ESTRACE^® TABLETS
(estradiol tablets, USP)

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.

ESTRACE^® (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. It has an empirical formula of C₁₈H₂₄O₂ and molecular weight of 272.37. The structural formula is:

ESTRACE tablets, 0.5 mg, contain the following inactive ingredients: acacia, dibasic calcium phosphate, lactose, magnesium stearate, colloidal silicon dioxide, starch (corn), and talc.

ESTRACE tablets, 1 mg, contain the following inactive ingredients: acacia, D&C Red No. 27 (aluminum lake), dibasic calcium phosphate, FD&C Blue No. 1 (aluminum lake), lactose, magnesium stearate, colloidal silicon dioxide, starch (corn), and talc.

ESTRACE tablets, 2 mg, contain the following inactive ingredients: acacia, dibasic calcium phosphate, FD&C Blue No. 1 (aluminum lake), FD&C Yellow No. 5 (tartrazine) (aluminum lake), lactose, magnesium stearate, colloidal silicon dioxide, starch (corn), and talc.

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.

ESTRACE (estradiol tablets, USP) is indicated in the:

• Treatment of moderate to severe vasomotor symptoms associated with the menopause.
• Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
• Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
• Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
• Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
• Prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

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:

• Undiagnosed abnormal genital bleeding.
• Known, suspected or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease.
• Known or suspected estrogen-dependent neoplasia.
• Active deep vein thrombosis, pulmonary embolism or history of these conditions.
• Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
• Liver dysfunction or disease.
• ESTRACE should not be used in patients with known hypersensitivity to its ingredients. ESTRACE (estradiol tablets, USP), 2 mg, contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
• Known or suspected pregnancy. There is no indication for ESTRACE in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS.)

See BOXED WARNINGS.

Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.

Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)

It is unknown whether these findings apply to estrogen alone therapy.

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe ESTRACE.

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.)

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.

ESTRACE 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 ESTRACE 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 ESTRACE 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.

See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.

The following additional adverse reactions have been reported with estrogen and/or progestin therapy.

• 1.Genitourinary system
•  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
• 2.Breasts
•  Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer
• 3.Cardiovascular
•  Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure
• 4.Gastrointestinal
•  Nausea, vomiting
•  Abdominal cramps, bloating
•  Cholestatic jaundice
•  Increased incidence of gallbladder disease
•  Pancreatitis
•  Enlargement of hepatic hemangiomas
• 5.Skin
•  Chloasma or melasma that may persist when drug is discontinued
•  Erythema multiforme
•  Erythema nodosum
•  Hemorrhagic eruption
•  Loss of scalp hair
•  Hirsutism
•  Pruritus, rash
• 6.Eyes
•  Retinal vascular thrombosis
•  Steepening of corneal curvature
•  Intolerance to contact lenses
• 7.Central Nervous System
•  Headache, migraine, dizziness
•  Mental depression
•  Chorea
•  Nervousness, mood disturbances, irritability
•  Exacerbation of epilepsy
•  Dementia
• 8.Miscellaneous
•  Increase or decrease in weight
•  Reduced carbohydrate tolerance
•  Aggravation of porphyria
•  Edema
•  Arthralgias; leg cramps
•  Changes in libido
•  Urticaria
•  Angioedema
•  Anaphylactoid/anaphylactic reactions
•  Hypocalcemia
•  Exacerbation of asthma
•  Increased triglycerides

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.

ESTRACE^® (estradiol tablets, USP) 0.5 mg; round, white scored tablets imprinted with 021 and MJ on one side.

N 0430-0021-24      Bottles of 100

ESTRACE^® (estradiol tablets, USP) 1 mg; round, lavender scored tablets imprinted with 755 and MJ on one side.

N 0430-0023-24      Bottles of 100
N 0430-0023-30      Bottles of 500

ESTRACE^® (estradiol tablets, USP) 2 mg; round, turquoise scored tablets imprinted with 756 and MJ on one side.

N 0430-0024-24      Bottles of 100
N 0430-0024-30      Bottles of 500

Store at controlled room temperature 15°-30° C (59°-86° F).

Dispense in a tight, light-resistant container as defined in the USP.

(Updated March 2005)

ESTRACE^® TABLETS
(estradiol tablets, USP)

INTRODUCTION

Read this PATIENT INFORMATION before you start taking ESTRACE and read what you get each time you refill ESTRACE. 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.

• Estrogens increase the chances of getting cancer of the uterus.
  
  Report any unusual vaginal bleeding right away while you are taking estrogens. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
  
  
• Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes.
  
  Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens with progestins may increase your risk of dementia. You and your healthcare provider should talk regularly about whether you still need treatment with ESTRACE.