Head-to-head clinical analysis & difference comparison: details on mechanism of action, dosing, half-life, interactions, and maternal-fetal safety.
NORTREL 0.5/35-28 vs ALYACEN 1/35
Clinician-reviewed, head-to-head comparison of mechanism, dosing, pharmacokinetics, and safety profiles.
Last clinically reviewed: July 2026 · OpiCalc Medical Review Team
Norethindrone and ethinyl estradiol are a combination hormonal contraceptive. Norethindrone suppresses gonadotropin release (FSH and LH) from the pituitary, inhibiting ovulation. Ethinyl estradiol stabilizes the endometrium and enhances the contraceptive effect by inhibiting gonadotropin secretion.
Combination hormonal contraceptive: ethinyl estradiol suppresses gonadotropin release via negative feedback on hypothalamic-pituitary axis; norethindrone induces progestational effects including cervical mucus thickening and endometrial changes, inhibiting ovulation and sperm penetration.
Prevention of pregnancy,Oral contraceptive (off-label: treatment of acne, abnormal uterine bleeding, dysmenorrhea)
Prevention of pregnancy
1 tablet orally once daily for 28 days (21 active tablets containing 0.5 mg norethindrone and 35 mcg ethinyl estradiol, followed by 7 placebo tablets).
One tablet (norethindrone 1 mg and ethinyl estradiol 35 mcg) orally once daily for 21 consecutive days, followed by 7 days of placebo or no tablets.
Norethindrone: 7.2-9.2 hours; Ethinyl estradiol: 13-27 hours. Clinical context: Steady state reached in 5-7 days; half-life supports once-daily dosing.
Norethindrone: 8-11 hours (terminal); ethinyl estradiol: 10-20 hours (terminal). The half-life supports once-daily dosing for oral contraceptive efficacy.
Norethindrone: primarily hepatic via reduction and sulfation; CYP3A4 involved. Ethinyl estradiol: hepatic via CYP3A4; undergoes first-pass metabolism and enterohepatic recirculation.
Ethinyl estradiol: primarily hepatic via CYP3A4; norethindrone: hepatic reduction and sulfate conjugation.
Renal: ~40% as metabolites; Biliary/Fecal: ~60% as metabolites; <5% unchanged.
Renal excretion of metabolites (primarily ethinyl estradiol and norethindrone conjugates) accounts for approximately 50-60% of elimination; fecal excretion accounts for 30-40%. Unchanged drug excretion is minimal (<5%).
Norethindrone: 61% bound to albumin, 36% to SHBG; Ethinyl estradiol: 97% bound to albumin, 2% free.
Norethindrone: 61% bound to albumin and SHBG; ethinyl estradiol: 97-98% bound to albumin.
Norethindrone: 3.6-4.3 L/kg; Ethinyl estradiol: 2.3-3.7 L/kg; indicates extensive tissue distribution.
Norethindrone: 3.8-4.5 L/kg; ethinyl estradiol: 2.0-4.0 L/kg. Large Vd indicates extensive tissue distribution.
Oral: Norethindrone ~64% (extensive first-pass metabolism); Ethinyl estradiol ~43-45% (due to first-pass and gut wall metabolism).
Oral: Norethindrone ~64%, ethinyl estradiol ~38-48% (due to first-pass metabolism).
No dose adjustment required for GFR ≥30 m L/min. Use is not recommended in patients with GFR <30 m L/min or on dialysis due to potential decrease in hormone clearance and increased risk of adverse effects.
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 electrolyte disturbances.
Contraindicated in patients with Child-Pugh class B or C hepatic impairment. For Child-Pugh class A, use is not recommended due to potential reduced hormone metabolism.
Contraindicated in patients with hepatic impairment, including Child-Pugh class B or C, due to impaired metabolism of estrogen and progestin. Not recommended in patients with active liver disease or history of liver tumors.
Not indicated for use in pediatric patients before menarche. For post-menarcheal adolescents, dosing is same as adults: 1 tablet orally once daily for 28 days.
Not indicated for use before menarche. For postmenarchal adolescents, same dosing as adults. Safety and efficacy established for contraception; weight-based dosing not applicable.
Not indicated for use in postmenopausal women. No specific dosing adjustments for elderly patients as the drug is not used in this population for contraception.
