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Drugs 2008; 68 (12): 1741-1770

0012-6667/08/0012-1741/$53.45/0

ADIS DRUG EVALUATION

2008 Adis Data Information BV. All rights reserved.

Ciclesonide
A Review of its Use in the Management of Asthma
Emma D. Deeks and Caroline M. Perry
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Health, Conshohocken, Pennsylvania, USA
Various sections of the manuscript reviewed by:
K.R. Chapman, Asthma & Airway Centre, Toronto Western Hospital, University Health Network, Toronto,
Ontario, Canada; F. Chung, Royal Brompton & Harefield NHS Trust, London, England; K. Mortimer,
Division of Respiratory Medicine, Nottingham University City Hospital, Nottingham, England; D. Ukena,
Pneumologie, Bremen, Germany; M. Zitt, Queens Long Island Medical Group, State University of
Klinik fur
New York, New York, New York, USA.
Data Selection
Sources: Medical literature published in any language since 1980 on ciclesonide, identified using MEDLINE and EMBASE, supplemented
by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of
published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing
the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ciclesonide. Searches were last updated 8 July 2008.
Selection: Studies in patients with asthma who received ciclesonide. Inclusion of studies was based mainly on the methods section of the
trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and
pharmacokinetic data are also included.
Index terms: Ciclesonide, asthma, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1742
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1743
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1744
2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1744
2.2 Anti-Inflammatory Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1744
2.2.1 Effects on Markers of Airway Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1746
2.3 Pulmonary Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1746
2.4 Systemic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1746
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1748
3.1 Deposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1748
3.2 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1748
3.3 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1749
3.4 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1749
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1749
4.1 Adults and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1750
4.1.1 Versus Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1752
4.1.2 Versus Active Comparators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1754
4.1.3 Effects on Health-Related Quality of Life (HR-QOL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1757
4.2 Paediatric Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1758
4.2.1 Versus Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1759
4.2.2 Versus Active Comparators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1760
4.2.3 Effects on HR-QOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1761
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1761

1742

Deeks & Perry

5.1 General Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1761


5.2 Versus Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1762
5.3 Versus Active Comparators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1762
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1764
7. Place of Ciclesonide in the Management of Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1764

Summary
Abstract

Pharmacological
Properties

Ciclesonide (Alvesco) is an inhaled corticosteroid used in the preventative


treatment of persistent bronchial asthma in adults, adolescents and, in some
countries, children. The drug is delivered by a non-chlorofluorocarbon hydrofluoroalkane (HFA) metered-dose inhaler (MDI). In the lungs, ciclesonide is
converted to an active metabolite, which is responsible for the beneficial effects of
the drug in patients with asthma. Ciclesonide and its active metabolite have low
systemic bioavailability and therefore have a low potential to produce systemic
adverse events. Inhaled ciclesonide delivered by HFA-MDI is effective in the
prophylactic treatment of persistent asthma in adults, adolescents and children,
and is generally well tolerated.
In general, ciclesonide improves lung function and reduces asthma symptoms
and rescue medication use in adults and adolescents with asthma of varying
severity. The drug is generally no less effective than other inhaled corticosteroids
with regard to maintaining or improving lung function and may have a more
favourable tolerability profile than some other agents in this class. Ciclesonide has
also shown efficacy in paediatric patients with asthma. Data on its long-term
effects on other clinical outcomes, such as asthma exacerbations, would be of
interest. Further comparative and long-term studies would also be beneficial in
order to definitively position ciclesonide with respect to other inhaled corticosteroids. In the meantime, ciclesonide offers an effective and well tolerated first-line
preventative treatment option for persistent asthma.
Ciclesonide is a corticosteroid prodrug that is converted to its active metabolite,
desisobutyryl-ciclesonide (des-CIC), primarily in the lung. Compared with
ciclesonide, des-CIC exhibits greater glucocorticoid receptor binding affinity and
generally has greater anti-inflammatory effects in vitro. Ciclesonide reduces
airway hyper-responsiveness to various stimuli and attenuates bronchoconstriction induced by allergens and exercise. The drug is also associated with the
inhibition of, or reduction in, levels of pro-inflammatory mediators, such as
cytokines and eosinophils. Short- and long-term treatment with inhaled ciclesonide at therapeutic dosages was associated with negligible systemic effects in
adults, adolescents and children.
The lung deposition of ciclesonide delivered by HFA-MDI was high (52%),
and the oropharyngeal deposition of the drug was significantly lower than that of
budesonide and fluticasone propionate administered via chlorofluorocarbon-MDI
and HFA-MDI devices, respectively. After inhalation, the oral bioavailability of
ciclesonide and des-CIC is negligible and systemic exposure to non-plasma
protein bound ciclesonide and des-CIC is low (12% of the dose absorbed by the
lung). Pulmonary retention of ciclesonide may be facilitated by the formation of
reversible des-CIC fatty acid conjugates in lung tissue. Systemic ciclesonide
appears to be extensively metabolized by the liver, primarily via the cytochrome
P450 (CYP) isoenzyme CYP3A4, to inactive metabolites. At steady state, the
mean elimination half-life of des-CIC in healthy volunteers was 6.72 hours.

2008 Adis Data Information BV. All rights reserved.

Drugs 2008; 68 (12)

Ciclesonide: A Review

Therapeutic Efficacy

Tolerability

1743

In well designed, placebo-controlled, short-term trials, inhaled ciclesonide was


effective in maintaining or improving lung function in adult and adolescent
patients with asthma of varying severity, most of whom had previously received
corticosteroid treatment. Ciclesonide also generally produced significant benefits
in these patients in terms of asthma symptom scores and rescue medication use
compared with placebo. Moreover, in two 12-week studies in adult patients with
persistent asthma, significantly fewer ciclesonide recipients experienced lack of
efficacy compared with placebo recipients. Longer term, the beneficial effects of
ciclesonide at individualized dosages on lung function were maintained up to
52 weeks after the start of treatment in adult patients with mild to moderate,
persistent asthma.
In general, ciclesonide was no less effective than inhaled fluticasone propionate, budesonide or beclometasone with regard to improving or maintaining lung
function in adults and adolescents with asthma in clinical trials of 824 weeks
duration. Ciclesonide 320 and 640 g/day was significantly more effective than
budesonide 400 g/day and beclometasone 800 g/day, respectively, in improving some lung function parameters in two recent, well designed trials. Recipients
of ciclesonide also generally experienced improvements from baseline in asthma
symptom scores and rescue medication use, with ciclesonide 640 g/day demonstrating significantly greater efficacy than beclometasone in this regard in one
study.
Ciclesonide also showed beneficial effects as a prophylactic treatment in
paediatric patients with persistent asthma. In a large, well designed, 12-week trial,
ciclesonide generally produced significant improvements in lung function, asthma
symptom scores and rescue medication use compared with placebo in children
with persistent asthma of varying severity. Furthermore, in additional short-term
trials, ciclesonide 160 g/day was noninferior to, or generally as effective as,
fluticasone propionate or budesonide, in improving lung function in paediatric
patients with persistent or moderate to severe asthma. Ciclesonide was also
noninferior to, or as effective as, these inhaled corticosteroids in improving
asthma symptom scores and rescue medication use.
In addition, treatment with inhaled ciclesonide for 12 weeks was effective in
improving the health-related quality of life of adult and paediatric patients with
asthma in placebo-controlled studies. Moreover, the drug was generally no less
effective than fluticasone propionate or budesonide in this regard in studies of 12
or 24 weeks duration.
Inhaled ciclesonide was generally well tolerated in adults and adolescents with
asthma in clinical trials, with adverse events generally being mild to moderate in
severity. Ciclesonide was also well tolerated in paediatric patients with asthma.
The tolerability profile of ciclesonide may be more favourable than that of other
inhaled corticosteroids (fluticasone propionate, budesonide and beclometasone)
in terms of local oropharyngeal adverse events, such as oral candidiasis and
hoarseness.

