TRI-LEGEST 21
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRI-LEGEST 21 (TRI-LEGEST 21).
Combination estrogen-progestin contraceptive; suppresses gonadotropins (FSH, LH), inhibits ovulation, alters cervical mucus and endometrium.
| Metabolism | Ethinyl estradiol: primarily via CYP3A4; levonorgestrel: primarily via CYP3A4 and reduction, conjugation. Both undergo enterohepatic recirculation. |
| Excretion | Renal: approximately 50-60% as metabolites; fecal: approximately 40-50% (ethinyl estradiol and norgestimate metabolites excreted in bile and feces); less than 1% unchanged in urine. |
| Half-life | Ethinyl estradiol: 13-27 hours (mean ~17 hours); norgestimate active metabolite (norelgestromin): 22-36 hours (mean ~28 hours). Steady-state achieved within 5-10 days. |
| Protein binding | Ethinyl estradiol: ~97-98% bound to albumin and sex hormone-binding globulin (SHBG); norelgestromin: ~98% bound to albumin and SHBG. |
| Volume of Distribution | Ethinyl estradiol: 2-4 L/kg; norelgestromin: 2-4 L/kg. Indicates extensive tissue distribution. |
| Bioavailability | Oral: approximately 38-48% for ethinyl estradiol due to first-pass metabolism; norgestimate is a prodrug, rapidly deacetylated to norelgestromin with high presystemic conversion. |
| Onset of Action | Oral administration: inhibition of ovulation occurs within 7-10 days of continuous daily dosing (based on hormone level suppression). |
| Duration of Action | Once-daily oral dosing maintains contraceptive efficacy for 24 hours; withdrawal bleed occurs 2-3 days after last active pill. |
| Molecular Weight | 352.46 |
One tablet orally once daily for 21 days, followed by 7 tablet-free days. Each tablet contains norgestimate 0.18 mg/ethinyl estradiol 0.025 mg (days 1-7), norgestimate 0.215 mg/ethinyl estradiol 0.025 mg (days 8-14), norgestimate 0.25 mg/ethinyl estradiol 0.025 mg (days 15-21).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Use is contraindicated in severe renal impairment (GFR <30 mL/min) due to potential fluid retention and electrolyte disturbances. |
| Liver impairment | Contraindicated in acute hepatic disease, hepatic adenomas or carcinomas, and Child-Pugh Class B or C cirrhosis (severe hepatic impairment). No dose adjustment recommended for mild hepatic impairment (Child-Pugh Class A) but caution is advised. |
| Pediatric use | Approved for use in postmenarchal females. Dose is same as adult: one tablet orally once daily for 21 days, then 7 days off. Not indicated for premenarchal females. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific geriatric dose adjustments, but elderly women should be evaluated for contraindications such as thromboembolic disease and cardiovascular risk. |
| 1st trimester | Avoid use due to increased risk of teratogenicity, including cardiovascular and neural tube defects, from progestins and estrogens. Combination hormonal contraceptives are contraindicated during pregnancy. |
| 2nd trimester | Contraindicated. Use during second trimester may be associated with adverse outcomes such as induction of fetal anomalies and potential virilization of female fetus from androgenic progestins. |
| 3rd trimester | Contraindicated. Use in third trimester may cause fetal harm including premature closure of the ductus arteriosus (due to progestin component) and neonatal complications. |
Clinical note
Comprehensive clinical and safety monograph for TRI-LEGEST 21 (TRI-LEGEST 21).
| Placental transfer | Both ethinyl estradiol and norgestimate (and its active metabolite norelgestromin) readily cross the placenta. Animal studies show placental transfer; human data confirm fetal exposure. |
| Breastfeeding |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptives. Risk increases with age (especially over 35 years) and with heavy smoking (≥15 cigarettes/day). Women who use combination hormonal contraceptives should be strongly advised not to smoke.
