Generic: estradiol
is used for the treatment of
Breast NeoplasmsHemorrhageHypogonadismLiver DiseasesMenopause, PrematureMenorrhagiaNeoplasms, Hormone-DependentPorphyriasPregnancyProstatic NeoplasmsPulmonary EmbolismThromboembolismThrombophlebitisOsteoporosis, PostmenopausalPrimary Ovarian InsufficiencyHot FlashesVenous Thrombosis
Pregnancy Risk
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.
Evamist 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 an oral contraceptive inadvertently during early
pregnancy.
Evamist should not be used during pregnancy [see
Contraindications (4)]. There appears to be little or
no increased risk of birth defects in children born to women who have used
estrogens and progestins as an oral contraceptive inadvertently during early
pregnancy.
Evamist should not be used during lactation. 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.
Boxed Warning
Boxed Warning Section
WARNING -- ENDOMETRIAL CANCER, CARDIOVASCULAR AND OTHER RISKS
ENDOMETRIAL CANCER
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 [see
Warnings and Precautions (5.2)].
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of
cardiovascular disease or dementia [see Warnings and
Precautions (5.1) and (5.3) and Clinical
Studies (14.4 and 14.5)].
The Women's Health Initiative (WHI) estrogen alone substudy reported
increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women
(50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of
treatment with daily oral conjugated estrogens (CE 0.625 mg), relative to
placebo [see Warnings and Precautions (5.1) and Clinical Studies (14.4)].
The estrogen plus progestin WHI substudy reported increased risk of
myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and DVT
in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment
with daily oral CE 0.625 mg combined with medroxyprogesterone acetate (MPA 2.5
mg), relative to placebo [see Warnings and Precautions (5.1) and (5.2) and Clinical Studies (14.4)].
The Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI,
reported increased risk of developing probable dementia in postmenopausal women
65 years of age or older during 5.2 years of treatment with daily CE 0.625 mg
alone and during 4 years of treatment with daily CE 0.625 mg combined with MPA
2.5 mg, relative to placebo. It is unknown whether this finding applies to
younger postmenopausal women [see Warnings and Precautions
(5.3), Use in Specific Populations (8.5)
and Clinical Studies (14.5)].
In the absence of comparable data, these risks should be assumed to be
similar for other doses of CE and MPA and other combinations and dosage forms of
estrogens and progestins. 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.
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR
DISORDERS, BREAST CANCER, AND PROBABLE DEMENTIASee full prescribing information for complete boxed
warning.
There is an increased risk of endometrial cancer in women
with a uterus who use unopposed estrogens (5.2)
Women's Health Initiative substudies reported increased
risks of stroke, deep vein thrombosis, pulmonary embolism, invasive breast
cancer, myocardial infarction, and probable dementia (14.4,
14.5)
Estrogens with or without progestins should not be used for
the prevention of cardiovascular disease or dementia (5.1, 5.3)
Use estrogens with or without progestins at the lowest dose
and for the shortest duration consistent with treatment goals and individual
risks (2)
WARNING -- ENDOMETRIAL CANCER, CARDIOVASCULAR AND OTHER RISKS ENDOMETRIAL CANCER
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 [see
Warnings and Precautions (5.2)].
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of
cardiovascular disease or dementia [see Warnings and
Precautions (5.1) and (5.3) and Clinical
Studies (14.4 and 14.5)].
The Women's Health Initiative (WHI) estrogen alone substudy reported
increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women
(50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of
treatment with daily oral conjugated estrogens (CE 0.625 mg), relative to
placebo [see Warnings and Precautions (5.1) and Clinical Studies (14.4)].
The estrogen plus progestin WHI substudy reported increased risk of
myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and DVT
in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment
with daily oral CE 0.625 mg combined with medroxyprogesterone acetate (MPA 2.5
mg), relative to placebo [see Warnings and Precautions (5.1) and (5.2) and Clinical Studies (14.4)].
The Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI,
reported increased risk of developing probable dementia in postmenopausal women
65 years of age or older during 5.2 years of treatment with daily CE 0.625 mg
alone and during 4 years of treatment with daily CE 0.625 mg combined with MPA
2.5 mg, relative to placebo. It is unknown whether this finding applies to
younger postmenopausal women [see Warnings and Precautions
(5.3), Use in Specific Populations (8.5)
and Clinical Studies (14.5)].
In the absence of comparable data, these risks should be assumed to be
similar for other doses of CE and MPA and other combinations and dosage forms of
estrogens and progestins. 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.
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR
DISORDERS, BREAST CANCER, AND PROBABLE DEMENTIA
See full prescribing information for complete boxed
warning.
There is an increased risk of endometrial cancer in women
with a uterus who use unopposed estrogens (5.2)
Women's Health Initiative substudies reported increased
risks of stroke, deep vein thrombosis, pulmonary embolism, invasive breast
cancer, myocardial infarction, and probable dementia (14.4,
14.5)
Estrogens with or without progestins should not be used for
the prevention of cardiovascular disease or dementia (5.1, 5.3)
Use estrogens with or without progestins at the lowest dose
and for the shortest duration consistent with treatment goals and individual
risks (2)
1 Indications And Usage
Evamist (estradiol transdermal spray) is an estrogen indicated for the treatment
of moderate to severe vasomotor symptoms due to menopause.
Evamist is an estrogen indicated for the treatment of moderate to
severe vasomotor symptoms due to menopause (1)
2 Dosage And Administration
Enter section text here
One spray once daily to forearm as a starting dose (2.2)
Increase to two or three sprays daily to forearm based upon clinical
response (2.2)
2.1 General Dosing Information
When estrogen is prescribed for a postmenopausal woman with a
uterus, generally, a progestin should also be initiated to reduce the risk of
endometrial cancer. A woman without a uterus does not need progestin.
