Drug Interaction Report

MONITOR: Coadministration with tebentafusp may increase the plasma concentrations of drugs that are metabolized by CYP450 pathways. The formation of hepatic CYP450 enzymes is down-regulated by increased levels of certain proinflammatory cytokines that are transiently released during initiation of tebentafusp treatment. Thus, tebentafusp may suppress CYP450 enzymes resulting in increased exposures of some CYP450 substrates. Clinical data are currently lacking but risk of an interaction is expected to be greatest during the first 24 hours of the first 3 tebentafusp doses.

MANAGEMENT: Caution is advised when tebentafusp is coadministered with drugs that are CYP450 substrates, particularly those with narrow therapeutic ranges (e.g., antiarrhythmics, anticonvulsants, immunosuppressants, theophylline) or sensitive substrates where increases in plasma levels may be significant or undesirable (e.g., statins, benzodiazepines, opioids). Clinical and/or laboratory monitoring should be considered following the initiation or withdrawal of tebentafusp, and the dosage(s) of the CYP450 substrate(s) adjusted accordingly.

GENERALLY AVOID: Theoretically, the coadministration with grapefruit juice may increase the plasma concentrations of pimozide. The mechanism is decreased clearance of pimozide due to inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The use of pimozide alone has been associated with dose-dependent prolongation of the QT interval. Although clinical data are lacking, this interaction may result in potentiation of the proarrhythmic effect of pimozide and consequently an increased risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes. In addition, alcohol may potentiate some of the pharmacologic effects of pimozide. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: The manufacturer recommends avoiding grapefruit juice (and probably grapefruits) during therapy with pimozide. Patients should also be advised to avoid or limit consumption of alcohol.