Ethinyl Estradiol And Segesterone Acetate

Introduction Overview

Generic Name

ethinyl estradiol and segesterone acetate

Brand Name

Annovera

Dosage Form

vaginal ring

Drug Class

Contraceptive

Pharmacokinetics

Absorption

Annovera is a vaginal ring designed for the sustained and controlled release of two female hormones, ethinyl estradiol and segesterone acetate, directly into the vaginal mucosa. Once released, these hormones are absorbed through the vaginal epithelium into the systemic circulation. The vaginal route facilitates bypassing first-pass hepatic metabolism that occurs with oral administration, allowing more consistent plasma levels. Ethinyl estradiol achieves steady-state plasma concentrations within the first few days of ring insertion, while segesterone acetate also maintains a stable concentration throughout use. The absorption of both steroids is relatively slow and sustained due to the silicone polymer matrix of the ring, enabling continuous delivery over 21 days of placement.

Distribution

After absorption, ethinyl estradiol and segesterone acetate bind extensively to plasma proteins. Ethinyl estradiol has high affinity for sex hormone-binding globulin (SHBG) and albumin, whereas segesterone acetate binds primarily to albumin with minimal affinity for SHBG. Both hormones distribute widely into body tissues, including reproductive organs. The volume of distribution reflects their lipophilic nature, facilitating tissue penetration. Steady-state levels in tissues sustain contraceptive activity without significant accumulation due to continuous release and elimination balance.

Metabolism

Ethinyl estradiol undergoes extensive hepatic metabolism primarily via cytochrome P450 enzymes, including CYP3A4. It is subject to significant first-pass metabolism when administered orally, but the vaginal delivery of Annovera circumvents much of this effect. Segesterone acetate, a synthetic progestin, is metabolized by hepatic enzymes predominantly via hydroxylation and conjugation to inactive metabolites. Both drugs may be affected by hepatic enzyme inducers or inhibitors, potentially influencing plasma concentrations and efficacy.

Elimination

Elimination of ethinyl estradiol and segesterone acetate occurs mainly through hepatic metabolism and subsequent excretion of conjugated metabolites via urine and feces. The half-life of ethinyl estradiol is approximately 15-20 hours, while segesterone acetate exhibits a similar elimination half-life suitable for once-daily dosing via the vaginal route. The continuous release from the ring permits steady plasma levels with daily clearance maintaining systemic balance. Metabolic clearance can be influenced by coadministered drugs affecting liver enzymes and patient-specific hepatic function.

Dosage Forms

Adults

Annovera is provided as a single silicone vaginal ring impregnated with a combination of 0.150 mg ethinyl estradiol and 0.013 mg segesterone acetate releasing approximately 0.013 mg and 0.150 mg per day, respectively. The ring is intended for cyclic use—worn inside the vagina for 21 consecutive days, followed by 7 days ring-free, completing a 28-day cycle. This regimen is repeated continuously for up to 13 cycles (1 year), reusing the same ring each cycle.

Adolescents

Use of Annovera in adolescents is indicated only after the onset of menstruation and based on clinical judgment. The dosing regimen mirrors that of adults, maintaining 21 days of insertion followed by 7 days off. Careful counseling on proper use, potential side effects, and adherence is essential. Effectiveness and tolerability in adolescents are consistent with adults.

Special Populations

Annovera is contraindicated in pregnancy and women over 35 who smoke due to increased thrombotic risk. It is not recommended for use during breastfeeding, hepatic impairment, or in patients with a history of thromboembolic disorders. No dosage adjustments are specifically recommended for renal impairment as metabolism is hepatic. The continuous use of the same vaginal ring for one year necessitates attention in patients with vaginal infections or irritation, where use may be interrupted upon medical advice. Special considerations are warranted for women with elevated cardiovascular risk factors, and it is contraindicated in women with uncontrolled hypertension, significant liver disease, or history of hormone-sensitive cancers. Clinical guidance discourages use in women who have not had their first menstrual period or those who have recently given birth (within 4 weeks).

Mechanism Of Action

Annovera functions primarily by delivering a controlled combination of two hormones: ethinyl estradiol (an estrogen) and segesterone acetate (a synthetic progestin) directly into the vaginal mucosa, allowing systemic absorption. The ethinyl estradiol component exerts negative feedback on the hypothalamic-pituitary axis, suppressing the mid-cycle surge of luteinizing hormone (LH), thereby preventing ovulation. Alongside, segesterone acetate complements by inhibiting follicular development and stabilizing the endometrium. Segesterone acetate binds with high affinity to progesterone receptors, blocking ovulation and inducing endometrial changes unfavorable for implantation. This dual mechanism effectively prevents fertilization and pregnancy. The vaginal ring's sustained hormone release supports consistent plasma hormone levels to maintain suppression across the entire cycle. In addition to ovulation inhibition, Annovera thickens cervical mucus, hindering sperm penetration, and induces endometrial alterations that reduce the likelihood of implantation. This multifaceted contraceptive effect aligns with combination hormonal contraceptive principles but benefits from vaginal delivery which reduces hepatic first-pass metabolism and potentially lowers estrogen-related systemic side effects. Clinical evidence supports the efficacy of Annovera in maintaining suppressive hormonal levels across cycles with the convenience of a single ring reusable over one year, differentiating it from monthly vaginal rings or daily oral contraceptives. This profile provides an effective and user-friendly approach for reversible contraception.

