Asthma Management Handbook

Guide to preventers: inhaled corticosteroid/long-acting beta-2 agonist combinations

Preventers are used in maintenance treatment to reduce airway inflammation. They include combination inhaled corticosteroid/long-acting beta2 agonist medicines (budesonide/formoterol, fluticasone furoate/vilanterol, fluticasone propionate/formoterol and fluticasone propionate salmeterol).

Table. Classification of asthma medicines Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/table/show/79

More information

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.1 Combination treatment was not associated with an increase in in symptom-free days or a reduction in reliever use, compared with inhaled corticosteroid alone.1

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.2 3 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.4,5, 6 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.6 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 children7 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.7

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.1 Subsequent to the publication of this and similar studies in adults,8 regulators in the USA and Australia removed previous ‘black box’ warnings from combination inhaled corticosteroid–long-acting beta2 agonist products for asthma.9

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

Close
Inhaled corticosteroid/long-acting beta-2 agonist combinations for adults: overview
  • To avoid the possibility of patients taking a long-acting beta2 agonist without an inhaled corticosteroid, long-acting beta2 agonists should (whenever possible) be prescribed as inhaled corticosteroid/long-acting beta2 agonist combination in a single inhaler, rather than in separate inhalers. If no combination product is available for the desired medications, carefully explain to the patient that it is very important that they continue taking the inhaled corticosteroid.

Meta-analysis of evidence from randomised controlled clinical trials shows that, for adult patients already taking an inhaled corticosteroid, concomitant treatment with an inhaled corticosteroid and a long-acting beta2 agonist:10

  • reduces the risk of flare-ups, compared with increasing the dose of corticosteroids
  • reduces the risk of flare-ups, compared with inhaled corticosteroids alone.

The studies included in this meta-analysis evaluated mainly budesonide/formoterol and fluticasone propionate/salmeterol.10

Each of the following inhaled corticosteroid/long-acting beta2 agonist combinations is available as a single inhaler:

  • budesonide/formoterol
  • fluticasone furoate/vilanterol
  • fluticasone propionate/salmeterol
  • fluticasone propionate/formoterol.

There are two types of dosing regimens for inhaled corticosteroid/long-acting beta2 agonist combination therapy:

  • maintenance-only regimens (applicable to all available combinations)
  • maintenance-and-reliever regimen (applicable only to the budesonide/formoterol combination).

Maintenance-only regimens

The fluticasone propionate/salmeterol combination and budesonide/formoterol combination appear to be equally effective when used for regular maintenance treatment, based on meta-analysis of evidence from clinical trials.11 Most of the evidence for inhaled corticosteroid/long-acting beta2 agonist combination therapy is from studies using these combinations.

Less evidence from double-blind randomised controlled clinical trials is available for the newer combinations: fluticasone furoate/vilanterol and fluticasone propionate/formoterol:

  • The fluticasone furoate/vilanterol combination is equivalent to a medium-to-high dose of inhaled corticosteroids.12 In adults and adolescents already taking inhaled corticosteroids, once-daily fluticasone furoate/vilanterol 100/25 microg reduced the risk of severe flare-ups (requiring oral corticosteroids or hospitalisation) and improved lung function, compared with fluticasone furoate alone.13 Efficacy data for the comparison of fluticasone furoate/vilanterol with other inhaled corticosteroid/long-acting beta2 agonist combinations is not available.
  • In adults and adolescents with persistent asthma and FEV1 50–80% at baseline, fluticasone propionate/formoterol achieved improvement in FEV1 comparable to that achieved with budesonide/formoterol in a 12-week randomised double-blind clinical trial.14 Other 12-week open-label studies have reported that fluticasone propionate/formoterol was as effective as budesonide/formoterol in improving lung function in adults and adolescents with poorly controlled asthma,15 and was as effective as fluticasone propionate/salmeterol in adults.16

Long-acting beta2 agonists should not be used without inhaled corticosteroids in the management of asthma.17181920 Long-acting beta2 agonists are well tolerated when given in combination with inhaled corticosteroids.1121

Maintenance-and-reliever regimen

The low-dose budesonide/formoterol combination can be used as both maintenance and reliever. Under this regimen, the combination is used for relief of asthma symptoms (instead of using a short-acting beta2 agonist reliever), in addition to its use as regular maintenance treatment.

