1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause.

2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

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 before covering the site with clothing. The site should not be washed for at least one hour. Application of Evamist to other skin surfaces has not been adequately studied. Evamist should not be applied to skin surfaces other than the forearm.

Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to estradiol from Evamist-treated skin. Women should cover the Evamist application site with clothing if another person may come into contact with that area of skin after the spray dries. Additional precautions to minimize unintentional secondary exposure are outlined in Patient Counseling Information [see Patient Counseling Information (17.2)] and in the Patient Information Leaflet at the end of the prescribing information.

5.1 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.

Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

5.2 Malignant Neoplasms

5.3 Probable Dementia

In the WHIMS estrogen-alone ancillary study of the 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[see Use in Specific Populations (8.5) and Clinical Studies (14.3)].

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[see Use in Specific Populations (8.5) and Clinical Studies (14.3)].

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[see Use in Specific Populations (8.5) and Clinical Studies (14.3)].

5.4 Unintentional Secondary Exposure to Estrogen

Postmarketing reports of breast budding and breast masses in prepubertal females and gynecomastia and breast masses in prepubertal males following unintentional secondary exposure to Evamist have been reported. In most cases, the condition resolved with removal of Evamist exposure.

Unexpected changes in breast tissue or other signs of abnormal sexual development in prepubertal children as well as the possibility of unintentional secondary exposure to Evamist should be brought to the attention of a physician. The physician should identify the cause of abnormal sexual development in the child. If unexpected breast development or changes are determined to be the result of unintentional exposure to Evamist, the physician should counsel the woman on the appropriate use and handling of Evamist when around children. Women should cover the Evamist application site with clothing if another person may come into contact with the site. Consideration should be given to discontinuing Evamist if conditions for safe use cannot be met [see Patient Counseling Information (17.2)].

5.5 Gallbladder Disease

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

5.6 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.

5.7 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.

5.8 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.

5.9 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.

5.10 Hypertriglyceridemia

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

5.11 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.

5.12 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.

5.13 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 impairment, warrant careful observation when estrogen-alone is prescribed.

5.14 Hypocalcemia

Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

5.15 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.

5.16 Hereditary Angiodema

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

5.17 Exacerbation of Other Conditions

Estrogen therapy 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.

5.18 Alcohol-Based Products are Flammable

Avoid fire, flame or smoking until the spray has dried.

5.19 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.

5.20 Laboratory Tests

Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms.

5.21 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, 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/rennin substrate, alpha-1-antitrypsin, ceruloplasmin).

Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels.

Impaired glucose tolerance.

6.1 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 clinical practice.

In a 12-week, randomized, placebo-controlled trial of Evamist in 454 women, 80 to 90 percent of women randomized to active drug received at least 70 days of therapy and 75 to 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.

Application site reactions were reported in 3 out of 226 (1.3%) women treated with Evamist.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Evamist. 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.

Breasts: Breast swelling, breast mass, breast enlargement

Cardiovascular: Heart rate increased

Central nervous system: Dizziness, dysgeusia, paresthesia, lethargy, hypoesthesia

Eyes: Eye irritation, ocular hyperemia

Gastrointestinal: Abdominal pain, diarrhea, constipation, abdominal distension, dry mouth, decreased appetite

Genitourinary system: Vaginal bleeding

Musculoskeletal: Muscle spasms, arthritis

Psychiatric: Insomnia, mood swings, anxiety, irritability, mood altered, depression

Respiratory tract: Cough, dyspnea, dry throat

Skin: Nipple and areola discoloration, usually on the same side of the body as the inner forearm on which Evamist is applied, rash, pruritus, alopecia, urticaria, dry skin, skin discoloration, chloasma

Miscellaneous: Weight increased, malaise, fatigue, asthenia

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 (Hypericum perforatum) preparations, 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.

8.1 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 women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the milk of women receiving estrogen-alone therapy. Caution should be exercised when Evamist is administered to a nursing woman.

8.4 Pediatric Use

Evamist is not intended in children. Clinical studies have not been conducted in the pediatric population.

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.

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 [see Clinical Studies (14.2)].

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 [see Clinical Studies (14.2)].

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 [see Warnings and Precautions (5.3), and Clinical Studies (14.3)].

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 [see Warnings and Precautions (5.3), and Clinical Studies (14.3)].

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of Evamist has not been studied.

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Evamist has not been studied.

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 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 feed back mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

12.2 Pharmacodynamics

There are no pharmacodynamic data for Evamist.

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)

PK Parameter	Number of Daily Sprays of Evamist
	1 Spray (N = 24)	2 Spray (N = 23)	3 Spray (N = 24)
1 Values expressed are arithmetic means (%CV) 2 Values expressed are medians (minimum-maximum)
Cmax (pg/mL)1 Cmin (pg/mL)1 Cavg (pg/mL)1  AUC0-24 (pg*hr/mL)1 Tmax (hours)2	36.4 (62) 11.3 (52) 19.6 (49) 471 (49) 20 (0-24)	57.4 (94) 18.1 (51) 30.7 (43) 736 (43) 18 (0-24)	54.1 (50) 19.6 (27) 30.9 (30) 742 (30) 20 (0-24)

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.

