Drug Interaction Report

MONITOR: Based on in vitro inhibition data, coadministration with ulipristal may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) transporter. The proposed mechanism is decreased clearance in the intestine, liver, and/or kidney due to inhibition of P-glycoprotein-mediated drug efflux by ulipristal. However, the interaction has not been studied or reported clinically.

MANAGEMENT: Caution is advised when ulipristal is used concurrently with drugs that are known P-gp substrates, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ulipristal is added to or withdrawn from therapy.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of naldemedine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In pharmacokinetic studies, naldemedine systemic exposure (AUC) was increased approximately 90% by the moderate CYP450 3A4 inhibitor fluconazole and nearly 200% by the potent inhibitor itraconazole. The interaction has not been studied with grapefruit juice. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to naldemedine may precipitate opioid withdrawal symptoms such as hyperhidrosis, lacrimation, rhinorrhea, chills, diarrhea, abdominal pain, anxiety, insomnia, irritability, restlessness, and yawning.

Food does not significantly affect the overall bioavailability of naldemedine. When administered with a high-fat meal, the rate of naldemedine absorption was decreased, but not the extent. Specifically, naldemedine peak plasma concentration (Cmax) was decreased by approximately 35% and time to achieve Cmax was delayed from 0.75 hours in the fasted state to 2.5 hours in the fed state, while naldemedine AUC was not significantly changed.

MANAGEMENT: Naldemedine may be taken with or without food. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with naldemedine.