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Published in:

01-07-2006 | Review Article

Clinical Safety of Inhaled Corticosteroids for Asthma in Children

An Update of Long-Term Trials

Author: Dr Søren Pedersen

Published in: Drug Safety | Issue 7/2006

Abstract

Inhaled corticosteroids are established as the mainstay of maintenance therapy for chronic asthma. However, there remains some debate regarding the safety of long-term use of these agents, particularly in children. This concern mainly stems from the findings of short-term studies assessing the effects of inhaled corticosteroids on lower leg growth rate or the hypothalamic-pituitary-adrenal axis. However, the clinical relevance of these findings to long-term treatment is unknown and significant uncertainty exists regarding the predictive value of changes in cortisol levels and clinically relevant changes in growth or bone mineral density.

To assess the safety of long-term use of inhaled corticosteroids in children with asthma, a systematic review of the literature was performed focusing on randomised, controlled studies of ≥12 months’ duration, to obtain data with maximum relevance to clinical practice. Specific searches were conducted to identify studies examining each of the following three areas: growth, bone mineral density and cortisol levels.

Fourteen studies met the inclusion criteria for statural growth, four for bone mineral density, and ten for cortisol levels. There was some evidence of a small decrease in statural growth during the initial period of inhaled corticosteroid therapy. This effect was more marked at daily doses of >200μg and did not apply to all treatment regimens. Studies examining final attained adult height found no difference between patients treated with inhaled corticosteroids and those receiving nonsteroidal therapy. None of the studies investigating effects on bone mineral density found any adverse effects of inhaled corticosteroid therapy. Finally, recommended doses of inhaled corticosteroids generally had little or no effect on plasma- or urinary-cortisol levels versus nonsteroidal therapy.

In conclusion, this literature review supports the theory that recommended doses of inhaled corticosteroids can be administered to children for the long-term management of asthma with minimal risk of clinically relevant adverse effects on growth, bone density or cortisol levels.

The use of trade names is for product identification purposes only and does not imply endorsement.

Skoner DP. Balancing safety and efficacy in pediatric asthma management. Pediatrics 2002; 109: 381–92PubMed

O’Riordan TG. Optimizing delivery of inhaled corticosteroids: matching drugs with devices. J Aerosol Med 2002; 15: 245–50PubMedCrossRef

Eid NS. Update on National Asthma Education and Prevention Program pediatric asthma treatment recommendations. Clin Pediatr (Phila) 2004; 43: 793–802CrossRef

Pocket guide for asthma management and prevention in children [online]. Available from URL: http://www.ginasthma.com/ [Accessed 2005 Jul 21]

British guideline on the management of asthma [online]. Available from URL: www.sign.ac.uk/pdf/sign63.pdf [Accessed 2005 Jul 21]

Vermeire PA, Rabe KF, Soriano JB, et al. Asthma control and differences in management practices across seven European countries. Respir Med 2002; 96: 142–9PubMedCrossRef

Rabe KF, Adachi M, Lai CK, et al. Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. J Allergy Clin Immunol 2004; 114: 40–7PubMedCrossRef

van Grunsven PM. The magnitude of fear of adverse effects as a reason for nonparticipation in drug treatment: a short review. J Asthma 2001; 38: 113–9PubMedCrossRef

Data on file. GlaxoSmithKline. 2004

10.

Data on file. AstraZeneca. 2004

11.

Pedersen S. Do inhaled corticosteroids inhibit growth in children? Am J Respir Crit Care Med 2001; 164: 521–35PubMed

12.

Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000; 343: 1064–9PubMedCrossRef

13.

Merkus PJ, van Essen-Zandvliet EE, Duiverman EJ, et al. Long-term effect of inhaled corticosteroids on growth rate in adolescents with asthma. Pediatrics 1993; 91: 1121–6PubMed

14.

Roux C, Kolta S, Desfougeres JL, et al. Long-term safety of fluticasone propionate and nedocromil sodium on bone in children with asthma. Pediatrics 2003; 111: e706–13PubMedCrossRef

15.

