TRI-LEGEST FE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRI-LEGEST FE (TRI-LEGEST FE).
Tri-Legest FE is a combination oral contraceptive containing ethinyl estradiol and norethindrone acetate. It prevents ovulation by inhibiting gonadotropin release (FSH and LH) and alters cervical mucus and endometrial lining to impede sperm penetration and implantation.
| Metabolism | Ethinyl estradiol is metabolized primarily by CYP3A4; norethindrone acetate is hydrolyzed to norethindrone, which is metabolized by reduction and conjugation (glucuronidation and sulfation). |
| Excretion | Renal: ~60% (metabolites), Fecal: ~30% (metabolites), Biliary: minor (~5% as conjugates) |
| Half-life | Norethindrone: 7-8 hours; Ethinyl estradiol: 18 hours (terminal). Steady-state reached after 7 days; clinical contraceptive efficacy requires consistent dosing. |
| Protein binding | Norethindrone: ~80% bound to SHBG and albumin; Ethinyl estradiol: >95% bound to albumin. |
| Volume of Distribution | Norethindrone: 3-4 L/kg; Ethinyl estradiol: 2-3 L/kg. Indicates extensive tissue distribution. |
| Bioavailability | Oral: Norethindrone ~60% (first-pass metabolism); Ethinyl estradiol ~45-55% (first-pass and gut wall metabolism). |
| Onset of Action | Oral: Contraceptive effect begins after 7 days of consistent dosing; requires 7-day interval for full ovulatory suppression. |
| Duration of Action | Oral: 24 hours per active pill; continuous suppression of ovulation maintained with daily dosing. After last active pill, withdrawal bleed occurs within 2-3 days. |
| Molecular Weight | 340.46 |
One tablet orally once daily for 28-day cycle: 21 days active tablets (norethindrone/ethinyl estradiol) followed by 7 days placebo. For contraception only.
| Dosage form | TABLET |
| Renal impairment | No specific guidelines exist; use with caution in renal impairment due to potential for fluid retention and hyperkalemia. |
| Liver impairment | Contraindicated in severe hepatic disease or active liver disease (Child-Pugh Class C). Use with caution in mild to moderate impairment (Child-Pugh A/B) without specific dose adjustment. |
| Pediatric use | Not indicated in premenarchal females; after menarche, same dosing as adults but only for contraception after assessment of skeletal maturity. |
| Geriatric use | Not indicated for use in postmenopausal women; no specific dose adjustments in elderly females of reproductive age. |
| 1st trimester | Use is contraindicated in pregnancy. Ethinyl estradiol and norethindrone are associated with fetal harm; data suggest increased risk of cardiac defects and other malformations. |
| 2nd trimester | Use is contraindicated. Exposure during the second trimester may affect fetal development; estrogenic and progestogenic effects are not recommended. |
| 3rd trimester | Use is contraindicated. Late pregnancy exposure may cause adverse effects such as fetal genital abnormalities, and potential long-term reproductive tract effects. |
Clinical note
Comprehensive clinical and safety monograph for TRI-LEGEST FE (TRI-LEGEST FE).
| Placental transfer | Both ethinyl estradiol and norethindrone cross the placenta. Norethindrone reaches fetal concentrations approximately 10-15% of maternal levels; ethinyl estradiol crosses but data are limited. |
| Breastfeeding | Norethindrone and ethinyl estradiol are excreted in human milk. Estrogens may reduce milk production and quality, particularly with high doses. Use only if clearly needed and with caution, monitoring infant for jaundice, lethargy, and growth disturbances. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, especially in women over 35 years, and with number of cigarettes smoked. Women over 35 who smoke should not use combination oral contraceptives.
| Serious Effects |
PregnancyCurrent or history of thromboembolic disordersCerebrovascular or coronary artery diseaseKnown or suspected breast carcinomaUndiagnosed abnormal genital bleedingCholestatic jaundice of pregnancy or jaundice with prior pill useHepatic adenomas or carcinomasActive liver disease or impaired liver functionKnown or suspected estrogen-dependent neoplasia
| Precautions | Thrombotic disorders (venous thromboembolism, stroke, myocardial infarction), Hepatic disease (jaundice, liver tumors), Hypertension, Gallbladder disease, Carbohydrate and lipid metabolism effects, Headache/migraine, Bleeding irregularities, Depression, Cervical cancer risk |
| Food/Dietary | No significant food interactions. Grapefruit juice may slightly increase estrogen levels but not clinically meaningful. Avoid excessive alcohol intake as it may impair liver metabolism and increase risk of breakthrough bleeding. |
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| Lactation Rating | L3 (Moderately Safe) - Limited data; consider risk-benefit. |
| Teratogenic Risk | Pregnancy category X. Combination hormonal contraceptives (CHCs) are contraindicated in pregnancy. First trimester use may cause small increased risk of limb reduction defects and cardiovascular anomalies; second and third trimester exposure is associated with masculinization of female fetuses due to progestin component. Discontinue immediately if pregnancy occurs. |
| Fetal Monitoring | Monitor blood pressure at baseline and periodically. Assess for signs of thromboembolism, hepatic dysfunction, headaches, visual disturbances, and mood changes. She may require close monitoring for hypertension, glucose intolerance, and contraceptive efficacy; pregnancy tests if pregnancy suspected. |
| Fertility Effects | Reversible suppression of ovulation. After discontinuation, return to fertility may be delayed (usually normal within 1-3 months for most, but can be up to 1 year). No permanent adverse effect on fertility. |
| Clinical Pearls | Tri-Legest Fe is a combination oral contraceptive containing estradiol and norethindrone. Its 91-day extended-cycle regimen (84 active pills followed by 7 low-dose estrogen pills) reduces menstruation frequency to once every 3 months. Use caution in patients with migraine with aura, hypertension, or smoking over age 35 due to increased thromboembolic risk. The low-dose estrogen pills (10 mcg ethinyl estradiol) during week 13 help maintain hormone levels and reduce breakthrough bleeding. Advise patients to take at the same time daily; missed pills increase pregnancy risk. |
| Patient Advice | Take one pill daily at the same time; missing pills increases pregnancy risk. · You will have a period only once every 3 months (during the last week of each cycle). · Use backup contraception if you miss 2 or more active pills in a row. · Common side effects include spotting, nausea, breast tenderness, and mood changes. · Do not smoke while taking this medication, especially if over 35. · This does not protect against STIs; use condoms for prevention. · Inform your doctor if you have migraines, high blood pressure, or a history of blood clots. |