Use of estrogen, alone or in combination with a progestin, should be with the
lowest effective dose and for the shortest duration consistent with treatment
goals and risks for the individual woman. Postmenopausal women should be
re-evaluated periodically as clinically appropriate (for example at 3-month to
6-month intervals) to determine if treatment is still necessary.
2.2 Treatment of Moderate to Severe Vasomotor Symptoms
Evamist therapy should be initiated with one spray per day.
Dosage adjustment should be guided by the clinical response.
Before applying the first dose from a new applicator, the pump should be
primed by spraying 3 sprays with the cover on. The container should be held
upright and vertical for spraying.
One, two or three sprays are applied each morning to adjacent,
non-overlapping areas on the inner surface of the forearm, starting near the
elbow. Sprays should be allowed to dry for approximately 2 minutes and the site
should not be washed for 30 minutes. Application of Evamist to other skin
surfaces has not been adequately studied. Evamist should not be applied to skin
surfaces other than the forearm.
3 Dosage Forms And Strengths
Evamist is an estradiol transdermal spray. One spray delivers 90 mcL that
contains 1.53 mg of estradiol.
One spray delivers 90 mcL that contains 1.53 mg estradiol
4 Contraindications
Evamist should not be used in women with any of the following
conditions:
Undiagnosed abnormal genital bleeding
Known, suspected, or history of cancer of the breast
Known or suspected estrogen-dependent neoplasia
Active deep vein thrombosis, pulmonary embolism, or history of these
conditions
Active or recent (within the past year) arterial thromboembolic disease (for
example, stroke and myocardial infarction)
Known liver dysfunction or disease
Known or suspected pregnancy
Undiagnosed abnormal genital bleeding (4)
Known, suspected, or history of cancer of the breast (4,
5.2)
Known or suspected estrogen-dependent neoplasia (4, 5.2)
Active deep vein thrombosis, pulmonary embolism, or history of these
conditions (4, 5.1)
Active or recent (within the past year) arterial thromboembolic disease (for
example, stroke and myocardial infarction) (4, 5.1)
Known liver dysfunction or disease (4, 5.9)
Known or suspected pregnancy (4, 8.1)
5 Warnings And Precautions
Enter section text here
An increased risk of stroke, deep vein thrombosis, pulmonary embolism,
myocardial infarction, and probable dementia has been reported with the use of
estrogens with or without progestins (5.1, 5.3)
An increased risk of invasive breast cancer has been reported with the use
of estrogens plus progestins (5.2)
Estrogens increase the risk of gallbladder disease (5.4)
Discontinue estrogens if severe hypercalcemia, loss of vision, severe
hypertriglyceridemia or cholestatic jaundice occurs (5.5, 5.6, 5.9, 5.10)
Monitor thyroid function in women on thyroid hormone replacement therapy (5.11, 5.19)
5.1 Cardiovascular Disorders
An increased risk of stroke and deep vein thrombosis (DVT) has
been reported with estrogen alone therapy. An increased risk of stroke, DVT,
pulmonary embolism, and myocardial infarction has been reported with estrogen
plus progestin therapy. Should any of these occur or be suspected, estrogens
with or without progestins should be discontinued immediately.
Risk factors for arterial vascular disease (for example, hypertension,
diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous
thromboembolism (for example, personal history or family history of venous
thromboembolism [VTE], obesity, and systemic lupus erythematosus) should be
managed appropriately. Stroke
In the Women's Health Initiative (WHI) estrogen alone substudy, a
statistically significant increased risk of stroke was reported in women
receiving daily conjugated estrogens (CE 0.625 mg) compared to placebo (45
versus 33 per 10,000 women-years). The increase in risk was demonstrated in year
1 and persisted1[see Clinical Studies
(14.4)].
In the estrogen plus progestin substudy of WHI, a statistically significant
increased risk of stroke was reported in women receiving daily CE 0.625 mg plus
medroxyprogesterone acetate (MPA 2.5 mg) compared to placebo (31 versus 24 per
10,000 women-years). The increase in risk was demonstrated after the first year
and persisted [see Clinical Studies (14.4)]. Coronary heart disease
In the estrogen alone substudy of WHI, no overall effect on coronary heart
disease (CHD) events (defined as non-fatal myocardial infarction [MI], silent
MI, or CHD death) was reported in women receiving estrogen alone compared to
placebo2[see Clinical Studies (14.4)].
In the estrogen plus progestin substudy of the WHI, no statistically
significant increase of CHD events was reported in women receiving CE/MPA
compared to women receiving placebo (39 versus 33 per 10,000 women-years). An
increase in relative risk was demonstrated in year 1, and a trend toward
decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.4)].
In postmenopausal women with documented heart disease (n = 2,763, average age
66.7 years), 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/MPA 2.5 mg 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 (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/MPA group and the placebo group in HERS, HERS II, and overall. Venous Thromboembolism (VTE)
In the estrogen alone substudy of WHI, the risk of VTE (DVT and pulmonary
embolism [PE]) was reported to be increased for women receiving daily CE
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 two
years3[see Clinical Studies (14.4)].
In the estrogen plus progestin substudy of WHI, a statistically significant
two-fold greater rate of VTE was reported in women receiving daily CE/MPA
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 observed during the first year and
persisted [see Clinical Studies (14.4)].
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.
5.2 Malignant Neoplasms
Endometrial Cancer
An increased risk of endometrial cancer has been reported with the use of
unopposed estrogen therapy in women with a uterus. The reported endometrial
cancer risk among unopposed estrogen users is about 2 to 12 times greater than
in nonusers, 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 an increased risk 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 plus progestin therapy 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 most important randomized clinical trial providing information about this
issue in estrogen alone users is the Women's Health Initiative (WHI) substudy of
daily conjugated estrogens (CE 0.625 mg). In the estrogen alone substudy of WHI,
after an average of 7.1 years of follow-up, daily CE 0.625 mg was not associated
with an increased risk of invasive breast cancer (relative risk [RR] 0.80, 95
percent nominal confidence interval [nCI] 0.62-1.04) [see
Clinical Studies (14.4)].
