Drug Interactions between dronedarone and nintedanib

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.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of nintedanib. After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions. Absorption was also delayed, as indicated by an increase in the median time to reach maximum plasma concentration (Tmax) from 2 hours in the fasted state to approximately 4 hours under fed conditions, irrespective of the type of food ingested. In an in vitro study, mixing nintedanib capsules with a small amount of apple sauce or chocolate pudding for up to 15 minutes did not have any impact on their pharmaceutical quality, but swelling and deformation of the capsules were observed with longer exposure time due to water uptake of the gelatin capsule shell. Therefore, administration with soft food would not be expected to alter the clinical effect of nintedanib when taken immediately.

GENERALLY AVOID: Grapefruit and grapefruit juice may increase the plasma concentrations of nintedanib, which has been shown to be a substrate of the P-glycoprotein (P-gp) efflux transporter and a minor substrate of the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of both P-gp-mediated efflux in the gut wall as well as CYP450 3A4-mediated first-pass metabolism in the intestinal tract by certain compounds present in grapefruit.

MANAGEMENT: Nintedanib should be administered with food to reduce the incidence of gastrointestinal effects. Nintedanib capsules may be taken with water or a small amount (teaspoonful) of cold or room temperature soft food, such as apple sauce or chocolate pudding, and must be swallowed whole (unchewed) immediately, to ensure the capsule stays intact. Food containing grapefruit, grapefruit juice, Seville orange (a citrus relative of the grapefruit), or Seville orange juice should be avoided during treatment with nintedanib.