TRI-LO-MILI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRI-LO-MILI (TRI-LO-MILI).
Combination oral contraceptive: ethinyl estradiol suppresses gonadotropin release via negative feedback on the hypothalamic-pituitary axis; norgestimate binds to progesterone receptors, inhibiting ovulation and altering cervical mucus and endometrial receptivity.
| Metabolism | Ethinyl estradiol: primarily metabolized by CYP3A4 via hydroxylation; undergoes glucuronidation and sulfation. Norgestimate: rapidly hydrolyzed to norelgestromin and levonorgestrel; norelgestromin further metabolized to levonorgestrel; both undergo hydroxylation and conjugation, primarily by CYP3A4. |
| Excretion | Renal: approximately 50% as metabolites; biliary/fecal: approximately 40% as metabolites; 10% unchanged in urine. |
| Half-life | Terminal elimination half-life: 20-24 hours; allows once-daily dosing for contraceptive efficacy. |
| Protein binding | Norgestimate: 99% bound to albumin and SHBG; ethinyl estradiol: 97% bound to albumin. |
| Volume of Distribution | Norgestimate: approximately 2.5 L/kg; ethinyl estradiol: approximately 1.5 L/kg; indicates moderate tissue distribution. |
| Bioavailability | Oral: norgestimate ~90%; ethinyl estradiol ~40% (due to first-pass metabolism). |
| Onset of Action | Oral: 7 days for full contraceptive effect; immediate if started on first day of menses. |
| Duration of Action | Contraceptive protection: 24 hours per dose; requires daily dosing without missing pills; no missed-pill window for 7 days after last active pill. |
One tablet orally once daily for 21 days, followed by 7 days of placebo.
| Dosage form | TABLET |
| Renal impairment | No dosage adjustment required for mild to moderate renal impairment. Contraindicated in severe renal impairment (GFR <30 mL/min) or acute renal failure. |
| Liver impairment | Contraindicated in acute or chronic hepatic disease, including Child-Pugh Class A, B, or C. No dose adjustment possible. |
| Pediatric use | Not indicated for use before menarche. For post-menarchal adolescents: same as adult dosing. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific geriatric dosage adjustment defined due to lack of indication. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TRI-LO-MILI (TRI-LO-MILI).
| Breastfeeding | Excreted in human milk; may reduce milk production and affect infant. M/P ratio not established. Use in breastfeeding is not recommended, especially in early postpartum period due to potential estrogenic effects on infant and milk supply. |
| Teratogenic Risk | Pregnancy Category X. Use is contraindicated in pregnancy. Tri-Lo-Mili (norgestimate/ethinyl estradiol) is associated with increased risk of fetal harm, including cardiovascular defects and limb reduction defects, when taken inadvertently during early pregnancy. First trimester exposure carries highest risk; second and third trimester use associated with potential for other adverse outcomes, including neonatal withdrawal. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptive use. Risk increases with age (especially >35 years) and with number of cigarettes smoked. Women who use combination oral contraceptives should be strongly advised not to smoke.
| Serious Effects |
Current or past thrombosis (e.g., DVT, PE), cerebrovascular or coronary artery disease, known thrombophilia, history of myocardial infarction or stroke, uncontrolled hypertension, diabetes with vascular involvement, headache with focal neurological symptoms (e.g., migraine with aura if age >35), major surgery with prolonged immobilization, known or suspected pregnancy, breastfeeding, liver disease (including tumors), undiagnosed abnormal genital bleeding, known or suspected estrogen-dependent neoplasia, age >35 and smoking ≥15 cigarettes/day, hypersensitivity to any component.
| Precautions | Thrombotic and cardiovascular events (e.g., stroke, MI, thromboembolism), hepatic disease (including liver tumors), hypertension, gallbladder disease, carbohydrate/lipid metabolic effects, headache, irregular bleeding, depression, fluid retention, hereditary angioedema, chloasma, retinal thrombosis, use in pregnancy and postpartum. |
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| Fetal Monitoring | If accidental exposure during pregnancy, discontinue immediately and perform fetal ultrasound to assess for anomalies. No routine monitoring recommended in non-pregnant women; monitor blood pressure, liver function, and glucose annually. In pregnancy, no indication for use. |
| Fertility Effects | Does not appear to cause permanent impairment of fertility, but transient delay in return to fertility may occur after discontinuation. Long-term fertility effects not established. |