14.1 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 ≥ 56 moderate to severe vasomotor symptoms per week (≥ 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.

14.2 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 cause. 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 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 7.1 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 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 to placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years.

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. 10

Timing of the 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 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.

Timing of the 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)].

14.3 Women’s Health Initiative Memory Study

The WHIMS estrogen-alone ancillary study of the 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, and 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) 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 this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (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 [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5)].

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, 1.12-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed type (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 [see Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].

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). 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)].

16.1 How Supplied

Evamist (NDC 64011-215-41) 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 deliver 56 sprays of 90 mcL after priming. One spray contains 1.53 mg estradiol.

16.2 Storage and Handling

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 room temperature 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F). Do not freeze.

17.1 Vaginal Bleeding

Inform postmenopausal women of the importance of reporting unusual vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.2)].

17.2 Unintentional Secondary Exposure to Evamist

Provide the following information about secondary exposure to Evamist:

•

Apply Evamist as directed and keep children from contacting exposed application site(s). If direct contact with the application site occurs, the contact area should be washed thoroughly with soap and water. Women should cover the Evamist application site, after the 2 minute drying period, with clothing if another person may come in contact with that area of skin. [See FDA-Approved Patient Information Leaflet at the end of the prescribing information.]

•

Look for signs of unexpected sexual development, such as breast mass or increased breast size in prepubertal children.

•

If signs of unintentional secondary exposure are noticed:

•

Have children evaluated by a healthcare provider.

•

Discontinue Evamist until the cause(s) is identified for any unexpected sexual development in children under their care.

•

Women should contact their healthcare provider and discuss the appropriate use and handling of Evamist when around children.

•

If conditions for safe use cannot be met, Evamist should be discontinued and alternative treatments for menopausal signs and symptoms should be considered.

•

Pets may also be unintentionally exposed to Evamist if above precautions are not followed.

17.3 Possible Serious Adverse Reactions with Estrogen-Alone Therapy

Inform postmenopausal women of the possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.1, 5.2, 5.3)].

17.4 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.

P6003-3
Revised 03/2014

Manufactured by DPT Laboratories, Ltd San Antonio, TX 78215

For Ther-Rx Corporation Chesterfield, MO 63005

© 2013 Ther-Rx Corporation 03/2014

Patient Information

EVAMIST (EE-vuh-mist)

(estradiol transdermal spray)

Read this Patient Information before you start using EVAMIST 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.

What is EVAMIST?

EVAMIST is a prescription medicine spray that contains estradiol (an estrogen hormone).

What is EVAMIST used for?

EVAMIST spray 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, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.”

When the estrogen levels begin dropping, some women 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 to use estrogens. 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
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.

•

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

•

currently have or have had blood clots

•

currently have or have had liver problems

•

have been diagnosed with a bleeding disorder

•

are allergic to EVAMIST or any of its ingredients
See the list of ingredients in EVAMIST at the end of this leaflet

•

think you may be pregnant
EVAMIST is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not use EVAMIST if the test is positive and talk to your healthcare provider.

What should I tell my healthcare provider before I use EVAMIST?

Before you use EVAMIST, tell your healthcare provider if you:

•

have any unusual vaginal bleeding
Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any vaginal bleeding to find out the cause.

•

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

•

are going to have surgery or will be on bed rest
Your healthcare provider will let you know if you need to stop using EVAMIST.

•

are breast feeding
The hormone in EVAMIST can pass into your breast milk.

Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Some medicines may affect how EVAMIST works. EVAMIST may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I use EVAMIST?

For detailed instructions, see the step-by-step instructions for using EVAMIST at the end of this Patient Information.

•

Use EVAMIST exactly as your healthcare provider tells you to use it.

•

EVAMIST is for skin use only.

•

Apply EVAMIST at the same time each day.

•

If you use sunscreen 1 hour after you use EVAMIST, it may reduce the amount of EVAMIST absorbed by your skin.

•

The estrogen in EVAMIST spray can transfer from the area of skin where it was sprayed to other people or pets. Do not allow other people, especially children to come into contact with the area of your skin where you have sprayed EVAMIST.

•

If another person accidentally touches the area of your skin where you have sprayed EVAMIST, that area of their skin should be washed with soap and water right away.

•

Do not let pets lick or touch your arm where you have sprayed EVAMIST, especially small pets. EVAMIST may harm them. Cover your skin with clothing where you have sprayed EVAMIST if you think a pet could come in contact with that area of your skin.

•

If a pet accidentally comes in contact with the area of your skin where you have sprayed EVAMIST, the area of the pet’s skin should be washed with soap and water right away.

•

Young children who are accidentally exposed to estrogen through contact with women using EVAMIST may show signs and symptoms of puberty that are not expected. Signs and symptoms in children of exposure to EVAMIST may include:

•

breast budding or breast lumps

•

other signs of abnormal sexual development

 

    If a child shows signs and symptoms of accidental exposure to EVAMIST:

•

have the child checked right away by their healthcare provider.

