Drug Interaction Report

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.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.