Comparative Pharmacology
Head-to-head clinical analysis: ORTHO TRI CYCLEN 28 versus ORTHO NOVUM 1 35 21.
Peer-Reviewed Evidence
Head-to-head clinical analysis: ORTHO TRI CYCLEN 28 versus ORTHO NOVUM 1 35 21.
ORTHO TRI-CYCLEN 28 vs ORTHO-NOVUM 1/35-21
Head-to-head clinical comparison of therapeutic indices and safety profiles.
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.
Combination estrogen-progestin contraceptive; suppresses gonadotropin (FSH and LH) secretion via negative feedback, inhibiting ovulation. Increases cervical mucus viscosity and alters endometrial lining, impairing sperm penetration and implantation.
FDA-approved: Prevention of pregnancyOff-label: Treatment of moderate acne vulgaris in females ≥15 years of age who have no known contraindications and desire oral contraception
Prevention of pregnancyOral contraception
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.
One tablet orally once daily for 21 days, followed by 7 placebo tablets. Each tablet contains 1 mg norethindrone and 0.035 mg ethinyl estradiol.
None Documented
None Documented
Norethindrone: ~8 hours; Ethinyl estradiol: ~15 hours (biphasic, terminal: 15-20 hours). Steady-state achieved within 7-14 days.
Norethindrone: 7-9 hours (terminal); Ethinyl estradiol: 13-27 hours (terminal). At steady state, clinical contraceptive efficacy is maintained with daily dosing.
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.
Norethindrone: primarily hepatic metabolism via reduction and sulfation, with CYP3A4 involvement. Ethinyl estradiol: hepatic metabolism via CYP3A4, also undergoes conjugation (glucuronidation and sulfation). Undergoes enterohepatic recirculation.
Renal: ~60% (metabolites); Fecal: ~40% (metabolites); unchanged drug <1%
Renal (approx. 40% as metabolites, <10% unchanged), fecal (approx. 60% as metabolites, primarily via bile).
Norethindrone: ~97% (albumin, SHBG); Ethinyl estradiol: ~98% (albumin, SHBG).
Norethindrone: 61-77% bound, primarily to SHBG and albumin; Ethinyl estradiol: 97-98% bound, primarily to albumin.
Norethindrone: 3-4 L/kg; Ethinyl estradiol: 2-3 L/kg. Indicates extensive tissue distribution.
Norethindrone: 4-5 L/kg; Ethinyl estradiol: 2-5 L/kg. Indicates extensive tissue distribution exceeding total body water.
Norethindrone: ~65% (first-pass metabolism); Ethinyl estradiol: ~45% (first-pass metabolism).
Oral: Norethindrone 50-70%; Ethinyl estradiol 40-50% due to first-pass metabolism.
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.
No dose adjustment required for mild to moderate renal impairment. Insufficient data for severe renal impairment (GFR <30 mL/min/1.73 m²); use caution and monitor for adverse effects.
Contraindicated in Child-Pugh class B and C (moderate to severe hepatic impairment). No data for Child-Pugh A; use with caution.
Contraindicated in severe hepatic disease (Child-Pugh class C). For moderate impairment (Child-Pugh class B), avoid use as oral contraceptives may exacerbate liver dysfunction. Mild impairment (Child-Pugh class A): use with caution and monitor liver function.
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.
Safety and efficacy not established in premenarchal girls. Dosing for adolescents post-menarche is same as adults; use with caution and monitor for thromboembolic risk.
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.
Not indicated for postmenopausal women due to absence of ovulation. In perimenopausal women, use lowest effective dose; monitor cardiovascular risk and bone density.
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.
Cigarette smoking increases risk of serious cardiovascular events from combination oral contraceptive use (e.g., myocardial infarction, thromboembolism, stroke). Risk increases with age (>35 years) and number of cigarettes smoked. Women who use combination hormonal contraceptives should be strongly advised not to smoke.
