ESTRADIOL VALERATE; ESTRADIOL VALERATE; DIENOGEST
Clinical safety rating: avoid
Inducers of CYP450 enzymes (eg carbamazepine) may decrease estrogen levels Increases risk of thromboembolic disorders and endometrial cancer.
Estradiol valerate is a prodrug of estradiol, an estrogen receptor agonist. Dienogest is a progestin with partial antiandrogenic activity, acting as a progesterone receptor agonist with antiovulatory and endometrial antiproliferative effects.
| Metabolism | Estradiol valerate is hydrolyzed to estradiol and valeric acid; estradiol undergoes hepatic metabolism via CYP3A4 to estrone and estriol. Dienogest is metabolized primarily via CYP3A4 to inactive metabolites. |
| Excretion | Estradiol valerate and dienogest: Urinary excretion accounts for approximately 50-60% of total clearance, primarily as glucuronide conjugates of estradiol and dienogest metabolites. Fecal/biliary excretion accounts for 30-40% of dienogest and its metabolites. For estradiol valerate, about 30% of metabolites are excreted in bile and feces. |
| Half-life | Estradiol valerate: Terminal half-life is approximately 13-14 hours for estradiol. Dienogest: Terminal half-life is about 10-11 hours. The combination allows for once-daily dosing with sustained hormone levels. |
| Protein binding | Estradiol: Approximately 97-99% bound, mainly to sex hormone-binding globulin (SHBG) and albumin. Dienogest: About 90-91% bound to albumin, not SHBG. Estradiol valerate increases SHBG levels. |
| Volume of Distribution | Estradiol: Vd approximately 0.6-0.7 L/kg. Dienogest: Vd approximately 0.8-1.0 L/kg. These values indicate distribution into total body water and some tissue binding. |
| Bioavailability | Estradiol valerate: Oral bioavailability is approximately 10-15% due to extensive first-pass metabolism. Dienogest: Oral bioavailability is about 90% due to minimal first-pass effect. |
| Onset of Action | Oral: Clinical effects (e.g., cycle control, endometrial changes) begin within 24-48 hours of first dose. Suppression of ovulation may take several days to establish with continuous dosing. |
| Duration of Action | Oral: Duration is 24 hours due to once-daily dosing. Clinical effect on endometrium and ovulation suppression is maintained with continuous daily administration. Withdrawal bleeding occurs during the 7-day placebo interval. |
One tablet daily containing estradiol valerate 2 mg and dienogest 3 mg (oral).
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustment recommended; use with caution in severe renal impairment. |
| Liver impairment | Contraindicated in Child-Pugh C; avoid in Child-Pugh A and B due to lack of data. In mild hepatic impairment, use with caution if benefit outweighs risk. |
| Pediatric use | Not indicated in pediatric patients; no established dosing. |
| Geriatric use | Not indicated for postmenopausal women; consider lower dose estradiol if needed for vasomotor symptoms with careful monitoring. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Inducers of CYP450 enzymes (eg carbamazepine) may decrease estrogen levels Increases risk of thromboembolic disorders and endometrial cancer.
| FDA category | Positive |
| Breastfeeding | Estradiol and dienogest are excreted into breast milk. Estradiol may reduce milk production and composition. Dienogest has been detected in breast milk with a milk-to-plasma ratio of approximately 0.5. Use during breastfeeding is not recommended due to potential adverse effects on the infant and reduced milk supply. |
| Teratogenic Risk |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events from combined hormonal contraceptives. Women over 35 who smoke should not use.
| Common Effects | osteoporosis prevention |
| Serious Effects |
["Breast cancer or other estrogen-dependent neoplasia (known or suspected)","Undiagnosed abnormal uterine bleeding","Liver tumor (benign or malignant) or active liver disease","Thrombophlebitis or thromboembolic disorders (current or history)","Cerebrovascular or coronary artery disease","Pregnancy or suspected pregnancy","Hypersensitivity to any component"]
| Precautions | ["Thrombotic disorders (venous thromboembolism, arterial thrombosis)","Cerebrovascular disease","Hepatic tumors (benign or malignant)","Gallbladder disease","Hypertension","Carbohydrate/lipid effects","Uterine bleeding irregularities","Depression","Contact lens intolerance"] |
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| Pregnancy category X. Use is contraindicated during pregnancy. First trimester: exposure associated with increased risk of congenital anomalies including cardiovascular defects, limb reduction defects, and hypospadias. Second and third trimesters: potential feminization of male fetus, vaginal adenosis, and cervical/vaginal cancer later in life. Estrogens and progestins are not recommended for use during pregnancy. |
| Fetal Monitoring | Before and during therapy: pregnancy test to exclude pregnancy (highly recommend monthly). Monitor for signs of thromboembolism, hypertension, depression, and glucose intolerance. In case of accidental exposure during pregnancy, ultrasound to assess fetal development. |
| Fertility Effects | Suppresses ovulation and thus impairs fertility. After discontinuation, return to normal fertility is generally prompt, but may be delayed in some women. No permanent effects on fertility. |