Asthma

Managing moderate-­to-­severe paediatric

asthma: a scoping review of the efficacy
and safety of fluticasone propionate/
salmeterol
Paulo Marcio Pitrez ‍ ‍,1 Sira Nanthapisal,2 Ana Paula Beltran Moschione Castro,3
Chirag Teli,4 Abhijith P G5

To cite: Pitrez PM, ABSTRACT

Nanthapisal S, Castro APBM, Background Fluticasone propionate/salmeterol xinafoate WHAT IS ALREADY KNOWN ON THIS TOPIC
et al. Managing moderate-­ (FP/SAL) is an inhaled corticosteroid (ICS) and long-­acting ⇒ Fluticasone propionate/salmeterol xinafoate
to-­severe paediatric β2-­agonist (LABA) combination, indicated for the regular (FP/SAL) is indicated for the regular treatment
asthma: a scoping review treatment of children (aged >4 years) with asthma that of children (aged >4 years) with asthma. Clinical
of the efficacy and safety
is inadequately controlled with ICS monotherapy plus as-­ efficacy data are more limited in paediatric pa-
of fluticasone propionate/
salmeterol. BMJ Open Respir
needed short-­acting β2-­agonists, or already adequately tients compared with the adult population.
Res 2023;10:e001706. controlled with ICS/LABA.
Objective Compared with the adult population, fewer WHAT THIS STUDY ADDS
doi:10.1136/
bmjresp-2023-001706 clinical studies have investigated the efficacy of FP/SAL ⇒ We conducted a rigorous literature review of the
in paediatric patients with moderate and moderate-­to-­ efficacy and safety of FP/SAL in the paediatric pop-
► Additional supplemental ulation considering a variety of asthma outcomes
severe asthma. In this review, we synthesise the available
material is published online
evidence for the efficacy and safety of FP/SAL in the including hospitalisation, rescue medication use and
only. To view, please visit the
paediatric population, compared with other available exercise-­induced bronchoconstriction.
journal online (http://​dx.​doi.​
org/​10.​1136/​bmjresp-​2023-​ therapies indicated for asthma in children.
HOW THIS STUDY MIGHT AFFECT RESEARCH,
001706). Eligibility criteria A literature review identified
PRACTICE OR POLICY
randomised controlled trials and observational studies
Received 8 March 2023 of FP/SAL in the paediatric population with moderate-­to-­ ⇒ Our review reinforces FP/SAL as a reliable and safe
Accepted 20 July 2023 severe asthma. alternative to treat asthma in different situations in
Sources of evidence The Medline database was appropriate paediatric patients, providing potential
searched using PubMed (https://pubmed.ncbi.nlm.​ corticosteroid-­sparing effects when used in a step-­
nih.gov/), with no publication date restrictions. Search up strategy.
strategies were developed and refined by authors.
Charting methods Selected articles were screened for
clinical outcome data (exacerbation reduction, nocturnal INTRODUCTION
awakenings, lung function, symptom control, rescue Asthma is a chronic, heterogeneous disease
medication use and safety) and a table of key parameters affecting approximately 262 million people
developed. worldwide,1 characterised by chronic airway
Results Improvements in asthma outcomes with FP/SAL inflammation, bronchoconstriction, and
include reduced risk of asthma-­related emergency department airway hyper-­ responsiveness triggered by
visits and hospitalisations, protection against exercise-­induced allergens and environmental factors.2
asthma and improvements in measures of lung function. Asthma is the most common chronic
Compared with FP monotherapy, greater improvements in disease in the paediatric population,3 and its
measures of lung function and asthma control are reported. In
prevalence is increasing.2 According to the
addition, reduced incidence of exacerbations, hospitalisations
and rescue medication use is observed with FP/SAL compared
European Lung Foundation, approximately
© Author(s) (or their with ICS and leukotriene receptor antagonist therapy. one in three people will be diagnosed with
employer(s)) 2023. Re-­use asthma between the ages of 5 and 80 years,
permitted under CC BY-­NC. No
Furthermore, FP/SAL therapy can reduce exposure to both
commercial re-­use. See rights inhaled and oral corticosteroids. with many patients being diagnosed before
and permissions. Published by Conclusions FP/SAL is a reliable treatment option in the age of 20 years.4
BMJ. patients not achieving control with ICS monotherapy Parents can underestimate their child’s
For numbered affiliations see or a different ICS/LABA combination. Evidence shows asthma severity and overestimate their level of
end of article. that FP/SAL is well tolerated and has a similar safety asthma control.5 In a global survey of parents
profile to FP monotherapy. Thus, FP/SAL provides an of children/adolescents with asthma, 73%
Correspondence to effective option for the management of moderate-­t o-­
Professor Paulo Marcio considered their child’s asthma to be mild or
severe asthma in the paediatric population.
Pitrez; ​ppitrez70@​gmail.​com intermittent, despite 35% reporting severe

