NORTREL 1/35-28
Clinical safety rating
cautionComprehensive clinical and safety monograph for NORTREL 1/35-28 (NORTREL 1/35-28).
Combination of ethinyl estradiol and norethindrone inhibits gonadotropin secretion via negative feedback on the hypothalamic-pituitary-ovarian axis, suppressing ovulation. Additionally, increases cervical mucus viscosity and alters endometrial receptivity.
| Metabolism | Primarily hepatic via CYP3A4; ethinyl estradiol undergoes first-pass metabolism; norethindrone is metabolized via reduction and conjugation. |
| Excretion | Renal 60-70% (as glucuronide and sulfate conjugates), fecal 20-30% (via biliary excretion). |
| Half-life | Norethindrone: 5-14 hours (terminal); ethinyl estradiol: 13-27 hours (terminal). Context: steady-state after 5-7 days; dose adjustment in hepatic impairment. |
| Protein binding | Norethindrone: 99% bound (SHBG, albumin); ethinyl estradiol: 98% bound (albumin, SHBG). |
| Volume of Distribution | Norethindrone: 4-5 L/kg (extensive tissue distribution); ethinyl estradiol: 2-4 L/kg (significant tissue uptake). |
| Bioavailability | Norethindrone: 47-73% (oral); ethinyl estradiol: 38-48% (oral, first-pass metabolism). |
| Onset of Action | Oral: 7 days for contraceptive effect (suppression of ovulation); 2-3 hours for peak serum levels. |
| Duration of Action | 24 hours (contraceptive coverage requires daily dosing); sustained effect after 7 days of consecutive therapy. |
| Molecular Weight | Norethindrone: 298.42 Da; Ethinyl estradiol: 296.40 Da. Combined product: not applicable. |
One tablet (norethindrone 1 mg + ethinyl estradiol 35 mcg) orally once daily for 28 days, followed by a 7-day placebo period (if using 28-day pack) or continuous if using 21-day pack with 7-day off. Start on first day of menstrual period.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (GFR >=30 mL/min). Not recommended for use in severe renal impairment (GFR <30 mL/min) due to potential for hormonal disturbances and adverse effects. |
| Liver impairment | Contraindicated in acute liver disease, active hepatitis, or severe cirrhosis (Child-Pugh class C). For mild (Child-Pugh A) or moderate (Child-Pugh B) impairment, use is not recommended due to potential for altered metabolism; alternative contraception advised. |
| Pediatric use | Not indicated for use in postmenarchal pediatric patients; safety and efficacy established for contraception in females of reproductive age. For adolescents, standard adult dosing may be used after menarche; individualize based on clinical judgment. |
| Geriatric use | Not indicated for use in postmenopausal women; estrogen-containing contraceptives are not appropriate for this age group. No specific geriatric dosage adjustments applicable as therapy is not recommended. |
| 1st trimester | Combined hormonal contraceptives are not recommended during pregnancy due to potential risk of early pregnancy loss and congenital anomalies; however, available data do not show a consistently increased risk of major birth defects. If inadvertently used, discontinue upon pregnancy confirmation. |
| 2nd trimester | Use is contraindicated during pregnancy as it is not indicated for any condition during gestation. Exposure during second trimester is associated with potential adverse effects on fetal development, though data are limited. |
| 3rd trimester | Use is contraindicated during pregnancy. Third-trimester exposure may theoretically affect fetal steroid metabolism; no specific safety data exist for this period. |
Clinical note
Comprehensive clinical and safety monograph for NORTREL 1/35-28 (NORTREL 1/35-28).
| Placental transfer | Both ethinyl estradiol and norethindrone cross the placenta. Norethindrone achieves significant fetal concentrations; ethinyl estradiol transfer is limited but present. |
| Breastfeeding | Combined oral contraceptives (COCs) containing ethinyl estradiol and norethindrone can reduce milk production and alter milk composition. Use is generally avoided during breastfeeding, especially in the early postpartum period. If used, monitor infant for jaundice and growth. The American Academy of Pediatrics considers COCs compatible with breastfeeding, but alternative contraception is preferred. |
| Lactation Rating | L3 (Moderately Safe) - Limited data; potential for adverse effects on lactation or infant. Some sources rate as 'Contraindicated' in early postpartum. |
| Teratogenic Risk | Pregnancy category X. Significant risk of fetal harm in the first trimester (limb defects, cardiac anomalies) and second/third trimesters (genital abnormalities, neurodevelopmental effects). Use contraindicated in pregnancy. |
| Fetal Monitoring | Monitor blood pressure, liver function, glucose tolerance, and thyroid function. Fetal ultrasound for anomalies if accidental exposure occurs. |
| Fertility Effects | Suppresses ovulation, may delay return to fertility after discontinuation. No permanent impact on fertility. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular side effects from oral contraceptive use. Risk increases with age and heavy smoking (≥15 cigarettes/day). Women over 35 who smoke should not use this product.
| Serious Effects |
Current or history of thromboembolic disorders (e.g., deep vein thrombosis, pulmonary embolism)Cerebrovascular or coronary artery diseaseKnown or suspected pregnancyUndiagnosed abnormal uterine bleedingKnown or suspected breast cancer or other estrogen-sensitive neoplasiaHepatic adenoma or carcinoma, or active liver disease with abnormal liver functionMajor surgery with prolonged immobilizationSmoking in women over 35 years of ageUncontrolled hypertension (systolic ≥160 mm Hg or diastolic ≥100 mm Hg)Diabetes with vascular involvementMigraine with aura (current or history) in women over 35Systemic lupus erythematosus with positive antiphospholipid antibodies
| Precautions | Increased risk of thromboembolic disorders, Cigarette smoking increases cardiovascular risk, Elevated blood pressure, Hepatic neoplasia, Gallbladder disease, Glucose intolerance, Ocular lesions (e.g., retinal thrombosis), Headache/migraine, Menstrual irregularities and breakthrough bleeding |
| Food/Dietary | Grapefruit and grapefruit juice may increase ethinyl estradiol levels and risk of adverse effects. Avoid grapefruit products. No other significant food interactions; however, maintain consistent dietary habits as high-fat meals may delay absorption but not reduce overall bioavailability. |
| Clinical Pearls | NORTREL 1/35-28 contains norethindrone 1 mg and ethinyl estradiol 35 mcg. For COCs, consider that CYP3A4 inducers (e.g., rifampin, St. John's wort) may reduce contraceptive efficacy. If a patient misses two or more pills, use backup contraception for 7 days. The 28-day pack includes 21 active pills and 7 placebo pills to maintain the regimen. |
| Patient Advice | Take one pill daily at the same time for 28 days; start the next pack immediately after finishing the current pack. · Do not skip pills; if you miss one, take it as soon as remembered. If you miss two or more, use backup contraception for 7 days. · This drug does not protect against HIV or other sexually transmitted infections. · Common side effects include nausea, headache, breast tenderness, and spotting. Contact your provider if you have severe abdominal pain, chest pain, or leg pain. · Do not smoke; smoking increases the risk of serious cardiovascular side effects, especially in women over 35. |
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