Respiratory Medicine (2012) 106(S1), S20S28

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/rmed

Fluticasone/formoterol: a new single-aerosol

combination therapy for patients with asthma
Sanjeeva Dissanayake a, *, Birgit Grothe a , Kirsten Kaiser b
a
b

Mundipharma Research Ltd, Cambridge Science Park, Milton Road, Cambridge, Cambs CB4 0GW, UK
SkyePharma AG, Eptingerstrasse 61, 4132 Muttenz, Switzerland

KEYWORDS
Asthma management
Clinical trial data
Combination therapy
Fluticasone propionate
Formoterol fumarate
Single-aerosol inhaler

Summary
International asthma management guidelines recommend a long-acting b2 -agonist (LABA) as
add-on therapy in patients whose asthma is not controlled by low-dose inhaled corticosteroid
(ICS) monotherapy. Treatment with a single inhaler containing an ICS/LABA combination is
advocated because it may facilitate adherence to a regimen. When prescribing ICS/LABA
combination therapy, the potency of the ICS and the speed of onset of the LABA are
considered important factors; therefore, an inhaled therapy containing components with
these properties may be valued by physicians. The ICS uticasone propionate (uticasone)
has potent and sustained anti-inammatory effects, and the LABA formoterol fumarate
(formoterol) provides rapid bronchodilation; the efcacy and safety proles of these agents
have been well established in clinical practice. Fluticasone and formoterol have been
combined, for the rst time, in a single hydrouoroalkane-based aerosol (utiform ;
uticasone propionate/formoterol fumarate). Here, we review data from the published
randomized, controlled, clinical trials that demonstrate the efcacy and tolerability of this
product. It has been shown that uticasone/formoterol is more efcacious than uticasone
or formoterol given alone, and provides similar improvements in lung function to uticasone
and formoterol administered concurrently via separate inhalers. Fluticasone/formoterol
has similar efcacy and tolerability proles to budesonide/formoterol and uticasone/
salmeterol, but with the additional benet of more rapid bronchodilation than uticasone/
salmeterol.
2012 Elsevier Ltd. All rights reserved.

Introduction
International asthma management guidelines recommend
that a long-acting b2 -agonist (LABA) is prescribed as an
add-on therapy for patients whose asthma is not controlled
by low-dose inhaled corticosteroid (ICS) monotherapy.1
A substantial evidence base shows that co-administration
of a LABA and an ICS results in better clinical effectiveness
than that achieved with an ICS alone.2 4 It has also been
shown that the addition of a LABA to existing low-dose
ICS therapy is more effective at reducing the risk of a
* Corresponding author.
Tel.: +44 1223 424 900; fax: +44 1223 425 794.
E-mail address: Sanjeeva.Dissanayake@
mundipharma-rd.eu (S. Dissanayake).
0954-6111/$

severe exacerbation or a poorly controlled asthma day

than doubling the dose of ICS administered.5 Combining
an ICS and a LABA in a single inhaler may encourage
improved adherence to the treatment regimen and may be
preferred by patients to the use of separate inhalers.6,7
Until recently, only three ICS/LABA xed-dose combinations
were available in Europe, and data from randomized,
controlled, clinical trials have demonstrated that each of
these products is highly efcacious.8 13 However, many
patients do not achieve control of their asthma even
when they are prescribed ICS/LABA therapy.14,15 There
are several possible reasons for this: the effectiveness of
any inhaled asthma therapy in everyday clinical practice
is inuenced by drug efcacy and delivery, and requires
the correct inhalation technique, handling of the device
and patient adherence to their treatment regimen.16,17

see front matter 2012 Elsevier Ltd. All rights reserved.

