Drug Interaction Report

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR: Coadministration with inducers of CYP450 3A4 and/or P-glycoprotein (P-gp) may decrease the plasma concentrations of larotrectinib. According to the prescribing information, larotrectinib is metabolized primarily by the CYP450 3A4 isoenzyme and is a substrate of the P-gp and BCRP efflux transporters in vitro. When a single 100 mg dose of larotrectinib was coadministered with rifampin (600 mg once daily for 11 days), a potent CYP450 3A4 and P-gp inducer, larotrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 71% and 81%, respectively, compared to administration of larotrectinib alone. Coadministration with efavirenz, a moderate CYP450 3A4 inducer, is predicted to decrease larotrectinib steady-state Cmax by 60% and AUC by approximately 72%. Reduced efficacy of larotrectinib may occur.

MANAGEMENT: The potential for diminished pharmacologic effects of larotrectinib should be considered during coadministration with CYP450 3A4 and/or P-gp inducers. Alternative treatments may be required if an interaction is suspected.

MONITOR: Coadministration with inducers of CYP450 3A4 and/or P-glycoprotein (P-gp) may decrease the plasma concentrations of larotrectinib. According to the prescribing information, larotrectinib is metabolized primarily by the CYP450 3A4 isoenzyme and is a substrate of the P-gp and BCRP efflux transporters in vitro. When a single 100 mg dose of larotrectinib was coadministered with rifampin (600 mg once daily for 11 days), a potent CYP450 3A4 and P-gp inducer, larotrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 71% and 81%, respectively, compared to administration of larotrectinib alone. Coadministration with efavirenz, a moderate CYP450 3A4 inducer, is predicted to decrease larotrectinib steady-state Cmax by 60% and AUC by approximately 72%. Reduced efficacy of larotrectinib may occur.

MANAGEMENT: The potential for diminished pharmacologic effects of larotrectinib should be considered during coadministration with CYP450 3A4 and/or P-gp inducers. Alternative treatments may be required if an interaction is suspected.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

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.