Asthma Management Handbook

Stepping up treatment in adults

Recommendations

Before considering any increase in dose or addition to treatment regimen (step up), document the person’s current level of asthma control and risk factors. Carefully check (all of):

  • adherence
  • inhaler technique
  • exposure to triggers
  • the possibility that symptoms are due to comorbid or alternative diagnoses (e.g. allergic rhinitis or rhinosinusitis, de-conditioning, obesity, cardiac disease or upper airway dysfunction).

Table. Definition of levels of recent asthma symptom control in adults and adolescents (regardless of current treatment regimen)

Good control

Partial control

Poor control

All of:

  • Daytime symptoms ≤2 days per week
  • Need for reliever ≤2 days per week
  • No limitation of activities
  • No symptoms during night or on waking

One or two of:

  • Daytime symptoms >2 days per week
  • Need for reliever >2 days per week
  • Any limitation of activities
  • Any symptoms during night or on waking

Three or more of:

  • Daytime symptoms >2 days per week
  • Need for reliever >2 days per week
  • Any limitation of activities
  • Any symptoms during night or on waking

† Not including SABA taken prophylactically before exercise. (Record this separately and take into account when assessing management.)

Note: Recent asthma symptom control is based on symptoms over the previous 4 weeks.

Adapted from:

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA, 2012. Available from: http://www.ginasthma.org/

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Table. Risk factors for adverse asthma outcomes in adults and adolescents Opens in a new window Please view and print this figure separately: https://www.asthmahandbook.org.au/table/show/40

Table. Management of risk factors for adverse asthma outcomes in adults

Risk factor

Clinical action †

Any risk factor for flare-ups

Check patient has an appropriate action plan

Carefully check inhaler technique and adherence, and identify any barriers to good adherence

Review frequently (e.g. every 3 months)

Hospitalisation or ED visit for asthma or any asthma flare-up during the previous 12 months

Ask about triggers for flare-ups, and lead time

History of intubation or intensive care unit admission for asthma

Ensure action plan recommends early medical review when asthma worsens

Hospitalisation or ED visit for asthma in the past month

Emphasise importance of maintaining regular ICS use after symptoms improve

Confirm that patient has resumed using SABA only when needed for symptoms

High SABA use (>2 canisters per month)

Check lung function

If SABA use appears to be habitual, investigate causes and consider alternative strategies, e.g. short-term substitution of ipratropium for SABA

Long-term high-dose ICS

Consider gradual reduction of ICS dose if symptoms stable

Monitor regularly (e.g. assessment of bone density, regular eye examinations)

For local side-effects, ensure inhaler technique is appropriate

Poor lung function (even if few symptoms)

Consider 3-month trial of higher ICS dose, then recheck lung function

Consider referral for detailed specialist investigation

Sensitivity to unavoidable allergens (e.g. Alternaria species of common moulds)

Refer for further investigation and management

Exposure to cigarette smoke (smoking or environmental exposure)

Emphasise the importance of avoiding smoke

Provide quitting strategies

Consider increasing ICS dose (higher dose of ICS likely to be necessary to control asthma)

Refer for assessment of asthma–COPD overlap

Difficulty perceiving airflow limitation or the severity of exacerbations

Regular PEF monitoring

Action plan should recommend early review and measurement of lung function

No current written asthma action plan

Provide and explain written asthma action plan

† In addition to actions applicable to all risk factors

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How this recommendation was developed

Consensus

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

If asthma is only partly controlled despite low-dose inhaled corticosteroids, good adherence and correct inhaler technique, consider stepping up to a low dose of an inhaled corticosteroid/long-acting beta2 agonist combination.

Note: TGA-registered fluticasone furoate/vilanterol combinations contain moderate-to-high doses of inhaled corticosteroid (100/25 mcg and 200/25 mcg respectively).

