TRIPHASIL-21
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRIPHASIL-21 (TRIPHASIL-21).
Combination of ethinyl estradiol and levonorgestrel suppresses gonadotropin release, inhibiting ovulation; alters cervical mucus to impair sperm penetration and endometrial receptivity.
| Metabolism | Ethinyl estradiol undergoes first-pass metabolism via CYP3A4 in liver and intestinal mucosa; also undergoes conjugation and enterohepatic circulation. Levonorgestrel is metabolized primarily by CYP3A4 and undergoes reduction and conjugation. |
| Excretion | Renal: 30-50% (ethinyl estradiol and levonorgestrel metabolites as glucuronide and sulfate conjugates). Fecal: 30-50% (biliary excretion of unconjugated metabolites). Unchanged drug: negligible. |
| Half-life | Levonorgestrel: 10-45 hours (terminal, biphasic); ethinyl estradiol: 10-27 hours (terminal, triphasic). Clinical context: Steady state reached after 7-14 days with daily dosing. |
| Protein binding | Levonorgestrel: 97-99% bound to sex hormone-binding globulin (SHBG) and albumin; ethinyl estradiol: 98-99% bound to albumin and SHBG (inducible). |
| Volume of Distribution | Levonorgestrel: 1.8-2.1 L/kg (extensive distribution into tissues including breast); ethinyl estradiol: 2.5-4.0 L/kg (large Vd due to lipophilicity and tissue binding). |
| Bioavailability | Oral: Levonorgestrel ~100% (high, minimal first-pass); ethinyl estradiol ~40-60% (due to first-pass metabolism and presystemic conjugation). |
| Onset of Action | Oral: Inhibition of ovulation achieved within 7 days of consistent daily dosing (peak contraceptive efficacy requires 7 days of use). |
| Duration of Action | Contraceptive protection persists for 24 hours per daily dose. Missed dose increases pregnancy risk; backup contraception needed if >12 hours late. |
One tablet orally daily for 21 days, followed by 7 drug-free days. Each tablet contains levonorgestrel 0.05 mg and ethinyl estradiol 0.03 mg (days 1-6), levonorgestrel 0.075 mg and ethinyl estradiol 0.04 mg (days 7-11), and levonorgestrel 0.125 mg and ethinyl estradiol 0.03 mg (days 12-21).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required in mild-to-moderate renal impairment. Use is contraindicated in severe renal disease or acute renal failure due to potential fluid retention and hyperkalemia. |
| Liver impairment | Contraindicated in acute or chronic hepatocellular disease, including Child-Pugh A, B, or C cirrhosis, and in liver tumors. Use is contraindicated in any hepatic impairment due to altered steroid metabolism. |
| Pediatric use | Not indicated for use in pediatric patients before menarche. Post-menarche, use the same dosing as adults. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific dosing adjustments in elderly, as use is contraindicated after menopause due to increased risk of thromboembolic events, myocardial infarction, and stroke. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TRIPHASIL-21 (TRIPHASIL-21).
| Breastfeeding | Combined oral contraceptives (COCs) like Triphasil-21 can reduce milk production and quality. Levonorgestrel and ethinyl estradiol are excreted into breast milk in small amounts (levonorgestrel M/P ratio approximately 0.3-0.5; ethinyl estradiol M/P ratio approximately 0.02). Use is generally not recommended during breastfeeding, especially in the first 6 months postpartum or in women with established lactation. Progestin-only contraceptives are preferred if hormonal contraception is desired. |
| Teratogenic Risk | Triphasil-21 (levonorgestrel/ethinyl estradiol) is contraindicated in pregnancy. First trimester exposure carries no known increased risk of major birth defects, but postfertilization effects may include cardiovascular anomalies and limb defects. Second and third trimester exposure is associated with an increased risk of fetal genital abnormalities (e.g., hypospadias) and possible long-term reproductive tract changes in female fetuses. Use during pregnancy is not indicated. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combined oral contraceptives. Risk increases with age and heavy smoking (≥15 cigarettes/day). Women over 35 who smoke should not use this product.
| Serious Effects |
["History of or current venous thromboembolism","Known thrombophilic disorders","Cerebrovascular or coronary artery disease","Valvular heart disease with complications","Uncontrolled hypertension","Diabetes with vascular involvement","Headaches with focal neurological symptoms","Breast cancer or other estrogen-sensitive cancer","Hepatic tumors or liver disease","Undiagnosed abnormal uterine bleeding","Known or suspected pregnancy","Age ≥35 and smoking ≥15 cigarettes/day"]
| Precautions | ["Increased risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE)","Risk of myocardial infarction and stroke, especially in smokers over 35","Hepatic neoplasia risk","Gallbladder disease","Elevated blood pressure","Carbohydrate and lipid metabolism effects","Ocular lesions (retinal thrombosis)","Headache/migraine exacerbation","Irregular bleeding","Depression"] |
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| Fetal Monitoring | If inadvertently used during pregnancy, monitor fetal growth via ultrasound and assess for potential anomalies. No specific monitoring is required if discontinued upon pregnancy confirmation. In lactating women, monitor infant for jaundice, weight gain, and potential hormonal effects. No routine maternal laboratory monitoring is required beyond standard contraceptive counseling. |
| Fertility Effects | Triphasil-21 suppresses ovulation and may cause transient menstrual irregularities upon discontinuation, but does not cause permanent infertility. Return to fertility is typically immediate after cessation of use. Long-term use is not associated with reduced fertility. |