Drug interactions between astemizole and clarithromycin

CONTRAINDICATED: Coadministration with the ketolide, telithromycin, as well as certain macrolide antibiotics may significantly increase the plasma concentrations of astemizole and terfenadine. The mechanism is inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of astemizole and terfenadine. High plasma levels of these agents 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 9 healthy volunteers, erythromycin (500 mg every 8 hours for 7 days) increased the mean steady-state peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of the pharmacologically active metabolite of terfenadine (60 mg twice a day) by 107% and 170%, respectively, compared to administration of terfenadine alone. Three of the subjects also had accumulation of unmetabolized terfenadine. Electrocardiographic data revealed changes in the QT interval in a subset of subjects who demonstrated drug accumulation.

MANAGEMENT: Given the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of astemizole and terfenadine, the use of these agents with clarithromycin, erythromycin, troleandomycin, or telithromycin is considered contraindicated. Loratadine, cetirizine, or fexofenadine may be safer alternatives during therapy with telithromycin or macrolides. Depending on organism susceptibility, azithromycin and dirithromycin may be appropriate alternatives during therapy with astemizole or terfenadine.