1. Introduction
Inhaled corticosteroids are currently the gold
standard preventative treatment for persistent asthma.[1,2] However, concerns about the potential local
2008 Adis Data Information BV. All rights reserved.

and systemic adverse events associated with these


agents and their frequency of administration has
prompted the development of new agents with more
favourable safety and tolerability profiles.
Drugs 2008; 68 (12)

1744

Ciclesonide (Alvesco)1 is a synthetic corticosteroid formulated for oral inhalation via an hydrofluoroalkane (HFA) metered-dose inhaler (MDI) for
use in the treatment of persistent asthma in adults,
adolescents and, in some countries, children. This
article reviews the pharmacological properties of
ciclesonide and its efficacy and tolerability in the
treatment of adult and paediatric patients with asthma.
Throughout this review, ex-actuator doses (ExA;
the dose delivered from the mouthpiece) are reported where available. Ex-valve doses (i.e. the metered
dose within the inhaler) are referred to as ExV. The
ciclesonide HFA-MDI delivers an ExV dose of
50 g from the valve with a corresponding ExA
dose of 40 g from the actuator, an ExV dose of
100 g from the valve with a corresponding ExA
dose of 80 g from the actuator or an ExV dose of
200 g from the valve with a corresponding ExA
dose of 160 g from the actuator. Thus, ciclesonide
HFA-MDI ExA doses of 40, 80, 160, 320 and
640 g are equivalent to 50, 100, 200, 400 and
800 g ExV doses.[3-5] The pharmacology and clinical profile of ciclesonide have been reviewed previously in Drugs.[6]
2. Pharmacodynamic Properties
Discussion here focuses on the pharmacodynamics of ciclesonide delivered via an HFA-MDI
where possible. In addition, for completeness, data
from studies using the Cyclohaler dry powder inhaler (DPI) are also included.[7,8] The type of inhalation device was reported as a MDI,[9-14] a chlorofluorocarbon (CFC)-free MDI[15] or was not specified[16-20] in some studies.
The pharmacodynamic properties of both the Rand S-epimers of ciclesonide were evaluated in
some studies; however, this section focuses only on
the properties of the R-epimer (table I), which underwent development for clinical use.[21]
Data are from studies in adults, adolescents and
children with asthma,[7,8,12,13,15,18-20,22-35] patients
with an asthma exacerbation,[36] healthy volunteers,[14] clinical trials discussed in section
4,[4,5,9-11,16,17,37-42] and several in vitro[43-49] and in
vivo or ex vivo animal studies.[48-51] Additional data
1

Deeks & Perry

are sourced from the manufacturers prescribing information;[21] some data are only available as abstracts.[9,10,22,24,28,30,36,42,44,46,47,50]
2.1 Mechanism of Action

Ciclesonide is a nonhalogenated, inhaled corticosteroid prodrug that is converted by esterases in the


lung (see section 3) to its clinically active metabolite
desisobutyryl-ciclesonide (des-CIC; also known as
R-M1, ciclesonide active principal and ciclesonide
active metabolite).[21] Corticosteroids exert anti-inflammatory effects by binding to glucocorticoid receptors with subsequent transrepression or transactivation of genes involved in inflammatory and antiinflammatory processes.[52]
Ex vivo studies in rats suggest a marked affinity
of ciclesonide for lung tissue following intratracheal
administration.[50] The relative binding affinity of
des-CIC to the glucocorticoid receptor is high and is
100-fold greater than that of ciclesonide, according
to in vitro binding assays.[48,49]
2.2 Anti-Inflammatory Effects

Several studies have demonstrated the anti-inflammatory effects of ciclesonide in vitro.[43-48] In


general, des-CIC appeared to confer greater antiinflammatory activity than ciclesonide.[46-48]
In vitro, ciclesonide and/or des-CIC were generally effective in inhibiting pro-inflammatory functions, including the stimulated expression of intracellular adhesion molecule-1[43,45] and the stimulated release of inflammatory mediators, such as
granulocyte-macrophage colony-stimulating factor,[45,46] monocyte chemoattractant protein-1
(MCP-1),[43] interferon (IFN)-,[48] interleukin (IL)2,[48] IL-4,[48] IL-5,[48] IL-8[45] and tumour necrosis
factor-.[47] Ciclesonide and des-CIC also inhibited
the induced proliferation of immune system cells
(human peripheral blood mononuclear cells, CD4+
lymphocytes and rat spleen cells[48]) [table I] as well
as human airway smooth muscle cells (table I),[46]
the hyperplasia of which is characteristic in patients
with asthma.[53]
The anti-inflammatory effects of ciclesonide
treatment have been confirmed in patients with mild

The use of trade names is for product identification purposes only and does not imply endorsement.

2008 Adis Data Information BV. All rights reserved.

Drugs 2008; 68 (12)

Ciclesonide: A Review

1745

Table I. Overview of the pharmacodynamic properties of ciclesonide (CIC; R-epimer) and desisobutyryl-CIC
Anti-inflammatory effects
Generally inhibits release of inflammatory mediators and proliferation of inflammatory cells and airway smooth muscle cells in vitro[43-48]
Inhibits TGF-1-induced upregulation of -smooth muscle actin expression in human lung fibroblasts in vitro[43]
Inhibits the levels of pro-inflammatory cytokines in sputum of patients with mild persistent asthma[18]
Attenuates allergen-induced 2-fold increases in the production of some cytokines and reduces chemokine (CCL17)-induced T-cell
migration in patients with atopic asthma[13]
Attenuates increases in eosinophils and mediators of inflammation induced by antigen in in vivo rat studies[48,49]
Inhibits bradykinin-induced mucosal leakage into the trachea[48] and dextran gel-induced lung oedema[49] in in vivo rat models
Prevents and reverses allergen-induced airway inflammation, remodelling and bronchial hyper-responsiveness in rats[51]
Stronger local than systemic anti-inflammatory effects in an in vivo rat model[48]
Effects on markers of airway inflammation
Reduces percentage of eosinophils in sputum[7,15,35] and serum levels of ECP[7,15] in patients with asthma
Attenuates allergen-induced levels of eosinophils in sputum[23,31] and ECP in serum[31] in patients with asthma
Attenuates allergen-induced reductions in interferon--positive CD4+ T cells after allergen provocation at some dosages in patients with
atopic asthma[23]
Reduces exhaled nitric oxide levels in patients with asthma[15,18-20,32,35]
Pulmonary effects
Attenuates airway responsiveness to AMP[7,15,18,20,34,35] and methacholine[20,32] in patients with mild to moderate asthma
Improves some, but not all, measures of airway trapping indicative of small airway obstruction in patients with mild to moderate
asthma[20]
Reduces early- and/or late-phase allergen-induced bronchoconstriction in patients with atopic[13,23] or mild allergic[8,31] asthma
Attenuates exercise-induced bronchoconstriction in patients with asthma[12]
Systemic effects
No clinically relevant HPA-axis suppression at therapeutic doses in healthy adults,[14] or adults, adolescents and children with
asthma[4,5,7-11,16,17,22,24-30,32,34,38-42]
Negligible impact on markers of bone formation in patients with moderate to severe asthma[9,10]
No appreciable effect on growth velocity, height or skeletal maturity in children with mild asthma[25,29,37]
AMP = adenosine monophosphate; ECP = eosinophil cationic protein; HPA = hypothalamic-pituitary-adrenal; TGF-1 = transforming growth
factor-1.

persistent asthma. In a small (n = 21), randomized,


double-blind, crossover trial,[18] once-daily ciclesonide 320 g significantly (p < 0.05 vs placebo)
inhibited levels of IL-12 and MCP-1 in sputum
within 4 hours of administration. Inhibition of IL-12
and MCP-1 levels, as well as levels of other cytokines, including IL-1, IL-6, IL-7 and IL-8, in sputum was observed within 4 hours of patients receiving twice-daily ciclesonide 640 g (all p < 0.01 vs
placebo). In addition, levels of IFN-inducible protein-10 were significantly (p < 0.001) inhibited compared with placebo after 1 week of treatment with
ciclesonide 640 g twice daily.[18]
Furthermore, once-daily ciclesonide 80 g attenuated allergen-induced 2-fold increases in the production of some cytokines (IL-4 and IL-5), according to data from one centre (n = 5 evaluable patients)
of a randomized, double-blind, placebo-controlled
crossover study in patients with mild atopic asth 2008 Adis Data Information BV. All rights reserved.

ma.[13] The drug also significantly (p < 0.05) reduced chemokine (CCL17)-induced T-cell migration versus placebo, both prior to, and 6 hours after,
allergen challenge (table I), with such migration also
significantly (p < 0.05) lower after than before allergen challenge in ciclesonide recipients.[13]
Potent anti-inflammatory effects of ciclesonide
have also been demonstrated in several in vivo
animal studies (table I).[48,49,51] Furthermore, in rats,
ciclesonide exhibited stronger local than systemic
anti-inflammatory activity (no statistical analyses
reported)[48] and was up to 44-fold less potent than
fluticasone propionate in producing systemic effects.[49]
Smooth muscle actin reduction has been shown
to correlate with improvements in airway function in
patients with asthma.[54] Ciclesonide has demonstrated an ability to downregulate transforming growth
Drugs 2008; 68 (12)

