bd on day 1 and 200 mg bd on day 2 (56c). Fluconazole increased the AUC of S-(þ)-ibuprofen to 183% and the Cmax to 116% of the control values and prolonged the terminal half-life from 2.4 to 3.1 hours; this was probably due to inhibition of CYP2C9. Voriconazole had weak effects on the pharmacokinetics of R-(–)-ibuprofen. Similarly, voriconazole increased the AUC of S-(þ)-ibuprofen to 205% and the Cmax to 122% of the control values and prolonged the terminal half-life from 2.4 to 3.2 hours; this was probably due to inhibition of CYP2C9. Voriconazole had weak effects on the pharmacokinetics of R-(–)-ibuprofen. The authors recommended that the dosage of ibuprofen should be reduced when it is co-administered with fluconazole or voriconazole, especially when the initial ibuprofen dose is high. Imidafenacin The effect of itraconazole on the pharmacokinetics of imidafenacin, a muscarinic receptor antagonist, has been investigated in 12 healthy subjects in an open study (57c). After a single oral dose of imidafenacin 0.1 mg, they took oral itraconazole in ‘multiple doses’ of 200 mg for 9 days and a single oral dose of imidafenacin 0.1 mg on day 8. Itraconazole increased the Cmax of imidafenacin 1.32 times (90% CI = 1.12, 1.56) and the AUC 1.78 times(1.47, 2.16). The authors concluded that itraconazole or other potent CYP3A4 inhibitors should be used carefully in patients taking imidafenacin.
pharmacokinetics of maraviroc 100 mg bd, a chemokine receptor (CCR5) antagonist, ketoconazole 400 mg/day increased mara viroc steady-state AUC (59c). Nevirapine The interaction of itraconazole with nevirapine has been studied in 12 healthy volunteers, who were randomized to nevirapine 200 mg/day for 7 days or itraconazole 200 mg/day for 7 days, followed by the combination (60C). Itraconazole disposition was altered by nevirapine, with significant reductions in Cmax (38%), AUC0!96 h (61%) and half-life (31%). Itraconazole did not alter the pharmacokinetics of nevirapine, but the authors suggested that a higher dosage might have an inhibitory effect. Nevirapine concentrations, adverse events and 36-week efficacy have been compared retrospectively in patients, mean age 36 years, who did not take fluconazole (n = 81) or who took fluconazole 200 or 400 mg/day (n = 41) (61c). Baseline characteristics in the two groups were similar. Fluconazole signifi cantly increased mean nevirapine concentra tions from 6.5 to 11.4 mg/l but there were no differences in the 36-week antiviral efficacy between the groups.
Ixabepilone In patients with cancer, co administration of ketoconazole 400 mg/day to ixabepilone resulted in a 79% increase in AUC, with evidence of a direct relation between ixabepilone pharmacokinetics, neutrophil counts and microtubule bundle formation in peripheral mononuclear cells (58c).
Phenytoin The interaction of phenytoin with posaconazole has been assessed in a randomized, open, parallel-group, multipledose study in 36 healthy men, who were randomly assigned for 10 days to either posaconazole 200 mg/day, phenytoin 200 mg/ day or the combination (62c). On day 1 the Cmax and AUC0!24 h were unchanged, but at steady state posaconazole reduced phenytoin Cmax by 44% and AUC by 52%, although there was a lot of interindividual variability. There was also a 90% increase in the steady-state clearance of oral posaconazole. Because co-administration of phenytoin and posaconazole significantly reduces posaconazole exposure and increases phenytoin concentrations in some subjects, concomitant use of these agents should generally be avoided.
Maraviroc In a two-way crossover study of the effect of CYP3A4 inhibitors on the
Praziquantel The interaction of ketocona zole with praziquantel has been investigated
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in healthy adult Thai men in an open, twophase crossover, randomized study (63c). Concurrent administration of ketoconazole with praziquantel significantly increased the mean AUC of praziquantel by 93% and the Cmax by 102%; the mean oral clearance of praziquantel was significantly reduced by 58%. The mechanism was possibly inhibition of CYP3A4. Rifabutin In a open, parallel-group, multiple-dose, non-randomized study of the pharmacokinetics of rifabutin 300 mg/day for 17 days and posaconazole 200 mg/day for the last 10 days in 24 healthy men, 4 subjects withdrew because of adverse events (64c). Rifabutin reduced steady-state posaconazole Cmax by 43% and AUC by 49%. Conversely, posaconazole increased steady-state rifabutin Cmax by 31% and AUC by 72%. Concomitant use of rifabutin and posaconazole should generally be avoided. Sirolimus Concurrent use of voriconazole and sirolimus is contraindicated but still occurs. In a retrospective single-center review of medical records, 23 inpatients received at least one dose of voriconazole and sirolimus concomitantly within a 24 hour period (65c). Sirolimus concentrations were not raised above 20 mg/l in patients who had been stabilized on voriconazole before starting low-dose sirolimus 0.5–1 mg/ day, or in those who had been stabilized with sirolimus 0.5–2 mg/day, who had baseline sirolimus concentrations of 12 ng/ml or lower, and whose sirolimus dose was reduced by 50% before the addition of voriconazole. In contrast, sirolimus concentrations were raised in patients who took doses of 4 mg/day or higher, who had sirolimus concentrations of 12 ng/ml or higher and whose sirolimus dose was not reduced before the addition of voriconazole. Thus, sirolimus and voriconazole can be safely co-administered as long as consideration is given to which agent the patient receives first, the sirolimus dosage, sirolimus concentrations, concurrent disease states and CYP3A inhibitors. Sirolimus concentrations should be closely and routinely monitored before, during, and
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after co-administration of voriconazole and other CYP3A inhibitors. • Supratherapeutic trough concentrations of sirolimus occurred when itraconazole 200 mg bd was added in a 20-year-old recipient of a hemopoietic stem cell transplant (66A). Sirolimus was withheld and reintroduced at a lower dosage when the sirolimus trough concentration had normalized. Both the itraconazole and sirolimus were eventually withdrawn.
SPP301 SPP301 is a potent, highly selective endothelin A receptor antagonist. In a randomized, open, two-period crossover study in 12 healthy men, ketoconazole co-administration increased the systemic availability of SPP301 and its hydroxymethyl metabolite threefold and prolonged their half-lives twofold; individual exposures increased by up to 5.9 times (67c). Statins A patient with prostate cancer tak ing simvastatin developed rhabdomyolysis after co-administration with fluconazole (68A). The rhabdomyolysis promptly resolved after withdrawal of fluconazole, suggesting a possible interaction. Tacrolimus The effect of oral posaconazole 400 mg bd on the pharmacokinetics of tacrolimus 0.05 mg/kg/ day has been assessed in a single-center, open, crossover study in 36 healthy adults (44C). Posaconazole increased the tacrolimus Cmax by 121% and AUC by 358%. Posaconazole pharmacokinetics were not altered. These findings suggest that the dosage of tacrolimus should be reduced when posaconazole is started and that plasma tacrolimus concentrations should be monitored during posaconazole therapy and after withdrawal, so that dosages are adjusted accordingly. Vinca alkaloids Although itraconazole should not be used with vincristine, further cases of neurotoxicity have been reported in patients with lymphoma who were given the combination (69A). Four patients had severe myalgia resembling polymyalgia rheumatica, with or without arthralgia. Two had
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constipation due to sub-ileus and one had a severe paralytic ileus. Appropriate manage ment, including withdrawal of itraconazole, resulted in recovery in each case. Potentiation of neurotoxicity from vincris tine by concurrent use of posaconazole has been reported (70A). • A 21-year-old man with acute lymphocytic leukemia who was taking posaconazole 400 mg/day was given vincristine 2 mg/week. Soon after the third weekly dose he developed bilateral foot paresthesia and within 10 days had foot drop and could not walk without assistance. He had a mixed axonal and demyelinating sensorimotor neuropathy with acute denervation. There was no improvement 5 months after withdrawal of vinca alkaloids and posaconazole.
Enhanced vindesine neurotoxicity has been reported in an adult with acute lympho blastic leukemia (71A), and a combination of neurotoxicity and severe myelosuppression in a boy with Hodgkin’s lymphoma after con current administration of vinblastine, doxor ubicin, methotrexate, and prednisone (VAMP) with itraconazole (72A). Inhibition of CYP isoenzymes and P glycoprotein are thought to interfere with the disposition of several anticancer agents.
Fluconazole
(SED-15, 1377; SEDA-29, 286; SEDA-30, 325; SEDA-31, 462)
Comparative studies In a randomized, double-blind, Phase III comparison of anidulafungin 100 mg/day and fluconazole 400 mg/day, in 245 mostly non-neutropenic patients with invasive candidiasis, the adverse effect profiles of the two drugs were very similar; the types and frequencies of adverse events were comparable and fewer than 5% of the patients withdrew because of drug-related adverse events (73C). Cardiovascular Antifungal azoles, as a class, can cause QTc interval prolongation and potentially fatal cardiac dysrhythmias
by a direct blocking action on IKr channels. • A 68-year-old woman with cerebellar and pontine cryptococcosis was given amphotericin and flucytosine but developed hypokalemia, hypomagnesemia and atrial fibrillation (74A). She was given electrolyte replacement and metoprolol, and conventional amphotericin was changed to ABLC for 6 weeks, after which high-dose oral fluconazole was initiated. However, 6 days later, she had a generalized tonic–clonic seizure and cardiopulmonary arrest. Her QTc interval was 556 ms and she had recurrent episodes of torsade de pointes. Fluconazole was withdrawn and amphotericin was reintroduced, but she died 2 days later. Autopsy showed no coronary artery disease or hemorrhagic transformation of the pontine cryptococcoma.
In some cases cardiac dysrhythmias can be precipitated by the concomitant use of other prodysrhythmic compounds. • An 11-year-old critically ill child was given fluconazole 150 mg bd for Candida peritonitis after a perforated gastric volvulus and developed torsade de pointes after being given amiodarone (75A). • A 33-year-old woman with systemic lupus erythematosus and a C. albicans pneumonia was given intravenous fluconazole 200 mg/day and the dosage was then adjusted according to renal function; she was also given domperidone (76A). Prolongation of the QTc interval and torsade de pointes occurred. Fluconazole and domperidone were withdrawn. Torsade de pointes recurred several weeks later when she was given fluconazole and resolved on withdrawal. • A 23-year-old woman with acute promyelo cytic leukemia developed torsade de pointes after 4 weeks of concomitant treatment with arsenic trioxide and fluconazole (77A).
Arsenic trioxide can cause electrocardio graphic abnormalities, such as ventricular tachycardia and prolongation of the QT interval, and both arsenic trioxide and flu conazole are metabolized by CYP. Endocrine Adrenal insufficiency occurred in a 38-year-old man with obstructive sleep apnea and polycythemia, who received fluconazole plus broad-spectrum antibiotics for pulmonary infiltrates during ventilation;
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he recovered after fluconazole was stopped (78A). The authors concluded that adrenal suppression attributable to fluconazole may be under-recognized and that critically ill patients who are given fluconazole should be monitored. Urinary tract A patient developed recurrent episodes of membranous nephropathy after taking fluconazole repeatedly (79A). Teratogenicity Fluconazole can be teratogenic when it is used continuously in a dosage of 400–800 mg/day. Common features include multiple synostoses (including craniosynostosis and digital synostosis), congenital heart defects, skeletal anomalies, and dysmorphic facial features (SEDA-28, 306). The association between maternal use of fluconazole during pregnancy and the risk of congenital malformations has been assessed in a population-based cohort study in northern Denmark in 1079 women who had a live birth or a stillbirth after the 20th week of gestation and who had redeemed at least one prescription for fluconazole during the first trimester (80c). The reference cohort comprised 170 453 pregnant women who had not redeemed a prescription for fluconazole during pregnancy. The prevalence odds ratio (POR) for congenital malformations after fluconazole exposure was adjusted for maternal smoking, parity, maternal age and concurrent prescriptions for anti-epileptic or antidiabetic drugs. Of the 1079 women who filled a fluconazole prescription during the first trimester, 797 (74%) took 150 mg/day, 235 (22%) took 300 mg/day, 24 (2%) took 350 mg/day, and 23 (2%) took 600 mg/day. These women gave birth to 44 (4.1%) children with congenital malformations. The 170 453 controls gave birth to 6152 (3.6%) children with congenital malformations. For congenital malformations overall, the adjusted POR associated with first-trimester fluconazole use was 1.0 (95% CI = 0.8, 1.4).
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Genotoxicity The genotoxic effects of fluconazole have been assessed using the chromosome aberration (CA) test in mouse bone-marrow cells in vivo, and CA, sister chromatid exchange (SCE) and micronucleus (MN) tests in human lymphocytes (81E). Fluconazole was used in doses of 12.5, 25, and 50 mg/kg for the in vivo assay and in concentrations of 12.5, 25, and 50 mg/l in the in vitro assay. In both test systems, a negative and a positive control were also included. In the in vivo test, fluconazole did not significantly increase the frequency of CAs. In the in vitro assays, CAs, SCEs, and MN frequencies were significantly increased in a dose-related manner compared with the negative control. The mitotic index, replication index and cytokinesis-block proliferation index (CBPI) were not affected. Thus, fluconazole is clastogenic and aneugenic in human lymphocytes, but these effects were not be observed in mice. Susceptibility factors High-risk extremely low birth weight infants Extremely low birth weight infants are at increased risk of invasive candidiasis and are sometimes given prophylactic fluconazole. In a historical comparison, 9 of 137 low-birth weight infants (6.6%) developed invasive candidiasis during a pre-prophylaxis period (January 1998 to February 2002) compared with none of 140 who were given fluconazole after that time (82c). However, of the infants who were given fluconazole, 60 (43%) developed conjugated hyper bilirubinemia compared with 12 (8.8%) of the controls. Thus, fluconazole prophylaxis was effective in preventing invasive candidiasis, and although there was an increase in the incidence of conjugated hyperbilirubinemia, the benefit-to-harm balance may be favorable. HIV-infected subjects receiving tuberculo static drugs The incidence and suscepti bility factors for severe hepatotoxicity in 144 HIV-positive patients taking antituber culosis drugs have been assessed in a prospective, 12-year analysis (83c). There was severe hepatotoxicity in 15 (11%), and
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the median time to development of hepato toxicity was 14 days. Independent suscept ibility factors included abnormal baseline AlT activity and bilirubin concentration and the use of fluconazole. Caution should be advised when fluconazole and antituber culosis drugs are used concomitantly. Drug-dosage regimens Different doses of fluconazole (800–2000 mg/day) for 10 weeks alone or combined with flucytosine 100 mg/ kg/day for the first 4 weeks have been investigated in a Phase II dose escalation study (84c). Increasing doses of fluconazole were associated with increased survival and a reduced time to conversion of the cerebrospinal fluid (CSF) from culturepositive to culture-negative. The addition of flucytosine to fluconazole improved outcomes in each dosing cohort.
Itraconazole (SED-15, 1932; SEDA-29, 286; SEDA-30, 326; SEDA-31, 463) Cardiovascular An otherwise healthy 30-year-old man who took itraconazole for onychomycosis developed palpitation and frequent ventricular extra beats (85A). A 12-lead electrocardiogram was normal, but Holter recording showed 17 484 (18%) monomorphic extra beats and four runs among 96 930 beats/day. Another Holter recording after withdrawal of itraconazole showed 1032 atrial extra beats but no ventricular extra beats. The QTc interval was 0.39 seconds without itraconazole, 0.41 seconds with itraconazole and 0.43 seconds when multiple ventricular extra beats were documented. The underlying mechanism for this effect is obscure. Liver In 54 studies of the frequency of adverse effects of antifungal agents in 9228 patients, itraconazole was the most hepatotoxic (32%) (86M). However, lack of standard definitions, heterogeneous patient pools, and differing protocols make large-scale comparisons between studies and agents difficult.
Skin A fixed drug eruption has been attributed to itraconazole (87A). Susceptibility factors Children In a pro spective study of itraconazole prophylaxis, in which dosages were adjusted to target plasma trough concentrations of 0.5 mg/l or more in 44 prophylactic cycles in 39 chil dren with cancer, a median dosage of 8 (3.5–16.0) mg/kg/day was required to achieve the dosing target (88c). Adverse effects (gastrointestinal, raised transamina ses, and one case of hemolysis) that required drug withdrawal were reported in 11% of courses. There were no break through infections.
Posaconazole (SED-15, 2905; SEDA-29, 286; SEDA-30, 327; SEDA-31, 463) Observational studies In 428 patients with refractory invasive fungal infections (n = 362) or febrile neutropenia (n = 66) who received posaconazole in two Phase II/III open trials, 109 took posaconazole for at least 6 months (89c). Treatmentrelated adverse events were reported in 38%, the most common being nausea (8%) and vomiting (6%). There were serious adverse events in 8%. There were low rates of treatment-related QTc and/or QT interval prolongation (1%) and raised hepatic enzymes (2%). The rates of adverse events were similar in patients who took posaconazole for more or less than 6 months. Comparative studies Posaconazole has been compared with fluconazole and itraconazole in antifungal prophylaxis in a randomized, international, multicenter, evaluator-blind study in 602 patients with prolonged neutropenia (90C). They received prophylaxis with each cycle of chemotherapy until recovery from neutropenia and complete remission, or until occurrence of an invasive fungal infection or for up to 12 weeks, whichever came first. A total of 304 patients were
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randomly assigned to posaconazole, 240 to fluconazole and 58 to itraconazole. There were significantly fewer invasive fungal infections and fewer cases of invasive aspergillosis, and survival was significantly longer in those who were given posaconazole. Serious adverse events that were possibly or probably related to treatment were reported by 19 patients (6%) given posaconazole and 6 (2%) given fluconazole or itraconazole. The most common treatment-related adverse events were gastrointestinal tract disturbances. Oral posaconazole has been compared with oral fluconazole for prophylaxis against invasive fungal infections in an international, randomized, double-blind trial in 600 patients with graft-versus-host disease who were receiving immunosuppressive therapy; 301 were assigned to posaconazole and 299 to fluconazole (91C). At the end of the fixed 112-day treatment period, posaconazole was as effective as fluconazole in preventing all invasive fungal infections and was superior to fluconazole in preventing proven or probable invasive aspergillosis. Mortality was similar in the two groups, as was the incidence of treatment-related adverse events (36% with posaconazole and 38% with fluconazole); the rates of treatment-related serious adverse events were 13% and 10% respectively. In comparative trials in HIV-positive patients with azole-refractory oropharyn geal and esophageal candidiasis, posacona zole 400 mg bd for up to 12 months was well tolerated; the most frequently reported treatment-related adverse event was vomit ing (4/100) during the early follow-up per iod (on or before day 105) and raised hepatic enzymes (3/51) during long-term fol low-up (after day 105) (92c). Drug-dosage regimens In 199 subjects with oropharyngeal and esophageal candidiasis, oral posaconazole 400 mg bd for 3 days followed by oral posaconazole 400 mg/day for 25 days was compared with oral posaconazole 400 mg bd for 28 days; the most common treatment-related adverse events were diarrhea (11%), neutropenia (7%), flatulence (6%), and nausea (6%),
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and 8 subjects withdrew because treatment-related adverse events (93c).
of
Voriconazole (SED-15, 3688; SEDA-29, 287; SEDA-30, 328; SEDA-31, 463) Observational studies All adverse events in patients taking voriconazole reported to the French Pharmacovigilance Database between 2002 and 2005 have been analysed (94c). There were 227 adverse events in 178 adults and 9 children; 66% occurred in male patients. The median age was 50 (2–80) years. Adverse events included liver function test abnormalities (23%), visual disturbances (18%), rashes (17%), neurological disturbances (14%), cardiovascular events (10%), hematological disorders (8%), and renal disturbances (4%). Other less common events included headache, nausea, vomiting, and diarrhea. There were drug–drug interactions in seven cases. According to the Naranjo criteria, 84% of the events were classified as possible, 7% as probable, 5% as highly probable, and 4% as doubtful. Cardiovascular A 14-year-old Tahitian girl with acute myeloid leukemia and suspected mucormycosis was given intravenous voriconazole 300 mg bd and caspofungin (95A). Because of worsening infection, voriconazole was switched to posaconazole, but 4 hours after the first dose of posaconazole she developed QT interval prolongation, torsade de pointes and reversible cardiac arrest. The voriconazole plasma concentration 15 hours after the last dose was 7 mg/l. Genotyping suggested that the patient was an extensive metabolizer with respect to CYP2C9 and CYP2C19. Hypomagnesemia and the additional use of ondansetron were thought to have increased her susceptibility to torsade de pointes, and she was eventually found to have a congenital long QT syndrome. Respiratory A 71-year-old man with chronic necrotizing pulmonary aspergillosis
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and Mycobacterium intracellulare infection developed dyspnea and cough after taking voriconazole for 15 days (96A). A computed tomography (CT) scan showed a new dif fuse ground-glass opacity in the left lower lobe; arterial blood gas analysis showed severe hypoxemia. Voriconazole was with drawn and a glucocorticoid was given. His symptoms and left-sided lesions resolved. Although a lymphocyte stimulation test for voriconazole was negative, the authors thought that this lesion may have been an adverse reaction to voriconazole. Nervous system Painful peripheral neuropathy can occur in association with voriconazole (SEDA-30, 328) and further cases have been reported. Two patients with hematological malignancies who received voriconazole for invasive aspergillosis developed neuropathy after 2 and 4 weeks (97A). Electromyography showed a pattern of sensorimotor neuropathy compatible with axonal disease. Other causes of peripheral neuropathy were excluded. After withdrawal of voriconazole, the effects abated. Liver The relationship between CYP polymorphisms and hepatotoxicity from voriconazole has been explored in a retro spective study of 86 immunocompromised patients (98c). Median serum bilirubin and liver enzyme activities rose during voricona zole treatment. However, there were no statistically significant differences in the maximum values or the maximum increases in relation to CYP2C9, CYP2C19 or CYP3A5 polymorphisms. Lack of cross-reactivity between voricona zole and posaconazole has been suggested by the case of a 70-year-old man with chronic lymphocytic leukemia who had persistent increases in liver function test values while taking voriconazole 200 mg bd, which resolved when posaconazole 400 mg bd was given instead (99A). Skin Another case of pseudoporphyria has been attributed to voriconazole in a lung transplant patient; it was controlled
with a sunscreen during continued voricon azole exposure (100A). The association of voriconazole with blistering of the skin after allogeneic hemo poietic stem cell transplantation may be difficult to establish and the diagnosis delayed by a history of graft-versus-host disease (101A). The recognition of voricon azole-induced blistering as a separate and distinct entity in patients with a history of graft-versus-host disease is important, because delayed withdrawal of voricona zole can cause unnecessary and potentially dangerous increases in immunosuppressive drug therapy. Musculoskeletal Of 27 lung transplant patients receiving voriconazole, 9 developed painful neuromuscular disorders, leading to drug withdrawal (102c). All but one had cystic fibrosis. The delay before onset of the symp toms varied considerably, from 2 weeks to 1 year. The intensity of symptoms was also diverse: from mild muscle and joint pains to sharp pain mainly in the legs, with numbness of both feet, leading to severe disability. There was no edema, rash, or arthritis. Ten don reflexes were present in most cases. Five patients underwent needle electromyogra phy and nerve conduction studies and in four cases there was a demyelinating neuro pathy motor predominance. Some patients worsened rapidly and had intolerable pain, whereas others had progressive pain. All other medications except tacrolimus were stopped, without improvement. Trough concentrations of voriconazole were highly variable (0.2–4.5 mg/l), and after withdrawal of voriconazole there was complete recovery in all cases within about 1 week. Tumorigenicity Because of reports of squamous cell carcinoma with prolonged use of voriconazole in an HIV-infected patient (103A) and a 69-year-old renal transplant patient (104A), voriconazole has been suggested to be involved in the development of multifocal invasive squamous cell carcinoma when complicated by a phototoxic reaction, in
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which case an alternative antifungal prophylaxis regimen should be considered. Severe retinoid-like photosensitivity (cheilitis and erythema, desquamation, and ulceration of light-exposed skin) has previously been attributed to voriconazole. The mechanism is unknown, but inhibition of retinoid metabolism or a direct phototoxic effect of voriconazole or one of its metabolites has been implicated (SEDA-30, 328). Photoageing caused by voriconazole therapy has previously been reported in a 15-year-old patient with residual solar elastotic changes, multiple lentigines, and ephelides on sun-exposed areas after withdrawal (105A). Susceptibility factors Renal disease The effect of renal impairment on the pharmacokinetics of oral and intravenous voriconazole has been studied in two prospective, open, parallel-group studies in healthy volunteers (106c). In the first study, 24 men without renal impairment, or with mild, moderate, or severe impairment, took oral voriconazole 200 mg. In the second study 13 men with no renal impairment or moderate impairment received multiple doses of intravenous voriconazole (6 mg/kg bd on day 1 followed by 3 mg/kg bd on days 2–7); the drug was dissolved in sulfobutylether beta-cyclodextrin. The pharmacokinetics of voriconazole were unaffected by renal impairment in both studies, but in the second study the clearance of sulfobutylether-beta cyclodextrin was proportional to creatinine clearance. Monitoring therapy Monitoring therapy with voriconazole has been studied in 52 patients, in whom 181 measurements were performed during 2388 treatment-days (107c). There was large variability in voriconazole trough blood concentrations, ranging from below 1 mg/l, the minimum inhibitory concentration at which 90% of most fungal pathogens are susceptible, in 25% of cases, to over 5.5 mg/l, a concentration that can be associated with toxicity, in 31% of cases. Lack of response to therapy was more frequent in six patients
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with voriconazole concentrations below 1 mg/l; in those cases blood concentrations over 1 mg/l were reached after increasing the dosage, with complete resolution of infection in all six. Of 16 patients with voriconazole trough blood concentrations over 5.5 mg/l, 5 had an encephalopathy, including 4 who were given intravenous voriconazole in a median dosage of 8 mg/ kg/day; none of the patients with concentrations below 5.5 mg/l developed neurological toxicity. Co-medication with omeprazole possibly contributed to voriconazole accumulation in four cases. In all cases, withdrawal of therapy resulted in prompt and complete neurological recovery. The authors concluded that voriconazole therapeutic drug monitoring improves the efficacy and safety of therapy in patients with invasive mycoses.
(SED-15, 1197; SEDA-29, 288; SEDA-30, 329; SEDA-31, 464)
ECHINOCANDINS
Anidulafungin Comparative studies Anidulafungin 100 mg/ day has been compared with fluconazole 400 mg/day for invasive candidiasis in a rando mized, double-blind, Phase III study in 245 mostly non-neutropenic patients (73C). The safety profile of anidulafungin was similar to that of fluconazole, and less than 5% of patients withdrew because of drug-related adverse events. Infusionrelated reactions after anidulafungin included flushing (2.3%), pruritus (2.3%), rashes (1.5%), and urticaria (0.8%). Other treatment-related adverse reactions included increased hepatic enzyme activities (5.3%), hypokalemia (3.1%), diarrhea (3.1%), and increased bilirubin (1.5%). Susceptibility factors Children Anidula fungin has been investigated in a multi center study in children with neutropenia, who were divided into two cohorts (aged 2–11 and 12–17 years) and received 0.75 or 1.5 mg/kg/day
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(108c). Plasma concentrations after the first and fifth doses were similar across patients, and, in contrast to caspofungin and micafun gin, weight-adjusted clearance rates were consistent across age. The pharmacokinetic parameters were similar to those observed in adults. There were no serious drug-related adverse events. Hepatic or renal disease The effects of hepatic and renal impairment on anidulafungin pharmacokinetics have been assessed (109c). A single intravenous dose 50 mg was given to subjects with varying degrees of hepatic or renal insufficiency or with end-stage renal disease; all were matched to healthy controls. Anidulafungin was well tolerated in both populations. The pharmacokinetic parameters did not different significantly between subjects with renal impairment and controls, and the drug was not detectable in dialysate. The pharmacokinetic parameters were not affected by mild or moderate hepatic insufficiency and small but statistically significant changes in AUC and Cmax in severe hepatic impairment were not clinically relevant. Thus, dosage adjustment of anidulafungin is not needed in subjects with hepatic or renal impairment or in those undergoing hemodialysis. Drug–drug interactions Ciclosporin Clini cally relevant pharmacokinetic or pharma codynamic interactions have not been found in vitro and in vivo between anidulafungin and ciclosporin (110c).
Tacrolimus The interaction of anidulafun gin 200 mg with tacrolimus 5 mg has been investigated in a single-sequence, open study in healthy volunteers; there were no pharmacokinetic interaction and no drugrelated serious adverse events (111c).
Caspofungin Observational studies In 104 consecutive courses of caspofungin for invasive
candidiasis, cure rates were 83% (57/69) for bloodstream infections and 84% (22/ 26) for abdominal infections (112c), response rates similar to those obtained in controlled trials. There were no withdrawals because of adverse events. In 48 patients with non-fungemic invasive candidiasis who received caspofungin 50 mg/day with the option of dosage escala tion of up to 150 mg/day for endocarditis, osteomyelitis or septic arthritis, the overall success rate was 81%. None of the patients had a serious drug-related adverse event or withdrew because of adverse effects (113c). Comparative studies The clinical useful ness of caspofungin for patients with invasive candidiasis has been further sub stantiated by the results of a randomized, double-blind, Phase III comparison of micafungin 100 mg/day and micafungin 150 mg/day with a standard dosage of caspofungin in 595 adults. There were similar success rates. The types and fre quen-cies of adverse events were similar, and less than 5% of patients withdrew prematurely because of drug-related adverse events (114c). Caspofungin has been compared with liposomal amphotericin in the management of febrile neutropenia or invasive fungal infections in an open study of 73 episodes in patients with hematological malignancy (115c). There were fewer episodes of drug toxicity with caspofungin than liposomal amphotericin (58% versus 84%). Response rate for episodes of febrile neutropenia were similar but there were more breakthrough fungal infections with caspofungin (33% versus 0%). None of four episodes of can didemia or hepatosplenic candidiasis responded to caspofungin compared with three of four episodes treated with liposo mal amphotericin. Mortality was signifi cantly higher with caspofungin than with liposomal amphotericin (6/24 versus 2/49), mainly because of an excess of fungal infections. The effectiveness and tolerability of caspofungin 35–50 mg/day for up to 100 days as primary prophylaxis in 123 stem
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cell transplant recipients (117 allogeneic) has been assessed retrospectively (116c). The median duration of caspofungin prophylaxis was 73 (range 10–100) days. Nine patients developed breakthrough invasive fungal infections; by day 100, there were five deaths, two of which were directly attributable to invasive fungal infec tions. There were no caspofungin-related adverse events. Combination studies In 53 adults with documented invasive aspergillosis who received caspofungin and one other mould-active antifungal agent as secondline therapy for an average of 31 days, success rates at the end of combination therapy and day 84 were 55% (29/53) and 49% (25/51) respectively (117c). There were two serious drug-related adverse events, both attributed to voriconazole. None of the patients stopped taking caspofungin because of adverse effects. In an open pilot study of a combination of liposomal amphotericin 3 mg/kg/day and caspofungin at the standard dose or monotherapy with high-dose amphotericin 10 mg/ kg/day for proven or probable invasive aspergillosis in 30 patients, the median durations of treatment were 18 and 17 days respectively (34c). There were signifi cantly more favorable overall responses in the combination group (10 of 15 patients versus 4 of 15 patients). Survival rates at 12 weeks were similar. Infusion-related reactions occurred in three patients in the high-dose monotherapy group. There was a twofold increase in serum creatinine in 4 of 17 patients who received high-dose monotherapy and 1 of 15 patients who received combination therapy; hypokalemia below 3 mmol/l occurred in three patients and two patients respectively. In 40 organ transplant recipients who received voriconazole and caspofungin as primary therapy for invasive aspergillosis compared with a historical control group of 47 consecutive transplant recipients who had received a lipid formulation of ampho tericin as primary therapy, combination
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therapy was independently associated with an improved 90-day survival; there was no evidence of increased risk of adverse effects with the combination regimen (118c). Susceptibility factors Elderly patients In a retrospective analysis of the use of caspofungin in 159 elderly patients, median age 71 (range 65–84) years, who received caspofungin in studies performed by the manufacturers, the median duration of caspofungin therapy was 12–28 days, depending on indication (119c). Adverse events related to caspofungin occurred in generally similar proportions of elderly versus non-elderly patients with invasive candidiasis (clinical 33% versus 27%; laboratory 17% versus 29%), with invasive aspergillosis (clinical 7% versus 13%; laboratory 13% versus 14%) or receiving empirical therapy (clinical 47% versus 47%; laboratory 24% versus 22%). Nephrotoxicity and infusion-related adverse effects developed in comparable proportions of elderly and non-elderly caspofungin recipients. Children In a dose-ranging study in children (aged 2–11 years) and adolescents (aged 12–17 years), 50 mg/m2/day provided comparable exposure to that in adult patients given the standard dose of 50 mg/ day (120c). In a survey of 64 immunocompromised children who were given caspofungin for a median of 37 days (range 3–218) as single agent (n = 20) or in combination (n = 44) at a median daily maintenance dosage of 1.1 (range 0.4–2.9) mg/kg or 34 (range 16–58) mg/m2 (121c), none withdrew because of adverse events. There were mild to mod erate adverse events in 34 patients. Transa minase activities were increased at the end of treatment, but serum bilirubin, alkaline phosphatase, and creatinine were not differ ent from baseline. Of 20 children with proven (n = 12) or probable (n = 8) invasive fungal infections who received caspofungin as monotherapy (n = 5) or in combination (n = 15), 9 had 11
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drug-related adverse events, none of which was severe and none of which led to drug withdrawal (122c). Of 56 patients with febrile neutropenia aged 1–17 years who received 67 courses of caspofungin, 10 had an adverse event that was probably or possibly attributable to caspofungin (123c). Rash and hypokalemia were the most common adverse effects. One of 19 children who received caspofun gin and ciclosporin concurrently developed hepatotoxicity possibly related to caspofungin. Hepatic disease In single-dose and multipledose studies in patients with mild and moderate hepatic insufficiency who received either a single dose of caspofungin of 70 mg or a loading dose of 70 mg followed by 50 mg/day (mild insufficiency) or 35 mg/ day (moderate insufficiency) for 14 days, there were no withdrawals because of adverse events (124c). Dosage adjustment was not required in patients with mild hepa tic insufficiency, but a reduction to 35 mg/ day was needed in patients with moderate hepatic insufficiency. Solid organ transplant recipients Of 22 patients aged 34–67 years with solid organ transplants and invasive candidiasis (n = 6) or invasive aspergillosis (n = 16) who received at least one dose of caspofungin 50–100 mg/day, none had a serious drugrelated adverse event or withdrew because of adverse effects (125c). Critically ill patients In a retrospective study of 224 patients with documented inva sive candidiasis who received caspofungin 50 mg/day or conventional amphotericin 0.6–1.0 mg/kg/day for 10–14 days, 97 (43%) received their first dose in the ICU (126c). After accounting for differences in Acute Physiology and Chronic Health Evaluation II (APACHE II) score, neutropenia status and geographic region, the patients who had their first dose in ICU were more likely to die, but had fewer drug-related adverse events.
Drug–drug interactions Ciclosporin In a retrospective chart analysis of 54 patients who received caspofungin as salvage monotherapy for invasive aspergillosis, the con comitant use of caspofungin and ciclosporin for over 7 days was an independent suscept ibility factor for raised liver transaminases, but clinically relevant hepatotoxicity was rare (127c). In a retrospective study in 12 liver trans plant recipients who received caspofungin with either ciclosporin or tacrolimus, there was no rise in liver enzymes and no cases of hepatotoxicity (128c).
Micafungin (SEDA-29, 290; SEDA-30, 331; SEDA-31, 464) Observational studies In 23 patients aged 27–82 years with hematological malignan cies and febrile neutropenia, the rate of success with micafungin was 74% (129c). There were one or more adverse events in five patients, but all were below grade 2. Among 18 patients with acute leukemia who developed febrile neutropenia, treat ment was successful in 14 patients (130c). None required withdrawal or dose reduc tion because of adverse events, except for one patient with severe hypokalemia.
Comparative studies Micafungin 100 mg/ day has been compared with liposomal amphotericin 3 mg/kg/day in 531 adults (32C). Candidemia constituted approxi mately 85% and 88% were non-neutro penic. The overall success rate in both treatment arms was similar (in about 90%), as was survival. There were fewer treatment-related adverse events with mica fungin than with liposomal amphotericin, including those that were serious or led to treatment withdrawal. Micafungin 100 mg/day and micafungin 150 mg/day have been compared with a standard dosage of caspofungin (50 mg/ day) in 595 mostly (92%) non-neutropenic
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adults with candidemia and other forms (15%) of invasive candidiasis (114c). At the end of blinded intravenous therapy, treatment was considered successful in 76% of the patients who received mica fungin 100 mg/day, in 71% of those who received micafungin 150 mg/day and in 72% of those who received caspofungin. There were no significant differences in time to culture negativity, mortality, or relapsing and emergent infections between treatments, and the patterns and types of adverse events were similar. Susceptibility factors Neonates In a Phase I, single-dose, multicenter, open study of three doses of intravenous micafungin (0.75, 1.5, and 3.0 mg/kg) in 18 premature infants weighing under 1000 g (6 in each dosage group) (131c). Another 5 infants (500–1000 g) were given 0.75 mg/kg only. The pharmacokinetics of micafungin in preterm infants were linear. However, the infants on average had a more rapid rate of clearance compared with published data in older children and
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adults. There were no serious drug-related adverse events. Transplant recipients The maximum tol erated dose of intravenous micafungin in patients undergoing hemopoietic stem cell transplantation has been explored in an open study of increasing doses of 3, 4, 6 or 8 mg/kg/day from 7 days to a maximum of 28 days or until neutropenia resolved (132c). The maximum tolerated dose was defined as the highest dose did not cause the same grade 3 or 4 adverse event in three or more patients. All 36 participants received treatment for at least 8 (median 18, range 8–28) days. One withdrew consent and another 11 withdrew and received another systemic antifungal agent for a suspected infection. Adverse events were those expected for patients undergoing hemopoietic stem cell transplantation. No patient had a grade 3 or 4 adverse event that was considered causally related to micafungin. Thus, the maximum tolerated dose of micafungin can be inferred to be 8 mg/kg/day or higher.
References 1. Paredes AH, Lewis JH. Terbinafine induced acute autoimmune hepatitis in the setting of hepatitis B virus infection. Ann Pharmacother 2007;41(5):880–4. 2. Perveze Z, Johnson MW, Rubin RA, Sellers M, Zayas C, Jones JL, Cross R, Thomas K, Butler B, Shrestha R. Terbina fine-induced hepatic failure requiring liver transplantation. Liver Transpl 2007;13(1): 162–4. 3. Pillans PI, Boyd IW. Toenails and agranu locytosis. Intern Med J 2007;37(8):572–5. 4. Møller M, Bygum A. Cutaneous lupus erythematosus induced by terbinafine. Ugeskr Laeg 2006;168(50):4427–8. 5. Nishiwaki F, Matsumura Y, Morita N, Kore-Eda S, Miyachi Y, Omoto M. Acro dermatitis continua of Hallopeau due to oral terbinafine. Br J Dermatol 2007;157(5): 1073–4.
6. Lorentz K, Booken N, Goerdt S, Goebeler M. Subacute cutaneous lupus erythemato sus induced by terbinafine: case report and review of literature. J Dtsch Dermatol Ges 2008;6(10):823–7, 823–8. 7. Hivnor CM, Hudkins ML, Bonner B. Terbinafine-induced subacute cutaneous lupus erythematosus. Cutis 2008;81(2): 156–7. 8. Danielsen AG, Thomsen JS, Svejgaard EL. Severe skin rash in patients treated with terbinafine. Ugeskr Laeg 2006;168(44): 3825–6. 9. Sidoroff A, Dunant A, Viboud C, Halevy S, Bavinck JN, Naldi L, Mockenhaupt M, Fagot JP, Roujeau JC. Risk factors for acute generalized exanthematous pustulosis (AGEP) – results of a multinational casecontrol study (EuroSCAR). Br J Dermatol 2007;157(5):989–96.
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117. Maertens J, Glasmacher A, Herbrecht R, Thiebaut A, Cordonnier C, Segal BH, Killar J, Taylor A, Kartsonis N, Patterson TF, Aoun M, Caillot D, Sable C, Caspofun gin Combination Therapy Study Group. Multicenter, noncomparative study of caspofungin in combination with other anti fungals as salvage therapy in adults with invasive aspergillosis. Cancer 2006;107(12): 2888–97. 118. Singh N, Limaye AP, Forrest G, Safdar N, Muñoz P, Pursell K, Houston S, Rosso F, Montoya JG, Patton P, Del Busto R, Aguado JM, Fisher RA, Klintmalm GB, Miller R, Wagener MM, Lewis RE, Kon toyiannis DP, Husain S. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Trans plantation 2006;81(3):320–6. 119. Dinubile MJ, Strohmaier KM, Lupinacci RJ, Meibohm AR, Sable CA, Kartsonis NA. Efficacy and safety of caspofungin therapy in elderly patients with proven or suspected invasive fungal infections. Eur J Clin Microbiol Infect Dis 2008;27(8): 663–70. 120. Walsh TJ, Adamson PC, Seibel NL, Flynn PM, Neely MN, Schwartz C, Shad A, Kaplan SL, Roden MM, Stone JA, Miller A, Bradshaw SK, Li SX, Sable CA, Kart sonis NA. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother 2005;49(11):4536–45. 121. Groll AH, Attarbaschi A, Schuster FR, Herzog N, Grigull L, Dworzak MN, Beutel K, Laws HJ, Lehrnbecher T. Treatment with caspofungin in immunocompromised paediatric patients: a multicentre survey. J Antimicrob Chemother 2006;57(3):527–35. 122. Merlin E, Galambrun C, Ribaud P, Blanc T, Michel G, Auvrignon A, Stéphan JL. Effi cacy and safety of caspofungin therapy in children with invasive fungal infections. Pediatr Infect Dis J 2006;25(12):1186–8. 123. Koo A, Sung L, Allen U, Naqvi A, DrynanArsenault J, Dekker A, Maloney AM, Dupuis LL. Efficacy and safety of caspofun gin for the empiric management of fever in
124.
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126.
127.
128.
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neutropenic children. Pediatr Infect Dis J 2007;26(9):854–6. Mistry GC, Migoya E, Deutsch PJ, Winchell G, Hesney M, Li S, Bi S, Dilzer S, Lasseter KC, Stone JA. Single- and multiple-dose administration of caspofungin in patients with hepatic insufficiency: implications for safety and dosing recommendations. J Clin Pharmacol 2007;47(8):951–61. Petrovic J, Ngai A, Bradshaw S, WilliamsDiaz A, Taylor A, Sable C, Vuocolo S, Kartsonis N. Efficacy and safety of caspo fungin in solid organ transplant recipients. Transplant Proc 2007;39(10):3117–20. DiNubile MJ, Lupinacci RJ, Strohmaier KM, Sable CA, Kartsonis NA. Invasive candidiasis treated in the intensive care unit: observations from a randomized clin ical trial. J Crit Care 2007;22(3):237–44. Morrissey CO, Slavin MA, O’Reilly MA, Daffy JR, Seymour JF, Schwarer AP, Szer J. Caspofungin as salvage monotherapy for invasive aspergillosis in patients with hae matological malignancies or following allo geneic stem cell transplantation: efficacy and concomitant cyclosporin A. Mycoses 2007;50 (Suppl 1):24–37. Saner F, Gensicke J, Rath P, Fruhauf N, Gu Y, Paul A, Radtke A, Malagó M, Broelsch C. Safety profile of concomitant use of cas pofungin and cyclosporine or tacrolimus in liver transplant patients. Infection 2006;34(6):328–32. Toubai T, Tanaka J, Ota S, Shigematsu A, Shono Y, Ibata M, Hashino S, Kondo T, Kakinoki Y, Masauzi N, Kasai M, Iwasaki H, Kurosawa M, Asaka M, Imamura M. Efficacy and safety of micafungin in febrile neutropenic patients treated for hematolo gical malignancies. Intern Med 2007;46(1): 3–9. Yanada M, Kiyoi H, Murata M, Suzuki M, Iwai M, Yokozawa T, Baba H, Emi N, Naoe T. Micafungin, a novel antifungal agent, as empirical therapy in acute leukaemia patients with febrile neutropenia. Intern Med 2006;45(5):259–64. Heresi GP, Gerstmann DR, Reed MD, van den Anker JN, Blumer JL, Kovanda L, Keirns JJ, Buell DN, Kearns GL. The phar macokinetics and safety of micafungin, a
Antifungal drugs
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novel echinocandin, in premature infants. Pediatr Infect Dis J 2006;25(12):1110–5. 132. Sirohi B, Powles RL, Chopra R, Russell N, Byrne JL, Prentice HG, Potter M, Koblinger S. A study to determine the
519 safety profile and maximum tolerated dose of micafungin (FK463) in patients undergoing haematopoietic stem cell transplantation. Bone Marrow Transplant 2006;38(1):47–51.
Oscar Ozmund Simooya
28
Antiprotozoal drugs
ANTIMALARIAL DRUGS 4-AMINOQUINOLINES (CHLOROQUINE AND CONGENERS) (SEDA-29, 294; SEDA-30, 336; SEDA-31, 469)
Amodiaquine
(SED-15, 178; SEDA-28, 315; SEDA-31, 469)
Hematologic Amodiaquine þ artesunate and artesunate þ lumefantrine are currently the preferred regimens for the treatment of malaria in most of sub-Saharan Africa. How ever, there are limited data on their safety and efficacy in human immunodeficiency virus (HIV)-infected populations. In a study in 26 HIV-positive and 134 HIV-negative children with malaria (35 and 258 episodes respectively) in Uganda, 12 of the former were taking antiretroviral drugs (1C). They were all given amodiaquine þ artesunate and those with HIV infection were also given co-trimoxazole prophylaxis and antiretro viral therapy according to national guide lines. The study lasted 18 and 29 months in the HIV-positive and HIV-negative subjects, respectively. There was a greater risk of malaria recurrence in the HIV-negative subjects (2.9% versus 13%). The risk of neutropenia after 14 days was higher among the HIV-positive children (45% versus 6%) and 16% of the episodes of neutropenia in the HIV-positive children were classified as severe to life-threatening (neutrophil count 30% fall in concentration
Figure 1 Algorithms for determining dosage regimens of sapropterin.
Continue sapropterin 5–20 mg/kg/day
N
Stop
Y
Continue sapropterin 5–20 mg/kg/day
> 30% fall in concentration
M.C. Allwood
Y
Continue sapropterin 20 mg/kg/day
Chapter 34
Measure × 3 Give sapropterin 20 mg/kg/day
Day 1
>30% fall in concentration
Vitamins, intravenous solutions, and drugs and formulations used in nutrition
concentration fell in all subgroups; the response was greater in those with lower baseline concentrations (23c). Most of the reported adverse events were mild and all resolved without complications. Adverse events that were reported by at least 2% of the patients were headache (n = 50, 10%), diarrhea (24, 5%), abdominal pain (23, 5%), nausea (16, 3%), upper respiratory tract infections (17, 3%), fatigue (14, 3%), flatulence (11, 2%), vomiting (9, 2%), reduced appetite (8, 2%), pharyngolaryngeal pain (9, 2%), hyper-reflexia (10, 2%) and tremor (9, 2%). The authors commented that the response to sapropterin dihy drochloride could not be predicted from the baseline phenylalanine concentration. Placebo-controlled studies The efficacy of sapropterin 10 mg/kg/day has been studied in 89 patients with phenylketonuria, mean age 20 years, in a Phase III, multicenter, randomized, double-blind, placebocontrolled trial for 6 weeks (24C). The blood concentration of phenylalanine fell from 843 to 236 µmol/l in those who were given sapropterin and rose by 3 µmol/l with placebo. There were adverse events that might have been drug-related in 11 of the 47 patients who took sapropterin and 8 of the 41 who took placebo; upper respiratory tract infections were the most common. In a 22-week, multicenter, randomized, placebo-controlled study in 80 patients aged at least 8 years, sapropterin reduced plasma phenylalanine concentrations dose-depen dently from 844 to 645 µmol/l (25c). There were adverse events in 68 patients; all but one were mild or moderate in intensity, but neither the severe nor any of the three serious adverse events was considered to have been related to sapropterin and none led to withdrawal. In an international, double-blind, rando mized, placebo-controlled study in 90 patients with phenylketonuria, sapropterin 20 mg/kg/ day caused the following adverse effects in more than 5% of subjects and more often than placebo: rhinorrhea (n = 7, 21%), headache (7, 21%), cough (5, 15%), pharyn golaryngeal pain, diarrhea, and vomiting (4 each, 12%), nasal congestion (3, 9%) and reduced appetite, erythema, excoriation,
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lymphadenopathy, and toothache (2 each, 6%); none was severe or serious (26C). Cardiovascular Sapropterin significantly increased endothelium-dependent vasodil atation in smokers but not in non-smokers (27c).
VITAMIN C (Ascorbic acid) (SED-15, 351; SEDA-30, 394; SEDA-31, 548) Metabolism Renal vitamin C is a precur sor of oxalate and promotes its absorption, potentially causing hyperoxaluria, the com monest cause being related to enzymic defi ciency. Less well recognized is subacute insidious nephropathy from secondary causes, for example excessive vitamin C intake and malabsorption, which causes cal cium chelation with fatty acids, producing enteric hyperoxaluria. This can be accentu ated by dehydration and hypocitraturia from diarrhea-induced metabolic acidosis (28A). • A 73-year-old man took an oxalate-rich diet plus vitamin C 680 mg/day and furosemide and developed chronic diarrhea and a serum creatinine of 740 µmol/l (compared with 106 µmol/l 4 months before; reference range 50–120). The cause was postulated as calcium oxalate-induced nephropathy, which was confirmed by hyperoxaluria and diffuse intraluminal crystals and extensive interstitial fibrosis on biopsy. He was haemodialysed six times to remove excess oxalate. Within 2 weeks of stopping vitamin C, his creatinine fell to 273 µmol/l, and 3 months later, on a low-oxalate diet and vitamin B6 100 mg/day, his urine oxalate-to-creatinine ratio fell from 0.084 to 0.02 (normal less than 0.035), while the creatinine fell and stabilized at 158 µmol/l.
High-dose vitamin C can cause hyperoxaluric nephropathy and progressive renal insufficiency, especially if aggravated by diarrhea, an oxalate-rich diet, metabolic acidosis, and dehydration. The authors
612
conclude that the diagnosis should be sus pected in patients with unexplained renal insufficiency when associated with these susceptibility factors and recommend mon itoring urinary oxalate in patients taking high-dose vitamin C and renal biopsy if necessary.
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M.C. Allwood
have been aggravated by the nephropathic adverse effects of tenofovir. However, after recovery of renal function, the tenofovir was restarted without further deterioration.
VITAMIN E (SED-15, 3677; SEDA-29, 355; SEDA-30, 395; SEDA-31, 549)
VITAMIN D ANALOGUES (SED-15, 3669; SEDA-29, 354; SEDA-30, 394; SEDA-31, 549) Mineral metabolism Hypercalcemia in patients with human immunodeficiency virus (HIV) infection is usually associated with conditions such as lymphoma and granulomatous diseases. Severe hypercal cemia secondary to vitamin D intoxication and secondary renal insufficiency in an HIV-positive patient has been described (29A). • A 38-year-old man developed acute symptoms of nausea, constipation, apathy, drowsiness, weakness, and polyuria. He had AIDS and had taken efavirenz, lamivudine, and tenofovir for 2 years. Physical examination was normal and there were no pulmonary, cardiac, or abdominal abnormalities. However, he had hypercalcemia (total serum calcium total 3.9 mmol/l; ionized plasma calcium 2.0 mmol/l) and renal insufficiency (creatinine 405 µmol/l); phosphate was normal. There were calcium oxalate crystals in the urine, and renal ultrasound showed normal-sized kidneys with a mild parenchymatous nephropathy reflecting acute renal insufficiency. There was ST segment elevation in leads V1 and V3 and diffuse T wave flattening. He had taken excess hormones and vitamins over 5 years, including multivitamin preparations, intramuscular testosterone and, for the last 4 months, a daily intramuscular veterinary injection of vitamins A (2 500 000 IU), D (700 000 IU), and E (700 IU). All medications were withdrawn and he was rehydrated and given furosemide. His condition slowly improved and his renal function returned to near normal after 7 days.
The authors suggested that the acute renal failure secondary to vitamin D abuse could
Infection risk In an analysis of the AlphaTocopherol, Beta-Carotene Cancer Preven tion (ATBC) study, a randomized con trolled trial of the effects of vitamin E 50 mg/day and beta-carotene 20 mg/day in 29 023 men aged 50–69 years with lung can cer in Finland in 1985–1993, neither vitamin E nor beta-carotene had any overall effect on the incidence of tuberculosis, but there was an effect of dietary vitamin C on the risk of tuberculosis associated with vitamin E (30c). Among participants who obtained 90 mg/day or more of vitamin C in foods (n = 13 502), vitamin E supplementation increased the risk of tuberculosis by 72% (95% confidence interval [CI] = 4, 185). This effect was restricted to those who smoked heavily. In those who were not given vitamin E supplements, dietary vita min C was negatively associated with the risk of tuberculosis. Death A meta-analysis of 11 randomized placebo-controlled trials of high-dose vita min E (over 400 IU/day) showed increased mortality (SEDA-29, 355). Its use has been studied in patients with cardiovascular disease (31c). After adjust ment for age and sex there was no associa tion between the use of vitamin E and mortality (adjusted hazard ratio [HR] = 0.93; 95% CI = 0.74, 1.15). Deaths were more frequent in those with a history of diabetes, stroke, coronary artery bypass graft surgery, or myocardial infarction, and were associated with the use of warfarin, nitrates, and diuretics. Mortality was increased in vitamin E users who had a
Vitamins, intravenous solutions, and drugs and formulations used in nutrition
history of stroke (adjusted HR = 3.64; CI = 1.73, 7.68), coronary bypass graft surgery (adjusted HR = 4.40; CI = 2.83, 6.83) or myo cardial infarction (adjusted HR = 1.95; CI = 1.29, 2.95), and independently in those taking nitrates (adjusted HR = 3.95; CI = 2.04, 7.65), warfarin (adjusted HR = 3.71; CI = 2.22, 6.21), and diuretics (adjusted HR = 1.83; CI = 1.35, 2.49).
PARENTERAL NUTRITION (SED-15, 2700; SEDA-29, 353; SEDA-31, 549) Liver A surgical patient with short bowel syndrome developed parenteral nutritionassociated liver disease and was successfully treated with fish oil-based lipids (32A). • A full-term neonate weighing 3.45 kg was referred at 60 days of age for surgery for short bowel secondary to a mid-gut volvulus. He was given parenteral nutrition and after 4 months developed conjugated hyper bilirubinemia. He was unable to tolerate enteral feeding, so parenteral nutrition was continued, despite jaundice. Infection and biliary obstruction were ruled out, and a range of treatments for jaundice were initiated without success. He continued to deteriorate despite cholecystectomy and irrigation of the biliary tree. After 80 days of parenteral nutrition, the lipid was changed from omega-6 lipids (Lipofundin®, B. Braun) and replaced by an omega-3 based emulsion (Omegaven®, Fresenius–Kabi), in an initial dose of 0.2 g/kg/day, increasing by 0.2 g/kg increments to 1.5 g/kg/day. His hepatic function improved rapidly over the following months, and was completely normal after 8 months, despite continuing cyclic parenteral nutrition with 50% enteral feeding.
This carefully investigated case provides further evidence for the potential value of fish oil-based fat emulsions to prevent and overcome parenteral nutrition-associated liver disease in neonates and small children. Biliary tract Cholestasis is a major complication of total parenteral nutrition,
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and is difficult to treat. It can progress to eventual cirrhosis and liver failure. The benefits of ursodeoxycholic acid (ursodiol) in the treatment of cholestasis can be explained by its effects on bile composition and flow and its cytoprotective, membranestabilizing, and immunomodulatory effects. The evidence for a role of ursodeoxycholic acid in parenteral nutrition-associated cholestasis has been reviewed (33R). In the short term it improves the biochemical and clinical signs and symptoms. However, this may not necessarily predict the outcome and it may not be effective in patients with short bowel syndrome or in those with resected terminal ileum because of reduced absorption of ursodeoxycholic acid. However, as optimal dosing, timing, duration of therapy, and long-term effects on the out come and prognosis in parenteral nutritionassociated cholestasis require further studies, its clinical effectiveness remains uncertain. Drug administration route Percutaneous central venous catheters are commonly inserted in neonatal intensive care nurseries. Placement of the catheter tip in a large central vein is desirable. Occasionally, owing to difficult venous access, catheter tips are left in places that are less than ideal (34A). • A female infant with complicated gastroschisis developed signs of short bowel syndrome after surgery. She was treated with a combination of enteral and parenteral nutrition. A central venous line was inserted through a scalp vein and the tip was in a vessel at the level of the mandible. About 2 weeks later she became unwell, with episodes of bradycardia and large milky pharyngeal aspirates, confirmed to contain parenteral nutrition fluid. Chest radiography showed aspiration. After withdrawal of parenteral nutrition, there was a dramatic reduction in oral secretions. The central venous line was removed because of presumed extravasation.
The authors recommended that when cathe ters are in unusual positions it may be helpful to obtain a second radiograph from a differ ent angle or an ultrasound scan to confirm the position of the catheter tip.
