Evista®
Raloxifene HCl
Selective Estrogen Receptor Modulator
Lilly
http://www.lilly.com/
Evista Monograph PDF download here.
Pharmacology
Evista (raloxifene hydrochloride) is a selective
estrogen receptor modulator (SERM) that belongs to the benzothiophene class of
compounds. The SERM profile of Evista includes estrogen agonist effects on bone
and lipid metabolism but not in uterine or breast tissues.
Pharmacokinetics
The disposition of raloxifene has been evaluated
in more than 3000 postmenopausal women in selected raloxifene osteoporosis
treatment and prevention clinical trials using a population approach.
Pharmacokinetic data were also obtained in conventional clinical pharmacology
studies in 292 postmenopausal women. Raloxifene exhibits high within-subject
variability (approximately 30%) of most pharmacokinetic parameters. Table 1
summarizes the pharmacokinetic parameters of raloxifene.
CPS:Evista_t1Click here for Table 1
Table 1: Evista
Summary of Raloxifene Pharmacokinetic Parameters
in the Healthy Postmenopausal Woman
|
|
Cmaxa
(ng/mL)/(mg/kg)
|
t½ (h)
|
AUC0-∞a
(ng·h/mL)/(mg/kg)
|
CL/F (L/kg·h)
|
V/F (L/kg)
|
|
|
Single Dose
|
|
Mean
|
0.50
|
27.7
|
27.2
|
44.1
|
2348
|
|
|
CV (%)
|
52
|
10.7 to 273b
|
44
|
46
|
52
|
|
|
Multiple Dose
|
|
Mean
|
1.36
|
32.5
|
24.2
|
47.4
|
2853
|
|
|
CV (%)
|
37
|
15.8 to 86.6b
|
36
|
41
|
56
|
|
a data normalized based on dose
in mg and body weight in kg.
b range of observed half-life.
Legend:Cmax=maximum plasma
concentration
t½=half-life
AUC=area under the curve
CL=clearance
F=bioavailability
V=volume of distribution
CV=coefficient of variation
Absorption
Raloxifene is absorbed rapidly after oral
administration. Approximately 60% of an oral dose is absorbed, but presystemic
glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is
2.0%. The time to reach average maximum plasma concentration and
bioavailability are functions of systemic interconversion and enterohepatic
cycling of raloxifene and its glucuronide metabolites.
Administration of raloxifene
HCI with a standardized, high-fat meal increases the absorption of raloxifene
slightly, but does not lead to clinically meaningful changes in systemic
exposure. Evista can be administered without regard to meals.
Distribution
Following oral administration of single doses
ranging from 30 to 150 mg of raloxifene HCI, the apparent volume of
distribution is 2348 L/kg and is not dose dependent.
Raloxifene and the
monoglucuronide conjugates are highly bound to plasma proteins. Raloxifene
binds to both albumin and α 1-acid glycoprotein, but not to sex steroid
binding globulin.
Metabolism
Biotransformation and disposition of raloxifene
in humans have been determined following oral administration of 14C-labeled
raloxifene. Raloxifene undergoes extensive first-pass metabolism to the
glucuronide conjugates: raloxifene-4'-glucuronide, raloxifene-6-glucuronide,
and raloxifene-6,4'-diglucuronide. No other metabolites have been detected,
providing strong evidence that raloxifene is not metabolized by cytochrome P450
pathways. Unconjugated raloxifene comprises less than 1% of the total
radiolabeled material in plasma. The terminal log-linear portion of the plasma
concentration curve for raloxifene and the glucuronides are generally parallel.
This is consistent with interconversion of raloxifene and the glucuronide
metabolites.
Following i.v.
administration, raloxifene is cleared at a rate approximating hepatic blood
flow. Apparent oral clearance is 44.1 L/kg·h. Raloxifene and its
glucuronide conjugates are interconverted by reversible systemic metabolism and
enterohepatic cycling, thereby prolonging its plasma elimination half-life to
27.7 hours after oral dosing.
Results from single
oral doses of raloxifene predict multiple-dose pharmacokinetics. Following
chronic dosing, clearance ranges from 40 to 60 L/kg·h. Increasing doses of
raloxifene HCI (ranging from 30 to 150 mg) result in slightly less than a
proportional increase in the area under the plasma time concentration curve
(AUC).
