Drug Safety

, Volume 30, Issue 1, pp 47–57 | Cite as

Clozapine-Associated Myocarditis

A Review of 116 Cases of Suspected Myocarditis Associated with the Use of Clozapine in Australia During 1993–2003
  • Steven J. Haas
  • Richard Hill
  • Henry Krum
  • Danny Liew
  • Andrew Tonkin
  • Lisa Demos
  • Karen Stephan
  • John McNeil
Original Research Article

Abstract

Background: Clozapine is an antipsychotic medication associated with a lower suicide rate compared with other antipsychotic agents. Clozapine is used specifically in patients for whom previous therapy was inadequate or not tolerated, and is the only antipsychotic agent associated with the development of myocarditis.

Objective: To retrospectively review all adverse drug reaction reports voluntarily submitted to the Australian Adverse Drug Reactions Unit mentioning suspected myocarditis in clozapine-treated patients.

Patients and methods: We accessed all electronic database entries and case reports citing suspected myocarditis associated with clozapine therapy from January 1993 through to December 2003, inclusive.

Results: 116 case reports of suspected myocarditis amongst clozapine-treated patients were identified during the specified time frame (incidence between 0.7% and 1.2% of treated patients). Median patient age for these cases was 30 years (SD 11.1 years) compared with 37 years from the Clopine® registry. The condition developed within a median 16 days (mean 19.8 days; SD 17.3 days) of commencing clozapine for the bulk of patients developing myocarditis within 6 months (n = 93, 80.2%). For all cases with known treatment commencement and cessation dates (n = 106), the condition developed within a median 17 days (mean 171.7 days, SD 530.9 days). Over nine-tenths of cases were prescribed clozapine within the dose range of 100 mg/day to 450 mg/day. Sixty patients (51.8%) recovered from their episode when reported or during follow-up reports, whereas 17 patients (14.7%) had not yet recovered: 27 patients (23.3%) had unknown outcome when reported and the remaining 12 patients (10.3%) died.

Conclusion: Clozapine is uncommonly but importantly related to myocarditis, often fatal or near fatal and sometimes in relatively young patients with early onset after treatment initiation. The most striking feature about this condition is the wide diversity of nonspecific symptoms that occur in afflicted patients. Additional pharmacovigilance, improved reporting systems and further investigation of mechanisms of drug-induced myocarditis and related cardiovascular conditions (such as heart failure) are clearly warranted. A case-control study would be suitable for investigation of baseline predictors.