1746

factor-1-induced -smooth muscle actin expression in human lung fibroblasts in vitro.[43]


2.2.1 Effects on Markers of Airway Inflammation

Asthma is associated with airway inflammation


and eosinophilia, with the latter a possible determinant of asthma severity.[55] In general, ciclesonide
significantly reduced the percentage of eosinophils
in induced sputum compared with pretreatment,[7,15]
run-in[35] or washout levels or placebo[35] in randomized, double-blind[7,35]/double-observer,[15] placebo[7,35] or active comparator-controlled,[15] crossover
trials in patients with asthma (table I).
Ciclesonide has also demonstrated beneficial effects on allergen-induced sputum eosinophil levels
in patients with atopic[23] or mild allergic[31] asthma
in randomized, double-blind, placebo-controlled,
crossover studies (n = 10[23] or 21[31]). The percentage of induced sputum eosinophils was significantly
attenuated with low-dose ciclesonide (40 and 80 g/
day) 24 hours after allergen challenge in one
study,[31] with the highest ciclesonide dosage (80 g/
day) also attenuating the number of induced sputum
eosinophils at this timepoint (all p < 0.025 vs placebo). In contrast, the number of allergen-induced
sputum eosinophils was significantly attenuated
with both ciclesonide 40 and 80 g/day 8 hours, but
not 24 hours, after allergen challenge in the other
study (p < 0.05 vs placebo).[23]
In sputum, levels of eosinophil cationic protein
(ECP), a product released by activated eosinophils,
were also significantly (p < 0.05) reduced from
pretreatment levels with ciclesonide 400 g/day (administered via DPI[7] or CFC-free MDI[15]) in patients with asthma in two studies. However, ciclesonide 100 and 1600 g/day had no effect on this
parameter in one study.[7] Allergen-induced levels of
serum ECP were significantly (p = 0.024) attenuated
with ciclesonide 80 g/day compared with placebo;
however, there was no significant difference between ciclesonide 40 g/day and placebo.[31]
IFN- is a potential anti-inflammatory modulator.[56,57] In a randomized, crossover study in ten
patients with atopic asthma,[23] ciclesonide 40 g/
day attenuated allergen-induced reductions in IFN-positive CD4+ T cells 24 hours after allergen
provocation (p < 0.05 vs placebo), although such
attenuation was not seen with ciclesonide 80 g/day.
2008 Adis Data Information BV. All rights reserved.

Deeks & Perry

In general, ciclesonide was also effective in reducing levels of exhaled nitric oxide, a potential
marker of airway inflammation, in patients with
asthma of mild to moderate severity.[15,18-20,32,35]
2.3 Pulmonary Effects

In general, treatment with ciclesonide significantly reduced airway responsiveness to adenosine


monophosphate[7,15,18,20,34,35] and methacholine challenge[20,32] in patients with asthma of mild to moderate severity (all p < 0.05 vs placebo or pretreatment,
where reported[7,15,18,20,32,34]) [table I]. Moreover, in
terms of reducing airway responsiveness, ciclesonide 3201280 g/day was as effective as fluticasone propionate 4401760 g/day,[24,32,33] and
there was no significant difference between ciclesonide 320 g/day and budesonide 400 g/day
(ExV),[15] in randomized, double-blind[24,32,33]/double-observer,[15] dose-escalating[24] or crossover[15,32,33] trials (15103 randomized patients)
with 2- to 4-week treatment periods.
In addition, ciclesonide 320 g/day improved
some, but not all, measures of air trapping indicative
of small airway obstruction (p < 0.05 vs placebo), in
patients with mild to moderate asthma in a randomized, double-blind, 5-week study (n = 16).[20]
Early- and/or late-phase bronchoconstriction responses to allergen challenge were generally also
reduced with ciclesonide treatment in patients with
atopic[13,23] or mild allergic[8,31] asthma (all p < 0.05
vs placebo).
Exercise-induced bronchoconstriction, experienced by 7080% of patients with asthma, was
attenuated to a clinically relevant extent in ciclesonide 320 g/day recipients.[12]
2.4 Systemic Effects

Inhaled corticosteroids may cause hypothalamicpituitary-adrenal (HPA)-axis suppression, which


may manifest as cataracts, reduced bone density and
retardation of growth velocity in children.[58,59]
Nevertheless, to date, no clinically relevant evidence of HPA-axis suppression, as measured by
serum cortisol levels (morning[7] or 24-hour profile[14]) or 24-hour urinary cortisol levels,[8] has been
observed following short-term treatment (1- to
2-week periods) with inhaled ciclesonide
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Ciclesonide: A Review

1001600 g/day in randomized, double-blind, placebo-controlled, crossover trials in adults with mild
to moderate asthma (aged 1846 years)[7,8] or
healthy volunteers (aged 2128 years)[14] [table I].
HPA-axis suppression was also negligible in
adults and adolescents receiving low to high doses
of ciclesonide (801280 g/day) in active comparator-[24,26,27,32,34] and placebo-controlled[26,27,32,34]
studies of 9 days to 12 weeks duration, and in
12-week clinical trials discussed in section
4.[4,5,9,11,17,39-41] In these studies, measures of HPAaxis suppression included overnight[32] or
24-hour[4,5,9,11,17,24,26,27,34,40,41] urinary cortisol levels,
serum cortisol levels,[4,5,9,39] 24-hour serum[24,27] or
plasma[34] cortisol levels and stimulated plasma[32]
or serum[17,26,27,39] cortisol levels.
Although data on the effects of ciclesonide on
HPA-axis function over the longer term are limited,
preliminary data from noncomparative[30] and comparative[22] multicentre extension studies in adults
and adolescents with mild to moderate[30] or severe[22] persistent asthma showed no clinically relevant or marked suppressive effects on low-dose
cosyntropin-stimulated serum cortisol levels or
24-hour urinary cortisol levels over 52 weeks in
patients who received therapeutic dosages of inhaled ciclesonide. Similar findings have been reported in long-term clinical studies discussed in
section 4.1.[10,42]
In children with asthma, HPA-axis function in
terms of 10-[25] or 12-hour[29] overnight urinary cortisol levels, 24-hour urinary cortisol levels[25,28] and
low-dose cosyntropin-stimulated serum cortisol
levels[28] was not suppressed following treatment
with ciclesonide 40160 g/day in short-[29] or longterm[25,28] randomized,[25,28,29] double-blind[25,29] or
nonblind[28] trials (table I). These data are supported
by the results of some,[16,38] but not all,[37] clinical
trials in children with asthma discussed in section 4.
Inhaled high-dose ciclesonide (640 g twice
daily) had a significantly (p < 0.0001) lower suppressive effect on serum cortisol levels than oral
prednisolone 40 mg once daily in patients with acute
asthma exacerbation.[36] Moreover, in some instances, HPA-axis suppression was significantly
(p < 0.05) lower with ciclesonide than with fluticasone propionate[24,26,27,32,34] (between-group statis 2008 Adis Data Information BV. All rights reserved.

1747

tical analyses not reported in one study[24]). However, results were mixed with regard to HPA-axis
suppression measured by 24-hour urinary cortisol
levels in trials comparing ciclesonide with budesonide.[11,37,40,41] In three of the trials,[11,37,40] HPA-axis
suppression was significantly (p < 0.05) lower with
some dosages of ciclesonide compared with budesonide. No significant difference in this parameter was
observed between ciclesonide and budesonide recipients in one study.[41]
Ciclesonide had a negligible effect on markers of
bone formation in one short-term study[9] and its
extension phase.[10] Levels of markers of bone formation were significantly (p < 0.05) increased compared with beclometasone pretreatment after 12[9]
(serum osteocalcin) and 52[10] (serum osteocalcin
and serum alkaline phosphatase) weeks of ciclesonide treatment in patients with moderate to severe
asthma. Furthermore, low-dose ciclesonide (40 or
160 g/day) had no effect on skeletal maturity in the
majority of prepubertal children with asthma in a
double-blind, placebo-controlled, 52-week study
(n = 661)[25] [table I].
Inhaled corticosteroids may inhibit growth velocity in children, although final adult height does not
appear to be affected.[60] Long term, low-dose
ciclesonide (40 or 160 g/day) was noninferior to
placebo with regard to mean linear growth velocity
in prepubertal children in a large (n = 661), doubleblind, 52-week trial (respective differences vs placebo of 0.02 cm/year [95% CI 0.19, 0.16] and
0.15 cm/year [95% CI 0.33, 0.03]; 0.5 cm/year
noninferiority limit).[25] Moreover, there was no significant difference between ciclesonide and placebo
recipients in terms of mean change from baseline in
height.[25] The mean lower-leg growth rate of children (n = 24) aged 612 years with mild asthma
receiving ciclesonide 40160 g/day was similar to
that of placebo recipients in a double-blind, crossover study with 2-week treatment periods[29] (table
I). Notably, the height of children treated with
ciclesonide 160 g/day (n = 58) increased significantly from baseline compared with budesonide
400 g/day (ExV) recipients (n = 26) [1.18 vs
0.70 cm; p = 0.0025] in a subgroup analysis of one
12-week trial.[37]
Drugs 2008; 68 (12)

