NORTREL 1/35-21
Clinical safety rating
cautionComprehensive clinical and safety monograph for NORTREL 1/35-21 (NORTREL 1/35-21).
Combination of ethinyl estradiol (estrogen) and norethindrone (progestin) suppresses gonadotropin (FSH and LH) release from the pituitary, inhibiting ovulation, altering cervical mucus to impede sperm penetration, and inducing endometrial changes that reduce implantation likelihood.
| Metabolism | Ethinyl estradiol undergoes hepatic metabolism primarily via CYP3A4 hydroxylation and conjugation; norethindrone is metabolized primarily via reduction and sulfate/glucuronide conjugation. |
| Excretion | Renal 50-60% as metabolites, fecal 40-50% as conjugates, <1% unchanged |
| Half-life | Norethindrone: 5-14 hours; Ethinyl estradiol: 17-24 hours. Steady-state achieved after 10 days. |
| Protein binding | Norethindrone: 80% bound to albumin and SHBG; Ethinyl estradiol: 98% bound to albumin and SHBG. |
| Volume of Distribution | Norethindrone: 2-4 L/kg; Ethinyl estradiol: 3-5 L/kg. Indicates extensive tissue distribution. |
| Bioavailability | Oral: Norethindrone ~65% (first-pass metabolism), Ethinyl estradiol ~40-50% (first-pass metabolism). |
| Onset of Action | Oral: 7 days of continuous use to inhibit ovulation; contraceptive effect begins after 7 days if started on day 1 of menses. |
| Duration of Action | 24 hours; requires daily dosing to maintain contraceptive effect. Withdrawal bleeding occurs during placebo week. |
| Molecular Weight | Norethindrone: 298.42 Da; Ethinyl estradiol: 296.40 Da. (Combination product, average MW ~297 Da) |
One tablet orally once daily for 21 days, followed by 7 days off, then repeat.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for renal impairment; use with caution in severe impairment. |
| Liver impairment | Contraindicated in acute liver disease, hepatocellular carcinoma, or active hepatitis. In Child-Pugh A: no adjustment; Child-Pugh B or C: contraindicated. |
| Pediatric use | Not indicated for use before menarche; after menarche, same as adult dosing. |
| Geriatric use | No specific dose adjustment; estrogen-containing contraceptives are generally not recommended after menopause. |
| 1st trimester | Contraindicated in pregnancy. Use during first trimester is associated with an increased risk of oral clefts and other congenital anomalies due to estrogen and progestin exposure. |
| 2nd trimester | Contraindicated. Use during second trimester may increase risk of fetal harm, including potential effects on sexual differentiation. |
| 3rd trimester | Contraindicated. Use in third trimester may cause adverse effects on fetal development and neonatal complications such as jaundice and respiratory distress. |
Clinical note
Comprehensive clinical and safety monograph for NORTREL 1/35-21 (NORTREL 1/35-21).
| Placental transfer | Both norethindrone and ethinyl estradiol cross the placenta. Norethindrone: approximately 0.1% of maternal dose reaches fetal circulation. Ethinyl estradiol: minimal transfer but detectable in fetal tissues. |
| Breastfeeding | Small amounts of norethindrone and ethinyl estradiol pass into breast milk. Use during lactation may reduce milk production and affect infant development. Alternative contraception recommended for breastfeeding mothers. |
| Lactation Rating | L3 (Moderately Safe) - limited data; potential for adverse effects in infants. |
| Teratogenic Risk | Category X. First trimester: No increased risk of major birth defects observed in clinical studies, but postmarketing data are insufficient. Second and third trimesters: Use associated with fetal harm, including cardiovascular defects, limb defects, and masculinization of female fetuses. Avoid during pregnancy. |
| Fetal Monitoring | Monitor blood pressure, blood glucose, and liver function monthly. For prolonged use, consider periodic hepatic and gynecologic exams. Fetal monitoring includes serial ultrasound if accidental pregnancy occurs during use. |
| Fertility Effects | Suppresses ovulation, thereby preventing pregnancy. After discontinuation, return to normal fertility may be delayed by up to 3 months but no permanent effects. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination hormonal contraceptive use. Risk increases with age and heavy smoking (≥15 cigarettes/day) and is significant in women over 35. Women over 35 who smoke should not use this product.
| Serious Effects |
Known or suspected pregnancyThrombophlebitis or thromboembolic disordersHistory of deep vein thrombosis or pulmonary embolismCerebrovascular diseaseCoronary artery diseaseUncontrolled hypertensionDiabetes mellitus with vascular involvementHeadaches with focal neurological symptoms (e.g., migraine with aura)Major surgery with prolonged immobilizationKnown or suspected breast cancer or other estrogen-dependent neoplasiaUndiagnosed abnormal genital bleedingCholestatic jaundice of pregnancy or jaundice with prior oral contraceptive useHepatic adenoma or carcinomaKnown or suspected endometrial hyperplasiaAge >35 years and smoking >15 cigarettes per day
| Precautions | Thrombotic disorders (venous thromboembolism, stroke, myocardial infarction) – discontinue if occur or suspected, Elevated risk of thromboembolic events in smokers, especially over 35, Increased risk of gallbladder disease, Hepatic neoplasia (benign and malignant) – discontinue if jaundice or liver function abnormalities develop, Elevated blood pressure – monitor regularly, Carbohydrate and lipid metabolism effects – monitor in diabetic or hyperlipidemic patients, Ocular lesions (retinal thrombosis) – discontinue if unexplained vision loss occurs, Headache – evaluate if new or worsening migraine patterns, Uterine bleeding irregularities – rule out pregnancy or pathology |
| Food/Dietary | No specific food restrictions; however, grapefruit juice may increase estrogen levels; avoid excessive consumption. Maintain consistent dietary patterns to avoid gastrointestinal interference with absorption. |
| Clinical Pearls | Nortrel 1/35-21 is a monophasic combined oral contraceptive containing 1 mg norethindrone and 35 mcg ethinyl estradiol. Administer 21 active tablets followed by 7 placebo tablets. Advise patients to take at the same time daily. Missed doses increase pregnancy risk; use backup contraception if missed. Not recommended in patients with BMI > 35 due to increased failure risk. Contraindicated in smokers over 35 years old. |
| Patient Advice | Take one pill at the same time each day, starting on the first day of your menstrual period. · If you miss a dose, take it as soon as remembered, and use a backup method for 7 days. · Do not smoke while taking this medication, especially if over 35 years old. · Common side effects include nausea, breast tenderness, and breakthrough bleeding. · Inform your doctor if you have liver disease, blood clots, breast cancer, or high blood pressure. |
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