Drug Interactions between Gleevec and ivacaftor / lumacaftor

ADJUST DOSE: Coadministration with moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ivacaftor, which is primarily metabolized by the isoenzyme. In study subjects, ivacaftor peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 2.5- and 3.0-fold when it was administered concomitantly with fluconazole, a moderate CYP450 3A4 inhibitor. When lumacaftor/ivacaftor was coadministered with ciprofloxacin, another moderate CYP450 3A4 inhibitor, lumacaftor Cmax and AUC decreased by 12% and 14%, respectively, while ivacaftor Cmax and AUC increased by 29% each. These changes are not considered clinically significant. Physiologically based pharmacokinetic (PBPK) simulations suggest that coadministration with moderate CYP450 3A4 inhibitors may increase elexacaftor AUC by 1.9- to 2.3-fold and tezacaftor AUC by approximately 2.1-fold.

MANAGEMENT: Please consult manufacturer's product labeling for complete dosing information.
For ivacaftor - For patients aged 6 months and older the frequency of dosing should be reduced to 1 tablet or packet once a day when coadministered with moderate CYP450 3A4 inhibitors. Patients should continue to receive the same tablet or oral granule packet strength, but instead of dosing twice a day, the frequency should be reduced to once a day. For example, ivacaftor 150 mg twice a day should be 150 mg once a day, ivacaftor 50 mg twice a day should be 50 mg once a day, etc. Use of ivacaftor with moderate or strong CYP450 3A4 inhibitors is not recommended in patients less than 6 months of age.
For lumacaftor/ivacaftor - No dosage adjustment is necessary when coadministered with moderate CYP450 3A4 inhibitors.
For tezacaftor/ivacaftor - The frequency of dosing should be reduced to a single morning dose of one tezacaftor/ivacaftor tablet alternating with one ivacaftor tablet every other morning during treatment with moderate CYP450 3A4 inhibitors. The evening dose of ivacaftor should not be taken.
For elexacaftor/tezacaftor/ivacaftor - The frequency of dosing should be reduced to a single morning dose of two elexacaftor /tezacaftor /ivacaftor tablets alternating with one ivacaftor tablet every other day during treatment with moderate CYP450 3A4 inhibitors. The evening dose of ivacaftor should not be taken.

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GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of imatinib, which is primarily metabolized by the isoenzyme. Therapeutic failure may occur. When a single 400 mg oral dose of imatinib was administered to 14 healthy adult volunteers following pretreatment with the potent CYP450 3A4 inducer rifampin (600 mg once daily for 8 days), mean imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 54% and 74%, respectively, compared to administration alone. The oral clearance of imatinib was increased by 3.8-fold during rifampin coadministration. Similar results were observed in patients with malignant gliomas receiving imatinib 400 to 1200 mg/day concomitantly with enzyme-inducing antiepileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone. The mean dose-normalized AUC for imatinib decreased by 73% compared to patients not on EIAEDs. In two published studies, concomitant administration of imatinib and a product containing St. John's wort led to a 30% to 32% reduction in the AUC of imatinib.

MANAGEMENT: Concomitant use of imatinib with potent CYP450 3A4 inducers should generally be avoided. Alternative therapeutic agents with less enzyme induction potential should be considered whenever possible. If coadministration with a potent CYP450 3A4 inducer is required, some authorities recommend increasing the dosage of imatinib by at least 50% while carefully monitoring clinical response. Imatinib dosages up to 1200 mg/day (600 mg twice daily) have been given to patients receiving concomitant potent CYP450 3A4 inducers.

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