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The black box warning in the professional product labeling or “package insert” for the atypical antipsychotic drug clozapine (CLOZARIL) has been expanded to warn about an increased risk of fatal heart inflammation (myocarditis). A black box warning is the strongest type of warning that the Food and Drug Administration (FDA) can require in a drug’s labeling.
The previously existing boxed warning has been prominently relocated to the beginning of the package insert. A subsection has also been...
The black box warning in the professional product labeling or “package insert” for the atypical antipsychotic drug clozapine (CLOZARIL) has been expanded to warn about an increased risk of fatal heart inflammation (myocarditis). A black box warning is the strongest type of warning that the Food and Drug Administration (FDA) can require in a drug’s labeling.
The previously existing boxed warning has been prominently relocated to the beginning of the package insert. A subsection has also been added to the WARNINGS section entitled “Myocarditis” to provide information and guidelines related to this issue.
The new risk information added to the black box follows:
3. MYOCARDITIS ANALYSES OF POSTMARKETING SAFETY DATABASES SUGGEST THAT CLOZAPINE IS ASSOCIATED WITH AN INCREASED RISK OF FATAL MYOCARDITIS, ESPECIALLY DURING, BUT NOT LIMITED TO, THE FIRST MONTH OF THERAPY. IN PATIENTS IN WHOM MYOCARDITIS IS SUSPECTED, CLOZAPINE TREATMENT SHOULD BE PROMPTLY DlSCONTINUED. |
The new information added to clozapine’s WARNING section appears in the box below. In the WARNINGS section reference is made to numbers of patient years. This is a term used by epidemiologists to reflect the exposure of patients to drugs and can be thought of this way: one patient year equals one patient taking clozapine for one year.
What You Can Do
You should consider the risk of myocarditis as part of an informed decision to consent to treatment with clozapine for you or a family member. If you are already using clozapine and developed symptoms such as shortness of breath during the night, edema, or heart palpitations after you started using the drug, report this to your doctor.
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Myocarditis Post-marketing surveillance data from four countries that employ hematological [blood] monitoring of clozapine-treated patients revealed: 30 reports of myocarditis with 17 fatalities in 205,493 U.S. patients (August 2001); 7 reports of myocarditis with 1 fatality in 15,600 Canadian patients (April 2001); 30 reports of myocarditis with 8 fatalities in 24,108 U.K. patients (August 2001); 15 reports of myocarditis with 5 fatalities in 8,000 Australian patients (March 1999). These reports represent an incidence of 5.0, 16.3, 43.2, and 96.6 cases/100,000 patient years, respectively. The number of fatalities represent an incidence of 2.8, 2.3, 11.5, and 32.2 cases/100,000 patient years, respectively. The overall incidence rate of myocarditis in patients with schizophrenia treated with antipsychotic agents is unknown. However, for the established market economies (WHO), the incidence of myocarditis is 0.3 cases/100,000 patient years and the fatality rate is 0.2 cases/100,000 patient years. Therefore, the rate of myocarditis in clozapine treated patients appears to be 17-322 times greater than the general population and is associated with an increased risk of fatal myocarditis that is 14-161 times greater than the general population. The total reports of myocarditis for these four countries was 82 of which 51 (62%) occurred within the first month of clozapine treatment, 25 (31%) occurred after the first month of therapy and 6 (7%) were unknown. The median duration of treatment was 3 weeks. Of 5 patients rechallenged with clozapine, 3 had a recurrence of myocarditis. Of the 82 reports, 31 (38%) were fatal and 25 patients who died had evidence of myocarditis at autopsy. These data also suggest that the incidence of fatal myocarditis may be highest during the first month of therapy. Therefore, the possibility of myocarditis should be considered in patients receiving Clozaril (clozapine) who present with unexplained fatigue, dyspnea [difficult breathing, tachypnea [fast breathing], fever, chest pain, palpitations, other signs or symptoms of heart failure, or electrocardiographic [EKG or ECG] or findings such as ST-T wave abnormalities or arrhythmias. It is not known whether eosinophilia [an increase in the number of certain white cells] is a reliable predictor of myocarditis. Tachycardia [rapid heart rate], which has been associated with Clozaril (Clozapine) treatment, has also been noted as a presenting sign in patients with myocarditis. Therefore, tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis. Prompt discontinuation of Clozaril (clozapine) treatment is warranted upon suspicion of myocarditis. Patients with clozapine-related myocarditis should not be rechallenged [restarted] with Clozaril (clozapine). |
