NORETHIN 1/35E-21
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NORETHIN 1/35E-21 (NORETHIN 1/35E-21).
Combination estrogen-progestin oral contraceptive; suppresses gonadotropin release from pituitary, inhibits ovulation, thickens cervical mucus, alters endometrial lining.
| Metabolism | Ethinyl estradiol: primarily CYP3A4; Norethindrone: primarily CYP3A4, with reduction and conjugation. |
| Excretion | Norethindrone and ethinyl estradiol are primarily excreted via urine (approximately 60-80% as metabolites) and feces (about 10-30%). Renal excretion accounts for the majority, with biliary/fecal elimination contributing a minor but significant fraction. |
| Half-life | Norethindrone: terminal half-life ~7-8 hours (range 5-12 h). Ethinyl estradiol: terminal half-life ~13-27 hours (mean ~17 h). The half-life supports once-daily dosing with stable serum concentrations achieved after 3-5 days. |
| Protein binding | Norethindrone: ~97% bound, primarily to albumin and sex hormone-binding globulin (SHBG). Ethinyl estradiol: ~97-98% bound, mainly to albumin. |
| Volume of Distribution | Norethindrone: apparent Vd ~2-4 L/kg (indicating extensive tissue distribution, particularly to fat and reproductive organs). Ethinyl estradiol: Vd ~2.5-4 L/kg. |
| Bioavailability | Oral: Norethindrone ~64% (range 50-80%) due to first-pass metabolism. Ethinyl estradiol ~38-48% due to presystemic conjugation. When combined, bioavailability is similar to individual components. |
| Onset of Action | Oral: Contraceptive effect (ovulation inhibition) begins after 7 days of consistent daily dosing. For hormone withdrawal bleeding regulation, effect seen within 21-day cycle. |
| Duration of Action | Oral: Contraceptive protection persists for 24 hours per tablet. Withdrawal bleeding typically occurs 2-3 days after last active tablet. Endometrial suppression maintained throughout 21-day regimen. |
1 tablet orally once daily for 21 days, followed by 7 days off, then repeat. Each tablet contains 1 mg norethindrone acetate and 0.035 mg ethinyl estradiol.
| Dosage form | TABLET |
| Renal impairment | No dosage adjustment required for mild to moderate renal impairment. For severe renal impairment (eGFR <30 mL/min/1.73 m²), use is not recommended due to lack of safety data. |
| Liver impairment | Contraindicated in Child-Pugh class B and C (moderate to severe hepatic impairment) due to impaired hormone clearance. For mild impairment (Child-Pugh class A), use with caution; no specific dose adjustment available. |
| Pediatric use | Post-menarcheal adolescents: Same dosing as adults (1 tablet orally once daily for 21 days, then 7 days off). Initiation after onset of first menses. Safety and efficacy not established in pre-menarcheal females. |
| Geriatric use | Not indicated for postmenopausal women. No specific geriatric dosing; use is limited to reproductive-age women. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NORETHIN 1/35E-21 (NORETHIN 1/35E-21).
| Breastfeeding | Combined oral contraceptives (estrogen + progestin) may reduce milk production and quality; use is generally not recommended during lactation. M/P ratio for norethindrone: approximately 1.4; estrogen (ethinyl estradiol) is excreted in low amounts. Prefer progestin-only contraceptives. |
| Teratogenic Risk | First trimester: No evidence of teratogenic effects from combined oral contraceptives in large studies; risk of congenital anomalies not significantly increased. Second/third trimesters: Use is contraindicated due to potential for fetal harm, including masculinization of female fetuses from progestin and possible estrogenic effects; may increase risk of fetal genital abnormalities with continued use. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events. Women over 35 who smoke should not use combination oral contraceptives.
| Serious Effects |
Thrombophlebitis or thromboembolic disorders, history of deep vein thrombosis or pulmonary embolism, cerebrovascular or coronary artery disease, known or suspected pregnancy, undiagnosed abnormal uterine bleeding, known or suspected breast cancer, hepatic adenoma or carcinoma, active liver disease, age >35 and smoking.
| Precautions | Increased risk of thromboembolic disorders, myocardial infarction, stroke, hepatic neoplasia, gallbladder disease, hypertension; monitor blood pressure; discontinue if jaundice or visual disturbances occur. |
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| Fetal Monitoring | If inadvertently used during pregnancy, monitor fetal development via ultrasound for potential genital abnormalities; assess maternal blood pressure and liver function due to risk of cholestasis; monitor for thromboembolic events. |
| Fertility Effects | No permanent effect on fertility; normal ovulation and fertility return within 1-2 menstrual cycles after discontinuation. No evidence of long-term impairment. |