Journal of the New Zealand Medical Association, 03-October-2008, Vol 121 No 1283
Clozapine and myocarditis: a case series from the New Zealand Intensive Medicines Monitoring Programme
Geraldine R Hill, Mira Harrison-Woolrych
Clozapine, marketed in New Zealand as Clozaril® (Novartis), is an atypical antipsychotic medicine indicated in patients with treatment-resistant schizophrenia. Clozapine has been shown to be more effective than typical neuroleptic medication for the treatment of schizophrenia,1 but because of the risk of agranulocytosis (which occurs in about 1% of patients in the first year of treatment)2 use of clozapine is limited to patients who have been non-responsive to, or intolerant of, at least two other antipsychotic agents.
Royal Australian and New Zealand College of Psychiatrists' clinical practice guidelines for the management of schizophrenia and related disorders recommend that clozapine be introduced as soon as treatment resistance to at least two antipsychotics has been demonstrated.3
The first case of myocarditis in a patient taking clozapine was reported in the literature in 1980,4 however, it was not recognised as an adverse reaction to clozapine until 1999 when Killian et al reported 15 cases of myocarditis (5 fatal) and 8 cases of cardiomyopathy (1 fatal) that had been notified to the Australian Adverse Reactions Advisory Committee (ADRAC) from among 8000 patients who had taken clozapine between January 1993 and March 1999.5
The incidence of clozapine-associated myocarditis reported by Killian et al was about 1 in 500 patients treated with clozapine, or 96.6 cases per 100,000 patient-years. The incidence has since been reported as 5.0, 16.3, and 43.2 cases per 100,000 patient years in the US, Canada, and UK, respectively.6
In 2001, a Bayesian neural network analysis by the World Health Organization’s programme for international drug monitoring, which received data from national pharmacovigilance centres in 60 countries, demonstrated a statistically significant association between clozapine and myocarditis that was much stronger than the association between any other antipsychotic agent and myocarditis.7
In February 2002, Novartis issued a ‘Dear Health Care Provider’ letter informing doctors of changes made to the boxed warning in the product data sheet to draw doctors’ attention to the risk of myocarditis.6
Haas et al8 recently reported a series of 116 cases of suspected myocarditis associated with use of clozapine in Australia during the period 1993–2003. They reported an estimated incidence between 0.7% and 1.2% of treated patients. The median time to onset was 17 days among those for whom treatment dates were known and the majority (88%) of cases developed myocarditis within 6 months of starting clozapine.
Clozapine has been available in New Zealand since 1993. A clozapine register is operated by Novartis to monitor weekly blood tests, a practice which, in the United States, has been shown to reduce the number of deaths from agranulocytosis.9 Monitoring of clozapine by the Intensive Medicines Monitoring Programme (IMMP) commenced in December 2000.
The aim of this study is to describe the New Zealand experience of clozapine-associated myocarditis by examining a series of cases reported to the IMMP.
The IMMP carries out post-marketing surveillance on selected medicines by conducting prospective observational cohort studies using prescription event monitoring (PEM).10 The cohort for each monitored medicine is established using prescription data collected at regular intervals from virtually all community and hospital pharmacies nationwide. Information collected includes the name, address, National Health Identification (NHI) number, gender and date of birth of the patient, doctor identification, date of dispensing, medicine name and formulation, dose, and quantity of medicine dispensed.
The IMMP has monitored four of the atypical antipsychotic medicines available in New Zealand: clozapine, olanzapine, quetiapine, and risperidone. A system of enhanced spontaneous reporting has been utilised to monitor these medicines. Accordingly, reports of adverse reactions were obtained through spontaneous reporting by doctors, nurses, pharmacists and pharmaceutical companies. All clinical events are assessed and coded by medical assessors using terms from a dictionary based on WHOART (World Health Organization Adverse Reaction Terminology).10 Causality assessment is performed for each event to determine the relationship with the medicine.11
For this case series, all cases in the IMMP database coded as “myocarditis” associated with clozapine were identified and reviewed. This term was only used when the diagnosis of myocarditis was confirmed by the reporter and/or by record linkage with NZHIS (New Zealand Health Information Service) databases where myocarditis was recorded as a discharge diagnosis.
The processes and practices of the IMMP have been set up to comply with the New Zealand Health Information Privacy Code and the Privacy Commissioner has been advised of the purpose and methods of the programme. The programme has ethical approval and as this study used routine IMMP methods additional ethical approval was not required.
IMMP case reports—Table 1 summarises the details of 25 case reports of myocarditis associated with clozapine reported to the IMMP between March 2000 and 15 November 2007. Fifteen cases were reported by the pharmaceutical company and the remaining 10 cases were reported spontaneously by the patient’s doctor.
Patient demographics—Of the 25 cases, 3 (12%) were female, 21 (84%) were male, and 1 was of unknown gender. The age of patients ranged from 17 to 72 years with a mean age of 35.5 years (median 30.5 years). Ethnicity data were available for 24 of the 25 cases: 17 (68%) patients were NZ European, 5 (20%) were NZ Maori, 1 (4%) was a Pacific Islander, and 1 was of other ethnicity. Patients were treated for myocarditis mainly in tertiary referral centres throughout New Zealand. About-two thirds of patients (17 of 25) were treated in the Auckland region.
Dose of clozapine—The dose of clozapine at the time of the adverse event was recorded for 20 patients. The dose ranged from 12.5 mg daily (for an elderly patient) to 500 mg daily. Among patients for whom dose was recorded, the mean daily dose was 256 mg and the median daily dose was 238 mg.
