Asthma Management Handbook

Managing severe asthma in adults and adolescents: add-on treatments

Recommendations

If an adult with confirmed severe asthma continues to experience frequent symptoms or flare-ups despite optimisation of inhaler technique and adherence, and treatment of comorbidities, a trial of add-on treatment with tiotropium or montelukast can be considered in primary care before referring for specialist assessment for monoclonal antibody therapy.

  • It is preferable to offer specialist referral without delay, because 6 months’ treatment by a specialist (or asthma diagnosis by a multidisciplinary severe asthma clinic team) is required before the patient can become eligible for monoclonal antibody therapy.

Note: The addition of tiotropium to inhaled corticosteroid and long-acting beta2 agonist may benefit some individuals with severe asthma.

There is very little evidence supporting the use of add-on montelukast for severe asthma. Limited evidence supports its use in the management of aspirin-exacerbated respiratory disease.

  • Warn patients about potential neuropsychiatric effects of montelukast.

Refer to PBS listings for adults and adolescents.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to named source(s):

  • Sobieraj et al. 20181

Last reviewed version 2.0

For a patient already using regular treatment with a high dose of an inhaled corticosteroid plus a long-acting beta2 agonist in a fixed-dose combination, consider changing to low-dose budesonide plus formoterol as single maintenance-and-reliever therapy.

Note: Review inhaler technique and adherence before trialling changes to the treatment regimen.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to named source(s):

  • Bousquet et al. 20072
  • Cates et al. 20133
  • Patel et al. 20134
  • Sobieraj et al. 20105

Last reviewed version 2.0

When add-on treatments are indicated, initiate each add-on therapy as a treatment trial. If no improvement in an individual’s asthma after an adequate trial, stop the treatment.

Notes: Adequate duration of a treatment trial depends on the agent. and the relevant clinical outcome. For treatment aimed at improving symptoms and/or lung function, a 3-month trial may be sufficient. For treatment aimed at reducing exacerbations, a trial of 6–12 months may be necessary.

Review inhaler technique and adherence before trialling changes to the treatment regimen.

Table. Steps for conducting a treatment trial

  1. Document baseline lung function.
  2. Document baseline asthma control using a validated standardised tool such as the Asthma Score.
  3. Discuss treatment goals and potential adverse effects with the person.
  4. Run treatment trial for agreed period (e.g. 4–8 weeks, depending on the treatment and clinical circumstances, including urgency).
  5. At an agreed interval, measure asthma control and lung function again and document any adverse effects.
  6. If asthma control has not improved despite correct inhaler technique and good adherence, resume previous treatment and consider referral for specialist consultation.

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How this recommendation was developed

Consensus

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

Last reviewed version 2.0

For a patient already using budesonide plus formoterol as single maintenance-and-reliever therapy, consider add-on options:

  • tiotropium via mist inhaler
  • monoclonal antibody therapy (specialist-only treatment)
  • montelukast.
  • Warn patients about potential neuropsychiatric effects of montelukast

Note: PBS status as at March 2019:

Adults: Tiotropium is subsidised by the PBS when used in combination with maintenance ICS+LABA treatment, for people with ≥ one documented severe exacerbation that required systemic corticosteroids in the previous 12 months despite maintenance treatment with inhaled corticosteroid (equivalent to 800 microg budesonide/day or higher) in combination with a long-acting beta2 agonist, and correct inhaler technique has been assessed, demonstrated and documented.

Adolescents aged up to 17 years: Tiotropium is subsidised by the PBS when used in combination with maintenance ICS+LABA treatment, for patients with severe asthma treated by (or in consultation with) a specialist, with frequent moderate exacerbations or ≥ one documented severe exacerbation that required systemic corticosteroids in the previous 12 months despite maintenance treatment with a medium-to-high dose of inhaled corticosteroid in combination with a long-acting beta2 agonist, and correct inhaler technique has been assessed, demonstrated and documented (see PBS for details).