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References 1. Saltzman MD, King EC. Central physeal arrests as a manifestation of hypervitamino sis A. J Pediatr Orthop 2007;27(3):351–3. 2. Penniston KL, Tanumihardjo SA. The acute and chronic affects of vitamin A. Am J Clin Nutr 2006;83:191–201. 3. Caballero MR, Lukawska J, Lee TH, Dugue P. Allergy to vitamin B12: two cases of suc cessful desensitization with cyanocobalamin. Eur J Allergy Clin Immunol 2007;62:1341–2. 4. Moloney FJ, Hughes R, O’Shea D, Kirby B. Type I immediate hypersensitivity reaction to cyanocobalamin but not hydroxycobala min. Clin Exp Dermatol 2008;33:412–4. 5. Pfab F, Willi R, Albert A, Huss-Marp J, Athanasiadis GI, Jakob T, Ollert M, Ring J, Darsow U. Anaphylactic reaction to folic acid verified by provocational testing. Eur J Allergy Clin Immunol 2007;62(7):823–4. 6. Thöny B, Auerbach G, Blau N. Tetrahydro biopterin biosynthesis, regeneration and functions. Biochem J 2000;347(Pt 1):1–16. 7. Burton BK, Kar S, Kirkpatrick P. Fresh from the pipeline: sapropterin. Nat Rev Drug Dis cov 2008;7:199–200. 8. Michals-Matalon K. Sapropterin dihydrochlor ide, 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin, in the treatment of phenylketonuria. Expert Opin Investig Drugs 2008;17(2):245–51. 9. Burnett JR. Sapropterin dihydrochloride (Kuvan/phenoptin), an orally active syn thetic form of BH4 for the treatment of phenylketonuria. Drugs 2007;10(11):805–13. 10. Sanford M, Keating GM. Spotlight on sapropterin in primary hyperphenylalanine mia. BioDrugs 2009;23(3):201–2. 11. Hegge KA, Horning KK, Peitz GJ, Hegge K. Sapropterin: a new therapeutic agent for phenylketonuria. Ann Pharmacother 2009; 43(9):1466–73. 12. Schaub J, Däumling S, Curtius HC, Nieder wieser A, Bartholomé K, Viscontini M, Schircks B, Bieri JH. Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis. Arch Dis Child 1978;53(8):674–6. 13. Doggrell SA. Is sapropterin treatment suita ble for all subjects with phenylketonuria? Expert Opin Pharmacother 2008;9(1):145–7.
14. Levy H, Burton B, Cederbaum S, Scriver C. Recommendations for evaluation of respon siveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment. Mol Genet Metab 2007;92(4):287–91. 15. Blau N, Bélanger-Quintana A, Demirkol M, Feillet F, Giovannini M, MacDonald A, Trefz FK, van Spronsen FJ. Optimizing the use of sapropterin (BH(4)) in the manage ment of phenylketonuria. Mol Genet Metab 2009;96(4):158–63. 16. Trefz FK, Scheible D, Götz H, FrauendienstEgger G. Significance of genotype in tetrahydrobiopterin-responsive phenylketo nuria. J Inherit Metab Dis 2009;32(1):22–6. 17. Muntau AC, Röschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA. Tetrahydrobiopterin as an alternative treatment for mild phenylketo nuria. N Engl J Med 2002;347(26):2122–32. 18. Zurfl€ uh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N. Molecular genetics of tetrahydrobiop terin-responsive phenylalanine hydroxylase deficiency. Hum Mutat 2008; 29(1):167–75. 19. Desviat LR, Pérez B, Bèlanger-Quintana A, Castro M, Aguado C, Sa´ nchez A, García MJ, Martínez-Pardo M, Ugarte M. Tetrahydro biopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype. Mol Genet Metab 2004;83(1–2):157–62. 20. Feillet F, Clarke L, Meli C, Lipson M, Morris AA, Harmatz P, Mould DR, Green B, Dor enbaum A, Giovannini M, Foehr E, Saprop terin Research Group. Pharmacokinetics of sapropterin in patients with phenylketonuria. Clin Pharmacokinet 2008;47(12):817–25. 21. Karacic I, Meili D, Sarnavka V, Heintz C, Thöny B, Ramadza DP, Fumic K, Mardesic D, Baric I, Blau N. Genotype-predicted tet rahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) defi ciency. Mol Genet Metab 2009;97(3):165–71. 22. Sanford M, Keating GM. Sapropterin: a review of its use in the treatment of primary hyperphenylalaninaemia. Drugs 2009;69(4): 461–76.
Vitamins, intravenous solutions, and drugs and formulations used in nutrition 23. Burton BK, Grange DK, Milanowski A, Vock ley G, Feillet F, Crombez EA, Abadie V, Hard ing CO, Cederbaum S, Dobbelaere D, Smith A, Dorenbaum A. The response of patients with phenylketonuria and elevated serum phe nylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. J Inherit Metab Dis 2007;30(5):700–7. 24. Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz FK, Whitley CB, Feillet F, Feigenbaum AS, Bebchuk JD, Christ-Schmidt H, Dorenbaum A, Saprop terin Research Group. Efficacy of saprop terin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine con centration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet 2007;370(9586):504–10. 25. Lee P, Treacy EP, Crombez E, Wasserstein M, Waber L, Wolff J, Wendel U, Doren baum A, Bebchuk J, Christ-Schmidt H, Sea shore M, Giovannini M, Burton BK, Morris AA. Sapropterin Research Group. Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. Am J Med Genet A 2008;146A(22):2851–9. 26. Trefz FK, Burton BK, Longo N, Casanova MM, Gruskin DJ, Dorenbaum A, Kakkis ED, Crombez EA, Grange DK, Harmatz P, Lipson MH, Milanowski A, Randolph LM, Vockley J, Whitley CB, Wolff JA, Bebchuk J, Christ-Schmidt H, Hennermann JB, Saprop terin Study Group. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind,
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placebo-controlled study. J Pediatr 2009;154 (5):700–7. 27. Ueda S, Matsuoka H, Miyazaki H, Usui M, Okuda S, Imaizumi T. Tetrahydrobiopterin restores endothelial function in long-term smokers. J Am Coll Cardiol 2000;35(1):71–5. 28. Rathi S, Kern W, Vitamin LK. C-induced hyperoxaluria causing reversible tubulointersti tial nephritis and chronic renal failure: a case report. J Med Case Reports 2007;1:155–60. 29. Tuon FF, Nihei CH, Gryschek RC, Seguro AC. Vitamin D intoxication: a cause of hypo calcaemia and acute renal failure in a HIV patient. Int J STD AIDS 2008;19:137–8. 30. Hemilä H, Vitamin KJ. E supplementation may transiently increase tuberculosis risk in males who smoke heavily and have high dietary vita min C intake. Br J Nutr 2008;100(4):896–902. 31. Hayden KM, Welsh-Bohmer KA, Wengreen HJ, Zandi PP, Lyketsos CG, Breitner JC. Cache County Investigators. Risk of morta lity with vitamin E supplements: the Cache County study. Am J Med 2007;120(2):180–4. 32. Ekema G, Falchetti D, Boroni G, Tanca AR, Altana C, Righetti L, Ridella M, Gambarotti M, Berchich L. Reversal of severe parenteral nutrition-associated liver disease in an infant with short bowel syndrome using parenteral fish oil (omega-3 fatty acids). J Pediatr Surg 2008;43:1191–5. 33. San Luis VA, Btaiche IF. Ursodiol in patients with parenteral nutrition-associated cholesta sis. Ann Pharmacother 2007;41:1867–72. 34. Jardine LA, Inglis GDT, Davies MW. Aspiration of parenteral nutrition – a pre viously unreported complication of central venous access in an infant: a case report. J Med Case Reports 2008;2:63–5.
J.K. Aronson
35
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
Editor’s note: The clotting factors, such as factor VIII, and anticoagulant proteins, such as activated factor C, are included in Chapter 33.
COUMARIN ANTICOAGULANTS
(SED-15, 983; SEDA-29, 358; SEDA-30, 399; SEDA-31, 553)
Cardiovascular Matrix g-carboxyglutamic acid protein, a vitamin K-dependent pro tein, is a potent in vivo inhibitor of arterial calcification (1E) and Growth Arrest Spe cific Gene 6 (Gas-6), which is also vitamin K-dependent, protects the vasculature by effects on vascular smooth muscle cell apoptosis and movement (2R). Unlike the coagulant factors, which are carboxylated in the liver, these two proteins are carboxy lated in blood vessels, but both are inhibited by warfarin. Furthermore, poly morphisms of the VKORC1 gene (the CC and CT genotypes) confer nearly twice the risk of vascular events (stroke, coronary artery disease, aortic dissection) and are associated with lower levels of osteocalcin and Protein Induced in Vitamin K Absence or Antagonism II (PIVKA-II, a des-gSide Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32035-6 2010 Elsevier B.V. All rights reserved.
carboxyprothrombin) than those with the TT genotype (3c). In this context it has therefore been suggested that three factors may influence arterial calcification: (a) the level of expression of matrix g-carboxyglu tamic acid protein; (b) vitamin K status; and (c) mutations or polymorphisms that affect the activities of either g-glutamyl carboxylase or vitamin K epoxide reduc tase complex (4Hr). One might therefore expect long-term warfarin treatment to be associated with an increased risk of vascu lar disease. Calciphylaxis (vascular calcification, thrombosis, and skin necrosis) has been attributed to warfarin in a patient with diabetes mellitus (5A). However, in 116 patients with diabetes and hypertension, half of whom were taking warfarin, there was no effect on systolic blood pressure or pulse pressure (6c). Arterial thrombosis has been attributed to the prothrombotic effect of warfarin in a patient with protein S deficiency (7A). Sensory systems The incidence of ocular bleeding has been studied in 210 patients taking warfarin and in 210 sex-matched and age-matched controls (8c). The inci dences of ocular bleeding were 11% in the patients and 3.8% in the controls; the risk was higher in older than in younger patients and was five times higher in patients with hypertension. A large subconjunctival hemorrhage occurred in a 76-year-old woman with an international normalized ratio (INR) of 10;
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the authors suggested that such abnormal ities could herald more serious risks (9A). Hematologic Thrombocytopenia with antibodies similar to those found in heparin-induced thrombocytopenia (HIT) has been reported in patients in whom there had been no previous exposure to heparin. In three cases the thrombocyto penia was preceded by an infectious or inflammatory episode (10A). In another case it was associated with warfarin (11A). • A 69-year-old woman with no previous known heparin exposure was given warfarin after a total knee replacement. After 7 days she developed thrombocytopenia and died after a complex postoperative course, which included multiple thrombotic events (adrenal necrosis presumably caused by adrenal vein thrombosis, digital infarcts, deep vein thrombosis), and disseminated intravascular coagulation. The presurgery serum was negative for HIT antibodies but three postoperative sera were strongly positive in three different assays. Her serum contained anti-PF4–heparin antibodies of the IgG class with strong platelet-activating properties, which is a feature of some HIT sera, especially those from patients with the delayed-onset type, the type that begins several days after stopping heparin.
The authors of these reports have called this syndrome ‘spontaneous HIT’, a potentially scatological nomenclature, which ought to be replaced, since it is also misleading, as it has nothing to do with heparin administration. Acquired hemophilia with antibodies to factor VIII has been reportedly masked by concurrent warfarin therapy, to which the prolonged activated partial thromboplastin time was falsely attributed (12A). Liver It has been hypothesized that the hepatotoxicity that has been attributed to warfarin in experimental animals is due to the formation of a toxic metabolite, o-hydroxyphenylacetylacetaldehyde, which is formed when warfarin is metabolized to 3-hydroxycoumarin, rather than 7-hydroxy coumarin; the former is more likely to be formed in patients with reduced CYP2A6 activity (13H).
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Skin Warfarin-induced skin necrosis (14A) can occur early in therapy because of local coagulation, since the anticoagulant factors protein C and protein S are vitamin Kdependent; it is more likely to occur in those who have deficiencies of these pro teins, as further reports have highlighted (15A), one in association with a leukocyto clastic vasculitis (16A). In one case there was also a mutation in the methylene tetrahydro folate reductase (MTFR) gene (17A), but this may have been coincidental. The necro sis usually affects areas with abundant sub cutaneous tissues and can start with painful plaques (18A); in one case painful prenecro tic lesions occurred in a patient with hetero zygous protein C deficiency (19A). A rare case affecting the eyelids has been reported (20A). In two other cases skin necrosis attrib uted to warfarin was accompanied by HIT (21A, 22A); it was not clear whether the two events were coincidental or mechanistically linked. However, skin and mucosal ulcera tion can occur in HIT in patients who have not received warfarin (23A); in one case skin necrosis was associated with deficiency of both protein C and protein S (24A). Musculoskeletal The effects of warfarin on bone mineral density have been assessed in 5533 men aged 65 years and older (25C). Warfarin users and 5212 non-users had similar baseline bone mineral density at the hip and spine and similar annualized bone loss at the total hip as 2683 non-users during a mean follow-up of 5.1 years; the risk of non-spinal fractures was similar in the two groups (adjusted HR = 1.06; 95% CI = 0.68, 1.65). Immunologic Coumarins can rarely cause hypersensitivity reactions. Leukocytoclastic vasculitis has been reported (26A, 27A). • A 48-year-old man who had taken warfarin sodium for 2 months developed acute renal failure and reddish purplish macules on his hypogastric regions and legs. Kidney biopsy showed allergic interstitial nephritis and a punch skin biopsy showed a leukocytoclastic vasculitis. Both biopsies also contained large numbers of eosinophils, highly suggestive of a drug-induced reaction.
Drugs that affect blood coagulation, fibrinolysis, and hemostasis • A leukocytoclastic vasculitis has been attributed to acenocoumarol in a 62-year-old woman because of the close temporal relation between exposure to the drug and the onset of the symptoms, and spontaneous resolution of the lesions after acenocoumarol was withdrawn.
Teratogenicity The teratogenic effects of warfarin (‘warfarin embryopathy’) include chondrodysplasia punctata, frontal bossing, a short neck, low birth weight, short limbs, polydactyly, and respiratory difficulty sec ondary to choanal atresia (28R, 29c). Neurological effects include optic atrophy and microcephaly (30c, 31A), the Dandy– Walker malformation and agenesis of the corpus callosum (32Ar), and cerebral hemi spheric atrophy and porencephaly (33A). Neurodevelopmental delay has also been described (34Ar). • A 27-year-old man, whose mother had taken warfarin throughout her pregnancy, had nasal and digital hypoplasia and thoracic kyphosis, delayed developmental milestones, bilateral deafness, and mild intellectual impairment. An MRI brain scan was normal but an MRI scan of the spinal cord showed cord thinning at mid-C2 and compression at C6 secondary to a posterior disc bulge; there was spinal cord compression at T4–T6 with focal thoracic kyphosis and posterior disc bulging.
In a study based on observational data collected by a Teratology Information Ser vice on 1186 pregnant women, of whom 173 had taken a coumarin anticoagulant (almost all phenprocoumon) and 1013 had not been exposed to potential teratogens, the crude rate for live births was higher in the controls (0.91 versus 0.53) and there were lower crude rates for induced abortion (0.02 ver sus 0.22) and spontaneous abortion (0.07 versus 0.25) (35c). When correction was introduced for potential biases, the rates for spontaneous abortion increased to 0.16 and 0.42 respectively. When adjustment was made for delayed entry, the rates of induced abortion were 0.04 (controls) and 0.29 (war farin) and for spontaneous abortion 0.05 and 0.36 respectively. Susceptibility factors Genetic In patients who were genotyped
201 for
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polymorphisms in 29 genes related to warfarin pharmacodynamics and pharmaco kinetics, polymorphisms in or flanking the genes VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX, and ORM1-ORM2, and haplotypes of VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2, and ORM1-ORM2 were significantly associated with dose (36c). The associations with VKORC1, CYP2C9, CYP2C18, and CYP2C19 remained significant after correction for multiple testing, but the associations with CYP2C18 and CYP2C19 were explained by linkage disequilibrium with CYP2C9*2 and/ or CYP2C9*3. PROC and APOE were both significantly associated with dose after cor rection within each gene. A multiple regres sion model with VKORC1, CYP2C9, PROC, and the non-genetic predictors age, body weight, drug–drug interactions, and indication for treatment jointly accounted for 62% of the variance in warfarin dose. The authors of this chapter were perhaps unduly optimistic about the potential contri bution of these findings to the clinical use of warfarin, as others have been (37R). Some have been less impressed (38r, 39r). It has been commented that while there is evidence of clinical validity of both VKORC1 and CYP2C9 genes in predicting stable warfarin doses (an intermediate outcome), there is little or no evidence that VKORC1 and CYP2C9 testing will reduce the risk of severe bleeding events (40R). The American College of Medical Genetics has concluded (February 2008) that ‘there is insufficient evidence, at this time, to recommend for or against routine CYP2C9 and VKORC1 test ing in warfarin-naive patients’ (41S). A pharmacogenetic algorithm has been developed based on a study in 1015 patients, in whom the independent predic tors of therapeutic dose were VKORC1 polymorphism 1639/3673 G> A (–28% per allele); body surface area (þ11% per 0.25 m2); CYP2C9*3 (–33% per allele); CYP2C9*2 (–19% per allele); age (–7% per decade); target INR (þ11% per 0.5 unit increase); amiodarone use (–22%); smoker status (þ10%); race (–9%); and cur rent thrombosis (þ7%) (42C). The algorithm
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explained just over 50% of the variability in the warfarin dose in a sample of 292 indivi duals in the cohorts. A clinical equation explained only about 20% of the variability. In a prospective study of the use of the algo rithm in patients initiating warfarin therapy, two had a major hemorrhage. The algorithm is available on the web (43H). African-Americans have slightly higher warfarin dosage requirements. Polymorph isms in the gene encoding apolipoprotein E (APOE) may partly explain this variability by altering transport of vitamin K to the liver, as has been shown in a prospective study of 232 individuals (52% Caucasian and 48% African-American) (44c). In multi variate analyses, the presence of the 4 allele was associated with a statistically signifi cantly higher dose of warfarin among Afri can-Americans (45 mg versus 35 mg) but not in Caucasians (38 mg versus 35 mg). In addi tion, the warfarin maintenance dose increased in African-Americans according to the genotypes that have previously asso ciated with differential hepatic chylomicron clearance (2/2 or 2/3, 30 mg; 3/3, 35 mg; 3/4 or 4/4, 45 mg), although the 4/4 genotype was rare and not clearly associated with higher doses. The association of APOE with warfarin dosing was independent of CYP2C9 and VKORC1 polymorphisms. In a prospective study in 362 patients with INRs of 2–3 the maintenance dose of warfarin was significantly related to CYP2C9 genotype in Caucasians but not in African-Americans; among the former, variant carriers (CYP2C9*2 and CYP2C9*3) needed 31 mg/week while wild-type carriers required 38 mg/week, even after adjustment for possible con founding factors (45c). Among the AfricanAmericans there was no difference based on CYP2C9 genotype. In another comparison of CYP2C9 and VKORC1 1173C/T genotypes and the risk of hemorrhage among African-Americans and European-Americans there were 44 major and 203 minor episodes of hemor rhage during 555 person-years in 446 patients (mean age 61 years, 50% men, 227 African-Americans) (46c). The variant CYP2C9 genotype conferred an increased
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risk of major hemorrhage (HR = 3.0; 95% CI = 1.1, 8.0) but not minor hemorrhage (HR = 1.3; 95% CI = 0.8, 2.1). The risk of major hemorrhage was 5.3 times higher (95% CI = 0.4, 64) before stabilization of therapy, 2.2 times higher (95% CI = 0.7, 6.5) after stabilization and 2.4 times higher (95% CI = 0.8, 7.4) during all periods when anticoagulation was not stable. The variant VKORC1 1173C/T genotype did not confer a significant increase in the risk of major hemorrhage (HR = 1.7; 95% CI = 0.7, 4.4) or minor hemorrhage (HR = 0.8; 95% CI = 0.5, 1.3). The distribution of genotypes of CYP2C9*2, CYP2C9*3, and VKORC1 Asp36Tyr genotypes in Ethiopians has been reported: 13/150 were heterozygous for CYP2C9*2; 7/150 were heterozygous for CYP2C9*3; and 39/154 were hetero zygous and 3/154 were homozygous for the Asp36Tyr polymorphism in VKORC1, which confers warfarin resistance (47c). In contrast to African-Americans, Asian patients require a much lower maintenance dose than Caucasians. In a study of five single nucleotide polymorphisms of the vita min K epoxide reductase complex subunit 1 gene (VKORC1) and the CYP2C9*3 var iant 108 Korean patients with atrial fibrilla tion, the genotypic frequencies of VKORC1 þ1173CT and CYP2C9*1/*3 were 18 and 10% respectively; VKORC1 þ1173CC and CYP2C9*3/*4 were found in one patient each (48c). Patients with at least one copy of the VKORC1 þ1173C allele or the H7 (group B) haplotype required a significantly higher dose of warfarin (n = 20; 5.5 mg/day) than those who were homozygous for the þ1173T allele or the H1 (group A) haplo type (3.8 mg/day). There were also statisti cally significant differences in warfarin dose between those with the CYP2C9*1/*1 var iant (4.3 mg/day) and those with the geno types CYP2C9*1/*3 and CYP2C9*3/*4 (2.7 mg/day). Of 66 Korean patients in whom CYP2C19 polymorphisms were evaluated, 25 were homozygous for the wild type, 4 had hetero zygous mutations at both loci and others had mutations on either the CYP2C19*2 or *3 locus (49c). There was a higher incidence of
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
bleeding complications in those with a higher allele frequency of CYP2C19. However, the distribution of polymorphisms was similar to that in a Caucasian population. In 191 patients taking warfarin, half of whom were Malays and half Chinese, two CYP2C9 genotypes were detected; 93% had CYP2C9 1/1 and 7% CYP2C9 1/3 (50c). Warfarin doses were higher in patients with the former genotype but patients with the latter genotype had a higher rate of serious and life-threatening episodes of bleeding (15 versus 6.2 per 100 patients per 6 months). Renal disease In a systematic review of case series, cohort studies and randomized controlled trials in patients undergoing dia lysis, the risk of bleeding associated with warfarin compared with no warfarin or subcutaneous heparin was reported as the number of bleeding episodes per number of patient-years of warfarin exposure or fol low-up (51M). Eight studies were eligible for analysis, seven of which evaluated the use of warfarin for the prevention of hemo dialysis access thrombosis. Formal meta analysis was not possible because of hetero geneity. Major bleeding episodes occurred at a rate of 0.1–0.54 events per patient-year of warfarin exposure, about twice as high as in patients who received either no warfarin or subcutaneous heparin. These results may have been confounded by co-morbidities. Dental extraction In 58 women and 92 men, mean age 66 years, the mean INR was 2.5 (range 0.9–4.2), and 49 (33%) had an INR over 2.5; 10 bled after dental extrac tion, 5 of whom had an INR over 2.5; they were all managed conservatively and none was admitted to hospital (52c). Drug administration route The successful use of intravenous warfarin has been reported in a 27-year-old woman with endstage Crohn’s disease, who was resistant to oral warfarin and unable to receive sub cutaneous low-molecular-weight heparin because of adverse effects (53A).
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In two patients who required long-term anticoagulation but had gastrointestinal dysmotility, sublingual warfarin was effec tive; the target INR was achieved within 6 days (54A). Drug overdose The anticoagulants in modern rodenticides, so-called ‘superwar farins’, have very long durations of action. In cases of overdose with such agents, prolonged therapy may be required before coagulation returns to normal, as another case has demonstrated (55A). Drug–drug interactions The frequency, severity, and preventability of cases of cerebral hemorrhage due to drug–drug interactions involving warfarin have been evaluated retrospectively in 593 patients; 59 were thought to have been related to warfarin, implying an incidence of 1.7/100 000 treatment-years (56c). Of the 59 cases, 26 (44%) had a fatal outcome, compared with 136 (25%) among the non warfarin-treated patients. A drug–drug interaction with warfarin could have con tributed in 24 patients, and in 7 of these the bleeding complication was thought to have been possibly avoidable. Antibacterial drugs Different antibacterial drugs can enhance the actions of coumarin anticoagulants in different ways. The risk of bleeding in patients taking acenocoumarol or phenprocoumon and a range of antibac terial drugs has been retrospectively assessed in a cohort study of 52 102 users of aceno coumarol and 7885 users of phenprocoumon, with 139 159 person-years of follow-up, dur ing which 838 patients (1.4%) were hospita lized for bleeding while taking coumarins (57c). Of the 62 different antibiotics they had taken, 19 were associated with a bleed ing episode and 10 were associated with a statistically significant increased risk. The relative risks of bleeding were 3–5 for amoxicillin, azithromycin, ciprofloxacin, co-amoxiclav, co-trimoxazole, doxycycline, and pheneticillin, 9 for tetracycline, and 43 for cefradine and neomycin.
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Antifungal azoles Azoles when given sys temically inhibit the metabolism of warfarin, potentiating its effects. Such an effect has also been described in six patients after topi cal use of the azoles econazole (n = 5) and bifonazole (n = 1), as lotions, powders, or creams (58A). Three were heterozygous for a CYP2C9 variant allele, all with INR values greater than 11. In most cases the azole had been applied to the vulva and/or groin. Benzethonium chloride A woman who took grapefruit seed extract for 3 days had a minor subcutaneous hematoma 3 days later, and her INR was 7.9 (59AE). The inhibitory effects of three constituents of the extract were tested in an in vitro baculosome assay. All three contained the synthetic preserva tive benzethonium chloride and no authentic grapefruit seed extract was found. Benzetho nium chloride was a potent inhibitor of CYP3A4 and CYP2C9 activity in vitro. Chitosan The use of chitosan on two sepa rate occasions prolonged the INR markedly in an 83-year-old man taking warfarin 2.5 mg/day (60A). Chitosan is a positively charged polymer that binds to negatively charged lipids and bile acids in the gastro intestinal tract and can reduce the absorption of vitamins A, D, E, and K. Reduced avail ability of vitamin K may have been respon sible for this proposed interaction; it is unlikely that chitosan altered (i.e. increased) the absorption of warfarin, as suggested by the authors of this report. Cinacalcet In a phase 1, randomized, dou ble-blind, placebo-controlled, two-treat ment, two-period, crossover study in 21 healthy subjects, oral cinacalcet 30 mg bd for 7 days and once on day 8 had no effect on the pharmacokinetics or pharmaco dynamics of a single dose of warfarin 25 mg on day 5, the R- and S-enantiomers being measured separately (61C). Coenzyme Q The risk of bleeding and supratherapeutic INRs associated with the
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use of complementary and alternative med icines (CAM) in patients receiving warfarin has been studied prospectively in an acute care, academic, and research hospital in Canada (62c). Of 171 patients, 87 (51%) reported at least one bleeding event and 36 (21%) had a supratherapeutic INR; 73 (43%) had used at least one CAM product previously reported to interact with war farin. Coenzyme Q was associated with an increased risk of self-reported bleeding (OR = 3.69; 95% CI = 1.88, 7.24). Doxycycline A patient who took oral doxycycline and warfarin developed promi nent ecchymoses on the arms associated with a marked rise in INR to 6.5; on withdrawal of the doxycycline the INR fell to 2.3 (63A). The authors attributed the interaction to dis placement of warfarin from albumin and possibly inhibition of the CYP isoenzymes; they did not discuss the possibility of a phar macodynamic interaction. Duloxetine Possible potentiation of aceno coumarol by duloxetine has been reported in a 44-year-old woman (64A). This would be consistent with inhibition of CYP2C9 by duloxetine. However, the opposite effect has been reported in a 63-year-old woman with Alzheimer’s disease (65A). Efavirenz Efavirenz has been reported to increase the INR in a patient taking war farin, an interaction that was attributed to inhibition of CYP2C9 (66A). Fluoroquinolones The possible inter actions of warfarin with the fluoroquino lones ciprofloxacin, levofloxacin, and moxifloxacin have been systematically reviewed (67M). There were 22 publications suitable for evaluation, including 16 case reports or case series, 2 retrospective cohort studies, and 4 prospective studies, which included 2 placebo-controlled studies. The six structured reports showed mean increases in prothrombin time and INR, but they were clinically insignificant.
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
However, some patients had significant increases above the target range. Increased anticoagulation was typically observed dur ing the first week of fluoroquinolone ther apy. Two patients died because of bleeding complications. This analysis suggests that, as often is the case with drug interactions, fluoroquinolones may potentiate the effects of warfarin only in susceptible individuals, the effect not being demonstrable in relatively small clinical trials. Case–control studies may be the best way of eliciting such effects. Glucocorticoids Of 29 children with can cer, those who were taking glucocorticoids had significantly lower warfarin require ments (68c). Glucosamine There is evidence of an inter action of warfarin with glucosamine (69AM). • A 71-year-old man, who had taken warfarin 7.5 mg/day for 5 years for atrial fibrillation and had had an INR of 2.5–3.2, had also taken glucosamine hydrochloride 500 mg þ chondroitin sulfate 400 mg bd for arthritis. He then trebled the dosage of glucosamine þ chondroitin and about 3 weeks later his INR rose to 3.9. The dosage of glucosamine þ chondroitin was halved, but his INR 16 days later was 4.7. The supplement was then withdrawn and his warfarin dosage was changed to 7.5/3.75 mg on alternate days; 16 days later his INR was 2.6.
A subsequent pharmacovigilance survey of spontaneously reported adverse events in warfarin-treated patients who had concomi tantly taken glucosamine, glucosamine þ chondroitin sulfate, or chondroitin sulfate, using the US MedWatch database, yielded 20 reports of increased INR, bleeding, or bruising in patients taking warfarin with glucosamine or glucosamine þ chondroitin sulfate; in some cases, when the dosage of glucosamine was reduced the INR returned to the previous target range. In one case there was an intraventricular hemorrhage and a subdural hematoma. The database of the Uppsala Monitoring Centre contained 21 spontaneous reports of increased INR asso ciated with glucosamine, 17 of which resolved when glucosamine was stopped. The mechan ism is not known.
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Influenza vaccine In a prospective audit of 106 patients taking long-term warfarin, influ enza immunization had no effect on anti coagulant control and no bleeding or thrombotic complications were reported (70c). Lopinavir + ritonavir A complicated inter action involved warfarin, co-trimoxazole and lopinavir þ ritonavir has been reported (71A). The main details were as follows: • A 42-year-old man, who was taking warfarin 5.5 mg/day (INR 2–3), was given high-dose co trimoxazole for Pneumocystis jiroveci pneumonia. His INR rose to 4.4. The dose of warfarin was reduced to 3.0 and 3.5 mg/day on alternate days and his INR fell to 2.1. Two weeks later the dosage of co-trimoxazole was reduced (INR not stated) and 2 weeks after that he was given zidovudine, lamivudine and lopinavir þ ritonavir. The INR fell to 1.1–1.3. When the dosage of warfarin was increased to 13 mg/day the INR rose to 2–3.
The possible mechanisms for this scenario are as follows: • poor adherence to therapy – the authors said that this was ruled out; • a change to a warfarin formulation with poor availability – this was not mentioned but seems unlikely; • an interaction with a change in diet – the authors said that this was ruled out; • a drug–drug interaction.
If this was a drug–drug interaction it could have been due to reduced absorption of warfarin (unlikely), displacement of war farin from plasma albumin causing increased clearance (unlikely, since such an effect would produce only a transient change in INR), induction of warfarin meta bolism by lopinavir þ ritonavir, or induction of co-trimoxazole metabolism, resulting in reduced inhibition by co-trimoxazole of warfarin metabolism. Of these, induction by lopinavir þ ritonavir of warfarin metabo lism by CYP2C9 seems the most likely, as such induction has been reported (72c). Another clearer report has also implicated lopinavir þ ritonavir (66A) and similar inter actions have been described with nelfinavir and nevirapine (73A, 74R). When combina tions of these drugs are used in HAART
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such interactions can be very complex (75A). Lycium barbarum (Chinese wolfberry) A rise in the INR in an 80-year-old Chinese woman has been attributed to a herbal tea containing Lycium barbarum (76A). Metronidazole Metronidazole inhibits the metabolism of S-warfarin, enhancing its anticoagulant effect, as another report, a case of intracerebral hemorrhage in a 78 year-old woman, has shown (77A). Nafcillin In a 39-year-old man warfarin dosage requirements increased from 32 to 88 mg/week 1 week after the introduction of nafcillin; when nafcillin was withdrawn the warfarin requirements slowly fell over sev eral weeks to 42–48 mg/week (78Ar). The authors attributed this to enzyme induction by nafcillin. Noscapine The Swedish adverse drug interactions register (SWEDIS) received eight reports of suspected interaction between noscapine and warfarin up to December 2006; there was bleeding in one case and an increased INR in the others; the effect occurred within 3 days to 3 weeks of the introduction of noscapine (79AcE). Stan dard pharmacovigilance methods for asses sing the strength of this putative signal suggested that it was real. In vitro, nosca pine inhibited CYP2C9 and CYP3A4, the former providing a possible mechanism for this interaction. NSAIDs Of 100 patients undergoing total hip replacement surgery who were screened for mutations in the CYP2C9 gene, 52 were using NSAIDs (80c). Patients with a CYP2C9 mutation had a mean INR curve similar to those without the mutation when NSAIDs were not co-administered. How ever, among the 30 patients who were het erozygous for a CYP2C9 mutation only concomitant use of an NSAID resulted in an INR over 4.9 (0% versus 39%).
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Paracetamol The interaction of paraceta mol with warfarin, in which long-term paracetamol prolongs the INR markedly (SEDA-23, 377; SEDA-29, 358), has again been reported anecdotally (81A). Rifampicin Since rifampicin is a power ful enzyme inducer, doses of coumarin anticoagulants may need to be increased markedly during co-administration, as has been reported again, in a 79-year-old man, in whom a 5- to 6-fold increase in warfarin dose was required to maintain an INR in the target range; after rifampi cin was withdrawn the dose of warfarin was gradually reduced over the next 2 months (82A). A similar course of events occurred in a 73-year-old woman taking acenocoumarol who needed a sixfold increase in dose after the introduction of rifampicin (83A). Selective serotonin reuptake inhibitors (SSRIs) The risk of bleeding associated with the concurrent use of SSRIs and the coumarins acenocoumarol or phenprocou mon has been compared in a case–control study with the risk in users of non-steroidal anti-inflammatory drugs, using a Dutch linkage system, including pharmacy and linked hospitalization records for about 2 million subjects (84c). There were 1848 patients with abnormal bleeding. Users of SSRIs were at significantly increased risk of hospitalization because of non-gastro intestinal tract bleeding (adjusted OR = 1.7; 95% CI = 1.1, 2.5) but not because of gastrointestinal tract bleeding (adjusted OR = 0.8; 95% CI = 0.4, 1.5). Users of non-steroidal anti-inflammatory drugs had a similar increased risk of nongastrointestinal bleeding (adjusted OR = 1.7; 95% CI = 1.3, 2.2), and a higher risk of gastrointestinal bleeding (adjusted OR = 4.6; 95% CI = 3.3, 6.5). Statins In a case–control study of 79 207 warfarin users with atrial fibrillation there were 1518 cases of upper gastrointestinal or intracranial bleed and 15 100 matched
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
controls without bleeding (85c). Long-term statin use (1 year or more) was associated with a lower risk of any bleeding (OR = 0.80; 95% CI = 0.66, 0.97). How ever, there was no association between bleeding and recent statin use ( 30% thrombocytopenia, clots in the extracorporeal circulation, posi tive for PF4/heparin antibodies, and improvement from HIT with the use of an alternative anticoagulant or another strategy for HIT (127c). HIV infection In a retrospective compari son of HIV-infected patients and uninfected patients, there was a higher incidence of HIT in the former (15/53 versus 0/106) after treat ment with unfractionated heparin and/or low-molecular-weight heparin (128c). Myeloproliferative disorders HIT is rarely reported in patients with myeloproliferative disorders; the authors of a report of three cases (two with essential thrombocythemia and one with polycythemia rubra vera) have suggested that this may be because of underdiagnosis, since these patients have high platelet counts (129A). Vascular surgery In a prospective study of the development and function of PF4/ heparin antibodies after infrainguinal bypass procedures blood samples were obtained from 79 patients before surgery and at 7, 14 and 28 days after; 67 reported previous expo sure to heparin (130c). There were PF4/ heparin antibodies before surgery in six, four of whom also had a positive result on an aggregation assay. After 28 days, 22
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subjects developed PF4/heparin antibodies and 5 of these also tested positive for plate let-activating antibodies. There were no cases of thrombocytopenia. There was early graft occlusion in three patients, but all were nega tive for antibodies and had normal platelet function. The authors concluded that patients who undergo vascular surgery often develop PF4/heparin antibodies, plate let-activating antibodies being detected in up to 11%, but that thrombocytopenia and vas cular graft thrombosis are uncommon.
Management HIT should be suspected whenever the platelet count falls by more than 50% from baseline or to below 150 109/l, 5–14 days after starting heparin (or sooner if there was prior heparin exposure), or if new thrombosis occurs during or soon after heparin treatment, other causes having been excluded. When HIT is suspected, heparin should be immediately withdrawn and an alternative anticoagulant used; alternatives have included danaparoid, fondaparinux, sulodexide (131A), and direct thrombin inhibitors such as argatroban, lepirudin, and bivalirudin. The American College of Chest Physi cians has issued guidelines on the recogni tion, treatment and prevention of HIT (132S). The key recommendations include the following: • for patients in whom the clinician considers the risk to be over 1.0%, the platelet count should be monitored during heparin therapy; • for those who are receiving heparin or have received heparin within the previous 2 weeks, HIT should be investigated if the platelet count falls by at least 50% and/or a thrombotic event occurs between days 5 and 14 inclusive after the start of heparin therapy, even if the patient is no longer receiving heparin when the thrombosis or thrombocytopenia occurs; • for those with strongly suspected or confirmed HIT, whether or not complicated by thrombosis, an alternative non-heparin anticoagulant should be used; • for those with strongly suspected or confirmed HIT, a coumarin should not be used until after the platelet count has substantially recovered (usually to at least 150 109/l); and when it is used it should be started in a low maintenance dose (maximum 5 mg of warfarin or 6 mg of
Drugs that affect blood coagulation, fibrinolysis, and hemostasis phenprocoumon); and the non-heparin anticoagulant should be continued until the platelet count has reached a stable plateau, the INR has reached the intended target range, and after a minimum overlap of at least 5 days between non-heparin anticoagulation and coumarin therapy; • for those who are taking a coumarin when HIT is diagnosed, vitamin K 10 mg orally or 5–10 mg intravenously should be given.
Metabolism Extreme hypertriglyceridemia in a 32-year-old man followed intravenous infusion of heparin for 5 days and was attrib uted to temporary depletion of lipoprotein lipase caused by heparin (133A). However, it is difficult to explain why this is the first reported case of this effect if lipoprotein lipase inhibition is the mechanism, since this is a well-known effect of heparin; severe lipoprotein lipase deficiency may have been partly due to other factors in this patient. Electrolyte balance Long-term use of heparin can cause hyperkalemia by inhibit ing aldosterone production. Heparin reduces the number and affinity of angio tensin-2 (AT2) receptors in the adrenal zona glomerulosa and reversibly suppresses aldosterone production within a few days. Hyperkalemia is more common in elderly patients and in those with renal insufficient and, as illustrated by another case report, diabetes mellitus (134A). Skin Delayed-type (class IV) hypersensitiv ity skin reactions to a low-molecular-weight heparin can be accompanied by cross-reac tivity to other heparins and heparinoids. When test doses of the low-molecular weight heparin bemiparin and several other heparins and heparinoids were given to eight patients with a history of local ecze matous reactions after subcutaneous enox aparin, seven had cross-reactivity to subcutaneous bemiparin, and nearly all the other substances that were tested caused local eczematous reactions in at least some patients, with the exception of fondapari nux, which was well tolerated by all (135c). Bemiparin had the highest cross-reactivity
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with enoxaparin. Substances with a lower molecular weight did not cross-react less often. The authors concluded that there was no relation between cross-reactivity and molecular weight. Delayed hypersensitivity skin reactions to enoxaparin and nadroparin did not show cross-reactivity to fondaparinux in a 30-year-old pregnant woman (136A). For reports of skin necrosis attributed to heparin, see warfarin above. Musculoskeletal The mechanism whereby heparin causes osteoporosis during longterm treatment is unknown. In animals, heparin reduces the number of osteoblasts and increases the number of osteoclasts, and these effects are accompanied by changes in biochemical markers of bone turnover, including a dose-related reduction in alkaline phosphatase and an increase in urinary type I collagen cross-linked-pyridi noline, a marker of bone resorption; in pregnant women taking long-term heparin there are subclinical reductions in bone density (137R). Osteoprotegerin, a glycoprotein that binds heparin, is a decoy receptor for RANKL, which is responsible for osteoclast development. Plasma concentrations of osteoprotegerin have been measured in 22 male students, who were given one of five regimens: • 5000 IU of unfractionated heparin intravenously followed by an infusion of 450 IU/kg/day for 3 days and then unfractionated heparin 5000 IU 4 and 24 hours later (n = 7); • subcutaneous low-molecular-weight heparin 200 IU/kg on 3 days and then unfractionated heparin 5000 IU 4 and 24 hours later (n = 8); • subcutaneous low-molecular-weight heparin 100 IU/kg once (n = 8); • subcutaneous unfractionated heparin 250 IU/kg once (n = 7); • a control infusion of saline for 12 hours (n = 7).
Bolus intravenous unfractionated heparin caused a prompt increase in plasma osteo protegerin from 0.68 to 1.13 µg/l, followed by a fall during continuous infusion, reaching baseline after 8 hours (138C). There were similar increases when repeated boluses of
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unfractionated heparin were given after the end of treatment. Subcutaneous low-molecu lar-weight heparin 200 IU/kg caused a modest but significant increase in plasma osteoprotegerin, similar to subcutaneous unfractionated heparin, but a threefold higher anti-Xa activity. Immunologic In a patient who had had a type I hypersensitivity reaction to heparin 2 years before, and no desensitization, bivalirudin did not elicit a reaction (139A). Drug resistance Resistance to heparin has been reviewed (140R). It is said to occur in up to 22% of patients who require cardio pulmonary bypass during cardiac surgery and is associated with reduced antithrombin concentrations. Treatment options include antithrombin or fresh frozen plasma. How ever, there have been no direct comparisons of these two treatments. Susceptibility factors Renal disease Low molecular-weight heparins can accumulate in renal insufficiency and cause bleeding, and the risk is greatest in patients with a creatinine clearance under 30 ml/minute (141R). There is some evidence that tinza parin does not accumulate to the same extent as enoxaparin (142R). Drug contamination Bacterial contamina tion Bacterial contamination is a risk asso ciated with the use of multiple-dose vials. In a 4-month study, multi-dose vials, singledose vials and vials containing locally pre pared mixtures were collected from various hospital wards for analysis, including 68 multi-dose vials containing sodium chloride 0.9% or heparin with added preservative, 17 single-dose vials containing water for injection or sodium chloride 0.9% and 11 vials containing preservative-free mixtures of heparin and sodium chloride 0.9% (143E). Four of the 96 vials were not sterile: two were contaminated with spore-forming bacteria and two with coagulase negative staphylococci. Three were multi-dose vials
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containing a preservative. The date of first use was not marked on 27 of the vials. In 15 of 68 multi-dose vials, the time limit after first use had been exceeded. In a systematic review of outbreaks of infection due to bacterial or viral contami nation, 2250 patients described in 128 arti cles were analysed; they were mostly from intensive care units or hematology depart ments (144M). Septicemia was the most frequent hospital-acquired infection. The most common source of infection was from contamination of blood products and heparin/sodium chloride solutions. The most frequent pathogens were hepatitis A virus, Yersinia enterocolitica, and Serratia spp. for blood products and Burkholderia cepacia and Enterobacter spp. for sub stances other than blood products. Morta lity was highest if erythrocytes or total parenteral nutrition formulas were contami nated. In 64 of the outbreaks multi-dose vials had been used against the manufac turers’ recommendations. The authors con cluded that drug-related outbreaks of infection are particularly likely when basic hygiene is not observed. They issued a cau tion about the use of multiple-dose vials. An outbreak of Burkholderia cepacia infection in 15 patients, which lasted for 3 months, was finally traced to contamination of a heparin vial (145c). An outbreak of infection due to Pseudo monas putida and Stenotrophomonas malto philia has also been reported in association with a contaminated heparin catheter-lock solution (146c). Of 154 patients who had had a catheter lock infused with solution from the lots that were suspected of being contaminated, 48 had central venous cathe ters, and by day 7 of the outbreak 18 of them had become symptomatic; of the 30 asymptomatic patients, 26 provided blood samples for culture, 10 of whom developed a fever soon after. There was P. putida bac teremia in 32 cases; 9 also had infection due to S. maltophilia. Oversulfated chondroitin sulfate After four deaths and 350 adverse events, 40% of which were serious, that were attributed
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
to a particular formulation of heparin of Chinese origin, the formulation was recalled (147r). It was subsequently discovered that it was contaminated by an oversulfated chondroitin sulfate that contained a disac charide repeat unit of glucuronic acid linked to a b-N-acetylgalactosamine; the disacchar ide unit had an unusual sulfation pattern, being sulfated at the 2-O and 3-O positions of the glucuronic acid as well as at the 4-O and 6-O positions of the galactosamine, and the traditional screening tests could not dif ferentiate between affected and unaffected batches (148E). The oversulfated chondroi tin sulfate was responsible for severe non IgE-mediated anaphylactic (anaphylactoid) reactions, directly activating the kinin– kallikrein pathway in human plasma, lead ing to generation of bradykinin and C3a and C5a, potent anaphylotoxins derived from complement proteins (149E). Activation of these two pathways was unexpectedly linked to and depended on fluid-phase acti vation of factor XII. However, it has been suggested that the recalled heparin formulations may also have contained several other heparin-like and non-heparin substances, many of which have not been fully investigated, and whose association with the reported adverse events has not been established (150R). In a Brazilian study, four different heparin solutions were evaluated by mag netic nuclear resonance, and significant differences were found, including contami nation with other dermatan sulfates (151E). Whatever the cause of the adverse effects of the Chinese product, various procedures have been initiated in an attempt to harmo nize international controls for quality assur ance of heparin formulations. Drug dosage regimens In a systematic review of twice-daily and thrice-daily administration of heparin 12 studies were identified involving 7978 patients; 1664 were given thrice-daily and 6314 twicedaily heparin (152M). After adjustment for baseline risks, there was no difference in the overall rate of venous thromboembolism. However, the risk of major bleeding was
Chapter 35
significantly greater with heparin (0.96 versus 0.35).
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thrice-daily
Drug administration route Inhalation Inha lation of the low-molecular-weight heparin the certoparin has been compared with sub cutaneous injection in healthy subjects in a crossover study (153c). Certoparin had a longer duration of action after inhalation than after injection. There were no changes in lung function or other adverse effects. Subcutaneous Local bruising is almost inevitable after subcutaneous injection of heparin. Three different injection techniques have been studied in 36 patients, each of whom received three injections by the same investigator (154c). There were significantly smaller and fewer bruises when the injection was given over 30 seconds and when a 10 second injection was followed by a delay of 10 seconds before withdrawing the needle. In a similar study in 50 patients, heparin was injected over 10 seconds on the right of the abdomen and over 30 seconds on the left (155c). Bruising occurred in 64% with injec tions of 10 seconds duration and 42% with those of 30 seconds; the size of the bruising was smaller after the latter and pain intensity and duration were also reduced.
Danaparoid sodium Danaparoid is a low-molecular-weight hepar inoid, consisting of a mixture of sulfated glycosaminoglycans – heparan sulfate (84%), dermatan sulfate (12%), and chondroitin sul fate (4%). It inhibits factors Xa and IIa in a ratio greater than heparin (over 20), with a minimal effect on platelet function (156R, 157R). It has little effect on activated partial thromboplastin time, prothrombin time, and thrombin time. It is as effective as heparins in inhibiting the formation of thrombi. Hematologic Severe bleeding is uncommon with danaparoid but was 3.1% in one series (158c).
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The major advantage of danaparoid over low-molecular-weight heparins is its low rate of cross-reactivity with heparin-associated anti bodies from patients with HIT (159R). It has therefore been used in patients with heparinassociated thrombocytopenia who require further anticoagulation after withdrawal of heparin (160A, 161c, 162R). However, crossreactivity has been described (163A–165A, 166c) and danaparoid is not always effective (167c). It should not be used if there is in vitro cross-reactivity between heparin and danapar oid, the risk of which is quite high: of 281 patients who underwent cardiovascular surgery 81 developed HIT and 23 (28%) had in vitro cross-reactivity to danaparoid sodium (168c). In a review of 51 pregnancies in 49 patients, all of whom had had heparin intol erance (32 due to HIT and 19 mainly due to heparin-induced skin rashes) and had a cur rent and/or past history of thromboembolic complications, danaparoid cross-reactivity was suspected in four patients with HIT and five with skin reactions; it was confirmed serologically in one of the two patients with HIT who were tested (169M). Of 1418 patients, 1291 had HIT, in 39% of whom there was thromboembolism (170c). Danaparoid was given instead, for 1 day to 3.5 years and follow-up was for a further 3 months; 84% of the patients survived; 64% had no or minor adverse events and 20% had serious non-fatal adverse events. Major bleed ing was reported in 8.1% of treatment epi sodes. Clinical cross-reactivity of danaparoid (new or persistent platelet count reduction and/or new or extended thrombosis) was con firmed serologically in 23 of 36 patients with positive pretreatment serological danaparoid cross-reactivity and in 22 of 32 additional patients tested at the time of the new event, that is, a total of 45 patients (3.2%). In one study of antibodies to PF4/heparin complexes in 63 patients, two types of anti bodies were identified: • antibodies that only or mainly bound to PF4/ heparin complexes (type 1 antibodies); most of the epitopes recognized probably involved both heparin and PF4; • antibodies that had similar reactivity to r-PF4 and PF4/heparin (type 2 antibodies); the antigens recognized were possibly neoepitopes
J.K. Aronson
mainly expressed by modified PF4 and by PF4/ heparin complexes.
Most of the samples (n = 59) contained IgG antibodies, often associated with IgA antibodies, which were more frequently type 2 antibodies, and/or IgM antibodies. With unfractionated heparin thrombocytopenia was associated with both types of antibodies, whereas only type 1 antibodies were detected after low-molecular-weight heparin. Further more, cross-reactivity with danaparoid sodium was present only in those with type 1 antibodies and mainly involved patients who had received low-molecular-weight heparin. Cross-reactivity between heparins and danaparoid is uncommon but can result in thrombotic complications, which can be fatal (171A). Skin Delayed hypersensitivity reactions have been reported in patients given dana paroid (172A–174A). They usually present as pruritic, eczematous lesions at the injection sites, but generalized eczema can also occur. There may be cross-reactivity with heparin (175A–177A). Susceptibility factors Renal disease Dana paroid sodium is excreted by the kidneys, and its action is prolonged in patients with renal failure (178C). Its half-life in hemo dialysis patients was 31 hours compared with 18 hours in healthy volunteers (179C).
DIRECT THROMBIN INHIBITORS (SED-15, 1142; SEDA-29, 362; SEDA-30, 409; SEDA-31, 559)
Argatroban Hematologic Argatroban has been suc cessfully used in patients with HIT (180A–182A, 183c–190c). Susceptibility factors Renal disease Since argatroban is predominantly metabolized
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
in the liver, in contrast to heparins and danaparoid, it is believed that no dosage adjustment is required in patients with renal insufficiency (191C). However, pro longed duration of action of argatroban has been described in patients with normal liver function but impaired renal function (192A); one had antiphospholipid antibo dies and end-stage renal disease maintained on peritoneal dialysis (193A).
Bivalirudin Hematologic Bivalirudin has been suc cessfully used in patients with HIT (194A, 195A, 196c, 197C).
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(n = 1162), starting the evening before sur gery (201C). There were episodes of venous thromboembolism in 60 (6.7%) of the 897 patients who were given enoxaparin, 53 (6.0%) of the 880 who were given dabigatran etexilate 220 mg, and 75 (8.6%) of the 874 who were given 150 mg. There were no sig nificant differences in major bleeding rates, increases in liver enzymes, or acute coronary events. In a double-blind, randomized study, 1896 patients undergoing unilateral total knee arthroplasty were randomized to oral dabigatran etexilate 220 or 150 mg/ day or subcutaneous enoxaparin 30 mg bd for 12–15 days after surgery (202C). Dabigatran was less efficacious than enox aparin, but bleeding rates were similar and no drug-related hepatic damage was recorded.
Dabigatran Dabigatran etexilate, a prodrug of dabiga tran, can be given orally. Its pharmacology has been reviewed (198R, 199R). Comparative studies Dabigatran versus enoxaparin In a double-blind, randomi zed, non-inferiority study in 2076 patients undergoing total knee replacement, oral dabigatran etexilate 150 or 220 mg/day was compared with subcutaneous enoxa parin 40 mg/day for 6–10 days; the patients were followed for 3 months (200C). Venous thromboembolism occurred in 193 of the 512 patients who were given enoxaparin, in 183 of the 503 who were given dabigatran etexilate 220 mg and in 213 of the 526 who were given 150 mg. The incidences of major bleeding did not differ significantly across the three groups (1.3, 1.5, and 1.3% respectively). There were no significant differences in the inci dences of liver enzyme rises or acute cor onary events. In a double-blind, non-inferiority study 3494 patients undergoing total hip replace ment were randomized to treatment for 28–35 days with dabigatran etexilate 220 mg/ day (n = 1157) or 150 mg/day (n = 1174) or subcutaneous enoxaparin 40 mg/day
Lepirudin Hematologic Lepirudin has been success fully used in patients with HIT (203A–206A, 207cr). Immunologic An anaphylactic reaction has been reported in a 57-year-old woman who had received five courses of lepirudin therapy uneventfully (208A).
Ximelagatran Liver In a systematic review of 13 randomi zed controlled trials in which ximelagatran and melagatran have been compared with conventional anticoagulants, 22 639 patients were included (209M). The indications for treatment were perioperative prophylaxis of deep vein thrombosis, management of deep vein thrombosis, and stroke prevention in atrial fibrillation. The risks of major adverse events (OR = 0.98; 95% CI = 0.83, 1.17) and major bleeding (OR = 1.01; 95% CI = 0.69, 1.47) did not differ significantly. However, there was a trend towards an increased risk of hepatotoxicity, with incidences of 5.8%
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versus 2.3% (OR = 1.74; 95% CI = 0.50, 6.01). The frequency of hepatotoxicity was markedly increased in patients with deep vein thrombosis (OR = 5.16; 95% CI = 3.38, 7.89), for treatment durations of at least 3 months (OR = 6.73; 85% CI = 5.01, 9.05), and in patients with atrial fibrillation (OR = 8.31; 95% CI = 5.65, 12). There were two fatal cases of liver damage with ximela gatran or melagatran. During follow-up after the EXTEND study, liver enzymes were assessed at post operative days 56 and 180 (210C). Rando mization and administration of the study drugs was stopped after a report of serious liver injury 3 weeks after completion of ximelagatran treatment. When the study was terminated, 1158 patients had been ran domized and 641 had completed the 35-day treatment; 303 patients took ximelagatran and 265 took enoxaparin up to day 56. Ala nine transaminase (AIT) activity increased to over twice the upper limit of the reference range in 58 of those who took enoxaparin and 27 of those who took ximelagatran; 3 of the latter also had symptoms of hepatotoxi city. Alanine transaminase activity increased after the end of the study in 11 patients taking ximelagatran. The mechanisms underlying rises in liver enzymes that occur during long-term therapy with ximelagatran (> 35 days) have been investigated in in vitro studies in fresh and cryopreserved hepatocytes, human hepa toma cell lines (HepG2 and HuH-7) and subcellular human liver fractions (211E). There was loss of cell viability only in HepG2 cells at ximelagatran concentrations of 100 µmol/l and in cryopreserved human hepatocytes at 300 µmol/l; HuH-7 cells were not affected by exposure for 24 hours up to 300 µmol/l. Calcium homeostasis was not affected in HepG2 cells. There was no evi dence of formation of reactive metabolites when cell systems were exposed to ximelaga tran. Expression of aspartate and alanine transaminases in human hepatoma cell lines was also unaffected, as were mitochondrial functions such as respiration, opening of the transition pore, mitochondrial membrane depolarization and b-oxidation. The authors suggested that these negative results may
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have occurred because the experimental systems did not reflect the characteristics of the human hepatocyte, because the expo sure time was too short, or because the pri mary mechanism of the liver damage due to ximelagatran is not on the parenchymal liver cell.
DIRECT FACTOR IXa INHIBITORS (SEDA-31, 561) Placebo-controlled studies In a multi center, double-blind, randomized study, 212 patients received oral TTP889 300 mg/ day) or placebo starting 6–10 days after hip fracture surgery and standard thromboprophylaxis for 5–9 days (212C). There was venous thromboembolism in 35 of the 109 who had been allocated to TTP889 and 29 of the 103 of who had been allocated to placebo. There were no major bleeding events and only two clini cally relevant non-major bleeding events with TTP889. REG1 consists of the drug RB006, an injectable RNA aptamer that specifically binds and inhibits factor IXa, and the anti dote RB007, the complementary oligo nucleotide that neutralizes its anti-IXa activity. REG1 has been evaluated in a dou ble-blind, randomized, placebo-controlled study in 50 subjects with coronary artery disease taking aspirin and/or clopidogrel, using four doses of RB006 (15, 30, 50, and 75 mg) and RB007 (30, 60, 100, and 150 mg) (213C). RB006 increased the activated partial thromboplastin time dose-depen dently; the median activated partial throm boplastin times at 10 minutes after a single intravenous boluses of 15, 30, 50, and 75 mg were 29, 35, 47, and 52 seconds. RB007 reversed the activated partial thrombo plastin time to baseline values within a med ian of 1 minute and there was no rebound increase over 7 days. There were no epi sodes of major bleeding or other serious adverse events.
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
DIRECT FACTOR Xa INHIBITORS (SEDA-30, 411; SEDA-31, 561)
Apixaban Comparative studies Apixaban versus enoxaparin Apixaban has been evaluated in a double-blind study in 1238 patients after total knee replacement (214C). They were randomized to 5, 10, or 20 mg/day given as a single dose or twice-daily divided doses, enoxaparin 30 mg bd, or warfarin (titrated to an INR of 1.8–3.0). Treatment lasted for 10–14 days and started 12–24 hours after surgery. Adverse effects were assessed in 1217 patients and efficacy in 856. Apixaban was less effective than the comparators, but there were significant and similar dose-related increases in the incidence of total bleeding events with once- and twice-daily apixaban. In a dose-ranging study 520 patients with deep vein thrombosis were randomized to apixaban 5 mg bd, 10 mg bd, or 20 mg/day, or to low-molecular-weight heparin for 84–91 days followed by a coumarin (215C). The four regimens had equal efficacy. There was major bleeding or non-major clinically relevant bleeding in 28 (7.3%) of the 385 patients who received apixaban and in 10 (7.9%) of the 126 who received conventional anticoagulants.
