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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
Estradiol vaginal cream, USP, 0.01% is indicated in the treatment of vulvar and vaginal atrophy.
Dosage
Use of Estradiol vaginal cream, USP, 0.01%, alone or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual woman. Patients should reevaluate periodically as clinically appropriate (for example, 3-month to 6-month intervals) to determine if treatment is still necessary. For treatment of vulvar and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals.
Usual Dosage: The usual dosage range is 2 to 4 g (marked on the applicator) daily for one or two weeks, then gradually reduced to one half initial dosage for a similar period. A maintenance dosage of 1 g, one to three times a week, may be used after restoration of the vaginal mucosa has been achieved.
NOTE: The number of doses per tube will vary with dosage requirements and patient handling.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Estradiol (vaginal) in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Estradiol (vaginal) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Estradiol (vaginal) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Estradiol (vaginal) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Estradiol (vaginal) in pediatric patients.
Contraindications
ESTRACE (estradiol vaginal cream, USP, 0.01%) should not be used in women with any of the following conditions:
Estradiol vaginal cream, USP, 0.01% should not be used in patients with known hypersensitivity to its ingredients.
Known or suspected pregnancy. There is no indication for Estradiol vaginal cream, USP, 0.01% 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.
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
Systemic absorption may occur with the use of estradiol vaginal cream, USP, 0.01%. The warnings, precautions, and adverse reactions associated with oral estrogen treatment should be taken into account.
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.
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 versus 30 per 10,000 women-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 versus 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.
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.
In the CE/MPA substudy of WHI, a 2-fold 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 women-years in the CE/MPA group compared to 16 per 10,000 women-years 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 has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens 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. 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 percent 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 the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95 percent confidence interval 1.01 to 1.54), and the overall absolute risk was 41 versus 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 versus 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 versus 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 percent were 70 to 74 years of age and 18 percent were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8 percent, n = 2,229) and 21 women in the placebo group (0.9 percent, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95 percent confidence interval 1.21 to 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women.
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.
Adverse Reactions
Clinical Trials Experience
Systemic absorption may occur with the use of estradiol vaginal cream, USP, 0.01%. The warnings, precautions, and adverse reactions associated with oral estrogen treatment should be taken into account.
The following additional adverse reactions have been reported with estrogen and/or progestin therapy.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Estradiol (vaginal) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Estradiol (vaginal) during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Estradiol (vaginal) with respect to nursing mothers.
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.
Geriatic Use
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 percent (n = 3,729) were 65 to 74 while 18 percent (n = 803) were 75 and over. Most women (80 percent) 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 percent of women that were older than 70
There have not been sufficient numbers of geriatric patients involved in studies utilizing Estradiol vaginal cream, USP, 0.01% to determine whether those over 65 years of age differ from younger subjects in their response to Estradiol vaginal cream, USP, 0.01%.
Gender
There is no FDA guidance on the use of Estradiol (vaginal) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Estradiol (vaginal) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Estradiol (vaginal) in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Estradiol (vaginal) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Estradiol (vaginal) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Estradiol (vaginal) in patients who are immunocompromised.
There is limited information regarding Monitoring of Estradiol (vaginal) in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Estradiol (vaginal) in the drug label.
Overdosage
Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
There is limited information regarding Pharmacodynamics of Estradiol (vaginal) in the drug label.
Pharmacokinetics
There is limited information regarding Pharmacokinetics of Estradiol (vaginal) in the drug label.
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Estradiol (vaginal) in the drug label.
Clinical Studies
There is limited information regarding Clinical Studies of Estradiol (vaginal) in the drug label.
How Supplied
ESTRACE® (estradiol vaginal cream, USP, 0.01%).
N 0430-3754-14: Tube containing 1 ½ oz (42.5 g) with a calibrated plastic applicator for delivery of 1, 2, 3, or 4 g.
Storage
Store at room temperature. Protect from temperatures in excess of 40° C (104° F).
Keep ESTRACE Vaginal Cream out of the reach of children.
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