Drug Interactions between amoxicillin / clarithromycin / omeprazole and Eliquis

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advised and pharmacologic effects of apixaban should be monitored more closely whenever clarithromycin is added to or withdrawn from therapy.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).

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.