References

  1. 1.
    Magnus A, Carr V, Mihalopoulos C, et al. Assessing cost-effectiveness of drug interventions for schizophrenia. Aust N Z J Psychiatry 2005 Jan-Feb; 39(1-2): 44–54PubMedCrossRefGoogle Scholar
  2. 2.
    Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophr Res 2005 Mar 1; 73(2-3): 139–45PubMedCrossRefGoogle Scholar
  3. 3.
    Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003 Jan; 60(1): 82–91PubMedCrossRefGoogle Scholar
  4. 4.
    Buckley NA, Sanders P. Cardiovascular adverse effects of antipsychotic drugs. Drug Saf 2000 Sep; 23(3): 215–28PubMedCrossRefGoogle Scholar
  5. 5.
    Kilian JG, Kerr K, Lawrence C, et al. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999 Nov 27; 354(9193): 1841–5PubMedCrossRefGoogle Scholar
  6. 6.
    Calabrese F, Thiene G. Myocarditis and inflammatory cardiomyopathy: microbiological and molecular biological aspects. Cardiovasc Res 2003 Oct 15; 60(1): 11–25PubMedCrossRefGoogle Scholar
  7. 7.
    Hagg S, Spigset O, Bate A, et al. Myocarditis related to clozapine treatment. J Clin Psychopharmacol 2001 Aug; 21(4): 382–8PubMedCrossRefGoogle Scholar
  8. 8.
    La Grenade L, Graham D, Trontell A. Myocarditis and cardiomyopathy associated with clozapine use in the United States. N Engl J Med 2001 Jul 19; 345(3): 224–5PubMedCrossRefGoogle Scholar
  9. 9.
    Young CR, Bowers Jr MB, Mazure CM. Management of the adverse effects of clozapine. Schizophr Bull 1998; 24(3): 381–90PubMedCrossRefGoogle Scholar
  10. 10.
    Coulter DM, Bate A, Meyboom RH, et al. Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study. BMJ 2001 May 19; 322(7296): 1207–9PubMedCrossRefGoogle Scholar
  11. 11.
    Fineschi V, Neri M, Riezzo I, et al. Sudden cardiac death due to hypersensitivity myocarditis during clozapine treatment. Int J Legal Med 2004 Oct; 118(5): 307–9PubMedCrossRefGoogle Scholar
  12. 12.
    Kirpekar VC, Deshpande SM, Joshi PP. Reversible myocarditis in a patient receiving clozapine. Indian Heart J 2001 Nov-Dec; 53(6): 779–81PubMedGoogle Scholar
  13. 13.
    Leo RJ, Kreeger JL, Kim KY. Cardiomyopathy associated with clozapine. Ann Pharmacother 1996 Jun; 30(6): 603–5PubMedGoogle Scholar
  14. 14.
    Merrill DB, Ahmari SE, Bradford JM, et al. Myocarditis during clozapine treatment. Am J Psychiatry 2006 Feb; 163(2): 204–8PubMedCrossRefGoogle Scholar
  15. 15.
    Phan KL, Taylor SF. Clozapine-associated cardiomyopathy [letter]. Psychosomatics 2002 May-Jun; 43(3): 248PubMedCrossRefGoogle Scholar
  16. 16.
    Pieroni M, Cavallaro R, Chimenti C, et al. Clozapine-induced hypersensitivity myocarditis. Chest 2004 Nov; 126(5): 1703–5PubMedCrossRefGoogle Scholar
  17. 17.
    Reinders J, Parsonage W, Lange D, et al. Clozapine-related myocarditis and cardiomyopathy in an Australian metropolitan psychiatric service. Aust & NZ J Psych 2004; 38: 915–22CrossRefGoogle Scholar
  18. 18.
    Tanner MA, Culling W. Clozapine associated dilated cardiomyopathy. Postgrad Med J 2003 Jul; 79(933): 412–3PubMedCrossRefGoogle Scholar
  19. 19.
    Wehmeier PM, Heiser P, Remschmidt H. Myocarditis, pericarditis and cardiomyopathy in patients treated with clozapine. J Clin Pharm Ther 2005 Feb; 30(1): 91–6PubMedCrossRefGoogle Scholar
  20. 20.
    Wooltorton E. Antipsychotic clozapine (Clozaril): myocarditis and cardiovascular toxicity. CMAJ 2002 Apr 30; 166(9): 1185–6PubMedGoogle Scholar
  21. 21.
    Razmina M, Salem Y, Devaki S, et al. Clozapine induced myopericarditis: early recognition improves clinical outcome. Am J Ther 2006 May-Jun; 13(3): 274–6CrossRefGoogle Scholar
  22. 22.
    Roh S, Anh DH, Nam JH, et al. Cardiomyopathy associated with clozapine. Exp Clin Psychopharmocol 2006 Feb; 14(1): 94–8CrossRefGoogle Scholar
  23. 23.
