Comparative Pharmacology
Head-to-head clinical analysis: ORTHO TRI CYCLEN 28 versus ORTHO NOVUM 1 35 28.
Peer-Reviewed Evidence
Head-to-head clinical analysis: ORTHO TRI CYCLEN 28 versus ORTHO NOVUM 1 35 28.
ORTHO TRI-CYCLEN 28 vs ORTHO-NOVUM 1/35-28
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 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 moderate acne vulgaris in females ≥15 years of age who have no known contraindications and desire oral contraception
Prevention of pregnancy (FDA-approved)Treatment of acne (off-label)
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.
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; Ethinyl estradiol: ~15 hours (biphasic, terminal: 15-20 hours). Steady-state achieved within 7-14 days.
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 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.
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.
Renal: ~60% (metabolites); Fecal: ~40% (metabolites); unchanged drug <1%
Renal 50-60% as metabolites; fecal 30-40% via biliary elimination; <1% unchanged in urine.
Norethindrone: ~97% (albumin, SHBG); Ethinyl estradiol: ~98% (albumin, SHBG).
Norethindrone: ~97% (mainly SHBG and albumin); ethinyl estradiol: ~98% (albumin and SHBG, induces SHBG synthesis).
Norethindrone: 3-4 L/kg; Ethinyl estradiol: 2-3 L/kg. Indicates extensive tissue distribution.
Norethindrone: 3-4 L/kg; ethinyl estradiol: 2-4 L/kg. Large Vd indicates extensive tissue distribution and binding.
Norethindrone: ~65% (first-pass metabolism); Ethinyl estradiol: ~45% (first-pass metabolism).
Oral: Norethindrone ~50-70% (first-pass metabolism); ethinyl estradiol ~40-50% (first-pass metabolism, variable).
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. Contraindicated in severe renal impairment or acute renal failure due to potential fluid retention and hyperkalemia.
Contraindicated in Child-Pugh class B and C (moderate to severe hepatic impairment). No data for Child-Pugh A; use with caution.
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 for use before menarche. For postmenarchal adolescents, same dosing as adults. Safety and efficacy not established in pediatric patients under 18 years for contraception.
Use after menarche. Same dosing as adults: 1 tablet daily for 28 days. Not indicated for use before menarche.
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. In elderly reproductive-age women, same dosing as adults; consider increased risk of thromboembolic events and cardiovascular disease with age.
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 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.
["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), 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"]
["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 (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 significant food interactions. Grapefruit juice may slightly increase ethinyl estradiol levels but not clinically relevant. Maintain consistent dietary habits to avoid variability in absorption.
No significant food interactions. Grapefruit juice may increase estrogen levels slightly but not clinically relevant. Taking with food can reduce nausea.
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.
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.
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 in small amounts; no adverse effects reported in infants. M/P ratio not established. Use with caution; may reduce milk production.
No dose adjustment applicable; contraindicated in pregnancy. If exposure occurs, discontinue immediately. No pharmacokinetic data indicate safe use or dose modifications during pregnancy.
Contraindicated in pregnancy; no dose adjustment applicable as drug is discontinued.
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.
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, 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, 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.