Fluticasone/formoterol single-aerosol therapy in asthma

Incomplete control of asthma disrupts the lives of patients
and has a large impact on their health and healthrelated quality of life.15,18,19 As a consequence, morbidity
associated with uncontrolled asthma remains a signicant
worldwide health and economic problem.1 The development
of alternative therapies is therefore required, especially for
the treatment of patients whose asthma responds poorly to
current therapies.20 A recent Delphi initiative (sponsored by
Mundipharma International Limited) has shown that a panel
of expert respiratory specialists considered the potency
of the ICS and speed of onset of the LABA among the
factors to be most important when prescribing an ICS/LABA
combination therapy for asthma.21 A rapid onset of action
is also important to patients; data show that patients want
to feel their combination therapy working quickly, while
providing lasting therapeutic benets.22 24 Importantly,
patients who were non-adherent to a regimen identied
rapid bronchodilation (If I could feel it helping my asthma
soon after taking it) among the leading factors that would
encourage adherence; indeed, a key reason given for poor
adherence to asthma maintenance therapy is the lack of a
rapid effect.25,26 Taken together, these data might suggest
that the combination of the ICS uticasone propionate
(uticasone), which has potent anti-inammatory effects,
and the LABA formoterol fumarate (formoterol), which
provides rapid bronchodilation,27 provides an additional
treatment option for asthma that may be valued by both
physicians (see Price and Bousquet28 in this supplement) and
patients.22 26
The efcacy and safety prole of uticasone is well
established; it is a widely prescribed,29 highly effective
maintenance treatment for asthma, both as a singleinhaler therapy30 and as the ICS component of the xeddose combination uticasone/salmeterol.12,13 Fluticasone
exhibits potent anti-inammatory activity in vitro and
in vivo .31 33 Furthermore, it undergoes a high level
of rst-pass metabolism and has a signicantly lower
oral bioavailability than budesonide or beclometasone
dipropionate (< 1% versus ~11% and 13 26%, respectively
[26 40% for the active metabolite beclometasone-17monopropionate]).34 36 The efcacy and safety prole of
formoterol is also well established.37 Formoterol provides
signicantly more rapid bronchodilation than salmeterol
comparable to that of the short-acting b2 -agonist salbutamol.38 41 Formoterol is the LABA component of the xeddose combinations of budesonide/formoterol and beclometasone/formoterol. Fluticasone and formoterol have
been combined for the rst time in a single hydrouoroalkane (HFA)-based pressurized metered-dose inhaler
(pMDI; utiform ). Fluticasone/formoterol is formulated
as a suspension aerosol; other available ICS/LABA aerosol
combinations are prepared in suspension (uticasone/
salmeterol; also available as a dry-powder inhaler) or
solution (beclometasone/formoterol) formulations. Across
most of Europe, budesonide/formoterol is only available in
a dry-powder inhaler.
Fluticasone/formoterol has been approved in Europe for
the regular treatment of asthma in adults and adolescents
(12 years and above) with symptoms that are uncontrolled
on an ICS alone, or controlled using an ICS in combination

S21
with a LABA.27 This review provides an overview of
the published data from a comprehensive clinical trial
programme that demonstrates the efcacy and tolerability
proles of uticasone/formoterol.

