Drug Interactions between cisapride and dronedarone

CONTRAINDICATED: Coadministration with grapefruit juice may increase the plasma concentrations of cisapride. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In a study of 14 healthy volunteers, administration with 250 mL of grapefruit juice increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of cisapride (10 mg single dose) by 34% and 39%, respectively, compared to water. A second single-dose study involving 12 healthy volunteers demonstrated an increase of 68% and 51% in cisapride Cmax and AUC, respectively, compared to water. In another 10 healthy volunteers, repeated ingestion of double-strength grapefruit juice (200 mL three times a day for 2 days, then with a 10 mg dose of cisapride and at 0.5 and 1.5 hours afterwards) resulted in an 81% and 144% increase in mean cisapride Cmax and AUC, respectively, compared to water. A high degree of intersubject variability in the grapefruit juice effect was observed in all three studies, but no patient experienced any changes in heart rate, blood pressure, or QT interval. However, high plasma levels of cisapride have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes; cardiac arrest; and sudden death.

GENERALLY AVOID: Coadministration with red wine may increase the plasma concentrations of cisapride in susceptible individuals. The exact mechanism of interaction is unknown but is believed to involve inhibition of CYP450 3A4 in the gut wall similar to grapefruit juice. In 12 healthy volunteers, administration with 250 mL of red wine (cabernet sauvignon) produced only minor and statistically insignificant changes in cisapride pharmacokinetics compared to water. However, one subject had a doubling in cisapride AUC and Cmax with red wine. The same subject also had the largest interaction with grapefruit juice, which suggests that a significant interaction may occur in certain individuals, perhaps those with a preexisting high intestinal CYP450 3A4 content.

MANAGEMENT: Patients receiving cisapride therapy should avoid the consumption of grapefruits and grapefruit juice. Because a significant interaction may occur with red wine in the occasional patient, red wine should preferably be avoided also during cisapride 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.