Estrogens should be used with caution in individuals with severe hypocalcemia.
Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Estradiol Tablets.
Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH) (See DOSAGE AND ADMINISTRATION section).
- Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
- Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
- Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
- Increased plasma HDL and HDL2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
- Impaired glucose tolerance.
- Reduced response to metyrapone test.
Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer (See BOXED WARNINGS , WARNINGS and PRECAUTIONS).
Long term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Estradiol Tablets should not be used during pregnancy (See CONTRAINDICATIONS).
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when estradiol is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time have been shown to accelerate epiphyseal closure, resulting in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. In patients in whom bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended.
Estrogen treatment of prepubertal children also induces premature breast development and vaginal cornification, and may potentially induce vaginal bleeding in girls. In boys, estrogen treatment may modify the normal pubertal process. All other physiological and adverse reactions shown to be associated with estrogen treatment of adults could potentially occur in the pediatric population, including thromboembolic disorders and growth stimulation of certain tumors. Therefore, estrogens should only be administered to pediatric patients when clearly indicated and the lowest effective dose should always be utilized.
The safety and efficacy of estradiol tablets in geriatric patients has not been established. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greatest frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70 (See WARNINGS, Dementia).
It is unknown whether these findings apply to estrogen alone therapy.
The following additional adverse reactions have been reported with estrogen and/or progestin therapy.
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting, dysmenorrhea
Increase in size of uterine leiomyomata
Vaginitis, including vaginal candidiasis
Change in amount of cervical secretion
Changes in cervical ectropion
Ovarian cancer; endometrial hyperplasia; endometrial cancer
Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer
Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure
Abdominal cramps, bloating
Increased incidence of gallbladder disease
Enlargement of hepatic hemangiomas
Chloasma or melasma that may persist when drug is discontinued
Loss of scalp hair
Retinal vascular thrombosis
Steepening of corneal curvature
Intolerance to contact lenses
Headache, migraine, dizziness
Nervousness, mood disturbances, irritability
Exacerbation of epilepsy
Increase or decrease in weight
Reduced carbohydrate tolerance
Aggravation of porphyria
Arthralgias; leg cramps
Changes in libido
Exacerbation of asthma
To report SUSPECTED ADVERSE REACTIONS, contact Epic Pharma, LLC at 1-888-374-2791, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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