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Activella

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Activella

Activella

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.

Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system.

Pharmacodynamics

There are no pharmacodynamic data known for Activella tablets.

Pharmacokinetics

Absorption

Estradiol

Estradiol is absorbed through the gastrointestinal tract. Following oral administration of Activella tablets, peak plasma estradiol concentrations are reached within 5 to 8 hours. The oral bioavailability of estradiol following administration of Activella 1 mg/0.5 mg when compared to a combination oral solution is 53%. Administration of Activella 1 mg/0.5 mg with food did not modify the bioavailability of estradiol.

Norethindrone Acetate

After oral administration, norethindrone acetate is absorbed and transformed to norethindrone. Norethindrone reaches a peak plasma concentration within 0.5 to 1.5 hours after the administration of Activella tablets. The oral bioavailability of norethindrone following administration of Activella 1 mg/0.5 mg when compared to a combination oral solution is 100%. Administration of Activella 1 mg/0.5 mg with food increases norethindrone AUC0-72 by 19% and decreases Cmax by 36%.

The pharmacokinetic parameters of estradiol (E2), estrone (E1), and norethindrone (NET) following oral administration of 1 Activella 1 mg/0.5 mg or 2 Activella 0.5 mg/0.1 mg tablet(s) to healthy postmenopausal women are summarized in Table 3.

TABLE 3 : PHARMACOKINETIC PARAMETERS AFTER ADMINISTRATION OF 1 TABLET OF ACTIVELLA 1 MG/0.5 MG OR 2 TABLETS OF ACTIVELLA 0.5 MG/0.1 MG TO HEALTHY POSTMENOPAUSAL WOMEN

  1 x Activella 1 mg/0.5 mg
(n=24)
Meana (%CV)b
2 x Activella 0.5 mg/0.1 mg
(n=24)
Meana (%CV)b
Estradiolc (E2)
AUQ)-t (pg/mL*h) 766.5 (48) 697.3 (53)
Cmax (pg/mL) 26.8 (36) 26.5 (37)
tmax (h): median (range) 6.0 (0.5-16.0) 6.5 (0.5-16.0)
t1/2 (h)d 14.0e (29) 14.5f (27)
Estronec (Et)
AUC(m (pg/mL*h) 4469.1 (48) 4506.4 (44)
Cmax (pg/mL) 195.5 (37) 199.5 (30)
tmax (h): median (range) 6.0 (1.0-9.0) 6.0 (2.0-9.0)
t1/2 (h)d 10.7 (44)g 11.8 (25)g
Norethindrone (NET)
AUCo-t (pg/mL*h) 21043 (41) 8407.2 (43)
Cmax (pg/mL) 5249.5 (47) 2375.4 (41)
tmax (h) : median (range) 0.7 (0.7-1.25) 0.8 (0.7-1.3)
t1/2 (h) 9.8 (32)h 11.4 (36)i
AUC = area under the curve, 0 – last quantifiable sample Cmax = maximum plasma concentration, tmax = time at maximum plasma concentration, t1/2 = half-life,
ageometric mean;
bgeometric % coefficient of variation;
cbaseline unadjusted data;
dbaseline unadjusted data ;
en=18;
fn=16;
gn=13;
hn=22;
in=21

Following continuous dosing with once-daily administration of Activella 1 mg/0.5 mg, serum concentrations of estradiol, estrone, and norethindrone reached steady-state within two weeks with an accumulation of 33 to 47% above concentrations following single dose administration. Unadjusted circulating concentrations of E2, E1, and NET during Activella 1 mg/0.5 mg treatment at steady state (dosing at time 0) are provided in Figures 1a and 1b.

Figure 1a: Mean Baseline-Uncorrected Estradiol and Estrone Serum Concentration-Time Profiles Following Multiple Doses of Activella 1 mg/0.5 mg (N=24)

Mean Baseline-Uncorrected Estradiol and Estrone Serum Concentration - Illustration

Figure 1b: Mean Baseline-Uncorrected Norethindrone Serum Concentration-Time Profile Following Multiple Doses of Activella 1 mg/0.5 mg (N=24)

Mean Baseline-Uncorrected Norethindrone Serum Concentration - Illustration

Distribution

Estradiol

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. Estradiol circulates in the blood bound to SHBG (37%) and to albumin (61%), while only approximately 1 to 2% is unbound.

