ANNOVERA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ANNOVERA (ANNOVERA).
Combination hormonal contraceptive containing segesterone acetate, a progestin, and ethinyl estradiol, an estrogen. Segesterone acetate suppresses gonadotropin release, preventing ovulation; ethinyl estradiol contributes to contraceptive efficacy by stabilizing the endometrium and inhibiting gonadotropin secretion.
| Metabolism | Segesterone acetate: primarily metabolized by CYP3A4 and CYP3A5 to active and inactive metabolites. Ethinyl estradiol: primarily metabolized by CYP3A4, with some contribution from CYP2C9; undergoes extensive first-pass metabolism and enterohepatic recirculation. |
| Excretion | Renal: ~60% as metabolites; fecal: ~35% as metabolites; biliary: minor. |
| Half-life | Terminal half-life of etonogestrel (ENG): ~25 hours; ethinylestradiol (EE): ~12 hours; steady-state achieved after 7-14 days. |
| Protein binding | ENG: 95-98% to albumin and SHBG; EE: 98% to albumin. |
| Volume of Distribution | ENG: ~1.5 L/kg; EE: ~2.5 L/kg; indicates extensive tissue distribution. |
| Bioavailability | Systemic bioavailability ~100% via intravaginal administration (bypasses first-pass metabolism). |
| Onset of Action | Contraceptive effect: immediate if inserted during first 5 days of menses; otherwise, 7 days for full suppression. |
| Duration of Action | 1 year (13 cycles), after which ring must be removed. |
One vaginal ring inserted and left in place for 3 weeks, followed by a 1-week ring-free interval. Each ring releases ethinyl estradiol 0.024 mg/day and segesterone acetate 0.15 mg/day over 21 days.
| Dosage form | RING |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not recommended in severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease due to lack of data. |
| Liver impairment | Contraindicated in acute hepatitis, severe cirrhosis (Child-Pugh class C), or liver tumors. For mild to moderate hepatic impairment (Child-Pugh A or B), use with caution; pharmacokinetics may be altered, but no specific dose adjustment guidelines exist. |
| Pediatric use | Not indicated for use in postmenarchal adolescents with a body weight <35 kg. For adolescents ≥35 kg, dosing is same as adults: one ring for 21 days followed by 7 days ring-free. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific geriatric dosing; safety and efficacy in women over 40 years have not been established. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ANNOVERA (ANNOVERA).
| Breastfeeding | Not recommended during breastfeeding. Combined hormonal contraceptives can reduce milk production and composition. Estrogen component may pass into breast milk (M/P ratio approximately 0.5 for ethinyl estradiol). Alternative contraception advised. |
| Teratogenic Risk | FDA Pregnancy Category X. Contraindicated in pregnancy due to increased risk of fetal harm, including neural tube defects, cardiovascular malformations, and oral clefts. Discontinue immediately if pregnancy occurs. No first, second, or third trimester use is safe. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use. This risk increases with age, especially in women over 35 years, and with the number of cigarettes smoked. Women who use combination hormonal contraceptives should be strongly advised not to smoke.
| Serious Effects |
["Current or history of thrombosis or thromboembolic disorders","Known thrombophilic conditions","Cerebrovascular or coronary artery disease","Valvular heart disease with complications","Persistent hypertension (systolic ≥160 mm Hg or diastolic ≥100 mm Hg)","Diabetes with vascular involvement","Headaches with focal neurological symptoms or migraine with aura (age ≥35)","Current or history of breast cancer or other hormone-sensitive cancer","Hepatic adenomas or hepatocarcinoma, or active liver disease","Undiagnosed abnormal uterine bleeding","Hypersensitivity to any component","Use of Hepatitis C combination therapy containing ombitasvir, paritaprevir, ritonavir, dasabuvir, glecaprevir, pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir"]
| Precautions | ["Thrombotic events and cardiovascular risks","Cigarette smoking","Liver disease","Hypertension","Gallbladder disease","Carbohydrate and lipid effects","Headache","Bleeding irregularities","Depression","Cervical cancer","Hereditary angioedema","Chloasma","Pregnancy","Lactation","Hepatic enzyme induction","Contact lens intolerance"] |
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| Fetal Monitoring |
| Perform pregnancy test before initiation and at any suspicion of pregnancy. Monitor for signs of thromboembolism, hypertension, and hepatic dysfunction. No fetal monitoring indicated; drug is contraindicated. |
| Fertility Effects | Reversible impairment of fertility occurs during use due to ovulation suppression. Upon discontinuation, normal ovulation and fertility typically resume within 1-3 cycles. No long-term adverse effects on fertility. |
| Food/Dietary | No clinically relevant food interactions have been reported for ANNOVERA. However, grapefruit juice may inhibit CYP3A4 and theoretically alter steroid hormone metabolism, though specific studies are lacking. No specific dietary restrictions are required. |
| Clinical Pearls | AnnovERA (segesterone acetate and ethinyl estradiol vaginal system) is a combined contraceptive vaginal ring inserted and replaced monthly over 21 days in, 7 days out. It delivers segesterone acetate, a novel progestin with high progestational activity and minimal androgenic effects. The ring must be stored refrigerated until dispensed but may be kept at room temperature for up to 7 days during use. Efficacy is comparable to other combined hormonal contraceptives. Patients should be advised to check ring placement and to reinsert a new ring if expulsion occurs. CYP3A4 inducers may reduce efficacy. |
| Patient Advice | Insert the ANNOVERA ring into the vagina and leave it in place for 21 continuous days, then remove it for 7 days (ring-free week). A new ring should be inserted after the 7-day break. · During the ring-free week, you may experience withdrawal bleeding. The ring must be replaced on the same day every 4 weeks. · Store ANNOVERA in the refrigerator at 2°C to 8°C (36°F to 46°F) until dispensed. After dispensing, you may keep it at room temperature (25°C/77°F) for up to 7 days. Do not expose to extreme temperatures or direct sunlight. · If the ring is accidentally expelled, rinse with cool water and reinsert within 2 hours. If out of the vagina for more than 2 hours, backup contraception is needed for 7 days. · Smoking increases your risk of serious cardiovascular side effects, especially if you are over 35 years old. Do not smoke while using ANNOVERA. · Use a backup barrier method (e.g., condoms) if you miss a ring insertion or if the ring is removed or expelled for more than 2 hours. · ANNOVERA does not protect against HIV or other sexually transmitted infections. |