Asthma Management Handbook

Guide to preventers: inhaled corticosteroids

Preventers are used in maintenance treatment to reduce airway inflammation. They include inhaled corticosteroids (beclometasone, budesonide, ciclesonide, fluticasone).

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

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Inhaled corticosteroids for children: efficacy

Role in treatment asthma in children

The effectiveness of ICS in children appears to depend on several factors including the child’s age, which triggers are causing symptoms, wheezing phenotype, tobacco smoke exposure and genotype.1 Overall, inhaled corticosteroids seem to be more effective in older children and those with more severe disease.2

Early introduction of inhaled corticosteroid for children with recurrent wheeze does not prevent airway remodelling, improve long-term lung function or prevent the onset of persistent asthma, according to current evidence from long-term randomised controlled clinical trials in preschool children and school-aged children with intermittent or mild persistent asthma.2

Current evidence does not support planned seasonal use of inhaled corticosteroids in children not taking preventer at other times.3

Children aged 1–5 years

Intermittent wheeze/asthma

In preschool children who only have wheezing episodes with viral respiratory infections, limited available evidence suggests that regular treatment with inhaled corticosteroids does not reduce the risk of hospitalisation, flare-ups that require oral corticosteroid use, or reduce the frequency and duration of acute episodes.14 Inhaled corticosteroid treatment does not reduce these children’s risk of developing persistent wheeze by age 6 years.5

Persistent wheeze/asthma

In preschool children who have episodes of wheezing from time to time, but also cough and wheezes at other times when they do not have a viral cold (e.g. when cries, plays or laughs), regular inhaled corticosteroids are moderately effective in controlling symptoms, though less effective than in older children.5 When wheeze improves markedly during a short treatment trial (e.g. 3 months), it is not possible to tell whether improvement was due to the treatment or spontaneous resolution of symptoms.5 However, this can be clarified by stopping inhaled corticosteroid treatment, monitoring symptoms, and re-starting.

In infants and preschoolers with persistent wheezing or asthma of at least 6 months’ duration, regular treatment with inhaled corticosteroids improves wheezing, asthma symptoms and lung function, and reduces flare-ups.26 

Children aged 6 years and over

Most clinical trials of regular inhaled corticosteroid treatment in children have been conducted among children with asthma symptoms every week or more often (‘persistent asthma’).2 

Beclometasone dipropionate, budesonide, ciclesonide and fluticasone propionate have all been shown to be effective in children. There have been relatively fewer studies of ciclesonide in children,2 but, overall, randomised clinical trials show that it is equally effective as budesonide or fluticasone propionate in improving asthma symptoms and reducing flare-ups.7 In some studies, ciclesonide was associated with less adrenal suppression or height than comparator inhaled corticosteroids.7

In a study of school-aged children with more than 2 days per week with symptoms, night waking more than twice per month due to asthma symptoms, or needing regular preventer, regular low-dose daily inhaled corticosteroid treatment reduced the rate of flare-ups that require treatment with oral corticosteroids, compared with no regular preventer treatment and as-needed short-acting beta2agonist for wheezing episodes.8

In a study of children aged 4–11 years with asthma diagnosed within the previous 2 years and symptoms more than weekly in the previous 3 months, regular preventer was associated with a reduction in serious flare-ups, school absence due to asthma, an increase in symptom-free days, and improved lung function, compared with placebo.9, 10

The Thoracic Society of Australia and New Zealand’s current position statement on the use of inhaled corticosteroids in children2 recommends regular treatment with inhaled corticosteroid:

  • as a first-choice preventer for children with asthma symptoms at least daily or night-time symptoms at least twice per week between flare-ups
  • as an alternative to cromones (nedocromil or sodium cromoglycate) or montelukast in children with any daytime or night-time symptoms between flare-ups, or those with flare-ups every 6 weeks or more.

Doses

In the majority of children, asthma control can be achieved with any of the following initial doses:2

  • budesonide up to 400 microg/day
  • beclometasone (Qvar) up to 200 microg/day
  • ciclesonide up to 160 microg/day
  • fluticasone propionate up to 200 microg/day.

