Drug Interactions between cobicistat / darunavir / emtricitabine / tenofovir alafenamide and ivacaftor / tezacaftor

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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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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MONITOR: Coadministration of tenofovir and darunavir-ritonavir or darunavir-cobicistat may result in increased plasma concentrations of tenofovir and darunavir. Increased tenofovir plasma concentration may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction is unknown; however, increased tenofovir concentrations may be related to inhibition of P-glycoprotein by darunavir, cobicistat, or ritonavir in the renal tubules. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. In 12 study subjects, administration of darunavir-ritonavir (300 mg-100 mg twice daily) with tenofovir (300 mg once daily) increased the systemic exposure (AUC) and trough plasma concentration (Cmin) of darunavir by 21% and 24%, respectively, compared to administration without tenofovir. Tenofovir AUC and Cmin also increased by 22% and 37%, respectively, in the presence of darunavir-ritonavir. Data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Caution and close monitoring of renal function is recommended if darunavir-ritonavir or darunavir-cobicistat is to be used in combination with tenofovir, particularly in patients with risk factors for renal impairment. No dose adjustments appear necessary during coadministration of darunavir-ritonavir with tenofovir. However, initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir) or is nephrotoxic.

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MONITOR: Concomitant use of tenofovir with cobicistat may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction has not been described. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. When given concomitantly with cobicistat, the systemic exposure (AUC) and trough plasma concentrations (Cmin) of tenofovir was also increased by 23% and 55%, respectively. However, data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir), or is nephrotoxic. If concomitant therapy is necessary, monitoring of renal function is recommended, particularly in patients with risk factors for renal impairment.

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GENERALLY AVOID: Cobicistat may increase the plasma concentrations of antiretroviral agents. The plasma concentrations of cobicistat may also be increased or reduced in the presence of antiretroviral agents. The proposed mechanism is cobicistat inhibition of the CYP450 3A4 isoenzyme, of which antiretroviral agents may be substrates, and the inhibition or induction of CYP450 3A4 by concomitant antiretroviral medications. Cobicistat is a mechanism-based inhibitor and substrate of CYP450 3A4 with no antiretroviral activity of its own. Rather, it is indicated in its capacity as a pharmacokinetic booster of CYP450 3A4 to increase the systemic exposure of some antiretroviral medications such as atazanavir, darunavir, and elvitegravir, which are substrates of this isoenzyme. Concomitant use of other antiretroviral agents with cobicistat may also increase the plasma levels and risk of side effects associated with these medicines. In contrast, concomitant use of cobicistat-boosted atazanavir or darunavir with CYP450 3A4 inducers nevirapine, etravirine, or efavirenz may reduce the plasma concentrations of cobicistat, darunavir, and atazanavir, leading to a potential loss of therapeutic effect and development of resistance to darunavir and atazanavir. Pharmacokinetic data are not available.

MANAGEMENT: Cobicistat is not intended for use with more than one antiretroviral medication that requires pharmacokinetic enhancement, such as two protease inhibitors or elvitegravir in combination with a protease inhibitor. In addition, cobicistat should not be used concomitantly with ritonavir due to their similar effects on CYP450 3A4. According to some authorities, use of the antiretroviral combinations of atazanavir-cobicistat or darunavir-cobicistat concomitantly with the CYP450 3A4 inducers efavirenz, etravirine, or nevirapine is also not recommended. Other authorities consider the administration of atazanavir-cobicistat with efavirenz or nevirapine to be contraindicated. Since dosing recommendations have only been established for a number of antiretroviral medications, product labeling and current antiretroviral treatment guidelines should be consulted.

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