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Climara Pro

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Climara Pro

Climara Pro

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 FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Levonorgestrel inhibits gonadotropin production resulting in retardation of follicular growth and inhibition of ovulation.

Studies to assess the potency of progestins using estrogen-primed postmenopausal endometrial biochemistry and morphologic features have shown that levonorgestrel counteracts the proliferative effects of estrogens on the endometrium.

Pharmacodynamics

There are no pharmacodynamic data for Climara Pro.

Pharmacokinetics

Absorption

Transdermal administration of Climara Pro produces mean maximum estradiol concentrations in serum in about 2 to 2.5 days. Estradiol concentrations equivalent to the normal ranges observed at the early follicular phase in premenopausal women are achieved within 12–24 hours after the first application.

In one study, steady state estradiol concentrations in serum were measured during week 4 in 44 healthy, postmenopausal women during four consecutive Climara Pro applications of two formulations (0.045 mg estradiol/0.03 mg levonorgestrel and 0.045 mg estradiol/0.015 mg levonorgestrel) to the abdomen (each dose was applied for four 7-day periods). Both formulations were bioequivalent in terms of estradiol and estrone Cmax and AUC parameters. A summary of Climara Pro single and multiple applications estradiol, estrone and levonorgestrel pharmacokinetic parameters is shown in Table 2.

Table 2: Summary of Mean Pharmacokinetic Parameters
Summary of Mean (± SD) Pharmacokinetic Parameters Following a Single Application of Climara Pro in 24 Healthy Postmenopausal Women

Parameter Units Estradiol Estrone Levonorgestrel
Single application Week 1 Data
Cave Pg/mL 37.7 ± 10.4 41 ± 15 136 ± 52.7
Cmax Pg/mL 54.3 ± 18.9 43.9 ± 14.9 138 ± 51.8
Tmax Hours 42 84 90
Cmin Pg/mL 27.2 ± 7.66 32.6 ± 14.3 110 ± 41.7
AUC Pg.h/mL 6340 ± 1740 6890 ± 2520 22900 ± 8860
Summary of Mean (± SD) Pharmacokinetic Parameters (Week 4) Following Four Consecutive Weekly Applications of Climara Pro in 44 Healthy Postmenopausal Women
Multiple application Week 4 Data
Cave Pg/mL 35.7 ± 11.4 45.5 ± 62.6 166 ± 97.8
Cmax Pg/mL 50.7 ± 28.6 81.6 ± 252 194 ± 111
Tmax Hours 36 48 48
Cmin Pg/mL 33.8 ± 28.7 72.5 ± 253 153 ± 69.6
AUC Pg.h/mL 6002 ± 1919 7642 ± 10518 27948 ± 16426

All mean parameters are arithmetic means except Tmax which is expressed as the median.

At steady state, Climara Pro maintains during the application period an average serum estradiol concentration of 35.7 pg/mL as depicted in Figure 1.

Figure 1: Mean Estradiol Concentration Profile (Week 4)
Following Four Consecutive Weekly Applications of Climara Pro

Mean Estradiol Concentration Profile - Illustration

Following the application of the Climara Pro transdermal system, levonorgestrel concentrations are maximum in about 2.5 days. At steady state, Climara Pro maintains during the application period an average serum levonorgestrel concentration of 166 pg/mL as depicted in Figure 2. The mean levonorgestrel pharmacokinetic parameters of Climara Pro are summarized in Table 2.

Figure 2: Mean Levonorgestrel Concentration Profile (Week 4)
Following Four Consecutive Weekly Applications of Climara Pro

Mean Levonorgestrel Concentration Profile - Illustration

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.

Levonorgestrel in serum is bound to both SHBG and albumin. Following four consecutive weekly applications of Climara Pro mean (± SD) SHBG concentrations declined from a predose value of 47.5 (25.8) to 41.2 (22.4) nmol/L at week 4.

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.

The most important metabolic pathway for levonorgestrel occurs in the reduction of the Δ4-and the 3-oxo-group as well as hydroxylations at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as the 17β-sulfate. In-vitro studies on the biotransformation of levonorgestrel in human skin did not indicate any significant metabolism of levonorgestrel during skin penetration.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Following patch removal, serum estradiol concentrations decline with a mean (± SD) terminal half-life of 3± 0.67 hours.

