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FDA Endocrine and Metabolic
Drugs Advisory Committee
October 7, 2003
Joseph S. Camardo, M.D.
Senior Vice President
Clinical Research
Agenda
Introduction and Overview: Use of
estrogen/progestin for osteoporosis
The clinical data for estrogen/progestin
The WHI data and clinical practice
Review of product information for Prempro
2
The Role of Estrogen/Progestin for
Prevention of Postmenopausal Osteoporosis
Prevention of osteoporosis is an important aspect of health care
especially for women in menopause
Prempro™ is effective for osteoporosis and it is one of a
relatively small number of medical options for osteoporosis
Estrogen/Progestin is the only therapy that can reduce
menopausal symptoms and prevent osteoporosis
Practitioners need to determine the use of HT for an individual
based on all the evidence available and the goal of treatment
The Prempro label provides accurate information
3
Prevention of Bone Loss Is An Important
Aspect of Health Care for Women
Bone mineral loss accompanies menopause
Bone loss increases the risk of hip, vertebral, and
other fractures
Fracture risk increases before bone loss has
progressed to the level of osteoporosis
Hip and vertebral fractures are associated with
increased mortality and significant disability
One year mortality after hip fracture can be as high as 20%
25% of women need nursing home care after hip fracture
Vertebral and other osteoporotic fractures can be disabling
4
Prempro Is Effective for Osteoporosis Prevention and
Treatment of Menopausal Symptoms
Prempro has been shown to reduce non-vertebral
fractures even in women who do not yet have
osteoporosis
Demonstrated by WHI data
Low dose Prempro reduces menopausal symptoms
and increases bone density (Women’s HOPE)
This is important because symptoms and bone loss may be concurrent
medical problems
5
Estrogen/Progestin Is One of a Small Number
of Therapies for Bone Health
A variety of therapies is essential to assure that treatments can be
tailored to the individual woman
Bisphosphonates prevent fractures but may not be suitable for all
women
Bisphosphonates have limited data in non-osteoporotic women
Bisphosphonates may have gastrointestinal side effects
Raloxifene prevents vertebral fractures but has not been shown to
prevent hip fracture
Hot flushes occur in about 20% of women and so it is not an appropriate
therapy for women with menopausal symptoms
Estrogen/Progestin prevents vertebral and non vertebral fractures
Estrogen/Progestin may be associated with increased risk of breast cancer
and cardiovascular disease in certain populations
6
The Risk/Benefit Decision Should Be Made
by an Individual Woman and the Practitioner
The decision for hormone therapy in younger women with
menopausal symptoms and at risk for bone loss cannot be
based only on the WHI
Women with significant menopausal symptoms were
discouraged from participation the WHI study
WHI was designed to assess
Selected potential benefits of long term use (e.g., fractures, colon cancer,
cardiovascular disease)
Selected potential long-term risks (e.g., breast cancer, DVT)
WHI was not designed to assess
The use of estrogen/progestin in women closer to menopause who have
bone loss and menopausal symptoms
7
The Prempro Label Provides Information
Helpful to Clinical Decision Making
Pertinent results from numerous trials are included
Safety information is updated regularly after medical
review of new evidence
WHI data are included in current version of label
Information is available to practitioners and women
Prescribing Information
Patient Package Insert
FDA educational campaign
8
The Role of Estrogen/Progestin for
Prevention of Postmenopausal Osteoporosis
Prevention of osteoporosis is an important aspect of health care
especially for women
Prempro™ is effective for osteoporosis and it is one of a
relatively small number of medical options for osteoporosis
HT is the only therapy that can reduce menopausal symptoms
and prevent osteoporosis
Practitioners need to determine the use of HT for an individual
based on all the evidence available and the goal of treatment
The Prempro label provides accurate information
9
The Clinical Data for
Estrogen/Progestin
Estrogen/Progestin Maintains Bone Health
Rapid and progressive bone loss that occurs early in
menopause can be prevented with estrogen/progestin
Most fractures occur in women who are osteopenic not
osteoporotic so early intervention may be important
Prempro at all doses improves bone density in
osteopenic women
Prempro in WHI reduced fractures significantly even in
women who were not osteoporotic
11
Bone Loss Follows Estrogen Loss and Can Be
Prevented With Early Use of Estrogen
Starting estrogen from
Oophorectomy
Starting 3 Years
44 After Oophorectomy
Metacarpal Bone Mineral
Starting 6 Years
42 After Oophorectomy
Content (mg/mm)
No Treatment
40
38
36
34
0 2 4 6 8 10 12 14 16
Years
Lindsay R, et al. Lancet. 1976;1:1038-41.
