NORTREL 0.5/35-21
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NORTREL 0.5/35-21 (NORTREL 0.5/35-21).
Combination hormonal contraceptive containing norethindrone (a progestin) and ethinyl estradiol (an estrogen). Norethindrone inhibits ovulation by suppressing gonadotropin release (LH and FSH) and alters cervical mucus and endometrial receptivity. Ethinyl estradiol provides negative feedback on the hypothalamic-pituitary-ovarian axis, further suppressing ovulation.
| Metabolism | Norethindrone: primarily hepatic via reduction and conjugation, with CYP3A4 involvement; ethinyl estradiol: hepatic via CYP3A4, undergoes sulfation and glucuronidation. Both are excreted in urine and feces. |
| Excretion | Norethindrone is primarily excreted renally (approximately 60-80% as metabolites) and approximately 20-40% fecally. Ethinyl estradiol is excreted renally (about 40%) and fecally (about 60%) as glucuronide and sulfate conjugates. |
| Half-life | Norethindrone: terminal half-life approximately 7-8 hours. Ethinyl estradiol: terminal half-life approximately 13-27 hours, mean about 17 hours. Ethinyl estradiol exhibits a longer half-life due to enterohepatic recirculation and extensive tissue distribution. |
| Protein binding | Norethindrone: 60-70% bound to albumin and SHBG. Ethinyl estradiol: 95-98% bound to albumin and 2-5% free; increases SHBG levels, which further affects norethindrone binding. |
| Volume of Distribution | Norethindrone: Vd approximately 4 L/kg (400 L/70kg), indicating extensive tissue distribution. Ethinyl estradiol: Vd approximately 2.5-4 L/kg (175-280 L/70kg), also widely distributed. |
| Bioavailability | Norethindrone: oral bioavailability approximately 50-70% due to first-pass metabolism. Ethinyl estradiol: oral bioavailability approximately 40-50% due to first-pass metabolism. |
| Onset of Action | Oral administration: contraceptive effect requires consistent daily dosing; follicular suppression begins within 2-3 days of first dose, but full contraceptive effect is achieved after 7 consecutive days of correct use. |
| Duration of Action | The contraceptive effect lasts as long as daily dosing is maintained. Missed pills reduce efficacy. Steady-state hormone levels are achieved within 1-2 cycles. The drug is cleared from the body within 5 half-lives (approximately 3-5 days after last dose). |
| Molecular Weight | 310.4 |
1 tablet orally once daily for 21 days, followed by 7 days off. Each tablet contains 0.5 mg norethindrone and 35 mcg ethinyl estradiol.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Contraindicated in severe renal impairment (GFR < 30 mL/min) due to potential for fluid retention and hyperkalemia. |
| Liver impairment | Contraindicated in acute hepatic disease, hepatic adenomas, or severe cirrhosis (Child-Pugh C). Use with caution in Child-Pugh A or B; dose adjustment not specifically defined, but monitor liver function. |
| Pediatric use | Not indicated for use before menarche. For post-menarchal adolescents, same dosing as adults: 1 tablet orally once daily for 21 days, then 7 days off. |
| Geriatric use | Not indicated for use in postmenopausal women due to increased risk of cardiovascular events and venous thromboembolism. No specific dose adjustment in elderly; avoid use in women over 35 who smoke. |
| 1st trimester | Contraindicated due to risk of teratogenicity (female genital abnormalities, cardiac defects). |
| 2nd trimester | Contraindicated due to risk of fetal harm (feminization of male fetus). |
| 3rd trimester | Contraindicated due to potential adverse effects on fetal development. |
Clinical note
Comprehensive clinical and safety monograph for NORTREL 0.5/35-21 (NORTREL 0.5/35-21).
| Placental transfer | Yes, crosses placenta; hormone levels in fetal circulation approximate maternal levels. |
| Breastfeeding | Excreted in breast milk; may cause jaundice and breast enlargement in infants. Use only if clearly needed. |
| Lactation Rating |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives. Women who use combination hormonal contraceptives should be strongly advised not to smoke, especially women over 35 years of age and those who smoke 15 or more cigarettes per day.
| Serious Effects |
Known or suspected pregnancyBreast cancer (current or history)Estrogen-dependent neoplasiaUndiagnosed abnormal genital bleedingActive thromboembolic disorders or history (e.g., DVT, PE)Cerebrovascular diseaseCoronary artery diseaseSevere hypertensionDiabetes with vascular involvementHeadaches with focal neurological symptomsMajor surgery with prolonged immobilizationKnown hypersensitivity to componentsHepatic adenoma or carcinomaAcute or chronic liver disease with abnormal function
| Precautions | Thrombotic disorders (DVT, PE, stroke, MI) – discontinue if occurs, Cigarette smoking increases cardiovascular risk, Lactic acidosis or liver disease, Elevated blood pressure, Gallbladder disease, Hepatic adenoma or malignancy, Ocular lesions (retinal thrombosis, papilledema), Carbohydrate and lipid effects, Depression, Uterine bleeding irregularities, Pregnancy – discontinue if suspected, Breast cancer risk (current or past) – avoid use |
Loading safety data…
| L4 - Possibly Hazardous |
| Teratogenic Risk | FDA Pregnancy Category X. Contraindicated in pregnancy. First trimester: Increased risk of congenital anomalies, including cardiac defects and limb reduction defects (odds ratio 1.5-2.0). Second and third trimesters: Risk of feminization of male fetus, hepatic adenoma, and other adverse effects. Exposure during pregnancy may increase risk of neurodevelopmental disorders. |
| Fetal Monitoring | Monitor for thromboembolic events, hypertension, liver function, and glucose tolerance. Fetal assessment: ultrasound for anomalies if inadvertent exposure. No routine fetal monitoring required during use as pregnancy is contraindicated. |
| Fertility Effects | Reversible inhibition of ovulation; returns to normal after discontinuation. No long-term adverse effects on fertility. May improve menstrual regularity in some conditions. |
| Food/Dietary |
| Grapefruit and grapefruit juice may increase ethinyl estradiol levels; avoid excessive intake. St. John's Wort and certain herbal supplements can reduce contraceptive efficacy. High-fat meals may slightly delay absorption but not significantly affect overall efficacy. |
| Clinical Pearls | NORTREL 0.5/35-21 is a combination oral contraceptive containing norethindrone 0.5 mg and ethinyl estradiol 35 mcg. It is a monophasic pill with 21 active tablets followed by 7 placebo tablets. Clinicians should note that the low-dose norethindrone may be less effective in preventing ovulation in some women, increasing the risk of breakthrough bleeding. This formulation is often used for cycle regulation and mild acne. Assess for contraindications including thrombotic disorders, migraine with aura, and smoking in women over 35. |
| Patient Advice | Take one pill daily at the same time. Missing pills increases pregnancy risk. · Use backup contraception (e.g., condoms) for 7 days if you miss a pill, especially in the first week. · Common side effects include nausea, breast tenderness, and breakthrough bleeding, especially in the first few months. · Do not smoke while taking this medication, especially if over age 35, due to increased risk of blood clots. · This medication does not protect against HIV or other sexually transmitted infections. · Notify your provider if you experience severe headache, chest pain, leg swelling, or vision changes. · Store at room temperature away from moisture and heat. |