PBS status as at March 2019: Montelukast treatment is not subsidised by the PBS for people aged 15 years or over. However, generic formulations are available as non-PBS prescriptions at lower cost to patients than in the past.

Note: There is very little evidence supporting the use of add-on montelukast for severe asthma. Limited evidence supports its use in the management of aspirin-exacerbated respiratory disease.

To date, studies of add-on therapies in patients with severe asthma have excluded those taking budesonide-and-formoterol maintenance and reliever therapy.

Review inhaler technique and adherence before trialling changes to the treatment regimen.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to named source(s):

  • Sobieraj et al. 20181
  • Anderson et al. 20156
  • Kew et al. 20167
  • Rodrigo et al. 20158
  • Bleecker et al. 20169
  • FitzGerald et al. 201610
  • Nair et al. 201711
  • Wang et al, 201612
  • Bel et al. 201413
  • Ortega et al. 201414
  • Lai et al. 201515
  • Norman et al. 201316
  • Normansell et al. 201417
  • Abraham et al. 201618
  • Gibson et al. 201619

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In specialist referral clinics, 6–12 months’ treatment with low-dose azithromycin or clarithromycin may be considered for an adult with confirmed moderate or severe asthma that remains poorly controlled despite treatment with a moderate-to-high dose of an inhaled corticosteroid plus a long-acting beta2 agonist.

Note: Macrolides should only be prescribed by specialists with expertise in severe asthma. Consultation with a local infectious diseases expert may be necessary.

Clinical response to macrolides is more likely in patients with a positive bacterial culture on sputum test.

Compared with standard doses for infections, macrolide doses evaluated in studies of long-term asthma treatment are generally lower.

Azithromycin and clarithromycin are not registered by the TGA for the long-term treatment of asthma.

Check PBS listings before prescribing.

  • Before prescribing, rule out atypical mycobacterial infection, refer for hearing test and check ECG for prolonged QT interval
  • Assess risk of toxicity (e.g. ototoxicity, hepatic toxicity, diarrhoea, QTc prolongation), assess potential for drug interactions, counsel patient about potential adverse effects.
  • Monitor treatment-related adverse effects during treatment, including ECG, audiology, liver function tests.
How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to named source(s):

  • Kew et al. 201520
  • Gibson et al. 201721
  • Brusselle et al. 201322

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A trial of maintenance treatment with oral corticosteroids can be considered for an adult or adolescent if asthma remains poorly controlled despite treatment with a high dose of an inhaled corticosteroid plus a long-acting beta2 agonist if both the following apply:

  • Other add-on therapies have been considered and found to be unsuitable, or have been trialled without success.
  • The person is not eligible for monoclonal antibody therapy.

Avoid daily treatment with oral corticosteroids, if possible (e.g. use every second day). Use the lowest effective dose.

  • Risk of reduced bone density should be managed in in patients taking oral corticosteroids (e.g. falls prevention, regular weight-bearing exercise and resistance training, adequate calcium and vitamin D intake, anti-osteoporosis treatment where indicated). Consider yearly DXA.
  • Monitor blood pressure and blood glucose in patients taking systemic corticosteroids
  • Monitor mental health and manage treatment-related adverse effects

Note: Arrange specialist referral for any patient for whom long-term maintenance oral corticosteroids for asthma have been prescribed or are being considered, or who requires frequent short courses of oral corticosteroids for acute asthma.

Bisphosphonates are recommended (and subsided by the PBS) for primary fracture prevention in:

  • patients with glucocorticoid-induced osteoporosis when the T-score is ≤–1.5

  • patients with osteopenia (T score ≤–1.0) treated with ≥7.5 mg prednisolone/day (or equivalent) for 3 months or more.

How this recommendation was developed

Consensus

Based on clinical experience and expert opinion (informed by evidence, where available), with particular reference to named source(s):

  • Buckley et al. 201723
  • RACGP 201724
  • Bell et al. 201225

Last reviewed version 2.0

More information

What is severe asthma?

