The Food and Drug Administration (FDA) announced in late February that Novartis Pharmaceuticals Corp. had agreed to add a new section to the boxed warnings in the labeling of its atypical antipsychotic, Clozaril (clozapine). In addition, the entire boxed-warnings section has been moved to the front of the labeling insert in an effort to emphasize the relative dangers of prescribing the drug.

The new section warns prescribers of the increased risk of patients on clozapine developing a potentially fatal myocarditis, most commonly in the initial three to six weeks of drug therapy. FDA officials said that the added warning further strengthens the recommendation that clozapine therapy be reserved for those patients whose schizophrenia has proven refractory to other approved treatments.

Overall, according to postmarketing surveillance data from four countries, 82 cases of myocarditis have been reported in patients receiving clozapine. They have resulted in 31 deaths—a 38 percent mortality rate.

The established incidence of myocarditis, according to the data, is 0.3 cases per 100,000 patient years of exposure to clozapine, with a fatality rate of 0.2 cases for 100,000 patient years. Although the incidence of myocarditis varies greatly between subgroups of the general population—for example, between children and the elderly—these rates represent an incidence among those taking clozapine of at least 17 times greater than the average of the overall general population and a mortality rate of at least 14 times greater than the general population.

According to cardiologists consulted by Psychiatric News, the development of myocarditis may be difficult to diagnose in patients with schizophrenia who are being treated with clozapine.

First of all, myocarditis in general presents with variable and usually vague symptoms. Most commonly patients have tachycardia, which has also been associated with patients on the drug who have no signs of myocarditis. Patients may experience palpitations. In patients whose heart muscle is inflamed, corresponding fatigue that is otherwise unexplained and shortness of breath are also common. Some patients may experience an atypical, hard-to-describe chest pain that could be referred to as dull, constant, or heavy. Fever, usually low grade, is often present, but may be entirely absent.

In addition, cardiologists told Psychiatric News that patients with myocarditis may have an elevated white blood count and/or elevated erythrocyte sedimentation rate (ESR) and often show an enlarged cardiac silhouette on a chest X-ray. Some patients’ electrocardiograms may show nonspecific ST-T wave abnormalities.

According to the new labeling, because tachycardia is the most common presenting symptom of myocarditis, patients who develop increased heart rates during the first month of clozapine therapy should be monitored closely for any other signs of developing myocarditis. If suspicion of myocarditis arises, clozapine should be discontinued immediately and a complete cardiac evaluation sought.

Patients who develop clozapine-related myocarditis should not be restarted on the drug once the myocarditis resolves as postmarketing data also revealed the majority of cases recur upon reinitiation of the drug.

Novartis and the FDA are urging psychiatrists to report any and all adverse events in patients taking clozapine to either the company’s surveillance program or the FDA’s MedWatch program, regardless of whether a direct connection to the medication is suspected.

Adverse events in patients taking clozapine should be reported to Novartis (for those taking the Clozaril brand) at (800) 448-5938 or online at www.novartis.com. Reports involving both the Novartis brand and the available generic may be reported to the FDA’s MedWatch program by phone at (800) FDA-1080, by fax at (800) FDA-0178, or on the Web at www.accessdata.fda.gov/scripts/medwatch. ▪