Estrace

Estradiol is a form of estrogen, a female sex hormone that's produced by the ovaries.

Estradiol comes in an oral form, a transdermal skin patch, a vaginal ring, or as a topical gel, spray, or emulsion.

The drug is available under several brand names such as Estrace (oral pill); EvaMist (spray); Vagifem (vaginal pill); Estring, Femring (vaginal rings); Climara, Alora (skin patches); and Divigel and Estrogel (topical gels).

Estradiol is used to treat and prevent hot flushes in women experiencing menopause. Estradiol gel is also used to treat vaginal dryness, itching, and burning in menopausal women.

Estradiol is also commonly combined with progestins in various doses in oral contraceptive pills that prevent pregnancy by preventing ovulation.

The medicine may also be used to prevent osteoporosis, replace estrogen in women with ovarian failure, or as part of a cancer treatment regimen.

Estradiol is in a class of drugs called estrogen hormones. It works by replacing the estrogen that the body normally produces.

Estradiol Warnings

Estradiol can increase the risk that you will develop endometrial cancer (cancer of the lining of the uterus). If you have not had a hysterectomy, you should take progestin along with estradiol to decrease this risk.

However, before taking these two medicines together, talk with your doctor about your risk for other health problems.

In one study, women who took estrogens (such as estradiol) by mouth with progestin had a higher risk of heart attacks, stroke, blood clots, breast cancer, and dementia.

Women who use topical estradiol alone or with progestin may also have a higher risk of developing these conditions.

Using topical estradiol may increase your risk of developing ovarian cancer and gallbladder disease. You should talk to your doctor about these risks.

Before taking estradiol, tell your doctor if you have or have ever had:

• A heart attack or stroke
• Heart disease
• Blood clots
• Any type of cancer
• Abnormal vaginal bleeding
• High blood pressure
• High cholesterol
• Diabetes
• Asthma
• Gallbladder disease
• A thyroid disorder
• Epilepsy or another seizure disorder
• Liver disease
• Lupus
• Breast lumps or abnormal mammogram results
• Uterine fibroids
• Yellowing of the skin or eyes (jaundice)
• Migraine headaches
• Endometriosis (a condition where the type of tissue that lines the uterus grows in other areas of the body, usually the abdomen or pelvis)
• Low levels of calcium in your blood
• Porphyria (a condition where abnormal substances build up in the blood)

Also, tell your doctor if you smoke or use tobacco products.

You should use the lowest dose of estradiol for the shortest time possible to control your symptoms.

Talk with your doctor every three to six months to determine if you should lower your dose or stop using this medicine.

You should conduct a breast self-exam every month and have a mammogram and clinical breast exam (a breast exam by a health professional) every year to help detect breast cancer.

Tell your doctor if you are having surgery or will be on bed rest while taking estradiol. Your doctor may tell you to stop taking the medication to decrease the risk of blood clots.

The topical medicine may harm other people who touch your skin. You should not let anyone else touch the skin where you applied estradiol for one hour after application.

If someone does touch the area, he or she should wash his or her hands with soap and water immediately.

Pregnancy and Estradiol

Estradiol can harm an unborn baby or cause birth defects. You should not use this medication while pregnant.

Tell your doctor right away if you become pregnant or might become pregnant while taking this drug.

Since estradiol can also pass into breast milk, talk to your doctor before breastfeeding while taking the drug.

Your dose of estradiol will depend on the condition that is being treated.

Estradiol tablets in doses of 0.5 milligrams (mg), 1 mg, or 2 mg are typically given on a daily basis.

They can also be prescribed to be taken for three weeks, followed by one week of no medication.

The tablets can be taken more than once a day for some conditions.

The topical gel or emulsions are applied to the skin at the same time each day.

The vaginal ring is inserted in the vagina and left for three months at a time.

The patch should be applied to a dry, clean, hairless part of the trunk (but not the breasts). It should not be placed on irritated or damaged skin.

You should rotate the site of application, with at least one week between repeated applications to any one site.

