Track topics on Twitter Track topics that are important to you
ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER
Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of "natural" estrogens results in a different endometrial risk profile than "synthetic" estrogens at equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. (See WARNINGS, Cardiovascular disorders.)
The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Estradiol Tablets, USP for oral administration contains 0.5, 1 or 2 mg of micronized estradiol per tablet. Estradiol (17β-estradiol) is a white, crystalline solid, chemically described as estra-1,3,5,(10)-triene-3, 17β-diol. The structural formula is:
Inactive Ingredients: Lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.
Most prospective studies of efficacy for this indication have been carried out in white menopausal women, without stratification by other risk factors, and tend to show a universally salutary effect on bone.
The results of a two-year, randomized, placebo-controlled, double-blind, dose-ranging study have shown that treatment with 0.5 mg estradiol daily for 23 days (of a 28 day cycle) prevents vertebral bone mass loss in postmenopausal women. When estrogen therapy is discontinued, bone mass declines at a rate comparable to the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores bone mass to premenopausal levels.
The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below:
For those outcomes included in the “global index,” the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
|Eventc|| Relative Risk
CE/MPA vs placebo
at 5.2 Years
n = 8102
n = 8506
|Absolute Risk per 10,000 Women-Years|
|a adapted from JAMA, 2002; 288:321-333|
|b includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer|
|c a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes|
|d not included in Global Index|
|* nominal confidence intervals unadjusted for multiple looks and multiple comparisons|
|Invasive breast cancerb||1.26 (1.00-1.59)||30||38|
|Pulmonary embolism||2.13 (1.39-3.25)||8||16|
|Colorectal cancer||0.63 (0.43-0.92)||16||10|
|Endometrial cancer||0.83 (0.47-1.47)||6||5|
|Hip fracture||0.66 (0.45-0.98)||15||10|
|Death due to causes other than the events above||0.92 (0.74-1.14)||40||37|
|Global Indexc||1.15 (1.03-1.28)||151||170|
|Deep vein thrombosisd||2.07 (1.49-2.87)||13||26|
|Vertebral fracturesd||0.66 (0.44-0.98)||15||9|
|Other osteoporotic fracturesd||0.77 (0.69-0.86)||170||131|
The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING and WARNINGS, Dementia.)
Estradiol Tablets, USP is indicated in the:
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.
Estrogens should not be used in individuals with any of the following conditions:
See BOXED WARNINGS .
a. Coronary heart disease and stroke.
b.Venous thromboembolism (VTE).
b. Breast cancer.
6. Visual abnormalities.
1. Addition of a progestin when a woman has not had a hysterectomy.
2. Elevated blood pressure.
4. Impaired liver function and past history of cholestatic jaundice.
6. Fluid retention.
8. Ovarian cancer.
9. Exacerbation of endometriosis.
10. Exacerbation of other conditions.
Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Estradiol Tablets, USP.
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.)
1. 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.
2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T levels (by column or by radioimmunoassay) or T levels by radioimmunoassay. Tresin uptake is decreased, reflecting the elevated TBG. Free T and free T concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
3. 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 or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
5. Impaired glucose tolerance.
6. 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, USP 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 Tablets, USP 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, USP 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.
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.
The following additional adverse reactions have been reported with estrogen and/or progestin therapy.
1. Genitourinary system
7. Central Nervous System
Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
Patients should be started at the lowest dose for the indication.
Estradiol Tablets, USP are available as:
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense with a child-resistant closure in a tight, light-resistant container.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Heritage Pharmaceuticals Inc.
Edison, NJ 08837
Ft. Lauderdale, FL 33309
Read this PATIENT INFORMATION before you start taking Estradiol Tablets, USP and read what you get each time you refill Estradiol Tablets, USP. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
WHAT IS ESTRADIOL TABLETS, USP?
Estradiol Tablets, USP is a medicine that contains estrogen hormones.
WHAT IS ESTRADIOL TABLETS, USP USED FOR?
Estradiol Tablets, USP is used to:
Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use Estradiol Tablets, USP only to prevent osteoporosis from menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you. You and your healthcare provider should talk regularly about whether you should continue with Estradiol Tablets, USP.
WHO SHOULD NOT USE ESTRADIOL TABLETS, USP?
Do not start taking Estradiol Tablets, USP if you:
See the end of this leaflet for a list of ingredients in Estradiol Tablets, USP.
These are some of the warning signs of the serious side effects:
Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.
Common side effects include:
Other side effects include:
These are not all the possible side effects of Estradiol Tablets, USP. For more information, ask your healthcare provider or pharmacist.
