NORETHINDRONE
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Norethindrone is a synthetic progestin that binds to progesterone receptors, suppressing gonadotropin (LH and FSH) release from the pituitary, inhibiting ovulation, and inducing secretory changes in the endometrium. It also has weak androgenic and estrogenic activity.
| Metabolism | Primarily hepatic via reduction and conjugation. Major enzyme: CYP3A4. Also undergoes glucuronidation and sulfation. |
| Excretion | Renal (30-50% as glucuronide conjugates, 5-10% unchanged), fecal (<10%) |
| Half-life | Terminal elimination half-life: 5-14 hours (mean 8-10 hours); clinical context: requires once-daily dosing for steady state after ~2 days (5 half-lives). |
| Protein binding | ~80% bound, primarily to sex hormone-binding globulin (SHBG) and albumin |
| Volume of Distribution | 4-7 L/kg (mean 5.5 L/kg); distribution into tissues, including breast milk, with lipophilic properties. |
| Bioavailability | Oral: 65-85% (extensive first-pass metabolism) |
| Onset of Action | Oral administration: 24-48 hours for progestational effect; IM injection (not typical for norethindrone): not applicable |
| Duration of Action | Oral: ~24 hours with single dose; continuous daily administration required for contraceptive effect (21-day cycle). |
5 mg orally once daily for 5 days starting on day 5 of menstrual cycle or 0.35 mg orally once daily for contraception.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR >30 mL/min; use with caution if GFR <30 mL/min due to potential fluid retention. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh C); for mild to moderate (Child-Pugh A or B), use with caution and reduce dose if needed. |
| Pediatric use | Not indicated for use in pediatric patients for contraceptive purposes; for endometriosis, 2.5-5 mg orally twice daily starting at age 18. |
| Geriatric use | No specific dose adjustment; use lowest effective dose due to increased risk of thromboembolic events and cognitive effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CYP3A4 inducers can decrease efficacy Can cause thromboembolic disorders.
| Breastfeeding | Norethindrone is excreted into breast milk with an estimated milk-to-plasma ratio (M/P) of approximately 0.09 (range 0.01-0.2). Infant dose is less than 1% of maternal weight-adjusted dose. No adverse effects reported in infants but theoretical risk of hormonal effects. Consider alternative progestin-only contraceptives with established safety in lactation. |
| Teratogenic Risk | First trimester: Association with cardiovascular defects (e.g., VSD), limb reduction defects, and neural tube defects based on observational studies; risk is dose-dependent. Second/third trimesters: Potential for androgenic effects on female fetuses (pseudohermaphroditism), feminization of male fetuses, and increased risk of low birth weight. Not recommended for use during pregnancy due to known risks. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events (e.g., thromboembolism, stroke, myocardial infarction) with combined hormonal contraceptives. Risk increases with age (especially over 35) and with heavy smoking (≥15 cigarettes/day). Norethindrone-only pills have lower risk, but smoking still increases cardiovascular risk.
| Common Effects | abnormal uterine bleeding |
| Serious Effects |
Breast cancer, undiagnosed vaginal bleeding, pregnancy, active liver disease, known or suspected pregnancy, history of thromboembolic disorders (e.g., DVT, PE), hypersensitivity to norethindrone.
| Precautions | Thromboembolic disorders, cardiovascular risk in smokers, liver disease, hypertension, diabetes, lipid effects, fluid retention, depression, migraine, irregular bleeding, ectopic pregnancy risk, reduced bone density with long-term use. |
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| Fetal Monitoring | Monitor fetal growth and development via ultrasonography if exposed during pregnancy. Assess for signs of virilization in female fetuses. Monitor maternal liver function, blood pressure, and glucose tolerance periodically. If used for contraception, ensure pregnancy exclusion before initiation. |
| Fertility Effects | Norethindrone can suppress ovulation and alter cervical mucus and endometrial morphology, leading to temporary reduced fertility. Fertility typically returns to baseline after discontinuation, though some users may experience a delay in ovulation recovery. No evidence of permanent impairment. |