Drug Interactions between amoxicillin / clarithromycin / omeprazole and ivacaftor / tezacaftor

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ivacaftor, which is primarily metabolized by the isoenzyme. In study subjects, ivacaftor systemic exposure (AUC) increased by 8.5-fold when it was administered concomitantly with ketoconazole, a potent CYP450 3A4 inhibitor. When lumacaftor/ivacaftor was coadministered with itraconazole, another potent CYP450 3A4 inhibitor, lumacaftor pharmacokinetics were not affected, but ivacaftor peak plasma concentration (Cmax) and AUC increased by an average of 3.7- and 4.3-fold, respectively. Due to the induction effect of lumacaftor on CYP450 3A4, at steady state the net AUC of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dosage of 150 mg every 12 hours (the approved dosage of ivacaftor monotherapy). For this reason, no dosage adjustment is recommended when CYP450 3A4 inhibitors are initiated in patients already receiving lumacaftor/ivacaftor, whereas a dosage reduction for lumacaftor/ivacaftor is recommended when initiating treatment in patients receiving potent CYP450 3A4 inhibitors. When tezacaftor/ivacaftor was coadministered with itraconazole, tezacaftor and ivacaftor AUC increased by 4-fold and 15.6-fold, respectively. Likewise, elexacaftor AUC has also been reported to increase 2.8-fold by itraconazole.

MANAGEMENT: Please consult manufacturer's product labeling for complete dosing information.
For ivacaftor - For patients aged 6 months and older the ivacaftor dose should be reduced from 1 tablet or 1 packet of oral granules twice a day to 1 tablet or 1 packet of oral granules twice a week (i.e., every 3 to 4 days) during coadministration with potent CYP450 3A4 inhibitors. For example, a patient taking ivacaftor 150 mg tablet twice a day should reduce their ivacaftor dose to a 150 mg tablet twice a week and a patient taking ivacaftor 50 mg oral granule packet twice a day should reduce their ivacaftor dose to 50 mg oral granule packet twice a week, 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 CYP450 3A4 inhibitors are initiated in patients who are already receiving lumacaftor /ivacaftor. However, the initial dose of lumacaftor/ivacaftor in patients who are currently receiving potent CYP450 3A4 inhibitors, should be reduced to 1 tablet once a day or 1 packet every other day for the first week of treatment, then increased to the recommended dose. If lumacaftor/ivacaftor is interrupted for more than one week and then re-initiated while receiving potent CYP450 3A4 inhibitors, the dosage should be similarly reduced to 1 tablet daily or 1 packet every other day for the first week of treatment re-initiation.
For tezacaftor/ivacaftor - The morning dose of tezacaftor/ivacaftor should be reduced to one tablet twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors.
For elexacaftor/tezacaftor/ivacaftor - The morning dose of 2 elexacaftor/tezacaftor/ivacaftor tablets once a day should be reduced to 2 tablets twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors.

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Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

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Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.

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