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Published: October 2000

Potentially fatal complications of clozapine therapy: myocarditis, venous thromboembolism and constipation

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

Prescriber Update 20: 14–18
October 2000

Medsafe Editorial Team

15 cases of myocarditis (five fatal) and eight of cardiomyopathy (one fatal) with clozapine have been reported to the Australian Adverse Drug Reactions Advisory Committee.  All cases of myocarditis occurred within the first three weeks of therapy.   Patients taking clozapine who present with flu-like symptoms, dyspnoea, tachycardia, chest pain and other signs and symptoms of heart failure should be investigated for myocarditis with immediate referral to a cardiac unit.
During an 11-year period six cases of pulmonary embolism (five fatal) and six of venous thrombosis were reported to the Swedish Adverse Drug Reactions Advisory Committee.  During the same period only three cases of VTE were reported in association with other antipsychotic medication.  Eight of the cases of VTE with clozapine occurred within the first three months of therapy.
Clozapine should be withdrawn promptly under the supervision of a psychiatrist if myocarditis or VTE develop, and alternative antipsychotic therapy should be commenced to avoid recurrence of schizophrenia.
At least five deaths from complications of bowel obstruction with clozapine have been recorded in the literature.  One study found 60% of patients taking clozapine had varying degrees of constipation.  Patients taking clozapine should be encouraged to exercise, take plenty of liquid and have a high fibre diet to reduce the risk of constipation.  Clinicians should ask about bowel habits and give a laxative, if necessary.
Despite the range of life-threatening adverse reactions, clozapine is effective and well tolerated in many patients.  One epidemiological study found that it reduced the risk of death, largely by reducing the suicide rate to a quarter of that found in past users of clozapine.

Myocarditis
Myocarditis risk highest in first weeks
Cardiomyopathy develops later in the course of therapy
Investigate patients with flu-like symptoms, dyspnoea, tachycardia
A psychiatrist should supervise clozapine withdrawal
Venous thromboembolism (VTE)
Six cases of pulmonary embolism (PE) with clozapine in Swedish data
The evidence favours a causal relationship between clozapine and VTE
Possible symptoms of DVT or PE should be investigated
Constipation
Five deaths from complications of gastrointestinal obstruction
Exercise, plenty of liquid and high fibre diet reduce risk of constipation
Epidemiological evidence: clozapine reduces schizophrenic suicide rate
References

Myocarditis

The need to consider myocarditis as one cause of flu-like symptoms in those taking clozapine was discussed in the June 1995 issue of Prescriber Update. 1  A recent study2 based on cases reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC) from January 1993 to March 1999 extends these concern.  During the six years of the study, 8000 patients started clozapine therapy in Australia and 15 cases of myocarditis and 8 of cardiomyopathy for which there was objective evidence of the diagnosis were reported.  

Myocarditis risk highest in first weeks

All cases of myocarditis developed within the first 21 days (median 15 days) of initiating therapy.  Five of the patients died, three with apparently no warning symptoms.  In the other patients symptoms included malaise, fatigue, chest pain, palpitations, dyspnoea and fever.  Six patients had peripheral blood eosinophilia; it is not clear whether all were checked.  The authors commented that the time to onset of symptoms was consistent with an IgE-mediated hypersensitivity reaction, and the eosinophilia was suggestive of an acute drug reaction.

The worldwide incidence of fatal myocarditis in 1990 was estimated to be 3.3 per 107 people per month.3  In this series, the rate was 5 per 8000 during the first month of clozapine.  The high relative rate points to a causal relationship with clozapine.

Cardiomyopathy develops later in the course of therapy

Of the eight cases of cardiomyopathy, one patient was reported to have died, and one to have improved.  The patient who died continued clozapine because of therapeutic benefit despite known cardiac dysfunction.  Symptoms of cardiomyopathy included dyspnoea, tachycardia, palpitations and symptoms and signs of acute heart failure.  These developed after 2-36 months (median 12 months).   The authors suggested that dilated cardiomyopathy may be a more chronic form of myocarditis.

Novartis has analysed 125 reports of myocarditis with clozapine.4  35 of these cases were fatal.  53% occurred in the first month of therapy, and a small number (4.8%) occurred more than 2 years after commencement of clozapine.  70% of the patients in this series were men.

The Centre for Adverse Reactions Monitoring (CARM) has received no reports of myocarditis, but one report of fatal cardiomyopathy.  For this case no data were supplied on duration of therapy or the course of the illness.

Investigate patients with flu-like symptoms, dyspnoea, tachycardia

If patients taking clozapine present with flu-like symptoms, fever, myalgia, dizziness or faintness, chest pain, dyspnoea, tachycardia or palpitations and other signs or symptoms of heart failure consideration should always be given to a diagnosis of myocarditis.  Suspicion should be heightened if the symptoms develop during the first 6-8 weeks of therapy. It should be noted, however, that flu-like symptoms may also occur during the titration period as a result of clozapine’s α-adrenergic properties. Patients in whom myocarditis is suspected should be referred immediately to a cardiac unit for evaluation.

A psychiatrist should supervise clozapine withdrawal

Consultation with a cardiologist and the prescribing psychiatrist is necessary to consider whether clozapine should be withdrawn pending such evaluation. If myocarditis is considered likely, withdrawal is recommended to reduce further cardiac damage.  It is important to recognise that withdrawal may lead to relapse of psychosis and that clozapine may not be as effective following reinitiation as it was during initial treatment.  Any withdrawal should be under the supervision of a psychiatrist with substitution of appropriate alternative therapy to avoid relapse.

