Head-to-head clinical analysis & difference comparison: details on mechanism of action, dosing, half-life, interactions, and maternal-fetal safety.
DEMULEN 1/35-21 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
Combination oral contraceptive containing ethinyl estradiol (estrogen) and ethynodiol diacetate (progestin). Inhibits gonadotropin secretion (FSH, LH) via negative feedback on hypothalamic-pituitary axis, suppressing ovulation. Additionally, thickens cervical mucus and alters endometrial receptivity.
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,Treatment of moderate acne vulgaris in women at least 15 years old who have achieved menarche and are seeking contraception,Oral contraceptive for women over 35 who smoke (off-label: not recommended due to increased cardiovascular risk)
Prevention of pregnancy
One tablet orally once daily for 21 days, followed by 7 days off. Each tablet contains 1 mg ethynodiol diacetate and 35 mcg ethinyl estradiol.
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.
Ethinyl estradiol: 13±3 hours (terminal); norethindrone: 8±3 hours. Steady-state achieved after ~5 days.
Norethindrone: 8-11 hours (terminal); ethinyl estradiol: 10-20 hours (terminal). The half-life supports once-daily dosing for oral contraceptive efficacy.
Ethinyl estradiol: primarily metabolized by CYP3A4 hydroxylation and conjugation; undergoes enterohepatic recirculation. Ethynodiol diacetate: rapidly deacetylated to norethindrone, which is metabolized by CYP3A4 and CYP2C9; undergoes reduction, hydroxylation, and conjugation.
Ethinyl estradiol: primarily hepatic via CYP3A4; norethindrone: hepatic reduction and sulfate conjugation.
Renal (primarily as glucuronide and sulfate conjugates): ~60%; fecal: ~40%
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%).
Ethinyl estradiol: 97–98% bound to albumin; norethindrone: 93–97% bound to albumin and SHBG
Norethindrone: 61% bound to albumin and SHBG; ethinyl estradiol: 97-98% bound to albumin.
Ethinyl estradiol: 2.5–4 L/kg; norethindrone: 3.5–5 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.
Ethinyl estradiol: ~45% (first-pass metabolism); norethindrone: ~65% (first-pass metabolism). Oral administration only.
Oral: Norethindrone ~64%, ethinyl estradiol ~38-48% (due to first-pass metabolism).
No dose adjustment required for renal impairment. However, caution in severe renal impairment due to potential fluid retention.
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 Child-Pugh class B and C (moderate to severe hepatic impairment). Use with caution in mild impairment (Child-Pugh A) with monitoring.
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 before menarche. Post-menarche: use same dosing as adults; monitor for bone health and growth.
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 due to lack of efficacy and increased thromboembolic risk.
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 risk of serious cardiovascular events from combination oral contraceptive use. Risk increases with age and heavy smoking (≥15 cigarettes/day). Women over 35 who smoke should not use this product.
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 thromboembolic disorders (e.g., stroke, DVT, PE),Increased risk of myocardial infarction, especially in smokers and women with hypertension or hyperlipidemia,Hepatic neoplasia (benign/malignant),Gallbladder disease,Hypertension,Carbohydrate and lipid metabolism changes,Ocular lesions (e.g., retinal thrombosis),Depression,Fluid retention,Irregular bleeding,Possible reduced efficacy with enzyme-inducing drugs (e.g., rifampin, anticonvulsants),Chloasma,Pregnancy (should be ruled out before use)
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
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,Known or suspected pregnancy,Benign or malignant liver tumor (current or history),Severe hepatic impairment or acute liver disease,Hypersensitivity to any component,Age over 35 and smoking (≥15 cigarettes/day),Uncontrolled hypertension (systolic ≥160 mm Hg or diastolic ≥100 mm Hg),Diabetes with vascular involvement,Migraine with focal aura (if age ≥35),Major surgery with prolonged immobilization
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 significant food interactions. Grapefruit juice may slightly increase estrogen levels but not clinically relevant. Avoid St. John's Wort as it reduces contraceptive efficacy. No dietary restrictions.
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: increased risk of cardiovascular defects (RR ~1.3) and oral clefts (RR ~1.1) with exposure; second and third trimesters: no proven association with major malformations, but may cause masculinization of female genitalia if high doses of progestins (ethynodiol diacetate is a weak progestin, risk low). Postnatal: potential for neonatal jaundice (due to estrogen).
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).
Excreted in breast milk in small amounts (estrogen and progestin levels ~1% of maternal dose; M/P ratio not well defined). May reduce milk quality and quantity; use only if benefits outweigh risks, preferably after weaning.
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.
No dose adjustments; contraindicated during pregnancy due to fetal risks. If used inadvertently, discontinue immediately.
Contraindicated in pregnancy; no dose adjustments applicable. Discontinue medication immediately upon pregnancy detection.
Demulen 1/35-21 (ethinyl estradiol 35 mcg, ethynodiol diacetate 1 mg) is a monophasic combined oral contraceptive. It has lower estrogen dose than many older pills but still carries thromboembolic risk. Advise patients to take at same time daily. Missed pill protocols: if missed >12 hours, take pill ASAP and continue; if missed 2 or more pills, use backup contraception for 7 days. Consider non-contraceptive benefits: improved cycle regularity, reduced dysmenorrhea, decreased acne. Monitor blood pressure and liver function. Contraindications: history of DVT/PE, active liver disease, breast cancer, pregnancy, migraine with aura. Smoking increases thromboembolic risk significantly, especially in women >35.
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 for 21 days, then no pills for 7 days; you will have withdrawal bleeding during the free week.,If you miss a pill by less than 12 hours, take it immediately and continue on schedule. If more than 12 hours, take the missed pill and use backup contraception (condoms) for the next 7 days.,Common side effects include nausea, headache, breast tenderness, breakthrough bleeding, and mood changes; these often improve after the first few months.,Seek medical help for symptoms of blood clots: sudden leg pain/swelling, chest pain, shortness of breath, sudden severe headache or vision changes.,Do not smoke while taking this medication; smoking increases risk of serious cardiovascular side effects, especially if over 35.,This pill does not protect against sexually transmitted infections; use condoms for STI prevention.
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 DEMULEN 1/35-21 vs ALYACEN 1/35, answered by our medical review team.
DEMULEN 1/35-21 is a Oral Contraceptive that works by Combination oral contraceptive containing ethinyl estradiol (estrogen) and ethynodiol diacetate (progestin). Inhibits gonadotropin secretion (FSH, LH) via negative feedback on hypothalamic-pituitary axis, suppressing ovulation. Additionally, thickens cervical mucus and alters endometrial receptivity.. 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 DEMULEN 1/35-21 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 DEMULEN 1/35-21 is: One tablet orally once daily for 21 days, followed by 7 days off. Each tablet contains 1 mg ethynodiol diacetate and 35 mcg ethinyl estradiol.. 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 DEMULEN 1/35-21 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. DEMULEN 1/35-21 is classified as Category C. First trimester: increased risk of cardiovascular defects (RR ~1.3) and oral clefts (RR ~1.1) with exposure; second and third trimesters: no proven association with major malformat. 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.