Otamixaban Otamixaban has been studied in a placebocontrolled study in 947 patients, who were randomized before percutaneous coronary intervention to unfractionated heparin 50–70 U/kg or one of five otamixaban regimens consisting of an intravenous bolus followed by a 3-hour infusion: • • • • •
0.025 mg/kg 0.045 mg/kg 0.080 mg/kg 0.120 mg/kg 0.140 mg/kg
followed by 0.035 mg/kg/hour; followed by 0.065 mg/kg/hour; followed by 0.120 mg/kg/hour; followed by 0.160 mg/kg/hour; followed by 0.200 mg/kg/hour.
The highest dose of otamixaban reduced the concentrations of prothrombin fragments
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1þ2 significantly more than unfractionated heparin, but there was no significant difference in the incidence of bleeding (216C). Antifactor Xa concentrations were 65, 155, 393, 571, and 691 µg/l with the five regimens of otamixaban. There was significant bleeding (major or minor) in 2.0, 1.9, 3.8, 3.9, and 2.6% of patients respectively and in 3.8% of those who received unfractionated heparin. Ischemic events occurred in 5.8, 7.1, 3.8, 2.5, and 5.1% of those who received otamixaban and in 5.6% of those who received unfractio nated heparin.
Rivaroxaban The pharmacology of rivaroxaban has been reviewed (217R–220R). Comparative studies Rivaroxaban versus enoxaparin Several comparisons of rivar oxaban and enoxaparin have suggested equal efficacy in preventing venous thromboembolism after orthopedic surgery and similar rates of adverse effects. In an analysis of pooled results from two phase 2, double-blind, randomized compar isons of rivaroxaban and enoxaparin after major orthopedic surgery in 1343 patients, episodes of major bleeding with rivaroxa ban occurred in 0.9, 1.3, 2.1, 3.9, and 7.0% of patients who received total daily doses of 5, 10, 20, 40, and 60 mg respectively, com pared with 1.7% of those who received enoxaparin (221M). In a double-blind, randomized, phase 3 com parison, 4541 patients undergoing total hip arthroplasty received rivaroxaban 10 mg/day or enoxaparin 40 mg/day (222C). There were episodes of major bleeding in 6 (0.3%) of 2209 who received rivaroxaban and in 2 (0.1%) of 2224 who received enoxaparin. In a double-blind, randomized compari son of oral rivaroxaban 10 mg/day and enoxaparin 40 mg/day in 2531 patients undergoing total knee arthroplasty, sympto matic events occurred less often with rivar oxaban (223C). Major bleeding occurred in 0.6% of those who received rivaroxaban
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and 0.5% of those who received enoxa parin. The incidences of drug-related adverse events, mainly gastrointestinal, were 12 and 13% respectively. In a double-dummy, placebo-controlled comparison, 2509 patients undergoing total hip arthroplasty were randomized to oral riv aroxaban 10 mg/day for 31–39 days (with pla cebo injection for 10–14 days; n = 1252) or subcutaneous enoxaparin 40 mg/day for 10–14 days (with a placebo tablet for 31–39 days; n = 1257) (224C). The incidence of any bleeding during treatment was similar in the two groups: 81 events (6.6%) in 1228 patients who received rivaroxaban versus 68 (5.5%) of 1229 patients who received enoxaparin.
INDIRECT FACTOR Xa INHIBITORS (SEDA-29, 362; SEDA-30, 412; SEDA-31, 563)
Fondaparinux Hematologic Fondaparinux has been successfully used in patients with HIT (225A, 226c, 227c, 228R). However, crossreactivity has been reported (229A). Bleeding with fondaparinux is uncom mon but can be serious when it occurs, as has been illustrated by a case of sponta neous retroperitoneal bleeding from a rup tured lumbar artery in a 78-year-old man with only one kidney (230A). Susceptibility factors Renal disease In a subgroup analysis of a randomized, controlled trial of fondaparinux in 19 979 patients in whom serum creatinine was mea sured at baseline, the absolute differences in favor of fondaparinux (efficacy and adverse effects) were most marked in patients with a GFR less than 58 ml/minute/1.73 m2; the lar gest differences being in major bleeding, which occurred in 2.8 and 6.4% (HR = 0.42; 95% CI = 0.32, 0.56) (231c). Fondaparinux has been studied in 12 patients treated with hemodialysis and
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compared with unfractionated heparin (232c). Mean peak anti-Xa activity increased from 0.61 µg/l after the first dose to 0.89 µg/l after dose 9, whereas predialysis anti-Xa activity rose steadily to 0.32 µg/l. Fondaparinux produced suffi cient anticoagulation but was slightly less effective than heparin. The digital com pression time necessary to achieve hemo stasis at the puncture site increased slightly but significantly with fondaparinux from 23.7 to 24.8 minutes and six of the patients reported minor bleeding problems between dialyses. The authors concluded that accumulation of fondaparinux increases anti-Xa activity between dialyses and should be reserved for patients who require systemic anticoagulation on nondialysis days.
Idraparinux The pharmacology of idraparinux has been reviewed (233R). Comparative studies In two randomized, open, non-inferiority comparisons of idra parinux and heparin followed by a cou marin for either 3 or 6 months bleeding rates at 6 months were similar (234c). In patients with deep venous thrombosis effi cacy was similar, but in patients with pul monary embolism, idraparinux was less efficacious than standard therapy. In an extension study in 1215 patients, major bleeding occurred in 11 (1.9%) of those who were given idraparinux and in none in the placebo group; of the 11 episodes, 3 were fatal intracranial hemorrhages (235c). A randomized comparison of subcuta neous idraparinux 2.5 mg/week and a cou marin (target INR 2–3) was stopped after 4576 patients had been randomized at a mean follow-up period of 11 months because of excess clinically relevant bleed ing with idraparinux (346 cases versus 226 cases; 20 versus 11 per 100 patient-years) (236C). There were 21 instances of intra cranial bleeding with idraparinux and 9 with coumarins (1.1 versus 0.4 per 100 patient
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
years); elderly patients and those with renal impairment were at greater risk.
THROMBOLYTIC AGENTS (SED-15, 3402; SEDA-29, 361; SEDA-30, 412; SEDA-31, 564)
Alteplase Observational studies Intrapleural instilla tion of alteplase 10–100 mg/day in 120 patients with complicated pleural effusions or empyemas who had failed simple chest tube placement and conventional medical treatment (52 with empyema, 41 with compli cated pleural effusions, 10 with hemothorax, and 17 with complicated malignant pleural effusions), there was complete resolution in 102 and partial resolution in 10; the 8 patients who failed to respond had either chronic empyemas or empyemas associated with lung abscesses (237c). Adverse effects were chest pain in seven patients and bleeding at the chest tube site in two. Systematic reviews In a review of four pro spective observational studies of 1966 patients with acute ischemic stroke treated within 3 hours with alteplase, the risk of sympto matic intracerebral hemorrhage was 4.7% (95% CI = 3.8, 5.8) and the risk was similar among patients with and without each of five selected characteristics (age over 70 years, baseline National Institute of Health Stroke Scale score over 20, diabetes mellitus, conges tive heart failure, and Hispanic origin) (238M).
Reteplase The pharmacology of reteplase has been reviewed (239R).
Streptokinase Urinary tract A patient with a mutation in the MTFR gene associated with deep vein
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thrombosis and massive pulmonary embo lism was given streptokinase and developed acute anuric renal failure without evidence of bleeding or an immunological reaction (240Ar). The authors reviewed all the possi ble causes of this association and could find no explanation.
Urokinase Hematologic In 114 patients with ischemic middle cerebral artery strokes, who presented within 6 hours of onset and who were randomized to intra-arterial urokinase or no extra treatment, there was an excess of episodes of cerebral hemorrhage in the treated group (9% ver sus 2%) (241c). The trial was stopped prematurely. The predictors of intracerebral hemor rhage after intra-arterial administration of urokinase have been assessed in 294 patients with strokes, 14 (4.8%) of whom had a subsequent hemorrhage (242c). Poor collaterals, early signs of ischemia on com puted tomography, a higher dose of urokinase, a lower recanalization rate, and a higher diastolic blood pressure on admission correlated with the risk of hemor rhage on univariate analysis; on multivari ate analysis, poor collaterals, urokinase dose, and early signs on computed tomogra phy remained predictors.
DRUGS THAT ALTER PLATELET FUNCTION (SEDA-29, 363; SEDA-30, 413; SEDA 31. 564)
Anagrelide Cardiovascular A cardiomyopathy has been attributed to anagrelide in a 50-year old Chinese man who took 2.5 mg bd for about 1 year; it resolved after withdrawal and did not recur when anagrelide was reintroduced in a lower dose (243A).
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Skin Painful leg ulcers on the lateral aspects of both ankles in a 38-year-old man occurred for the first time 6 weeks after starting treatment with anagrelide for thrombocythemia; no other causes could be found (244A).
Respiratory Pulmonary hemorrhage asso ciated with GP IIb/IIIa inhibitors is rare, but has been reported to be associated with abci ximab, eptifibatide, and tirofiban, with respective incidences of 0.7, 0.5, and 0.9% and an overall incidence of 0.68% (249c). Other cases have been reported (250A, 251A).
Dipyridamole (SED-15, 1140; SEDA-29, 365; SEDA-30, 413; SEDA-31, 564)
Hematologic In a series of 606 aneurysms treated by endovascular coil embolization, an intra-arterial thrombus developed in 32 (5.3%) (252c). Intra-arterial abciximab was administered at a concentration of 0.2 mg/ ml as a bolus of 4–15 mg over 15–30 min utes. Three patients had postprocedural rebleeding; one had severe thrombocyto penia and the other two showed a greater than 25% reduction in platelet count after abciximab. Abciximab-induced thrombocytopenia has been reported in a patient with a coro nary stent (253A). Thrombocytopenia that occurred 10 days after the use of tirofiban in a 57-year-old man was associated with tirofiban-depen dent anti-glycoprotein IIb/IIIa antibodies and responded to intravenous immuno globulin, suggesting a delayed hypersensitivity reaction (254A). In 305 patients given eptifibatide before percutaneous coronary intervention, the frequency of thrombocytopenia was 1.3% within 6 hours (255c). Another case has been reported (256A).
Cardiovascular Broadening of the P wave, which implies abnormal atrial depolariza tion, is associated with myocardial ischemia during treadmill exercise tolerance testing, but has also been reported during dipyrida mole stress imaging in five patients, without evidence of myocardial ischemia on subse quent myocardial perfusion imaging (245c). The mechanism is not clear. Coronary steal with ST segment elevation has also been described during dipyrida mole stress testing (246A).
Glycoprotein IIb–IIIa inhibitors (SED-15, 4; SEDA-29, 363; SEDA-30, 414; SEDA-31, 565) Comparative studies In a systematic review of comparisons of eptifibatide (n = 2812) and abciximab (n = 729), there were no dif ferences in the incidences of in-hospital death (4.1% with abciximab versus 3.5% with eptifibatide), recurrent myocardial infarction (0.8% versus 1.2%), or strokes/ transient ischemic attacks (0.7% versus 0.6%) (247M). There was no difference in the need for blood transfusion (12.4% ver sus 11.7%), but there was a higher incidence of gastrointestinal bleeding with abciximab (4.8% versus 2.8%). Cardiovascular Rupture of the ventricular septum has been reported after treatment with abciximab after myocardial infarction in a 55-year-old man, in the absence of thrombolysis, with which previous reports have all been associated (248A).
Susceptibility factors Renal disease In 2159 patients with coronary artery disease who underwent elective percutaneous cor onary intervention, the 30-day incidence of major adverse cardiac events in patients with moderate-to-severe renal insufficiency, mild renal insufficiency, and no renal insuf ficiency occurred in 5.2, 5.0, and 2.9% respectively in those who were given abcix imab and in 4.2, 3.8, and 4.0% respectively in those who were given placebo (257c). The corresponding figures for bleeding compli cations with abciximab were 8.9, 2.0, and 2.1%. Multivariate analysis identified GFR as an independent correlate of major adverse cardiac events and bleeding.
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
Drug overdose Reports of 17 cases of over dose of eptifibatide have been reviewed (258M). The adverse effects included chest pain, bradycardia, angioedema, hypotension, and alveolar hemorrhage. Management of overdose requires withdrawal of eptifibatide and monitoring for bleeding. Eptifibatide clearance is delayed in renal insufficiency, and in one case hemodialysis was benefi cial. Platelet transfusion is indicated when there is acute thrombocytopenia, but not otherwise.
(SED-15, 821; SEDA-29, 365; SEDA-30, 415; SEDA-31, 566)
THIENOPYRIDINES
Clopidogrel
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taste for 2 weeks followed by complete loss of taste; his sense of smell was pre served (260A). After withdrawal of clopido grel, his taste sensation started to improve, but it took 4 months before he had near complete recovery. Psychiatric Hallucinations have attributed to clopidogrel (261A).
been
• A 58-year-old-man who underwent coronary angiography was treated with a stent and was given a loading dose of clopidogrel 600 mg followed by 75 mg/day. His other medications included atorvastatin, bisoprolol, furosemide, gabapentin, insulin, isosorbide mononitrate, metformin, and ramipril. Within 48 hours of the start of clopidogrel therapy he reported visual hallucinations, described as visions of ghostly apparitions walking past him. He stopped taking the clopidogrel and within 24 hours the hallucinations resolved. Ticlopidine was given instead and the hallucinations did not recur.
Combination studies The use of the com bination of aspirin plus, a thienopyridine and warfarin has been subjected to systema tic review (259M). One randomized clinical trial has evaluated the safety and efficacy of adding warfarin to dual antiplatelet ther apy; other published data are from case series, observational studies, and case– control studies, primarily of patients under going percutaneous coronary intervention with intracoronary stenting. Four of 12 stu dies reported no increased risk of major bleeding events. In the other eight studies, there was a 3- to 6-fold increase in bleeding events with triple antithrombotic therapy. Ischemic events were reported in only six of the studies. In only two studies was there additional benefit from a reduced incidence of ischemic events; in one study there were worse ischemic outcomes with the triple regimen compared with dual therapy. The authors concluded that there is little evidence to support the combined use of aspirin, a thienopyridine, and warfarin.
Gastrointestinal Of 11 patients who had undergone gastric bypass operations and were taking clopidogrel, 4 had significant upper gastrointestinal bleeding after 25–234 days (266c). All stopped bleeding after drug withdrawal and treatment with an intra venous proton pump inhibitor. The authors suggested that patients who have had gas tric bypass operations may be at high risk of bleeding complications when taking clopidogrel.
Sensory systems Taste After taking clopido grel bisulfate 75 mg/day for about 3 weeks, a 71-year-old man developed diminished
Liver Clopidogrel-induced hepatotoxicity is very rare, but two new cases have been reported.
Hematologic The adverse effects of clopidogrel have been reviewed (262M), and it has been suggested that the risks of aplastic anemia, thrombocytopenia, and neutropenia have been underestimated (263R). Anecdotal reports of these adverse effects continue to appear (264A). Thrombotic thrombocytopenic purpura has been attributed to clopidogrel in an 80 year-old woman who had taken clopidogrel for 4 days (265A).
640 • Following elective percutaneous coronary intervention a 56-year-old man received clopidogrel 75 mg/day and 2 months later was found to have abnormal liver function tests (267A). Clopidogrel was withdrawn. Serology for acute viral hepatitis, antimitochondrial antibodies, and anti-smooth muscle antibodies were all negative and abdominal ultrasound was normal. His liver function tests improved. Clopidogrel was reintroduced but the liver function tests again became abnormal. Clopidogrel was withdrawn indefinitely. • Acute hepatitis occurred in a 63-year-old man after he had taken clopidogrel 75 mg/day for 2 weeks (268A).
Skin Two hypersensitivity reactions to clopi dogrel have been reported (269A). In one case there was immediate type I hypersensitivity with erythematous prurigo on both elbows and arms, which persisted for 15 days despite medication with glucocorticoids and antihist amines but resolved when clopidogrel was withdrawn; skin prick-testing was positive. In the other case there was delayed type IV hypersensitivity, with generalized pruritus, erythema, and desquamation; a prick test and an intradermal test were negative but oral rechallenge was positive within 24 hours. Immunologic Acute severe non-cardio genic pulmonary edema occurred in a 71-year-old man who had taken clopidogrel 75 mg/day for 2 days; it was attributed to a type III hypersensitivity reaction (270A). In another case a type III reaction caused fever and an urticarial rash in a 34-year-old woman after she had taken clopidogrel for 10 days (271A). Drug resistance Resistance to clopidogrel has been thoroughly reviewed (272R, 273R). Treatment failure is not synonymous with drug resistance, since thrombosis is multi factorial. Clopidogrel resistance is best defined by evidence of residual post-treat ment activity of its platelet receptor P2Y12, by measuring ADP-induced platelet aggre gation before and after treatment. Clopido grel non-responsiveness occurs in 5–44% of patients. It is more common in patients with diabetes mellitus and after a loading dose of 300 mg than 600 mg.
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The mechanisms underlying variability in responsiveness to clopidogrel are not well understood. Differences in pharmaco kinetics (intestinal absorption and hepatic conversion to the active metabolite) and pharmacodynamics (platelet receptor poly morphisms) have been suggested. Resistance to clopidogrel varies with time. In one study, 53–63% of patients were resistant to clopidogrel at 2 hours after stenting, 30% on days 1 and 5; and 13–21% on day 30 (274c). This may be because the 300 mg loading dose was inade quate to generate a sufficient concentration of the active metabolite to affect platelets in some patients. Clopidogrel non-responsiveness may be linked to an increase risk of thrombotic events, including stent thrombosis, reports of which continue to appear (275A–278A). Of 50 patients scheduled for neuro-inter ventional stent placement and 50 healthy blood donors, 14 of the former were clopi dogrel non-responders and 5 had adverse effects (279c). Two developed transient intrainterventional thrombosis and three had transient ischemic attacks or infarc tion, one with a permanent neurological deficit. All five were clopidogrel nonresponders. Dual antiplatelet drug resistance (to acetylsalicylic acid and clopidogrel) has also been reported (280A). Clopidogrel resistance can be managed by the use of higher doses. The value of adjusting the loading dose of clopidogrel according to the vasodilator-stimulated phosphoprotein index has been studied in a prospective, randomized, multicenter study in 162 patients with clopidogrel resis tance undergoing percutaneous coronary intervention; there were 84 controls and 78 patients in whom the dose was guided by the in vitro measurement (281C). Among the latter, dose adjustment was effective in 67 patients (86%). There were eight major adverse cardiac events during follow-up for 1 month but no difference in the rate of major or minor bleeding (5% versus 4%). An alternative strategy is to use combina tions of two or even three antiplatelet drugs (aspirin, clopidogrel, and cilostazol) (282c).
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
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Newer P2Y12 receptor antagonists, such as cangrelor and prasugrel may be helpful in future.
exposure to the active metabolite of clopi dogrel, SR62334, but tended to impair pla telet aggregation.
Susceptibility factors Genetic Conversion of clopidogrel to its active metabolite depends in part on the activity of CYP2C19, whose polymorphism CYP2C19 681G> A*2 has been associated with high residual platelet aggregation. Of 797 patients undergoing percutaneous coronary intervention, who were followed for 1 year while taking clopi dogrel 75 mg/day, 552 (69%) were homozy gous for wild-type CYP2C19 (*1/*1) and 245 (31%) carried at least one *2 allele (283c). Residual platelet aggregation at baseline did not differ significantly between the genotypes. However, during treatment with clopidogrel, residual platelet aggrega tion was significantly higher in CYP2C19 681G> A*2 carriers, who had a threefold increase (95% CI = 1.4, 6.8) in the 1-year incidence of death and myocardial infarction.
Statins Rhabdomyolysis has been attribu ted to an interaction of clopidogrel with ciclosporin and atorvastatin, which the patient had taken for more than 3 years without adverse effects or laboratory evi dence of muscle damage (286A). The symp toms and laboratory abnormalities resolved when all the drug were withdrawn and did not recur when ciclosporin and atorvastatin were restarted. The authors attributed this effect to competition for CYP3A4, causing increased atorvastatin concentrations. Conversely, it has been suggested that inhibition by some statins of CYP-mediated conversion of clopidogrel to its active meta bolite may reduce the action of clopidogrel (SEDA-28, 397). In 73 patients, 23 of whom had had a previous coronary stent thrombo sis and 50 of whom had not, platelet aggre gation was not affected by the addition of either atorvastatin 20 mg/day or pravastatin 40 mg/day to dual antiplatelet therapy with aspirin plus clopidogrel 75 mg/day (287c). However, this study does not solve the question of the clinical relevance of this putative interaction, since clopidogrel alone was not studied, since pravastatin is not a substrate of CYP3A4, and since the dose of atorvastatin may have been too low for it to have had an effect. In another study clopidogrel 75 mg/day had no effect on the pharmacokinetics of fluvastatin in healthy volunteers and fluva statin 80 mg/day did not alter the effect of clopidogrel on platelet function (288c). In a randomized placebo-controlled study of long-term clopidogrel 75 mg/day in patients with cardiovascular disease or multiple risk factors taking aspirin, a sec ondary analysis of the interaction of clopi dogrel with statins was performed (289c). The statins were categorized as those that are predominantly metabolized by CYP3A4 (atorvastatin, lovastatin, simvastatin) and those that are not (pravastatin, fluvastatin). Of 15 603 patients, 10 078 were taking a statin at baseline (8245 CYP3A4
Drug overdose Overdose with clopidogrel in 582 cases has been reviewed (284c). The majority (84%) involved a dose of no more than 150 mg and in 73% there were no adverse effects. The most common adverse clinical effects were vomiting (2.4%) and dizziness (2.4%). Drug–drug interactions Lansoprazole Clopidogrel and prasugrel are both prodrugs that are metabolized to active meta bolites, which inhibit platelet P2Y12 ADP receptors. The effects of the proton pump inhibitor lansoprazole on the pharmaco kinetics and pharmacodynamics of prasugrel and clopidogrel have been assessed in an open, four-period, crossover study in healthy subjects given single doses of clopi dogrel 300 mg and prasugrel 60 mg with and without concurrent lansoprazole 30 mg/day (285C). Lansoprazole reduced the AUC and Cmax of the active metabolite of prasugrel, R-138727, by 13 and 29% respectively, but did not affect platelet aggregation. In con trast, lansoprazole had no effect on
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J.K. Aronson
metabolized and 1748 non-CYP3A4 meta bolized) and 5496 were not. For the overall population, the primary end-point (a com posite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months) was 6.8% with clopidogrel and 7.3% with placebo; it was similar among patients taking the two different types of statin. The authors therefore con cluded that there was no evidence of an adverse interaction of clopidogrel with statins. The interaction of statins, especially those that are metabolized by CYP3A4 (atorvastatin and simvastatin), with the antiplatelet effects of a 600-mg loading dose of clopidogrel has been investigated in 1395 patients scheduled for coronary angiography (290c). Atorvastatin and sim vastatin had no effect on the antiplatelet activity of a loading dose of clopidogrel 600 mg and did not affect clinical outcomes after percutaneous coronary intervention.
Susceptibility factors Genetic The genetic risk factors for ticlopidine-induced hepato toxicity have been studied in 22 Japanese patients with ticlopidine-induced hepato toxicity and 85 who tolerated ticlopidine without adverse reactions (294c). There was a significant correlation between ti clopidine-induced hepatotoxicity and five human leukocyte antigen (HLA) alleles: HLA-A*3303, HLA-B*4403, HLA Cw*1403, HLA-DRB1*1302, and HLA DQB1*0604. In particular, HLA-A*3303 was present in 15 of the 22 patients with ticlopidine-induced hepatotoxicity and in 12 of the 85 controls (OR = 13; 95% CI = 4.4, 39). HLA-A*3303 was present in 12 of the 14 patients with ticlopidine induced cholestatic hepatotoxicity (OR = 37; 95% CI = 7.3, 184).
Management of adverse reactions A pre viously described desensitization protocol (SEDA-30, 416) has been used successfully in 24 patients (291c). Allergic reactions occurred in four and two required repeat desensitization; 6 months later 23 remained asymptomatic and 1 had persistent but improved pruritus controlled with oral anti histamines.
HEMOSTATIC AGENTS
Ticlopidine Observational studies Adverse effects of ticlopidine occurred in 41 (9.3%) of 440 patients who had a sirolimus-eluting stent implanted, including liver dysfunction (4.5% with one death), rashes (3.6%), and neutropenia (0.7%); 28% of the adverse effects occurred later than 8 weeks after the start of therapy (292c). Hematologic Neutropenia presented with necrotizing gingivitis in a 54-year-old Malaysian Chinese woman who had taken ticlopidine 250 mg bd for 3 weeks (293A).
Aprotinin
(SED-15, 331; SEDA-29, 367; SEDA-31, 566)
Withdrawal of aprotinin Aprotinin was temporarily withdrawn worldwide in 2007, after consultation with the German Federal Institute for Drugs and Medical Devices (BfArM), the US Food and Drug Administration (FDA), Health Canada, and other health authorities, pend ing the final results from the Canadian BART trial; it was permanently withdrawn in May 2008 (295S, 296R). The results of various studies have sug gested that aprotinin increases mortality when it is used in patients undergoing car diac surgery. Not all studies have shown such an effect, but mortality has not always been an end-point and some studies have concen trated on the effect of aprotinin on renal function. Studies that have been published since 2007 are briefly reviewed here in chronological order of publication.
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
Studies of mortality Long-term all-cause mortality has been studied in 3876 patients undergoing coronary artery bypass graft sur gery in an observational study conducted between November 1996 and December 2006 (297c). Aprotinin was associated with significantly increased mortality compared with controls. There were 223 deaths among 1072 patients (21% 5-year mortality) com pared with 128 deaths among 1009 control patients (13%) (co-variate adjusted hazard ratio for death = 1.48; 95% CI = 1.19, 1.85). Neither aminocaproic acid (132 deaths among 834 patients; 16%; adjusted hazard ratio for death = 1.03; 95% CI = 0.80, 1.33) nor tranexamic acid (65 deaths among 442 patients; 15%; adjusted hazard ratio for death = 1.07; 95% CI = 0.80, 1.45) was asso ciated with increased mortality. The effects of aprotinin on outcomes (mortality, cardiac events, renal failure, and cerebrovascular events) have been studied in 2064 patients undergoing cardiac surgery with cardiopulmonary bypass (298c). Post operative mortality and morbidity were higher in those who were given aprotinin, and this was related to an increased incidence of perioperative risk factors. Complex sur gery was the only independent variable asso ciated with postoperative cardiac events. Preoperative heart failure, a raised preopera tive creatinine concentration, and urgent and repeat surgery were the independent vari ables associated with postoperative hemodia lysis. Age over 70 years was the only independent variable associated with neuro logical dysfunction. In 2481 children, of whom 1251 received high-dose aprotinin compared with a histor ical cohort of 1230 who did not, univariate and multivariate analyses showed no signifi cant difference in operative mortality, acute renal failure, the need for temporary dialysis or neurologic complications; aprotinin had no effect on late mortality (299c). In 33 517 patients who received aprotinin and 44 682 who received aminocaproic acid on the day of coronary artery bypass graft ing, electronic administrative records showed that mortality was higher among the former (1512, 4.5%) than in the latter (1101, 2.5%) (300c). After adjustment for 41
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characteristics of patients and hospitals, the estimated risk of death was 64% higher with aprotinin (RR = 1.64; 95% CI = 1.50, 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital death in the apro tinin group was 1.78 (95% CI = 1.56, 2.02). The relative risk in a propensity score-matched analysis was 1.32 (95% CI = 1.08, 1.63). In an instrumental-variable analysis, aprotinin was associated with an excess risk of death of 1.59 per 100 patients (95% CI = 0.14, 3.04). Postoperative revas cularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid. In a retrospective analysis 1343 patients (13%) received aprotinin, 6776 (67%) received aminocaproic acid, and 2029 (20%) received no antifibrinolytic therapy (301c). All underwent coronary artery bypass grafting, and 1181 underwent com bined coronary artery bypass grafting and valve surgery. In a risk-adjusted model, sur vival was worse among patients treated with aprotinin, with a main-effects hazard ratio for death of 1.32 (95% CI = 1.12, 1.55) for the comparison with patients who received no antifibrinolytic therapy and 1.27 (95% CI = 1.10, 1.46) for the comparison with patients who received aminocaproic acid. Compared with aminocaproic acid or no antifibrinolytic agent, aprotinin was also associated with a higher risk-adjusted increase in the serum creatinine concentra tion, but not with a greater risk-adjusted inci dence of dialysis. In a multicenter, blinded trial, 2331 highrisk cardiac surgical patients were randomly assigned to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid (302C). The trial was terminated early because of a higher rate of death in those who received aprotinin. Of those given aprotinin 74 (9.5%) had mas sive bleeding compared with 93 (12%) of those who were given tranexamic acid and 94 (12%) of those given aminocaproic acid (RR for both comparisons = 0.79; 95% CI = 0.59, 1.05). However, at 30 days, the rate of death from any cause was 6.0% in those who received aprotinin compared with 3.9% of those given tranexamic acid
644
(RR = 1.55; 95% CI = 0.99, 2.42) and 4.0% of those given aminocaproic acid (RR = 1.52; 95% CI = 0.98, 2.36). The rela tive risk of death with aprotinin compared with that in the other two groups was 1.53 (95% CI = 1.06, 2.22). The authors con cluded that despite the modest reduction in the risk of massive bleeding, the strong and consistent increase in mortality associated with aprotinin compared with the lysine ana logues precludes its use in high-risk cardiac surgery. In a meta-analysis of nine prospective ran domized head-to-head trials of aprotinin ver sus tranexamic acid in patients undergoing cardiac surgery, there was a statistically sig nificant 45% increase in mortality with apro tinin (RR = 1.45; 95% CI = 1.0002, 2.11) (303M). Studies of renal dysfunction In a cohort study of 3348 patients undergoing cardio thoracic surgery in a single tertiary care medical center those who received aprotinin were less likely to experience a cerebro vascular event compared with controls and they did not have an increased risk of myo cardial infarction; however, they were more likely to experience postoperative renal dys function (304c). In a prospective study in 11 198 patients, of whom 2757 received aprotinin, the overall incidence of acute renal insufficiency was 1.6% (180/11 198) and it was significantly higher in the aprotinin subset (2.6%, 72/2757 versus 1.3%, 108/8441) (305c). The incidence of acute renal insufficiency directly and significantly increased with increasing transfusions of packed erythrocytes. The authors concluded that the increased risk of renal insufficiency in patients who were given aprotinin was directly related to the increased number of erythrocyte transfusions in that high-risk patient population and that aprotinin does not independently increase the risk. In a retrospective analysis of 674 patients who underwent cardiac surgery 550 received aprotinin either in a low-dose regimen (load ing dose 1 million units, 1 million units in the pump, and 1 million units after bypass or a
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continuous infusion of 0.25 million units/ hour) or a high-dose regimen (loading dose 2 million units, 2 million units in the pump, and 2 million units after bypass or a conti nuous infusion of 0.5 million units/hour) (306c). In multivariate regression analyses, the likelihood of renal complications was not significantly increased. In a prospective study of 657 children who underwent cardiac surgery with cardiopul monary bypass, the incidences of dialysis (9.6% versus 4.1%) and renal dysfunction (26% versus 16%) were higher in those who received aprotinin; however, propensity adjusted risk ratios were not significant (307c). The authors concluded that their study had not shown an independent role of aprotinin in renal dysfunction or dialysis. In an observational study of 8548 patients there was no significant association between aprotinin dosage and renal outcome (308c). The most relevant predictor was a preopera tively raised creatinine concentration (OR = 11; 95% CI = 9, 14). Patients with postoperative renal impairment or failure were at higher preoperative risk and/or underwent more complex procedures. In a retrospective analysis of 123 unran domized patients undergoing cardiac sur gery who had increased preoperative serum creatinine concentrations 82 received aminocaproic acid and 41 aprotinin (309c). Only the duration of the aortic cross-clamp and bypass were significantly associated with acute perioperative renal dysfunction. Although the patients who were given apro tinin had higher renal risk scores, aprotinin did not adversely affect renal outcomes. In a retrospective analysis of 9106 patients who underwent on-pump or off-pump car diac surgery the combination of aprotinin with ACE inhibitors during off-pump car diac surgery was associated with a significant risk of postoperative renal dysfunction (310c). In a prospective observational study in 369 patients undergoing cardiac surgery, of whom 205 received aprotinin and 164 received aminocaproic acid intraoperatively, 51 of the former (25%) developed acute renal injury compared with 19 of the latter (12%) (311c). Aprotinin was associated with
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
a twofold higher risk of acute renal damage when adjusted for potential confounders (age, Parsonnet score, preoperative serum creatinine, cardiopulmonary bypass, and cross-clamp times). Conclusions Most of the studies described above have been either retro spective or, if prospective, unrandomized. However, analyses of the prospective studies show that aprotinin increases mor tality in patients undergoing cardiac surgery. It also increases the risk of renal impairment, even if it is not an indepen dent risk factor.
Hematologic A hemolytic thrombotic microangiopathy has been attributed to aprotinin in a patient with acute myelogen ous leukemia (312A). • A 69-year-old man with acute monocytic leukemia received an intravenous bolus of aprotinin 1.5 million units followed by a continuous infusion of 200 000 units/hour, in addition to human fibrinogen 4 g. Within 48 hours the patient developed anuria, progressive thrombocytopenia, and livedo reticularis of both feet, with bluish discoloration of the left toes, suggesting cutaneous microvascular thrombosis. There was laboratory evidence of intravascular hemolysis and disseminated intravascular coagulation.
Immunologic Previous studies have sug gested that the risk of an allergic reaction to aprotinin is less than 0.1% on first sys temic exposure, but rises to 2.7% after reexposure; if re-exposure occurs within 6 months, the risk of a reaction is 5%, but if there is a delay of more than 6 months the risk is only 0.9% (313S). The risk of a severe allergic reaction after a second injection is 2.6% (314c). The incidence of hypersensitivity reac tions to aprotinin has been studied prospectively in 12 403 cases, with 801 re exposures in 697 patients (315c). There were 11 reactions to aprotinin (0.09%) after primary exposure; none was severe. There were 12 reactions (1.5%) after
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re-exposure, of which 5 were severe. All the severe reactions occurred in patients who had been re-exposed to aprotinin within 6 months. There were no reactions in 42 patients who were re-exposed within 3 days. The incidences of hypersensitivity reactions were 4.1, 1.9, and 0.4% in those who were re-exposed within less than 6 months, within 6–12 months, and after more than 12 months respectively. When aprotinin was still on the market for sys temic administration it was recommended that it should be avoided within 12 months of previous exposure. Although a test dose may predict an allergic reaction, reactions can occur despite a negative test dose, as a report illustrates (316A). • A 66-year-old man who was being prepared for cardiac surgery was given an intravenous bolus dose of aprotinin 20 000 units via a central venous catheter without adverse effects for 10 minutes thereafter. He was therefore given an intravenous loading dose of 2 million units but developed profound hypotension (systolic pressure 30–40 mmHg) within 3 minutes after the infusion had been started when only 200 000 units had been infused. The infusion was immediately stopped and he recovered after cardiopulmonary resuscitation.
The authors pointed out that a negative test dose is not a reliable predictor of anaphy laxis, but they also suggested that a test dose might act as a sensitizer, thus causing a reac tion rather than predicting one. Allergic reactions can certainly occur in response to test doses (317A, 318A). An anaphylactic reaction has been reported after primary exposure to a test dose of aprotinin in a child with a history of severe milk allergy; tests for aprotinin-specific IgG4 antibodies were positive but tests for aprotinin-specific IgE antibodies were negative (319A). The authors suggested that aprotinin should not be given to any one with a history of milk allergy. Systemic allergic reactions have been described in two women who had injections of aprotinin into their Achilles’ tendons for tendinopathy (320A). The risk is probably rare and would not warrant the use of a test dose. It has been suggested that a delay of 6
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weeks reduces the risk of systemic allergic reactions to local aprotinin, based on the results of a study in 223 patients with tendi nopathy who were usually treated with a rapid series of aprotinin injections spaced at intervals of 1–2 weeks and 158 who were given a single injection or had a delay of over 6 weeks between injections (321c). The risks of systemic allergic reac tions were 7% in the former and 2% in the latter. Injections given 2–4 weeks after a previous injection were significantly more likely to lead to allergic reactions (6%) than initial injections (0.3%) and injections given more than 6 weeks after a previous injection (0.9%).
Protamine
(SED-15, 2964; SEDA-30,
417) Comparative studies The concern that heparin reversal by protamine after carotid endarterectomy might increase the risk of thrombotic strokes has been studied in an unrandomized observational analysis of data derived from a randomized controlled study of anesthetic technique for carotid endarterectomy in 2107 patients, of whom 1513 received heparin alone and 594 had reversal with protamine (322A). The respec tive frequencies of the outcome events were
J.K. Aronson
stroke – 67/1513 (4.4%) versus 17/594 (2.9%); non-stroke or myocardial infarction death – 10/1513 (0.7%) versus 5/594 (0.8%); myocardial infarction – 6/1513 (0.4%) versus 3/594 (0.5%); hematoma – 157/1513 (10%) versus 44/594 (7.4%); re-operation – 51/1380 (3.7%) versus 18/565 (3.2%). Of these, only postoperative hematoma was more frequent when protamine was not used to reverse heparin. Cardiovascular Severe pulmonary vaso constriction occurred in a 62-year-old man within a few minutes of protamine adminis tration to reverse the effects of heparin after coronary bypass surgery; the systolic pressure fell to 50 mmHg, the central venous pressure rose rapidly to 15 mmHg, and there was mitral regurgitation and tricuspid regurgita tion with a gradient of 64 mmHg (323A). There was no evidence of anaphylaxis or myocardial ischemia, and the authors postu lated a direct myocardial depressant effect with secondary vasoconstriction. Hematologic A risk of using protamine to reverse anticoagulation with heparin after the insertion of a stent, in order to arrest bleeding, is thrombosis in the stent, as a report of two cases has underlined (324A).
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[Serum disease associated with clopidogrel.]
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276. Cuisset T, Bali L, Frere C, Quilici J, Saidi LN, Alessi MC, Bonnet JL. Implication de la résistance au clopidogrel dans la throm bose aiguë de stent? A propos d’un cas. [Acute stent thrombosis due to resistance to clopidogrel? A case report.] Arch Mal Coeur Vaiss 2007;100(2):145–8. 277. Schäfer A, Bonz AW, Eigenthaler M, Bauersachs J. Late thrombosis of a drugeluting stent during combined anti-platelet therapy in a clopidogrel nonresponsive dia betic patient: shall we routinely test platelet function? Thromb Haemost 2007;97(5): 862–5. 278. Sardella G, Bucciarelli-Ducci C, Mancone M, Colantonio R, Sangiorgi GM, Fedele F. Very late paclitaxel-eluting stent thrombosis despite 21 months of clopidogrel treatment after percutaneous coronary intervention. J Cardiovasc Med (Hagerstown) 2007;8(8): 625–8. 279. M€ uller-Schunk S, Linn J, Peters N, Spannagl M, Deisenberg M, Br€ uckmann H, Mayer TE. Monitoring of clopidogrel related platelet inhibition: correlation of nonresponse with clinical outcome in supra-aortic stenting. AJNR Am J Neuror adiol 2008;29(4):786–91. 280. Kuliczkowski W, Sikora J, Dyrbus K, Kacz marski J, Gasior M, Polonski L. Niepełna odpowiedz na podwójne leczenie przeciw płytkowe u kobiety uczulonej na klopido grel. [Dual antiplatelet drug resistance in a patient allergic to clopidogrel: a case report.] Kardiol Pol 2008;66(5):548–50. 281. Bonello L, Camoin-Jau L, Arques S, Boyer C, Panagides D, Wittenberg O, Simeoni MC, Barragan P, Dignat-George F, Paganelli F. Adjusted clopidogrel loading doses accord ing to vasodilator-stimulated phospho protein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol 2008;51(14):1404–11. 282. Shim CY, Yoon SJ, Park S, Kim JS, Choi JR, Ko YG, Choi D, Ha JW, Jang Y, Chung N, Shim WH, Cho SY. The clopidogrel resistance can be attenuated with triple antiplatelet therapy in patients undergoing drug-eluting stents implantation. Int J Cardiol 2009;134(3):351–5.
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eluting stent placement. J Am Coll Cardiol 2007;50(21):2039–43. Fukushima K, Kobayashi Y, Okuno T, Nakamura Y, Sakakibara M, Nakayama T, Kuroda N, Miyazaki A, Shimizu Y, Komuro I. Incidence of side-effects of ticlopidine after sirolimus-eluting stent implantation. Circ J 2007;71(4):617–9. Rajandram RK, Ramli R, Karim F, Rah man RA, Fun LC. Necrotizing gingivitis: a possible oral manifestation of ticlopidine induced agranulocytosis. N Z Med J 2007;120(1256):U2590. Hirata K, Takagi H, Yamamoto M, Matsumoto T, Nishiya T, Mori K, Shimizu S, Masumoto H, Okutani Y. Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study. Pharmacogenomics J 2008;8(1):29–33. Bayer Healthcare Pharmaceuticals. Bayer temporarily suspends global Trasylol® marketing. http://www.trasylol.com/ Trasylol_11_05_07.pdf. Sundt TM. The demise of aprotinin: our share of the blame. J Thorac Cardiovasc Surg 2008;135(4):729–31. Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, Hoeft A, Fontes ML, Hillel Z, Ott E, Titov T, Dietzel C, Levin J, Investigators of the Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Founda tion. Mortality associated with aprotinin dur ing 5 years following coronary artery bypass graft surgery. JAMA 2007;297(5):471–9. Van der Linden PJ, Hardy JF, Daper A, Trenchant A, De Hert SG. Cardiac surgery with cardiopulmonary bypass: does aprotinin affect outcome? Br J Anaesth 2007;99(5): 646–52. Backer CL, Kelle AM, Stewart RD, Suresh SC, Ali FN, Cohn RA, Seshadri R, Mavrou dis C. Aprotinin is safe in pediatric patients undergoing cardiac surgery. J Thorac Car diovasc Surg 2007;134(6):1421–6. Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronaryartery bypass grafting and risk of death. N Engl J Med 2008;358(8):771–83. Shaw AD, Stafford-Smith M, White WD, Phillips-Bute B, Swaminathan M, Milano
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C, Welsby IJ, Aronson S, Mathew JP, Peterson ED, Newman MF. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008;358(8): 784–93. Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussières JS, Côté D, Karski J, Marti neau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R, BART Investigators. A comparison of aprotinin and lysine ana logues in high-risk cardiac surgery. N Engl J Med 2008;358(22):2319–31. Takagi H, Manabe H, Kawai N, Goto SN, Umemoto T. Aprotinin increases mortality as compared with tranexamic acid in cardiac surgery: a meta-analysis of randomized head-to-head trials. Interact Cardiovasc Thorac Surg 2009;9(1):98–101. Coleman CI, Rigali VT, Hammond J, Kluger J, Jeleniowski KW, White CM. Evaluating the safety implications of apro tinin use: the Retrospective Evaluation of Aprotinin in Cardio Thoracic Surgery (REACTS). J Thorac Cardiovasc Surg 2007;133(6):1547–52. Furnary AP, Wu Y, Hiratzka LF, Grunke meier GL, Page 3rd US. Aprotinin does not increase the risk of renal failure in cardiac surgery patients. Circulation 2007;116 (11 Suppl):I127–33. Kertai MD, Varga KS, Royston D, London MJ, Szabolcs Z, Grebenik CR, Acsady G, Gal J. Aprotinin and perioperative compli cations in cardiac surgery. J Cardiovasc Surg (Torino) 2007;48(6):761–72. Székely A, Sa´ pi E, Breuer T, Kertai MD, Bodor G, Vargha P, Szatma´ri A. Aprotinin and renal dysfunction after pediatric cardiac surgery. Paediatr Anaesth 2008;18(2):151–9. Dietrich W, Busley R, Boulesteix AL. Effects of aprotinin dosage on renal function: an analysis of 8,548 cardiac surgical patients treated with different dosages of aprotinin. Anesthesiology 2008;108(2):189–98. Maslow AD, Chaudrey A, Bert A, Schwartz C, Singh A. Perioperative renal outcome in cardiac surgical patients with preoperative renal dysfunction: aprotinin versus epsilon aminocaproic acid. J Cardi othorac Vasc Anesth 2008;22(1):6–15.
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310. Mouton R, Finch D, Davies I, Binks A, Zacharowski K. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet 2008;371(9611):475–82. 311. Wagener G, Gubitosa G, Wang S, Borre gaard N, Kim M, Lee HT. Increased inci dence of acute kidney injury with aprotinin use during cardiac surgery detected with urinary NGAL. Am J Nephrol 2008;28(4): 576–82. 312. Langer F, Steinmetz O, Marx G, Amirkhos ravi A, Eifrig B, Bokemeyer C, Br€ ummen dorf T. Aprotinin-associated hemolytic thrombotic microangiopathy in a patient with acute myelogenous leukemia (AML) and systemic coagulopathy. Am J Hematol 2007;82(12):1122–4. 313. Bayer Healthcare Pharmaceuticals. Trasylol® (aprotinin injection). http://www.univgraph. com/bayer/inserts/trasylol.pdf. 314. Orchard J, Massey A, Rimmer J, Hofman J, Brown R. Delay of 6 weeks between apro tinin injections for tendinopathy reduces risk of allergic reaction. J Sci Med Sport 2008;11(5):473–80. 315. Dietrich W, Ebell A, Busley R, Boulesteix AL. Aprotinin and anaphylaxis: analysis of 12,403 exposures to aprotinin in cardiac surgery. Ann Thorac Surg 2007;84(4): 1144–50. 316. Beaulieu PL, Gandhi SD, Iqbal Z, Butler EG, Almassi GH, Pagel PS, Levy JH. Case 4-2007. Aprotinin-induced cardiovascular collapse after a negative test dose in a patient scheduled for repeat mitral valve surgery. J Cardiothorac Vasc Anesth 2007;21(4):597–601. 317. Weil DP, Stearns JD, Watson T, Horak J. An unusual fatal reaction to a test dose of aprotinin before elective thoracoabdominal aortic aneurysm repair. Eur J Anaesthesiol 2008;25(4):346–8. 318. Santos Silva F. Severe intraoperative ana phylactic reaction: aprotinin and rocuronium. J Cardiothorac Vasc Anesth 2008;22(5): 740–3. 319. Kaddoum RN, Chidiac EJ, Zestos MM, Rajan SD, Baraka A. An anaphylactic reac tion after primary exposure to an aprotinin test dose in a child with a severe milk
Drugs that affect blood coagulation, fibrinolysis, and hemostasis allergy. J Cardiothorac Vasc Anesth 2007;21(2):243–4. 320. Rukin NJ, Maffulli N. Systemic allergic reactions to aprotinin injection around the Achilles tendon. J Sci Med Sport 2007;10(5):320–2. 321. Orchard J, Massey A, Rimmer J, Hofman J, Brown R. Delay of 6 weeks between apro tinin injections for tendinopathy reduces risk of allergic reaction. J Sci Med Sport 2008;11(5):473–80. 322. Dellagrammaticas D, Lewis SC, Gough MJ, GALA Trial Collaborators. Is heparin reversal with protamine after carotid
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endarterectomy dangerous? Eur J Vasc Endovasc Surg 2008;36(1):41–4. 323. Hiong YT, Tang YK, Chui WH, Das SR. A case of catastrophic pulmonary vaso constriction after protamine administration in cardiac surgery: role of intraopera tive transesophageal echocardiography. J Cardiothorac Vasc Anesth 2008;22(5): 727–31. 324. Cosgrave J, Qasim A, Latib A, Aranzulla TC, Colombo A. Protamine usage following implantation of drug-eluting stents: a word of caution. Catheter Cardiovasc Interv 2008;71(7):913–4.
R. Ramnarace and H.R. Dalton
36
Gastrointestinal drugs
(SED-15, 243; SEDA-30, 423; SEDA-31, 573)
ANTACIDS Hydrotalcite
Comparative studies Hydrotalcite and famotidine have been compared in an open, randomized, parallel-group study in 53 patients with endoscopically proven gastro esophageal reflux disease, of whom 26 received a single dose of hydrotalcite 1 g and 27 a single dose of famotidine 10 mg for episodes of symptomatic reflux (1c). Hydrotalcite was significantly superior to famotidine in increasing the proportion of responders within the first 45 minutes, starting 10 minutes after drug administration. At 60–120 minutes, both compounds were equally efficacious. There were no adverse events in either group.
ANTIEMETICS AND DRUGS THAT AFFECT GASTROINTESTINAL MOTILITY (SEDA-29, 371; SEDA-30, 423; SEDA-31, 573)
Domperidone (SED-15, 1178; SEDA 30, 423) The pharmacology and uses of domperi done have been reviewed (2R). Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32036-8 � 2010 Elsevier B.V. All rights reserved.
Cardiovascular Cardiac dysrhythmias were reported after intravenous administration of high doses of domperidone, and this route of administration has therefore been discontin ued. Domperidone has electrophysiological properties similar to class III antidysrhythmic agents and can prolong the QT interval and predispose to ventricular dysrhythmias. This effect is more pronounced in the presence of hypokalemia. As with other class III antidysrhythmic agents, a QT interval of over 450 ms in men and 470 ms in women on the baseline electrocardiogram or sustained hypokalemia would be contraindications to domperidone. Nervous system Unlike metoclopramide, domperidone does not pass the blood–brain barrier well and therefore rarely causes nervous system symptoms. Extrapyramidal adverse effects have not been reported during controlled trials, although there have been a few anecdotal reports of such effects. Adverse effects with oral administration occur in less than 7% of patients and include headaches, dry mouth, diarrhea, anxiety, and changes in prolactin. Endocrine Like metoclopramide, domperi done can increase serum prolactin concentra tions and can therefore cause breast tenderness and enlargement, galactorrhea (uncommonly), and menstrual irregularities, including amenor rhea. Gynecomastia in men is infrequent. Domperidone stimulates thyroid-stimulating hormone, but this does not seem to have any clinical ramifications. Plasma concentrations of 18-hydroxycorticosterone, cortisol and plasma renin and angiotensin are not altered by domperidone. Domperidone does not stimulate aldosterone secretion.
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Drug–drug interactions Monoamine oxidase inhibitors Dopamine receptor antagonists should not be given in conjunction with monoamine oxidase (MAO) inhibitors. Stimulation of dopamine DA2 receptors causes inhibition of noradrenaline release from presynaptic nerve terminals. Antagonists of dopamine DA2 receptors would be expected to cause reduced inhibitory control, facilitating the release of noradrenaline, and concomitant administration of a monoamine oxidase (MAO) inhibitor would therefore impair the body’s ability to metabolize it. Because dopamine is broken down by MAO, it is possible that during long-term treatment with MAO inhibitors, dopamine could accumulate in sympathetic nerve terminals, leading to exaggerated end-organ response.
5-HT3 RECEPTOR ANTAGONISTS (SED-15, 1365; SEDA-29, 372; SEDA-30, 423; SEDA-31, 575)
Comparative studies In 50 patients with malignant tumors undergoing their first course of chemotherapy, who were randomized to ramosetron 0.3 mg/day or ondansetron 16 mg/day in a prospective crossover comparison, the two drugs had similar effects on chemotherapy-induced gastrointestinal adverse effects, emesis, and loss of appetite on day 1; however, by day 5, ramosetron was significantly better than ondansetron in controlling appetite loss (3c). From days 3 to 5, ramosetron tended to be more effective than ondansetron in its anti-emetic action. The incidences of headache, fatigue, and constipation were the same for the two drugs.
Alosetron (SEDA-29, 372; SEDA-30, 423; SEDA-31, 575) Placebo-controlled studies In a 12-week placebo-controlled study of alosetron 0.5 mg/ day, 1 mg/day, or 1 mg bd in 705 women with
Chapter 36
R. Ramnarace and H.R. Dalton
severe diarrhea-predominant irritable bowel syndrome, all doses of alosetron were effective (4C). Constipation was the most common adverse event in the three dosage groups (9%, 16%, and 19%, respectively). There was one case of intestinal obstruction and one of ischemic colitis with 0.5 mg/day and one case of fecal impaction with 1 mg bd All were self-limited and resolved without sequelae. Systematic reviews The efficacy of alosetron in diarrhea-predominant irritable bowel syndrome has been confirmed in a meta-analysis of eight placebo-controlled studies in 4170 patients (5M). The adverse events of statistical significance were constipation and abdominal pain and discomfort. Alosetron was associated with four cases of ischemic colitis (0.16%) and two cases of serious complications of constipation (0.08%); neither of these was reported in the placebo group. Alosetron was not associated with any deaths.
Dolasetron Drug overdose An overdose of dolasetron 20 � 100 mg in a 21-year-old woman was associated with prolongation of the QT interval and hypotension (6A). She was given intravenous fluids, inotropes, and sodium bicarbonate 400 mmol and the electrocardiogram normalized after 12 hours. The mechanism for the effects of overdose was postulated to be related to sodium channel blockade, and the authors suggested that more aggressive use of bicarbonate would lead to faster resolution of the widened QRS complex in sodium channel blockade. Dolasetron should be used with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly the QT interval. These include patients with hypokalemia or hypomagnesemia, patients taking diuretics with potential for inducing electrolyte abnormalities, patients with congenital long QT syndrome, and patients
Gastrointestinal drugs
Chapter 36
taking antidysrhythmic drugs or other drugs that lead to QT interval prolongation.
NK1 RECEPTOR ANTAGONISTS Aprepitant Substance P, a regulatory peptide that is the preferred endogenous ligand at neurokinin-1 (NK1) receptors, is found in the gastrointest inal tract (vagal afferents) and areas of the central nervous system thought to be involved in the vomiting reflex (including the nucleus tractus solitarius and area post rema). Aprepitant is the first NK1 receptor antagonist available for use as an anti emetic. It is a highly selective NK1 antagonist with a long half-life (9–12 hours) and is efficacious against opioid-induced emesis in animals. Comparative studies Aprepitant 40 mg and 125 mg have been compared with ondansetron 4 mg in 805 patients receiving general anesthesia for open abdominal surgery (7C). Aprepitant was not superior for complete response, control of nausea and rescue antiemesis, but it was better at preventing vomiting than ondansetron at both 24 and 48 hours. There were 69 adverse events in both the aprepitant arms of the study and 75 in the ondansetron arm. Nausea, constipation, and pruritus were the most common adverse events but there was no significant difference between the groups. There was slight prolongation of the QT interval, but usually not by more than 30 ms, and there were no adverse cardiovascular events. Special attention was given to the possibility of an interaction of aprepitant, which is an inhibitor of CYP3A4, and other drugs that are metabolized by CYP3A4 and that are commonly used peri operatively, such as fentanyl or midazolam. Aprepitant did not differ from ondansetron in terms of its effects on the pharmacodynamics of fentanyl or midazolam.
667
HISTAMINE H2 RECEPTOR ANTAGONISTS (SED-15, 1629; SEDA-29, 373; SEDA-30, 423; SEDA-31, 576)
Systematic reviews In a review of the addition of bedtime histamine H2 receptor antagonists for the control of nocturnal gastric acid breakthrough, eight small randomized controlled studies were identified, involving 137 participants in the intervention group and 137 in the control group (8M). In the short term (under 4 weeks), the addition of a histamine H2 receptor antagonist was beneficial in controlling nocturnal symptoms, but the effect was not significant during long-term use. There were no adverse events.
Nizatidine Gastrointestinal In a crossover, doubleblind, placebo-controlled trial, 16 patients were randomized either to nizatidine 150 bd for the first 2 months, followed by a 1-month washout period and a 2-month placebo period, or to placebo for 2 months, followed by a 1-month washout period and 2 months of nizatidine (9c). Gastric emptying was measured by scintigraphy, and dyspeptic symptoms and quality of life were evaluated at the end of both treatment periods. Nizatidine caused prolonged gastric emptying of solids.
PROTON PUMP INHIBITORS (SED-15, 2973; SEDA-29, 373; SEDA-30, 424; SEDA-31)
Lansoprazole (SEDA-31, 578) Gastrointestinal Two cases of collagenous colitis associated with lansoprazole have been reported, both in older women (10A). Each developed profuse watery diarrhea within weeks of starting lansoprazole for
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upper digestive disorders. Colonoscopy was normal and biopsies showed the typical features of collagenous colitis. There was rapid clinical improvement when lansoprazole was switched to rabeprazole, and the histology was normal in follow-up biopsies. Tumorigenicity In three large populationbased studies from the Netherlands (11c), Denmark (12c) and the United Kingdom (13c), there was no evidence of an increased incidence of colorectal cancer in users of proton pump inhibitors.
Omeprazole and esomeprazole (SED-15, 1252, 2615; SEDA-29, 373; SEDA 30, 424; SEDA-31, 578) Immunologic A drug reaction with eosino philia and systemic symptoms (DRESS) has been attributed to esome-prazole (14A). • A 41-year-old woman who had undergone surgery for a glioblastoma had recurrent episodes of DRESS 20 days later. All drugs were withdrawn and she was given topical glucocorticoids and then high-dose oral prednisolone 120 mg/day, gradually tapering. Her symptoms gradually improved over 4 months. Neither the doses of medications nor renal or immunological test results were reported. Skin patch tests were performed with valproate sodium, clobazam, esomeprazole, zopiclone, paracetamol, and co-trimoxazole as 1–10% solutions. Esomeprazole gave a positive reaction at 48 and 72 hours and all the other drugs were negative.
