Comparative Pharmacology
Head-to-head clinical analysis: ORTHO TRI CYCLEN 21 versus ORTHO NOVUM 1 35 28.
Peer-Reviewed Evidence
Head-to-head clinical analysis: ORTHO TRI CYCLEN 21 versus ORTHO NOVUM 1 35 28.
ORTHO TRI-CYCLEN 21 vs ORTHO-NOVUM 1/35-28
Head-to-head clinical comparison of therapeutic indices and safety profiles.
Combination estrogen-progestin oral contraceptive; suppresses gonadotropin secretion (FSH, LH) via negative feedback, preventing ovulation; increases cervical mucus viscosity and alters endometrial receptivity.
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.
Prevention of pregnancy
Prevention of pregnancy (FDA-approved)Treatment of acne (off-label)
One tablet daily for 21 days, followed by 7 days of placebo, then repeat. Each tablet contains 0.180 mg norgestimate and 0.035 mg ethinyl estradiol (days 1–7), 0.215 mg/0.035 mg (days 8–14), and 0.250 mg/0.035 mg (days 15–21). Oral route.
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
Norgestimate: ~24 hours (terminal); ethinyl estradiol: ~17 hours (terminal). Steady-state achieved within 5-7 days; clinical significance: missed doses may increase contraceptive failure risk.
Norethindrone: 5-14 hrs (terminal); ethinyl estradiol: 10-24 hrs. Steady-state achieved within 5-7 days; terminal half-life supports once-daily dosing.
Norgestimate: hydrolyzed to norelgestromin and norgestrel; metabolized by CYP3A4, CYP2C9, and CYP2C19. Ethinyl estradiol: metabolized by CYP3A4 and undergoes glucuronidation.
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: ~70% (metabolites, primarily glucuronide and sulfate conjugates of norgestimate and ethinyl estradiol); Fecal: ~30% (biliary elimination of unchanged drug and metabolites).
Renal 50-60% as metabolites; fecal 30-40% via biliary elimination; <1% unchanged in urine.
Norgestimate: ~99% bound to albumin and SHBG; ethinyl estradiol: ~98% bound to albumin; norethindrone (active metabolite) binds with similar high affinity.
Norethindrone: ~97% (mainly SHBG and albumin); ethinyl estradiol: ~98% (albumin and SHBG, induces SHBG synthesis).
Norgestimate: Vd ~6-8 L/kg; ethinyl estradiol: Vd ~3-5 L/kg. Large Vd indicates extensive tissue distribution including breast, uterine, and hepatic tissues; clinical relevance: potential for drug interactions (e.g., enzyme inducers).
Norethindrone: 3-4 L/kg; ethinyl estradiol: 2-4 L/kg. Large Vd indicates extensive tissue distribution and binding.
Oral: Norgestimate ~75% (first-pass metabolism limits bioavailability); ethinyl estradiol ~40-60% (substantial first-pass effect).
Oral: Norethindrone ~50-70% (first-pass metabolism); ethinyl estradiol ~40-50% (first-pass metabolism, variable).
No specific dose adjustment is provided in manufacturer labeling; use with caution in patients with renal impairment. GFR-based adjustments are not established.
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 hepatic disease or hepatocellular carcinoma. Child-Pugh class B or C: contraindicated. Child-Pugh class A: use with caution, no specific dose adjustment defined.
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.
Safety and efficacy established in postmenarchal females; dosing is same as adult: one tablet daily for 21 days. Weight-based dosing not applicable.
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 considerations available.
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 combination oral contraceptives (COCs). Women over 35 who smoke should not use COCs.
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 (e.g., thrombophlebitis, pulmonary embolism, stroke, myocardial infarction)","Hepatic disease (including hepatic adenoma or carcinoma)","Hypertension","Gallbladder disease","Carbohydrate/lipid metabolism disturbances","Headache (including migraine with focal symptoms)","Uterine bleeding irregularities"]
["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 history of thromboembolic disorders (e.g., DVT, PE)","Cerebrovascular or coronary artery disease","Known or suspected breast cancer or other estrogen-sensitive neoplasia","Undiagnosed abnormal genital bleeding","Hepatic adenoma or carcinoma, or active liver disease","Hypersensitivity to any component","Smoking in women over 35 years","Uncontrolled hypertension","Diabetes with vascular involvement","Migraine with aura if >35 years","Major surgery with prolonged immobilization"]
["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; however, grapefruit juice may increase estrogen levels (minor interaction). Avoid St. John's wort, which can reduce contraceptive efficacy.
No significant food interactions. Grapefruit juice may increase estrogen levels slightly but not clinically relevant. Taking with food can reduce nausea.
First trimester: Risk of congenital anomalies (limb defects, neural tube defects) based on case reports; overall risk low. Second/third trimester: Possible increased risk of intrauterine growth restriction and preterm birth. Postnatal: Potential for jaundice and transient hormonal effects in neonates.
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.
Contraindicated in breastfeeding due to estrogens reducing milk production and quality. Limited data; M/P ratio not established. Alternative methods preferred.
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 adjustments needed as drug is contraindicated during pregnancy. Discontinue immediately upon confirmed pregnancy; pharmacokinetic changes not applicable.
Contraindicated in pregnancy; no dose adjustment applicable as drug is discontinued.
Category C
Category C
ORTHO TRI-CYCLEN 21 contains norgestimate and ethinyl estradiol; it is a triphasic oral contraceptive with varying hormone doses across 21 active pills. Its progestin component has low androgenicity, making it suitable for patients with acne or hirsutism. Monitor for thromboembolic risk, especially in smokers over 35. Missed pill management: if one active pill is missed, take it as soon as remembered and continue; if two or more are missed, use backup contraception and consider emergency contraception.
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 7 placebo pills.Use backup contraception (e.g., condoms) for the first 7 days of initial use.Common side effects: nausea, breast tenderness, breakthrough bleeding; these often improve after 2-3 cycles.Report signs of blood clots: leg pain/swelling, chest pain, sudden shortness of breath, severe headache.Smoking increases blood clot risk; do not smoke while using this medication.If severe vomiting or diarrhea occurs within 4 hours after taking a pill, consider it missed and follow missed pill instructions.
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.