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| Journal of the New Zealand Medical Association,
03-October-2008, Vol 121 No 1283
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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.
MethodsThe 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.
ResultsIMMP 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.
DiscussionWe 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.harrison-woolrych@otago.ac.nz
References:
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