Asthma Management Handbook

Other regular treatments in children aged 1–5 years

Recommendations

Cromones can be considered for children who are unable to tolerate montelukast or where a nonsteroidal treatment option is preferred.

For children aged 1-2 years, sodium cromoglycate can be considered.

For children 2 years and older, sodium cromoglycate or nedocromil can be considered.

Note: Cromone inhaler device mouthpieces require meticulous daily washing to avoid blocking.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available).

Last reviewed version 2.0

Inhaled corticosteroid/long-acting beta2 agonist combinations are not recommended for children aged 5 years and under, unless on the advice of a paediatric physician or paediatrician.

Note: The combination of fluticasone propionate and salmeterol xinafoate in a single inhaler is approved by TGA for use in children aged 4 years and over. Other inhaled corticosteroid/long-acting beta2 agonist combinations are not recommended for children younger than 12 years.

How this recommendation was developed

Adapted from existing guidance

Based on reliable clinical practice guideline(s) or position statement(s):

  • van Asperen et al. 20101

Last reviewed version 2.0

Regular treatment with a theophyllines (aminophylline or theophylline) is not recommended for children aged 5 years and under.

How this recommendation was developed

Adapted from existing guidance

Based on reliable clinical practice guideline(s) or position statement(s):

  • Brand et al. 20082

Last reviewed version 2.0

Ipratropium is not recommended for the regular management of asthma in children aged 5 years and under.

Note: Ipratropium is used in the management of acute asthma.

How this recommendation was developed

Adapted from existing guidance

Based on reliable clinical practice guideline(s) or position statement(s):

  • Brand et al. 20082

Last reviewed version 2.0

More information

Cromones for children

0-5 years

Few clinical trials have assessed the use of inhaled sodium cromoglycate in preschool children and none have assessed nedocromil.2 Overall, sodium cromoglycate has not been shown to be effective in preschool children with multiple-trigger wheeze.2, 3

However, cromones are well tolerated and registered for use in infants. Therefore, a treatment trial can be considered before considering other preventers, particularly for children less than 2 years old.

6 years and over

Cromones are rarely prescribed in school-aged children.

Inhaled sodium cromoglycate might be effective in school-aged children, but interpretations of available evidence are inconsistent.1 Sodium cromoglycate is less effective than inhaled corticosteroid in achieving asthma control and improving lung function in children with persistent asthma.4

Nedocromil sodium appears to be have some benefit in children with persistent asthma, but its relative effectiveness compared with inhaled corticosteroids is not clear.5 Long-term (4–6 years) treatment with budesonide achieved better asthma control than long-term nedocromil in children with mild-to-moderate asthma aged 5–12 in a randomised placebo-controlled clinical trial.6

Practical issues

Cromones (sodium cromoglycate and nedocromil) may not be practical for most patients, because they require three–four times daily dosing until control is gained, and inhaler devices for cromones tend to block easily unless the mouthpiece is washed every day and dried for 24 hours before re-use.1

Nedocromil can cause an unusual or unpleasant taste7 and is not tolerated by some children.

Last reviewed version 2.0

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Inhaled corticosteroid/long-acting beta-2 agonist combinations for children aged 4–11 years

The combination of salmeterol plus fluticasone propionate in a single inhaler is TGA-registered for use in children 4 years and older.

Efficacy

A very large (n=6208) randomised controlled trial in children aged 4–11 years reported that, unlike in adults, the combination of inhaled corticosteroid and long-acting beta2 agonist was not associated with a significant reduction in severe flare-ups, compared with inhaled corticosteroid alone.8 Combination treatment was not associated with an increase in in symptom-free days or a reduction in reliever use, compared with inhaled corticosteroid alone.8

Safety

Clinical response to long-acting beta2 agonists partly depends on genetics. A beta2receptor genotype (Arg16 polymorphism in the beta2 receptor gene) pre-disposes children with asthma to down-regulation of the beta2 receptor and increased susceptibility to flare-ups during regular treatment with regular long-acting beta2agonists.9 10 However, routine genetic testing to tailor asthma therapy is not yet available in clinical practice.

Earlier systematic reviews and meta-analyses led to concern about the possibility that the use of long-acting beta-agonists (even in combination with inhaled corticosteroids) might even increase the risk of flare-ups that require treatment with oral steroids or hospital admission, or of severe flare-ups.1,11, 12 A meta-analysis commissioned by the US Food and Drug Administration found that the use of long-acting beta2 agonists was associated with increased risk of severe asthma-associated adverse events (both overall and among the subset of people using concomitant inhaled corticosteroid and long-acting beta2 agonist), and that this risk was greatest in children aged 4–11 years.12 However, the increased risk was only seen in studies where inhaled corticosteroid was not provided, or where inhaled corticosteroid and long-acting beta2 agonist were not combined in a single inhaler (i.e. where there was the possibility of selective non-adherence to the inhaled corticosteroid).

