Drug Interactions between azithromycin and pimozide

CONTRAINDICATED: Coadministration with the ketolide, telithromycin, as well as certain macrolide antibiotics may increase the plasma concentrations of pimozide. The mechanism is inhibition of pimozide metabolism via CYP450 3A4. High plasma levels of pimozide have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes; cardiac arrest; and sudden death. Macrolides that may significantly inhibit CYP450 3A4 include clarithromycin, erythromycin, and troleandomycin. In a study involving 12 healthy subjects, clarithromycin (500 mg orally every 12 hours for 5 days) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of pimozide (6 mg single oral dose) by 39% and 113%, respectively, compared to placebo. These alterations corresponded with significant prolongations of the maximum QTc interval that exceeded those produced by pimozide alone. Isolated cases of sudden death have been reported following addition of clarithromycin to ongoing pimozide therapy.

MANAGEMENT: The use of pimozide with telithromycin or macrolide antibiotics is considered contraindicated by the manufacturers, although azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4.