1748

Deeks & Perry

3. Pharmacokinetic Properties
This section focuses on the pharmacokinetics of
ciclesonide inhaled via an HFA-MDI, unless otherwise stated. Data are from studies in healthy volunteers,[3,61-66] patients with asthma[65,67-69] or undergoing lung surgery[70] and from a population pharmacokinetic study.[71] Additional data have been
obtained from the manufacturers prescribing information,[21] the summary of product characteristics[72,73] and from in vitro[43,45,74-82] and in vivo
animal[83] studies. Some data are available only as
abstracts.[66,70,71,80]
An overview of the pharmacokinetic properties
of ciclesonide and its active metabolite des-CIC is
provided in table II. The pharmacokinetics of desCIC do not appear to be affected by asthma severity,
gender, weight or race, according to a pooled population pharmacokinetic/pharmacodynamic analysis
model.[71] In elderly patients, des-CIC exposure may
be marginally increased compared with young patients,[21] although the changes are not clinically
relevant and require no dosage adjustment.[72,73]
Similarly, no clinically relevant changes in the pharmacokinetic profile of ciclesonide are observed in
patients with mild to moderate hepatic impairment;[21] dosage adjustments are not recommended
in this patient population.[72,73] Furthermore, the
pharmacokinetics of des-CIC after inhalation of a
single ciclesonide 320 g dose were not appreciably
different when ciclesonide was delivered with or
Table II. Summary of the pharmacokinetic properties of ciclesonide
(CIC) and desisobutyryl-CIC (des-CIC) after oral inhalation of a
single 320 g dosea in patients with asthma aged 1952 years
(n = 12[67] and 30[69]). Values are means unless specified otherwise
Parameter

CIC

Lung deposition (%)

52[67]

Oropharyngeal
deposition (%)

32.9[67]

des-CIC

Cmax (g/L)

0.91.9[67,69]

AUC0- (g h/L)

0.50.9

tmax (h)

0.25[67,69]

0.94,[67] 1.0[69]b

0.5,[69]

4.66.02[67,69]

[67,69]

0.57[67]

0.3,[69] 0.41[67]
1.3,[69] 1.87[67]

t /2 (h)
a Administered with[67,69] or without[67] a spacer.
1

Median value.

AUC0- = area under the serum concentration-time curve from time


0 to infinity; Cmax = maximum serum concentration; tmax = time to
reach Cmax; t1/2 = elimination half-life.

2008 Adis Data Information BV. All rights reserved.

without an AeroChamber Plus spacer in patients


with asthma.[69]
3.1 Deposition

The mean deposition of ciclesonide in the lung


was 52%, both in patients with mild asthma
(n = 12)[67] and in healthy volunteers (n = 8),[3] after
inhalation of a single radiolabelled dose of
320 g,[67] or after a single or multiple inhalations of
a radiolabelled 40 g dose.[3] Deposition occurred
throughout the lungs, but was greater in peripheral
regions containing the small airways and alveoli
than in central regions.[3,67] The mean oropharyngeal
deposition of ciclesonide was 32.9%[67] and 38.0%[3]
in the respective studies.
Oropharyngeal deposition of ciclesonide following inhalation via an HFA-MDI was lower than that
of budesonide[63] and fluticasone propionate[68] inhaled via a CFC-[63] and HFA-[68] MDI. Following
inhalation of a single dose of ciclesonide 640 g, the
oropharyngeal molar-adjusted area under the concentration-time curve (AUC) from time zero to
1 hour (AUC1) for des-CIC and total ciclesonide
(des-CIC and parent drug) was 4% and 47% that of
a single dose of budesonide 800 g (ExV; both
p < 0.0001) in healthy volunteers (n = 18),[63] and
8% and 53% that of a single dose of fluticasone
propionate 880 g (both p < 0.001) in patients with
asthma (n = 18).[68]
The amount of ciclesonide present in the oropharynx following inhalation of a 640 g dose of
ciclesonide rapidly decreased within 15 minutes in
healthy volunteers[63] and patients with asthma[68]
(both n = 18). Furthermore, the mean oropharyngeal
AUC1 for des-CIC was 8%[63] and 17%[68] that of
ciclesonide (point estimates), suggesting low oropharyngeal activation of ciclesonide to desCIC.[63,68]
3.2 Absorption and Distribution

The systemic absorption of ciclesonide is minimal, thus reducing the likelihood of systemic adverse events.[21] The maximum plasma concentration of ciclesonide and des-CIC is approximately
dose related following single inhaled doses of
ciclesonide 320 and 1280 g in patients with asthma.[65,67,69]
Drugs 2008; 68 (12)

Ciclesonide: A Review

In healthy volunteers, the absorption pharmacokinetics of des-CIC were generally similar at steady
state and after a single ciclesonide 320 g dose, with
no apparent accumulation of des-CIC.[21]
Airway inflammation associated with asthma appears not to affect the distribution of ciclesonide, as
the pharmacokinetic profile of both ciclesonide and
des-CIC in patients with asthma and a forced expiratory volume in 1 second (FEV1) of 6090% of
predicted did not markedly differ from that seen in
healthy volunteers.[65] Evidence suggests that desCIC does not accumulate in red blood cells.[21]
The oral bioavailability of ciclesonide and desCIC is <0.5% and <1.0% after ciclesonide inhalation.[21] Ciclesonide and des-CIC are highly plasma
protein bound (99% and >98%)[79] and systemic
exposure is low (12%) after ciclesonide inhalation.[21]
Ciclesonide has a mean volume of distribution of
2.91 L/kg following a single intravenous 800 g
dose in healthy volunteers.[66]
3.3 Metabolism and Elimination

Ciclesonide is hydrolyzed to des-CIC by esterases in the lungs;[21] such hydrolysis has been demonstrated in airway epithelial cells,[45,76,78] lung fibroblasts[43] and human lung tissue[81,82] in vitro, as
well as in human[70] and animal[83] lung tissue in
vivo. Des-CIC forms reversible lipophilic fatty acid
conjugates in lung tissue/cells according to in vitro[78,81,82] and in vivo[70,83] studies, which may facilitate its pulmonary retention.
Hydrolysis of ciclesonide to des-CIC and formation of des-CIC esters has also been demonstrated in
nasal epithelium cells[75] and in tracheal tissue[74] in
vitro. Some in vitro study data suggest retention of
the drug in airway tissue may be determined by
factors other than fatty acid esterification (e.g.
lipophilicity).[74]
Ciclesonide undergoes extensive first-pass metabolism in the liver.[64] In vitro data have shown that
the drug is predominantly metabolized by the cytochrome P450 (CYP) isoenzyme 3A4.[77]
Elimination of ciclesonide was predominantly
via faeces after administration of a single radiolabelled 6.9 mg oral (77.9%) or 0.64 mg intravenous
(66.0%) dose in six healthy volunteers, with com 2008 Adis Data Information BV. All rights reserved.

