Asthma Management Handbook

Guide to other asthma medicines

Overview

In addition to relievers and preventers, some other agents are occasionally used to manage asthma in specific circumstances, e.g. as add-on options for management of severe refractory asthma or severe acute asthma. They include:

  • anti-IgE (omalizumab)
  • anti-IL5 (mepolizumab)
  • long-acting muscarinic antagonists; also called long-acting anticholinergic bronchodilators (tiotropium via mist inhaler)
  • magnesium sulfate
  • theophyllines (aminophylline, theophylline).

Some additional long-acting bronchodilator medications are TGA-approved only for management of COPD, but might be used in addition to inhaled corticosteroid-containing therapy for the treatment of patients with asthma–COPD overlap. These include:

  • long-acting muscarinic antagonists; also called long-acting anticholinergic bronchodilators (aclidinium, glycopyrronium, tiotropium via dry-powder inhaler, umeclidinium)
  • long-acting beta2 agonists (e.g. vilanterol in combination with inhaled corticosteroid or long-acting muscarinic antagonist).

Note: The use of separate inhalers for concomitant treatment with an inhaled corticosteroid and a long-acting bronchodilator (long-acting beta2-agonist or long-acting muscarinic antagonist) in patients with asthma–COPD overlap should be avoided due to the risk of selective non-adherence with the inhaled corticosteroid. If no combination product is available for the desired combination, carefully explain to the patient that it is very important that they continue taking the inhaled corticosteroid, to reduce the risk of hospitalisation or death. 

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

Table. Long-acting bronchodilators for asthma–COPD overlap

Class

Dosing frequency

Agent

Brand name

ICS–LABA combinations

Once daily

Fluticasone furoate + vilanterol

Breo Ellipta#

Twice daily

Budesonide + formoterol

Symbicort Rapihaler

Symbicort Turbuhaler

Twice daily

Fluticasone propionate + formoterol

Flutiform

Twice daily

Fluticasone propionate + salmeterol

Fluticasone and Salmeterol Cipla

Seretide Accuhaler

Seretide MDI

LABAs*

Once daily

Indacaterol

Onbrez Breezhaler

Twice daily Formoterol

Oxis

Foradile

Twice daily Salmeterol

Serevent Accuhaler

LAMAs* Once daily Glycopyrronium

Seebri Breezhaler

Once daily

Tiotropium

Spiriva

Spiriva Respimat

Once daily

Umeclidinium

Incruse Ellipta

Twice daily Aclidinium

Bretaris Genuair

LABA–LAMA combinations*

Once daily

Indacaterol + glycopyrronium

Ultibro Breezhaler

Once daily

Olodaterol + tiotropium

Spiolto Respimat

Once daily

Vilanterol + umeclidinium

Anoro Ellipta

Twice daily

Formoterol + aclidinium

Brimica Genuair

  • * Ensure that patient is also using regular long-term ICS. LABAs and LAMAs should not be used by people with asthma or asthma–COPD overlap unless they are also taking an ICS, in combination or separately)

# Only the 100/25 mcg dose of fluticasone furoate/vilanterol is TGA-approved for treatment of COPD. The higher dose (200/25 mcg) is not TGA-approved for the treatment of COPD, so it should not be used in people with asthma–COPD overlap.

High doses of ICS (alone or in combination) are not recommended in patients with COPD and should therefore be used with caution in patients with asthma-COPD overlap, because of the risk of pneumonia.

Refer to PBS status before prescribing.

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Omalizumab

Omalizumab is a treatment option for some adults and children aged 6 years and over with severe allergic asthma.1 Omalizumab is given by subcutaneous injection every 2-4 weeks, with the dose based on the patient's weight and baseline total serum IgE level.

Omalizumab is approved by the Therapeutic Goods Administration for use in:2

  • adults and adolescents aged 12 years and over with moderate-to-severe allergic asthma that is not controlled while taking inhaled corticosteroid and who have raised IgE levels.
  • children aged 6 to 11 years with severe allergic asthma who have documented exacerbations despite daily high-dose inhaled corticosteroids and who have raised IgE levels.

