LEVONORGESTREL AND ETHINYL ESTRADIOL
Clinical safety rating: avoid
Inducers of CYP450 enzymes (eg carbamazepine) may decrease estrogen levels Increases risk of thromboembolic disorders and endometrial cancer.
Levonorgestrel is a progestin that suppresses gonadotropin release, inhibiting ovulation; ethinyl estradiol is an estrogen that stabilizes the endometrium and provides feedback inhibition on the hypothalamic-pituitary-ovarian axis, preventing follicular development and ovulation.
| Metabolism | Ethinyl estradiol is primarily metabolized via CYP3A4; also undergoes sulfation and glucuronidation. Levonorgestrel is metabolized by reduction and conjugation, primarily via CYP3A4. |
| Excretion | Levonorgestrel and ethinyl estradiol are primarily eliminated via renal excretion (40-68% as metabolites) and fecal excretion (20-45%). Less than 1% is excreted unchanged. |
| Half-life | Levonorgestrel: terminal half-life approximately 24-32 hours. Ethinyl estradiol: terminal half-life approximately 13-27 hours (mean ~17 hours). The half-lives are relevant for once-daily dosing, achieving steady state within 5-7 days. |
| Protein binding | Levonorgestrel: 97-99% bound to sex hormone-binding globulin (SHBG) and albumin. Ethinyl estradiol: 95-97% bound to albumin. Induces SHBG synthesis, increasing its own binding capacity. |
| Volume of Distribution | Levonorgestrel: Vd ~1.4 L/kg (range 0.6-2.5 L/kg). Ethinyl estradiol: Vd ~2.4-4.3 L/kg. Indicates extensive tissue distribution and binding to sex hormone receptors. |
| Bioavailability | Oral bioavailability: levonorgestrel ~100% (due to high oral absorption and minimal first-pass metabolism); ethinyl estradiol ~40-55% (due to extensive first-pass metabolism and intestinal sulfation). |
| Onset of Action | Oral administration: ovulation inhibition and contraceptive effects begin after 7 days of continuous dosing (if started on day 1 of menstrual cycle). Immediate if started on cycle day 1; delayed 7 days if started later. |
| Duration of Action | Contraceptive protection persists for 24 hours with once-daily dosing. After discontinuation, ovulation may resume within 1-2 weeks, though individual variation exists. |
| Molecular Weight | Levonorgestrel: 312.45 Da; Ethinyl estradiol: 296.40 Da |
Oral, 1 tablet daily containing 0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol, or 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol, taken at the same time each day for 21 days followed by 7 placebo tablets, or continuous daily dosing as per product labeling.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (GFR >=30 mL/min). For severe renal impairment (GFR <30 mL/min) or end-stage renal disease, use is not recommended due to potential accumulation of ethinyl estradiol and lack of safety data. |
| Liver impairment | Contraindicated in hepatocellular disease, acute or chronic liver disease, or history of liver tumors. For mild hepatic impairment (Child-Pugh A), use with caution and monitor liver function; dose adjustment not established. Moderate to severe impairment (Child-Pugh B or C) contraindicated. |
| Pediatric use | Approved for postmenarchal adolescents. Use same dosing as adults (tablet containing 0.1 mg levonorgestrel/0.02 mg ethinyl estradiol or 0.15 mg/0.03 mg, once daily). Weight-based dosing not required; adjust based on tolerability and efficacy. |
| Geriatric use | Not indicated for use in postmenopausal women; no specific dosing guidelines. Use only in nonmenopausal elderly women if benefits outweigh risks, with monitoring for cardiovascular and thromboembolic events. |
| 1st trimester | Contraindicated. Risk of congenital anomalies (e.g., cardiovascular, limb reduction). Use only if benefit outweighs risk. |
| 2nd trimester | Contraindicated. Potential for hepatotoxicity, cholestasis, and adverse effects on fetal growth. |
| 3rd trimester | Contraindicated. Increased risk of postpartum thrombosis, neonatal hepatic dysfunction, and feminization of male fetus. |
Clinical note
Inducers of CYP450 enzymes (eg carbamazepine) may decrease estrogen levels Increases risk of thromboembolic disorders and endometrial cancer.
| FDA category | Positive |
| Placental transfer | Crosses placenta; both agents reach fetal circulation. Ethinyl estradiol levels in fetal blood are ~5-10% of maternal levels; levonorgestrel levels are ~20-50%. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events from combined oral contraceptive use. This risk increases with age, especially in women over 35, and with the number of cigarettes smoked. Women who use combined oral contraceptives should be strongly advised not to smoke.
| Common Effects | osteoporosis prevention |
| Serious Effects |
Thrombophlebitis or thromboembolic disorders (current or history)Cerebrovascular or coronary artery diseaseKnown or suspected pregnancyUndiagnosed abnormal genital bleedingKnown or suspected breast cancerBenign or malignant liver tumor (current or history)Hepatic adenoma or active liver diseaseHypersensitivity to any component
| Precautions | Thrombotic disorders including venous thromboembolism, myocardial infarction, stroke, Hepatic neoplasia including hepatic adenomas and hepatocellular carcinoma, Elevated blood pressure, Gallbladder disease, Carbohydrate and lipid metabolic effects, Ocular lesions such as retinal thrombosis, Menstrual irregularities and breakthrough bleeding, Possible reduced efficacy with enzyme-inducing drugs, Use in pregnancy is contraindicated, Postpartum use in lactating women: may reduce milk production |
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| Breastfeeding |
| Excreted in breast milk in small amounts; may reduce milk production and volume. Use only if clearly needed, and prescribe progesterone-only alternatives when contraception is required. |
| Lactation Rating | L3 - Moderately Safe |
| Teratogenic Risk | First trimester: Exposure associated with minor malformations (cardiac defects, limb reduction) in some studies, but absolute risk low. Second/third trimester: Androgenic effects (clitoromegaly, labial fusion) in female fetuses; no major structural anomalies attributed. Avoid use during pregnancy. |
| Fetal Monitoring | Monitor blood pressure, liver function, and signs of thromboembolism in mother. Fetal ultrasound if inadvertent exposure occurs, particularly for cardiac anatomy and genital development. |
| Fertility Effects | Reversible suppression of ovulation. Return to fertility typically occurs within 1-2 cycles after discontinuation. No evidence of permanent impairment. |
| Food/Dietary | Take with or without food; food may reduce nausea. Avoid grapefruit and grapefruit juice as they may increase estrogen levels and risk of side effects. No significant dietary restrictions otherwise. |
| Clinical Pearls | 1) Counsel patients that missing pills increases risk of breakthrough bleeding and pregnancy; strict adherence is critical. 2) Consider potential for reduced efficacy with certain anticonvulsants (e.g., carbamazepine, phenytoin) and antibiotics (e.g., rifampin). 3) Not recommended in patients with BMI >35 due to increased failure risk. 4) Monitor blood pressure at follow-up; estrogen component may raise BP. 5) Advise that spotting/breakthrough bleeding is common in first 3 months; if persistent, consider alternative formulations or etiologies. |
| Patient Advice | Take one pill daily at the same time, without missing days. · If you miss a pill, follow package instructions; use backup contraception if needed. · Inform your provider if you smoke, especially if over 35; smoking increases risk of serious side effects. · Seek medical help immediately for signs of blood clot: leg pain/swelling, sudden chest pain, shortness of breath, or severe headache. · This medication does not protect against sexually transmitted infections; use condoms if protection needed. · If you experience severe vomiting or diarrhea, use additional contraception; absorption may be impaired. |