1. Food and Drug Administration Division of Pulmonary and Allergy Drug Products Pediatric Exclusivity 1-Year Adverse Event Reporting for Drug Products Containing Budesonide and Fluticasone Pediatric Advisory Committee Meeting September 15, 2004

2. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 2 Outline  Perspective on safety for orally inhaled and intranasal Budesonide and Fluticasone  Peter Starke, MD  Studies performed for pediatric Written Request  ShaAvhrée Buckman, MD, PhD  Adverse Events reported in the year following exclusivity  Joyce Weaver, PharmD  Summary remarks  Badrul Chowdhury, MD, PhD

3. Food and Drug Administration Division of Pulmonary and Allergy Drug Products Regulatory History, Labeling Changes, and Perspective on Safety for Orally Inhaled and Intranasal Budesonide and Fluticasone Propionate Drug Products Peter Starke, MD, FAAP Division of Pulmonary & Allergy Drug Products September 15, 2004

4. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 4 Outline  The burden of allergic rhinitis and asthma  NAEPP/NHLBI guidelines for the diagnosis and management of asthma*  Regulatory background and labeling chronology  Results of growth studies for budesonide and fluticasone  Current status of labeling for safety findings * Guidelines for the Diagnosis and Management of Asthma, 1997, 2002, National Heart, Lung, and Blood Institute, http://www.nhlbi.nih.gov/guidelines/index.htm http://www.nhlbi.nih.gov/guidelines/index.htm

5. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 5 The Burden of Allergic and Non-allergic Rhinitis*  Allergic Rhinitis is very common  Affects 20-40 million persons in US  10 to 30% of adults  Up to 40% of children  Estimated (1995) direct and indirect costs was 2.7 billion dollars, exclusive of costs of associated medical problems such as sinusitis or asthma * Joint Task Force on Practice Parameters in Allergy, Asthma, and Immunology, Diagnosis and Management of Rhinitis, 1998, http://www.jcaai.org/Param/Rhinitis/index.htm http://www.jcaai.org/Param/Rhinitis/index.htm

6. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 6 The Burden of Asthma*  Affects ~20 million persons, 6.1 million children (2002 National Health Interview Survey)  Estimated to be associated annually (1999) with  More than 100 million days of restricted activity  ~2 million emergency department visits  478,000 hospitalizations (all ages)  4,657 deaths (all ages) * Guidelines for the Diagnosis and Management of Asthma, 1997, 2002, National Heart, Lung, and Blood Institute, http://www.nhlbi.nih.gov/guidelines/index.htm http://www.nhlbi.nih.gov/guidelines/index.htm MMWR, 51(SS01); 1-13, March 19, 2002, Centers for Disease Control, http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5101a1.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5101a1.htm

7. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 7 The Burden of Asthma: Prevalence  Prevalence increased by 73.9% between 1980-1996 1980: 31.4 1996: 54.6 per thousand Source: National Health Interview Survey; National Center for Health Statistics

8. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 8 Asthma Mortality Rates* United States: 1979-2001 Source: Underlying Cause of Death; National Center for Health Statistics * Age-adjusted to 2000 U.S. population ICD-9ICD-10  Rate per million:1980: 14.41995: 21.92000: 16

9. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 9 Burden of Asthma: Summary  Represents a huge burden to individuals as well as to health care system  While the prevalence of asthma has  since 1980, mortality rates have  Overall increased since 1980, but not as much as the increase in prevalence  Peaked in 1995  Now declining

10. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 10 Asthma Medications  Quick-relief medications  Short-acting beta 2 -agonists  Long-term controller medications  Corticosteroids  Long-acting beta 2 -agonists  Leukotriene modifiers and receptor antagonists  Cromolyn sodium and nedocromil  Methylxanthines

11. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 11 Regulatory Background & Chronology  1980’s – 1990’s: Orally inhaled and intranasal corticosteroids approved, including budesonide and fluticasone  1994:  Pediatric Labeling Rule Required sponsors of approved products to examine the existing data in the product label to determine whether the Pediatric Use subsection should be updated Resulted in a number of pediatric efficacy supplements, i.e. approval for use of intranasal and orally inhaled products in children (various ages down to about 4-6y)  FDA Began to review labels for all orally inhaled & intranasal CS Many changes to labels to add adverse events

12. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 12 Regulatory Background & Chronology (con’t)  1997:  National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 2 Controller therapy for persistent asthma Orally inhaled CS as primary controller for moderate and severe persistent asthma (In 2002, this recommendation was changed to include all forms of persistent asthma)  One-year growth study with intranasal beclomethasone at a dose of 336 mcg/day showed statistically significant growth effect, but no significant effect on hypothalamic-pituitary-adrenal (HPA) axis function  Other growth studies submitted or published for orally inhaled products: beclomethasone, triamcinolone, budesonide, and fluticasone

13. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 13 Regulatory Background & Chronology (con’t)  1998:  Joint Task Force for Practice Parameters in conjunction with the American Academy of Allergy, Asthma, and Immunology recognized intranasal CS as the most effective medication class for treatment of severe allergic rhinitis  Joint Pulmonary Allergy and Endocrine and Metabolic Diseases Advisory Committee meeting Discussed results of growth studies Recommended labeling changes with addition of Growth studies ‘Class labeling’ for risks of adverse events  Advisory Committee recommendations implemented

14. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 14 FDA Action: ‘Class Labeling’ 1 of 2  PRECAUTIONS: General “Orally inhaled / Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients (see PRECAUTIONS, Pediatric Use).”  ADVERSE REACTIONS (If appropriate): “Cases of growth suppression have been reported for orally inhaled / intranasal corticosteroids including (product name) (see PRECAUTIONS, Pediatric Use).”

15. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 15 FDA Action: ‘Class Labeling’ 2 of 2  PRECAUTIONS: Pediatric Use  Orally inhaled or intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients  Growth effect may occur in the absence of laboratory evidence of hypothalamic-pituitary-adrenal axis suppression  The potential for "catch-up" growth following discontinuation of treatment not addressed  Growth should be monitored routinely  To minimize the systemic effects, each patient should be titrated his/her lowest effective dose

16. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 16 Growth Studies for Corticosteroids: General Comments  Growth reflects systemic exposure to the corticosteroid  Sensitive indicator of CS systemic effects  May be positive when HPA axis studies negative  Studies are designed to, as accurately as possible, characterize the difference in growth rate in patients treated with active and with control  Technically difficult to perform  Measurement, compliance, statistical design issues  Long-term: Baseline, ~1 year on-treatment (active vs control) growth evaluation, follow-up periods

17. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 17 Growth Studies for Corticosteroids: Cautions and Limitations Regarding Interpretation of Results  Studies are NOT designed to evaluate  Reversibility with continued use >1 year, or after stopping medication  Effects on final adult height  Clinical relevance to individual patient  Difficult to interpret out of the context of the study  No two studies used the same design  Cross-study comparison is limited

18. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 18 Growth Study: Inhaled Budesonide  Drug: Pulmicort Respules  Design: Randomized, placebo controlled, parallel group, open label (extension), one year  Inclusions:  Completion of 12 week, double-blind study  Age: 9 mos to 8 yrs (at start of double-blind phase)  Arms:  Inhaled budesonide 0.5 mg QD (n=170)  Nonsteroidal (n=81)  Analysis: separate analyses by age group  4 - 8 years  9 months - <4 years

19. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 19 Inhaled Budesonide Results  Age range: 4-8 years, mean ~6 years  Budesonide (n=102):5.98 ± 1.88 cm/yr (m, 5.78 cm)  Nonsteroidal (n=41):6.48 ± 2.10 cm/yr (m, 6.2 cm)  Delta: -0.50 cm/yr  Age range: 9 months to <4 years  Budesonide (n=48):7.85 ± 2.02 cm/yr  Nonsteroidal (n=17):9.65 ± 2.11 cm/yr  Delta: -1.8 cm/yr  There larger growth effect was noted in younger children  Interpretation of differences is limited

20. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 20 Growth Study: Inhaled Fluticasone Propionate  Drug: Flovent Rotadisk  Design: randomized, double blind, placebo controlled, parallel group, one year  Inclusions:  Prepubertal children with moderate asthma  Age range: boys 4-11 yrs girls 4-9 yrs  Arms:  Placebo BID (n=76)  FP 50 mcg BID (n=98)  FP 100 mcg BID (n=88)

21. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 21 Inhaled FP Results  Results:  Placebo: 6.32 ± 1.5 cm/yr (median 6.12 cm)  FP50 mcg BID:6.07 ± 1.5 cm/yr (median 5.78 cm)  FP100 mcg BID:5.66 ± 1.2 cm/yr (median 5.52 cm)  Delta: Placebo vs FP50:-0.26 cm/yr  Delta: Placebo vs FP100:-0.64 cm/yr  Delta: FP50 vs FP100:-0.38 cm/yr  There was some indication of a dose response

22. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 22 Regulatory Background & Chronology (con’t)  1998-2004:  Advisory Committee recommendations implemented  FDA Draft Growth Guidance published (2001)*  Labels are reviewed and updated New labeling supplements New post-marketing adverse events Pediatric Exclusivity studies, as appropriate Phase 4 growth studies * Evaluation of the Effects of Orally Inhaled and Intranasal Corticosteroids on Growth in Children, Clinical/Medical (Draft) #12, Posted 11/6/2001, http://www.fda.gov/cder/guidance/index.htm http://www.fda.gov/cder/guidance/index.htm

23. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 23 Growth Studies: Intranasal Budesonide and Fluticasone Moiety Dose mcg/day N Result* cm/year Delta95% CI Budesonide 64 1 1305.91 ± 0.11 -0.27 cm/year 0.07, -0.62 0616.19 ± 0.16 Fluticasone 200 2 566.16 ± 0.23 -0.137 cm/year 0.27, -0.54 0526.30 ± 0.23 Beclomethasone 336 2 494.75 -1.45 cm/year 0496.20 * Growth rate on one year of treatment. Results shown as Mean (budesonide) or LS Mean (fluticasone) ± SE. 1 Lowest approved dose 2 Highest approved dose

24. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 24 Labeling Status as of 2004  All labels  Clearly describe the potential risks for adverse events  HPA-axis studies  Class labeling Minor wording variations (ok)  Growth studies  All labels are being reviewed and updated as new labeling supplements are submitted

25. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 25 Labeling Status of Budesonide and Fluticasone  Budesonide and Fluticasone  Orally inhaled and intranasal products have HPA axis, growth, post-marketing adverse event data  Budesonide  New intranasal growth study information  Re-labeled as Pregnancy Category B New information from 3 Swedish birth registries Category B: Animal reproduction studies have shown an adverse effect but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester

26. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 26 Summary 1 of 2  Asthma is a chronic inflammatory disease of the airways  Represents a huge burden to individuals as well as to health care system  While the prevalence of asthma has  since 1980, mortality rates have declined since 1995  Corticosteroids are recommended as  Primary controller therapy for persistent asthma  Most effective therapy for severe allergic rhinitis

27. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 27 Summary 2 of 2  Types of adverse events expected with this class of compounds have been well documented  FDA continually reviews and updates labeling  Labels have changed dramatically over the last 10 years  Class labeling  HPA axis information  Growth studies  Adverse event data  The current labeling for these products is concurrent with the latest safety data for these products

28. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 28 "Inhaled corticosteroids improve health outcomes for children with mild or moderate persistent asthma, and the potential but small risk of delayed growth is well balanced by their effectiveness" * * NIH/NAEPP EPR-2 Update: Guidelines for the Diagnosis and Management of Asthma, 2002, National Heart, Lung, and Blood Institute, http://www.nhlbi.nih.gov/guidelines/index.htmhttp://www.nhlbi.nih.gov/guidelines/index.htm

29. Food and Drug Administration Division of Pulmonary and Allergy Drug Products 29 Division of Pulmonary and Allergy Drug Products Parklawn Building, Room 10B-45 5600 Fishers Lane, HFD-570 Rockville, MD 20857 Phone: 301-827-1050 Fax: 301-827-1271