For PBS-subsidised treatment with omalizumab, patients must meet several additional criteria (see Note).

When given in addition to inhaled corticosteroids in double-blind randomised placebo-controlled trials, omalizumab reduced rates of asthma flare-ups and hospitalisation in patients with moderate or severe allergic asthma.3 In non-blinded studies in patients with severe allergic asthma, omalizumab improved lung function and asthma control, reduced symptoms, severe flare-ups, work or school days lost due to severe flare-ups, and hospitalisations, and improved quality of life.4

Omalizumab treatment is generally well tolerated. The most common adverse events are injection site reactions and, in children aged 6-11 years, pyrexia, upper gastrointestinal pain and headache.2 Anaphylactoid reactions have been reported, including among Australian patients.5 Early reports suggested that omalizumab may be associated with an increased risk of malignancy. However, subsequent pooled results indicate that a causal relationship between omalizumab therapy and malignancy is unlikely.6, 2

Note: Omalizumab treatment in adults and adolescents is subsidised through the PBS for use in patients with severe allergic asthma who meet certain criteria, including monitoring for at least 12 months by a specialist (respiratory physician, clinical immunologist, allergist or general physician) experienced in the management of patients with severe asthma. PBS criteria for continuation of treatment include demonstration of a therapeutic response by recording asthma symptom control, at baseline and after 6 months of treatment, using the 5-item Asthma Control Questionnaire (ACQ-5).

Omalizumab treatment for children aged 6 to 11 years is subsidised through the PBS for use in patients with severe allergic asthma who meet certain criteria, including monitoring for at least 6 months by a specialist (paediatric respiratory physician, clinical immunologist, or paediatrician or general physician experienced in the management of patients with severe asthma, in consultation with a respiratory physician). PBS criteria for continuation of treatment include demonstration of a therapeutic response by recording asthma symptom control, at baseline and after 6 months of treatment, using either the ACQ-5 or Asthma Control Questionnaire interviewer administered version (ACQ-IA), or reduction in time-adjusted exacerbation rates compared with the 12 months before treatment.

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Mepolizumab

Mepolizumab is a biological humanised anti-interleukin-5 (IL-5) monoclonal antibody (human IgG1) which reduces the number of eosinophils in sputum and blood. It is indicated for add-on treatment of severe refractory eosinophilic asthma in patients aged 12 years or over and is administered by subcutaneous injection once every 4 weeks.7

In people with severe eosinophilic asthma, mepolizumab treatment has been shown to reduce the rate of asthma flare-ups, improve health-related quality of life, and reduce the need for systemic corticosteroids.8, 9, 10

Adverse effects include hypersensitivity reactions such as urticaria, angioedema, rash, bronchospasm, hypotension. These generally occur within hours of administration, but reactions up to days after administration have been recorded.7 No cases of anaphylaxis were recorded in a 52-week open-label study of subcutaneous mepolizumab, conducted among patients who had participated in two randomised controlled trials.11

Note: Mepolizumab treatment in adults and adolescents is subsidised through the PBS for use in patients with severe allergic asthma who meet certain criteria, including treatment by a specialist (respiratory physician, clinical immunologist, allergist or general physician) experienced in the management of patients with severe asthma. PBS criteria for continuation of treatment include demonstration of a therapeutic response by recording asthma symptom control, at base line and after 6 months of treatment, using the 5-item Asthma Control Questionnaire (ACQ-5).

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Ipratropium for children

Cochrane systematic reviews concluded that, overall, clinical trial evidence does not support the regular use of muscarinic antagonists (anticholinergic bronchodilators) in the maintenance treatment of asthma in children (i.e. outside the context of acute asthma).12

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Ipratropium for adults

Regular ipratropium bromide in addition to as-needed short-acting beta2 agonist does not appear to provide clinically significant benefit over as-needed short-acting beta2 agonists alone.13

Note: Ipratropium bromide may be used in the management of severe acute asthma.

