Drug Interaction Report

MONITOR: Coadministration with moderate inhibitors of CYP450 3A4 may increase the plasma concentrations of ticagrelor, which is primarily metabolized by the isoenzyme. In healthy volunteers, administration of ticagrelor in combination with the moderate CYP450 3A4 inhibitor diltiazem resulted in increased ticagrelor peak plasma concentration (Cmax) and systemic exposure (AUC) by 69% and 174%, respectively. For the active metabolite, the Cmax was decreased by 38% and the AUC was unchanged. Ticagrelor had no effect on the plasma levels of diltiazem.

MANAGEMENT: Although administration with moderate CYP450 3A4 inhibitors is thought to be generally safe, it may be advisable to monitor pharmacologic response to ticagrelor more closely following the addition and withdrawal of these agents. Discontinuation of the concomitant medication 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.