Drug Interactions between entrectinib and Viekira XR

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).

MONITOR: Coadministration with entrectinib may increase the plasma concentrations of drugs that are substrates of the breast cancer resistance protein (BCRP) transporter. The proposed mechanisms, based on in vitro data, is decreased clearance due to entrectinib-mediated inhibition of BCRP transport protein. There are no clinical data regarding the use of entrectinib with BCRP substrates.

MANAGEMENT: Caution is advised when entrectinib is prescribed with drugs that are BCRP substrates, particularly those with a narrow therapeutic range such as methotrexate, mitoxantrone, topotecan, and lapatinib. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever entrectinib is added to or withdrawn from therapy.

MONITOR: Coadministration with entrectinib may increase the plasma concentrations of drugs that are substrates of the breast cancer resistance protein (BCRP) transporter. The proposed mechanisms, based on in vitro data, is decreased clearance due to entrectinib-mediated inhibition of BCRP transport protein. There are no clinical data regarding the use of entrectinib with BCRP substrates.

MANAGEMENT: Caution is advised when entrectinib is prescribed with drugs that are BCRP substrates, particularly those with a narrow therapeutic range such as methotrexate, mitoxantrone, topotecan, and lapatinib. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever entrectinib is added to or withdrawn from therapy.

MONITOR: Coadministration with entrectinib may increase the plasma concentrations of drugs that are substrates of the breast cancer resistance protein (BCRP) transporter. The proposed mechanisms, based on in vitro data, is decreased clearance due to entrectinib-mediated inhibition of BCRP transport protein. There are no clinical data regarding the use of entrectinib with BCRP substrates.

MANAGEMENT: Caution is advised when entrectinib is prescribed with drugs that are BCRP substrates, particularly those with a narrow therapeutic range such as methotrexate, mitoxantrone, topotecan, and lapatinib. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever entrectinib is added to or withdrawn from therapy.