Definitions

Severe asthma is asthma that remains uncontrolled despite high-dose inhaled corticosteroids plus long-acting beta2 agonist (with correct inhaler technique and good adherence) or maintenance oral corticosteroids, or that requires such treatment to prevent it becoming uncontrolled.26

Severe asthma is sometimes also called ‘severe refractory asthma' or 'severe treatment-resistant asthma'. However, the introduction of monoclonal antibody therapies has demonstrated that significant improvements can be seen in asthma that was previously termed ‘refractory’.

Asthma is considered to be uncontrolled if any of the following are identified:

  • poor symptom control, e.g. during previous 4 weeks any of:
    • symptoms during night or on waking
    • limitation of activities due to asthma
    • daytime symptoms on more than 2 days per week
    • need for short-acting beta2 agonist reliever on more than 2 days per week (not including doses taken prophylactically before exercise).
  • frequent severe flare-ups (e.g. more than one flare-up requiring treatment with oral corticosteroids in the previous year)
  • serious flare-ups (e.g. hospital admission, intensive care unit admission, or mechanical ventilation in the previous year)
  • persistent airflow limitation (e.g. detected by spirometry).

Patients with severe asthma are a subgroup of those with difficult-to-treat asthma. Difficult-to-treat asthma is defined as asthma that remains uncontrolled despite treatment with a high dose of an inhaled corticosteroid combined with a long-acting beta2 agonist.

Not all patients with difficult-to-treat asthma have severe asthma. Difficult-to-treat asthma includes asthma that is uncontrolled due to suboptimal adherence, inappropriate or incorrect use of medicines, environmental triggers or comorbidities. Patients whose asthma control improves rapidly after such problems are corrected are not considered to have severe asthma.26

Prevalence

Severe asthma is uncommon. Less than 4% of adults with asthma have severe asthma.27

Description

Severe asthma appears to be a distinct disease (or group of diseases) with different pathobiology from that of milder forms of asthma. It is rare for mild asthma to progress to severe asthma.28

Severe asthma imposes a high burden of disease due to symptoms, flare-ups, medication-related adverse effects and costs.29, 30

Bronchiectasis, granulomas and other auto-immune disease processes can coexist with severe asthma.28, 31 Aspirin-exacerbated respiratory disease can present as severe asthma.

Patterns of airway inflammation vary among people with severe asthma,32 which suggests that the underlying pathophysiology varies.

Inflammatory patterns identified in adults in research studies include eosinophilic (elevated sputum eosinophil count), neutrophilic (elevated sputum neutrophil count), mixed (elevated sputum eosinophil and neutrophil counts) and paucigranulocytic (sputum eosinophil and neutrophil counts within normal range).33 However, these tests are not routinely available in practice to guide treatment.

Some patients with severe asthma show sustained eosinophilia on blood tests despite good adherence to treatment with high doses of inhaled corticosteroids28, 34

Current research aims to predict which treatments will be most effective in an individual according to the findings of a range clinical investigations (e.g. sputum cell counts, peripheral blood white cell counts, fraction of exhaled nitric oxide [FeNO]) and on other clinical features such as age of asthma onset, relationship of allergies to asthma symptoms or presence of nasal polyposis. Few studies have been conducted to identify severe asthma phenotypes among children with severe asthma.32

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Investigations for severe asthma

Allergy tests

Allergy tests (skin prick testing or specific IgE test) are used to identify sensitisation to potentially avoidable allergens that may be contributing to symptoms. Allergy tests should always be interpreted with consideration of the clinical history.

Specialist investigations before starting monoclonal antibody therapies

The following are required for PBS subsidy for monoclonal antibody therapies:

  • blood eosinophil count within the previous 12 months  – required for benralizumab and mepolizumab
  • total serum IgE level within the previous 12 months – required for omalizumab
  • allergy tests skin prick testing or specific IgE test – required for omalizumab.