Allen DB, Bronsky EA, LaForce CF, et al. Growth in asthmatic children treated with fluticasone propionate. Fluticasone Propionate Asthma Study Group. J Pediatr 1998; 132: 472–7PubMedCrossRef

16.

Price JF, Russell G, Hindmarsh PC, et al. Growth during one year of treatment with fluticasone propionate or sodium cromoglycate in children with asthma. Pediatr Pulmonol 1997; 24: 178–86PubMedCrossRef

17.

Bisgaard H, Allen D, Milanowski J, et al. Twelve-month safety and efficacy of inhaled fluticasone propionate in children aged 1 to 3 years with recurrent wheezing. Pediatrics 2004; 113: e87–94PubMedCrossRef

18.

Jonasson G, Carlsen KH, Jonasson C, et al. Low-dose inhaled budesonide once or twice daily for 27 months in children with mild asthma. Allergy 2000; 55: 740–8PubMedCrossRef

19.

Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343: 1054–63

20.

Verberne AA, Frost C, Roorda RJ, et al. One year treatment with salmeterol compared with beclomethasone in children with asthma. The Dutch Paediatric Asthma Study Group. Am J Respir Crit Care Med 1997; 156: 688–95PubMed

21.

Tinkelman DG, Reed CE, Nelson HS, et al. Aerosol beclometasone compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. Pediatrics 1993; 92: 64–77PubMed

22.

Simons FE. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group. N Engl J Med 1997; 337: 1659–65PubMedCrossRef

23.

Skoner DP, Szefler SJ, Welch M, et al. Longitudinal growth in infants and young children treated with budesonide inhalation suspension for persistent asthma. J Allergy Clin Immunol 2000; 105: 259–68PubMedCrossRef

24.

Irani AM, Cruz-Rivera M, Fitzpatrick S, et al. Effects of budesonide inhalation suspension on hypothalamic-pituitary-adrenal-axis function in infants and young children with persistent asthma. Ann Allergy Asthma Immunol 2002; 88: 306–12.PubMedCrossRef

25.

Scott MB, Skoner DP. Short-term and long-term safety of budesonide inhalation suspension in infants and young children with persistent asthma. J Allergy Clin Immunol 1999; 104: 200–9PubMedCrossRef

26.

Visser MJ, van der Veer E, Postma DS, et al. Side-effects of fluticasone in asthmatic children: no effects after dose reduction. Eur Respir J 2004; 24: 420–5PubMedCrossRef

27.

Visser MJ, Postma DS, Arends LR, et al. One-year treatment with different dosing schedules of fluticasone propionate in childhood asthma. Effects on hyperresponsiveness, lung function, and height. Am J Respir Crit Care Med 2001; 164: 2073–7PubMed

28.

de Benedictis FM, Teper A, Green RJ, et al. Effects of 2 inhaled corticosteroids on growth: results of a randomized controlled trial. Arch Pediatr Adolesc Med 2001; 155: 1248–54PubMed

29.

Rao R, Gregson RK, Jones AC, et al. Systemic effects of inhaled corticosteroids on growth and bone turnover in childhood asthma: a comparison of fluticasone with beclomethasone. Eur Respir J 1999; 13: 87–94PubMedCrossRef

30.

Allen DB. Systemic effects of inhaled corticosteroids in children. Curr Opin Pediatr 2004; 16: 440–4PubMedCrossRef

31.

Price J, Hindmarsh P, Hughe S, et al. Evaluating the effects of asthma therapy on childhood growth: what can be learnt from the published literature? Eur Respir J 2002; 19: 1179–93PubMedCrossRef

32.

Larsson L, Gerhardsson de Verdier M, Lindmark B, et al. Budesonide-treated asthmatic adolescents attain target height: a population-based follow-up study from Sweden. Pharmacoepidemiol Drug Saf 2002; 11: 715–20PubMedCrossRef

33.

Inoue T, Doi S, Takamatsu I, et al. Effect of long-term treatment with inhaled beclometasone on growth of asthmatic children. J Asthma 1999; 36: 159–64PubMedCrossRef

34.