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Tiotropium for adults

A meta-analysis of 13 randomised placebo-controlled clinical trials in patients with asthma found that tiotropium as an add-on in patients taking inhaled corticosteroids improved lung function, reduced the rate of flare-ups, and improved asthma symptom control.14 In patients with poorly controlled asthma despite treatment with medium-to-high doses of inhaled corticosteroids, tiotropium was not inferior to salmeterol.14

In patients taking a combination of an inhaled corticosteroid and salmeterol, the addition of tiotropium increased lung function, reduced the rate of flare-ups, and improved asthma symptom control.14

Tiotropium was well tolerated.14

A Cochrane review that included five double-blind, double-dummy trials found that the addition of tiotropium to inhaled corticosteroid therapy reduced the risk of flare-ups requiring systemic corticosteroids and improved lung function, compared with the same dose of inhaled corticosteroid, in adults not taking a long-acting betaagonist.15

Another Cochrane review concluded that tiotropium in addition to the combination of an inhaled corticosteroid and a long-acting beta2 agonist may have additional benefits over inhaled corticosteroid/long-acting betaagonist alone in reducing the need for rescue oral corticosteroids in adults with severe asthma.16

Note: Tiotropium via mist inhaler is approved by TGA as add-on maintenance bronchodilator treatment in adults currently treated with inhaled corticosteroids ≥800 mcg budesonide/day or equivalent plus a long-acting betaagonist who have had one or more severe asthma exacerbations in the previous year.17 Tiotropium via dry-powder inhaler is approved for the treatment of COPD.18

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Ipratropium in acute asthma

Ipratropium bromide alone is less effective than salbutamol alone in acute asthma.19

Early administration of ipratropium bromide in addition to beta2 agonists may reduce admission rates and improve lung function in children and adults with acute asthma, based on the findings of a systematic review of 32 randomised controlled trials.20

However, ipratropium bromide does not appear to benefit patients with less severe acute asthma (patients with acute asthma assessed as ‘mild’ in randomised controlled trials, e.g. FEV1 >70% predicted).20

Ipratropium bromide may be effective in patients with tolerance to the bronchodilator effect of short-acting beta-agonists caused by beta-receptor down-regulation.21

It is well tolerated in children with acute asthma.19

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Magnesium sulfate in acute asthma

MgSO4 versus beta2 agonists

Clinical trial evidence does not support the use of magnesium sulfate as a substitute for inhaled beta2 agonists.22

Intravenous MgSO4 plus beta2 agonist

In patients with life-threatening acute asthma (FEV1 25–30% predicted) or patients with a poor response to initial bronchodilator treatment, intravenous magnesium sulfate (2 g given as single infusion over 20 minutes) can reduce hospital admission rates.23 However, it may only be effective in patients with more severe acute asthma. In a recent large, well-conducted randomised controlled trial in adults with moderate-to-severe acute asthma treated in an emergency department (excluding those with life-threatening asthma), intravenous magnesium sulfate improved dyspnoea scores but did not reduce hospital admission rates.24

In children, intravenous magnesium sulfate improves lung function and reduces the need for hospital admission.25 Fewer studies have been conducted in children under 6 years.

Intravenous magnesium sulfate is inexpensive and generally well tolerated.2324

Inhaled MgSO4 plus beta2 agonist

Overall, evidence from randomised controlled clinical trials suggests that nebulised magnesium sulfate in addition to beta2 agonist (with or without ipratropium bromide) does not reduce hospital admissions or improve lung function in adults or children, compared with beta2 agonist alone.2224  

However, the results of some clinical trials suggest that the addition of nebulised magnesium sulfate improves lung function in patients with severe acute asthma (FEV1 <50% predicted).22 In a recent large randomised controlled clinical trial in children, nebulised magnesium sulfate was associated with a small improvement in asthma symptom scores at 60 minutes. The effect was greatest in the subgroups of children with more severe acute asthma, and those with a shorter duration of symptoms.26