Pitrez PM, et al. BMJ Open Respir Res 2023;10:e001706. doi:10.1136/bmjresp-2023-001706   

1
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exacerbations, requiring oral corticosteroids (OCSs) or delivered to a child (aged 4–11 years) from an inhaler
hospitalisation, at least once per year.5 When assessed is 100 µg FP and 50 µg SAL two times per day.11 Adoles-
with the Childhood Asthma Control Test (C-­ACT), 40% cents (aged >12 years) may be prescribed one inhalation
of children/adolescents had scores indicating inadequate of 100, 250 or 500 µg FP two times per day in combina-
control, and 85% had incompletely controlled asthma as tion with 50 µg SAL two times per day.11 FP/SAL can be
defined by the Global Initiative for Asthma (GINA).5 delivered as a pressurised metered-­dose inhaler (pMDI)
Paediatric asthma is one of the top 10 causes of or as a dry powder inhaler (DPI). Licensed dosages may
disability-­adjusted life years in children aged 5–14 years vary between countries.
and has a considerable societal burden.6 High levels of Compared with the adult population, limited clinical
absenteeism from school are reported for children with efficacy data are available for FP/SAL in children with
asthma, inhibiting academic achievement and social moderate and moderate-­ to-­
severe asthma. This review
interaction.6 aims to synthesise the available evidence of efficacy and
Low- and middle-­income countries often carry a higher safety by:
burden of asthma.7 Over half of Latin American coun- ► Identifying publications relating to FP/SAL in
tries have reported a higher prevalence of childhood children and adolescents (aged 4–16 years) with
asthma (>15%) than the USA (9.3%).7 In the Asthma moderate and moderate-­to-­severe asthma.
Insights and Reality in Latin America (AIRLA) Survey ► Discussing the efficacy of FP/SAL as step-­ up treat-
of parents of children with asthma in 11 Latin American ment from ICS monotherapy versus ICS (particularly
countries, 2.6% of children met all GINA criteria for high-­dose ICS), leukotriene receptor antagonists
asthma control, with 68% of children reporting limita- (LTRAs) and other available comparators.
tion in their activities and 58% reporting absence from ► Assessing outcomes including symptom control, exac-
school, due to asthma.8 erbation reduction, lung function, nocturnal awaken-
Paediatric asthma also has substantial economic costs.9 ings and rescue medication use.
The US Medical Expenditure Survey 2007–2013 reported ► Examining evidence relating to the safety and tolera-
total asthma-­related annual healthcare expenditure of bility of FP/SAL.
US$5.92 billion for school-­aged children.9