Silverstein MD, Yunginger JW, Reed CE, et al. Attained adult height after childhood asthma: effect of glucocorticoid therapy. J Allergy Clin Immunol 1997; 99: 466–74PubMedCrossRef

35.

Van Bever HP, Desager KN, Lijssens N, et al. Does treatment of asthmatic children with inhaled corticosteroids affect their adult height? Pediatr Pulmonol 1999; 27: 369–75PubMedCrossRef

36.

Norjavaara E, Gerhardsson De Verdier M, Lindmark B. Reduced height in Swedish men with asthma at the age of conscription for military service. J Pediatr 2000; 137: 25–9PubMedCrossRef

37.

Allen DB, Mullen M, Mullen B. A meta-analysis of the effect of oral and inhaled corticosteroids on growth. J Allergy Clin Immunol 1994; 93: 967–76PubMedCrossRef

38.

Jones A, Fay JK, Burr M, et al. Inhaled corticosteroid effects on bone metabolism in asthma and mild chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002; (1): CD003537PubMed

39.

Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996; 312: 1254–9PubMedCrossRef

40.

Allen DB. Limitations of short-term studies in predicting Long-term adverse effects of inhaled corticosteroids. Allergy 1999; 54Suppl. 49: 29–34PubMedCrossRef

41.

Kelly HW, Strunk RC, Donithan M, et al. Growth and bone density in children with mild-moderate asthma: a cross-sectional study in children entering the Childhood Asthma Management Program (CAMP). J Pediatr 2003; 142: 286–91PubMedCrossRef

42.

Gregson RK, Rao R, Murrills AJ, et al. Effect of inhaled corticosteroids on bone mineral density in childhood asthma: comparison of fluticasone propionate with beclomethasone dipropionate. Osteoporosis Int 1998; 8(5): 418–22CrossRef

43.

Schlienger RG, Jick SS, Meier CR. Inhaled corticosteroids and the risk of fractures in children and adolescents. Pediatrics 2004; 114: 469–73PubMedCrossRef

44.

van Staa TP, Bishop N, Leufkens HG, et al. Are inhaled corticosteroids associated with an increased risk of fracture in children? Osteoporos Int 2004; 15: 785–91PubMedCrossRef

45.

van Staa TP, Cooper C, Leufkens HG, et al. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 2003; 18: 913–8PubMedCrossRef

46.

Pedersen S, O’Byrne PM, Busse WW, et al. Fracture rate in patients with asthma receiving long-term early intervention with budesonide: the START study [abstract]. Annual meeting of the European Respiratory Society (ERS). Suplementum from the ERS meeting; 2005 Sep 17-21; Copenhagen, 1855

47.

Harris M, Hauser S, Nguyen TV, et al. Bone mineral density in prepubertal asthmatics receiving corticosteroid treatment. J Paediatr Child Health 2001; 37: 67–71PubMedCrossRef

48.

Jones G, Ponsonby AL, Smith BJ, et al. Asthma, inhaled corticosteroid use, and bone mass in prepubertal children. J Asthma 2000; 37: 603–11PubMedCrossRef

49.

Agertoft L, Pedersen S. Bone mineral density in children with asthma receiving long-term treatment with inhaled budesonide. Am J Respir Crit Care Med 1998; 157: 178–83PubMed

50.

Allen HD, Thong IG, Clifton-Bligh P, et al. Effects of high-dose inhaled corticosteroids on bone metabolism in prepubertal children with asthma. Pediatr Pulmonol 2000; 29: 188–93PubMedCrossRef

51.

Hansen OR, Nokkentved K. Adverse effects in children treated with ACTH in infantile spasm [in Danish]. Ugeskr Laeger 1989; 151: 2194–5PubMed

52.

Winzenberg T, Shaw K, Fryer J, et al. Calcium supplementation for improving bone mineral density in children. Cochrane Database Syst Rev 2006; (2): CD005119PubMed

53.