Eosinophil count and serum IgE level are arranged by the prescribing specialist. Eosinophil counts may be normal in patients taking oral corticosteroids. The dose is sometimes reduced before repeating the test.35

Other specialist investigations to identify severe asthma phenotype

Sputum eosinophil count may help predict response to benralizumab and mepolizumab therapy, but the optimal cut-off value for this purpose has not been identified.35

Fractional FeNO may help predict response to monoclonal antibody therapies, but the evidence is inconclusive.35

Specialist investigations to investigate severe asthma or rule out other conditions

High-resolution computed tomography of the chest is the most common imaging modality used in the investigation of severe asthma.33 Its main purpose is to exclude alternative diagnoses or comorbid conditions (e.g. bronchiectasis, emphysema, mucus plugging, fibrosis, paralysed hemidiaphragm, idiopathic interstitial pneumonia including eosinophilic pneumonia, allergic bronchopulmonary aspergillosis).

Bronchoscopy may be used to evaluate tissue inflammation and structural abnormalities.29 Its main purpose is to rule out other causes of symptoms.33

Transbronchial biopsy of peripheral airways might help identify specific lesions or diseases (e.g. malignancy, sarcoidosis).33

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Peripheral blood eosinophil count in adults and adolescents

White cell differential count on a peripheral blood sample is not currently recommended routinely in the investigation and management of asthma.

Two studies in severe asthma found that blood eosinophils correlated modestly with sputum eosinophil counts.36, 37 In severe asthma, higher blood eosinophil counts are associated with greater risk of poor symptom control and more frequent exacerbations.38 In patients with severe asthma, peripheral blood eosinophil count is important for predicting response to monoclonal antibody therapy and is a requirement for eligibility for some therapies.

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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.39, 40,  41,  4243, 44 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.45

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:41

  • 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):414647

  • 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.48

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).49 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.

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Tiotropium for adults and adolescents

Tiotropium via mist inhaler (not dry-powder inhaler) is approved by the TGA for add-on maintenance treatment in patients with moderate-to-severe asthma.50

Tiotropium is well tolerated.35, 8

Note: PBS status as at March 2019:

Adults: Tiotropium is subsidised by the PBS for use in combination with a maintenance combination of an inhaled corticosteroid and a long acting beta2 agonist for patients with severe asthma who have had at least one severe flare-up in the previous 12 months that required documented systemic corticosteroids, while receiving optimised asthma therapy with a combination of at least 800 mg budesonide per day or equivalent and a long acting beta2 agonist, and correct inhaler technique has been assessed, demonstrated and documented.

Children and adolescents aged 6–17 years: Tiotropium is subsidised by the PBS for use in combination with a maintenance combination of an inhaled corticosteroid and a long acting beta2 agonist for patients with severe asthma who have had at least one severe flare-up in the previous 12 months that required documented systemic corticosteroids, while receiving optimised asthma therapy with a combination of a medium-to-high dose of an inhaled corticosteroid and a long acting beta2 agonist, and correct inhaler technique has been assessed, demonstrated and documented.

Adults

Tiotropium added to inhaled corticosteroid therapy

A Cochrane review and meta-analysis 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 beta2 agonist.6

Another systematic review and meta-analysis of long-acting muscarinic antagonists (tiotropium or umeclidinium) in patients with poorly controlled asthma despite taking inhaled corticosteroids reported that the addition of a long-acting muscarinic antagonist significantly reduced the risk of an asthma flare-up requiring systemic corticosteroids, or of asthma worsening, compared with placebo.1 There were no significant effects on asthma control, reliever use or quality of life.1 In most included studies participants were adults with a mean age between 30 and 40 years.1

However, there is insufficient evidence overall to support the use of tiotropium as an alternative to a long-acting beta2 agonist as add-on therapy. In contrast, there is a large evidence base supporting the combination of inhaled corticosteroid and long-acting beta2 agonist in adults.