METHODS
Clinical recommendations: moderate and moderate-to-severe Publications investigating FP/SAL treatment in chil-
paediatric asthma dren and adolescents (aged 4–16 years) with moderate-­
Children and adolescents with mild, moderate and severe to-­severe asthma were reviewed in June 2022. Litera-
asthma are primarily managed with inhaled corticosteroid ture published in the Medline database was searched
(ICS) therapy, based on international treatment recommen- using PubMed (https://pubmed.ncbi.nlm.nih.gov/),
dations.2 For children (aged 6–11 years), the GINA 2022 with no publication date restrictions. Specific search
report recommends adding a long-­acting β2-­agonist (LABA) strings are presented in online supplemental table 1.
to low-­dose or medium-­dose ICS as the step 3/4 controller Reference lists of relevant publications were reviewed
option with as-­needed short-­acting β2-­agonists (SABAs) or, to identify potential studies not found in the database
alternatively, maintenance and reliever therapy (MART) search.
with very low or low-­dose ICS/formoterol (ICS/FORM).2 Publications were screened and selected based on
For adolescents (aged ≥12 years old), GINA proposes two inclusion of:
treatment tracks at step 3/4: ICS/FORM as MART (track ► Information relating to treatment with FP/SAL in
1) or low-/medium-­dose ICS/LABA with as-­needed SABA the paediatric population with moderate-­ to-­
severe
(track 2).2 asthma.
► Data comparing FP/SAL with other comparators. The
Fluticasone propionate/salmeterol xinafoate: maintenance literature search did not exclude any comparators
therapy for paediatric asthma (including other ICS/LABA combinations); however,
Fluticasone propionate (FP) is a synthetic corticos- targeted searches were conducted for comparators of
teroid with glucocorticoid activity. 10 Salmeterol xina- greatest clinical relevance (placebo, high-­dose and
foate (SAL) is a selective LABA with a bronchodilator low-­dose ICS monotherapy, and LTRA).
effect lasting >12 hours. 10 FP/SAL is a fixed-­ d ose Study types were limited to randomised controlled
combination inhalation agent approved for use in trials (RCTs) and observational studies. Publications
children (aged 4–11 years). 11–14 not stratifying results for adult and paediatric popu-
FP/SAL is indicated for the regular treatment of chil- lations were excluded. Studies including patient ages
dren and adolescents (aged ≥4 years) with asthma, where above 4–16 years were not excluded, but only results
use of a combination product is appropriate (ie, asthma for patients aged <18 years were considered. Studies
not adequately controlled with ICS monotherapy and including the off-­ l abel use of FP/SAL were also
as-­needed SABA, or already adequately controlled with excluded. Selected articles were screened for clinical
ICS/LABA).11 In Europe, the licensed dosage of FP/SAL outcome data (exacerbation reduction, nocturnal

