[U.S. Food and Drug Administration]

FDA Medical Bulletin * October 1996 * Volume 26 Number 3

PIMOZIDE (ORAP) CONTRAINDICATED
WITH CLARITHROMYCIN (BIAXIN)
AND OTHER MACROLIDE ANTIBIOTICS

The labeling for pimozide (Orap), approved for the treatment of TouretteĀ$Ās disorder, has been updated to contraindicate use of pimozide in patients receiving macrolide antibiotics such as clarithromycin, erythromycin, azithromycin, and dirithromycin. Two sudden deaths have been reported when clarithromycin was added to ongoing pimozide therapy.

Pimozide prolongs the QT interval of the electrocardiogram, an effect that is believed to predispose patients to fatal cardiac arrhythmias. Because of this, pimozide is not intended as a first-choice treatment for TouretteĀ$Ās disorder. Electrocardiogram monitoring is recommended, and the dose of pimozide should not exceed 10 mg daily. Pimozide is contraindicated with other drugs that prolong the QT interval.

A plausible explanation for the cases of sudden death with concomitant clarithromycin and pimozide is a metabolic interaction that leads to increased pimozide plasma concentrations and thus an increased risk of cardiac arrhythmia. The macrolide antibiotics are inhibitors of the metabolic enzyme cytochrome P450 3A. Preliminary in vitro data suggest that clarithromycin is capable of inhibiting the metabolism of pimozide, which appears to be a substrate for cytochrome P450 3A (Flockhart DA, Richard E, Woosley RL, et al. A metabolic interaction between clarithromycin and pimozide may result in cardiac toxicity. Clin Pharmacol Ther. 1996;59:189. Abstract).

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