N.E.E. 1/35 28
Clinical safety rating
cautionComprehensive clinical and safety monograph for N.E.E. 1/35 28 (N.E.E. 1/35 28).
Combination oral contraceptive; ethinyl estradiol and norethindrone suppress gonadotropin (FSH and LH) release, preventing ovulation. Also cause cervical mucus thickening and endometrial changes.
| Metabolism | Ethinyl estradiol: primarily metabolized by CYP3A4; undergoes sulfation and glucuronidation. Norethindrone: metabolized in the liver via reduction and glucuronidation. |
| Excretion | Renal: ~50-60% (metabolites, primarily glucuronide conjugates); Fecal: ~30-40% (biliary excretion of metabolites); Unchanged drug: <5% |
| Half-life | Ethinyl estradiol: ~15-19 hours (linear pharmacokinetics); Norethindrone: ~7-9 hours (terminal half-life; steady-state achieved within 5-7 days) |
| Protein binding | Ethinyl estradiol: ~97-98% bound primarily to albumin; Norethindrone: ~96-97% bound to albumin and SHBG |
| Volume of Distribution | Ethinyl estradiol: ~2.5-4 L/kg; Norethindrone: ~3.5-5 L/kg; reflects extensive tissue distribution |
| Bioavailability | Oral: Ethinyl estradiol ~40-50% (first-pass metabolism); Norethindrone ~65-70% (first-pass metabolism) |
| Onset of Action | Oral: Contraceptive effect requires 7 days of continuous dosing to achieve full suppression of ovulation; some immediate effects on cervical mucus within 24-48 hours |
| Duration of Action | Contraceptive coverage persists for the duration of daily dosing; after discontinuation, ovulation may return within 1-2 weeks (variable per individual) |
| Molecular Weight | Ethinyl estradiol: 296.4 Da; Norethindrone: 298.4 Da |
One tablet orally once daily for 28 days; each tablet contains norethindrone 1 mg and ethinyl estradiol 35 mcg.
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustment recommended; use with caution in patients with renal impairment. |
| Liver impairment | Contraindicated in patients with acute hepatitis, severe cirrhosis, or liver tumors (benign or malignant). For Child-Pugh Class C: contraindicated. For Child-Pugh Class A or B: use with caution and monitor liver function. |
| Pediatric use | Postmenarchal adolescents: same as adult dosing (one tablet orally once daily). Safety and efficacy established for use after menarche. |
| Geriatric use | Not indicated for postmenopausal women due to lack of need for contraception and potential increased risk of thromboembolism and cardiovascular events. |
| 1st trimester | Use is contraindicated in pregnancy due to risk of fetal harm; ethinyl estradiol and norethindrone are known to cause fetal abnormalities and should not be used during pregnancy. |
| 2nd trimester | Contraindicated; use of oral contraceptives during second trimester is associated with increased risk of fetal harm. |
| 3rd trimester | Contraindicated; use during third trimester may lead to adverse effects such as jaundice and other fetal complications. |
Clinical note
Comprehensive clinical and safety monograph for N.E.E. 1/35 28 (N.E.E. 1/35 28).
| Placental transfer | Both ethinyl estradiol and norethindrone cross the placenta with documented fetal exposure. The degree of transfer is significant, with fetal plasma levels approximately 50-80% of maternal levels. |
| Breastfeeding | Small amounts of ethinyl estradiol and norethindrone pass into breast milk. Use may reduce milk production and affect infant development. Use is not recommended during breastfeeding, especially in nursing women with low milk supply. |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | First trimester: No increased risk of major birth defects from combined oral contraceptives based on population data; however, inadvertent use is not recommended. Second/third trimester: Avoid use due to potential adverse fetal effects including hormonal disruption. Category X for pregnancy contraindication. |
| Fetal Monitoring | Monitor for signs of thromboembolism, hypertension, and hepatic dysfunction. In pregnant patients (if exposed), assess fetal growth and development via ultrasound if prolonged use occurs. |
| Fertility Effects | Reversible suppression of ovulation. Fertility returns to baseline within 1-3 months after discontinuation. No long-term impairment. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptives. Risk increases with age (>35 years) and heavy smoking (>15 cigarettes/day). Women over 35 who smoke should not use this product.
| Serious Effects |
Known or suspected pregnancyBreast cancer (current or history)Undiagnosed abnormal uterine bleedingHepatic adenoma or active liver diseaseThrombophlebitis or thromboembolic disordersHigh risk of venous or arterial thrombosis (e.g., thrombophilia, uncontrolled hypertension, diabetes with vascular disease, migraine with focal aura, age ≥35 and smoking ≥15 cigarettes/day)
| Precautions | Thrombotic disorders (venous thromboembolism, stroke, MI), Hepatic neoplasia, Gallbladder disease, Hypertension, Carbohydrate/lipid effects, Ocular lesions (retinal thrombosis), Carcinoma (breast, cervical), Hereditary angioedema, Chloasma, Pregnancy (discontinue if pregnant), Lactation (may reduce milk production) |
| Food/Dietary | No significant food interactions. Grapefruit juice may slightly increase ethinyl estradiol levels but no dose adjustment needed. High-fat meals do not affect absorption. |
| Clinical Pearls | N.E.E. 1/35 28 is a monophasic combined oral contraceptive containing norethindrone and ethinyl estradiol. Monitor for thromboembolic events, especially in smokers over 35. Efficacy may be reduced with hepatic enzyme inducers. Bleeding irregularities are common in the first 3 cycles. |
| Patient Advice | Take one tablet daily at the same time, in the order listed on the pack. · Missed pill instructions: if one pill is missed, take it as soon as remembered; if two or more are missed, use back-up contraception for 7 days. · Common side effects include nausea, breast tenderness, and breakthrough bleeding. · Seek immediate medical attention for symptoms of blood clots: leg pain/swelling, sudden chest pain, shortness of breath, or severe headache. · Do not smoke while taking this medication, as smoking increases the risk of serious cardiovascular side effects. · Inform your healthcare provider if you are breastfeeding or have a history of migraines, hypertension, or liver disease. |
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