Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of dronedarone, which is extensively and primarily metabolized by the isoenzyme. According to the prescribing information, administration with 600 mg once daily rifampin, a potent CYP450 3A4 inducer, decreased dronedarone systemic exposure (AUC) by 80% with no major change in the AUC of its active N-debutyl metabolite. Reduced efficacy of dronedarone may occur. The interaction has not been studied with other, less potent CYP450 3A4 inducers.

MANAGEMENT: The potential for diminished pharmacologic effects of dronedarone should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

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.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.