Drug Interaction Report

Coadministration with inducers of CYP450 3A4 or dual P-glycoprotein (P-gp) and CYP450 3A4 inducers may decrease the plasma concentrations and effects of unconjugated monomethyl auristatin E (MMAE), the cytotoxic component of enfortumab vedotin. Enfortumab vedotin is an antibody-drug conjugate (ADC) that releases MMAE, via proteolytic cleavage. MMAE has been shown in vitro to be primarily metabolized by CYP450 3A4 as well as being a substrate of P-gp. According to physiologically-based pharmacokinetic (PBPK) modeling, concomitant use of enfortumab vedotin with rifampin, a dual P-gp and strong CYP450 3A4 inducer, is predicted to decrease unconjugated MMAE peak plasma concentration (Cmax) by 28% and systemic exposure (AUC) by 53%, with no change in ADC exposure. Some authorities suggest that the PBPK model may underestimate the full impact of rifampin on the Cmax of MMAE. The clinical significance of the interaction is unclear, since the intact ADC is required to bind to Nectin-4, an adhesion protein found on the surface of cells, which allows for internalization and cleavage by lysosomal proteases to enable intracellular delivery of MMAE. It is not known if, and to what extent, enfortumab vedotin may interact with less potent CYP450 3A4 inducers.

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

ADJUST DOSING INTERVAL: Food enhances the oral absorption and bioavailability of rufinamide. In healthy volunteers, administration of a single 400 mg dose of rufinamide with food resulted in an approximately 56% increase in mean peak plasma concentration (Cmax) and a 34% increase in systemic exposure (AUC) compared to administration during a fasting state.

MANAGEMENT: To ensure maximal oral absorption, it is preferable to administer rufinamide with food. Patients receiving rufinamide should be advised to avoid consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how rufinamide affects them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.