ETHINYL ESTRADIOL; LEVONORGESTREL
Clinical safety rating: avoid
Inducers of CYP450 enzymes (eg carbamazepine) may decrease estrogen levels Increases risk of thromboembolic disorders and endometrial cancer.
Combination of ethinyl estradiol and levonorgestrel suppresses gonadotropins (FSH and LH) from the anterior pituitary, inhibiting ovulation. Also increases cervical mucus viscosity and induces endometrial changes that reduce implantation likelihood.
| Metabolism | Ethinyl estradiol is primarily metabolized by CYP3A4, undergoes first-pass metabolism with sulfate conjugation in the gut wall. Levonorgestrel is metabolized by CYP3A4 and to a lesser extent by CYP2C9, with conjugation to glucuronide and sulfate metabolites. |
| Excretion | Renal: Ethinyl estradiol ~40% as glucuronide and sulfate conjugates; levonorgestrel ~20% as metabolites. Fecal: Ethinyl estradiol ~60%; levonorgestrel ~80% via biliary excretion. |
| Half-life | Ethinyl estradiol: ~13-27 hours (terminal); Levonorgestrel: ~16-33 hours (terminal). Clinically, steady-state is reached within 5-7 days; elimination half-life supports once-daily dosing with potential accumulation. |
| Protein binding | Ethinyl estradiol: ~95-97% bound to albumin; Levonorgestrel: ~97-99% bound to albumin and SHBG (sex hormone-binding globulin). |
| Volume of Distribution | Ethinyl estradiol: ~2.5-4.5 L/kg; Levonorgestrel: ~1.4-2.1 L/kg. High Vd indicates extensive tissue distribution, including reproductive organs and breast tissue. |
| Bioavailability | Oral: Ethinyl estradiol ~40-55% (first-pass metabolism); Levonorgestrel ~90-100% (minimal first-pass). |
| Onset of Action | Oral: Contraceptive effect begins after 7 days of continuous dosing (if started on day 1-5 of cycle); for emergency contraception, onset within 72 hours of unprotected intercourse. |
| Duration of Action | Contraceptive efficacy persists as long as daily oral dosing continues; after discontinuation, ovulation returns typically within 2-4 weeks. Emergency contraception: single dose effective for that cycle only. |
| Molecular Weight | Ethinyl estradiol: 296.4 Da; Levonorgestrel: 312.4 Da; Combination: average ~304.4 Da |
1 tablet (0.03 mg ethinyl estradiol / 0.15 mg levonorgestrel) orally once daily for 21 consecutive days, followed by 7 days of placebo
| Dosage form | TABLET |
| Renal impairment | No dosage adjustment required for mild-to-moderate renal impairment. Use caution in severe renal impairment (GFR <30 mL/min) due to potential fluid retention; avoid if dialysis required. |
| Liver impairment | Contraindicated in acute liver disease or decompensated cirrhosis (Child-Pugh class B or C). For compensated cirrhosis (Child-Pugh class A), use only if benefits outweigh risks; no specific dose adjustment established. |
| Pediatric use | Approved for post-menarchal adolescents; same dosing as adults (1 active tablet daily). Weight-based dosing not recommended. |
| Geriatric use | Not indicated for postmenopausal women. No specific studies; use generally not appropriate due to increased thrombotic risk and lack of efficacy in this population. |
| 1st trimester | Contraindicated in first trimester due to risk of congenital anomalies, particularly cardiovascular defects and neural tube defects. Use during early pregnancy is not recommended. |
| 2nd trimester | Contraindicated in second trimester. Prolonged exposure may increase risk of adverse fetal outcomes, including fetal toxicity. |
| 3rd trimester | Contraindicated in third trimester. Estrogens can suppress lactation and have feminizing effects on male fetuses. Progestins may cause androgenic effects. |
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 | Both ethinyl estradiol and levonorgestrel cross the placenta. Ethinyl estradiol can cause female fetal feminization; levonorgestrel has low molecular weight and readily crosses. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptive use. Risk increases with age and smoking intensity (especially in women over 35 years of age). Women who use combination oral contraceptives should be strongly advised not to smoke.
| Common Effects | osteoporosis prevention |
| Serious Effects |
Known or suspected pregnancyUndiagnosed abnormal genital bleedingBreast cancer (current or history)Estrogen-dependent neoplasiaActive or history of thromboembolic disorders (e.g., deep vein thrombosis, pulmonary embolism)Cerebrovascular or coronary artery diseaseSevere hypertension (uncontrolled)Diabetes with vascular involvementHeadaches with focal neurological symptoms (migraine with aura, especially in women >35 years smoking)Major surgery with prolonged immobilizationLiver tumors (benign or malignant) or active liver diseaseKnown thrombophilic conditions (e.g., Factor V Leiden, prothrombin mutation, protein C/S deficiency)Current or history of pancreatitis associated with hypertriglyceridemia
| Precautions |
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| Breastfeeding | Excreted in breast milk in small amounts; may reduce milk production and affect infant development. Use is generally not recommended during breastfeeding due to potential adverse effects on the infant, including jaundice and breast enlargement. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | First trimester: Use is contraindicated due to increased risk of cardiovascular defects, neural tube defects, and limb reduction defects; post-conception exposure should be avoided. Second and third trimesters: Exposure associated with fetal adrenal suppression, virilization of female fetuses, and potential hepatotoxicity; not recommended at any stage of pregnancy. |
| Fetal Monitoring | Not applicable as drug is contraindicated in pregnancy. In case of inadvertent exposure, monitor fetal growth, anatomy via ultrasound, and neonatal outcomes. |
| Fertility Effects | Reversible ovulation suppression while on therapy; normal fertility returns after discontinuation. No evidence of permanent impairment. |
| Increased risk of thromboembolic disorders including venous thromboembolism and arterial thrombosis, Increased risk of myocardial infarction in smokers over 35, Increased risk of stroke, Possible increased blood pressure, Possible gallbladder disease, Hepatic impairment, Carbohydrate/lipid metabolic effects, Hereditary angioedema exacerbation, Chloasma, Ocular complications (retinal thrombosis, optic neuritis) |
| Food/Dietary | Grapefruit juice may inhibit CYP3A4 and increase ethinyl estradiol levels; avoid large amounts of grapefruit juice. St. John's wort reduces contraceptive efficacy; avoid concurrent use. No specific food restrictions. |
| Clinical Pearls | Ethinyl estradiol is a CYP3A4 substrate; coadministration with strong inducers (e.g., rifampin, carbamazepine) reduces contraceptive efficacy. Levonorgestrel is a progestin with minimal androgenic activity; suited for women with acne or hirsutism. First pill should be taken on the first day of menses for immediate contraceptive effect. Nausea is common; consider taking with food or at bedtime. Missed pills increase breakthrough bleeding and pregnancy risk; use backup contraception if >1 pill missed. Monitor blood pressure annually; estrogen can elevate BP. |
| Patient Advice | Take one pill at the same time every day; if you miss a pill, follow the package insert instructions and use backup contraception like condoms. · Common side effects include nausea, breast tenderness, and spotting between periods. These often improve within 2-3 months. · Contact your doctor immediately if you experience severe headache, chest pain, calf pain, or visual disturbances (signs of thromboembolism). · Do not smoke while taking this medication; smoking increases the risk of serious cardiovascular side effects, especially if you are over 35. · This medication does not protect against HIV or other sexually transmitted infections; always use condoms for STI prevention. |