Time to onset/treatment duration—Information on the time from start of clozapine treatment to onset of myocarditis was available for 24 of the 25 cases. Twenty cases (80%) began within 1 month of starting clozapine, 1 case presented 2.5 months after starting clozapine, and 3 cases presented more than a year after starting the medicine (including 1 which presented more than 9 years after starting treatment).
Outcome—Two patients (8%) died from clozapine associated myocarditis and 23 patients survived this event (although 2 died at a later date). Whether or not clozapine was continued at the time of the myocarditis event was reported for all patients in this series. Of the 23 patients who survived, clozapine was stopped in 21 patients and continued in 2 patients. In 14 of the 21 patients who stopped clozapine there was evidence of recovery following withdrawal of the medicine (positive dechallenge). Of the remaining 7 patients, the outcome following withdrawal of clozapine was unknown for 5 patients, and 2 patients had not yet recovered at the time of reporting.
Causality assessment—Causality assessment was performed for all 25 cases on the basis of the available information reported to IMMP. In 14 cases, the relationship of myocarditis with clozapine was assessed as ‘probable’ as all these patients had a positive dechallenge (as described above). For the remaining 11 cases the relationship was assessed as ‘possible’.
Concomitant use of another atypical antipsychotic medicine—Four (16%) of the cases were known to be taking another atypical antipsychotic (2 risperidone, 1 quetiapine, and 1 quetiapine plus olanzapine) in addition to clozapine at the time myocarditis developed. These were in addition to patients who were down-titrating from other atypical antipsychotic medicines whilst starting clozapine, in whom concomitant atypical medicines were not recorded as concomitant medication.
We have presented a New Zealand case-series of clozapine-associated myocarditis which includes 25 patients whose information has been reported to IMMP from March 2000 until July 2007.
Demographic data from these New Zealand cases are generally similar to those reported in other case series.5,8,12–14 The recent Australian review (Haas et al)8 of 116 cases of suspected myocarditis associated with the use of clozapine (between 1993 and 2003) reported that 77.6% of cases were male and the median age was 30 years. This is comparable to the male preponderance (84%) and median age of 30.5 years observed in our series.
Most of the cases of myocarditis reported to the IMMP (80%) developed within one month of commencing clozapine treatment. This is consistent with other case series. In the original Australian report by Killian et al, all 15 cases of myocarditis developed within 1 month of starting clozapine.5 In the larger, more recent series by Haas et al, 79% of cases developed within 1 month of starting clozapine and nearly 90% developed within 6 months of initiating clozapine therapy.8 However, it should be noted that clozapine-associated myocarditis occurred in several cases more than a year after starting treatment and the diagnosis should therefore not be overlooked in patients who have been on the medicine for some time. It should also be noted that one of the cases in this series developed myocarditis while taking a very low clozapine dose of 12.5 mg daily.
The proportion of cases in which myocarditis had a fatal outcome (8%) is similar in this case series to that reported in the recent Australian case series in which 12 (10.3%) of 106 patients with clozapine-associated myocarditis died.8 Similarly, the proportions of patients in the Australian series who had recovered, had not yet recovered at the time of reporting, and in whom the outcome was unknown were also comparable to those reported in this New Zealand series.
Clozapine-associated myocarditis is thought to be a drug-induced, acute hypersensitivity (type I, IgE-mediated) reaction, although other mechanisms have also been proposed including a type III allergic reaction or a direct toxic effect on the heart.5 Genetic variation and environmental differences have also been postulated to explain variable incidence rates in different countries.15 A case-control study is currently underway in Australia to examine risk factors for myocarditis.16 The study aims to identify possible genetic markers, in particular polymorphisms in the genes that code for enzymes involved in clozapine metabolism and the generation of the immune response.
The IMMP relies on data provided by the reporting doctors and the pharmaceutical company. While reporting rates are high, it is likely that more cases of clozapine induced myocarditis occurred than were reported to the IMMP. Cases were only included in this case series if the report included a diagnosis of myocarditis.
The methods used in this study were similar to methods used recently by Haas et al to describe the Australian case-series of suspected clozapine-associated myocarditis.8 However, unlike the earlier study by Killian et al,5 strict criteria for case-definition based on clinical and histological evidence were not applied.
Further examination of all clozapine reports in the IMMP database for events which may be presenting symptoms of myocarditis (such as fever, tachycardia, eosinophilia, sudden death) might identify more cases of myocarditis associated with clozapine. A further record-linkage study using national morbidity and mortality datasets would provide a fuller picture of the incidence of clozapine-associated myocarditis in New Zealand.
Funding statement: This work was supported by the NZ Ministry of Health (Medsafe) who provide the majority of IMMP funding for post-marketing surveillance. The IMMP has also received general unconditional donations towards monitoring from pharmaceutical companies, including Novartis, the sponsor of Clozaril in NZ. However, pharmaceutical companies have no role in the analysis or interpretation of IMMP data, or in the decision to submit articles for publication.
Author information: Geraldine R Hill, Research Fellow; Mira Harrison-Woolrych, Director; Intensive Medicines Monitoring Programme, Department of Preventive and Social Medicine, University of Otago, Dunedin
Acknowledgement: We thank all the New Zealand doctors who actively support the IMMP.
Correspondence: M Harrison-Woolrych, Intensive Medicines Monitoring Programme, Department of Preventive and Social Medicine, University of Otago, PO Box 913, Dunedin, New Zealand. Fax: +64 3 4797150; email: Mira.email@example.com
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