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Evamist (Estradiol Transdermal) - Description and Clinical Pharmacology

 
 



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 deliver 56 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 each morning to adjacent non-overlapping 20 cm2 areas on the inner surface of the arm between the elbow and the wrist and allowed to dry.

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

There are no pharmacodynamic data for Evamist.

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)

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)

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 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.

Use in Specific Populations

No pharmacokinetic studies were conducted with Evamist in specific populations, including women with renal or hepatic impairment.

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. A 4% increase in serum estradiol exposure was observed in persons who came in contact with the application site. The possibility of unintentional secondary exposure to Evamist should be brought to the attention of physicians and Evamist users.

Effect of Application Site Washing

Site washing with warm water and soap 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.

NONCLINICAL TOXICOLOGY

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.

CLINICAL STUDIES

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.

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)
a Mean change and difference based on raw data
b Evamist versus placebo
c Tests for pairwise differences using ANCOVA

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

<0.0001

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)
a Severity score calculated as: (2 x number moderate +3 x number severe)/ number moderate + number severe)
b Mean change and difference based on raw data
c Evamist versus placebo
d Tests for pairwise differences using ANCOVA

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

<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

<0.0001

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.

Table 5. Relative and Absolute Risk Seen in the Estrogen Alone Substudy of WHIa
Event Relative Risk
CE vs. Placebo
(95% nCIb)
CE
(n = 5,310)
Placebo
(n = 5,429)
Absolute Risk per 10,000 Women-Years
a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
c Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
d Not included in “global index”.
e Results are based on an average follow-up of 6.8 years.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.
g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast
   cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.

CHD eventsc
   Non-fatal MIc
   CHD deathc

0.95 (0.78-1.16)
0.91 (0.73-1.14)
1.01 (0.71-1.43)

54
40
16

57
43
16

All strokesc
   Ischemic strokec

1.33 (1.05-1.68)
1.55 (1.19-2.01)

45
38

33
25

Deep vein thrombosisc,d

1.47 (1.06-2.06)

23

15

Pulmonary embolismc

1.37 (0.90-2.07)

14

10

Invasive breast cancerc

0.80 (0.62-1.04)

28

34

Colorectal cancere

1.08 (0.75-1.55)

17

16

Hip fracturec

0.65 (0.45-0.94)

12

19

Vertebral fracturesc,d

0.64 (0.44-0.93)

11

18

Lower arm/wrist fracturesc,d

0.58 (0.47-0.72)

35

59

Total fracturesc,d

0.71 (0.64-0.80)

144

197

Death due to other causese,f

1.08 (0.88-1.32)

53

50

Overall mortalityc,d

1.04 (0.88-1.22)

79

75

Global indexg

1.02 (0.92-1.13)

206

201

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.

Table 6. Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Yearsa,b
Event Relative Risk CE/MPA vs. Placebo
(95% nCIc)
CE/MPA
(n = 8,506)
Placebo
(n = 8,102)
Absolute Risk per 10,000 Women-Years
a Adapted from numerous WHI publications, WHI publications can be viewed at www.nhlbi.nih.gov/whi
b Results are based on centrally adjudicated data.
c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
d Not included in “global index”.
e Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.
f All deaths, except from breast or colorectal cancer, definite or probably CHD, PE or cerebrovascular disease.
g A subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast
   cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.

CHD events
   Non-fatal MI
   CHD death

1.23 (0.99-1.53)
1.28 (1.00-1.63)
1.10 (0.70-1.75)

41
31
8

34
25
8

All strokes
   Ischemic stroke

1.31 (1.03-1.68)
1.44 (1.09-1.90)

33
26

25
18

Deep vein thrombosis d

1.95 (1.43-2.67)

26

13

Pulmonary embolism

2.13 (1.45-3.11)

18

8

Invasive breast cancere

1.24 (1.01-1.54)

41

33

Colorectal cancer

0.61 (0.42-0.87)

10

16

Endometrial cancer d

0.81 (0.48-1.36)

6

7

Cervical cancer d

1.44 (0.47-4.42)

2

1

Hip fracture

0.67 (0.47-0.96)

11

16

Vertebral fractures d

0.65 (0.46-0.92)

11

17

Lower arm/wrist fractures d

0.71 (0.59-0.85)

44

62

Total fractures d

0.76 (0.69-0.83)

152

199

Overall Mortality f

1.00 (0.83-1.19)

52

52

Global Index g

1.13 (1.02-1.25)

184

165

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)].

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 and Use in Specific Populations].

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)].

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