Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of entrectinib, which is primarily metabolized by the isoenzyme. When a single 100 mg dose of entrectinib was administered with itraconazole, a potent CYP450 3A4 inhibitor, entrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.7- and 6-fold, respectively. Increased exposure to entrectinib may increase the risk and/or severity of adverse effects such as cognitive impairment, mood disorders, dizziness, sleep disturbances, liver enzyme elevations, hyperuricemia, congestive heart failure, edema, myocarditis, QT prolongation, vision problems, anemia, and neutropenia.

MANAGEMENT: Concomitant use of entrectinib with potent CYP450 3A4 inhibitors should be avoided when possible. If coadministration is necessary, the dosage of entrectinib should be reduced to 100 mg once daily for adults and pediatrics patients (12 years and older) with a body surface area (BSA) greater than 1.5 m2. Following discontinuation, and after an appropriate washout period of the CYP450 3A4 inhibitor (i.e., 3 to 5 half-lives), the entrectinib dosage taken prior to initiating the CYP450 3A4 inhibitor may be resumed. For pediatric patients with a body surface area of 1.5 m2 or less, concomitant use of entrectinib with potent CYP450 3A4 inhibitors should be avoided. Some authorities recommend if coadministration is unavoidable, adult patients should follow dose reduction guidance as described above while limiting coadministration to 14 days and do not recommend coadministration in pediatric patients (UK).

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of entrectinib, which is primarily metabolized by the isoenzyme. When a single 100 mg dose of entrectinib was administered with itraconazole, a potent CYP450 3A4 inhibitor, entrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.7- and 6-fold, respectively. Increased exposure to entrectinib may increase the risk and/or severity of adverse effects such as cognitive impairment, mood disorders, dizziness, sleep disturbances, liver enzyme elevations, hyperuricemia, congestive heart failure, edema, myocarditis, QT prolongation, vision problems, anemia, and neutropenia.

MANAGEMENT: Concomitant use of entrectinib with potent CYP450 3A4 inhibitors should be avoided when possible. If coadministration is necessary, the dosage of entrectinib should be reduced to 100 mg once daily for adults and pediatrics patients (12 years and older) with a body surface area (BSA) greater than 1.5 m2. Following discontinuation, and after an appropriate washout period of the CYP450 3A4 inhibitor (i.e., 3 to 5 half-lives), the entrectinib dosage taken prior to initiating the CYP450 3A4 inhibitor may be resumed. For pediatric patients with a body surface area of 1.5 m2 or less, concomitant use of entrectinib with potent CYP450 3A4 inhibitors should be avoided. Some authorities recommend if coadministration is unavoidable, adult patients should follow dose reduction guidance as described above while limiting coadministration to 14 days and do not recommend coadministration in pediatric patients (UK).

GENERALLY AVOID: Grapefruit juice and Seville oranges may increase the plasma concentrations of entrectinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit and Seville oranges Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but pharmacokinetic data are available for the potent CYP450 3A4 inhibitor, itraconazole. When a single 100 mg dose of entrectinib was administered with itraconazole, entrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.7- and 6-fold, respectively. Coadministration of entrectinib with a moderate CYP450 3A4 inhibitor is predicted to increase entrectinib Cmax and AUC by 2.9- and 3-fold, respectively. 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 entrectinib may increase the risk and/or severity of adverse effects such as cognitive impairment, mood disorders, dizziness, sleep disturbances, liver enzyme elevations, hyperuricemia, congestive heart failure, edema, myocarditis, QT prolongation, vision problems, anemia, and neutropenia.

MANAGEMENT: Patients should avoid consumption of grapefruit, grapefruit juice, and Seville oranges during treatment with entrectinib.

ADJUST DOSING INTERVAL: Administration of atazanavir with food enhances oral bioavailability and reduces pharmacokinetic variability. According to the manufacturer, administration with a light meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single 400 mg dose of atazanavir by 57% and 70%, respectively, relative to the fasting state. Administration with a high-fat meal resulted in a mean increase of 35% in atazanavir AUC and no change in Cmax compared to fasting. The coefficient of variation of AUC and Cmax decreased by approximately one-half when given with either a light or high-fat meal compared to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atazanavir should be administered with or immediately after a meal.