If these doses do not achieve control of symptoms, possible explanations include alternative diagnoses, adherence, incorrect inhaler technique, psychosocial factors and exposure to tobacco smoke or other triggers such as allergens.2

Dose–response studies of inhaled corticosteroids show that the maximal efficacy is generally achieved at a dose equivalent to approximately 200 microg/day fluticasone propionate,2 while the risk of adrenal suppression increases exponentially at doses above 500 microg/day.2 Therefore (based on theoretical equivalents between different agents), upper limits of daily doses for children are:

  • budesonide 800 microg/day
  • beclometasone dipropionate [Qvar] 400 microg/day
  • ciclesonide 320 microg/day
  • fluticasone propionate 500 microg/day.

Higher doses are unlikely to be more effective, and are likely to cause systemic effects.2

Most studies of inhaled corticosteroids in children have used twice-daily dosing.2 Fluticasone propionate is only approved for twice-daily dosing, but the other inhaled corticosteroids are approved for once daily dosing. Ciclesonide is effective when given once daily.2

Note: 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 children

Inhaled corticosteroid

Daily dose (microg)

Low

High

Beclometasone dipropionate

100–200

>200 (maximum 400)

Budesonide

200–400

>400 (maximum 800)

Ciclesonide

80–160

>160 (maximum 320)

Fluticasone propionate

100–200

>200 (maximum 500)

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

‡ Ciclesonide is registered by the TGA for use in children aged 6 and over

Source

van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: 
http://www.thoracic.org.au/clinical-documents/area?command=record&id=14

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Inhaled corticosteroids for children: 0–5 years

In preschool children with episodic (viral) wheeze, limited available evidence suggests that regular treatment with inhaled corticosteroids does not reduce the risk of hospitalisation, flare-ups that require oral corticosteroid use, or reduce the frequency and duration of acute episodes.14 Inhaled corticosteroid treatment does not reduce these children’s risk of developing persistent wheeze by age 6 years.5

Regular treatment with inhaled corticosteroids improves wheezing, asthma symptoms and lung function and reduces flare-ups in infants and preschoolers with persistent (at least 6 months) wheezing or asthma.26 

In preschool children with multiple-trigger wheeze, regular inhaled corticosteroids are moderately effective in controlling symptoms, but less effective than in older children.5 When multiple-trigger wheeze improves markedly during a short treatment trial (e.g. 3 months), it is not possible to tell whether improvement was due to the treatment or natural resolution of symptoms.5

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Inhaled corticosteroids for children: 6 years and over

Most clinical trials of regular inhaled corticosteroid treatment in children have been conducted among children with persistent asthma.2 Beclometasone dipropionate, budesonide, ciclesonide and fluticasone propionate have all been shown to be effective in children. However, there have been relatively fewer studies of ciclesonide (a newer inhaled corticosteroid)2 but, overall, randomised clinical trials show that it is equally effective as budesonide or fluticasone propionate in improving asthma symptoms and reducing flare-ups.7

In school-aged children with mild persistent asthma, regular low-dose daily inhaled corticosteroid treatment reduces the rate of flare-ups that require treatment with oral corticosteroids, compared with no regular treatment and as-needed short-acting beta2 agonist for wheezing episodes.8

The Thoracic Society of Australia and New Zealand’s current position statement on the use of inhaled corticosteroids in children recommends regular treatment with inhaled corticosteroid for school-aged children with moderate-to-severe persistent asthma, or those with frequent intermittent asthma or mild persistent asthma if symptoms are not controlled by a 2- to 4-week treatment trial with a cromone (nedocromil or sodium cromoglycate) or montelukast.2

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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 (microg)
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.11

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.12, 1314,  15, 16, 1718, 192021

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 microg/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). 15, 17, 18
  • 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 microg/day) improved lung function,22 reduced airway hyperresponsiveness and inflammation,2223 and reduced the risk of mild flare-ups.22, 23

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).19 In that study, breaks in the use of inhaled corticosteroid of up to 3 months were associated with increased risk of death.20
  • In adults and adolescents with mild asthma who were not taking inhaled corticosteroids, starting low-dose inhaled corticosteroid (budesonide 200 microg/day) reduced the risk of asthma flare-ups severe enough to require oral corticosteroids, and improved symptom control (evidence from a large clinical trial).16
  • 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 microg/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). 15, 17, 18

Note: PBS status as at March 2019: Fluticasone furoate is not subsidised by the PBS, except in combination with vilanterol.

