DEMULEN 1/50-21
Clinical safety rating
cautionComprehensive clinical and safety monograph for DEMULEN 1/50-21 (DEMULEN 1/50-21).
DEMULEN 1/50-21 is a combined oral contraceptive containing ethinyl estradiol and ethynodiol diacetate. Ethinyl estradiol and progestins inhibit gonadotropin release (FSH and LH) from the pituitary, suppressing ovulation. Progestins also increase cervical mucus viscosity and alter endometrial receptivity, impeding sperm penetration and implantation.
| Metabolism | Ethinyl estradiol undergoes first-pass metabolism in the gut wall and liver, with hydroxylation by CYP3A4 and conjugation via glucuronidation and sulfation. Ethynodiol diacetate is rapidly deacetylated to norethindrone, which is metabolized by reduction and conjugation, with CYP3A4 as a minor pathway. |
| Excretion | Renal (approx. 50% as metabolites, <1% unchanged), fecal (approx. 40%, largely as ethinylestradiol conjugates), biliary (minor, enterohepatic recirculation of ethinylestradiol) |
| Half-life | Ethinylestradiol: 13 ± 3 h (biphasic; terminal phase used for dosing interval). Clinical context: steady-state achieved after ~3 days; missed dose may reduce contraceptive efficacy if >36 h. |
| Protein binding | Ethinylestradiol: 97-98% bound to serum albumin (primarily) and SHBG; ethynodiol diacetate: >95% bound to albumin and SHBG. |
| Volume of Distribution | Ethinylestradiol: 2.8-4.3 L/kg (extensive tissue distribution, including breast and reproductive tissues); ethynodiol: 1.5-2.0 L/kg. |
| Bioavailability | Oral: Ethinylestradiol 38-48% (first-pass metabolism); ethynodiol diacetate ~60% (rapid hydrolysis to active norethindrone). |
| Onset of Action | Oral: Contraceptive effect begins after 7 days of consistent dosing; ovulation suppression achieved by day 10-14 of first cycle if started Day 1. |
| Duration of Action | Contraceptive protection persists for 24 h per daily dose; after last dose, ovulation suppression continues for 7 days; return of fertility expected within 1-3 months. |
| Molecular Weight | 384.5 |
1 tablet (ethinyl estradiol 50 mcg, norethindrone 1 mg) orally once daily for 21 days, followed by 7 days off.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild-moderate renal impairment. Avoid use in severe renal impairment or dialysis due to potential fluid retention and electrolyte disturbances. |
| Liver impairment | Contraindicated in acute or chronic hepatic dysfunction, including Child-Pugh class A, B, or C. Use in mild hepatic impairment not recommended. |
| Pediatric use | Not indicated for use before menarche. For post-menarcheal adolescents, same dosing as adults. Safety and efficacy established in post-pubertal females. |
| Geriatric use | Not indicated after menopause. Risk of thromboembolic events outweighs benefits in women over 35 who smoke or have cardiovascular risk factors. |
| 1st trimester | Avoid use during first trimester; increased risk of cardiovascular and limb defects. Ethinyl estradiol/ethynodiol diacetate is pregnancy category X. |
| 2nd trimester | Contraindicated; risk of fetal harm, including potential virilization of female fetuses and other adverse effects. |
| 3rd trimester | Contraindicated; risk of fetal harm and potential adverse effects on fetal development. |
Clinical note
Comprehensive clinical and safety monograph for DEMULEN 1/50-21 (DEMULEN 1/50-21).
| Placental transfer | Crosses placenta; ethinyl estradiol and progestins are known to transfer to fetal circulation. |
| Breastfeeding | Excreted in breast milk in small amounts; may reduce milk production and quality. Use only if benefits outweigh risks, considering alternative contraception. |
| Lactation Rating | L3 - Moderately Safe |
| Teratogenic Risk | First trimester: Use contraindicated due to increased risk of congenital anomalies, particularly cardiovascular defects and limb reduction defects, associated with sex hormones. Second and third trimesters: Avoid due to risk of fetal harm, including masculinization of female fetus with progestins; also associated with increased risk of neonatal jaundice and liver dysfunction. |
| Fetal Monitoring | Monitor maternal blood pressure, blood glucose, and liver function regularly. If inadvertently exposed during pregnancy, fetal ultrasound for anatomic survey should be considered. |
| Fertility Effects | Demulen 1/50-21 suppresses ovulation via inhibition of gonadotropin release. Upon discontinuation, return of fertility is usually prompt; no permanent adverse effects on fertility have been documented. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events from oral contraceptive use. This risk increases with age and with the number of cigarettes smoked, and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
| Serious Effects |
Known or suspected pregnancyBreast cancer (current or history)Estrogen-dependent neoplasiaThrombophlebitis or thromboembolic disordersCerebrovascular or coronary artery diseaseUndiagnosed abnormal genital bleedingKnown hypersensitivity to any componentHepatic adenoma or carcinoma (current or history)Severe hepatic impairment or diseaseSmoking in women over 35 yearsMigraine with focal neurological symptomsSystemic lupus erythematosus with antiphospholipid antibodiesUncontrolled hypertension
| Precautions | Increased risk of thrombotic disorders (venous thromboembolism, stroke, myocardial infarction), Cigarette smoking increases cardiovascular risk, especially in women over 35, Increased risk of hypertension, gallbladder disease, and hepatic neoplasia, Risk of retinal thrombosis; discontinue if unexplained vision loss occurs, May cause fluid retention; use with caution in conditions affected by fluid retention, May induce cholestatic jaundice; discontinue if jaundice develops, May cause carbohydrate and lipid metabolism changes |
| Food/Dietary | No specific food interactions. Oral contraceptives may increase caffeine levels; limit caffeine intake if side effects like jitteriness occur. Grapefruit and grapefruit juice do not significantly affect this medication. |
| Clinical Pearls | DEMULEN 1/50-21 is a monophasic oral contraceptive containing ethinyl estradiol 50 mcg and ethynodiol diacetate 1 mg. Use with caution in patients over 35 who smoke due to increased cardiovascular risk. Monitor for breakthrough bleeding, especially in the first three cycles. Consider drug interactions with rifampin, anticonvulsants, and broad-spectrum antibiotics. Administer at the same time daily to maintain efficacy. The 21-day regimen requires a 7-day pill-free interval. Instruct to start on first day of menses or first Sunday after onset. |
| Patient Advice | Take one tablet daily at the same time, starting on the first day of your menstrual period or the first Sunday after your period begins. · Swallow tablet whole with water, with or without food. · After finishing all 21 tablets, wait 7 days before starting a new pack. You will have a withdrawal bleed during this time. · If you miss a tablet by less than 12 hours, take it immediately. If more than 12 hours, take the missed tablet and use backup contraception for 7 days. · Seek emergency medical care for symptoms of blood clots (sudden severe headache, chest pain, shortness of breath, leg pain/swelling), stroke (sudden numbness/weakness, slurred speech), or liver problems (yellowing skin/eyes, dark urine). · Avoid smoking while taking this medication, especially if over age 35, due to increased risk of cardiovascular events. · Inform your healthcare provider about all other medications (including over-the-counter drugs, herbal supplements like St. John's Wort) as they may reduce contraceptive efficacy. · This medication does not protect against HIV or other sexually transmitted infections. |
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