LEVONORGESTREL AND ETHINYL ESTRADIOL 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.
Combination hormonal contraceptive: ethinyl estradiol suppresses gonadotropin release, inhibiting ovulation; levonorgestrel alters cervical mucus and endometrial lining to prevent fertilization and implantation.
| Metabolism | Ethinyl estradiol undergoes first-pass metabolism in the liver via CYP3A4; levonorgestrel is metabolized by CYP3A4. Both undergo conjugation and enterohepatic recirculation. |
| Excretion | Levonorgestrel: 45% renal, 32% fecal; Ethinyl estradiol: 40% renal, 60% fecal. Both undergo enterohepatic recirculation. |
| Half-life | Levonorgestrel: ~25 hours; Ethinyl estradiol: ~13 hours. Steady-state achieved within 5-7 days; clinical efficacy maintained by daily dosing. |
| Protein binding | Levonorgestrel: 97-99% bound to sex hormone-binding globulin (SHBG) and albumin; Ethinyl estradiol: 98-99% bound to albumin, with some SHBG affinity. |
| Volume of Distribution | Levonorgestrel: 1.8 L/kg; Ethinyl estradiol: 2.5-4.0 L/kg. Reflects extensive tissue distribution, including breast and reproductive tissues. |
| Bioavailability | Oral: Levonorgestrel ~100%; Ethinyl estradiol ~40-45% (due to first-pass metabolism in gut and liver). |
| Onset of Action | Oral: Contraceptive effect begins after 7 days of continuous dosing (ovulation suppression); withdrawal bleeding occurs 2-3 days after last active pill. |
| Duration of Action | Oral: 24 hours (daily dosing required). Missed pills increase pregnancy risk; extended cycles (e.g., 84 days) possible with continuous regimens. |
| Molecular Weight | Levonorgestrel: 312.446 Da; Ethinyl estradiol: 296.403 Da |
One tablet containing 0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol (or 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol) orally once daily for 21 days, followed by 7 days of placebo or ethinyl estradiol 0.01 mg alone. For extended-cycle regimens, dosing may be continuous for up to 84 days.
| Dosage form | TABLET |
| Renal impairment | No dosage adjustment required for mild to moderate renal impairment. Contraindicated in severe renal impairment or acute renal failure due to potential for fluid retention and electrolyte disturbances. |
| Liver impairment | Contraindicated in Child-Pugh class B or C (moderate to severe hepatic impairment). Use with caution in Child-Pugh class A (mild) with reduced initial dose; specific guidelines are not established. |
| Pediatric use | Use only after menarche. For adolescents, same dosing as adults: one combination tablet daily for 21 days plus 7 placebo or low-dose estrogen tablets. No weight-based adjustment required. |
| Geriatric use | Not indicated in postmenopausal women. In elderly women of reproductive age, same dosing as adults; consider increased risk of thromboembolism and cardiovascular events. |
| 1st trimester | Contraindicated due to risk of congenital defects (limb deficiencies, heart defects) and potential for fetal harm. Use in first trimester is avoided unless absolutely necessary with clear benefit over risk. |
| 2nd trimester | Not recommended; may be used only if clearly needed and no alternative. Potential risks include fetal abnormalities and adverse effects on fetal development. Associated with increased risk of cardiovascular and other abnormalities in retrospective studies. |
| 3rd trimester | Contraindicated due to risk of fetal harm, including possible feminization of male fetuses and other teratogenic effects. Estrogens can cause delayed skeletal maturation and other developmental issues. |
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 |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptives. Risk increases with age (>35 years) and with heavy smoking (≥15 cigarettes/day). Women who use combination hormonal contraceptives should be strongly advised not to smoke.