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Inhaled corticosteroids for children: doses

In the majority of children, asthma control can be achieved with any of the following initial doses:2

  • budesonide 400 microg/day
  • beclometasone (Qvar) 200 microg/day
  • ciclesonide 160 microg/day
  • fluticasone propionate 200 microg/day.

If these doses do not achieve control of symptoms, possible explanations include alternative diagnoses, adherence, incorrect inhaler technique, psychosocial factors and exposure to tobacco smoke or other triggers such as allergens.2

Dose–response studies of inhaled corticosteroids show that the maximal efficacy is generally achieved at a dose equivalent to approximately 200 microg/day fluticasone propionate,2 while the risk of adrenal suppression increases exponentially at doses above 500 microg/day.2 Therefore (based on theoretical equivalents between different agents), upper limits of daily doses for children are:

  • budesonide 800 microg/day
  • beclometasone dipropionate [Qvar] 400 microg/day
  • ciclesonide 320 microg/day
  • fluticasone propionate 500 microg/day.

Higher doses are unlikely to be more effective, and are likely to cause systemic effects.2

Most studies of inhaled corticosteroids in children have used twice-daily dosing.2  Ciclesonide is effective when given once daily.2 The dose of inhaled corticosteroid delivered to the lungs will depend on many factors, including the delivery device, the age of the child, individual variation in inhaler technique, and adherence.2

Note: 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 children

Inhaled corticosteroid

Daily dose (microg)

Low

High

Beclometasone dipropionate

100–200

>200 (maximum 400)

Budesonide

200–400

>400 (maximum 800)

Ciclesonide

80–160

>160 (maximum 320)

Fluticasone propionate

100–200

>200 (maximum 500)

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

‡ Ciclesonide is registered by the TGA for use in children aged 6 and over

Source

van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: 
http://www.thoracic.org.au/clinical-documents/area?command=record&id=14

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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 microg budesonide per day,2425 200 microg HFA beclometasone, 160 microg ciclesonide or 200 microg fluticasone propionate).

On average, higher doses provide relatively little extra benefit, but are associated with a higher risk of adverse effects.26 However, a small proportion of individuals may need a higher dose to achieve asthma control.26, 24, 25

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 microg/day for fluticasone propionate, 400–800 microg/day for budesonide, or 200–400 microg/day beclometasone.27
  • A starting dose higher than 800 microg/day budesonide, 400 microg/day fluticasone propionate, or 400 microg beclometasone does not provide enough clinical benefit over lower doses to warrant routinely starting with high doses.27
  • Starting with a moderate dose of inhaled corticosteroid is as effective as commencing with a high dose and down-titrating.27 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,27 but this may not equate to a clinical benefit.

Meta-analyses2829 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 (microg)
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 children: adverse effects

Local adverse effects

Hoarseness and pharyngeal candidiasis are not commonly reported among preschool children or school-aged children talking inhaled corticosteroids. 5, 2, 30

Topical effects can be reduced by use of spacer devices (which reduce oropharyngeal deposition), and by mouth-rinsing and spitting after use.2 Immediate quick mouth-rinsing removes more residual medicine in the mouth than delayed rinsing.31

There is limited evidence that inhaled asthma medication can affect dental health.2, 32 Mouth rinsing might reduce this risk.

Systemic adverse effects

Systemic effects of inhaled corticosteroids in children depend on the dose, but clinically significant adverse effects are uncommon.2

The use of spacers and mouth rinsing will not reduce systemic effects, but the use of a spacer may increase efficacy so that a lower dose is required.