2 Pitrez PM, et al. BMJ Open Respir Res 2023;10:e001706. doi:10.1136/bmjresp-2023-001706

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awakenings, lung function, symptom control, rescue improvements in asthma control with FP/SAL versus ICS
medication use and safety). alone in this population.23–25
In the multicentre, double-­ blind VIAPED RCT of
children (aged 4–16 years), FP/SAL (100 µg/50 µg
Patient and public involvement two times per day) gave 8.7% more symptom-­free days
There was no patient or public involvement in this and 8.0% more reliever-­ free days compared with FP
research. monotherapy (200 µg two times per day) over 8 weeks
following a 14-­day run-­in period with FP (100 µg two
RESULTS times per day).26 Another double-­blind RCT of children
Screening identified 18 RCTs (N=11 384) and 4 obser- (aged 4–11 years) with asthma judged as ‘not-­controlled’
vational studies (N=1.1 million) including patients aged for 2/4 weeks of the run-­in period reported that 75%
4–17 years with moderate-­to-­severe asthma. A scoping of patients treated with FP/SAL (100/50 µg) achieved
review of all key outcomes was determined as the best a well-­controlled week by week 4, while 75% of patients
approach for this article. A list of 20 selected studies and in the FP group (200 µg two times per day) achieved a
their key outcomes is presented in online supplemental well-­controlled week by week 6.24 A ‘well-­controlled week’
table 2; 2 studies were not reported here as further anal- was defined as no nocturnal awakenings/exacerbations,
ysis showed that study drugs were used outside of their emergency department (ED) visits or treatment-­related
licensed indications. Although studies of FP/SAL versus adverse events (AEs) and having ≥2 of: symptoms on
any comparators which met the criteria were included, <3 days, SABA use on <3 days and daily morning PEF
the discussion focuses on those comparators of greatest ≥80% predicted.24
clinical relevance (high-­dose and low-­dose ICS mono- Three studies report similar benefits of FP/SAL, FP or
therapy, and LTRA). FP/FORM on asthma symptom/sleep disturbance scores,
SABA use, nocturnal awakenings or asthma control
days.23 24 26 In the paediatric population, significant
Pharmacodynamics and pharmacokinetics: FP/SAL improvements in lung function with ICS/LABA versus
The pharmacokinetic (PK) and pharmacodynamic (PD) ICS monotherapy do not necessarily translate to improve-
profiles of FP and SAL are well established in adults ments in symptoms and exacerbations, in contrast to the
and children.15–17 Negligible oral bioavailability (<1%) adult population23; differences in interpretation of lung
is reported for FP.11 18 19 Inhaled absolute bioavailability function results or unreliable subjective reports from
varies between 5% and 11%.11 FP also has a high relative paediatric patients may contribute to this anomaly.23
glucocorticoid receptor affinity.20
Step-up therapy: FP/SAL versus high-dose ICS and ICS+LTRA
Concurrent therapy versus combination therapy The efficacy of FP/SAL compared with high-­ dose
The PK properties of FP and SAL are similar whether ICS monotherapy is a key consideration for step-­up
they are administered separately or in combination. therapy, as long-­term use of high-­dose ICS has been
No systemic PK/PD interactions exist between the two associated with increased risk of local and systemic
therapies given together.17 21 Data on the PK/PD profile side effects.27 Evidence comparing high-­dose ICS with
of combination FP/SAL are limited in the paediatric ICS/LABA is limited in the paediatric population28;
population. In a randomised study, 257 children (aged however, FP/SAL is reported to have efficacy equal to
4–11 years) with asthma who remained symptomatic or greater than double-­dose FP (200 µg two times per
on ICS alone (beclomethasone dipropionate (BDP), day) in measures of symptom control in children with
budesonide (BUD) or flunisolide 400–500 µg/day, or moderate asthma.24 26 29
FP 200–250 µg/day) received FP/SAL 100/50 µg two For children aged 6–11 years, the stepwise GINA recom-
times per day either in combination or as two inhalers mendations also indicate that ICS+LTRA may be consid-
administered concurrently.22 Adjusted mean morning ered as an alternative controller option to ICS/LABA at
and evening peak expiratory flow (PEF) improved step 3, although evidence supporting this approach is
through 12 weeks using both regimens (by 33 L/min limited.2 It should be noted that LTRAs have been asso-
and 29 L/min for the FP/SAL combination and 28 L/ ciated with neuropsychiatric AEs and LTRA prescription
min and 25 L/min for concurrent therapy) and treat- should consider all benefits and risks, with the provision
ment groups were found to be clinically equivalent.22 of patient counselling.2 30
The most appropriate step-­up therapy for paediatric
patients (aged 6–17 years) with asthma uncontrolled on
Clinical outcomes low-­dose ICS was investigated in a crossover RCT based
Asthma control on a composite of exacerbations, asthma-­ control days
Comparative evidence: FP/SAL versus ICS and forced expiratory volume in 1 s (FEV1).31 While each
Achieving asthma control and reducing symptom burden of the step-­up treatments improved responses, step-­up
and limitation of daily activities are key when managing to FP/SAL 100/50 µg was significantly more likely to
childhood asthma. A small number of studies have shown provide a better response than step-­up of ICS dose to

Pitrez PM, et al. BMJ Open Respir Res 2023;10:e001706. doi:10.1136/bmjresp-2023-001706 3

