Estradiol (transdermal)

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Estradiol (transdermal)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]

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Black Box Warning

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA
See full prescribing information for complete Boxed Warning.
Estrogen-Alone Therapy:
  • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens
  • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia
  • The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT)
  • The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older
  • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens
  • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia
  • The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT)
  • The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older

Estrogen Plus Progestin Therapy:

  • Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia
  • The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism (PE), and myocardial infarction (MI)
  • The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer
The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older

Overview

Estradiol (transdermal) is an estrogen that is FDA approved for the treatment of moderate to severe vasomotor symptoms, symptoms of vulvar and vaginal atrophy due to menopause, hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, postmenopausal osteoporosis and prevention of postmenopausal osteoporosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include breast pain, upper respiratory tract infections, headaches, abdominal pain, pain, and edema.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

  • Dosing information:
  • Oral tablet, 1 to 2 mg ORALLY daily in a cyclical pattern (3 weeks on, 1 week off); adjust dose to control symptoms; attempt to reduce dose or discontinue therapy at 3 to 6 month intervals.

Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause

Limitation of Use:

  • When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, topical vaginal products should be considered.
  • Dosing information:
  • Atrophic vulva (Moderate to Severe) - Menopause: Oral tablet, 1 to 2 mg ORALLY daily in a cyclical pattern (3 weeks on, 1 week off); adjust to lowest dose to control symptoms, attempt to taper or discontinue at 3 to 6 month intervals.
  • Atrophy of vagina (Moderate to Severe) - Menopause: Oral tablet, 1 to 2 mg ORALLY daily in a cyclical pattern (3 weeks on, 1 week off); adjust to lowest dose to control symptoms, attempt to taper or discontinue at 3 to 6 month intervals.

Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure

  • Dosing information:
  • oral tablet, 1 to 2 mg ORALLY daily; titrate and adjust to the lowest dose as necessary to control symptoms

Prevention of Postmenopausal Osteoporosis

Limitation of Use:

  • When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.
  • Dosing information:
  • Oral tablet, 0.5 mg ORALLY daily for 23 days of a 28-day cycle.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Estradiol patch in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Estradiol patch in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Climara is not indicated in children. Clinical studies have not been conducted in the pediatric population.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Estradiol patch in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Estradiol patch in pediatric patients.

Contraindications

Climara is contraindicated in women with any of the following conditions:

Warnings

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA
See full prescribing information for complete Boxed Warning.
Estrogen-Alone Therapy:
  • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens
  • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia
  • The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT)
  • The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older
  • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens
  • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia
  • The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT)
  • The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older

Estrogen Plus Progestin Therapy:

  • Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia
  • The WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism (PE), and myocardial infarction (MI)
  • The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer
The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older

Cardiovascular Disorders

  • An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.

Stroke

  • In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.

Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1

In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women years). The increase in risk was demonstrated after the first year and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

Coronary Heart Disease

  • Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1
  • In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.
  • In postmenopausal women with documented heart disease (n = 2,763), average 66.7 years of age, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus 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 plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. A total of 2,321 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 plus MPA group and the placebo group in HERS, HERS II, and overall.

Venous Thromboembolism

  • In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years3. Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.
  • In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted4. Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.
  • 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:

  • An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times 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 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
  • Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital 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 in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Breast Cancer

  • The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer (relative risk (RR) 0.80)5.
  • The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA.
  • In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus 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 versus 25 cases per 10,000 women-years for CE plus 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 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) 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 groups6.
  • Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.
  • The use of estrogen-alone and 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.

Ovarian Cancer:

  • The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 In some epidemiological studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association.

Probable Dementia

  • In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.


  • After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8.
  • In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia.The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8.
  • When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8.

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 women 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 women 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.

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 that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

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.

Hypertriglyceridemia

  • In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.

Hepatic Impairment and/or Past History of Cholestatic Jaundice

  • Estrogens may be poorly metabolized in women with impaired liver function. For women 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.

Hypothyroidism

  • Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women 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. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Fluid Retention

  • Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal impairment, warrant careful observation when estrogen-alone is prescribed.

Hypocalcemia

Exacerbation of Endometriosis

  • A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

Hereditary Angioedema

Exacerbation of Other Conditions

Laboratory Tests

Drug-Laboratory Test Interactions


  • 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 antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
  • Increased TBG levels 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. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
  • Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-l-antitrypsin, ceruloplasmin).
  • Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, and increased triglyceride levels.
  • Impaired glucose tolerance.