Efcacy of uticasone/formoterol versus its

components administered alone
Data from four clinical trials have demonstrated that
uticasone/formoterol is superior to its components administered as monotherapies for improvement in measures of
lung function and asthma control.42 45 Two of these studies
have been published and are summarized here.42,43 Both
studies compared uticasone/formoterol with uticasone
or formoterol administered as monotherapies, and with
a placebo over a 12-week period, and both were of
double-blind, placebo- and active-controlled, parallel-group
design. These studies assessed the contribution of the
individual components to the efcacy of the ICS/LABA
combination as co-primary endpoints. The contribution of
the ICS component was assessed by comparing uticasone/
formoterol with formoterol alone for mean change in forced
expiratory volume in 1 second (FEV1 ) from morning pre-dose
at baseline to pre-dose at week 12. The contribution of the
LABA component was assessed by comparing uticasone/
formoterol with uticasone alone for mean change in
FEV1 from morning pre-dose at baseline to 2 hours postdose at week 12. The third co-primary endpoint, time
to discontinuation due to lack of efcacy, was used to
evaluate the efcacy of uticasone/formoterol compared
with placebo. Primary efcacy analyses were carried out
using the full analysis set (all patients who received at least
one dose of treatment and had measurements for pre-dose
baseline FEV1 , at least one post-baseline pre-dose FEV1 and
at least one post-baseline post-dose FEV1 ).
The rst study assessed the efcacy of low-dose
uticasone/formoterol in 475 adolescent and adult patients
with asthma (60 85% predicted FEV1 at baseline), who
were randomly assigned to receive uticasone/formoterol
(100/10 mg twice daily [b.i.d.]), uticasone alone (100 mg
b.i.d.), formoterol alone (10 mg b.i.d.) or placebo, all
administered via an HFA-based pMDI (EudraCT number:
2007-002866-36; US NCT number: NCT00393991).43
Fluticasone/formoterol was superior to formoterol administered alone for increase from baseline to week 12 in mean
morning pre-dose FEV1 (least-squares [LS] mean betweentreatment difference: 0.101 L; 95% condence interval [CI]:
0.002, 0.199; p = 0.045), demonstrating the contribution of
the uticasone component of the combination treatment.
In addition, uticasone/formoterol provided signicantly
greater improvement in mean morning FEV1 than uticasone
monotherapy from pre-dose at baseline to 2 hours post-dose
at week 12 (LS mean between-treatment difference: 0.200 L
(95% CI: 0.109, 0.292; p < 0.001), which highlighted the
contribution of formoterol to the combination. Fluticasone/
formoterol was associated with a signicantly longer time to
discontinuation due to lack of efcacy (assessed as either an
asthma exacerbation or a loss of asthma control; p = 0.015),
compared with placebo. Furthermore, fewer patients in

S22
the uticasone/formoterol treatment group discontinued
therapy due to lack of efcacy (6.1%) compared with
the uticasone, formoterol or placebo groups (7.7%, 11.2%
and 16.2%, respectively).43
Fluticasone/formoterol provided a signicant reduction
in rescue medication use compared with uticasone alone
(p = 0.008). Fluticasone/formoterol also provided greater
improvement than uticasone alone in several clinically
meaningful secondary endpoints, such as decrease in
symptom-free days (p = 0.027) and asthma control days
(p = 0.017). Although these endpoints had a p value of
0.05 versus uticasone alone, they were not considered
statistically signicant per the sequential gatekeeper
approach used in the study.43
In the second study, which assessed medium-dose
uticasone/formoterol versus its individual components
administered alone, 557 adolescent and adult patients
with asthma (40 80% predicted FEV1 at baseline) were
randomly assigned to treatment with uticasone/formoterol
(medium dose, 250/10 mg b.i.d. for the co-primary endpoints), uticasone alone (250 mg b.i.d.), formoterol alone
(10 mg b.i.d.) or placebo; patients were also assigned
to a uticasone/formoterol exploratory group (low dose,
100/10 mg b.i.d.); all treatments were administered via an
HFA-based pMDI (EudraCT number: 2006-005989-39; US NCT
number: NCT00393952).42
Medium-dose uticasone/formoterol was superior to
formoterol administered alone for change in mean FEV1
from pre-dose at baseline to pre-dose at week 12
(LS mean between-treatment difference: 0.189 L; 95% CI:
0.079, 0.298; p < 0.001). Similarly, uticasone/formoterol
was superior to uticasone monotherapy for change in
mean FEV1 from pre-dose at baseline to 2 hours post-dose at
week 12 (LS mean between-treatment difference: 0.146 L;
95% CI: 0.042, 0.250; p = 0.006). As described previously,
these data are indicative of the relative contributions of the
uticasone and formoterol components to the improvements
in lung function observed with uticasone/formoterol.
Medium-dose uticasone/formoterol also demonstrated a
signicantly longer time to discontinuation due to lack of
efcacy (assessed as either an asthma exacerbation or a loss
of asthma control) than placebo (p < 0.001). Furthermore,
fewer patients in the uticasone/formoterol treatment
group discontinued therapy due to lack of efcacy (10.2%)
than in the uticasone, formoterol or placebo groups
(12.8%, 20.9% and 39.0%, respectively).42
Analysis of clinically meaningful secondary endpoints also
supported the greater efcacy of uticasone/formoterol
compared with uticasone monotherapy. Fewer patients
in the uticasone/formoterol group had an exacerbation
of any severity (p = 0.030) than in the uticasone-alone
group. In addition, uticasone/formoterol was associated
with more rescue-medication-free days (p = 0.042) and
more asthma control days (dened as days with an
asthma symptom score indicating no symptoms; p = 0.027)
than uticasone alone. Although these endpoints had a
p value of 0.05 versus uticasone alone, they were
not considered statistically signicant per the sequential
gatekeeper approach used in the study.42

