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 by peripheral tissues. Thus, estrone and the sulfate- conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
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 feed back mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
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)
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2 Values expressed are medians (minimum-maximum)
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PK Parameter | Number of Daily Sprays of Evamist |
| 1 Spray
(N = 24) | 2 Spray
(N = 23) | 3 Spray
(N = 24) |
| Cmax (pg/mL)1 | 36.4 (62) | 57.4 (94) | 54.1 (50) |
| Cmin (pg/mL)1 | 11.3 (52) | 18.1 (51) | 19.6 (27) |
| Cavg (pg/mL)1 | 19.6 (49) | 30.7 (43) | 30.9 (30) |
| AUC0-24 (pg*hr/mL)1 | 471 (49) | 736 (43) | 742 (30) |
| Tmax (hours)2 | 20 (0-24) | 18 (0-24) | 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 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 the 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.
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.
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CLINICAL STUDIES
Effects on Vasomotor Symptoms
In a 12-week, randomized, double-blind, placebo-controlled clinical trial, a total of 454 postmenopausal women (average age 53 years, 70% Caucasian and 24% 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) |
a Mean change and difference based on raw data
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b Evamist versus placebo
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c Tests for pairwise differences using ANCOVA
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| 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 | <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 |
a Severity score calculated as: (2 x number moderate +3 x number severe)/ number moderate + number severe)
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b Mean change and difference based on raw data
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c Evamist versus placebo
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d Tests for pairwise differences using ANCOVA
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| 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 (o.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 |
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.
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.
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 age 63 years, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 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 were 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 with 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 with 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 age of 63 years, range 50 to 79; 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.
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b Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
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c Results are based on an average follow-up of 6.8 years.
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d Not included in global index.
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e All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.
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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.
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| Event | Relative Risk
CE vs. | Placebo
(n = 5,429) | CE
(n = 5,310) |
| Placebo
(95% nCIa) | Absolute Risk per 10,000 Women- Years |
| CHD eventsb | 0.95 (0.79-1.16) | 56 | 53 |
| Non-fatal MI b | 0.91 (0.73-1.14 | 43 | 40 |
| CHD death b | 1.01 (0.71-1.43) | 16 | 16 |
| Strokeb | 1.37 (1.09-1.73) | 33 | 45 |
| Ischemic b | 1.55 (1.19-2.01) | 25 | 38 |
| Deep vein thrombosisb,d | 1.47 (1.06-2.06) | 15 | 23 |
| Pulmonary embolismb | 1.37 (0.90-2.07) | 10 | 14 |
| Invasive breast cancerb | 0.80 (0.62-1.04) | 34 | 28 |
| Colorectal cancerc | 1.08 (0.75-1.55) | 16 | 17 |
| Hip fracturec | 0.61 (0.41-0.91) | 17 | 11 |
| Vertebral fracturesc,d | 0.62 (0.42-0.93) | 190 | 192 |
| Total fracturesc,d | 0.70 (0.63-0.79) | 195 | 139 |
| Death due to other causes | 1.08 (0.88-1.32) | 50 | 53 |
| Overall mortalityc,d | 1.04 (0.88-1.22) | 78 | 81 |
| Global indexc,f | 1.01 (0.91-1.12) | 190 | 192 |
Women's Health Initiative Memory Study
The estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45 percent were aged 65 to 69 years, 36 percent were 70 to 74 years, 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 with 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 and Use in Specific Populations].
The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were age 65 to 69 years, 35 percent were 70 to 74 years, 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 with 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 (8.4)].
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).
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b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
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c Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.
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| Event | Relative Risk CE/MPA vs. | Placebo
(n = 8,102) | CE/MPA
(n = 8,506) |
| Placebo
(95% nCI b ) | Absolute Risk per 10,000 Women-Years |
| CHD events | 1.24 (1.00-1.54) | 33 | 39 |
| Non-fatal MI | 1.28 (1.00-1.63) | 25 | 31 |
| CHD death | 1.10 (0.70-1.75) | 8 | 8 |
| All strokes | 1.31 (1.02-1.68) | 24 | 31 |
| Ischemic stroke | 1.44 (1.09-1.90) | 18 | 26 |
| Deep vein thrombosis | 1.95 (1.43-2.67) | 13 | 26 |
| Pulmonary embolism | 2.13 (1.45-3.11) | 8 | 18 |
| Invasive breast cancerc | 1.24 (1.01-1.54) | 33 | 41 |
| Invasive colorectal cancer | 0.56 (0.38-0.81) | 16 | 9 |
| Endometrial cancer | 0.81 (0.48-1.36) | 7 | 6 |
| Cervical cancer | 1.44 (0.47-4.42) | 1 | 2 |
| Hip fracture | 0.67 (0.47-0.96) | 16 | 11 |
| Vertebral fractures | 0.65 (0.46-0.92) | 17 | 11 |
| Lower arm/wrist fractures | 0.71 (0.59-0.85) | 62 | 44 |
| Total fractures | 0.76 (0.69-0.83) | 199 | 152 |
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