•

stop using EVAMIST and call your healthcare provider right away.

•

talk to your healthcare provider about the correct use of EVAMIST when around children.

•

Talk to your healthcare provider about other treatments for your menopause symptoms if accidental exposure to EVAMIST cannot be avoided.

•

You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with EVAMIST.

What should I avoid while using EVAMIST?

•

Do not allow others to make contact with the area of skin where you have applied the EVAMIST spray.

•

EVAMIST contains alcohol, which is flammable. Avoid fire, flame, or smoking until the area of your skin where you have applied EVAMIST has dried.

What are the possible side effects of EVAMIST?

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:

•

heart attack

•

stroke

•

blood clots

•

dementia

•

breast cancer

•

cancer of the lining of the uterus (womb)

•

cancer of the ovary

•

high blood pressure

•

high blood sugar

•

gallbladder disease

•

liver problems

•

changes in your thyroid hormone levels

•

enlargement of benign tumors of the uterus (“fibroids”)

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

•

new breast lumps

•

unusual vaginal bleeding

•

changes in vision or speech

•

sudden new severe headaches

•

severe pains in your chest or legs with or without shortness of breath, weakness and fatigue

Less serious, but common side effects include:

•

headache

•

breast pain

•

irregular vaginal bleeding or spotting

•

stomach or abdominal cramps, bloating

•

nausea and vomiting

•

hair loss

•

fluid retention

•

vaginal yeast infection

These are not all the possible side effects of EVAMIST. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or does not go away. You may report side effects to Ther-Rx at 1-877-567-7676 or to FDA at 1-800-FDA-1088.

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 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 something else.

•

If members of your family have had breast cancer or if you have ever 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.

How should I store EVAMIST?

•

Store EVAMIST at room temperature 68°F to 77°F (20°C to 25°C )

•

Do not freeze.

•

Safely throw away medicine that is out of date or no longer needed.

Keep EVAMIST and all medicines out of the reach of children.

General information about the safe and effective use of EVAMIST.

Medicines are sometimes prescribed for conditions other than those listed 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.

This leaflet summarizes 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.

For more information, go to www.Evamist.com or call Ther-Rx at 1-877-567-7676.

What are the ingredients in EVAMIST?

Active ingredient: estradiol

Inactive ingredients: octisalate, alcohol

Instructions for Use

EVAMIST (EE-vuh-mist)

(estradiol transdermal spray)

Read this Instructions for Use before you start using EVAMIST 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 of your treatment.

The parts of your EVAMIST applicator

EVAMIST comes in a spray applicator that delivers a measured amount of estradiol to your skin with each spray (see Figure A).

 

Figure A

 

Step 1. Priming your EVAMIST

•

Before you use your EVAMIST applicator for the first time, the applicator must be primed.

•

Hold the EVAMIST applicator upright. Keep the cover on. Fully press down the pump button 3 times with your thumb or index finger (see Figure B). After priming, the EVAMIST applicator is ready to use.

•

The EVAMIST applicator should be primed only 1 time when you first start using a new applicator. Do not prime the EVAMIST applicator before your dose each day.

Figure B

Step 2. Using your EVAMIST

•

Remove the plastic cover.

•

Apply EVAMIST to a clean, dry, unbroken skin area on the inside of your forearm between the elbow and the wrist (see Figure C). This area must be clean, dry, and the skin must be without open wounds, cuts, abrasions, or rashes.

•

Hold the EVAMIST applicator upright and rest the plastic cone flat against your 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 (see Figure C).

•

Press the pump button down fully 1 time (see Figure C).

 

Figure C

 

If your healthcare provider tells you to increase your dose to 2 or 3 sprays, move the cone before applying the second or third spray to an area of your skin next to but not touching the area of the previous spray (see Figure D).

 

Figure D

•

Do not apply EVAMIST to your breasts or in and around your vagina.

•

Do not massage or rub EVAMIST into your skin.

•

Let EVAMIST spray dry on your skin for at least:

•

2 minutes before you cover your skin with clothing.

•

1 hour before you wash your skin.

 

Step 3. After you use EVAMIST

•

Place the plastic cover back on the EVAMIST applicator cone.

•

EVAMIST is flammable until dry. Avoid fire, flame, or smoking until the area of your skin where you have applied EVAMIST has completely dried.

 

Step 4. Throwing away used EVAMIST applicators

•

Your EVAMIST applicator contains enough medicine to allow for initial priming of the pump with 3 sprays and application of 56 sprays.

•

Do not use your EVAMIST applicator for more than 56 application sprays even though the bottle may not be completely empty. You may not get the correct dose.

•

Always replace the cover over the cone of your EVAMIST applicator before you throw it away to prevent accidental exposure to other people or pets.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

P0000
Revised 03/2014

Manufactured by
DPT Laboratories. Ltd
San Antonio, TX 78215

For
Ther-Rx Corporation
Chesterfield, MO 63005

© 2013 Ther-Rx Corporation 03/14