The most important randomized clinical trial providing information about this
issue in estrogen plus progestin users is the Women's Health Initiative (WHI)
substudy of daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg). In
the estrogen plus progestin substudy, after a mean follow-up of 5.6 years, the
WHI substudy reported an increased risk of breast cancer in women who took daily
CE/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 (95 percent nCI 1.01-1.54), and the absolute risk was 41
versus 33 cases per 10,000 women-years, for estrogen plus progestin compared
with placebo, respectively. 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 estrogen plus progestin
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 estrogen plus progestin 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 [see
Clinical Studies (14.4)].
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 found
significant variation in the risk of breast cancer among different estrogens or
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 estrogen plus progestin substudy of the WHI reported that daily CE/MPA
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
percent nCI, 0.77-3.24) but was not statistically significant. The absolute risk
for CE/MPA vs. placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some
epidemiologic studies, the use of estrogen-only products, in particular for 10
or more years, has been associated with an increased risk of ovarian cancer.
Other epidemiologic studies have not found these associations.
5.3 Dementia
In the estrogen alone Women's Health Initiative Memory Study
(WHIMS), a substudy of the WHI, a population of 2,947 hysterectomized women 65
to 79 years of age was randomized to daily conjugated estrogens (CE 0.625 mg) or
placebo. In the estrogen plus progestin WHIMS substudy, a population of 4,532
postmenopausal women 65 to 79 years of age was randomized to daily CE 0.625 mg
plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo.
In the estrogen alone substudy, after an average follow-up of 5.2 years, 28
women in the CE 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-years [see Use in Specific Populations (8.5) and Clinical Studies (14.5)].
In the estrogen plus progestin substudy, after an average follow-up of 4
years, 40 women in the CE/MPA group and 21 women in the placebo group were
diagnosed with probable dementia. The relative risk of probable dementia for
CE/MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of
probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000
women-years [see Use in Specific Populations (8.5) and Clinical Studies (14.5)].
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). Since both substudies were conducted in women 65 to 79
years of age, it is unknown whether these findings apply to younger
postmenopausal women [see Use in Specific Populations (8.5) and Clinical Studies (14.5)].
5.4 Gallbladder Disease
A two- to four-fold increase in the risk of gallbladder disease requiring
surgery in postmenopausal women receiving estrogens has been reported.
5.5 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.
5.6 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.
5.7 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 a
possible increased risk of breast cancer, adverse effects on lipoprotein
metabolism (lowering HDL, raising LDL), and impairment of glucose tolerance.
5.8 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.
5.9 Hypertriglyceridemia
In women with preexisting hypertriglyceridemia, estrogen therapy may be
associated with elevations of plasma triglycerides leading to pancreatitis and
other complications. Consider discontinuation of treatment if pancreatitis or
other complications develop.
5.10 Impaired Liver Function and 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.
5.11 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 hormone replacement
therapy. These women should have their thyroid function monitored in order to
maintain their free thyroid hormone levels in an acceptable range.
5.12 Fluid Retention
Estrogens may cause some degree of fluid retention. Women who have conditions
that might be influenced by this factor, such as a cardiac or renal dysfunction,
warrant careful observation when estrogens are prescribed.
5.13 Hypocalcemia
Estrogens should be used with caution in women with preexisting severe
hypocalcemia.
5.14 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 women known
to have residual endometriosis post-hysterectomy, the addition of progestin
should be considered.
5.15 Exacerbation of Other Conditions
Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy,
migraine, porphyria, systemic lupus erythematosus and hepatic hemangiomas and
should be used with caution in women with these conditions.
5.16 Alcohol-Based Products are Flammable
Avoid fire, flame or smoking until the spray has dried.
5.17 Application of Sunscreen
When sunscreen is applied approximately one hour after application of Evamist,
estradiol absorption was decreased by 11 percent. When sunscreen is applied
approximately one hour before the application of Evamist, no significant change
in estradiol absorption was observed.
5.18 Laboratory Tests
Serum follicle stimulating hormone and estradiol levels have not been shown to
be useful in the management of moderate to severe vasomotor symptoms.
5.19 Drug and 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
levels, 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 hormone
replacement therapy may require higher doses of thyroid hormone.
Other binding proteins may be elevated in serum (corticosteroid binding
globulin [CBG], SHBG), leading to increased total circulating corticosteroids
and sex steroids, respectively. Free hormone concentrations, such as
testosterone and estradiol, may be decreased. As with other transdermal
estradiol products, a slight increase in SHBG was seen with Evamist active drug
compared with baseline.
Most common adverse reactions (≥5%) are: headache, breast
tenderness and nipple pain, nausea, back pain, and nasopharyngitis (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Ther-Rx
Corporation at 1-877-567-7676 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Study 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.
In a 12-week, randomized, placebo-controlled trial of Evamist in 454 women,
80-90 percent of women randomized to active drug received at least 70 days of
therapy and 75-85 percent randomized to placebo received at least 70 days of
therapy.
The adverse reactions that occurred in at least 5 percent of women in any
treatment group are shown in Table 1.