Growth

Short-term suppression of linear growth has been demonstrated in children taking inhaled corticosteroids.33,34 The effect seems to be maximal during the first year of therapy and only one study has reported an effect in subsequent years of treatment.34 A Cochrane systematic review concluded that regular use of inhaled corticosteroid at low or medium daily doses is associated with a mean reduction of 0.48 cm per year in linear growth velocity and 0.61 cm less gain in height during 1 year of treatment in children with mild to moderate persistent asthma.34

One study of patients who participated in a clinical trial of inhaled corticosteroids as children, reported a reduction in adult height of approximately 1 cm,33, 35, 36, 37 whereas several studies have reported that children taking inhaled corticosteroids attained normal adult height.18, 38, 39

The effect is dose-dependent36,37 and may be more likely in children who begin inhaled corticosteroid treatment before age 10.35

Other factors affect growth in children with asthma. Uncontrolled asthma itself reduces growth and final adult height.40 One study found that inhaled corticosteroid equivalent to budesonide 400 microg/day affected growth less than low socioeconomic status.39

Bone density

Inhaled corticosteroids have not been associated with effects on bone density or fractures in children. 2 However, data from a recent study in Australia suggested asthma itself is associated with increased incidence of fractures in children, independent of medication.41

Given that the total dose of corticosteroids (both inhaled corticosteroids and oral corticosteroids) influences bone health, the aim of asthma management is to maintain symptom control using the lowest inhaled corticosteroid dose required, and to avoid repeated courses of oral corticosteroids.

Adrenal suppression

Biochemical testing in a research setting suggests that hypothalamic–pituitary–adrenal axis suppression may occur in up to two-thirds of children treated with inhaled corticosteroids, and may occur at even low doses.42 The risk is higher among children receiving concomitant intranasal steroids and those with lower body mass index,42 and is influenced by genetics.43

Clinical adrenal insufficiency in children taking inhaled corticosteroids is rare but has been reported, 44, 45, 46 including cases in Australia.46 Most cases have involved children given more than 500 microg per day fluticasone propionate.44

Adrenal suppression is associated with hypoglycaemia, hypotension, weakness, failure to grow, and is potentially fatal. Hypothalamic–pituitary–adrenal axis suppression may not be detected until adrenal crisis is precipitated by physical stress.47

Written information (e.g. a steroid alert card) can be prepared for children receiving long-term high-dose inhaled corticosteroids. Parents/carers can be instructed to present the card if the child ever needs to go to the emergency department (for any reason) or be admitted to hospital. A steroid alert card should state that child has asthma and the inhaled corticosteroid dose. A medical alert bracelet could also be considered.

There are no nationally accepted protocols for routine assessment of adrenal function in primary care because it has not yet been possible to identify precisely which children should be tested, to interpret test results reliably, to identify the appropriate interval for retesting, and because a clinical benefit has not been clearly demonstrated.

Regular monitoring of height might help detect adrenal suppression, based on the findings of a study in which a reduction in linear growth velocity occurred before adrenal suppression.48

Table. Definitions of ICS dose levels in children

Inhaled corticosteroid

Daily dose (microg)

Low

High

Beclometasone dipropionate

100–200

>200 (maximum 400)

Budesonide

200–400

>400 (maximum 800)

Ciclesonide

80–160

>160 (maximum 320)

Fluticasone propionate

100–200

>200 (maximum 500)

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

‡ Ciclesonide is registered by the TGA for use in children aged 6 and over

Source

van Asperen PP, Mellis CM, Sly PD, Robertson C. The role of corticosteroids in the management of childhood asthma. The Thoracic Society of Australia and New Zealand, 2010. Available from: 
http://www.thoracic.org.au/clinical-documents/area?command=record&id=14

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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:49

  • The rate of of dysphonia among patients taking inhaled corticosteroids has been estimated at 5–20%.50 However, higher rates of up to 58% have been reported in some studies.51 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.50

When taking inhaled corticosteroids via pressurised metered-dose inhalers, the use of a spacer reduces the risk of dysphonia and candidiasis.52 Spacers improve delivery of the medicine to the airways.

