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. |
| Molecular Weight | 144.21 |
| Action Class | Combination hormonal contraceptive (estrogen-progestin) |
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 | Contraindicated in first trimester due to risk of congenital malformations, particularly cardiovascular and neural tube defects. |
| 2nd trimester | Contraindicated; use associated with fetal harm including cranial and facial anomalies, cardiac defects, and developmental delays. |
| 3rd trimester | Contraindicated; may cause neonatal bleeding, hypoglycemia, and withdrawal symptoms. |
Clinical note
Comprehensive clinical and safety monograph for TRI-LO-MILI (TRI-LO-MILI).
| Placental transfer | Demonstrated; valproic acid and derivatives cross the placenta with cord blood levels approximately equal to maternal levels. |
| Breastfeeding | Excreted into breast milk; potential for serious adverse effects in nursing infants including bleeding, hypoglycemia, and developmental toxicity. Use is contraindicated during breastfeeding. |
■ 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.
| Common Effects | Nausea, Headache, Breast tenderness, Breakthrough bleeding or spotting, Weight changes, Mood changes, Acne |
| Serious Effects | Venous thromboembolism (deep vein thrombosis, pulmonary embolism), Arterial thromboembolism (myocardial infarction, stroke), Hypertension, Hepatic adenoma or hepatocellular carcinoma, Gallbladder disease, Thrombotic thrombocytopenic purpura (TTP) in patients with factor V Leiden mutation |
Pregnancy (all trimesters)BreastfeedingActive liver disease or significant hepatic dysfunctionKnown hypersensitivity to valproate derivativesUrea cycle disorders
| 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. |
Loading safety data…
| Lactation Rating | L5 (Contraindicated) |
| 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. |
| 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. |
| Food/Dietary | No significant food interactions. Grapefruit juice may slightly increase estrogen levels; avoid large quantities. May be taken with or without food. Maintain consistent dietary intake of folate-rich foods; some oral contraceptives may affect folate metabolism. |
| Clinical Pearls | Tri-Lo-Mili (norgestimate/ethinyl estradiol) is a triphasic oral contraceptive with varying hormone levels across three phases. Prescribe with a fixed dosing schedule; missed pills increase breakthrough bleeding risk. Be aware of increased venous thromboembolism risk, especially in smokers over 35. May reduce efficacy with enzyme-inducing drugs. Monitor for hypertension, hyperkalemia (due to drospirenone component if applicable - note: Tri-Lo-Mili contains norgestimate, not drospirenone). Consider alternative if patient has migraine with aura. |
| Patient Advice | Take one tablet daily at the same time each day. · If you miss a pill, follow the package instructions or consult your healthcare provider. · Use a backup contraceptive method (e.g., condoms) for the first 7 days of starting Tri-Lo-Mili. · Report signs of blood clots (leg pain, chest pain, sudden shortness of breath) or stroke (sudden severe headache, vision changes). · Do not smoke while taking this medication, especially if over 35 years old. · Inform your doctor about all medications, including antibiotics and herbal supplements (e.g., St. John's wort). |