Table 1. Frequency of Adverse Reactions (≥ 5%) in Any Treatment Group
in a Controlled Study of Evamist
Frequency n (%)
System Organ Class Preferred Term
1
Spray
2
Sprays
3
Sprays
Placebo (N = 77)
Evamist (N = 76)
Placebo (N = 76)
Evamist (N = 74)
Placebo (N = 75)
Evamist (N = 76)
Reproductive System and Breast Disorders
Breast tenderness
0 (0)
4 (5)
4 (5)
5 (7)
0 (0)
4 (5)
Nipple pain
0 (0)
2 (3)
0 (0)
5 (7)
0 (0)
1 (1)
Gastrointestinal Disorders
Nausea
5 (7)
1 (1)
1 (1)
2 (3)
4 (5)
2 (3)
Infections and Infestations
Nasopharyngitis
1 (1)
4 (5)
2 (3)
3 (4)
1 (1)
1 (1)
Musculoskeletal and Connective Tissue Disorders
Back pain
1 (1)
2 (3)
2 (3)
4 (5)
1 (1)
2 (3)
Arthralgia
1 (1)
1 (1)
4 (5)
1 (1)
0 (0)
3 (4)
Nervous system
Headache
4 (5)
7 (9)
5 (7)
9 (12)
7 (9)
8 (11)
Application site reactions were reported in 3 out of 226 (1.3%) women treated
with Evamist.
6.2 Additional Adverse Reactions Reported With Estrogen and/or Progestin Therapy
The following additional adverse reactions have been reported
with estrogen and/or progestin therapy. Genitourinary System
Abnormal uterine bleeding/spotting, dysmenorrhea/pelvic pain, increase in
size of uterine leiomyomata, vaginitis including vaginal candidiasis, change in
amount of cervical secretion, changes in cervical ectropion, ovarian cancer,
endometrial hyperplasia, endometrial cancer. Breasts
Tenderness, enlargement, pain, nipple discharge, galactorrhea, fibrocystic
breast changes, breast cancer. Cardiovascular
Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis,
myocardial infarction, stroke, increase in blood pressure. Gastrointestinal
Nausea, vomiting, abdominal cramps, bloating, cholestatic jaundice, increased
incidence of gallbladder disease, pancreatitis, enlargement of hepatic
hemangiomas. Skin
Chloasma or melasma, that may persist when drug is discontinued; erythema
multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair,
hirsutism, pruritus, rash. Eyes
Retinal vascular thrombosis, intolerance to contact lenses. Central Nervous System
Headache, migraine, dizziness, mental depression, exacerbation of chorea,
nervousness, mood disturbances, irritability, exacerbation of epilepsy,
dementia. Miscellaneous
Increase or decrease in weight, glucose intolerance, aggravation of
porphyria, edema, arthralgias, leg cramps, changes in libido, urticaria,
angioedema, anaphylactoid/anaphylactic reactions, hypocalcemia (preexisting
condition), exacerbation of asthma, increased triglycerides.
7 Drug Interactions
No formal drug interaction studies have been conducted for Evamist.
Estrogen products may interact with inducers and inhibitors of CYP3A4 (7.1)
7.1 Metabolic Interactions
In vitro and in vivo studies have shown that estrogens are metabolized partially
by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may
affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort
preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin
may reduce plasma concentrations of estrogens, possibly resulting in a decrease
in therapeutic effects and/or changes in the uterine bleeding profile.
Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole,
itraconazole, ritonavir and grapefruit juice may increase plasma concentrations
of estrogens and may result in side effects.
8 Use In Specific Populations
Enter section text here
Nursing Mothers: Estrogen administration to nursing mothers has been shown
to decrease the quantity and quality of the breast milk (8.3)
Geriatric Use: An increased risk of probable dementia in women over 70 years
of age was reported in the two substudies of the Women's Health Initiative
Memory Study (8.5)
8.1 Pregnancy
Evamist should not be used during pregnancy [see
Contraindications (4)]. There appears to be little or
no increased risk of birth defects in children born to women who have used
estrogens and progestins as an oral contraceptive inadvertently during early
pregnancy.
8.3 Nursing Mothers
Evamist should not be used during lactation. 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.
8.4 Pediatric Use
Evamist is not intended for pediatric use and no clinical data have been
collected in children.
8.5 Geriatric Use
There have not been sufficient numbers of geriatric women
involved in studies utilizing Evamist to determine whether those over 65 years
of age differ from younger subjects in their response to Evamist.
In the estrogen alone substudy of the Women's Health Initiative (WHI) study,
46 percent (n = 4,943) of women were 65 years of age and older, while 7.1
percent (n = 767) of women were 75 years of age and older. There was a higher
relative risk (daily conjugated estrogens [CE 0.625 mg] versus placebo) of
stroke in women less than 75 years of age compared to women 75 years of age and
older.
In the estrogen alone substudy of the Women's Health Initiative Memory Study
(WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women, 65 to
79 years of age, was randomized to receive daily conjugated estrogens (CE 0.625
mg) or placebo. After an average follow-up of 5.2 years, the relative risk (CE
versus placebo) of probable dementia was 1.49 (95 percent CI, 0.83-2.66). The
absolute risk of developing probable dementia with estrogen alone was 37 versus
25 cases per 10,000 women-years compared to placebo.
Of the total number of women in the estrogen plus progestin substudy of WHI,
44 percent (n = 7,320) were 65 years of age and older, while 6.6 percent
(n = 1,095) were 75 years of age and older. In women 75 years of age and older
compared to women less than 75 years of age, there was a higher relative risk of
non-fatal stroke and invasive breast cancer in the estrogen plus progestin group
versus placebo. In women greater than 75 years of age, the increased risk of
non-fatal stroke and invasive breast cancer observed in the estrogen plus
progestin group compared to placebo was 75 versus 24 per 10,000 women-years and
52 versus 12 per 10,000 women-years, respectively.
In the estrogen plus progestin WHIMS substudy, a population of 4,532
postmenopausal women, 65 to 79 years of age, was randomized to receive daily CE
0.625 mg/MPA 2.5 mg or placebo. In the estrogen plus progestin group, after an
average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of
probable dementia was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of
developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000
women-years compared to placebo.
