Drug Interaction Report

MONITOR: Patients with gastrointestinal conditions may have an increased risk of gastrointestinal bleeding during concomitant treatment with dabigatran etexilate and proton pump inhibitors or H2 blockers. In addition, pantoprazole resulted in an approximately 30% decrease in dabigatran systemic exposure (AUC). Diminished clinical effect may occur, although no dosage adjustment is recommended for dabigatran etexilate. The pharmacokinetics of pantoprazole were not significantly altered by dabigatran. Pantoprazole and other proton pump inhibitors were also coadministered with dabigatran in clinical trials for the prevention of venous thromboembolic events after hip- or knee-replacement surgery, and no effects on bleeding or efficacy were observed. Ranitidine had no significant effects on the absorption of dabigatran.

MANAGEMENT: Patients should be monitored for signs of gastrointestinal bleeding and advised to promptly report any symptoms to their physician, such as abdominal pain, dizziness, lightheadedness, vomiting blood, anorexia, and/or black, tarry stools.

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.

Coadministration with clarithromycin may slightly increase the bioavailability of dabigatran following oral administration of dabigatran etexilate. The proposed mechanism is clarithromycin inhibition of the P-glycoprotein efflux transporter, of which dabigatran etexilate is a substrate. When dabigatran etexilate was coadministered with clarithromycin 500 mg twice a day in healthy volunteers, increases in dabigatran peak plasma concentration (Cmax) by about 15% and systemic exposure (AUC) by about 19% were observed without any clinical safety concern. Dabigatran had no significant effect on the pharmacokinetics of clarithromycin. No dosage adjustment for dabigatran etexilate is recommended during coadministration with clarithromycin, but caution may be advisable.

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.