Drug Interactions between cobicistat / elvitegravir / emtricitabine / tenofovir alafenamide and Liptruzet

MONITOR: Coadministration with ezetimibe may rarely increase the risk of myopathy and serum transaminase elevations associated with HMG-CoA reductase inhibitors (i.e., statins). The mechanism of interaction is unknown. A case report describes two patients whose serum creatine kinase increased after ezetimibe was added to their statin therapy (atorvastatin and fluvastatin, respectively). One of the patients also developed myalgia and tendinopathy, which resolved promptly after withdrawal of both drugs. Statin therapy was subsequently reintroduced at the previous dosage without incident. In the other patient, serum creatine kinase returned to normal within 4 weeks after discontinuation of ezetimibe while the statin was continued. On the contrary, no cases of myopathy or tendinopathy occurred in a study of 33 hypercholesterolemic patients treated with ezetimibe and atorvastatin or simvastatin. There were also no reports of myopathy or significant increases in serum creatine kinase in a study of 32 subjects treated with ezetimibe and fluvastatin. In controlled clinical studies, the incidence of consecutive elevations (greater than 3 times the upper limit of normal) in serum transaminases was 1.3% for patients treated with ezetimibe in combination with a statin versus 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.

MANAGEMENT: Until further information is available, use of a statin in combination with ezetimibe should be approached with caution. Patients should be advised to promptly report to their physician any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. The drugs should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. In addition, liver function tests should be performed at initiation of therapy and according to the recommendations of the HMG-CoA reductase inhibitor.

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MONITOR: Coadministration with cobicistat may increase the plasma concentrations of most HMG-CoA reductase inhibitors (i.e., statins) to varying degrees. Cobicistat is a potent inhibitor of CYP450 3A4 and can significantly increase exposure to statins that are primarily metabolized by the isoenzyme (e.g., atorvastatin, lovastatin, simvastatin). Cobicistat may also inhibit the OATP 1B1- and 1B3- mediated hepatic uptake of statins, thus even those that are not metabolized by CYP450 3A4 may be affected. High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

MANAGEMENT: Caution is advised when statins are prescribed with cobicistat-containing regimens. The lowest starting dosage of the statin is recommended, then titrated as needed based on clinical response and tolerance. Some statins such as lovastatin and simvastatin are contraindicated for use with cobicistat. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

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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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