Estradiol Overdose

Symptoms of an overdose include the following:

• Nausea or vomiting
• Heavy vaginal bleeding
• Drowsiness
• Tender breasts
• Discolored urine
• Headache

If you suspect an overdose, you should contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at (800) 222-1222.

Missed Dose of Estradiol

If you miss a dose of oral estradiol, take it as soon as you remember.

However, if it's almost time for your next scheduled dose, skip the missed dose and continue on your regular schedule. Do not double up on doses.

If you forget a dose of estradiol gel but remember more than 12 hours before your next scheduled dose, apply the missed dose immediately.

However, if you remember less than 12 hours before your next dose, skip the missed dose and continue on your regular dosing schedule.

Do not apply extra gel to make up for a missed one.

If you forget to apply estradiol emulsion in the morning, apply it as soon as you remember.

Don't apply extra emulsion to make up for a missed dose.

Included as part of the PRECAUTIONS section.

See BOXED WARNINGS.

Cardiovascular Disorders

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.

Coronary Heart Disease And Stroke

In the Women's Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 person years). The increase in risk was observed in year one and persisted.

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

Venous Thromboembolism (VTE).

In the Women's Health Initiative (WHI) study, an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies .)

In the CE/MPA substudy of WHI, a 2fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 womenyears in the CE/MPA group compared to 16 per 10,000 womenyears in the placebo group. The increase in VTE risk was observed during the first year and persisted.

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Malignant Neoplasms

Endometrial Cancer

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12- fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use—with increased risks of 15- to 24- fold for five to ten years or more—and this risk persists for 8 to over 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations is important (see PRECAUTIONS). 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 of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Breast Cancer

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies ). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.

The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during theclinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01- 1.54), and the overall absolute risk was 41 vs 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Dementia

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 womenyears. 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.

Gallbladder Disease

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

Hypercalcemia

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.

Visual Abnormalities

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.

If you take/use too much Estrace, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Estrace is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

• Store Estrace at room temperature. 
• Keep this and all medicines out of the reach of children.

WARNING: 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 CURRENTLY NO EVIDENCE THAT THE USE OF “NATURAL” ESTROGENS RESULTS IN A DIFFERENT ENDOMETRIAL RISK PROFILE THAN SYNTHETIC ESTROGENS OF EQUIVALENT ESTROGEN DOSE.

CARDIOVASCULAR AND OTHER RISKS 

ESTROGENS WITH AND WITHOUT PROGESTINS SHOULD NOT BE USED FOR THE PREVENTION OF CARDIOVASCULAR DISEASE OR DEMENTIA.

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.

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.

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.

This section provides information on the proper use of a number of products that contain estrogen. It may not be specific to Estrace. Please read with care.

Vaginal estrogen products usually come with patient directions. Read them carefully before using this medicine.

Wash your hands before and after using the medicine. Also, keep the medicine out of your eyes. If this medicine does get into your eyes, wash them out immediately, but carefully, with large amounts of tap water. If your eyes still burn or are painful, check with your doctor.

Use this medicine only as directed. Do not use more of it and do not use it for a longer time than your doctor ordered. It can take up to 4 months to see the full effect of the estrogens. Your doctor may reconsider continuing your estrogen treatment or may lower your dose several times within the first one or two months, and every 3 to 6 months after that. Sometimes a switch to oral estrogens may be required for added benefits or for higher doses. When using the estradiol vaginal insert or ring, you will need to replace it every 3 months or remove it after 3 months.

For vaginal creams or suppositories:

• Vaginal creams and some vaginal suppositories are inserted with a plastic applicator. Directions for using the applicator are supplied with your medicine. If you do not see your dose marked on the applicator, ask your health care professional for more information.
• To fill the applicator for cream dosage forms:
  • Screw the applicator onto the tube.
  • Squeeze the medicine into the applicator slowly until it is measured properly.
  • Remove the applicator from the tube. Replace the cap on the tube.
• To fill the applicator for suppository dosage form:
  • Place the suppository into the applicator.
• To place the dose using the applicator for cream and suppository dosage forms:
  • Relax while lying on your back with your knees bent or stand with one foot on a chair.
  • Hold the full applicator in one hand. Slide the applicator slowly into the vagina. Stop before it becomes uncomfortable.
  • Slowly press the plunger until it stops.
  • Withdraw the applicator. The medicine will be left behind in the vagina.
• To care for the applicator for cream and suppository dosage forms:
  • Clean the applicator after use by pulling the plunger out of the applicator and washing both parts completely in warm, soapy water. Do not use hot or boiling water.
  • Rinse well.
  • After drying the applicator, replace the plunger.