    Degner D, Bleich S, Grohmann R, et al. Myocarditis associated with clozapine treatment [letter]. Aust N Z J Psychiatry 2000 Oct; 34(5): 880PubMedCrossRefGoogle Scholar
  24. 24.
    Kendell KR, Day JD, Hruban RH, et al. Intimate association of eosinophils to collagen bundles in eosinophilic myocarditis and ranitidine-induced hypersensitivity myocarditis. Arch Pathol Lab Med 1995 Dec; 119(12): 1154–60PubMedGoogle Scholar
  25. 25.
    Adnet P, Lestavel P, Krivosic-Horber R. Neuroleptic malignant syndrome. Br J Anaesth 2000 Jul; 85(1): 129–35PubMedCrossRefGoogle Scholar
  26. 26.
    Baciewicz AM, Chandra R, Whelan P. Clozapine-associated neuroleptic malignant syndrome. Ann Intern Med 2002 Sep 3; 137(5 Part 1): 374PubMedGoogle Scholar
  27. 27.
    Karagianis JL, Phillips LC, Hogan KP, et al. Clozapine-associated neuroleptic malignant syndrome: two new cases and a review of the literature. Ann Pharmacother 1999 May; 33(5): 623–30PubMedCrossRefGoogle Scholar
  28. 28.
    Phua J, Lim TK, Lee KH. B-type natriuretic peptide: issues for the intensivist and pulmonologist. Crit Care Med 2005 Sep; 33(9): 2094–13PubMedCrossRefGoogle Scholar
  29. 29.
    Sechtem U, Mahrholdt H, Hager S, et al. New non-invasive approaches for the diagnosis of cardiomyopathy: magnetic resonance imaging. Ernst Schering Res Found Workshop 2006; (55): 261–85PubMedCrossRefGoogle Scholar
  30. 30.
    Novartis Pharmaceuticals Australia. Clozaril and Myocarditis: Clinical Guidelines. North Ryde, N.S.W., Australia: Novartis Pharmaceuticals Australia, 1999 Dec 16Google Scholar
  31. 31.
    Novartis Pharmaceuticals Corporation. Clozaril (clozapine) tablets - Prescribing Information [online]. Available from URL: http://www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf [Accessed 2006 May 30]Google Scholar
  32. 32.
    The Royal College of Pathologists of Australasia. RCPA Manual [online]. Available from URL: http://www.rcpamanual.edu.au/sections/clinicalproblem.asp?s=25&i=466 [Accessed 2006 May 30]Google Scholar
  33. 33.
    Apple FS. Standardization of cardiac markers. Scand J Clin Lab Invest Suppl 2005; 240: 107–11PubMedCrossRefGoogle Scholar
  34. 34.
    Allison FS. An historical review of quality control in hematology. Am J Med Technol 1983 Sep; 49(9): 625–32PubMedGoogle Scholar
  35. 35.
    Ng CH, Chong SA, Lambert T, et al. An inter-ethnic comparison study of clozapine dosage, clinical response and plasma levels. Int Clin Psychopharmacol 2005 May; 20(3): 163–8PubMedCrossRefGoogle Scholar
  36. 36.
    Herdeiro MT, Figueiras A, Polonia J, et al. Physicians’ attitudes and adverse drug reaction reporting: a case-control study in Portugal. Drug Saf 2005; 28(9): 825–33PubMedCrossRefGoogle Scholar
  37. 37.
    State Coroner of Victoria. Clozapine Alert! Coronial Communique 2004 Nov; 2 (4): 1Google Scholar
  38. 38.
    Chan YC, Hankins MB. Clozapine as a short-term antipsychotic medication in patients with schizophrenia. Schizophr Res 2006 Jan 1; 81(1): 115–7PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Steven J. Haas
    • 1
    • 2
    • 3
  • Richard Hill
    • 4
  • Henry Krum
    • 1
    • 3
  • Danny Liew
    • 1
    • 3
  • Andrew Tonkin
    • 3
  • Lisa Demos
    • 3
  • Karen Stephan
    • 3
  • John McNeil
    • 3
  1. 1.Department of Epidemiology & Preventive Medicine, NHMRC Centre of Clinical Research Excellence in Therapeutics, Faculty of Medicine, Nursing & Health SciencesMonash University, Alfred HospitalMelbourneAustralia
  2. 2.Pharmacy DepartmentAlfred HospitalMelbourneAustralia
  3. 3.Department of Epidemiology & Preventive Medicine, Medication Safety Group, Faculty of Medicine, Nursing & Health SciencesMonash University, Alfred HospitalMelbourneAustralia
  4. 4.Adverse Drug Reactions Unit (ADRU)Therapeutic Goods AdministrationWodenAustralia

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