Norethindrone Acetate

Norethindrone also binds to a similar extent to SHBG (36%) and to albumin (61%).

Metabolism

Estradiol

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.

Norethindrone Acetate

The most important metabolites of norethindrone are isomers of 5α-dihydro-norethindrone and tetrahydro-norethindrone, which are excreted mainly in the urine as sulfate or glucuronide conjugates.

Excretion

Estradiol

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life of estradiol following single dose administration of Activella 1 mg/0.5 mg is 12 to 14 hours.

Norethindrone Acetate

The terminal half-life of norethindrone is about 8 to 11 hours.

Use in Specific Populations

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

Clinical Studies

Effects on Vasomotor Symptoms

In a 12-week randomized clinical trial involving 92 subjects, Activella 1 mg/0.5 mg was compared to 1 mg of estradiol and to placebo. The mean number and intensity of hot flushes were significantly reduced from baseline to week 4 and 12 in both the Activella 1 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see Figure 2).

Figure 2 : Mean Weekly Number of Moderate and Severe Hot Flushes in a 12-Week Study

Mean Weekly Number of Moderate and Severe Hot Flushes - Illustration

In a study conducted in Europe a total of 577 postmenopausal women were randomly assigned to either Activella 0.5 mg/0.1 mg, 0.5 mg E2/0.25 mg NETA, or placebo for 24 weeks of treatment. The mean number and severity of hot flushes were significantly reduced at week 4 and week 12 in the Activella 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E2/0.25 mg NETA groups compared to placebo.

Figure 3 : Mean Number of Moderate to Severe Hot Flushes for Weeks 0 Through 12

Mean Number of Moderate to Severe Hot Flushes - Illustration

Effects on the Endometrium

Activella 1 mg/0.5 mg reduced the incidence of estrogen-induced endometrial hyperplasia at 1 year in a randomized, controlled clinical trial. This trial enrolled 1,176 subjects who were randomized to one of 4 arms: 1 mg estradiol unopposed (n=296), 1 mg E2 + 0.1 mg NETA (n=294), 1 mg E2 + 0.25 mg NETA (n=291), and Activella 1 mg/0.5 mg (n=295). At the end of the study, endometrial biopsy results were available for 988 subjects. The results of the 1 mg estradiol unopposed arm compared to Activella 1 mg/0.5 mg are shown in Table 4.

TABLE 4 : INCIDENCE OF ENDOMETRIAL HYPERPLASIA WITH UNOPPOSED ESTRADIOL AND ACTIVELLA 1 MG/0.5 MG IN A 12-MONTH STUDY

  1 mg E2
(n=296)
Activella 1 mg E2/0.5 mg NETA
(n=295)
1 mg E2/0.25 mg NETA
(n=291 )
1 mg E2/0.1 mg NETA
(n=294 )
No. of subjects with histological evaluation at the end of the study 247 241 251 249
No. (%) of subjects with endometrial hyperplasia at the end of the study 36 (14.6%) 1 (0.4%) 1 (0.4%) 2 (0.8%)

Effects on Uterine Bleeding or Spotting

During the initial months of therapy, irregular bleeding or spotting occurred with Activella 1 mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with Activella 1 mg/0.5 mg, about 86 percent of women were amenorrheic (see Figure 4).

Figure 4 : Patients Treated with Activella 1 mg/0.5 mg with Cumulative Amenorrhea over Time
Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 13 Intent to Treat Population, LOCF

Percentage of Women with no Bleeding or Spotting - Illustration

Note: the percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).

In the clinical trial with Activella 0.5 mg/0.1 mg, 88 percent of women were amenorrheic after 6 months of treatment (See Figure 5).