A recent study showed no benefit in adults for hospitalisation or dyspnoea with add-on nebulised magnesium compared with standard therapy alone, but this study excluded patients with life-threatening acute asthma as defined in this handbook.24

Fewer studies have been conducted in children than in adults.22

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Theophyllines in acute asthma

Aminophylline versus short-acting beta2 agonist

Intravenous aminophylline may be as effective as intravenous short-acting beta2 agonist in the management of acute asthma in adults and children, but is associated with a higher rate of adverse effects including giddiness, nausea and vomiting.27

Aminophylline plus beta2 agonist (adults)

Overall, evidence from randomised clinical trials in adults with acute asthma treated in emergency departments suggests that intravenous aminophylline given in addition to inhaled beta2 agonists does not achieve greater bronchodilation or reduce hospital admissions, compared with inhaled beta2 agonists alone.28 No sub-groups that benefit from intravenous aminophylline have been clearly identified.28 Aminophylline is associated with vomiting and cardiac arrhythmias.28

Theophylline is metabolised mainly by the liver and commonly interacts with other medicines. Its concentration in plasma should be monitored closely in older people or those with comorbid conditions.29

  • Avoid short-acting theophylline for a patient who is already using long-acting theophylline.

Aminophylline plus beta2 agonist (children)

Overall, evidence from randomised clinical trials in children with acute asthma requiring hospital admission suggests that the addition of intravenous aminophylline to beta2-agonists and corticosteroids, with or without muscarinic antagonists (anticholinergic bronchodilators), improves lung function within 6 hours of treatment, but does not appear to improve symptoms or shorten hospital stay.30 Aminophylline is associated with a significant increased risk of vomiting in children.30

