FDA Endocrine and Metabolic Drugs Advisory Committee October 7, 2003

1. FDA Endocrine and Metabolic Drugs Advisory CommitteeOctober 7, 2003 Joseph S. Camardo, M.D. Senior Vice President Clinical Research

2. 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

3. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. The Clinical Data for Estrogen/Progestin

11. 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

12. Starting estrogen from Oophorectomy Starting 3 Years After Oophorectomy Starting 6 Years After Oophorectomy No Treatment 44 42 40 38 36 34 0 2 4 6 8 10 12 14 16 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. 1976;1:1038-41.

13. 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 < –3.5 –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. 2001;286:2815-22.

14. …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 < –3.5 –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. 2001;286:2815-22.

15. 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

16. HIP Women’s 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. 2002;287:2668-76.

17. 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%

18. 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

19. 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

20. The Women’s Health Initiative and Clinical Practice

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. Prempro Product Information

28. 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

29. 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

30. 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.

31. 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.

32. 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

33. 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

34. 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

35. 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

36. FDA Endocrine and Metabolic Drugs Advisory CommitteeOctober 7, 2003