Drug Interaction Report

MONITOR: The concomitant administration of some macrolide antibiotics may reduce the metabolic activation of the prodrug clopidogrel and its antiplatelet effects. The proposed mechanism is inhibition of CYP450 3A4 enzymatic activity, which is responsible for the conversion of clopidogrel to its active metabolite. After coadministration of erythromycin stearate 250 mg four times a day and clopidogrel 75 mg/day to healthy subjects (n=9), the percent platelet aggregation was 42% with clopidogrel alone, 55% with clopidogrel plus erythromycin, and 93% at baseline. After coadministration of single doses of troleandomycin 500 mg and clopidogrel 450 mg, the percent platelet aggregation was 45% with clopidogrel alone, 78% with clopidogrel plus troleandomycin, and 93% at baseline. Clarithromycin also inhibits CYP450 3A4 activity and is also expected to affect clopidogrel metabolism.

MANAGEMENT: Until more information is available, monitoring for altered efficacy of clopidogrel may be advisable if a macrolide is coadministered with clopidogrel. Azithromycin and dirithromycin do not inhibit CYP450 3A4 and are theoretically not expected to interact with clopidogrel.