NORGESTREL 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.
Norgestrel is a progestogen that suppresses gonadotropin secretion, primarily LH, inhibiting ovulation and altering cervical mucus to impede sperm penetration. Ethinyl estradiol is an estrogen that stabilizes the endometrium and provides negative feedback on gonadotropin release, contributing to contraceptive efficacy.
| Metabolism | Norgestrel is primarily metabolized via reduction, hydroxylation, and conjugation; CYP3A4 is involved. Ethinyl estradiol is metabolized primarily by CYP3A4, with conjugation to sulfate and glucuronide; undergoes enterohepatic recirculation. |
| Excretion | Norgestrel: 45% renal, 32% fecal as metabolites; Ethinyl estradiol: 40% renal, 60% fecal as glucuronide and sulfate conjugates. |
| Half-life | Norgestrel: terminal half-life ~45 hours (range 24–50 h), supporting once-daily dosing; Ethinyl estradiol: terminal half-life ~17 hours (range 10–24 h). |
| Protein binding | Norgestrel: ~99% bound to SHBG and albumin; Ethinyl estradiol: ~97% bound to albumin. |
| Volume of Distribution | Norgestrel: ~2.5 L/kg, indicating extensive tissue distribution; Ethinyl estradiol: ~4.5 L/kg. |
| Bioavailability | Oral: Norgestrel ~80-100%; Ethinyl estradiol ~55% (first-pass metabolism reduces bioavailability). |
| Onset of Action | Oral: Contraceptive effect requires 7 days of consistent dosing; for emergency contraception, effect within 72 hours of unprotected intercourse. |
| Duration of Action | Contraceptive protection persists for the duration of daily dosing; after discontinuation, fertility returns typically within 1–3 months. |
| Molecular Weight | Norgestrel 312.45 Da; Ethinyl Estradiol 296.40 Da |
One tablet (0.3 mg norgestrel/0.03 mg ethinyl estradiol) orally once daily, taken at the same time each day.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Use with caution in severe renal impairment (GFR <30 mL/min/1.73 m²) due to potential fluid retention. Contraindicated in acute or chronic hepatic disease with impaired renal function. |
| Liver impairment | Contraindicated in hepatic adenomas, active liver disease, or Child-Pugh B/C cirrhosis. No dose adjustment recommended for Child-Pugh A, but use with caution. |
| Pediatric use | For postmenarchal adolescents, same dosing as adults (one tablet orally once daily). Not indicated for premenarchal use. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific dose recommendations; contraindicated in postmenopausal women due to lack of efficacy and increased risk of adverse events. |
| 1st trimester | Contraindicated due to increased risk of congenital anomalies (e.g., cardiovascular, limb defects). |
| 2nd trimester | Contraindicated based on historical data; may increase risk of cholestasis and fetal anomalies. |
| 3rd trimester | Contraindicated due to risk of fetal harm (e.g., feminization of male fetuses) and possible withdrawal bleeding in newborn. |
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 norgestrel and ethinyl estradiol cross the placenta; degree is significant and may cause fetal effects. |
| Breastfeeding |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events (e.g., myocardial infarction, stroke, thromboembolism) from combined oral contraceptive use, particularly in women over 35 years of age and those who smoke 15 or more cigarettes daily.
| Common Effects | osteoporosis prevention |
| Serious Effects |
PregnancyBreast cancer (current or history)Estrogen-dependent neoplasiaHistory of deep vein thrombosis or pulmonary embolismCerebrovascular or coronary artery diseaseValvular heart disease with complicationsSevere hypertension (≥160/100 mm Hg)Diabetes with vascular involvementMigraine with focal neurological symptoms (in women over 35)Major surgery with prolonged immobilizationSmoking (≥15 cigarettes/day) in women over 35Active liver disease or hepatic tumors (benign or malignant)Known or suspected pregnancyUndiagnosed abnormal uterine bleeding
| Precautions | Increased risk of thrombotic disorders (e.g., venous thromboembolism, stroke, myocardial infarction); hypertension; hepatic neoplasia; gallbladder disease; carbohydrate and lipid effects; ocular changes including retinal thrombosis; migraine headache; breakthrough bleeding; use in smokers over 35; use in obesity; postpartum Use; lactation. |
Loading safety data…
| Small amounts excreted in breast milk; may reduce milk production and quality; use only if benefit outweighs risk. |
| Lactation Rating | L3 (Moderately Safe) – limited data suggest risk. |
| Teratogenic Risk | Pregnancy category X. Contraindicated in pregnancy. First trimester: increased risk of cardiovascular defects, limb reduction defects, and neural tube defects. Second and third trimesters: reported association with fetal genital tract abnormalities (e.g., hypospadias), low birth weight, and preterm delivery. Use during pregnancy is not recommended. |
| Fetal Monitoring | Monitor for signs of thromboembolism, hypertension, and hepatic dysfunction. If inadvertent use during pregnancy, ultrasound to assess fetal anatomy. Monitor for fetal growth restriction in late pregnancy exposure. |
| Fertility Effects | Reversible suppression of ovulation. Normal fertility typically resumes promptly after discontinuation. No known permanent effects on fertility. |
| Food/Dietary | Grapefruit and grapefruit juice may increase estrogen levels and side effects; avoid excessive consumption. Food does not significantly alter absorption; can be taken with or without food. St. John's Wort reduces contraceptive efficacy; avoid concurrent use. |
| Clinical Pearls | For perimenopausal patients, consider use for heavy menstrual bleeding; progestin-only pills may be preferred in breastfeeding or those with migraine with aura. In epilepsy patients on enzyme-inducing antiepileptics, consider higher estrogen dose (50 mcg) or alternative contraception. Obtain blood pressure at baseline and follow-up; discontinue if hypertension develops or uncontrolled. Counsel on increased VTE risk, especially in smokers over 35. Use lowest effective dose; 30-35 mcg EE is standard for cycle control. Breakthrough bleeding is common in first 3 months; evaluate if persists beyond 3 cycles. Missed pill protocol: if 1 missed >12 hours, take last missed and continue; if 2 or more missed, consider emergency contraception. |
| Patient Advice | Take one pill at the same time every day; do not skip days. · If you miss a pill by more than 12 hours, take the missed pill as soon as you remember and use backup contraception. · Common side effects include nausea, breast tenderness, and breakthrough bleeding, which often improve after 3 months. · Serious risks include blood clots, stroke, and high blood pressure; seek help for leg pain, chest pain, or sudden severe headache. · Do not smoke while taking this medication; smoking increases risk of clots, especially if over 35. · This medication does not protect against sexually transmitted infections; use condoms for STI prevention. |