Comparative Pharmacology
Head-to-head clinical analysis: ORTHO TRI CYCLEN 28 versus ORTHO NOVUM 2 21.
Peer-Reviewed Evidence
Head-to-head clinical analysis: ORTHO TRI CYCLEN 28 versus ORTHO NOVUM 2 21.
ORTHO TRI-CYCLEN 28 vs ORTHO-NOVUM 2-21
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 of estrogen (ethinyl estradiol) and progestin (norethindrone) inhibits ovulation via negative feedback on the hypothalamic-pituitary-ovarian axis, suppressing gonadotropin release. Additionally, induces changes in cervical mucus and endometrium.
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 in women who elect to use oral contraceptivesTreatment of moderate acne vulgaris in females at least 15 years of age who have no known contraindications and have achieved menarche
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.
One tablet orally once daily for 21 days followed by 7 days off. Each tablet contains norethindrone 2 mg and ethinyl estradiol 0.1 mg.
None Documented
None Documented
Norethindrone: ~8 hours; Ethinyl estradiol: ~15 hours (biphasic, terminal: 15-20 hours). Steady-state achieved within 7-14 days.
Norethindrone: terminal half-life 5-12 hours; ethinyl estradiol: terminal half-life 7-20 hours (enterohepatic recirculation may prolong effect). Steady-state achieved after 5-7 days.
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 is metabolized primarily via CYP3A4, with contributions from CYP2C9 and CYP2C19. Norethindrone is metabolized via CYP3A4 and reduction pathways.
Renal: ~60% (metabolites); Fecal: ~40% (metabolites); unchanged drug <1%
Renal (approx. 60% as metabolites), fecal (approx. 40% as metabolites). Norethindrone and ethinyl estradiol are extensively metabolized; less than 5% excreted unchanged in urine.
Norethindrone: ~97% (albumin, SHBG); Ethinyl estradiol: ~98% (albumin, SHBG).
Norethindrone: ~60% bound to albumin, ~1.5% to SHBG; ethinyl estradiol: ~97% bound to albumin (not to SHBG).
Norethindrone: 3-4 L/kg; Ethinyl estradiol: 2-3 L/kg. Indicates extensive tissue distribution.
Vd for norethindrone: ~3.1±0.5 L/kg; for ethinyl estradiol: ~3.5–4.5 L/kg. Indicates extensive tissue distribution.
Norethindrone: ~65% (first-pass metabolism); Ethinyl estradiol: ~45% (first-pass metabolism).
Oral: norethindrone ~64% (first-pass metabolism reduces it); ethinyl estradiol ~38-48% (high first-pass metabolism).
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 dosage adjustment required for mild to moderate renal impairment. For severe renal impairment (GFR <30 mL/min) or dialysis, use is not recommended due to potential fluid retention and hypertension.
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 or chronic hepatocellular disease with abnormal liver function, including Child-Pugh class B or C. Adjustment not applicable in mild hepatic impairment (Child-Pugh class A) but use caution and monitor.
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.
Not indicated for use before menarche. After menarche, dosing is same as adult (one tablet daily for 21 days, then 7 days off). Weight-based guidelines are not established.
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. No specific geriatric dosing adjustments have been studied.
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 the risk of serious cardiovascular events from combination oral contraceptive use. Risk increases with age (especially in women over 35) and with heavy smoking (≥15 cigarettes/day). Women who use 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"]
["Thrombotic events (venous and arterial)","Cardiovascular risks in smokers over 35","Hepatic neoplasia","Hypertension","Gallbladder disease","Carbohydrate/lipid metabolism effects","Ocular lesions (retinal thrombosis)","Reduced efficacy with hepatic enzyme inducers"]
["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","Known or suspected pregnancy","Undiagnosed abnormal genital bleeding","Known or suspected breast cancer or estrogen-dependent neoplasia","Hepatic adenoma or carcinoma (current or history)","Jaundice or liver disease (acute or chronic)","Hypersensitivity to any component","Smoking in women over 35 (<15 cigarettes/day is relative; >15 is absolute)"]
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 specific food restrictions; grapefruit juice may alter estrogen metabolism but clinical significance is unclear. Maintain consistent diet to avoid GI upset. Avoid excessive alcohol intake.
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.
Category X: Contraindicated in pregnancy. First trimester: Increased risk of cardiovascular and limb reduction defects. Second and third trimesters: Associated with feminization of male fetuses and potential for other teratogenic effects.
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.
Contraindicated during breastfeeding due to potential for reduced milk production and excretion of estrogen/progestin into breast milk. M/P ratio: Not established.
No dose adjustment applicable; contraindicated in pregnancy. If exposure occurs, discontinue immediately. No pharmacokinetic data indicate safe use or dose modifications during pregnancy.
No dosing adjustments applicable as drug is contraindicated in pregnancy. Pharmacokinetic changes in pregnancy (e.g., increased hepatic metabolism, volume of distribution) are not relevant due to contraindication.
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.
Monitor for thromboembolic events, especially in smokers over 35. Counsel about missed dose protocol: take as soon as remembered, use backup contraception if >12 hours late. Caution with hepatic enzyme inducers (e.g., rifampin, anticonvulsants) reducing efficacy. Check BP at baseline and periodically. Consider VTE risk with obesity or immobilization. Not for use in pregnancy or breastfeeding.
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 tablet daily at the same time, even if not sexually active.If you miss a dose, take it as soon as you remember; if more than 12 hours late, use backup contraception for 7 days.Smoking increases risk of serious cardiovascular side effects, especially in women over 35.Notify your doctor if you experience leg pain/swelling, chest pain, shortness of breath, severe headache, or vision changes.This medication does not protect against HIV or other STDs.Inform all healthcare providers that you are taking this drug.