Excretion
Raloxifene is primarily excreted in feces, and
negligible amounts are excreted unchanged in urine. Less than 6% of the
raloxifene dose is eliminated in urine as glucuronide conjugates.
Special Populations
Geriatrics: The pharmacokinetics of raloxifene
are independent of age (42 to 84 years).
Pediatric: The pharmacokinetics of raloxifene
have not been evaluated in a pediatric population.
Gender: Total extent of exposure and oral
clearance, normalized for lean body weight, are not significantly different
between age-matched male and female volunteers.
Race: Pharmacokinetic differences due to race
have been studied in 1712 women including 97.5% Caucasian, 1.0% Asian,
0.7% Hispanic, and 0.5% Black in the osteoporosis treatment trial and in 1053
women including 93.5% Caucasian, 4.3% Hispanic, 1.2% Asian, and 0.5% Black in
the osteoporosis prevention trials. There were no discernible differences in
raloxifene plasma concentrations among these groups. The influence of race can
not be conclusively determined because of the small numbers of non-Caucasians.
Renal Insufficiency: Since negligible amounts of
raloxifene are eliminated in urine, a study in patients with renal
insufficiency was not conducted. In the osteoporosis treatment and prevention
trials, raloxifene and metabolite concentrations were not affected by renal
function in women having estimated creatinine clearance as low as
21 mL/min (0.35 mL/s).
Hepatic Dysfunction: Raloxifene was studied, as
a single dose, in Child-Pugh Class A patients with cirrhosis and total serum
bilirubin ranging from 0.6 to 2.0 mg/dL (10.3 to 34.2 µmol/L).
Plasma raloxifene concentrations were approximately 2.5 times higher than in
controls and correlated with bilirubin concentrations. Safety and efficacy have
not been evaluated further in patients with hepatic insufficiency (see
Warnings).
Drug Interactions
Clinically significant drug-drug interactions
are discussed in Precautions.
Ampicillin and Other Oral Antimicrobials: Peak
concentrations of raloxifene are reduced with coadministration of ampicillin.
The reduction in peak concentrations is consistent with reduced enterohepatic
cycling associated with antibiotic reduction of enteric bacteria. Since the
overall extent of absorption and the elimination rate of raloxifene are not
affected, raloxifene can be concurrently administered with ampicillin. In the
osteoporosis treatment trial, coadministered oral antimicrobial agents
(including amoxicillin, cephalexin, ciprofloxacin, macrolide antibiotics,
sulfamethoxazole/trimethoprim and tetracycline) had no effect on plasma
raloxifene concentrations.
Corticosteroids: The chronic administration of
raloxifene in postmenopausal women has no effect on the pharmacokinetics of
methylprednisolone given as a single oral dose.
Digoxin: Raloxifene has no effect on the
pharmacokinetics of digoxin. In the osteoporosis treatment trial,
coadministered digoxin had no effect on plasma raloxifene concentration.
Gastrointestinal Medications: Concurrent
administration of calcium carbonate or aluminum and magnesium
hydroxide-containing antacids does not affect the systemic exposure of
raloxifene. In the osteoporosis treatment trial, coadministered
gastrointestinal medications (including bisacodyl, cisapride, docusate, H2-antagonists,
laxatives, loperamide, omeprazole and psyllium) had no effect on plasma
raloxifene concentration.
Highly Protein-Bound Drugs: Raloxifene is more
than 95% bound to plasma proteins. The influence of co-administered highly
protein-bound drugs (including diazepam, gemfibrozil, ibuprofen, naproxen and
warfarin) on raloxifene plasma concentrations was evaluated in the osteoporosis
treatment trial. No clinically significant effects of these agents on
raloxifene plasma concentrations were identified. In vitro, raloxifene did not
affect the binding of phenytoin, tamoxifen or warfarin.
Highly Glucuronidated Drugs: Raloxifene
undergoes extensive first-pass metabolism to glucuronide conjugates. The
influence of co-administered highly glucuronidated drugs (including
acetaminophen, ketoprofen, morphine and oxazepam) on raloxifene plasma
concentrations was evaluated in the osteoporosis treatment trial. No clinically
significant effects of these agents on raloxifene plasma concentrations were
identified.