Last reviewed version 2.0

Close
Inhaled corticosteroid/long-acting beta-2 agonist combinations for exercise-induced bronchoconstriction
  • To avoid the possibility of patients taking a long-acting beta2 agonist without an inhaled corticosteroid, long-acting beta2 agonists should (whenever possible) be prescribed as inhaled corticosteroid/long-acting beta2 agonist combination in a single inhaler, rather than in separate inhalers. If no combination product is available for the desired medications, carefully explain to the patient that it is very important that they continue taking the inhaled corticosteroid.

Intermittent long-acting beta2 agonists administered by inhalation before exercise are effective in protecting against exercise-induced bronchoconstriction:22

  • for formoterol, onset of bronchodilation and bronchoprotective action is 1-3 minutes after administration23
  • for salmeterol, onset of bronchodilation and bronchoprotective action is 10 - 30 minutes after administration24

The duration of effect of both formoterol and salmeterol is up to 12 hours for patients who have not taken a short-acting beta2 agonist or long-acting beta2 agonist within the previous 72 hours. However, the duration of bronchoprotection is reduced for subsequent doses due to receptor tolerance.22

Close
Combination budesonide/formoterol maintenance-and-reliever regimen in adults and adolescents: overview of efficacy

Low-dose budesonide/formoterol combination can be used as reliever for asthma symptoms (instead of using a short-acting beta2 agonist reliever), in addition to its use as regular long-term preventer treatment.25, 26,  27,  2829, 30 The following formulations can be used in maintenance-and-reliever regimens:

  • dry-powder inhaler (Symbicort Turbuhaler) 100/6 microg or 200/6 microg
  • pressurised metered-dose inhaler (Symbicort Rapihaler) 50/3 microg or 100/3 microg.

Neither the 400/12 microg dry-powder inhaler nor the 200/6 microg pressurised metered-dose inhaler should be used in this way.

Overall, clinical trials show that budesonide/formoterol combination as maintenance and reliever reduces the risk of flare-ups that require oral corticosteroids, compared with other current preventer regimens and compared with a fixed higher dose of inhaled corticosteroids.31

Pooled data from five randomised controlled trials assessing budesonide/formoterol maintenance-and-reliever regimens showed that similar or better levels of asthma control were achieved with budesonide/formoterol maintenance-and-reliever compared with the conventional maintenance regimen comparators:27

  • higher-dose budesonide
  • same dose budesonide/formoterol
  • higher-dose inhaled corticosteroid/long-acting beta2 agonist (budesonide/formoterol or fluticasone propionate/salmeterol).

In randomised clinical trials in patients with a history of asthma flare-up within the previous 12 months (and therefore at greater risk of flare-up in the next 12 months), the use of formoterol/budesonide as maintenance-and-reliever regimen reduced the risk of asthma flare-ups that required treatment with oral corticosteroids, compared with the use of any of the following (plus a short-acting beta2 agonist reliever as needed):273233

  • the same combination as maintenance treatment only
  • higher-dose combination as maintenance treatment only
  • higher-dose inhaled corticosteroids.

Meta-analysis of six randomised controlled trials found that maintenance-and-reliever treatment with budesonide/formoterol reduced the risk of severe asthma flare-ups (use of oral corticosteroids for 3 days or more, hospitalisation or emergency department visits), compared with higher-dose inhaled corticosteroid alone, or in combination with a long-acting beta2 agonist.34

In open-label studies in which patients were not selected for a previous history of flare-ups, there was no overall difference in time to first flare-up between budesonide/formoterol as maintenance-and-reliever regimen and conventional maintenance regimens (including inhaled corticosteroid or inhaled corticosteroid/long-acting beta2 agonist combinations, leukotriene receptor antagonists, xanthines or any other asthma medicines) with rapid-onset beta2 agonist reliever (selected according to clinician’s choice).35 However, the inhaled corticosteroid dose was higher with conventional maintenance regimens.

