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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 with inducers of CYP450 3A4 may decrease the plasma concentrations of ribociclib, which is a substrate of the isoenzyme. Physiologically-based pharmacokinetic simulations (PBPK) suggest that a moderate CYP450 3A4 inducer, efavirenz, may decrease ribociclib Cmax and AUC by 37% and 60%, respectively. However, data with less potent CYP450 3A4 inducers are limited.

MANAGEMENT: The potential for diminished therapeutic effects of ribociclib should be considered when prescribed with inducers of CYP450 3A4, particularly moderate inducers including efavirenz and nevirapine. Pharmacologic effects of ribociclib should be monitored more closely whenever an inducer is added to or withdrawn from therapy. Alternative treatment may be required if an interaction is suspected.

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.