Quick mouth rinsing immediately after inhaling effectively removes a high proportion of remaining medicine.31 This may reduce the risk of oropharyngeal candidiasis ('thrush').

The incidence of dysphonia and candidiasis is significantly lower with ciclesonide than with equivalent doses of fluticasone propionate.53 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.54

Systemic adverse effects

Cross-sectional population studies have reported lower bone mineral density with long-term use of high doses of inhaled corticosteroid,55 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.56

Cross-sectional studies show a dose–response relationship between inhaled corticosteroid use for asthma or COPD, and risk of cataracts in adults.57

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 microg/day or higher).58

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.59 Mid and high doses are consistently associated with a higher intensity and a higher prevalence of reported adverse effects, after controlling for other factors.59

A high proportion of people with asthma may have misunderstandings and fears about using inhaled corticosteroids,6061 such as fears about weight gain, unwanted muscle development, bone fractures, susceptibility to infections and reduction of efficacy of the medicine over time.60 Most people do not discuss their concerns about inhaled corticosteroid treatment with health professionals.60 Safety concerns are a major reason for poor adherence, particularly general concerns about corticosteroids rather than concerns about specific adverse effects.62

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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,63 and are potentially distributed more widely in the large, intermediate, and small airways.63 Although there are theoretical advantages with fine-particle formulations, including in severe asthma, the clinical implications have not been established.64

Randomised controlled trials comparing ciclesonide with fluticasone propionate in adults and adolescents have observed lower rates of patient-reported side-effects,65 and confirmed dysphonia and oral candidiasis,53 among patients using ciclesonide than among those using fluticasone propionate.

A small randomised controlled trial reported that ciclesonide treatment reduced sputum eosinophil counts in patients with refractory asthma who has previously shown persistent airway eosinophilia despite high-dose inhaled corticosteroids.66 However, this study did not provide any comparison with a higher dose of the patient’s existing inhaled corticosteroid.

Evidence from clinical trials of ciclesonide is limited. There have been no high quality double-blind studies to date, and observational studies have not been properly designed to avoid confounding factors such as prescriber bias.64

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Pneumonia risk with inhaled corticosteroids in patients with COPD

In people with COPD, the risk of pneumonia is increased by the use of regular inhaled corticosteroids.67686970 Most of the available evidence is from patients treated with fluticasone propionate.7071727374, 75 Increased pneumonia rates have also been observed in studies of patients with COPD using fluticasone furoate/vilanterol.76 The higher dose of fluticasone furoate/vilanterol (Breo Ellipta 200/25 microg) is not indicated for patients with COPD.

Increased risk of pneumonia with inhaled corticosteroids has not been established in patients with asthma.76, 77 However, the risk of pneumonia in patients with asthma–COPD overlap is unknown, so caution is advised, particularly if high doses are being considered.

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Inhaled corticosteroids for exercise-induced bronchoconstriction

Inhaled corticosteroids taken regularly long term (4 weeks or more78) are effective in reducing the frequency and severity of exercise-induced bronchoconstriction in 30–60% of people with asthma.79 The degree of protection experienced by individuals ranges from complete to minimal.79

Patients may need to take inhaled corticosteroid for 12 weeks to experience maximal therapeutic effect.79 If exercise-induced symptoms have resolved, the person may no longer need to take a beta2 agonist before exercise.79 However, some patients taking regular inhaled corticosteroids may still need to take short-acting beta2 agonists before exercise.79

Few comparative studies have compared the effectiveness of inhaled corticosteroid with that of other classes of medicines.78

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Inhaled corticosteroids in acute asthma

Inhaled corticosteroid treatment in acute care

Clinical trial evidence does not support the use of inhaled corticosteroids in place of systemic corticosteroid treatment in the treatment of acute asthma.80

Some randomised clinical trials suggest that inhaled corticosteroid treatment may reduce hospital admission rates when given in addition to systemic corticosteroids, but the evidence is conflicting.80 Overall, evidence from randomised clinical trials does not show that inhaled corticosteroid therapy achieves clinically important improvement in lung function or clinical scores when used in acute asthma in addition to systemic corticosteroids.80

Inhaled corticosteroid treatment in post-acute care - short term effects

Current standard follow-up treatment after acute asthma includes a course of systemic corticosteroids, and continuation of inhaled corticosteroids for patients already taking this treatment.

