Comparative Pharmacology
Head-to-head clinical analysis: ORTHO TRI CYCLEN versus ORTHO NOVUM 1 35 28.
Peer-Reviewed Evidence
Head-to-head clinical analysis: ORTHO TRI CYCLEN versus ORTHO NOVUM 1 35 28.
ORTHO TRI-CYCLEN vs ORTHO-NOVUM 1/35-28
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 oral contraceptive containing ethinyl estradiol and norethindrone. Inhibits ovulation by suppressing gonadotropin release (FSH and LH) from the pituitary; increases viscosity of cervical mucus, impeding sperm penetration; alters endometrial lining, reducing implantation likelihood.
FDA-approved: Prevention of pregnancyOff-label: Treatment of acne vulgaris, management of menstrual disorders
Prevention of pregnancy (FDA-approved)Treatment of acne (off-label)
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.
1 tablet (norethindrone 1 mg / ethinyl estradiol 35 mcg) orally once daily for 28 consecutive days. Placebo tablets on days 22-28 if included.
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: 5-14 hrs (terminal); ethinyl estradiol: 10-24 hrs. Steady-state achieved within 5-7 days; terminal half-life supports once-daily dosing.
Ethinyl estradiol: primarily metabolized by CYP3A4; norgestimate: rapidly hydrolyzed to norelgestromin (active) then levonorgestrel, metabolized by CYP3A4 and CYP2C9.
Ethinyl estradiol primarily metabolized via CYP3A4, with phase II conjugation (glucuronidation and sulfation). Norethindrone metabolized via reduction and conjugation, primarily as glucuronide conjugates. Both undergo enterohepatic recirculation.
Norethindrone: 60-80% renal (as metabolites), 20-40% fecal. Ethinyl estradiol: ~40% renal, ~60% fecal. Biliary excretion contributes to fecal elimination.
Renal 50-60% as metabolites; fecal 30-40% via biliary elimination; <1% unchanged in urine.
Norethindrone: ~97% bound to albumin and SHBG. Ethinyl estradiol: ~98% bound to albumin.
Norethindrone: ~97% (mainly SHBG and albumin); ethinyl estradiol: ~98% (albumin and SHBG, induces SHBG synthesis).
Norethindrone: 3-4 L/kg (large distribution into tissues, including breast and reproductive tissues). Ethinyl estradiol: 2-3 L/kg (distributes widely).
Norethindrone: 3-4 L/kg; ethinyl estradiol: 2-4 L/kg. Large Vd indicates extensive tissue distribution and binding.
Norethindrone: ~65% (oral). Ethinyl estradiol: ~40-45% (oral) due to first-pass metabolism.
Oral: Norethindrone ~50-70% (first-pass metabolism); ethinyl estradiol ~40-50% (first-pass metabolism, variable).
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. Contraindicated in severe renal impairment or acute renal failure due to potential fluid retention and hyperkalemia.
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 acute hepatic disease, hepatocellular carcinoma, and Child-Pugh class C cirrhosis. Use with caution in Child-Pugh class A or B; no specific dose adjustment established, but reduced metabolism may increase estrogen exposure.
Not indicated in prepubertal children. Postmenarchal adolescents: same dosing as adults. Safety and efficacy not established in children <18 years.
Use after menarche. Same dosing as adults: 1 tablet daily for 28 days. Not indicated for use before menarche.
Not indicated for use after menopause. No specific geriatric dosing; contraindicated in postmenopausal women.
Not indicated for postmenopausal women. In elderly reproductive-age women, same dosing as adults; consider increased risk of thromboembolic events and cardiovascular disease with age.
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 oral contraceptive use. Risk increases with age (especially in women over 35) and with heavy smoking (≥15 cigarettes/day). Women taking oral 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), especially in smokers, obese, or hypertensive patients","Risk of myocardial infarction and stroke","Hepatic neoplasia (benign and malignant) reported","Increased risk of gallbladder disease","Elevated blood pressure","Carbohydrate and lipid metabolic effects","Ocular lesions (retinal thrombosis) reported","Headache including migraine","Uterine bleeding irregularities","Depression","Discontinue if jaundice, visual disturbances, or thromboembolic symptoms occur"]
["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 (current or history)","Cerebrovascular or coronary artery disease (current or history)","Known or suspected breast carcinoma","Known or suspected estrogen-dependent neoplasia","Undiagnosed abnormal genital bleeding","Pregnancy (known or suspected)","Benign or malignant liver tumors (current or history)","Active liver disease or impaired liver function","Hypersensitivity to any component","Heavy smoking (≥15 cigarettes/day) in women over 35"]
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.
No significant food interactions. Grapefruit juice may increase estrogen levels slightly but not clinically relevant. Taking with food can reduce nausea.
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.
First trimester: No increased risk of major birth defects based on large epidemiological studies. Second/third trimester: Exposure may increase risk of intrauterine growth restriction, preterm birth, and neonatal complications such as respiratory distress syndrome. Postnatal: May cause hormonal withdrawal effects in neonate.
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 in small amounts; no adverse effects reported in infants. M/P ratio not established. Use with caution; may reduce milk production.
No dosing adjustments applicable; drug is contraindicated during pregnancy. If used inadvertently, discontinue immediately.
Contraindicated in pregnancy; no dose adjustment applicable as drug is discontinued.
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.
Ortho-Novum 1/35-28 is a monophasic oral contraceptive containing 1 mg norethindrone and 35 mcg ethinyl estradiol. Use 28-day packs with 21 active pills and 7 placebos. Counsel patients to take at same time daily to maintain hormone levels. Missed pill management: if missed one active pill, take as soon as remembered; if missed two or more, use backup contraception for 7 days. Consider drug interactions with rifampin, certain anticonvulsants, and St. John's wort.
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, preferably after an evening meal to reduce nausea.The 28-day pack includes 21 hormone pills (white) and 7 reminder pills (green). Start a new pack the day after finishing the previous one.If you miss a pill, refer to the package insert for instructions. Use backup contraception (e.g., condoms) if needed.Common side effects include nausea, breast tenderness, spotting, and weight changes; these often improve after 2-3 cycles.This medication does not protect against sexually transmitted infections (STIs). Use condoms for STI prevention.Smoking increases risk of serious cardiovascular side effects; women over 35 who smoke should not use this pill.Report signs of blood clots: leg pain/swelling, chest pain, shortness of breath, sudden severe headache, vision changes.