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, which is 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 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 Menostar.
Pharmacokinetics
Absorption
The bioavailability of estradiol following application of a Menostar transdermal system, relative to that of a transdermal system delivering 25 mcg per day, was investigated in 18 healthy postmenopausal women, mean age 66 years (range 60 to 80 years). The mean serum estradiol concentrations upon administration of the two patches to the lower abdomen are shown in Figure 1. Transdermal administration of Menostar produced geometric mean serum concentration (Cavg) of estradiol of 13.7 pg/mL. No patches failed to adhere during the one week application period of both transdermal systems. Following application of the Menostar transdermal system to the abdomen, it is estimated to provide an average nominal in-vivo daily delivery of 14 mcg estradiol per day.
The Menostar transdermal delivery system continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7-day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first pass metabolism when estradiol is given by the transdermal route.
Figure 1: Mean Uncorrected Serum 17ß-Estradiol Concentrations vs. Time Profile Following Application of the Menostar Transdermal System and the Climara® 6.5 cm2 Transdermal System
Table 2 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of the Menostar transdermal system using baseline uncorrected serum concentrations.
Summary of Estradiol Pharmacokinetic Parameters (Abdomen Application)
Table 2: Summary of Estradiol Pharmacokinetic Parameters (Abdomen Application)
|
Product
|
Estradiol Daily Delivery Rate, mcg/day
|
AUC
(0-tlast)
pg•h/mL
|
Cmax
pg/mL
|
Cavg
pg/mL
|
Tmax
h
|
Cmin
pg/mL
|
|
Menostar
|
14
|
2296
|
20.6
|
13.7
|
42
|
12.6
|
|
Climara 6.5 cm2
|
25
|
4151
|
37.2
|
24.7
|
42
|
20.4
|
Pharmacokinetic parameters are expressed in geometric means except for the Tmax which represents the median estimate and the Cmin which is expressed as the arithmetic mean. The estimated estradiol daily delivery rate for Climara 6.5 cm2 is quoted from the Climara labeling.
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 the blood largely bound to SHBG and albumin. In the clinical study with 208 patients on Menostar, SHBG concentration (mean ± SD) remained essentially unchanged over the 2 year period (baseline 45.1 ± 20.1 nmol/L, 24-month visit 46.4 ± 20.9 nmol/L).
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.
Adhesion
In a Menostar transdermal system pharmacokinetic study with 18 postmenopausal women, no patches failed to adhere during the one week application period
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 Bone Mineral Density
The efficacy of Menostar in the prevention of postmenopausal osteoporosis was investigated in a 2-year double blind, placebo-controlled, multicenter study in the United States. A total of 417 postmenopausal women, 60 to 80 years of age, with an intact uterus were enrolled in the study. All patients received supplemental calcium and vitamin D.
At lumbar spine Menostar increased BMD by 2.3 percent after 1 year and 3 percent after 2 years compared with a 0.5 percent increase after 1 and 2 years of treatment with placebo. At the hip Menostar increased BMD by 0.9 percent after one year and 0.84 percent after two years compared with a mean decrease of 0.22 percent after 1 year and 0.71 percent after 2 years of placebo treatment. The changes in BMD from baseline were statistically significantly (p <0.001) greater during treatment with Menostar than during treatment with placebo for both the spine and hip after 1 and 2 years (Table 3).
Table 3: Mean Percent BMD Change from Baseline in Lumbar Spine and Total Hip (Full Analysis Set)
|
Lumbar spine
|
Total hip
|
|
Time points
|
Menostar
N
= 208
|
Placebo
N = 209
|
p-value
|
Time points
|
Menostar
N = 208
|
Placebo
N = 209
|
p-value
|
|
|
n
= 189
|
n = 186
|
|
|
n = 189
|
n =184
|
|
|
12-month Endpoint
|
+2.29
|
+0.51
|
< 0.001
|
12-month Endpoint
|
+0.90
|
-0.22
|
< 0.001
|
|
|
n = 189
|
n = 186
|
|
|
n = 189
|
n = 185
|
|
|
24-month Endpoint
|
+2.99
|
+0.54
|
< 0.001
|
24-month Endpoint
|
+0.84
|
-0.71
|
< 0.001
|
The BMD data of the study were analyzed according to baseline estradiol levels of the patients. Overall, estimated treatment effects on lumbar spine and total hip BMD after 2 years were approximately twice as large in the subgroup with baseline estradiol levels < 5 pg/mL than in the subgroup with baseline estradiol levels ≥ 5 pg/mL (Table 4).
