NORETHINDRONE AND ETHINYL ESTRADIOL (10/11)
Clinical safety rating: avoid
CYP3A4 inducers can decrease efficacy Can cause thromboembolic disorders.
Combination oral contraceptive; ethinyl estradiol suppresses follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion, inhibiting ovulation; norethindrone alters cervical mucus, endometrial lining, and sperm penetration.
| Metabolism | Norethindrone: primarily metabolized by CYP3A4 to reduced metabolites; ethinyl estradiol: primarily metabolized by CYP3A4, also undergoes sulfation and glucuronidation. Both undergo enterohepatic recirculation. |
| Excretion | Norethindrone and ethinyl estradiol are primarily eliminated via renal excretion. Norethindrone is excreted as glucuronide and sulfate conjugates, with ~50% renal and ~20-30% fecal. Ethinyl estradiol is extensively metabolized; ~40% renal and ~60% fecal as conjugates. |
| Half-life | Norethindrone: terminal half-life ~7-8 hours. Ethinyl estradiol: terminal half-life ~13-27 hours (mean ~17 hours). Clinical context: Steady-state achieved within ~5-10 days; dosing interval based on maintaining contraceptive efficacy. |
| Protein binding | Norethindrone: ~61% bound to albumin and SHBG; ethinyl estradiol: ~98% bound to albumin. |
| Volume of Distribution | Norethindrone: Vd ~4 L/kg; ethinyl estradiol: Vd ~2-4 L/kg. Large Vd indicates extensive tissue distribution. |
| Bioavailability | Norethindrone: oral bioavailability ~64% (first-pass metabolism). Ethinyl estradiol: oral bioavailability ~38-48% (first-pass metabolism and gut wall conjugation). |
| Onset of Action | Oral administration: contraceptive effect requires consistent dosing; ovarian suppression begins within 2-3 days, but full contraceptive effect after 7 days of daily dosing. |
| Duration of Action | Duration ~24 hours based on daily dosing schedule. Clinical note: missed pills reduce efficacy; withdrawal bleed occurs during placebo week. |
One tablet (norethindrone 0.5 mg/ethinyl estradiol 35 mcg for days 1-10; norethindrone 1 mg/ethinyl estradiol 35 mcg for days 11-21) orally once daily for 21 days, followed by 7 days of placebo or no tablets.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not recommended in severe renal impairment or dialysis due to potential accumulation. |
| Liver impairment | Contraindicated in Child-Pugh class B or C. Use caution in mild impairment (Child-Pugh A) with monitoring for adverse effects. |
| Pediatric use | Not indicated for use in postmenarchal children. Safety and efficacy not established. |
| Geriatric use | Not FDA-approved for use in postmenopausal women. Elderly patients typically do not require this combination for contraception. |
| 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 pass into breast milk (M/P ratio approximately 0.8). May reduce milk production and quality; not recommended for breastfeeding women. Use alternative contraception. |
| Teratogenic Risk | First trimester: No major teratogenic effects; postfertilization exposure not associated with increased risk of congenital anomalies. Second/third trimester: High doses may cause fetal feminization (female pseudohermaphroditism) if exposure occurs during critical period of genital development. General: Avoid use during pregnancy; contraindicated if known or suspected. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptives (e.g., thromboembolism, stroke, myocardial infarction). Risk increases with age and number of cigarettes smoked, especially 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 |
["Thrombophlebitis or thromboembolic disorders","History of deep vein thrombosis or pulmonary embolism","Cerebrovascular or coronary artery disease","Known or suspected carcinoma of the breast","Known or suspected estrogen-dependent neoplasia","Undiagnosed abnormal genital bleeding","Known or suspected pregnancy","Benign or malignant liver tumor (active or history)","Active liver disease (including jaundice) with abnormal liver function tests","Hypersensitivity to any component","Smoking and age over 35 years"]
| Precautions | ["Thrombotic disorders (venous thromboembolism, arterial thromboembolism, stroke, myocardial infarction)","Elevated blood pressure","Gallbladder disease","Hepatic neoplasia","Carcinoma of the breast and reproductive organs","Ocular lesions (e.g., retinal thrombosis, optic neuritis)","Carbohydrate and lipid metabolism effects","Headache (including migraine)","Uterine bleeding irregularities","Drug interactions (e.g., anticonvulsants, antibiotics, rifampin, St. John's wort)","Use in smokers over 35 is contraindicated"] |
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| Fetal Monitoring | Monitor for signs of thromboembolism, hypertension, hepatic dysfunction; routine prenatal care including blood pressure, urine protein, and glucose screening. No specific fetal monitoring required beyond standard obstetrical surveillance. |
| Fertility Effects | Suppresses ovulation; return to fertility typically occurs within 1-3 months after discontinuation. No permanent impact on fertility. |