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Efficacy and Safety of Combination ICS/LABAs in Single Inhaler Devices for Asthma
and budesonide plus formoterol 160/4.5µg two inhalations twice recommend a flexible approach to asthma therapy, where ICS
daily (OR 1.289, 95% confidence interval [CI] 0.981–1.694) after dosage can be increased accordingly in deteriorating asthma
one month of treatment.
20
An open-extension period over six control.
2,3,27
This active management of asthma symptoms has
additional months showed that the total rate of asthma shown similar, if not superior, improvements in asthma control,
28,29
exacerbations over seven months was 0.041/month under fixed- while also presenting a more cost-effective option.
30–33
It may also
dose fluticasone plus salmeterol, which was greater than the rate be the case that fixed-dosage regimens can lead patients to
of 0.036/month with fixed-dose budesonide plus formoterol. After experience occasional under- and over-treatment because of
one month of treatment, patients treated with fixed-dose naturally occurring fluctuations in asthma symptoms. It is worth
budesonide plus formoterol showed significantly greater exploring adjustable dosages in combination therapy and
improvements in forced expiratory volume in one second (FEV
1
) comparing the safety and efficacy of adjustable-dose regimens
compared with those receiving fixed-dose fluticasone plus relative to fixed doses.
salmeterol (0.175 versus 0.125l, 95% CI -0.099 to -0.001; p<0.05);
this advantage with budesonide plus formoterol was maintained Safety
throughout the six-month open-extension period. A study by Aalbers et al. reported similar rates of adverse events in
each fixed-dose treatment group; most were of mild or moderate
The Exacerbation Control Evaluated in a Six-month-long (EXCEL) severity. Although serious adverse events did occur, some of which
study was a double-blind, double-dummy, parallel-group study in were related to asthma, the study investigator did not consider these
which patients were randomised to fixed doses of fluticasone plus events to be causally related to the study drugs.
20
Similarly, Dahl et al.
salmeterol 250/50µg one inhalation twice daily or budesonide plus reported that both combination therapies were similar in incidence
formoterol 200/6µg two inhalations twice daily.
21
The mean rate of and type of adverse effects; the adverse events that occurred were
exacerbations over 24 weeks, the majority of which were mild, was not unexpected in patients diagnosed with moderate to severe
similar in both treatment groups. The prevention of exacerbations asthma. Drug-related adverse events were reported to be <10% in
appeared to have a significant time-dependence, with a 30% both groups, the most common of which were hoarseness/
reduction occurring in weeks nine to 16 (95% CI 24–36%; p<0.001) dysphonia (fluticasone plus salmeterol 2%, budesonide plus
and a 36% reduction in weeks 17–24 (95% CI 30–42%; p<0.001) formoterol 2%), candidiasis (fluticasone plus salmeterol 2%,
compared with the initial eight weeks. An equal proportion of budesonide plus formoterol 1%) and headaches (fluticasone plus
patients achieved a week of well-controlled asthma in each study salmeterol 1%, budesonide plus formoterol 2%).
21
These data are
group (70%). No significant difference was observed between the supported by a Cochrane meta-analysis that found that the
treatments in terms of mean FEV
1
or morning peak expiratory flow frequency of adverse events and study withdrawals was similar
(PEF) over the course of the study. between fixed-dose regimens of fluticasone plus salmeterol and
budesonide plus formoterol.
22
Salmeterol combined with ICS
A recently published Cochrane review supports the similar efficacy decreases the risk of severe exacerbations, does not seem to alter
profiles between fixed-dose regimens of budesonide plus the risk of asthma-related hospitalisations and may not alter the risk
formoterol and fluticasone plus salmeterol.
22
The meta-analysis of asthma-related deaths or intubations compared with ICS alone.
34
evaluated data from five studies, including the two mentioned
previously.
20,21,23–25
The studies included in the meta-analysis involved Adjustable Dosing Regimens of Inhaled
patients with chronic asthma treated with fixed-dose regimens of Corticosteroid/Long-acting β
2
-adrenergic
the combination products budesonide plus formoterol and Agonist Combination Preparations
fluticasone plus salmeterol in single inhaler devices for a minimum Several recent randomised, double-blind trials have investigated
of 12 weeks, and efficacy was evaluated based on asthma control, the efficacy of adjustable dosing regimens of ICS plus LABA
safety and lung function.
22
No significant difference was reported combination preparations and have demonstrated the superiority
between fixed-dose regimens of the two preparations in the of adjustable-dose therapy over fixed-dose ICS plus LABA therapy
primary outcome of an exacerbation leading to the administration
of oral steroids or hospital admission. Similarly, there were no
significant differences in lung function as measured by FEV
1
,
International guidelines recommend a
asthma symptoms, use of rescue medication and exacerbations
requiring a visit to the emergency department or hospital
flexible approach to asthma therapy,
admission. The formoterol plus beclometasone formulation was
where inhaled corticosteroid dosage
found to have a similar effect to the budesonide plus formoterol
combination.
26
Therefore, regular maintenance therapy with fixed-
can be increased accordingly in
dose regimens of budesonide plus formoterol or fluticasone plus
deteriorating asthma control.
salmeterol can improve asthma symptoms and lung function while
also reducing the rate of exacerbations in adult patients with
persistent asthma. plus a SABA as relief therapy.
23,35–39
These studies demonstrated that
adjustable dosing regimens with combination budesonide plus
However, there are limitations associated with fixed-dose regimens. formoterol resulted in a longer time to first exacerbation, a
Fixed combinations of a LABA and an ICS lack dosing flexibility, and reduced rate of severe exacerbations and reductions in oral and
this is crucial when viewed in the context of the variable and ICS doses, although some showed similar improvements with
natural fluctuations of asthma control and airway inflammation comparator regimens in terms of symptoms, peak flow rates and
characteristic of the disease. Indeed, international guidelines quality of life.
23,37
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