Other Medications: The influence of concomitant
medications on raloxifene plasma concentrations was evaluated in the
osteoporosis treatment clinical trial. The 152 most commonly co-administered
medications were grouped by pharmacological class based on their therapeutic
use. Frequently co-administered drugs included: ACE inhibitors and angiotensin
antagonists, alpha agonists and antagonists, anticholinergics, antidepressants,
antimicrobials, antipsychotics, benzodiazepines, β -blockers and
-agonists, bisphosphonates, calcium channel blockers, diuretics, estrogen
preparations, glucocorticoids, guaifenesin, H1-antagonists, H2-antagonists
and proton pump inhibitors, hypoglycemics, hypolipidemics, iron preparations,
muscle relaxants, nitrates, non-benzodiazepine hypnotics, non-steroidal
anti-inflammatory drugs (NSAIDs), opioid analgesics, theophylline and thyroid
hormone. No clinically relevant effects of the co-administration of any of
these agents on raloxifene plasma concentrations were observed.
Pharmacodynamics
General: Postmenopausal women have an increased
risk of chronic illnesses such as osteoporosis and atherosclerotic
cardiovascular disease resulting from estrogen deficiency. Estrogen replacement
reduces the risk of osteoporosis and may reduce the risk of coronary artery
disease, but it also increases the risk of endometrial carcinoma and possibly
breast cancer. The selective estrogen receptor modulator (SERM) profile of
Evista includes estrogen agonist effects on bone and lipid metabolism, and
estrogen antagonist effects in uterine and breast tissues. Thus, Evista is a
first line option for the treatment and prevention of postmenopausal
osteoporosis.
Raloxifene's biological
actions, like those of estrogen, are mediated through high-affinity binding to
estrogen receptors and regulation of gene expression. This binding results in
differential expression of multiple estrogen-regulated genes in different
tissues. Recent data suggest that the estrogen receptor can regulate gene
expression by at least two distinct pathways which are ligand-, tissue-
and/or gene-specific.
Effects on the Skeleton
During early to middle adult life, bone
undergoes continuous remodeling. In this process, local areas of bone
resorption are refilled completely by ensuing bone formation; that is,
resorption and formation are in balance. The result is that bone mass remains
relatively constant. Ovarian estrogen is important for maintenance of this
balance in bone turnover. Marked decreases in estrogen availability, such as
after oophorectomy or menopause, lead to marked increases in bone resorption,
accelerated bone loss and increased risk of fracture. After menopause, bone is
initially lost rapidly because the compensatory increase in bone formation is
inadequate to offset resorptive losses.
This imbalance between
resorption and formation may be related to loss of estrogen, or to age-related
impairment of osteoblasts or their precursors. Estrogen replacement therapy
reduces resorption of bone by inhibiting the formation and action of
osteoclasts and decreases overall bone turnover. These effects on bone are
manifested as reductions in the serum and urine levels of bone turnover
markers, histologic evidence of decreased bone resorption and formation, and
increased bone mineral density (BMD). Although Evista increases BMD to a lesser
extent than estrogen, the effects of Evista on bone turnover in postmenopausal
women parallel those of estrogen, as shown by studies of bone mineral
densitometry, radiocalcium kinetics, bone markers and bone histomorphometry.
Treatment of Osteoporosis: The effects of Evista
on fracture incidence and BMD in postmenopausal women with osteoporosis were
examined at 3 years in a large, randomized, placebo-controlled, double-blind
multinational osteoporosis treatment trial. The study population consisted of
7705 postmenopausal women with osteoporosis as defined by: a) low BMD
(vertebral or hip bone mineral density at least 2.5 standard deviations below
the mean value for healthy young women) without baseline vertebral fractures,
or b) one or more baseline vertebral fractures. Women enrolled in this
study had a median age of 67 years (range 31 to 80) and a median time
since menopause of 19 years. All women received calcium (500 mg/day) and
vitamin D (400 to 600 IU/day).Evista, 60 mg administered once
daily, decreased the incidence of one or more vertebral fractures by as much as
55% ( Table 2) and increased BMD compared to an active therapy of calcium plus
vitamin D supplemented placebo. Evista reduced the incidence of vertebral
fractures whether or not patients had experienced a previous fracture. The
decrease in incidence of vertebral fracture was greater than could be accounted
for by increase in BMD alone ( Figure 1).
