Comparative Pharmacology
Head-to-head clinical analysis: ORTHO TRI CYCLEN 28 versus ORTHO NOVUM 10 11 21.
Peer-Reviewed Evidence
Head-to-head clinical analysis: ORTHO TRI CYCLEN 28 versus ORTHO NOVUM 10 11 21.
ORTHO TRI-CYCLEN 28 vs ORTHO-NOVUM 10/11-21
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 norethindrone (progestin) and ethinyl estradiol (estrogen). Prevents ovulation primarily by suppressing gonadotropin release, including FSH and LH. Also increases cervical mucus viscosity, impeding sperm penetration, and alters endometrial structure, 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 pregnancyTreatment of moderate acne vulgaris in females ≥15 years of ageOral contraception with a biphasic hormone regimen providing a low-dose alternative
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 (10 mg norethindrone/0.035 mg ethinyl estradiol) orally once daily for 21 days, followed by 7 placebo days. Start on first Sunday after menstrual period begins or on day 1 of cycle.
None Documented
None Documented
Norethindrone: ~8 hours; Ethinyl estradiol: ~15 hours (biphasic, terminal: 15-20 hours). Steady-state achieved within 7-14 days.
Norethindrone: 7-8 hours (terminal); Ethinyl estradiol: 10-20 hours (terminal). Clinically, steady state reached within 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.
Norethindrone undergoes extensive first-pass metabolism in the liver via reduction and conjugation, primarily by CYP3A4. Ethinyl estradiol is metabolized by hydroxylation and conjugation, involving CYP3A4 and sulfate conjugation. Both undergo enterohepatic recirculation.
Renal: ~60% (metabolites); Fecal: ~40% (metabolites); unchanged drug <1%
Renal: ~50% (metabolites as glucuronide and sulfate conjugates); Fecal: ~30% (via bile); Urinary unchanged: <1%.
Norethindrone: ~97% (albumin, SHBG); Ethinyl estradiol: ~98% (albumin, SHBG).
Norethindrone: ~97% bound to albumin and SHBG; Ethinyl estradiol: ~98% bound to albumin (not SHBG).
Norethindrone: 3-4 L/kg; Ethinyl estradiol: 2-3 L/kg. Indicates extensive tissue distribution.
Norethindrone: ~2-4 L/kg; Ethinyl estradiol: ~2-3 L/kg; indicates extensive tissue distribution and binding.
Norethindrone: ~65% (first-pass metabolism); Ethinyl estradiol: ~45% (first-pass metabolism).
Oral: Norethindrone ~60-70% (first-pass metabolism); Ethinyl estradiol ~40-50% (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 specific dose adjustment recommended. Use with caution in patients with severe renal impairment; monitor for fluid retention.
Contraindicated in Child-Pugh class B and C (moderate to severe hepatic impairment). No data for Child-Pugh A; use with caution.
Contraindicated in severe hepatic disease (Child-Pugh class C). For mild to moderate impairment (Child-Pugh A or B): use only if benefits outweigh risks, as hormonal contraceptives may worsen cholestasis.
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. For postmenarchal adolescents: same dosing as adults (one tablet daily for 21 days, then 7 placebo). Regular menstrual cycles should be established before initiation.
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 after menopause. No specific dosing studies in elderly; estrogen-containing contraceptives are contraindicated in women over 35 who smoke or have cardiovascular risk factors.
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 contraceptives. Risk increases with age and heavy smoking (≥15 cigarettes/day). Women over 35 years old who smoke should not use this product.
["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., venous thrombosis, stroke, MI); discontinue if symptoms occur","Elevated blood pressure; monitor regularly","Hepatic neoplasia risk (benign and malignant); discontinue if jaundice or liver abnormalities","Cholestatic jaundice; caution in patients with history","Risk of retinal thrombosis; discontinue if unexplained vision loss","Altered glucose tolerance; caution in diabetics","Depression; discontinue if severe","Headache (including migraine); discontinue if new pattern or worsening","Breakthrough bleeding and spotting; rule out pregnancy if persistent","Gallbladder disease risk"]
["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","Cerebrovascular or coronary artery disease","Known or suspected breast carcinoma","Estrogen-dependent neoplasia (e.g., endometrial cancer)","Undiagnosed abnormal genital bleeding","Acute liver disease, hepatic adenoma, or impaired liver function","History of cholestatic jaundice with prior OC use","Age >35 years and smoking","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 clinically significant food interactions. However, grapefruit juice may increase ethinyl estradiol levels by inhibiting CYP3A4; avoid large amounts. Take with food if gastrointestinal upset occurs.
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: Increased risk of neural tube defects (OR 1.2-1.4), cardiovascular malformations (OR 1.1-1.3). Second/third trimester: No significant increase in major malformations; possible association with low birth weight, preterm delivery. Postnatal: No known long-term 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.
Excretion into breast milk minimal; estimated relative infant dose <1% of maternal weight-adjusted dose; M/P ratio not reported. American Academy of Pediatrics compatible with breastfeeding; avoid high-dose formulations.
No dose adjustment applicable; contraindicated in pregnancy. If exposure occurs, discontinue immediately. No pharmacokinetic data indicate safe use or dose modifications during pregnancy.
No dose adjustment recommended during pregnancy; drug should be discontinued as soon as pregnancy is detected. No pharmacokinetic studies indicating need for change.
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.
For ORTHO-NOVUM 10/11-21 (norethindrone/ethinyl estradiol), a biphasic oral contraceptive, patients must take the 10 white tablets (0.5 mg norethindrone, 35 mcg ethinyl estradiol) for 10 days, followed by 11 peach tablets (1 mg norethindrone, 35 mcg ethinyl estradiol) for 11 days. Missed pills increase breakthrough bleeding and pregnancy risk; if one pill missed, take as soon as remembered, next at regular time. If two consecutive pills missed, take two pills for two days and use backup contraception for 7 days. Advise about increased thromboembolic risk, especially in smokers over 35. Prescribe only after thorough medical history and blood pressure measurement.
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 the pills exactly as directed: white pills for 10 days, then peach pills for 11 days, followed by 7 placebo days.Use backup contraception (e.g., condoms) if you miss any pills, especially during the first week of a new pack.Smoking while on this pill increases risk of serious cardiovascular side effects; avoid smoking, especially if over 35 years old.Contact your doctor immediately if you experience severe leg pain, chest pain, shortness of breath, severe headache, or vision changes.Notify all healthcare providers that you are taking this medication before any surgery or prolonged immobility.This prescription does not protect against HIV or other sexually transmitted infections.