Drug Interactions between dasabuvir / ombitasvir / paritaprevir / ritonavir and Prezcobix

GENERALLY AVOID: Coadministration with ombitasvir/paritaprevir/ritonavir plus dasabuvir may decrease the plasma concentrations of darunavir. The mechanism of interaction has not been established. In 8 study subjects, administration of darunavir 800 mg once daily in the morning in combination with once daily morning doses of ombitasvir/paritaprevir/ritonavir (25 mg/150 mg/100 mg) plus twice daily doses of dasabuvir resulted in decreases of approximately 8%, 24% and 48% in mean darunavir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin), respectively, compared to administration of darunavir 800 mg plus ritonavir 100 mg in the morning. Similarly, when darunavir 600 mg twice daily plus ritonavir 100 mg once daily in the evening was given with the same regimen of ombitasvir/paritaprevir/ritonavir plus dasabuvir to 7 study subjects, darunavir Cmax, AUC and Cmin decreased by 13%, 20% and 43%, respectively, compared to darunavir 600 mg plus ritonavir 100 mg given in the morning and evening. When darunavir 800 mg plus ritonavir 100 mg once daily in the evening (12 hours after morning doses of ombitasvir/paritaprevir/ritonavir plus dasabuvir) was studied in 10 subjects, darunavir Cmax decreased by 21%, AUC increased by 34%, and Cmin decreased by 46% compared to darunavir 800 mg plus ritonavir 100 mg administered in the evening. In the studies, plasma concentrations of ombitasvir, paritaprevir, and dasabuvir were also decreased by darunavir plus ritonavir to varying degrees.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of darunavir plus ritonavir and ombitasvir/paritaprevir/ritonavir plus dasabuvir is not recommended.

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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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MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of paritaprevir, which is primarily metabolized by the isoenzyme. In 12 study subjects, ketoconazole 400 mg given once daily increased single-dose paritaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 37% and 98%, respectively. The risk of hyperbilirubinemia may be increased, as paritaprevir can cause elevations in indirect (unconjugated) bilirubin via inhibition of OATP1B1/1B3.

MANAGEMENT: Caution is advised if paritaprevir is prescribed in combination with potent CYP450 3A4 inhibitors. Patients should be monitored for signs and symptoms of hepatotoxicity (i.e., ALT and bilirubin elevations).

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