| Serious Effects |
Known or suspected pregnancyCurrent or history of thrombophlebitis or thromboembolic disordersCerebrovascular or coronary artery diseaseKnown or suspected carcinoma of the breastUndiagnosed abnormal genital bleedingCholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive useHepatic adenoma or carcinomaKnown hypersensitivity to any component
| Precautions | Thromboembolic disorders, cardiovascular disease risk, cerebrovascular events, hypertension, gallbladder disease, hepatic neoplasia, impaired liver function, glucose intolerance, lipid effects, headache, irregular bleeding, depression. |
| Food/Dietary | No specific food interactions are reported for Tri-Legest 21. Grapefruit juice may increase ethinyl estradiol levels but is not considered clinically significant. Patients should avoid St. John's Wort (herbal supplement) as it may reduce contraceptive efficacy. No dietary restrictions are required; however, a balanced diet is recommended to manage potential nausea. Caffeine metabolism may be affected by oral contraceptives; monitor for increased caffeine effects if consumed in excess. |
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| Combination hormonal contraceptives pass into breast milk and may reduce milk production and alter milk composition. Use is generally avoided during breastfeeding, especially in the early postpartum period. Progestin-only contraceptives are preferred. If used, monitor infant for jaundice, breast enlargement, and withdrawal bleeding. Insufficient data to recommend use. |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | First trimester: Epidemiologic studies have not found an increased risk of neural tube defects or other major malformations with combined oral contraceptives. Second and third trimesters: Fetal exposure to estrogen and progestin may cause masculinization of female genitalia if ethinyl estradiol/levonorgestrel is used inadvertently. No known association with congenital heart defects or other structural anomalies. |
| Fetal Monitoring | Monitor blood pressure monthly due to potential estrogen-induced BP elevation. Assess for thromboembolic events (deep vein thrombosis, pulmonary embolism) given increased risk in pregnancy. Evaluate for signs of hepatic adenoma (abdominal pain, mass) or gallbladder disease. Perform pregnancy test if pregnancy is suspected. In case of inadvertent use during pregnancy, no specific fetal monitoring is required beyond routine prenatal care. |
| Fertility Effects | No permanent effect on fertility. After discontinuation, return to normal ovulation and fertility is typically immediate or within one to two cycles. There is no evidence of prolonged infertility or increased time to conception following cessation of combined oral contraceptives. |
| Clinical Pearls | Tri-Legest 21 is a triphasic oral contraceptive containing ethinyl estradiol and norethindrone. For first-time users, start on the first Sunday after menstrual period onset; if starting on any other day, use backup contraception for 7 days. Missed pill management: if one pill is missed, take it as soon as remembered and next pill at usual time; if two consecutive pills are missed in week 1 or 2, take two pills daily for two days and use backup contraception for 7 days; if two pills missed in week 3 or three pills missed anytime, discard remaining pills, start a new pack on the same day (if Sunday starter, continue daily) and use backup contraception for 7 days. Monitor for breakthrough bleeding, especially in first 3 cycles; if persistent, rule out pregnancy or consider alternative formulation. Check for contraindications including migraine with aura, hypertension (BP >160/100), smokers over 35, history of thromboembolic events, and liver disease. Evaluate for drug interactions with rifampin, certain anticonvulsants (phenytoin, carbamazepine, topiramate), and St. John's Wort which may decrease efficacy. |
| Patient Advice | Take one pill daily at the same time each day for 21 days, then no pills for 7 days; withdrawal bleeding usually occurs during the pill-free week. · If you miss a pill, refer to the package insert or call your healthcare provider; general rule: take missed pill as soon as remembered and continue regular schedule; use backup contraception (condoms) if needed. · Common side effects include nausea, breast tenderness, headache, and breakthrough spotting, especially in first few months; these often improve with time. · This medication does not protect against sexually transmitted infections (STIs); use condoms for STI prevention. · Do not smoke while taking this medication; smoking increases risk of serious cardiovascular side effects, especially if you are over 35. · Tell your healthcare provider if you have unexplained leg pain or swelling, sudden severe headache, vision changes, or chest pain; these could be signs of a blood clot. · Inform all healthcare providers (including dentists) that you are taking an oral contraceptive. · If you experience severe upper abdominal pain or yellowing of skin/eyes, stop medication and contact your healthcare provider immediately. |