Figure. Stepped approach to adjusting asthma medication in adults Opens in a new window Please view and print this figure separately: https://www.asthmahandbook.org.au/figure/show/31

Table. Guide to selecting and adjusting asthma medication for adults and older adolescents

Clinical situation

Action

Newly diagnosed asthma

Consider low-dose ICS (plus SABA as needed)

If symptoms severe at initial presentation, consider one of:

  • ICS plus a short course of oral corticosteroids
  • a short initial period of high-dose ICS then step down
  • (private prescription) combination ICS/LABA

See: Table. Initial treatment choices (adults and adolescents not already using a preventer) 

Good recent asthma symptom control

If maintained 2–3 months, no flare-up in previous 12 months and low risk for flare-ups, step down where possible (unless already on low-dose ICS)

Partial recent asthma symptom control

Review inhaler technique and adherence – correct if suboptimal

If no improvement, consider increasing treatment by one step and reviewing (if still no improvement, return to previous step, review diagnosis and consider referral)

Poor recent asthma symptom control

Review inhaler technique and adherence – correct if suboptimal

Confirm that symptoms are likely to be due to asthma

Consider increasing treatment until good asthma control is achieved, then step down again when possible

Difficult-to-treat
asthma ‡

Consider referral for assessment or add-on options

Patient with risk
factors §
 

Tailor treatment to reduce individual risk factors

† PBS status as at October 2016: ICS/LABA combination therapy as first-line preventer treatment is not subsidised by the PBS, except for patients with frequent symptoms while taking oral corticosteroids.

‡ Poor recent asthma symptom control despite ICS/LABA combination at high–medium dose with good adherence and inhaler technique.

§ Risk factors for asthma events or adverse treatment effects, irrespective of level of recent asthma symptom control.

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How this recommendation was developed

Consensus

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

  • Sin et al. 20041
  • Ducharme et al. 20102
  • Ducharme et al. 20103
  • Ducharme et al. 20114
  • Gibson et al. 20055

The combination of budesonide/formoterol can be used as maintenance-and-reliever treatment.

For patients using the maintenance-and-reliever regimen, prescribe a standard initial maintenance dose of (any of):

  • 100/6 mcg dry-powder inhaler – two actuations twice daily
  • 200/6 mcg dry-powder inhaler – one or two actuations twice daily
  • 50/3 mcg pressurised metered-dose inhaler – two or four actuations twice daily
  • 100/3 mcg pressurised metered-dose inhaler – two or four actuations twice daily.

Instruct the patient to take extra as-needed doses for relief of symptoms (1 extra actuation for dry-powder inhalers or 2 actuations for pressurised metered-dose inhalers, repeated after several minutes if symptoms persist, up to a maximum of 72 mcg formoterol per day in total).

Note: The following formulations should not be used in maintenance-and-reliever regimens:

  • 400/12 mcg dry-powder inhaler
  • 200/6 mcg pressurised metered-dose inhaler.
How this recommendation was developed

Consensus

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

  • Aubier et al. 20116
  • Aubier et al. 20107
  • AstraZeneca Pty Ltd 20108
  • AstraZeneca Pty Ltd 20129 
  • Bateman et al. 201010
  • Bousquet et al. 200711
  • Demoly et al. 200912
  • Lundborg et al. 200613
  • Kuna et al. 200714
  • Patel et al. 201315
  • Reddel et al. 201116
  • Taylor et al. 200817
  • Vogelmeier et al. 200518

For most patients, high doses of inhaled corticosteroids should be used for short periods only. If a patient seems to need prolonged high-dose inhaled corticosteroids to control asthma, refer to a specialist for assessment.

Table. Definitions of ICS dose levels in adults

Inhaled corticosteroid Daily dose (mcg)
Low Medium High
Beclometasone dipropionate † 100–200 250–400 >400
Budesonide 200–400 500–800 >800
Ciclesonide 80–160 240–320 >320
Fluticasone furoate* 100 200
Fluticasone propionate 100–200 250–500 >500

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate).

*Fluticasone furoate is not available as a low dose. TGA-registered formulations of fluticasone furoate contain a medium or high dose of fluticasone furoate and should only be prescribed as one inhalation once daily.

Note: The potency of generic formulations may differ from that of original formulations. Check TGA-approved product information for details.

Sources

Respiratory Expert Group, Therapeutic Guidelines Limited. Therapeutic Guidelines: Respiratory, Version 4. Therapeutic Guidelines Limited, Melbourne, 2009.

GlaxoSmithKline Australia Pty Ltd. Product Information: Breo (fluticasone furoate; vilanterol) Ellipta. Therapeutic Goods Administration, Canberra, 2014. Available from: https://www.ebs.tga.gov.au/

GlaxoSmithKline Australia Pty Ltd. Product Information: Arnuity (fluticasone furoate) Ellipta. Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/

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How this recommendation was developed

Consensus

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

If a patient taking maintenance preventer treatment has been using frequent short-acting beta2 agonist reliever for a prolonged period (e.g. 6–8 puffs per day for several weeks), and common causes of poor asthma control have been investigated and ruled out, consider referral to a respiratory physician.

