NORETHIN 1/35E-28
Clinical safety rating
cautionComprehensive clinical and safety monograph for NORETHIN 1/35E-28 (NORETHIN 1/35E-28).
Combination estrogen-progestin oral contraceptive. Ethinyl estradiol suppresses FSH and LH, preventing ovulation. Norethindrone alters cervical mucus and endometrial lining, inhibiting sperm penetration and implantation.
| Metabolism | Hepatic: ethinyl estradiol undergoes CYP3A4-mediated hydroxylation and glucuronidation; norethindrone metabolized via reduction and conjugation. |
| Excretion | Norethindrone is excreted primarily in urine as glucuronide and sulfate conjugates, with about 50-60% excreted renally; approximately 20-30% is excreted in feces via biliary elimination. Ethinyl estradiol is excreted in urine (40-60%) and feces (20-40%) after enterohepatic recirculation. |
| Half-life | Norethindrone: terminal elimination half-life approximately 8-11 hours. Ethinyl estradiol: terminal elimination half-life approximately 10-20 hours (mean ~13 hours). Clinical context: Steady-state achieved within 5 days; once-daily dosing maintains therapeutic levels. |
| Protein binding | Norethindrone: ~97% bound, primarily to serum albumin and sex hormone-binding globulin (SHBG). Ethinyl estradiol: ~98% bound, primarily to albumin, with slight binding to SHBG. |
| Volume of Distribution | Norethindrone: Vd approximately 3-4 L/kg (distributes widely into body tissues). Ethinyl estradiol: Vd approximately 1.5-2.5 L/kg (moderately distributed, concentrated in reproductive tissues). |
| Bioavailability | Oral: Norethindrone: ~64% (due to first-pass metabolism). Ethinyl estradiol: ~40-60% (due to first-pass metabolism and variable absorption). |
| Onset of Action | Oral: Contraceptive effect requires 7 days of continuous dosing for full ovulation inhibition; initial effect on cervical mucus occurs within 24-48 hours. |
| Duration of Action | Contraceptive protection persists during daily dosing; after discontinuation, ovulation may resume within 1-3 months. Duration of effect on cervical mucus is approximately 24 hours after each dose. |
| Molecular Weight | 340.5 |
One tablet orally once daily for 28 days (21 active tablets containing norethindrone 1 mg and ethinyl estradiol 35 mcg, followed by 7 inert tablets).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not studied in severe renal impairment; consider alternative contraception. |
| Liver impairment | Contraindicated in Child-Pugh class B or C (moderate to severe hepatic impairment). Use with caution in Child-Pugh class A; monitor liver function. |
| Pediatric use | Postmenarchal adolescents: same dosing as adults (one tablet daily for 28-day cycle). Use only after menarche; not indicated before. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific geriatric dose; estrogen-containing contraceptives are not appropriate in this population due to increased risk of thromboembolism and cardiovascular events. |
| 1st trimester | Contraindicated due to risk of fetal harm; use of oral contraceptives during pregnancy is not recommended. |
| 2nd trimester | Contraindicated due to risk of fetal harm; use of oral contraceptives during pregnancy is not recommended. |
| 3rd trimester | Contraindicated due to risk of fetal harm; use of oral contraceptives during pregnancy is not recommended. |
Clinical note
Comprehensive clinical and safety monograph for NORETHIN 1/35E-28 (NORETHIN 1/35E-28).
| Placental transfer | Yes, contraceptive steroids cross the placenta. Animal studies have shown adverse effects, and there are no adequate and well-controlled studies in pregnant women. |
| Breastfeeding | Small amounts of contraceptive steroids and/or metabolites have been identified in breast milk. Use is generally not recommended during breastfeeding as it may reduce milk production and composition. Alternative contraception methods should be considered. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | Pregnancy category X. First trimester: major congenital anomalies including limb defects, neural tube defects, and cardiovascular anomalies. Second and third trimesters: increased risk of fetal genital abnormalities (e.g., clitoral hypertrophy, labial fusion in females, ambiguous genitalia in males), and potential long-term neurodevelopmental effects. |
| Fetal Monitoring | Pregnancy test before initiation. Monitor for signs of thromboembolism, hypertension, hepatic dysfunction, and glucose intolerance. During pregnancy, discontinue immediately; perform ultrasound for fetal anomalies and growth. |
| Fertility Effects | Suppresses ovulation and endometrial receptivity, used as contraceptive. Reversible inhibition of fertility; normal menstrual cycles typically resume within 1-3 months after discontinuation. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events. Women over 35 who smoke should not use combination oral contraceptives.
| Serious Effects |
Known or suspected pregnancyUndiagnosed abnormal genital bleedingKnown or suspected carcinoma of the breastKnown or suspected estrogen-dependent neoplasiaActive or history of thrombophlebitis, deep vein thrombosis, or thromboembolic disordersActive or history of cerebrovascular diseaseActive or history of myocardial infarctionActive or history of coronary artery diseaseActive liver disease or impaired liver functionKnown hypersensitivity to any component of the productUse with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir
| Precautions | Increased risk of thromboembolic disorders, stroke, MI, especially in smokers, Hepatic neoplasia, Gallbladder disease, Hypertension, Worsening of migraine, Depression, Fluid retention, Carbohydrate/lipid effects |
| Food/Dietary | No significant food interactions. Grapefruit juice may slightly increase ethinyl estradiol levels but not clinically relevant. Consistent intake recommended to maintain steady hormone levels. |
| Clinical Pearls | Norethindrone 1 mg/ethinyl estradiol 35 mcg is a monophasic oral contraceptive. Counsel patients that breakthrough bleeding is common in first 3 cycles. If pregnancy occurs, exclude ectopic pregnancy as progestins may slow tubal motility. Monitor for hypertension and hyperkalemia in patients on spironolactone or ACE inhibitors. |
| Patient Advice | Take one tablet daily at the same time, even if no bleeding expected. · Missed dose: if within 12 hours, take immediately; if >12 hours, take and use backup contraception for 7 days. · Common side effects include nausea, breast tenderness, breakthrough bleeding, and headaches. · Do not smoke while on this medication due to increased risk of blood clots. · Seek medical help for sudden leg pain, chest pain, vision changes, or severe headache. |
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