Drug interactions between cisapride and clarithromycin

CONTRAINDICATED: Coadministration with the ketolide, telithromycin, as well as certain macrolide antibiotics may significantly increase the plasma concentrations of cisapride. The mechanism is inhibition of cisapride metabolism via CYP450 3A4. High plasma levels of cisapride 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. Azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4. In a study of 12 healthy volunteers, coadministration of clarithromycin (500 mg twice a day) and cisapride (10 mg four times a day) led to threefold increases in cisapride concentrations and an average QTc increase of 25 ms above pretreatment values. In contrast, monotherapy with cisapride was associated with a concentration-dependent QTc elevation that amounted to 6 ms during steady state. Repeated doses of telithromycin have been reported to increase steady-state cisapride peak plasma concentrations by 95%, resulting in significant increases in QTc interval. MANAGEMENT: Given the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of cisapride, the use of cisapride with clarithromycin, erythromycin, troleandomycin, or telithromycin is considered contraindicated. Depending on organism susceptibility, azithromycin and dirithromycin may be appropriate alternatives during therapy with cisapride.