Comparative Pharmacology
Head-to-head clinical analysis: ORTHO TRI CYCLEN versus ORTHO NOVUM 1 35 21.
Peer-Reviewed Evidence
Head-to-head clinical analysis: ORTHO TRI CYCLEN versus ORTHO NOVUM 1 35 21.
ORTHO TRI-CYCLEN vs ORTHO-NOVUM 1/35-21
Head-to-head clinical comparison of therapeutic indices and safety profiles.
Combined estrogen-progestin oral contraceptive; suppresses gonadotropin release, inhibiting ovulation; increases cervical mucus viscosity and alters endometrial lining.
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 acne vulgaris, management of menstrual disorders
Prevention of pregnancyOral contraception
One tablet (norgestimate 0.180-0.215-0.250 mg/ethinyl estradiol 0.035 mg) orally once daily for 21 days, followed by 7 days of placebo or no tablets.
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 (terminal). Ethinyl estradiol: ~12-15 hours (terminal). Clinical context: Steady-state achieved within 5-7 days; contraceptive efficacy maintained with daily dosing.
Norethindrone: 7-9 hours (terminal); Ethinyl estradiol: 13-27 hours (terminal). At steady state, clinical contraceptive efficacy is maintained with daily dosing.
Ethinyl estradiol: primarily metabolized by CYP3A4; norgestimate: rapidly hydrolyzed to norelgestromin (active) then levonorgestrel, 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.
Norethindrone: 60-80% renal (as metabolites), 20-40% fecal. Ethinyl estradiol: ~40% renal, ~60% fecal. Biliary excretion contributes to fecal elimination.
Renal (approx. 40% as metabolites, <10% unchanged), fecal (approx. 60% as metabolites, primarily via bile).
Norethindrone: ~97% bound to albumin and SHBG. Ethinyl estradiol: ~98% bound to albumin.
Norethindrone: 61-77% bound, primarily to SHBG and albumin; Ethinyl estradiol: 97-98% bound, primarily to albumin.
Norethindrone: 3-4 L/kg (large distribution into tissues, including breast and reproductive tissues). Ethinyl estradiol: 2-3 L/kg (distributes widely).
Norethindrone: 4-5 L/kg; Ethinyl estradiol: 2-5 L/kg. Indicates extensive tissue distribution exceeding total body water.
Norethindrone: ~65% (oral). Ethinyl estradiol: ~40-45% (oral) due to first-pass metabolism.
Oral: Norethindrone 50-70%; Ethinyl estradiol 40-50% due to first-pass metabolism.
No dose adjustment required for mild to moderate renal impairment. Insufficient data for severe impairment (GFR <30 mL/min); use alternative contraception.
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 patients with acute hepatitis, cholestatic jaundice of pregnancy or prior OCP use, or severe cirrhosis (Child-Pugh C). Use with caution in Child-Pugh A/B; dose adjustment not defined but consider lower estrogen options.
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 in prepubertal children. Postmenarchal adolescents: same dosing as adults. Safety and efficacy not established in children <18 years.
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 after menopause. No specific geriatric dosing; contraindicated in postmenopausal women.
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 risk of serious cardiovascular events from combined hormonal contraceptive use. Risk increases with age and number of cigarettes smoked, especially in women over 35.
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.
["Thrombotic disorders (venous thromboembolism, stroke, myocardial infarction)","Hepatic neoplasia (benign/malignant)","Gallbladder disease","Hypertension","Carbohydrate/lipid effects","Hereditary angioedema","Chloasma","Retinal thrombosis","Depression"]
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.
["Thrombophlebitis or thromboembolic disorders","Cerebrovascular or coronary artery disease","Known or suspected breast carcinoma","Undiagnosed abnormal genital bleeding","Pregnancy","Active liver disease or benign/malignant liver tumors","Hypersensitivity to any component","Heavy smoking in women over 35"]
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 specific food restrictions. Grapefruit may slightly increase estrogen levels; avoid large amounts. Alcohol consumption may increase hepatic toxicity risk; limit to moderate intake.
Grapefruit and grapefruit juice may increase estrogen levels; avoid excessive consumption. No specific food restrictions; maintain consistent dietary habits to avoid fluctuations in absorption.
Contraindicated in pregnancy. First trimester: associated with cardiovascular defects and limb reduction defects. Second and third trimesters: no increased risk of major malformations, but may cause fetal harm due to hormonal effects; use only if clearly needed.
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.
Small amounts of ethinyl estradiol and norgestimate pass into breast milk; may reduce milk production and composition. M/P ratio not established. Generally avoided during breastfeeding; alternative contraception recommended.
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 dosing adjustments applicable; drug is contraindicated during pregnancy. If used inadvertently, discontinue immediately.
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
Contains norgestimate 0.180/0.215/0.250 mg and ethinyl estradiol 0.035 mg. Triphasic regimen mimics natural cycle. Monitor for breakthrough bleeding, especially during first 3 cycles. Use with caution in patients with migraine with aura, hypertension, or history of VTE. Effective for acne vulgaris (FDA-approved indication). Counsel that efficacy may be reduced with concurrent rifampin, certain anticonvulsants, and St. John's wort. Consider switching to monophasic pill if persistent breakthrough bleeding after 3 months.
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 for 21 days, then placebo pills for 7 days.If you miss a pill within 12 hours, take it as soon as remembered. If more than 12 hours late, use backup contraception (e.g., condoms) for 7 days.Do not smoke while taking this medication; smoking increases risk of blood clots and stroke, especially if over 35.Common side effects: spotting between periods, nausea, breast tenderness, headache. These often improve after a few cycles.Seek emergency medical attention for signs of blood clot: leg pain/swelling, sudden chest pain, difficulty breathing, severe headache, vision changes.This medication does not protect against HIV or other sexually transmitted infections.
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.