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). |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NORTREL 0.5/35-21 (NORTREL 0.5/35-21).
| Breastfeeding | Excreted in breast milk in small amounts (M/P ratio unknown for specific formulation; estrogen M/P ratio approximately 0.5, progestin variable). Can reduce milk production and composition. Generally not recommended; use alternative contraception if breastfeeding. Consider benefits versus risks. |
| 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. |
■ 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 |
["Thrombophlebitis or thromboembolic disorders (current or history)","Cerebrovascular or coronary artery disease (current or history)","Known or suspected breast cancer","Carcinoma of the endometrium or other estrogen-dependent neoplasia","Undiagnosed abnormal genital bleeding","Cholestatic jaundice of pregnancy or jaundice with prior pill use","Hepatic adenoma or carcinoma","Known or suspected pregnancy","Hypersensitivity to any component"]
| 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"] |
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| 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. |