1749

plete elimination achieved 80120 hours after administration.[64] The clearance of ciclesonide and
des-CIC (assuming complete ciclesonide activation)
was 152 and 228 L/h after intravenous administration.[21]
In patients with asthma, the mean serum elimination half-life (t1/2) of ciclesonide was rapid compared
with that of des-CIC after inhalation of a single
320 g dose of ciclesonide (table II).[67,69] Furthermore, the serum t1/2 values for both ciclesonide and
des-CIC following administration of a single
ciclesonide 320 g dose were generally similar regardless of spacer use in patients with asthma.[69] At
steady state, the mean t1/2 of des-CIC was 6.72 hours
in healthy volunteers (n = 18) after ciclesonide
320 g inhalation.[21]
3.4 Drug Interactions

Ciclesonide appears to have a low potential to


interact with drugs metabolized by CYP isoenzymes, based on the results of in vitro studies.[80]
However, it is anticipated that ciclesonide may interact with strong inhibitors of the CYP3A4 system
(e.g. nelfinavir, ritonavir and itraconazole). When
inhaled ciclesonide 320 g/day was coadministered
with ketoconazole 400 mg/day (a strong inhibitor of
CYP3A4) in healthy volunteers, the geometric least
squares mean values for des-CIC Cmax and AUC
during the 24 hour dosage interval increased 2- and
3.5-fold.[61] However, there were no significant
changes in the pharmacokinetic profile of ciclesonide upon coadministration of ketoconazole with
regard to these parameters.[61]
4. Therapeutic Efficacy
The efficacy of ciclesonide in the prophylactic
treatment of asthma has been compared with that
of placebo and several active comparators in numerous randomized trials in adults and adolescents (section 4.1)[4,5,11,17,39-42,84-93] and children (section
4.2).[16,37,38,94,95] The estimated dose equivalence between ciclesonide and other inhaled corticosteroids
of relevance to this section in both adults and children are shown in table III.
Ciclesonide was delivered via an HFA-MDI in
most studies;[4,5,37-41,84,86,88-93,95] ciclesonide inhalers
were reported as MDIs[11,94] or were not clearly
Drugs 2008; 68 (12)

1750

Deeks & Perry

Table III. Estimated daily dose equivalence between ciclesonide


and other inhaled corticosteroids in both adults and children, according to current treatment guidelines[1]
Agent

Dose range (g)


low

medium

high

Adults
Ciclesonide

80160

>160320

>3201280

Budesonide

200400

>400800

>8001600

Fluticasone
propionate

100250

>250500

>5001000

Beclometasone

200500

>5001000

>10002000

Children
Ciclesonide

80160

>160320

>320

Budesonide

100200

>200400

>400

Fluticasone
propionate

100200

>200500

>500

Beclometasone

100200

>200400

>400

specified[16,17,85,87] in some trials. In active comparator-controlled studies, fluticasone propionate was


delivered via an HFA-MDI,[38,84,86,92,93,95] MDI[94]
or DPI,[91] budesonide was delivered via a
DPI[11,37,40,41,90] or HFA-MDI,[89] and beclometasone
was administered via a CFC inhaler.[88] ExA doses
are reported for MDIs, whereas ExV doses are reported for DPIs.
4.1 Adults and Adolescents

The clinical efficacy of ciclesonide has been


compared with that of placebo,[4,5,17,39,85,87] budesonide,[11,40,41,89,90] fluticasone propionate[84,86,91-93] and
beclometasone[88] in randomized,[4,5,11,17,39-41,84-93]
double-blind[4,5,11,17,39,41,84-87,90,92] or nonblind[88,91,93]
trials of 824 weeks duration. Patients (n >100)
were adults and adolescents aged 12 years with
mild to moderate,[4,5,17,40,84,85] moderate,[41,91] moderate to severe,[88,93] severe[11,39,87] and stable[86] asthma, where stated (reported as persistent in most
studies[4,5,11,17,39,41,87-93]). In general, patients had
been previously treated with corticosteroids, where
stated.[4,5,11,39-41,84-86,88-90,92,93] In some studies, patients not using inhaled corticosteroids[17] (i.e. receiving only rescue medication,[41,92] bronchodilators[91] or non-steroidal controllers[91]) or those using
inhaled corticosteroids 30 days prior to screening[17]
were eligible. Overall, patients had an FEV1 predicted of 52101% at baseline, where reported.[4,5,11,17,39-41,84-93] Treatment was double-blind
2008 Adis Data Information BV. All rights reserved.

with respect to ciclesonide and nonblind for budesonide in two trials.[40,89] A nonblind, 40-week extension[42] of one 12-week study[4] has also been reported, and the trials by Pearlman et al.[17] and Knox et
al.[86] each report combined data from two identical
placebo-[17] or active comparator-controlled[86]
trials. Some of the study data are available only as
abstracts.[42,87]
Other studies include randomized, double-blind,
12-week, dose comparison[9,96] and regimen (i.e.
morning vs evening administration)[97] trials and a
40-week continuation[10] of one trial;[9] some data
are available only as abstracts.[9,10] In the regimen
study,[97] the efficacy of ciclesonide 160 g/day was
generally similar when administered in the morning
or the evening, although morning peak expiratory
flow (PEF) was improved to a significantly
(p < 0.05) greater extent with evening administration. In one dosage comparison,[9] ciclesonide
640 g twice daily was not superior to ciclesonide
320 g twice daily in treating patients with moderate
to severe bronchial asthma. Moreover, patients who
completed the dose comparison[9] and subsequently
received ciclesonide 1280 g/day for 4 weeks, had
sustained beneficial effects with individualized
ciclesonide dosages throughout a 40-week extension
period.[10] However, in another study,[96] twice-daily
ciclesonide 320 g was superior in efficacy to oncedaily ciclesonide 160 g in patients with severe
asthma with regard to most parameters, including
the time to first asthma exacerbation (primary endpoint). Ciclesonide was delivered via an MDI[9,10]
(specified as an HFA-MDI[97]), where clearly reported. These studies are not discussed further within
this review.
Eligibility criteria for the clinical trials in adults
and adolescents are summarized in table IV; one
study was conducted only in Japanese patients.[85]
Most trials excluded patients who had received
recent treatment with systemic or injectable corticosteroids,[5,11,17,40,41,84-86,88-93] with some excluding
those who had received recent treatment with oral
corticosteroids,[4,5,17,40] inhaled corticosteroids,[40]
long-acting 2-adrenoceptor agonists (LABAs)[5,86]
or an inhaled corticosteroid plus a LABA.[92]
During a baseline period of up to 28 days, patients received placebo,[17] oral prednisone,[39] inhaled corticosteroids,[4,5,11,39,85,86,88-91,93] rescue medDrugs 2008; 68 (12)

Ciclesonide: A Review

1751

Table IV. Eligibility criteria for the enrolment and randomization of adult and adolescent patients with asthma in randomized, comparative,
clinical trials of ciclesonide
Trial eligibility criteria
History of asthma[4,5,11,17,40,41,84,86,89-93] or oral corticosteroid-dependent asthma[39] of 6[11,17,40,41,84,86,89-93] or 12[39] months duration
Previous treatment with inhaled corticosteroids[4,5,11,39,41,85,88,93] for 28 days[4,5,11,41,85,88,93] or 6 months[39] prior to the study, with no
change in regimen/dose, where stated[4,5,11,41,93]
Previous treatment with inhaled corticosteroids 30 days prior to screening or receiving no such therapy[17]
Oral prednisone treatment during 5 of the 6 months before the trial[39]
Maintenance of asthma control with an inhaled corticosteroid within 1[84,89] or 3[86] months prior to the study
Previous treatment with asthma medications (at stable regimens where stated[41,91]) 2830 days preceding the study[17,41,91]
Eligibility criteria for randomization
FEV1 predicted value of: 6090%,[5] 5090%,[41] 6190%,[92] 90%[86] or >50% to <80%;[11] 80% in patients previously treated with
inhaled corticosteroids;[91] 6080% in patients previously treated with bronchodilator/nonsteroidal controller therapy without inhaled
corticosteroids;[91] 6090%,[4] 6085%,[17] 4080%,[39] 5090%,[84] >69%[89] or 80%[93] after 4[84,89,93] or 6[17,39] hours without rescue
medication[17,39,84,89,93] or bronchodilator[4] use, and 24 hours after controller use[93]
Reversibility of FEV1 of 12%[4,17,39,86,89,91,93] or 15%[5,11,40,41,84,92] in response to a 2-adrenoceptor agonist[4,5,11,17,40,41,84,86,89,91,93] or
inhaled medication[39]
Morning PEF predicted value of 6090%[85] or 80%[88] and 15% reversibility of airflow limitation[88]
PEF variability of 15%,[4,5,40,41,84,91-93] >20%[17] or <20%[89]
10% decrease in FEV1 after discontinuation of pretrial inhaled corticosteroid therapy[40,41,84]
FEV1 = forced expiratory volume in 1 second; PEF = peak expiratory flow.