How this recommendation was developed

Consensus

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

Occasionally, for a person who experiences a predictable seasonal pattern of asthma symptoms and has no asthma symptoms at all during the rest of the year, it may be appropriate to start treatment with inhaled corticosteroids beginning well before the predicted risk period and continuing throughout it.

For example, for patients with asthma who have allergic rhinitis in springtime and are sensitised to ryegrass pollen, but have no asthma symptoms at any other time of the year, consider prescribing an inhaled corticosteroid commencing at least 2 weeks (ideally 6 weeks) before the spring and summer thunderstorm season and discontinuing only after pollen levels decrease (e.g. in Victoria this would involve preventive treatment from 1 September to 31 December).

Note:

This applies to a very small proportion of patients only. Purely seasonal asthma is very rare in Australia. There is no available evidence on the safety of treating adults or adolescents with inhaled corticosteroids for only part of the year.

Refer to ASCIA's Pollen calendar for information on local high-risk periods.

How this recommendation was developed

Consensus

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

More information

Assessing risk factors for adverse asthma outcomes in adults

Predicting poor asthma outcomes

As well as assessing recent asthma symptom control, it is necessary to assess each patient’s risk of future asthma events or adverse treatment effects. (Recent asthma symptom control and risk of adverse events are both components of overall asthma control.)

Table. Risk factors for adverse asthma outcomes in adults and adolescents Opens in a new window Please view and print this figure separately: https://www.asthmahandbook.org.au/table/show/40

Table. Management of risk factors for adverse asthma outcomes in adults

Risk factor

Clinical action †

Any risk factor for flare-ups

Check patient has an appropriate action plan

Carefully check inhaler technique and adherence, and identify any barriers to good adherence

Review frequently (e.g. every 3 months)

Hospitalisation or ED visit for asthma or any asthma flare-up during the previous 12 months

Ask about triggers for flare-ups, and lead time

History of intubation or intensive care unit admission for asthma

Ensure action plan recommends early medical review when asthma worsens

Hospitalisation or ED visit for asthma in the past month

Emphasise importance of maintaining regular ICS use after symptoms improve

Confirm that patient has resumed using SABA only when needed for symptoms

High SABA use (>2 canisters per month)

Check lung function

If SABA use appears to be habitual, investigate causes and consider alternative strategies, e.g. short-term substitution of ipratropium for SABA

Long-term high-dose ICS

Consider gradual reduction of ICS dose if symptoms stable

Monitor regularly (e.g. assessment of bone density, regular eye examinations)

For local side-effects, ensure inhaler technique is appropriate

Poor lung function (even if few symptoms)

Consider 3-month trial of higher ICS dose, then recheck lung function

Consider referral for detailed specialist investigation

Sensitivity to unavoidable allergens (e.g. Alternaria species of common moulds)

Refer for further investigation and management

Exposure to cigarette smoke (smoking or environmental exposure)

Emphasise the importance of avoiding smoke

Provide quitting strategies

Consider increasing ICS dose (higher dose of ICS likely to be necessary to control asthma)

Refer for assessment of asthma–COPD overlap

Difficulty perceiving airflow limitation or the severity of exacerbations

Regular PEF monitoring

Action plan should recommend early review and measurement of lung function

No current written asthma action plan

Provide and explain written asthma action plan

† In addition to actions applicable to all risk factors

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Poor clinical control, as indicated by frequent asthma symptoms and frequent reliever use, is a very strong predictor of the risk of flare-ups in the future. Any asthma flare-up during the previous 12 months indicates higher risk of flare-up over the next 12 months. A history  of artificial ventilation due to acute asthma, and admission to an intensive care unit due to acute asthma have been associated with increased risk of near-fatal asthma,19 but there is not enough evidence to indicate how long this risk may persist over a person’s lifetime. Other risk factors indicate increased probability of future flare-ups or accelerated decline in lung function, independent of the person’s level of recent asthma symptom control. 202122

Other factors may increase a person’s risk of treatment-associated adverse effects. The most important of these are prescription of high dose treatment and frequent courses of oral steroids.

People with risk factors need more frequent asthma review, a carefully tailored written asthma action plan, and close attention to adherence and correct inhaler technique.

Inflammatory markers

Inflammatory markers, such as sputum eosinophil percentage or exhaled nitric oxide, are used in research and for managing severe asthma in patients attending secondary or tertiary care. Elevated sputum eosinophil levels and, to a lesser extent, elevated exhaled nitric oxide, are associated with increased risk of flare-ups. At present, treatment based on inflammatory markers is not recommended for routine use in primary care.

