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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Inducers of CYP450 enzymes (eg carbamazepine) may decrease estrogen levels Increases risk of thromboembolic disorders and endometrial cancer.
| FDA category | Positive |
| Breastfeeding | Levonorgestrel and ethinyl estradiol are excreted in breast milk in small amounts. M/P ratio for levonorgestrel approximately 1.1; ethinyl estradiol approximately 0.04. May reduce milk production and quality. Not recommended for use during breastfeeding, especially in early postpartum period. |
| Teratogenic Risk |
■ 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 |
["Known or suspected pregnancy","Current or past history of thrombophlebitis or thromboembolic disorders","Cerebrovascular or coronary artery disease","Known or suspected carcinoma of the breast or endometrium","Undiagnosed abnormal genital bleeding","Cholestatic jaundice of pregnancy or jaundice with prior pill use","Hepatic adenomas or carcinomas","Known hypersensitivity to any component","Heavy smoking (≥15 cigarettes/day) and age ≥35 years","Uncontrolled hypertension or diabetes with vascular involvement","Migraine with aura if age ≥35"]
| 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"] |
Loading safety data…
| 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. |