Drug Interactions between cobicistat / elvitegravir / emtricitabine / tenofovir disoproxil and medroxyprogesterone

ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration of ritonavir or cobicistat alone or in combination with other antiretroviral agents may increase or decrease the plasma concentrations of hormonal contraceptives. Increases in estrogens and decreases in progestins are the predominant effect seen when used in combination with ritonavir or cobicistat. However, ritonavir or cobicistat formulations have also been associated with increased plasma concentrations of some transdermal formulations of ethinyl estradiol and reduced plasma concentrations of norethindrone. In a pharmacokinetic study, 22 of 23 healthy women who received single doses of an oral contraceptive containing ethinyl estradiol 50 mcg and ethynodiol 1 mg had reduced serum levels of ethinyl estradiol following the addition of ritonavir (500 mg twice a day) for 2 weeks. Specifically, the systemic exposure (AUC) decreased by 41%. In additional pharmacokinetic studies, the AUC of ethinyl estradiol decreased by 30% and 25% when used in combination with darunavir-cobicistat and elvitegravir-cobicistat, respectively. Furthermore, the AUC of drospirenone increased 2.3-fold following coadministration with atazanavir-cobicistat. The exact mechanism of this interaction is unknown but decreases in plasma concentrations of hormonal contraceptives may involve ritonavir- and cobicistat-mediated induction of glucuronosyltransferase or CYP450 1A2 or 2C9 and increases in plasma concentrations of hormonal contraceptives may involve ritonavir- and cobicistat-mediated inhibition of CYP450 3A4.

MANAGEMENT: Women using hormonal contraceptives should be advised of the risk of breakthrough bleeding and unintended pregnancy during concomitant therapy with formulations containing ritonavir or cobicistat. Patients should also be monitored for signs of estrogen or progestin toxicity including ALT elevations, insulin resistance, dyslipidemia, acne, and venous thrombosis. Alternative or additional methods of contraception should be used during and for at least 4 weeks after treatment with formulations containing ritonavir or cobicistat. If a combination oral contraceptive pill is used, a regimen containing at least 35 mcg of ethinyl estradiol per day or equivalent should be selected for most ritonavir-containing regimens and at least 30 mcg of ethinyl estradiol per day or equivalent are recommended by some authorities for most cobicistat-containing regimens. Product labeling for the antiretroviral therapy and/or the hormonal contraceptive should be consulted for specific dosing recommendations related to hormonal contraception. For emergency contraception, a non-hormonal emergency contraceptive (e.g., copper intrauterine device) is considered preferable. No precautions or recommendations are available for women using hormone-releasing intrauterine systems, but a significant interaction with these systems is thought to be unlikely due to their local action.

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.

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.