S. Dissanayake et al.
In both studies described above, uticasone/formoterol
had a tolerability prole similar to that of its individual
components. Adverse events (AEs) were mostly mild-tomoderate in severity, with a numerically smaller proportion
of patients in the uticasone/formoterol group reporting
treatment-emergent AEs compared with those in the
uticasone, formoterol or placebo groups.42,43

Efcacy of uticasone/formoterol compared

with its components administered
concurrently via separate inhalers
The efcacy of high-dose uticasone/formoterol was compared with uticasone + formoterol administered together
via separate inhalers in a double-blind, double-dummy,
randomized, parallel-group, 8-week study. In this study,
620 adults with persistent, reversible asthma (40% to 80%
predicted FEV1 at baseline) were randomly assigned to
8 weeks of treatment with high-dose uticasone/formoterol
(500/20 mg b.i.d.), uticasone (500 mg b.i.d.) plus formoterol (24 mg b.i.d.), uticasone alone (500 mg b.i.d.) or lowdose uticasone/formoterol (100/10 mg b.i.d.; included as
a secondary comparator); all treatments were administered
via an HFA-based pMDI (EudraCT number: 2007-001633-34;
US NCT number: NCT00734318). The primary analysis
population for the non-inferiority comparison (high-dose
uticasone/formoterol versus uticasone + formoterol) was
the per-protocol population (PPP; dened as all patients
who completed the study without major protocol violations
affecting the primary endpoint), with conrmatory analyses
performed in the intent-to-treat (ITT) population (all
patients randomized who received at least one dose of
study treatment and had at least one post-dose primary
efcacy [FEV1 ] measurement). The co-primary endpoints
were mean change in morning pre-dose FEV1 from baseline
to week 8, and mean change in morning FEV1 from predose at baseline to 2 hours post-dose at the end of week 8;
non-inferiority for the co-primary efcacy endpoints was
concluded if the lower limit of the 95% CI for the betweentreatment difference was 0.2 L.46
The uticasone/formoterol combination (500/20 mg b.i.d.)
was non-inferior to its components administered concurrently (500 mg + 24 mg, b.i.d.) for both co-primary efcacy endpoints. Fluticasone/formoterol and uticasone +
formoterol demonstrated similar mean increases in morning
pre-dose FEV1 between baseline and week 8 (LS mean of
the treatment difference: 0.060 L; 95% CI: 0.059, 0.180)
(Fig. 1). For mean change in FEV1 from pre-dose at baseline
to 2 hours post-dose at study end, the increase was similar in
the uticasone/formoterol (500/20 mg b.i.d.) group and the
uticasone + formoterol group (LS mean of the treatment
difference: 0.018 L; 95% CI: 0.098, 0.135).46
Fluticasone/formoterol also provided similar improvements to uticasone + formoterol for several clinically
relevant measures of asthma control, including rescue
medication use, sleep disturbance, asthma symptom and
health status scores, as assessed in the ITT population.
Fluticasone/formoterol had a similar tolerability prole
to uticasone + formoterol; 19.5% of patients in the

Fluticasone/formoterol single-aerosol therapy in asthma

S23

Mean change in FEV1 (L)

0.5

(a)