Overall, evidence from short term randomised clinical trials suggests that inhaled corticosteroid treatment, given at discharge from the emergency department after acute asthma, does not provide additional short-term benefit in patients who are also receiving oral corticosteroids.81

Some randomised clinical trials suggest that high-dose inhaled corticosteroid treatment at discharge from the emergency department may be as effective as oral corticosteroids in patients with mild acute asthma, but overall evidence does not support replacing oral corticosteroids with inhaled corticosteroids.81

These clinical trials were designed to assess short term effects of inhaled corticosteroid in managing the current acute asthma episode. This evidence does not suggest that inhaled corticosteroids should be stopped after or during an acute asthma episode.81 Regular inhaled corticosteroid treatment is highly effective for preventing asthma flare-ups, including in patients with a recent asthma hospitalisation. A large case-control study showed that, after hospitalisation for asthma, regular ICS were associated with a 39% reduction in the risk of re-hospitalisation within the following 12 months.82

Rationale for prescribing inhaled corticosteroids at discharge from acute care

Inhaled corticosteroid treatment reduces the frequency and severity of asthma flare-ups, reduces the risk of asthma hospitalisation and rehospitalisation, and reduces the risk of death due to asthma. 19, 83

Regular inhaled corticosteroid treatment is therefore indicated for all adults and older adolescents who have experienced a flare-up within the last 12 months, as well as for those with asthma that is not well controlled (asthma symptoms twice or more during the past month, or waking due to asthma symptoms once or more during the past month).

At the time of discharge from the emergency department or hospital, there is an opportunity to start inhaled corticosteroid treatment and to ensure that the patient's usual GP will review the treatment regiment at the follow-up visit.

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Step-up options in children with asthma that is not controlled by low-dose inhaled corticosteroids

In children whose asthma is inadequately controlled by low-dose inhaled corticosteroids alone (and adherence is good, inhaler technique is correct and diagnosis has been confirmed), treatment options include:

  • increasing the inhaled corticosteroid dose
  • adding montelukast
  • switching to inhaled corticosteroid/long-acting beta2 agonist combination.

Table. Step-up options for children when good asthma control is not achieved with low-dose ICS

Option

TGA-registered indications for add-on therapy

PBS considerations

High-dose ICS

N/A

Subsidised

ICS plus montelukast

2 years and over

2–5 years: not subsidised*

6–14 years: not subsidised unless for exercise-induced bronchoconstriction despite ICS treatment

15 years and over: not subsidised

ICS/long-acting beta2 agonist combination

4 years and over for fluticasone propionate/ salmeterol xinafoate

12 years and over for budesonide/formoterol fumarate dihydrate

Subsidised

  • Advise parents about potential adverse psychiatric effects of montelukast

* Montelukast is not subsidised for use in combination with other preventers or for children who require inhaled corticosteroids.

 Montelukast is subsidised for prevention of exercise-induced asthma if asthma is otherwise well controlled while taking optimal-dose inhaled corticosteroids – it is not otherwise subsidised in combination with inhaled corticosteroids (or inhaled corticosteroid/long-acting beta2 agonist combinations). 

‡ Montelukast is not subsidised for people aged over 15 years.