Seventy-nine (79) percent of the cases of probable dementia occurred in women
that were older than 70 for the CE alone group, and 82 percent of the cases of
probable dementia occurred in women who were older than 70 in the CE/MPA group.
The most common classification of probable dementia in both the treatment groups
and placebo groups was Alzheimer's disease.
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). Since both substudies were conducted in women 65 to 79
years of age, it is unknown whether these findings apply to younger
postmenopausal women [see Warnings and Precautions (5.3)].
10 Overdosage
Overdosage of estrogen may cause nausea and vomiting, breast tenderness,
dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur
in women. Treatment of overdose consists of discontinuation of Evamist together
with institution of appropriate symptomatic care.
11 Description
Evamist (estradiol transdermal spray) is designed to deliver
estradiol to the blood circulation following topical application to the skin of
a rapidly drying solution from a metered-dose pump.
Evamist is a homogeneous solution of 1.7% estradiol USP (active ingredient)
in alcohol USP and octisalate USP formulated to provide sustained release of the
active ingredient into the systemic circulation.
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 C18H24O2·1/2 H2O and molecular weight of 281.4.
The structural formula is:
Each metered-dose pump contains 8.1 mL and is designed to accurately deliver
75 sprays of 90 mcL each after priming. One spray of Evamist contains 1.53 mg
estradiol. The metered-dose pump should be held upright and vertical for
spraying. Before a new applicator is used for the first time, the pump should be
primed by spraying 3 times into the cover.
One, two or three sprays are applied daily to adjacent non-overlapping 20
cm2 areas on the inner surface of the arm between the
elbow and the wrist and allowed to dry.
12 Clinical Pharmacology
Enter section text here
12.1 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, secreted by the adrenal cortex, to
estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form,
estrone sulfate, are the most abundant circulating estrogens in postmenopausal
women.
12.2 Pharmacodynamics
Estrogens act through binding to nuclear receptors in
estrogen-responsive tissues. To date, two estrogen receptors have been
identified. These vary in proportions from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins,
luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a
negative feedback mechanism. Estrogens act to reduce the elevated levels of
these hormones seen in postmenopausal women.
12.3 Pharmacokinetics
Absorption
In a multiple-dose study, 72 postmenopausal women were treated for 14 days
with Evamist to the inner forearm. Serum concentrations of estradiol appeared to
reach steady state after 7 to 8 days of application of one, two, or three 90-mcL
sprays of Evamist per day (Figure 1).
Figure 1. Mean (±SD) Serum Estradiol Concentrations
on Day 14 Following Topical Application for 14 Days of One, Two or Three Sprays
of Evamist (Unadjusted for Baseline)
Pharmacokinetics parameters for estradiol from one, two, or three 90-mcL
sprays of Evamist, as assessed on Day 14 of this study, are described in Table 2.
Table 2. Estradiol Pharmacokinetic Parameters on Day 14 (Unadjusted for
Baseline)
1 Values expressed are arithmetic
means (%CV)
2 Values expressed are medians
(minimum-maximum)
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 blood largely bound to sex hormone binding globulin (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
Estradiol, estrone and estriol are excreted in the urine along with
glucuronide and sulfate conjugates.
13 Nonclinical Toxicology
Enter section text here
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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.
14 Clinical Studies
Enter section text here
14.1 Effects on Vasomotor Symptoms
In a 12-week, randomized, double-blind, placebo-controlled
clinical trial, a total of 454 postmenopausal women (average 53 years of age, 70
percent Caucasian and 24 percent African-American) were randomized and received
at least one dose of Evamist (one, two or three 90-mcL sprays) or placebo.
Generally healthy postmenopausal women were enrolled with a mean total frequency
of greater than or equal to 56 moderate to severe vasomotor symptoms per week (greater than or equal to 8 per day).
Efficacy was determined as a statistically significant and clinically
significant (at least two per day or 14 per week difference) reduction in hot
flush frequency and a statistically significant reduction in severity for
Evamist versus placebo. One, two or three daily sprays of Evamist were shown to
be better than placebo for relief of frequency (Table 3) and
severity (Table 4) of moderate to severe vasomotor symptoms at
Week 4 and Week 12.
Table 3. Effect of Treatment on the Daily Frequency of Moderate to
Severe Vasomotor Symptoms at Week 4 and Week 12 (Intent-To-Treat Population,
LOCF)
Mean Change from Baselinea(SD)
Treatment(N)
Baseline
Mean (SD)
Week 4
Mean (SD)
Week 12
Mean (SD)
1 Spray
Evamist (N=76)
11.81 (4.07)
-6.26 (4.01)
-8.10 (4.02)
Placebo (N=77)
12.41 (5.59)
-3.64 (5.30)
-4.76 (5.84)
Differenceb
—
-2.62
-3.34
p-valuec
—
0.0010
0.0004
2 Sprays
Evamist (N=74)
12.66 (7.33)
-7.30 (6.93)
-8.66 (6.65)
Placebo (N=76)
12.13 (6.10)
-4.74 (4.38)
-6.19 (5.77)
Differenceb
—
-2.56
-2.47
p-valuec
—
0.0027
0.0099
3 Sprays
Evamist (N=76)
10.78 (3.58)
-6.64 (4.23)
-8.44 (4.50)
Placebo (N=75)
12.55 (11.94)
-4.54 (7.40)
-5.32 (6.30)
Differenceb
—
-2.10
-3.12
p-valuec
—
0.0002
less than 0.0001
a Mean change and difference based on raw data
b Evamist versus placebo
c Tests for pairwise differences using ANCOVA
Table 4. Effect of Treatment on the Weekly Severity of Moderate to
Severe Vasomotor Symptoms at Week 4 and Week 12 (Intent-To-Treat Population,
LOCF) a
Mean Change from Baselineb(SD)
Treatment(N)
Baseline
Mean (SD)
Week 4
Mean (SD)
Week 12
Mean (SD)
1 Spray
Evamist (N=76)
2.53 (0.25)
-0.47 (0.80)
-1.04 (1.01)
Placebo (N=77)
2.55 (0.25)
-0.19 (0.55)
-0.26 (0.60)
Differencec
—
-0.28
-0.78
p-valued
—
0.0573
less than 0.0001
2 Sprays
Evamist (N=74)
2.54 (0.21)
-0.57 (0.83)
-0.92 (1.01)
Placebo (N=76)
2.54 (0.22)
-0.25 (0.64)
-0.54 (0.89)
Differencec
—
-0.32
-0.38
p-valued
—
0.0160
0.0406
3 Sprays
Evamist (N=76)
2.58 (0.25)
-0.43 (0.66)
-1.07 (1.01)
Placebo (N=75)
2.54 (0.24)
-0.13 (0.53)
-0.31 (0.75)
Differencec
—
-0.30
-0.76
p-valued
—
0.0031
less than 0.0001
a Severity score calculated as: (2 x number moderate +3 x number severe)/ number moderate + number severe)
b Mean chane and difference based on raw data
c Evamist versus placebo
d Tests for pairwise differences using ANCOVA
14.2 Effect of Application Site Washing
Site washing one hour after the application of three 90-mcL sprays to the inner
forearm did not have a significant effect on average 24-hour serum
concentrations of estradiol.
