SPL Set ID: eb18194f-2021-41fa-8bdf-31e0c0eb646b

ANNOVERA (segesterone acetate and ethinyl estradiol vaginal system) is a toroidal- shaped (ring), nonbiodegradable, flexible, opaque white vaginal system containing two active components, a progestin, segesterone acetate, and an estrogen, ethinyl estradiol. When placed in the vagina, each ANNOVERA releases an approximate average 0.15 mg/day of segesterone acetate and 0.013 mg/day of ethinyl estradiol over the 21 days in-use period of each cycle for up to 13 cycles (total of 273 days). Each cycle is 28 days, with 21 days in and 7 days out. The inactive ingredients are dibutyltin dilaurate, silicone elastomers, silicone medical adhesive, and titanium dioxide. The elastomers are all methyl siloxane-based polymers. The vaginal system body has an overall diameter of 56 mm and a cross-sectional diameter of 8.4 mm. It contains two channels of approximately 3.0 mm diameter and 27 mm length into which steroid-containing cores are inserted. Each ANNOVERA contains 103 mg of SA distributed throughout both cores and 17.4 mg of EE distributed throughout only one core. The core containing 40% SA and 12% EE of its mass is 3 mm in diameter and 18 mm in length. The core containing 50% SA of its mass is 3 mm in diameter and 11 mm in length. Contact between the cores and the vaginal system body is fixed by coating the channels with silicone medical adhesive before introducing the cores. After insertion of the cores, the channels are sealed with the silicone medical adhesive. The structural formulas, and properties for the active components are shown below: STRUCTURAL FORMULAS: Segesterone Acetate (SA) Ethinyl Estradiol (EE) PROPERTIES: Established Name: Segesterone Acetate Chemical Name: 16-methylene-17α-acetoxy-19-nor-pregn-4-ene-3,20-dione Molecular Formula: C 23 H 30 O 4 Molecular Weight: 370.5 Physical Form: White, or yellowish white powder Solubility: Slightly soluble in n-hexane, soluble in ethyl acetate and methanol, freely soluble in acetone (USP classification) Melting Point: 173°C–177°C Established Name: Ethinyl Estradiol Chemical Name: 19-Nor-17α -pregna-1,3,5(10)-trien-20-yne-3,17-diol Molecular Formula: C 20 H 24 O 2 Molecular Weight: 296.4 Physical Form: White to slightly ye ll owish-white crysta ll ine powder Solubility: Practically insoluble in water, freely soluble in alcohol, it dissolves in alkaline solution Melting Point: 181°C–185°C The steroids diffuse out of the vaginal system with release rates that vary over time. Based on in vitro data, the daily release rates of SA and EE are higher during each initial 24–48 hours of use achieving a somewhat lower steady-state with continued use over the subsequent days in each cycle. The vaginal system is designed to be used for 13 cycles (1 year) on a 21/7 days in/out schedule. The total in-use time with the 21/7 days in/out schedule over 13 cycles is 273 days. Based on the residual amount of drug in vaginal systems used in clinical trials over 13 cycles, a total of 41.3 mg of SA and 3.4 mg of EE are released over this period. This translates to an approximate average daily dose of 0.15 mg of segesterone acetate and 0.013 mg of ethinyl estradiol with higher release rate expected at the beginning of dosing and a lower release rate toward the end. Chemical Structure Chemical Structure