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FP 250 µg (relative probability, 1.7; 95% CI, 1.2 to 2.4) In another retrospective, observational cohort study of
or step-­up to FP 100 µg+LTRA (relative probability, pharmacy claims, after matching for ICS, OCS and hospi-
1.6; 95% CI, 1.1 to 2.3).31 Although these data support talisation/ED visit history, incidence of asthma-­related
the GINA recommendation for ICS/LABA as preferred hospitalisations and ED visits were significantly lower
step-­up controller medication for children, several char- for children who started FP/SAL (3.5%) than those
acteristics, including race, Asthma Control Test score and who started ICS+LTRA (5.7%) with a 96% lower risk of
presence of eczema may affect the treatment response.31 asthma-­related hospitalisation.36
Many children had a best response to LTRA step-­up,
so regular monitoring and adjustment of each child’s
Rescue medication use
therapy is important before stepping up further.31
FP/SAL is highly effective and clinically equivalent in paedi-
FP/SAL can provide similar benefit to high-­dose FP
atric patients when administered via the DPI Diskus or
while reducing corticosteroid exposure.29 An RCT of 158
pMDI.37 In an RCT of children with asthma aged 4–11 years
children (aged 6–16 years) with moderate asthma, symp-
receiving BDP, BUD, flunisolide (up to 500 µg/day) or FP
tomatic on moderately dosed ICS monotherapy, reported
(up to 200 µg/day), patients who switched to FP/SAL either
the efficacy of FP/SAL (100/50 µg two times per day)
via Diskus or pMDI experienced the same increase in median
as equal to doubling the dose of FP (200 µg two times
percentage of medication-­ free days to 99%, following a
per day) in terms of symptom control.29 Mean-­adjusted
2-­week run-­in with ICS.37
difference in symptom-­free days between FP and FP/SAL
A retrospective, observational study of healthcare claims
over 10 weeks was 0.4% (95% CI, −9.1% to 9.9%) in the
of 9192 children aged 4–17 years found that those treated
intention-­to-­treat analysis, showing negligible difference
with FP, LTRA, ICS+SAL and ICS+LTRA were 14%, 22%,
between treatments and non-­inferiority for FP/SAL.29
32% and 83%, respectively, more likely to fill a prescrip-
Non-­inferiority of FP/SAL (and potential superiority)
tion for SABA therapy compared with those treated with
to double-­dose FP monotherapy has been recognised in
FP/SAL.38 Children treated with FP/SAL were also less
the GINA step 3 recommendations.2 GINA also recom-
likely to receive an additional SABA prescription during
mends low-­dose ICS/FORM as MART in track 1 at step
the post-­index period.38
3/4 for children (aged 6–11 years),2 although evidence
for the efficacy of ICS/FORM as MART versus FP/SAL in
Step-up therapy: FP/SAL versus high-dose ICS
this cohort is lacking.
FP/SAL effectively reduces exacerbation risk and rescue
medication use in paediatric patients versus higher doses
Step-down of FP/SAL
of ICS monotherapy, although the evidence for improve-
Step-­
down of therapy can be considered once good
ment in lung function is limited.24–26 29
asthma control has been achieved, in order to prescribe
In children aged 4–11 years with asthma, previously
the minimum effective treatment while maintaining
treated with ICS (FP 100 µg two times per day for a
symptom and exacerbation control.2 This can minimise
4-­week run-­in period), the proportion achieving 100%
the cost of treatment and risk of potential side effects.2
rescue medication-­free days through week 12 has been
A Japanese RCT demonstrated that in 121 children
reported as 29% (43 of 150) for those randomised to
(aged 5–15 years) with asthma controlled by FP/SAL
FP/SAL (100/50 µg) compared with 19% (29 of 153)
(200 µg per day) for at least 12 weeks, step-­d own of
for those randomised to double-­dose FP monotherapy.24
therapy to halve the dose of FP/SAL to 25/50 µg
In an RCT of 158 children (aged 6–16 years) with
two times per day and/or switching to FP (100 µg
moderate asthma who were symptomatic on moderate
two times per day) resulted in the same high level of
doses of ICS monotherapy during a 4-­ week run-­in
asthma control.32 33
period, the percentage of days with SABA use decreased
from 38% to 22% with FP/SAL (100/50 µg two times
Exacerbations and hospitalisations
per day) treatment. This was not significantly different
Regular dosing with FP/SAL treats underlying inflamma-
to FP (200 µg two times per day) treatment, with which
tion in paediatric asthma, reducing the risk of asthma-­
SABA use decreased from 35% to 20%.29
related ED visits and hospitalisations versus treatment
with ICS monotherapy and LTRA.34–36
A large, retrospective, observational study of healthcare Exercise
claims showed that following treatment with FP/SAL in the Exercise-­induced bronchoconstriction (EIB) is an impor-
summer, the incidence of asthma-­related ED visits in the fall tant consideration for the management of paediatric
was reduced from 5.4% to 3.4% (adjusted OR, 0.60; 95% CI, asthma, because physical activity levels are high among
0.54 to 0.67) and hospitalisations was reduced from 1.3% to children and adolescents,39 and exertion is a major
0.7% (OR, 0.49; 95% CI, 0.39 to 0.61).34 This suggests that precipitating factor for asthma symptoms.40 FP/SAL
administration of FP/SAL throughout the summer prevents produces greater protection from EIB than FP alone and
worsening of asthma in the fall, with an estimated number could be used as a regular controller in children with
needed to treat of 50 to prevent one ED visit and 167 to persistent EIB who are not adequately controlled on ICS
prevent one hospitalisation.34 monotherapy.40 41

