Drug Interactions between Brukinsa and ibrutinib

GENERALLY AVOID: Coadministration with grapefruit, grapefruit juice, or Seville oranges may significantly increase the plasma concentrations of ibrutinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Pharmacokinetic modeling suggests that other moderate CYP450 3A4 inhibitors such as diltiazem and erythromycin may increase ibrutinib systemic exposure (AUC) by 6- to 9-fold under fasting condition. The safety and efficacy of these exposures are unknown. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 to 1400 mg) given for 28 days, which yielded single dose AUC values that were approximately 50% greater than steady-state exposures seen at the highest indicated dose of 560 mg.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ibrutinib. The mechanism of interaction is unknown. According to the product labeling, administration with food increases ibrutinib exposure approximately 2-fold compared to administration after overnight fasting.

MANAGEMENT: Patients treated with ibrutinib should avoid consumption of Seville oranges, grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ibrutinib should be taken once daily at approximately the same time each day.

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.

The recommended maximum number of medicines in the 'BTK inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'BTK inhibitors' category:

• Brukinsa (zanubrutinib)
• ibrutinib

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.