DEMULEN 1/35-21
Clinical safety rating
cautionComprehensive clinical and safety monograph for DEMULEN 1/35-21 (DEMULEN 1/35-21).
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.
| Metabolism | 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. |
| Excretion | Renal (primarily as glucuronide and sulfate conjugates): ~60%; fecal: ~40% |
| Half-life | Ethinyl estradiol: 13±3 hours (terminal); norethindrone: 8±3 hours. Steady-state achieved after ~5 days. |
| Protein binding | Ethinyl estradiol: 97–98% bound to albumin; norethindrone: 93–97% bound to albumin and SHBG |
| Volume of Distribution | Ethinyl estradiol: 2.5–4 L/kg; norethindrone: 3.5–5 L/kg. Indicates extensive tissue distribution. |
| Bioavailability | Ethinyl estradiol: ~45% (first-pass metabolism); norethindrone: ~65% (first-pass metabolism). Oral administration only. |
| Onset of Action | Oral contraception: inhibition of ovulation occurs within 1–2 days of first dose; full contraceptive effect may require 7 days of continuous dosing. |
| Duration of Action | The contraceptive effect persists as long as daily dosing is maintained. After discontinuation, ovulation may resume within 2–4 weeks, but return of fertility can occur in the first cycle. |
| Molecular Weight | Ethinyl estradiol: 296.4 Da; Ethynodiol diacetate: 384.5 Da; combination drug product. |
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.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for renal impairment. However, caution in severe renal impairment due to potential fluid retention. |
| Liver impairment | Contraindicated in Child-Pugh class B and C (moderate to severe hepatic impairment). Use with caution in mild impairment (Child-Pugh A) with monitoring. |
| Pediatric use | Not indicated for use before menarche. Post-menarche: use same dosing as adults; monitor for bone health and growth. |
| Geriatric use | Not indicated for use in postmenopausal women due to lack of efficacy and increased thromboembolic risk. |
| 1st trimester | Contraindicated due to risk of oral clefts and cardiovascular defects; estrogen/progestin combination increases risk of thromboembolism. |
| 2nd trimester | Contraindicated due to potential adverse effects on fetal development and increased risk of thromboembolic events during pregnancy. |
| 3rd trimester | Contraindicated due to possible feminization of male fetuses and other hormonal effects; avoid use in pregnancy. |
Clinical note
Comprehensive clinical and safety monograph for DEMULEN 1/35-21 (DEMULEN 1/35-21).
| Placental transfer | Ethinyl estradiol and ethynodiol diacetate cross the placenta; degree is significant with fetal exposure. |
| Breastfeeding | Excreted in breast milk in small amounts; may reduce milk production and quality; use only if clearly needed and benefits outweigh risks. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | 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). |
| Fetal Monitoring | Monitor liver function, blood pressure, and glucose tolerance during pregnancy. Fetal ultrasound for anomaly detection if exposed in first trimester. No specific monitoring required after exposure in later trimesters. |
| Fertility Effects | Returns to normal after discontinuation; no permanent impairment. May cause transient anovulation post-pill, typically resolving within 1-3 cycles. |
■ FDA Black Box Warning
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.
| Serious Effects |
PregnancyHistory of or current thromboembolic disordersCerebrovascular or coronary artery diseaseKnown or suspected breast cancerUndiagnosed abnormal genital bleedingCholestatic jaundice of pregnancy or jaundice with prior pill useHepatic adenoma or carcinomaActive liver disease with abnormal liver functionKnown hypersensitivity to components
| Precautions | 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) |
| Food/Dietary | 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. |
| Clinical Pearls | 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. |
| Patient Advice | 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. |
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