Coadministration is not recommended as it may significantly decrease elvitegravir/cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Coadministration of elvitegravir/cobicistat (150 mg/150 mg once daily) and rifabutin (300 mg once daily alone or 150 mg every other day with elvitegravir/cobicistat) decreased elvitegravir Cmin by 67%. Rifabutin exposure was similar to values obtained alone, but 25-O-desacetylrifabutin exposures were 4.8 to 6.3 fold higher. The European SPC suggests that if the combination is needed, to use rifabutin 150 mg 3 times per week on set days (e.g. Monday-Wednesday-Friday) with increased monitoring for rifabutin associated adverse reactions including neutropenia and uveitis due to increased desacetyl rifabutin exposure. Further dose reduction of rifabutin has not been studied and a twice weekly dose of 150 mg may not provide an optimal exposure to rifabutin leading to a risk of rifamycin resistance and a treatment failure. Rifabutin could decrease the exposure of tenofovir alafenamide (induction of intestinal transporters). However, a drug-drug interaction study demonstrated that coadministration of emtricitabine/tenofovir alafenamide (200/25 mg once daily) and rifampicin (600 mg once daily) in healthy volunteers gave intracellular tenofovir-DP exposures which were 4.2-fold higher than those achieved by standard dose tenofovir-DF alone (300 mg once daily).

Coadministration has not been studied. Coadministration may significantly decrease cobicistat plasma concentrations and consequently those of darunavir being boosted. Coadministration of elvitegravir/cobicistat (150 mg/150 mg once daily) and rifabutin (150 mg every other day) decreased cobicistat Ctrough by 66%. Rifabutin exposure was similar to values obtained alone, but 25-O-desacetylrifabutin exposures were increased (AUC, Cmax and Cmin were increased by 525%, 384% and 394%). Coadministration is not recommended in the Symtuza product labels. The European SmPC for Symtuza recommends that if the combination is needed, to use rifabutin 150 mg 3 times per week on set days (e.g. Monday-Wednesday-Friday); the US prescribing information for Symtuza recommends rifabutin 150 mg every other day. Both labels recommend increased monitoring for rifabutin associated adverse reactions including neutropenia and uveitis due to increased rifabutin exposure. Further dose reduction of rifabutin has not been studied and a twice weekly dose of 150 mg may not provide an optimal exposure to rifabutin leading to a risk of rifamycin resistance and a treatment failure. Rifabutin could decrease the exposure of tenofovir alafenamide (induction of intestinal transporters). However, a drug-drug interaction study demonstrated that coadministration of emtricitabine/tenofovir alafenamide (200/25 mg once daily) and rifampicin (600 mg once daily) in healthy volunteers gave intracellular tenofovir-DP exposures which were ~4.2-fold higher than those achieved by standard dose tenofovir-DF alone (300 mg once daily).