The clinical significance of this report is dubious, as there was insufficient evidence to exclude an alternative diagnosis. Drug–drug interactions Antiplatelet drugs In a double-blind, placebo-controlled study, 140 consecutive patients undergoing coronary artery stent implantation received aspirin 75 mg/day and clopidogrel 75 mg/day and were randomized to either omeprazole 20 mg/day or placebo for 7
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days (15c). Platelet reactivity was tested on days 1 and 7. Platelet reactivity on day 7 was reduced by omeprazole from 43% to 33%. There was one episode of stent thrombosis in each group. There were no deaths. This result is of clinical importance. Clopidogrel and aspirin are used in combination in patients undergoing coronary artery re-vascularization for optimal inhibition of platelet activity and proton pump inhibitors are also commonly used. The authors pointed out that proton pump inhibitors inhibit CYP2C19, which metabolizes clopidogrel to its active metabolite, and so reduce its antiplatelet activity. Further evaluation to ascertain whether this results in increase of adverse coronary events is required; at present, no immediate change in practice can be recommended.
LAXATIVES AND ORAL BOWEL PREPARATIONS (SED-15, 2008; SEDA-29, 374; SEDA-30, 426; SEDA-31, 581)
Phosphates
(SED-15, 2820; SEDA-29, 375; SEDA-30, 427, SEDA-31, 581)
Electrolyte balance In 82 studies poly ethylene glycol and sodium phosphate were the most frequently used formulations for bowel cleansing. Case series have shown that sodium phosphate is associated with the highest risk of clinically significant electrolyte disturbances (16M). Urinary tract The US Food and Drug Administration (FDA) has issued an alert notifying health-care professionals and consumers of the risk of acute phosphate nephropathy associated with the use of oral sodium phosphate products for bowel cleansing before colonoscopy or other procedures (17S). The FDA has required the manufacturers of two products that are
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available by prescription only (Visicol and OsmoPrep) to add a boxed warning to the labels of these products and to develop and implement a risk evaluation and mitigation strategy, including a medication guide. The agency has recommended that in light of the risk, over-the-counter laxatives containing sodium phosphate should not be used for bowel cleansing.
AMINOSALICYLATES (SED-15, 138; SEDA-29, 377; SEDA-30, 428; SEDA-31, 583)
Balsalazide
(SEDA 29, 377; SEDA-31,
583) Balsalazide 2.25 g/day on 10 days per month in combination with a high-potency probio tic mixture (VSL#3) 450 billion/day for 15 days has been compared with VSL#3 alone for 15 days in maintaining remission after an attack of acute uncomplicated diverticu litis (18c). There was no significant differ ence in response between the groups and no adverse effects during the 12-month followup in both groups.
Mesalazine (5-aminosalicylic acid, mesalamine) (SEDA-29, 378; SEDA-30, 428; SEDA-31, 583) Cardiovascular Pericarditis occurred in a 44-year-old man with a 4-year history of Crohn’s disease taking mesalazine 3 g/day (19A). There were also electrocardiographic changes that mimicked Brugada syndrome. Drug formulations MMX mesalazine, which is marketed as Lialda in the USA, as Mezavant XL in the United Kingdom and Ireland, and as Mezavant elsewhere, uses the MMX Multi Matrix System technology, which delivers mesalazine throughout the colon. Combined data from two 8-week, doubleblind, placebo-controlled trials in 517
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patients have been analysed (20C, 21C, 22M). The patients were randomized to MMX mesalazine 2.4 g/day (either once daily or as 1.2 g bd), 4.8 g/day (once daily), or placebo. The 8-week remission rates were 37% and 35% with MMX mesalazine 2.4 g/ day and 4.8 g/day respectively, and 18% with placebo. The 8-week complete mucosal heal ing rates were 32% in both mesalazine groups and 16% with placebo. Most of the adverse events were mild or moderate. Gas trointestinal disorders (including abdominal pain, worsening ulcerative colitis, diarrhea, flatulence, and nausea) were the most com mon adverse events in all treatment groups, and occurred in 18%, 12%, and 24% with mesalazine 2.4, 4.8 g/day, and placebo respectively. The most common individual adverse events reported with mesalazine 2.4 and 4.8 g/day were headache (in 5.6% and 3.4% of patients respectively, versus 0.6% with placebo) and flatulence (4.0%, 2.8%, and 2.8%). The most frequently reported severe adverse events (10 out of a total of 13 individual events) were gastrointestinal disorders, and 7 were described by the inves tigator as colitis or ulcerative colitis. There were two cases of pancreatitis (one in each of the mesalazine 2.4 and 4.8 g/day groups); both were attributed to mesalazine hypersen sitivity reactions (in patients who had not taken mesalazine for at least 6 weeks before entering the study) and followed a benign course before completely resolving without sequelae after withdrawal from the study.
Drug dosage regimens Oral mesalazine 1.6 g/day has been compared with mesalazine 1.6 g/day for 10 days per month in patients with recurrent symptomatic uncomplicated diverticular disease; daily dosing was more effective than cyclic dosing in maintaining remission (23c).
Sulfasalazine Respiratory A 68-year-old woman who had taken sulfasalazine for rheumatoid
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arthritis for 6 months developed bronchiolitis obliterans organizing pneumonia (BOOP) associated with an eosinophilia of 970 � 106/l (24A). Pancreas In a survey of 1590 cases of acute pancreatitis in Denmark from 1991 to 2002 and 15 913 age- and sex-matched controls, there was an increased risk of acute pancreatitis in patients with Crohn’s disease (odds ratio [OR] = 3.7; 95% confidence interval [CI] = 1.9, 7.6) and a non-significant 1.5-fold increased risk of ulcerative colitis (25c). The use of 5-aminosalicylic acid or sulfasalazine was not associated with an increased risk of acute pancreatitis. In all patients taking 5-aminosalicylic acid and sulfasalazine, the adjusted ORs for acute pancreatitis were 0.7 (95% CI = 0.4, 2.2) and 1.5 (95% CI = 0.4, 5.2) respectively. Restricted to patients with inflammatory bowel diseases only, the respective adjusted ORs for acute pancreatitis were 0.7 (95% CI = 0.1, 3.8) and 0.6 (95% CI = 0.1, 6.7). Immunologic Sulfonamide hypersensitivity reaction has been attributed to sulfasalazine (26A). • A 34-year-old man with a history of occasional mild episodes of presumed Crohn’s disease developed a perirectal abscess and was given sulfasalazine 1 g qds. After withdrawal of sulfasalazine for a few weeks, the dose was started again and a day later he developed a macular rash over his arms, which later spread to his trunk and legs. He subsequently developed recurrent fevers of 103–104°F, moderate diarrhea and diffuse abdominal pain. His liver function tests were abnormal and his white cell count was raised at 15.4 � 109/l. The sulfasalazine was withdrawn and he was given broad-spectrum antibiotics. Hepatitis serologies, a monospot test and blood cultures were all negative, but Epstein– Barr virus serology showed a positive viral capsid immunoglobulin G (IgG) and negative immunoglobulin M (IgM). An abdominal CT scan showed enlarged mesenteric and inguinal lymph nodes and a slightly enlarged spleen. Over the next 4 days he developed progressively worse liver function tests, a leukocytosis and a prolonged prothrombin time. He developed bloody diarrhea and
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needed transfusions. He became confused and had episodes of hallucinations. He improved rapidly with methylprednisolone 40 mg bd
The authors proposed that this illness was due to a sulfonamide hypersensitivity reac tion exacerbated by Epstein–Barr virus infection.
ANTIDIARRHEAL AGENTS Hyoscine hydrochloride (scopolamine) Drug formulations Transdermal hyoscine (scopolamine, TDS) patches 1.5 mg have been compared with intravenous ondan setron 4 mg and droperidol 1.25 mg for antiemetic prophylaxis in 150 at-risk surgical patients (27c). There were no significant differences in any of the emetic outcomes or the need for rescue antiemetics in any of the groups in the first 72 hours after surgery. The complete response rates varied from 41 to 51% and did not differ significantly among the groups. The overall incidence of dry mouth was significantly more frequent in those who used the patches than in those who received droperidol or ondansetron (21% versus 3%).
Loperamide Immunologic Death has been reported in a patient who had an anaphylactic reaction to loperamide (28A). • A 37-year-old man took two loperamide tablets and, despite shortness of breath soon afterwards, took a further two tablets (4 mg) 8 hours later, which resulted in acute breathlessness. An ambulance was called and he was given adrenaline at the scene, without improvement. He later died on ITU despite treatment for suspected sepsis. A post-mortem showed evidence of a systemic allergic reaction, with raised mast cell tryptase and a large number of
Gastrointestinal drugs intra-alveolar eosinophils.
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inflammatory
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with
The cause of death was given as an ana phylactic reaction due to loperamide, with coronary artery atherosclerosis as a con tributing factor. However, the activity of mast cell tryptase was not diagnostic of anaphylaxis. There has been a previous report of anaphylaxis with loperamide in a 10-year-old who survived with treatment for anaphylaxis, but this is the first report of death associated with loperamide.
LAXATIVES Bisacodyl Comparative studies In a comparison of sodium picosulfate and bisacodyl in 144 patients with chronic constipation, there were similar responses to the two drugs with regards to stool frequency, consistency, and straining (29c). There were 7 adverse events with bisacodyl and 14 with sodium picosulfate. Neither treatment had any effect on serum electrolytes. Sodium phosphate 48 g has been com pared with polyethylene glycol 2 l plus bis acodyl 20 mg in 411 patients (30C). All four gastrointestinal adverse effects listed on the patient questionnaire (nausea, vomiting, bloating, and abdominal pain) were reported significantly less often by those who took sodium phosphate. Most of the adverse effects were mild or moderate in intensity. In another report, electrolyte dis turbances were more frequent and of greater severity in those who took sodium phosphate (31C). Drug-dosage regimens Bisacodyl 10 mg and 20 mg have been compared in 445 patients before colonoscopy (32c). There were 17 adverse events in each group. However the 10 mg dose was tolerated significantly better
with regards to abdominal cramping (14 versus 31) and nausea (28 versus 47). The other adverse effects reported included vomiting and stomach bloating. There were no deaths and no clinically significant changes in physical examination, weight, temperature, pulse, or blood pressure.
Sodium picosulfate Placebo-controlled studies In a randomized study in 57 patients with chronic constipation, sodium picosulfate 7 mg nightly for 3 days was compared with placebo (33c). Sodium picosulfate resulted in a treatment response in 86% of patients. There were no serious adverse events. In each treatment group one patient had diarrhea and one had abdominal pain. There were no cardiovascular effects or changes in hematocrit, creatinine, or electrolytes in either group.
CHLORIDE CHANNEL ACTIVATORS Lubiprostone Lubiprostone, a member of a new class of compounds called prostones, activates type 2 chloride channels (ClC-2) without affect ing the cystic fibrosis transmembrane con ductance regulator. By activating ClC-2, lubiprostone increases the chloride concen tration in intestinal fluid, causing an increase in intestinal fluid secretion without disturbing serum electrolyte balance. This increase in chloride-rich intestinal fluid may facilitate intestinal transit, thereby increasing the passage of stool and alleviat ing symptoms associated with chronic constipation. Placebo-controlled studies There was a significant increase in the incidence of nausea associated with lubiprostone in a 4-week double-blind, placebo-controlled
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study (34C) in 244 patients who were randomized to lubiprostone of 24 µg bd or placebo. There were no other significant adverse events, no deaths and no serum electrolyte disturbances. Drug-dosage regimens Of 127 patients who were randomized and took at least one dose of the study drug, 78 had at least one adverse event: 13 in the placebo arm (39%), and 18 (62%), 24 (75%), and 23 (70%) of those who took lubiprostone 24, 48 and 72 micrograms respectively (35c). Nausea was the most commonly reported adverse event, in 31 of those who took lubiprostone (33%); 12 had at least one adverse event that was reported to be severe in intensity. Diarrhea and headache (in four patients on placebo and two patients on lubipro-stone 72 micrograms) were the only severe adverse events reported by more than one patient in either arm. Abdominal pain (one with placebo and one with lubiprostone 48 micrograms) and nausea (one each with lubiprostone 48 and 72 micrograms) were the only other severe adverse events with more than one patient overall. One patient stopped taking the study drug because of severe diarrhea (lubiprostone 72 micrograms). No patients required hospitalization or fluid replacement for diarrhea. Four patients withdrew because of nausea, one taking lubiprostone 24 micrograms (moderate intensity), two taking lubiprostone 48 micrograms (one moderate and one severe) and one taking lubiprostone 72 micrograms (severe).
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ANTISPASMODIC AGENTS Hyoscine butylbromide Systematic reviews The use of rectal hyoscine bromide in the management of cramping abdominal pain has been reviewed in a systematic review of 10 placebo-controlled studies (36M). Hyoscine butylbromide was beneficial in all of the trials, which included 3699 patients, of whom 911 received oral (n = 868) or rectal (n = 43) hyoscine butylbromide. Because the drug is hardly absorbed, it is generally well tolerated. Two large studies compared hyoscine butylbromide 30 mg/day with placebo (and paracetamol); 597 patients took hyoscine butylbromide and 592 took placebo. There were 75 adverse events with hyoscine butylbromide and 51 with placebo, which was not a significant difference. Anticholinergic adverse effects, such as nausea, constipation, dry mouth, blurred vision, tachycardia, and urinary retention, were infrequent (under 1.5%) and were mild and self-limiting.
CHOLELITHOLYTIC AGENTS Systematic reviews In a systematic review of 27 randomized studies of the use of bile salts in hepatitis B and hepatitis C, there was improvement in serum transaminase activities with bile salts compared with placebo but no effect on viral load or fibrosis; there were no adverse events (37M).
References 1. Konturek JW, Beneke M, Koppermann R, Petersen-Braun M, Weingärtner U. The efficacy of hydrotalcite compared with OTC famotidine in the on-demand treatment of
gastroesophageal reflux disease: a non-infer iority trial. Med Sci Monit 2007;13(1):CR44–9. 2. Reddymasu SC, Soykan I, McCallum RW. Domperidone: review of pharmacology and
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clinical applications in gastroenterology. Am J Gastroenterol 2007;102(9):2036–45. 3. Yuankai Shi, Xiaohui He, Sheng Yang, Bin Ai, Changgong Zhang, Dingzhi Huang, Mei Dong, Peng Liu, Shengyu Zhou, Xiaohong Han. Ramosetron versus ondansetron in the prevention of chemotherapy-induced gastro intestinal side effects: a prospective random ized controlled study. Chemotherapy 2007;53:44–50. 4. Krause R, Ameen V, Gordon SH, West M, Heath AT, Perschy T, Carter EG. A rando mized, double-blind, placebo-controlled study to assess efficacy and safety of 0.5 mg and 1 mg alosetron in women with severe diarrhea-predominant IBS. Am J Gastroen terol 2007; 102(8):1709–19. 5. Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of alosetron for the treat ment of irritable bowel syndrome in women and men: a meta-analysis of eight rando mized, placebo-controlled, 12-week trials. Clin Ther 2008;30(5):884–901. 6. Rochford M, Kiernan TJ, Aziz A. Dolase tron overdose resulting in prolonged QTc interval and severe hypotension: a case report and literature review. Emerg Med J 2007;24(7):515–7. 7. Gan TJ, Apfel CC, Kovac A, Philip BK, Singla N, Minkowitz H, Habib A, Knighton J, Carides AD, Zhang H, Horgan, Kevin J, Evans JK, Lawson F. A randomized, doubleblind comparison of the nk1 antagonist, aprepitant, versus ondansetron for the pre vention of postoperative nausea and vomit ing. Anesth Analg 2007;104(5):1082–9. 8. Wang Y, Pan T, Wang Q, Guo Z. Additional bedtime H2-receptor antagonist for the control of nocturnal gastric acid breakthrough. Cochrane Database Syst Rev 2009;(4):CD004275. 9. Koskenpato J, Punkkinen JM, Kairemo K, Färkkilä M. Nizatidine and gastric emptying in functional dyspepsia. Dig Dis Sci 2008;53 (2):352–7. 10. Chande N, Driman DK. Microscopic colitis associated with lansoprazole: report of two cases and a review of the literature. Scand J Gastroenterol 2007;42(4):530–3. 11. Van Soest EM, Van Rossum LGM, Dieleman JP, Van Oijen MGH, Siersema PD, Sturken boom MCJM, Kuipers EJ. Proton pump
673 inhibitors and the risk of colorectal cancer. Am J Gastroenterol 2008;103(4):966–73. 12. Robertson DJ, Larsson H, Friis S, Pedersen L, Baron JA, Sorensen HT. Proton pump inhibitor use and risk of colorectal cancer: a population-based, case-control study. Gas troenterology 2007;133(3):755–60. 13. Yang Y, Hennessy S, Propert K, Hwang W, Sedarat A, Lewis J. Chronic proton pump inhibitor therapy and the risk of colorectal cancer. Gastroenterology 2007;133(3):748–54. 14. Caboni S, Gunera-Saad N, Ktiouet-Abassi S, Berard F, Nicolas JF. Esomeprazole-induced DRESS syndrome. Studies of cross-reactivity among proton-pump inhibitor drugs. Eur J Allergy Clin Immunol 2007;62(11):1342–3. 15. Gilard M, Arnaud B, Cornily JC, LeGal G, Lacut K, LeCalvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J. Influence of ome prazole on the antiplatelet action of clopido grel associated with aspirin: the randomized, double-blind OCLA (Omeprazole Clopido grel Aspirin) study. J Am Coll Cardiol 2008;51(3):256–60. 16. Belsey J, Epstein O, Heresbach D. Systema tic review: oral bowel preparation for colo noscopy. Aliment Pharmacol Ther 2007;25 (4):373–84. 17. Anonymous. Oral sodium phosphate pro ducts. New alert on acute phosphate nephro pathy. WHO Newslett 2009;1:1. 18. Tursi A, Brandimarte G, Giorgetti GM, Elisei W, Aiello F. Balsalazide and/or highpotency probiotic mixture (VSL#3) in main taining remission after attack of acute, uncomplicated diverticulitis of the colon. Int J Colorectal Dis 2007;22(9):1103–8. 19. Hermida JS, Six I, Jarry G. Drug-induced pericarditis mimicking Brugada syndrome. Europace 2007;9(1):66–8. 20. Lichtenstein GR, Kamm MA, Boddu P, Gubergrits N, Lyne A, Butler T, Lees K, Joseph RE, Sandborn WJ. Effect of onceor twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol 2007;5:95–102. 21. Kamm MA, Sandborn WJ, Gassull M, Schreiber S, Jackowski L, Butler T, Lyne A, Stephenson D, Palmen M, Joseph RE.
674 Once-daily high concentration MMX mesa lamine in active ulcerative colitis. Gastroen terology 2007;132:66–75. 22. Sandborn WJ, Kamm MA, Lichtenstein GR, Lyne A, Butler T, Joseph RE. MMX multi matrix system mesalazine for the induction of remission in patients with mild-to-moder ate ulcerative colitis: a combined analysis of two randomized, double-blind, placebocontrolled trials. Aliment Pharmacol Ther 2007;26(2):205–15. 23. Tursi A, Brandimarte G, Giorgetti GM, Elisei W. Continuous versus cyclic mesalazine therapy for patients affected by recurrent symptomatic uncomplicated diverticular disease of the colon. Dig Dis Sci 2007;52 (3):671–4. 24. Ulubaş B, Sahin G, Ozer C, Aydin O, Ozg€ ur E, Apaydin D. Bronchiolitis obliterans orga nizing pneumonia associated with sulfasala zine in a patient with rheumatoid arthritis. Clin Rheumatol 2004;23(3):249–51. 25. Munk EM, Pedersen L, Floyd A, Nørgård B, Rasmussen HH, Sørensen HT. Inflammatory bowel diseases, 5-aminosalicylic acid and sul fasalazine treatment and risk of acute pan creatitis: a population-based case-control study. Am J Gastroenterol 2004;99(5):884–8. 26. Halmos B, Anastopoulos HT, Schnipper LE, Ballesteros E. Extreme lymphoplasmacytosis and hepatic failure associated with sulfasala zine hypersensitivity reaction and a concur rent EBV infection – case report and review of the literature. Ann Hematol 2004;83 (4):242–6. 27. White PF, Tang J, Song D, Coleman JE, Wender RH, Ogunnaike B, Sloninsky A, Kapu R, Shah M, Webb T. Transdermal sco polamine: an alternative to ondansetron and droperidol for the prevention of postopera tive and postdischarge emetic symptoms. Anesth Analg 2007;104(1):92–6. 28. Srinivasa MR, Phelan C. Death due to ana phylactic shock after ingestion of Imodium Instants (loperamide). Eur J Allergy Clin Immunol 2007;62(8):965–6. 29. Kienzle-Horn S, Vix JM, Schuijt C, Peil H, Jordan CC, Kamm MA. Comparison of bisa codyl and sodium picosulphate in the
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treatment of chronic constipation. Curr Med Res Opin 2007;23(4):691–9. 30. Lichtenstein GR,Grandhi N, Schmalz M, Lottes SR, Forbes WP, Walker K, Zhang B. Sodium phosphate tablets are preferred and better tolerated by patients compared to polyethylene glycol solution plus bisacodyl tablets for bowel preparation. Aliment Phar macol Ther 2007;26(10):1361–70. 31. Johanson JF, Popp JW, Cohen LB, Lottes SR, Forbes WP, Walker K, Carter E, Zhang B, Rose M. A randomized, multicen ter study comparing the safety and efficacy of sodium phosphate tablets with 2L poly ethylene glycol solution plus bisacodyl tablets for colon cleansing. Am J Gastroen terol 2007;102(10):2238–46. 32. DiPalma JA, McGowan J, Cleveland MV. Clinical trial: an efficacy evaluation of reduced bisacodyl given as part of a poly ethylene glycol electrolyte solution prepara tion prior to colonoscopy. Aliment Pharmacol Ther 2007;26(8):1113–9. 33. Wulkow R, Vix JM, Schuijt C, Peil H, Kamm MA, Jordan C. Randomised, placebo-con trolled, double-blind study to investigate the efficacy and safety of the acute use of sodium picosulphate in patients with chronic constipation. Int J Clin Pract 2007;61 (6):944–50. 34. Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, double-blind, random ized, placebo-controlled trial of lubipros tone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol 2008;103 (1):170–7. 35. Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a doubleblind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Phar macol Ther 2007;25(11):1351–61. 36. Tytgat GN. Hyoscine butylbromide: a review of its use in the treatment of abdominal cramping and pain. Drugs 2007;67(9):1343–57. 37. Chen W, Liu J, Gluud C. Bile acids for viral hepatitis. Cochrane Database Syst Rev 2007; (4):CD003181.
Felix Braun, Nadja Rifaie, Dieter C. Broering, and Matthias Behrend
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Drugs that act on the immune system: cytokines and monoclonal antibodies
COLONY-STIMULATING FACTORS (SEDA-29, 383; SEDA-30, 435; SEDA-31, 589)
Granulocyte colony-stimulating factor (G-CSF) and granulocytemacrophage colony-stimulating factor (GM-CSF) (SED-15, 1542; SEDA-29, 383; SEDA-30, 435; SEDA-31, 589) Hematologic In a survey by the European group for Blood and Marrow Transplanta tion 840 patients received immuno-suppres sive therapy for severe aplastic anemia and 43% also received G-CSF. The incidence of myelodysplastic syndrome or acute myeloid leukemia was 11% in those who were treated with G-CSF as opposed to 5.8% in those who only received immunosuppres sion. Thus, G-CSF is associated with a significantly higher hazard (1.9) of myelo dysplastic syndrome or acute myeloid leukemia (227C). A 57-year-old man with refractory cardiac ischemia who received a course of G-CSF 10 micrograms/kg/day during an angiogen esis trial developed severe thrombocytope nia (nadir 5 109/l) (1A). Investigations suggested an immune-mediated mechanism. Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32037-X 2010 Elsevier B.V. All rights reserved.
A 53-year-old man with plasma cell mye loma received chemotherapy and then after 11 days of treatment GM-CSF 5 mg/kg/day and G-CSF 10 mg/kg/day; 1 week later he presented with a ruptured spleen (2A). Musculoskeletal A boy was treated with long-term daily injections of G-CSF 25–50 micrograms/kg from the age of 1 month for severe congenital neutropenia (3A). At the age of 9 years he developed recurrent headaches. Skull radiography showed thickening of the skull with the hair on-end sign that is usually associated with thalassemia. He also had generalized osteo penia with reduced vertebral height, ‘bone in bone’ appearance of some vertebrae, and thickened but decalcified ribs. The authors attributed the severe thickening of the skull to expansion of white blood cell precursors in the marrow and thought that it was the probable cause of the recurrent headaches.
Filgrastim Sensory systems One week after starting therapy with intravenous filgrastim 300 micrograms/day for 3 consecutive days, a 66-year-old woman developed bilateral kera titis, with epithelial defects and peripheral cor neal infiltrates (4A). Since her symptoms resolved 3 days after withdrawal of filgrastim, it is likely that the drug caused keratitis. Hematologic A 71-year-old man with mye lodysplasia was given pegfilgrastim 6 mg for
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persistent neutropenia and developed florid histiocytic hemophagocytosis (5A).
Insulin-like growth factor (SED-15, 1792; SEDA-26, 466) Immunologic Mecasermin (rDNA; Incre lex; Tercica, Inc.) is a recombinant insulinlike growth factor-I (IGF-I), which has been approved to treat growth failure in children with severe primary IGF-I deficiency. A 13-year-old boy developed life-threatening anaphylaxis early in the course of Increlex therapy (6A).
INTERFERONS (SED-15, 1841; SEDA-29, 384; SEDA-30, 436; SEDA-31, 591) Interferon alfa (SED-15, 1793; SEDA-29, 386; SEDA-30, 436; SEDA-31, 591) Sensory systems A 40-year-old man with multiple sclerosis taking interferon beta-1a developed cotton wool spots in the optic fundi, which seem to have been related to interferon (7A). Psychiatric The well-known psychiatric adverse effects of pegylated interferons have again been reported. Of 56 patients with hemophilia infected with hepatitis C who were treated with peginterferon alfa 2b 1.5 micrograms/kg/week and ribavirin 800–1200 mg/day, 22% developed depression that warranted the use of antidepressants; one developed a psychosis; 11% discontinued therapy owing to adverse effects (8c). Of 375 patients with renal cell carcinoma who were treated with subcutaneous inter feron alfa 9 MU three times a week, 12% developed grade 3 or 4 fatigue (9c). Endocrine Among 100 patients with chronic hepatitis C who were treated with
subcutaneous interferon alfa-2b (3 million units three times a week) and oral ribavirin (1000–1200 mg/day), overt thyroid disease (hyper- and hypothyroidism) developed in 13% and subclinical thyroid disease in 5% (10c). Hematologic In 91 patients with HCV/ HIV co-infection mean hemoglobin fell by 5.0 g/dl within 1 week of the start of interferon þ ribavirin combination therapy; increases in erythropoietin and reticulocyte counts were blunted in response to anemia compared with controls (11c). Immunologic Of 44 patients who under went liver transplantation and were treated with peginterferon alfa-2b and ribavirin for HCV infection for at least 6 months, nine developed graft dysfunction despite clear ance of HCV RNA in all but one case; his tological evaluation suggested probable autoimmune hepatitis (12c). Three other developed the following definite auto immune disorders: overlap antimitochondrial antibody-positive cholangitis, autoimmune thyroiditis, and systemic lupus erythematosus. Infection risk A 48-year-old man received a living donor liver transplant and was subsequently given peginterferon alfa-2a and ribavirin for recurrent hepatitis C. He developed cryptosporidial enterocolitis and recovered after withdrawal of interferon and ribavirin and intermittent lowering of the dose of immunosuppressant (13A).
(SED-15, 1842; SEDA-29, 394; SEDA-30, 438; SEDA-31, 592)
INTERLEUKINS
Aldesleukin (interleukin2, IL-2) (SED-15, 58; SEDA-29, 394; SEDA-30, 438) Skin Thickening of the skin has been attributed to aldesleukin (14A).
Drugs that act on the immune system: cytokines and monoclonal antibodies • A 49-year-old woman with relapsed renal cell carcinoma was given subcutaneous aldesleukin 11 106 U/m2 three times a week for 1 month and 3 weeks later developed rapidly progres sive thickening of the skin involving her legs and arms.
Respiratory Inhaled aldesleukin in three cycles of 36 MIU/day for 5 days/week or for 3 out of 4 weeks for 12 weeks has been investigated in 51 patients with pulmonary metastases from renal cell carcinoma (15c). In 40% of the cycles, inhalation of aldes leukin was associated with cough and 7% had fatigue.
Interleukin-4 (IL-4) (SED-15, 1845) Observational studies In 41 patients with relapsed or refractory indolent or aggressive non-Hodgkin’s lymphoma who received 2.5 or 5.0 µg/kg of interleukin-4 subcutaneously for 28 days of a 42-day cycle, repeated 2–6 times, adverse effects included edema (66%), malaise (56%), and abnormal liver function tests (56%) (16c).
Anakinra (interleukin-1 receptor antagonist) (SED-15, 215; SEDA-29, 394; SEDA-31, 592) Cardiovascular A 29-year-old woman with adult-onset Still’s disease was given anakinra 100 mg/day and 3 months later died of what seems to have been a dilated cardiomyopathy; she had had some cardiac dysfunction before the incident (17A). Infection risk The risk of serious infections and systemic inflammatory response syn drome (SIRS) during treatment with ana kinra is still diversely discussed. In a meta-analysis it was suggested that the risk needs to be taken seriously only during high-dose therapy in patients with signifi cant co-morbidities (18M). However, in con trast to this suggestion is the case of a man with Still’s disease who was treated with
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anakinra and had SIRS and ARDS and required 10 days of intensive care (19A). Of 35 patients with Still’s disease or sys temic juvenile onset rheumatoid arthritis enrolled in a trial of anakinra, two stopped taking the drug because of severe skin re actions, and two because of infections, one visceral leishmaniasis and one varicella (20c). Another patient with rheumatoid arthri tis who was given anakinra for 23 months developed reactivation of pulmonary tuber culosis (21A). In a 2-year observational study of the efficacy of anakinra in 60 patients with rheumatoid arthritis there were four cases of pneumonitis, of which two were hospita lized, and one of tuberculosis (previously treated with infliximab); the patients were given subcutaneous anakinra 100 mg/day in combination with intramuscular methotrex ate 7.5–10 mg/week or leflunomide 20 mg/ day (22c).
TUMOR NECROSIS FACTOR ALFA (TNF-a) ANTAGONISTS (SEDA-29, 395; SEDA-30, 439; SEDA-31, 592) Cardiovascular The risk of hospitaliza tion for heart failure has been studied in 1002 users of TNF-a antagonists and 5593 users of methotrexate aged at least 65 years with rheumatoid arthritis (23C). The adjusted hazard ratio for hospitaliza tion for heart failure comparing TNF-a antagonists and methotrexate was 1.70 (95% CI = 1.07, 2.69). Sensory systems TNF-a antagonists can cause uveitis, and etanercept seems to be associated with significantly more reports than infliximab and adalimumab (24c). Gastrointestinal There have been a few reports of new-onset or exacerbation of ulcerative colitis associated with TNF-a antagonists (25A).
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Skin There have been over 130 reports of the development of psoriasis during treat ment with TNF-a antagonists (26A–28A). This is a paradoxical adverse effect, as TNF-a antagonists have also been success fully used in the treatment of psoriasis (29H). Immunologic Of 440 patients who received unspecified TNF-a antagonists for rheumatoid arthritis, two had vasculitis that was attributed to the treatment (30c). Of 53 reported cases of drug-induced lupus-like syndrome due to TNF-a antago nists, 17 had cutaneous manifestations alone and three had overlap syndromes and mixed connective tissue disease (31c). Criteria for systemic drug-induced lupus erythematosus were fulfilled in 33 cases; 21 were due to infliximab, 10 due to eta nercept and only 2 were related to adalimumab. Few cases of properly reported hypersen sitivity reactions to TNF-a antagonists have been reported, but they may not be as rare as has been assumed. Whether these reac tions are immunoglobulin-mediated hyper sensitivity reactions or immune balance syndromes is a matter of debate (32H). Infection risk The risk of serious infec tions attributable to TNF-a antagonists is still controversial. When comparing patients with rheuma toid arthritis receiving TNF-a antagonists as opposed to methotrexate and glucocorti coids, serious infections are significantly more likely to occur during the first 3–6 months of treatment; the apparent differ ences in opinions and reports of serious infections attributable to TNF-a antagonists could be explained by the timing of the surveys (33R, 34c, 35c). In a meta-analysis of 21 studies of 5356 patients with Crohn’s disease, TNF-a antagonists did not increase the risks of death, malignancy, or serious infections (36M). Similarly, in a large cohort study of patients aged at least 65 years with rheumatoid arthritis there was no signifi cant increase in serious infections (37C).
In 200 patients with various rheumatoid diseases, severe infections occurred in 2% of patients receiving TNF-a antagonists (38c). Bacterial infections The mechanisms whereby TNF-a keeps Mycobacterium tuberculosis at bay are numerous and diffi cult to dissect. However, as it is a primary signal of granuloma formation antagonizing TNF-a alters control of initial and chronic infection. When comparing different studies and their incidences of reactivation of or increased susceptibility to tuberculosis, geographical factors must be kept in mind. The risk of TNF-a antagonist treatment in a country with a low incidence is likely to be less than in areas of moderate to high incidence. It should also not be forgotten that it is not just pulmonary tuberculosis that can develop: two women received adalimumab and developed peritoneal tuberculosis (39A, 40A). Comparing the different TNF-a antago nists the risk of tuberculosis reactivation by infliximab was 12 times higher than by etanercept (41c). In a survey of mycobacterial infections in 49 North American patients receiving TNFa antagonists, non-tuberculosis mycobacter ial infections were twice as common as tuberculosis; 16% of the patients died dur ing treatment for the infection (42c). Fungal infections In a meta-analysis of 281 cases of invasive fungal infections associated with TNF-a antagonists, 226 (80%) were associated with infliximab, 44 (16%) with etanercept and 11 (4%) with adalimumab (43R). The most common cau sative fungi were histoplasmosis (n = 84, 30%), candidiasis (n = 64, 23%), and asper gillosis (n = 64, 23%). Pneumonia was the most common pattern of infection. • A 63-year-old man taking prednisone and methotrexate for rheumatoid arthritis also received etanercept for 3 months and then adalimumab for 4 months; he subsequently developed systemic nocardiosis (44A). • Nocardiosis occurred in a 75-year-old man taking adalimumab (dosage not reported) for rheumatoid arthritis (45A).
Drugs that act on the immune system: cytokines and monoclonal antibodies
Adalimumab
(SED-15, 2380; SEDA-29, 397; SEDA-30, 439; SEDA-31, 597) Respiratory A 48-year-old man with rheu matoid arthritis was treated with infliximab and etanercept without any serious adverse events; however, when he received ada limumab for the second time he developed severe bronchospasm (46A).
Ear, nose, throat Within a few weeks of starting adalimumab four patients with chronic rheumatoid arthritis developed newly diagnosed recurring sinusitis refrac tory to standard treatment, which resolved after adalimumab was withdrawn (47c). Sensory systems A 60-year-old woman received subcutaneous adalimumab 40 mg every 2 weeks for 2 months and developed optic neuropathy in one eye (48A). Metabolism In two cases patients with rheumatoid arthritis, a 66-year-old man and a 40-year-old woman, there was a marked reduction in fructosamine concen trations after 1 month, suggesting that ada limumab might have improved insulin resistance (49A). Hematologic A 42-year-old woman with Crohn’s disease was given adalimumab 5 mg/kg at 0, 2, and 6 weeks and subse quently every 8 weeks (50A). She developed thrombocytopenia after 8 months and had platelet-associated IgG. Adalimumab was withdrawn and 5 months later reintroduced at a dose of 80 mg. One week after the first dose she again developed thrombocyto penia. The platelet count recovered after withdrawal of adalimumab. Skin Alopecia totalis has been described in two patients (51A, 52A). • A 38-year-old woman with rheumatoid arthri tis was treated with adalimumab for 2 years and then rapidly developed alopecia totalis. • A 48-year-old man received adalimumab 40 mg fortnightly for 6 months and developed alopecia totalis.
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Other dermatological effects possibly related to adalimumab have included pityr iasis rosea (53A), acute generalized skin eruptions (54A), cutaneous lupus (55A), and lichenoid reactions (56A). • A 51-year-old woman developed a pustular drug eruption on the flexural areas of her limbs while being treated with adalimumab (57A). • A 32-year-old man was given adalimumab 40 mg fortnightly for ankylosing spondylitis and developed urticaria (58A).
Musculoskeletal A 44-year-old woman with Crohn’s disease was treated with ada limumab in an initial dose of 160 mg fol lowed by 80 mg in week 2, when she developed severe myalgia; other causes were excluded (59A). Reproductive system A 32-year-old mor bidly obese white woman received adalimu mab 40 mg every other week for 4 months for psoriatic disease and developed menor rhagia and severe menstrual pain, which resolved when adalimumab was withdrawn (60A). Immunologic Adalimumab seems to have immunogenic effects, despite its fully human sequence, since 13 of 15 patients in a trial developed antibodies (61c). Such antibodies could lead to treatment failure. Other immunological reactions to adali mumab have been reported. • A 60-year-old woman with rheumatoid arthritis and a history of hypersensitivity to infliximab was given adalimumab 40 mg fortnightly (62A). After the seventh dose she developed edema of the hands and lips, erythema of the face and urticaria-like skin reactions on the trunk. She also had a husky voice, dyspnea, and hypotension. • A 82-year-old woman with rheumatoid arthritis developed giant cell arteritis after taking adalimumab for 2 years (63A). • A 63 year-old woman was treated with adalimumab for rheumatoid arthritis and developed ANCA-positive renal vasculitis (64A). • A 57-year-old woman, a heavy smoker, devel oped symmetrical synovitis affecting the meta carpophalangeal joints and the feet, without joint deformities or radiological erosions. She
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complained of Raynaud’s phenomenon and pain in the shoulders and knees without fever. She as given pulse methylprednisolone followed by prednisone 20 mg/day and sub cutaneous methotrexate 15 mg/week. After 6 months she was given subcutaneous adalimu mab 40 mg every other week because pred nisolone and methotrexate were insufficient. Adalimumab resulted in rapid clinical improvement, prednisone was withdrawn within 3 months, and adalimumab and metho trexate were continued. However, 8 months later her condition gradually worsened, with fatigue, weight loss, pruritus, proximal muscle pain, and progressive symmetrical proximal muscle weakness, without a rheumatic flare. She developed a rash over the thighs and abdomen. Skin biopsy showed non-specific inflammatory changes in the dermis. Both drugs were withdrawn, but her condition dete riorated further. Her erythrocyte sedimenta tion rate was 13 mm/hour, C-reactive protein 3 mg/l, creatine kinase 3223 U/l (reference range up to 190 U/l), and aldolase 147 U/l (up to 8 U/l). She had positive antinuclear anti bodies, anti-dsDNA, rheumatoid factor, anticyclic citrullinated peptide antibodies (anti-CCP) and anti-polymyositis–scleroderma antibodies (anti-PM-Scl). Deltoid muscle biopsy showed severe muscle necrosis with dense mono nuclear cell infiltrates, but no vasculitis. The diagnosis was an undifferentiated overlap syn drome, with features of polyarthritis, myositis and scleroderma, possibly caused or exacerbated by adalimumab. Prednisone 50 mg/day improved her muscle strength, normalized the muscle enzyme activities and normalized the titers of autoantibodies, except for the anti-PM-Scl antibodies, although her CK activity rose progressively over the next 8 months. She later had a serious relapse of the myositis accompanied by a flare of auto immunity similar to that seen initially. Treat ment with prednisone and methotrexate improved the symptoms.
In the last case it was uncertain whether the patient had initially true rheumatoid arthri tis or an overlap syndrome with prominent rheumatic symptoms. However, polymyo sitis/dermatomyositis can occasionally develop in patients with rheumatoid arthri tis. Also, she developed a definite polymyo sitis along with a flare in autoimmunity, which might have reflected active systemic lupus erythematosus. There has been a report of 12 patients who developed defi nite systemic lupus erythematosus while taking a TNF-a antagonist (infliximab in nine, etanercept in three) for various
rheumatic diseases (65A). However, the precise role of adalimumab in the occur rence of myositis is unclear (66Ar). Infection risk There have been further reports of infections in association with adalimumab. • A 69-year-old woman with rheumatoid arthritis had been treated with subcutaneous adalimumab 40 mg every 2 weeks for 1 year when she developed invasive cryptococcosis of one finger (67A). • A woman developed Pneumocystis jiroveci pneumonia when treated with adalimumab for rheumatoid arthritis (68A). • A 42-year-old woman with rheumatoid arthritis received subcutaneous adalimumab 40 mg/week for 70 weeks and developed recurrent varicella (69A).
Alefacept Alefacept is a bioengineered fusion protein of soluble lymphocyte function antigen (LFA-3) with Fc fragments of IgG1. It blocks the LFA-3/CD2 interaction neces sary for activation and proliferation of memory effector T cells by binding to CD2 expressed on the surface of T cells. It has been used in the treatment of psoriasis and psoriatic arthritis. There has also been a small pilot study of its use in rheumatoid arthritis (70c). Its uses and efficacy have been reviewed (71R, 72R). The reported adverse effects of alefacept are generally minor and include headache, nasopharyngitis, rhinitis, influenza, upper respiratory tract infections, pruritus, arth ralgias, fatigue, nausea, accidental injury, and increases in liver enzymes (73R). A few patients develop antibodies against alefacept. Observational studies In an open study in 11 patients with active psoriatic arthritis who were given alefacept for 12 weeks the most common adverse effects that were probably or definitely associated with the drug were a flu-like syndrome (54%) and infections (18%) (74c). There were two severe adverse events, which were both judged to be unrelated to alefacept.
Drugs that act on the immune system: cytokines and monoclonal antibodies
Placebo-controlled studies In a random ized, double-blind, placebo-controlled trial in 185 patients with psoriatic arthritis aged 18–70 years, alefacept 15 mg or placebo was given intramuscularly once a week for 12 weeks in combination with methotrexate, followed by 12 weeks of observation during which only methotrexate was continued (75C). Back pain and a raised alanine trans aminase activity were more common than in those given placebo. Adverse events led to withdrawal of treatment in two patients tak ing alefacept, one because of worsening and one because of increased transaminase activ ities to 3–5 times the upper limit of normal; in the latter the transaminases returned to normal after withdrawal of alefacept. There were serious adverse events in two patients who received alefacept (metrorrhagia, recto cele, and emphysema) and in three who received placebo (intervertebral disc protru sion, non-infectious gastroenteritis and breast cancer). Most of the recorded adverse events were mild to moderate in intensity and none of the serious events was attributed to the drug. There were no opportunistic infections or malignancies. Systematic reviews In a systematic review of double-blind, randomized, controlled trials of alefacept (n = 3), efalizumab (n = 5), etanercept (n = 4), and infliximab (n = 4); in patients with psoriasis the rela tive risks of one or more adverse events were significantly increased compared with placebo:
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Tumorigenicity Lymphoproliferative dis orders are more common in individuals taking immunosuppressive drugs, and mycosis fungoides has been reported in a 72-year-old patient with a psoriasiform dermatitis taking alefacept (79A). The authors suggested that alefacept should be used with caution in patients with known mycosis fungoides or an unclassified atypical lymphocytic infiltrate of the skin. Drug administration route In two open studies in healthy men a single dose of alefacept 0.15 mg/kg was given in one of three ways: a 30-second intravenous bolus (n = 12); 0.04 mg/kg intramuscularly (n = 8); or 0.04 mg/kg as a 30-minute intravenous infusion (n = 8) (80c). The intramuscular availability was about 60%. The half-life was about 12 days. In a randomized, open, crossover com parison of subcutaneous and intramuscular alefacept 15 mg in 50 healthy volunteers, the systemic availabilities were similar (81c).
Etanercept
(SED-15, 1279; SEDA-29, 397; SEDA-30, 440; SEDA-31, 600) Respiratory Another case of pulmonary nodulosis in a patient taking etanercept has been reported (82A).
• alefacept: RR = 1.09; NNTH = 15; • efalizumab: RR = 1.15; NNTH = 9; • infliximab: RR = 1.18; NNTH = 9.
• A 50-year-old woman with rheumatoid arthri tis was given etanercept 25 mg twice weekly and after 9 months developed pulmonary nodulosis. The etanercept was continued and there was no further progression of the nodu losis. Her symptoms resolved over time.
Serious adverse events were increased in a sensitivity analysis of four efalizumab trials (n = 2443; RR = 1.92; NNTH = 60) (76M).
In three cases interstitial lung disease was exacerbated during standard dosage treat ment regimens with etanercept (83A, 84A).
Hematologic Because of its pharmacologi cal action, the CD4þ count is reduced by alefacept. It has therefore been suggested that the CD4þ count should be monitored regularly to ensure that it does not fall below 250 106/l (77R); however, the usefulness of doing this has not been demonstrated (78R).
Nervous system There have been further reports of demyelinating disorders in patients taking etanercept. • A 37-year-old woman with rheumatoid arthri tis was given subcutaneous etanercept 25 mg twice a week and developed demyelinating
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disease, which resolved after withdrawal of etanercept (85A). • After 24 months of treatment with etanercept 50 mg a week for rheumatoid arthritis a 66-year-old woman developed demyelination in the spinal cord and cerebral cortex (86A). • After 3 months treatment for rheumatoid arthritis with etanercept 25 mg twice weekly a 60-year-old patient developed reversible posterior leukoencephalopathy syndrome (87A). • A 36-year-old woman received etanercept 25 mg twice weekly for psoriasis arthritis and developed multiple sclerosis after 4 months; even though the etanercept was withdrawn relapsing remitting multiple sclerosis persisted (88A). • A 74-year-old woman developed progressive multifocal leukoencephalopathy after receiving a standard dosage of etanercept for rheumatoid arthritis for 7 months (89A). • A 46-year-old woman with rheumatoid arthritis was given etanercept and after 22 months developed ophthalmic manifestations of demyelination of the central nervous system (90A). Etanercept was withdrawn. Her symptoms abated but progressed about 2 months later. She was reported to have sequelae of the demyelination, despite some improvement 1 year after diagnosis.
Metabolism A 54-year-old white woman with long-standing rheumatoid arthritis and type 2 diabetes mellitus developed episodes of hypoglycemia after starting to take subcutaneous etanercept 25 mg twice weekly (91A). Hypoglycemia occurred only on the day after each etanercept injection. The investigators suggested that the hypo glycemia was due to increased lipogenesis in the liver and adipose tissue. However, the exact mechanism is unclear. Marked hypoglycemia in female mice has been reported 2 hours after the administration of TNF-a (92E). Gastrointestinal There have been a few cases of Crohn’s disease after treatment with etanercept for 11–26 months (93A–95A). The diagnosis was confirmed histologically and responded to standard treatment and withdrawal of etanercept. Those who were not re-exposed to etanercept remained free of further flares. Liver Hepatitis has been suggested to have been aggravated by etanercept (96A, 97A).
• A 50-year-old woman with rheumatoid arthri tis received etanercept 25 mg twice weekly after non-steroidal anti-inflammatory drugs and methotrexate were not effective. Mild rises in AlT and AsT activity were thought to be due to NSAID-induced liver damage. How ever, 2 weeks after the first dose of etanercept, she developed progressive rises in AsT and AlT and had right upper quadrant tenderness and hepatomegaly. Etanercept was withdrawn. Liver biopsy showed lymphoplasmacytic inflammatory cell infiltration mainly in the portal tracts, consistent with autoimmune hepatitis. Glucocorticoids normalized liver function and produced stable joint symptoms. • A 17-year-old Caucasian woman developed pauciarticular erosive arthritis, which became polyarticular. Therapy included intra-articular and systemic glucocorticoids, non-steroidal anti-inflammatory drugs, sulfasalazine, metho trexate, gold, and ciclosporin, but active syno vitis and joint damage continued. She was therefore given subcutaneous etanercept 25 mg twice weekly, and the arthritis improved. The methotrexate was withdrawn and the dosage of prednisone was reduced to 3 mg/day. Later the etanercept was withdrawn but her arthritis flared and it was reintroduced in a dosage of 25 mg weekly. After 4 months, her liver function tests rose over 4 months and etanercept was again withdrawn. A liver biopsy showed granulomatous hepatitis with out fibrosing steatosis, as expected in metho trexate-associated hepatotoxicity.
Urinary tract A 67-year-old woman with rheumatoid arthritis developed minimal change nephrotic syndrome while under treatment with etanercept (98A). Acute interstitial nephritis occurred in a 58-year-old woman with rheumatoid arthri tis after therapy with etanercept 25 mg/ week for 3 months (99A). Skin There have been reports of tinea versicolor (100A), interstitial granulomatous dermatitis (101A), and lichen planopilaris (102A) in patients receiving etanercept. • A 71-year-old man with widespread psoriasis was given etanercept 25 mg twice a week and rapidly developed squamous cell carcinoma on the penis (103A). • A 55-year-old woman with rheumatoid arthri tis was given etanercept monotherapy 50 mg/ week and 1 year later developed a cutaneous pseudolymphoma (104A).
Immunologic A 52-year-old woman with rheumatoid arthritis was given etanercept
Drugs that act on the immune system: cytokines and monoclonal antibodies
25 mg twice a week and after 40 weeks the drug was withdrawn because of cold agglu tinin disease (105A). Sarcoidosis has been associated with etanercept. • Three women aged 46–65 with rheumatoid arthritis received etanercept 25 mg twice weekly and developed sarcoidosis 6 months to 2 years later; their symptoms abated when etanercept was withdrawn (106A, 107A). • A 35-year-old woman with sarcoidosis in remission relapsed after taking etanercept 50 mg/week for 3 weeks (108A). • A 40-year-old man’s pulmonary sarcoidosis was associated with etanercept; it did not resolve completely after withdrawal (109A). • A 52-year-old woman with rheumatoid arthritis took etanercept for 18 months and developed sarcoid-like granulomata with respiratory and parotid involvement (110A).
Infection risk Various infections have been associated with etanercept. • A 71-year-old woman with rheumatoid arthritis received methotrexate for 11 years and etanercept for 2 years and developed spontaneous purulent pericarditis (111A). • A 58-year-old woman who received etanercept and methotrexate for rheumatoid arthritis developed tuberculous uveitis (112A). • A 58-year-old man with severe chronic plaque psoriasis was given subcutaneous etanercept 50 mg twice a week. After 1 month he developed recurrent varicella. It was treated and etanercept was re-introduced. The varicella did not recur (113A). • A 41-year-old man who received etanercept 25 mg twice weekly developed Pneumocystis jiroveci pneumonia 3 years after the introduction of etanercept for psoriatic arthritis (114A).
Occult hepatitis B and etanercept-induced hepatitis B virus (HBV) reactivation have been reported (115A). • A 73-year-old white man with ankylosing spondylitis developed secondary amyloidosis. He was given subcutaneous etanercept 25 mg twice weekly and prednisone 5 mg/day. He was anti-HBs positive but HBsAg negative. AntiHBc and HBe antibodies and liver tests were normal. After 14 months therapy with etanercept and prednisone he developed malaise, right upper quadrant abdominal discomfort and increased activities of serum AsT 141 IU/l, AlT 65 IU/l, and gamma glutamyl transferase 121 IU/l; total bilirubin
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was 34 mmol/l. There was progressive disappearance of anti-HBs and seroreversion, with reappearance of HBsAg and HBV DNA. Withdrawal of etanercept and therapy with lamivudine 100 mg/day resulted in negative HBV DNA and seroconversion from HBsAg positive to anti-HBs-positive. Etanercept was restarted 4 months later, lamivudine was maintained and there was no flare-up of HBV infection during follow-up.
Hepatitis B virus reactivation is well known in HBsAg-positive patients undergoing immunosuppressive therapy. HBV serology should be monitored closely in such patients and nucleoside or nucleotide analogues should be given in case of HBV reactivation. Visceral leishmaniasis has been reported in a patient after etanercept treatment (116A).
Infliximab (SED-15, 1747; SEDA-29, 398; SEDA-30, 440; SEDA-31, 601) Observational studies In an analysis of the FDA’s AERS database, infliximab was identified as the suspect medication in 18 220 reports (117M). There were signals for lymphoma (EB05, the lower bound of the 90% confidence interval around the Empirical Bayes Geometric Mean = 6.9), neuropathy (EB05 = 3.8), infection (EB05 = 2.9), and bowel obstruction (EB05 = 2.8). The signal for granulomatous infections was stronger than the signal for non-granulomatous infections (EB05 = 13 and 2.4 respectively). The signals for bowel obstruction and infusion reaction were spe cific to patients with inflammatory bowel disease; this suggests potential confounding by indication, especially for bowel obstruction. During post-marketing surveillance for 6 months of 5000 patients treated with inflix imab for rheumatoid arthritis, 28% had adverse drug reactions, of which 6.2% were severe (118C). Bacterial pneumonia occurred in 2.2%, tuberculosis in 0.3%, Pneumocystis jiroveci pneumonia in 0.4%, and interstitial pneumonitis in 0.5%. There were serious infusion reactions in 0.5%.
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In 147 patients with inflammatory bowel disease who received 1924 infusions of infliximab, 21 were hospitalized because of serious infections that were considered to have been at least possibly related to inflix imab (119c). Nine patients (6%) developed malignancies during follow-up: four had colorectal carcinoma, one had a carcinoid tumor with another primary signet-ring cell carcinoma of the small bowel, one had a breast cancer, two had skin cancers, and one had a superficial melanoma. Of 165 patients who were treated with infliximab 3 mg/kg every 8 weeks, serious infections occurred in 8.5% (120c). In 78 patients with juvenile idiopathic arthritis reactions during infusion, such as dyspnea, flushing, chills, headache, hypoten sion, anxiety, and throat edema, occurred in 29 (35%) (121c). Anti-DNA antibodies were present in seven, but none developed a lupus-like syndrome. Cardiovascular A 78-year-old woman with rheumatoid arthritis and first-degree heart block was given infliximab 3 mg/kg fortnightly and after the third dose pro gressed to complete heart block (122A). Sensory systems A 65-year-old woman was given intravenous infliximab 3 mg/kg for rheumatoid arthritis, in addition to pre dnisolone 2.5 mg/day, methotrexate 2.5 mg/ week, folic acid, disodium etidronate, ome prazole, and thyroxine, and developed endophthalmitis (123A). Metabolism Infliximab was associated with very high concentrations of triglycerides in 32 patients with rheumatoid arthritis (124c). Hematologic The FDA’s Adverse Event Reporting System has received 8 reports of hepatosplenic T cell lymphoma in young patients receiving infliximab in combination with other immunosuppressants (125S). A 63-year-old woman with rheumatoid arthritis, who received methotrexate, predni solone and infliximab developed an EBVassociated lymphoproliferative disorder after 30 months; on withdrawal of infliximab the disorder resolved rapidly (126A).
Skin There is a multitude of reports of the adverse effects of infliximab on the skin, including palmoplantar pustulosis (127A), alopecia areata (128A), halo nevi (129A), cutaneous mucormycosis (130A), sub erythrodermic psoriasis (131A), dermatitis herpetiformis (132A), pustular psoriasis (133A, 134A), atopic dermatitis (135A), acne (136A, 137A), an overlap of exanthematous pustulosis and toxic epidermal necrolysis (138A), and an oral lichenoid reaction (139A). Immunologic Antinuclear antibodies at low titers occurred after 6 months in 13 of 20 patients with Behçet’s disease who received infliximab 5 mg/kg at weeks 0, 4, and 8 and every 6–8 weeks thereafter. Another patient developed anti-beta2 gly coprotein-I IgM antibodies (anti-beta(2) GPI). None had manifest disease due to the antibodies (140c). Autoimmune hepatitis has been reported in patients receiving infliximab (141A, 142Ar). • A 56-year-old woman with ankylosing spondylitis developed autoimmune hepatitis within 3 months of infliximab therapy; the effects of withdrawal were not reported. • A 39-year-old woman receiving infliximab developed autoimmune hepatitis; she devel oped liver failure and needed transplantation.
Lupus-like syndrome has been attributed to infliximab (143A, 144A). • A 34-year-old woman with ulcerative colitis was given infliximab 5 mg/kg at weeks 0, 2, and 6 and then every 8 weeks; after 5 months she developed a lupus-like syndrome with autoimmune hepatitis. • A 39-year-old man with Crohn’s disease was given infliximab 5 mg/kg at 0, 2, and 6 weeks and then bimonthly; co-medications included azathioprine 75 mg/day and mesalazine 2 g/day. He developed pleuritic chest pain associated with nausea and weakness; he was afebrile but had a tachycardia. An electrocardiogram showed mild inferolateral ST segment eleva tion; troponin I and CK-MB activities were normal. There was cardiomegaly on a chest X-ray and echocardiography showed a pericar dial effusion with normal left ventricular func tion. Coronary angiography was normal. He was given analgesics and prednisolone for pericarditis secondary to infliximab, which was nevertheless continued. Seven weeks
Drugs that act on the immune system: cytokines and monoclonal antibodies after the next infusion of infliximab he devel oped severe arthralgia in all small joints. Anti nuclear antibodies and anti-dsDNA antibodies were strongly positive, histone antibodies were weakly positive, and C3 and C4 were normal. A high-resolution CT scan showed pleural thickening. The infliximab was withdrawn and there was no recurrence of the lupus-like symptoms.
In Crohn’s disease, 6% of patients have a serious adverse event, and 8.2% have an infectious event related to infliximab with an overall mortality of 1%. Positive anti nuclear antibodies associated with TNF-a antagonists in Crohn’s disease have been reported to occur in 57% of patients after 1 year. However, drug-induced lupus has only been associated with infliximab in 0.6–1.6% of cases and pericarditis has not previously been reported. Vasculitis has been attributed to inflixi mab (145A). • A 31-year-old Caucasian man with active sero positive rheumatoid arthritis, despite treat ment with sulfasalazine, hydroxychloroquine, leflunomide, methotrexate, and ciclosporin, was given intravenous infliximab 3 mg/kg every 8 weeks. This was later increased to 5 mg/kg and after 12 weeks he developed wor sening joint pain and a tachycardia. He had pustular purpuric lesions and hemorrhagic papules over the elbows, hands and feet, and synovitis in the metacarpophalangeal and proximal interphalangeal joints, wrists, elbows, ankles and feet. Blood urea was 18 mmol/l (reference range 2.1–7.6) and serum creatinine 349 µmol/l (51–107). The urine contained blood and a trace of protein. Methotrexate, ciclosporin, and infliximab were withdrawn. Klebsiella infection was treated with trimetho prim. Antinuclear antibodies and c-ANCA were positive. Renal biopsy showed pauci immune crescentic glomerulonephritis.