0.4
0.3
0.2
0.1

Fluticasone/formoterol 500/20 g b.i.d. (n = 133)

Fluticasone 500 g b.i.d. + formoterol 24 g b.i.d. (n = 140)

0
0

4
Treatment week

Mean change in FEV1 (L)

0.6
0.5

(b)

0.4
0.3
0.2
Fluticasone/formoterol 500/20 g b.i.d. (n = 132)
Fluticasone 500 g b.i.d. + formoterol 24 g b.i.d. (n = 138)

0.1

4
Treatment week

Figure 1. Fluticasone/formoterol administered as a combination therapy via a single inhaler has an efcacy prole similar to that
of its components administered concurrently (uticasone + formoterol). Data show (a) the mean change in morning predose forced expiratory volume in 1 second (FEV1 ) from baseline to week 8, and (b) change in morning pre-dose FEV1
from baseline to 2 hours post-dose at week 8, for the per-protocol population.46 b.i.d., twice daily. Figures adapted from
Bodzenta-Lukaszyk A, Pulka G, Dymek A, Bumbacea D, McIver T, Schwab B, Mansikka H, Efcacy and safety of uticasone
and formoterol in a single pressurized metered dose inhaler. Respiratory Medicine 2011;105(5):674 82. Copyright 2011,
with permission from Elsevier.

uticasone/formoterol 500/20 mg b.i.d. group reported

an AE, compared with 19.9% in the uticasone + formoterol
group, 18.7% in the uticasone/formoterol 100/10 mg b.i.d.
group and 14.2% in the uticasone alone group. Most AEs
were mild-to-moderate in intensity, with headache, nasopharyngitis, viral infection, pharyngitis and asthma being
the most common AEs.46

Efcacy of uticasone/formoterol versus

uticasone/salmeterol
A phase 3 clinical trial compared the efcacy and
tolerability of uticasone/formoterol and uticasone/
salmeterol.47 In this open-label, active-controlled, randomized, parallel-group, multicentre study (EudraCT number:
2006-005926-22; US NCT number: NCT00476073), 202 adults
with asthma (40% and 85% predicted FEV1 at baseline)
were randomly assigned to 12 weeks of treatment with
uticasone/formoterol (100/10 mg or 250/10 mg, b.i.d.) or
uticasone/salmeterol (100/50 mg or 250/50 mg, b.i.d.),
both administered via HFA-based pMDI with a spacer.
Allocation to treatment dose was stratied by prior ICS dose;
approximately three quarters of patients were assigned
to the higher study drug dose in each treatment group.

Endpoint analyses were performed for the full analysis set

(FAS; all randomized patients who received study treatment
and had at least one post-dose primary efcacy [FEV1 ]
measurement) and the PPP (all FAS patients who completed
the study without major protocol violations affecting the
primary efcacy [FEV1 ] endpoint).47
Fluticasone/formoterol was as effective as uticasone/
salmeterol for mean pre-dose FEV1 at week 12 (primary
endpoint, with a LS mean of the treatment difference of
0.061 L; 95% CI: 0.161, 0.040; assessed in the PPP). Noninferiority was concluded because the lower limit of the
95% CI was greater than 0.2 L. A key secondary objective
of this study was to assess the time to bronchodilation
(dened as the rst post-dose measurement at which
FEV1 was at least 12% greater than the pre-dose value).
Fluticasone/formoterol provided signicantly more rapid
bronchodilation than uticasone/salmeterol over the 12week study period (overall hazard ratio: 1.64; 95% CI:
1.28, 2.10; p < 0.001; FAS).47 The bronchodilatory effects
of study treatments were further explored in a series of
post hoc analyses. On the rst day of treatment, the
odds of a patient achieving the pre-dened bronchodilation
criterion at 5 minutes post-dose was fourfold greater with
uticasone/formoterol than with uticasone/salmeterol

S24

S. Dissanayake et al.
LS mean difference: 4.70% (95% CI: 1.57, 7.83); p = 0.003

25

Change in FEV1 from

pre-dose (%)

