Drug Interaction Report

GENERALLY AVOID: Coadministration with mobocertinib may decrease the plasma concentrations of hormonal contraceptives and possibly render them ineffective. The proposed mechanism is mobocertinib-mediated induction of CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of hormonal contraceptives. Based on interaction data with midazolam, a sensitive CYP450 3A4 substrate, mobocertinib appears to be a weak inducer of CYP450 3A4. In addition, mobocertinib can cause fetal harm when administered to a pregnant woman.

MANAGEMENT: Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable during concomitant therapy with mobocertinib. Women using hormonal contraceptives should be advised of the risk of breakthrough bleeding and unintended pregnancy when receiving mobocertinib. Because use of mobocertinib may cause embryo-fetal harm, it is particularly important that patients not become pregnant during treatment. Therefore, hormonal contraceptives should not be used as method of birth control in women of childbearing potential treated with mobocertinib. Female patients of reproductive potential should use a highly effective, non-hormonal method of contraception during treatment and for 1 month after treatment. Male patients with female partners of reproductive potential should use effective contraception during treatment with mobocertinib and for 1 week after treatment.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of mobocertinib. The mechanism may involve inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice. Based on drug interaction studies using model-informed approaches, coadministration of mobocertinib with multiple doses of itraconazole or ketoconazole (strong CYP450 3A4 inhibitors) is predicted to increase the steady-state combined molar AUC (systemic exposure) of mobocertinib and its active metabolites by 374% to 419%, while coadministration with multiple doses of a moderate CYP450 3A4 inhibitor is predicted to increase this value by approximately 100% to 200%. 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. Elevated plasma concentrations of mobocertinib may increase the risk for adverse effects such as QT prolongation, heart failure or reduced ejection fraction, cardiomyopathy, heart block, diarrhea, rash, stomatitis, fatigue, and musculoskeletal pain.

MANAGEMENT: Patients should avoid consumption of grapefruit and grapefruit juice during treatment with mobocertinib.