NORETHIN 1/35E-28
Clinical safety rating: caution
Comprehensive 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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NORETHIN 1/35E-28 (NORETHIN 1/35E-28).
| Breastfeeding | Excreted in human breast milk; can reduce milk production and affect infant development. M/P ratio not established. Contraindicated in breastfeeding. |
| 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. |
■ 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 |
["Thrombophlebitis or thromboembolic disorders","Cerebrovascular or coronary artery disease","Known or suspected breast carcinoma","Estrogen-dependent neoplasia","Undiagnosed abnormal genital bleeding","Pregnancy","Known or suspected pregnancy","Hepatic adenoma or carcinoma","Active liver disease (if LFTs not returned to normal)","Hypersensitivity to any component"]
| 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"] |
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| 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. |