Drug Interaction Report

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ruxolitinib, which is primarily metabolized by the isoenzyme. In healthy subjects, administration of a single 10 mg dose of ruxolitinib following pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for four days) resulted in a 33% increase in ruxolitinib peak plasma concentration (Cmax) and a 91% increase in systemic exposure (AUC) compared to administration of ruxolitinib alone. The half-life was also prolonged from 3.7 to 6.0 hours in the presence of ketoconazole. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole.

MANAGEMENT: Indication specific dose modifications should be made when ruxolitinib is coadministered with strong CYP450 3A4 inhibitors. Ruxolitinib 10 mg twice a day is the recommended starting dose for patients with myelofibrosis (MF) coadministered strong CYP450 3A4 inhibitors when the platelet count is at least 100 X 10(9)/L and 5 mg once a day when the platelet counts is at least 50 X 10(9)/L and less than 100 x 10(9)/L. The recommended starting dose for patients with Polycythemia vera (PV) coadministered potent CYP450 3A4 inhibitors is ruxolitinib 5 mg twice a day. For patients with MF or PV who are stabilized on ruxolitinib 10 mg twice a day or greater and starting a potent CYP450 3A4 inhibitor, the ruxolitinib dose should be reduced by 50% (rounded up to the closest available tablet strength). For patients with MF or PV stabilized on a dose of 5 mg twice a day and starting fluconazole (at a dose of 200 mg per day or less), the ruxolitinib dose should be reduced to 5 mg once a day. For patients with MF or PV stabilized on ruxolitinib 5 mg once a day, concomitant use of strong CYP450 3A4 inhibitors should be avoided or ruxolitinib therapy interrupted for the duration of strong CYP450 3A4 inhibitor use. For patients with for acute graft versus host disease (GVHD) coadministered strong CYP450 3A4 inhibitors, the ruxolitinib dose should be reduced to 5 mg once a day with concomitant ketoconazole use; however, no dose adjustments are necessary with other potent CYP450 3A4 inhibitors. For patients with GVHD receiving itraconazole, blood counts should be monitored more frequently for toxicity and ruxolitinib dose adjustments made, if necessary. Additional dosage modifications should be made with careful monitoring of safety and efficacy.

ADJUST DOSING INTERVAL: Food reduces the oral absorption and bioavailability of voriconazole. According to the product labeling, administration of multiple doses of voriconazole with high-fat meals decreased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 34% and 24%, respectively, when the drug is administered as a tablet, and by 58% and 37%, respectively, when administered as the oral suspension.

MANAGEMENT: To ensure maximal oral absorption, voriconazole tablets and oral suspension should be taken at least one hour before or after a meal.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ruxolitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients treated with ruxolitinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ruxolitinib may be administered with or without food.