Clozapine-related neutropenia, myocarditis and cardiomyopathy adverse event reports in Australia 1993–2014
- 263 Downloads
Clozapine is the gold-standard medicine for treating refractory schizophrenia but there are some notable serious adverse events (AE). We aimed to analyse reported rates of clozapine cardiac and haematological AEs in Australia.
Using data from the Therapeutic Goods Administration, we examined all reported clozapine AEs (1993–2014) with a specific focus on neutropenia, myocarditis and cardiomyopathy. We related AEs to clozapine-dispensing data in Queensland, scaled up to Australia.
There were 8561 AEs reported: neutropenia (13.7%), myocarditis (9.3%) and cardiomyopathy (3.8%). Reported rates of myocarditis and cardiomyopathy increased after 1999 following a myocarditis case series from Sydney. Cardiomyopathy AE rates have remained stable since then but myocarditis AEs have increased steadily. Neutropenia was more common in women, while cardiomyopathy and myocarditis were more common in men. There were five reported deaths from neutropenia and cardiomyopathy.
The rates of serious AEs (including deaths) are low and likely an underestimate of true rates and need to be considered by clinicians in balancing the risks and benefits. Continued education on the monitoring and treatment of these AEs for consumers, carers and health professionals is essential and reporting these to the relevant national reporting agency is crucial.
KeywordsClozapine Adverse events Myocarditis cardiomyopathy Neutropenia Agranulocytosis Pharmacovigilance
The authors thank the Therapeutic Goods Administration (TGA) of the Australian Government Department of Health for the data on adverse events. The authors thank Dr. Jenny Curnow from the University of Sydney for reviewing the haematological death cases. We acknowledge the research assistance of Mr. Andrew Kolomensky.
This study was funded from existing salaries. Dan Siskind is supported in part by an NHMRC Early Career fellowship (APP1111136). This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Compliance with ethical standards
Conflict of interest
The authors report no conflicts of interest.
No ethical approval was required as we used only secondary de-identified data sources.
- Andreassen OA, Djurovic S, Thompson WK, Schork AJ, Kendler KS, O'Donovan MC, Rujescu D, Werge T, van de Bunt M, Morris AP, McCarthy MI, International Consortium for Blood Pressure G, Diabetes Genetics R, Meta-analysis C, Psychiatric Genomics Consortium Schizophrenia Working G, Roddey JC, McEvoy LK, Desikan RS, Dale AM (2013) Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. Am J Hum Genet 92:197–209CrossRefPubMedPubMedCentralGoogle Scholar
- Australian Consensus Panel for Treatment-Refractory Schizophrenia (2010) Targeting treatment-refractory schizophrenia: a multidimensional outcomes approach to the diagnosis and management of incomplete recovery. https://www.trsconsensus.com.au. Accessed 10 August 2017
- Committee on Safety of Medicines (1993) Myocarditis with antipsychotics: recent cases with clozapine (Clozaril). Curr Prob Pharmacovigil 19:9–10Google Scholar
- De Hert M, Cohen D, Bobes J, Cetkovich-Bakmas M, Leucht S, Ndetei DM, Newcomer JW, Uwakwe R, Asai I, Moller HJ, Gautam S, Detraux J, Correll CU (2011) Physical illness in patients with severe mental disorders. II. Barriers to care, monitoring and treatment guidelines, plus recommendations at the system and individual level. World Psychiatry 10:138–151CrossRefPubMedGoogle Scholar
- Every-Palmer S, Ellis PM (2017) Clozapine-induced gastrointestinal hypomotility: a 22-year bi-national pharmacovigilance study of serious or fatal “slow gut” reactions, and comparison with international drug safety advice. CNS Drugs doi: https://doi.org/10.1007/s40263-017-0448-6
- MedDRA Maintenance and Support Services Organization (2013) Introductory guide MedDRA version 16.1. Chantilly. https://www.meddra.org/sites/default/files/guidance/file/intguide_16_1_english.pdf. Accessed 22 March 2018
- Orsolini L, Tomasetti C, Valchera A, Vecchiotti R, Matarazzo I, Vellante F, Iasevoli F, Buonaguro EF, Fornaro M, Fiengo AL, Martinotti G, Mazza M, Perna G, Carano A, De Bartolomeis A, Di Giannantonio M, De Berardis D (2016) An update of safety of clinically used atypical antipsychotics. Expert Opin Drug Saf 15:1329–1347CrossRefPubMedGoogle Scholar
- Siskind D, McCartney L, Kisely, S (2017a) Clozapine in treatment-resistant schizophrenia, author’s reply. Br J Psychiatry 210:299–300Google Scholar
- Siskind DJ, Harris M, Phillipou A, Morgan VA, Waterreus A, Galletly C, Carr VJ, Harvey C, Castle D (2017b) Clozapine users in Australia: their characteristics and experiences of care based on data from the 2010 National Survey of High Impact Psychosis. Epidemiol Psychiatr Sci 26:325–337CrossRefPubMedGoogle Scholar