Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly 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. Loss of therapeutic effect may occur.

MANAGEMENT: Concomitant use of ponatinib with potent CYP450 3A4 inducers should generally be avoided. Alternative agents with no or minimal CYP450 3A4 induction potential are recommended whenever possible. Patients should be monitored for reduced efficacy of ponatinib if use of potent CYP450 3A4 inducers is required.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Elexacaftor and tezacaftor are also CYP450 3A4 substrates in vitro and may interact similarly with grapefruit juice, whereas lumacaftor is not expected to interact.

ADJUST DOSING INTERVAL: According to prescribing information, systemic exposure to ivacaftor increased approximately 2.5- to 4-fold, systemic exposure to elexacaftor increased approximately 1.9- to 2.5-fold, and systemic exposure to lumacaftor increased approximately 2-fold following administration with fat-containing foods relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with ivacaftor-containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit or Seville oranges. All ivacaftor-containing medications should be administered with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products. A typical cystic fibrosis diet will satisfy this requirement.

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.