ication,[4,40,41,84,90-92] theophylline[4,93] and/or other


asthma medications.[93] Patients in one trial[90] received high-dose budesonide (1280 g/day exmouthpiece via DPI) during a post-baseline 2- or
4-week pretreatment phase. Eligibility criteria for
randomization, where stated, are summarized in
table IV.
Some studies permitted the use of concomitant
medications including short-acting 2-adrenoceptor
agonists,[4,5,11,17,39,41,86,89-91,93] low-potency corticosteroid cream/ointment,[17,39] sodium cromoglicate,[17,39] antihistamines,[17,39] intranasal corticosteroids (for the treatment of rhinitis),[39] maintenance
immunotherapy[17] and other asthma medications.[39,89,93] Asthma medications other than systemic corticosteroids, injectable -adrenoceptor agonists and theophilline were permitted in one
study.[85]
Primary and secondary efficacy outcomes, where
stated, are shown in table V. Among patient selfmeasurements, where reported, were asthma
scores,[4,5,11,17,39-41,85,86,88,90,91,93] including daytime
scores (on a 5-point scale from 0 [no asthma symptoms] to 4 [asthma symptoms disrupting sleep and
daytime activities]) and night-time scores (on a
5-point scale from 0 [no symptoms, undisturbed
sleep] to 4 [awake during the night because of
2008 Adis Data Information BV. All rights reserved.

asthma]),
and
use
of
rescue
medication[5,11,17,39-41,85,88,90,91,93]
or
prednisone.[39]
Where stated, analyses were last-observation-carried-forward for lung function variables[4] (primary[5,17,40,41] and secondary[17,40] endpoints where
specified).
Trial discontinuation was required in the event
of an asthma exacerbation in some studies,[11,40,41,89,91-93] and the rate of such discontinuation was a coprimary endpoint in one trial.[93] Asthma exacerbations were defined as an increase[41,92]
or worsening[93] of asthma symptoms, reduction in
lung function[41,92,93] or deterioration of asthma[91]
requiring oral corticosteroids.[41,91-93] Some studies
specified trial discontinuation in the event of asthma
exacerbations requiring oral corticosteroids,[40,89]
twice the patients dose of inhaled corticosteroid or
salbutamol (albuterol)[89] or additional asthma medication (excluding rescue medication).[11]
The noninferiority of ciclesonide compared with
budesonide[11,40,41,89,90] or fluticasone propionate[84,91-93] was analyzed in some studies in adults
and adolescents[40,41,84,89-93] or adolescents alone,[11]
using noninferiority acceptance limits of
0.2[40,41,84,89-93] or 0.15[11] L for FEV1[11,40,41,84,89-93]
and forced vital capacity (FVC),[11,41,84,89-91,93]
25[40,41,84,89-91,93] or 20[11] L/min for PEF (both
Drugs 2008; 68 (12)

1752

Table V. Primary and secondary efficacy outcomes in randomized,


comparative, clinical trials of ciclesonide in the treatment of asthma
in adults and adolescents
Primary efficacy outcomes
FEV1[11,17,40,41,84,89-93]a
Morning PEF[4,5,84,85,88]b
FVC[84]b
Prednisone use[39]c
Lack of efficacy[4,5]d
Withdrawal rate due to asthma exacerbation[93]
Percentage of days without asthma symptoms and without rescue
medication use[11,86]
Night-time asthma symptom score[92]
Days free of asthma symptoms[86]
Days free of rescue medication use[86]
Days free of night-time awakenings[86]
Secondary efficacy outcomes
FEV1[4,5,86]
FVC[11,41,86,89-91,93]
Morning PEF[11,17,40,41,86,89,90,93]
Evening PEF[4,5,11,17,41,84,89,90,93]
Diurnal variability in PEF[4]
Rescue medication use[4,5,11,17,40,89,93]
Asthma symptom scores[4,5,11,17,40,89,93]
Percentage of days without asthma symptoms and without rescue
medication use[93]
a

Change from baseline to end of trial,[17,40,84,93] end of


treatment[41,84,89,90,92,93] or last observation.[11,17,40,41,91]

Change from baseline to end of treatment.

Change from baseline to end of trial or termination.

Defined as a 20% decrease from baseline in FEV1 or a


50% decrease in predicted FEV1; asthma exacerbation; a
daytime asthma score of 3 on 4 days within the week prior
to a study visit; a night-time asthma score of 2 on 4 nights
or 3 on 2 nights within the week before a visit,[4,5] a
reduction from baseline of 20% in PEF[4] or another lung
function deterioration that compromized health.[5]

FEV1 = forced expiratory volume in 1 second; FVC = forced vital


capacity; PEF = peak expiratory flow.

morning and evening), +0.15 for night-time asthma


symptom score,[92] +5% for the withdrawal rate due
to asthma exacerbation[93] and 8% for the percentage of days without asthma symptoms and rescue
medication use.[11] One study[88] evaluated the
noninferiority of ciclesonide compared with
beclometasone in adults and adolescents, using a
predefined noninferiority margin of 22.4 L/min for
morning PEF, and tested for superiority if noninferiority was shown. Noninferiority was based on the

2008 Adis Data Information BV. All rights reserved.

Deeks & Perry

95%[11,41,84,88-93] or 97.5%[40] confidence intervals


(CIs) for differences between groups.
In placebo-controlled trials, the efficacy of
ciclesonide was analysed in the intent-to-treat
(ITT)[4,85] or modified ITT[5,17,39] population.
Where stated, most noninferiority studies used the
per-protocol population for efficacy analyses,[11,40,41,84,89-93] with subsequent confirmatory
analyses performed in the ITT[84,90] or modified
ITT[40,89] population where specified. In one trial,[41]
further analyses were performed in the full analysis
set to test for the superiority of ciclesonide over
budesonide if noninferiority was initially demonstrated. Other active comparator-controlled studies[86,88] used the ITT patient population to assess the
efficacy of ciclesonide.
Four studies evaluated health-related quality of
life (HR-QOL) using the Asthma Quality of Life
Questionnaire (AQLQ),[17,87,91,93] which consists of
32 questions within four domains (symptoms, activities, emotional function and environmental exposure). Each question is scored on a 1- to 7-point
scale; higher scores denote a better HR-QOL.[98] In
addition, a study in adolescents (aged 1217 years)
used the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) to evaluate HR-QOL.[11] The
PAQLQ consists of 23 items across three domains
(symptoms, emotional function and activity limitations); questions are scored from 1 to 7, with a
higher score indicative of a better HR-QOL.[99] The
HR-QOL results of Weinstein et al.[87] are available
in a separate abstract.[100] HR-QOL data for another
placebo-controlled study[17] were also obtained from
an abstract.[101] In active comparator-controlled
trials, the noninferiority acceptance limit for
AQLQ[91,93] and PAQLQ[11] scores was 0.5, based
on the lower limit of the 95% CI for the betweengroup differences.
4.1.1 Versus Placebo

Ciclesonide 80640 g/day was effective in


maintaining or improving lung function in adults
and adolescents with asthma in placebo-controlled
trials of 8 or 12 weeks duration (table VI).[4,5,17,85,87]
Where stated, there were generally no significant
differences between the various ciclesonide dosages
in terms of efficacy.[4,5,17]

Drugs 2008; 68 (12)

2008 Adis Data Information BV. All rights reserved.

Percentage change from baseline.

12.7c

24.5#c,i

21.2*c,i

0.17c

0.31#c

0.29#c

0.28#c

0.03c

0.19##c

0.13***c

0.144c

0.003*c,d

0.010**c,d

0.15

0.03*

0.02#

0.01***

50c

23##c

36**c

63

31##

30##

2.70

2.67

2.52

2.62

1.15f

1.00f

1.43f

0.57f

0.86f

1.00f

4.95

5.78

5.72

6.49

3.05
3.20

0.70#c
0.61#c

3.17

3.21

0.58#c

0.15c

1.93f

1.43f

2.14f

NR

NR

NR

0.40

0.51

0.42

0.57

baseline

0.42c

1.04##c

1.02##c

0.86##c

0.5f

0.0***f

0.0***f

0.57d,f

0.00##d,f

0.00##d,f

0.64

0.03#

0.01**

change
from
baseline
0.20#

Rescue medication
use (times/day)

1.0f

0.0##f

0.0##f

0.43d,f

0.00#d,f

0.00#d,f

0.75d

0.20**d

0.04d

0.00d

change
from
baseline

Asthma symptom
score

(% of pts)b baseline

Lack of
efficacy

FEV1 = forced expiratory volume in 1 second; NR = not reported; PEF = peak expiratory flow; * p < 0.05, ** p < 0.01, *** p < 0.005, # p 0.001, ## p 0.0001 vs PL; p < 0.01,
p < 0.001, p < 0.0001 vs baseline; p < 0.01 vs CIC 80 g/day.

Overall pt population; number of pts in individual treatment groups not reported.

Median.

Abstract. This study also included a fluticasone propionate plus PL treatment arm.

