Drug Interaction Report

MONITOR: Coadministration with dronedarone may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme, CYP450 3A4 isoenzyme, and/or P-glycoprotein (P-gp) efflux transporter. The mechanism is decreased clearance via these routes due to inhibition by dronedarone. When given with the CYP450 2D6 substrates metoprolol and propranolol, dronedarone increased metoprolol systemic exposure (AUC) by 1.6-fold and propranolol AUC by 1.3-fold. Similarly, dronedarone coadministration led to 1.4- to 1.5-fold increases in the AUC of diltiazem, nifedipine and verapamil, which are CYP450 3A4 substrates. Dronedarone also increased the AUC of digoxin, a P-glycoprotein substrate, by 2.5-fold.

MANAGEMENT: Caution is advised when dronedarone is used concomitantly with drugs that are substrates of CYP450 2D6, CYP450 3A4 and/or P-gp, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever dronedarone is added to or withdrawn from therapy.

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.