The long-term goals of asthma management
are to achieve good symptom control, to maintain normal activity levels and to
minimise future risk of exacerbations, fixed airflow limitation and side
effects of treatment.1 The 2017 Global Initiative for Asthma (GINA) guidelines
recommend that treatment with regular daily low dose inhaled corticosteroids
(ICS) is highly effective in reducing asthma symptoms and in reducing the risk
of asthma-related exacerbations.1 For patients with persistent
symptoms and/or exacerbations despite low dose ICS, the preferred step-up
treatment (Step 3) is combination low dose ICS/long-acting beta2-agonist
(LABA) therapy.1

new ICS/LABA combination

Innuvair® inhaler contains the ICS/LABA
combination of beclomethasone dipropionate and formoterol.2 It is
indicated in South Africa for the regular treatment of asthma in adults where
use of a combination product is appropriate2:

Patients not adequately
controlled with inhaled corticosteroids and an ‘as-needed’ inhaled short-acting

Patients already adequately
controlled on both an inhaled corticosteroid and a long-acting beta2-agonist

new technology

The phasing out of chlorofluorocarbons
(CFCs) led to the development of pressurised metered dose inhalers (pMDIs) that
use hydrofluoroalkane (HFA) propellants.3 More recently, using
Modulite® technology, new pMDIs have been developed which use compounds
reformulated into solutions (as opposed to currently available HFA suspensions).3
While HFA suspensions retain the same particle size, deposition and efficacy
profiles as their CFC counterparts, HFA solutions can be manipulated to vary
particle size distribution permitting precise control of delivered dose and
optimised drug delivery to allow the drugs to penetrate the deeper regions of
the lung more effectively.4

Innuvair inhaler, developed with Modulite®
technology, contains ‘extra-fine’ drug particles with a particle size less than
µm, which is suitable for homogeneous
distribution of the medication throughout the bronchial tree.5  The rationale for developing an
extra-fine formulation lies in the fact that asthma is characterised by airway
inflammation in the entire lung, including the large as well as the small

the small airways

Lung deposition is a critical factor for
the optimal treatment of asthma and particle size is a major determinant of the
proportion of drug that reaches the lung.4,7 Inflammation of the
small airways (internal diameter less than 2 mm) is an important feature of
asthma and treatment of inflammation in both the large and the small airways
may be key for effective asthma control.7  

Most conventional inhaler devices achieve
relatively poor levels of total lung deposition (TLD).8 At best,
10-20% of the inhaled drug deposits in the lungs, leading to four-fifths of the
dose being wasted. 8 Inhaler devices that can emit smaller drug
particles at slower velocities achieve better total lung deposition (30-50%)
and importantly, allow effective penetration of the drug into the smaller
airways. 8 Deposition studies in asthmatic patients with Innuvair®
inhaler showed approximately one-third peripheral (small airway) deposition and
two-thirds central (large airways) lung deposition as a proportion of total
lung dose. 8

Taken together, lung deposition data in
asthmatic patients show that extra-fine aerosols not only achieve better lung
deposition, but also effective penetration into the peripheral lung, thereby
reaching not only the large but also the small airways. 8

dose reduction

The beclomethasone dipropionate/formoterol
µg/6 µg pMDI is an extra-fine solution formulation in which the
beclomethasone dipropionate (BDP) dose is 2.5-fold lower than conventional
beclomethasone dipropionate CFC formulations (100
µg of BDP per actuation instead of 250 µg of non-extra-fine BDP).6 The dose reduction is possible
due to improved lung deposition of a smaller particle.9

The reduction in BDP nominal dose, together
with the extra-fine particle size, allows a similar dose of the drug to reach
the lower airways and less drug to be deposited in the upper airways,
potentially improving the efficacy/safety ratio of the ICS.6


Although beclomethasone and formoterol are
well-known molecules of proven efficacy and safety, the clinical development of
the extra-fine beclomethasone/formoterol combination involved a series of
clinical trials conducted in patients with asthma.7 Clinical trials
were designed to explore whether use of extra-fine formulations improved lung
function, asthma control and health-related quality-of-life compared with inhaled
drugs delivered as non-extra-fine formulations.10

The efficacy of the beclomethasone
dipropionate/formoterol (BDP/F) combination was evaluated in a 3-month
randomised controlled trial in patients with moderate to severe asthma who were
still symptomatic despite receiving low-dose ICS (up to 500
µg of BDP or equivalent.6

·        Extra-fine BDP/F given as one
inhalation twice daily proved to be more effective at improving lung function
than a double equipotent dose of BDP non-extra-fine.6

A second investigation was carried out in
patients with more severe asthma, documented by recurrent symptoms and impaired
lung function despite treatment with up to 1000
µg/day BDP or equivalent.6

·        Extra-fine BDP/F given as two
inhalations twice daily showed improvement in peak expiratory flow (PEF) and
forced expiratory volume in 1 second (FEV1), comparable with that of
an equipotent non-extra-fine regimen of BDP and formoterol administered via
separate inhalers.6

·        Furthermore, the extra-fine
BDP/F fixed combination was superior to BDP plus formoterol in separate
inhalers in terms of asthma control.6,7 This study represents the
first randomised controlled trial to show a difference in asthma control
between an ICS and a LABA administered as a fixed combination compared with
separate inhalers.6,7

Two head-to-head clinical trials assessed
the efficacy and tolerability of BDP/F versus budesonide/formoterol and versus
fluticasone propionate/salmeterol in patients with moderate to severe asthma.6,11,12

