ORTHO TRI-CYCLEN 28
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ORTHO TRI-CYCLEN 28 (ORTHO TRI-CYCLEN 28).
Combination of ethinyl estradiol and norgestimate primarily suppresses gonadotropin (FSH and LH) secretion via negative feedback on the hypothalamic-pituitary-ovarian axis, inhibiting ovulation. Additionally, it increases cervical mucus viscosity and alters endometrial structure to impede fertilization and implantation.
| Metabolism | Ethinyl estradiol undergoes oxidative metabolism primarily via CYP3A4 and undergoes conjugation (glucuronidation and sulfation). Norgestimate is extensively metabolized to its active metabolite norelgestromin via first-pass hepatic (hydrolysis) and further to levonorgestrel; norelgestromin is metabolized by CYP3A4 and CYP2C9. |
| Excretion | Renal: ~60% (metabolites); Fecal: ~40% (metabolites); unchanged drug <1% |
| Half-life | Norethindrone: ~8 hours; Ethinyl estradiol: ~15 hours (biphasic, terminal: 15-20 hours). Steady-state achieved within 7-14 days. |
| Protein binding | Norethindrone: ~97% (albumin, SHBG); Ethinyl estradiol: ~98% (albumin, SHBG). |
| Volume of Distribution | Norethindrone: 3-4 L/kg; Ethinyl estradiol: 2-3 L/kg. Indicates extensive tissue distribution. |
| Bioavailability | Norethindrone: ~65% (first-pass metabolism); Ethinyl estradiol: ~45% (first-pass metabolism). |
| Onset of Action | Oral: Contraceptive effect begins after 7 days of continuous dosing; menstrual cycle regulation within 1-2 cycles. |
| Duration of Action | Oral: 24 hours (requires daily dosing for continuous contraception); withdrawal bleeding occurs during placebo week. |
One tablet daily for 28 days: 21 active tablets (norgestimate 0.180 mg/ethinyl estradiol 0.035 mg, norgestimate 0.215 mg/ethinyl estradiol 0.035 mg, norgestimate 0.250 mg/ethinyl estradiol 0.035 mg) followed by 7 inert tablets. Route: oral.
| Dosage form | TABLET |
| Renal impairment | No specific GFR-based dose adjustments established. Use with caution in severe renal impairment (GFR <30 mL/min) due to potential fluid retention and electrolyte disturbances. |
| Liver impairment | Contraindicated in Child-Pugh class B and C (moderate to severe hepatic impairment). No data for Child-Pugh A; use with caution. |
| Pediatric use | Not indicated for use before menarche. For postmenarchal adolescents, same dosing as adults. Safety and efficacy not established in pediatric patients under 18 years for contraception. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific dosing adjustments; risks of thromboembolic events outweigh benefits in women over 35 who smoke or have cardiovascular risk factors. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ORTHO TRI-CYCLEN 28 (ORTHO TRI-CYCLEN 28).
| Breastfeeding | Not recommended during breastfeeding. Combined hormonal contraceptives reduce milk production and nutrient content. Limited ethinyl estradiol and norgestimate transfer into breast milk; M/P ratio not well defined. Use alternative contraception. |
| Teratogenic Risk | Pregnancy category X. Contraindicated in pregnancy. First trimester: increased risk of neural tube defects, cardiovascular anomalies, and oral clefts. Second and third trimesters: association with fetal genital abnormalities (e.g., hypospadias in males, virilization of female fetuses). No safe use established. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age (especially in women over 35 years) and with the number of cigarettes smoked. Women who use combination hormonal contraceptives should be strongly advised not to smoke.
| Serious Effects |
["Known or suspected pregnancy","Current or past thrombophlebitis or thromboembolic disorders (e.g., deep vein thrombosis, pulmonary embolism)","Current or past arterial thromboembolic disease (e.g., stroke, myocardial infarction)","Cerebrovascular disease","Known or suspected breast carcinoma or other estrogen- or progestin-sensitive cancer","Undiagnosed abnormal genital bleeding","Cholestatic jaundice of pregnancy or jaundice with prior pill use","Hepatic adenomas or carcinomas","Known liver disease or impaired liver function, including active viral hepatitis","Uncontrolled hypertension (>160/100 mmHg)","Diabetes with vascular involvement","Headaches with focal neurological symptoms (e.g., migraine with aura)","Major surgery with prolonged immobilization","Smoking in women over 35 years","Hypersensitivity to any component of the product"]
| Precautions | ["Thromboembolic disorders: increased risk of venous thromboembolism and arterial thrombosis","Cigarette smoking increases cardiovascular risk","Hypertension: may cause or worsen hypertension","Gallbladder disease: increased risk of gallbladder disease","Hepatic tumors: risk of hepatic adenomas (rare) and possible hepatocellular carcinoma","Carbohydrate and lipid effects: may affect glucose tolerance and lipid profile","Ocular lesions: retinal thrombosis (discontinue if unexplained vision loss occurs)","Depression: may precipitate or worsen depression","Bleeding irregularities: breakthrough bleeding and spotting common","Hereditary angioedema: may exacerbate symptoms"] |
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| Fetal Monitoring | Perform pregnancy test prior to initiation. Monitor liver function tests, blood pressure, and signs of thromboembolism. If unintentional use during pregnancy, monitor fetal growth and anatomy via ultrasound. |
| Fertility Effects | Reversible suppression of ovulation. After discontinuation, return to fertility may be delayed by up to 3 months. No long-term impact on fertility. |