NORETHINDRONE AND ETHINYL ESTRADIOL
Clinical safety rating: avoid
CYP3A4 inducers can decrease efficacy Can cause thromboembolic disorders.
Combination estrogen-progestin contraceptive. Suppresses gonadotropin release (FSH, LH) via negative feedback on hypothalamic-pituitary axis, inhibiting ovulation. Thickens cervical mucus to inhibit sperm penetration. Alters endometrium to reduce implantation likelihood.
| Metabolism | Norethindrone: primarily hepatic via reduction and conjugation; CYP3A4 minor role. Ethinyl estradiol: extensively metabolized by CYP3A4; also undergoes conjugation and enterohepatic circulation. Metabolites excreted in urine and feces. |
| Excretion | Norethindrone: ~50% renal (as metabolites), ~50% fecal (biliary). Ethinyl estradiol: ~40% renal, ~60% fecal (primarily as glucuronide conjugates). |
| Half-life | Norethindrone: 6-8 hours (terminal); Ethinyl estradiol: 13-27 hours (terminal, mean ~17 hours). Half-life supports once-daily dosing for contraceptive efficacy. |
| Protein binding | Norethindrone: ~60-70% bound to albumin and SHBG. Ethinyl estradiol: ~95-98% bound to albumin (not SHBG). |
| Volume of Distribution | Norethindrone: ~4 L/kg (distributes extensively into tissues, including breast and adipose). Ethinyl estradiol: ~2 L/kg (moderate distribution). |
| Bioavailability | Norethindrone: ~50-65% (oral, first-pass metabolism). Ethinyl estradiol: ~40-55% (oral, first-pass metabolism; may increase with food). |
| Onset of Action | Oral: Contraceptive effect requires 7 days of consistent dosing (inhibition of ovulation). For withdrawal bleeding, within 2-3 days after placebo. |
| Duration of Action | Contraceptive effect: 24 hours (requires daily dosing). Withdrawal bleeding typically lasts 2-5 days. Missed pills risk ovulation if >24-hour gap. |
One tablet (norethindrone 1 mg / ethinyl estradiol 0.035 mg) 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 (GFR ≥30 mL/min). Not recommended for use in severe impairment (GFR <30 mL/min) or end-stage renal disease due to potential estrogen accumulation and cardiovascular risks. |
| Liver impairment | Contraindicated in acute hepatitis, decompensated cirrhosis (Child-Pugh class B or C), or liver tumors. Use with caution in mild hepatic impairment (Child-Pugh A) if liver function tests are stable; otherwise, avoid. |
| Pediatric use | Not indicated for premenarcheal girls. For postmenarcheal adolescents, use same dose as adults (one tablet daily) after evaluation of bone age and growth potential. |
| Geriatric use | Not indicated for use in elderly women due to increased risks of thromboembolism, cardiovascular disease, and osteoporosis. Do not use for postmenopausal hormone replacement therapy. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CYP3A4 inducers can decrease efficacy Can cause thromboembolic disorders.
| FDA category | Positive |
| Breastfeeding | Norethindrone and ethinyl estradiol are secreted in breast milk. M/P ratio not established. May reduce milk production and quality. Use not recommended during breastfeeding. |
| Teratogenic Risk | First trimester: Increased risk of neural tube defects, congenital heart defects, and oral clefts. Second and third trimesters: Associated with masculinization of female fetuses, adrenal suppression, and potential for hepatic tumors. Use contraindicated in pregnancy. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events (stroke, myocardial infarction, thromboembolism) from combination hormonal contraceptive use. Risk increases with age and heavy smoking (≥15 cigarettes/day). Women over 35 who smoke should not use this drug.
| Common Effects | abnormal uterine bleeding |
| Serious Effects |
["Breast cancer (known, suspected, or history)","Other estrogen-dependent neoplasia","Undiagnosed abnormal genital bleeding","Liver disease (acute or chronic, including adenomas)","Pregnancy or suspected pregnancy","Current or history of thromboembolic disorders (DVT, PE)","Cerebrovascular or coronary artery disease","Known thrombophilic conditions (e.g., Factor V Leiden, antiphospholipid syndrome)","Uncontrolled hypertension","Diabetes with vascular involvement","Headaches with focal neurological symptoms (e.g., migraine with aura) in women >35","Major surgery with prolonged immobilization","Hypersensitivity to any component","Smoking in women >35 years"]
| Precautions | ["Increased risk of thromboembolic disorders (DVT, PE, stroke, MI)","Hepatic adverse effects: cholestatic jaundice, hepatic adenoma, hepatocellular carcinoma","Elevated blood pressure","Gallbladder disease","Glucose intolerance (diabetes mellitus risk)","Ocular lesions (retinal thrombosis, optic neuritis)","Depression exacerbation","May cause fluid retention; caution in cardiac/renal impairment","Hereditary angioedema exacerbation","Chloasma; avoid UV exposure","Irregular bleeding; rule out pregnancy or pathology","Reduced efficacy with enzyme-inducing drugs or vomiting/diarrhea","Requires annual Pap smear and breast exam"] |
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| Fetal Monitoring | Monitor liver function tests, blood pressure, and lipid profile. Assess for thromboembolic events. Inadvertent fetal exposure: ultrasound for fetal anomalies. |
| Fertility Effects | Suppresses ovulation; reversible upon discontinuation. No long-term impact on fertility. Return to baseline ovulation typically within 1-3 months after stopping. |