Pharmacological Actions

Suppresses ovulation via hypothalamic-pituitary axis inhibition
Thickens cervical mucus to prevent sperm penetration
Alters endometrial lining, reducing implantation potential
Provides continuous systemic hormone release over 21 days
Maintains contraceptive hormone levels with vaginal delivery
Bypasses first-pass hepatic metabolism for more consistent levels
Dual hormone action improves contraceptive efficacy
Reusability for up to 13 cycles (1 year) improves user adherence

Therapeutic Clinical Uses

Prevention of pregnancy in women seeking contraception
Long-acting reversible contraceptive option with non-daily dosing
Suitable for women preferring vaginal delivery over oral or injectable contraceptives
Contraception for women contraindicated or intolerant to other hormonal methods
Use in women desiring yearly regimen without daily or monthly replacement

Side Or Adverse Effects

Headache, including migraine exacerbation
Nausea, vomiting, and gastrointestinal upset
Vaginal itching, discharge, or irritation
Breakthrough or irregular vaginal bleeding
Breast tenderness or pain
Menstrual cramps or dysmenorrhea
Pain or burning sensation during urination
Symptoms related to increased blood pressure
Rare but serious: thromboembolism including deep vein thrombosis or pulmonary embolism
Skin hyperpigmentation or melasma
Mood changes, including depression or anxiety
Allergic reactions potentially causing rash or swelling

Precautions

Do not use in women with uncontrolled hypertension or cardiovascular disease
Screen for history of thrombosis or thromboembolic disorders before use
Avoid use in women with history of hormone-sensitive cancers
Monitor for signs of hepatic dysfunction during treatment
Caution in women with migraine headaches, especially with aura
Not recommended during breastfeeding due to potential hormone transfer
Avoid use in smokers over 35 years due to elevated cardiovascular risks
Advise proper insertion technique to maintain ring placement
Instruct to avoid oil-based vaginal products that may degrade the ring
Use backup contraception if ring is removed for over 2 hours during use phase

Warnings

Increased risk of serious cardiovascular events such as heart attack and stroke
Higher thromboembolism risk in smokers and women over 35
Risk of liver disease or liver tumors with estrogen-containing contraceptives
Potential for vaginal infections or toxic shock syndrome
Not protective against sexually transmitted infections including HIV
Avoid use if history of undiagnosed abnormal vaginal bleeding
Warning for potential mood or psychiatric changes
Do not use in the presence of breast, uterine, cervical, or vaginal cancer

Contraindications

Pregnancy or suspicion of pregnancy
Current or history of thrombotic or thromboembolic disorders
Uncontrolled hypertension or significant cardiovascular disease
Liver disease or liver cancer
Undiagnosed abnormal vaginal bleeding
Known or suspected breast cancer or other estrogen- or progestin-sensitive cancers
Severe headaches with focal neurological symptoms or migraines with aura
Use with certain hepatitis C medications (e.g., ombitasvir/paritaprevir/ritonavir)
Smoking in women older than 35 years
Hypersensitivity to ethinyl estradiol, segesterone acetate, or silicone components

Drug Interactions

Enzyme inducers such as anticonvulsants (e.g., phenytoin, carbamazepine) may decrease contraceptive effectiveness
Antifungal agents can affect hormone metabolism
Certain antiviral agents for HIV/HCV may reduce plasma hormone levels
St. John's wort may reduce contraceptive efficacy via CYP450 induction
Aprepitant and bosentan may interact and reduce hormone levels
Protease inhibitors like ritonavir may affect metabolism
Blood pressure medications may have altered effectiveness
Seizure medications can increase clearance of contraceptive hormones
Steroid therapy may influence hormone levels or side effects
Thyroid medications might require dose adjustments
Tuberculosis treatment agents like rifampin reduce hormone levels
Grapefruit juice may increase hormone blood levels causing side effects

Preparations Of The Drug

Silicone vaginal ring impregnated with ethinyl estradiol and segesterone acetate
Single ring delivering sustained hormone release for 21 days per cycle
Ring designed for reuse up to 13 cycles (1 year)
Comes with storage case for ring when removed
Supplied in sterile packaging with patient instructions
Not available in multiple dose strengths as dosing is standardized
Non-oral, non-daily administration format for contraception