Guide to preventers: inhaled corticosteroids
Preventers are used in maintenance treatment to reduce airway inflammation. They include inhaled corticosteroids (beclometasone, budesonide, ciclesonide, fluticasone).
- Inhaled corticosteroids for children: overview
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.2Close
- 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.1, 3 Inhaled corticosteroid treatment does not reduce these children’s risk of developing persistent wheeze by age 6 years.4
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.2, 5
In preschool children with multiple-trigger wheeze, regular inhaled corticosteroids are moderately effective in controlling symptoms, but less effective than in older children.4 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.4Close
- 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.6
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.7
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.2Close
- 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)
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.8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19
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). 13, 15, 16
- 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,20 reduced airway hyperresponsiveness and inflammation,20, 21 and reduced the risk of mild flare-ups.20, 21
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).17 In that study, breaks in the use of inhaled corticosteroid of up to 3 months were associated with increased risk of death.18
- 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).14
- 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). 13, 15, 16
Note: PBS status as at October 2016: Fluticasone furoate is not subsidised by the PBS, except in combination with vilanterol.Close
- 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 mcg/day
- beclometasone (Qvar) 200 mcg/day
- ciclesonide 160 mcg/day
- fluticasone propionate 200 mcg/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 mcg/day fluticasone propionate,2 while the risk of adrenal suppression increases exponentially at doses above 500 mcg/day.2 Therefore (based on theoretical equivalents between different agents), upper limits of daily doses for children are:
- budesonide 800 mcg/day
- beclometasone dipropionate [Qvar] 400 mcg/day
- ciclesonide 320 mcg/day
- fluticasone propionate 500 mcg/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.Close
- 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,22, 23 200 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.9 However, a small proportion of individuals may need a higher dose to achieve asthma control.9, 22, 23
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.24
- 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.24
- Starting with a moderate dose of inhaled corticosteroid is as effective as commencing with a high dose and down-titrating.24 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,24 but this may not equate to a clinical benefit.
Meta-analyses25, 26 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).
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.Close
- Inhaled corticosteroids for children: adverse effects
Inhaled corticosteroids, particular dry-powder formulas with pH <5.5, may dissolve tooth enamel in children.2
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.27
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 may increase efficacy so that a lower dose is required.
Short-term suppression of linear growth has been demonstrated in children, but only minimal long-term effects on growth or bone density have been reported.2 Some children may experience delay in the normal pubertal growth spurt due to asthma itself.2 Treatment beginning before puberty is associated with a small (mean approximately 1 cm) reduction in adult height.28
A research study using biochemical testing in a research setting showed 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.29 However, clinically cases are rare.
Cases of symptomatic, clinically significant adrenal insufficiency in children due to inhaled corticosteroid treatment have been reported,30, 31 including cases in Australia.32 Most cases have involved children given more than 500 mcg per day fluticasone propionate.30
The risk of hypothalamic–pituitary–adrenal axis suppression is higher among children receiving concomitant intranasal steroids and those with lower body mass index.29 Risk is lower in obese children.29
There are no nationally accepted protocols for routine assessment of adrenal function 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.Close
- 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:33
- The rate of of dysphonia among patients taking inhaled corticosteroids has been estimated at 5–20%.34 However, higher rates of up to 58% have been reported in some studies.35 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.34
When taking inhaled corticosteroids via pressurised metered-dose inhalers, the use of a spacer reduces the risk of dysphonia and candidiasis.36 Spacers improve delivery of the medicine to the airways.
Rinsing the mouth with water after inhaling reduces the risk of oropharyngeal candidiasis.36 Quick mouth rinsing immediately after inhaling effectively removes a high proportion of remaining medicine.27
The incidence of dysphonia and candidiasis is significantly lower with ciclesonide than with equivalent doses of fluticasone propionate.37 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.38
Systemic adverse effects
Cross-sectional population studies have reported lower bone mineral density with long-term use of high doses of inhaled corticosteroid,39 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.40
Cross-sectional studies show a dose–response relationship between inhaled corticosteroid use for asthma or COPD, and risk of cataracts in adults.41
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).42
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.43 Mid and high doses are consistently associated with a higher intensity and a higher prevalence of reported adverse effects, after controlling for other factors.43
A high proportion of people with asthma may have misunderstandings and fears about using inhaled corticosteroids,44, 45 such as fears about weight gain, unwanted muscle development, bone fractures, susceptibility to infections and reduction of efficacy of the medicine over time.44 Most people do not discuss their concerns about inhaled corticosteroid treatment with health professionals.44 Safety concerns are a major reason for poor adherence, particularly general concerns about corticosteroids rather than concerns about specific adverse effects.46Close
- 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,47 and are potentially distributed more widely in the large, intermediate, and small airways.47 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,48 and confirmed dysphonia and oral candidiasis,37 among patients using ciclesonide than among those using fluticasone propionate.Close
- 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.49, 50, 51, 52 Most of the available evidence is from patients treated with fluticasone propionate.52, 53, 54, 55, 56, 57 Increased pneumonia rates have also been observed in studies of patients with COPD using fluticasone furoate/vilanterol.58 The higher dose of fluticasone furoate/vilanterol (Breo Ellipta 200/25 mcg) is not indicated for patients with COPD.