Levonorgestrel and its metabolites are primarily excreted in the urine. Mean (± SD) terminal half-life for levonorgestrel was determined to be 28 ± 6.4 hours.

Adhesion

A study of the adhesion potential of Climara Pro was conducted in 104 healthy women of 45–75 years of age. Each woman applied a placebo patch, containing only the Climara Pro adhesive without active ingredient, to the upper outer abdominal areas weekly for three weeks. The adhesion assessment was done visually on Days 2, 4, 5, 6 and 7 of each of the three weeks using a four-point scale. The mean scores ranked in the highest category possible on the 0 to 4 scale demonstrating clinically acceptable adhesion performance.

Clinical Studies

Effects on Vasomotor Symptoms

The efficacy of 0.045 mg estradiol/0.03 mg levonorgestrel administered weekly versus placebo in the relief of moderate to severe vasomotor symptoms in postmenopausal women was studied in one 12-week clinical trial (n=183, average age 52.1 ± 4.93, 82 percent Caucasian). The 0.045 mg estradiol/0.03 mg levonorgestrel dosage strength was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the number and severity of moderate to severe hot flushes. See Tables 3 and 4. Climara Pro and the 0.045 mg estradiol/0.03 mg levonorgestrel dosage strength are bioequivalent in terms of estradiol delivery [See CLINICAL PHARMACOLOGY].

Table 3: Summary of Mean Daily Number of Moderate to Severe Hot Flushes-ITTa

    Baselineb Week 4 Week 8 Week 12
Placebo nc 88 82 73 69
  Mean (SD)d 10.8 (5.803) 6.13 (4.311) 5.35 (4.095) 5.59 (4.93)
  Mean Change from baseline (SD) NA -4.23 (4.374) -4.8 (4.448) -4.55 (5.407)
0.045/.03 n c 92 88 80 73
  Mean (SD)d 10.13 (3.945) 2.69 (4.455) 1.22 (2.804) 1.06 (3.187)
  Mean Change from baseline (SD)d NA -7.4 (4.715) -8.68 (4.146) -8.82 (4.336)
p-Value e   NA < 0.001f NA < 0.001f
aITT = Intent-to-Treat population
b A subject was included at baseline only if the subject had a post-baseline mean score. The post-baseline mean score required 3 days in one week.
c n = Number of subjects in a treatment group in a cycle; number of subjects varied from cycle to cycle due to missing data
d SD = standard deviation
e p-value for comparison to placebo, adjusted by the method of Bonferroni
f p < 0.025

Table 4: Summary of Mean Severity of Moderate to Severe Hot Flushes-ITTa

    Baselineb Week 4 (day 7) Week 8 (day 7) Week 12 (day 7)
Placebo n c 89 76 68 57
  Mean (SD)d 2.42 (0.282) 1.99 (0.875) 1.93 (0.955) 1.8 (1.034)
  Mean Change from baseline (SD)d NA -0.4 (0.865) -0.48 (0.922) -0.57 (1.044)
0.045/.03 n c 92 83 72 55
  Mean (SD)d 2.48 (0.295) 1.1 (1.191) 0.82 (1.226) 0.44 (0.96)
  Mean Change from baseline (SD)d NA -1.4 (1.164) -1.67 (1.245) -2.06 (1.005)
  p-value e NA < 0.001f NA < 0.001f
aITT= Intent-to-Treat population
bA subject was included at baseline only if the subject had at least 1 post-baseline value.
c n= Number of subjects in a treatment group in a cycle; number of subjects varied from cycle to cycle due to missing data
d SD= standard deviation Severity scores are: 1 = Mild, 2 = Moderate, 3 = Severe. Mean severity of hot flushes by day is [(2X number of moderate hot flushes) + (3X number of severe hot flushes)] / total number of moderate to severe hot flushes on that day. If no moderate to severe hot flush was indicated, the mean severity was 0.
e p-value for comparison to placebo, adjusted by the method of Bonferroni
f p < 0.025

Effects on the Endometrium

In a 1-year clinical trial of 412 postmenopausal women (with intact uteri) treated with a continuous regimen of Climara Pro or with an continuous estradiol-only transdermal system, results of evaluable endometrial biopsies show that no hyperplasia was seen with Climara Pro. Table 5 below summarizes these results (Intent-to-Treat populations).

