NORETHINDRONE AND ETHINYL ESTRADIOL AND FERROUS FUMARATE
Clinical safety rating: avoid
CYP3A4 inducers can decrease efficacy Can cause thromboembolic disorders.
Norethindrone is a progestin that suppresses gonadotropin release, inhibiting ovulation. Ethinyl estradiol is an estrogen that provides negative feedback on the hypothalamic-pituitary axis, further suppressing ovulation and altering cervical mucus and endometrial lining. Ferrous fumarate is an iron supplement for replacement of menstrual iron loss.
| Metabolism | Norethindrone is extensively metabolized primarily via reduction and sulfate conjugation; CYP3A4 is involved in minor pathways. Ethinyl estradiol is metabolized by CYP3A4 and undergoes first-pass metabolism in the liver and gut wall, with sulfation and glucuronidation. |
| Excretion | Norethindrone: ~80% renal (as glucuronide and sulfate conjugates), ~20% fecal. Ethinyl estradiol: ~40% renal, ~60% fecal via enterohepatic recirculation. Ferrous fumarate: iron is absorbed and incorporated; excess excreted in feces as unabsorbed. |
| Half-life | Norethindrone: 5-8 hours (terminal). Ethinyl estradiol: 13-27 hours (terminal). Clinical context: dosing interval is 24 hours based on ethinyl estradiol half-life. |
| Protein binding | Norethindrone: ~60-65% bound to albumin and SHBG. Ethinyl estradiol: ~97-98% bound to albumin (not SHBG). |
| Volume of Distribution | Norethindrone: ~4 L/kg. Ethinyl estradiol: ~3-4 L/kg. Clinical meaning: extensive distribution into tissues, including breast and reproductive organs. |
| Bioavailability | Oral: Norethindrone ~50-77% due to first-pass metabolism; Ethinyl estradiol ~40-50% due to first-pass metabolism. Ferrous fumarate: iron bioavailability ~10-15% (dose-dependent). |
| Onset of Action | Oral: contraceptive effect requires 7 days of continuous use for inhibition of ovulation; maximal suppression achieved after 1-2 cycles. |
| Duration of Action | Contraceptive effect persists for the duration of daily use; missing doses leads to risk of ovulation. Withdrawal bleeding occurs during placebo week. |
One tablet (norethindrone 1 mg, ethinyl estradiol 10 mcg, and ferrous fumarate 75 mg) orally once daily at the same time each day for 28 consecutive days, starting on day 1 of menstrual cycle.
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustment recommended for renal impairment; use with caution in patients with significantly impaired renal function due to potential electrolyte disturbances from ferrous fumarate. |
| Liver impairment | Contraindicated in patients with Child-Pugh class B or C (moderate to severe hepatic impairment). For Child-Pugh class A, use with caution and monitor liver function; no specific dose adjustment defined. |
| Pediatric use | Not indicated for use before menarche. For postmenarchal adolescents weighing ≥35 kg, same as adult dosing: one tablet orally once daily. No weight-based dosing defined; use same regimen as adults. |
| Geriatric use | Not indicated for postmenopausal women; use is inappropriate for contraception or hormone replacement in this age group due to increased risk of thromboembolic events and lack of benefit. |
| 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 | Contraindicated during breastfeeding. Norethindrone and ethinyl estradiol are excreted in breast milk; M/P ratio not well established. May reduce milk production and quality, and affect infant development. |
| Teratogenic Risk | First trimester: Use is contraindicated due to increased risk of neural tube defects, cardiovascular anomalies, and oral clefts. Second trimester: Risk of genital tract abnormalities, including vaginal adenosis and clear-cell adenocarcinoma in female offspring. Third trimester: Possible withdrawal bleeding and hormonal effects in the neonate. Postnatal: Potential long-term effects on reproductive development. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular adverse events from combination oral contraceptive use. This risk increases with age and with heavy smoking (≥15 cigarettes per day) and is quite marked in women over 35 years of age. Women who use combination hormonal contraceptives should be strongly advised not to smoke.
| Common Effects | abnormal uterine bleeding |
| Serious Effects |
["High risk of arterial or venous thrombotic diseases (e.g., current or history of DVT, PE, stroke, MI)","Current or history of breast cancer or other estrogen-sensitive neoplasia","Hepatic impairment or active liver disease","Undiagnosed abnormal uterine bleeding","Pregnancy (ferrous fumarate contraindicated in pregnancy for iron deficiency anemia except in definite need)","Known or suspected pregnancy (contraceptive use)","Hypersensitivity to any component","Hemochromatosis or iron overload disorders (ferrous fumarate)"]
| Precautions | ["Thromboembolic disorders and cardiovascular risk","Cigarette smoking increases risk","Elevated blood pressure","Gallbladder disease","Carbohydrate and lipid effects","Hepatic neoplasia","Ocular lesions","Bleeding irregularities and amenorrhea","Ectopic pregnancy","Depression","Iron overload with ferrous fumarate (hemochromatosis)"] |
Loading safety data…
| Fetal Monitoring | Before initiation: Rule out pregnancy via sensitive test. During use: Monitor for signs of pregnancy; if pregnancy occurs, discontinue immediately. Perform ultrasound to assess fetal development if exposure occurs. |
| Fertility Effects | Combined oral contraceptives suppress ovulation, thus temporarily impair fertility. Fertility returns upon discontinuation; no permanent effects. Ferrous fumarate does not affect fertility. |