The value of inflammatory markers is being evaluated:

  • Adjusting asthma treatment by monitoring exhaled nitric oxide does not reduce the rate of flare-ups or improve asthma control in adults and children, compared with adjusting treatment according to clinical symptoms or spirometry, based on a meta-analysis of randomised controlled clinical trials.23 However, many of the studies were not optimally designed to answer this question,24 and some comparator regimens did not match current recommended treatment options.
  • In some studies, asthma treatment algorithms based on monitoring sputum eosinophil counts reduced flare-ups, compared with control-based management.17, 25 However, most studies assessing treatment guided by sputum eosinophilia have been conducted in selected populations in a few research centres, and therefore may not apply to the general community population. Assessment of sputum inflammatory cells is not generally available at present even in secondary care.
  • Limited evidence26 suggests that patients whose symptoms do not match their degree of eosinophilic inflammation may benefit more from treatment monitoring using sputum eosinophil count than other patients.
  • Monitoring inflammatory markers might enable safer down-titration of maintenance inhaled corticosteroid doses.
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Inhaled corticosteroids for adults: overview

Inhaled corticosteroid preventer medicines available in Australia

The following inhaled corticosteroids are registered by the TGA:

  • beclometasone dipropionate (low to high doses available)
  • budesonide (low to high doses available, including in combination with a long-acting beta2 agonist)
  • ciclesonide (low to high doses available)
  • fluticasone furoate (medium to high doses available, including in combination with a long-acting beta2 agonist)
  • fluticasone propionate (low to high doses available, including in combination with a long-acting beta2 agonist)

Table. Definitions of ICS dose levels in adults

Inhaled corticosteroid Daily dose (mcg)
Low Medium High
Beclometasone dipropionate † 100–200 250–400 >400
Budesonide 200–400 500–800 >800
Ciclesonide 80–160 240–320 >320
Fluticasone furoate* 100 200
Fluticasone propionate 100–200 250–500 >500

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate).

*Fluticasone furoate is not available as a low dose. TGA-registered formulations of fluticasone furoate contain a medium or high dose of fluticasone furoate and should only be prescribed as one inhalation once daily.

Note: The potency of generic formulations may differ from that of original formulations. Check TGA-approved product information for details.

Sources

Respiratory Expert Group, Therapeutic Guidelines Limited. Therapeutic Guidelines: Respiratory, Version 4. Therapeutic Guidelines Limited, Melbourne, 2009.

GlaxoSmithKline Australia Pty Ltd. Product Information: Breo (fluticasone furoate; vilanterol) Ellipta. Therapeutic Goods Administration, Canberra, 2014. Available from: https://www.ebs.tga.gov.au/

GlaxoSmithKline Australia Pty Ltd. Product Information: Arnuity (fluticasone furoate) Ellipta. Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/

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Clinical benefits

Inhaled corticosteroids are the most effective preventer medicines for adults.1, 20, 27

Inhaled corticosteroids are effective in reducing asthma symptoms, improving quality of life, improving lung function, decreasing airway hyperresponsiveness, controlling airway inflammation, reducing the frequency and severity of asthma flare-ups, and reducing the risk of death due to asthma.1202829,  30, 31, 3233, 343536

Most adults with asthma benefit from regular inhaled corticosteroid treatment

The current recommendation to initiate inhaled corticosteroid treatment for adults with asthma symptoms twice or more during the past month, or who experience waking due to asthma symptoms once or more during the past month, is based on consideration of clinical trial evidence that even patients with infrequent symptoms benefit from regular use of inhaled corticosteroids:

  • In patients with recent-onset (diagnosis within 2 years) mild asthma (45% with symptoms 2 days/week or less), low-dose inhaled corticosteroid (budesonide 400 mcg/day) reduced the risk of severe flare-ups, increased symptom-free days and lung function, and protected against long-term decline in lung function associated with severe asthma flare-ups (evidence from a 5-year large randomised clinical trial). 30, 32, 33
  • In small clinical trials in adults with symptoms or reliever use twice per week or less, the use of regular inhaled corticosteroids (fluticasone propionate 250 mcg/day) improved lung function,37 reduced airway hyperresponsiveness and inflammation,3738 and reduced the risk of mild flare-ups.37, 38

The current recommendation replaces the previous higher threshold for inhaled corticosteroid treatment (asthma symptoms three times a week or more, or waking at least one night per week with asthma symptoms), which was based on consensus.