Increased risk of pneumonia with inhaled corticosteroids has not been established in patients with asthma.58, 59 However, the risk of pneumonia in patients with asthma–COPD overlap is unknown, so caution is advised, particularly if high doses are being considered.Close
- Inhaled corticosteroids for exercise-induced bronchoconstriction
Inhaled corticosteroids taken regularly long term (4 weeks or more60) are effective in reducing the frequency and severity of exercise-induced bronchoconstriction in 30–60% of people with asthma.61 The degree of protection experienced by individuals ranges from complete to minimal.61
Patients may need to take inhaled corticosteroid for 12 weeks to experience maximal therapeutic effect.61 If exercise-induced symptoms have resolved, the person may no longer need to take a beta2 agonist before exercise.61 However, some patients taking regular inhaled corticosteroids may still need to take short-acting beta2 agonists before exercise.61
Few comparative studies have compared the effectiveness of inhaled corticosteroid with that of other classes of medicines.60Close
- 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.62
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.62 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.62
Inhaled corticosteroid treatment in post-acute care
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 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.63
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.63
These clinical trials were designed to assess 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.63 Regular inhaled corticosteroid treatment is effective for preventing future flare-ups.16Close
- 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.
In the majority of children with persistent asthma that requires preventive treatment, control can be achieved with one of these options.2
Increasing inhaled corticosteroid dose versus adding a long-acting beta2 agonist
In children with persistent asthma taking regular inhaled corticosteroid, the addition of long-acting beta2 agonists improves lung function and reduces reliever use, compared with placebo or increasing the dose of inhaled corticosteroid, but does not appear to reduce the rate of asthma flare-ups requiring treatment with oral corticosteroids.64, 65, 66
Overall, evidence from randomised clinical trials suggests that, for children and adolescents (aged 4–18 years) with persistent asthma that is inadequately controlled despite treatment with regular inhaled corticosteroids, increasing the dose of inhaled corticosteroid is equally effective as maintaining the inhaled corticosteroid dose but adding a long-acting beta2 agonist (i.e. switching to long-acting beta2 agonist/inhaled corticosteroid combination therapy) in in reducing the rate of asthma flare-ups that require treatment with systematic corticosteroids.66
Children appear to benefit less from combination inhaled corticosteroid/long-acting beta2 agonist treatment than adolescents. 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.67
Adding montelukast versus adding a long-acting beta2 agonist
There is insufficient evidence from randomised clinical trials to determine, overall, whether adding a long-acting beta2 agonist or adding montelukast is more effective overall in children whose asthma is not controlled by regular inhaled corticosteroids.68
Clinical response to long-acting beta2 agonists partly depends on genetics. A beta2 receptor 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 beta2 agonists.69 However, routine genetic testing to tailor asthma therapy is not yet available in clinical practice.
Among children 6 years and over with asthma that is not controlled by low-dose inhaled corticosteroids, the optimal regimen varies between individuals.70 Responses vary between individuals: best response is achieved in some children by adding a long-acting beta2 agonist, others by adding montelukast, and others by increasing the dose of inhaled corticosteroid or adding montelukast.70
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.71 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.71
Overall, adding montelukast is the best option when effects on exercise-induced symptoms and safety are also considered.72Close
- 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,73 or treating with a high dose of inhaled corticosteroids,74, 75, 76 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.77
- 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.78 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,73 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.73 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.73
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- 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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- Kramer S, Rottier BL, Scholten RJ, Boluyt N. Ciclesonide versus other inhaled corticosteroids for chronic asthma in children. Cochrane Database Syst Rev. 2013; Issue 2: CD010352. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010352/full
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