Average unspecified.

Values estimated from a graph.

Least squares mean values.

pts, where stated.

or modified

Morning PEF,[4,5,85] FEV1[17] and lack of efficacy[4,5] were primary endpoints in some studies.

1.77

2.45

1.82

1.48c

2.48

9.69c

384.56

1.70c

14.59*c

2.40

2.42

20.71##c

388.02

17.22#c

18.06*c

1.78

368.64

2.55c

2.55c

2.55c

2.61

2.66

2.70

2.30

2.32

2.25

2.31

baseline change from


baseline

18.11##c

379.32

21.06#c

9.89*c

12.0c

4.0***c

2.0*

17.0e

0.7***e

3.5**e

23.28

2.64#

3.38#

1.58#

change
from
baseline

FEV1
(L)b

327.23

PL bid

ITT[5,17]

323.63

CIC 320 bid + PL bid

367.43

PL od [249]
311.25

371.41

CIC 320 od [255]

CIC 160 bid + PL bid


[531h]

354.80

CIC 160 od [250]

362.26

PL od [119]

CIC 80 od [257]

425c

18.0c

413c

CIC 320 od [113]


10.93#c

425c

3.0#c

413c

CIC 80 od [113]

425c

NR

2.0***c

NR

PL od [110]

NR

0.4##c,d
28.0c

367.28

24.95c

413c

NR

CIC 640 od [112]

389.81

0.40#c
NR

362.81

3.75#c

4.0##c,d

375.25

4.23#c

baseline

Evening PEF
(L/min)

ITT[4,85]

Weinstein et al.[87]g
[12]

[12]

al.[17]

al.[5]

Pearlman et

[12]

Langdon et

[12]

NR

360.41

PL od [79]

CIC 160 od [107]

385.97

CIC 320 od [83]

Chapman et

357.31

CIC 160 od [71]

[8]

al.[4]

367.31

CIC 80 od [78]

Adachi et al.[85]

change
from
baseline

Morning PEF
(L/min)b
baseline

Treatment regimen
(g) [no. of ptsa]

wk]

Study
[treatment duration;

Table VI. Efficacy of ciclesonide (CIC) in the treatment of asthma in adults and adolescents. Results of randomized, double-blind, placebo (PL)-controlled, multicentre, 8- or
12-week trials in adult[4,5] or adult and adolescent[17,85,87] patients (pts) with mild to moderate[4,5,17,85] or severe[87] asthma receiving CIC or PL once daily (od) or twice daily (bid)
administered via a hydrofluoroalkane metered-dose[4,5] or unspecified[17,85,87] inhaler. Ex-actuator doses and intent-to-treat (ITT) or modified ITT analyses are presented; mean
values unless otherwise noted

Ciclesonide: A Review
1753

Drugs 2008; 68 (12)

1754

Ciclesonide maintained asthma control, in terms


of morning PEF (primary endpoint[4,5,85]), compared
with placebo in patients with mild to moderate asthma,[4,5,85] with significant reductions from baseline
generally seen with placebo[4,5] (table VI). Morning
PEF was also significantly increased from baseline
with ciclesonide compared with placebo in other
studies in patients with mild to moderate[17] or severe[87] asthma, with improvements ranging from
10.93 to 21.06 L/min (table VI).
In addition, ciclesonide produced improvements
from baseline in FEV1 (primary endpoint[17]) after
12 weeks of treatment that were significantly greater
than those seen with placebo (table VI).[17,87]
Ciclesonide also significantly improved[5] or maintained[4,85] FEV1 relative to placebo in patients specified as being switched from an inhaled corticosteroid treatment regimen, with FEV1 significantly increased with ciclesonide[5] and reduced with
placebo[4] relative to baseline in some of the studies
(table VI).
During treatment, lack of efficacy (primary endpoint) was experienced by a significantly greater
proportion of placebo than ciclesonide recipients
with persistent asthma (table VI).[4,5] In one study,[5]
the likelihood of experiencing lack of efficacy was
significantly lower with ciclesonide 320 g/day than
with 80 g/day. No significant difference was found
between ciclesonide 160 and 640 g/day in terms of
this parameter in another study.[4]
Ciclesonide maintained or significantly improved evening PEF (secondary endpoint) from
baseline in comparison with placebo in adults and
adolescents with asthma (table VI).[4,5,17,85] Notably,
in one trial in adults,[4] mean diurnal PEF variability
was reduced to a significantly greater extent with
ciclesonide 160 and 640 g/day than with placebo
(0.8% and 0.4% vs +0.7%; both p < 0.05) from
respective mean baseline values of 6.5%, 6.1% and
7.3%.
Ciclesonide was also generally effective with
regard to other secondary endpoints, such as asthma
symptom scores and rescue medication use, in adult
and adolescent patients (table VI).[4,5,17,85] In general, these parameters remained stable or were significantly improved from baseline with ciclesonide versus placebo.[4,5,17,85] Notably, both asthma symptom
scores and rescue medication use significantly wors 2008 Adis Data Information BV. All rights reserved.

Deeks & Perry

ened compared with baseline in recipients of placebo in some studies.[4,5]


The use of oral prednisone was reduced to a
greater extent with ciclesonide than with placebo in
patients aged 12 years with severe, persistent,
prednisone-dependent asthma in a double-blind,
multicentre trial.[39] Patients were randomized to
receive ciclesonide 320 g (n = 47), ciclesonide
640 g (n = 49) or placebo (n = 45) twice daily for
12 weeks. At each weekly visit, patients were evaluated for prednisone dose adjustment eligibility in
line with specified criteria. Treatment with ciclesonide 640 and 1280 g/day reduced mean prednisone
use from baseline to a significantly greater extent
than placebo at study end (47.4% and 62.5% vs
+4.2%; p = 0.0003 and p = 0.0001); there was no
significant difference between individual ciclesonide dosages.[39]
Preliminary data from a 40-week, nonblind extension (n = 283)[42] of one 12-week double-blind
study[4] showed that FEV1 was significantly improved from baseline (quantitative data not reported) with ciclesonide (640 g/day for 4 weeks followed by individualized dosages) irrespective of the
treatment regimen received during the double-blind
phase (ciclesonide 160 g/day, p = 0.0133; ciclesonide 640 g/day, p = 0.0003; placebo, p = 0.0001).
4.1.2 Versus Active Comparators

Ciclesonide inhaled once or twice daily was generally no less effective than fluticasone propionate
or budesonide in terms of improving or maintaining
lung function in adults and adolescents with asthma
of varying severity in large, randomized trials (table
VII).[11,40,41,84,89-93]
In general, ciclesonide produced significant increases from baseline in mean FEV1 (the primary
endpoint in most studies). The mean change from
baseline in this parameter ranged from 0.18 to
0.52 L after 12 weeks of treatment in recipients of
ciclesonide 320 g/day (table VII).[11,40,41,90,91] A
reduction from baseline in FEV1 was observed in
ciclesonide 320 g/day recipients in only one trial
that had a high-dose budesonide pretreatment
phase;[90] however, FEV1 was reduced from baseline
to a similar extent with budesonide 400 g/day
(ExV) in this study (table VII). In addition, ciclesonide 320 g once daily was more effective than
Drugs 2008; 68 (12)

2008 Adis Data Information BV. All rights reserved.

a
b
c
d

CIC 320 od [160]


BUD 400 odj,k [160]
CIC 80 od [166]
CIC 320 od [179]
BUD 200 bidj,k [164]
CIC 160 od am [139]
CIC 160 od pm [131]
BUD 200 bidk [133]
CIC 320 od [198]
BUD 400 odj,k [201]
CIC 320 odp [249]
BUD 800 odj,k [122]

CIC 320 bid [209]


FP 330 bid [237]
CIC 320 od [201]
FP 200 bidj,k [193]
CIC 160 od [230]
FP 88 bid [221]
CIC 80 od [246]
CIC 160 od [232]
FP 88 bid [219]

(g) [no. of ptsd]

2.91
2.74
2.47g
2.47g
2.47g
2.24g,n
2.24g,n
2.24g,n
2.32
2.34
2.29g
2.29g

2.93g
2.93g
2.78i
2.78i
2.35
2.46
2.72
2.73
2.68

0.18#g (0.015, 0.121)h


0.23#g
0.26***g (0.206, 0.023)
0.27***g (0.191, 0.027)h
0.36***g
0.11***g,n (0.120, 0.045)h
0.11g,n (0.061, 0.105)h
0.11*g,n
0.42#g (0.016, 0.174)
0.32#g
0.52#g (0.122, 0.091)h
0.53#g

0.01g (0.093, 0.040)h


0.04g
0.20#g (0.121, 0.059)h
0.23#g
0.51#g (0.113, 0.053)h
0.54#g
0.44#g (0.123, 0.067)h
0.39#g (0.171, 0.019)h
0.47#g

baseline change from baseline


(95% CIe,f)

FEV1 (L)a

0.01
CIC 320 od [106]
1.92
CIC 320 bid [107]
1.86
0.09
1.98
0.02
BDP 400 bidk,q [106]
Primary endpoint in all studies, with the exception of Adachi et al.[88]
Coprimary endpoint in one study.[84]
Primary[88] or coprimary[84] endpoint in some studies.
ITT,[41,88] modified ITT[89] or per-protocol[11,40,84,90-93] pts.

