NORTREL 1/35-21
Clinical safety rating: caution
Comprehensive 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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NORTREL 1/35-21 (NORTREL 1/35-21).
| Breastfeeding | Excreted in breast milk in small amounts; M/P ratio for estrogen is 0.2, for progestin is 0.3. No adverse effects reported in nursing infants. American Academy of Pediatrics considers use compatible with breastfeeding, but may reduce milk production and quality. Use only if clearly needed. |
| 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. |
■ 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 |
["Thrombophlebitis or thromboembolic disorders (current or history)","Cerebrovascular or coronary artery disease","Known or suspected breast carcinoma or estrogen-dependent neoplasia","Undiagnosed abnormal genital bleeding","Pregnancy (known or suspected)","Hepatic adenoma or carcinoma (benign or malignant liver tumors)","Jaundice or impaired liver function (active liver disease)","Hypersensitivity to any component","Smoking in women over 35","Uncontrolled hypertension","Diabetes with vascular involvement","Migraine with focal neurological symptoms (if over 35)"]
| 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"] |
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| 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. |