Comparative Pharmacology
Head-to-head clinical analysis: ORTHO TRI CYCLEN versus ORTHO NOVUM 1 50 21.
Peer-Reviewed Evidence
Head-to-head clinical analysis: ORTHO TRI CYCLEN versus ORTHO NOVUM 1 50 21.
ORTHO TRI-CYCLEN vs ORTHO-NOVUM 1/50 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 oral contraceptive consisting of mestranol (estrogen) and norethindrone (progestin). Mestranol is converted to ethinyl estradiol, which suppresses gonadotropin release (FSH, LH) from the pituitary, inhibiting ovulation. Norethindrone induces changes in cervical mucus (increasing viscosity) and endometrial lining, creating a hostile environment for sperm implantation.
FDA-approved: Prevention of pregnancyOff-label: Treatment of acne vulgaris, management of menstrual disorders
Prevention of pregnancy
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 tablet-free days. Each tablet contains 1 mg norethindrone and 50 mcg mestranol.
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: biphasic terminal half-life 7-9 hours for parent compound, 8-11 hours for metabolites; clinical steady-state achieved after 5-7 days.
Ethinyl estradiol: primarily metabolized by CYP3A4; norgestimate: rapidly hydrolyzed to norelgestromin (active) then levonorgestrel, metabolized by CYP3A4 and CYP2C9.
Mestranol is rapidly demethylated to ethinyl estradiol, primarily by CYP2C9 and CYP3A4. Ethinyl estradiol and norethindrone undergo hepatic metabolism via CYP3A4, with conjugation and excretion in urine and feces.
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 glucuronide and sulfate conjugates of norethindrone and mestranol/metabolites; fecal 20-30% via biliary elimination.
Norethindrone: ~97% bound to albumin and SHBG. Ethinyl estradiol: ~98% bound to albumin.
Norethindrone: 97-98% bound to albumin and sex hormone-binding globulin (SHBG); mestranol: 95-97% bound 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: Vd 3-4 L/kg (approx. 210-280 L for 70 kg adult), indicating extensive tissue distribution; mestranol: Vd 1.5-2 L/kg.
Norethindrone: ~65% (oral). Ethinyl estradiol: ~40-45% (oral) due to first-pass metabolism.
Norethindrone: oral bioavailability 40-60% due to first-pass metabolism; mestranol rapidly converted to ethinyl estradiol with oral bioavailability 40-50%.
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); use with caution.
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 Child-Pugh class B or C (moderate to severe hepatic impairment). For 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.
Not indicated for use before menarche. Post-menarche: same as adult dosing (one tablet daily for 21 days) after evaluating individual risk factors.
Not indicated for use after menopause. No specific geriatric dosing; contraindicated in postmenopausal women.
Not indicated for use in postmenopausal women due to increased risk of thrombotic events and lack of benefit.
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 the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, especially in women over 35, and with the 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 (e.g., DVT, PE) and cardiovascular events (MI, stroke).","Elevated blood pressure.","Increased risk of gallbladder disease.","Hepatic adenoma or hepatocellular carcinoma.","Glucose intolerance and adverse effects on lipid metabolism.","Chloasma (melasma) exacerbated by UV exposure.","Retinal thrombosis or other ocular effects.","Menstrual irregularities and amenorrhea.","Cervical cancer risk (HPV-related)."]
["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"]
["Known or suspected pregnancy.","Current or history of thrombophlebitis or thromboembolic disorders.","History of DVT or PE.","Cerebrovascular or coronary artery disease.","Known or suspected breast carcinoma or estrogen-dependent neoplasia.","Undiagnosed abnormal genital bleeding.","Cholestatic jaundice of pregnancy or jaundice with prior OC use.","Hepatic adenoma or carcinoma.","Known hypersensitivity to any component."]
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. However, grapefruit juice may increase estrogen levels, but clinically negligible. Avoid excessive alcohol as it may worsen liver metabolism.
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: Mestranol and norethindrone are associated with a slightly increased risk of congenital anomalies, particularly cardiovascular defects and limb reduction defects, although absolute risk is low. Second and third trimesters: Continued exposure may lead to fetal adrenal suppression, liver impairment, and pseudointersexuality in female fetuses due to androgenic effects of norethindrone. Overall, contraceptive use during pregnancy is contraindicated.
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; M/P ratio not established. May reduce milk production and quality, especially with high-dose estrogens. Use during lactation is generally not recommended, particularly in early postpartum. Consider non-hormonal contraception.
No dosing adjustments applicable; drug is contraindicated during pregnancy. If used inadvertently, discontinue immediately.
Contraindicated during pregnancy; no dose adjustments apply as it should be discontinued immediately if pregnancy occurs.
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 1/50 21 is a combination oral contraceptive containing 1 mg norethindrone and 50 mcg mestranol. It has higher estrogen content than modern pills, increasing thromboembolic risk. Counsel patients to avoid smoking, especially over age 35. Use as directed for 21 days on, 7 days off. Missed pills require backup contraception.
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 consecutive days, then none for 7 days.If you miss a pill, take it as soon as remembered; if more than 24 hours late, use backup contraception for 7 days.Do not smoke while taking this medication, especially if over 35, due to increased risk of blood clots.Common side effects include nausea, breast tenderness, and breakthrough bleeding, especially in the first few months.This pill does not protect against HIV or other sexually transmitted infections.