Drug Interactions between clopidogrel and Stribild

MONITOR CLOSELY: Coadministration with cobicistat or ritonavir may reduce the efficacy of clopidogrel, whose antiplatelet effect is dependent in part on bioactivation to a pharmacologically active metabolite via various CYP450 isoenzymes including CYP450 2C19 and 3A4/5, as well as CYP450 1A2 and 2B6 to a lesser extent. Since cobicistat and ritonavir are potent inhibitors of CYP450 3A4 used primarily as pharmacokinetic boosters, they may interfere with the formation of the active metabolite of clopidogrel. In a study consisting of 9 HIV-infected male subjects receiving cobicistat or ritonavir boosted antiretroviral therapy and 12 healthy male subjects receiving no background medications, mean peak plasma concentration (Cmax) and systemic exposure (AUC) of the active metabolite following a single 300 mg dose of clopidogrel were 3.2-fold lower in HIV subjects compared to healthy subjects. In addition, platelet inhibition was considered insufficient (i.e., platelet reactivity units above cut-off value at 4 hours post-dose) in 44% of HIV subjects, while adequate platelet inhibition was demonstrated in all healthy subjects. Overall, there was a general consistency between platelet inhibition and the AUC of the active metabolite of clopidogrel. In the same study, a 60 mg dose of prasugrel led to almost complete platelet inhibition in all HIV and healthy subjects, despite a 1.7- and 2.1-fold lower Cmax and AUC of its active metabolite, respectively, in the HIV subjects. In another study conducted in 12 healthy volunteers, investigators reported that coadministration of ritonavir (100 mg twice daily on days 1 to 5) and clopidogrel (300 mg on day 3, followed by 75 mg on days 4 and 5) decreased the Cmax and AUC of the active metabolite of clopidogrel by 48% and 51%, respectively, compared to clopidogrel administered alone. The average inhibition of platelet aggregation was 31% with ritonavir and 51% without ritonavir, and the maximal platelet inhibition by clopidogrel was 40% versus 60% with and without ritonavir. A case report has also been published describing clopidogrel resistance in a patient with HIV, latent tuberculosis, and cardiovascular disease due to a suspected interaction with isoniazid and ritonavir.

MANAGEMENT: The potential for reduced efficacy of clopidogrel should be considered in patients receiving cobicistat or ritonavir boosted pharmacologic regimens. This may be particularly relevant in populations that may rely more on CYP450 3A4 for bioactivation of clopidogrel, such as patients with genetic polymorphisms of CYP450 2C19 and/or 3A5 resulting in reduced or absent activity of those isoenzymes or taking concomitant drugs that inhibit those isoenzymes. Close clinical and laboratory monitoring for evidence of diminished antiplatelet effects is recommended, or consider using alternative antiplatelet agents.

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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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