July 30, 2015
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Estrasorb

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Estrasorb




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 its 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 follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacodynamics

There are no pharmacodynamic data for ESTRASORB.

Pharmacokinetics

Absorption

In a multiple-dose study, 125 women were treated for 28 days once daily with placebo or ESTRASORB containing 2.875 mg, 5.75 mg, or 8.625 mg of estradiol. The mean change from baseline in serum estradiol concentrations increased in a dose-dependent manner compared with placebo (Figure 1 below).

Figure 1: Mean serum estradiol concentrations (pg/mL) following topical application of placebo or ESTRASORB containing 2.875 mg, 5.75 mg, 8.625 mg of estradiol

Mean serum estradiol concentrations - Illustration

Serum estradiol concentrations were also assessed in a second study involving 200 postmenopausal women, who applied either a daily dose of ESTRASORB (containing 8.625 mg of estradiol; n = 100) or placebo (n = 100) for 12 weeks. Trough estradiol concentrations in the ESTRASORB treatment group increased from a mean of 8.9 pg/mL at baseline to 58.6 pg/mL and 70.2 pg/mL at Weeks 2 and 4, respectively (Figure 2). Trough levels of ESTRASORB remained at a plateau throughout the rest of the study: 67.3 pg/mL at Week 8 and 63.0 pg/mL at the end of the study.

Figure 2: Mean (SE) Trough Serum Estradiol Concentrations Following Daily Topical Application of 3.45 Grams of ESTRASORB Containing 2.5 mg of Estradiol per Gram for 12 weeks.

Mean (SE) Trough Serum Estradiol Concentrations - Illustration

SE = Standard error of the mean

Distribution

No specific investigation of the tissue distribution of estradiol absorbed from ESTRASORB in humans has been conducted. 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 the 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 intestines, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exists 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.

Application of sunscreen

Application of SPF15 sunscreen 10 minutes prior to the application of ESTRASORB containing 8.7 mg of estradiol increased the exposure to estradiol by approximately 38%. When SPF15 sunscreen is applied 25 minutes after the application of ESTRASORB containing 8.7 mg of estradiol, the increase in exposure to estradiol was approximately 46%.

Potential for Estradiol Transfer

Estradiol was detected on the skin at 2 and 8 hours post-application. Washing the application area with soap and water 8 hours post-application removed detectable estradiol from the application site. Upon physical contact made by adult males for 2 minutes to the thighs of females who received daily doses of ESTRASORB containing 8.7 mg of estradiol over a two day period at 2 and 8 hours post-application in a separate study, a mean increase of approximately 25 percent in serum estradiol exposure was identified [see DOSAGE AND ADMINISTRATION].

Clinical Studies

Effects On Vasomotor Symptoms

In a 12-week randomized, placebo-controlled clinical trial, a total of 200 postmenopausal women (average 52 years of age, range 46 to 58, 79 percent Caucasian in the ESTRASORB treatment group; average 51.8 years of age, range 45.8 to 57.8, 72 percent Caucasian in the placebo treatment group) were assigned to receive ESTRASORB (3.45 grams containing 2.5 mg of estradiol per gram) or placebo for a 12 weeks duration. ESTRASORB was shown to be statistically better than placebo at Weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms (p-value < 0.001 for Weeks 4 and 12). Frequency results are shown in Table 2. Severity results are shown in Table 3.

