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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

Coadministration with mild or moderate inhibitors of CYP450 3A4 may modestly increase the plasma concentrations of ruxolitinib, which is primarily metabolized by the isoenzyme. In healthy subjects, administration of a single 10 mg dose of ruxolitinib following pretreatment with the moderate CYP450 3A4 inhibitor erythromycin (500 mg twice daily for four days) resulted in an 8% increase in ruxolitinib peak plasma concentration (Cmax) and a 27% increase in systemic exposure (AUC) compared to administration of ruxolitinib alone. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding exposure information. No dosage adjustment is recommended when ruxolitinib is coadministered with mild or moderate CYP450 3A4 inhibitors. However, clinical data for topical ruxolitinib are not available. Consultation with individual package labeling, as well as relevant institutional protocols, may be advisable for further guidance.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ruxolitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients treated with ruxolitinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ruxolitinib may be administered with or without food.

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.