Atazanavir and Estradiol Transdermal Patch: Interaction Details

a) Concomitant use of atazanavir (with or without ritonavir) and a combination ethinyl estradiol/norgestimate or norethindrone oral contraceptive has resulted in substantial increases in progesterone exposure. Long-term effects of increases in progestational agent bioavailability are not known and could result in an increased risk of insulin resistance, dyslipidemia, and acne. Concomitant use of atazanavir 300 mg plus ritonavir 100 mg once daily with an ethinyl estradiol/norgestimate oral contraceptive resulted in decreased ethinyl estradiol and increased norgestimate exposure. Coadministration of atazanavir 400 mg once daily with an ethinyl estradiol/norethindrone contraceptive resulted in increased exposure to both ethinyl estradiol and norethindrone. No studies have been conducted on the concomitant use of atazanavir (with or without ritonavir) with other hormonal contraceptives (eg, patch, vaginal ring, or injection), with oral contraceptives that contain progestins other than norethindrone or norgestimate, or with oral contraceptives that contain less than a 25-mcg dose of ethinyl estradiol ¹.

b) In a pharmacokinetic study in healthy HIV-negative women (n=20; mean age 28 years), coadministration of atazanavir/ritonavir and an oral contraceptive containing ethinyl estradiol (EE) and norgestimate (NGM) resulted in increased exposure of norgestimate and decreased exposure of ethinyl estradiol; however the reduction in ethinyl estradiol levels was not expected to decrease contraceptive efficacy. In this open-label, three-period study, participants received in the lead-in period a full 28-day cycle of Ortho Tri-CyClen(R) (EE 0.035 mg plus NGM 0.18/0.215/0.25 mg). This was followed by period 1 in which participants received a second cycle of daily Ortho Tri-CyClen(R) (treatment A). Participants with satisfactory safety assessments began a third cycle on day 29 of Ortho Tri-Cyclen LO(R) (EE 0.025 mg plus NGM 0.18/0.215/0.25 mg) coadministered with atazanavir 300 mg/ritonavir 100 mg once daily for 14 days (treatment B). A dose normalization was performed to account for the different EE doses in the 2 treatments and to estimate the magnitude of reduction in EE exposures. Coadministration of atazanavir/ritonavir plus dose-normalized EE/NGM resulted in geometric mean reductions in EE of 16%, 19%, and 37% for Cmax, AUC, and Cmin, respectively. For NGM exposure, Cmax, AUC, and Cmin were increased by 68%, 85%, and 102%, respectively. Results of this study indicate that an oral contraceptive containing at least 30 mcg of EE would be sufficient to maintain adequate exposure of EE. Since the contraceptive efficacy of Ortho Tri-Cyclen(R) is primarily dependent on progestin, the contraceptive efficacy was not expected to be compromised ².