ESTROSTEP FE
Clinical safety rating
cautionComprehensive clinical and safety monograph for ESTROSTEP FE (ESTROSTEP FE).
Combination estrogen-progestin contraceptive: ethinyl estradiol suppresses gonadotropin release via negative feedback on hypothalamic-pituitary axis; norethindrone acetate produces progestational effects including endometrial transformation and cervical mucus thickening, inhibiting sperm penetration and implantation.
| Metabolism | Ethinyl estradiol: primarily metabolized by CYP3A4; undergoes sulfation and glucuronidation. Norethindrone acetate: hydrolyzed to norethindrone, then metabolized by reduction and glucuronidation. |
| Excretion | Renal: ~40% as metabolites; fecal: ~30% (biliary); remainder as conjugates. |
| Half-life | Ethinyl estradiol: 13-27 hours (terminal); norethindrone acetate: 5-14 hours. Clinical context: Steady-state reached within 7-10 days. |
| Protein binding | Ethinyl estradiol: 97-98% bound to albumin and SHBG; norethindrone acetate: 91-95% bound to albumin and SHBG. |
| Volume of Distribution | Ethinyl estradiol: 2.3-3.6 L/kg; norethindrone acetate: 1.5-2.5 L/kg. Indicates extensive tissue distribution. |
| Bioavailability | Oral: Ethinyl estradiol ~45% (first-pass metabolism); norethindrone acetate ~64%. |
| Onset of Action | Oral: contraceptive effect begins after 7 days of continuous dosing. |
| Duration of Action | Contraceptive effect persists for 24 hours with daily dosing; missed dose guidelines recommend backup contraception. |
| Molecular Weight | Ethinyl estradiol: 296.40 Da; Norethindrone: 298.42 Da. Combined product: the molecular weights of the active ingredients are 296.40 and 298.42 Da respectively. |
One tablet daily orally, each tablet contains norethindrone acetate 1 mg and ethinyl estradiol 20 mcg (24 active tablets) followed by ferrous fumarate 75 mg tablets (4 placebo tablets).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment is recommended for patients with mild to moderate renal impairment. Use is contraindicated in patients with severely impaired renal function (GFR <30 mL/min/1.73 m²) due to potential for fluid retention and hyperkalemia. |
| Liver impairment | Contraindicated in patients with acute or chronic hepatic dysfunction (Child-Pugh class B or C). For mild hepatic impairment (Child-Pugh class A), use with caution and monitor liver function; no specific dose adjustment guidelines are established. |
| Pediatric use | Safety and efficacy have not been established in pediatric patients below 16 years of age. Post-pubertal adolescents may be dosed as adults, with careful consideration of risks (e.g., bone density). |
| Geriatric use | Not indicated for use in women over 65 years due to lack of efficacy and safety data, and increased risk of cardiovascular and thrombotic events. |
| 1st trimester | Contraindicated: Estrogens and progestins are associated with risk of fetal harm; may cause congenital anomalies (e.g., cardiovascular, limb reduction) if used inadvertently during early pregnancy. |
| 2nd trimester | Contraindicated: Use during second trimester is not recommended due to potential adverse effects on fetal development and risk of pregnancy complications. |
| 3rd trimester | Contraindicated: Estrogens can delay parturition, cause fetal distress, and increase risk of postpartum complications; use should be avoided. |
Clinical note
Comprehensive clinical and safety monograph for ESTROSTEP FE (ESTROSTEP FE).