CPS:Evista_t2Click here for Table 2
Table 2: Evista
Effect of Evista on Risk of Vertebral Fractures
|
|
Number of Patients
|
Relative Risk
|
|
Evista
|
Placebo
|
(95% Cl)
|
|
|
Patients with no baseline fracturea
|
n=1401
|
n=1457
|
|
|
|
Number of patients with ≥ 1 new
vertebral fracture
|
27
|
62
|
0.45 (0.29, 0.71)
|
|
|
Patients with ≥ 1 baseline fracturea
|
n=858
|
n=835
|
|
|
|
Number of patients with ≥ 1 new
vertebral fracture
|
121
|
169
|
0.70 (0.56, 0.86)
|
|
|
All randomized patients
|
n=2557
|
n=2576
|
|
|
|
Number of patients with ≥ 1 new clinical
(painful) vertebral fracture
|
47
|
81
|
0.59 (0.41, 0.83)
|
|
|
|
|
|
|
|
a Includes all patients with
baseline and at least one follow-up radiograph.
Figure 1:
Evista
Correlation Between Vertebral Fracture Risk and
Percent Change in Femoral Neck BMD at 3 yrs
Changes in BMD do not fully account for
vertebral fracture risk reduction. This figure shows the correlation between
vertebral fracture risk and percent change in femoral neck BMD at 3 years based
on a logistic regression analysis of the clinical trial data. For any given
change in BMD from baseline, Evista-treated patients had a lower risk for
vertebral fracture compared to placebo.
Retrospective analysis
of the patients in the osteoporosis treatment study, demonstrates that there
was a statistically significant reduction (p<0.001) in the risk of clinical
(symptomatic) vertebral fracture after 12 months of treatment. At 12 months the
risk of clinical vertebral fractures was decreased by 68% (95% CI, 0.13-0.79)
in postmenopausal women taking Evista 60 mg per day.
The same osteoporosis
treatment study was extended by 12 months to a 4th year during which, patients
were permitted the use of concomitant medications, including bisphosphonates,
calcitonins and fluorides. The statistically significant reduction in vertebral
fractures and increase in BMD seen at 3 years continued into the 4th year
extension of the osteoporosis treatment study. The sustained reduction in
vertebral fractures is illustrated in Figure 2, a Kaplan-Meier analysis of
time to first vertebral fracture over the 48 months of the study.
Figure 2:
Evista
Time To Event For Vertebral Fractures Over 48
Months
Overall osteoporotic
fracture risk was significantly reduced with Evista therapy. Over 4 years there
was no difference seen in nonvertebral fracture incidence in women treated with
raloxifene compared to placebo. At 3 years, the risk of individual nonvertebral
fractures versus placebo decreased with increasing exposure to Evista.
At every time point,
the mean percentage change in BMD from baseline for Evista was significantly
greater than for placebo at each skeletal site measured ( Table 3).
CPS:Evista_t3Click here for Table 3
Table 3: Evista
Evista (60 mg once daily) Related Increases in
BMD for the Osteoporosis Treatment Study Expressed as Mean Percentage Increase
Versus Calcium- and Vitamin D-supplemented Placeboa
|
Site
|
Time
|
|
12 Months %
|
24 Months %
|
36 Months %
|
|
|
Lumbar Spine
|
2.0
|
2.6
|
2.6
|
|
|
Femoral Neck
|
1.3
|
1.9
|
2.1
|
|
|
Ultradistal Radius
|
ND
|
2.2
|
ND
|
|
|
Distal Radius
|
ND
|
0.9
|
ND
|
|
|
Total Body
|
ND
|
1.1
|
ND
|
|
a Intent-to-treat analysis; last
observation carried forward.
Legend:ND=not done (total body and radius BMD
were measured only at 24 months).
Note: All BMD increases were statistically
significant (p<0.001).
Discontinuation from
the study was required when excessive bone loss or multiple incident vertebral
fractures occurred. Such discontinuation was significantly more frequent in the
calcium- and vitamin D-supplemented placebo group (3.9%) than in the Evista
group (1.1%).
Prevention of Osteoporosis: The effects of Evista
on BMD in postmenopausal women were examined in three large randomized,
placebo-controlled, double-blind osteoporosis prevention trials: (1) a
North American trial enrolled 544 women; (2) a European trial, 601 women;
and (3) an international trial, 619 women who had undergone
hysterectomy. In these trials, all women received calcium supplementation (400
to 600 mg/day). Evista, 60 mg raloxifene HCI administered once daily,
produced significant increases in bone mass versus calcium supplementation
alone, as reflected by dual-energy x-ray absorptiometric (DXA) measurements of
hip, spine and total body BMD. The increases in BMD were statistically
significant at 12 months and were maintained at 24 months ( Table 4).
