Drug Interaction Report

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

GENERALLY AVOID: Coadministration with moderate inducers of CYP450 3A4 may decrease the plasma concentrations of brigatinib, which is partially metabolized by the isoenzyme. When a single 180 mg dose of brigatinib was administered with the potent CYP450 3A4 inducer rifampin (600 mg once daily), brigatinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 60% and 80%, respectively, compared to brigatinib administered alone. Based on simulations from a physiologically-based pharmacokinetic model, moderate CYP450 3A inducers may decrease the AUC of brigatinib by approximately 50%.

MANAGEMENT: Concomitant use of brigatinib with moderate CYP450 3A4 inducers should generally be avoided. If coadministration cannot be avoided, the dose of brigatinib should be increased in 30 mg increments as tolerated every 7 days up to a maximum of twice the brigatinib dose that was tolerated prior to initiating the moderate CYP450 3A4 inducer. After discontinuation of the moderate CYP450 3A4 inducer, the brigatinib dose tolerated prior to initiating the moderate CYP450 3A4 inducer should be resumed. The potential for diminished pharmacologic effects of brigatinib should be considered during coadministration with CYP450 3A4 inducers.

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.