ETHINYL ESTRADIOL; ETONOGESTREL
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
ETHINYL ESTRADIOL is an estrogen; ETONOGESTREL is a progestin. The combination suppresses gonadotropin (FSH and LH) release from the pituitary, inhibiting ovulation, thickening cervical mucus to impede sperm penetration, and altering endometrial receptivity.
| Metabolism | ETHINYL ESTRADIOL: Primarily metabolized by CYP3A4, with contributions from CYP2C9 and CYP2C19. Undergoes first-pass metabolism and enterohepatic recirculation. ETONOGESTREL: Primarily metabolized by CYP3A4. |
| Excretion | Urine (60-70% as metabolites, <10% unchanged), feces (20-30% via biliary elimination). |
| Half-life | Ethinyl estradiol: ~13 hours (range 7-20 h); etonogestrel: ~25 hours (range 15-36 h). At steady state, elimination half-life extends to 20-30 h for etonogestrel. |
| Protein binding | Ethinyl estradiol: 98% bound to albumin and SHBG; etonogestrel: 66-79% bound to SHBG, 31% to albumin. |
| Volume of Distribution | Ethinyl estradiol: 2.5-5 L/kg; etonogestrel: 2.0-3.5 L/kg. Large Vd indicates extensive tissue distribution (e.g., reproductive organs, liver, fat). |
| Bioavailability | Vaginal ring: approximately 100% for both steroids (systemic absorption). Oral (combination pill): ethinyl estradiol ~40-55% (first-pass metabolism); etonogestrel ~70-100%. |
| Onset of Action | Contraceptive effect: immediate if initiated on day 1 of menstrual cycle; otherwise, 7 days of continuous use required. Vaginal ring: consistent serum concentrations achieve ovulation suppression within 48-72 hours of insertion. |
| Duration of Action | Contraceptive effect persists as long as ring remains in place (3 weeks continuous use). Rapid return of ovulation after removal (within 2-4 weeks). |
One vaginal ring (0.120 mg etonogestrel/0.015 mg ethinyl estradiol per day) inserted vaginally and left in place for 3 weeks, followed by a 1-week ring-free period.
| Dosage form | RING |
| Renal impairment | No dose adjustment recommended for mild to moderate renal impairment. Contraindicated in severe renal impairment or acute renal failure due to potential hormonal accumulation and electrolyte disturbances. |
| Liver impairment | Contraindicated in patients with severe hepatic impairment (Child-Pugh C). Use with caution in mild to moderate impairment (Child-Pugh A or B) as estrogen metabolism may be reduced; consider alternative contraception. |
| Pediatric use | Dosage as per adult guidelines after menarche. Safety and efficacy established in adolescents; no weight-based adjustment required. |
| Geriatric use | Not indicated for use in postmenopausal women. Contraindicated due to increased risk of thromboembolic events and lack of contraceptive need in this age group. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Hepatic enzyme inducers may decrease efficacy and increase breakthrough bleeding Must be removed if a patient becomes pregnant.
| Breastfeeding | Etonogestrel and ethinyl estradiol are excreted in human milk in small amounts. Estimated infant dose is <1% of maternal weight-adjusted dose. Milk-to-plasma ratio for etonogestrel is approximately 0.5. Use is not recommended during breastfeeding due to potential effects on milk production and infant development. |
| Teratogenic Risk | First trimester: Epidemiological studies have not shown an increased risk of major congenital anomalies. Second and third trimesters: Use is contraindicated due to risk of hormonal disruption to the developing fetus. Postnatal effects: Potential for feminization of male fetuses and virilization of female fetuses. Overall risk is low but not zero. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptives (CHCs). This risk increases with age, especially in women over 35, and with the number of cigarettes smoked. Women who use CHCs should be strongly advised not to smoke.
| Common Effects | Headache |
| Serious Effects |
["Thrombophlebitis or thromboembolic disorders (current or history)","Cerebrovascular or coronary artery disease (current or history)","Known or suspected breast carcinoma","Endometrial or other estrogen-dependent neoplasia","Undiagnosed abnormal genital bleeding","Cholestatic jaundice of pregnancy or jaundice with prior pill use","Hepatic adenoma or carcinoma (benign or malignant)","Known or suspected pregnancy"]
| Precautions | ["Increased risk of thromboembolic disorders (e.g., stroke, myocardial infarction, pulmonary embolism), especially in smokers and women with hypertension, diabetes, or hyperlipidemia.","Hepatic neoplasia (benign and malignant) reported.","Elevated blood pressure; monitor regularly.","Gallbladder disease; may exacerbate.","Glucose intolerance; monitor in prediabetic/diabetic patients.","Depressed mood; discontinue if significant.","Hereditary angioedema; may trigger or exacerbate.","Chloasma; may occur.","Jaundice or cholestasis; discontinue if develops.","Impaired liver function; use contraindicated."] |
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| Fetal Monitoring | Monitor for pregnancy symptoms, signs of thromboembolism, and hepatic function. Assess fetal growth and development via ultrasound if inadvertent exposure occurs during pregnancy. No specific monitoring required due to contraindication. |
| Fertility Effects | Reversible suppression of ovulation. Return to fertility is typically rapid after discontinuation. No known long-term adverse effects on fertility. |