For vaginal insert or ring dosage form:

• To place the vaginal insert:
  • Relax while lying on your back with your knees bent or stand with one foot on a chair.
  • Pinch or press the sides of the vaginal insert together, between your forefinger and middle finger.
  • With one hand, part the folds of skin around your vagina.
  • Slide the vaginal insert slowly into the upper third of your vagina. Stop before it becomes uncomfortable. The exact location is not too important but it should be comfortable.
  • If it seems uncomfortable, then carefully push the vaginal insert higher into the vagina.
• To remove the vaginal insert:
  • Stand with one foot on a chair.
  • Slide one finger into the vagina and hook it around the closest part of the vaginal insert.
  • Slowly pull the vaginal insert out.
  • Dispose of the vaginal insert by wrapping it up and throwing it into the trash. Do not flush it down the toilet.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For conjugated estrogens
• For vaginal dosage form (cream):
  • For treating inflammation of the vagina (atrophic vaginitis):
    • Adults—At first, 0.5 gram (g) of conjugated estrogens inserted into the vagina once a day or as directed by your doctor to achieve the lowest dose possible. Usually your doctor will want you to use this medicine for only three weeks of each month (three weeks on and one week off). Your doctor may increase your dose as needed. However, the dose is usually not more than 2 grams per day.
  • For treating a genital skin condition (vulvar atrophy):
  • Adults—0.5 gram (g) of conjugated estrogens inserted into the vagina two times per week. Usually your doctor will want you to use this medicine for only three weeks of each month (three weeks on and one week off).

For estradiol
• For vaginal dosage form (cream):
  • For treating a genital skin condition (vulvar atrophy) and inflammation of the vagina (atrophic vaginitis):
    • Adults—200 to 400 micrograms (mcg) of estradiol (two to four grams of cream) inserted into the vagina once a day for one to two weeks, decreasing the dose by one half over two and four weeks. After four weeks, your doctor will probably ask you to use the medicine less often, such as 100 mcg (one gram of cream) one to three times a week and for only three weeks of each month (three weeks on and one week off).
• For vaginal dosage form (insert or ring):
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis) in postmenopausal women, and inflammation of the urethra (urethritis) in postmenopausal women:
    • Adults—One insert containing 2 to 24.8 milligrams (mg) of estradiol inserted into the vagina every three months. The insert will slowly release estradiol at a rate of 7.5 to 100 micrograms (mcg) every twenty-four hours with continuous use.

For estrone
• For vaginal dosage form (cream):
  • For treating a genital skin condition (vulvar atrophy) and inflammation of the vagina (atrophic vaginitis) in postmenopausal women:
    • Adults—2 to 4 milligrams (mg) of estrone (two to four grams of cream) inserted into the vagina once a day or as directed by your doctor.
• For vaginal dosage form (suppository):
  • For treating a genital skin condition (vulvar atrophy) and inflammation of the vagina (atrophic vaginitis) in postmenopausal women:
    • Adults—250 to 500 micrograms (mcg) inserted into the vagina once a day or as directed by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

When using the suppository or cream several times a week: If you miss a dose of this medicine and remember it within 1 or 2 days of the missed dose, use the missed dose as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

When using the cream or suppositories more than several times a week: If you miss a dose of this medicine, use it as soon as possible if remembered within 12 hours of the missed dose. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Do not keep outdated medicine or medicine no longer needed.