Table 2: Mean Number and Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms Per Day (Intent-to-Treat Population)

Time point Treatment Group
Placebo ESTRASORB
Baseline (observed value) (N = 100) (N = 100)
Mean Number of Hot Flushes (SD) 13.63 (5.48) 13.05 (5.78)
Week 4 (N = 97) (N = 96)
Mean Number of Hot Flushes (SD) 7.46 (6.42) 4.42 (5.60)
Mean Change from Baseline (SD) -5.97 (4.76) -8.56 (6.19)
P-value vs. Placebo NA < 0.001
Week 12 (N = 90) (N = 90)
Mean Number of Hot Flushes (SD) 5.88 (6.17) 2.00 (3.64)
Mean Change from Baseline (SD) -7.20 (5.39) -11.11 (6.84)
P-value vs. Placebo NA < 0.001
SD = Standard Deviation; NA = Not applicable

Table 3: Mean Change from Baseline in the Severity Scorea of Hot Flushes Per Day, Intent-to-Treat Population, Most Recent Value Carried Forward

Time point Treatment Group
Placebo ESTRASORB
Baseline (observed value) (N = 100) (N = 100)
Mean Severity Score per Day (SD) 2.44 (0.37) 2.36 (0.36)
Week 4 (N = 97) (N = 96)
Mean Severity Score per Day (SD) 1.99 (0.81) 1.47 (1.03)
Mean Change from Baseline (SD) -0.45 (0.75) -0.89 (1.04)
P-value vs. Placebo NA < 0.001
Week 12 (N = 90) (N = 90)
Mean Severity Score per Day (SD) 1.88 (0.98) 0.92 (1.00)
Mean Change from Baseline (SD) -0.55 (0.91) -1.44 (1.04)
P-value vs. Placebo NA < 0.001
SD = Standard Deviation; NA = Not applicable
aThe severity score per day is determined by calculating the sum of recorded daily severity and dividing this number by the total number of hot flushes on that day.

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; 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 4.

Table 4: 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
CHD eventsc 0.95 (0.78-1.16) 54 57
Non-fatal MIc 0.91 (0.73-1.14) 40 43
CHD deathc 1.01 (0.71-1.43) 16 16
All strokesc 1.33 (1.15-1.68) 45 33
Ischemic strokec 1.55 (1.19-2.01) 38 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
aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
bNominal confidence intervals unadjusted for multiple looks and multiple comparisons.
cResults are based on centrally adjudicated data for an average follow-up of 7.1 years.
dNot included in “global index”.
eResults are based on an average follow-up of 6.8 years.
fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE, or cerebrovascular disease.
gA 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.

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 fractures9. 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 subtype 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 nonsignificant 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 estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 5. 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 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
CHD events 1.23 (0.99-1.53) 41 34
Non-fatal MI 1.28 (1.00-1.63) 31 25
CHD death 1.10 (0.70-1.75) 8 8
All strokes 1.31 (1.03-1.68) 33 25
Ischemic stroke 1.44 (1.09-1.90) 26 18
Deep vein thrombosisd 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 cancerd 0.81 (0.48-1.36) 6 7
Cervical cancerd 1.44 (0.47-4.42) 2 1
Hip fracture 0.67 (0.47-0.96) 11 16
Vertebral fracturesd 0.65 (0.46-0.92) 11 17
Lower arm/wrist fracturesd 0.71 (0.59-0.85) 44 62
Total fracturesd 0.76 (0.69-0.83) 152 199
Overall mortalityf 1.00 (0.83-1.19) 52 52
Global Indexg 1.13 (1.02-1.25) 184 165
aAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.
bResults are based on centrally adjudicated data.
cNominal confidence intervals unadjusted for multiple looks and multiple comparisons.
dNot included in “global index”.
eIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.
fAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE, or cerebrovascular disease.
gA 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.

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 for 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 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)-alone 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 WARNING AND PRECAUTIONS, and Use In Specific Populations].

The WHIMS estrogen plus progestin ancillary study enrolled 4532 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, 1.21-3.48). 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 WARNING AND PRECAUTIONS, and Use in Specific Populations].

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 WARNING AND PRECAUTIONS, and Use in Specific Populations].

REFERENCES

8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958.

9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res. 2006; 21:817-828.

10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006; 113:2425-2434.

Last reviewed on RxList: 3/23/2015
This monograph has been modified to include the generic and brand name in many instances.

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