(a)

20

*
*

15

10
5

Fluticasone/formoterol 100/10 g or 250/10 g b.i.d. (n = 101)

Fluticasone/salmeterol 100/50 g or 250/50 g b.i.d. (n = 100)

0
0

10

Change in FEV1 from

pre-dose (%)

60
Time from dosing (minutes)

90

120

LS mean difference: 2.79% (95% CI: 0.65, 4.93); p = 0.011

25

(b)

30

Fluticasone/formoterol 100/10 g or 250/10 g b.i.d. (n = 98)

Fluticasone/salmeterol 100/50 g or 250/50 g b.i.d. (n = 100)

20
15
10

30

60
Time from dosing (minutes)

90

5
0
0

10

120

Figure 2. Fluticasone/formoterol provides more rapid bronchodilation than uticasone/salmeterol. Values are shown as percentage
change in least-squares (LS) mean forced expiratory volume in 1 second (FEV1 ) from morning pre-dose at baseline
standard error. *p  0.05. Data from a post hoc analysis are shown for the full analysis set. Improvement in lung function
was assessed by change in FEV1 from morning pre-dose at 5, 10, 30, 60, 90 and 120 minutes post-dose, on (a) day 0
and (b) day 84.48 Figure reproduced with kind permission from Springer Science+Business Media B.V. from Figure 2 of
Aalbers R, Brusselle G, Bodzenta-Lukaszyk A, Onset of bronchodilation with uticasone/formoterol combination versus
uticasone/salmeterol in an open-label, randomized study. Advances in Therapy 2012;29(11):958 69.

treatment (odds ratio [OR]: 4.0; 95% CI: 2.0, 8.0). Moreover,
the odds of achieving bronchodilation at 5 minutes after
dosing were almost tenfold greater with uticasone/
formoterol after 12 weeks treatment (OR: 9.6; 95% CI:
2.1, 42.9).48 Fluticasone/formoterol also provided greater
increases than uticasone/salmeterol in LS mean post-dose
FEV1 in the 2 hours following dosing, both on day 0 and
after 12 weeks (overall change on day 0: 17.3% versus 12.6%,
respectively, p = 0.003; day 84: 8.9% versus 6.2%, p = 0.011)
(Fig. 2).48
Fluticasone/formoterol and uticasone/salmeterol demonstrated similar efcacy for other lung function parameters, rescue medication use, asthma symptom scores, sleep
disturbance scores, asthma exacerbations and health status
scores. Fluticasone/formoterol had a similar tolerability
prole to that of uticasone/salmeterol.47

Efcacy of uticasone/formoterol versus

budesonide/formoterol
The efcacy and tolerability of uticasone/formoterol
(250/10 mg b.i.d.) compared with budesonide/formoterol
(400/12 mg b.i.d.) was assessed in a double-blind, doubledummy, randomized, two-arm, parallel-group study in 279

adolescent and adult patients with persistent, reversible

asthma (50 80% predicted FEV1 at baseline; EudraCT
number: 2009-017223-25; US NCT number: NCT01099722).
For the primary study endpoint, uticasone/formoterol and
budesonide/formoterol provided similar changes in mean
morning pre-dose FEV1 from baseline to week 12 (LS mean
treatment difference: 0.044 L; 95% CI: 0.130, 0.043). Noninferiority was concluded because the lower limit of the
95% CI for treatment difference was greater than 0.2 L.
Both treatments demonstrated similar efcacy for several
measures of asthma control, including improvements in
asthma symptom scores and sleep disturbance scores and
in number of asthma control days, symptom-free days and
awakening-free nights. The tolerability proles were similar
in both treatment groups.49

Long-term safety and efcacy of uticasone/

formoterol
The long-term safety and efcacy of uticasone/formoterol
(100/10 or 250/10 mg b.i.d.) was assessed in an open-label,
multicentre study over 6 or 12 months in 472 adult and
adolescent patients with asthma (40 85% predicted FEV1
at baseline; EudraCT number: 2005-003518-14; US NCT