Not indicated for use after menopause due to lack of benefit and increased risks (e.g., cardiovascular, thromboembolic events). If used, monitor for fluid retention, hypertension, and glucose intolerance.
Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive use. The risk increases with age and heavy smoking (≥15 cigarettes per day) and is significant in women over 35 years old. Women over 35 who smoke should not use combined hormonal contraceptives.
Cigarette smoking increases risk of serious cardiovascular events from combined oral contraceptives. Risk increases with age and heavy smoking (≥15 cigarettes/day). Women over 35 who smoke should not use this product.
Increased risk of thrombotic disorders (venous thromboembolism, stroke, myocardial infarction),Hepatic neoplasia (benign and malignant),Elevated blood pressure,Gallbladder disease,Carbohydrate/lipid metabolism effects,Headache/migraine,Irregular bleeding,Ocular changes (retinal thrombosis),Depression,Hereditary angioedema,Pregnancy (discontinue if pregnancy occurs)
Thrombotic disorders (e.g., DVT, PE, stroke, MI),Cerebrovascular disease,Hepatic neoplasia,Gallbladder disease,Hypertension,Carbohydrate and lipid effects,Ocular lesions,Hereditary angioedema,Chloasma,Menstrual irregularities,Pregnancy exclusion prior to initiation
Known or suspected pregnancy,Current or history of venous thrombotic disease (deep vein thrombosis, pulmonary embolism),Cerebrovascular or coronary artery disease,Current or history of migraine with aura (if age ≥35),Breast cancer or other estrogen-sensitive neoplasia,Undiagnosed abnormal genital bleeding,Cholestatic jaundice of pregnancy or jaundice with prior oral contraceptive use,Active liver disease or benign/malignant liver tumors,Hypersensitivity to any component,Smoking cigarettes and age >35 years
Venous or arterial thrombotic/thromboembolic disease (current or history),Cerebrovascular disease,Coronary artery disease,Known or suspected breast cancer,Endometrial or other estrogen-dependent neoplasia,Undiagnosed abnormal genital bleeding,Cholestatic jaundice of pregnancy or jaundice with prior pill use,Hepatic adenoma or carcinoma,Known or suspected pregnancy,Hypersensitivity to any component,Smoking in women over 35
No specific food restrictions. Grapefruit juice may increase ethinyl estradiol levels; avoid large amounts. Alcohol may increase risk of liver toxicity; limit intake.
No significant food interactions. Grapefruit juice may increase estrogen levels, but clinically not a concern. Avoid excessive alcohol, which may impair liver function and increase estrogen exposure. Maintain a healthy diet, as weight gain is possible.
First trimester: No increased risk of major birth defects based on large cohort studies. Second and third trimesters: Associated with masculinization of female fetuses (clitoral hypertrophy, labial fusion) and possible altered pubertal development. Risk of pseudohermaphroditism is dose-dependent.
Pregnancy category X. Use of ALYACEN 1/35 (norethindrone/ethinyl estradiol) is contraindicated during pregnancy. First trimester: Increased risk of congenital anomalies, including cardiovascular defects and limb reduction defects. Second/third trimesters: Potential for urogenital abnormalities and feminization of male fetus. Exposure is associated with subsequent development of clear cell adenocarcinoma of vagina/cervix in female offspring (DES-related).
Norethindrone and ethinyl estradiol are excreted in breast milk. Estrogen components may reduce milk production. M/P ratio for norethindrone is approximately 0.7; ethinyl estradiol is <1. Use is generally not recommended during lactation.
Small amounts of contraceptive steroids and/or metabolites have been identified in breast milk. M/P ratio: Not specifically determined for this combination; ethinyl estradiol M/P ratio ~0.02-0.04. Use may reduce milk production and quality. Breastfeeding not recommended during use. Alternative contraception advised.
Contraindicated in pregnancy; no dose adjustments recommended. Discontinue immediately if pregnancy occurs.
Contraindicated in pregnancy; no dose adjustments applicable. Discontinue medication immediately upon pregnancy detection.
NORTREL 0.5/35-28 is a monophasic combined oral contraceptive containing 0.5 mg norethindrone and 35 mcg ethinyl estradiol. Administer daily at the same time. Breakthrough bleeding is common in the first 3-6 months. Monitor blood pressure at baseline and annually. Consider VTE risk in smokers over 35. Missed pill protocol: if one pill is missed, take as soon as remembered; if two or more, use backup contraception for 7 days.