Tiotropium versus long-acting beta2 agonist added to inhaled corticosteroids

Few studies have compared tiotropium with long-acting beta2 agonists as add-on therapy in patients taking inhaled corticosteroids. Direct evidence is mainly limited to studies of less than 6 months’ duration comparing tiotropium with salmeterol. Meta-analysis of these studies showed no significant difference between treatment groups in flare-ups requiring oral corticosteroids, lung function, symptom control or asthma-related quality of life.1

While there is insufficient evidence to support the use of tiotropium as an alternative to a long-acting beta2 agonist as add-on therapy in patients taking an inhaled corticosteroid, it may be a suitable alternative for patients who have experienced adverse effects of long-acting beta2 agonist therapy.

Tiotropium added to the combination of inhaled corticosteroid and long-acting beta2 agonist

The addition of tiotropium bromide via mist inhaler therapy is effective in improving lung function and reducing worsening asthma in adults and adolescents with asthma that is uncontrolled despite taking a combination of inhaled corticosteroid and long-acting beta2 agonist, but does not reduce the rate of severe flare-ups requiring oral corticosteroid.1

A Cochrane review7 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 beta2 agonist alone in reducing the need for oral corticosteroids in adults with severe asthma.

Another systematic review and meta-analysis found that the addition of a long-acting muscarinic antagonist (tiotropium or umeclidinium) to the combination an inhaled corticosteroid and a long-acting beta2 agonist in adults significantly reduced the rate of worsening asthma, but not the rate of severe flare-ups requiring oral corticosteroids, and had no significant effect on other outcomes including lung function or symptom control.1

Adolescents

Tiotropium added to inhaled corticosteroid therapy

A meta-analysis of randomised placebo-controlled clinical trials in adolescents 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.8 In those with poorly controlled asthma despite treatment with medium-to-high doses of inhaled corticosteroids, tiotropium was not inferior to salmeterol.8

Another systematic review and meta-analysis of clinical trials of long-acting muscarinic antagonists in patients with poorly controlled asthma included only two trials evaluating tiotropium in adolescents aged 12–17 years. Tiotropium added to inhaled corticosteroid treatment was associated with numerical improvements in lung function, but this reached significance in comparison with placebo in only one study. Both studies in adolescents reported large placebo effects, which may have been due to improved adherence to inhaled corticosteroids during the trial.1

Tiotropium added to the combination of inhaled corticosteroid and long-acting beta2 agonist

A meta-analysis of randomised placebo-controlled clinical trials in adolescents with asthma reported that, among 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.8

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Monoclonal antibody therapy for severe asthma

Three monoclonal antibody therapies (omalizumab, mepolizumab and benralizumab) are available in Australia for the treatment of patients with severe asthma whose asthma is uncontrolled despite optimised standard treatment including high-dose inhaled corticosteroids and long-acting beta2 agonists.

Table. Monoclonal antibody therapies currently available in Australia for severe asthma

Name Description Indication*

Dosage & route of

administration

Benralizumab (Fasenra)

Anti-IL-5 receptor

Humanised monoclonal antibody directed against IL-5 receptor Rα on surface of eosinophils and basophils

Add-on treatment for uncontrolled severe eosinophilic asthma in adults and adolescents aged ≥ 12 years

Prefilled syringe for SC injection

30 mg SC every 4 weeks for three injections then every 8 weeks
Mepolizumab (Nucala)

Anti-IL-5

Humanised monoclonal antibody directed against IL-5
Add-on treatment for uncontrolled severe eosinophilic asthma in adults and adolescents ≥12 years

Powder for SC injection in a single-use vial

100 mg SC every 4 weeks
Omalizumab (Xolair)

Anti-IgE

Humanised monoclonal antibody directed against IgE

Add-on treatment for uncontrolled severe allergic asthma in adults, adolescents and children aged ≥6 years

Prefilled syringe for SC injection

Dose calculated according to baseline IgE and body weight. Usual dose every 2–4 weeks (larger doses divided in 2 and administered every 2 weeks)