14.3 Potential for Estradiol Transfer
The effect of estradiol transfer was evaluated in 20 healthy postmenopausal
women who applied three 90-mcL sprays of Evamist to the inner forearm once
daily. One hour after applying Evamist, subjects held the dosed forearm against
the inner forearm of a non-dosed (recipient) male subject for one 5-minute
period of continual contact. No significant transfer of estradiol was observed
in persons who came in contact with the application site of estradiol-treated
individuals.
14.4 Women's Health Initiative Studies
The Women's Health Initiative (WHI) enrolled approximately 27,000
predominantly healthy postmenopausal women in two substudies to assess the risks
and benefits of either the use of daily oral conjugated estrogens (CE 0.625 mg)
alone or in combination with medroxyprogesterone acetate (MPA 2.5 mg) compared
to placebo in the prevention of certain chronic diseases. The primary endpoint
was the incidence of coronary heart disease (CHD) (nonfatal myocardial
infarction [MI], silent MI and CHD death), with invasive breast cancer as the
primary adverse outcome studied. A “global index” included the earliest
occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE),
endometrial cancer (only in the CE/MPA substudy), colorectal cancer, hip
fracture, or death due to other cause. These substudies did not evaluate the
effects of CE or CE/MPA on menopausal symptoms.
The 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 risks 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 years of age; 75.3 percent White,
15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average
follow-up of 6.8 years are presented in Table 5.
For those outcomes included in the WHI “global index” that reached
statistical significance, the absolute excess risk 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 6 fewer hip fractures. The absolute excess
risk of events included in the “global index” was a non-significant 2 events per
10,000 women-years. There was no difference between the groups in terms of
all-cause mortality [see Warnings and Precautions (5)].
Final centrally adjudicated results for CHD events and centrally adjudicated
results for invasive breast cancer incidence from the estrogen alone substudy,
after an average follow-up of 7.1 years, reported 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 to placebo (see Table 5).2,4
Centrally adjudicated results for stroke events from the estrogen alone
substudy, after an average follow-up of 7.1 years, reported no significant
differences in distribution of stroke subtypes or severity, including fatal
strokes, in women receiving CE alone compared to placebo. Estrogen alone
increased the risk for ischemic stroke, and this excess risk was present in all
subgroups of women examined (see Table 5).1
The estrogen plus progestin substudy was also stopped early. According to the
predefined stopping rule, after an average follow-up of 5.2 years of treatment,
the increased risk of 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 (relative
risk [RR] 1.15, 95 percent nCI, 1.03-1.28).
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/MPA were 6 more CHD events,
7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the
absolute risk reduction per 10,000 women-years were 7 fewer colorectal cancers
and 5 fewer hip fractures [see Warnings and Precautions (5)].
Results of the estrogen plus progestin substudy, which included 16,608 women
(average 63 years of age, range 50 to 79 years of age; 83.9 percent White, 6.5
percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 6. These results reflect centrally adjudicated data after
an average follow-up of 5.6 years.
Table 5. Relative and Absolute Risk Seen in the Estrogen Alone Substudy
of WHI
a Nominal confidence intervals
unadjusted for multiple looks and multiple comparisons.
b Results are based on centrally
adjudicated data for an average follow-up of 7.1 years.
c Results are based on an average
follow-up of 6.8 years.
d Not included in global
index.
e All deaths, except from breast
or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.
f A subset of the events was
combined in a “global index,” defined as the earliest occurrence of CHD events,
invasive breast cancer, stroke, pulmonary embolism, endometrial cancer,
colorectal cancer, hip fracture, or death due to other causes.
14.5 Women's Health Initiative Memory Study
The estrogen alone Women's Health Initiative Memory Study
(WHIMS), a substudy of theWHI, enrolled 2,947 predominantly healthy
postmenopausal women 65 years of age and older (45 percent were 65 to 69 years
of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of
age and older) to evaluate the effects of daily conjugated estrogen (CE 0.625
mg) on the incidence of probable dementia (primary outcome) compared to
placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen alone group
(37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000
women-years) were diagnosed with probable dementia. The relative risk of
probable dementia in the estrogen alone group was 1.49 (95 percent CI,
0.83-2.66) compared to placebo. It is unknown whether these findings apply to
younger postmenopausal women [see Warnings and Precautions
(5.3) and Use in Specific Populations (8.5)].
The estrogen plus progestin WHIMS substudy 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
medroxyprogesterone acetate (MPA 2.5 mg) on the incidence of probable dementia
(primary outcome) compared to placebo.