Clinical benefits are achieved with low doses

Low doses of inhaled corticosteroids are sufficient to achieve benefits in most patients:

  • Regular use of low-dose inhaled corticosteroids reduced the risk of hospitalisation for acute asthma and death due to asthma (evidence from a large population cohort study).34 In that study, breaks in the use of inhaled corticosteroid of up to 3 months were associated with increased risk of death.35
  • In adults and adolescents with mild asthma who were not taking inhaled corticosteroids, starting low-dose inhaled corticosteroid (budesonide 200 mcg/day) reduced the risk of asthma flare-ups severe enough to require oral corticosteroids, and improved symptom control (evidence from a large clinical trial).31
  • In patients with recent-onset (diagnosis within 2 years) mild asthma (45% with symptoms 2 days/week or less), low-dose inhaled corticosteroid (budesonide 400 mcg/day) reduced the risk of severe flare-ups, increased symptom-free days and lung function, and protected against long-term decline in lung function associated with severe asthma flare-ups (evidence from a 5-year large randomised clinical trial). 30, 32, 33

Note: PBS status as at October 2016: Fluticasone furoate is not subsidised by the PBS, except in combination with vilanterol.

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Inhaled corticosteroids for adults: doses

Most of the benefit of inhaled corticosteroid is achieved with doses at the upper limit of the low-dose range (i.e. equivalent to 400 mcg budesonide per day,3940 200 mcg HFA beclometasone, 160 mcg ciclesonide or 200 mcg fluticasone propionate).

On average, higher doses provide relatively little extra benefit, but are associated with a higher risk of adverse effects.20 However, a small proportion of individuals may need a higher dose to achieve asthma control.20, 39, 40

The recommendation to start inhaled corticosteroid at low dose is based on the following evidence.

A meta-analysis of results from randomised controlled trials comparing different doses of inhaled corticosteroids showed:

  • An effective starting dose is 200–400 mcg/day for fluticasone propionate, 400–800 mcg/day for budesonide, or 200–400 mcg/day beclometasone.41
  • A starting dose higher than 800 mcg/day budesonide, 400 mcg/day fluticasone propionate, or 400 mcg beclometasone does not provide enough clinical benefit over lower doses to warrant routinely starting with high doses.41
  • Starting with a moderate dose of inhaled corticosteroid is as effective as commencing with a high dose and down-titrating.41 Although it may be reasonable to use a high starting dose then reduce the dose, down-titration cannot be ensured in practice (e.g. if the person does not return for planned review).
  • High doses of inhaled corticosteroids may be more effective than a moderate or low dose for controlling airway hyperresponsiveness,41 but this may not equate to a clinical benefit.

Meta-analyses4243 of inhaled corticosteroid safety have shown that the risk of local adverse effects (e.g. hoarseness, oral candidiasis) and the risk of systemic adverse effects (e.g. changes in hypothalamic-pituitary-adrenal function) increase significantly at higher doses. The risk of adrenal suppression should be considered whenever high doses are used (particularly of more potent inhaled corticosteroids), or when the patient uses concomitant medicines that inhibit cytochrome P450 (e.g. ritonavir, erythromycin or ketoconazole).

Notes 

Dose equivalent for beclometasone applies to Qvar CFC-free formulation. Other brands may differ.

Do not use beclometasone dose recommendations from outdated or overseas guidelines based on older formulations containing CFC propellant – doses are different.

Table. Definitions of ICS dose levels in adults

Inhaled corticosteroid Daily dose (mcg)
Low Medium High
Beclometasone dipropionate † 100–200 250–400 >400
Budesonide 200–400 500–800 >800
Ciclesonide 80–160 240–320 >320
Fluticasone furoate* 100 200
Fluticasone propionate 100–200 250–500 >500

† Dose equivalents for Qvar (TGA-registered CFC-free formulation of beclometasone dipropionate).

*Fluticasone furoate is not available as a low dose. TGA-registered formulations of fluticasone furoate contain a medium or high dose of fluticasone furoate and should only be prescribed as one inhalation once daily.

Note: The potency of generic formulations may differ from that of original formulations. Check TGA-approved product information for details.

Sources

Respiratory Expert Group, Therapeutic Guidelines Limited. Therapeutic Guidelines: Respiratory, Version 4. Therapeutic Guidelines Limited, Melbourne, 2009.