Several hypotheses have been postulated for autoantibody induction during treatment with infliximab. The presence of nuclear or cytoplasmic debris as a result of cell apopto sis may be a trigger, and reduced TNF concentrations could induce autoreactivity. However, the precise mechanism involved in the development of vasculitis after treat ment with TNF-a antagonists is elusive. Other immunological adverse effects have been attributed to infliximab.
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• A 41-year-old woman with rheumatoid arthritis was given infliximab 3 mg/kg at intervals of 6–8 weeks combined with methotrexate; after 5 years she developed sarcoidosis, mainly involving the eyes and the central nervous system (146A). • A 67-year-old woman received infliximab 5 mg/kg in weeks 0, 2 and 6 and then every 8 weeks for psoriasis (147A). After eight infusions she developed acute ischemia in both legs due to arterial thrombosis. She was found to have antiphospholipid antibodies.
Infection risk The risk of mycobacterial infections, such as tuberculosis, is discussed above. There are many case reports of odd or opportunistic infections possibly asso ciated with the use of infliximab, such as Listeria meningoencephalitis (148A) and other Listeria infections (149A), Pneumo cystis jiroveci pneumonia (150A, 151A), pul monary actinomycosis (152A), visceral leishmaniasis (153A), coccidioidomycosis pneumonia (154A), severe malaria (155A), invasive trichophyton rubrum infection (156A), cryptococcal meningitis (157A), and severe adenovirus pneumonia (158A). In 11 patients with chronic hepatitis B infection, who were treated with infliximab for rheumatoid arthritis, hepatitis was reac tivated, but the two patients who were trea ted with etanercept did not have such a reaction (159A). An HBV mutant has been reported in patient who was given lamivudine for hepa titis B and infliximab for Crohn’s disease (160A). • A 29-year-old man with Crohn’s disease devel oped chronic hepatitis B (HBeAg and HBV DNA positive), which responded to lamivu dine 100 mg/day. However, his Crohn’s disease relapsed and did not respond to azathioprine 2.5 mg/kg/day. He was given three doses of infliximab followed by 8-weekly maintenance treatment, with a complete sustained response. About 2 years later his transaminase activities increased and 2 months later he developed weakness, malaise and nausea. IgM anti-HBc antibodies and high serum HBV DNA poly merase activities were detected. The pre viously positive HbeAg was negative at this time, suggesting lamivudine resistance with reactivation of a mutant B virus. Infliximab was withdrawn and adefovir dipivoxil was added. He became totally asymptomatic over the next few months.
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The authors suggested that caution should be taken when giving TNF-a antagonists to HBV-infected patients. In another report a 43-year-old woman who received lamivu dine prophylaxis did not develop an HBV mutant (161A). • A 25-year-old man with neurological Behçet’s disease was given infliximab 5 mg/kg in addi tion to monthly cyclophosphamide, interferon, and a combination of ciclosporin and azathioprine; he developed cytomegalovirus colitis 52 days after the first infusion of inflix imab (162A).
In 523 patients with ulcerative colitis, complications were 3.54 times more com mon in the 85 who were receiving inflix imab; the odds of sepsis were 14:1 and the odds of late complications 2.2 times greater (163c).
MONOCLONAL ANTIBODIES (SED-15, 2380; SEDA-29, 404; SEDA-30, 442; SEDA-31, 602)
Abciximab See Chapter 35 (Glycoprotein IIb–IIIa inhibitors).
Adalimumab See TNF-a antagonists above.
Alemtuzumab (Campath-1H®)
neutropenia (77%), anemia (76%), thrombo cytopenia (71%), pyrexia (69%), chills (53%), cytomegalovirus viremia (56%), and cytomegalovirus infection (16%) (164S). Other infections were reported in 90% of subjects. Skin manifestations included urti caria (16%), other rashes (13%), and erythema (4%). There was also hypotension (16%), hypertension (14%), headache (14%), tremor (3%), dyspnea (14%), diar rhea (10%), insomnia (10%), anxiety (8%), and tachycardia (10%). Respiratory A 26-year-old man with Alport’s syndrome underwent retransplantation with a renal allograft and was subsequently treated with a single intravenous dose of alemtuzumab 30 mg; on the second post-operative day he developed diffuse alveolar hemorrhage (165A). A patient with chronic lymphocytic leukemia received alemtuzumab for 3 weeks as salvage therapy and developed interstitial pneumonitis, which was not associated with either infection or the neoplasm (166A). Hematologic Of 357 pancreas transplant recipients, 20 developed red cell aplasia, autoimmune hemolytic anemia, and/or idio pathic thrombocytopenic purpura during therapy with alemtuzumab, daclizumab, and mycophenolate mofetil (167c). Alemtuzumab was used as induction therapy immediately before surgery in a man who received a living donor real trans plant; during surgery he developed a severe coagulopathy, which improved after 24 hours but recurred within 3 hours after a second dose of alemtuzumab, given exactly 24 hours after the first (168A).
(SED-15, 71; SEDA-29, 404; SEDA-30, 442; SEDA-31, 602)
Immunologic Immune reconstitution syn drome has been reported in two cases after the use of alemtuzumab (169A, 170A).
Observational studies On 19 September 2007 alemtuzumab was approved by the FDA as a single agent for the treatment of B-cell chronic lymphocytic leukemia. The common reported adverse effects in the CAM 307 trial include lymphopenia (99%),
• A 53-year-old man with Sézary syndrome received alemtuzumab 30 mg thrice weekly for 3 months. The disease responded, but 3 months later he developed sarcoidosis, which was thought to have resulted from T-cell reconstitution. • A 55-year-old man received alemtuzumab thrice weekly for T-cell prolymphocytic
Drugs that act on the immune system: cytokines and monoclonal antibodies leukemia and went into remission after 26 doses. A few weeks later, while he still had profound cellular immunodeficiency, he had a cryptococcal infection. After 10 months in remission he developed what was thought to be an immune reconstitution inflammatory response specific to Cryptococcus neoformans.
Infection risk Of 547 organ transplant recipients 65% of whom received induction therapy with alemtuzumab only, 56 devel oped subsequent opportunistic infections, including infections with cytomegalovirus (n = 16), BK virus (12), Candida (12), invasive molds (4), Nocardia (4), mycobacteria (3), Cryptococcus neoformans (2), and HHV 6, parvovirus, Balamuthia mandrillaris, and Toxoplasma (one each) (171c). Patients who received alemtuzumab for allograft rejection were significantly more likely to develop an opportunistic infection than patients who received alemtuzumab for induction therapy only (4.5% versus 21%). Of 113 patients with chronic lympho proliferative disorders who received alem tuzumab-based therapy, 25 had reactivation of cytomegalovirus; the only significant difference between the groups was a low serum albumin concentration in those in whom reactivation occurred (172c). In a study of 67 patients with chronic lymphocytic leukemia, 33% of those who received salvage therapy developed an infection while none of those who received consolidation therapy had a similar response (173c). Of 67 patients who were Toxoplasma IgG-positive when they were given alemtu zumab at the time of hemopoietic stem cell transplantation, and were therefore classi fied as being at high risk of Toxoplasma reactivation, and were covered with co-tri moxazole prophylaxis after transplantation, two developed Toxoplasma invasive disease with cerebral involvement at 2 and 4 months after transplantation (174A). Comparing these results with those of stu dies of other T-cell replete cohorts receiving hemopoietic stem cell transplantation, there was no significant difference in the incidence of Toxoplasma reactivation. In 477 patients who received induction with alemtuzumab for renal transplantation
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the incidences of subsequent fungal and tuberculous infections were 0.6 and 0.4% respectively (175c).
Basiliximab
(SED-15, 418;
SEDA-29, 407; SEDA-30, 443; SEDA-31,
603)
Immunologic Of 18 renal transplant recipi ents who received basiliximab, two devel oped anaphylactic reactions on initial exposure to basiliximab; both had a history of allergies (bronchial asthma and drug allergy) (176A).
Bevacizumab See Chapter 47.
Daclizumab
(SED-15, 1047; SEDA-29, 408; SEDA-30, 444; SEDA-31, 605) Cardiovascular Three patients who were given intravenous daclizumab 1 mg/kg after liver transplantation developed sinus bradycardia for 6–9 days starting after 12–40 hours (177A).
Musculoskeletal Of 15 children who were treated with daclizumab for acute graft versus-host disease, one developed a reactive arthritis that was thought to be linked to the drug (178c). Infection risk Of 57 patients with acute graft-versus-host disease after allogeneic hemopoietic stem cell transplantation treated with daclizumab, 54 developed opportunistic infections; 33% of the deaths were due to graft-versus-host disease with infection (179c). Of 58 patients who underwent renal allo transplantation and induction with a single dose of daclizumab 1 mg/kg 2 hours before the operation, 10 developed an infection; how ever, the incidence was the same in those who did not receive daclizumab at all (180c).
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Of five patients with active non-infectious uveitis treated with daclizumab 8 mg/kg on day 0 and 4 mg/kg on day 14, one developed a left lower lobe pneumonia (181A).
Efalizumab (SEDA-29, 409; SEDA-30, 445; SEDA-31, 605) On 8 April 2009 the FDA recalled efalizu mab because of the risk of progressive multifocal leukoencephalopathy and lifethreatening infections (182S). Observational studies Among 49 patients with psoriasis who received subcutaneous efalizumab 1 mg/kg once a week for 12 weeks, the reported adverse effects were headache (35%), arthralgia/arthritis (29%), psoriasis (de novo or exacerbated; 27%), and pruritus (22%) (183c). Nervous system Aseptic meningitis has been reported in a 32-year-old woman receiving efalizumab for severe psoriasis (184A). Drug-induced aseptic meningitis is mainly caused by non-steroidal anti-inflam matory drugs, antibiotics, intravenous immunoglobulin and monoclonal antibo dies such as muromonab, intrathecal agents, and vaccines. Patients with autoimmune dis eases seem to be more susceptible, but the pathogenic mechanisms are not known. Efalizumab might cause aseptic meningitis by blocking LFA-1 and ICAM-5 interac tions or by binding to a cross-reacting neural antigen, thereby inciting local inflammation, as has been suggested by some authors for muromonab. Hematologic Of 39 patients who under went renal transplantation and were kept on a regimen with ciclosporin, mycopheno late mofetil, glucocorticoids, and subcuta neous efalizumab 0.5 or 2 mg/kg/week for 12 weeks, 8% developed lymphoprolifera tive disorders; all had received the higher dose of efalizumab (185C). Other cases have been reported (186A). The risk of thrombocytopenia associated with efalizumab is well established and has
been reported again (187A–189A). The guidelines suggest monthly monitoring platelet counts for 3 months after the start of treatment and every 3 months thereafter, but there seems to be an increased risk within at least the first 6 months (190cr) (i.e. an intermediate time-course). This is also applicable to autoimmune hemolysis, which can also develop beyond the first 6 months of treatment (191A). Skin Inflammatory papules developed in 15 patients who were receiving efalizumab (192A). As there was no increase in eosinophils in the papules, these lesions were thought not to be allergic. Immunohistochemistry showed an increase in CD11bþ, CD11cþ, and iNOSþ cells in the papules, with relatively few CD3þ T cells. Other reports of dermatological adverse events in patients receiving efalizumab have included hypertrichosis (193A), plantar ex foliation and desquamation (194A), severe exacerbation of chronic plaque psoriasis (195A), and guttate psoriasis (196A). • A 44-year-old Caucasian woman with recalcitrant psoriasis was given efalizumab 1 mg/kg/week and after 8 months developed multiple eruptive dermatofibromata, which resolved 6 months after withdrawal of efalizumab (197A). • A 60-year-old woman with psoriasis was given weekly efalizumab and 9 weeks later developed pityriasis rubra pilaris; the lesions responded to standard treatment and withdrawal of efalizumab (198A).
Musculoskeletal In a multicenter study newonset psoriatic arthritis occurred in 16 patients who were receiving efalizumab for psoriasis; one responded to withdrawal alone, eight required further treatment and two relapsed on reintroduction of efalizu mab (199c). Immunologic Immunological reactions to efalizumab have been reported. • A 58-year-old woman with psoriasis and a history of autoimmune hepatitis was given efalizumab 0.8 ml/week, and after a few
Drugs that act on the immune system: cytokines and monoclonal antibodies months developed a lupus-like syndrome, with a combination of polyarthralgia, hepatitis, pericarditis and immunological disorders; she improved shortly after drug withdrawal (200A). • A 52-year-old man developed a drug reaction with eosinophilia and systemic symptoms (DRESS) after receiving efalizumab 1.0 mg/ kg/week for 4 weeks for psoriasis; the symp toms persisted for 4 months after the drug was withdrawn (201A).
Infection risk Various infections have been reported in patients receiving efalizumab. • A 45-year-old woman with recalcitrant psoria sis had a flare-up and developed skin papules after re-treatment with efalizumab. There was complete remission after she had received efa lizumab for 12 weeks. Efalizumab was with drawn 3 months later. When the psoriasis relapsed she was again given efalizumab. After 3 weeks she developed eruptive whitish papules on the face and neck, resistant to topi cal glucocorticoids and vitamin D analogues, and her psoriasis flared up. The papules were due to disseminated giant molluscum contagio sum. Efalizumab was withdrawn and the papules resolved with methotrexate 15 mg/ week and narrow-band UVB.
This report suggests that under certain con ditions efalizumab might encourage the development of viral infections and defeat the immune system (202A). Disseminated cryptococcosis occurred in a patient with severe psoriasis who received efalizumab, ciclosporin, and methotrexate (203A). • A 34-year-old woman received subcutaneous efalizumab 1 mg/kg/week in addition to metho trexate 20 mg/week and ciclosporin 150 mg bd for severe pustular psoriasis. After 1 year she developed a progressive bilateral retro-orbital headache, which lasted 6 months. She also had weight loss of 2 kg and a solitary 0.5 cm umbi licated erythematous lesion on her right cheek resembling a nodular basal cell carcinoma. Histologically, the lesion showed encapsulated yeasts with occasional budding, consistent with Cryptococcus infection. The titer of serum cryptococcal antigen was 1:128. The cerebro spinal fluid contained fungal spores, encapsu lated yeasts, and there was a lymphocytic pleocytosis (35 106/l), raised protein (0.83 g/l) and a low glucose (1.4 mmol/l). Cere brospinal fluid cryptococcal antigen was positive (titer 1:128) and culture yielded Cryptococcus neoformans var. neoformans sensitive to amphotericin, flucytosine and fluconazole.
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The authors suggested that efalizumab had contributed to disseminated cryptococcal infection, because the patient had no oppor tunistic infections while taking metho trexate and ciclosporin for many years. However, triple drug immunosuppressive therapy is a risk factor for opportunistic infections such as cryptococcosis. Leishmaniasis has been associated with efalizumab (204A). • A 42-year-old man with generalized plaque psoriasis was given subcutaneous efalizumab 1 mg/kg/week and reported that his dog had died of leishmaniasis 10 weeks after the start of treatment; 2 weeks later he developed visceral leishmaniasis (205A).
Body temperature Efalizumab has been associated with fever of unknown origin (206A).
Gemtuzumab ozogamicin Liver The form of hepatotoxicity called sinusoidal obstructive syndrome in adults with acute myeloblastic leukemia who received gemtuzumab ozogamicin in clinical trials has been reviewed in the Research on Adverse Drug Events and Reports (RADAR) project (207M). The incidence was 3% at doses of 6 mg/m2 or more if used as monotherapy or in combination with nonhepatotoxic agents versus 28% if used with thioguanine and 15% when used as monotherapy in a dosage of 9 mg/m2. In observa tional studies the frequency of the syndrome was 15–40% if a stem cell transplantation was performed within 3 months of therapy with gemtuzumab ozogamicin. The FDAmandated Prospective Observational Regis try of patients who have received care at 60 medical centers has identified the sinusoidal obstructive syndrome associated with gem tuzumab ozogamicin in 14% of patients in whom stem cell transplantation is performed and 9% otherwise. Urinary tract Hemorrhagic cystitis has been associated with gemtuzumab ozogamicin (208A).
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• A 52-year-old man with acute promyelocytic leukemia received gemtuzumab ozogamicin after cord blood transplantation and 20 days later developed hemorrhagic cystitis with detection of adenovirus and BK virus. On days 218 and 232 he received gemtuzumab ozogamicin 9 mg/m2 again as part of a consolidation regimen, and on day 233 again developed a hemorrhagic cystitis, but without detection of microbial agents.
Immunologic A fatal hypersensitivity reac tion was reported in a 75-year-old man with acute myelogenous leukemia who received gemtuzumab ozogamicin 9 mg/m2 and a con comitant platelet transfusion; he had been given gemtuzumab ozogamicin and platelet transfusions before without adverse effects, but never on the same day (209A).
Infliximab See TNF-a antagonists above.
Natalizumab
(SEDA-30, 447)
Nervous system Natalizumab was with drawn from the market 3 months after its approval in February 2005 and was sus pended from all clinical trials because of reports of a rare neurological disease, pro gressive multifocal leukoencephalopathy, associated with the JC virus, a human poly omavirus, in patients with multiple sclerosis being treated with natalizumab (210A–212A, 213C). The Food and Drug Administration asked that all clinical trials involving drugs that target a4b1/VLA-4 be suspended until the full results of the TysabriTM safety data were completed (214R). Of three cases that occurred during clinical trials of natalizu mab in patients with multiple sclerosis, two were fatal (estimated incidence of 1 per 1000; 95% CI 0.2–2.8; mean treatment per iod 18 months). The risk of this viral infec tion, which is usually symptomatic only in severely immunosuppressed patients, was estimated at about 1 case per 1000 patients on natalizumab. During 2 years of treat ment, 6% of patients developed persistent
anti-natalizumab antibodies, leading to reduced efficacy and a higher incidence of reactions during infusion, as well as hyper sensitivity reactions (215R, 216R). Immunologic Hypersensitivity reactions have been associated with natalizumab. In one survey of 625 patients with multiple sclerosis, anti-natalizumab antibodies were detected in 57 (9%); 20 (3%) were transi ently positive and 37 (6%) were persistently positive (217c). In the latter there was loss of efficacy of natalizumab. The incidence of infusion-related adverse events was signifi cantly higher in persistently positive patients. Type III hypersensitivity reactions occurred in 4 of 40 patients with relapsing– remitting multiple sclerosis after infusion of natalizumab in one center (218A). Tumorigenicity Melanoma occurred in two women with multiple sclerosis who were treated with natalizumab (219A). In an experimental mouse model of melanoma, expression of the a4b1 integrin on melanoma cells promoted homotypic intercellular adhesion and a reduced ability to invade extracellular matrix gels, thus inhibiting the metastasis of melanoma at the earliest, invasive stage of the metastatic cascade (220E). Melanoma inhibitory activity protein is secreted by melanoma cells, promotes invasion and migration and binds to a4b1 integrin and down-regulates its activity (221E). Anti– a4 integrin antibodies potentially downregulate the immune system, both at the primary tumor site and in the regional nodal basin, thereby promoting spread of melanoma. Natalizumab should therefore not be given to patients with a personal or family history of melanoma or to those with atypical moles or ocular nevi.
Omalizumab
(SED-15, 2614;
SEDA-30, 447) Immunologic Of 39 510 patients with asthma, 35 had 41 episodes of anaphylaxis
Drugs that act on the immune system: cytokines and monoclonal antibodies
(0.09% of patients) associated with omalizumab; 22 (61%) reactions occurred in the first 2 hours after one of the first 3 doses and five (14%) of the events after the fourth or later doses occurred within 30 minutes (222C). In a review of reports of anaphylaxis to omalizumab submitted to the FDA, there were 124 cases of anaphylaxis in patients with asthma (223S). Many had a delayed onset of symptoms beyond 2 hours after administration and a number of cases were characterized by protracted progression. Non-IgE-mediated anaphylactic (i.e. ana phylactoid) reactions have been reported in two patients after successful long-term treat ment for asthma with omalizumab (224A).
Ranibizumab See Chapter 47.
TGN1412 TGN1412 is an agonistic anti-CD28 mono clonal antibody. CD28 is a co-stimulatory receptor on CD4 and many CD8 T lympho cytes. TGN1412 was genetically engineered, by a company called TeGenero, by transfer of the complementarity determining regions (CDRs) from heavy and light chain variable region sequences of a monoclonal mouse anti-human CD28 antibody into human heavy and light chain variable region frame works. Humanized variable regions were subsequently recombined with two human genes, one coding for the IgG4 � chain and one coding for a � chain. The intention was that TGN1412 would activate and expand regulatory T lymphocytes and induce anti-inflammatory cytokines. The proposed indications were B-cell chronic lymphocytic leukemia and rheumatoid arthritis. At a research unit in Northwick Park Hos pital in North London on 13 March 2006, six healthy volunteers received TGN1412 and two received placebo in a first-in-human study run by a company called Parexel. Within
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hours all six who had been given TGN1412 were in intensive care with severe inflamma tory reactions that progressed to multiorgan failure (225S). Their symptoms were as fol lows: headache within 50–90 minutes; lum bar myalgia, rigors within 58–120 minutes and a fever over 38°C within 2.5–6.5 hours. They subsequently developed hypotension, tachycardia, dyspnea and tachypnea, respiratory failure, radiological pulmonary infiltrates, and evidence of disseminated intravascular coagulation; two had periph eral limb ischemia; one developed dry gang rene of the fingers and toes. All developed lymphopenia, with significant falls in CD3, CD4þ and CD8þ counts. All recovered, but had prolonged memory problems, head aches, and inability to concentrate. This syndrome was due to a massive cyto kine storm. Serum concentrations of TNF-� rose markedly within 1 hour, and TNF-�, IL-2, IL-4, IL-6, and IL-10 all increased over days 1 and 2; there were very large increases in interferon gamma at 4 hours and on day 2. T lymphocytes normally require both anti gen receptor stimulation and co-stimulation of the CD28 receptors to become fully acti vated. However, TGN1412 was a superagonist that stimulated T (and B) lymphocyte activity without the need for con current antigen receptor stimulation. In vitro experiments had not predicted this effect. Following an enquiry by an independent expert scientific group, chaired by Sir Gor don Duff, Chairman of the Commission on Human Medicines (CHM, which was formed in February 2005 by conjoining the former Medicines Commission and the Committee on Safety of Medicines, CSM), the following 22 recommendations were made (226S): 1. The strategy for preclinical development of a new medicine and the experimental approaches used to assemble information rele vant to the safety of phase I trials must be regarded as science-based decisions, made and justified case by case by investigators with appropriate training. 2. Developers of medicines, research funding bodies, and regulatory authorities should expedite the collection of information on unpublished preclinical studies and phase I
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trials, and explore the feasibility of open access to this database. 3. Regulatory authorities should consider ways to expedite the sharing between regulators world wide of information on Suspected Unexpected Serious Adverse Reactions (SUSARs) in phase I trials, and explore the feasibility of open access to these data. 4. A broader approach to dose calculation, beyond reliance on the “No Effect Level ” or “No Adverse Effect Level” in animal studies, should be taken. The calculation of starting dose should use all relevant information. Factors to be taken into account include the novelty of the agent and its mechanism of action, the degree of species specificity of the agent, the dose-response curves of biological effects in human and animal cells, dose-response data from in vivo animal studies where relevance to human has been validated, the calculation of receptor occupancy versus concentration, and the calculated exposure of targets or target cells in humans in vivo. The “MABEL” approach is a good option for achieving this. 5. If different methods give different estimates of a safe dose in humans, the lowest value should be taken as the starting point in first-in-human trials and a margin of safety should be introduced. 6. When it is likely that preclinical information, for any reason, may be a poor guide to human responses in vivo, the starting dose in first-in human trials should be calculated to err on the side of caution. 7. Careful consideration should be given to the route and the rate of administration of the first dose in first-in-human trials, with careful monitoring for an exaggerated response. 8. Decisions on the starting dose and dose escalation should be made on a case-by-case basis, and should be scientifically justifiable, taking account of all relevant information. 9. The decision whether to conduct a first-in man trial in healthy volunteers or in volunteer patients should be carefully considered and fully justified, taking into account all factors relevant to the safety of the subjects and the value of the scientific information that is likely to be obtained. 10. Principal Investigators in first-in-human trials should always be appropriately qualified and satisfy themselves that they know enough about the agent, its target, and its mechanism of action to be in a position to make informed clinical judgements. 11. In first-in-man studies in which there is a predictable risk of certain types of severe adverse reaction, a treatment strategy should be considered beforehand. This should include the availability of specific antidotes, when they exist, and a clear plan of supportive treatment, including the pre-arranged contingency availability of ITU facilities.
12. First-in-human studies of higher-risk medicines should always be conducted in an appropriate clinical environment, supervised by staff with appropriate levels of training and expertise, with immediate access to facilities for the treatment and stabilization of individuals in an acute emergency and with pre-arranged contingency availability of ITU facilities. 13. New agents in first-in-human trials should be administered sequentially to subjects with an appropriate period of observation between dosing. 14. The interval of observation between sequential dosing of the subjects should be related to the kind of adverse reactions that might be anticipated based on the nature of the agent, its target, and the recipient. 15. A similar period of monitoring should occur between sequential doses during dose escalation. 16. More communication should be encouraged between developers and the regulator at an ear lier stage before an application is filed, espe cially for higher-risk agents, to ensure that there is time for appropriate consideration of any safety concerns, without introducing undue delay in product development. Ways to increase communication between the regulator and research ethics committees should also be considered. 17. For appraisal of applications for trials of higher-risk agents, as defined by the nature of the agent, its degree of novelty, its intended pharmacological target, and its intended recipient, the regulator should have access to additional opinions from independent, specialist experts with research knowledge of their fields. 18. An Expert Advisory Group (EAG) of the Commission on Human Medicines, or a similar body, might undertake this role, with a core membership of appropriate experts and the ability to co-opt additional experts as the need dictates. 19. Consideration should be given to introducing some flexibility in the time-scale of clinical trial appraisal in exceptional cases of unusual complexity. 20. The availability of ‘hands-on’ experience in the planning and conduct of clinical trials should be widened, for example by secondment periods to commercial organizations within postgraduate training programmes, or the development of specialist centres within the [UK’s] NHS and Universities (see next recommendation). 21. The feasibility of developing specialist centres for phase I clinical trials of higher-risk agents and advanced medicinal products should be explored. 22. The regulatory process for first-in-human trials of higher-risk agents and advanced medicinal products based on innovative technologies should be subject to frequent review.
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Drugs that act on the immune system: immunosuppressive and immunostimulatory drugs
Ciclosporin
(SED-15, 743; SEDA-29, 426; SEDA-30, 452; SEDA-31, 619)
Cardiovascular Hypertension is a wellknown adverse effect of calcineurin inhibitor therapy. The mechanisms have not been elucidated and are still controversial. In a patient undergoing hemodialysis, cardio thoracic bioimpedance showed evidence of raised systemic vascular resistance with nor mal blood volume (1A). She stopped taking ciclosporin and her blood pressure fell. Ciclosporin was restarted in a dosage of 25 mg/day and her systemic vascular resis tance was 1275 dyne/s5. When the dosage was increased to 100 mg/day, her blood pressure rose to 200/80 mmHg and her sys temic vascular resistance to 1874 dyne/s5, with normal cardiac output and a low-normal intrathoracic fluid volume.
Nervous system Ciclosporin can cause pseudotumor cerebri (2A). • A 15-year-old girl with hypodiploid acute lym phoblastic leukemia took methotrexate and ciclosporin 1.5 mg/kg after bone marrow
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32038-1 � 2010 Elsevier B.V. All rights reserved.
transplantation and 30 days later developed a continuous frontal headache with bilateral papilledema. Her blood ciclosporin concentra tion was 85 µg/l. A CT scan showed mild pro minence of the lateral and third ventricles with no intracranial masses or obstructing lesions. The cerebrospinal fluid (CSF) was normal. Ciclosporin was withdrawn and replaced by tacrolimus. After a few days her headache resolved and fundoscopy showed less disc edema. • A 12-year-old boy with myelodysplastic syndrome took methotrexate and ciclosporin 1.5 mg/kg after stem cell transplantation and the blood ciclosporin concentration was kept at 150–200 µg/l. After 45 days he developed persistent unexplained nausea and vomiting with no headache, unresponsiveness to antiemetics and bilateral papilledema. A CT scan showed no evidence of intracranial masses and the CSF was normal. He was given acetazola mide and ciclosporin was replaced by myco phenolate mofetil. His symptoms resolved after a short course of methylprednisolone and the papilledema improved.
In 20–40% of liver transplant recipients taking calcineurin inhibitors, central nervous system toxicity presents a wide spectrum of mild to severe neurological and psychiatric disorders, for which intravenous lipid may be beneficial. Of 45 Japanese patients who received living-donor transplants, 10 devel oped neurological complications, such as changes in mental status, confusion, seizures, altered level of consciousness, neuralgia, headache, and tremor; 3 were taking ciclosporin and 7 tacrolimus (3c). If the
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blood–brain barrier is impaired, unbound calcineurin inhibitors might be able to enter the brain more readily. Based on this hypothesis, five patients (two of whom were taking ciclosporin and three tacrolimus) received an intravenous lipid supplement of 20% soybean oil 0.1–0.2 ml/kg/hour for 2–3 days, after which, and without a change in the dosage of the calcineurin inhibitor, their neurological symptoms improved remarkably. Metabolism In an international multicenter study of the incidence of diabetes mellitus after renal transplantation, the primary safety end point was a composite of new-onset diabetes or impaired fasting glucose within the first 6 months (4C). The primary efficacy end point was a composite of biopsy-proven acute rejection, graft loss or death at 6 months after transplantation. The patients were randomized to ciclosporin microemul sion (n = 336) or tacrolimus (n = 346) with mycophenolic acid, a glucocorticoid and basiliximab. Diabetes susceptibility factors, glucocorticoid doses and demographics were similar between the groups. There was new-onset diabetes or impaired fasting glucose at 6 months in 26% of those who were given ciclosporin and 34% of those who were given tacrolimus. The primary efficacy end points occurred in 13% of those who were given ciclosporin and 9.8% of those who were given tacrolimus. Mean glomerular filtration rate (GFR), mean serum creatinine and mean blood pressure were similar in the two groups at 6 months, but median total cholesterol, LDL cholesterol and triglycerides were significantly higher at 6 months with ciclosporin. The possible adverse effects of ciclosporin (mean dose 233 mg/day) on first- and second-phase insulin secretion have been investigated using a 3-hour hyperglycemic glucose clamp technique in nine non-diabetic patients on hemodialysis, seven men and two women, mean age 61 years, before and after 2 weeks of treatment with ciclosporin (5c). The average fasting concentration of C-peptide rose significantly from 1.65 to
1.93 nmol/l after 2 weeks of treatment with ciclosporin. First-phase insulin secretion did not change significantly, but second-phase secretion was significantly inhibited by ciclosporin and second-phase C-peptide secretion also fell in eight patients. Mouth Ciclosporin can cause oral nongingival inflammatory fibrovascular hyper plasia (6A). • A 14-year-old boy had a hemopoietic cell transplantation for acute lymphocytic leuke mia and was given ciclosporin. He had exophy tic, polypoid, multinodular masses on the tongue, measuring 2 1 and 0.5 0.5 cm. • An 8-year-old boy had a hemopoietic cell transplantation for acute leukemia followed by ciclosporin therapy. He later developed a 2 1 cm, ulcerated, slightly tender, exophytic, polypoid, multinodular mass on the right side of the tongue. • A 3-year-old boy had a hemopoietic cell transplantation for purine nucleoside phos phorylase deficiency and was later given first ciclosporin and then tacrolimus for graft versus-host disease involving the buccal mucosa and the tongue. He subsequently developed two polypoid, multinodular masses on the right and left dorsum and lateral bor ders of the tongue. • A 58-year-old woman underwent right lung transplantation for severe chronic obstructive pulmonary disease followed by immunosup pression with tacrolimus and prednisone. She later developed two linear, exophytic, slightly tender, sessile, polypoid soft-tissue masses in her lip.
In all cases the lesions were excised and histology showed granulation and fibrous tissue with collagenization and edema, overlying ulceration, and acute and chronic inflammation. Urinary tract Treatment with calcineurin inhibitors is often associated with chronic renal insufficiency and conversion to myco phenolate may improve renal function (7c). In a single-center study, 49 patients who underwent liver transplantation between 1986 and 2002 were given a combination of calcineurin inhibitors and glucocorti coids; azathioprine was used as adjuvant therapy in 71%, but was withdrawn before the introduction of mycophenolate, starting at 500 mg bd during the first week,
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followed by an increase every week up to 1 g bd. The daily dose of calcineurin inhibi tor was reduced by 10–20% stepwise every 4 weeks after the optimal dose of mycophe nolate was reached; the calcineurin inhibi tors were withdrawn if possible within 6 months. Mean creatinine clearance was 43 ml/minute when mycophenolate was introduced and in 45 patients it was less than 60 ml/minute. Of 39 patients who responded to a reduced dose of calcineurin inhibitor, 18 recovered completely and 21 had partial recovery of renal function; 10 were non-responders; 14 patients in whom the calcineurin inhibitor was completely withdrawn at 1 year after mycophenolate introduction tended to have a higher increase in creatinine clearance (22 ml/min ute). Patients with alcoholic cirrhosis had the worst deterioration in renal function and a smaller improvement after dosage reduction. In one patient, mycophenolate was withdrawn because of severe diarrhea. In 32 patients other adverse effects were easily controlled with symptomatic treat ment or a reduction in dosage. In 40 patients with renal dysfunction (creatinine clearance 40–80 ml/minute) who randomized to continue calcineurin inhibi tor therapy or switch to sirolimus, renal function improved in the latter within 3 months (75 versus 56 ml/minute) (8C). At 12 months this difference persisted (72 ver sus 58 ml/minute) but was not significant. Two patients developed steroid-sensitive rejection, one in each arm. Other adverse effects were mild, and included mouth sores (25%), hyperlipidemia requiring treatment (15%), and pruritus (5%). Infection risk Fungal infection Fungal infections are common in organ transplant recipients. In a prospective, multicenter, international study of the variables that affect the risk of dissemination and out comes, 111 transplant recipients with Cryp tococcus neoformans infection were studied (9C). Cryptococcus neoformans infection was defined as follows: positive cultures in specimens, including blood cultures; or histopathological or cytopathological exam ination of specimens from needle aspiration
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or biopsies showing encapsulated yeast cells; or positive cryptococcal antigen in the blood or CSF in a patient with a compatible clin ical presentation. Cryptococcosis occurred a median of 21 months after transplantation; 54% of the patients had pulmonary infec tions, 52% had nervous system infections, and 8.1% had skin, soft-tissue, or osteoarti cular infections. There was disseminated cryptococcosis in 61%, and in 32% the infection was limited to the lungs. Patients who were taking ciclosporin or tacrolimus were significantly less likely to have nervous system infections and were more likely to have cryptococcosis limited to the lungs. There were nervous system infections in 50% of the patients who took ciclosporin, 47% of those taking tacrolimus, and 80% of those taking azathioprine or mycophenolate mofetil. The risk of disseminated infection was significantly higher after liver transplan tation. The mortality rate at 90 days was 14%. The mortality rate was 20% in patients taking ciclosporin, 7.9% in those taking tacrolimus, and 40% in those taking azathioprine or mycophenolate mofetil. The mortality rate was significantly higher in patients with abnormal mental status, renal insufficiency at baseline, fungemia, and dis seminated infection, and was lower in patients taking a calcineurin inhibitor. Tumorigenicity In a single-center study, 10 patients who developed de novo neoplasms or had a recurrence of hepatocellular carci noma were switched from ciclosporin or tacrolimus to everolimus (10c). The median time from transplantation to diagnosis of the neoplasm was 38 (range 82–142) months. The median time from diagnosis to the start of everolimus therapy was 4 (range 2–32) months. Target everolimus trough concen trations were 3–8 ng/ml. At the end of fol low-up, seven patients were alive; five were in complete remission, and two had tumor stability without significant growth or distant metastases. Three patients died, one because of disease progression and the other two because of hepatic lymphoma and laryngeal cancer. Median survival from tumor diagno sis was 21 (range 7.5–41) months. In the control group of 14 patients, who took
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ciclosporin, prednisone, and azathioprine or mycophenolate mofetil, median survival was 5.3 (range 0–70) months. The probability of survival was significantly greater with everolimus. Drug–drug interactions Antiepileptic drugs In a 14-year-old girl levetiracetam did not affect the ciclosporin plasma concentra tion, but oxcarbazepine reduced it from 170 ng/l to 70 ng/l, despite an increase in ciclosporin dosage from 310 to 600 mg/ day (11A). When levetiracetam was used in stead of oxcarbazepine 750mg bd, the dose of ciclosporin was reduced to 340 mg/day, with satisfactory plasma concentrations. Itraconazole Co-medication with itra conazole causes a flattening of the ciclos porin blood concentration profile in lung transplant recipients (12c). The pharmaco kinetic profiles before and after itracona zole 200–400 mg/day in 13 lung transplant recipients were comparable. Food–drug interactions Tangerine juice did not alter the AUC0!12 h of whole-blood ciclosporin in children with renal transplants (13C). Management of adverse effects In patients taking ciclosporin there are increased con centrations of specific cytokines, particu larly transforming growth factor (TGF) beta, in hyperplastic gingival tissue, suggest ing that this growth factor plays a role in accumulation of extracellular matrix. Roxithromycin inhibits the production of TGF-beta by inflammatory cells and may reduce ciclosporin-induced gingival over growth (14c).
Everolimus (SDA-RAD) (SED-15, 1306; SEDA-29, 433; SEDA-30, 453; SEDA-31, 622) Respiratory There have been several reports of bronchiolitis obliterans organizing
pneumonia in patients taking everolimus (15A, 16A). • A 56-year-old woman took ciclosporin, azathioprine, and a glucocorticoid after renal transplantation. After excision of a lip malig nancy she was given everolimus instead, and 2 months later developed a cough, dyspnea, and a low-grade fever. A chest X-ray showed a lesion at the base of the left lung compati ble with pneumonitis. Bronchoscopy showed bronchiolitis obliterans organizing pneumo nia, which responded to a corticosteroid within 3 days. • A 45-year-old man took ciclosporin, azathio prine, and prednisone after heart transplanta tion, but developed worsening renal function and was given everolimus instead of ciclos porin; 4 months later he developed a fever, dry cough, dyspnea, and pleuritic chest pain. A chest X-ray and CT scan showed bilateral lesions predominantly in the superior lobes and on the left side. Bronchoscopy and alveo lar lavage showed no evidence of infection and he was given ciclosporin again. A transbron chial biopsy showed intra-alveolar fibrinous exudates with fibroblastic foci and scanty lym phoid interstitial infiltration. After withdrawal of everolimus he improved and the CT scan became normal. • A 66-year-old man took ciclosporin and azathioprine after heart transplantation but converted to everolimus because of progres sive renal dysfunction and 2 months later developed a fever, dry cough and pleuritic chest pain. A chest X-ray showed basal lesions on the right side. Transbronchial biopsy showed intra-alveolar fibrinous exudates with fibroblastic foci in the alveolar and bronchial lumens and a scanty lymphoid interstitial infil trate. Everolimus was withdrawn and ciclo sporin restarted. He improved rapidly and became asymptomatic within 6 months.
Infection risk In a short-term study in eight kidney transplant recipients who were switched from a calcineurin inhibitor to everolimus, renal biopsies were per formed in six and showed chronic allograft nephropathy grades 1A–2. In six cases the calcineurin inhibitor was withdrawn and in two the dosage was reduced by 30% (17c). Everolimus was started on the day after; the initial dose was 0.75 mg bd. Three patients had infections (pneumonia, ocular viral infection, and herpes zoster), which responded to antibiotics and everolimus dosage reduction.
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Leflunomide
(SED-15, 2015; SEDA-29, 435; SEDA-30, 454; SEDA-31, 625)
Observational studies BK virus, which is closely related to the JC virus, is the most frequent polyomavirus. It was first isolated in 1971 from the urine of a kidney transplant patient. Polyomavirus-associated nephropa thy affects 1–10% of kidney transplant reci pients, and there is graft failure/loss in about 90%. Treatment with leflunomide, besides reducing immunosuppression, improves graft function in such cases. In a single-center study, leflunomide was used to treat poly omavirus-associated nephropathy in 11 of 346 kidney transplant recipients (18c). The initial dose was 100 mg/day for 5 days, fol lowed by 40 mg/day, maintaining serum con centrations at 40–80 mg/l. The median follow-up time was 16 months, after which median serum creatinine concentration was 150 (90–378) µmol/l versus 189 (92–265) µmol/l at baseline and estimated creatinine clearance was 45 (19–95) versus 36 ml/min ute. There were no significant increases in liver enzymes. Platelet counts were reduced below 100 109/l in only three patients and there were no bleeding events. Four patients developed fungal pneumonia 2 weeks after leflunomide treatment, and were successfully treated with voriconazole. Respiratory In a prospective study of 136 patients with active rheumatoid or psoriatic arthritis taking leflunomide 20 mg/ day, 5 developed cavitating pneumonia after the start of leflunomide treatment (19c). Of 1010 patients who took leflunomide for rheumatoid arthritis for at least 1 month, 10 developed interstitial lung dis ease; the risk was greater in those with pre existing lung diseases (20c). Pulmonary nodulosis has been associated with leflunomide (21A). Thoracoscopic biopsy showed fibrinoid necrosis with palli sading macrophages and a few giant cells, suggestive of a rheumatoid nodule; Ziehl– Nielsen staining for mycobacteria was nega tive. Leflunomide was withdrawn and the pulmonary nodules regressed within 6 months.
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Nervous system In 32 patients with rheu matoid arthritis taking leflunomide or other disease-modifying antirheumatic drugs, leflu nomide was associated with an apparent increase in the symptoms of peripheral neuropathy after 6 months; however, the symptoms did not correlate with neuro physiological studies (22c). In 16 patients with rheumatoid arthritis taking leflunomide and 16 who were taking disease-modifying antirheumatic drugs, 54% of the former and 8% of the controls had increased neuropathy symptom scores 6 months into the study (23c). However, there was no significant difference between the two groups in upper and lower limb sensory and motor amplitudes. One developed both clinical and neurophysiological evidence of a peripheral neuropathy 5 months into the study and improved after withdrawal of leflunomide. Acid base balance Renal tubular acidosis has been associated with leflunomide (24A). • A 35-year-old woman with seronegative arthritis developed renal tubular acidosis after taking leflunomide 20 mg/day for 9 months; she had a metabolic acidosis with a normal anion gap; the urine pH was 6.9. Leflu nomide was withdrawn and she was given colestyramine to accelerate the clearance of leflunomide. The serum bicarbonate normal ized within 3 weeks and was still normal 8 months later.
Hematologic Reports of suspected adverse reactions associated with the use of leflunomide have been evaluated in Australia (25c). Pancytopenia was defined by the following diagnostic criteria: severe anemia (hemoglobin concentration below 10 g/dl), neutropenia (polymorphonuclear leukocyte count below 1.5 109/l), and thrombocytopenia (platelet count below 100 109/l). There were 11 cases from January 2000 to September 2002 that met these criteria. Three had fatal outcomes, in two cases due to sepsis. Five patients had recovered at the time of reporting and three had not. Nine were also taking methotrexate; of these, six had been taking doses of 7.5–20 mg/week when they started taking leflunomide. The other three
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patients had taken leflunomide and devel oped pancytopenia after methotrexate was taken in addition. In two cases, when methotrexate was added, pancytopenia occurred after 19 and 32 weeks of combina tion therapy.
RNA synthesis. Unlike other cell types that can recycle nucleotides via the salvage pathway, B and T lymphocytes depend on de novo synthesis and the action of myco phenolate is therefore directed against this specific cell group.
Skin Leflunomide-induced subacute cuta neous lupus erythematosus with erythema multiforme-like lesions (26A), leflunomide induced skin necrosis (27A) and progressive generalized blistering and a widespread pru nosus skin rash (28A) have been described.
Observational studies In a retrospective analysis 70 patients were identified who had received mycophenolate for inflamma tory bowel disease; 19 had ulcerative colitis and 51 had Crohn’s disease (31c). There were 40 women and 30 men; the mean age was 42 years. The average dose was 1.5 g/day. The mean duration of therapy was 3.9 months. Adverse effects were attrib uted to mycophenolate in 19 patients, 2 of whom continued taking it; one had a rash that resolved and the other had deranged liver function tests, which resolved after withdrawal of mycophenolate; on restarting treatment, the liver function tests remained normal. The other patients had to stop taking mycophenolate because of severe adverse effects, such as non-specific malaise, beha vioral changes (including depression), joint pains, rashes, pancreatitis, diarrhea, abnor mal liver function tests, and alopecia. Of six patients with myositis refractory to conventional immunosuppressive therapy, two had dermatomyositis, three had poly myositis, and one fulfilled the clinical cri teria for SLE and developed myositis (32c). They took mycophenolate for a mean of 22 months in a mean dosage of 1.6 g/day þ prednisolone. Two patients developed mild adverse effects, nausea and headaches, which did not require the with drawal of mycophenolate. In a retrospective analysis of the use of mycophenolate in uveitis in 17 children (10 boys, 7 girls, aged 2–13 years), there was a steroid-sparing effect in 88% (33c). There were mild adverse effects, such as headache, rash, or gastrointestinal discom fort, in seven patients, and withdrawal was required in one child. In a single-center study of mycopheno late in moderate to severe atopic dermatitis in 20 patients aged 54–79 years, all of whom had failed or developed dependence on systemic corticosteroids, and had failed
Infection risk Cytomegalovirus antigen emia rapidly increased following lefluno mide administration in a 46-year-old man with a diffuse large B-cell lymphoma, wor sening renal function and incompletely con trolled multidrug-resistant cytomegalovirus infection after an autologous stem cell transplantation (29A). Teratogenicity Congenital malformations have been described after maternal expo sure to leflunomide during the first tri mester of pregnancy (30A). • A 43-year-old woman with rheumatoid arthri tis became pregnant while taking leflunomide, which was withdrawn after 16 weeks of gesta tion. She gave birth 9 weeks prematurely to a boy who was blind in the right eye and had cerebral palsy with left-sided spasticity.
Leflunomide reversibly binds dihydro orotate dehydrogenase, the rate-limiting mitochondrial enzyme in the synthesis of pyrimidine ribonucleotide uridine mono phosphate. This leads to reduced DNA synthesis, inhibiting T cell clonal expansion.
Mycophenolate mofetil
(SED-15, 2402; SEDA-29, 445; SEDA-30, 455; SEDA-31, 627) Mycophenolate acid is a non-competitive, reversible inhibitor of inositol monophos phate dehydrogenase, an enzyme required for de novo guanosine nucleotide biosynth esis, and it subsequently affects DNA and
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or experienced adverse effects from other systemic therapies and/or phototherapy, mycophenolate produced improvement in 18 cases (34c). One patient withdrew at 4 weeks because of persistent severe pruritus. Another improved, but mycophenolate was withdrawn because of nausea; however, the patient later responded to and tolerated a second course. There were few adverse effects, the commonest ones being nausea, constipation, diarrhea, stomach pains, fati gue, anorexia, and headache. Four patients developed herpes zoster at 8–56 weeks after the start of mycophenolate therapy, and all responded promptly to standard antiviral therapy. In one patient, the white blood cell count fell but normalized on a lower dose. In a retrospective analysis of the use of mycophenolate in 14 children with atopic dermatitis (9 boys, 5 girls) aged 2–16 years, all of whom had failed to respond to con ventional topical treatment and/or oral glucocorticoids and ciclosporin, 4 responded completely, 4 had an excellent response, 5 had a good response and 1 had an inade quate response (35c). Two patients devel oped mild gastrointestinal upsets during the first week of treatment. One patient had a history of recurrent simplex viral infections and two requiring systemic antimicrobial therapy for episodes of extensive impetigi nization and folliculitis and recurrent sta phylococcal furunculosis. Metabolism Immunosuppressive drug ther apy causes hyperlipidemia. During com bined therapy for 12 months with a glucocorticoid þ mycophenolate or azathio prine, there were no significant differences between the groups in total cholesterol, high-density lipoprotein (HDL), LDL or very-low-density lipoprotein (VLDL) (36c). Mouth Mycophenolate can cause mouth ulcers (37A). • A 60-year-old woman with liver cirrhosis, taking ciclosporin and methylprednisolone, started taking mycophenolate when she had an acute episode of rejection and 5 days later developed ulcers on her tongue and hard palate. She was given aciclovir and
711 mycophenolate was withdrawn; 5 days later, the ulcers disappeared. • A 31-year-old woman who regularly took paracetamol and piroxicam olamine for polyarthralgia developed subacute liver failure and hepatic encephalopathy and underwent liver transplantation. Her immunosuppression con sisted of ciclosporin and methylprednisolone. One week later she developed biliary stenosis from choledochal kinking and required retro grade cholangiopancreatography and stent instillation. She was then given mycophenolate and developed oral ulcers. The mycophenolate was withdrawn and 1 week later the ulcers had completely disappeared.
Gastrointestinal Mycophenolate in induc tion and maintenance therapy of severe lupus nephritis has been compared with cyclophosphamide and azathioprine in a meta-analysis of randomized controlled trials (38M). Compared with cyclophospha mide, mycophenolate significantly reduced the risk of infection but there was no differ ence in the risk of end-stage renal disease. Mycophenolate increased the risk of gastro intestinal symptoms, but the results were not statistically significant. Compared with azathioprine, mycophenolate did not reduce the incidence of death, end-stage renal dis ease, relapse or doubling of serum creati nine. Gastrointestinal symptoms such as diarrhoea or nausea and vomiting occurred more often with mycophenolate than azathioprine. Teratogenicity Experimental studies and clinical observations have shown terato genic effects after in utero exposure to mycophenolate (39A). • A 25-year-old Spanish woman underwent renal transplantation. She took tacrolimus 12 mg/day and mycophenolate 500 mg/day and 2 years later became pregnant. Myco phenolate was discontinued at 10 weeks of gestation. At 20 weeks ultrasonography showed fetal cleft lip and palate. Amniocentesis was performed and a normal female karyotype was diagnosed. At 41 weeks a girl was delivered with bilateral upper cleft lip and complete cleft palate, bilateral microtia, hypertelorism, micro gnathia and mild left ptosis. A CT scan of the temporal bone showed bilateral absence of the external ear canals and small tympanic cavities. A CT scan of the brain and cerebellum was normal. At the age of 9 months the girl needed
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hearing aids, but her physical and neuro development were normal for her age.
Pimecrolimus (SED-15, 2833; SEDA-29, 449;SEDA-30, 456; SEDA-31, 628) Skin Pimecrolimus ointment can cause allergic contact dermatitis (40A). • A 9-year-old boy with atopic dermatitis devel oped allergic contact dermatitis after using tacrolimus ointment 0.1% for 8 months. A provocative test in the preauricular area resulted in a few isolated papules and a double-blind, vehicle-controlled test on the arms resulted in non-confluent erythematous papules on the side treated with pimecrolimus.
Sirolimus (rapamycin) (SED-15, 3148; SEDA-29, 449; SEDA-30, 457; SEDA-31, 628) Observational studies In a single-center study of drug-eluting stents in 64 patients, sirolimus-eluting stents were used in 57 and paclitaxel-eluting stents in 7 (41c). There was procedural success in 63 patients. One 87-year-old patient died in hospital due to papillary muscle rupture and refractory heart failure. There were no 30-day cases of stent thrombosis, re-infarction or target vessel re-intervention. During follow-up, one patient died in a rehabilitation facility 52 days after intervention due to nosoco mial pneumonia and sepsis. There were no late cases of stent thrombosis, re-infarction, or target vessel re-intervention. Systematic reviews Sirolimus-eluting stents and bare-metal stents have been compared in a meta-analysis of 14 trials in 4958 patients (42M). There was no significant effect on overall long-term survival and sur vival free from myocardial infarction. Siro limus-eluting stents were associated with a sustained reduction in the need for re-inter vention but with an overall risk of stent thrombosis that was at least as high as that seen with bare-metal stents.
Respiratory Sirolimus can cause alveolar hemorrhage (43A). • A 55-year-old man, who had undergone heart transplantation 8 years before for ischemic cardiomyopathy, and who was taking ciclo sporin and mycophenolate, was given siro limus. After 2 months he developed an intermittent low-grade fever with occasional spikes to 39°C, accompanied by chills, for about 4 weeks; he also had shortness of breath, a dry cough, a few episodes of diar rhea, weight loss of about 9 kg and worsen ing fatigue. There were bilateral basal coarse crackles in the lungs. The oxygen saturation was 93%, the PaO2 7.9 kPa, PaCO2 3.5 kPa, pH 7.48 and hemoglobin 8.4 g/dl. The serum creatinine rose from 159 to 283 µmol/l on day 4. A chest X-ray showed bilateral interstitial infiltrates, predominantly in the lower lobe, and a CT scan showed ground-glass parench ymal opacities. Opportunistic pulmonary infections were ruled out by serological tests and blood cultures. Bronchoscopy showed diffuse bloody secretions and bronchoalveo lar lavage showed diffuse alveolar hemor rhage; there were no malignant cells or organisms. Sirolimus was withdrawn and he was given prednisone 40 mg bd. He improved and 6 days later was asymptomatic.
Sirolimus can cause interstitial pneumonitis (44A–46A). • A 61-year-old man took azathioprine and methylprednisolone after kidney transplanta tion for chronic glomerulonephritis but later developed allograft nephropathy and multiple precancerous skin lesions. Azathioprine was withdrawn and sirolimus 2 mg/day introduced. After 1 month the dose was increased to 3 mg/ day and 2 weeks later he developed a fever and dyspnea on exertion and at rest. A CT scan showed bilateral interstitial infiltrates in the lower lobes. Sirolimus was withdrawn and he recovered rapidly. • A 67-year-old man took ciclosporin, myco phenolate, and methylprednisolone after renal transplantation for secondary focal seg mental glomerulosclerosis. After 2 years he was switched to sirolimus 4 mg/day þ methyl prednisolone because of a skin tumor and 2 weeks later developed stomatitis, progressive shortness of breath on exertion, and a non-pro ductive cough. A chest X-ray showed bilateral lower lobe infiltrates and a CT scan showed extensive interstitial changes. Transbronchial biopsy showed lymphocytic alveolitis with no evidence of infection. Sirolimus was withdrawn and methylprednisolone given. His symptoms improved immediately.
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• A 62-year-old man took ciclosporin þ methyl prednisolone after renal transplantation but developed borderline rejection and calcineurin inhibitor toxicity. His immunosuppression was switched to sirolimus 2 mg/day þ methylpred nisolone and 2 weeks later he developed shortness of breath on exertion, subfebrile temperatures, a non-productive cough, weight loss and fatigue. A chest X-ray and CT scan showed bilateral interstitial infiltrates in both lower lobes. Sirolimus was withdrawn and methylprednisolone given; he recovered immediately. • A 42-year-old woman was given thymoglobulin, high-dose methylprednisolone, tacrolimus, and mycophenolate for acute vascular rejection after kidney transplantation for systemic lupus erythematosus. Later, mycophenolate was switched to sirolimus 2–3 mg/day and she was subsequently given diltiazem 270 mg/day. After 3 weeks she developed leg edema and progressive dyspnea on exertion and at rest. The sirolimus trough concentration was 21 µg/l. Despite withdrawal of diltiazem and normaliza tion of sirolimus concentrations, the symptoms did not resolve. An X-ray and a CT scan showed interstitial pneumonitis. Sirolimus was with drawn and the dose of methylprednisolone was increased. Her symptoms improved and the infil trates vanished. • A 62-year-old man was given ciclosporin and glucocorticoids after liver transplantation for alcoholic liver cirrhosis but developed progres sive graft dysfunction. Ciclosporin was switched to tacrolimus þ mycophenolate. Later, siro limus 3 mg/day was introduced and tacrolimus withdrawn because of worsening renal func tion. Despite progressive dosage reduction the sirolimus concentration remained high (at around 20 µg/l) and after 3 months he devel oped progressive dyspnea, a low-grade fever, chills, a dry cough, and fatigue. He improved slightly with antibiotic therapy but relapsed 1 week later. Withdrawal of sirolimus led to rapid clinical improvement. • A 1-year-old girl was given tacrolimus, pred nisolone and mycophenolate after heart transplantation but developed intractable diarrhea. The dosage of mycophenolate was reduced and subsequently replaced by siro limus 1 mg/m2. After 3 days she developed dyspnea, hypoxemia and respiratory acidosis. A chest X-ray showed bilateral infiltrates. The sirolimus trough concentration was 23 µg/l. Despite broad-spectrum antimicrobial drug therapy, intubation and mechanical ventilation were required. Echocardiography showed nor mal allograft function and microbiological stu dies were all negative. After withdrawal of sirolimus and intravenous administration of hydrocortisone, there was pronounced clinical improvement.