Note: The fluticasone propionate/formoterol combination is approved by the Therapeutic Goods Administration only for regular maintenance therapy.

Last reviewed version 2.0

Close
Managing flare-ups in adults: adjusting budesonide/formoterol maintenance-and-reliever treatment

When asthma symptoms worsen, patients taking budesonide/formoterol 100/6 microg or 200/6 microg as maintenance-and-reliever treatment can increase as-needed inhalations:

  • for budesonide/formoterol 100/6 microg or 200/6 microg via dry-powder inhaler, up to a maximum of 12 actuations per day (total of maintenance and reliever inhalations) 26
  • for budesonide/formoterol 50/3 microg or 100/3 microg via pressurised metered-dose inhaler, up to a maximum of 24 actuations per day (total of maintenance and reliever inhalations).36

A written asthma action plan template developed by Australian clinicians for adults using budesonide/formoterol maintenance and reliever regimen suggests that the patient should commence oral corticosteroids and/or see a doctor after 2–3 days if asthma is worsening, or symptoms are not improving, despite taking 6 reliever inhalations of budesonide/formoterol per day in addition to maintenance doses.

Last reviewed version 2.0

Close

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. Pharmaceutical Benefits Scheme,. Post-market review. PBS medicines used to treat asthma in children. Report to PBAC. Final Report. 2017.
  8. 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
  9. 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
  10. Sin DD, Man J, Sharpe H, Gan MS. Pharmacological management to reduce exacerbations in adults with asthma: A systematic review and meta-analysis. JAMA. 2004; 292: 367-376. Available from: http://jama.jamanetwork.com/article.aspx?articleid=199101
  11. Lasserson TJ, Ferrara G, Casali L. Combination fluticasone and salmeterol versus fixed dose combination budesonide and formoterol for chronic asthma in adults and children. Cochrane Database Syst Rev. 2011; 3: CD004106. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004106.pub4/full
  12. GlaxoSmithKline Australia Pty Ltd. Product Information: Breo (fluticasone furoate; vilanterol) Ellipta. Therapeutic Goods Administration, Canberra, 2014. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf
  13. Bateman ED, O'Byrne PM, Busse WW, et al. Once-daily fluticasone furoate (FF)/vilanterol reduces risk of severe exacerbations in asthma versus FF alone. Thorax. 2014; 69: 312-319. Available from: http://thorax.bmj.com/content/69/4/312.full
  14. Bodzenta-Lukaszyk A, Buhl R, Balint B, et al. Fluticasone/formoterol combination therapy versus budesonide/formoterol for the treatment of asthma: a randomized, controlled, non-inferiority trial of efficacy and safety. J Asthma. 2012; 49: 1060-70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23102189
  15. Cukier A, Jacob CMA, Rosario Filho, NA, et al. Fluticasone/formoterol dry powder versus budesonide/formoterol in adults and adolescents with uncontrolled or partly controlled asthma. Respir Med. 2013; 107: 1330-1338. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23849625
  16. Bodzenta-Lukaszyk A, Dymek A, McAulay K, Mansikka H. Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study. BMC Pulm Med. 2011; 11: 28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21605396
  17. Ducharme FM, Lasserson TJ, Cates CJ. Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma. Cochrane Database Syst Rev. 2011; Issue 5: CD003137. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003137.pub4/full
  18. Walters EH, Gibson PG, Lasserson TJ, Walters JA. Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid. Cochrane Database Syst Rev. 2007; Issue 1: CD001385. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001385.pub2/full
  19. Chowdhury BA, Dal Pan G. The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med. 2010; 362: 1169-1171. Available from: http://www.nejm.org/doi/full/10.1056/NEJMp1002074