GlaxoSmithKline Australia Pty Ltd. Product Information: Breo (fluticasone furoate; vilanterol) Ellipta. Therapeutic Goods Administration, Canberra, 2014. Available from: https://www.ebs.tga.gov.au/

GlaxoSmithKline Australia Pty Ltd. Product Information: Arnuity (fluticasone furoate) Ellipta. Therapeutic Goods Administration, Canberra, 2016. Available from: https://www.ebs.tga.gov.au/

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Inhaled corticosteroids for adults: adverse effects

Local adverse effects

Hoarseness (dysphonia) and candidiasis are the most common local adverse effects of inhaled corticosteroids with both pressurised metered-dose inhalers and dry-powder inhalers:44

  • The rate of of dysphonia among patients taking inhaled corticosteroids has been estimated at 5–20%.45 However, higher rates of up to 58% have been reported in some studies.46 The risk varies with the device used.
  • The rate of oropharyngeal candidiasis among adults using inhaled corticosteroids has been estimated at 5–7%, with positive mouth culture for Candida albicans in approximately 25% of patients. However, higher rates of up to 70% have been reported in some studies. The risk depends on the formulation, dose and dose frequency.45

When taking inhaled corticosteroids via pressurised metered-dose inhalers, the use of a spacer reduces the risk of dysphonia and candidiasis.47 Spacers improve delivery of the medicine to the airways.

Rinsing the mouth with water after inhaling reduces the risk of oropharyngeal candidiasis.47 Quick mouth rinsing immediately after inhaling effectively removes a high proportion of remaining medicine.48

The incidence of dysphonia and candidiasis is significantly lower with ciclesonide than with equivalent doses of fluticasone propionate.49 This may an important consideration for patients who experience dysphonia, particularly for those for whom voice quality is important (e.g. singers, actors, teachers). With ciclesonide, the rate of adverse effects may not differ when taken with or without a spacer.50

Systemic adverse effects

Cross-sectional population studies have reported lower bone mineral density with long-term use of high doses of inhaled corticosteroid,51 but the effect on fracture risk in patients with asthma is unclear.

A meta-analysis of randomised controlled trials in adults older than 40 years with COPD (in which osteoporosis is more common) or asthma found no association between the use of inhaled corticosteroid and fracture risk overall, but found a slight increase in fracture risk among those using high doses.52

Cross-sectional studies show a dose–response relationship between inhaled corticosteroid use for asthma or COPD, and risk of cataracts in adults.53

Long-term inhaled corticosteroid use for asthma or COPD is associated with a small increase in the risk of developing diabetes, and in the risk of diabetes progression. These risks are greatest at higher doses (equivalent to fluticasone propionate 1000 mcg/day or higher).54

The incidence of osteoporosis, cataracts and diabetes increases with age, and these conditions are also more common in smokers and in patients with COPD. Few studies have assessed risk specifically in patients with asthma.

Patients at risk of osteoporosis should be referred for bone density screening, screened for vitamin D and/or calcium deficiency, and provided with advice about maintaining bone health.

Patient concerns about adverse effects

The prevalence of side effects that patients consider troubling increases with increasing dose of inhaled corticosteroids.55 Mid and high doses are consistently associated with a higher intensity and a higher prevalence of reported adverse effects, after controlling for other factors.55

A high proportion of people with asthma may have misunderstandings and fears about using inhaled corticosteroids,5657 such as fears about weight gain, unwanted muscle development, bone fractures, susceptibility to infections and reduction of efficacy of the medicine over time.56 Most people do not discuss their concerns about inhaled corticosteroid treatment with health professionals.56 Safety concerns are a major reason for poor adherence, particularly general concerns about corticosteroids rather than concerns about specific adverse effects.58

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Inhaled corticosteroids for adults and adolescents: particle size

Medicines with small particle size (CFC-free beclometasone [Qvar] and ciclesonide) achieve a greater proportion of medicine deposited in the lungs,59 and are potentially distributed more widely in the large, intermediate, and small airways.59 However, the clinical implications have not been established.

Randomised controlled trials comparing ciclesonide with fluticasone propionate in adults and adolescents have observed lower rates of patient-reported side-effects,60 and confirmed dysphonia and oral candidiasis,49 among patients using ciclesonide than among those using fluticasone propionate.