Estrogens should not be used in individuals with any of the following conditions:

1. Undiagnosed abnormal genital bleeding. 2. Known, suspected or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease. 3. Known or suspected estrogen-dependent neoplasia. 4. Active deep vein thrombosis, pulmonary embolism or history of these conditions. 5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction). 6. Liver dysfunction or disease. 7. Estrace should not be used in patients with known hypersensitivity to its ingredients. Estrace tablets 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. 8. 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.)

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. 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.

A. General

1. Addition of a progestin when a woman has not had a hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks which may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer.

2. Elevated blood pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

3. Hypertriglyceridemia

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

4. Impaired liver function and past history of cholestatic jaundice

Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

5. Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

6. Fluid retention

Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

7. Hypocalcemia

Estrogens should be used with caution in individuals with severe hypocalcemia.

8. Ovarian cancer

The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77 to 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.

9. Exacerbation of endometriosis

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.

10. Exacerbation of other conditions

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.

Estrace tablets 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.

B. Patient Information

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

C. Laboratory Tests

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.)

D. Drug/Laboratory Test Interactions

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), 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. 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 hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). 4. Increased plasma HDL and HDL2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. 5. Impaired glucose tolerance. 6. Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

F. Pregnancy Category X

Estrace should not be used during pregnancy. (See CONTRAINDICATIONS.)

G. Nursing Mothers

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.

H. Pediatric Use

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.

I. Geriatric Use

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.

Estrace® TABLETS

  (estradiol tablets USP)

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.

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Estrace (AN ESTROGEN HORMONE)? • 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.

WHAT IS Estrace?

Estrace is a medicine that contains estrogen hormones.

WHAT IS Estrace USED FOR?

Estrace 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 Estrace.

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 Estrace to control these problems. If you use Estrace 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 Estrace 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 Estrace.

WHO SHOULD NOT USE Estrace?

Do not start taking Estrace 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 Estrace.

(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 Estrace or any of its ingredients

See the end of this leaflet for a list of ingredients in Estrace.

Estrace 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 Estrace 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 Estrace works. Estrace 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.

HOW SHOULD I TAKE Estrace?

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 Estrace.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF ESTROGENS?

Less common but serious side effects include:

• Breast cancer • Cancer of the uterus • Stroke • Heart attack • Blood clots • Dementia • Gallbladder disease • Ovarian cancer

These are some of the warning signs of the serious side effects:

• Breast lumps • Unusual vaginal bleeding • Dizziness and faintness • Changes in speech • Severe headaches • Chest pain • Shortness of breath • Pains in your legs • Changes in vision • Vomiting

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:

• Headache • Breast pain • Irregular vaginal bleeding or spotting • Stomach/abdominal cramps, bloating • Nausea and vomiting • Hair loss

Other side effects include:

• High blood pressure • Liver problems • High blood sugar • Fluid retention • Enlargement of benign tumors (“fibroids”) of the uterus • A spotty darkening of the skin, particularly on the face • Vaginal yeast infection

These are not all the possible side effects of Estrace. For more information, ask your healthcare provider or pharmacist.

WHAT CAN I DO TO LOWER MY CHANCES OF A SERIOUS SIDE EFFECT WITH Estrace?

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 Estrace.

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 Estrace. 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)

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

GENERAL INFORMATION ABOUT SAFE AND EFFECTIVE USE OF Estrace

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

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

KEEP Estrace OUT OF THE REACH OF CHILDREN

This leaflet provides a summary of the most important information about Estrace. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Estrace that is written for health professionals. You can get more information by calling the toll free number 1-800-678-1605.

WHAT ARE THE INGREDIENTS IN Estrace?

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.

Mfd by: Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454

Marketed by: Allergan USA, Inc.

Irvine, CA 92612

1-800-678-1605

Estrace® is a registered trademark of Allergan Pharmaceuticals International Limited.

© 2016 Allergan. All rights reserved.

Rev. A 5/2016

Estradiol is a form of estrogen, a female sex hormone that regulates many processes in the body.

Estradiol is used to treat menopause symptoms such as hot flashes and vaginal changes, and to prevent osteoporosis (bone loss) in menopausal women.

Estradiol may also be used for purposes not listed in this medication guide.

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.