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In the majority of children with persistent asthma that requires preventive treatment, control can be achieved with one of these options.2

Few studies have been conducted in preschool-aged children. The preferred step-up option for children aged 6–12 years is controversial and guidelines differ in their recommendations.84

Increasing inhaled corticosteroid dose versus adding a long-acting beta2 agonist

In school-aged children with persistent asthma taking regular inhaled corticosteroid, the addition of a long-acting beta2 agonist does not reduce the rate of asthma flare-ups requiring systemic steroids compared with the same or higher doses of inhaled corticosteroid.85, 86 However, the long-acting beta2 agonist–inhaled corticosteroid was superior for improving lung function.85  Growth is reduced in children treated with higher-dose inhaled corticosteroid, compared with those taking same dose plus a long-acting beta2 agonist.85 

Adolescents may benefit more from combination inhaled corticosteroid/long-acting beta2 agonist treatment than children under 12 years. In adolescents with persistent asthma that is not controlled by a low dose of inhaled corticosteroids, the combination of a long-acting beta2 agonist and an inhaled corticosteroid is modestly more effective in reducing the risk of flare-ups requiring oral corticosteroids than a higher dose of inhaled corticosteroids.87

Adding montelukast versus adding a long-acting beta-2 agonist or increasing inhaled corticosteroid dose

Children aged 1–5 years

In one study in children aged 5 years or less with persistent asthma/wheeze requiring preventer treatment, raised blood eosinophil levels and atopy predicted better short-term response to high-dose inhaled corticosteroid than to montelukast.88 However, routine eosinophil counts are currently not recommended to guide treatment in children.

In children aged 1–5 years with asthma/wheeze that is not adequately controlled by low-dose inhaled corticosteroid alone, adding montelukast is preferable to increasing the dose of inhaled corticosteroids when the safety profiles of these options are compared.89 Long-acting beta2 agonists are not recommended for this age group.

  • Montelukast use has been associated with behavioural and/or neuropsychiatric adverse effects.

Note: Montelukast is TGA-approved for children aged 2 years and over.

Children aged 6 years and over

Among children 6 years and over with asthma that is not controlled by low-dose inhaled corticosteroids, the optimal regimen varies between individuals.90 In one study of children selected for high adherence with maintenance treatment, short-term responses varied between individuals: in some children the best response was achieved by adding a long-acting beta2 agonist, in others by adding montelukast, and in others by increasing the dose of inhaled corticosteroid.90

Note: The use of inhaled corticosteroids and long-acting beta2 agonists in separate inhalers is not recommended for either children or adults because of the potential for increased risk due to selective non-adherence to the inhaled corticosteroid.91

Overall, the addition of montelukast to an inhaled corticosteroid does not reduce the need for rescue oral corticosteroids or hospital admission, compared with the same or an increased dose of inhaled corticosteroids, in children aged 6 years and over or adolescents with mild-to-moderate asthma.92

For children aged 6–14 years with persistent asthma and exercise-induced bronchoconstriction, adding montelukast is more effective in protecting against exercise-induced bronchoconstriction than switching to a combination of inhaled corticosteroid and a long-acting beta2 agonist.93 The use of montelukast also avoids beta-receptor tolerance associated with long-acting beta2 agonists, so a short-acting beta2 agonist taken after exercise produces a greater bronchodilator response than it does in children taking regular long-acting beta2 agonist.93

A treatment trial of montelukast for 4–6 weeks is the best option when effects on exercise-induced symptoms and safety are also considered.89

  • Montelukast use has been associated with behavioural and/or neuropsychiatric adverse effects.

See: Investigation and management of exercise-induced bronchoconstriction

 

Genetic influence on effect of long-acting beta2 agonists

Clinical response to long-acting beta2 agonists partly depends on genetics. A beta2receptor genotype  (Arg16 polymorphism in the beta2 receptor gene) pre-disposes children with asthma to down-regulation of the beta2 receptor and increased susceptibility to flare-ups during regular treatment with regular long-acting beta2agonists.94 However, routine genetic testing to tailor asthma therapy is not yet available in clinical practice.

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Managing flare-ups in adults: adjusting inhaled corticosteroid dose

Several randomised clinical trials have assessed whether increasing the inhaled corticosteroid dose is an effective strategy in avoiding the need for oral corticosteroids or acute medical care during flare-ups in adults with asthma taking daily maintenance inhaled corticosteroid or daily maintenance inhaled corticosteroid/long-acting beta2 agonist combination treatment.

