NORLESTRIN 21 1/50
Clinical safety rating
cautionComprehensive clinical and safety monograph for NORLESTRIN 21 1/50 (NORLESTRIN 21 1/50).
Combination oral contraceptive containing norethindrone (progestin) and ethinyl estradiol (estrogen). Inhibits ovulation via suppression of gonadotropins (LH, FSH). Enhances cervical mucus viscosity, reducing sperm penetration. Thins endometrium, decreasing implantation likelihood.
| Metabolism | Norethindrone: primarily hepatic via reduction and conjugation; also CYP3A4-mediated hydroxylation. Ethinyl estradiol: hepatic via CYP3A4, also undergoes sulfation and glucuronidation; enterohepatic recirculation. |
| Excretion | Norethindrone: renal (33% as metabolites), fecal (50%); ethinyl estradiol: renal (40% as glucuronide conjugates), fecal (60%) |
| Half-life | Norethindrone terminal half-life: 5-14 hours; ethinyl estradiol terminal half-life: 10-20 hours. Clinical context: steady-state reached within 5-7 days, clinically significant for missed dose management. |
| Protein binding | Norethindrone: 61% bound to albumin, 36% bound to SHBG; ethinyl estradiol: >97% bound to albumin. |
| Volume of Distribution | Norethindrone: 4.3 L/kg; ethinyl estradiol: 2.8-4.5 L/kg. Clinical meaning: extensive distribution into tissues, including breast and reproductive organs. |
| Bioavailability | Oral: norethindrone ~64% (first-pass metabolism), ethinyl estradiol ~45% (first-pass metabolism); transdermal and vaginal routes have higher bioavailability. |
| Onset of Action | Oral: contraceptive effect begins after 7 consecutive days of dosing; peak plasma levels achieved 1-2 hours post-dose. |
| Duration of Action | Contraceptive protection persists for 24 hours with daily dosing; after last dose, ovulation may return within 7-14 days. |
| Molecular Weight | 340.46 |
One tablet (1 mg norethindrone acetate/50 mcg ethinyl estradiol) orally once daily for 21 days, followed by 7 days off therapy.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min; avoid use in patients with GFR <30 mL/min due to potential fluid retention and hypertension. |
| Liver impairment | Contraindicated in Child-Pugh class B or C; use with caution in Child-Pugh class A with monitoring for adverse effects. |
| Pediatric use | Not indicated for use before menarche; dosing based on adult regimen for postmenarchal adolescents. |
| Geriatric use | Not indicated for postmenopausal women; avoid use in elderly due to increased risk of thrombotic events. |
| 1st trimester | Avoid in first trimester due to risk of fetal harm; contraindicated in pregnancy. |
| 2nd trimester | Avoid; use during second trimester may cause adverse fetal effects. |
| 3rd trimester | Avoid; third trimester use may be associated with fetal anomalies and neonatal complications. |
Clinical note
Comprehensive clinical and safety monograph for NORLESTRIN 21 1/50 (NORLESTRIN 21 1/50).
| Placental transfer | Both components cross the placenta; detectable in fetal tissues and cord blood. |
| Breastfeeding | Norethindrone and ethinyl estradiol are excreted in breast milk. May reduce milk production and composition. Use alternative contraception during breastfeeding unless benefits outweigh risks. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | FDA Pregnancy Category X. Combination hormonal contraceptives (estrogen-progestin) are contraindicated during pregnancy due to association with fetal harm, including cardiovascular defects and limb reduction defects with first-trimester exposure. No increased risk of major malformations reported from inadvertent exposure in early pregnancy, but use is not indicated. Second and third trimester exposure may increase risk of neonatal jaundice and hepatic adenoma in the mother. |
| Fetal Monitoring | None required as drug is contraindicated in pregnancy. In case of inadvertent use, monitor for fetal anomalies via ultrasound; no specific fetal monitoring protocol. Maternal monitoring includes blood pressure, liver function, and signs of thromboembolism. |
| Fertility Effects | Suppresses ovulation via gonadotropin inhibition. After discontinuation, return to fertility may be delayed by 1-3 months but no permanent impairment. No evidence of long-term fertility reduction. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events (e.g., stroke, myocardial infarction) from COC use. Risk increases with age (especially >35 years) and number of cigarettes smoked. Women >35 who smoke should not use COCs.
| Serious Effects |
Known or suspected pregnancyUndiagnosed abnormal genital bleedingHistory of or current thrombophlebitis or thromboembolic disordersCerebrovascular or coronary artery diseaseKnown or suspected breast carcinomaEstrogen-dependent neoplasiaHepatic adenoma or carcinomaActive liver disease or impaired liver functionHypersensitivity to any component
| Precautions | Increased risk of thromboembolic disorders (DVT, PE), stroke, MI. Hepatic neoplasia. Cigarette smoking. Hypertension. Gallbladder disease. Carbohydrate/lipid metabolism effects. Headache/migraine. Unscheduled bleeding. Depression. Ocular lesions (retinal thrombosis). Hepatic impairment. Pregnancy (must be ruled out before initiation). Lactation: may reduce milk production. |
| Food/Dietary | No significant food interactions. Grapefruit juice may slightly increase estrogen levels; avoid excessive consumption. No specific dietary restrictions. Take with or without food. |
| Clinical Pearls | NORLESTRIN 21 1/50 (norethindrone 1 mg, ethinyl estradiol 50 mcg) is a high-dose combined oral contraceptive. Due to higher estrogen content, it carries increased risk of venous thromboembolism, especially in smokers over 35. Counsel about skipping inactive pills to avoid withdrawal bleed if extended cycle needed. Monitor for breakthrough bleeding and counsel about missed pill management: if one active pill missed, take as soon as remembered, and use backup contraception for 7 days. |
| Patient Advice | Take one active pill daily at the same time for 21 days, then 7 days off. Withdrawal bleed usually occurs during off week. · If you miss a pill, take it as soon as you remember, even if it means taking two in one day. Use backup contraception (condoms) for the next 7 days. · Do not smoke while taking this medication, especially if over 35, due to increased risk of blood clots. · Contact your healthcare provider immediately if you experience signs of blood clots: sudden leg pain/swelling, chest pain, shortness of breath, or sudden severe headache. · This medication does not protect against sexually transmitted infections (STIs). Use condoms for STI prevention. |
Loading safety data…