NORETHINDRONE AND ETHINYL ESTRADIOL (7/14)
Clinical safety rating: avoid
CYP3A4 inducers can decrease efficacy Can cause thromboembolic disorders.
Norethindrone is a progestin that suppresses gonadotropin release, preventing ovulation. Ethinyl estradiol is an estrogen that provides negative feedback on the hypothalamic-pituitary axis, further inhibiting ovulation. The combination also alters cervical mucus and endometrial lining to impede fertilization and implantation.
| Metabolism | Norethindrone is primarily metabolized via reduction and conjugation; CYP3A4 may be involved. Ethinyl estradiol is metabolized by CYP3A4 and undergoes glucuronidation and sulfation. |
| Excretion | Norethindrone: ~50% renal, ~50% fecal; Ethinyl estradiol: ~50% renal, ~50% fecal, with enterohepatic circulation. |
| Half-life | Norethindrone: 8-11 hours; Ethinyl estradiol: 17-27 hours. Achieves steady state within 5-10 days, permitting once-daily dosing. |
| Protein binding | >95% bound; binds to albumin and SHBG. Norethindrone: 60-70% to albumin, 35% to SHBG; Ethinyl estradiol: ~98% to albumin. |
| Volume of Distribution | Norethindrone: 3-4 L/kg; Ethinyl estradiol: 3-4 L/kg. Distribution into total body water and breast tissue. |
| Bioavailability | Oral: Norethindrone ~64%; Ethinyl estradiol ~40-50% due to first-pass metabolism. |
| Onset of Action | Oral: Inhibition of ovulation occurs within 7 days of consistent daily dosing; peak serum concentrations at 1-2 hours. |
| Duration of Action | Oral: 24 hours (once-daily dosing). Withdrawal bleeding occurs 2-3 days after last active tablet during placebo week. |
One tablet (norethindrone 0.5 mg/ethinyl estradiol 35 mcg) orally once daily for 21 days (7 active tablets of norethindrone 0.5 mg/ethinyl estradiol 35 mcg followed by 14 active tablets of norethindrone 1 mg/ethinyl estradiol 35 mcg). Start on day 1 of menstrual cycle.
| Dosage form | TABLET |
| Renal impairment | No adjustment required for mild to moderate renal impairment. Contraindicated in severe renal impairment or acute renal failure (due to potential fluid retention and hyperkalemia). |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: caution, reduce dose or consider alternative; Child-Pugh C: contraindicated (impaired steroid metabolism). |
| Pediatric use | Not indicated for use before menarche. After menarche, same dosing as adults (one tablet daily for 21 days) for contraception; use lowest effective dose in adolescents. |
| Geriatric use | Not indicated for use after menopause due to risk of thromboembolism and cardiovascular events. If used for hormone therapy, lowest effective dose and shortest duration. |
| 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 are excreted in breast milk. M/P ratio not well established. May reduce milk production and quality. Recommended to avoid use in breastfeeding mothers, especially in the early postpartum period. |
| Teratogenic Risk | Combination oral contraceptives are contraindicated during pregnancy. First trimester: No increased risk of major birth defects based on large cohort studies. Second and third trimesters: Exposure may increase risk of fetal complications including low birth weight, preterm delivery, and potentially congenital anomalies (e.g., cardiovascular, limb defects) although data are inconsistent. Hormonal effects may cause feminization of male fetus, but clinical significance is unclear. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events (e.g., myocardial infarction, stroke, thromboembolism) from combined hormonal contraceptive use, especially in women over 35 and those who smoke 15 or more cigarettes per day.
| Common Effects | abnormal uterine bleeding |
| Serious Effects |
Thrombophlebitis or thromboembolic disorders. Cerebrovascular or coronary artery disease. Known or suspected breast carcinoma. Endometrial carcinoma or other estrogen-dependent neoplasia. Undiagnosed abnormal genital bleeding. Cholestatic jaundice of pregnancy or jaundice with prior pill use. Hepatic adenoma or carcinoma. Known or suspected pregnancy. Active liver disease with abnormal function. Hypersensitivity to any component.
| Precautions | Increased risk of cardiovascular events (thrombosis, stroke, MI) especially in smokers and women >35. Elevated blood pressure. Liver disease or tumors. Gallbladder disease. Headache including migraine. Depression. Irregular bleeding. Fluid retention. Hereditary angioedema. Reduced efficacy with enzyme inducers. Monitoring: blood pressure, lipid profile, glucose, liver function. |
Loading safety data…
| Fetal Monitoring | If inadvertently used during pregnancy, monitor fetal growth and development via ultrasound. Assess for signs of thromboembolism in mother. No routine fetal monitoring required. |
| Fertility Effects | Normal fertility returns upon discontinuation; transient delay in ovulation may occur. No permanent impact on fertility. |