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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:1

  • 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.1

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.61 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.62 In adults and adolescents already taking inhaled corticosteroids, once-daily fluticasone furoate/vilanterol 100/25 mcg reduced the risk of severe flare-ups (requiring oral corticosteroids or hospitalisation) and improved lung function, compared with fluticasone furoate alone.63 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.64 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,65 and was as effective as fluticasone propionate/salmeterol in adults.66

Long-acting beta2 agonists should not be used without inhaled corticosteroids in the management of asthma.4676869 Long-acting beta2 agonists are well tolerated when given in combination with inhaled corticosteroids.6170

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.

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Inhaled corticosteroid/long-acting beta-2 agonist combinations for adults: stepping up from inhaled corticosteroid alone
  • 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.

Note: Before any step-up in asthma treatment is considered, inhaler technique and adherence should be assessed and corrected.

In adults who experience asthma symptoms when taking inhaled corticosteroids (any dose) the addition of a long-acting beta2 agonist reduces the rate of asthma flare-ups that require treatment with oral corticosteroids, improves lung function, reduces symptoms, and also reduces requirement for short-acting beta2 agonists by a small amount.2

Most adults with asthma that is not controlled by low-dose inhaled corticosteroid alone (despite good adherence and correct inhaler technique) will achieve better asthma control by switching to the combination of an inhaled corticosteroid and a long-acting beta2 agonist.

In adults whose asthma is not well controlled by taking low-dose inhaled corticosteroids:

  • the combination of an inhaled corticosteroid and a long-acting beta2 agonist as maintenance treatment is a little more effective (reducing the rate of asthma flare-ups that require treatment with oral corticosteroids, improving lung function, reducing symptoms and reducing requirement for short-acting beta2 agonists) than a higher dose of inhaled corticosteroids.3
  • the addition of long-acting beta2 agonists is more effective than the addition of leukotriene receptor antagonists in reducing the risk of asthma flare-ups that require treatment with oral corticosteroids.4
  • the combination of low-dose budesonide and formoterol in a maintenance-and-reliever regimen is much more effective in reducing the risk of asthma flare-ups that require treatment with oral corticosteroids than a higher dose of inhaled corticosteroids.71

In adults using moderate-to-high doses of inhaled corticosteroid, the addition of a long-acting beta2 agonist can reduce the inhaled corticosteroid dose requirement.5

The fluticasone furoate/vilanterol combination is suitable only for patients who require a moderate-to-high dose of inhaled corticosteroid in combination with a long-acting beta2 agonist. It should be prescribed only as one inhalation once daily.62 The higher dose of fluticasone furoate/vilanterol (200/25 mcg) should not be used for patients with asthma who also have COPD, because of the increased risk of pneumonia.

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Inhaled corticosteroid/long-acting beta-2 agonist combinations for adults: patients not already taking regular inhaled corticosteroid

Initial treatment with an inhaled corticosteroid/long-acting beta2 agonist combination is not generally recommended for patients who have not already begun taking inhaled corticosteroids.

In patients not taking regular inhaled corticosteroids, starting preventer treatment with a combination of long-acting beta2 agonist and inhaled corticosteroid:72

  • is not more effective in reducing the risk of asthma flare-ups that require treatment with oral corticosteroids than starting with the same dose of inhaled corticosteroid alone. However, starting with combination therapy improves lung function, reduces symptoms and marginally reduces requirement for short-acting beta2 agonists, compared with starting with the same dose of inhaled corticosteroid
  • is less effective in reducing the risk of asthma flare-ups that require treatment with oral corticosteroids than starting with a higher dose of inhaled corticosteroid.

Note: PBS status as at October 2016: ICS/LABA combination therapy as first-line preventer treatment is not subsidised by the PBS, except for patients with frequent symptoms while taking oral corticosteroids.

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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.7, 8,  10,  1113, 17 The following formulations can be used in maintenance-and-reliever regimens:

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

Neither the 400/12 mcg dry-powder inhaler nor the 200/6 mcg 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.73

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:10

  • 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):101516

  • 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.74

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).12 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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Combination budesonide/formoterol maintenance-and-reliever regimen: dosage considerations

Starting dose

When switching from inhaled corticosteroid to budesonide/formoterol combination as maintenance and reliever, it is expected that the maintenance dose of inhaled corticosteroid will be reduced.

