Drug Interaction Report

Coadministration with inhibitors of P-glycoprotein (P-gp) may increase the plasma concentrations of fidaxomicin and its main metabolite, OP-1118, both of which are substrates of the intestinal efflux transporter. When fidaxomicin 200 mg was administered in combination with cyclosporine 200 mg in 14 study subjects, fidaxomicin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by an average of 4.2- and 1.9-fold, respectively, compared to when administered alone. The Cmax and AUC of OP-1118 was increased by 9.5- and 4.1-fold, respectively, with cyclosporine. Theoretically, concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e., gastrointestinal tract) due to P-gp inhibition. However, concomitant use of a P-gp inhibitor had no attributable effect on safety or efficacy of fidaxomicin in controlled clinical trials. No dosage adjustment is recommended when fidaxomicin is coadministered with P-gp inhibitors.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of dronedarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. According to the product labeling, administration with grapefruit juice resulted in a 2.5-fold increase in dronedarone peak plasma concentration and a 3-fold increase in systemic exposure. Because dronedarone is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of dronedarone. The mechanism of interaction is unknown. According to the product labeling, the absolute bioavailability of dronedarone increases from about 4% when administered in the fasted state to approximately 15% when administered with a high-fat meal.

MANAGEMENT: Patients treated with dronedarone should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Dronedarone should be taken twice daily with the morning and evening meals.