Detection of Growth Suppression in Children During Treatment With Intranasal Beclomethasone Dipropionate

Abstract

Objective.: Intranasal beclomethasone dipropionate (BDP) has generally been considered to have no systemic activity at recommended doses, but the potential for long-term effects on growth has not previously been evaluated. This study was undertaken to assess the effects of 1 year of treatment with intranasal BDP on growth in children. Study Design.: In this double-blind, randomized, parallel-group study, 100 prepubertal children 6 to 9 years old with perennial allergic rhinitis were treated with aqueous BDP 168 μg twice daily (n = 51) or placebo (n = 49) for 1 year. Subjects' baseline heights were required to be between the 5th and 95th percentile, and skeletal age as determined by left wrist radiograph was required to be within 2 years of chronological age. Washout periods for medications known to affect growth, including other forms of corticosteroids, were established, and these medications were prohibited during the study. However, short courses of oral prednisolone lasting no more than 7 days, and short courses of dermatologic corticosteroids lasting no more than 10 days, were allowed. Height was measured with a stadiometer after 1, 2, 4, 6, 8, 10, and 12 months of treatment. The hypothalamic-pituitary-adrenocortical axis was assessed by measurements of 8 am basal cortisol concentrations and response to .25 mg cosyntropin stimulation. The primary safety parameter was the rate of change in standing height. Statistical analyses were based on all randomized subjects who received at least 1 dose of medication (intent-to-treat principle). The rate of change in standing height was analyzed for all subjects who entered the study and for those completing the full 12 months of treatment (n= 80). The rate of change in standing height over the 1-year study was calculated as the slope of a linear regression line fitted to each subject's height measurements over time. Because there was a statistically significant between-group difference in standing height at baseline, an analysis of covariance was performed for all analyses of standing height data. Results.: Of the 100 subjects enrolled, 90 completed the study. The 2 treatment groups were generally comparable at baseline; however, at baseline, mean age and mean height were significantly greater in the BDP treatment group that the in placebo treatment group. In both analyses, overall growth rate was significantly slower in BDP-treated subjects than placebo-treated subjects. The mean change in standing height after 1 year was 5.0 cm in the BDP-treated subjects compared with 5.9 cm in the placebo-treated subjects. The difference in growth rates was evident as early as the 1-month treatment visit, suggesting that the effect on growth occurred initially. The growth-suppressive effect of BDP remained consistent across all age and gender subgroups, and among subjects with and without a previous history of corticosteroid use. Use of additional exogenous corticosteroids during the study was similar in both groups and did not affect the results. Because there was a baseline imbalance in height, a supplemental analysis of the differences in prestudy growth rates was performed. This analysis found no baseline imbalance in prestudy growth rates. To determine whether the difference in growth rates during the study could be attributed to preexisting growth rates, a z score analysis was performed. The heights of both groups were normalized at baseline and at the end of the study using the US National Center for Health Statistics data for mean and standard deviations of height. This analysis confirmed that the difference in growth rates between the 2 groups was primarily attributable to the treatment rather than to any preexisting difference in growth. Additional analyses confirmed that the results were not influenced by outlier values. No significant between-group difference were found in the hypothalamic-pituitary-adrenocortical axis assessments. No unusual adverse events were observed. No evidence of other systemic effects of BDP was found, including analysis for fluid and electrolyte imbalances; alterations in protein, lipid, or carbohydrate metabolism; alterations in formed elements in blood; and alterations in differential white blood cell counts, including eosinophils. Conclusions.: Additional study is warranted to define the clinical relevance of these findings. This study suggests, however, that intranasal BDP may slow growth rate in children without suppressing basal 6 am cortisol concentrations or the response to cosyntropin stimulation, which are commonly used clinically to test for adrenal suppression. The effect on final height is unknown. Alterative explantations for the finding of drug-induced growth suppression, including the possibility that the results were affected by either differences in height and age at baseline between the 2 groups or by outlier values, were discounted upon additional analysis. The results of this study were considered by the Food and Drug Administration in the development of recently proposed new class labeling for all inhaled and intranasal corticosteroids, which states that these agents may cause a reduction in growth velocity in pediatric patients (see reference 21). However, both the Food and Drug Administration and several professional bodies in the United States concur that, depending on disease severity, the benefits of intranasal corticosteroid therapy may outweigh the risks (see reference 22). Because the effect, if any, on final height in not known, the height of children receiving long-term therapy should be monitored periodically during treatment, and should be plotted on a growth or growth-velocity chart to monitor for growth suppression. To minimize the risks of systemic corticosteroid exposure, including growth suppresson, dose-reduction strategies should be considered. For patients who concomitantly receive exogenous corticosteroids via other routes for other conditions, such as inhaled corticosteroids for asthma, clinicians should consider the total corticosteroid exposure and titrate each patient to the lowest effective dose. Clinicians should also consider each medication's potential for systemic effects when selecting among the various available corticosteroids. beclomethasone dipropionate, intranasal corticosteroids, growth, allergic rhinitis, pediatric.