12
Fracture incidence increases as bone density
decreases…
Fracture rate per 1000 person-years
Fracture rate
60
50
40
30
20
10
0
>1.0 0.5 to 0.0 –0.5 to –1.0 –1.5 to –2.0 –2.5 to –3.0 < –3.5
1.0 to 0.5 0.0 to –0.5 –1.0 to –1.5 –2.0 to –2.5 –3.0 to –3.5
Osteopenia Osteoporosis
BMD T-scores
Adapted from Siris ES, et al. JAMA. 2001;286:2815-22.
13
…but the number of fractures is highest in
women with osteopenia since it is most common
450
# Fractures 400
350
# Fractures
300
250
200
150
100
50
0
>1.0 0.5 to 0.0 –0.5 to –1.0 –1.5 to –2.0 –2.5 to –3.0 < –3.5
1.0 to 0.5 0.0 to –0.5 –1.0 to –1.5 –2.0 to –2.5 –3.0 to –3.5
BMD T-scores Osteopenia Osteoporosis
Adapted from Siris ES, et al. JAMA. 2001;286:2815-22.
14
Women’s HOPE Evaluated Low Doses of
Prempro in Women at Risk for Bone Loss
2,805 women were randomized to various doses of
Prempro, Premarin, or Placebo
The average age was 53 and the average time since
menopause was 4.7 years
Endpoints included reduction in vasomotor symptoms,
improvement in bone density, and endometrial
protection
Bone density substudy was two years long
15
Women’s HOPE Study Shows That All Doses of
Prempro Improve Bone Mineral Density
4 SPINE 4 HIP
Percent Change From Baseline
3 3
2 2
1 1
0 0
-1 -1
-2 -2
CEE 0.625/MPA 2.5 mg/day CEE 0.625/MPA 2.5 mg/day
CEE 0.45/MPA 1.5 mg/day CEE 0.45/MPA 1.5 mg/day
-3 -3
CEE 0.3/MPA 1.5 mg/day CEE 0.3/MPA 1.5 mg/day
Placebo Placebo
-4 -4
Baseline 6 mo 12 mo 18 mo 24 mo Baseline 6 mo 12 mo 18 mo 24 mo
Intent-to-treat population.
Lindsay R, et al. JAMA. 2002;287:2668-76.
16
WHI Confirms That Prempro Prevents
Fractures in Postmenopausal Women
All fractures reduced by 24%
Hip fractures reduced by 33%
Vertebral fractures reduced by 35%
Arm and wrist fractures reduced by 29%
17
The WHI Data Indicate a Reliable and Robust
Clinical Effect for Fracture Prevention
Low bone mineral density or prior fracture was not a
requirement for study entry
Only about 4-6% of the women met criteria for osteoporosis
End-point was limited to clinical/symptomatic
fractures, not radiographic morphometric
Potentially 2/3 of vertebral fractures were not identified
A reduction in fractures was observed within the first
year of treatment
18
The Evidence for Estrogen/Progestin for
Bone Health
Rapid bone loss in early menopause can be prevented
Fracture incidence increases as bone density
decreases but most fractures occur in women who are
osteopenic not osteoporotic
Prempro at all doses improves bone density in
osteopenic women close to menopause
Prempro in WHI reduced fractures significantly even in
women who were not osteoporotic
19
The Women’s Health Initiative
and Clinical Practice
Applying the Data from WHI to Clinical
Practice and Individual Women
In general women who receive hormone therapy are
younger than the women in WHI and they have
menopausal symptoms
The risk benefit assessment in WHI did not take into
account all vertebral (clinical and morphometric) and
nonvertebral fractures as well as other benefits and
risks
The WHI global index is a clinical trial tool but it cannot
be used to assess risk/benefit in individual women
The data provide important information but clinical
practice requires individual patient management
21
Most Women Who Take Estrogen/Progestin
Are Younger Than Women in WHI
In Women’s HOPE and other studies of
estrogen/progestin in menopause the women in the
study were within five years of menopause
This is approximately 10 years younger than the average age of the WHI
population (Average age of 53 versus 63 for WHI)
In WHI, women less than 10 years since menopause
appear to have no excess cardiac risk
In younger women symptoms and osteoporosis are
more likely to coexist
Estrogen/Progestin is the only therapy to concomitantly treat menopausal
symptoms and prevent osteoporosis
22
The Risk/Benefit Assessment Did Not Take
Into Account All Osteoporotic Fractures
The failure to include all osteoporotic fractures in the
calculation of the global index may underestimate the
benefit of HT for the prevention of osteoporosis
Disability from any type of fracture may have a
significant impact on an individual woman and change
the individual risk/benefit of HT
23
The WHI Global Index is a Clinical Trial Tool
Not a Risk Management Tool for Individuals
Clinical trials evaluate population results
Clinical practice considers individual risk/benefit
The individual may or may not match closely the population that was
evaluated in the WHI trial
Age, BMI, time from menopause, menopausal symptoms, degree of
osteopenia and perceived need for osteoporosis prevention are some
differences
Extending the results beyond the specific trial population requires that the
practitioner use judgment
24
Data Provide Guidance but Clinical Practice
Requires Individual Patient Management
