FDA Endocrine and Metabolic Drugs Advisory Committee October 7, 2003

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FDA Endocrine and Metabolic Drugs Advisory
CommitteeOctober 7, 2003

• Joseph S. Camardo, M.D.
• Senior Vice President
• Clinical Research

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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

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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

4
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

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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 (Womens HOPE)
• This is important because symptoms and bone loss
  may be concurrent medical problems

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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

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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

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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

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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

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The Clinical Data for Estrogen/Progestin

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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

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Bone Loss Follows Estrogen Loss and Can Be
Prevented With Early Use of Estrogen
Metacarpal Bone Mineral Content (mg/mm)
Years
Lindsay R, et al. Lancet. 197611038-41.
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Fracture incidence increases as bone density
decreases
Fracture rate
Fracture rate per 1000 person-years
1.0
0.5 to 0.0
0.5 to 1.0
1.5 to 2.0
2.5 to 3.0
1.0 to 1.5
1.0 to 0.5
0.0 to 0.5
2.0 to 2.5
3.0 to 3.5
Osteopenia
Osteoporosis
BMD T-scores
Adapted from Siris ES, et al. JAMA.
20012862815-22.
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but the number of fractures is highest in women
with osteopenia since it is most common
Fractures
Fractures
1.0
0.5 to 0.0
0.5 to 1.0
1.5 to 2.0
2.5 to 3.0
1.0 to 1.5
1.0 to 0.5
0.0 to 0.5
2.0 to 2.5
3.0 to 3.5
Osteopenia
Osteoporosis
BMD T-scores
Adapted from Siris ES, et al. JAMA.
20012862815-22.
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Womens 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

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Womens HOPE Study Shows That All Doses of
Prempro Improve Bone Mineral Density
SPINE
Percent Change From Baseline
Intent-to-treat population. Lindsay R, et al.
JAMA. 20022872668-76.
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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

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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

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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

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The Womens Health Initiative and Clinical
Practice

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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

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Most Women Who Take Estrogen/Progestin Are
Younger Than Women in WHI

• In Womens 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

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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

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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

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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

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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

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Prempro Product Information

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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

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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

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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.

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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.

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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

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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

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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

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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

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FDA Endocrine and Metabolic Drugs Advisory
CommitteeOctober 7, 2003