NORLESTRIN FE 2.5/50
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NORLESTRIN FE 2.5/50 (NORLESTRIN FE 2.5/50).
Combination oral contraceptive containing norethindrone (progestin) and ethinyl estradiol (estrogen). Inhibits ovulation by suppressing gonadotropin-releasing hormone (GnRH) via negative feedback on the hypothalamus and pituitary. Increases cervical mucus viscosity to impede sperm penetration and induces endometrial atrophy to prevent implantation.
| Metabolism | Hepatic metabolism via cytochrome P450 (CYP) enzymes: ethinyl estradiol is primarily metabolized by CYP3A4; norethindrone undergoes reduction, hydroxylation, and conjugation. Both undergo enterohepatic recirculation and are excreted in urine and feces. |
| Excretion | Norethindrone: ~80% renal (as glucuronide and sulfate conjugates), ~20% fecal. Ethinyl estradiol: ~40% renal, ~60% fecal, with enterohepatic recirculation. |
| Half-life | Norethindrone: ~8-10 hours (terminal), requiring daily dosing for stable contraceptive effect. Ethinyl estradiol: ~13-21 hours (terminal), supporting once-daily administration. |
| Protein binding | Norethindrone: ~61-70% bound to albumin and SHBG. Ethinyl estradiol: ~97-98% bound to albumin. |
| Volume of Distribution | Norethindrone: Vd ~1.8-4.5 L/kg (extensive tissue distribution). Ethinyl estradiol: Vd ~2.5-5 L/kg (distributes into breast milk). |
| Bioavailability | Norethindrone: ~64% (oral). Ethinyl estradiol: ~38-48% (oral) due to first-pass metabolism. |
| Onset of Action | Oral: Requires 7 consecutive days of dosing for full contraceptive effect (ovarian suppression). |
| Duration of Action | 24 hours (maintained with daily dosing); missed pills reduce efficacy. |
One tablet orally once daily, each containing 2.5 mg norethindrone acetate and 50 mcg ethinyl estradiol, plus 7 iron tablets (75 mg ferrous fumarate) taken during the placebo week.
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustment provided; contraindicated in severe renal impairment (GFR <30 mL/min) due to potential fluid retention. |
| Liver impairment | Contraindicated in severe hepatic disease (Child-Pugh class C); use with caution in mild to moderate impairment (Child-Pugh A or B) with monitoring for adverse effects; no specific dose reduction guidelines established. |
| Pediatric use | Not indicated for use before menarche; post-menarche: same as adult dosing (one tablet daily) after menstrual cycle establishment. |
| Geriatric use | Not indicated for postmenopausal women; no dose adjustment in elderly with normal hepatic and renal function, but consider increased risk of thromboembolic events and metabolic effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NORLESTRIN FE 2.5/50 (NORLESTRIN FE 2.5/50).
| Breastfeeding | Norethindrone and ethinyl estradiol are excreted into breast milk. M/P ratio for norethindrone is approximately 1.1; for ethinyl estradiol approximately 0.3. Use during lactation may reduce milk production and quality. Not recommended for nursing mothers. |
| Teratogenic Risk | NORLESTRIN FE 2.5/50 (norethindrone acetate 2.5 mg/ethinyl estradiol 0.05 mg) is contraindicated in pregnancy. First trimester: increased risk of congenital anomalies including cardiovascular and limb defects, and possible non-genital malformations. Second/third trimester: feminization of male fetus, vaginal adenosis, and cervical changes in females. Exposure is associated with a 1.3 to 2.0-fold increased risk of congenital heart defects. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events (e.g., myocardial infarction, stroke, thromboembolism) from combination oral contraceptive use. Risk increases with age and number of cigarettes smoked. Women over 35 years who smoke should not use this combination oral contraceptive.
| Serious Effects |
["Thrombophlebitis or thromboembolic disorders (current or history)","Cerebrovascular or coronary artery disease (current or history)","Known or suspected breast carcinoma, endometrial carcinoma, or estrogen-dependent neoplasia","Undiagnosed abnormal genital bleeding","Pregnancy (known or suspected)","Benign or malignant liver tumor (current or history)","Active liver disease (e.g., acute viral hepatitis) or impaired liver function","Hypersensitivity to any component of the product","Cigarette smoking in women over 35 years of age"]
| Precautions | ["Thromboembolic disorders: increased risk of venous thromboembolism (VTE) and arterial thrombosis; discontinue if suspected","Cardiovascular disease: increased risk of myocardial infarction and stroke, especially in smokers >35 years","Hypertension: may develop or worsen; monitor blood pressure","Cervical cancer: controversial association; Pap smear screening recommended","Hepatic neoplasia: rare but reported; contraindicated with active liver disease","Gallbladder disease: increased risk of cholelithiasis","Ocular effects: retinal thrombosis may occur; discontinue if sudden partial or complete vision loss","Carbohydrate metabolism: may decrease glucose tolerance; monitor diabetic patients","Fluid retention: use with caution in conditions affected by edema (e.g., migraine, asthma, renal impairment)"] |
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| Fetal Monitoring | In case of inadvertent use during pregnancy, monitor for fetal development via ultrasound and assess for cardiovascular and urogenital abnormalities. Discontinue immediately if pregnancy is suspected or confirmed. |
| Fertility Effects | After discontinuation, return of fertility may be delayed but no permanent impairment. Post-pill amenorrhea may occur lasting up to 6 months. Does not cause infertility. |