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All these patients were given a loading dose at the start of therapy and/or had an increase in the dose of sirolimus or trough con centration before the onset of symptoms. Additional potential susceptibility factors included allograft dysfunction and male sex. Metabolism The effects of sirolimus and everolimus on serum triglycerides have been analysed retrospectively in 55 heart transplant patients (47c). In 28 patients taking sirolimus, median triglyceride con centrations increased significantly by up to 65% and were clearly above the upper limit of the reference range. Total cholesterol concentrations increased by 25%. The use of statins increased significantly from 48% at baseline to 93% at 12 months. LDL con centrations were higher in those taking sirolimus. Sirolimus inhibits the growth of tumor cell lines in vitro and in vivo. In 25 patients who were converted from a calcineurin inhi bitor-based immunosuppressive regimen to sirolimus (concentrations over 6 µg/l) after detection of a tumor (11 lymphomas, 10 skin cancers, 1 thyroid, 1 lung, 1 native kid ney, and 1 laryngeal carcinoma), serum cho lesterol rose significantly from 4.58 mmol/l at baseline to 5.60 mmol/l after 1 year; LDL rose from 2.65 to 3.30 mmol/l at 1 year and triglycerides from 1.66 to 2.05 mmol/l at 3 months; creatinine clearance increased from 60 to 66 ml/minute at 1 year (48c). Urinary tract Sirolimus can cause protein uria. In a single-center study in 78 patients (43 men, 35 women; mean age 37 years) after transplantation, 63 were converted from calcineurin inhibitors þ mycopheno late þ glucocorticoids to sirolimus; 16 devel oped proteinuria (49c). In addition, 2 of 15 patients who had received sirolimus de novo developed proteinuria. The protei nuria occurred at a mean of 11 months after the start of sirolimus therapy. The mean value was 2.6 g/day. In 5 patients it reached nephritic levels, and there was edema in 13. In five patients an angiotensinconverting enzyme (ACE) inhibitor or
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angiotensin II receptor antagonist was used. Sirolimus was withdrawn in six patients. At the time of proteinuria, sirolimus trough concentrations were 4.4–15.3 µg/l, but there was no correlation between proteinuria and trough concentrations. Withdrawal of siro limus was associated with resolution. Fertility Oligospermia has been attributed to sirolimus (50A). • A 26-year-old man was given sirolimus, tacro limus, and a glucocorticoid after heart–lung transplantation for severe pulmonary hyper tension. The glucocorticoid was withdrawn after 6 months. About 3 years later he devel oped a benign Leydig-cell tumor of the left testicle with widespread testicular atrophy and severely reduced spermatogenesis. Siroli mus was withdrawn and replaced by mycophe nolate and 1 year later spermatogenesis had improved.
Tacrolimus
(SED-15, 3279;
SEDA-29, 453; SEDA-30, 458; SEDA-31,
630)
Observational studies Tacrolimus prolongs graft survival and may be considered after high-risk keratoplasty. In a comparison of the effect of systemic tacrolimus on the survival of corneal grafts, high-risk patients (n = 47) were defined as having at least two quadrants of stromal vascularization and/or a history of previous graft failure (51c). Oral tacrolimus was begun at a dose of 2 mg/day on the day of surgery and was adjusted to achieve a whole blood tacrolimus trough concentration of 1–12 µg/l. The mean dosage was 2.5 mg/day. All the patients also used topical steroids. Tacrolimus was continued for 18 months postoperatively or until the sutures were removed; in patients who had episodes of rejection it was contin ued for 1 year after the last episode. Four patients stopped taking tacrolimus because of adverse effects and were excluded from the analysis; four died at various stages of follow-up. In the 43 patients who were analysed, the graft was clear in 28 at the time of the last follow-up or death. Eight patients had episodes of rejection while taking
tacrolimus, of whom three had multiple epi sodes that were controlled by intravenous steroids. Five had irreversible rejection resulting in graft failure. Four had episodes of rejection after discontinuing tacrolimus. Graft failure occurred in one patient because of rejection and in nine because of non-immune causes, including raised intra ocular pressure, stem cell failure, and bac terial keratitis. In 30 of 39 patients who were included in the 2-year survival analy sis, eligible grafts were clear at 2 years; 6 failed grafts were not related to rejection and 3 were due to rejection. Increased blood pressure attributed to tacrolimus was con trolled with low-dose ACE inhibitors. Other adverse effects were headaches, malaise (n = 4), paresthesia (n = 3), and insomnia, pancreatitis, folliculitis, diabetes, lymphopenia, and a reversible increase in serum creatinine (1 each). Nervous system Tacrolimus can cause sei zures. In a single-center study of 132 liver transplant patients, 12 had tacrolimus-related seizures during the early postoperative per iod (52c). In 5 patients with posterior leukoencephalopathy syndrome, MRI scans showed the characteristic findings of hyperintensity of the white matter on T2 weighted images; there were no abnormalities in the other 7 patients. Ciclosporin was substituted in 11 patients and sirolimus in 1, and all received antiepileptic drug therapy. After 3 months the MRI findings resolved. Antiepileptic drug therapy was withheld in 5 patients at an average follow-up of 20 months. Tacrolimus can cause cerebellar ataxia (53A). • A 58-year-old woman took tacrolimus þ prednisone after living-donor liver transplan tation for hepatic cirrhosis. After 7 days she developed slurred speech, an intention tremor and a swaying gait. Tacrolimus was withdrawn and she was given ciclosporin instead. An MRI scan showed no abnormal intensities. The dose of ciclosporin was reduced from 200 to 100 mg/day and mycophenolate 1 g/day was added. Her blood ciclosporin concentration fell below the usual target range. The next day, the cerebellar ataxia improved and she was able to walk for at least 20 minutes.
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Tacrolimus can cause cerebellar atrophy (54A). • A 31-year-old man developed cerebellar ataxia 9 years after heart transplantation while taking tacrolimus þ mycophenolate. An MRI scan showed dilated sulci in the cerebellar region and an atrophic cerebellum. Tacrolimus was switched to sirolimus and although the symptoms improved they did not resolve com pletely. He also had hyperthyroidism and underwent thyroidectomy.
Chronic sensorimotor polyneuropathy may be an adverse effect of tacrolimus (55A). • A 44-year-old woman took tacrolimus 3 mg bd after living-donor kidney transplantation for focal glomerular sclerosis. After 10 months she complained of ‘twitching’ of the right side of the face followed by that of the left side, associated with facial numbness. She had difficulty in chewing and drinking through a straw and complained of gait imbalance. There was bilateral, symmetrical, moderately severe peripheral facial weakness, and severe weakness of bilateral intrinsic hand muscles, hip flexors, hamstrings, extensor hallucis longus, and extensor digitorum brevis muscles. The serum tacrolimus concentration was 9.3 µg/l. Electromyography and nerve conduc tion studies showed typical findings of a demyelinating motor neuropathy involving limb and cranial nerves. She was given intra venous immunoglobulin for 5 days, and 3 months later her symptoms had completely resolved. • A 53-year-old man took tacrolimus 7 mg bd (trough concentration 7.3 µg/l) after a cada veric kidney transplant for hypertensive end-stage renal disease. Immediately post operatively he complained numbness of the medial three fingers of the right hand and 5 days later developed stiffness and pain in that region. Cranial nerve examination was normal but he had severe weakness of toe dorsiflexion bilaterally. Vibration sensation was reduced at both ankles and in the med ial three fingers of the right hand. Gait and coordination were unremarkable. The ankle jerks were absent bilaterally. Nerve conduc tion studies showed diffuse low-amplitude evoked responses in both arms and absent motor-evoked response in the legs, suggestive of diffuse, predominantly axonal neuropathy, except for partial conduction block in the left ulnar nerve. The dose of tacrolimus was reduced to 2 mg bd and 6 weeks later his sen sory symptoms resolved and the neurological examination returned to normal.
Tacrolimus binds to plasma proteins and accumulates in erythrocytes. In an unusual
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case, a woman with a trough tacrolimus concentration of 75 µg/l developed tacroli mus toxicity, with disorientation in space, time and person, somnolence and dys arthria; she recovered when her serum concentration fell to 75 µg/l after a gastro intestinal hemorrhage (56A). Tumorigenicity A kidney transplant recipient with unrecognized Muir–Torre syndrome used a tacrolimus-based mainte nance regimen and developed 33 sebaceous gland tumors over 2 years (57A). • A 51-year-old man underwent renal transplan tation and was given tacrolimus. At 39 years of age, he had had a sigmoid cancer treated by resection and 5 years later a transitional cell carcinoma of the renal pelvis treated by nephrectomy, after which his renal function deteriorated and hemodialysis was eventually necessary. Five months after transplantation he developed a rapid eruption of wart-like lesions on his face and chest wall, and during the next 2 years numerous lesions were removed. There was one sebaceous carcinoma, one basal cell carcinoma, one kerato acanthoma, and several sebaceous adenomas. Altogether he developed 33 sebaceous neo plasms and was found to have six adenomatous polyps in the colon. Muir–Torre syndrome was confirmed by genetic analysis. Therapy was switched to sirolimus, and during the next 5 weeks he developed no new sebaceous adeno mata. Owing to persistent severe weakness, muscle cramps and impaired concentration, he was switched back to tacrolimus and within 2 months developed numerous new sebaceous lesions. Sirolimus was again used and no new skin lesions occurred.
Muir–Torre syndrome is a rare autosomal dominant condition in which multiple pri mary tumors and sebaceous gland tumors co-occur. This report suggests that the risk of the latter may be enhanced by tacrolimus. Drug route of administration Topical application Tacrolimus ointment applied to the external auditory canal is being used in the treatment of chronic non-infectious external otitis refractory to other therapy. In an evaluation of tacrolimus for this indication in 53 patients (92 ears; 27 men and 26 women, aged 5–83 years), an ear wick containing Protopic 0.1% was inserted
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into the external auditory canal every sec ond or third day and continued until the symptoms resolved (58c). In the short term (days 9–12), there was improvement in 45 patients (77 ears). There were mild adverse effects, including a feeling of heat, occa sional skin burning or stinging, and tempora rily increased pruritus. There was bacterial superinfection in two cases, treated suc cessfully with local antibiotics. During longterm treatment (10–22 months), the number of episodes was reduced and only 15 patients complained of recurrence. There was com plete healing in 24 patients at the end of follow-up. In an open study in 466 children, aged 2–15 years, a thin coat of tacrolimus oint ment was applied twice daily to affected areas during episodes of active atopic der matitis (59c). Initially 0.03% tacrolimus ointment was used either for 2 weeks or until the lesions cleared, whichever was first. Then 0.1% ointment was used. There were 138 withdrawals during the study (30%), about half being for admin istrative reasons; 38 (8.2%) were because of lack of efficacy and 16 (3.4%) because of an adverse effect. The most common adverse effects were pruritus and a burning sensation in the skin. There was no increase in the incidence of viral infections. Topical tacrolimus is an alternative treatment for lichen sclerosus, a chronic relapsing disease. In 11 patients, all of whom had been unresponsive or poorly responsive to super-potent topical cortico steroids, tacrolimus 0.1% ointment was applied twice daily for 6 weeks and then tapered over a further 6 weeks (60c). The adverse effects were pruritus and burning, but these effects were always mild and transient and disappeared after a few applications. Drug–drug interactions Cinacalcet Co administration of tacrolimus 2 mg bd with cinacalcet 30 mg/day caused a fall in tacro limus concentrations from 4–8 µg/l to 2.6 µg/ l after 1 week (61A). The dosage of tacro limus was adjusted and after 19 days cina calcet was withdrawn, after which the tacrolimus concentration rose. During the
interaction renal function worsened and did not recover. Cinacalcet is mostly meta bolized by CYP3A4, CYP2D6, and CYP1A2 and it inhibits CYP2D6; tacrolimus is meta bolized by CYP3A4. Both are also highly protein-bound, and displacement of tacro limus by cinacalcet may have contributed to this interaction.
Temsirolimus Temsirolimus is a specific inhibitor of rapa mycin (mTOR) kinase, a component of intracellular signaling pathways involved in the growth and proliferation of cells and the response of such cells to hypoxic stress. Compared with the interferons, temsirolimus improves overall survival among patients with metastatic renal cell carcinoma and a poor prognosis. Observational studies The effect of temsiro limus on survival in renal cell carcinoma has been studied in a multicenter phase III trial in 626 patients (62c). The patients had advanced renal cell carcinoma, stage IV or recurrent disease, and a Karnofsky index 60, and had not received previous systemic therapy. They were divided into three groups, who were given interferon alfa-2a 3 million units three times a week (to a maximum of 18 million units if tolerated) (n = 207), temsiro limus 25 mg/week as a 30-minute intra venous infusion (n = 209) or the combination (n = 210) (temsirolimus 15 mg/week and interferon 3–6 million units three times a week). Treatment was continued as long as there was no disease progression, sympto matic deterioration or intolerable adverse events. Those who received temsirolimus alone had longer overall survival and progression-free survival times than those who received interferon alone (respective median overall survival times 10.9 and 7.3 months) The most common adverse effects of temsiro limus were rash, peripheral edema, hyper glycemia, and hyperlipidemia. Weakness was more common with interferon. Temsirolimus was associated with fewer serious adverse effects than interferon.
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THIOPURINES Liver Treatment with thiopurines can cause three types of hepatotoxicity: hypersensitivity, idiosyncratic cholestatic reactions, and endothelial cell injury (which can cause raised portal pressure, veno-occlusive disease or peliosis hepatis) (63M).
Azathioprine
(SED-15, 377; SEDA-29, 424; SEDA-30, 459; SEDA-31, 635) Cardiovascular Azathioprine has been associated with atrial fibrillation (64A).
• A 52-year-old man with steroid-dependent ulcerative colitis relapsed and was given azathioprine, which was withdrawn some months later because of episodes of lipo thymia, with bouts of palpitation, nausea, and vomiting. During an exacerbation 2 years later he was given azathioprine 50 mg and 2 hours later developed nausea, vomiting, and general malaise. He had an irregular heart beat, and an electrocardiogram showed atrial fibrillation with a ventricular rate of 120/minute. Azathioprine was withdrawn and propafenone given. Repeated electrocar diography showed sinus rhythm and there were no further episodes of atrial fibrillation.
Respiratory Bronchiolitis obliterans and non-infective pneumonia have been attribu ted to azathioprine (65A) • For a 71-year-old man with Crohn’s colitis, in whom prednisone 20 mg/day and mesalazine had been incompletely effective, the mesala zine was withdrawn and azathioprine 100 mg/ day was started. After 2 weeks he developed a fever, worsening diarrhea and abdominal pain. Intravenous glucocorticoids and then intravenous infliximab and ciclosporin were ineffective. He then developed shortness of breath and a non-productive cough, and required oxygen. There was a leukocytosis (> 20 109/l) and a CT scan showed ground glass opacities predominantly in the upper lobes of the lungs bilaterally. A biopsy sug gested bronchiolitis obliterans. Azathioprine was withdrawn and within 3 days the white cell count normalized and his clinical status improved. • A 43-year-old woman taking prednisone for ulcerative colitis was given azathioprine 100 mg/day for 3 weeks. She developed increasing cough and shortness of breath, and
717 continued to deteriorate despite oral anti biotics. She was cyanotic and hypoxic, and required intubation and ventilation. A CT scan showed a right middle lobe pneumonia with bibasal consolidation. Microbiology was negative. Azathioprine was withdrawn and she was given intravenous hydrocortisone. She improved and was weaned off the ventila tor 5 days later. Her respiratory function normalized.
Liver Azathioprine can cause nodular regenerative hyperplasia, a rare hepatic lesion defined by diffuse nodularity of the hepatic parenchyma, without annular fibro sis, with alternating areas of atrophy and hyperplasia. In a multicenter study of patients taking azathioprine between 1994 and 2005, 37 cases were identified (66c). The median dose of azathioprine was 2 mg/ kg/day. The median time to diagnosis was 48 months after the start of therapy. Portal hypertension was the presenting feature in 31 patients with complications in 14, includ ing 9 with acute variceal bleeding and 5 with ascites; 15 underwent primary or secondary treatment for portal hypertension, including beta-blockers and nitrates (n = 11), endo scopic therapy (n = 9), embolization (n = 2), and transjugular intrahepatic portosystemic shunting (n = 2). One patient underwent liver transplantation for hepatic encephalo pathy following TIPS insertion. There were no deaths or cases of hepatocellular carcinoma. Skin Acute generalized exanthematous pustulosis has been associated with azathioprine (67A). • A 54-year-old woman with diabetes was given prednisolone and azathioprine 50 mg/day for pemphigus foliaceus and after 20 days devel oped disabling arthralgia, a fever (40.7°C), hypotension (85/45 mmHg), and a generalized, non-follicular pustular eruption with back ground erythema over 24 hours. Initially she was treated for septic shock with intravenous fluids and cefuroxime. However, later her symptoms were thought to be consistent with hypersensitivity to azathioprine, which was withdrawn. She improved over the next 48 hours and the pustular eruption and systemic symptoms resolved, with mild desquamation. Patch and prick tests with azathioprine were negative.
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Susceptibility factors Genetic Homo zygous polymorphisms associated with absence of thiopurine methyltransferase (TPMT) can cause life-threatening azathiopr ine-induced myelotoxicity (68A).
pelvis and the mid and lower poles, with infil tration into surrounding structures. A large renal tumor engulfing the hilar vessels and infiltrating the duodenum and the inferior caval vein was excised. It was a well-differentiated squamous cell carcinoma. Postoperatively, azathioprine was withdrawn, and 1 year later the patient was asymptomatic.
• An 85-year-old man with idiopathic pulmonary fibrosis was given azathioprine 100 mg/day and prednisone 40 mg/day and after 6 weeks devel oped fatigue, increasing dyspnea and respira tory failure and required ventilation. There was leukopenia (0.4 109/l), anemia (hemo globin 65 g/l), and thrombocytopenia (17 109/l). Fibre-optic bronchoscopy showed diffuse bleeding and cultures of the bronchoal veolar lavage fluid grew Staphylococcus aureus. He was homozygous for the TPMT*3A muta tion and was therefore likely to have little or no TPMT activity. He died with respiratory failure.
Teratogenicity The effects of azathioprine have been studied in pregnancy in 419 women, 189 taking azathioprine and 230 controls (70c). Azathioprine 50–100 mg/day was associated with lower birth weight (2995 versus 3252 g) and gestational age (37.8 versus 39.1 weeks) and more cases of prematurity (21% versus 5.2%).
Tumorigenicity Long-term use of azathioprine can cause squamous cell carci noma of the kidney (69A).
6-Thioguanine
• A 43-year-old man took azathioprine for more than 2 years for a demyelinating neuropathy and developed vague right-sided abdominal pain with no urinary or bowel symptoms. Ultrasonography, unremarkable 2 years before, showed a large right renal mass and a CT scan showed a large contrast-enhancing mass in the right kidney involving the renal
Treatment with 6-thioguanine can cause hepatic nodular regenerative hyperplasia in patients with inflammatory bowel dis ease, resulting in an increased hepatic venous pressure gradient and clinically sig nificant portal hypertension (71c).
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7. Creput C, Blandin F, Deroure B, Roche B, Saliba F, Charpentier B, Samuel D, Durr bach A. Long-term effects of calcineurin inhibitor conversion to mycophenolate mofe til on renal function after liver transplanta tion. Liver Transpl 2007;13(7):1004–10. 8. Shenoy S, Hardinger KL, Crippin J, Desai N, Korenblat K, Lisker-Melman M, Lowell JA, Chapman W. Sirolimus conversion in liver transplant recipients with renal dysfunction: a prospective, randomized, single-center trial. Transplantation 2007;83(10):1389–92. 9. Singh N, Alexander BD, Lortholary O, Dromer F, Gupta KL, John GT, Del Busto R, Klintmalm GB, Somani J, Lyon GM, Pursell K, Stosor V, Munoz P, Limaye AP, Kalil AC, Pruett TL, Garcia-Diaz J, Humar A, Hous ton S, House AA, Wray D, Orloff S, Dowdy LA, Fisher RA, Hitman J, Wagener MM, Husain S. Cryptococcus neoformans in organ transplant recipients: impact of calci neurin-inhibitor agents on mortality. J Infect Dis 2007;195(5):756–64. 10. Gomez-Camarero J, Salcedo M, Rincon D, Lo IO, Ripoll C, Hernando A, Sanz C, Clem ente G, Banares R. Use of everolimus as a rescue immunosuppressive therapy in liver transplant patients with neoplasms. Trans plantation 2007;84(6):786–91. 11. Franzoni E, Sarajlija J, Garone C, Malaspina E, Marchiani V. No kinetic interaction between levetiracetam and cyclosporine: a case report. J Child Neurol 2007;22(4):440–2. 12. Irani S, Fattinger K, Schmid-Mahler C, Achermann E, Speich R, Boehler A. Blood concentration curve of cyclosporine: impact of itraconazole in lung transplant recipients. Transplantation 2007;83(8):1130–3. 13. Sorkhi H, Moghadamnia AA, Oaliaee F, Pouramir M, Firoozjahi AR, Pasha AA, Goodarzi MR. Effect of tangerine juice on cyclosporine levels in renal transplant chil dren. Pediatr Nephrol 2008;23(3):499–501. 14. Condé SA, Aarestrup FM, Vieira BJ, Bastos MG. Roxithromycin reduces cyclosporine induced gingival hyperplasia in renal trans plant patients. Transplant Proc 2008;40(5): 1435–8. 15. Carreno CA, Gadea M. Case report of a kidney transplant recipient converted to everolimus due to malignancy: resolution of bronchiolitis obliterans organizing
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leflunomide. Rheumatology (Oxford) 2007; 46(6):1040. McEwen J, Purcell PM, Hill RL, Calcino LJ, Riley CG. The incidence of pancytopenia in patients taking leflunomide alone or with methotrexate. Pharmacoepidemiol Drug Saf 2007;16(1):65–73. Marzano AV, Ramoni S, Del Papa N, Barbareschi M, Alessi E. Leflunomide induced subacute cutaneous lupus erythema tosus with erythema multiforme-like lesions. Lupus 2008;17(4):329–31. Gros C, Delesalle F, Gautier S, Delaporte E. Leflunomide-induced skin necrosis. Ann Dermatol Venereol. 2008;135(3):205–8. Jian X, Guo G, Ruan Y, Lin D, Li X. Severe cutaneous adverse drug reaction to lefluno mide: a report of two cases. Cutan Ocul Tox icol 2008;27(1):5–9. Battiwalla M, Paplham P, Almyroudis NG, McCarthy A, Abdelhalim A, Elefante A, Smith P, Becker J, McCarthy PL, Segal BH. Leflunomide failure to control recurrent cyto megalovirus infection in the setting of renal failure after allogeneic stem cell transplanta tion. Transpl Infect Dis 2007;9(1):28–32. Neville CE, McNally J. Maternal exposure to leflunomide associated with blindness and cerebral palsy. Rheumatology (Oxford) 2007;46(9):1506. Palaniappan S, Ford AC, Greer D, Everett SM, Chalmers DM, Axon AT, Hamlin PJ. Mycophenolate mofetil therapy for refrac tory inflammatory bowel disease. Inflamm Bowel Dis 2007;13(12):1488–92. Pisoni CN, Cuadrado MJ, Khamashta MA, Hughes GR, D’Cruz DP. Mycophenolate mofetil treatment in resistant myositis. Rheu matology (Oxford) 2007;46(3):516–8. Doycheva D, Deuter C, Stuebiger N, Biester S, Zierhut M. Mycophenolate mofetil in the treatment of uveitis in children. Br J Ophthalmol 2007;91(2):180–4. Murray ML, Cohen JB. Mycophenolate mofetil therapy for moderate to severe ato pic dermatitis. Clin Exp Dermatol 2007;32(1): 23–7. Heller M, Shin HT, Orlow SJ, Schaffer JV. Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol 2007;157(1):127–32.
36. Akman B, Uyar M, Afsar B, Sezer S, Ozdemir FN, Haberal M. Lipid profile during azathioprine or mycophenolate mofetil combi nations with cyclosporine and steroids. Trans plant Proc 2007;39(1):135–7. 37. Naranjo J, Poniachik J, Cisco D, Contreras J, Oksenberg D, Valera JM, Diaz JC, Rojas J, Cardemil G, Mena S, Castillo J, Rencoret G, Godoy J, Escobar J, Rodriguez J, Leyton P, Fica A, Toledo C. Oral ulcers produced by mycophenolate mofetil in two liver trans plant patients. Transplant Proc 2007;39(3): 612–4. 38. Zhu B, Chen N, Lin Y, Ren H, Zhang W, Wang W, Pan X, Yu H. Mycophenolate mofetil in induction and maintenance ther apy of severe lupus nephritis: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant 2007;22(7):1933–42. 39. Perez-Aytes A, Ledo A, Boso V, Saenz P, Roma E, Poveda JL, Vento M. In utero exposure to mycophenolate mofetil: a char acteristic phenotype? Am J Med Genet A 2008;146A(1):1–7. 40. Shaw DW, Maibach HI, Eichenfield LF. Allergic contact dermatitis from pimecro limus in a patient with tacrolimus allergy. J Am Acad Dermatol 2007;56(2):342–5. 41. Novaro GM, Cherla A, Fromkin KR, Bush HS. Drug-eluting stent implantation in STelevation acute myocardial infarction: ‘real world’ 30-day and mid-term results. Cardio vasc Revasc Med 2007;8(1):5–8. 42. Kastrati A, Mehilli J, Pache J, Kaiser C, Valgimigli M, Kelbaek H, Menichelli M, Sabaté M, Suttorp MJ, Baumgart D, Seyfarth M, Pfisterer ME, Scho¨ mig A. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007;356(10): 1030–9. 43. Khalife WI, Kogoj P, Kar B. Sirolimus induced alveolar hemorrhage. J Heart Lung Transplant 2007;26(6):652–7. 44. Morath C, Schwenger V, Ksoll-Rudek D, Sommerer C, Beimler J, Schmidt J, Zeier M. Four cases of sirolimus-associated inter stitial pneumonitis: identification of risk fac tors. Transplant Proc 2007;39(1):99–102. 45. Perez MJ, Martin RO, Garcia DM, Rey JM, de la Cruz LJ, Rodrigo Lopez JM. Interstitial pneumonitis associated with sirolimus in
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liver transplantation: a case report. Trans plant Proc 2007;39(10):3498–9. 46. Das BB, Shoemaker L, Subramanian S, Johnsrude C, Recto M, Austin EH. Acute sirolimus pulmonary toxicity in an infant heart transplant recipient: case report and literature review. J Heart Lung Transplant 2007;26(3):296–8. 47. Tenderich G, Fuchs U, Zittermann A, Muckelbauer R, Berthold HK, Koerfer R. Comparison of sirolimus and everolimus in their effects on blood lipid profiles and haematological parameters in heart trans plant recipients. Clin Transplant 2007;21(4): 536–43. 48. Lopez V, Gutierrez C, Cabello M, Burgos D, Sola E, Gonzalez-Molina M. Conversion to sirolimus in posttransplant renal neoplasms. Transplant Proc 2007;39(7):2264–6. 49. Franco AF, Martini D, Abensur H, Noronha IL. Proteinuria in transplant patients asso ciated with sirolimus. Transplant Proc 2007; 39(2):449–52. 50. Deutsch MA, Kaczmarek I, Huber S, Schmauss D, Beiras-Fernandez A, Schmoeckel M, Ochsenkuehn R, Meiser B, Mueller-Hoecker J, Reichart B. Sirolimus associated infertility: case report and litera ture review of possible mechanisms. Am J Transplant 2007;7(10):2414–21. 51. Joseph A, Raj D, Shanmuganathan V, Powell RJ, Dua HS. Tacrolimus immunosup pression in high-risk corneal grafts. Br J Ophthalmol 2007;91(1):51–5. 52. Sevmis S, Karakayali H, Emiroglu R, Akkoc H, Haberal M. Tacrolimus-related seizure in the early postoperative period after liver transplantation. Transplant Proc 2007;39 (4):1211–3. 53. Yamaguchi I, Ichikawa T, Nakao K, Hamasaki K, Hirano K, Eguchi S, Takatsuki M, Kawasita Y, Kanematsu T, Eguchi K. Cere bellar ataxia in a patient receiving calci neurin inhibitors after living donor liver transplantation: a case report. Transplant Proc 2007;39(10):3495–7. 54. Kaczmarek I, Schmauss D, Sodian R, BeirasFernandez A, Oberhoffer M, Daebritz S, Schoenberg SO, Reichart B. Late-onset tacrolimus-associated cerebellar atrophia in a heart transplant recipient. J Heart Lung Transplant 2007;26(1):89–92.
721 55. Bhagavati S, Maccabee P, Muntean E, Sumrani NB. Chronic sensorimotor poly neuropathy associated with tacrolimus immunosuppression in renal transplant patients: case reports. Transplant Proc 2007; 39(10):3465–7. 56. Renner FC, Staak A, Bur Am OL, Walmrath HD, Weimer R. Tacrolimus intoxication resolved by gastrointestinal bleeding: case report. Transplant Proc 2007;39(2):522–5. 57. Levi Z, Hazazi R, Kedar-Barnes I, Hodak E, Gal E, Mor E, Niv Y, Winkler J. Switching from tacrolimus to sirolimus halts the appearance of new sebaceous neoplasms in Muir–Torre syndrome. Am J Transplant 2007;7(2):476–9. 58. Caffier PP, Harth W, Mayelzadeh B, Haupt H, Sedlmaier B. Tacrolimus: a new option in therapy-resistant chronic external otitis. Laryngoscope 2007;117(6):1046–52. 59. Remitz A, Harper J, Rustin M, Goldschmidt WF, Palatsi R, van der Valk PG, Sharpe G, Smith CH, Dobozy A, Turjanmaa K. Longterm safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in chil dren. Acta Derm Venereol 2007;87(1):54–61. 60. Virgili A, Lauriola MM, Mantovani L, Cor azza M. Vulvar lichen sclerosus: 11 women treated with tacrolimus 0.1% ointment. Acta Derm Venereol 2007;87(1):69–72. 61. Maass E, Mueller GA, Heller T, Koziolek MJ. Decrease in serum tacrolimus level and rise in serum creatinine under late addition of cinacalcet in a renal transplant recipient with hyperparathyroidism: a case report. Transplant Proc 2007;39(10):3468–70. 62. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356(22):2271–81. 63. Gisbert JP, Gonza´ lez-Lama Y, Maté J. Thio purine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol 2007;102(7): 1518–27. 64. Cassinotti A, Massari A, Ferrara E, Greco S, Bosani M, Ardizzone S, Bianchi PG. New onset of atrial fibrillation after introduction
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of azathioprine in ulcerative colitis: case report and review of the literature. Eur J Clin Pharmacol 2007;63(9):875–8. Ananthakrishnan AN, Attila T, Otterson MF, Lipchik RJ, Massey BT, Komorowski RA, Binion DG. Severe pulmonary toxicity after azathioprine/6-mercaptopurine initiation for the treatment of inflammatory bowel disease. J Clin Gastroenterol 2007;41(7):682–8. Vernier-Massouille G, Cosnes J, Lemann M, Marteau P, Reinisch W, Laharie D, Cadiot G, Bouhnik Y, De Vos M, Boureille A, Duclos B, Seksik P, Mary JY, Colombel JF. Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut 2007;56(10):1404–9. Elston GE, Johnston GA, Mortimer NJ, Harman KE. Acute generalized exanthema tous pustulosis associated with azathioprine hypersensitivity. Clin Exp Dermatol 2007; 32(1):52–3. Perri D, Cole DE, Friedman O, Piliotis E, Mintz S, Adhikari NK. Azathioprine and
diffuse alveolar haemorrhage: the pharmaco genetics of thiopurine methyltransferase. Eur Respir J 2007;30(5):1014–7. 69. Nair B, Sukumar S, Poolari GK, Appu T. Azathioprine-induced squamous cell carci noma of the kidney. Scand J Urol Nephrol 2007;41(2):173–5. 70. Goldstein LH, Dolinsky G, Greenberg R, Schaefer C, Cohen-Kerem R, Diav-Citrin O, Malm H, Reuvers-Lodewijks ME. Rost van Tonningen-van Driel MM, Arnon J, Ornoy A, Clementi M, Di Gianantonio E, Koren G, Braunstein R, Berkovitch M. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects Res A Clin Mol Teratol 2007;79(10):696–701. 71. Ferlitsch A, Teml A, Reinisch W, Ulbrich G, Wrba F, Homoncik M, Gangl A, Peck-Rado savljevic M, Vogelsang H. 6-Thioguanine associated nodular regenerative hyperplasia in patients with inflammatory bowel disease may induce portal hypertension. Am J Gastroenterol 2007;102(11):2495–503.
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Corticotrophins, corticosteroids, and prostaglandins
Editor’s notes: In this chapter adverse effects arising from the oral or intravenous administration of corticosteroids (glucocorti coids and mineralocorticoids) are covered in the section on systemic administration. Other routes of administration are dealt in the sec tions after that; inhalation and nasal adminis tration are dealt in Chapter 16, topical administration to the skin in Chapter 14, and ocular administration in Chapter 47. All the uses of prostaglandins are covered in this chapter, apart from topical administration to the eyes, which is covered in Chapter 47.
SYSTEMIC GLUCOCORTICOIDS (SED-15, 906; SEDA-29, 480; SEDA 30, 463; SEDA-31, 651) Observational studies All consecutive pat ients (n = 88) starting long-term ( � 3 months), high-dosage prednisone therapy ( � 20 mg/day) were enrolled in a study of the frequency of adverse events, susceptibil ity factors and patients’ opinions in two French centers (1c). Lipodystrophy was the most frequent adverse event (63%, range 51–73); it was considered the most distres sing by the patients and was most frequent in Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32039-3 � 2010 Elsevier B.V. All rights reserved.
women and young patients. Neuropsychiatric disorders occurred in 42 patients (53%, 41– 64), and needed hospitalization in five cases. There were skin disorders in 37 patients (46%, 35–58), more often in women. Muscle cramps and proximal muscle weakness were reported by 32% (22–44) and 15% (8–25) respectively. New hypertension occurred in 8.7% (2.9–20). Lastly, 39% (20–61) of the premenopausal women reported menstrual disorders. Long-term adverse effects of glucocorti coids are well characterized, but there are few data on the incidence and likelihood of short-term adverse effects. The records of all eligible kidney or pancreas–kidney transplant recipients have been examined, to determine the incidence of adverse effects potentially related to early administration of glucocorti coids and to determine the probability that the adverse effect was due to the glucocorti coid (2c). Adverse reactions were identified in all 103 patients by an average of 8 days. The mean number of adverse reactions per patient was 3.26. There was weight gain in 80%, hypertension in 72%, diabetes mellitus in 52%, hyperglycemia in 48, leukocytosis in 31%, insomnia in 27%, anxiety in 11%, and psychosis in 1.9%. According to the Naranjo algorithm, leukocytosis was judged as ‘prob able’ and weight gain and psychosis were ‘possible to probable’. Diabetes, hyperglyce mia, hypertension, and insomnia were ‘possi ble’, and anxiety was ‘possible to doubtful’. Systematic reviews The effects of systemic glucocorticoids in chronic obstructive
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pulmonary disease (COPD) have been sum marized in two Cochrane systematic reviews assessing chronic stable and acute exacerba tions of the disease (3M). In stable COPD, compared with placebo, oral glucocorticoid treatment increased mean FEV1 by 53 ml and mean 12-minute walking distance by 29 m, but at an increased risk of any drugrelated adverse event (OR = 7.7; 95% CI = 2.3, 25.7). In acute exacerbations, oral glucocorticoids reduced the risk of treat ment failure (OR = 0.48; 95% CI = 0.34, 0.68), improved mean FEV1 at 72 hours by 140 ml, and improved arterial blood gases, but increased the risk of drug-related adverse events (OR = 2.3; 95% CI = 1.6, 3.3). The authors commented that treatment of stable and acute exacerbations of COPD with systemic glucocorticoids results in sta tistically significant average benefits, but at an increased risk of adverse effects. In stable COPD, there is little support for the use of systemic glucocorticoid treatment, as data on long-term outcomes are lacking. For acute exacerbations, the evidence in support of the use of systemic glucocorticoids is stronger, but further research is required to define the optimum dose, route, and duration. Cardiovascular Andersen’s syndrome is a form of long QT syndrome. It is a rare genetic disorder, inherited in an autosomal dominant pattern and caused by muta tions in the KCNJ2 gene that encodes for Kir2.1, an inward rectifier potassium chan nel. Periodic paralysis, cardiac arrhyth mias, and bone features are the hallmarks of this syndrome. Rest following strenuous physical activity, carbohydrate ingestion, emotional stress, and exposure to cold are precipitating triggers. Two families with this disorder have been identified (4c). They had periodic paralysis and cardiac abnormalities, but only discrete develop mental features. One patient reported hav ing had symptoms twice during the day after glucocorticoids treatment and alle viated after withdrawal. Cardiac rhythm disturbances, both tachy dysrhythmias and bradydysrhythmias, have been reported in adults after high-dose
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intravenous pulse methylprednisolone, but much less often in children. Five children with rheumatic diseases developed sinus bradycardia during daily therapy with intra venous pulse methylprednisolone (5A). There were reductions in resting heart rate of 35–50% of baseline in each case. All the patients were asymptomatic and all recov ered spontaneously over a variable period of time after the end of pulse therapy. In a nested case–control study of the risk of acute myocardial infarction associated with oral glucocorticoids in 404 183 patients, aged 50–84 years, without cancer from the general UK population 4795 deaths from acute myocardial infarction or coronary heart disease were included (6c). A sample of 20 000 controls was randomly selected, frequency matched by age, sex, and calendar year. Relative risks were estimated using unconditional logistic regression. The adjus ted odds ratio for acute myocardial infarc tion in current users of oral glucocorticoids compared with non-users was 1.42 (95% CI = 1.17, 1.72). The risk during the first 30 days of use (OR = 2.24; 95% CI = 1.56, 3.20) was greater than with longer duration (OR = 1.22; 95% CI = 0.98, 1.52). The risk was more pronounced (OR = 2.15; 95% CI = 1.45, 3.14) among users of prednisolone equivalent doses over 10 mg/day. The dose effect was observed among patients with and without coronary heart disease or COPD/ asthma. These results suggest a small increased risk of acute myocardial infarction with oral glucocorticoids, with a greater risk in users of high doses. Oral glucocorticoids reduce the risk of re-stenosis after percutaneous coronary intervention. Of 220 patients, 28 had adverse effects that were probably related to prednisone: gastric pain (4%), increased arterial pressure needing increased anti hypertensive treatment (4%), edema (1.8%), and concomitant infections (1.4%) (7A). In three asymptomatic patients (1.4%), who were also taking a thienopyridine, there was neutropenia, detected during routine blood cell count 4 weeks after the interven tion. It resolved completely after withdra wal of prednisone and thienopyridine in all cases. Neutropenia after prednisone had
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never been reported before. However, a direct cause-and-effect relation between thienopyridines or prednisone (alone or in combination) and neutropenia cannot be proved because of lack of rechallenge. The authors hypothesized that prednisone, by increasing CYP3A4 activity, may enhance the formation of an active thienopyridine metabolite, possibly amplifying the risk of adverse effects. Nervous system A rare but reversible com plication of glucocorticoids therapy, poste rior reversible encephalopathy syndrome, has been reported in patients with renal diseases or hematological malignancies and in patients with bone marrow and solid organ trans plants. However, the patients were either acutely ill or had been exposed to other agents implicated in causing the syndrome (i.e. immunosuppressive agents or cytotoxic drugs). It has now been reported with highdose dexamethasone in a patient who was not taking concomitant medications (8A). Sensory systems Triamcinolone has been used to visualize the vitreous during ocular surgery, including pars plana vitrectomy and anterior vitrectomy. Few studies have repor ted complications. Post-operative infectious endophthalmitis has been reported after triamcinolone-assisted anterior vitrectomy in complicated cataract surgery (9A). The symptoms were mild and the absence of ocu lar pain kept the patient from returning earlier for care. The authors remarked that adequate patient instructions are necessary to detect the early signs and symptoms of endophthalmitis. Glucocorticoids can increase intraocular pressure, which can cause interlamellar stromal edema after laser in situ kerato mileusis (LASIK) (10A). Metabolism The authors of a prospective study in two French tertiary centers have described corticosteroid-induced lipodys trophy (11c). They enrolled 88 consecutive patients who started long-term ( � 3 months), high dosage ( � 20 mg/day) systemic gluco corticoid therapy and assessed the develop ment of lipodystrophy from standardized
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head and neck photographs. Arterial blood pressure and fasting blood glucose concentra tions were assessed at baseline and then every 3 months until month 12. Total choles terol, HDL-cholesterol, LDL-cholesterol, and triglycerides were recorded at baseline, month 3 and month 12. The mean age of the patients was 57 years and the mean baseline dosage of prednisolone was 56 mg/day; 64 patients were still taking glucocorticoids at month 12 (mean dosage 11 mg/day). The cumulative incidences of lipodystrophy at months 3 and 12 were 61 and 69% respec tively. Baseline characteristics were similar in those who developed lipodystrophy and those who did not, except with regard to baseline body mass index, which was higher in the former (24 kg/m2 versus 21 kg/m2). Blood pressure was significantly higher in patients with lipodystrophy at month 9 (135/78 mmHg versus 127/73 mmHg) and month 12 (141/81 mmHg versus 128/ 72 mmHg). Those with lipodystrophy had significantly higher plasma concentrations of fasting blood glucose, triglycerides, and total cholesterol and lower HDL-choles terol concentrations during follow-up. The prevalence of glucocorticoid-induced diabetes mellitus and susceptibility factors have been determined in patients with primary renal diseases (12c). During gluco corticoid therapy (initial dose of predniso lone 0.75 mg/kg/day), diabetes mellitus was newly diagnosed in 17 of 42 patients by hyperglycemia 2 hours after lunch, although they had normal fasting blood glucose con centrations. Age (OR = 1.40, 95% CI = 1.06, 1.84) and body mass index (OR = 1.87, 95% CI = 1.03, 3.38) were independent suscept ibility factors for glucocorticoid-induced diabetes mellitus. Liver Acute severe liver damage has been reported sporadically in patients who have received intravenous methylprednisolone pulse therapy for Graves’ ophthalmopathy, with fatal acute liver failure in four patients so far. In a prospective observational study in 13 patients with dysthyroid optic neuropathy (group A) and in 14 patients with moderately severe Graves’ ophthalmopathy (group B), who were given high-dose (group A) or
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low-dose (group B) intravenous methylpred nisolone pulse therapy; cumulative gluco corticoid doses were 8.45 g in group A and 4.5 g in group B, and the follow-up time was 24 weeks (13c). There were slight increases in serum transaminases (AlT more than AsT) in seven patients, exceeding the upper refer ence limit of 40 U/l. These changes were more prominent in group A than in group B, as was also evident from a reduced AsT/ AlT ratio in group A but not in group B. Changes in serum transaminases occurred especially during the first 6 weeks of therapy and became smaller thereafter with reduc tions in methylprednisolone dosage. Pre treatment liver steatosis or diabetes were not related to liver damage, but pre-existent viral hepatitis was. Intravenous methylpred nisolone pulse therapy in patients with Graves’ ophthalmopathy causes dose-related liver damage by a direct toxic effect on hepa tocytes. Nevertheless, it seems to be safe if cumulative doses exceeding 8 g are avoided and liver function is checked before and at regular intervals during therapy. • A 34-year-old man with multiple sclerosis devel oped acute central hepatic necrosis while receiv ing high-dose intravenous methylprednisolone (14A). He was initially given intravenous methylprednisolone 1 g/day for 5 days, and was then maintained on intravenous methylpred nisolone 1 g/month. AsT, AlT, and bilirubin were normal before the start of treatment, but rose 5 months later. AsT and AlT continued to worsen and peaked 8 months after the start of treatment. Tests for hepatitis A, B, and C, anti nuclear antibody, antimitochondrial antibody, and double-stranded DNA were negative. A liver biopsy showed striking centrilobular hepatic cell necrosis. His liver disease remitted after methylprednisolone was withdrawn.
The temporal relation between central hepa tic necrosis and the use of high-dose intrave nous methylprednisolone suggested that methylprednisolone was the cause. Exposure to a high total dosage of gluco corticoids has been associate with non alcoholic steatohepatitis (15A). Non-alcoholic steatohepatitis involves histological changes similar to those in alcoholic liver disease in patients without alcohol abuse; it occasionally progresses to hepatic cirrhosis, which is com mon in those with obesity, diabetes mellitus or hyperlipidemias. The association between
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glucocorticoids and non-alcoholic steatohepa titis has been studied in two groups of 48 patients with systemic lupus erythematosus (31 autopsy cases and 17 liver biopsy cases), a low total dose group (14 cases; total dose of prednisolone 10 g, duration of therapy 2–20 years) (16c). They had no major susceptibility factors for non alcoholic steatohepatitis, which was found in two patients in the high total dosage group. Skin Perioral dermatitis has been associated with topical glucocorticoids but rarely with sys temic administration. A 37-year-old woman with myasthenia gravis was given oral predni sone 100 mg/day and pyridostigmine, and after 3 weeks developed perioral dermatitis, with asymptomatic 1–2-mm erythematous papules distributed circumferentially around her mouth and over her chin (17A). Dermatofibromata are common, benign, dermal tumors, often occurring as single lesions on the legs of young adults. Multiple eruptive dermatofibromata are rare and are usually associated with autoimmune dis eases, immunosuppressant therapy or both. A 28-year-old woman with dermatomyositis developed multiple eruptive dermatofibro mata after undergoing methotrexate and cor ticosteroid treatment (18A). Musculoskeletal EIDOS classification: Extrinsic species: Glucocorticoids Intrinsic species: Osteoblasts and osteoclasts Distribution: Bone Outcome: Atrophy Sequela: Osteoporosis from glucocorticoids DoTS classification: Dose-relation: Collateral reaction Time-course: Late Susceptibility factors: Age (elderly patients); sex (female sex, post menopausal) The current evidence on susceptibility factors for glucocorticoid-induced osteoporosis, the
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prevention and treatment of consequent frac tures, and guidelines for management pub lished since 2000 have been summarized (19R). There is significant bone loss and an increased risk of fracture is seen with pred nisone doses as low as 5 mg/day. Alternate-day glucocorticoid therapy can lead to similar bone loss. There is no conclusive evidence for a safe minimum dose or duration of gluco corticoid exposure. Physicians should consider susceptibility factors for involutional osteo porosis, such as older age, post-menopausal status and baseline bone density measure ments, as they assess patients for prevention or treatment. Bisphosphonates reduce gluco corticoid-related vertebral fractures, but the data on hip fractures are inconclusive. Hor mone replacement therapy and parathyroid hormone analogues are effective in preser ving bone density. The risk of osteoporosis and fractures should be routinely assessed in patients receiving glucocorticoid therapy. Effective prevention and treatment options are available and can result in reduced mor bidity and mortality. Current guidelines for management recommend bisphosphonates, especially alendronate and risedronate, as first-line agents, and the preventive use of bisphosphonates early in glucocorticoid ther apy in high-risk patients. The risk of fractures has been evaluated in 191 752 patients over 40 years old taking inter mittent high-dose oral glucocorticoids using the UK General Practice Database (20c). Relative risks were estimated using Cox pro portional hazards models, adjusted for age, sex, body mass index, smoking, disease his tory, and drug history. Fractures of the radius/ ulna, humerus, rib, femur/hip, pelvis, or ver tebrae were evaluated. Patients who took intermittent high-dose glucocorticoids (at least 15 mg/day) and had no or little previous exposure to glucocorticoids (cumulative expo sure under 1 g) had a small increase in the risk of osteoporotic (but not hip/femur) fracture; this risk increased substantially with increas ing cumulative exposure. Among patients who took at least 30 mg/day and whose cumu lative exposure was over 5 g, the relative risk (RR) of an osteoporotic fracture was 3.63 (95% CI = 2.54, 5.20), of fracture of the hip/ femur 3.13 (95% CI = 1.49, 6.59) and of ver tebral fracture 14 (95% CI = 8.3, 25).
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The prevalence of asymptomatic verteb ral fractures has been assessed in 551 post menopausal women taking long-term gluco corticoids in a multicenter, cross-sectional out-patient study (21c). Inclusion criteria inclu ded age over 45 years, glucocorticoid therapy for at least 6 months with a cumulative dose of at least 1.35 g of a prednisone equivalent, and a diagnosis of rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, other vasculitides or connective tissue diseases, asthma, or COPD. There were one or more asymptomatic vertebral fractures in 37%, and 14% had two or more fractures. The distribu tion was bimodal, with peak incidences at thor acic vertebrae T7 and T11. The prevalence of asymptomatic vertebral fractures increased with age; 48% of participants aged over 70 years had at least one fracture. There was no correlation between fracture prevalence and cumulative glucocorticoid dose or duration of therapy. Lumbar spine and hip-bone mineral density, calcaneal bone stiffness, and healthrelated quality of life were not associated with the number of vertebral fractures or their severity. Time since menopause and a history of non-vertebral fractures were both signifi cantly associated with asymptomatic vertebral fractures. The disparity between bone quantity and quality in glucocorticoid-induced osteo porosis makes bone mineral density or ultra sonography inadequate for identifying patients at risk of glucocorticoid-associated fractures. Sexual function The persistent sexual arou sal syndrome is a newly described entity in which a woman becomes involuntarily geni tally aroused for extended periods of time in the absence of sexual desire and is distressed by this. The cause of this sexual problem is not well understood. A case in which the subjective feelings were confirmed by observing genital engorgement has been published (22A). The syndrome arose after the use of the mineralocorticoid fludrocorti sone for hypotension and bradycardia asso ciated with an atrial septal defect. The authors argued that the combined effect of the atrial septal defect and fludrocortisone may have increased the concentrations of atrial natriuretic peptide, causing profound vasodilatation and vascular leakage.
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Infection risk The incidence of recurrence of hepatitis B after liver transplantation has been reduced by prophylaxis with hepatitis B immunoglobulin and lamivudine. The fac tors associated with recurrence of hepatitis B have been analysed in 203 recipients who underwent liver transplantation for hepatitis B in three major centers in Korea over 4 years (23c). There was a far higher incidence of recurrence of hepatitis B in patients who received glucocorticoid pulse therapy (21% versus 7.9%), in those who had a recurrence of hepatocellular carcinoma (31% versus 8.6%) and in patients who received chemotherapy to prevent recur rence of hepatocellular carcinoma (25% ver sus 4.4%). The cumulative glucocorticoid dose was higher in patients who had recur rence of hepatitis B. Community-acquired pneumonia with splenomegaly related to Q fever has been reported in a 49-year-old man with Crohn’s disease who was taking glucocorticoids (24A). Patients with limited small cell lung cancers can be cured with an aggressive approach (chest irradiation plus chemo therapy) followed by prophylactic cranial irradiation, during which dexamethasone is usually prescribed prophylactically to mini mize acute radiation-induced brain edema. This approach may cause immunosup pression, as in a case of reactivation of endogenous latent Herpes simplex virus infection and fatal acute encephalitis (25A). Infantile hemangiomas are common, benign and self-limited tumors. There are no approved treatments by the US FDA, but current practice includes the use of high-dose glucocorticoids. Pneumocystis jiroveci pneu monia occurred in an infant who was given oral glucocorticoids for hemangioma (26A). • A girl with a large facial infantile hemangi oma was given oral prednisolone 15 mg/day beginning at age 2 months. At 7 months, she developed severe respiratory distress with a fever, an increased respiratory rate, intercostal retraction, grunting, and bilateral lung infil trates on chest radiography. Pneumocystis jir oveci was isolated from endotracheal tube aspirates. There was no underlying primary immunodeficiency, and her infection was attributed to immunosuppression secondary to prednisolone.
Chapter 39
J. Costa and M. Farré
Tumorigenicity Glucocorticoid-induced im munosuppression may play a role in skin carcinogenesis. In a population-based study of non-melanoma skin cancers oral gluco corticoids are associated with a nearly six fold increased risk of squamous cell carcinoma among individuals with a common genetic variant in the glucocorticoid receptor (NR3C1) gene (27c). Teratogenicity The relation between the use of glucocorticoids during pregnancy and orofacial clefts in the offspring has been assessed by telephone interviews of the mothers of 1141 babies with cleft lip with or without cleft palate, 628 with cleft palate, and 4143 controls (28c). The mothers of 33 infants with cleft lip and palate (2.9%), the mothers of 6 infants with cleft palate (1.0%), and 72 controls (1.7%) reported glucocorti coid use from 4 weeks before conception to 12 weeks after. The results suggest a moder ately increased risk of cleft lip and cleft palate among women who use glucocorti coids during early pregnancy. Susceptibility factors Diseases Netherton’s syndrome is a rare autosomal recessive con dition characterized by ichthyosiform ery throderma, trichorrhexis invaginata, atopy, and increased percutaneous absorption. An 11-year-old boy with Netherton’s syndrome developed Cushing’s syndrome after appli cation of 1% hydrocortisone ointment to his entire body for more than 1 year (29A). Even low-potency steroid ointments should be used with caution in Netherton’s syndrome. Drug dosage regimens Most established topical glucocorticoids, such as betametha sone valerate and hydrocortisone, are applied at least twice daily, but three newer drugs (mometasone, fluticasone, and methylprednisolone) can be used once daily. It has been suggested that topical glucocorticoids can be applied only once daily without loss of efficacy and that that might reduce the risk of local adverse effects (30rH).
Corticotrophins, corticosteroids, and prostaglandins
PROSTAGLANDINS AND ANALOGUES (SED-15, 2955; SEDA-29, 487; SEDA-30, 465; SEDA-31, 651)
Alprostadil (prostaglandin E1) (SED-15, 94; SEDA-29, 487)
Observational studies Prostaglandin E1 (PGE1) is a routine palliative therapy for maintaining ductal patency in ductus arterio sus. It is usually given as an infusion of short duration. At the start of the treatment, sev eral adverse effects, usually reversible, can occur. However, in some neonates, therapy longer than 2 weeks may be needed. There has been a retrospective analysis of nine patients who received alprostadil for more than 14 days (31c). The leukocyte count remained high throughout the treatment period, and the proportion of neutrophils was over 50%. There were transient feeding difficulties, abdominal distension, and possi ble signs of gastric-outlet obstruction in two cases. In three patients, cortical hyperostosis developed after different cumulative doses (1584, 3384, and 4320 micrograms/kg). There were significant correlations between the doses of alprostadil and serum potassium concentrations and bicarbonate concentra tions. The three patients who received the largest cumulative doses developed pseudo Bartter’s syndrome. Musculoskeletal Hyperostosis occurred after a 4-day-old girl was given alprostadil for 38 days (32A).
Bimatoprost
(SED-15, 517;
SEDA-31, 655) Skin Periocular pigmentation has been stu died retrospectively in 400 consecutive patients treated with latanoprost (n = 263) or bimatoprost (n = 137) for 12 months (33c). There was periocular pigmentation in 0.8% of those treated with latanoprost and 5.8% of those treated with bimatoprost within 12 months of beginning treatment.
Chapter 39
Iloprost
729
(SED-15, 1716)
Sensory systems A 22-year-old man devel oped sudden bilateral hearing loss, tinnitus, and dizziness during the second of a series of five planned daily intravenous infusions of iloprost (0.5–2 nanograms/kg/minute) for Raynaud’s syndrome. The infusion was immediately interrupted and the dizziness subsided quickly. The tinnitus persisted for another 2 days and the hearing loss for 4 days. Audiography returned to normal within 8 days. The authors suspected endolymphatic hydrops as the cause of these symptoms, sec ondary to dysregulation of inner-ear pressure with iloprost, which leads to either increased production or reduced absorption of endolymph (34A).
Latanoprost
(SED-15, 2002; SEDA-29, 489; SEDA-30, 465; SEDA-31, 655) Sensory systems Choroidal detachment is a well-recognized early complication of trabec ulectomy, if the eye is hypotonic in the early post-operative period. Delayed choroidal detachment and hypotony have been reported in association with the use of topical prostaglandin analogues. Late-onset choroidal detachment after combined cata ract and glaucoma surgery (phacoemuls ification and trabeculectomy) has been associated with the use of topical latanoprost in the fellow eye (35A).
• An 89-year-old white woman developed gra dual reduction of vision in her left eye after combined phacoemulsification and trabeculect omy 11 months before. She was using topical latanoprost 0.005% once daily in her right eye only. Examination of the left eye showed visual acuity of hand movements, an intraocular pres sure of 0 mmHg, a deep anterior chamber and a non-leaking trabeculectomy bleb. Gonioscopy showed an open anterior chamber angle, Schaeffer grade III. There was no cyclodialysis. Left fundoscopy showed extensive choroidal detachment in all quadrants, confirmed by B-scan ultrasonography. Intraocular pressure in the right eye was 10 mmHg. Latanoprost was withdrawn. Over the next 6 weeks, the choroidal detachment in the left eye resolved
730 completely, the intraocular pressure rose to 12 mmHg, and Snellen visual acuity improved to 6/9. The intraocular pressure in the right eye remained within the reference range without treatment. The Naranjo causality scale sugges ted that the adverse reaction was possibly due to latanoprost. The choroidal detachment had not recurred at 1-year follow-up after with drawal of latanoprost.
Late choroidal detachment after trabeculect omy is rare in the absence of a leaking bleb. It has been reported up to 5 years after trabecu lectomy in association with topical latanoprost in the involved eye. In this patient, latanoprost 0.005% was being used once daily in only the fellow eye. The eye absorbs about 1% of topical latanoprost, and the remainder is absorbed into the systemic circulation. In stu dies in which patients have been treated with latanoprost in one eye only, intraocular pres sure in the fellow eye was reduced by only 0.4–1.2 mmHg. However, previous glaucoma surgery is likely to alter dose-responsiveness to intraocular pressure-lowering agents. In addition, individual patient sensitivity is likely to vary. The authors suggested that the patient’s sensitivity to systemically absorbed latanoprost, combined with the altered intraocular milieu after previous surgery, had been sufficient to cause chronic hypotony and choroidal detachment. In a prospective observer-masked study of the effect of patient age on the incidence of latanoprost-induced increases in iris pig mentation in 36 patients under 60 years and 36 patients older than 75 years with primary open-angle glaucoma has shown that age is an important susceptibility factor for latano prost-induced iris color change, because 28 of the older patients developed an increase in iris pigmentation compared with eight of the younger (36c). The morphological and melanin granule changes in irises have been studied after exposure to latanoprost for variable times (37c). Melanin granules in the anterior bor der melanocytes of the latanoprost-induced iris darkening eyes were significantly larger than those in the controls. There was a trend towards bigger melanin granules in the deep stroma, but this difference did not reach significance.
