NORETHINDRONE ACETATE AND ETHINYL ESTRADIOL AND ETHINYL ESTRADIOL AND FERROUS FUMARATE
Clinical safety rating: avoid
CYP3A4 inducers can decrease efficacy Can cause thromboembolic disorders.
Combination of norethindrone acetate (progestin) and ethinyl estradiol (estrogen) suppresses gonadotropin (FSH and LH) release from the pituitary, inhibiting ovulation, thickening cervical mucus to impede sperm penetration, and altering endometrial lining to reduce implantation. Ethinyl estradiol (in 7-day extended regimen) maintains hormone levels. Ferrous fumarate provides iron supplementation.
| Metabolism | Norethindrone acetate is hydrolyzed to norethindrone, which is primarily metabolized by CYP3A4 to various metabolites. Ethinyl estradiol is metabolized by CYP3A4 and undergoes first-pass metabolism in the liver and gut wall, with sulfation and glucuronidation. |
| Excretion | Norethindrone acetate: Urine (39% as metabolites, 1% unchanged); Feces (35% as metabolites). Ethinyl estradiol: Urine (40% as glucuronide conjugates, <1% unchanged); Feces (40% as metabolites). Ferrous fumarate: Iron absorbed and utilized; unabsorbed iron excreted in feces. |
| Half-life | Norethindrone: Terminal half-life approximately 8–11 hours. Ethinyl estradiol: Terminal half-life approximately 13–27 hours (mean 17 hours). Clinical context: Steady state reached after 5–7 days. |
| Protein binding | Norethindrone: ~36% bound to sex hormone-binding globulin (SHBG) and 61% to albumin. Ethinyl estradiol: ~98% bound to albumin. Ferrous fumarate: Iron is transported by transferrin (binding not typically reported as percent). |
| Volume of Distribution | Norethindrone: Vd ~4 L/kg (indicating extensive tissue distribution). Ethinyl estradiol: Vd ~2–4 L/kg. Ferrous fumarate: Iron distributes to hemoglobin, myoglobin, and storage proteins; Vd not applicable. |
| Bioavailability | Norethindrone acetate: Oral bioavailability ~64% (first-pass metabolism). Ethinyl estradiol: Oral bioavailability ~38–48%. Ferrous fumarate: Iron absorption ~10–35% depending on iron stores and presence of food. |
| Onset of Action | Oral: Onset of contraceptive effect occurs within 7 days of consistent daily dosing; peak serum concentrations achieved in 1–2 hours. Iron supplementation effect on hemoglobin is gradual over weeks. |
| Duration of Action | Contraceptive effect lasts for the duration of daily dosing; after discontinuation, ovulation may resume within 1–3 months. Iron stores are replenished over months of supplementation. |
One tablet (containing norethindrone acetate 1 mg, ethinyl estradiol 20 mcg, and ferrous fumarate 75 mg) orally once daily for 28-day cycle (21 active pills, 7 placebo with ferrous fumarate).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Contraindicated in severe renal impairment or acute renal failure due to potential fluid retention and hyperkalemia from ferrous fumarate. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: use alternative contraceptive due to reduced metabolism of ethinyl estradiol. Child-Pugh C: contraindicated. |
| Pediatric use | Not indicated for pediatric use before menarche. For post-menarchal adolescents, dose same as adult. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific elderly dosing as use is limited to reproductive-age women. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CYP3A4 inducers can decrease efficacy Can cause thromboembolic disorders.
| FDA category | Positive |
| Breastfeeding | Small amounts of ethinyl estradiol and norethindrone excreted in breast milk (M/P ratio not well defined for this combination; estimated <1 for steroids). May reduce milk quantity and quality. Use only if benefits outweigh risks; alternative contraception recommended. Ferrous fumarate is compatible with breastfeeding. |
| Teratogenic Risk |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptives. Women over 35 who smoke should not use this product.
| Common Effects | abnormal uterine bleeding |
| Serious Effects |
["Thrombophlebitis or thromboembolic disorders","Cerebrovascular or coronary artery disease","Known or suspected breast carcinoma","Known or suspected estrogen-dependent neoplasia","Undiagnosed abnormal genital bleeding","Pregnancy or suspected pregnancy","Benign or malignant liver tumor (active)","Active liver disease or impaired liver function","Hypersensitivity to any component"]
| Precautions | ["Thrombotic disorders: venous thromboembolism, arterial thromboembolism, stroke, myocardial infarction","Cardiovascular disease risk: hypertension, hyperlipidemia","Hepatic neoplasia: benign and malignant liver tumors","Gallbladder disease","Carbohydrate and lipid metabolism effects","Hereditary angioedema exacerbation","Chloasma","Retinal thrombosis"] |
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| Pregnancy category X. Contraindicated in pregnancy due to risk of fetal harm. First trimester: Exposure associated with congenital anomalies including cardiovascular and limb defects, and possible increased risk of neural tube defects. Second and third trimesters: Continued risk of fetal harm; no change in risk profile. Postnatal: Potential long-term effects unknown; use postpartum only if not breastfeeding. |
| Fetal Monitoring | Pregnancy test before initiation if pregnancy suspected. Monitor for signs of thromboembolism, hypertension, hepatic dysfunction, and glucose intolerance. No specific fetal monitoring required if used inadvertently; discontinue if pregnancy confirmed. |
| Fertility Effects | Suppresses ovulation; normal fertility typically returns within 1-3 months after discontinuation. No permanent negative effects on fertility. Iron supplementation (ferrous fumarate) does not affect fertility. |