Decision to use Estrogen/Progestin in menopause will be
influenced by the presence and severity of symptoms and bone
density measurement
The potential benefit of estrogen/progestin therapy on bone health should not be
ignored in younger women in early post menopause
The physician and the woman have to evaluate the benefit in light of the potential
risk of vascular disease (stroke and MI) and breast cancer
Use of estrogen/progestin in women with bone loss but no
menopausal symptoms will be based on the need to treat women
at high risk for bone loss and the unsuitability of other therapies
25
Applying the Data from WHI to Clinical
Practice and Individual Women
In general women who take estrogen/progestin are younger than
the average age of the population in WHI
The risk benefit assessment did not include all fractures and
these may be important in practice
The WHI global index is a clinical trial tool but it cannot determine
the risk/benefit for each woman
The data provide guidance but clinical practice requires individual
patient management
The product information provides information useful for practice
decisions
Estrogen/Progestin remains an important therapeutic option
26
Prempro Product Information
The Prempro Label is Clear and Balanced
The product information strikes a balance so that clinical
practice is guided but use is not inappropriately expanded or
limited
Label information for prescribers includes summaries of
results from a variety of clinical and epidemiologic studies
Balance includes statements regarding the risks that have
been reported
Conservative interpretations of safety data are presented
New data are considered for inclusion as they become
available
28
Recommendations for Prempro Use Are Based
on the Available Evidence
For women with menopausal symptoms
Prempro can reduce menopausal symptoms and prevent bone loss
The clinical trial results on bone density are cited
For women without menopausal symptoms
Prempro is recommended only for women at significant risk for
osteoporosis in whom non-estrogen treatments have been carefully
considered
This change was made based on results of WHI
29
The Indication for Prempro Addresses the
Symptoms of Menopause
PREMPRO or PREMPHASE is indicated for:
1. Treatment of moderate to severe vasomotor symptoms
associated with the menopause.
2. Treatment of moderate to severe symptoms of vulvar and
vaginal atrophy associated with the menopause. When
prescribing solely for the treatment of symptoms of vulvar and
vaginal atrophy, topical vaginal products should be considered.
30
The Indication Also Addresses the
Preservation of Bone
3. Prevention of postmenopausal osteoporosis.
When prescribing solely for the prevention of
postmenopausal osteoporosis, therapy should only be
considered for women at significant risk of
osteoporosis and non-estrogen medications should be
carefully considered.
31
Certain Information is Highlighted to Promote
Awareness
Estrogen/Progestin should not be used for prevention
of cardiovascular disease
The risks of myocardial infarction, stroke, invasive
breast cancer, pulmonary emboli, and DVT as reported
in WHI are prominently and repeatedly noted
Specific information on breast cancer and coronary
heart disease from WHI and information on dementia
from WHIMS are included
The relative risks of the outcomes in the Global Index published in JAMA
(July 2002) are reproduced in the product information
Therapy should be prescribed at lowest effective dose
Duration of treatment should be only as long as
required to meet objectives for the particular woman
A boxed warning was added
32
Changes in the Labeling Were Accompanied
by a Communications Program
Practitioners were notified by letter of the results of the
WHI and the changes in the product information
Data from WHI were distributed to practitioners by mail
and by Wyeth representatives
Patient Package Insert includes information about
cardiovascular disease and breast cancer, and other
risks
33
Data on the Pattern of Use of Prempro is
Consistent with New Recommendations
About 25% of new prescriptions are for low dose
The change represents only four months after the low dose
(0.45/ 1.5) became available
Currently 94% of women initiate Prempro for
menopausal symptom relief
Younger women thus constitute by far the majority treated
34
Summary and Conclusion
Osteoporosis is an important medical problem
Fractures are associated with an increase in mortality and significant
disability
There are limited treatment options currently available for
osteoporosis
Estrogen/Progestin is the only therapy demonstrated to treat
menopausal symptoms and prevent osteoporosis
Prempro™ prevents osteoporosis and reduces the incidence of
all fractures, including hip fractures
35
FDA Endocrine and Metabolic
Drugs Advisory Committee
October 7, 2003
