ESTRADIOL TABLETS, USP

Rx  only

 11001016

(Three Patient Information Leaflets Enclosed - Tear at Perforation)

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:

C₁₈H₂₄O₂ Molecular Weight: 272.37

Inactive Ingredients: Colloidal silicon dioxide, corn starch, dibasic calcium phosphate, lactose monohydrate, magnesium stearate, and sodium starch glycolate. In addition, the 1 mg also contains FD&C blue no. 1 aluminum lake and D&C red no. 27 aluminum lake. The 2 mg also contains FD&C blue no. 1 aluminum lake and FD&C yellow no. 5 (tartrazine) aluminum lake.

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.

Estradiol Tablets, USP are 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 500 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.
• Estradiol Tablets, USP should not be used in patients with known hypersensitivity to its ingredients. 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 estradiol tablets 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.

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.

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.

1. For treatment of moderate to severe vasomotor symptoms, vulval and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible.

Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals. The usual initial dosage range is 1 to 2 mg daily of estradiol adjusted as necessary to control presenting symptoms. The minimal effective dose for maintenance therapy should be determined by titration. Administration should be cyclic (e.g., 3 weeks on and 1 week off).

2. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.

Treatment is usually initiated with a dose of 1 to 2 mg daily of estradiol, adjusted as necessary to control presenting symptoms; the minimal effective dose for maintenance therapy should be determined by titration.

3. For treatment of breast cancer, for palliation only, in appropriately selected women and men with metastatic disease.

Suggested dosage is 10 mg three times daily for a period of at least three months.

4. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only.

Suggested dosage is 1 to 2 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient.

5. For prevention of osteoporosis.

When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.

The lowest effective dose of estradiol has not been determined.

Estradiol Tablets, USP are available as:

0.5 mg:	White to off-white, oval, flat-faced, beveled-edge, scored tablet. Debossed with 899 / ½ on the scored side and stylized b on the other side. Available in bottles of:
	100 Tablets NDC 0555-0899-02

1 mg:	Light purple, oval, flat-faced, beveled-edge, scored tablet. Debossed with 886 / 1 on the scored side and stylized b on the other side. Available in bottles of:
	30 Tablets NDC 0555-0886-01
	90 Tablets NDC 0555-0886-14
	100 Tablets NDC 0555-0886-02
	500 Tablets NDC 0555-0886-04

2 mg:	Green, oval, flat-faced, beveled-edge, scored tablet. Debossed with 887 / 2 on the scored side and stylized b on the other side. Available in bottles of:
	30 Tablets NDC 0555-0887-01
	90 Tablets NDC 0555-0887-14
	100 Tablets NDC 0555-0887-02
	500 Tablets NDC 0555-0887-04

Store at 20º to 25º C (68º to 77ºF) [See USP Controlled Room Temperature].

Dispense with a child-resistant closure in a tight, light-resistant container.

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

Estradiol is a medicine that contains estrogen hormones.

Estradiol is used to:

• reduce moderate to severe hot flashes

Estrogens are hormones made by a woman's ovaries. Between ages 45 and 55, the ovaries normally stop making estrogens. This leads to a drop in body estrogen levels which causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause”.

When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with estradiol.

Weight-bearing exercise, like walking or running, and taking calcium with vitamin D supplements may also lower your chances for getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your healthcare provider before starting them.

• treat dryness, itching, and burning in or around the vagina, difficulty or burning on urination associated with menopause

You and your healthcare provider should talk regularly about whether you still need treatment with estradiol to control these problems. If you use estradiol only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

• treat certain conditions in which a young woman's ovaries do not produce enough estrogen naturally
• treat certain types of abnormal vaginal bleeding due to hormonal imbalance when your doctor has found no serious cause of the bleeding
• treat certain cancers in special situations, in men and women
• prevent thinning of bones

Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use estradiol 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.

Do not start taking estradiol if you:

• have unusual vaginal bleeding which has not been evaluated by your doctor (see BOXED WARNINGS)

Unusual vaginal bleeding can be a warning sign of cancer of the uterus, especially if it happens after menopause. Your doctor must find out the cause of the bleeding so that he or she can recommend the proper treatment. Taking estrogens without visiting your doctor can cause you serious harm if your vaginal bleeding is caused by cancer of the uterus.

• currently have or have had certain cancers

Estrogens may increase the risk of certain types of cancer, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take estradiol.

(For certain patients with breast or prostate cancer, estrogens may help.)

• had a stroke or heart attack in the past year
• currently have or have had blood clots
• have or have had liver problems
• are allergic to Estradiol Tablets or any of its ingredients

See the end of this leaflet for a ul of ingredients in Estradiol Tablets.

Estradiol Tablets, USP 2 mg tablets contain 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.

• think you may be pregnant

Tell your healthcare provider:

• if you are breast feeding

The hormone in estradiol can pass into your milk

• about all of your medical problems

Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.

• about all the medicines you take

This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how estradiol tablets work. Estradiol tablets may also affect how your other medicines work.

• if you are going to have surgery or will be on bed rest

You may need to stop taking estrogens.

1. Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you.

2. Estrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with estradiol.

If you use estrogens, you can reduce your risks by doing these things:

• Talk with your healthcare provider:

1. While you are using estrogens, it is important to visit your doctor at least once a year for a check-up.

2. If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you.

3. See your healthcare provider right away if you have vaginal bleeding while taking estradiol tablets.

4. Have a breast exam and mammogram (breast x-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast x-ray), you may need to have more frequent breast examinations.

5. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease.

6. Talk with your healthcare provider regularly about whether you should continue taking estradiol tablets. You and your doctor should reevaluate whether or not you still need estrogens at least every six months.

• Be alert for signs of trouble

If any of these warning signals (or any other unusual symptoms) happen while you are using estrogens, call your doctor immediately:

Abnormal bleeding from the vagina (possible uterine cancer)

Pains in the calves or chest, sudden shortness of breath, or coughing blood (possible clot in the legs, or lungs)

Severe headache or vomiting, dizziness, faintness, changes in vision or speech, weakness or numbness of an arm or leg (possible clot in the brain or eye)

Breast lumps (possible breast cancer; ask your doctor or health professional to show you how to examine your breasts monthly)

Yellowing of the skin or eyes (possible liver problem)

Pain, swelling, or tenderness in the abdomen (possible gallbladder problem)

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.

Do not take estradiol for conditions for which it was not prescribed. Do not give estradiol to other people, even if they have the same symptoms you have. It may harm them.

This leaflet provides a summary of the most important information about estradiol. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about estradiol tablets that is written for health professionals.

Inactive Ingredients: Colloidal silicon dioxide, corn starch, dibasic calcium phosphate, lactose monohydrate, magnesium stearate, and sodium starch glycolate. In addition, the 1 mg also contains FD&C blue no. 1 aluminum lake and D&C red no. 27 aluminum lake. The 2 mg also contains FD&C blue no. 1 aluminum lake and FD&C yellow no. 5 (tartrazine) aluminum lake.