Fluticasone/formoterol single-aerosol therapy in asthma

100

80

Deposition (%)

number: NCT00394121).50 In total, 413 patients (87.5%)

completed the study (of whom 175 participated for
12 months). Overall rates of AEs reported (36.9%) were consistent with those observed in a 1-year study of uticasone/
salmeterol (250/50 mg b.i.d.) and budesonide/formoterol
(adjustable maintenance dosing).51 The majority of AEs
were mild-to-moderate in severity. Asthma exacerbations
were reported by 11.2% of patients (9.7% with mild-tomoderate exacerbations and 1.9% with severe exacerbations
[dened as requiring additional therapy, hospitalization
or a visit to an emergency department]). Signicant
improvements from pre-treatment baseline lung function
(FEV1 , % predicted FEV1 , peak expiratory ow rate and
forced vital capacity) were maintained over the 6- or 12month treatment period.50

S25

60

40

20

0
0.5

Drug particle size and lung deposition: the

importance of particle size and ne particle
fraction
Both proximal and distal airways are implicated in the
pathophysiology of asthma; inammation extends from the
large bronchi to the alveoli.52 Therefore, it is necessary for
ICSs to be delivered to both proximal and distal airways;
however, to date no clear clinical benet of targeting
ICSs to the latter has been demonstrated.53 In contrast,
although b2 -receptors are located in all parts of the airways
and are found in greatest density in the alveolar walls,54
the bronchodilatory effects of b2 -agonists are due to their
actions on smooth muscle in the proximal airways. Thus,
targeting of b2 -agonists to the proximal airways may be more
important than deposition in distal airways for providing
effective bronchodilation.55 It is therefore logical that
the lung deposition prole of an ICS/LABA combination
product should demonstrate a balance between targeting
bronchoconstriction in the proximal airways and generalized
inammation throughout the lungs, in order to achieve
optimal distribution of deposited drug.
The particle size of inhaled drugs has been identied as
one of the critical determinants of both the total lung dose
and their regional pulmonary deposition pattern.56 58
However, the extent of lung deposition of polydisperse
aerosols is less dependent on the single particle size
summary statistic (mass median aerodynamic diameter;
MMAD) than it is on particle size distribution around
the MMAD.56,59 The seminal publication by Heyder and
colleagues,57 exploring the relationship between particle
size and regional lung deposition, demonstrated that
particles in the range 2 6 mm are associated with both
central and alveolar deposition (Fig. 3).56 58 Therefore,
there is an apparent lower limit of 2 mm for an effective
particle size; particles < 2 mm are prone to deposit largely
in the alveoli and those < 1 mm are transported to the
alveoli but can also be easily exhaled (and would thus not
exert a therapeutic effect).56,57,60 In light of these data,
it is instructive to note the stage-by-stage particle size
distribution of the uticasone/formoterol aerosol: in the
eight-stage Andersen Cascade Impactor, operated under
standard pharmacopoeial conditions, the largest individual

Alveolar
Bronchial
Extra-thoracic
Total

10

20

Size (m)

Figure 3. Extent and site of lung deposition of inhaled particles

relative to their size (based on the International Commission
Radiological Protection model).58 Copyrighted material reproduced with permission from Mary Ann Liebert, Inc. Publishers,
from Pritchard JN, The inuence of lung deposition on clinical
response. J Aerosol Med 2001;14(Suppl 1):S19 26.

