TRIPHASIL-28
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRIPHASIL-28 (TRIPHASIL-28).
Combination estrogen-progestin contraceptive; suppresses gonadotropin secretion, inhibits ovulation, alters cervical mucus and endometrium.
| Metabolism | Metabolized primarily via CYP3A4; ethinyl estradiol undergoes hydroxylation and conjugation; levonorgestrel undergoes reduction and conjugation. |
| Excretion | Renal (about 50-60% as metabolites, <10% unchanged), fecal (about 30-40% via biliary elimination). Ethinyl estradiol undergoes enterohepatic recirculation. |
| Half-life | Levonorgestrel: terminal half-life 11-45 hours (mean 24-30 h); Ethinyl estradiol: terminal half-life 10-27 hours (mean 17 h). Steady-state reached after 5-7 days. |
| Protein binding | Levonorgestrel: 98-99% bound to SHBG and albumin; Ethinyl estradiol: 97-98% bound to albumin (not SHBG). |
| Volume of Distribution | Levonorgestrel: 1.1 L/kg; Ethinyl estradiol: 2.5-3.5 L/kg. Large Vd indicates extensive tissue distribution. |
| Bioavailability | Oral: Levonorgestrel ~100%; Ethinyl estradiol ~40-48% (due to first-pass metabolism). |
| Onset of Action | Oral: contraceptive effect requires 7 days of consistent dosing; immediate if started on day 1 of menstruation. |
| Duration of Action | 24 hours per dose; contraceptive effect persists for the 7-day pill-free interval; ovulation may resume after 2-4 weeks. |
1 tablet orally once daily for 28 days; each tablet contains levonorgestrel 0.050 mg and ethinyl estradiol 0.030 mg (6 days), levonorgestrel 0.075 mg and ethinyl estradiol 0.040 mg (5 days), levonorgestrel 0.125 mg and ethinyl estradiol 0.030 mg (10 days), followed by 7 inert tablets. The first dose is taken on the first Sunday after onset of menstruation or on day 1 of the menstrual cycle.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment; contraindicated in severe renal impairment or acute renal failure due to risk of hyperkalemia and fluid retention. |
| Liver impairment | Contraindicated in severe hepatic disease (Child-Pugh Class C) or hepatocellular carcinoma; for mild to moderate impairment (Child-Pugh A or B), use with caution and monitor liver function, as estrogen metabolism may be impaired. |
| Pediatric use | Safety and efficacy have not been established in pediatric patients before menarche. Post-menarcheal adolescents: same dosing as adults (1 tablet daily for 28 days) after initiation of menstruation. |
| Geriatric use | Not indicated for use in postmenopausal women. In women over 35 who smoke, contraindicated due to increased cardiovascular risk. For non-smoking women >35, use only if low risk for cardiovascular disease and with careful monitoring of blood pressure and metabolic parameters. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TRIPHASIL-28 (TRIPHASIL-28).
| Breastfeeding | Lactation: Levonorgestrel and ethinyl estradiol are excreted in breast milk. M/P ratio for levonorgestrel is approximately 0.5-0.6; ethinyl estradiol M/P ratio is approximately 0.4. Combination OCs may reduce milk production and affect infant growth; use during lactation is generally not recommended until weaning is complete. |
| Teratogenic Risk | TRIPHASIL-28 (levonorgestrel/ethinyl estradiol) is contraindicated in pregnancy. First trimester inadvertent exposure does not appear to increase risk of major malformations, based on epidemiological studies. Second and third trimester exposure is associated with fetal harm including genital abnormalities in female fetuses (vaginal adenosis, clitoral hypertrophy) and possibly cardiovascular anomalies. Risk of jaundice and neonatal withdrawal syndrome may occur with late pregnancy exposure. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combined hormonal contraceptives. Women over 35 who smoke should not use this product.
| Serious Effects |
["Thrombophlebitis or thromboembolic disorders","Cerebrovascular or coronary artery disease","Known or suspected breast cancer","Carcinoma of the endometrium or other estrogen-dependent neoplasia","Undiagnosed abnormal genital bleeding","Cholestatic jaundice of pregnancy or jaundice with prior pill use","Hepatic adenoma or carcinoma","Known or suspected pregnancy","Active liver disease with abnormal liver function","Age >35 and smoking","Diabetes with vascular involvement","Uncontrolled hypertension","Migraine with focal aura at any age","Major surgery with prolonged immobilization","Known hypercoagulopathies"]
| Precautions | ["Increased risk of venous thromboembolism (VTE) and arterial thrombosis","Risk of myocardial infarction and stroke, especially in smokers","Increased risk of gallbladder disease","Hepatic neoplasia risk","Elevated blood pressure","Carbohydrate and lipid metabolism effects","Ocular lesions (e.g., retinal thrombosis)","Headache and migraine exacerbation","Uterine bleeding irregularities","Depression"] |
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| Fetal Monitoring | Monitor for signs of thromboembolism, hypertension, and liver function in pregnant patients inadvertently exposed. For accidental pregnancy during use, discontinue immediately and assess fetal anatomy via ultrasound; follow pregnancy for potential adverse outcomes. |
| Fertility Effects | TRIPHASIL-28 suppresses ovulation via inhibition of gonadotropins. Return to fertility may be delayed for up to 3 months after discontinuation; no permanent impairment. |