Adverse Reactions

Clinical Trials Experience

  • Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
  • The data described below reflect pooled data from 5 clinical trials of Climara. A total of 614 women were exposed to Climara for 3 months (193 women at 0.025 mg per day, 201 women at 0.05 mg per day, 194 women at 0.1 mg per day) in randomized, double-blind trials of clinical efficacy versus placebo and versus active comparator. All women were postmenopausal, had a serum estradiol level of less than 20 pg/mL, and a minimum of five moderate to severe hot flushes per week or a minimum of 15 hot flushes per week of any severity at baseline. Included in this table are an additional 25 postmenopausal hysterectomized women exposed to Climara 0.025 mg per day for 6 to 24 months (N=16 at 24 months) in a randomized, double-blind, placebo-controlled study of Climara for the prevention of osteoporosis.
Estradiol adv reactions.png

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of the Climara transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Genitourinary System:
  • Breast:
  • Cardiovascular:
  • Gastrointestinal:
  • Skin:
  • Eyes:
  • Visual disturbances, contact lens intolerance,
  • Central Nervous System:
  • Miscellaneous:

Drug Interactions

Metabolic Interactions

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Climara should not be used during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as oral contraceptives inadvertently during early pregnancy.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Estradiol (transdermal) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Estradiol (transdermal) during labor and delivery.

Nursing Mothers

  • Climara should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of women receiving estrogen therapy. Caution should be exercised when the Climara transdermal system is administered to a nursing woman.

Pediatric Use

  • Climara is not indicated in children. Clinical studies have not been conducted in the pediatric population.

Geriatic Use

  • There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Climara to determine whether those over 65 years of age differ from younger subjects in their response to Climara.

The Women’s Health Initiative Studies

  • In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age.
  • In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age.

The Women’s Health Initiative Memory Study

  • In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo.
  • Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8.

Gender

There is no FDA guidance on the use of Estradiol (transdermal) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Estradiol (transdermal) with respect to specific racial populations.

Renal Impairment

  • In postmenopausal women with end stage renal disease (ESRD) receiving maintenance hemodialysis, total estradiol serum levels are higher than in normal subjects at baseline and following oral doses of estradiol. Therefore, conventional transdermal estradiol doses used in individuals with normal renal function may be excessive for postmenopausal women with ESRD receiving maintenance hemodialysis.

Hepatic Impairment

  • Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Estradiol (transdermal) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Estradiol (transdermal) in patients who are immunocompromised.

Administration and Monitoring

Administration

DOSAGE AND ADMINISTRATION

  • Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer. A woman without a uterus does not need a progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a 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. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

  • Start therapy with 0.025 mg per day applied to the skin once weekly. Therapy should be started at the lowest effective dose and the shortest duration consistent with the treatment goals. Attempts to taper or discontinue the medication should be made at 3 to 6 month intervals.

Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause

  • Start therapy with 0.025 mg per day applied to the skin once weekly. Therapy should be started at the lowest effective dose and the shortest duration consistent with the treatment goals. Attempts to taper or discontinue the medication should be made at 3 to 6 month intervals.

Treatment of Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure

  • Start therapy with 0.025 mg per day applied to the skin once weekly. The dose should be adjusted as necessary to control symptoms. Clinical responses (relief of symptoms) at the lowest effective dose should be the guide for establishing administration of the Climara transdermal system, especially in women with an intact uterus.

Prevention of Postmenopausal Osteoporosis

  • Start therapy with 0.025 mg per day applied to the skin once weekly.

Application of the Climara Transdermal System

Site Selection:

  • The adhesive side of Climara should be placed on a clean, dry area of the lower abdomen or the upper quadrant of the buttock.
  • Climara should not be applied to or near the breasts.
  • The sites of application must be rotated, with an interval of at least 1-week allowed between applications to the same site.
  • The area selected should not be oily, damaged, or irritated. The waistline should be avoided, since tight clothing may rub the transdermal system off.
  • Application to areas where sitting would dislodge Climara should also be avoided.

Application:

  • Climara should be applied immediately after opening the pouch and removing the protective liner.
  • Climara should be pressed firmly in place with the fingers for at least 10 seconds, making sure there is good contact, especially around the edges.
  • If the system lifts, apply pressure to maintain adhesion.
  • In the event that a system should fall off reapply it to a different location. If the system cannot be reapplied, a new system should be applied for the remainder of the 7-day dosing interval.
  • Only one system should be worn at any one time during the 7-day dosing interval.
  • Swimming, bathing, or using a sauna while using Climara has not been studied, and these activities may decrease the adhesion of the system and the delivery of estradiol.