Figure 5 : Patients Treated with Activella 0.5 m g/0.1 mg with Cumulative Amenorrhea over Time
Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 6, Intent to Treat Population, LOCF

Percentage of Women with no Bleeding or Spotting - Illustration

Effects on Bone Mineral Density

The results of two randomized, multicenter, calcium-supplemented (500-1000 mg per day), placebo-controlled, 2 year clinical trials have shown that Activella 1 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. A total of 462 postmenopausal women with intact uteri and baseline BMD values for lumbar spine within 2 standard deviations of the mean in healthy young women (T-score > -2.0) were enrolled. In a US trial, 327 postmenopausal women (mean time from menopause 2.5 to 3.1 years) with a mean age of 53 years were randomized to 7 groups (0.25 mg, 0.5 mg, and 1 mg of estradiol alone, 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and 2 mg estradiol with 1 mg norethindrone acetate, and placebo.) In a European trial (EU trial), 135 postmenopausal women (mean time from menopause 8.4 to 9.3 years) with a mean age of 58 years were randomized to 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and placebo. Approximately 58 percent and 67 percent of the randomized subjects in the two clinical trials, respectively, completed the two clinical trials. BMD was measured using dual-energy x-ray absorptiometry (DXA).

A summary of the results comparing Activella 1 mg/0.5 mg and estradiol 0.5 mg to placebo from the two prevention trials is shown in Table 5.

TABLE 5 : PERCENTAGE CHANGE (MEAN ± SD) IN BONE MINERAL DENSITY (BMD) FOR ACTIVELLA 1 MG/0.5 MG AND 0.5 MG E2 † (Intent to Treat Analysis, Last Observation Carried Forward)

  US Trial EU Trial
Placebo
(n=37)
0.5 mg E2
(n=31)
Activella 1 mg/0.5 mg
(n=37)
Placebo
(n=40)
Activella 1 mg/0.5 mg
(n=38)
Lumbar spine -2.1 ± 2.9 2.3 ± 2.8 * 3.8 ± 3.0 * -0.9 ± 4.0 5.4 ± 4.8 *
Femoral neck -2.3 ± 3.4 0.3 ± 2.9 ** 1.8 ± 4.1 * -1.0 ± 4.6 0.7 ± 6.1
Femoral trochanter -2.0 ± 4.3 17 ± 4 1*** 3.7 ± 4.3 * 0.8 ± 6.9 6.3 ± 7.6 *
US= United States, EU = European
† While Activella 0.5 mg/0.1 mg was not directly studied in these trials, the US trial showed that addition of NETA to estradiol enhances the effect on BMD; therefore the BMD changes expected from treatment with Activella 0.5 mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg.
* Significantly (p < 0.001) different from placebo
** Significantly (p < 0.007) different from placebo
***Significantly (p < 0.002) different from placebo

The overall difference in mean percentage change in BMD at the lumbar spine in the US trial (1000 mg per day calcium) between Activella 1 mg/0.5 mg and placebo was 5.9 percent and between estradiol 0.5 mg and placebo was 4.4 percent. In the European trial (500 mg per day calcium), the overall difference in mean percentage change in BMD at the lumbar spine was 6.3 percent. Activella 1 mg/0.5 mg and estradiol 0.5 mg also increased BMD at the femoral neck and femoral trochanter compared to placebo. The increase in lumbar spine BMD in the US and European clinical trials for Activella 1 mg/0.5 mg and estradiol 0.5 mg is displayed in Figure 6.

Figure 6 : Percentage Change in Bone Mineral Density (BMD) ± SEM of the Lumbar Spine (L1-L4) for Activella 1 mg/0.5 mg and Estradiol 0.5 mg (Intent to Treat Analysis with Last Observation Carried Forward)

Percentage Change in Bone Mineral Density - Illustration

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 plus MPA or CE-alone on menopausal symptoms.

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 reductions 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 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 versus 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, 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 by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44-1.07)].

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 7.

Table 7: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa

Event Relative Risk CE versus Placebo (95% nCIb) CE
n = 5,310
Placebo
n = 5,429
Absolute Risk per10,000 Women-Years
CHD eventsc 0.95 (0.78-1.16) 54 57
  Non-fatal Mlc 0.91 (0.73-1.14) 40 43
  CHD deathc 1.01(0.71-1.43) 16 16
All strokesc 1.33 (1.05-1.68) 45 33
   Ischemic strokeb 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, pulmonary embolism, 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 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 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 non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].

Women's Health Initiative Memory Study

The WHIMS estrogen plus progestin ancillary study of WHI 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, 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 this 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-alone ancillary study of WHI study 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 this 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: 11/4/2013
This monograph has been modified to include the generic and brand name in many instances.

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