Drug Interaction Report

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of ponatinib, which is a substrate of the isoenzyme. In 22 healthy volunteers, administration of a single 15 mg oral dose of ponatinib in combination with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily) increased ponatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 47% and 78%, respectively, compared to administration of ponatinib alone.

MANAGEMENT: Caution is recommended if concomitant use is required, and the dosage of ponatinib should be reduced according to the manufacturer's recommendations. Patients may be at increased risk for adverse effects such as thromboembolism, ischemia, congestive heart failure, hypertension, hepatotoxicity, pancreatitis, myelosuppression, hemorrhage, and fluid retention. Some authorities recommend that, following discontinuation and after an appropriate washout period of the CYP450 3A4 inhibitor (i.e., 3 to 5 half-lives), the ponatinib dosage taken prior to initiating the potent CYP450 3A4 inhibitor may be resumed (US).

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.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.