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. |
| Molecular Weight | 312.4 |
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 | Contraindicated in pregnancy. Use during first trimester is associated with risk of congenital defects, particularly cardiovascular and limb defects, due to hormonal effects. |
| 2nd trimester | Contraindicated in pregnancy. Use during second trimester may cause adverse effects on fetal development; risk of fetal harm outweighs potential benefits. |
| 3rd trimester | Contraindicated in pregnancy. Use during third trimester may cause fetal harm, including masculinization of female fetuses and other endocrine disruption. |
Clinical note
Comprehensive clinical and safety monograph for TRIPHASIL-28 (TRIPHASIL-28).
| Placental transfer | Yes, both ethinyl estradiol and levonorgestrel cross the placenta. Animal studies show transfer; human data limited but consistent with animal findings. Degree of transfer is sufficient to cause fetal effects. |
| Breastfeeding | Small amounts of hormones (estrogen and progestin) may be excreted in breast milk. Use with caution; may reduce milk production and quality. Generally not recommended during breastfeeding due to potential effects on infant. |
■ 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 |
Known or suspected pregnancyHistory of or current thrombophlebitis or thromboembolic disordersCerebrovascular or coronary artery diseaseActive liver disease or impaired liver functionKnown or suspected breast cancer, endometrial cancer, or other estrogen-dependent neoplasiaUndiagnosed abnormal genital bleedingHypersensitivity to any component
| 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 |
| Food/Dietary | No significant food interactions. Grapefruit juice may slightly increase estrogen levels but is not considered clinically significant. Consistent dietary habits recommended to avoid gastrointestinal upset. |
Loading safety data…
| Lactation Rating | L4 (Possibly Hazardous) - Avoid use if possible; consider alternative methods. |
| 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. |
| 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. |
| Clinical Pearls | Triphasil-28 is a triphasic oral contraceptive containing levonorgestrel and ethinyl estradiol. The varying hormone doses across the three phases mimic the natural menstrual cycle and may reduce breakthrough bleeding compared to monophasic pills. It is important to take the pills in the correct order (by day of the week) to maintain the phasic pattern. Missed pills, especially in phase 1, may increase ovulation risk. Advise use of backup contraception if pills are missed or if vomiting/diarrhea occurs. Monitor for venous thromboembolism risk, especially in smokers over 35 or those with migraine with aura. |
| Patient Advice | Take one pill daily at the same time, following the order on the pack. · If you miss a pill, refer to the package insert or consult your healthcare provider; use backup contraception. · Common side effects include nausea, breast tenderness, and spotting, which often improve after a few cycles. · Do not smoke while taking this medication, especially if over 35, due to increased risk of blood clots. · Inform your doctor if you experience severe headache, chest pain, leg pain, or vision changes. · This medication does not protect against HIV or other sexually transmitted infections. |