Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of ponatinib. In vitro, ponatinib has been shown to undergo Phase I metabolism primarily via CYP450 3A4 and to a lesser extent, CYP450 2C8, 2D6 and 3A5. When a single 45 mg dose of ponatinib was administered to healthy subjects following 7 days of continuous daily dosing of 600 mg rifampin, a potent CYP450 3A4 inducer, mean ponatinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 42% and 62%, respectively, compared to ponatinib administered alone. Similar results were observed with thrice daily administration of 100 mg oral phenytoin, another potent CYP450 3A4 inducer, using physiologically based pharmacokinetic modeling. The extent to which other, less potent CYP450 3A4 inducers may interact with ponatinib is unknown.

MANAGEMENT: The potential for diminished pharmacologic effects of ponatinib should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of ponatinib, which is primarily metabolized by CYP450 3A4. However, the interaction has not been studied. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: The consumption of grapefruit, grapefruit juice, and supplements that contain grapefruit extract should be avoided during treatment with ponatinib.