After an average follow-up of 4 years, 40 women in the estrogen plus
progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per
10,000 women-years) were diagnosed with probable dementia. The relative risk of
probable dementia in the hormone therapy group was 2.05 (95 percent CI, 1.21-
3.48) compared to placebo.
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 [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5)].
Table 6. Relative and Absolute Risk Seen in the Estrogen Plus Progestin
Substudy of WHI at an Average of 5.6 Yearsa
a Results are based on centrally
adjudicated data. Mortality data was not part of the adjudicated data; however,
data at 5.2 years of follow-up showed no difference between the groups in terms
of all-cause mortality (RR 0.98, 95 percent nCI, 0.82-1.18).
b Nominal confidence intervals
unadjusted for multiple looks and multiple comparisons.
c Includes metastatic and
non-metastatic breast cancer, with the exception of in situ breast cancer.
15 References
Hendrix, SL, et al. Effects of conjugated equine estrogen on stroke in the
Women's Health Initiative. Circulation.
2006;113:2425-2434.
Hsia J, et al. Conjugated equine estrogens and coronary heart disease. Arch Int Med. 2006;166:357–365.
Curb JD, et al. Venous thrombosis and conjugated equine estrogen in women
without a uterus. Arch Int Med. 2006; 166:772-780.
Stefanick ML, et al. Effects of conjugated equine estrogens on breast cancer
and mammography
16 How Supplied/storage And Handling
Evamist (NDC 54868-6157-0) is supplied as a homogeneous solution
of estradiol USP, octisalate USP and alcohol USP. The liquid formulation of
Evamist is packaged in a glass vial fitted with a metered-dose pump. The unit is
encased in a plastic housing with a conical bell opening that controls the
distance, angle, and area of application of the metered-dose spray. Each
metered-dose pump contains 8.1 mL and is designed to accurately deliver 75
sprays of 90 mcL after priming. One spray contains 1.53 mg estradiol.
Keep out of reach of children.
Alcohol and alcohol-based liquids are flammable. Avoid fire, flame or smoking
until the spray has dried
Store at 25°C (77°F) with excursion permitted to 15° to 30°C (59° to 86°F).
Do not freeze.
Inform women of the importance of reporting vaginal bleeding to their healthcare
provider as soon as possible.
17.2 Common Adverse Reactions with Estrogen
Inform women of the possible side effects of estrogen therapy such as headache,
breast pain and tenderness, nausea and vomiting.
17.3 Fda-approved Patient Labeling
Evamist (estradiol transdermal spray)
Instructions for use. Read carefully.
Read this PATIENT INFORMATION before you start using Evamist and read the
patient information each time you refill your Evamist prescription. There may be
new information. This information does not take the place of talking to your
healthcare provider about your menopausal symptoms and their treatment.
WHAT IS THE MOST
IMPORTANT INFORMATION I SHOULD KNOW ABOUT EVAMIST (AN ESTROGEN
HORMONE)?
Estrogens increase the chance of getting cancer of the uterus. Report
any unusual vaginal bleeding right away while you are using Evamist. 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, strokes or dementia. Using estrogens, with or without
progestins, may increase your chance of getting heart attacks, strokes, breast
cancer, and blood clots. Using estrogen, with or without progestins, may
increase your chance of getting dementia, based on a study of women 65 years of
age or older. You and your healthcare provider should talk regularly about
whether you still need treatment with Evamist.
What is Evamist?
Evamist is a medicine that contains estradiol (an estrogen hormone). When
applied to the skin, estradiol is absorbed through the skin into the
bloodstream.
What is Evamist used for?
Evamist is used after menopause to:
Reduce moderate to severe hot flashes
Estrogens are hormones made by a woman's ovaries. The ovaries normally stop
making estrogens when a woman is between 45 and 55 years old. This drop in body
estrogen levels causes the “change of life” or menopause (the end of monthly
menstrual periods). Sometimes, a woman's ovaries are removed during an operation
that causes “surgical menopause.”
When the estrogen levels begin dropping, some women get 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 estrogen treatment. In
other women, symptoms can be more severe. You and your healthcare provider
should talk regularly about whether you still need treatment with Evamist.
Who should not use Evamist?
Do not start using Evamist if you:
Have unusual vaginal bleeding
Currently have or have had certain cancers
Estrogens may increase the chance of getting certain types of cancers,
including cancer of the breast or uterus. If you have or have had cancer, talk
with your healthcare provider about whether you should use Evamist.
Had a stroke or heart attack in the past year
Currently have or have had blood clots
Currently have or have had liver problems
Are allergic to any of the ingredients in Evamist
See the ul of ingredients in Evamist at the end of this leaflet
Think you may be pregnant
Tell your healthcare provider:
If you are breastfeeding
The hormone in Evamist can pass into your breast milk.
About all 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, or 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 Evamist works. Evamist 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 use Evamist?
Evamist is available in a spray applicator that delivers a measured amount of
estradiol to the skin with each spray (see Illustration 1).
Illustration 1
It is important that you read and follow these directions on how to use
Evamist properly.
Before using the applicator for the first time, it must be primed. With the
cover on, and the applicator upright, fully depress the applicator three times
with your thumb or index finger. This is called priming (see Illustration 2). After priming, the applicator is ready to use.
The applicator should be primed only once when you first start using a new
applicator. DO NOT PRIME THE APPLICATOR BEFORE EACH DAY'S DOSE.
Illustration 2
Apply Evamist at the same time each day.
Apply your daily dose of Evamist to clean, dry, unbroken skin on the inside
of the forearm between the elbow and the wrist (see Illustration
3). Do not apply Evamist to other areas of the skin. To apply the dose,
remove the plastic cover, hold the applicator upright and rest the plastic cone
flat against the skin. You may need to change the position of your arm or the
position of the cone on your arm so that the cone is flat against your skin and
there are no gaps between the cone and your skin. Depress the pump fully once.
