DEMULEN 1/35-21
Clinical safety rating: caution
Comprehensive 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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DEMULEN 1/35-21 (DEMULEN 1/35-21).
| Breastfeeding | 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. |
| 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). |
■ 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 |
["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 mmHg or diastolic ≥100 mmHg)","Diabetes with vascular involvement","Migraine with focal aura (if age ≥35)","Major surgery with prolonged immobilization"]
| 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)"] |
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| 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. |