["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"]
Increased risk of thromboembolic disorders (venous and arterial), stroke, myocardial infarction; hepatic neoplasia; gallbladder disease; hypertension; carbohydrate/lipid effects; ocular lesions (retinal thrombosis); headache/migraine; breakthrough bleeding/spotting; depression; fluid retention; hereditary angioedema; chloasma; liver function impairment.
["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"]
Thrombophlebitis or thromboembolic disorders; cerebral vascular or coronary artery disease; known or suspected pregnancy; undiagnosed abnormal genital bleeding; known/suspected breast cancer; estrogen-dependent neoplasia; benign/malignant liver tumor (active); known or suspected pregnancy; hypersensitivity to any component; smoking in women >35 years; uncontrolled hypertension; diabetes with vascular disease; migraines with focal aura; major surgery with prolonged immobilization.
Data Pending Review
Data Pending Review
No significant food interactions. Grapefruit juice may slightly increase ethinyl estradiol levels but not clinically relevant. Maintain consistent dietary habits to avoid variability in absorption.
Grapefruit and grapefruit juice may increase estrogen levels; avoid excessive consumption. No specific food restrictions; maintain consistent dietary habits to avoid fluctuations in absorption.
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 Pregnancy Category X; contraindicated in pregnancy. First trimester: increased risk of neural tube defects, cardiovascular anomalies, and limb reduction defects due to progestin component. Second/third trimesters: feminization of male fetus, potential for congenital anomalies, and possible long-term reproductive effects. No safe use in pregnancy.
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.
Excreted in breast milk; may reduce milk production and quality. M/P ratio not established for this combination; progestin-only contraceptives preferred. Use only if benefits outweigh risks; monitor infant for jaundice or growth delay.
No dose adjustment applicable; contraindicated in pregnancy. If exposure occurs, discontinue immediately. No pharmacokinetic data indicate safe use or dose modifications during pregnancy.
Discontinue immediately if pregnancy suspected or confirmed. No dose adjustment is recommended as drug is contraindicated. Pharmacokinetic changes in pregnancy (increased clearance) are not applicable for a contraindicated drug.
Category C
Category C
Ortho Tri-Cyclen 28 is a triphasic oral contraceptive containing norgestimate and ethinyl estradiol. The triphasic dosing mimics natural hormonal fluctuations and may reduce breakthrough bleeding. It is also FDA-approved for moderate acne vulgaris in women at least 15 years old who desire contraception. Monitor for thromboembolic events, especially in smokers over 35. CYP3A4 inducers (e.g., rifampin, carbamazepine) may reduce efficacy. Advise backup contraception during concurrent antibiotic use.
Contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Monophasic combination oral contraceptive. Risk of venous thromboembolism is dose-dependent; use lowest effective estrogen dose. CYP3A4 inducers (e.g., rifampin, anticonvulsants) may reduce efficacy. Prescribe for cycle control and contraception. Monitor blood pressure at baseline and follow-up. Avoid in smokers over 35 and those with migraine with aura.
Take one pill daily at the same time, preferably after a meal.The 28-day pack has 21 active pills and 7 placebo pills; always start a new pack immediately after finishing the previous one.If you miss a pill, check the package insert: take missed pill as soon as remembered and use backup contraception.Common side effects include nausea, breast tenderness, and breakthrough bleeding; these often improve after 3 months.Seek medical attention for severe headache, vision changes, leg pain, or shortness of breath (thrombosis symptoms).Do not smoke while taking this medication, as it increases risk of blood clots and stroke.This pill does not protect against sexually transmitted infections (STIs).
Take one pill daily at the same time for 21 days, then none for 7 days.Use backup contraception (e.g., condoms) if you miss a pill or start late.Common side effects include nausea, breast tenderness, and breakthrough bleeding.Seek emergency care for severe leg pain, chest pain, sudden severe headache, or vision changes.Do not smoke while taking this medication, especially if over 35.Notify your doctor if you develop jaundice, depression, or unexplained weight gain.This medication does not protect against HIV or other sexually transmitted infections.