Drug Interactions between aripiprazole and ivacaftor / lumacaftor

ADJUST DOSE: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of aripiprazole and its active metabolite, dehydro-aripiprazole. Clinical and in vitro data indicate that aripiprazole is extensively metabolized in the liver primarily via three enzymatic pathways (dehydrogenation, hydroxylation, and N-dealkylation) mediated by CYP450 2D6 and 3A4. When aripiprazole 30 mg once daily was coadministered with the potent CYP450 3A4 inducer carbamazepine at 200 mg twice daily in schizophrenic patients, mean aripiprazole peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 68% and 73%, respectively, compared to administration of aripiprazole alone. Likewise, mean Cmax and AUC of dehydro-aripiprazole were decreased by 69% and 71%, respectively, in the presence of carbamazepine. Reduced efficacy of aripiprazole may occur.

MANAGEMENT: When aripiprazole is administered orally, the prescribing information recommends doubling the usual dosage over 1 to 2 weeks following the addition of a potent CYP450 3A4 inducer. Additional dosage adjustments should be based on clinical evaluation. Upon discontinuation of the inducer, aripiprazole dosage should be reduced to the original level over 1 to 2 weeks. When given as an immediate-acting intramuscular injection, the aripiprazole dosage should also be doubled in patients receiving potent CYP450 3A4 inducers. For patients receiving extended-release intramuscular formulations of aripiprazole, concomitant use of potent CYP450 3A4 inducers should generally be avoided for greater than 14 days, although some formulations may be administered, with or without a dosage adjustment depending on the dose. The prescribing information for individual aripiprazole products should be consulted for specific recommendations regarding concomitant use with potent CYP450 3A4 inducers.

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MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or 2D6 may increase the plasma concentrations of aripiprazole, which is primarily metabolized by these isoenzymes. According to the product labeling, administration of a single 15 mg dose of aripiprazole during treatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg/day for 14 days) increased the systemic exposure (AUC) to aripiprazole and its active metabolite, dehydro-aripiprazole, by 63% and 77%, respectively, compared to administration of aripiprazole alone. Likewise, administration of a 10 mg dose of aripiprazole with the potent CYP450 2D6 inhibitor quinidine (166 mg/day for 13 days) increased aripiprazole AUC by 112%, although dehydro-aripiprazole AUC was reduced by 35%.

MANAGEMENT: Pharmacologic response to aripiprazole should be monitored more closely whenever a CYP450 3A4 and/or 2D6 inhibitor is added to or withdrawn from therapy, and the aripiprazole dosage adjusted as necessary. The manufacturer recommends that aripiprazole dosage be reduced to one-half the normal dosage during concomitant administration with ketoconazole or quinidine, and additional dosage adjustments be made based on clinical evaluation. No dosage recommendations are available for concomitant administration with less potent CYP450 2D6 or 3A4 inhibitors.

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