| Placental transfer | Estrogens (ethinyl estradiol) and progestins (norethindrone) cross the human placenta. Fetal serum levels are approximately 1-10% of maternal levels, with evidence of measurable concentrations in fetal tissues. |
| Breastfeeding | Estrostep FE components (ethinyl estradiol and norethindrone) are excreted in breast milk in small amounts. Estrogens may reduce milk production and quality, especially in early postpartum period. Use is generally not recommended during breastfeeding; alternative contraception should be considered. |
| Lactation Rating | L3 - Moderately Safe (limited data; potential for adverse effects, especially on milk production; benefit may outweigh risk in some cases) |
| Teratogenic Risk | Category X. Estrostep FE (norethindrone acetate/ethinyl estradiol/ferrous fumarate) is contraindicated in pregnancy. First trimester: increased risk of neural tube defects, cardiovascular anomalies, and limb reduction defects from sex hormones. Second/third trimester: feminization of male fetus, potential for urogenital malformations, and long-term reproductive tract effects. Postnatal: possible increased risk of childhood cancers. |
| Fetal Monitoring | Monitor for pregnancy if considering use; urine HCG before initiation. Inadvertent use during pregnancy: ultrasound for fetal anatomy. No routine monitoring required if used as directed. |
| Fertility Effects | Suppresses ovulation via gonadotropin inhibition. After discontinuation, return to fertility may be delayed by 1-2 cycles but no permanent effect. No known impact on oocyte quality or long-term fertility. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptives. Risk increases with age and smoking intensity (especially >35 years). Women >35 years who smoke should not use this product.
| Serious Effects |
Pregnancy or suspected pregnancyBreast cancer (known or suspected)Estrogen-dependent neoplasia (e.g., endometrial cancer)Undiagnosed abnormal genital bleedingActive or history of thromboembolic disorders (e.g., deep vein thrombosis, pulmonary embolism)Active or history of cerebrovascular diseaseActive or history of myocardial infarction or coronary artery diseaseKnown thrombophilic conditions (e.g., protein C, S, or antithrombin deficiency, factor V Leiden)Significant liver disease or impaired liver function (including benign/malignant liver tumors)Diabetes with vascular involvementUncontrolled hypertensionMigraine with focal aura at any ageCholestatic jaundice of pregnancy or jaundice with prior pill useRenal disease with vascular involvementKnown hypersensitivity to any componentHeavy smoking (≥15 cigarettes/day) and age ≥35 years
| Precautions | Thromboembolic disorders, cardiovascular disease (MI, stroke), hypertension, gallbladder disease, hepatic neoplasia, lipid effects, glucose intolerance, headache, breakthrough bleeding, depression, contact lens intolerance, fluid retention, hereditary angioedema. |
| Food/Dietary | No specific food interactions are reported for Estrostep Fe. Grapefruit juice may slightly increase estrogen levels but is not considered clinically significant. There are no dietary restrictions. However, patients should maintain a consistent intake of folic acid if planning pregnancy; iron supplements can be taken with food to reduce GI upset. |
| Clinical Pearls | Estrostep Fe is a combined oral contraceptive containing norethindrone acetate and ethinyl estradiol. It is unique among OCPs for its step-up estrogen regimen (20, 30, 35 mcg EE) intended to mimic natural menstrual cycle. Clinicians should note that it is not FDA-approved for acne treatment, though it is often used off-label; only Estrostep (non-Fe) is approved for acne. The iron (ferrous fumarate) in the last 7 tablets is a placebo. It is a low-dose pill; missed doses more likely cause breakthrough bleeding. Contraindications include smoking >35, history of DVT/PE, migraine with aura, liver disease, breast cancer. Counsel patients to take at same time daily; if missed, follow standard missed pill protocol. |
| Patient Advice | Take one pill at the same time each day. The first 21 pills contain active hormones; the last 7 pills are iron tablets (not hormones). · If you miss a pill, refer to the package insert or contact your healthcare provider. Use backup contraception (condoms) if pills are missed. · Common side effects include nausea, breast tenderness, headache, and breakthrough bleeding, especially in the first few months. · Estrostep Fe does not protect against sexually transmitted infections (STIs). Always use condoms for STI prevention. · Smoking while using this pill increases risk of serious cardiovascular events. Do not smoke. · Contact your doctor if you experience signs of a blood clot: sudden leg pain/swelling, chest pain, shortness of breath, or sudden severe headache. · The iron in the last 7 pills is to help with iron levels but does not provide hormonal contraception during that week. |
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