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

Abstract

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 g 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 basel...

Intranasal Triamcinolone and Growth Velocity

“…Consistent with results of a previous study, 18 this study detected an effect of INCs on growth in the absence of an effect on the HPA axis function, supporting the position that growth suppression is a more sensitive indicator of systemic bioavailability than HPA axis suppression. The fact that nasally administered TAA-AQ does not suppress HPA axis function at therapeutic dosages has also been observed previously.…”

“…These contrasting results may be because our study was designed to reduce the data variability from the following several aspects: prepubertal subjects (3-9 years) usually show a linear growth pattern; height was recorded at multiple visits during the treatment period and multiple measurement readings were taken at each visit to reduce the measurement error; and, most importantly, there was a long study duration, because the variability (SD) of GV is inversely proportional to the length of the time interval of evaluation. The effect size of TAA-AQ in this study was smaller than that in the BDP INC study 18 (mean change in standing height from baseline at 12 months was 5.0 cm for the BDP-treated patients and 5.9 cm for the placebo-treated patients, P , .01), and its detection was likely facilitated by the use of FDArecommended rigorous design elements. The designs in the previous negative TAA-AQ studies may not have been sufficiently sensitive to detect the small effect.…”

“…[15][16][17][18] Treatment with fluticasone propionate, 15 budesonide, 16 and mometasone furoate 17 aqueous nasal sprays showed no significant differences in GVs after 1 year of treatment using study designs that did not conform to the FDA guidelines for evaluating effects of INCs on growth of children. In contrast, significantly lower growth rates were observed with beclomethasone dipropionate (BDP) 18 and fluticasone furoate nasal spray (unpublished data conforming to FDA guidelines). 19 These differences might be attributed to the inherent dissimilarities in the pharmacodynamic profiles and bioavailability of the drugs 15,20 or the heterogeneity in the methods used to assess the pharmacodynamics and level of compliance with the FDA guidelines.…”

“…13,14 INCs seem to exert their effect on growth within a few months of treatment initiation. Evident differences in GVs in the first 4 to 6 weeks of treatment were noted in prepubescent children with PAR treated with intranasal BDP for 1 year 18 and children with asthma treated with orally inhaled BDP for 30 weeks. 22 Similarly, in our study, the difference in GVs between TAA-AQ and placebo groups was observed within the first 2 months of treatment, suggesting that the effect of exogenous corticosteroids on growth occurs early and stabilizes during the treatment period.…”

Management of Allergic Rhinitis

“…Pediatric studies have assessed growth suppression as well as adrenocortical suppression and bone metabolism. [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] Intranasal corticosteroids in current use have minimal systemic effects due to low bioavailability. 64 …”