Drug Interactions between Kisqali Femara Co-Pack and tisotumab vedotin

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 of unconjugated monomethyl auristatin E (MMAE), the anti-mitotic and cytotoxic component of tisotumab vedotin. Tisotumab vedotin is an antibody-drug conjugate (ADC) that releases MMAE via proteolytic cleavage, and MMAE has been shown in vitro to be primarily metabolized by CYP450 3A4. Although tisotumab vedotin has not been studied with CYP450 3A4 inhibitors, data for another ADC that contains MMAE (brentuximab vedotin) have been reported. When brentuximab vedotin was administered with the potent CYP450 3A4 inhibitor ketoconazole, MMAE peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 25% and 34%, respectively, with no change in ADC exposure. Using a model-based approach to account for the fact that MMAE exposures are decreased after multiple doses by 20% to 50% compared to the first dose, the adjusted increase in MMAE AUC by ketoconazole is predicted to be 73%. Similar effects on unconjugated MMAE and ADC are expected for tisotumab vedotin when coadministered with potent CYP450 3A4 inhibitors. It is not known if, and to what extent, tisotumab vedotin may interact with less potent CYP450 3A4 inhibitors.

MANAGEMENT: Caution is advised when tisotumab vedotin is used concomitantly with CYP450 3A4 inhibitors. Patients should be closely monitored for development or exacerbation of toxicities such as ocular disorders (dry eyes, conjunctivitis, blepharitis, keratitis, corneal ulceration, blurred vision, vision loss), peripheral neuropathy, hemorrhage and pneumonitis, and the dosing of tisotumab vedotin adjusted or withheld as necessary in accordance with the product labeling.