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ARTICLE: Stanley P. Galant, Isaac R. Melamed, Anjuli S. Nayak, Kathryn V. Blake, Barbara A. Prillaman, Kenneth D. Reed, Cindy K. Cook, Edward E. Philpot, and Kathleen A. Rickard Lack of Effect of Fluticasone Propionate Aqueous Nasal Spray on the Hypothalamic-Pituitary-Adrenal Axis in 2- and 3-Year-Old Patients Pediatrics 2003; 112: 96-100 [Abstract] [Full text] [PDF]

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Safety of Fluticasone Propionate Nasal Spray in Children

Peter R Starke, Badrul Chowdhury   (24 November 2003)

The authors reply to "Safety of Fluticasone Propionate Nasal Spray in Children"

Edward E. Philpot, MD, Stanley P. Galant, MD Clinical Trials of Orange County, Orange, CA.   (10 December 2003)

Safety of Fluticasone Propionate Nasal Spray in Children 24 November 2003
Peter R Starke, Acting Medical Team Leader/ Medical Reviewer Division of Pulmonary and Allergy Drug Products, US Food and Drug Administration, Badrul Chowdhury Send letter to journal: Re: Safety of Fluticasone Propionate Nasal Spray in Children starkep{at}cder.fda.gov Peter R Starke, et al.	To the Editor, Dr. Galant et. al. presented data from an HPA axis study to support the safety of fluticasone propionate nasal spray (Flonase®) when used in children 24-47 months of age.1 This study was one of several studied performed in response to a Written Request from the US Food and Drug Administration for pediatric studies with fluticasone propionate. We reviewed the protocol and study results in depth, and duplicated some of the results from submitted electronic datasets.2 We believe that some of the conclusions presented are not supported by the data. There were many shortcomings in study design, and therefore the authors’ statement that the Flonase group was equivalent to placebo is misleading. There were problems with collection of specimens (younger children not toilet trained), due to lack of a 24-hour collection (12-hour collection may miss the early morning cortisol peak), and correction for urinary creatinine (problematic because of incomplete collection). Interpretation of the results is severely limited by the lack of a positive control to establish assay sensitivity. An active comparator arm such as a short course of oral steroid would have provided the assay sensitivity needed to adequately interpret the results.3 Finally, while the protocol did have the objective of showing equivalence between Flonase and placebo, the statistical analysis was too insensitive to evaluate equivalence, with equivalence bounds (±20 mcg/g) so large as to be meaningless.4 The authors only discuss the results in the context of other negative Flonase HPA axis studies. We believe that growth is a far more sensitive indicator of the systemic effects of corticosteroids than evaluation of HPA axis.5 Some corticosteroids have shown clinically relevant growth effects despite a negative HPA axis study. While the systemic bioavailability of fluticasone is quite small, and fluticasone exhibits high first-pass hepatic metabolism which theoretically might metabolize any excess swallowed fluticasone, the results cannot ensure that there is no safety risk for patients who do experience systemic exposure. The article does not report the fact that fluticasone levels were performed in this study at one time-point.2 Seven patients in the treatment group had detectable levels of fluticasone, of whom six had decreased creatinine-corrected urine cortisols. The implication remains that some susceptible patients do have systemic exposure and may be at risk. Finally, the authors omitted information on the current indication, dosage, and age limits for Flonase. By omitting this information, the article implies that Flonase is safe for use in children ages 2-4 years when in fact Flonase is not indicated for use below 4 years of age.6 The article also implies that the dosage of Flonase is 200 mcg daily, when the recommended starting dose for adolescents and children is 100 mcg per day. Peter R. Starke, MD and Badrul A. Chowdhury, MD, PhD, Division of Pulmonary and Allergy Drug Products, US Food and Drug Administration 1 Galant, S P, Melamed, I R, et al. Lack of Effect of Fluticasone Propionate Aqueous Nasal Spray on the Hypothalamic-Pituitary-Adrenal Axis in 2- and 3-Year-Old Patients. Pediatrics. 