Removal of the Climara Transdermal System

  • Removal of Climara should be done carefully and slowly to avoid irritation of the skin.
  • Should any adhesive remain on the skin after removal of the Climara system, allow the area to dry for 15 minutes. Then gently rubbing the area with an oil-based cream or lotion should remove the adhesive residue.
  • Used patches still contain some active hormones. Each patch should be carefully folded in half so that it sticks to itself before throwing it away.

DOSAGE FORMS AND STRENGTHS

  • Climara (estradiol transdermal system), 0.025 mg per day—each 6.5 cm2 system contains 2 mg of estradiol
  • Climara (estradiol transdermal system), 0.0375 mg per day—each 9.375 cm2 system contains 2.85 mg of estradiol
  • Climara (estradiol transdermal system), 0.05 mg per day—each 12.5 cm2 system contains 3.8 mg of estradiol
  • Climara (estradiol transdermal system), 0.060 mg per day—each 15 cm2 system contains 4.55 mg of estradiol
  • Climara (estradiol transdermal system), 0.075 mg per day—each 18.75 cm2 system contains 5.7 mg of estradiol
  • Climara (estradiol transdermal system), 0.1 mg per day—each 25.0 cm2 system contains 7.6 mg of estradiol

Monitoring

  • Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

IV Compatibility

There is limited information regarding the compatibility of Estradiol (transdermal) and IV administrations.

Overdosage

  • Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of Climara therapy with institution of appropriate symptomatic care.

Pharmacology

Estradiol image.png

Mechanism of Action

  • 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, which is secreted by the adrenal cortex, to estrone in the 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 FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Structure

  • Climara (estradiol transdermal system), is designed to release estradiol continuously upon application to intact skin. Six (6.5, 9.375, 12.5, 15, 18.75 and 25 cm2) systems are available to provide nominal in vivo delivery of 0.025, 0.0375, 0.05, 0.06, 0.075 or 0.1 mg respectively of estradiol per day. The period of use is 7 days. Each system has a contact surface area of either 6.5, 9.375, 12.5, 15, 18.75 or 25 cm2, and contains 2, 2.85, 3.8, 4.55, 5.7 or 7.6 mg of estradiol USP respectively. The composition of the systems per unit area is identical.
  • Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5(10)-triene-3, 17β-diol. It has an empirical formula of C18 H24 O2 and molecular weight of 272.38. The structural formula is:
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  • The Climara transdermal system comprises three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are:
  • A translucent polyethylene film.
  • An acrylate adhesive matrix containing estradiol USP.
  • A protective liner of siliconized or fluoropolymer-coated polyester film is attached to the adhesive surface and must be removed before the system can be used.

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  • The active component of the transdermal system is estradiol. The remaining components of the transdermal system (acrylate copolymer adhesive, fatty acid esters, and polyethylene backing) are pharmacologically inactive.

Pharmacodynamics

  • There are no pharmacodynamic data for Climara.

Pharmacokinetics

Absorption

  • Transdermal administration of Climara produces mean serum concentrations of estradiol comparable to those produced by premenopausal women in the early follicular phase of the ovulatory cycle. The pharmacokinetics of estradiol following application of the Climara transdermal system were investigated in 197 healthy postmenopausal women in six studies. In five of the studies, the Climara transdermal system was applied to the abdomen, and in a sixth study, application to the buttocks and abdomen were compared.
  • The Climara transdermal delivery system continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7-day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first pass metabolism when estradiol is given by the transdermal route.
  • In a bioavailability study, the Climara 6.5 cm2 was studied with the Climara 12.5 cm2 as reference. The mean estradiol levels in serum from the two sizes are shown in Figure 1.
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  • Dose proportionality was demonstrated for the Climara 6.5 cm2 transdermal system as compared to the Climara 12.5 cm2 transdermal system in a 2-week crossover study with a 1-week washout period between the two-transdermal systems in 24 postmenopausal women.
  • Dose proportionality was also demonstrated for the Climara transdermal system (12.5 cm2 and 25 cm2) in a 1-week study conducted in 54 postmenopausal women. The mean steady state levels (Cavg) of the estradiol during the application of Climara 25 cm2 and 12.5 cm2 on the abdomen were about 80 and 40 pg/mL, respectively.
  • In a 3-week multiple application study in 24 postmenopausal women, the 25 cm2 Climara transdermal system produced average peak estradiol concentrations (Cmax) of approximately 100 pg/mL. Trough values at the end of each wear interval (Cmin) were approximately 35 pg/mL. Nearly identical serum curves were seen each week, indicating little or no accumulation of estradiol in the body. Serum estrone peak and trough levels were 60 and 40 pg/mL, respectively.
  • In a single dose, randomized, crossover study conducted to compare the effect of site of application, 38 postmenopausal women wore a single Climara 25 cm2 transdermal system for 1 week on the abdomen and buttocks. The estradiol serum concentration profiles are shown in Figure 2. Values of Cmax and Cavg were, respectively, 25 percent and 17 percent higher with the buttock application than with the abdomen application.
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  • The relative standard deviation of each pharmacokinetic parameter after application to the abdomen averaged 50 percent, which is indicative of the considerable intersubject variability associated with transdermal drug delivery. The relative standard deviation of each pharmacokinetic parameter after application to the buttock was lower than that after application to the abdomen (for example, for Cmax 39 percent versus 62 percent, and for Cavg 35 percent versus 48 percent).

