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. |
| Molecular Weight | Ethinyl estradiol: 296.4 Da; Levonorgestrel: 312.45 Da; average for components: ~304 Da |
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 | Contraindicated due to risk of teratogenicity (limb defects, cardiovascular anomalies) from hormonal exposure during organogenesis. Non-hormonal contraception should be used. |
| 2nd trimester | Contraindicated due to potential adverse effects on fetal development and pregnancy outcomes. Risk of fetal genital abnormalities and other endocrine effects. |
| 3rd trimester | Contraindicated due to risk of fetal harm, including withdrawal bleeding, and potential long-term endocrine effects. No safe use established. |
Clinical note
Comprehensive clinical and safety monograph for TRIPHASIL-21 (TRIPHASIL-21).
| Placental transfer | Yes, ethinyl estradiol and levonorgestrel readily cross the placenta. Evidence from studies shows detectable levels in fetal serum and amniotic fluid. |
| Breastfeeding | Combined oral contraceptives like Triphasil-21 are generally not recommended during breastfeeding as estrogen can reduce milk production and quality. Progestin-only methods are preferred. Small amounts of hormones may pass into milk but are unlikely to cause harm in older infants. Weigh benefits against risks. |
■ 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 |
Pregnancy or suspected pregnancyCurrent or history of thromboembolic disorders (e.g., deep vein thrombosis, pulmonary embolism)Cerebrovascular or coronary artery disease (e.g., stroke, MI)Known or suspected breast cancer or estrogen-dependent neoplasiaUndiagnosed abnormal genital bleedingHepatic adenomas or carcinomas, or active liver disease (e.g., hepatitis, cirrhosis)Uncontrolled hypertension (BP >160/100 mmHg)Diabetes with vascular involvementMigraine with aura or focal neurological symptomsMajor surgery with prolonged immobilizationKnown hypersensitivity to any component
| 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 |
Loading safety data…
| Lactation Rating | L4 (Possibly Hazardous) – Limited data, potential for adverse effects in nursing infant. |
| 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. |
| 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. |
| Food/Dietary |
| No specific food interactions are known. Grapefruit juice may slightly increase ethinyl estradiol levels but is not considered clinically significant. Maintain a balanced diet; avoid excessive alcohol consumption. |
| Clinical Pearls | Triphasil-21 is a triphasic oral contraceptive with varying hormone doses across three phases. The tablets are color-coded: brown (6 tablets, 50 mcg levonorgestrel/30 mcg ethinyl estradiol), white (5 tablets, 75 mcg levonorgestrel/40 mcg ethinyl estradiol), and yellow (10 tablets, 125 mcg levonorgestrel/30 mcg ethinyl estradiol). The last week consists of placebo tablets. Breakthrough bleeding is most common during the first few cycles. Missed pills require specific instructions depending on the week. Estrogen-containing contraceptives increase risk of venous thromboembolism, especially in smokers over 35. Efficacy of the contraceptive may be reduced by concurrent use of hepatic enzyme inducers like rifampin. |
| Patient Advice | Take one pill at the same time each day, starting on the first day of your menstrual period. · The pill pack contains 21 active pills followed by 7 placebo pills; you will have a withdrawal bleed during the placebo week. · If you miss one active pill, take it as soon as you remember and continue the pack; no backup contraception is needed. · If you miss two active pills in week 1 or 2, take two pills on the day you remember and two the next day, then continue; use backup contraception for 7 days. · If you miss two pills in week 3, or miss three or more pills at any time, discard the current pack and start a new pack the same day; use backup contraception for 7 days. · Missed pills increase the risk of ovulation and pregnancy. · Common side effects include nausea, breast tenderness, and breakthrough bleeding; these often improve after a few cycles. · Smoking increases the risk of serious cardiovascular side effects, especially in women over 35. · Use backup contraception (e.g., condoms) if starting any new medication, especially antibiotics or anticonvulsants, and ask your healthcare provider about interactions. · Seek emergency medical attention if you experience severe headache, chest pain, leg pain or swelling, sudden shortness of breath, or visual disturbances. |