Drug Interactions between ethinyl estradiol and nirmatrelvir / ritonavir

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.