In contrast, the calcium-supplemented placebo groups lost approximately 1% of
BMD over 24 months.
CPS:Evista_t4Click here for Table 4
Table 4: Evista
Evista Increases in BMD For the
3 Osteoporosis Prevention Studies Expressed as Percentage Increase Versus
Calcium-Supplemented Placebo at 24 Months
|
Site
|
Study
|
|
NA %
|
EU %
|
INTa %
|
|
|
Total Hip
|
2.0
|
2.4
|
1.3
|
|
|
Femoral Neck
|
2.1
|
2.5
|
1.6
|
|
|
Trochanter
|
2.2
|
2.7
|
1.3
|
|
|
Intertrochanter
|
2.3
|
2.4
|
1.3
|
|
|
Lumbar Spine
|
2.0
|
2.4
|
1.8
|
|
a All women in the study had
previously undergone hysterectomy.
Legend:NA=North American, EU=European,
INT=international.
Evista also increased
BMD compared with placebo in the total body by 1.3% to 2% and in Ward's
Triangle (hip) by 3.1% to 4%. In the international trial, conjugated
equine estrogen 0.625 mg/day (ERT) was used as an active comparator. The
mean increases in BMD at 24 months for estrogen compared with placebo
were: lumbar spine, 5.4%; total hip, 2.9%.
Thus, in postmenopausal
women, Evista preserves bone mass and increases BMD significantly relative to
calcium alone at 24 months. The effect on hip bone mass is similar to that
for the spine.
Assessments of Bone Turnover: In a 31-week
radiocalcium kinetics study, Evista was associated with reduced bone resorption
and a positive shift in calcium balance (+60 mg Ca/day), due
primarily to decreased urinary calcium losses. These findings were similar to
those observed with hormone replacement therapy.
In both the
osteoporosis treatment and prevention trials, Evista therapy resulted in
consistent, statistically significant suppression of bone resorption, bone
formation, and overall bone turnover, as reflected by changes in serum and
urine markers of bone turnover (e.g., bone-specific alkaline phosphatase,
osteocalcin, and collagen breakdown products). The suppression of bone turnover
markers was evident by 3 months and persisted throughout the 36-month and
24-month observation periods, respectively.
Bone Histomorphometry: In the treatment study,
bone biopsies for qualitative and quantitative histomorphometry were obtained at
baseline and after 2 years of treatment. There were 56 paired
biopsies evaluable for all indices. In Evista-treated patients, there were
significant decreases in bone formation rate per tissue volume, consistent with
a reduction in bone turnover. Normal bone quality was maintained; specifically,
there was no evidence of osteomalacia, marrow fibrosis, cellular toxicity or
woven bone after 2 years of treatment.
The tissue- and
cellular-level effects of raloxifene were assessed by quantitative measurements
(bone histomorphometry) on animal bones and human iliac crest bone biopsies
taken after administration of a fluorochrome substance to label areas of
mineralizing bone. The effects of Evista on bone histomorphometry were
determined by pre-and post-treatment biopsies in a 6-month study of
postmenopausal women. Bone in Evista-treated women was histologically normal,
showing no evidence of mineralization defects, woven bone, or marrow fibrosis.
The patterns of change were consistent with reduced bone turnover, although
most changes were not statistically significant. In another bone
histomorphometry study, postmenopausal women were treated for 6 months
with raloxifene HCI at a higher dose (150 mg/day). Bone was also
histologically normal, with no woven bone, marrow fibrosis, or mineralization
defects.
In rats, raloxifene
prevented increased bone resorption and bone loss after ovariectomy and
preserved bone strength in biomechanical studies. Ovariectomized cynomolgus
monkeys were treated with raloxifene for 2 years, equivalent at the bone
level to 6 years in humans. The biomechanical properties of bone from the
raloxifene-treated monkeys were normal. Histologic examination of bone from
rats and monkeys treated with raloxifene showed normal cancellous bone morphology,
and no evidence of woven bone, marrow fibrosis, or mineralization defects.