2003; 112(1): 96-100 2 BPCA Medical Review Summary, Fluticasone – Flonase. FDA/CDER, Pediatrics, Best Pharmaceuticals for Children Act, Summaries of Medical and Clinical Pharmacology Reviews of Pediatric Studies Web Page, http://www.fda.gov/cder/pediatric/Summaryreview.htm, accessed 7/9/2003 3 CDER Guidance Document. Allergic Rhinitis: Clinical Development Programs for Drug Products (Issued 6/2000, Posted 6/20/2000). FDA/CDER, Regulatory Guidance, Guidance Documents Web Page, http://www.fda.gov/cder/guidance/index.htm, Clinical/Medical (Draft) #1, accessed 7/9/2003 4 CDER Guidance Document. Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (Posted 4/2/2003). FDA/CDER, Regulatory Guidance, Guidance Documents Web Page, http://www.fda.gov/cder/guidance/index.htm, Biopharmaceutics (Draft) #1, accessed 7/9/2003 5 CDER Guidance Document. Evaluation of the Effects of Orally Inhaled and Intranasal Corticosteroids on Growth in Children (Posted 11/6/2001). FDA/CDER, Regulatory Guidance, Guidance Documents Web Page, http://www.fda.gov/cder/guidance/index.htm, Clinical/Medical (Draft) #13, accessed 7/9/2003 6 Current label for Flonase® Nasal Spray, 50 mcg. GlaxoSmithKline, Product, Prescription Medicine Web Page, http://www.gsk.com/products/prescriptionmedicines.shtml, accessed 7/9/03
The authors reply to "Safety of Fluticasone Propionate Nasal Spray in Children" 10 December 2003
Edward E. Philpot, MD, Senior Director, Allergy, GlaxoSmithKline GlaxoSmithKline, Research Triangle Park, NC., Stanley P. Galant, MD Clinical Trials of Orange County, Orange, CA. Send letter to journal: Re: The authors reply to "Safety of Fluticasone Propionate Nasal Spray in Children" Edward.E.Philpot{at}gsk.com Edward E. Philpot, MD, et al.	This article(1) presented the results of a pediatric study conducted to evaluate the safety of fluticasone propionate aqueous nasal spray (Flonase) in 2-3 year-old subjects. As mentioned by Dr. Starke, the study was among those included in the FDA's Written Request(2) for submission of certain studies to determine if the use of fluticasone propionate could have meaningful health benefits in the pediatric population. At the time the study was conducted in 2000, twelve-hour creatinine- corrected urinary free cortisol measurements were considered an acceptable method for evaluation of HPA axis function, and at the time, the FDA recommended "creatinine normalized, timed, urinary free cortisol excretion" as an appropriate test of adrenal function in its Written Request. It has been demonstrated that overnight or early morning creatinine-corrected urinary free cortisol excretion is as sensitive as 24 -hour collection in detecting adrenal suppression in healthy subjects treated with inhaled cortocosteroids.(3) Furthermore, accurate 24-hour collection of urine from young subjects is more difficult than 12-hour collection, and may have required the participation of daycare providers for some subjects. Therefore, we opted for twelve-hour collection of urine specimens between 8 PM and 8 AM the following morning, during which the early morning cortisol peaks should have been captured. As Dr. Starke suggested, the inclusion of an active comparator arm, such as a short course of oral steroid, may have increased assay sensitivity and aided in the interpretation of the study results. Although we had considered this option as part of the study design, safety concerns precluded our introducing oral steroid therapy in 2-3 year-old subjects. It was also suggested that the a priori equivalence bounds defined in this study were so large as to have been meaningless. The power calculations for this study were partly based on the FDA's Written Request for at least 24 subjects per treatment group and partly on prior experience with another study of inhaled fluticasone propionate(4) in which the standard deviation of the mean change from baseline in 12-hour creatinine-corrected urinary free cortisol within a treatment group was estimated to be 20mcg/g. Based on this information and input from the FDA, we determined that 24 completed subjects per treatment group would provide at least 85% power to demonstrate equivalence between the Flonase 200 mcg once-daily and placebo treatment groups within 20mcg/g in the mean change from baseline in 12-hour creatinine-corrected urinary free cortisol. This