4 Pitrez PM, et al. BMJ Open Respir Res 2023;10:e001706. doi:10.1136/bmjresp-2023-001706

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Comparison of lung function following exercise Other lung function endpoints (forced expiratory flow,
challenge was investigated in an RCT of 248 paedi- PEF) showed improvements pre-­dose and 2 hours post-­
atric patients (aged 4–17 years) with persistent dose for FP/SAL versus FP monotherapy.23
asthma, receiving daily ICS before the study, and An RCT of 24 children aged 4–11 years with moderate-­
switched to either FP (100 µg two times per day) or severe asthma demonstrated that lung function improve-
FP/SAL (100/50 µg two times per day) with albuterol ment was superior with FP/SAL (100 µg/50 µg two times
as needed. 40 By week 4, maximal decline in FEV 1 per day) versus high-­dose FP (200 µg two times per day),
following exercise challenge was significantly better measured using specific airway resistance (sRaw), a poten-
with FP/SAL (9.5%) than with FP alone (12.7%); tially more applicable measure than FEV1 or PEF for
64% of the FP/SAL treatment group had a <10% young children. After 6 weeks of treatment, children who
decrease in FEV 1 compared with 47% of the FP treat- were taking daily BDP or equivalent (200–800 µg) and
ment group. 40 Additionally, 14% of patients receiving switched to FP/SAL had a 19% greater reduction in sRaw
FP/SAL had a ≥20% decrease in FEV 1, vs 20% of (95% CI, 3% to 32%) than those switched to higher-­dose
patients receiving FP. 40 FP.25

Corticosteroid ‘bursts’ Step-up therapy: FP/SAL versus high-dose ICS

Sparing corticosteroid exposure in children with asthma Limited evidence is available in paediatric patients
is an important consideration. Adverse drug reactions comparing lung function improvements with FP/SAL
have been reported in children (aged 28 days–18 years) versus higher doses of ICS monotherapy.24–26 29 31 One
following short courses of OCS, with the most frequent RCT directly compared FP/SAL (100/50 µg two times
reactions being vomiting, behavioural changes, sleep per day) with double-­dose FP (200 µg two times per day)
disturbances and increased susceptibility to infection.42 to assess effect on morning PEF over 12 weeks in 321 chil-
OCS bursts in children with mild-­to-­moderate asthma dren (aged 4–11 years) with asthma previously treated
have also been associated with dose-­dependent reduction with ICS (BDP 400 µg/day or equivalent). After demon-
in bone mineral accretion over a period of years, with strating non-­inferiority of FP/SAL to high-­dose FP for
increased risk of osteopenia in boys.43 Attention to corti- mean change in morning PEF, the treatment difference
costeroid exposure should also include high-­dose ICS in between treatment groups of 7.6 L/min (95% CI, 1.7 to
light of concerns about long-­term ICS use in children.27 13.5) showed that FP/SAL was superior to FP.24
Children (aged 4–17 years) treated with FP/SAL are In the VIAPAED Study, FP/SAL was non-­inferior to
significantly less likely (p≤0.009) to have received a high-­dose FP for change from baseline in mean morning
prescription for OCS compared with those receiving PEF after 8 weeks of therapy (p<0.0004).26 In the
LTRA, ICS+SAL and ICS+LTRA.38 FP/SAL can be also intention-­to-­
treat population, mean morning PEF was
prescribed for patients who fail to gain adequate symptom higher with FP/SAL than FP monotherapy (+8.6 L/min;
control while taking ICS, minimising the risk of systemic 95% CI, 1.3–infinity).26
effects from high-­dose ICS and OCS ‘bursts’.44

