Drug Interaction Report

Coadministration with inhibitors of P-glycoprotein (P-gp) and/or weak inhibitors of CYP450 3A4 may increase the plasma concentrations of naloxegol, which is a substrate of both the efflux transporter and the isoenzyme. When a single 25 mg dose of naloxegol was administered with a single 600 mg dose of quinidine, a potent P-gp inhibitor and weak CYP450 3A4 inhibitor, naloxegol peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 147% and 39%, respectively. These changes are not considered clinically significant; therefore, no dosage adjustments are necessary.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of naloxegol. 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, naloxegol systemic exposure (AUC) was increased approximately 3.5-fold by the moderate CYP450 3A4 inhibitor diltiazem and nearly 13-fold by the potent inhibitor ketoconazole. 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 naloxegol may precipitate opioid withdrawal symptoms such as hyperhidrosis, lacrimation, rhinorrhea, chills, diarrhea, abdominal pain, anxiety, insomnia, irritability, restlessness, and yawning.

ADJUST DOSING INTERVAL: Food may increase the rate and extent of naloxegol absorption. When administered with a high-fat meal, naloxegol peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 30% and 45%, respectively. In clinical trials, naloxegol was given on an empty stomach approximately 1 hour prior to the first meal in the morning.

MANAGEMENT: Patients treated with naloxegol should avoid consumption of grapefruit and grapefruit juice. Naloxegol should be taken on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours after the meal.

ADJUST DOSING INTERVAL: Food increases the systemic exposure of givinostat. An open-label, randomized, crossover, single dose food effect study conducted in 12 healthy males used givinostat liquid filled capsules. Subjects received a single oral dose of givinostat (100 mg) in the fasting state or after a high-fat standard meal, with a washout period of at least 1 week in between. The high-fat standard meal resulted in an increase in systemic exposure (AUC) and maximum plasma concentration (Cmax) of about 40% and 23%, respectively, when compared to the fasted state. Additionally, the time to maximum concentration (Tmax) was delayed slightly from 2 to 3 hours.

MANAGEMENT: Givinostat should be administered with food to increase its absorption. In the case of the oral suspension, this can also help mask its bitter taste.