Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of larotrectinib, which is primarily metabolized by the isoenzyme. When a single 100 mg dose of larotrectinib was coadministered with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily for 7 days), larotrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.8- and 4.3-fold, respectively, compared to administration of larotrectinib alone. Increased exposure to larotrectinib may increase the risk of adverse effects such as neurotoxicity (delirium, dysarthria, dizziness, gait disturbance, paresthesia, encephalopathy, memory impairment, tremor) and hepatotoxicity (elevations in liver transaminases).

MANAGEMENT: Concomitant use of larotrectinib with potent CYP450 3A4 inhibitors should generally be avoided. If coadministration is required, the manufacturer recommends reducing the larotrectinib dose by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, the larotrectinib dose that was taken prior to initiating the inhibitor may be resumed.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of larotrectinib. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of larotrectinib by certain compounds present in grapefruit. When a single 100 mg dose of larotrectinib was coadministered with itraconazole, a potent CYP450 3A4 inhibitor, larotrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.8- and 4.3-fold, respectively, compared to administration of larotrectinib alone. 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 larotrectinib may increase the risk of adverse effects such as neurotoxicity (delirium, dysarthria, dizziness, gait disturbance, paraesthesia, encephalopathy, memory impairment, tremor) and hepatotoxicity (elevations in liver transaminases).

Food does not alter the pharmacokinetics of larotrectinib to a clinically significant extent. When a single 100 mg dose of larotrectinib was administered with a high-fat meal (approximately 900 calories; 58 g carbohydrate, 56 g fat, 43 g protein) in healthy study subjects, larotrectinib peak plasma concentration (Cmax) was reduced by 35% while systemic exposure (AUC) was similar compared to administration in the fasted state.

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