Lung function Safety

Clinically significant improvements in lung function have Safety studies are especially critical in the paediatric
been observed with FP/SAL treatment in children aged population, to avoid risks to this vulnerable group.45
4–11 years with documented history of asthma receiving Absence of safety data may lead to overdosing and
ICS.37 In a 12-­week study, morning PEF (±SE) from base- resultant AEs or underdosing and undertreatment.45
line improved by 37.7±3.1 L/min and 38.6±3.0 L/min Specific safety concerns for FP/SAL relate to the effect
with FP/SAL via Diskus or pMDI, respectively.37 of ICS on statural growth, the potential of LABA mono-
therapy to increase the risk of asthma-­related death in
Comparative evidence: FP/SAL versus ICS adults and risk of asthma-­related hospitalisation in paedi-
Lung function improvements with FP/SAL are superior atric patients.11 29 46
to those achieved with FP monotherapy in children, FP/SAL (100/50 µg or 250/50 µg two times per day) has
and similar to FP/FORM.23 24 An RCT of 512 children a similar safety profile to FP (100 µg or 200 µg two times
(aged 5–11 years) with persistent asthma, inadequately per day) and carries similar risk of serious asthma-­related
controlled with ICS alone (≤500 µg/day FP or equiv- events.47 In the prospective VESTRI trial of 6208 children
alent) or controlled with an ICS/LABA combination (aged 4–11 years) who required daily maintenance treat-
(≤200 µg FP or equivalent), investigated the change in ment and had a history of asthma exacerbation in the
FEV1 from baseline to 2 hours post-­dose.23 Although the previous year, FP/SAL (100/50 µg or 250/50 µg) did not
primary comparison was FP/FORM versus FP mono- increase the risk of serious asthma-­related events (death,
therapy, results suggested that mean change in FEV1 over endotracheal intubation or hospitalisation) compared
12 weeks was greater with FP/SAL (100/50 µg two times with FP monotherapy (100 or 250 µg).47 The HR for a
per day: 0.22 L; 95% CI, 0.18 to 0.26) than with FP alone serious asthma-­related event with FP/SAL versus FP mono-
(100 µg two times per day: 0.15 L; 95% CI, 0.11 to 0.19).23 therapy was 1.28 (95% CI, 0.73 to 2.27), demonstrating

Pitrez PM, et al. BMJ Open Respir Res 2023;10:e001706. doi:10.1136/bmjresp-2023-001706 5

