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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 inhibitors of CYP450 3A4 may increase the plasma concentrations and effects of unconjugated monomethyl auristatin E (MMAE). Enfortumab vedotin is an antibody-drug conjugate (ADC) that releases MMAE, a microtubule-disrupting agent believed to induce cell cycle arrest and apoptosis, via proteolytic cleavage. MMAE has been shown in vitro to be primarily metabolized by CYP450 3A4. According to physiologically-based pharmacokinetic (PBPK) modeling, concomitant use of enfortumab vedotin with ketoconazole, a dual P-gp and strong CYP450 3A4 inhibitor, is predicted to increase unconjugated MMAE peak plasma concentration (Cmax) by 15% and systemic exposure (AUC) by 38%, with no change in ADC exposure. In one case report, a 70-year-old man on stable doses of raltegravir and the CYP450 3A4 inhibitors darunavir and ritonavir, experienced severe toxicity after receiving 2 infusions of enfortumab vedotin (1.25 mg/kg on days 1 and 8 of his 28-day cycle). He was hospitalized with a severe generalized pruritic rash, thrush, mucositis, anorexia, diarrhea, acute kidney injury, and pancytopenia. Enfortumab vedotin was withheld and the patient returned to baseline after being treated with supportive measures. About a year later, he was rechallenged with enfortumab vedotin while on an antiretroviral regimen consisting of dolutegravir, doravirine, and valacyclovir. He was able to tolerate a reduced dose of 1 mg/kg, with mild expected toxicity including skin blisters and peripheral neuropathy. It is not known if, and to what extent, enfortumab vedotin may interact with less potent CYP450 3A4 inhibitors.

MANAGEMENT: Patients should be closely monitored for development or exacerbation of toxicities including, but not limited to skin reactions (maculopapular rash, pruritus, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, palmar-plantar erythrodysesthesia, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)); hyperglycemia (including diabetic ketoacidosis); pneumonitis or interstitial lung disease; peripheral neuropathy; and ocular disorders (dry eyes, keratitis, blurred vision, limbal stem cell deficiency). Refer to the product labeling for dose adjustment or discontinuation of therapy recommendations depending on the severity or Grade of the adverse reactions, should they occur.

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.