ALYACEN 1/35 is a combination oral contraceptive containing ethinyl estradiol 35 mcg and norgestimate 1 mg. It is indicated for the prevention of pregnancy and for the treatment of moderate acne vulgaris in females ≥15 years of age who desire an oral contraceptive. Monitor for thromboembolic events, especially in smokers over 35 or those with migraine with aura. Use with caution in patients with liver impairment or history of cholestatic jaundice. The pill-free interval should not exceed 7 days; missed pills increase ovulation risk. Consider non-hormonal backup if vomiting or diarrhea occurs within 4 hours of dosing.
Take one pill daily at the same time, in the order shown on the blister pack.,If you miss a pill, follow the package insert instructions and use backup contraception if needed.,Common side effects include nausea, breast tenderness, and spotting between periods.,Do not smoke while taking this medication, especially if over 35 years old.,Report symptoms of blood clots, including leg pain/swelling, chest pain, or sudden shortness of breath.,This medication does not protect against HIV or other sexually transmitted infections.
Take one tablet daily at the same time each day; do not skip doses.,Use an additional non-hormonal contraceptive (e.g., condoms) if you miss a pill, have vomiting, or diarrhea.,Smoking while on this pill increases the risk of blood clots and stroke, especially if you are over 35.,Contact your healthcare provider immediately if you have chest pain, leg pain/swelling, sudden vision changes, or severe headache.,This medication does not protect against HIV or other sexually transmitted infections.,Store at room temperature, away from moisture and heat.
No interactions on record
No interactions on record
Explore head-to-head clinical comparisons of other medications in the same therapeutic classes.
Common clinical questions about NORTREL 0.5/35-28 vs ALYACEN 1/35, answered by our medical review team.
NORTREL 0.5/35-28 is a Oral Contraceptive that works by Norethindrone and ethinyl estradiol are a combination hormonal contraceptive. Norethindrone suppresses gonadotropin release (FSH and LH) from the pituitary, inhibiting ovulation. Ethinyl estradiol stabilizes the endometrium and enhances the contraceptive effect by inhibiting gonadotropin secretion.. ALYACEN 1/35 is a Oral Contraceptive that works by Combination hormonal contraceptive: ethinyl estradiol suppresses gonadotropin release via negative feedback on hypothalamic-pituitary axis; norethindrone induces progestational effects including cervical mucus thickening and endometrial changes, inhibiting ovulation and sperm penetration.. They differ in pharmacokinetic profiles, FDA-approved indications, and side effect profiles.
Potency comparisons between NORTREL 0.5/35-28 and ALYACEN 1/35 depend on the specific clinical indication. These are both Oral Contraceptive agents and are not directly interchangeable by dose. A physician or clinical pharmacist should guide any therapeutic switching decisions.
The standard adult dose of NORTREL 0.5/35-28 is: 1 tablet orally once daily for 28 days (21 active tablets containing 0.5 mg norethindrone and 35 mcg ethinyl estradiol, followed by 7 placebo tablets).. The standard adult dose of ALYACEN 1/35 is: One tablet (norethindrone 1 mg and ethinyl estradiol 35 mcg) orally once daily for 21 consecutive days, followed by 7 days of placebo or no tablets.. Dosing should always be individualized based on indication, renal and hepatic function, age, and other patient factors.
No direct drug-drug interaction has been formally documented between NORTREL 0.5/35-28 and ALYACEN 1/35 in current clinical databases. However, individual patient risk factors including other medications, organ function, and comorbidities should always be evaluated by a qualified healthcare provider.
The maternal-fetal safety profiles differ. NORTREL 0.5/35-28 is classified as Category C. First trimester: No increased risk of major birth defects based on large cohort studies. Second and third trimesters: Associated with masculinization of female fetuses (clitoral hy. ALYACEN 1/35 is classified as Category C. Pregnancy category X. Use of ALYACEN 1/35 (norethindrone/ethinyl estradiol) is contraindicated during pregnancy. First trimester: Increased risk of congenital anomalies, including . Always consult a maternal-fetal medicine specialist before taking either drug during pregnancy or lactation.