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Elestrin

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Elestrin

Elestrin

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

Pharmacodynamics

Currently, there are no pharmacodynamic data known for ELESTRIN.

Pharmacokinetics

Absorption

Steady-state serum concentrations of estradiol are achieved in approximately 3 days following daily application of ELESTRIN to the upper arm.

Pharmacokinetic parameters for estradiol on Day 14 following daily application of 0.87 g or 1.7 g of ELESTRIN are summarized in Table 2. Dose dependent PK parameters for ELESTRIN 0.87 g and 1.7 g indicated the dose and serum estradiol (E2) concentrations to be linearly related but not dose-proportional (i.e., doubling in dose led to a 2.5-to 3.0-fold increase in PK parameters). The nominal mean delivery rates of estradiol using the baseline-adjusted average serum concentrations from pharmacokinetic studies using 0.87 g per day and 1.7 g per day are 0.0125 mg per day and 0.0375 mg per day, respectively.

TABLE 2 :Summary of Unadjusted PK Parameters for Estradiol after 14 Days of Dosing

Pharmacokinetic Parameter 0.87 g ELESTRIN (0.52 mg/d Estradiol) Mean 1.7 g ELESTRIN (1.04 mg/d Estradiol) Mean
AUC0-24 (pg'hr/mL) 335.2 940.2
Cmax (pg/mL) 21.6 66.7
Cave (pg/mL) 15.4 39.2
Cmin (pg/mL) 9.4 21.1
Tmax (h)a 18 (1 – 20) 4 (1 – 20)
Fluctuation Index 0.8 1.16
E2:E1b ratio 0.53 0.98
aTmax shown as median (range)
bE2:E1 (estradiol:estrone) ratio Mean concentrations of estradiol over a 24-hour period on Day 14 are shown in Figure 1.

Figure 1 :Mean Serum Estradiol Concentrations (Unadjusted) After Multiple Doses.
Error bars represent standard deviations.

Mean Serum Estradiol Concentrations (Unadjusted) After Multiple Doses - Illustration

Based on the Cave values at steady state, the E2:E1 ratio was 0.53 for the 0.87 g and 0.98 for the 1.7 g doses. The significance of this finding is that the 1.7 g dose produced an E2:E1 ratio of a premenopausal woman. The 1.7 g dose of ELESTRIN reached the goal of restoring the E2:E1 ratio (~1.0) to that observed in premenopausal women in the early follicular phase of the menstrual cycle.

Application of sunscreen 10 minutes before application of ELESTRIN increased the exposure to estradiol by approximately 55 percent. No significant change in estradiol exposure was observed when sunscreen was applied 25 minutes after application of ELESTRIN. In the same study, prolonged (7 days) concomitant application of sunscreen to the site of ELESTRIN application increased exposure to estradiol by about 2-fold, regardless of whether it was applied before or after application of ELESTRIN.

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 in specific populations, including women with renal or hepatic impairment.

Potential for Estradiol Transfer

The potential for estradiol transfer between treated postmenopausal female subjects and their untreated male partners was evaluated. Two and 8 hours after women applied 2.6 g ELESTRIN to one arm (12 women per time point), they engaged in direct arm-to-arm contact with a male partner for 5 minutes. No significant changes in estradiol pharmacokinetic parameters were observed in the male partners after contact.

Less than 10 percent of the estradiol dose was measured on the skin at 2 and 8 hours after application. After washing the application site with soap and water at 8 hours after application, about 1 percent of the dose of estradiol was measurable.

Clinical Studies

Effects On Vasomotor Symptoms

A randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy of 12-week treatment with three different daily doses of ELESTRIN for the treatment of vasomotor symptoms in 484 postmenopausal women between 28 and 74 years of age (mean 54 years; 83-88 percent Caucasian per group) who had at least 60 moderate-to-severe hot flushes per week at baseline. At baseline, mean hot flushes is 13 per day, mean serum estradiol is 11.2-13.2 pg/mL, and prior hormone/estrogen therapy is 75.7-84.5 percent. Subjects applied placebo, ELESTRIN 1.7 g (1.04 mg estradiol), or 2.6 g (1.56 mg estradiol) once daily to the upper arm. The study was amended to identify the lowest effective dose of ELESTRIN and limit the number of subjects exposed to the 2.6 g dose. After the study amendment, ELESTRIN 0.87 g (0.52 mg estradiol) was added and the 2.6 g was discontinued from further enrollment. Reduction in both the frequency and severity of moderate to severe hot flushes was statistically significant for the ELESTRIN 1.7 g per day dose compared to placebo at week 4. Statistically significant reductions in both the frequency and severity of moderate to severe hot flushes when compared to placebo were delayed for the ELESTRIN 0.87 g per day dose to week 5. Both the 0.87 g per day and 1.7 g per day doses were statistically significant compared to placebo at week 12. Statistically significant reductions in the frequency and severity of daily moderate-to-severe hot flush rate compared to placebo were noted beginning at week 3 for the 1.7 g per day ELESTRIN treatment (data on file). The reductions in frequency and severity are shown in Table 3.

TABLE 3 :Mean Change From Baselinea in the Number and Severity of Hot Flushes after ELESTRIN Treatment

Evaluation Placebo
(N=137)
ELESTRIN 0.87 g/day
(N=136)
ELESTRIN 1.7 g/day
(N=142)
Number of Daily Hot Flushes
Baseline (Mean ± SD)b 13.5 ± 4.5 13.3 ± 4.6 13.1 ± 6.5
  Mean Change: Week 4 -5.1 -6.5# -8.0***
  Week 5 -5.1 -7.5* -8.8***
  Week 12 -5.4 -8.5*** -10.0***
Daily Hot Flush Severityc
Baseline (Mean ± SD)b 2.4 ± 0.3 2.4 ± 0.3 2.4 ± 0.3
  Mean Change: Week 4 -0.2 -0.5# -0.7***
  Week 5 -0.2 -0.5* -0.8***
  Week 12 -0.3 -0.8*** -1.2***
aDifferences from baseline based on LS means derived from the ANCOVA model with factors for baseline, treatment, site, and treatment-by-baseline interaction.
bUnadjusted means and standard deviations, based on the first 14 days of the Screening Period.
c Severity score: 1=mild, 2=moderate, 3=severe.
SD: standard deviation #P=ns, *P < 0.01, **P < 0.001, ***P < 0.0001 for treatment comparison with placebo (Dunnett's test).

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 risk and benefits of estrogen-alone in predetermined 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 MI c 0.91 (0.73-1.14) 40 43
  CHD deathc 1.01 (0.71-1.43) 16 16
All Strokec 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 cancerc 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
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, pulmonary embolism, 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 risks 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 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 with 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 difference in the distribution of stroke subtype and severity, including fatal strokes, in women receiving estrogen-alone compared to placebo. Estrogen-alone therapy increased the risk of ischemic stroke, and this excess risk was present in all subgroups of women examined.10

Timing of 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; 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 Stroke 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 fractures 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
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 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, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.

Timing of 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 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 the 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, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in the study included AD, VaD and mixed types (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].

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, and Use in Specific Populations].

REFERENCES

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: 3/17/2014
This monograph has been modified to include the generic and brand name in many instances.

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