Most available evidence is from clinical trials using the dry-powder inhaler combination product:

  • A maintenance dose of 200 budesonide/6 mcg formoterol via dry-powder inhaler (1 actuation) twice daily appears to be equally effective as double this dose, regardless of the person’s previous dose of inhaled corticosteroid.6
  • For patients with poor lung function7 or those whose asthma is not well controlled on regular inhaled corticosteroid or by the combination of an inhaled corticosteroid plus a long-acting beta2 agonist combination via dry-powder inhaler, a starting dose of 200/6 mcg two actuations twice daily may be more effective than lower doses as starting dose.13

For the newer pressurised metered-dose inhaler combination product, an equivalent maintenance dose would be 100 mcg budesonide/3 mcg formoterol (2 actuations twice daily).

For dose instructions:

Corticosteroid exposure

Compared with conventional inhaled corticosteroid/long-acting beta2 agonist maintenance regimens, the use of budesonide/formoterol via pressurised metered-dose inhaler as maintenance and reliever reduces oral corticosteroid requirement, and may either increase, decrease or have a neutral effect on the total dose of inhaled corticosteroid (depending on the regimen).

Most available evidence is from clinical trials using the dry-powder inhaler combination product:

  • In a randomised clinical trial in adults with a recent flare-up, the use of budesonide/formoterol in a maintenance-and-reliever regimen (200 mcg/6 mcg 2 puffs via dry-powder inhaler twice daily maintenance; 200 mcg/6 mcg 1 actuations as needed for relief of symptoms) resulted in higher mean daily exposure to inhaled corticosteroids, but lower exposure to systemic corticosteroids, compared with the use of budesonide/formoterol as maintenance only (200 mcg/6 mcg 2 actuations via dry powder inhaler twice daily).15
  • In a randomised clinical trial in adults and adolescents, a budesonide/formoterol maintenance-and-reliever regimen (200 mcg/6 mcg 2 actuations via dry powder inhaler twice daily plus 200 mcg/6 mcg as needed) and a conventional salmeterol/fluticasone propionate maintenance regimen (50 mcg/250 mcg twice daily) resulted in similar mean daily inhaled corticosteroid doses, while the budesonide/formoterol maintenance-and-reliever regimen significantly reduced severe flare-ups requiring oral corticosteroids.18
  • In another randomised clinical trial in adults and adolescents who had experienced a flare-up within the previous year, a budesonide/formoterol maintenance-and-reliever regimen (200 mcg/6 mcg 2 actuations via dry powder inhaler twice daily plus 200 mcg/6 mcg as needed) resulted in a lower mean dose of inhaled corticosteroid than a conventional maintenance dose of salmeterol/fluticasone propionate 50 mcg/500 mcg twice daily and reduced the rate of flare-ups requiring oral corticosteroids.11
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Beta-2 receptor tolerance

Short-acting beta2 agonists

In laboratory studies, regular use of short-acting beta2 agonists leads to receptor tolerance (down-regulation) to their bronchoprotective and bronchodilator effects.75

In clinical trials, regular use of short-acting beta2 agonists is associated with greater instability of lung function and a higher risk of asthma flare-ups.7677

In clinical practice, frequent use of short-acting beta2-agonists may lead to worsening of asthma symptoms. This may be improved by deliberately reducing short-acting beta2 agonist use and, in some cases, using ipratropium bromide as an alternative reliever medicine medication to allow restoration of beta2-receptor responsiveness.78

Long-acting beta2 agonists

In laboratory studies, regular use of long-acting beta2 agonists results in reduced duration of protection against airway hyperresponsiveness, and prolonged recovery of airway function after short-acting beta2 agonist, which is thought to be due to receptor tolerance (down-regulation) of beta2 receptors in bronchial smooth muscle and mast cells (evidence from laboratory studies).79 These findings have led to concerns about reduced effectiveness of beta2 agonists when needed for preventing exercise-induced bronchoconstriction or reversing acute asthma due to trigger exposure.79 Sensitivity to short-acting beta2 agonists returns to normal within 72 hours of stopping long-acting beta2 agonist treatment.79

However, the clinical effects of beta receptor tolerance in patients taking long-acting beta2 agonists are unclear.80 Clinical trials assessing regular use of long-acting beta2 agonists in combination with inhaled corticosteroids have not reported clinically significant adverse effects attributable to beta receptor tolerance.70 Two Emergency Department studies in patients with acute asthma did not observe increased risk of hospitalisation among those taking salmeterol.8182

The use of budesonide/formoterol as a reliever may result in lower total use of beta2 agonist compared with the use of short-acting beta2 agonist relievers, based on a study in patients taking regular maintenance budesonide/formoterol, which monitored inhaler actuations electonically.15

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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.83

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

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