Illustration 3
If your healthcare provider tells you to increase the dose to 2 or 3 sprays, you
should move the cone before applying the second or third spray to an area of the
skin next to but not touching the area of the previous spray (see Illustration 4).
Illustration 4
Always place the protective cover back on the cone of the applicator.
Do not massage or rub Evamist into the skin. Simply allow the spray to dry
for at least 2 minutes before dressing, and at least 30 minutes before washing.
Evamist contains alcohol, and alcohol-based liquids are flammable. Avoid
fire, flame or smoking when using Evamist until the spray has dried. Do not
apply Evamist while standing near a flame.
Never apply Evamist directly to the breast or in or around the vagina.
Start at the lowest dose (1 spray) and talk to your healthcare provider about
how well that dose is working for you. Treatment with estrogen should be started
at the lowest dose possible, and used only for as long as needed to provide
relief of moderate to severe hot flashes associated with menopause. You and your
healthcare provider should talk regularly (every 3-6 months) about the dose you
are taking and whether you still need treatment with Evamist.
The Evamist applicator contains enough product to allow for initial priming
of the pump with three sprays plus application for 75 sprays. The product will
last approximately 75 days if you use 1 spray each day, 37 days if you use 2
sprays each day and 25 days if you use 3 sprays each day.
Do not use this applicator for more than 75 sprays even though the bottle may
not be completely empty.
Evamist can be stored in a clean, dry place at room temperature (15° to 30°C
or 59° to 86°F) and does not need refrigeration. Do not freeze. Evamist should
not be used after the expiration date. When the applicator has been used for 75
sprays you can discard it in normal household waste.
What should I do if I miss a dose?
If you miss a dose, do not double the dose on the next day to catch up. If
your next dose is less than 12 hours away, it is best just to wait and apply
your normal dose the next day. If it is more than 12 hours until the next dose,
apply the dose you missed and resume your normal dosing the next day.
What should I avoid while using Evamist?
Do not allow others to make contact with the area of skin where you applied
the spray for at least 30 minutes after application.
Evamist contains alcohol and alcohol-based liquids are flammable. Avoid
fire, flame or smoking until the spray has dried.
What are the possible side effects of estrogens?
Side effects are grouped by how serious they are and how often they happen
when you are treated.
Serious but less common side effects include:
Breast cancer
Cancer of the uterus
Stroke
Heart attack
Blood clots
Dementia
Gallbladder disease
Ovarian cancer
High blood pressure
Liver problems
High blood sugar
Enlargement of benign tumors of the uterus (“fibroids”)
 Some of the warning signs of these serious side effects include:
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
Yellowing of the skin, eyes or nail beds
 Call your healthcare provider right away if you get any of these warning
signs, or any other unusual symptoms that concern you. Less serious but common side effects include:
Headache
Breast pain
Irregular vaginal bleeding or spotting
Stomach/abdominal cramps, bloating
Nausea and vomiting
Hair loss
Fluid retention
Vaginal yeast infection
These are not all of the possible side effects of Evamist. For more
information, ask your healthcare provider or pharmacist.
What can I do to lower my chances of a serious side effect
with Evamist?
Talk with your healthcare provider regularly about whether you should
continue using Evamist.
If you have a uterus, talk with your healthcare provider about whether the
addition of a progestin (a different prescribed hormone medication) is right for
you. The addition of a progestin is generally recommended for women with a
uterus to reduce the chance of getting cancer of the uterus.
See your healthcare provider right away if you get vaginal bleeding while
using Evamist.
Have a pelvic exam, breast exam, and mammogram (breast X-ray) every year
unless your healthcare provider tells you otherwise. If members of your family
have had breast cancer or if you have had breast lumps or an abnormal mammogram,
you may need to have breast exams more often.
If you have high blood pressure, high cholesterol (fat in the blood),
diabetes, are overweight, or if you use tobacco, you may have a higher chance of
getting heart disease. Ask your healthcare provider for ways to lower your
chances of getting heart disease.
General information about the safe and effective use of
Evamist.
Medicines are sometimes prescribed for conditions that are not mentioned in
patient information leaflets. Do not use Evamist for conditions for which it was
not prescribed. Do not give Evamist to other people, even if they have the same
symptoms you have. It may harm them.
Keep Evamist out of the reach of children.
This leaflet provides a summary of the most important information about
Evamist. If you would like more information, talk with your healthcare provider
or pharmacist. You can ask for information about Evamist that is written for
health professionals.
You can get more information by calling the toll free number (877)
567-7676.
What are the ingredients in Evamist?
Active ingredient: estradiol (an estrogen hormone)
Inactive ingredients: octisalate (a common active ingredient in some
sunscreens used to enhance skin penetration), alcohol (to dissolve the drug)
Manufactured by DPT San Antonio, TX 78215
for Ther-Rx Corporation St. Louis, MO 63044
Relabeling of "Additional Barcode Label" by:
Physicians Total Care, Inc.Tulsa, OKÂ Â Â Â Â Â 74146
Evamist (estradiol transdermal spray)
Applicator
Evamist
(estradiol transdermal spray)
For Topical Use Only
Metered-dose pump delivers75 sprays. Each spraycontains 1.53 mg of
estradiol.
See Patient Leaflet fordosing information.
Important: Applicatornot child resistant.Keep
out of the reach of children.
Flammable: Avoidfire, flame, or smoking during
use.
Store at room temperature15° to 30°C(59° to 86°F).
Do not freeze.
Rx Only 0.27 fl oz. (8.1 mL)
Marketed by Ther-Rx CorporationSt. Louis, Mo 63044 P6000 07/09
"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."
"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."
"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."
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