  20. Chowdhury BA, Seymour SM, Levenson MS. Assessing the safety of adding LABAs to inhaled corticosteroids for treating asthma. N Engl J Med. 2011; 364: 2473-2475. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21714647
  21. Cates CJ, Jaeschke R, Schmidt S, Ferrer M. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database Syst Rev. 2013; 3: CD006922. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006922.pub3/full
  22. Weiler JM, Anderson SD, Randolph C, et al. Pathogenesis, prevalence, diagnosis, and management of exercise-induced bronchoconstriction: a practice parameter. Ann Allergy Asthma Immunol. 2010; 105: S1-47. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21167465
  23. AstraZeneca Pty Ltd. Product Information: Oxis (eformoterol fumarate dihydrate) Turbuhaler. Therapeutic Goods Administration, Canberra, 2008. Available from: https://www.ebs.tga.gov.au/
  24. GlaxoSmithKline Australia Pty Ltd. Product Information: Serevent Accuhlaer. Therapeutic Goods Administration, Canberra, 2013. Available from: https://www.ebs.tga.gov.au/
  25. Aubier M, Buhl R, Ekström T, et al. Comparison of two twice-daily doses of budesonide/formoterol maintenance and reliever therapy. Eur Respir J. 2010; 36: 524-530. Available from: http://erj.ersjournals.com/content/36/3/524.long
  26. AstraZeneca Pty Ltd. Product Information: Symbicort (budesonide and eformoterol fumarate dihydrate) Turbuhaler. Therapeutic Goods Administration, Canberra, 2010. Available from: https://www.ebs.tga.gov.au/
  27. Bateman ED, Reddel HK, Eriksson G, et al. Overall asthma control: the relationship between current control and future risk. J Allergy Clin Immunol. 2010; 125: 600-608. Available from: http://www.jacionline.org/article/S0091-6749(09)01770-9/fulltext
  28. Bousquet J, Boulet LP, Peters MJ, et al. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir Med. 2007; 101: 2437-46. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17905575
  29. Lundborg M, Wille S, Bjermer L, et al. Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma: an efficacy and cost-effectiveness study. Curr Med Res Opin. 2006; 22: 809-21. Available from: http://informahealthcare.com/doi/abs/10.1185/030079906X100212
  30. Taylor DR, Bateman ED, Boulet LP, et al. A new perspective on concepts of asthma severity and control. Eur Respir J. 2008; 32: 545-554. Available from: http://erj.ersjournals.com/content/32/3/545.long
  31. Cates CJ, Karner C. Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children. Cochrane Database Syst Rev. 2013; 4: Cd007313. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23633340
  32. Patel M, Pilcher J, Pritchard A, et al. Efficacy and safety of maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial. Lancet. 2013; 1: 32-42. Available from: http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(13)70007-9/abstract
  33. Reddel HK, Jenkins C, Quirce S, et al. Effect of different asthma treatments on risk of cold-related exacerbations. Eur Respir J. 2011; 38: 584-593. Available from: http://erj.ersjournals.com/content/38/3/584.full
  34. Edwards SJ, von Maltzahn R, Naya IP, Harrison T. Budesonide/formoterol for maintenance and reliever therapy of asthma: a meta analysis of randomised controlled trials. Int J Clin Pract. 2010; 64: 619-27. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20456215
  35. Demoly P, Louis R, Søes-Petersen U, et al. Budesonide/formoterol maintenance and reliever therapy versus conventional best practice. Respir Med. 2009; 103: 1623-1632. Available from: http://www.resmedjournal.com/article/S0954-6111(09)00255-8/fulltext
  36. AstraZeneca Pty Ltd. Product Information: Symbicort (budesonide and eformoterol fumarate dihydrate) Rapihaler. Therapeutic Goods Administration, Canberra, 2012. Available from: https://www.ebs.tga.gov.au/