Table 5: Incidence of Endometrial Hyperplasia during Continuous Combined Treatment with Climara Pro, ITTf

  Climara Pro E2 0.045 mg / LNG 0.015 mg
na = 210
Estradiol E2 0.045 mg
n a = 202
No. of Patients with Biopsies at > 6 monthsb 124 139
No. of Patients with Biopsies at 1 yearc 102 110
No. (%) of Patients with Hyperplasiad 0 (0%)e 19 (17.3%)
95% Confidence Interval 0-3.55% 9.75–24.79%
an = number of intent-to-treat subjects.
b Defined as at least 180 days of treatment.
c Defined as ≥ 323 days of treatment.
d Includes hyperplasia occurring at any time after initiation of treatment as a proportion of patients with biopsies at 1 year.
e p < 0.0167 p-value for comparison to unopposed estradiol dose using the Fisher Exact test. P-values were adjusted by the method of Bonferroni.
f ITT = Intent-to-Treat population.

Effects on Uterine Bleeding or Spotting

The effects of Climara Pro on uterine bleeding or spotting, as recorded using an interactive voice response system, were evaluated in one 12-month clinical trial. Results are shown in Figure 3.

Figure 3: Cumulative Proportion of Subjects at Each Cycle with No Bleeding/Spotting Through the End of Cycle 13
Last Observation Carried Forward

Cumulative Proportion of Subjects at Each Cycle with No Bleeding/Spotting -  Illustration

  • Percent based upon the number of subjects with data
  • Last non-missing cycle carried forward through cycle 13
  • Bleeding associated with endometrial biopsies not included

Effects on Bone Mineral Density

The effects on bone mineral density (BMD) were studied in a randomized, double-blind, placebo-controlled clinical trial of transdermal systems (patches) containing only estradiol (E2). The patients were postmenopausal women with hysterectomies, 40–83 years of age (mean=51.4 years), and 77.3 percent Caucasian. Patients received calcium supplements if they appeared deficient on a questionnaire. Vitamin D supplements were not given.

A total of 154 patients were randomized in a 2:2:3 ratio to weekly application of 22 cm² patches containing 2.2 mg E2, 4.4 mg E2, or placebo, for 728 days of continuous treatment (26 28-day cycles). Only the results for the estradiol dose in Climara Pro (4.4 mg E2) and for placebo are presented.

Statistically significant increases in the primary efficacy variable, BMD of the lumbar spine (A-P view, L2-L4), were seen for 4.4 mg E2 compared to placebo (see Table 5 and Figure 4). BMD was also measured at the hip (total, non-dominant side) and radius (midshaft, non-dominant side) with statistically significant treatment effects only observed for the hip (see Table 6).

Table 6: Mean Bone Mineral Density (Standard Deviation)a

  4.4 mg E2b Placebo
Total Lumbar Spine n=36 n=46
Baseline (g/cm²) 1.1 (0.2) 1.1 (0.2)
% Change from baseline LOCF +1.7% (4.4) -2.9%
P-value compared to placebo < 0.0001 (3.8)
Total Hip n=36 n=48
Baseline (g/cm²) 0.97 (0.1) 0.94 (0.1)
% Change from baseline LOC +1.3% (4.2) -0.9% (5.2)
F P-value compared to placebo 0.05
a Intent-to-treat population with on-treatment efficacy data
b E2=estradiol; LOCF= Last Observation Carried Forward

Figure 4: Percent Change From Baseline in Bone Mineral Density (g/cm²) of Lumbar Spine (A-P View, L2–L4) by Treatment Group and Cycle (Mean ± SE)*

Percent Change From Baseline in Bone Mineral Density - Illustration

* Data in the figure is for 21 patients on 4.4 mg E2 and 27 placebo patients who completed the study; approximately 44 percent of randomized patients.

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 7. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 7: 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 fracturec 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
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, 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 age of 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 7.1 years are presented in Table 8.

Table 8: 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 (1.05-1.68) 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
aAdapted 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/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, 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 to 79 years of age (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 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 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-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 years of age and older (45 percent were age 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 groups 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;21:817828.

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: 11/6/2013
This monograph has been modified to include the generic and brand name in many instances.

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