Drug Interaction Report

MONITOR: Coadministration of brigatinib with other agents that can also slow the heart rate may potentiate the risk of severe bradycardia. In one clinical trial, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients who received brigatinib 90 mg and 7.6% of patients who had the dosage increased from 90 mgto 180 mg. Grade 2 bradycardia occurred in 0.9% of patients in the 90 mg group.

MANAGEMENT: Caution is advised if brigatinib is used concomitantly with beta-blockers, calcium channel blockers, digitalis, or other drugs that can slow the heart rate or atrioventricular conduction such as alectinib, atazanavir, fingolimod, flecainide, ivabradine, lacosamide, lithium, mefloquine, moricizine, propafenone, succinylcholine, thalidomide, H2-receptor antagonists, tricyclic antidepressants, and anticholinesterase or cholinergic agents. Heart rate and blood pressure should be monitored frequently, and patients should be advised to seek medical attention if they experience dizziness, lightheadedness, fainting, or irregular heartbeat. For symptomatic bradycardia, withhold brigatinib until recovery to asymptomatic bradycardia or to a resting heart rate >=60 bpm, then resume brigatinib (at the same or reduced dose depending on whether concomitant medication is discontinued or dose-adjusted) or permanently discontinue in accordance with the recommendations in the product labeling.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of brigatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. 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. Itraconazole, a potent CYP450 3A4 inhibitor, has been shown to double brigatinib systemic exposure (AUC) in healthy volunteers. Increased exposure to brigatinib may increase the risk of adverse effects such as nausea, vomiting, diarrhea, hypertension, bradycardia, hyperglycemia, visual disturbances, lymphopenia, anemia, and elevations in pancreatic enzymes and creatine phosphokinase.

Food does not significantly affect the oral bioavailability of brigatinib. When brigatinib was administered to healthy volunteers after a high-fat meal (920 calories; 59 g fat, 58 g carbohydrates, 40 g proteins), brigatinib peak plasma concentration (Cmax) decreased by 13% and systemic exposure (AUC) did not change compared to administration after overnight fasting.

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

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.