Drug Interactions between Inrebic and zanubrutinib

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the plasma concentrations of zanubrutinib. 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 zanubrutinib was coadministered with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily), zanubrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased 157% and 278%, respectively, in healthy volunteers. Data evaluating coadministration of zanubrutinib, in patients with B-cell lymphoma, and several other known CYP450 3A4 inhibitors have been reported. When zanubrutinib was coadministered with another CYP450 3A4 inhibitor, clarithromycin (250 mg twice daily), zanubrutinib Cmax and AUC increased 101% and 92%, respectively. The moderate CYP450 3A4 inhibitor diltiazem (180 mg once daily) increased both zanubrutinib Cmax and AUC increased by 62%. Another moderate CYP450 3A4 inhibitor, fluconazole (400 mg once daily), increased zanubrutinib Cmax and AUC 81% and 88%, respectively. Clinical data for less potent inhibitors are not available. In general, the effects of grapefruit products are concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit (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 zanubrutinib exposure may potentiate the risk of toxicities such as hemorrhage, infection, cytopenias, malignancies, and serious cardiac arrhythmias, primarily atrial fibrillation and atrial flutter.

Food does not affect the oral bioavailability of zanubrutinib. No clinically significant differences in zanubrutinib Cmax or AUC were observed following administration of a high-fat meal (approximately 1000 calories; 50% from fat) in healthy subjects.

MANAGEMENT: Zanubrutinib may be administered with or without food. Patients should avoid consumption of grapefruit, grapefruit juice, Seville oranges (a citrus relative of the grapefruit), and Seville orange juice during treatment with zanubrutinib. Close clinical monitoring for development of zanubrutinib-related toxicities, dosage adjustments, and/or withholding treatment in accordance with product labeling is advised. Additional consultation with individual package labeling, as well as relevant institutional protocols, may be advisable for further guidance.

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.