Distribution

  • 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 SHBG and albumin.

Metabolism

  • 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 a 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 intestine 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.

Excretion

Adhesion

  • An open-label study of adhesion potentials of placebo transdermal systems that correspond to the 6.5 cm2 and 12.5 cm2 sizes of Climara was conducted in 112 healthy women of 45 to 75 years of age. Each woman applied both transdermal systems weekly, on the upper outer abdomen, for 3 consecutive weeks. It should be noted that lower abdomen and upper quadrant of the buttock are the approved sites of application for Climara.
  • The adhesion assessment was done visually on Days 2, 4, 5, 6, 7 of each week of transdermal system wear. A total of 1,654 adhesion observations were conducted for 333 transdermal systems of each size.
  • Of these observations, approximately 90 percent showed essentially no lift for both the 6.5 cm2 and 12.5 cm2 transdermal systems. Of the total number of transdermal systems applied, approximately 5 percent showed complete detachment for each size. Adhesion potentials of the 18.75 cm2 and 25 cm2 sizes of transdermal systems (0.075 mg per day and 0.1 mg per day) have not been studied.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Clinical Studies

Effects on Vasomotor Symptoms

  • A study of 214 women 25 to 74 years of age met the qualification criteria and were randomly assigned to one of the three treatment groups: 72 to the 0.05 mg estradiol patch, 70 to the 0.1 mg estradiol patch, and 72 to placebo. Potential subjects were postmenopausal women in good general health who experienced vasomotor symptoms. Natural menopause patients had not menstruated for at least 12 months and surgical menopause patients had undergone bilateral oophorectomy at least 4 weeks before evaluation for study entry. In order to enter the 11-week treatment phase of the study, potential subjects must have experienced a minimum of five moderate to severe hot flushes per week, or a minimum of 15 hot flushes of any severity per week, for 2 consecutive weeks. Women wore the patches in a cyclical fashion (three weeks on and one week off).
  • During treatment, all subjects used diaries to record the number and severity of hot flushes. Subjects were monitored by clinic visits at the end of weeks 1, 3, 7, and 11 and by telephone at the end of weeks 4, 5, 8, and 9.
  • Adequate data for the analysis of efficacy was available from 191 subjects. The results are presented as the mean ± SD number of flushes in each of the 3 treatment weeks of each 4-week cycle. In the 0.05 mg estradiol group, the mean weekly hot flush rate across all treatment cycles decreased from 46 ± 6.5 at baseline to 20 ± 3 (-67 percent). The 0.1 mg estradiol group had a decline in the mean weekly hot flush rate from 52 ± 4.4 at baseline to 16 ± 2.4 (-72 percent). In the placebo group, the mean weekly hot flush rate declined from 53 ± 4.5 at baseline to 46 ± 6.5 (-18.1 percent). Compared with placebo, the 0.05 mg and 0.1 mg estradiol groups showed a statistically significantly larger mean decrease in hot flushes across all treatment cycles (P<0.05). When the response to treatment was analyzed for each of the three cycles of therapy, similar statistically significant differences were observed between both estradiol treatment groups and the placebo group during all treatment cycles.
  • In a double-blind, placebo-controlled, randomized study of 187 women receiving Climara 0.025 mg per day or placebo continuously for up to three 28-day cycles, the Climara 0.025 mg per day dosage was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms.

