ESTROSTEP 21
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ESTROSTEP 21 (ESTROSTEP 21).
Estrostep 21 is a combination oral contraceptive containing ethinyl estradiol and norethindrone acetate. It works primarily by suppressing gonadotropin-releasing hormone (GnRH) from the hypothalamus, reducing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion from the pituitary, thereby inhibiting ovulation. Additionally, it thickens cervical mucus to impede sperm penetration and alters the endometrium to reduce implantation likelihood.
| Metabolism | Ethinyl estradiol is metabolized primarily via CYP3A4 and undergoes glucuronidation and sulfation. Norethindrone acetate is deacetylated to norethindrone, which is metabolized by CYP3A4 and other CYP enzymes, and undergoes reduction and glucuronidation. |
| Excretion | Biliary/fecal (40-50% as metabolites) and renal (30-40% as glucuronide and sulfate conjugates) |
| Half-life | Ethinyl estradiol: 13-27 hours (terminal); norethindrone acetate: 5-14 hours (terminal). Steady-state achieved within 3-5 days. |
| Protein binding | Ethinyl estradiol: 97-98% bound to albumin; norethindrone: 95-97% bound to albumin and SHBG. |
| Volume of Distribution | Ethinyl estradiol: 2.5-4.5 L/kg; norethindrone: 3.5-5.5 L/kg. Indicates extensive tissue distribution. |
| Bioavailability | Ethinyl estradiol: 38-48% (oral, first-pass metabolism); norethindrone acetate: 50-70% (oral, deacetylation to norethindrone). |
| Onset of Action | Oral: contraceptive effect requires 7 days of continuous dosing; suppression of ovulation begins within 3 days. |
| Duration of Action | Oral: 24 hours; daily dosing required to maintain hypothalamic-pituitary suppression and contraceptive efficacy. |
One tablet orally once daily for 21 days, each tablet contains norethindrone acetate 1 mg and ethinyl estradiol 20 mcg.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Contraindicated in severe renal impairment or acute renal failure. |
| Liver impairment | Contraindicated in acute hepatitis, severe cirrhosis, benign or malignant liver tumors, or Child-Pugh class C cirrhosis. Use with caution in Child-Pugh class A or B; consider alternative therapy. |
| Pediatric use | Not indicated for use before menarche. Post-menarche: same dosing as adults; use lowest effective dose for shortest duration. |
| Geriatric use | Not indicated for postmenopausal women; no established dosing in elderly. Consider alternative therapies as necessary. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ESTROSTEP 21 (ESTROSTEP 21).
| Breastfeeding | Estrostep 21 is excreted in breast milk in small amounts; ethinyl estradiol M/P ratio approximately 0.1; norethindrone M/P ratio ~0.5. May reduce milk production and quality, especially in early lactation. Use generally avoided during breastfeeding; consider progestin-only alternatives. |
| Teratogenic Risk | Estrostep 21 (norethindrone acetate/ethinyl estradiol) is contraindicated in pregnancy. First trimester: increased risk of cardiovascular malformations, limb reduction defects, and neural tube defects. Second and third trimesters: associated with fetal genital abnormalities, feminization of male fetuses, and potential long-term reproductive effects. Use in early pregnancy for emergency contraception is not recommended due to potential risks. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events from oral contraceptive use. This risk increases with age (especially in women > 35 years) and with the number of cigarettes smoked. Women who use oral contraceptives should be strongly advised not to smoke.
| Serious Effects |
["Thrombophlebitis, thromboembolic disorders, or history thereof (e.g., deep vein thrombosis, pulmonary embolism)","Cerebrovascular disease (e.g., stroke, TIA)","Coronary artery disease (e.g., myocardial infarction, angina)","Known or suspected breast cancer, endometrial cancer, or other estrogen-dependent neoplasia","Undiagnosed abnormal genital bleeding","Cholestatic jaundice of pregnancy or jaundice with prior oral contraceptive use","Benign or malignant liver tumors","Known or suspected pregnancy","Hypersensitivity to any component","Smoking in women over 35 years of age"]
| Precautions | ["Increased risk of thromboembolic disorders (e.g., venous thromboembolism, stroke, myocardial infarction), especially in smokers and women over 35","Hepatic neoplasia (benign and malignant) reported","Hypertension and gallbladder disease","Carbohydrate and lipid effects; monitor in diabetic patients","Ocular lesions (e.g., retinal thrombosis); discontinue if unexplained vision loss or proptosis occurs","Hereditary angioedema exacerbation","Chloasma; avoid sun exposure","Menstrual irregularities (e.g., breakthrough bleeding, amenorrhea)","Depression; discontinue if severe"] |
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| Fetal Monitoring | Monitor for signs of thromboembolism, hypertension, hepatic dysfunction, and depression. Fetal monitoring includes ultrasound for structural anomalies if accidental exposure during pregnancy. Contraception counseling and pregnancy testing before initiation. |
| Fertility Effects | Suppresses ovulation via gonadotropin inhibition; reversible upon discontinuation. No long-term effects on fertility; return to ovulation may be delayed in some women but typically within 3 months. |