Table 4: Mean Percent Change in Lumbar Spine and Total Hip BMD at 24 months by Subgroups of Baseline Estradiol Level (< 5 pg/mL, 5 pg/mL)
|
Lumbar spine
|
Total hip
|
|
Baseline estradiol levels
|
Menostar
|
Placebo
|
Treatment difference
|
Menostar
|
Placebo
|
Treatment difference
|
|
< 5 pg/mL
|
n
= 101
|
n = 97
|
|
n = 101
|
n = 96
|
|
|
|
+3.50
|
+0.29
|
3.21
|
+1.04
|
-1.09
|
2.13
|
|
|
|
|
(p < 0.001)
|
|
|
(p < 0.001)
|
|
≥ 5 pg/mL
|
n = 88
|
n = 89
|
|
n = 88
|
n = 89
|
|
|
|
+2.40
|
+0.81
|
1.59
|
+0.61
|
-0.31
|
0.92
|
|
|
|
|
(p = 0.002)
|
|
|
(p = 0.045)
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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 causes. 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 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 5.
Table 5: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI
| Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. |
|
Eventb
|
Relative Risk
CE vs. Placebo
(95% nCI
)
|
CE
n = 5,310
|
Placebo
n = 5,429
|
|
Absolute Risk per 10,000
Women-years
|
|
CHD events
|
0.95 (0.78-1.16)
|
54
|
57
|
|
Non-fatal MI
|
0.91 (0.73-1.14)
|
40
|
43
|
|
CHD death
|
1.01 (0.71-1.43)
|
16
|
16
|
|
All strokes
|
1.33 (1.05-1.68)
|
45
|
33
|
|
Ischemic stroke
|
1.55 (1.19-2.01)
|
38
|
25
|
|
Deep vein thrombosis
,
|
1.47 (1.06-2.06)
|
23
|
15
|
|
Pulmonary embolism
|
1.37 (0.90-2.07)
|
14
|
10
|
|
Invasive breast cancer
|
0.8 (0.62-1.04)
|
28
|
34
|
|
Colorectal cancer
|
1.08 (0.75-1.55)
|
17
|
16
|
|
Hip fracture
|
0.65 (0.45-0.94)
|
12
|
19
|
|
Vertebral fractures
,
|
0.64 (0.44-0.93)
|
11
|
18
|
|
Lower arm/wrist fractures
,
|
0.58 (0.47-0.72)
|
35
|
59
|
|
Total fractures
,
|
0.71 (0.64-0.80)
|
144
|
197
|
|
Death due to causes
,
|
1.08 (0.88-1.32)
|
53
|
50
|
|
Overall mortality,
|
1.04 (0.88-1.22)
|
79
|
75
|
|
Global Index
|
1.02 (0.92-1.13)
|
206
|
201
|
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 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 with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years. See Table 5.
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 increased the risk of ischemic stroke, and this excess risk was present in all subgroups of women examined.10 See Table 5.
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, 6.5 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 Years
| Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. WHI publications can be viewed at www.nhlbi.nih.gov/whi. |
|
Event
|
Relative Risk
CE/MPA vs. placebo
(95% nCI
)
|
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
|
|
|
1.28 (1.00-1.63)
|
31
|
25
|
|
|
1.10 (0.70-1.75)
|
8
|
8
|
|
All strokes
|
1.31 (1.03-1.68)
|
33
|
25
|
|
|
1.44 (1.09-1.90)
|
26
|
18
|
|
Deep vein thrombosis
|
1.95 (1.43-2.67)
|
26
|
13
|
|
Pulmonary embolism
|
2.13 (1.45-3.11)
|
18
|
8
|
|
Invasive breast cancer
|
1.24 (1.01-1.54)
|
41
|
33
|
|
Colorectal cancer
|
0.61 (0.42-0.87)
|
10
|
16
|
|
Endometrial cancer
|
0.81 (0.48-1.36)
|
6
|
7
|
|
Cervical cancer
|
1.44 (0.47-4.42)
|
2
|
1
|
|
Hip fracture
|
0.67 (0.47-0.96)
|
11
|
16
|
|
Vertebral fractures
|
0.65 (0.46-0.92)
|
11
|
17
|
|
Lower arm/wrist fractures
|
0.71 (0.59-0.85)
|
44
|
62
|
|
Total fractures
|
0.76 (0.69-0.83)
|
152
|
199
|
|
Overall mortality
|
1.00 (0.83-1.19)
|
52
|
52
|
|
Global Index
|
1.13 (1.02-1.25)
|
184
|
165
|
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; 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 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].
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]
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