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FDA Advisory Board Meeting October

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FDA Advisory Board Meeting October Powered By Docstoc
					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

				
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