Drug Interaction Report

MONITOR: Coadministration with clarithromycin, a combined P-glycoprotein (P-gp) and strong CYP450 3A4 inhibitor, may increase the plasma concentrations of apixaban, which is a substrate of the efflux transporter as well as the isoenzyme. According to the manufacturer, clarithromycin (500 mg twice a day) led to 1.6- and 1.3-fold increases in apixaban AUC and Cmax, respectively. The clinical significance of these changes has not been established. In a retrospective cohort study that used data from the Taiwan National Health Insurance database and included 91,330 patients with nonvalvular atrial fibrillation who received at least 1 non-vitamin K oral anticoagulant (NOAC) prescription for apixaban, dabigatran, or rivaroxaban, the adjusted incidence rate for major bleeding was approximately 40% lower for concurrent use of clarithromycin or erythromycin compared to NOAC use alone.

MANAGEMENT: No dosage adjustment for apixaban is recommended during coadministration with clarithromycin. However, caution is advised and pharmacologic effects of apixaban should be monitored more closely whenever clarithromycin is added to or withdrawn from therapy. Patients should be routinely evaluated for signs and symptoms suggesting blood loss such as a decrease in hemoglobin and/or hematocrit, hypotension, or fetal distress (in pregnant women).

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.