The animal and human
bone histomorphometric results are consistent with data from studies of
radiocalcium kinetics and markers of bone metabolism and demonstrate that
Evista is a skeletal antiresorptive agent.
Effects on Lipid Metabolism
In animal studies, the effects of raloxifene on
cholesterol metabolism were mediated through the estrogen receptor.
The effects of Evista
on cardiovascular intermediate endpoints were evaluated in a 6-month study of
390 postmenopausal women. Evista was compared with continuous combined
estrogen/progestin (0.625 mg conjugated equine estrogen plus 2.5 mg
medroxyprogesterone acetate, [HRT]) and placebo ( Table 5). Evista decreased serum
total and LDL cholesterol without significant effects on serum total HDL
cholesterol or triglycerides. Evista significantly increased HDL-2 cholesterol
subfraction. In addition, Evista significantly decreased serum fibrinogen and
lipoprotein (a).
CPS:Evista_t5Click here for Table 5
Table 5: Evista
Evista and HRT Effects on Cardiovascular
Intermediate Endpoints in a 6-Month Study—Median Percentage Change from
Baseline
|
Endpoint
|
Treatment Group
|
|
Placebo
(N=98)
%
|
Evista
(N=95)
%
|
HRT
(N=96)
%
|
|
|
Total Cholesterol
|
0.9
|
-6.6
|
-4.4
|
|
|
LDL Cholesterol
|
1.0
|
-10.9
|
-12.7
|
|
|
HDL Cholesterol
|
0.9
|
0.7
|
10.6
|
|
|
HDL-2 Cholesterol
|
0.0
|
15.4
|
33.3
|
|
|
Fibrinogen
|
-2.1
|
-12.2
|
-2.8
|
|
|
Lipoprotein (a)
|
3.3
|
-4.1
|
-16.3
|
|
|
Triglycerides
|
-0.3
|
-4.1
|
20.0
|
|
Legend:HRT=continuous combined estrogen/progestin
(0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone
acetate).
Consistent with results
from the 6-month study, in the osteoporosis treatment (36 months) and
prevention (24 months) studies Evista significantly decreased serum total and
LDL cholesterol, but did not increase HDL cholesterol or triglycerides. In the
osteoporosis treatment study, significantly fewer Evista-treated patients
required initiation of hypolipidemic therapy compared to placebo.
Effects on the Uterus
Postmenopausal estrogen deficiency leads to
endometrial atrophy. Estrogen replacement therapy is associated with
endometrial proliferation and hyperplasia and increased risk of endometrial
carcinoma. All forms of hormone replacement therapy are often accompanied by
spotting and bleeding. In contrast, Evista has no endometrial stimulatory
effect and does not induce spotting or bleeding.
In the osteoporosis
treatment trial, endometrial thickness was evaluated annually in a subset of
the study population (1781 patients) for 3 years. Endometrial thickness
measurements in Evista-treated women were not different from baseline after 3
years of therapy. Placebo-treated women had a 0.27 mm decrease from baseline in
endometrial thickness over 3 years. There was no difference between Evista- and
placebo-treated women in the incidences of endometrial carcinoma, vaginal
bleeding or vaginal discharge.
In placebo-controlled
osteoporosis prevention trials, endometrial thickness was evaluated every
6 months (for 24 months) by transvaginal ultrasonography (TVU), a
non-invasive method of visualizing the uterus. A total of 2,978 TVU
measurements were collected from 831 women in all dose groups.
Raloxifene-treated women consistently had endometrial thickness measurements indistinguishable
from placebo. Furthermore, there were no differences between the raloxifene and
placebo groups with respect to the incidence of reported vaginal bleeding.
In a 6-month study
comparing Evista to conjugated equine estrogens (0.625 mg/day [ERT]),
endpoint endometrial biopsies demonstrated stimulatory effects of ERT which
were not observed for raloxifene ( Table 6). All samples from Evista-treated
women showed nonproliferative endometrium.
CPS:Evista_t6Click here for Table 6
Table 6: Evista
Evista and ERT Effects on Endometrial Histology
After 6–Months of Therapy
|
Endpoint Biopsy Result
|
Treatment Group
|
|
Evista (n=10)
|
ERT (n=8)
|
|
|
Nonproliferative Endometriuma
|
10
|
2
|
|
|
Proliferative Tissue
|
0
|
