ETHINYL ESTRADIOL AND LEVONORGESTREL
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 provides estrogenic activity, levonorgestrel provides progestational activity, suppressing gonadotropin (LH and FSH) release from the pituitary, inhibiting ovulation, and altering cervical mucus and endometrial lining to reduce sperm penetration and implantation.
| Metabolism | Ethinyl estradiol is metabolized primarily via CYP3A4; undergoes first-pass metabolism in the liver and gut wall; also undergoes glucuronidation and sulfation. Levonorgestrel is metabolized via reduction and conjugation; undergoes extensive hepatic metabolism, primarily via CYP3A4, and glucuronidation. |
| Excretion | Urine (40% ethinyl estradiol metabolites, 40% levonorgestrel metabolites); feces (40% ethinyl estradiol, 20% levonorgestrel). |
| Half-life | Ethinyl estradiol: 13-27 hours (terminal). Levonorgestrel: 18-30 hours (terminal). Clinical context: steady state achieved in 5-7 days; missed doses may require backup contraception. |
| Protein binding | Ethinyl estradiol: 97-98% bound (albumin and SHBG). Levonorgestrel: 97-99% bound (SHBG and albumin). |
| Volume of Distribution | Ethinyl estradiol: 2.5-5 L/kg. Levonorgestrel: 1.8-2.6 L/kg. Clinical meaning: extensive distribution into tissues, including breast and reproductive organs. |
| Bioavailability | Oral: Ethinyl estradiol 38-48% (first-pass metabolism). Levonorgestrel 100% (no first-pass effect). |
| Onset of Action | Oral: Inhibition of ovulation occurs within 2-3 days of first dose; contraceptive effect immediate if started on day 1 of menses. |
| Duration of Action | 24 hours for contraceptive efficacy. Clinical note: missed pill >24 hours reduces contraceptive reliability; backup needed if >48 hours. |
One tablet containing 0.02-0.05 mg ethinyl estradiol and 0.1-0.15 mg levonorgestrel orally once daily for 21 days, followed by 7 days of placebo or no tablets.
| Dosage form | TABLET |
| Renal impairment | No dosage adjustment required for mild to moderate renal impairment. Avoid use in severe renal failure (CrCl <30 mL/min) due to limited data and potential for decreased contraceptive efficacy. |
| Liver impairment | Contraindicated in Child-Pugh class B or C (moderate to severe hepatic impairment). Use with caution in Child-Pugh class A; monitor liver function. |
| Pediatric use | Same dosing as adults for postmenarchal adolescents. Use according to standard weight recommendations (≥42 kg for some formulations); consult specific product labeling. |
| Geriatric use | Not indicated for postmenopausal women due to lack of contraceptive need and increased risk of thromboembolic events and hormonal adverse effects. |
| 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 | Small amounts excreted in breast milk; M/P ratio for ethinyl estradiol ~0.04, levonorgestrel ~0.01. May reduce milk production and quality, especially in early postpartum. Use is generally not recommended; alternative contraception advised during breastfeeding. |
| Teratogenic Risk |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptive use. Risk increases with age and smoking ≥15 cigarettes per day. Women over 35 who smoke should not use this product.
| Common Effects | osteoporosis prevention |
| Serious Effects |
["Breast cancer or other estrogen- or progestin-sensitive cancer","Hepatic tumors or acute liver disease","Undiagnosed abnormal uterine bleeding","Known or suspected pregnancy","Current or history of thromboembolic disorders (e.g., deep vein thrombosis, pulmonary embolism, stroke)","Cerebrovascular or coronary artery disease","Uncontrolled hypertension","Migraine with focal aura (women over 35 or smokers)","Diabetes with vascular involvement","Major surgery with prolonged immobilization","Active hepatitis C (if using ombitasvir/paritaprevir/ritonavir regimen)"]
| Precautions | ["Increased risk of thromboembolic disorders (venous and arterial)","Increased risk of myocardial infarction and stroke, especially in smokers over 35","Hepatic neoplasia (benign and malignant)","Gallbladder disease","Elevated blood pressure","Carbohydrate and lipid metabolism effects","Headache including migraine","Unscheduled bleeding and spotting","Potential drug interactions (CYP3A4 inducers/inhibitors)"] |
Loading safety data…
| Pregnancy category X. Contraindicated in pregnancy. First trimester: Increased risk of congenital anomalies, including cardiovascular defects and limb reduction defects, due to estrogenic and progestogenic effects. Second and third trimesters: No direct fetal risks as drug not used; if inadvertently continued, risk of maternal and fetal complications such as thromboembolism, jaundice, and fetal growth restriction. |
| Fetal Monitoring | Regular blood pressure monitoring, assessment for thromboembolic symptoms (leg pain, chest pain, dyspnea), liver function tests if jaundice, and pregnancy testing if withdrawal bleed missed. In case of unintentional use during pregnancy, ultrasound for fetal anatomy and growth. |
| Fertility Effects | Reversible suppression of ovulation. After discontinuation, normal fertility typically resumes within 1-3 months. Long-term use does not cause permanent infertility. |
| Food/Dietary | Avoid grapefruit juice as it may increase estrogen levels. No other significant food interactions. |
| Clinical Pearls | Monitor for thromboembolic events, especially in smokers >35 years. Counsel on strict adherence to 21-day regimen. Consider CYP3A4 inducer/inhibitor interactions. For missed pills, follow manufacturer's algorithm. Use caution in migraine with aura, hypertension, or history of DVT. |
| Patient Advice | Take one tablet daily at the same time for 21 days, then 7 pill-free days. · Missed pill: If <12 hours late, take immediately; if >12 hours, take and skip missed dose; if >2 pills missed, use backup contraception for 7 days. · Common side effects: nausea, breast tenderness, breakthrough bleeding (usually resolves). · Seek emergency care for sudden severe headache, chest pain, leg pain/swelling, vision changes, or jaundice. · Tell your doctor about all medications, especially antibiotics, antifungals, anticonvulsants, and St. John's wort. · Smoking increases risk of serious cardiovascular side effects; avoid smoking. |