Table 3: Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms Intent to Treat (ITT)

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Effects on Bone Mineral Density

  • A two-year clinical trial enrolled a total of 175 healthy, hysterectomized, postmenopausal, non-osteoporotic (that is, lumbar spine bone mineral density >0.9 gm/cm2) women at 10 study centers in the United States. A total of 129 subjects were allocated to receive active treatment with 4 different doses of estradiol patches (6.5, 12.5, 15, 25 cm2) and 46 subjects were allocated to receive placebo patches. Seventy-seven percent of the randomized subjects (100 on active drug and 34 on placebo) contributed data to the analysis of percent change of anterior-posterior (A-P) spine BMD, the primary efficacy variable (see Figure 3). A statistically significant overall treatment effect at each timepoint was noted, implying bone preservation for all active treatment groups at all timepoints, as opposed to bone loss for placebo at all timepoints.
  • Figure 3: Mean Percent Change from Baseline in Lumbar Spine (A-P View) Bone Mineral Density By Treatment

and Time Last Observation Carried Forward

  • Figure 3: Mean Percent Change from Baseline in Lumbar Spine (A-P View) Bone Mineral Density By Treatment and Time Last Observation Carried Forward
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Percent change in BMD of the total hip (see Figure 4) was also statistically significantly different from placebo for all active treatment groups. This figure is based on 74 percent of the randomized subjects (95 on active drug and 34 on placebo).

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Women's Health Initiative Studies

  • The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.

WHI Estrogen-Alone Substudy

  • The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risk and benefits of estrogen-alone in predetermined primary endpoints.
  • Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79: 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 4.
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  • For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risks per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9 The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.
  • No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years. See Table 4.
  • Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in the distribution of stroke subtype and severity, including fatal strokes, in women receiving estrogen-alone compared to placebo. Estrogen-alone increased the risk of ischemic stroke, and this excess risk was present in all subgroups of women examined.10 See Table 4.
  • Timing of initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk-benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].

WHI Estrogen Plus Progestin Substudy

  • The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.
  • For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.
  • Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.5 percent Black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 5 . These results reflect centrally adjudicated data after an average follow-up of 5.6 years.
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  • Timing of initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)].

Women's Health Initiative Memory Study

  • The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.
  • After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in the study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.
  • The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.
  • After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in the study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.
  • When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women.

How Supplied

  • Climara (estradiol transdermal system), 0.025 mg per day — each 6.5 cm2 system contains 2 mg of estradiol USP
  • Individual Carton of 4 systems NDC 50419-454-04
  • Climara (estradiol transdermal system), 0.0375 mg per day — each 9.375 cm2 system contains 2.85 mg of estradiol USP
  • Individual Carton of 4 systems NDC 50419-456-04
  • Climara (estradiol transdermal system), 0.05 mg per day — each 12.5 cm2 system contains 3.8 mg of estradiol USP
  • Individual Carton of 4 systems NDC 50419-451-04
  • Climara (estradiol transdermal system), 0.06 mg per day — each 15 cm2 system contains 4.55 mg of estradiol USP
  • Individual Carton of 4 systems NDC 50419-459-04
  • Climara (estradiol transdermal system), 0.075 mg per day — each 18.75 cm2 system contains 5.7 mg of estradiol USP
  • Individual Carton of 4 systems NDC 50419-453-04
  • Climara (estradiol transdermal system), 0.1 mg per day — each 25 cm2 system contains 7.6 mg of estradiol USP
  • Individual Carton of 4 systems NDC 50419-452-04

Storage

  • Store at 20°C to 25°C (66°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Do not store above 86°F (30°C).
  • Do not store unpouched. Apply immediately upon removal from the protective pouch.
  • Used transdermal systems still contain active hormone. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet

Images

Drug Images

Package and Label Display Panel

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Patient Counseling Information

See FDA-approved patient labeling (Patient Information and Instructions for Use)

Vaginal Bleeding

  • Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible.

Possible Serious Adverse Reactions with Estrogen-Alone Therapy

  • Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including cardiovascular disorders, malignant neoplasms, and probable dementia.

Possible Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy

  • Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting.
  • Patient Package Insert
  • Patient Information

Climara (Klī-mâr-uh)

(estradiol transdermal system)

  • Read this Patient Information before you start using Climara and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.
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Precautions with Alcohol

Alcohol-Estradiol patch interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Alora Climara Esclim, Estrace, Estraderm, Estrasorb, Estring, EstroGel.

Look-Alike Drug Names

There is limited information regarding Estradiol (transdermal) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.


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