SC: subcutaneous

*Refer to TGA-approved indications and PBS criteria

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Monoclonal antibody therapy reduces the rate of severe flare-ups requiring systemic corticosteroids.[REFERENCE226], 1351, 9, 10, 18, 12, 1417, 16, 52 Many patients also experience improvement in asthma symptoms11, 13, 9, 10, 1814, 52, 53, 19 and quality of life.11, 18, 12, 15 Some studies have also shown a reduction in oral corticosteroid in patients with severe asthma.11, 13, 22, 18, 16, 52

These therapies are generally well tolerated.11, 9, 10, 17, 54 Injection site reactions are among the most common adverse events. Systemic reactions, including anaphylaxis, are rare but can occur.55

Monoclonal antibody therapies are funded by PBS only when prescribed by specialists (respiratory physician, clinical immunologist, allergist or general physician or paediatrician experienced in severe asthma management), for patients attending a public or private hospital, and when patients meet certain general and product-specific criteria. After treatment is initiated by a specialist, ongoing maintenance doses can be administered in primary care, but regular review for continuing PBS-funded treatment must be carried out by the specialist.

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Montelukast for adults: efficacy

In adults and adolescents with asthma that is not controlled by low-dose inhaled corticosteroid, the addition of a leukotriene receptor antagonist is less effective than the addition of a long-acting beta2 agonist in reducing the rate of asthma flare-ups that require treatment with oral corticosteroids.56 The addition of a leukotriene receptor antagonist is also associated with lesser improvement in lung function and quality of life than the addition of a long-acting beta2 agonist.56

Montelukast taken 1 hour before exercise can be used to manage exercise-induced bronchoconstriction, but it is less effective than short-acting beta2 agonists.57

Montelukast may improve lung function, reduce short-acting beta2 bronchodilator use, reduce symptoms, and improve quality of life in patients with aspirin-exacerbated respiratory disease.58

Montelukast is sometimes prescribed as add-on treatment for adults with severe asthma. Current evidence does not support its long-term use unless the patient shows a clear improvement in symptoms during a treatment trial.33

Note: PBS status as at March 2019: Montelukast treatment is not subsidised by the PBS for people aged 15 years or over. Special Authority is available for DVA gold card holders or white card holders with approval for asthma treatments.

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Azithromycin for moderate-to-severe-asthma

Macrolide antibiotics have both anti-inflammatory effects and antimicrobial effects.  Azithromycin and clarithromycin are used in the management of cystic fibrosis,59 bronchiectasis60 and COPD32 to reduce exacerbation rates.

Efficacy in asthma

The role of macrolides in the treatment of severe asthma is uncertain.32, 20 The long-term use of azithromycin in adults with severe asthma may reduce flare-ups and improve symptom control, based on limited evidence.35

An Australian placebo-controlled randomised controlled trial reported that 48 weeks’ treatment with azithromycin 500 mg three times weekly reduced flare-ups and improved quality of life in adults with symptomatic asthma despite treatment with a moderate or high dose of inhaled corticosteroid and long-acting bronchodilator.21 Although long-term macrolide therapy was initially expected to be of most benefit patients with neutrophilic asthma, in this study a significant reduction in exacerbations was seen both in patients with eosinophilic and those with non-eosinophilic asthma. The greatest benefit was in those with positive bacterial culture. The study reported a nonsignificant increase in azithromycin-resistant organisms in sputum of patients treated with azithromycin, compared with placebo, but it was not adequately powered to fully assess this effect.

An earlier 6-month placebo-controlled randomised controlled trial in patients with severe asthma reported that low-dose azithromycin added to inhaled corticosteroids and long-acting beta2 agonist improved quality of life, but did not reduce the rate of severe flare-ups, improve asthma control or improve lung function.22 However, among the subgroup of patients with non-eosinophilic severe asthma, azithromycin significantly reduced the rate of a combined endpoint of either severe flare-ups or lower respiratory tract infections requiring antibiotics.22 Azithromycin was associated with an increased rate of oropharyngeal carriage of macrolide-resistant streptococci.22

Compared with standard doses for infections, macrolide doses evaluated in studies of long-term asthma treatment are generally lower.

