Food and Drug Administration Division of Pulmonary and Allergy Drug Products Summary Comments - Orally Inhaled and Intranasal Budesonide and Fluticasone Propionate Drug Products Badrul A. Chowdhury, MD, PhD Director, Division of Director, Division of Pulmonary & Allergy Drug Products, Center for Drug Evaluation and Research, US FDA

Food and Drug Administration Division of Pulmonary and Allergy Drug Products 2 Asthma and Allergic Rhinitis  Asthma and allergic rhinitis are common diseases and impose significant burdens on the healthcare system and to individuals  Prevalence of asthma is increasing, but hospitalization rates and mortality rates have recently tended to decline  Corticosteroids  Primary controller therapy for persistent asthma  Most effective therapy for allergic rhinitis  Orally inhaled and nasal corticosteroids are not free of adverse effects - particularly effects related to HPA axis, but the benefits of the appropriate use of these drugs outweigh their safety concerns

Food and Drug Administration Division of Pulmonary and Allergy Drug Products 3 Pediatric Indication and Use  Approval for pediatric use is generally based on extrapolation from adults with supportive pediatric data  Identify appropriate dose  Establish safety of the dose  Safety assessment  Monitoring of adverse events, laboratory parameters, etc, during controlled clinical studies  Direct assessment of HPA axis by Cosyntropin stimulation test, plasma cortisol, urinary cortisol, etc  Assessment of linear growth  Monitoring post-marketing adverse event reports

Food and Drug Administration Division of Pulmonary and Allergy Drug Products 4 Pediatric Clinical Studies  Budesonide  Asthma: 12-week efficacy and safety study in children ages 6 months to <1 years  Allergic Rhinitis: 6-week HPA axis safety study in children ages 2 to <6 years  Fluticasone  Asthma: 12-week efficacy and safety studies in children ages 6 months to <4 years  Allergic Rhinitis: 6-week HPA axis safety study in children ages 2 to <4 years

Food and Drug Administration Division of Pulmonary and Allergy Drug Products 5 Assessment of Systemic Effects  Budesonide  Direct assessment of HPA axis described in product labels – generally negative at recommended doses  Linear growth study – numerically small effect  Fluticasone  Direct assessment of HPA axis described in product labels– generally negative at recommended doses  Linear growth study – numerically small effect

Food and Drug Administration Division of Pulmonary and Allergy Drug Products 6 Notable Post-marketing Adverse Events  Budesonide  Systemic corticosteroid effect or suppression of HPA axis  Fluticasone  Systemic corticosteroid effect or suppression of HPA axis  Worsening of asthma Reported with use of Advair

Food and Drug Administration Division of Pulmonary and Allergy Drug Products 7 Concluding Remarks  Safety concerns with the use of orally inhaled and intranasal budesonide and fluticasone are well characterized and adequately described in the product labels  New data obtained under pediatric study initiatives and analyses of post-marketing adverse events are reassuring and support the use of these products in pediatric patients as labeled