Chapter 39
J. Costa and M. Farré
Misoprostol (SED-15, 2357; SEDA-29, 490; SEDA-30, 466; SEDA-31, 655) Hematologic Acute hemolytic anemia has been attributed to high-dose misoprostol (4 mg) for medical abortion in a 21-year-old Nigerian woman (38A). The major causes of inherited and immune hemolytic anemias were excluded. Her peripheral blood smear showed acanthocytosis and anisopoikilocyto sis, which progressively disappeared in the days after ingestion. The intracellular erythrocyte sodium and potassium concen trations were reduced and there were abnormalities in membrane cation transport pathways and in calcium-activated potassium (Gardos) channels, suggesting possible direct effects of misoprostol on erythrocytes. Reproductive system Misoprostol should be used with caution in women with a pre viously scarred uterus, even in the first tri mester. Uterine rupture occurred at 8 weeks of gestation after the use of oral misoprostol 600 mg for management of delayed miscar riage (39A). Teratogenicity Poland syndrome is a rare abnormality characterized by the presence of unilateral symbrachydactyly and ipsilat eral aplasia of the sternocostal head of the pectoralis major muscle. Variable defects of other pectoral, chest wall, and upper limb components can occur. Other anomalies have also been described. Although most published cases have been sporadic, familial reports also have been published, suggest ing different patterns of inheritance. Some authors have also considered a possible vas cular origin for Poland syndrome, involving interruption of the subclavian artery proxi mal to the origin of the internal thoracic artery and distal to the origin of the verteb ral artery, during weeks 6–7 of gestation. Misoprostol is a well-known vascular teratogen associated with several congenital abnormalities, but never with Poland syn drome. There has been a report of a patient with Poland syndrome associated with an aberrant subclavian artery and vascular
Corticotrophins, corticosteroids, and prostaglandins
Chapter 39
abnormalities of the retina, whose mother had used misoprostol during pregnancy (40A).
eye. She had used timolol and dorzolamide combination therapy for 1 year, and then travoprost was added to the left eye. Her symptoms began after only two doses. She stopped using travoprost and 10 days later the discomfort resolved. Latanoprost was then added without adverse effects.
Drug overdose A death related to miso prostol overdose has been published (41A). • An adolescent developed upper gastrointest inal bleeding after self-medication with oral misoprostol 12 mg to cause abortion. She developed multiorgan failure, acute abdominal signs and hemodynamic instability. Emergency laparotomy showed gastric and esophageal necrosis. After several episodes of cardiac arrest, and despite efforts at resuscitation, she died.
The mechanism implicating misoprostol in gastrointestinal ischemia and necrosis was unknown.
Travoprost
(SED-15, 3481; SEDA-30, 466; SEDA-31, 655)
Sensory systems Acute iritis and corneal edema developed after only two doses of travoprost (42A). • A 70-year-old Caucasian woman with primary open-angle glaucoma developed redness, discomfort and blurring of vision in her left
731
Hair Prostaglandins cause growth of lashes and ancillary hairs around the eyelids. Mani festations include greater thickness and length of lashes, additional lash rows and conversion of vellus to terminal hairs in canthal areas as well as in regions adjacent to rows of eyelashes. Vellus hairs of the lower eyelids also undergo increased growth and pigmentation. Eyelash hypertrichosis has been reported in 75% of patients in clin ical trials evaluating efficacy of the PGF2a analogue travoprost in the treatment of ocu lar hypertension. Prostaglandin analogues are believed to prolong the anagen phase of eyelashes. Travoprost has therefore been proposed as a possible treatment for alope cia areata involving the eyelashes. Periocular skin pigmentation developed in three patients during treatment with topical travo prost for alopecia areata involving the eye lashes (43A).
References 1. Fardet L, Flahault A, Kettaneh A, Tiev KP, Genereau T, Toledano C, Lebbe C, Cabane J. Corticosteroid-induced clinical adverse events: frequency, risk factors and patient’s opinion. Br J Dermatol 2007;157(1):142–8. 2. Mathis AS, Liu MT, Adamson RT, Nambi SS, Patel AM. Retrospective analysis of early steroid-induced adverse reactions in kidney and kidney–pancreas transplant recipients. Transplant Proc 2007;39(1):199–201. 3. Wood-Baker R, Walters J, HaydnWalters E. Systemic corticosteroids in chronic obstruc tive pulmonary disease: an overview of Cochrane systematic reviews. Respir Med 2007;101(3):371–7. 4. Bendahhou S, Fournier E, Gallet S, Menard D, Larroque M-M, Barhanin J.
Corticosteroid-exacerbated symptoms in an Andersen’s syndrome kindred. Hum Mol Genet 2007;16(8):900–6. 5. Akikusa JD, Feldman BM, Gross GJ, Silverman ED, Schneider R. Sinus brady cardia after intravenous pulse methylpred nisolone. Pediatrics 2007;119(3): e778–82. 6. Varas-Lorenzo C, Rodriguez LAG, Maguire A, Castellsague J, Perez-Gutthann S. Use of oral corticosteroids and the risk of acute myocardial infarction. Atherosclerosis 2007;192(2):376–83. 7. Ribichini F, Ferrero V, Feola M, Rognoni A, Brunelleschi S, Vacca G, Vassanelli C. Neutropenia in patients treated with thieno pyridines and high-dose oral prednisone after percutaneous coronary interventions. J Interv Cardiol 2007;20(3):209–13.
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732 8. Irvin W, MacDonald G, Smith JK, Kim WY. Dexamethasone-induced posterior reversi ble encephalopathy syndrome. J Clin Oncol 2007;25(17):2484–6. 9. Lee SM, Shin YJ, Park KH. Postoperative infectious endophthalmitis after triamcino lone-assisted anterior vitrectomy. J Cataract Refract Surg 2007;33(4):731–2. 10. Miyai T, Yonemura T, Nejima R, Otani S, Miyata K, Amano S. Interlamellar flap edema due to steroid-induced ocular hyper tension after laser in situ keratomileusis. Jpn J Ophthalmol 2007;51:228–30. 11. Fardet L, Cabane J, Kettaneh A, Lebbé C, Flahault A. Corticosteroid-induced lipodystro phy is associated with features of the metabolic syndrome. Rheumatology 2007;46(7):1102–6. 12. Uzu T, Harada T, Sakaguchi M, Kanasaki M, Isshiki K, Araki S, Sugiomoto T, Koya D, Haneda M, Kashiwagi A, Yamauchi A. Glu cocorticoid-induced diabetes mellitus: preva lence and risk factors in primary renal diseases. Nephron Clin Pract 2007;105(2): c54–7. 13. Le Moli R, Baldeschi L, Saeed P, Regensburg N, Mourits MP, Wiersinga WM. Determi nants of liver damage associated with intravenous methylprednisolone pulse ther apy in Graves’ ophthalmopathy. Thyroid 2007;17(4):357–62. 14. Lee HM, Ditelberg JS, Kaplan MM. Pericen tral liver cell necrosis associated with the use of high-dose intravenous methylpredniso lone. Dig Dis Sci 2007;52(6):1533–4. 15. Matsumoto T, Yamasaki S, Arakawa A, Abe K, Abe H, Kon K, Kobayashi S, Takasaki Y. Exposure to a high total dosage of glucocor ticoids produces non-alcoholic steatohepati tis. Pathol Int 2007;57(6):388–9. 16. Toshiharu M, Shigetaka Y, Atsushi A, Keiko A, Hiroshi A, Kazuyoshi K, Shigeto K, Yoshi nari T. Exposure to a high total dosage of glucocorticoids produces non-alcoholic stea tohepatitis. Pathol Int 2007;57:388–9. 17. Goss JM, Nord KM, Olarte MR, Grossman ME. Perioral dermatitis in a patient with myasthenia gravis following sys temic corticosteroid treatment. Br J Derma tol 2007;156(3):582. 18. Huang P-Y, Chu C-Y, Hsiao C-H. Multiple eruptive dermatofibromas in a patient with dermatomyositis taking prednisolone and
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methotrexate. J Am Acad Dermatol 2007;57 (5 Suppl):S81–4. Gourlay M, Franceschini N, Sheyn Y. Pre vention and treatment strategies for gluco corticoid-induced osteoporotic fractures. Clin Rheumatol 2007;26(2):144–53. De Vries F, Bracke M, Leufkens HGM, Lammers J-W J, Cooper C, Van Staa TP. Fracture risk with intermittent high-dose oral glucocorticoid therapy. Arthritis Rheum 2007;56(1):208–14. Weinstein RS. Is long-term glucocorticoid therapy associated with a high prevalence of asymptomatic vertebral fractures? Nat Clin Pract Endocrinol Metab 2007;3(2):86–7. Bell C, Richardson D, Goldmeier D, Crow ley T, Kocsis A, Hill S. Persistent sexual arousal in a woman with associated cardiac defects and raised atrial natriuretic peptide. Int J STD AIDS 2007;18(2):130–1. Yi NJ, Suh KS, Cho JY, Kwon CH, Lee KW, Joh JW, Lee SK, Kim SI, Lee KU. Recur rence of hepatitis B is associated with cumu lative corticosteroid dose and chemotherapy against hepatocellular carcinoma recurrence after liver transplantation. Liver Transplant 2007;13(3):451–8. Nausheen S, Cunha BA. Q fever communityacquired pneumonia in a patient with Crohn’s disease on immunosuppressive therapy. Heart Lung 2007;36(4):300–3. Silvano G, Lazzari G, Resta F, Buccoliero G, Pezzella G, Pisconti S. Herpes simplex virus-1 fatal encephalitis following chemo-radiother apy, steroids and prophylactic cranial irradia tion in a small cell lung cancer patient. Lung Cancer 2007;57(2):243–6. Maronn ML, Corden T, Drolet BA. Pneu mocystis carinii pneumonia in infant treated with oral steroids for hemangioma. Arch Dermatol 2007;143(9):1224–5. Patel AS, Karagas MR, Perry AE, Spencer SK, Nelson HH. Gene–drug interac tion at the glucocorticoid receptor increases risk of squamous cell skin cancer. J Invest Dermatol 2007;127(8):1868–70. Carmichael SL, Shaw GM, Ma C, Werler MM, Rasmussen SA, Lammer EJ. Maternal corticosteroid use and orofacial clefts. Am J Obs Gynecol 2007;197(6):585.e 1–7. Halverstam CP, Vachharajani A, Mallory SB. Cushing syndrome from percutaneous
Corticotrophins, corticosteroids, and prostaglandins
30.
31.
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33.
34.
35.
36.
37.
absorption of 1% hydrocortisone ointment in Netherton syndrome. Pediatr Dermatol 2007;24(1):42–5. Williams HC. Established corticosteroid creams should be applied only once daily in patients with atopic eczema. BMJ 2007;334 (7606):1272. Talosi G, Katona M, Turi S. Side-effects of long-term prostaglandin E1 treatment in neonates. Pediatr Int 2007;49(3):335–40. Estes K, Nowicki M, Bishop P. Cortical hyperostosis secondary to prostaglandin E1 therapy. J Pediatr 2007;151(4):441. Sharpe ED, Reynolds AC, Skuta GL, Jen kins JN, Stewart WC. The clinical impact and incidence of periocular pigmentation asso ciated with either latanoprost or bimatoprost therapy. Curr Eye Res 2007;32(12):1037–43. Dursun E, Dogru S, Cincik H, Cekin E, Gungor A, Poyrazoglu E. Iloprost-induced sudden hearing loss. J Laryngol Otol 2007;121:609–10. Horgan N,Kirwan RP, O’Brien CJ. Choroi dal detachment associated with latanoprost use in the fellow eye. Ann Pharmacother 2007;41(1):161–2. Arranz-Marquez E, Teus MA. Effect of age on the development of a latanoprost-induced increase in iris pigmentation. Ophthalmology 2007;114(7):1255–8. Kathryn PB, Cracknell KP, Grierson I, Hogg P. Morphometric effects of long-term
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exposure to latanoprost. Ophthalmology 2007;114(5):938–48. 38. Filippini A, Villa G, Corrocher R, De Fran ceschi L. Acute hemolytic anemia with acanthocytosis associated with high-dose misoprostol for medical abortion. Ann Emerg Med 2007;50(3):289–91. 39. Khan S, Alison G. Uterine rupture at 8 weeks’ gestation following 600 µg of oral misoprostol for management of delayed miscarriage. J Obstet Gynaecol 2007;27 (8):869–70. 40. Rosa RFM, Travi GM, Valiatti F, Zen PRG, Pinto LL, Kiss A, Graziadio C, Paskulin GA. Poland syndrome associated with an aber rant subclavian artery and vascular abnorm alities of the retina in a child exposed to misoprostol during pregnancy. Birth Defects Res A Clin Mol Teratol 2007;79(6):507–11. 41. Henriques A, Lourenço AV, Ribeirinho A, Ferreira H, Graça LM. Maternal death related to misoprostol overdose. Obstet Gynecol 2007;109(2 Pt 2):489–90. 42. Aydin S, Ozcura F. Corneal oedema and acute anterior uveitis after two doses of travoprost. Acta Ophthalmol Scand 2007;85 (6):693–4. 43. Feletti F, Vincenzi C, Pazzaglia M, Tosti A. Periocular pigmentation associated with use of travoprost for the treatment of alopecia areata of the eyelashes. J Eur Acad Derma tol Venereol 2007;21(3):421–3.
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40
Sex hormones and related compounds, including hormonal contraceptives
Author’s note: Sex hormones, particularly estrogens and progestogens, can be used separately or in combination, and for var ious purposes. It is often not possible to determine to which compound or combina tion a particular adverse reaction can be attributed; information on particular types of adverse effects may therefore need to be sought under a series of differing headings.
GONADOTROPHINS (SED-15, 1536; SEDA-29, 493; SEDA-30, 468; SEDA-31, 656) Reproductive system It is increasingly necessary to avoid ovarian hyperstimulation in view of growing evidence of its serious consequences. In one patient (1A) hyper stimulation led to a catastrophic antiphospho lipid syndrome, which in turn led to thrombotic complications in the heart and brain and apparently also to cardiac ischemia. Unfortunately, apart from the general principle that when inducing ovulation it is sensible to use moderate doses of gonado trophins, there seem to be few concrete principles that can usefully be observed to
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32040-X 2010 Elsevier B.V. All rights reserved.
reduce the risk of ovarian hyperstimulation syndrome (OHSS). In a study of the rele vant risk factors in Thailand (where the average body weight of women is relatively low), 13 of 117 patients enrolled for in vitro fertilization and treated with gonadotro phins had moderate OHSS and 1 had severe OHSS; all recovered (2c). Patients with OHSS were significantly younger, had sig nificantly lower body mass index and had significantly higher estradiol concentrations before injection of human chorionic gona dotrophin (hCG), and had a higher total number of follicles, a greater number of oocytes retrieved and higher total white cell and neutrophil counts after injection of hCG. Patients with the polycystic ovary syn drome were significantly more likely to develop OHSS. C-reactive protein (CRP) concentrations were higher in patients with OHSS, but the difference was not signifi cant. Multiple logistic regression showed that the combination of serum estradiol peak concentration of 4500 ng/l or more and a total number of oocytes retrieved of at least 15 predicted the occurrence of mod erate to severe OHSS; 12 of 14 patients who met these criteria had OHSS. Tumorigenicity In a case-cohort study of 54 362 women among whom 112 malignant melanomas were identified, there was no significantly increased risk with clomiphene, gonadotrophins, hCG or gonadorelin; how ever, the use of gonadotrophins (RR = 2.29; 95% CI = 1.16, 4.52) or gonadorelin
735
736
(RR = 3.26; 95% CI = 1.50, 7.09) was associated with a significant increased risk among parous women (3c). In 2768 women the risk of invasive ovarian cancer in those who had received gonadotro phins for non-ovulatory disorders was raised (standardized incidence ratio [SIR] = 5.89; 95% CI = 1.91, 14); however, there were only five cases and four reported hCG treat ment only, making the association biologically implausible. Multivariate analysis showed that treatment with gonadotrophins only was associated with an increased risk of invasive cancer (RR = 5.28; 95% CI = 1.70, 16). For borderline tumors, there was a more than threefold overall increase (SIR = 3.61; 95% CI = 1.45, 7.44), mostly attributable to clomiphene (4c). Pregnancy Some of the adverse effects of infertility treatment are in fact a troublesome consequence of its success rather than adverse effects of the drugs used. Pregnancies resulting from infertility treatments have, for example, a higher incidence of gestational hypertension and pre-eclampsia than spontaneous conceptions do. This increased risk is largely explained by a higher frequency of multiple gestations (5A).
(SED-15, 1253; SEDA-29, 494; SEDA-30, 469; SEDA-31, 657)
ESTROGENS
Comparative studies The originally ambi tious long-term international general practice trial of estrogens in the menopause (WIS DOM), which had been intended to continue for 10 years (6C), was suspended after 12 months when the results of the Women’s Health Initiative cast doubt on the acceptabi lity of this treatment. The abbreviated trial, as published in 2007, nevertheless accumulated data on 6498 women-years, and has provided a helpful picture of adverse events in 2196 trea ted women compared with 2198 untreated controls. The number of women who took estrogens alone was almost the same as the
Chapter 40
M.N.G. Dukes
number who took combined estrogen þ pro gestogen treatment. Compared with placebo, the treated group had significantly more major cardiovascular events (7 versus 0) and episodes of venous thromboembolism (22 versus 3). However, there was no statistically significant difference in the numbers of breast or other cancers, cerebrovascular events, fractures or overall deaths. The findings in those who took estrogens alone were very similar to those in women who took combined treat ment. It should be borne in mind that these women were recruited for treatment at a rela tively advanced age (50–69 years at randomi zation) and that the findings might be different from those in women in whom treatment was begun shortly after the menopause. Various writers have advanced other rea sons for regarding the findings of this study with a degree of caution. Ellen Grant has pointed out that of the women randomized to take part, 55% had already used hor mone replacement therapy (HRT) for a median of 5.3 years (7r); in addition, many of the women must previously have used estrogens and progestogens for contracep tion. Women who had developed serious conditions or had died because of past hor mone use would not be willing or available for randomization to take more of HRT. What is more, many of the women must have entered the study in their early fifties and could not truly be regarded as late starters. Nervous system Estrogens can precipitate attacks of migraine (SED-15, 1255) and the problem has been reviewed, both as regards post-menopausal treatment (8R) and the use of estrogens in male-to-female transsexuals (9R). The problem cannot be avoided in susceptible subjects, but it currently appears to be treatable in the same way as menstruation-related migraine, e.g. using sumatriptan 50–100 mg as required. Gastrointestinal At various times it has been suggested that HRT or oral contracep tives increase the risk of symptoms of gastro esophageal reflux by a relaxing effect on the
Sex hormones and related compounds, including hormonal contraceptives
lower esophageal sphincter. A Swedish group has examined this possible link using telephone interviews with individuals listed in the national register of twins (10C). His tories of estrogen use were compared in 4365 twins with reflux problems and 17 321 twins without such symptoms. In everusers of estrogens, the risk of reflux symp toms was increased by 32% (OR = 1.32; 95% CI = 1.18, 1.47). This association per sisted in the nested case–control analyses and increased slightly with higher body mass index. There was a similar pattern with the use of progestogens in the crosssectional design, but the association did not persist in the nested case–control analysis. The use of oral contraceptives was not asso ciated with an increased risk of reflux symptoms. Pancreas In view of scattered impressions that some instances of acute pancreatitis might have been triggered by HRT, a Danish group carried out a population-based case–control study in 1054 patients with a hospital discharge diagnosis of acute pancreatitis and a control group of healthy women, individuals in both groups being checked for a history of past or current HRT (11C). There was only a minimal difference in the treatment histories in the two groups and the authors concluded that the data did not support a substantial association. Immunologic Estrogens can have various adverse immunologic effects (SED-15, 1258). They are also believed to play a role in the etiology of both human and murine systemic lupus erythematosus (SLE), presumably through the agency of their cellular receptor proteins; indeed, SLE and other immune disorders are generally more common in women. Work on mice at the University of Arizona is throwing progressively more light on this problem (12E). From the therapeutic point of view the cardinal question is whether it is safe for patients with SLE to take estrogens. In an authoritative editorial, Bermas concluded, in the light of studies then becoming available, that it was
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defensible to prescribe estrogen-containing oral contraceptives for women with mild or moderate SLE, especially in view of their ability to counter the adverse effects of glucocorticoids on bone metabolism (13r). However, the question of using estrogens in patients with severe active SLE remains unsolved; they are probably better avoided (14R). Tumorigenicity Breast cancer In earlier volumes in this series, attention has been devoted to various factors that might explain the different incidences of breast cancer in different races and ethnic groups; relevant factors include body weight and differences in the frequency of use of hormonal treatment (SEDA-31, 471). A little additional light has been thrown on the matter by a study in Los Angeles County in 1277 women, all of Chinese, Japanese or Filipino origin (15C). In postmenopausal women the risk of breast cancer increased with increasing recent body weight. However, hormone treatment was also a significant and independent susceptibility factor; the risk increased by 26% for every 5 years of current use of estrogen and progestogen therapy. Both of these influences may explain the rapid increase in the rate of breast cancer among Asian-American women. To this must now be added evidence from France (16C). The prospective ‘MISSION’ study was published in 2007, data having been collected prospectively from 4949 patients over 30 months between 2004 and 2006. The patients were divided into two groups: an ‘exposed group’ of women taking HRT regimens that are commonly prescribed in France or who had stopped at least 5 years before, and an ‘unexposed group’ of women who had never taken HRT or who had stopped more than 5 years before. The two groups were of similar size; however, the women in the exposed group were younger and less overweight, and fewer had a firstdegree family history of breast cancer. The incidence of new cases of breast cancer was 0.64% in the exposed group and 0.70% in the unexposed group (relative risk exposed/
738
unexposed = 0.914, 95% CI = 0.45, 1.86; not modified when adjusted for age). The mean age at time of diagnosis was similar in the two groups. The incidence of breast cancer in the exposed group was not significantly affected by the route of estradiol administration (cuta neous 0.69%; oral 0.52%) or the type of HRT (estradiol alone 0.28%; estradiol þ progester one 0.40%; estradiol þ synthetic progestin 0.94%). The authors concluded that there was no evidence for an increased risk of breast cancer in women exposed to HRT. A positive conclusion such as this has to be accepted cautiously, in view of the fact that the risk of developing breast cancer during HRT has been documented by many authors and that the risk almost cer tainly varies with the patient population (see above) and with the treatment regi men. The same variation probably applies as regards the degree of malignancy of any breast cancer that results, which is sufficient reason to regard with some reservations even a well-documented study from Sweden, from which the authors concluded that HRT-induced breast cancers are relatively benign (17C). An epidemiological study in Norway has also shown, not unex pectedly, that the risk of breast cancer in users of HRT is relatively higher in those women who have used oral contraceptives in the past (18C). A thoughtful article has raised the ques tion why different studies of menopausal hormone therapy give different results for the same outcome (19r). Colorectal cancer A novel but still puzzling and incomplete finding relates to the effect of estrogens on the incidence of colorectal cancer. The most recent work on this was inspired by the fact that in several large prospective studies calcium and vitamin D intake were consistently inversely associated with the risk of colorectal cancer, whereas in the Women’s Health Initiative no such effect was found. However, in the main reports from the latter, the possible interaction with estrogens was not examined. In 2008, therefore, Ding et al. returned to the database of the Women’s Health Initiative to examine precisely this
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M.N.G. Dukes
point (20R). Their re-analysis showed that concurrent oestrogen therapy was a strong effect modifier of calcium and vitamin D supplementation on the risk of colorectal cancer. While calcium plus vitamin D supplements among women concurrently assigned to estrogens suggested an increase in risk (HR = 1.50, 95% CI = 0.96, 2.33), among women concurrently assigned to placebo arms in estrogen trials, calcium plus vitamin D appeared to confer benefit. One can only agree with the authors that this confusing picture demands further study. Hemangiomas Very occasional instances of hemangiomas have been reported in oral contraceptive users ever since these formulations were introduced 50 years ago, and some instances have concerned estrogens alone. An unusual case reported was that of a 42-year-old woman who had taken estrogens for many years; she had a giant splenic hemangioma and multiple hepatic hemangiomas (21A). Pancreatic cancer In a Japanese woman a mucinous cystadenocarcinoma of the pancreas developed during HRT (22A). Although this is the first report of its type, this is a disorder that is most prevalent in women who express estrogen receptors and is in some way associated with pregnancy; furthermore, the ability of HRT to induce other neoplasms is recognized. Susceptibility factors Adolescence The use of estrogens in girls to prevent excessive growth in height has often been questioned on grounds of safety, with concerns about thromboembolism dominating the discus sion. Looking back on their experience with this treatment over 15 years, Rask et al. concluded that their routine is effec tive and safe, at least as regards the risk of adverse effects on coagulation (23A). The 63 girls treated in their series received a median initial dose of ethinylestradiol of 300 micrograms/day. In some subjects, there were genetic susceptibility factors for thrombosis. After a year of treatment, concentrations of antithrombin and von
Sex hormones and related compounds, including hormonal contraceptives
Willebrand factor were significantly reduced, but there was no change in the concentra tions of plasminogen inhibitor type 1. There were no cases of venous thromboembolism or major adverse effects.
Diethylstilbestrol
(SED-15, 1119;
SEDA-31, 657) Cardiovascular The effect of stilbestrol in prostate cancer has been studied in 29 patients, who were given diethylstilbestrol 1 mg/day and 5 mg on the day before docetaxel, then docetaxel 36 mg/m2 intravenously weekly for 3 weeks of a 4-week cycle (24c). The median number of cycles was 6. Prophylactic anticoagulation was used in all cases. The combination of diethylstilbestrol and docetaxel produced a significant fall in prostate-specific antigen (PSA) and a measurable disease response rate. However, 15 patients had grade 3/4 adverse effects, 2 died of causes unrelated to therapy and another died from a glucocorticoid-induced ulcer; 6 patients developed thrombosis, and of those tested 75% had factor V mutations. The adverse effects pattern was similar to that seen without stilbestrol, except for venous thrombosis. Second-generation effects Evidence of the effects of stilbestrol on the fetus still accumulates, more than a generation after its use in pregnancy was abandoned (SEDA-31, 657). There is, for example, a higher incidence of pre-eclampsia when women who have themselves been exposed in utero to stilbestrol become pregnant (25c). The theory that exposure to estrogens could induce various abnormalities in the male reproductive system, including hypo spadias, cryptorchidism, and testicular can cer (thought to represent together a ‘testicular dysgenesis syndrome’), often linked with impaired spermatogenesis, has been studied in a meta-analysis of 12 stu dies that had not appeared in earlier sys tematic reviews (26M). Stilbestrol exposure doubled the risk of the syndrome, although
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the reviewers stressed that other factors could in many cases have been involved. A further case of primary vaginal clear cell carcinoma has been described in a 43-year-old woman who had been exposed to stilbestrol in utero (27A). The tumor metastasized to the right frontal lobe of the brain. The authors stressed the continu ing need to monitor patients with a history of vaginal carcinoma after stilbestrol expo sure. Epidemiological evidence now becom ing available also seems to show that the stilbestrol-associated increase in clear cell adenocarcinoma remains high throughout the reproductive years (28R). Third-generation effects There has long been a fear, backed by some evidence, that the effects of stilbestrol in pregnancy might extend not merely to the offspring but also to the third generation. In 2007 a group of authors in the Netherlands examined the transgenerational drug history of children with esophageal atresia and tracheo-esophageal fistulas (29C). Of 117 infants with these conditions, 4 (3.4%) had a mother who had been exposed to diethylstilbestrol in utero; in a much larger group of healthy children, only 0.37% had such a maternal history. It is very tempting to incriminate diethylstilbestrol on this score, but some caution is needed; in families with entirely healthy children there may be poor recall or even an understandable reluctance to admit to a history of maternal in utero exposure to stilbestrol.
Equine estrogens Drug formulations A Zurich group has noted that in the WISDOM study some of the women were treated with equine estrogens (30r). They have argued that a mixture of hormones derived from horse urine is not suitable and should not be regarded as replacement of natural human estrogens, such as 17-beta-estradiol, because equine hormones also contain androgens and several sex steroids of yet
740
unknown vascular activity. Regulation of estrogen targets, estrogen receptors alpha and beta and the novel membrane estrogen receptor G protein-coupled receptor 30 (GPR30), which is highly expressed in structurally intact human arteries, is sensitive to naturally occurring estrogens. The Zurich group has raised this point before in greater detail (31R), and it merits comment. Equine estrogens are indeed claimed to be derived from the urine of mares, but it was pointed out many years ago that the sales volume of products of this type much exceeded the supply that could possibly be derived from the existing mare population, and it appears that the equine material has long been supplemented during manufacturing by the addition of certain synthetic estrogens (SED-15, 1253). The ‘equine’ and ‘natural’ merits sometimes claimed for these products may therefore be poetic rather than scientific.
Hormone replacement therapy (HRT) (SED-15, 1684, 1686, 1692; SEDA-29, 496; SEDA-30, 469; SEDA-31, 659)
Hormone replacement therapy and ovarian cancer The possibility that HRT might increase the risk of subsequent ovarian malignancies was one of the reasons for the decline in this form of treatment after data from the Women’s Health Initiative were published from 1996 onwards. However, concerns regarding this particular risk subsequently faded into the background, when society became much more concerned about evi dence that HRT could increase the risk of malignancies in the breast and the endometrium. Since then, the evidence has progressively shifted towards the point where a causal link with ovarian cancer must be regarded as proven. Early in 2007, the Million Women
Chapter 40
M.N.G. Dukes
Study, a UK study of postmenopausal women, showed that those who took HRT were on average 20% more likely to develop and die from ovarian cancer than women who had never taken such therapy (32C). The authors estimated that in the 16 years to the time of their publication, HRT had resulted in some 1300 additional ovarian cancers and 1000 additional deaths from this malignancy in the UK alone. Similarly, in the United States USA, a prospective observational study in 82 905 postmenopausal women, including 389 women with ovarian cancer, in the Nurses’ Health Study from 1976 to 2002, showed that both current users (RR = 1.41, 95% CI = 1.07, 1.86) and past users for at least 5 years (RR = 1.52, 95% CI = 1.01, 2.27) had a significantly higher risk of ovarian cancer than never-users (33C). Examined by hor mone type in continuous years, use of unop posed estrogen was associated with a significant increase in the risk of epithelial ovarian cancer. In a study from Denmark of some 909 000 women over 10 years, there was a markedly increased rate of ovarian cancer in women who had used HRT (34C). The increase appeared to be independent of the nature of the drug used, and it was evident even in women who had been treated for as little as 6 months. The study included all Danish women aged 50–79 between 1995 and 2005, and data were obtained from the National Register of Medicinal Product Statistics and from cancer and pathology registers. During an average of 8 years of follow-up, 3068 ovarian cancers were detected. Of these, 2681 were epithelial tumors. Compared with never-users, current users of HRT had an overall 38% increased risk of ovarian cancer. When restricting the analyses to epithelial ovarian cancer, the relative risk among current HRT users was 44% higher, and previous users had a 15% increased risk compared with women who had never used HRT. The risks of ovarian cancer and epithelial ovarian cancer did not increase significantly with increasing duration of HRT. However, the risk of ovar ian cancer fell with longer time since last HRT
Sex hormones and related compounds, including hormonal contraceptives
use. The absolute risk is one extra ovarian cancer for every 8300 women taking hormone therapy each year. There have been other, less widely quoted, papers during the last decade that have pointed in the same direction (35C, 36C), and despite sporadic attempts to discredit these findings they must now be regarded as established and mutually supportive. A meta-analysis of the published evidence, con ducted in China in 2008, has provided further confirmation (37M). HRT thus significantly increases the risk of at least three types of female neoplasms and in the great majority of women does not offer any benefit that can possibly outweigh these dangers. HRT has declined very greatly since the Women’s Health Initiative was published and with it there has been a marked reduc tion in the incidence of endometrial and mammary malignancies. These new find ings with respect to ovarian cancer only add to one’s conviction that the massive commercial, medical, and propagandistic pressures that launched HRT more than a generation ago as a supposed elixir of health or fountain of everlasting youth for every postmenopausal woman (38R) was a seriously flawed step in the wrong direction.
HORMONAL CONTRACEPTIVES
(SED-15, 1642; SEDA-29, 499; SEDA-30, 473; SEDA-31, 663) Observational studies In the European Active Surveillance Study (EURAS), a multinational, prospective, non interventional cohort study of new users of drospirenone, levonorgestrel and other progestin-containing oral contraceptives, 58 674 women were followed for 142 475 women-years (39C). Loss to follow-up was 2.4%. Serious adverse and fatal
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events were rare, and rate ratios were close to unity. Cox regression analysis of cardiovascular outcomes yielded hazard ratios for drospirenone-containing versus levonorgestrel-containing and other oral contraceptives of 1.0 and 0.8 (upper 95% confidence limits = 1.8 and 1.3) for venous thromboembolism and 0.3 and 0.3 (1.2 and 1.5) for arterial thromboembolism. Similar results have been observed in a study of 22 429 women who took ethinyl estradiol þ drospirenone initiators and 44 858 other oral contraceptive users, who were followed for an average of 7.6 months (40C). Although those who used the latter had a slightly higher risk of thromboembo lism it was not significant (RR = 0.9; 95% CI = 0.5, 1.6), and more than 9000 women would have to be studied to observe a dif ference of one case.
Cardiovascular In a prospective Swedish cohort study over 11 years there was no evidence of increased risk of myocardial infarction in those taking oral contraceptives, either in the population as a whole or in particular subgroups (41C). Retinal central artery occlusion occurred in a young woman after she had taken a drospirenone-containing oral contraceptive for 10 days (42A).
Electrolyte balance Yasmin-28 contains ethinylestradiol 30 micrograms þ drospire none 3 mg. The latter is a progestin with anti-mineralocorticoid activity and has a potassium-sparing diuretic effect similar to that of spironolactone. However, in 32 healthy postmenopausal women who took indometacin alone for 5 days, estradiol þ drospirenone alone for 12 days and the combination for 5 days, there was no increased risk of hyperkalemia (43c).
Skin During the last decade there has been an increase in the incidence of lichen sclerosus among young women, and the hypothesis that this might be due to the
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use of oral contraceptives has been examined (44c). Of 40 premenopausal women with lichen sclerosus, all had been using oral contraceptives, compared with 66% of healthy women in a similar control group. The women with lichen sclerosus also appeared to have been more likely to have been exposed to oral contraceptives that have antiandrogenic activity (chlormadinone acetate, cyproterone acetate, dienogest, and drospirenone). These limited data suggest, but by no means prove, a link between lichen sclerosus and this form of contraception.
M.N.G. Dukes
medications for about 8 000 000 members of a large nationally dispersed health plan, showed that among women aged 10–59 years old who took Yasmin-28 or other oral contraceptives, although potassium monitoring was generally more frequent among those taking concomitant hyper kalemic drugs only 40% of 466 Yasmin users had serum potassium measured (47C).
Emergency contraception (SEDA-29, 501)
Reproductive system Vulvar vestibulitis syndrome, a distressing condition of unknown etiology, has generally not been regarded as being related to drug treatment, but a study in Israel has suggested that this possibility merits attention, at least where hormonal contraception is concerned (45c). Whereas in Israel the use of lowdose estrogen oral contraceptives is approximately equal to that of high-dose estrogen products, the bulk of the women with vulvar vestibulitis syndrome seen at the authors’ clinic, insofar as they were using hormonal contraception, were making use of the low-dose products. Pregnancy A single report has appeared of false pregnancy (pseudocyesis) in a teenage girl who over a long period had made use of oral contraceptives (46A). Monitoring drug therapy Potassium mon itoring is recommended during the first month of use in women concurrently taking Yasmin-28 (ethinylestradiol þ drospire none) plus medications that can increase serum potassium, because of the anti-miner alocorticoid action of drosperinone. However, a study of compliance with this recommendation using data from the Ingenix Research Datamart, which includes insurance claims for reimbursement for medical services and prescription
Cardiovascular Apart from nausea and vomiting, which are common after the use of ‘morning-after pill’, emergency contraception is reasonably well tolerated. However, it remains a technique that should probably be used only in exceptional circumstances, and one might expect its repeated or routine use to have certain ill effects, especially in patients predisposed to thrombotic or other complications. Such a case has been described, in which repeated use of this method was followed by cerebral venous thrombosis (48A). • A 45-year-old woman developed progressive headache, blurred vision and vomiting over 2 weeks and had papilledema. Eight months before, after unprotected coitus, she had taken the Yuzpe regimen, involving two doses of ethinylestradiol 0.1 mg combined with levonorgestrel 0.5 mg, the doses being taken 12 hours apart. She took the same course at least three times more during the months that followed. Magnetic resonance imaging (MRI) showed thrombosis of the superior sagittal, right transverse and right sigmoid sinuses. She was successfully treated with heparin followed by oral anticoagulation. She had low concentrations of antithrombin III and persistently high concentrations of factor VIII.
The high concentrations of factor VIII could have increased the risk of thrombosis in this case. A single report of retinal vein thrombosis after emergency contracep tion is to be found in the older literature (49A).
Sex hormones and related compounds, including hormonal contraceptives
ANTI-ESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) (SEDA-29, 502; SEDA-30, 474; SEDA-31, 664) Management of adverse drug reactions Aromatase inhibitors can cause bone loss, and the bisphosphonate zoledronic acid appears to be effective in countering this effect and hence reducing the risk of fractures. Of 602 patients who took letrozole for early-stage breast cancer, half were given zoledronic acid 4 mg intravenously every 6 months from the start of therapy, while in the remainder the use of zoledronic acid was delayed until the T score for the lumbar spine or the total hip assessment fell to less than –2.0, or until a non-traumatic fracture occurred (50C). Follow-up at 1 year suggested that early zoledronic acid prevented bone loss, whereas delayed treatment did not. An Austrian study has shown similarly favorable results with the same zoledronic acid regimen in patients taking anastrozole þ goserelin regimen (51c), and these find ings have been further confirmed in a 12-month analysis (52c).
Anastrozole Liver Various liver complications have been reported with selective estrogen receptor modulators, including tamoxifen, and it is not surprising to encounter a very short report of severe acute hepatitis in a patient taking anastrozole (53A). At present, the data are too limited to determine whether these complications occur more readily with one member of the series than another.
Clomifene (SED-15, 812; SEDA-30, 474; SEDA-31, 665) Cardiovascular A 33-year-old woman who had used clomiphene citrate had an anterolateral myocardial infarction when
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pregnant at 5 weeks; a subsequent exercise stress test and coronary angiography were normal (54A). Central retinal vein occlusion occurred in a 36-year-old woman who took eight courses of clomiphene citrate (55A). Sensory systems Bilateral anterior uveitis occurred during the use of clomiphene citrate in a 30-year-old woman with polycystic ovary syndrome; re-challenge with clomiphene 3 months later resulted in recurrence (56A). Psychiatric Acute mania has been associated with clomiphene (57A). • A 35-year-old woman with a history of bipolar disorder, successfully treated with lithium and lamotrigine, took clomiphene for 20 days before artificial insemination. After 6 days she felt ‘a little revved up’ and 9 days after completing the course of clomiphene suddenly began to have mood swings, increased energy, rapid thinking, crying spells, sleeplessness, and episodes of persecutory delusions. She was dishevelled and confused. She was evasive and unable to answer many questions coherently. Her speech ranged from soft and mumbled to pressured, loud outbursts filled with foul language. She was not oriented in time or place and was easily distracted. Her thoughts were extremely rapid, illogical and full of loose associations. She was given lithium, without much benefit, and then five courses of ECT, after which she recovered.
Clomiphene can occasionally cause psy choses, and another case has been reported (58Ar). • A 35-year-old woman with a history of depression took clomiphene 25 mg/day and after 1 day noticed a ‘vanishing of background noise’. She had the impression that colleagues talked only to her, and that no other conversations took place. After 3 days she started to have paranoid ideas and after 1 week had the idea that the whole working environment was nothing more than a test of her capabilities and that she was being evaluated by a hidden team. Her husband became the center of a complex conspiracy. She was given olanzapine 10 mg/day, and neurological examination, electroencephalography, an MRI scan of the brain and laboratory tests were normal. She gradually improved after withdrawal of clomiphene.
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The authors suggested that clomipheneinduced psychotic states might be caused by a similar mechanism to estrogen with drawal psychosis. Liver After the use of clomiphene citrate in two consecutive cycles, a 30-year-old woman each time developed intense right upper quadrant pain and on the second occasion had raised serum transaminases, which resolved over 2 months and did not recur; no other causes were discovered (59A). Pancreas Acute pancreatitis without hypertriglyceridemia on two occasions has been attributed to clomiphene (60A). Reproductive system A ruptured ovarian cyst in an ovary that had been hyperstimulated by clomiphene caused hemoperitoneum and was initially misinterpreted as OHSS in a 22-year-old woman (61A). Massive ovarian edema has been reported during pregnancy after induction of ovulation using clomiphene citrate (62A). Three men with oligospermia developed azoospermia after taking clomiphene citrate (63c). It was not clear that this was not merely due to the natural history of the condition; however, 3 months after with drawal of clomiphene, the sperm counts recovered to their previous oligospermic levels. Tumorigenicity In a case–control study of 42 women with borderline ovarian tumors and 257 controls with benign ovarian pathology, there were no differences between the groups (14% versus 27% respectively) in terms of infertility history, nor in the type of drug used, whether clomiphene citrate (9.5% versus 6.2%) or gonadotrophins (7.1% versus 10%); analysis in terms of the number of cycles also failed to reveal any differences (64C). However, in 2768 women the risk of borderline ovarian tumors was increased
M.N.G. Dukes
more than threefold (SIR = 3.61; 95% CI = 1.45, 7.44) in women taking clomi phene or gonadotrophins; women exposed to clomiphene because of ovulatory disor ders had the highest risk (SIR = 7.47; 95% CI = 1.54, 22) (4c). In a case-cohort study of 54 362 women among whom 29 thyroid cancers were iden tified, the use of clomiphene (RR = 2.28; 95% CI = 1.08, 4.82) or progesterone (RR = 10; 95% CI = 1.93, 53) was asso ciated with an increased risk of thyroid can cer, although the latter estimate was based on very few cases (65c). When stratifying for parity status, the risk was primarily asso ciated with clomiphene (RR = 3.09; 95% CI = 1.21, 7.88) in parous women. There was no significantly increased risk with gonadotrophins, hCG or gonadorelin. In the same cohort 112 malignant mela nomas were identified, but there was no association with the use of clomiphene (3c).
Exemestane
(SEDA-31, 665)
Musculoskeletal Fractures New data from the multinational Intergroup Exemestane Study (IES) have shown that 2–3 years after the end of treatment, 2362 postmenopausal women with estrogensensitive early breast cancer who switched to exemestane after taking tamoxifen for 2–3 years were 15–17% more likely to be alive, compared with 2380 patients who continued to take tamoxifen for the full 5 years of therapy (66C). There was a reduced risk of recurrence of breast cancer or of its appearance in the other breast. The withdrawal rate due to adverse events was 6.3% in patients with early breast cancer receiving adjuvant treatment with exemestane. Most of the adverse effects were mild, reflecting estrogen deprivation (hot flushes 22%, arthralgia 17%, fatigue 17%). Fractures occurred in 162 exemestane-treated patients (7%) and 115 tamoxifen-treated patients (4.9%). The investigators suggested that during adjuvant treatment with exemestane women with osteoporosis or at risk of osteoporosis
Sex hormones and related compounds, including hormonal contraceptives
should have their bone mineral density formally assessed by bone densitometry at the start of treatment. Rheumatoid arthritis Several reports during the last few years, when taken together, have raised the possibility that aromatase inhibitors might cause rheumatoid arthritis. This suspicion was voiced from France in 2007 (67Ar) in the light of earlier papers reporting that these agents could induce benign arthralgia (68c, 69C) and a single observation. • A 64-year-old woman, who for some 3 years had taken tamoxifen 20 mg/day for advanced breast cancer without adverse effects, was switched to exemestane 25 mg/day. Within days she developed arthralgia affecting the hips, shoulders, knees, wrists, and hands associated with morning stiffness. Treatment with non-steroidal anti-inflammatory drugs was not helpful. About 4 weeks later she developed symmetrical active arthritis, with swelling of the joints of the wrist and hands. Erythrocyte sedimentation rate and CRP concentration were raised (30 mm/hour and 15 mg/l). After 4 months, exemestane was withdrawn and tamoxifen restarted. However, this switch did not produce regression of her joint symptoms. Full examination confirmed the picture of rheumatoid arthritis.
This case suggests a role of aromatase inhi bitors in the induction (or aggravation) of rheumatoid arthritis, a condition that is alle viated during pregnancy and aggravated post-partum, as well as being more common in the menopause. There was some evidence of erosions before the use of exemestane, and so she may already have had rheuma toid arthritis with low disease activity, which became worse when aromatase inhibitors were used. However, arthralgias in women receiving aromatase inhibitors should be better evaluated to estimate the incidence of rheumatoid arthritis in these patients.
Raloxifene
(SEDA-31, 666)
Nervous system Reports lodged with national adverse reaction monitoring systems can be valuable in characterizing the
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nature of adverse effects, although they do not provide absolute data on their incidence or prove cause-and-effect relations. In view of published reports of stroke among subjects in two large trials (70A, 71A), the US Food and Drug Administration (FDA) in 2007 examined the reports that it had received of stroke associated with raloxifene (72c). From 1997 to September 2006 the FDA had received 6200 reports of adverse effects attributed to raloxifene, including 155 reports of stroke, 9 of which were fatal. The type of stroke was specified in about half the reports, the most common being ischemic. The stroke tended to occur within 6 months of starting the drug; the mean reporting age at the time of stroke was 70 years. In 67 of the reported cases there was at least one other susceptibility factor present in addition to age (e.g. hypertension, atrial fibrillation); 8 reports explicitly stated that no other susceptibility factors were present. In the light of these findings the FDA recommended consideration of the benefit to-harm balance when using raloxifene in postmenopausal women in whom any predisposition for stroke may be present. Raloxifene is, it is stressed, not indicated for cardioprotection and should not be used for this purpose.
Tamoxifen
(SED-15, 3296; SEDA-29, 503; SEDA-30, 475; SEDA-31, 667)
Placebo-controlled studies Even today, after many years of experience in the use of tamoxifen to prevent breast cancer in susceptible subjects, it remains very difficult to weigh the benefits against the harms, since on both scores the reported data vary so greatly (SEDA-29, 503). The Italian Randomized Tamoxifen Prevention Trial, originally published in 2000, found on the one hand no reduction at all in the risk of breast cancer with tamoxifen, whereas, on the other hand, in the United States USA, the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial, which had enrolled patients from 1992 to 1997, concluded that tamoxifen
746
reduced the risk of estrogen receptorpositive breast cancer. A follow-up report on the Italian study was rather more encouraging than its predecessor (73C). After 11 years of follow-up, 136 women (74 taking placebo, 62 taking tamoxifen) developed breast cancer (RR = 0.84, 95% CI = 0.60, 1.17; annual rates 2.48 and 2.07 per 1000 women-years respectively). The rates of breast cancer in the two groups were similar among women who had had bilateral oophorectomy and among women at low risk of hormone receptor-positive disease but were much lower in the tamoxifen group among women at high risk (placebo, 6.26 per 1000 women-years; tamoxifen, 1.50 per 1000 women-years). Against these results one must set adverse effects. During the treatment period, women taking tamoxifen reported more hot flushes (RR = 1.78, 95% CI = 1.57, 2.00), vaginal discharge (RR = 3.44, 95% CI = 2.90, 4.09), and urinary disturbances (RR = 1.52, 95% CI = 1.23, 1.89); hypertriglyceridemia, thromboembolic events and cardiac dysrhy thmias were also significantly more frequent with tamoxifen than placebo, but headaches were less common. Important support for these positive con clusions comes from what is probably the longest follow-up of this type of prophylac tic treatment to date, namely the blinded 20-year follow-up of the Royal Marsden trial in Britain (74C). Of the 2471 eligible participants (1238 tamoxifen and 1233 pla cebo), 186 developed invasive breast cancer (82 tamoxifen, 104 placebo; HR = 0.78, 95% CI = 0.58, 1.04). Of these 186 cancers, 139 were estrogen receptor-positive (53 tamoxifen, 86 placebo; HR = 0.61, 95% CI = 0.43, 0.86). The risk of estrogen receptor-positive breast cancer was not sta tistically significantly lower in the tamoxifen arm than in the placebo arm during the 8-year treatment period, but was statistically significantly lower in the post-treatment period (23 tamoxifen, 47 placebo; HR = 0.48, 95% CI = 0.29, 0.79). The authors concluded that there was a statisti cally significant reduction in the incidence of estrogen receptor-positive breast cancer with tamoxifen arm that occurred
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predominantly during the post-treatment follow-up. Cardiovascular pointed to the possible role of tamoxifen can cause thrombosis and embolism (SED-15, 3298). In an unusual case reported since then, a 64-year-old man, who was taking tamoxifen for gynecomastia and also had atrial fibrillation, developed an acute anterior wall myocardial infarction due to embolism (75A). Sensory systems Tamoxifen is deposited in the cornea, but this does not appear to result in structural or functional changes (SEDA-31, 667). However, any resultant belief that the effects on the eye are not of practical importance may need to be modified in view of a study in which the effects of tamoxifen and anastrozole on optic cup size were studied using confocal scanning laser ophthalmoscopy (76C). After treatment for up to 2 years with tamoxifen or anastrozole for breast cancer in generally accepted doses, there were significantly smaller cup volumes in the tamoxifen users than the cup volumes in the anastrozole users, which were indistinguishable from normal. The effect was particularly marked in women over 50. The authors suggested that the optic nerve head should be assessed biomorphometrically in tamoxifen users who report any visual change that cannot be attributed to causes other than tamoxifen. They also suggested that the results of modern intraocular imaging techniques suggest that tamoxifen causes astrocyte swelling. Tamoxifen can also affect the eye in various other ways (77c).When the eyes of a group of 30 women who had taken tamox ifen for 2 years were compared with those of 17 other breast cancer patients who had not taken it and the eyes of 21 healthy women, 2 of those who had used tamoxifen had diffuse color vision loss despite normal fundi, 2 others had refractile retinal crystals and 1 had a keratopathy (78A). However, some slight defects were also found in the cohort. This suggests that multiparameter measurements of ocular structure and
Sex hormones and related compounds, including hormonal contraceptives
function, which are in any case advisable in middle age, should be carried out before and during treatment with tamoxifen. Hematologic A rare case of thrombo cytopenia has been reported in a patient taking tamoxifen for breast cancer (79A). Skin Purpuric vasculitis has attributed to tamoxifen (80A).
been
Susceptibility factors Genetic The evi dence that tamoxifen can increase the risk of endometrial cancer (and possibly ovarian cancer as well) is still disputed in some quarters, but evidence of a causal association continues to mount (SEDA-31, 668). In a large prospective study 857 women aged 45–70 carrying a breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) gene were followed prospectively looking for endometrial or ovarian cancers (81C). After an average follow-up period of 3.3 years, there were 6 cases of endometrial cancer, compared with 1.13 cancers expected on the basis of population statistics. Four of these six patients had used tamoxifen in the past. The risk among women who had never taken tamoxifen treatment was not significantly increased, but among the 226 participants who had used tamoxifen (220 for treatment and 6 for primary prevention of breast cancer) the relative risk for endometrial cancer was 12. It now also seems clear that various other genotypes may be important in determining the degree of risk. In a case–control study there was good evidence that a subgroup of breast cancer patients who carry the CYP3A4*1B allele may be at particular risk of endometrial cancer when they take tamoxifen (82C). Management of adverse effects The authors of the BRCA study above suggested that the benefits and harms of prophylactic hysterectomy should be discussed with women with a BRCA mutation who are considering tamoxifen therapy. However, there are alternatives to hysterectomy.
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The possibility that adding an aromatase inhibitor (primarily in order to complement the treatment of the breast condition) might actually counter the unwanted endometrial proliferation has been considered for some years (SEDA 26, 445). In 36 postmenopausal women who had used tamoxifen for an average of 36 months, among those who had simultaneously taken aromatase inhibitors (not specified in the paper) during the later months of tamoxifen treatment, endometrial thickness was generally reduced significantly, although in a minority of women there was no effect (83c). Giving aromatase inhibitors for a longer period seemed to enhance the favorable effect. This treatment of an adverse effect therefore seems promising, but there is room for further study using alternative doses and periods of administration.
PROGESTOGENS (SED-15, 2930; SEDA-29, 505; SEDA-30, 477; SEDA-31, 669) Psychological Little attention has been devoted to whatever mental effects the progestogens or their metabolites may have; they have at most been regarded as uncertain adverse effects when progestogens are used to affect physical functions. However, the authors of a review and a small study have pointed out that progesterone’s neuroactive metabolite allopregnanolone modulates amygdala activity and thereby influences anxiety; it also appears to have an effect on cognition and memory (84Rc). In their study, a single oral dose of progesterone was given to healthy young women in a double-blind, crossover, placebo-controlled design, and the participants were asked to memorize and recognize faces while undergoing functional MRI. Progesterone reduced recognition accuracy without affecting reaction times. The imaging results showed that the amygdala, hippocampus, and fusiform
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gyrus supported memory formation. Importantly, progesterone reduced responses to faces in the amygdala and fusiform gyrus during memory encoding, whereas it increased hippocampal responses. The progesterone-induced reduction in neural activity in the amygdala and fusiform gyrus predicted the reduction in memory performance across subjects. However, progesterone did not modulate the differential activation between subsequently remembered and subsequently forgotten faces in these areas. There was a similar pattern of results in the fusiform gyrus and prefrontal cortex during memory retrieval. Whether further work in this area might result in certain progestogens acquiring a role in the treatment of mental conditions (or conversely form the basis for warnings or contraindications) is not yet clear. Teratogenicity Nearly 50 years ago, much optimism was engendered by the development of a series of synthetic progestogens that were thought to offer a promising approach to the treatment of threatened and habitual abortion. Several of these have faded from view, but there is a persistent trail of evidence that at least some instances of abortion are attributable to an insufficient supply of progesterone and can be prevented by the administration of either progesterone itself or substances closely related to it. However, a major consideration is that the treatment should not bring with it any appreciable risk to the fetus: masculinization of female fetuses is for example a real possibility if progestogens with androgenic properties are used. The authors of a massive review of this issue, which can only be briefly alluded to here, looked in particular for evidence from clinical and animal studies, despite the dubious relevance of the latter (85R). Two of the largest clinical trials conducted to date provided a signal for some embryo–fetal toxicity attributable to 17a-hydroxyprogesterone caproate, the most widely used agent in this area, and work in monkeys and rodent may be
M.N.G. Dukes
interpreted as supporting this finding. However, studies of children born at the end of pregnancies during which 17a-progesterone caproate was adminis tered continue to show that they have suffered no effects. A US study in 194 such children, and including comparison with a control group, showed that 17a-hydroxyprogesterone caproate seems to be safe for the fetus when given in the second and third trimesters (86c). Drug administration route Intrauterine administration of progestogens is generally well tolerated (SEDA-31, 670). The same appears to apply when progesterone itself is used intravaginally for luteal support (e.g. after in vitro fertilization), irrespective of the form in which it is administered. However, a Croatian study in 285 women gave the impression that Crinone 8% vagi nal gel 90 mg/day is somewhat better toler ated than Utrogestan vaginal capsules 200 mg tds (87c). More detailed documenta tion would be welcome.
Lynestrenol Liver There has been some evidence in the past of a link between hepatic adeno matosis and female sex hormones (SED-15, 1660), although the condition does occur in men as well. In a woman who had been taking the androgenic pro gestogen lynestrenol for 10 years, andro gen receptors were detected in the adenomatous material; the condition regressed markedly within 6 months after lynestrenol was withdrawn and at that time the androgen receptors were no longer detectable (88A). The authors sug gested that in some cases of hepatic ade nomatosis the androgenic progestogens must be held responsible.
Drospirenone
(SEDA-31, 670)
See ‘Hormonal contraceptives’.
Sex hormones and related compounds, including hormonal contraceptives
Medroxyprogesterone
(SED-15,
2225) Musculoskeletal Medroxyprogesterone acetate can cause reversibly reduced bone density, but the effect has not been found to be constant and it may vary with age. Bone density, bone turnover, and hormones have been measured in individually matched case–control pairs of women, of whom 50 pairs were aged 18–25 years and 50 pairs 35–45 (89c). Use of depot medroxyprogesterone was associated with a 5% bone density deficit at the lumbar spine and hip in women who started using it before the age of 20 but not after the age of 34. Bone turnover was increased in users in both age groups: medroxyprogesterone users had lower estradiol and higher inuslin-like growth factor I (IGF-I) than controls, and younger users had higher dehydroepiandrosterone sulphate than controls. In a multiple regression model, estradiol and IGF-I were associated with bone turnover, but addition of medroxyprogesterone to the model rendered the association with estradiol non significant. It can be concluded that use of depot medroxyprogesterone acetate is associated with a bone density deficit at the spine and hip when used before peak bone mass, and that it acts on the skeleton mainly through estrogen deficiency. A complementary study of this in a Scottish city confirmed that women who had used medroxyprogesterone for at least 5 years (mean 12 years) had a lower bone density than controls, but no new evidence as to the reversibility of the effect was provided (90c). Drug–drug interactions Antiretroviral drugs In a pharmacokinetic study in human immunodeficiency virus (HIV)-infected women, interactions were examined between depot medroxyprogesterone acetate (used as a contraceptive) and nucleoside analogues alone (n = 16) or combined with nelfinavir (n = 21), efavirenz (n = 17) or nevirapine (n = 16) (91c). The kinetics of all the substances, assessed regularly over 12 weeks, were virtually unaffected; nor was there any evidence of an
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interaction in the reverse direction, contraceptive efficacy being maintained.
Megestrol acetate
(SED-15, 1679,
2932; SEDA-31, 670) Endocrine Three men who took meges trol acetate 400–800 mg/day for metastatic cancers developed adrenal insufficiency and hypogonadism (92A). Adrenal insuffi ciency also occurred in a 74-year-old woman with infiltrating ductal breast carci noma refractory to prolonged hormonal treatment with megestrol acetate (93A).
Death In a case–control cohort study of 17 328 nursing home residents who had lost either 5% of total body weight within 3 months or 10% within 6 months, megestrol acetate was associated with an increase in all-cause mortality and no increase in body weight (94c). Of 709 patients who took megestrol acetate, 281 (40%) were alive and in the nursing home at last follow-up, 149 (21%) were alive and discharged to another facility or to home, and 279 (39%) died in the nursing home. Among the controls, 651 (46%) were alive and in the nursing home, 308 (22%) were discharged to another facility or to home, and 459 (32%) died in the nursing home.
