Comparative Pharmacology
Head-to-head clinical analysis: ORTHO TRI CYCLEN 28 versus ORTHO NOVUM 1 50 21.
Peer-Reviewed Evidence
Head-to-head clinical analysis: ORTHO TRI CYCLEN 28 versus ORTHO NOVUM 1 50 21.
ORTHO TRI-CYCLEN 28 vs ORTHO-NOVUM 1/50 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 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 moderate acne vulgaris in females ≥15 years of age who have no known contraindications and desire oral contraception
Prevention of pregnancy
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 tablet-free days. Each tablet contains 1 mg norethindrone and 50 mcg mestranol.
None Documented
None Documented
Norethindrone: ~8 hours; Ethinyl estradiol: ~15 hours (biphasic, terminal: 15-20 hours). Steady-state achieved within 7-14 days.
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 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.
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.
Renal: ~60% (metabolites); Fecal: ~40% (metabolites); unchanged drug <1%
Renal 50-60% as glucuronide and sulfate conjugates of norethindrone and mestranol/metabolites; fecal 20-30% via biliary elimination.
Norethindrone: ~97% (albumin, SHBG); Ethinyl estradiol: ~98% (albumin, SHBG).
Norethindrone: 97-98% bound to albumin and sex hormone-binding globulin (SHBG); mestranol: 95-97% bound to albumin.
Norethindrone: 3-4 L/kg; Ethinyl estradiol: 2-3 L/kg. Indicates extensive tissue distribution.
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% (first-pass metabolism); Ethinyl estradiol: ~45% (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 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. Insufficient data for severe renal impairment (GFR < 30 mL/min); use with caution.
Contraindicated in Child-Pugh class B and C (moderate to severe hepatic impairment). No data for Child-Pugh A; use with caution.
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 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. Post-menarche: same as adult dosing (one tablet daily for 21 days) after evaluating individual risk factors.
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 use in postmenopausal women due to increased risk of thrombotic events and lack of benefit.
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. 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.
["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 (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)."]
["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"]
["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 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. However, grapefruit juice may increase estrogen levels, but clinically negligible. Avoid excessive alcohol as it may worsen liver metabolism.
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: 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.
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; 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 dose adjustment applicable; contraindicated in pregnancy. If exposure occurs, discontinue immediately. No pharmacokinetic data indicate safe use or dose modifications during pregnancy.
Contraindicated during pregnancy; no dose adjustments apply as it should be discontinued immediately if pregnancy occurs.
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 1/50 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, 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 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.