The PBAC Post-market review of medicines used to treat asthma in children13 concluded that there was insufficient evidence to ascertain whether tolerance to long-acting beta2 agonist could explain why it is less effective than montelukast and inhaled corticosteroids in managing exercise-induced asthma symptoms.13

A very large randomised controlled trial of children aged 4–11 years, stratified by asthma symptom control and pre-study treatment, found no increased risk of serious adverse outcomes with combination fluticasone propionate and salmeterol in a single inhaler, compared with fluticasone propionate alone.8 Subsequent to the publication of this and similar studies in adults,14 regulators in the USA and Australia removed previous ‘black box’ warnings from combination inhaled corticosteroid–long-acting beta2 agonist products for asthma.15

PBS status as at March 2019: All formulations that contain a combination of inhaled corticosteroid plus long-acting beta2 agonist are listed as ‘Authority  required - streamlined’. Patient using these combinations for asthma must have previously had frequent episodes of asthma while receiving treatment with oral corticosteroids or optimal doses of inhaled corticosteroids.

Last reviewed version 2.0

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References

  1. van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: https://www.thoracic.org.au/journal-publishing/command/download_file/id/25/filename/The_role_of_corticosteroids_in_the_management_of_childhood_asthma_-_2010.pdf
  2. Brand PL, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008; 32: 1096-1110. Available from: http://erj.ersjournals.com/content/32/4/1096.full
  3. van der Wouden JC, Uijen JH, Bernsen RM, et al. Inhaled sodium cromoglycate for asthma in children. Cochrane Database Syst Rev. 2008; Issue 4: CD002173. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002173.pub2/full
  4. Guevara JP, Ducharme F M, Keren R, et al. Inhaled corticosteroids versus sodium cromoglycate in children and adults with asthma. Cochrane Database Syst Rev. 2006; Issue 2: CD003558. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003558.pub2/full
  5. Sridhar AV, McKean M. Nedocromil sodium for chronic asthma in children. Cochrane Database Syst Rev. 2006; Issue 3: CD004108. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004108.pub2/full
  6. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med. 2000; 343: 1054-63. Available from: http://www.nejm.org/doi/full/10.1056/NEJM200010123431501#t=article
  7. Sanofi-Aventis Australia Pty Ltd. Product information: Tilade CFC-free (nedocromil sodium). Therapeutic Goods Administration, Canberra, 2008. Available from: https://www.ebs.tga.gov.au/
  8. Stempel, D. A., Szefler, S. J., Pedersen, S., et al. Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med. 2016; 375: 840-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27579634
  9. Lipworth BJ, Basu K, Donald HP, et al. Tailored second-line therapy in asthmatic children with the Arg(16) genotype. Clin Sci (Lond). 2013; 124: 521-528. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23126384
  10. Finkelstein Y, Bournissen FG, Hutson JR, Shannon M. Polymorphism of the ADRB2 gene and response to inhaled beta- agonists in children with asthma: a meta-analysis. J Asthma 2009; 46: 900-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19905915
  11. van Asperen PP. Long-acting beta agonists for childhood asthma. Aust Prescr. 2012; 35: 111-3. Available from: https://www.nps.org.au/australian-prescriber/articles/long-acting-beta2-agonists-for-childhood-asthma
  12. McMahon AW, Levenson MS, McEvoy BW, et al. Age and risks of FDA-approved long-acting β2-adrenergic receptor agonists. Pediatrics. 2011; 128: e1147-1154. Available from: http://pediatrics.aappublications.org/content/128/5/e1147.long
  13. Pharmaceutical Benefits Scheme,. Post-market review. PBS medicines used to treat asthma in children. Report to PBAC. Final Report. 2017.
  14. Busse WW, Bateman ED, Caplan AL et al. Combined analysis of asthma safety trials of long-acting beta2-agonists. N Engl J Med 2018; 378: 2497-505. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29949492
  15. Seymour SM, Lim R, Xia C et al. Inhaled corticosteroids and LABAs - removal of the FDA's boxed warning. N Engl J Med 2018; 378: 2461-3. Available from: https://www.nejm.org/doi/10.1056/NEJMp1716858