WHAT CAN I DO TO LOWER MY CHANCES OF A SERIOUS SIDE EFFECT WITH ESTRADIOL TABLETS, USP?
If you use estrogens, you can reduce your risks by doing these things:
If any of these warning signals (or any other unusual symptoms) happen while you are using estrogens, call your doctor immediately:
GENERAL INFORMATION ABOUT SAFE AND EFFECTIVE USE OF ESTRADIOL TABLETS, USP
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take Estradiol Tablets, USP for conditions for which it was not prescribed. Do not give Estradiol Tablets, USP to other people, even if they have the same symptoms you have. It may harm them.
KEEP ESTRADIOL TABLETS, USP OUT OF THE REACH OF CHILDREN
This leaflet provides a summary of the most important information about Estradiol Tablets, USP. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Estradiol Tablets, USP that is written for health professionals. You can get more information by calling the toll free number 1-866-901-DRUG(3784).
WHAT ARE THE INGREDIENTS IN ESTRADIOL TABLETS, USP?
Inactive Ingredients: Lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088
Heritage Pharmaceuticals Inc.
Edison, NJ 08837
Ft. Lauderdale, FL 33309
|0.5 mg:||White to off-white, round, convex, scored tablets, embossed “H/4” on one side.|
|Bottles of 100||NDC 23155-013-01|
|1.0 mg:||White to off-white, round, convex, scored tablets, embossed “H/5” on one side.|
|Bottles of 100||NDC 23155-014-01|
|Bottles of 500||NDC 23155-014-05|
|2.0 mg:||White to off-white, round, convex, scored tablets, embossed “H/6” on one side.|
|Bottles of 100||NDC 23155-015-01|
|WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT ESTRADIOL TABLETS, USP (AN ESTROGEN HORMONE)?|
Estradiol Tablets, USP, 0.5 mg, 100 tablets
Estradiol Tablets, USP, 1 mg, 100 tablets
Estradiol Tablets, USP, 2 mg, 100 tablets
Levonorgestrel and Ethinyl Estradiol Tablets USP, (0.1 mg/0.02 mg) and Ethinyl Estradiol Tablets USP, (0.01 mg)
Fluconazole Tablets USP
ELESTRIN (estradiol gel)
Estradiol/Norethindrone Acetate Tablets
Estradiol treatment is effective at reducing vasomotor symptoms (eg, hot flushes) in postmenopausal women. Vivus has a proprietary spray delivery system (Evamist) for estradiol. This stu...
The purpose of this study is to evaluate potential mechanisms by which estradiol deficiency accelerates fat gain and abdominal fat accumulation in women.
This study is designed to compile the reasons and specific indications for the prescription of Cyproterone Acetate combined with Ethinyl Estradiol by Health Care Providers. The primary obj...
This clinical trial investigates a new vaginal delivery system made of silicone rubber, containing Nestorone®, a 19—nor progesterone derivative and a low dose of serum estradiol (E2). T...
The purpose of this study was to evaluate the effectiveness and safety of norgestimate-ethinyl estradiol as comparted with cyproterone acetate-ethinyl estradiol among female patients with ...
Transdermal estradiol patches are primarily designed for adult women. No low-dose patches are licensed for pubertal induction in hypogonadal girls. Low doses can be achieved by cutting a matrix patch ...
A series consisting of substituted benzoylbenzamide derivatives of 17α-E-vinyl estradiol 6a-i and 7a-d was prepared in good overall yields from the corresponding novel iodinated benzoylbenzamide prec...
Estradiol and progesterone bioavailability for moderate to severe vasomotor symptom treatment and endometrial protection with the continuous-combined regimen of TX-001HR (oral estradiol and progesterone capsules).
In the REPLENISH trial, women receiving TX-001HR-an oral, softgel capsule, combining 17β-estradiol (E2) and progesterone (E2 mg/P4 mg 1/100, 0.5/100), had significantly improved vasomotor symptoms, w...
Estradiol was historically measured by gas chromatography-mass spectrometry before development of immunoassays. Although immunoassays were fast requiring low sample volume, they had specificity issues...
This study aimed to investigate the action mechanism of β-estradiol in MCF-7 breast cancer (BC) cells.
Bladder Cancer Brain Cancer Breast Cancer Cancer Cervical Cancer Colorectal Head & Neck Cancers Hodgkin Lymphoma Leukemia Lung Cancer Melanoma Myeloma Ovarian Cancer Pancreatic Cancer ...
Women's Health - key topics include breast cancer, pregnancy, menopause, stroke Follow and track Women's Health News on BioPortfolio: Women's Health News RSS Women'...
Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer th...