Venous thromboembolism (VTE)

Six cases of pulmonary embolism (PE) with clozapine in Swedish data

Recently a case series5 of six cases of pulmonary embolism, of which five were fatal, and six cases of venous thrombosis was published, based on reports collected by the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) over an 11-year period. Each diagnosis was confirmed by necropsy, computed tomography or phlebography.  In eight of the cases, the adverse reaction occurred within the first three months of clozapine therapy.  Only one of the cases was taking an oral contraceptive.  No information was available on the presence of factor V Leiden mutation, or other types of thrombophilia.  The authors calculated an incidence of 1 case per 2000 to 6000 treated patients based on Swedish pharmacy sales for clozapine.  

The evidence favours a causal relationship between clozapine and VTE

The authors of the article presenting the Swedish data5 observed that only three cases of thromboembolism in people aged 18-60 years who were taking other antipsychotic agents were reported to SADRAC over the period of their study.  They concluded that venous thromboembolism is not associated with psychoses nor is it a class effect of antipsychotics.  A large study6 of mortality with clozapine which used American data found a death rate from pulmonary embolism of 30 per 100,000 person-years in users of clozapine aged 10-54 years, compared with no deaths in recent users.  The balance of evidence points to a causal association between clozapine and venous thromboembolism,7,8 but further confirmation is required.

Possible symptoms of DVT or PE should be investigated

Patients taking clozapine who develop possible symptoms of deep vein thrombosis or pulmonary embolism should be investigated to exclude or confirm these conditions.  The risk should be considered to be heightened if patients present within the first three months of therapy.

Clozapine should be withdrawn immediately following a positive diagnosis or if there is a high level of suspicion.  The patient’s psychiatrist should supervise the discontinuation and initiation of alternative therapy.

Constipation

Five deaths from complications of gastrointestinal obstruction

Constipation is known to occur with any anticholinergic medication, particularly at high doses, but it appears that constipation with clozapine is more common than with other similar agents.  Furthermore, in the literature,9,10,11 there are at least five reports of death from complications of gastrointestinal obstruction associated with clozapine.  Two of the patients9,10 were found to have died following aspiration of faeculent vomitus secondary to bowel obstruction.  Neither patient was taking any other anticholinergic medication.

In one study9 of 53 patients taking clozapine, 60% were found to have constipation.  Only six of the total 53 were taking other anticholinergic medication.   Most of the cases were mild, but 12% required repeated use of enemas.

The CARM database holds two reports of constipation and two of paralytic ileus with clozapine.  None of these cases was fatal.  In one case a man of about 45 years who had been taking clozapine for about 20 months was admitted with a pain in the left shoulder blade.  He was found to have a grossly distended upper intestine.  The problem was managed with daily lactulose and clozapine was continued.  Delayed diagnosis is a characteristic of the cases of severe constipation with clozapine.

Exercise, plenty of liquid and high fibre diet reduce risk of constipation

Patients taking clozapine should be encouraged to exercise, take plenty of fluids and have a high fibre diet in order to reduce the risk of serious constipation.9 Clinicians should regularly ask about bowel habits and give a laxative, if required.  Slower titration of the clozapine dose on initiation of therapy may also be helpful.9  Clozapine need not usually be withdrawn if constipation develops, but the problem requires vigilance and careful management, especially if it is serious.

Epidemiological evidence: clozapine reduces schizophrenic suicide rate

Despite a range of life-threatening adverse reactions, including agranulocytosis and diabetic ketoacidosis,12 together with the events described here, clozapine is an important agent in the treatment of refractory schizophrenia and other psychoses, and it is well-tolerated by most patients.  The epidemiological study of deaths in users and former users of clozapine by Walker et al6 found that the rate of death was lower among current users (322 per 100,000 person-years) than among past users (696 per 100,000 person-years).   The reduction in death rate during current use was largely accounted for by a reduction in suicide rate compared with past use (relative risk 0.25;  95% CI 0.10-0.30). This reduction in suicide rate is testimony to the therapeutic efficacy of clozapine.

References
  1. Clozapine and myocarditis.  Prescriber Update No.9, June 1995, p.7-8.
  2. Kilian JG, Kerr K, Lawrence C, Celermajer DS.  Myocarditis and cardiomyopathy associated with clozapine.  Lancet 1999;354:1841-45.
  3. Murray CJ, Lopez AD.  Global health statistics: a compendium of incidence, prevalence, and mortality estimates for over 200 conditions.  In: Global Burden of Disease and Injury Series, Vol II.  Boston: Harvard University Press, 1992:1-33.
  4. Warner B, Schadelin J.  Clinical safety and epidemiology.  Leponex/Clozaril and myocarditis.  Novartis Pharma AG, Basel, Switzerland, November 1999.
  5. Hagg S, Spigset O, Soderstrom TG.  Association of venous thromboembolism and clozapine.   Lancet 2000;355:1155-6.
  6. Walker AM, Lanza LL, Arellano F, Rothman KJ.  Mortality in current and former users of clozapine.  Epidemiology 1997;8:671-7.
  7. Coodin S, Ballegeer T.  Clozapine therapy and pulmonary embolism.  Can J Psychiatry 2000;45(5):395.
  8. Suttmann I, Ditter S, Landgraf R, Schulze J, Folwaczny C.  Clozapine and sudden death.  Lancet 2000;355:842-3.
  9. Hayes G, Gibler B.  Clozapine-induced constipation.  Am J Psychiatry 1995;152:298.
  10. Drew L, Herdson P.  Clozapine and constipation: a serious issue.  Aust NZ J Psychiatry 1997;31:149-50.
  11. Clozapine - gastrointestinal obstruction.  WHO Pharmaceuticals Newsletter Nos. 3&4, Mar/Apr 1999, p.6.
  12. Clozapine and hyperglycaemia.  Prescriber Update No.18, June 1999, p.36-8.