PROGESTERONE ANTAGONISTS (SEDA-29, 506; SEDA-30, 477; SEDA-31, 671)
Mifepristone
(SED-15, 2344; SEDA-29, 506; SEDA-30, 477; SEDA-31, 671) Hematologic Thrombotic thrombocyto penic purpura occurred in a case in which mifepristone was used to terminate early pregnancy (95A).
750
Teratogenicity Little information seems to be available on the adverse effects on the fetus if elective abortion is unsuccessful. A boy with Möbius syndrome was delivered at 33 weeks, after an unsuccessful attempt to abort a pregnancy using mifepristone and misoprostol (96A). Möbius syndrome is characterized by unilateral or bilateral palsy of the abducens and facial cranial nerves; other cranial nerves (e.g. the hypoglossal) can also be affected and there may be craniofacial or orofacial anomalies and limb malformations. The usual etiology remains largely unknown and probably involves multiple factors; the most likely hypothesis is disruption of the developing vascular system, with transient ischemia (particularly of the vertebral arteries) and fetal hypoxia. A teratogenic cause of Möbius syndrome has previously been suggested. The critical period for the development of Möbius syndrome after teratogen exposure appears to be 5–8 weeks of gestation.
SEX HORMONE AGONISTS Tibolone (SEDA-29, 514; SEDA-30, 485; SEDA-31, 671) Reproductive system In a comparison of tibolone (up to 2.5 mg/day for 1–2 years) and combined estrogen þ progestogen therapy in more than 3000 postmenopausal women, tibolone did not induce endometrial hyperplasia or carcinoma and was associated with a better vaginal bleeding profile than estrogen þ progestogen (97C). However, these apparently reassuring data do not remove all doubts regarding the adverse effects of tibolone. In a study of endometrial histology in 17 patients over the age of 60 who had taken tibolone for long periods, 7 patients had a thickened endometrium of more than 4 mm (98c). Three had an area of translucency in the subendometrial space. Of the 10 women with an endometrial thickness less than 4 mm, 4 had subendometrial fluid.
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Hysteroscopy was performed in five women; in all five the endometrial cavity was reported as atrophic and the histology showed an inactive basal type. In two of the five cases examined histologically, there were additional changes suggesting endometrial polyps. The investigators noted that similar find ings have been described in women using selective estrogen receptor modulators and they suggested that tibolone may perhaps be regarded as belonging to this class of agents.
SEX HORMONE ANTAGONISTS Danazol (SEDA-29, 514; SEDA-31, 672) Metabolism Hungarian investigators have reported that when danazol is used prophylactically in hereditary angio edema, it has adverse effects on the lipid profile (99c). Patients with hereditary angio-edema taking danazol have been compared with similar patients not taking danazol and healthy subjects. Serum concentrations of high-density lipoprotein (HDL) and apolipoprotein A-I were significantly lower, whereas low-density lipoprotein (LDL) and apolipoprotein B-100 were higher in those who took danazol. Those who took danazol had a 12 times higher risk of abnormally low HDL concentrations and a 4.4 times lower risk of high LDL concentrations. Monitoring of HDL and LDL concentrations at regular intervals is therefore recommended during treatment with danazol. Biochemical findings do not of course provide absolute proof of an increased risk of atherosclerosis and one should take note of a more recent paper from these same investigators who have reported that longterm danazol prophylaxis in such patients did not lead to thickening of the carotid intima (100c). It seems clear that further evidence must be awaited.
Sex hormones and related compounds, including hormonal contraceptives
ANDROGENS, ANABOLIC STEROIDS, AND RELATED COMPOUNDS (SED-15, 216; SEDA-29, 507; SEDA-30, 477; SEDA-31, 672)
Androgens Endocrine The possibility that the use of testosterone gel by a man may on occasion affect his partner is raised by a curious case (101A). • A 63-year-old woman developed both physical and biochemical signs of virilization. Her husband had been using a testosterone gel and the authors had reason to believe that transmission of the androgen had occurred not through direct skin contact but because the couple shared a washcloth on which the testosterone had been deposited when the man made use of it.
Metabolism In a multicenter randomized study (102c) of the effects of testosterone gel in 75 HIV-positive men with abdominal obesity and low testosterone compared with placebo, the gel was associated with a greater reduction in whole body, total and subcutaneous abdominal fat mass and a greater increase in lean mass. However, changes in visceral fat mass were not significantly different. Further studies were recommended to determine the effects of testosterone on insulin sensitivity and cardiovascular risk. Tumorigenicity The long-standing contro versy about whether androgen replacement in men increases the risk of prostatic neo plasms (SEDA-31, 672) is no closer to being settled. The original evidence of this supposed risk was based on a single case report and it has been argued that even in men with a history of prostate cancer the risk is negligible or absent (103R, 104r). Susceptibility factors Sex The debate about the use of androgens in women (SEDA-29, 510), largely to stimulate
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sexual interest and desire, continues, and papers tend to dwell on the moral and social aspects, rather than on adverse effects. Although some women have androgen insufficiency, the indications (if any) for treatment are still poorly defined and the quality of the literature leaves much to be desired (105R). Evidence on treatment for longer periods is still needed, as is assurance of the reversibility of some particular effects, for example on the endometrium. There are also insufficient long-term safety data regarding possible adverse effects on the breast, endometrium and heart. However, the data available to date on shorter periods of use are reassuring, and it has been suggested that in postmenopausal women testosterone administration that results in physiological to slightly supra-physiological serum-free testosterone concentrations is safe for at least 2 years (106R). One would feel rather more comfortable with this conclusion if the data were of better quality.
Long-term medical and social consequences of androgenic anabolic steroid abuse The fact that both the mental and physical consequences of anabolic steroid abuse are commonly overlooked is becoming particu larly serious, with the apparently continuing increase in the prevalence of such misuse. The fact that the generation that first acquired this habit is now approaching mid dle age makes it necessary to consider the long-term consequences for society of the presence of a drug-injured population group of significant size. As a major paper by a Harvard group (to which the present review is much indebted) has pointed out, the bulk of misusers have never been profes sional sportsmen; they are simply individuals who want to improve their bodily condition and mistakenly turn to anabolic steroids for this purpose (107R). This large population of ‘amateur’ abusers began to grow in the late 1970s and early 1980s, but has remained less visible than most other populations of
752
substance abusers, as they rarely seek treat ment, rarely come to the attention of physi cians in general and frequently distrust health-care professionals. Field studies show that they commonly take two or more sub stances simultaneously (a practice known as ‘stacking’), often ingesting a total anabolic steroid dose equivalent to testosterone 600–1000 mg/week, and sometimes even 3000–5000 mg/week, which is 50–100 times greater than the natural weekly production of testosterone by the normal male testes. Illicit users typically take these compounds in repeated courses, or ‘cycles’, each lasting several weeks to several months, sometimes adding up to several years of cumulative life time exposure. It has also been argued that there is evidence, in part from animal studies, that anabolic steroids can cause dependence (108r), which would exacerbate this. Further more, dysphoric feelings associated with hypogonadism may prompt some former users to resume taking the drugs again and yet again. Although many of these individuals no longer use anabolic steroids when they reach middle age, accumulating evidence suggests that they may still be vulnerable to long-term psychiatric and medical effects from their former drug use. Even using the conservative figures from the US health sta tistics for 1991, it would follow that about half a million American men with a history of anabolic steroid use will have passed the age of 45 by the year 2010. This estimate would be even higher – well over a million – if we were to extrapolate from the higher figures generated by anonymous surveys of American high-school students in the 1980s. Similar data are available from several other Western countries. Cardiovascular Supraphysiological doses of anabolic steroids appear to produce a range of adverse cardiovascular effects, including hypertension, cardiomyopathy and left ventricular hypertrophy, dyslipidemia (increased low-density lipoprotein and reduced high-density lipoprotein cholesterol), with potential acceleration of atherosclerosis and myocardial ischemia, adverse effects on
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coagulation and platelet aggregation, and a predisposition to dysrhythmias. Some of these effects remit after the anabolic steroids are discontinued, but effects such as atherosclerosis and cardiomyopathy are likely to be irreversible. These effects have been blamed for numerous premature deaths among athletes in their twenties and thirties known or believed to have used anabolic steroids – either from cardiac disease or strokes. In Finland mortality among 62 male powerlifters who had been placed first to fifth in Finnish championships during 1977–1982 (all being likely to have used ster oids) was compared with that among 1094 male controls (109c). Of the powerlifters 13% had died compared with only 3.1% of controls – a ratio of 4.16:1 (95% CI = 2.04, 10.45). Three of the eight deaths among powerlifters were ascribed to myocardial infarction, and the authors speculated that these deaths may have been attributable to use of anabolic steroids. Similarly, in a comparison of 20 anabolic steroid-using bodybuilders, mean age 33 years, with 25 age-matched non-anabolic steroid-using bodybuilders and 25 non-athletic controls, using Doppler echocardiography, Doppler myocardial imaging, strain rate imaging and an electrocardiographic treadmill test, the users, although studied a mean of several years after their last exposure to the drugs, still had impaired myocardial function (110c). The investigators found, for example, that middle intraventricular septum strain rates among users were strongly associated both with the mean reported number of weeks of drug use per year and indepen dently with the mean reported weekly dose of anabolic steroid. Two cases of sudden cardiac death have been reported in previously healthy body builders who were chronic users (111A). Autopsy in both cases pointed to cardiac fail ure, probably attributable to the combined effect of the anabolic steroids and the vigorous weight training in which they had engaged. Nervous system Although abuse of anabolic steroids can cause stimulation of
Sex hormones and related compounds, including hormonal contraceptives
the nervous system, the resulting symptoms generally amount only to euphoria or insomnia, and convulsions are not a recognized consequence. Nor has premature death as such been clearly recorded as an epidemic consequence of anabolic steroid abuse. However, these effects were observed, among others, in an analysis of official patient care records in Sweden (112C). Diagnoses, mortality and adverse events were examined in 248 patients who had been taking anabolic steroids and 1215 patients who had not. The proportions of patients who had received institutionalized care for substance abuse, psychiatric disorder or central thoracic pain were significantly higher in those who had taken anabolic steroids (RR = 2.2, 95% CI = 1.2, 4.2; RR = 2.1, 95% CI = 1.4, 3.2; RR = 3.5, 95% CI = 1.1, 11 respectively). Furthermore, unspecified convulsions occurred in 11 subjects using anabolic steroids (4.4%), one of whom died during a seizure, but in only one of the subjects without a history of anabolic steroid use. The effect was thus highly over-represented in the anabolic steroid users (RR = 54, 95% CI = 7, 416). The standardized mortality ratios in the anabolic steroid users and non-users were 20 (95% CI = 11, 36) and 6.02 (95% CI = 3.77, 9.12) respectively. Thus, use of anabolic steroids appeared to be an indicator of increased risk of premature death in several categories of patients. Speculation as to the mechanism that might underlie the occurrence of seizures in users of anabolic steroids continues (113H). A less common complication of anabolic steroid abuse is ischemic stroke, despite the fact that these compounds can increase vas cular tone, arterial tension and platelet aggre gation. A case of this type in a male amateur athlete aged 26 has been reported (114A). Psychological Finally, anabolic steroid users may suffer from prominent bodyimage disorders, such as muscle dysmorphia, a form of body dysmorphic disorder in which they become preoccupied that they do not appear sufficiently strong and muscular (115R). This syndrome, sometimes
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also called ‘reverse anorexia nervosa’, is associated with considerable psychiatric morbidity, and may be both a cause and a consequence of using anabolic steroids. Also, as a result of their concerns about body image, anabolic steroid abusers may abuse a wide range of additional substances, including street drugs, to gain muscle, lose fat or otherwise affect body appearance. Psychiatric The psychiatric effects of anabolic steroid abuse are all too often overlooked. They include hypomania, aggressiveness and other disorders that justify increasing social concern regarding the dangers posed by these agents (see below). A particularly severe case of psychiatric imbalance resulting from the use of anabolic steroids has been described (116A). They can also cause major depressive illness (117C). The various types of psychiatric disorders that anabolic steroids can cause have been demonstrated mainly in current users and not in former users; even if they are con firmed in the latter, some doubt is likely to persist as to whether one is dealing with a true adverse after-effect or with mental char acteristics likely to be relatively frequent in the type of individual who is particularly prone to abuse anabolic steroids. However, recent Scandinavian studies have offered some cause for concern on this score. In one study (118C), suicide was significantly more common among deceased former ana bolic steroid users than among other types of substance users. Also, in the study of older powerlifters noted above, three of the eight deaths were from suicides. Recently, another Swedish group mailed a structured question naire to 996 former Swedish elite male ath letes; former anabolic steroid users were much more likely than other individuals to have sought treatment for psychiatric symp toms: for example, 13% of users had sought treatment for depression, compared with 5.0% of non-users, a difference that was highly significant (119c). Endocrine There are also concerns about neuroendocrine function in long-term users
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of anabolic steroids, which suppress the hypothalamic–pituitary–testicular axis. When a ‘cycle’ of anabolic steroid use ends, male users will often become temporarily hypogonadal. Although function usually recovers spontaneously within a few weeks to a few months, there are reports of men in whom hypogonadism persisted for more than a year after discontinuation, and several reports have documented hypogonadism of similar duration after abuse of anabolic steroids. Persistent suppression of hypothalamic–pituitary–testicular function can have serious clinical consequences, including infertility (120r). Liver Over a long period, volumes in this series have reported adverse effects of current anabolic steroid use involving the liver, including peliosis hepatitis, intrahepatic cholestasis, hepatocellular adenomas or carcinomas, hepatic angiosarcomas, and spontaneous hepatic rupture. Such reports continue to appear (121C). However, there is no clear evidence that these complications are more frequent in the later life of anabolic steroid abusers than in the remainder of the population. Tumorigenicity As the anabolic steroids are androgens, there is obvious reason to suspect that in the long term their use might increase the incidence of prostatic hyperplasia or even cancer, but there is virtually no evidence about this; prostatic cancer has been incidentally described in former users of anabolic steroids, but the association could have been fortuitous. Conclusions There is a risk that, as some authors have suggested, political and moral forces have excessively demonized the use of anabolic steroids and that the risks are therefore being much exaggerated (122R, 123R). Certainly these arguments deserve consideration – but on the other hand, there are several reasons to suspect that we might be underestimating, rather than overestimating, the public health consequences of long-term
M.N.G. Dukes
use of anabolic steroids, if only because a large proportion of former users may not admit to their true history of drug abuse. To adopt almost literally the conclusion advanced by Kanayama et al. (107R), the frequency and severity of anabolic steroidinduced morbidity and mortality are still poorly understood, largely because these effects often do not declare themselves until users enter middle or old age – and investigators have examined at most small samples of ageing users. However, as they point out, this is poised to change, as hundreds of thousands of former (and sometimes still current) illicit users begin to pass the age of 45. As this wave of ageing users approaches, it is imperative to initiate larger and more systematic studies of the long-term effects of anabolic steroids, so that we can better inform both current and future generations.
Stanozolol Observational studies In some centers, anabolic steroids are still in use to control attacks of hereditary angio-edema. The safety of this treatment, which obviously needs to be maintained over very long periods, has been evaluated by a questionnaire in 21 patients who had taken stanozolol since 1987 (124c). The minimal initial effective dosage of stanozolol was 0.5–2.0 mg/day, although most patients achieved symptomatic control and reduced the dose and frequency of intake as the number of attacks decreased. Treatmentrelated symptoms developed in 10 patients. Interruption of stanozolol therapy was not required, because symptoms subsided with a reduction in the stanozolol dosage. Adverse events included hirsutism, weight gain, menstrual irregularities or postmenopausal bleeding, acne, and mood changes. Liver enzyme assays showed no persistent abnormalities, although liver ultrasonography in three of eight cases showed changes unrelated to therapy. Five patients had reduced HDL cholesterol concentrations, and two had raised triglycerides.
Sex hormones and related compounds, including hormonal contraceptives
Respiratory A single previously reported case of obstructive sleep apnea was attributed to testosterone but could have been coincidental (SED-15, 217). Since then, there have been other scattered reports of this possible complication, and the sparse literature has been reviewed (125r). The cases are very few compared with the large numbers of men treated with testosterone, sometimes in supraphysiological doses and generally beyond middle age. There has been one double-blind, placebo-controlled study of the matter and it did point to an association, but other work seems to have discounted it. Bearing in mind that obstructive sleep apnea is associated with ageing in men, and perhaps to some extent with an increase in body weight, there is every reason for confusion and the connection between testosterone and this adverse event must probably still be regarded as unproven.
(SEDA-29, 510; SEDA-30, 479; SEDA-31, 673)
ANTIANDROGENS Bicalutamide
Breasts Tamoxifen 20 mg/day might help in reducing the gynecomastia and breast pain that are often caused by bicalutamide (SEDA-30, 480). A little more case material tending to confirm this finding has appeared (126r), but longer-term experience was still awaited. In a review of the literature on the subject tamoxifen was found to be
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remarkably effective, both in preventing gynecomastia during bicalutamide treatment and in causing it to regress (often completely) when it was already present (127R).
Dutasteride
(SEDA-31, 675)
Breasts Gynecomastia has been reported in a 66-year-old man with chronic obstructive pulmonary disease who took dutasteride 0.5 mg/day (128A).
Finasteride (SED-15, 3132; SEDA-30, 480; SEDA-31, 675) Sensory systems Two men underwent bilateral cataract surgery having taken finasteride for benign prostatic hyperplasia and both developed the intraoperative floppy iris syndrome (IFIS) (129A). In patients scheduled for cataract surgery it is therefore essential to take a medication history to determine whether they are taking finasteride, since IFIS raises considerable problems for cataract removal.
Flutamide
(SED-15, 1427; SEDA-29, 513; SEDA-30, 484; SEDA-31, 675) Skin Photosensitive dermatitis attribut able to flutamide was followed in one case by the appearance of vitiliginous lesions (130A).
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Thyroid hormones, iodine, and antithyroid drugs
Thyrotropin-releasing hormone (TRH, protirelin) (SEDA-31, 683)
patients and a transient increase in thyroid volume and tenderness in the first week of treatment (2R). Most patients also have a short period (2–4 weeks) of hyperthyroidism.
Endocrine The TRH test is generally safe for evaluating pituitary function, but pituitary apoplexy has been reported (1A). • A 41-year-old woman with acromegaly due to a pituitary macroadenoma developed pituitary apoplexy after a TRH 200-micro gram intravenous stimulation test. There was no acute hemorrhage or infarction on com puted tomography (CT) or magnetic reso nance imaging (MRI) scans, but 2 days later, the pituitary gland, removed trans sphenoidally, showed ischemic necrosis and acute hemorrhage.
Thyrotropin (thyroid-stimulating hormone, TSH) (SEDA-31, 683) Endocrine Recombinant human TSH (rhTSH) has been used to increase 131I uptake in patients with toxic and non toxic multinodular goiter. This procedure changes the distribution of 131I in the thy roid, lowers the absorption dose and reduces the volume of the goitre to 50– 75% of the baseline volume. However, a major disadvantage is induction of hypothy roidism in a relatively large number of Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32041-1 � 2010 Elsevier B.V. All rights reserved.
THYROID HORMONES (SED-15, 3409; SEDA-29, 520; SEDA-30, 490; SEDA-31, 687) Uses Overt hypothyroidism is widely recognized as a susceptibility factor for atherosclerosis by its association with other factors, including lipid disturbances (3C). Much controversy continues to surround the management of patients with subclinical hypothyroidism (raised serum TSH concen trations with normal serum free T3 and free T4 concentrations). There have been two reports of improved atherogenic lipid con centrations in patients taking levothyroxine for subclinical hypothyroidism compared with patients taking placebo (4c, 5c). How ever, despite these findings, there is cur rently insufficient evidence that the use of levothyroxine in patients with subclinical hypothyroidism is associated with reduc tions in long-term morbidity and mortality. There is a well-recognized association between hypothyroidism and psychiatric ill ness. Two studies have shown augmentation of the effects of serotonergic antidepressants by levothyroxine (6c) and L-triiodothyro nine (7c). Both reports indicated significant
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improvements in depression rating scores in patients undergoing combination therapy with thyroid hormones and a number of selective serotonin uptake inhibitors (SSRIs), suggesting that thyroid hormones can be used to accelerate antidepressant response and improve overall outcome in patients with refractory depression. Sensory systems There has been a previous report of an increased risk of age-related macular degeneration in patients taking thy roid hormones (8C). However, in a large population-based matched case–control study of patients with age-related macular degeneration, there were no significant associations between treatment with thyroid hormones or antithyroid drugs and the risk of macular degeneration (9C). Susceptibility factors Diseases Treatment with high doses of levothyroxine reduces the risk of recurrence of thyroid cancer. A novel phenomenon of reduced serum free T4 and increased serum free T3 concentra tions resulting in T3 thyrotoxicosis in patients taking fixed doses of levothyroxine has been described. These effects were only observed in subjects with large metastases from follicular thyroid and are thought to be due to increased conversion of T4 to T3 in tumor cells expressing high activities of the deiodinase enzymes D1 and D2 (10C). Drug–drug interactions Sevelamer Many substances, including the phosphate binders aluminium hydroxide and calcium carbonate, interfere with absorption of levothyroxine. There has been a further report that the phosphate binder sevelamer increased serum TSH concentrations in a patient with chronic renal insufficiency and hypothyroidism (11A). The administration of sevelamer and levothyroxine separately with an interval of several hours reversed the situation, showing that this phosphate binder directly binds levothyroxine in the gastrointestinal tract.
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IODINE AND IODIDES (SED-15, 1896; SEDA-30, 490; SEDA-31, 688) Endocrine Iodine deficiency remains a problem in several areas, including the southern part of Poland, which was a region of moderate iodine deficiency at the end of the twentieth century. Following the implementation of iodine prophylaxis by mandatory household salt iodization in this region, there were significant increases in the prevalence of antithyroid microsomal anti bodies and in the prevalence of hyperthyroid ism (defined as serum TSH concentrations below the reference range) (12C). These early adverse effects appear to be transient and are acceptable, in view of the evident benefits of adequate iodine intake.
Radioactive iodine Radioactive iodine 131 I is used in the treat ment of patients with hyperthyroidism and in those with thyroid cancer. 131I-labelled compounds are also used in the treatment of other cancers. In a small study there was a high rate response and prolonged survival after intra-arterial injection of 131 I-iodine-labelled lipiodol in the treat ment of patients with advanced hepato cellular carcinoma not amenable to surgery or local treatment (13c). Respiratory Two cases of acute airways obstruction following the administration of 131 I for Graves’ disease have been reported (14A). In both instances rapid resolution of the respiratory symptoms was obtained with administration of histamine H1 receptor antagonists and hydrocortisone. Salivary glands Salivary glands accumu late 131I, and acute salivary gland pain, swelling and inflammation, and xerostomia have been described following administra tion of radioiodine. Patients who receive larger doses of 131I for thyroid cancer are
Thyroid hormones, iodine, and antithyroid drugs
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especially at risk. In 76 patients there was acute salivary gland toxicity in 26% and chronic toxicity typically manifesting as xerostomia in 21%; these complications were more likely to occur after repeated doses of radioiodine (15c).
markers, including classical antineutrophil cytoplasmic antibody (c-ANCA) and proto plasmic-staining antineutrophil cytoplasmic antibody (p-ANCA), and without histo pathological evidence of capillaritis has been described (19A). An eosinophilic pleural effusion after long-term treatment with propylthiouracil has been reported. After withdrawal of pro pylthiouracil and a short course of low-dose glucocorticoids, the pleural effusion rapidly resolved (20A).
Fetotoxicity Pregnancy is an absolute contraindication to 131I therapy, and women of child-bearing age should undergo routine pregnancy testing before the admin istration of radioactive iodine. There have been three reports of inadvertent radio iodine administration during pregnancy despite negative pregnancy tests in two cases. Doses of 400 MBq (16A) and 500 MBq (17A) were associated with neonatal hypothyroidism, which was successfully trea ted with levothyroxine. A dose of 3700 MBq, administered to a patient with differentiated thyroid cancer, resulted in fetal death. Drug–drug interactions Antithyroid drugs Patients with hyperthyroidism are commonly treated with antithyroid drugs (propylthiour acil or carbimazole) before radioiodine ther apy. There is continuing disagreement about their beneficial and detrimental effects and the optimal sequencing of these drugs before and after 131I administration. In 14 rando mized controlled trials in a total of 1306 participants, adjunctive antithyroid medica tion was associated with an increased risk of treatment failure (RR = 1.28; 95% CI = 1.07, 1.52) and a reduced risk of hypothyroidism (RR = 0.68; 0.53, 0.87). There were no dif ferences in summary estimates for the differ ent antithyroid drugs or when the drugs were given before or after radioiodine treatment (18M).
ANTITHYROID DRUGS (SED-15, 3387; SEDA-29 520; SEDA-30, 490; SEDA-31, 689) Respiratory An atypical presentation of propylthiouracil-induced diffuse alveolar hemorrhage with negative serological
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Hematologic Drug-induced agranulo cytosis is the most serious disorder asso ciated with thionamide therapy; it can be life-threatening, with a reported mortality of 5–15%.
EIDOS classification: Extrinsic species: Thionamides Intrinsic species: Whiteblood cells Distribution: Bone marrow Outcome: Not known Sequela: Agranulocytosis due to thionamides DoTS classification: Dose-relation: Collateral Time-course: Intermediate Susceptibility factors: Exogenous (other drugs that can cause agranulocytosis)
The incidences of idiosyncratic neutropenia and agranulocytosis in England and Wales have been estimated at 120 and 7 cases per million per year respectively. Current users of drugs classed as ‘thyroid inhibitors’ had the highest adjusted odds ratios for neutro penia (adjusted OR = 35; 95% CI = 12, 100) and for agranulocytosis (OR = 21; 95% CI = 3.3, 1) compared with other classes of drug associated with this complication (21C). In a multinational case–control study in Latin America there was a relatively low overall incidence rate of agranulocytosis (0.38 cases per 1 million inhabitant-years). Patients who developed this hematological
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complication more often took medications already associated with agranulocytosis than controls, mainly methimazole (OR = 44; 95% CI = 6.8, 1) (22C). There has been a report of a patient who developed agranulocytosis, plasmacytosis, and thrombocytosis due to methimazoleinduced bone marrow toxicity. After withdra wal of methimazole and administration of granulocyte colony-stimulating factor (G-CSF) and methylprednisolone, the hema tological abnormalities rapidly resolved (23A). Acute myeloid leukemia occurred in a patient who had taken propylthiouracil for 15 years (24Ar). It has been proposed that combined immunosuppression, partly from chronic use of propylthiouracil and partly from pregnancy and the puerperium, could have been causative in this case. Liver There has been a report of methim azole-induced cholestatic jaundice in an elderly patient with hyperthyroidism (25A). Serial changes in liver function tests have been reported in 23 patients with Graves’ disease taking thionamide drugs compared with 14 patients with subacute thyroiditis not undergoing active treatment (26C). It is therefore plausible that some of the observed increases in AsT and AlT activ ities after starting antithyroid drugs are caused by changes in thyroid function, rather than by the drug treatment. The efficacy and adverse effects of meth imazole 15 mg/day, methimazole 30 mg/day or propylthiouracil 300 mg/day have been stu died in 240 patients (27C). The results sug gested that larger doses of methimazole are advisable for patients with severe hyperthy roidism, whereas methimazole 15 mg/day is suitable for mild and moderate hyperthyroid ism. Adverse effects, mainly mild hepatotoxi city, were most common with propylthiouracil and significantly less so with methimazole 15mg/day versus 30 mg/day. Skin Juvenile dermatomyositis has been reported in a 10-year-old girl after treatment with carbimazole for 3 months; drug with drawal resulted in rapid resolution of the symptoms and signs (28A).
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Immunologic Antithyroid drugs, and especially propylthiouracil, can be asso ciated with ANCA-positive vasculitis, often manifesting as renal disease. In one study propylthiouracil inhibited the activity of myeloperoxidase and induced ANCA against myeloperoxidase in a dose-related manner, suggesting that these effects may be involved in propylthiouracil-induced vasculitis (29c). Teratogenicity During pregnancy, propyl thiouracil is preferred to methimazole or carbimazole, and a meta-analysis has con firmed previous anecdotal evidence that propylthiouracil crosses the placenta less well, is associated with a lower frequency of fetal hypothyroidism and causes fewer teratogenic effects than methimazole (30M). Propylthiouracil should therefore still be considered as the first-line agent for Graves’ disease during pregnancy. However, it should be noted that one of the major hazards of antithyroid drugs in pregnancy is over-treatment, and hence induction of fetal hypothyroidism and goiter. It is there fore important to monitor maternal thyroid status carefully and to use the lowest possi ble dose of antithyroid drug sufficient to maintain maternal euthyroidism. Aplasia cutis congenita and choanal atre sia have been reported in association with maternal carbimazole therapy, suggesting a causative link either with the drug or with underlying hyperthyroidism. A rare case of a monozygotic twin with aplasia cutis con genita and complex skull defects after meth imazole exposure in utero has been reported (31A). The second child did not have any skin or skull defects, and the exact mechanisms underlying this rare adverse effect of methimazole remain unclear. Drug–drug interactions Warfarin Concomi tant therapy with warfarin and drugs that alter thyroid hormone concentrations, such as methimazole, warrants frequent monitoring of both thyroid function and the international normalized ratio (INR) (32A).
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References 1. Wang HF, Huang CC, Chen YF, Ho DM, Lin HD. Pituitary apoplexy after thyrotropinreleasing hormone stimulation test in a patient with pituitary macroadenoma. J Chin Med Assoc 2007;70(9):392–5. 2. Medeiros-Neto G, Marui S, Knobel M. An outline concerning the potential use of recombinant human thyrotropin for improving radioiodine therapy of multinodular goiter. Endocrine 2008;33(2):109–17. 3. Franklyn JA, Sheppard MC, Maisonneuve P. Thyroid function and mortality in patients treated for hyperthyroidism. J Am Med Assoc 2005;294(1):71–80. 4. Teixeira PF, Reuters VS, Ferreira MM, Almeida CP, Reis FA, Melo BA, Buescu A, Costa AJ, Vaisman M. Treatment of sub clinical hypothyroidism reduces atherogenic lipid levels in a placebo-controlled doubleblind clinical trial. Horm Metab Res 2008; 40(1):50–5. 5. Teixeira P, Reuters VS, Ferreira MM, Almeida CP, Reis FA, Buescu A, Costa AJ, Vaisman M. Lipid profile in different degrees of hypothyroidism and effects of levothyroxine replacement in mild thyroid failure. Transl Res 2008;151(4):224–31. 6. Lojko D, Rybakowski JK. L-Thyroxine augmentation of serotonergic antidepressants in female patients with refractory depression. J Affect Disord 2007;103(1–3):253–6. 7. Posternak M, Novak S, Stern R, Hennessey J, Joffe R, Prange Jr. A, Zimmerman M. A pilot effectiveness study: placebo-controlled trial of adjunctive L-triiodothyronine (T3) used to accelerate and potentiate the anti depressant response. Int J Neuropsycho pharmacol 2008;11(1):15–25. 8. Age-Related Eye Disease Study Research Group. Risk factors associated with agerelated macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study report num ber 3. Ophthalmology 2000;107(12):2224–32. 9. Douglas IJ, Cook C, Chakravarthy U, Hubbard R, Fletcher AE, Smeeth L. A case-control study of drug risk factors for age-related macular degeneration. Ophthal mology 2007;114(6):1164–9.
10. Miyauchi A, Takamura Y, Ito Y, Miya A, Kobayashi K, Matsuzuka F, Amino N, Toyoda N, Nomura E, Nishikawa M. 3,5,3’ Triiodothyronine thyrotoxicosis due to incre ased conversion of administered levothyroxine in patients with massive metastatic follicular thyroid carcinoma. J Clin Endocrinol Metab 2008;93(6):2239–42. 11. Arnadottir M, Johannesson AJ. Phosphate binders and timing of levothyroxine admin istration. Nephrol Dial Transplant 2008; 23(1):420. 12. Golkowski F, Buziak-Bereza M, Trofimiuk M, Baldys-Waligorska A, Szybinski Z, Huszno B. Increased prevalence of hyper thyroidism as an early and transient side-effect of implementing iodine prophylaxis. Public Health Nutr 2007;10(8):799–802. 13. Boucher E, Garin E, Guylligomarc’h A, Olivié D, Boudjema K, Raoul JL. Intra arterial injection of iodine-131-labeled lipiodol for treatment of hepatocellular carcinoma. Radiother Oncol 2007;82(1):76–82. 14. Kinuya S, Yoneyama T, Michigishi T. Airway complication occurring during radioiodine treatment for Graves’ disease. Ann Nucl Med 2007;21(6):367–9. 15. Hyer S, Kong A, Pratt B, Harmer C. Salivary gland toxicity after radioiodine therapy for thyroid cancer. Clin Oncol (R Coll Radiol) 2007;19(1):83–6. 16. Perry RJ, Ainine A, Butler S, Donaldson MD. Hypoechoic thyroid nodules on ultra sound 4 years after prenatal exposure to radio iodine: resolution with thyroxine therapy. Acta Paediatr 2008;97(4):509–12. 17. Berg G, Jacobsson L, Nystrom E, Gleisner KS, Tennvall J. Consequences of inadvertent radioiodine treatment of Graves’ disease and thyroid cancer in undiagnosed pregnancy. Can we rely on routine pregnancy testing? Acta Oncol 2008;47(1):145–9. 18. Walter MA, Briel M, Christ-Crain M, Bonnema SJ, Connell J, Cooper DS, Bucher HC, M€ uller-Brand J, M€ uller B. Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomised controlled trials. BMJ 2007; 334(7592):514.
768 19. Hadjiangelis NP, Harkin TJ. Propylthioura cil-related diffuse alveolar hemorrhage with negative serologies and without capillaritis. Respir Med 2007;101(4):865–7. 20. Sen N, Ermis H, Karatasli M, Habesoglu MA, Eyuboglu FO. Propylthiouracil-associated eosinophilic pleural effusion: a case report. Respiration 2007;74(6):703–5. 21. van Staa TP, Boulton F, Cooper C, Hagenbeek A, Inskip H, Leufkens HG. Neutropenia and agranulocytosis in England and Wales: incidence and risk factors. Am J Hematol 2003;72(4):248–54. 22. Hamerschlak N, Maluf E, Biasi Cavalcanti A, Avezum Júnior A, Eluf-Neto J, Passeto Falcão R, Lorand-Metze IG, Goldenberg D, Leite Santana C, de Oliveira Werneck Rodrigues D, Nascimento da Motta Passos L, Oliveira de Miranda Coelho E, Tostes Pintão MC, Moraes de Souza H, Borbolla JR, Pasquini R. Incidence and risk factors for agranulocytosis in Latin American coun tries – the Latin Study: a multicenter study. Eur J Clin Pharmacol 2008;64(9):921–9. 23. Oh EJ, Chae HJ, Park YJ, Park JW, Han K. Agranulocytosis, plasmacytosis, and thrombo cytosis due to methimazole-induced bone mar row toxicity. Am J Hematol 2007;82(6):500. 24. Focosi D, Caracciolo F, Galimberti S, Papineschi F, Petrini M. Long-term pro pylthiouracil use and acute myeloid leukemia: a case report and review of the literature. Ann Hematol 2008;87(3):233–5. 25. Ramos-Bonner LS, Goldberg TH, Moyer S, Anastasopoulou C. Methimazole-induced cholestatic jaundice in an elderly hyperthyroid patient. Am J Geriatr Pharmacother 2007;5(3): 236–40.
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26. Matsumoto Y, Amino N, Kubota S, Ikeda N, Morita S, Nishihara E, Ohye H, Kudo T, Ito M, Fukata S, Miyauchi A. Serial changes in liver function tests in patients with thyr otoxicosis induced by Graves’ disease and painless thyroiditis. Thyroid 2008;18(3): 283–7. 27. Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease. J Clin Endocrinol Metab 2007;92(6): 2157–62. 28. Alvarez F, Pagot C, Vabre-Latre CM, Uro-Coste E, Paul C, Chaix Y, MazereeuwHautier J. Carbimazole-induced juvenile der matomyositis. Br J Dermatol 2008;158(1): 196–7. 29. Zhang AH, Chen M, Gao Y, Zhao MH, Wang HY. Inhibition of oxidation activity of myeloperoxidase (MPO) by propylthiour acil (PTU) and anti-MPO antibodies from patients with PTU-induced vasculitis. Clin Immunol 2007;122(2):187–93. 30. Chattaway JM, Klepser TB. Propylthiouracil versus methimazole in treatment of Graves’ disease during pregnancy. Ann Pharmaco ther 2007;41(6):1018–22. 31. Iwayama H, Hosono H, Yamamoto H, Oshiro M, Ueda N. Aplasia cutis congenita with skull defect in a monozygotic twin after exposure to methimazole in utero. Birth Defects Res A Clin Mol Teratol 2007; 79(10):680–4. 32. Akin F, Yaylali GF, Bastemir M, Yapar B. Effect of methimazole on warfarin anticoa gulation in a case of Graves’ disease. Blood Coagul Fibrinolysis 2008;19(1):89–91.
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GLUCAGON
Insulin, other hypoglycemic drugs, and glucagon (SED-15, 1510;
SEDA-31, 689) Gastrointestinal Parenteral glucagon is used to treat hypoglycemia. In 10 men aged 18–47 years, body mass index (BMI) 22–24 kg/m2, without diabetes, who received rectal suppositories containing indometacin 100 mg and varying doses of glucagon (0.1, 0.5, and 1 mg), two had mild nausea and colicky abdominal pain after the 1 mg dose (1c). Peak concentrations of glucagon were 200 ng/l compared with peaks of 1800 ng/l found after intramuscular glucagon 1 mg. This dose of rectal glucagon did not aid recovery from hypoglycemia in six men with type 1 diabetes.
(SED-15, 1761; SEDA-29, 523; SEDA-30, 494; SEDA-31, 689)
INSULIN
Metabolism Hypoglycemia In a review of studies of tight blood glucose control in intensive care, there were increased risks of hypoglycemia in patients who received intensive insulin therapy (2R). The risk was greatest in those with sepsis. In those with conventional insulin therapy and sepsis, the Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32042-3 2010 Elsevier B.V. All rights reserved.
risk of hypoglycemia was 2.9% compared with 1.2% in those without sepsis. When septic patients received intensive insulin therapy, the risk of hypoglycemia was 20% compared with 6.8% in those without sepsis. The risk of hypoglycemia coincided with an increased death rate in all patients, regard less of whether they received intensive or conventional insulin therapy (odds ratio [OR] = 3.2 in the surgical intensive care unit [ICU] study and 2.9 in the medical ICU study). However, hypoglycemia was not thought to be directly responsible for the increased death rate, more a marker of those at increased risk. Larger studies appro priately designed to achieve normoglycemia are required to answer questions about the adverse effects and benefits of using inten sive insulin therapy in this setting. Insight into a possible mechanism of this increased mortality has come from a study of patients with subarachnoid hemorrhage who received continuous intravenous insulin if they had hyperglycemia. Although blood glucose concentrations remained within the reference range at above 4.4 mmol/l, 19 of 24 patients receiving insulin had a reduction in cerebral glucose concentration to less than 0.6 mmol/l, assessed using microdialysis sam ples. However three of seven patients who were not receiving insulin also had reduced cerebral glucose concentrations. This reduc tion occurred at about 4 days after the insulin infusion was started. This suggests that very low concentrations of cerebral glucose, which are harmful, can occur regardless of the blood glucose concentration. However, as patients did not become hypoglycemic, it is
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not known whether hypoglycemia would have lowered the cerebral glucose concentra tions further (3c). Insulin glargine (n = 76) has been com pared with neutral protamine of Hagedorn (NPH) insulin þ lente (n = 81) in a multidose regimen in adolescents (mean age 13 years, 45% girls) with type 1 diabetes. There were more episodes of blood glucose concentrations below 4 mmol/l in those who received glargine (116 events per patientyear compared with 94), but there were no differences in severe hypoglycemic events (4c). In a review in which insulin glargine was compared with NPH insulin in type 2 diabetes, although overall symptomatic hypoglycemia was not reduced in all studies, nocturnal hypoglycemia did appear to be reduced (5R). Body weight Of 12 981 patients with type 2 diabetes who took part in the PREDIC TIVE study, an open observational study of patients taking insulin detemir, 2377 required basal insulin (6C). Those with a BMI of more than 25 kg/m2 had a slight reduction in weight proportional to their baseline BMI, and those with a BMI of more than 31 kg/m2 had the greatest reduc tion in weight (1.5 kg). Patients with a BMI of less than 25 kg/m2 had a slight weight gain (0.55 kg). There are many possible explanations for this, including the fact that the study was not randomized. How ever, others have reported similar findings. Pooled data from two randomized studies of 900 people with type 2 diabetes, lasting 22 and 24 weeks, showed that patients with a BMI of more than 35 kg/m2 who used NPH insulin gained a mean of 2.4 kg and those who used insulin detemir lost a mean of 0.5 kg (7R). Patients with a BMI of less than 35 kg/m2 gained weight, but those who took detemir gained less than those who took NPH insulin. Skin Lispro insulin has been reported to cause lipoatrophy in a patient in whom other forms of insulin did not (8A). • A 4-year-old Saudi girl with a 1-year history of type 1 diabetes used Actrapid and Insulatard
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insulin. After 5 months the Actrapid was chan ged to lispro insulin to try to improve blood glucose concentrations, and 2 months later she developed lipoatrophy, which worsened despite instructions on site rotation. On returning to Actrapid no new areas appeared.
Lipoatrophy is a well-recognized but uncommon adverse effect of insulin. The exact pathogenesis remains uncertain, but it is more common in women and is asso ciated with insulin antibodies. This patient had high concentrations of immunoglobulin G (IgG) insulin antibodies. Immunologic A review of the immune response to exogenous insulin describes types 1, 3, and 4 hypersensitivity. Type 4, although the most common type, is still rare. The exact nature of a hypersensitivity response can be difficult to determine in an individual, and mixed reactions can occur (9R). Insulin autoantibodies can be present in individuals who have not received exo genous insulin. They occur more often in those using insulin, although they are less common with modern human and analogue insulins than with animal insulins. Although studies have suggested links between anti body development and various problems relating to diabetes management, there is no conclusive evidence. In a study of 582 insulin-naive patients with type 2 diabetes, mean age 59 years, who were randomized to insulin detemir or glargine once daily, 231 who used detemir completed the study (79%) compared with 252 (87%) who used glargine (10C). Of those who used insulin detemir, 13 (4.5%) had a reaction at the injection site compared with 4 (1.4%) of those who used insulin glargine. Three had allergic reactions from detemir and one from glargine. There were skin reactions, including pruritus and rash, in six patients who used detemir and in one who used glargine. Withdrawals because of adverse events during therapy with detemir included two possible cases of cutaneous allergy and five injection site reactions. Pregnancy In a case-control comparison of 32 pregnant women (10 with type 1
Insulin, other hypoglycemic drugs, and glucagon
diabetes and 22 with gestational diabetes) who used insulin glargine and 32 women who used isophane or insulin zinc suspension, there were no differences in fetal outcomes relating to macrosomia, hypoglycemia or mode of delivery (11c). This was a small study and it is unlikely that any differences would have been detected. Insulin aspart has been compared with Actrapid insulin þ NPH insulin in the man agement of type 1 diabetes before and during pregnancy in 322 women, mean age 29 years (12C). Outcomes, including congenital abnormality rates (4.3% insulin aspart, n = 6, and 6.6% Actrapid, n = 9), were not different. In a multicenter, retrospective compari son of 72 pregnancies in women with type 1 diabetes who used lispro and 298 pregnancies in women who used regular insulin, malfor mations occurred with similar frequencies; there were 12 babies with malformations (4.5%) in those who used regular insulin compared with 3 (4.3%) in those who used lispro (13C). Drug administration route Continuous subcutaneous insulin infusion (CSII) Methods of insulin delivery have been com pared in a retrospective study in which two patients with type 1 diabetes treated with multiple-dose insulin injections (n = 60; mean age 29 years) were compared with each patient treated with CSII (n = 30; mean age 30 years) (14c). There was an increased risk of neonatal hypoglycemia babies of those using CSII (11 versus 8; 36% versus 13%). The maternal risk of hypoglycemia was similar in the two groups, but keto acidosis was more frequent in those who used CSII (4 versus 1; 13% versus 1.6%). Ketoacidosis was mild and due to mechan ical failure of the pump. Thus there were potential problems with CSII in pregnancy, without apparent benefits. In 50 patients with type 1 diabetes, mean age 13 years (26 women), who had used CSII for at least 6 months, common findings were scars of less than 3 mm (n = 47), erythema tous subcutaneous nodules (21) and lipo hypertrophy (22) (15c). There was no difference between men and women. Two patients had required oral antibiotics for
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local infections and 13 patients had used topical antibiotics. Patients who used non metal catheters inserted at 90° had fewer problems than those who had inserted them at smaller angles. BMI was negatively corre lated with the severity of the skin changes. Skin infections were more common with CSII in earlier studies, and further studies looking at longitudinal changes and the effects of cannula insertion are required. CSII has mainly been used by people with type 1 diabetes. In 382 patients with newly diagnosed type 2 diabetes, mean age 51 years, BMI 25 kg/m2, who were random ized to CSII, multiple daily injections or oral hypoglycemic drugs to achieve rapid normoglycemia, therapy was stopped after 2 weeks of achieving fasting blood glucose concentrations of less than 6.1 mmol/l and 2 hour postprandial glucose concentrations of less than 8 mmol/l (16C). There were no episodes of severe hypoglycemia, but there was a non-significant increase in the number of episodes of minor hypoglycemia in those who used CSII (42 of 137; 31%) and multi ple injections (35 of 124; 28%) compared with oral hypoglycemic drugs (23 of 121; 19%). Target blood glucose concentrations were achieved at a mean of 4 days in 133 of 137 patients who used CSII, 5.6 days in 118 of 124 who used multiple injections and 9.3 days in 101 of 121 who used oral drugs. • A 45-year-old man with a family history of type 2 diabetes, who had had type 1 diabetes for 18 years, started using CSII, taking 85 units of insulin in a day, half of which was basal to control raised blood glucose concentrations (17A). The dosage of insulin was gradually reduced to 43 units/day. There was no weight gain at 3 months (BMI 20.8 kg/m2), when blood glucose control was good. At 15 months his BMI had increased to 27 kg/m2 and his blood glucose control had deter iorated. He had hepatic steatosis. Metformin was added and improved his blood glucose concentrations.
The authors suggested that ease of manage ment led to increased calorie intake, causing excessive weight gain, allowing him to develop features of type 2 diabetes. This is not specific to CSII and can be seen in those who use other insulin regimens.
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Inhaled insulin Exubera, a formulation of insulin for inhalation, was withdrawn in 2008 for commercial reasons (SEDA-31, 691). However, other products remain in develop ment, and inhaled insulin remains of interest. AIR® insulin is inhaled as dry powder parti cles of more than 2–5 µm. In 24 chronic smo kers without diabetes, mean age 25 years, euglycemic glucose clamps were used to study the effect of smoking cessation with or without nicotine replacement and acute re-exposure to smoke (18c). Smoking cessa tion for 4 weeks without nicotine reduced the maximum insulin concentration (Cmax) by 32%, but when nicotine was used the Cmax was reduced by 56%. The cause of this was unclear and requires further investigation. In two studies of Exubera before its with drawal there was a higher incidence of cough. In 189 non-smoking patients with type 1 dia betes, aged 25–65 years, who were rando mized to Exubera or pre-meal subcutaneous insulin for 24 weeks, cough was reported in 31% of those who used Exubera and in 8% of those who used subcutaneous insulin (19c). The cough was usually mild and non-produc tive and occurred shortly after dosing. Two withdrawals were due to cough, which resolved on stopping Exubera. In a compar ison of Exubera with oral therapy alone for 104 weeks in patients with type 2 diabetes the crude rates of coughs per patient-month were small, although greater in those taking Exu bera: 0.014 compared with 0.004 in those taking metformin alone and 0.002 in those taking a sulfonylurea (20c). In a review of inhaled insulin in patients with asthma and chronic obstructive pul monary disease (COPD) in a preliminary study of Exubera, 52-week data were avail able on 27 subjects with asthma, 10 using inhaled insulin and 17 others (21c). Cough and respiratory adverse events were more common in those who used inhaled insulin. There were three withdrawals in those who used inhaled insulin, due to respiratory pro blems, two of which were due to exacerba tions of asthma. Users of Exubera inhaled insulin without lung disease have a small but significant fall in forced expiratory volume in 1 second (FEV1), which occurs early and appears to stabilize (22R).
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Preliminary data in patients with asthma and COPD who used Exubera suggest that there may be a greater reduction in pulmon ary function than in those without lung disease. The Technosphere delivery system, an ordered lattice array of Technosphere and recombinant human insulin, produced no change in pulmonary function after use for 6 months in 306 patients with diabetes without lung disease (21R). Drug overdose Insulin overdose has been reported in 25 patients (14 women), mean age 46 years (23c). A delay of more than 6 hours and a requirement for more than 48 hours of mechanical ventilation were predictors of a poor outcome. There were two deaths. Insu lin toxicokinetics and toxicodynamics were studied, with attempts to quantify the need for glucose repletion. However, careful monitoring and appropriate individual adjust ments are needed in management, owing to the variability in response.
ALPHA-GLUCOSIDASE INHIBITORS (SED-15, 85; SEDA 29, 526; SEDA-30,496; SEDA-31, 691)
Acarbose Gastrointestinal In a non-randomized, prospective, post-marketing surveillance study in 2550 people of Asian or Oriental origin (88% type 2 diabetes, 12% with impaired glucose tolerance), the mean length of observation was 14 weeks (24c). Most of the participants (about 84%) were given acarbose 150 mg/day and 91% of them found that they tolerated it well or very well; however, 14 patients (12 with type 2 diabetes) had abdominal distention, which resolved by the end of the study. This rate of adverse events is low compared with other studies. Possible explanations include the low dose of acarbose or an effect of post-marketing surveillance, in which patients must report events spontaneously.
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AMYLIN ANALOGUES (SEDA-29, 526; SEDA-30,496; SEDA-31, 692)
Pramlintide Metabolism Body weight Studies suggest that pramlintide is associated with a small amount of weight loss. In 137 subjects who used subcutaneous pramlintide 60 micro grams tds initially, the dose was increased by 30 micrograms every 4 days up to a max imum tolerated dose of 240 micrograms before meals over 4 weeks (25c). They then continued for a further 12 weeks at one of the following maintenance doses: 120, 180 or 240 micrograms, depending on the previous maximum tolerated dose; 88% used 240 micrograms tds and 8% used 180 micrograms tds. At 16 weeks ther apy was stopped. They were compared with 67 subjects who used placebo with a similar non-forced increase in the dose of subcuta neous injection therapy. The adverse effects of pramlintide included nausea (52 versus 15) and mild hypoglycemia (11 ver sus 1). Those who used pramlintide lost weight, which appeared to be independent of nausea. Placebo-corrected weight loss was 3.6 kg. In an open study 166 insulin-treated patients with type 2 diabetes (51% men) had pramlintide 120 µg added before meals (26c). The dose of insulin was adjusted depending on blood glucose concentration. Mean weight at the start of the study was 112 kg. Body weight fell by 2.3 kg at 3 months and by 2.8 kg 6 months. Only 127 patients completed treatment for 6 months. Withdrawals were mainly due to adverse events, withdrawal of consent and investi gator decisions; information was not given about the reasons for the last two. Gastrointestinal Eight subjects with type 1 diabetes, mean age 17 years (6 men), received either a pre-meal bolus of pramlin tide or an infusion of pramlintide 4–6 weeks apart (27c). The dose of pramlintide was calculated based on the insulin bolus taken with the meal, 5 micrograms of pramlintide
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per unit of insulin. There were reduced glu cagon concentrations and impaired gastric emptying when a bolus of pramlintide was used compared with an infusion. There are still uncertainties about the most effective way of using pramlintide.
BIGUANIDES (SED-15, 506; SEDA-29, 526; SEDA-30,497; SEDA-31, 692) Metformin Metabolism In 48 HIV-positive people (27 men), mean age 42 years, with increased abdominal girth, who were randomized to placebo or metformin, gradually increased to a dose of 0.5 mg tds over 4 weeks, visceral adipose tissue, assessed using CT scanning, was not different at 24 weeks, but there was a trend towards a reduction in the appendicular fat mass, suggesting that metformin may worsen peripheral lipoa trophy in this patient group (28c). Nutrition The association of metformin with vitamin B12 deficiency has been well documented, and patients who also take histamine H2 receptor antagonists or proton pump inhibitors in combination with met formin are at particular risk (29r). Acid base balance Lactic acidosis is often reported anecdotally in patients taking met formin, especially in patients with renal impairment, and more reports have appeared (30A, 31Ar, 32A, 33A). • A 77-year-old Caucasian woman with type 2 diabetes took metformin 3 g/day, perindopril 8 mg/day, and simvastatin 20 mg/day after making a full recovery from a stroke. One month later she was admitted with abdominal pain and vomiting. The serum creatinine was 530 µmol/l, pH 6.87, and blood lactate 16 mmol/l. • A 69-year-old man with type 2 diabetes took metformin 4 g/day and developed a bradycardia due to complete atrioventricular block, with a pulse of 30/minute, and an undetectable blood pressure. His serum creatinine was 195 µmol/l, pH 6.7, and lactate 18 mmol/l.
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Both patients received continuous veno venous haemodiafiltration and recovered fully. The authors suggested that renal impair ment in these cases may have been due to metformin, although there were other possi ble reasons – in the first case the use of peri ndopril and in the second severe hypotension. In both cases the doses of metformin were high – 4 g/day is above the licensed dosage. • A 78-year-old woman taking metformin 1500 mg bd, glibenclamide, rofecoxib, furosemide, levothyroxine, prednisone, azathioprine, and propranolol developed abdominal pain, nausea, vomiting, and anorexia. She was hypothermic (34.4°C), her blood pressure was 115/51 mmHg and pulse 104/minute, and the arterial pH was 7.0, serum creatinine 784 µmol/l, estimated glomerular filtration rate (eGFR) 57 ml/minute/ 1.73 m2, serum lactate 1.1 mmol/l, and serum metformin 17 mg/l (usual target range 1–2 mg/l). • A 64-year-old woman taking metformin 500 mg bd, lisinopril and ibuprofen developed nausea and vomiting. She was hypothermic (34.5°C), hypotensive (blood pressure, 85/38 mmHg) and tachypneic (28/minute). The arterial pH was 6.78, serum creatinine 520 µmol/l, eGFR 59 ml/minute/1.73 m2, serum lactate 2.4 mmol/l, and serum metformin 31 mg/l. • A 58-year-old woman with type 2 diabetes, taking metformin 500 mg bd, developed lactic acidosis and died. • A 61-year-old man with type 2 diabetes took metformin 1 g bd and fosinopril 40 mg/day and developed diarrhea and vomiting. His serum creatinine was 973 µmol/l, pH 7.15, and blood lactate 26 mmol/l. He received urgent treatment including dialysis and recovered.
It is important to provide information and education to people taking metformin about discontinuing therapy and seeking medical help when they are unwell. Gastrointestinal In a review of the use of metformin for weight management in patients without type 2 diabetes, there were similar adverse effects to those reported in patients with type 2 diabetes. Nausea, vomiting, and other gastrointestinal adverse effects were the most frequent (34R). Pregnancy Metformin crosses the pla centa, but it is not thought to increase the risk of congenital abnormalities (35R). In a randomized comparison of metformin and insulin in pregnancy in 733 women with
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gestational diabetes at 20–33 weeks, 195 women used metformin alone, 168 met formin þ insulin, and 370 insulin (36C). The initial dosage of metformin was 500 mg once or twice daily and it was titrated to a maximum of 2.5 g/day. Insulin was added if blood glucose targets were not met. Infor mation was not given about the insulin regi mens used. Severe hypoglycemia (blood glucose below 1.6 mmol/l) was less common in those who used metformin. Preterm birth (before 37 weeks) was more common in those who used metformin (44 versus 28; 12% versus 7.6%). Further follow-up is being undertaken to establish the longterm safety of metformin. Susceptibility factors Age In 30 obese Chinese children aged 10–16 years with metabolic syndrome who took metformin 500 mg bd and underwent lifestyle modifica tions, 20 completed 3 months of treatment (37c). Adverse effects were similar to those seen in adults taking metformin: seven had a reduced appetite, two had nausea, and two had increased bowel movements during the first week of treatment. Drug overdose An overdose of metformin reportedly caused rhabdomyolysis (38A). • A 46-year-old man with type 2 diabetes took metformin 56 g, ramipril 35 mg and alcohol 500 ml. He developed vomiting and abdominal pain. His serum creatinine was 368 µmol/l, pH 7.24, and blood lactate 11.6 mmol/l. The pH fell and the lactate increased further after admission. On day 2 he developed rhabdomyolysis with a creatine kinase activity of 12478 U/l. He required an above-knee amputation, but was discharged with normal renal function.
DIPEPTIDYL PEPTIDASE 4 INHIBITORS (SEDA-30, 498; SEDA-31, 693) The activity of dipeptidyl peptidase type 4 (DPP-4) correlates inversely with inflamma tion in bony tissues in patients with chronic sinusitis. The enzyme also attenuates the
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pro-inflammatory actions of substance P during sensory nerve activation (39r). DPP-4 is expressed on many cell types, including lymphocytes (40R). It also inacti vates the chemokine CXCL12, which is thought to be important in the homing of hemopoietic stem cells to bone marrow (41r). Thus, the use of DPP-4 inhibitors needs long-term follow-up to ensure safety.
Sitagliptin Gastrointestinal Although sitagliptin is mainly well tolerated, nausea and vomiting have been reported (42R). Immunologic Hypersensitivity reactions have been reported, including anaphylaxis, angioedema, and urticaria. There is insuffi cient information to assess the frequency (43c). Pregnancy Sitagliptin appears in the milk of lactating rats, but the extent of excretion in human milk is unknown (42R). It is not recommended, as there are alternative drugs known to be safe in breast-feeding mothers. Susceptibility factors Renal disease Sita gliptin is excreted mainly unchanged in the urine. Dosage adjustment is required in patients with moderate renal impairment (creatinine clearance 30–50 ml/minute) or severe renal impairment (