| Common Effects | osteoporosis prevention |
| Serious Effects |
Known or suspected pregnancyBreastfeeding (early postpartum period)History of or current thrombophlebitis or thromboembolic disordersCerebrovascular or coronary artery diseaseKnown or suspected carcinoma of the breastEstrogen-dependent neoplasia (e.g., endometrial cancer)Undiagnosed abnormal genital bleedingCholestatic jaundice of pregnancy or jaundice with prior pill useHepatic adenomas or carcinomasActive liver disease or impaired liver function (e.g., acute viral hepatitis, decompensated cirrhosis)Known hypersensitivity to any componentSmoking in women over 35 years of age
| Precautions | Increased risk of thromboembolic events (especially in smokers >35 years), Increased risk of hepatic adenoma and HCC with long-term use, May increase blood pressure, May cause fluid retention and exacerbate conditions such as migraine, asthma, or renal disease, May affect glucose tolerance in diabetic patients |
Loading safety data…
| Both levonorgestrel and ethinyl estradiol cross the placenta. Ethinyl estradiol is extensively transferred to fetal circulation, reaching maternal-equivalent levels, and may accumulate. Levonorgestrel also crosses with fetal-to-maternal ratio approximately 0.3-0.5. |
| Breastfeeding | Both levonorgestrel and ethinyl estradiol are excreted in breast milk in small amounts. Estrogens may reduce milk production and alter milk composition, especially in early postpartum period. Use is generally not recommended during breastfeeding; alternative contraception methods are preferred. If used, monitor infant for potential side effects such as jaundice, breast enlargement, and vaginal bleeding in girls. |
| Lactation Rating | L4 (Possibly Hazardous) - Contraindicated in breastfeeding due to potential for reduced milk production and adverse effects in the infant. Alternative methods strongly advised. |
| Teratogenic Risk | First trimester: Major birth defects not significantly increased in large studies; no known organ-specific teratogenicity. Second trimester: No known fetal risks. Third trimester: Potential for fetal adverse effects from estrogen/progestin exposure, including respiratory distress, transient adrenal insufficiency, and withdrawal bleeding; however, no specific teratogenic effects. Overall: Not recommended for use during pregnancy due to lack of benefit. |
| Fetal Monitoring | If inadvertently used during pregnancy, no specific monitoring required beyond routine prenatal care. Monitor for signs of pregnancy if delayed withdrawal bleeding occurs. |
| Fertility Effects | Contraceptive effect is reversible; return to fertility may be delayed for a few cycles after discontinuation. No permanent adverse effects on fertility. |
| Food/Dietary | No significant food interactions. Grapefruit juice may slightly increase ethinyl estradiol levels but not clinically relevant. Avoid excessive alcohol consumption as it may impair judgment and adherence. High-fat meals may reduce absorption if taken with food? Actually, food does not significantly alter absorption. Administer with or without food. |
| Clinical Pearls | Levonorgestrel/ethinyl estradiol is a combined oral contraceptive (COC). The ethinyl estradiol component is present in two phases (biphasic) or constant dose with variable progestin. Nausea is common initially; administer with food. Missed pill management: if one pill missed, take as soon as remembered; if two or more missed, use backup contraception for 7 days. Risk of venous thromboembolism (VTE) increased, especially in smokers over 35. Do not prescribe with CYP3A4 inducers (e.g., rifampin, St. John's wort) which reduce efficacy. Check blood pressure at baseline and annually. |
| Patient Advice | Take one pill daily at the same time to maintain contraceptive efficacy. · If you miss a pill, consult the package insert or your healthcare provider for instructions. · Use backup contraception (e.g., condoms) if you miss more than one pill, start a new pack late, or have vomiting/diarrhea. · This medication does not protect against sexually transmitted infections (STIs). · Common side effects include nausea, breast tenderness, and breakthrough bleeding; these often improve after 2-3 cycles. · Smoking increases risk of serious cardiovascular events; avoid smoking, especially if over 35. · Seek emergency medical attention for symptoms of blood clots: sudden leg pain/swelling, chest pain, shortness of breath, or severe headache. · Inform all healthcare providers you are taking this medication. |