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non-­inferiority.47 Asthma-­related hospitalisations were the patients.49 50 Positive efficacy outcomes and reported
only reported serious asthma-­related events, at a rate of ~1.5 equivalence to high-­dose FP support these recommenda-
per 100 patient-­years (consistent with the known rate of tions.26 29 Children treated with FP/SAL are expected to
hospitalisations among children aged 5–14 years48), with no be less likely to receive additional OCS for asthma exac-
deaths or asthma-­related intubations.47 erbations/ED visits, because FP/SAL improves asthma
Other studies have demonstrated a similar safety profile control compared with other therapies; however, the
and rate of associated AEs with FP/SAL compared with need for OCS may vary with asthma severity and pheno-
FP alone23 29 44; nasopharyngitis is the most common AE type.38
for both treatments.23 In conclusion, FP/SAL is a reliable alternative to ICS
Similar effects on statural growth are noted for FP step-­up in appropriate paediatric patients with moderate
and FP/SAL. 29 In three studies in children (aged and moderate-­to-­severe asthma not controlled with low-­
4–11 years), urinary/serum cortisol levels remain dose ICS, and provides potential corticosteroid-­sparing
within normal limits with no evidence of hypotha- effects when used in a step-­up strategy. Since FP/SAL is
lamic–pituitary–adrenal axis suppression following a key therapy considered for paediatric asthma, treat-
administration of FP (100 µg two times per day) or ment plans should be tailored to each child and their
FP/SAL (50/100 µg two times per day) in the studies suitability for step-­up to FP/SAL should be regularly
that assessed cortisol levels. 22 37 44 assessed. However, further studies of FP/SAL in paedi-
atric asthma, including comparison with ICS/FORM as
DISCUSSION MART and low-­dose ICS monotherapy, would be bene-
FP/SAL evidently improves the burden of asthma in ficial to establish stronger evidence to aid physicians in
the paediatric population with moderate and moderate-­ clinical decision-­making and improve management of
to-­severe asthma, versus ICS monotherapy and LTRA, childhood asthma.
owing to the reduced exacerbation/hospitalisation
risk and improvements from baseline in lung function, Author affiliations
1
nocturnal awakenings, rescue medication-­free days and Pediatric Pulmonology Division, Hospital Santa Casa de Porto Alegre, Porto
asthma control experienced with FP/SAL treatment. Alegre, Rio Grande do Sul, Brazil
2
Department of Pediatrics, Faculty of Medicine, Thammasat University,
FP/SAL can also be beneficial in reducing OCS ‘bursts’, Pathum Thani, Thailand
as it improves asthma control, reduces exacerbations 3
Faculdade de Medicina, Hospital das Clínicas, Instituto da Criança e do
and can minimise the need for OCS use.2 49 50 FP/SAL Adolescente, Universidade de São Paulo, São Paulo, Brazil
4
is well tolerated and shares a similar safety profile to FP General Medicines, GSK, Mumbai, India
5
monotherapy in paediatric patients23 29 44; and while no General Medicines, GSK, Singapore
evidence of growth retardation or cortisol suppression
Contributors All named authors contributed to the conception and design of
was reported in the studies that assessed them, relatively this review article, in addition to writing, editing and providing final approval of
few studies assessed these key safety measures in paedi- the submitted version of the article. All authors meet the International Committee
atric populations.22 37 44 51 of Medical Journal Editors (ICJME) criteria for authorship for this article and take
responsibility for the integrity of the work as a whole. PMP is the contributing
author and is responsible for the overall content as the guarantor.
Limitations
Funding Editorial support (in the form of writing assistance, including preparation
Conclusions that can be drawn from this review are of the draft manuscript under the direction and guidance of the authors,
restricted by the narrow evidence base in the paediatric incorporating authors’ comments for each draft, assembling tables and figures,
population and the limitations of the studies presented. grammatical editing and referencing) was provided by Nichola Nolan, of Fishawack
Indicia, UK, part of Fishawack Health, and was funded by GSK.
For example, studies without a placebo arm cannot prop-
Competing interests PMP has acted as a speaker/consultant for AstraZeneca,
erly assess absolute clinical effects of individual treat- GSK, Novartis, Boehringer Ingelheim and Sanofi. SN has acted as a speaker/
ments,24 25 29 44 52 53 and open-­label, non-­blinded trials consultant for AstraZeneca, GSK, Novartis, Boehringer Ingelheim and Sanofi. APMC
carry a risk of bias that may affect subjective measures has acted as a speaker/consultant for Danone, Nutricia, AbbVie and Sanofi. CT and
of efficacy.32 The studies identified generally had short APG are full-­time employees of GSK and hold shares in GSK.
durations (4–12 weeks) which may be considered insuf- Patient consent for publication Not required.
ficient to gather meaningful data.22–26 32 37 40 44 52 In addi- Ethics approval Not applicable.
tion, a range of outcome measures are reported, making Provenance and peer review Not commissioned; externally peer reviewed.
comparisons across studies difficult. Data availability statement Data are available upon reasonable request.
Some RCTs also reported small sample sizes with limita- Supplemental material This content has been supplied by the author(s). It has
tions in representative subgroup analyses.25 32 Obser- not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
peer-­reviewed. Any opinions or recommendations discussed are solely those
vational healthcare claim studies have limited accuracy of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
within patient records and cannot confirm whether responsibility arising from any reliance placed on the content. Where the content
dispensed medications were used correctly.34 38 includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
CONCLUSIONS and/or omissions arising from translation and adaptation or otherwise.
FP/SAL is recommended by national asthma guidelines Open access This is an open access article distributed in accordance with the
in several countries for treatment step-­up in paediatric Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which

6 Pitrez PM, et al. BMJ Open Respir Res 2023;10:e001706. doi:10.1136/bmjresp-2023-001706

 Open access

permits others to distribute, remix, adapt, build upon this work non-­commercially, 23 Płoszczuk A, Bosheva M, Spooner K, et al. Efficacy and safety of
and license their derivative works on different terms, provided the original work is fluticasone propionate/formoterol fumarate in pediatric asthma
properly cited, appropriate credit is given, any changes made indicated, and the patients: a randomized controlled trial. Ther Adv Respir Dis
use is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. 2018;12:1753466618777924.
24 de Blic J, Ogorodova L, Klink R, et al. Salmeterol/Fluticasone
ORCID iD propionate vs. double dose fluticasone propionate on lung
Paulo Marcio Pitrez http://orcid.org/0000-0001-7319-1133 function and asthma control in children. Pediatr Allergy Immunol
2009;20:763–71.
25 Murray CS, Custovic A, Lowe LA, et al. Effect of addition of
salmeterol versus doubling the dose of fluticasone propionate on
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