VIVELLE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VIVELLE (VIVELLE).
Estradiol is an estrogen that binds to estrogen receptors, activating gene transcription and resulting in estrogenic effects in various tissues.
| Metabolism | Metabolized primarily via CYP3A4 to estrone and estriol; undergoes enterohepatic recirculation and conjugation (glucuronidation, sulfation). |
| Excretion | Estradiol is primarily metabolized in the liver to estrone and estriol, which are conjugated with glucuronic or sulfuric acid. Approximately 90% of the metabolites are excreted renally, with the remainder eliminated in the feces via biliary excretion. Less than 10% is excreted unchanged. |
| Half-life | The terminal elimination half-life of estradiol is approximately 12-24 hours, with a mean of about 14 hours. This supports once- or twice-weekly transdermal dosing, maintaining steady-state levels. |
| Protein binding | Estradiol is approximately 98% bound to plasma proteins, primarily to sex hormone-binding globulin (SHBG) and albumin. |
| Volume of Distribution | The apparent volume of distribution is approximately 1.2 L/kg, indicating extensive distribution into body tissues and fluids, including adipose tissue. |
| Bioavailability | Transdermal: Bioavailability is approximately 3-10% relative to oral administration due to avoidance of first-pass hepatic metabolism. Absolute bioavailability is about 80% compared to intravenous administration, as the drug is absorbed directly into systemic circulation. |
| Onset of Action | Transdermal: Clinical effects (e.g., relief of vasomotor symptoms) may be observed within 1-2 weeks of continuous therapy. Steady-state serum estradiol levels are achieved within 2-4 hours after patch application. |
| Duration of Action | Transdermal: Each patch provides sustained estradiol release for 3-4 days (84-96 hours). Replacement every 3.5 days (twice weekly) maintains continuous therapeutic levels. Clinical benefit persists as long as the patch is applied regularly. |
| Molecular Weight | 272.38 |
Transdermal, 0.0375 to 0.1 mg/day applied twice weekly (every 3-4 days); adjust dose based on response.
| Dosage form | FILM, EXTENDED RELEASE |
| Renal impairment | No specific dose adjustment required for renal impairment; use with caution in severe renal disease due to potential fluid retention. |
| Liver impairment | Contraindicated in severe hepatic disease (Child-Pugh class C). In moderate impairment (Child-Pugh B), start at lowest dose and monitor. |
| Pediatric use | Not indicated for use in pediatric patients; safety and efficacy not established. |
| Geriatric use | Use lowest effective dose; increase risk of thromboembolic events and dementia in women >65 years. Avoid use for prevention of chronic conditions. |
| 1st trimester | Estrogens are contraindicated in pregnancy. Data suggest increased risk of congenital anomalies, including cardiac defects and genitourinary tract anomalies. Use is not recommended. |
| 2nd trimester | Estrogens are contraindicated in pregnancy. May cause fetal harm. Use is not recommended. |
| 3rd trimester | Estrogens are contraindicated in pregnancy. Exposure may cause urogenital tract abnormalities and long-term effects. Use is not recommended. |
Clinical note
Comprehensive clinical and safety monograph for VIVELLE (VIVELLE).
| Placental transfer | Estradiol crosses the placenta. Studies show transfer of estradiol and its metabolites, with potential for fetal exposure. |
| Breastfeeding | Estradiol is excreted in breast milk in small amounts, but may reduce milk production and composition. Although no adverse effects have been reported in infants, caution is advised. Use only if clearly needed. |
■ FDA Black Box Warning
Estrogen therapy increases the risk of endometrial cancer in women with an intact uterus. Unopposed estrogen use is associated with increased risk of endometrial hyperplasia and carcinoma. Estrogen plus progestin therapy has been associated with increased risk of breast cancer, stroke, and deep vein thrombosis/pulmonary embolism.
| Serious Effects |
Known or suspected pregnancyUndiagnosed abnormal genital bleedingKnown or suspected breast cancer (except in select cases)Known or suspected estrogen-dependent neoplasiaActive or past history of thromboembolic disorders (e.g., deep vein thrombosis, pulmonary embolism)Active or recent arterial thromboembolic disease (e.g., stroke, myocardial infarction)Liver dysfunction or disease as long as liver function tests have not returned to normalKnown hypersensitivity to any component of the product
| Precautions | Cardiovascular disorders (stroke, DVT, PE): increased risk, Malignant neoplasms: endometrial cancer, breast cancer, Dementia: possible increased risk in women >65 years, Gallbladder disease, Hypercalcemia in patients with breast cancer and bone metastases, Retinal vascular thrombosis, Fluid retention, Exacerbation of endometriosis, Exacerbation of asthma, diabetes, epilepsy, migraine, porphyria, SLE, hepatic hemangiomas, Hypothyroidism: estrogen increases thyroid-binding globulin, may require thyroid hormone dose adjustment |
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| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Estrogen use during pregnancy is contraindicated. First trimester exposure has been associated with a potential increased risk of congenital anomalies, including cardiovascular defects and limb reduction defects. Second and third trimester use may increase risk of vaginal adenosis, cervical and vaginal clear cell adenocarcinoma in female offspring, and urogenital abnormalities in male offspring. Overall, estrogens should not be used during pregnancy. |
| Fetal Monitoring | Monitor maternal blood pressure, weight, and signs of thrombosis. Assess for adverse effects such as nausea, headache, and edema. No specific fetal monitoring is required if pregnancy occurs, but pregnancy testing should be performed if pregnancy is suspected. Inadvertent exposure during pregnancy necessitates counseling and ultrasound for fetal anatomy. |
| Fertility Effects | Estrogen replacement therapy does not impair fertility. In women with ovarian failure, exogenous estradiol can support endometrial growth for embryo implantation when used with progestogens. However, use for contraception is not indicated. |
| Food/Dietary | No clinically significant food interactions. Grapefruit juice may slightly alter estradiol metabolism but not considered clinically relevant. Advise maintaining consistent diet if on concurrent anticoagulants (e.g., warfarin) as estrogens may affect INR. |
| Clinical Pearls | VIVELLE (estradiol transdermal system) delivers continuous 17β-estradiol. Apply to clean, dry, non-hairy, non-irritated skin on lower abdomen or buttock; rotate sites. Avoid same site within 1 week. Do not apply on or near breasts. Use lowest effective dose for shortest duration consistent with treatment goals. In women with intact uterus, must co-administer progestogen (e.g., medroxyprogesterone acetate) to prevent endometrial hyperplasia. Monitor for signs of thromboembolism, gallbladder disease, and breast cancer. Discontinue if migraine, visual disturbances, or jaundice occur. |
| Patient Advice | Apply patch to clean, dry skin on lower abdomen or buttock; do not apply on breasts or in same spot within 7 days. · Change patch twice weekly (every 3-4 days) as directed; set a reminder schedule. · If patch falls off, reapply a new patch and continue original schedule; do not reapply the same patch if soiled. · Do not expose patch to heat sources (heating pads, saunas, tanning beds) as it may increase absorption. · Report any unusual vaginal bleeding, breast lumps, swelling/pain in legs, sudden severe headache, or vision changes immediately. · You must take a progestin (e.g., Prometrium) if you have a uterus to lower risk of endometrial cancer. · Do not stop or change dose without consulting prescriber. · Keep patches out of reach of children and pets; used patches still contain hormone. |