The evidence for the use of macrolides in children and adolescents with severe asthma is limited and inconclusive due to a lack of completed trials.35

Safety

Although azithromycin is generally well tolerated, rare adverse effects include QTc prolongation and hearing impairment.61, 21 Patients with either of these problems were excluded from the randomised controlled trials assessing the use of azithromycin in the treatment of moderate-to-severe or severe asthma.22

There are also concerns about the potential for development of resistance. Specialist advice is recommended, including consultation with a local infectious diseases expert, before prescribing macrolides for asthma.

Atypical mycobacterial infections, hearing impairment and prolonged QT interval should be ruled out before prescribing. Treatment-related adverse effects should be monitored by ECG, audiology and liver function tests.

Note: Azithromycin and clarithromycin are not registered by the TGA for the long-term treatment of asthma.

Note: Azithromycin is not subsidised by the PBS for long-term use.

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Oral corticosteroids for severe chronic asthma in adults

In an Australian severe asthma registry study, 24% of patients with severe asthma who had been referred to a severe asthma specialist for assessment were being treated with oral corticosteroids in addition to inhaled corticosteroids and long-acting beta2 agonists.62

Efficacy

Maintenance treatment with oral corticosteroids for severe asthma has not been evaluated in randomised placebo-controlled trials.32

Small randomised trials of intramuscular depot triamcinolone in adults and children with severe asthma, in addition to maintenance or frequent oral corticosteroids, have reported reductions in hospitalisations and emergency department visits, improvement in lung function, and reduced eosinophilic inflammation.32 However, the use of triamcinolone is associated with more adverse effects than other systemic corticosteroids.

Maintenance treatment with oral corticosteroids should be avoided, if possible, because of the high risk of serious adverse effects.63, 64, 65

Monoclonal antibody therapy is one strategy to reduce oral corticosteroid use in adults with severe asthma.11, 13, 22

Other strategies for reducing oral corticosteroid use are being evaluated, such as internet-guided titration based on home monitoring of symptoms and fraction of exhaled nitric oxide (FeNO).66

Safety

Oral corticosteroid use in adults with asthma is associated with serious adverse events including severe infections, peptic ulcers, affective disorders, cataracts, cardiovascular events including acute myocardial infarction and hypertension, diabetes, fractures and osteoporosis.67, 68

Dose–response relationships have been demonstrated for these adverse effects.67, 68

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Home Medicines Review and MedsCheck

Home Medicines Review

A Home Medicines Review involves the patient, their GP, an accredited pharmacist and a community pharmacy. Referral (Medicare Item 900) may be either direct to an accredited pharmacist, or to a community pharmacy that uses the services of an accredited pharmacist.

The accredited pharmacist visits the patient at their home, reviews their medicine regimen and provides a report to the person’s GP and usual community pharmacy. The GP and patient then agree on a medication management plan.

The aims of Home Medicines Review include detecting and overcoming any problems with the person’s medicines regimen, and improving the patient’s knowledge and understanding of their medicines.

Patients could be eligible for a Home Medicines Review if they (any of):

  • take more than 12 doses of medicine per day
  • have difficulty managing their own medicines because of literacy or language difficulties, or impaired eyesight
  • visit multiple specialists
  • have been discharged from hospital in the previous four weeks
  • have changed their medicines regimen during the past 3 months
  • have experienced a change in their medical condition or abilities
  • are not showing improvement in their condition despite treatment
  • have problems managing their delivery device
  • have problems taking medicines because of confusion, limited dexterity or poor eyesight.

MedsCheck

MedsCheck involves review of a patient’s medicines by a registered pharmacist within the pharmacy.

Patients are eligible if they take multiple medicines, and they do not need a referral from a GP.

The pharmacist makes a list of all the person’s medicines and medication or monitoring devices, and discusses them with the patient to identify any problems. If necessary, the pharmacist refers any issues back to the person’s GP or other health professional.

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References

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