Leflein JG, Szefler SJ, Murphy KR, et al. Nebulized budesonide inhalation suspension compared with cromolyn sodium nebulizer solution for asthma in young children: results of a randomized outcomes trial. Pediatrics 2002; 109: 866–72PubMedCrossRef

54.

55.

Bacharier LB, Raissy HH, Wilson L, et al. Long-term effect of budesonide on hypothalamic-pituitary-adrenal axis function in children with mild to moderate asthma. Pediatrics 2004; 113: 1693–9PubMedCrossRef

56.

Verona E, Petrov D, Cserhati E, et al. Fluticasone propionate in asthma: a long term dose comparison study. Arch Dis Child 2003; 88: 503–9PubMedCrossRef

57.

Donnelly R, Williams KM, Baker AB, et al. Effects of budesonide and fluticasone on 24-hour plasma cortisol: a dose-response study. Am J Respir Crit Care Med 1997; 156: 1746–51PubMed

58.

Grahnen A, Jansson B, Brundin RM, et al. A dose-response study comparing suppression of plasma cortisol induced by fluticasone propionate from Diskhaler and budesonide from Turbuhaler. Eur J Clin Pharmacol 1997; 52: 261–7PubMedCrossRef

59.

Dahl R, Lundback B, Malo JL, et al. A dose-ranging study of fluticasone propionate in adult patients with moderate asthma. International Study Group. Chest 1993; 104: 1352–8PubMedCrossRef

60.

Bisgaard H, Damkjaer Nielsen M, Andersen B, et al. Adrenal function in children with bronchial asthma treated with beclometasone or budesonide. J Allergy Clin Immunol 1988; 81: 1088–95PubMedCrossRef

61.

Martin RJ, Szefler SJ, Chinchilli VM, et al. Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med 2002; 165: 1377–83PubMedCrossRef

62.

Todd GR, Acerini CL, Ross-Russell R, et al. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002; 87: 457–61PubMedCrossRef

63.

DIN-LINK data. Compufile Ltd. 2003 Oct

64.

Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999; 159: 941–55PubMedCrossRef

65.

Allen DB. Safety of inhaled corticosteroids in children. Pediatr Pulmonol 2002; 33: 208–20PubMedCrossRef

66.

Argenti D, Jensen B, Vaccaro S. Pharmacokinetic evaluation of single doses of oral and inhaled triamcinolone acetonide with or without administration of oral charcoal. Asthma Theory to Treatment. Abstract book from the joint AAAAI and ATS; 1995, Chicago

67.

Holliday SM, Faulds D, Sorkin EM. Inhaled fluticasone propionate: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma. Drugs 1994; 47: 318–31PubMedCrossRef

68.

Pavord I, Knox A. Pharmacokinetic optimisation of inhaled steroid therapy in asthma. Clin Pharmacokinet 1993; 25: 126–35PubMedCrossRef

69.

Ryrfeldt A, Andersson P, Edsbacker S, et al. Pharmacokinetics and metabolism of budesonide, a selective glucocorticoid. Eur J Respir Dis Suppl 1982; 122: 86–95PubMed

70.

Agertoft L, Larsen FE, Pedersen S. Posterior subcapsular cataracts, bruises and hoarseness in children with asthma receiving long-term treatment with inhaled budesonide. Eur Respir J 1998; 12: 130–5PubMedCrossRef

71.

Silverman M, Sheffer AL, Diaz PV, et al. Safety and tolerability of inhaled budesonide in children in the steroid treatment as regular therapy in early asthma (START) trial. Pediatr Allergy Immunol 2006; 17Suppl. 17: 14–20PubMedCrossRef

Title: Clinical Safety of Inhaled Corticosteroids for Asthma in Children
An Update of Long-Term Trials
Author: Dr Søren Pedersen
Publication date: 01-07-2006
Publisher: Springer International Publishing
Published in: Drug Safety / Issue 7/2006
Print ISSN: 0114-5916
Electronic ISSN: 1179-1942
DOI: https://doi.org/10.2165/00002018-200629070-00005

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Clinical Safety of Inhaled Corticosteroids for Asthma in Children

An Update of Long-Term Trials

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

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