particle size fractions (reaching stages of the apparatus that

correspond to regions of the lungs) of uticasone/formoterol
are captured in stage 3 (corresponding to particles with
a diameter of 3.3 4.7 mm) and stage 4 (corresponding to
particles with a diameter of 2.1 3.3 mm).61 These data
support the notion that the particle size characteristics of
the uticasone/formoterol aerosol are very well suited to
the deposition requirements for an ICS/LABA combination;
however, the clinical impact of such characteristics in realworld use is yet to be established.
In addition to the distribution of particle sizes, the
ne particle fraction is a key in vitro parameter for
orally inhaled drugs.62 The ne particle fraction is the
percentage of the drug mass that has greatest potential
for penetrating beyond the oropharynx and depositing
throughout the airways.62 In the European Pharmacopoeia,
the ne particle fraction is dened as the proportion
of aerosol drug particles that are < 5 mm in aerodynamic
diameter.62 The ne particle fraction correlates with
in vivo drug deposition (as measured by scintigraphy and
pharmacokinetic assessment).63,64 A high ne particle fraction reects a desirable balance of high lung deposition and
relatively low oropharyngeal drug deposition. Deposition of
ICS particles in the oropharynx can contribute to systemic
and local adverse effects, including oral candidiasis and
hoarseness/dysphonia, but not to therapeutic benet.63,65
Given these collective observations, it is encouraging that
the in vitro ne particle fraction of the new uticasone/
formoterol suspension aerosol is high at ~40% (as assessed
at 28.3 L/min). Importantly, this ne particle fraction is
consistent at ow rates of 28.3 L/min and 60.0 L/min,
in vitro .66
In summary, particle size and ne particle fraction are
the principal in vitro parameters that determine potential
in vivo lung deposition and the risk benet prole of the
aerosol. The in vitro characteristics of the uticasone/

S26
formoterol aerosol are indicative of the potential for
high drug deposition in the lung, an effective regional
lung deposition pattern and a favourable oropharyngeal to
pulmonary deposition ratio. The consistent delivery of a high
ne particle fraction with uticasone/formoterol may be a
useful characteristic in an inhaled therapy, because patients
often exhibit variability in inhalation ow rate in the dayto-day use of their inhaler.

S. Dissanayake et al.
Conict of interest statement
S.F., B.G. and S.D. are employees of Mundipharma
Research Limited. K.K. is an employee of SkyePharma AG.

Prescribing information
Prescribing information can be obtained from:
http://www.medicines.org.uk/emc/medicine/26954

Conclusions

References

Fluticasone/formoterol brings together a rapid-acting LABA

with a potent ICS in a single-aerosol inhaler. A robust
clinical data set demonstrates that uticasone/formoterol
is superior to either component administered as a monotherapy. Fluticasone/formoterol has similar efcacy and tolerability proles to uticasone and formoterol administered
concurrently via separate inhalers. Similarly, uticasone/
formoterol has similar efcacy and tolerability proles
to budesonide/formoterol and uticasone/salmeterol and,
importantly, offers the additional benet of more rapid
bronchodilation than uticasone/salmeterol.47 The fast
onset of bronchodilation with formoterol, together with
the sustained anti-inammatory effects of uticasone, are
important treatment characteristics because patients want
a maintenance treatment that they can feel working quickly
and that provides lasting therapeutic benets.22 26 These
attributes may encourage patients to adhere to their
treatment regimen, a factor that has been associated with
real-world improvements in asthma control.7,67 The emitted
aerosol consistently contains a high ne particle fraction
between ow rates, an attribute that may be valuable given
patient variability in inhalation manoeuvres. In summary,
the uticasone/formoterol combination aerosol described in
this review represents an additional therapeutic option for
the treatment of asthma in adults who require an ICS/LABA,
with attributes that may be important for effectiveness in
clinical practice.

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Acknowledgments
The authors thank Sarah Fletcher for her advice and
comments during the development of the paper. The
authors wish to thank Oxford PharmaGenesis Limited
(Oxford, UK) for providing medical writing and editorial
support. This work was arranged and funded by Mundipharma International Limited (Cambridge, UK).
Funding
This paper forms part of a supplement commissioned and
funded by Mundipharma International Limited entitled
A new combination therapy for asthma; bridging the gap
between effectiveness in trials and clinical practice? The
supplement contains papers based on presentations from
an advisory meeting of health-care professionals held on
22 June 2010, which was also arranged and sponsored
by Mundipharma International Limited. All participants
received travel expenses and an honorarium from
Mundipharma International Limited for their attendance
and participation in the advisory meeting.

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