There is some evidence that quadrupling the maintenance dose of inhaled corticosteroids,95 or treating with a high dose of inhaled corticosteroids,969798 reduces the severity of asthma flare-ups. For patients taking inhaled corticosteroid/long-acting beta2 agonist combinations, this can be achieved by adding a separate high-dose inhaled corticosteroid inhaler to the patient’s usual maintenance treatment for 7–14 days. This strategy may be useful for patients who experience clinically important side-effects with oral corticosteroids, but may not be suitable for patients who cannot afford the extra medicine or who experience hoarseness with high dose inhaled corticosteroid.

However, overall evidence from randomised clinical trials does not support the use of inhaled corticosteroids as a substitute for oral corticosteroids during most flare-ups in adults:

  • A self-initiated increase (e.g. increasing the dose by a factor of two to five) after asthma worsened did not reduce the overall risk of flare-ups requiring rescue oral corticosteroids in a meta-analysis of randomised controlled clinical trials mainly in adults.99
  • Doubling the dose in response to specific criteria for worsening lung function (with or without worsening asthma symptoms) did not reduce the proportion of people who needed oral corticosteroids.100 However, in two of the three clinical trials that evaluated the efficacy of doubling the dose, patients did not begin taking the higher dose (active or placebo) until approximately one week after asthma began to worsen. Therefore, there is insufficient evidence to judge the effectiveness of doubling the dose of inhaled corticosteroid at the first sign of worsening symptoms.
  • In another clinical trial,95 patients taking a range of inhaled corticosteroid-based regimens at baseline were randomised to one of two treatment strategies when any of the following occurred: when peak expiratory flow rate fell (by 15% or more on 2 consecutive days, or by 30% or more on 1 day), when they believed their asthma was worsening, or they developed a cold. Treatment strategies were (1) increasing the dose of inhaled corticosteroid to four times higher than the maintenance dose, regardless of baseline regimen, or (2) continuing usual dose. Overall, the group randomised to the increased dose strategy did not have a reduced risk of flare-ups that required oral corticosteroid treatment.95 However, fewer than one quarter of patients started the study inhaler. Among those patients who did begin taking the high-dose (or placebo) inhaler due to perceived worsening asthma, quadrupling the dose was associated with a significant (almost halving) reduction in the rate of severe flare-up.95
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Increasing the inhaled corticosteroid dose to control flare-ups in children

In children taking regular inhaled corticosteroid-containing preventers, there is conflicting evidence for whether, and by how much, the dose should be increased when symptoms worsen or at the onset of an acute flare-up.

Overall, current evidence from highly controlled randomised controlled trials does not support increasing the dose of inhaled corticosteroid as part of a self-initiated action plan to manage flare-ups in children younger than 12 years.101

There is some evidence that high doses of inhaled steroids used pre-emptively might be effective in preventing severe acute asthma in children aged under 5 years, based on studies in children not taking regular inhaled corticosteroids.102 However, very high pre-emptive doses affect children’s growth103 and are not recommended.

Recent randomised controlled trials reported a lack of effect with a range of dose increases:

  • A five-fold increase in the inhaled corticosteroid dose at early signs of worsening asthma did not reduce the rate of severe acute asthma in children aged 5–11 years with well-controlled asthma while taking maintenance inhaled corticosteroid treatment (with high adherence).104 This strategy was associated with a small reduction in linear growth.104
  • Dose increases of four or eight times usual inhaled corticosteroid maintenance dose at the onset of an acute flare-up in children aged 2–17 years did not reduce requirement for oral corticosteroids, compared with doubling the dose.105

A Cochrane systematic review101 in children and adults reported that increasing the inhaled corticosteroid dose did not prevent severe flare-ups, regardless of how soon the increase was initiated after the onset of symptoms or the magnitude of the dose increase (doubling versus quadrupling). The results did not differ between children under 15 and adults or older adolescents.101 However, there were too few studies in children to make firm conclusions.

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