Drug Interactions between Pradaxa and quinine

MONITOR: Coadministration with inhibitors of P-glycoprotein (P-gp) may increase the bioavailability of dabigatran following oral administration of dabigatran etexilate, which is a substrate of the efflux transporter. Ketoconazole, a potent P-gp inhibitor, increased dabigatran peak plasma concentration (Cmax) and systemic exposure (AUC) by 135% and 138%, respectively, after a single dose of 400 mg, and 149% and 153%, respectively, after multiple daily doses of 400 mg. In three female study subjects administered dabigatran with 600 mg quinidine sulfate, another potent P-gp inhibitor, systemic exposure to dabigatran was approximately twice that expected with dabigatran alone. In a separate study, administration of dabigatran over 3 days following pretreatment with quinidine (200 mg every 2 hours up to a total dose of 1000 mg) resulted in a 56% increase in dabigatran Cmax and a 53% increase in AUC compared to administration without quinidine. When dabigatran etexilate was coadministered with a single 600 mg oral dose of amiodarone, also considered a potent P-gp inhibitor, dabigatran Cmax and AUC increased by 50% and 58%, respectively. Another P-gp inhibitor, dronedarone, increased dabigatran AUC by 1.7- to 2-fold. In contrast, when dabigatran etexilate was coadministered with the potent P-gp inhibitor clarithromycin (500 mg twice a day) in healthy volunteers, dabigatran Cmax increased by only 15% and AUC by only 19%. Due to the wide variation in magnitude of interaction, these results should not be extrapolated to other P-gp inhibitors that have not been studied.

MANAGEMENT: Pharmacologic response to dabigatran should be monitored more closely whenever a P-gp inhibitor is added to or withdrawn from therapy, and the dabigatran dosage adjusted as necessary. Patients should be monitored for the development of anemia and bleeding complications during coadministration. Particular caution is advised in elderly patients aged 75 years or older and in patients with renal impairment. P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran, and these two factors combined are expected to have greater effects than either factor alone. Concomitant use of dabigatran with P-gp inhibitors in patients with severe renal impairment (CrCl <30 mL/min) should be avoided. For the treatment and risk reduction of recurrence of deep venous thrombosis (DVT) and pulmonary embolism (PE) and for the prophylaxis of DVT and PE following hip replacement surgery, concomitant use of P-gp inhibitors in patients with CrCl <50 mL/min should be avoided.

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