·        In the first trial, patients
given BDP/F as two inhalations twice daily showed improvement in lung function,
measured by morning pre-dose PEF, which was comparable with that of an
equipotent regimen of budesonide/formoterol (200/6
µg) administered as two inhalations twice daily.6,11 Both
therapies were equally effective at improving asthma symptoms and increasing
the percentage of days without the use of rescue medication.6,11

·        In the second trial, BDP/F was
compared with fluticasone propionate/salmeterol pMDI, both administered as two
puffs twice daily.6,12 BDP/F demonstrated improvement in PEF and FEV1
comparable to that of fluticasone propionate/salmeterol.6,12
However, the extra-fine BDP/F combination demonstrated a greater and more
specific effect on variables directly related to small airways function, as
shown by the significant difference in forced vital capacity (FVC).6,10,12

The above studies are controlled clinical
trials involving highly selected asthma patients fulfilling strict inclusion
and exclusion criteria, which may not reflect patients seen in ‘real-life’
daily clinical practice. 8

·        Real-life studies with Innuvair
inhaler have shown significantly higher levels of asthma control, better
quality of life and the use of lower daily ICS doses when compared with large
particle ICS/LABA pMDIs. 8

and tolerability

BDP and formoterol are not new chemical
entities and are therefore not likely to expose patients to the risk of unexpected
or unknown side effects.6 The lower dose of the ICS, as a result of
the improved drug delivery of the extra-fine formulation, results in an
improved safety margin due to less drug being available for systemic absorption.10
In addition, reduction in the amount of ICS deposited in the oropharynx
limits local side effects of the ICS, such as hoarseness, dysphonia and

Key issues

The new fixed combination of
beclomethasone/formoterol has the following properties:

·        Extra-fine hydrofluoroalkane-propelled
solution, characterised by a small particle size and high particle deposition
throughout the bronchial tree (Modulite® technology).13

·       High efficacy coupled with
low systemic bioavailability.13

·       Comparable efficacy on lung
function and a greater efficacy in terms of asthma symptom scores and asthma
control when compared with BDP and formoterol administered via separate

·       Comparable efficacy in
improving lung function outcomes (PEF, FEV1) when compared with
other ICS/LABA fixed combinations, using lower equivalent doses of BDP.11,12,13

·       Significantly higher levels
of asthma control, better quality of life and the use of lower daily ICS
doses when compared with large particle ICS/LABA pMDIs as demonstrated in
real-life studies. 8

·       Improved safety and
tolerability profile due to lower systemic absorption and a reduction in the
amount of ICS deposited in the oropharynx.10

article was originally published in South
African Family Practice
2018; 60(3):5-6 and S Afr Pharm J 39 2018 Vol 85 No 3


  1. 1.      
    Global Initiative for Asthma.
    Global Strategy for Asthma Management and Prevention, 2017. Available from:
  2. 2.       Innuvair approved package insert. July 2017.
  3. 3.      
    Bousquet J, Poli G, Acerbi D, et
    al. Systemic exposure and implications for lung deposition with an extra-fine
    hydrofluoroalkane beclomethasone dipropionate/formoterol fixed combination. Clin
    Pharmacokinet 2009;48(6):347-358.
  4. 4.      
    Acerbi D, Brambilla G, Kottakis
    I. Advances in asthma and COPD management: Delivering CFC-free inhaled therapy
    using Modulite® technology. Pulm Pharmacol & Ther 2007;20:290-303.
  5. 5.      
    Dhillon S, Keating GM.
    Beclometasone dipropionate/formoterol in an HFA-propelled pressurised
    metered-dose inhaler. Drugs 2006;66(11):1475-1483.
  6. 6.      
    Nicolini G, Scichilone N, Bizzi
    A, et al. Beclomethasone/formoterol fixed combination for the management of
    asthma: patient considerations. Therapeutics & Clinical Risk Management 2008;4)5):855-864.
  7. 7.      
    Huchon G, Magnussen H,
    Chuchalin A, et al. Lung function and asthma control with beclomethasone and
    formoterol in a single inhaler. Resp Med 2009;103:41-49.
  8. 8.      
    Usmani OS. Small-airway disease
    in asthma: pharmacological considerations. Curr Opin Pulm Med 2015;21(1):55-67.
  9. 9.      
    Fabbri LM, Nicolini G, Olivieri
    D, et al. Inhaled beclomethasone dipropionate/formoterol extra-fine fixed
    combination in the treatment of asthma: evidence and future perspectives. Expert
    Opin Pharmacother 2008;9(3):479-490.
  10. 10.  
    Scichilone N, Spatafora M,
    Battaglia S, et al. Lung penetration and patient adherence considerations in
    the management of asthma: role of extra-fine formulations. J Asthma &
    Allergy 2013;6:11-21.
  11. 11.  
    Papi A, Paggiaro PL, Nicolini
    G, et al. Beclomethasone/formoterol versus budesonide/formoterol combination
    therapy in asthma. Eur Respir J 2007;29:682-689. DOI:
  12. 12.  
    Papi A, Paggiaro P, Nicolini G,
    et al. Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination
    in moderate to severe asthma. Allergy 2007;62:1182-1188.
  13. 13.  
    Paggiaro P, Nicolini G, Papi A.
    Extrafine beclomethasone dipropionate/formoterol hydrofluoroalkane-propelled
    inhaler in asthma. Expert Rev Resp Med 2008;2(2):161-165.