NORTREL 0.5/35-28
Clinical safety rating
cautionComprehensive clinical and safety monograph for NORTREL 0.5/35-28 (NORTREL 0.5/35-28).
Norethindrone and ethinyl estradiol are a combination hormonal contraceptive. Norethindrone suppresses gonadotropin release (FSH and LH) from the pituitary, inhibiting ovulation. Ethinyl estradiol stabilizes the endometrium and enhances the contraceptive effect by inhibiting gonadotropin secretion.
| Metabolism | Norethindrone: primarily hepatic via reduction and sulfation; CYP3A4 involved. Ethinyl estradiol: hepatic via CYP3A4; undergoes first-pass metabolism and enterohepatic recirculation. |
| Excretion | Renal: ~40% as metabolites; Biliary/Fecal: ~60% as metabolites; <5% unchanged. |
| Half-life | Norethindrone: 7.2-9.2 hours; Ethinyl estradiol: 13-27 hours. Clinical context: Steady state reached in 5-7 days; half-life supports once-daily dosing. |
| Protein binding | Norethindrone: 61% bound to albumin, 36% to SHBG; Ethinyl estradiol: 97% bound to albumin, 2% free. |
| Volume of Distribution | Norethindrone: 3.6-4.3 L/kg; Ethinyl estradiol: 2.3-3.7 L/kg; indicates extensive tissue distribution. |
| Bioavailability | Oral: Norethindrone ~64% (extensive first-pass metabolism); Ethinyl estradiol ~43-45% (due to first-pass and gut wall metabolism). |
| Onset of Action | Oral: 24-48 hours for ovulation suppression; maximum effect after 7 days. |
| Duration of Action | 24 hours with once-daily dosing; contraceptive protection persists with consistent daily use; missed dose decreases protection. |
| Molecular Weight | 340.46 |
1 tablet orally once daily for 28 days (21 active tablets containing 0.5 mg norethindrone and 35 mcg ethinyl estradiol, followed by 7 placebo tablets).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min. Use is not recommended in patients with GFR <30 mL/min or on dialysis due to potential decrease in hormone clearance and increased risk of adverse effects. |
| Liver impairment | Contraindicated in patients with Child-Pugh class B or C hepatic impairment. For Child-Pugh class A, use is not recommended due to potential reduced hormone metabolism. |
| Pediatric use | Not indicated for use in pediatric patients before menarche. For post-menarcheal adolescents, dosing is same as adults: 1 tablet orally once daily for 28 days. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific dosing adjustments for elderly patients as the drug is not used in this population for contraception. |
| 1st trimester | Contraindicated due to risk of congenital malformations, particularly cardiovascular and limb defects. Use of hormonal contraceptives is not recommended during first trimester. |
| 2nd trimester | Contraindicated due to risk of fetal harm, including potential for virilization of female fetus and other adverse effects. Should not be used during second trimester. |
| 3rd trimester | Contraindicated due to risk of fetal harm, including potential for virilization of female fetus and other adverse effects. Should not be used during third trimester. |
Clinical note
Comprehensive clinical and safety monograph for NORTREL 0.5/35-28 (NORTREL 0.5/35-28).
| Placental transfer | Both noretindrone and ethinyl estradiol cross the placenta and reach the fetus. Transfer is significant with measurable levels in fetal tissues. |
| Breastfeeding | Noretindrone and ethinyl estradiol are excreted in breast milk in small amounts. Can reduce milk production and quality. Use alternative contraception if possible. Use only when clearly needed and with caution. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | First trimester: No increased risk of major birth defects based on large cohort studies. Second and third trimesters: Associated with masculinization of female fetuses (clitoral hypertrophy, labial fusion) and possible altered pubertal development. Risk of pseudohermaphroditism is dose-dependent. |
| Fetal Monitoring | Monitor for fetal adrenal androgenization (ultrasound for ambiguous genitalia). Maternal monitoring: blood pressure, liver function, glucose tolerance, and signs of thromboembolism. |
| Fertility Effects | No permanent adverse effects on fertility. Reverses promptly after discontinuation. Contraindicated during confirmed pregnancy. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive use. The risk increases with age and heavy smoking (≥15 cigarettes per day) and is significant in women over 35 years old. Women over 35 who smoke should not use combined hormonal contraceptives.
| Serious Effects |
Known or suspected pregnancyHistory of thrombophlebitis or thromboembolic disordersCerebral vascular diseaseCoronary artery diseaseKnown or suspected breast cancerUndiagnosed abnormal genital bleedingHepatocellular carcinoma or active liver diseaseHypersensitivity to any component
| Precautions | Increased risk of thrombotic disorders (venous thromboembolism, stroke, myocardial infarction), Hepatic neoplasia (benign and malignant), Elevated blood pressure, Gallbladder disease, Carbohydrate/lipid metabolism effects, Headache/migraine, Irregular bleeding, Ocular changes (retinal thrombosis), Depression, Hereditary angioedema, Pregnancy (discontinue if pregnancy occurs) |
| Food/Dietary | No specific food restrictions. Grapefruit juice may increase ethinyl estradiol levels; avoid large amounts. Alcohol may increase risk of liver toxicity; limit intake. |
| Clinical Pearls | NORTREL 0.5/35-28 is a monophasic combined oral contraceptive containing 0.5 mg norethindrone and 35 mcg ethinyl estradiol. Administer daily at the same time. Breakthrough bleeding is common in the first 3-6 months. Monitor blood pressure at baseline and annually. Consider VTE risk in smokers over 35. Missed pill protocol: if one pill is missed, take as soon as remembered; if two or more, use backup contraception for 7 days. |
| Patient Advice | Take one pill daily at the same time, in the order shown on the blister pack. · If you miss a pill, follow the package insert instructions and use backup contraception if needed. · Common side effects include nausea, breast tenderness, and spotting between periods. · Do not smoke while taking this medication, especially if over 35 years old. · Report symptoms of blood clots, including leg pain/swelling, chest pain, or sudden shortness of breath. · This medication does not protect against HIV or other sexually transmitted infections. |
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