sample size calculation was based on a 2-sided t-test with alpha = 0.05. While we acknowledge that our results reflect a much smaller treatment difference than that anticipated by the power calculations in the protocol, we note that there is no consensus in the medical community regarding appropriate equivalence bounds in the context of cortisol measurements of any type. The plasma fluticasone levels evaluated in this study were inconclusive due to technical problems with the assay and were therefore not reported in the published article. There were inadequate numbers of samples to complete population pharmacokinetics. It is true that six of seven Flonase-treated subjects with detectable levels of fluticasone had decreases relative to baseline in 12-hour creatinine-corrected urinary free cortisol values. However, decreases from baseline were also observed in the placebo group. The decreases from baseline in the placebo group ranged from -0.2mcg/g to -54.4mcg/g, while the decreases from baseline in the Flonase group ranged from -0.2mcg/g to -34.3mcg/g.(5) We agree with Dr. Starke that growth is a more sensitive indicator of systemic effects than HPA axis evaluation and acknowledge that some intranasal corticosteroids have exhibited growth suppressive effects.(6,7) To address this issue, we conducted a randomized, double-blind, placebo- controlled study of Flonase administered daily for 1 year (at the maximum recommended dose of 200 mcg once-daily) to evaluate its potential effects on growth in prepubescent children with perennial allergic rhinitis and published the results(8) prior to the publication of the present trial.(1) We did not intend to suggest or imply that Flonase was indicated in children less than 4. Flonase is approved for the management of nasal symptoms of seasonal allergic rhinitis, perennial allergic rhinitis, and non-allergic rhinitis in adults and pediatric patients 4 years of age and above. This study was published in Pediatrics to broaden the safety literature on Flonase in a younger age group. As was done in the Flonase growth study in prepubescent children,(8) the maximum recommended dose of 200 mcg once-daily was used in the present trial(1) as a more conservative approach to safety evaluation. Sincerely, Stanley P. Galant, MD Clinical Trials of Orange County, Orange CA. Edward E. Philpot, MD Senior Director, Allergy, GlaxoSmithKline, Research Triangle Park, NC. 1 Galant SP, Melamed IR, Nayak AS, et al. Lack of effect of fluticasone propionate aqueous nasal spray on the hypothalamic-pituitary- adrenal axis in 2- and 3-year-old patients. Pediatrics 2003;112:96-100. 2 Guidance for Industry: Qualifying for Pediatric Exclusivity under Section 505A of the Federal Food, Drug, and Cosmetic Act. U.S. Department of Health and Human Services, FDA Center for Drug Evaluation and Research. Revised September 1999. Available at http://www.fda.gov/cder/guidance/2891fnl.htm 3 McIntyre HD, Mitchell CA, Bowler SE, et al. Measuring the systemic effects of inhaled beclomethasone: timed morning urine collections compared with 24 hour specimens. Thorax 1995;50:1280-1284. 4 Data on file, GlaxoSmithKline Clinical Study Report for Protocol FLD-220 (No. UCR/95/024): A randomized, double-blind, parallel-group, comparative trial assessing the long term safety of inhaled fluticasone propionate rotadisks via diskhaler 50mcg bid and 100mcg bid versus placebo in patients aged 4 to 11 years with mild to moderate chronic asthma. 5 Data on file, GlaxoSmithKline Clinical Study Report for Protocol FNM40183 (No. RM2001/00056/00): A multi-center, randomized, double-blind, placebo-controlled, parallel-group study to assess the potential effects of a six-week course of fluticasone propionate aqueous nasal spray (200mcg QD) on the HPA-axis in >/=2 to <4 year old subjects with allergic rhinitis. 6 Skoner DP, Rachelefsky GS, Meltzer EO, et al. Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate. Pediatrics [electronic pages] 105:e23, 2000. 7 Data on file, AstraZeneca. Integrated Summary of Safety for Rhinocort Aqua (budesonide). Available at www.fda.gov/cder/approval/index.htm. 8 Allen DB, Meltzer EO, Lemanske RF, et al. No growth suppression in children treated with the maximum recommended dose of fluticasone propionate aqueous nasal spray for one year. Allergy Asthma Proc 2002;23:407-413.