Drug Interactions between fedratinib and naloxegol

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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of fedratinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When a single 300 mg oral dose of fedratinib (0.75 times the recommended dose) was coadministered with 200 mg twice daily ketoconazole, a potent CYP450 3A4 inhibitor, fedratinib total systemic exposure (AUC(inf)) increased by approximately 3-fold. Using physiologically based pharmacokinetic (PBPK) simulations, coadministration of fedratinib 400 mg once daily and ketoconazole 400 mg once daily is predicted to increase fedratinib AUC at steady state by 2-fold. Coadministration with the moderate CYP450 3A4 inhibitors, erythromycin (500 mg three times daily) or diltiazem (120 mg twice daily), is predicted to increase fedratinib AUC by approximately 1.5- to 2-fold following single-dose administration and by approximately 1.2-fold at steady state. 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 fedratinib exposure may potentiate the risk of adverse reactions such as nausea, vomiting, diarrhea, anemia, thrombocytopenia, neutropenia, encephalopathy (including Wernicke's), liver (ALT, AST) and pancreatic (amylase, lipase) enzyme elevations, increased blood creatinine, and secondary malignancies.

Food does not affect the oral bioavailability of fedratinib to a clinically significant extent. Administration of a single 500 mg dose (1.25 times the recommended dose) with a low-fat, low-calorie meal (162 calories; 6% from fat, 78% from carbohydrate, 16% from protein) or a high-fat, high-calorie meal (815 calories; 52% from fat, 33% from carbohydrate, 15% from protein) increased fedratinib peak plasma concentration (Cmax) and systemic exposure (AUC) by up to 14% and 24%, respectively.

MANAGEMENT: Fedratinib may be taken with or without food. However, administration with a high-fat meal may help reduce the incidence of nausea and vomiting. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with fedratinib.