Published: May 2008
ADR update

Clozapine and Achy Breaky Hearts (Myocarditis and Cardiomyopathy)

Information on this subject has been updated. Read the most recent information.

Prescriber Update 29(1): 10–12
May 2008

Medsafe Editorial Team

Clozapine can cause myocarditis, which may be fatal. It has also been associated with cardiomyopathy.  While risk factors are unknown, pre-treatment cardiovascular screening is recommended.  Myocarditis generally occurs one to two months after commencing clozapine; cardiomyopathy usually presents later, at around nine months.  Common presenting symptoms of myocarditis include chest pain, tachycardia, and flu-like symptoms.  These warrant immediate investigation and withholding of clozapine.

Clozapine-associated myocarditis is uncommon but serious

Prescribers are reminded that clozapine is associated with an increased risk of cardiac disorders, the most serious being myocarditis.  While not a common adverse effect, clozapine-associated myocarditis can be fatal, affects relatively young people, can have a rapid onset, and is not necessarily dose-related.1  In one published case series, fatalities occurred in 10.3% of the clozapine-treated patients who developed myocarditis.1  Compared to the general population, clozapine-treated patients have a 17 to 322 times greater rate of myocarditis, and a 14 to 161 times greater rate of fatal myocarditis.2

The initial symptoms of myocarditis can be non-specific, such as tachycardia, fever, and flu-like symptoms.3  The most probable mechanism is a medicine-induced, acute hypersensitivity (type 1, IgE-mediated) reaction, which may be part of a drug hypersensitivity syndrome.2

Cardiomyopathy also appears to be a risk associated with clozapine

To a lesser extent, clozapine has also been linked to cardiomyopathy.  However, there is uncertainty if this is a consequence of myocarditis being unrecognised in the early stages, or whether cardiomyopathy is a clinically distinct and chronic cardiac disorder.1,4

Estimates of the incidence of clozapine-associated myocarditis range from 1 in 10,000 to 1 in 500 patients;5 and for cardiomyopathy with clozapine, about 1 per 2000 patient-years.4  True incidences are difficult to calculate due, in part, to the non-specificity of presenting signs and symptoms, and incomplete definitive diagnostic evidence, making interpretation of case reports complex.5

Characteristics of local cases reflect those reported in Australia

In New Zealand, 25 cases of clozapine-associated myocarditis and 17 of cardiomyopathy were reported between March 2000 and November 2007. In Australia, there were 116 cases of myocarditis (including 12 deaths) and 90 cases of cardiomyopathy associated with clozapine use reported during the January 1993-December 2003 time period. The median age of the patients was 30 years, and 84 of the cases developed myocarditis within four weeks of commencing clozapine.1

Risk factors remain elusive but dose probably not a contributor

To date, no clear risk factors have been identified for clozapine-associated myocarditis and cardiomyopathy.  The rate of upward dose titration has been questioned as a possible contributor but there is no clear evidence to support this theory.1  In one published case series, over 90% of the cases of clozapine-associated myocarditis reported a daily dosage range of 100-450mg, suggesting that dose is not necessarily a risk factor.1

Onset of myocarditis is often within the first month of clozapine treatment

Common presenting symptoms of clozapine-associated myocarditis include fever, dyspnoea, flu-like symptoms, tachycardia, and chest pain.  Clinical findings commonly include ECG abnormalities, elevated creatine kinase (CK) and troponin levels, and eosinophilia.  Most cases of myocarditis develop within one month of commencing clozapine treatment.1,2  In comparison, cardiomyopathy usually has a more latent onset, at approximately nine months after starting clozapine.3

Conduct cardiovascular assessment before starting patients on clozapine

Pre-treatment cardiovascular screening should include a full history of pre-existing cardiac problems.6  Use of clozapine in patients with severe cardiac disorders (e.g. myocarditis) is contraindicated.7,8  There are guidelines for myocarditis which recommend baseline tests of ECG, and measurement of troponin (I or T), serum creatinine and eosinophils; then repeating ECG and troponin (I or T) at 7 and 14 days after starting clozapine; but these are not New Zealand-specific guidelines.9  Consider repeating troponin (I or T) and ECG once full maintenance dose is achieved.6  Echocardiography at six months has been suggested to screen for possible developing cardiomyopathy.9  Prescribers should bear in mind that the sensitivity of CK for myocarditis may be very low,9 and it is not known whether eosinophilia is a reliable predictor of myocarditis.7,8

Prescribers, patients and caregivers need to be vigilant during treatment

Tachycardia that persists at rest, accompanied by arrhythmias, shortness of breath or signs and symptoms of heart failure, may rarely occur during the first month of clozapine treatment and very rarely thereafter.  The occurrence of these signs and symptoms necessitates an urgent diagnostic evaluation for myocarditis, especially during the titration period.7,8

The possibility of myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, dyspnoea, tachypnoea, fever, chest pain, tachycardia, palpitations, other signs and symptoms of heart failure, ECG changes (such as ST-T wave abnormalities) or arrhythmias - particularly during the first two months of clozapine treatment.7,8  Patients taking clozapine and their caregivers should be advised to maintain vigilance (especially in the first two months) for the development of these symptoms which are suggestive of myocarditis and to see their doctor immediately if these occur.

Promptly investigate if suspicious and avoid re-exposure if diagnosis confirmed

Prescribers should have a high index of suspicion with a low threshold for cardiologist referral, especially in young patients without cardiac disease risk factors.5,10  In patients where myocarditis is suspected, further doses of clozapine should be withheld and the patient referred urgently to a cardiologist for investigations; additionally, it may be useful for the GP to arrange an immediate ECG and troponin test, as this will inform the urgency of the cardiologist appointment and possibly also indicate if hospital admission is warranted.

If diagnosis of myocarditis is confirmed, clozapine treatment should be stopped and future exposure avoided.6  Reporting such events to the Centre for Adverse Reactions Monitoring in Dunedin will ensure that a warning or danger alert is entered into the national Medical Warning System for that patient, so that the risk of re-exposure to clozapine can be avoided when the patient accesses health care in the future.  If myocarditis is ruled out, consider other possible diagnoses such as cardiomyopathy.1

Competing interests (authors): none declared.

  1. Haas SJ, Hill R, Krum H, et al. Clozapine-associated myocarditis: A review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993-2003. Drug Safety 2007;30(1):47-57.
  2. Adverse Drug Reactions Advisory Committee (ADRAC). Serotonin syndrome. Australian Adverse Drug Reactions Bulletin 2007;26(3).
  3. Merrill DB, Dec GW, Goff DC. Adverse cardiac effects associated with clozapine. Journal of Clinical Psychopharmacology 2005;25(1):32-41.
  4. Kilian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354:1841-1845.
  5. Tanner M A, Culling W. Clozapine associated dilated cardiomyopathy. Postgrad Med J 2003;79:412-413.
  6. Personal communication, July 2007 and February 2008. Cardiologist, Wellington.
  7. Novartis New Zealand Limited. Clozaril (clozapine) data sheet 2 October 2007.
  8. Douglas Pharmaceuticals Ltd. Clopine (clozapine) data sheet September 2007.
  9. Novartis Pharmaceuticals Australia Pty Ltd. Clozaril and Myocarditis: Clinical Guidelines. 16 December 1999.
  10. Magnani JW, Dec GW. Myocarditis: Current trends in diagnosis and treatment. Circulation 2006;113:876-890.