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References

  1. Chung, K. F., Wenzel, S. E., Brozek, J. L., et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. The European respiratory journal. 2014; 43: 343-73. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24337046
  2. Novartis Pharmaceuticals Australia Pty Ltd. Product Information: Xolair (omalizumab). Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/
  3. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. **. 2014; : . Available from: https://www.ncbi.nlm.nih.gov/pubmed/24414989
  4. Abraham I, Alhossan A, Lee CS, et al. 'Real-life' effectiveness studies of omalizumab in adult patients with severe allergic asthma: systematic review. **. 2016; : 593-610. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26644231
  5. Gibson PG, Reddel HK, McDonal VM, et al. Effectiveness and response predictors of omalizumab in a severe allergic asthma population with a high prevalence of comorbidities: the Australian Xolair Registry. **. 2016; 46: 1054-1062. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27350385
  6. Busse W, Buhl R, Fernandez Vidaurre C, et al. Omalizumab and the risk of malignancy: results from a pooled analysis. J Allergy Clin Immunol. 2012; 129: 983-9.e6. Available from: http://www.jacionline.org/article/S0091-6749(12)00069-3/fulltext
  7. GlaxoSmithKline Australia Pty, Ltd. Product Information: Nucala (mepolizumab). Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/
  8. Powell, Colin, Milan, Stephen J., Dwan, Kerry, et al. Mepolizumab versus placebo for asthma. **. 2015; : . Available from: http://dx.doi.org/10.1002/14651858.CD010834.pub2
  9. Menzella, F., Lusuardi, M., Montanari, G., et al. Clinical usefulness of mepolizumab in severe eosinophilic asthma. Therapeutics and clinical risk management. 2016; 12: 907-16. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27354806
  10. Bel, E. H., Wenzel, S. E., Thompson, P. J., et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. The New England journal of medicine. 2014; 371: 1189-97. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25199060
  11. Lugogo, N., Domingo, C., Chanez, P., et al. Long-term Efficacy and Safety of Mepolizumab in Patients With Severe Eosinophilic Asthma: A Multi-center, Open-label, Phase IIIb Study. Clinical therapeutics. 2016; 38: 2058-2070.e1. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27553751
  12. McDonald N, Bara A, McKean MC. Anticholinergic therapy for chronic asthma in children over two years of age. Cochrane Database Syst Rev. 2003; Issue 1: CD003535. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003535/full
  13. Westby M, Benson M, Gibson P. Anticholinergic agents for chronic asthma in adults. Cochrane Database Syst Rev. 2004; Issue 3: CD003269. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003269.pub2/full
  14. Rodrigo, G. J., Castro-Rodriguez, J. A.. Tiotropium for the treatment of adolescents with moderate to severe symptomatic asthma: a systematic review with meta-analysis. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2015; 115: 211-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26231467
  15. Anderson, D. E., Kew, K. M., Boyter, A. C.. Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus the same dose of ICS alone for adults with asthma. The Cochrane database of systematic reviews. 2015; : Cd011397. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011397.pub2/full
  16. Kew, K. M., Dahri, K.. Long-acting muscarinic antagonists (LAMA) added to combination long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma. The Cochrane database of systematic reviews. 2016; : Cd011721. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011721.pub2/abstract
  17. Boehringer Ingelheim Pty Limited. Product Information: Spiriva (tiotropium bromide) Respimat. Therapeutic Goods Administration, Canberra, 2016. Available from: https://ebs.tga.gov.au/
  18. Boehringer Ingelheim Pty Limited. Product Information: Spiriva (tiotropium bromide). Therapeutic Goods Administration, Canberra, 2016. Available from: https://ebs.tga.gov.au
  19. Teoh L, Cates CJ, Hurwitz M, et al. Anticholinergic therapy for acute asthma in children. Cochrane Database Syst Rev. 2012; 4: CD003797. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003797.pub2/full
  20. Rodrigo J, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax. 2005; 60: 740-746. Available from: http://thorax.bmj.com/content/60/9/740.full
  21. Haney S, Hancox RJ. Overcoming beta-agonist tolerance: high dose salbutamol and ipratropium bromide. Two randomised controlled trials. Respir Res. 2007; 8: 19. Available from: http://respiratory-research.com/content/8/1/19
  22. Powell C, Dwan K, Milan SJ, et al. Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database Syst Rev. 2012; 12: CD003898. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002308.pub2/full
  23. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA, 2012. Available from: http://www.ginasthma.org
  24. Goodacre S, Cohen J, Bradburn M, et al. Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial): a double-blind, randomised controlled trial. Lancet Respir Med. 2013; 1: 293-300. Available from: http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(13)70070-5/fulltext
  25. Mohammed S, Goodacre S. Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis. Emerg Med J. 2007; 24: 823-830. Available from: http://emj.bmj.com/content/24/12/823.long
  26. Powell C, Kolamunnage-Dona R, Lowe J, et al. MAGNEsium Trial In Children (MAGNETIC): a randomised, placebo-controlled trial and economic evaluation of nebulised magnesium sulphate in acute severe asthma in children. Health Technol Assess. 2013; 17: 1-216. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24144222
  27. Travers AH, Jones AP, Camargo CA, et al. Intravenous beta(2)-agonists versus intravenous aminophylline for acute asthma. Cochrane Database Syst Rev. 2012; 12: CD010256. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010256/full
  28. Nair P, Milan SJ, Rowe BH. Addition of intravenous aminophylline to inhaled beta(2)-agonists in adults with acute asthma. Cochrane Database Syst Rev. 2012; 12: CD002742. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002742.pub2/full
  29. Gupta P, O'Mahony MS. Potential adverse effects of bronchodilators in the treatment of airways obstruction in older people: recommendations for prescribing. Drugs Aging. 2008; 25: 415-43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18447405
  30. Mitra AA, Bassler D, Watts K, et al. Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators. Cochrane Database Syst Rev. 2005; Issue 2: CD001276. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001276.pub2/full