Drug Interaction Report

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

MONITOR: Coadministration of capmatinib with moderate CYP450 3A4 inhibitors may increase the risk and severity of capmatinib adverse effects, such as interstitial lung disease, pneumonitis, and hepatotoxicity. The proposed mechanism is decreased clearance due to inhibition of CYP450 3A4, which is one of the primary enzymes responsible for the metabolic clearance of capmatinib. Coadministration with itraconazole (a strong CYP450 3A4 inhibitor) increased the systemic exposure (AUC) of capmatinib by 42%, but did not affect the peak plasma concentration (Cmax) of capmatinib. Data are not available for other, less potent inhibitors.

MANAGEMENT: Close monitoring is recommended whenever capmatinib is used with a moderate CYP450 3A4 inhibitor. Clinical and laboratory monitoring should be considered whenever a moderate CYP450 3A4 inhibitor is added to or withdrawn from therapy with capmatinib, and the dosage adjusted as necessary based on clinical response and toxicity. Patients should be monitored for the development of adverse effects.

GENERALLY AVOID: Pomegranates and grapefruit may increase the systemic exposure to ribociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Increased exposure to ribociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, fatigue, headache, and abnormal liver function may be increased.

MANAGEMENT: Patients receiving ribociclib should avoid consumption of pomegranates or pomegranate juice and grapefruit or grapefruit juice during treatment.