Ukena et al.[41]m,o
(db) [12]
Vermeulen et al.[11]
(db) [12]
Versus BDP
Adachi et al.[88]
(nb) [8]

Niphadkar et al.[89]m,o
(db/nb) [12]

Versus BUD
Boulet et al.[90]
(db) [12]
Hansel et al.[40]o
(db/nb) [12]

[treatment duration;
wk]
Versus FP
Bateman et al.[93]
(nb) [24]
Boulet et al.[91]
(nb) [12]
Buhl et al.[84]
(db) [12]
Magnussen et al.[92]
(db) [12]

Study (design details) Treatment regimen

2.75
2.79
2.86

NR
NR
NR
NR
NR
2.92g
2.92g

3.69
3.40

3.85g
3.85g
3.72i
3.72i
3.16
3.36
4.06
4.09
4.03

0.01
0.09
0.02

NR (0.084, 0.094)h
NR (0.088, 0.092)h
NR
0.46#g (0.01, 0.20)
0.35#g
0.50#g (0.129, 0.103)h
0.52#g

0.12#g (0.024, 0.172)


0.22#g

0.01g (0.111, 0.033)h


0.05*g
0.20#g (0.134, 0.066)h
0.23#g
0.53#g (0.082, 0.099)h
0.52#g
0.31#g (0.070, 0.145)h,l
0.28#g (0.096, 0.120)h,l
0.27#g

baseline change from baseline


(95% CIe)

FVC (L)b

300
286
306

388
372
368g
368g
368g
319
325
318
365
352
370g
370g

449g
449g
395i
395i
362
372
406m
406m
397m

Continued next page

16g (1.02, 21.24)h


24g (6.97, 29.17)
6g

3g (2, 18)h
11**g
16**g (20, 9)h
18***g (17, 11)h
21***g
6g (16.4, 7.5)h
8g (2.8, 21.5)h
1g
46#g (2, 23)h
36#g
8*g (10.6, 14.7)h
6g

36#g (0.4, 28.7)h


22#g
9*g,h
3g
29#g (18, 3)h
36#g
37#l,m,n
37#h,l,m,n
46#m,n

baseline change from baseline


(95% CIe)

Morning PEF (L/min)c

Table VII. Efficacy of ciclesonide (CIC) vs inhaled fluticasone propionate (FP), budesonide (BUD) or beclometasone (BDP) in the treatment of asthma in adults and adolescents.
Results of randomized trials of 824 weeks duration in patients (pts) with mild to moderate,[40,84] moderate,[41,91] moderate to severe[88,93] or severe[11] asthma receiving CIC, FP,
BUD or BDP administered via a hydrofluoroalkane (HFA) metered-dose inhaler (MDI), unless otherwise noted. Mean values, per-protocol analyses and ex-actuator doses are
reported unless stated otherwise

Ciclesonide: A Review
1755

Drugs 2008; 68 (12)

Treatment was db for CIC, but nb for BUD.

Administered via a MDI, not specified as an HFA-MDI.

Administered via a CFC-inhaler.

2008 Adis Data Information BV. All rights reserved.

am = morning; bid = twice daily; CFC = chlorofluorocarbon; db = double-blind; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; ITT = intent-to-treat;
nb = nonblind; NR = not reported; od = once daily; PEF = peak expiratory flow; pm = evening; * p < 0.05, ** p < 0.01, *** p 0.001, # p 0.0001 vs baseline; p < 0.05,
p = 0.001 vs comparator.

Values estimated from a graph.

Noninferiority analyses and/or acceptance limits not reported.


l

Ex-valve dose.
k

m ITT[41] or modified ITT[89,92] analyses; quantitative data from per-protocol analyses not reported.

Average was not specified.

Noninferior to active comparator.


h

Administered via a dry powder inhaler[11,40,41,90,91] (specified as a Diskus[91] or Turbohaler/[11,41,90]).

Least squares mean.


g

Some 95% CIs are reported as mL.[11,93]


f

95% CI for the difference between CIC and comparator. In one study,[40] a 97.5% CI for the difference between treatments is reported.

Deeks & Perry

Table VII. Contd

1756

budesonide 400 g (ExV) once daily, based on


primary endpoint (FEV1) data in a recent study
reported by Ukena et al.[41] (table VII). The remaining noninferiority trials showed that ciclesonide was
generally no less effective than fluticasone propionate[84,91-93] or budesonide[11,40,89,90] in terms of its
effect on FEV1.
In most instances, ciclesonide significantly increased mean FVC and morning PEF from baseline
(coprimary endpoints in one study[84]) and was generally no less effective in this regard than fluticasone
propionate or budesonide (table VII).[11,40,84,89-93]
Notably, both mean FVC (table VII) and PEF (80 vs
61 L/min) were improved from baseline to a significantly (p < 0.05) greater extent in ciclesonide
320 g/day than budesonide 400 g/day (ExV) recipients in one study.[41] In another trial,[90] although
FVC was reduced significantly from baseline with
both ciclesonide 320 g/day and budesonide
400 g/day (ExV), the reduction in FVC was significantly greater with budesonide (table VII).
Where reported, ciclesonide also produced significant (p < 0.001) improvements from baseline in
night-time asthma symptom scores in four[40,41,84,92]
of five[40,41,84,91,92] studies (a coprimary endpoint in
one trial[92]). Ciclesonide demonstrated noninferiority to fluticasone propionate 176 g/day with regard
to this parameter at dosages of both 80 (95% CI
0.12, 0.02) and 160 g/day (95% CI 0.10, 0.05) in
one study,[92] with ciclesonide 80320 g/day generally as effective as fluticasone propionate 176 g/
day (ExA)[84] or 400 g/day (ExV),[91] or budesonide 400 g/day (ExV)[40,41,90] in other trials (quantitative data not reported in one study[90]).
Furthermore, the percentage of days without
asthma symptoms and without rescue medication
use (a coprimary endpoint in one study[11]) ranged
from 74% to 91% with ciclesonide 160640 g/
day,[11,89,91,93] demonstrating noninferiority to
budesonide in one study (95% CI lower limit of
2.5% for the between-group difference)[11] and an
efficacy not markedly different from that of budesonide[89] or fluticasone propionate[91,93] in other trials.
In 12- and 24-week trials, where reported, trial
discontinuation due to asthma exacerbations (referred to as lack of efficacy in one trial;[89] a primary
endpoint[93]) occurred in 0.75.0% of ciclesonide
80640 g/day recipients,[41,89,91-93] 0.42.6% of
Drugs 2008; 68 (12)

Ciclesonide: A Review

fluticasone propionate 176660 g/day (ExA) recipients,[91-93] and 0.5%[41] and 1.5%[89] of budesonide
400 g/day (ExV) recipients (based on ITT[41,93] or
modified ITT[89,91,92] populations). Where specified,
ciclesonide 640 g/day was no less effective than
fluticasone propionate 660 g/day in this regard
(noninferiority criteria were met in both the perprotocol [95% CI 0.016, 0.043 for the difference
between treatments] and ITT [95% CI 0.031,
0.028] patient populations).[93]
In general, ciclesonide significantly (p < 0.01)
improved from baseline both asthma symptom
scores and rescue medication use,[11,40,41,84,91-93] although such improvements were generally not significantly different to those seen with budesonide or
fluticasone propionate, where stated. However, in
one 12-week study,[90] ciclesonide 320 g once daily
was significantly (p = 0.026) more effective in reducing rescue medication use than budesonide
400 g (ExV) once daily in patients with persistent
asthma (0.73 vs 0.05 times/day; respective baseline rescue medication use was 1.14 and 0.7 times/
day [median values estimated from graph]).
Patients whose stable asthma is maintained with
twice-daily fluticasone propionate 220 g (ExA), or
equivalent, can be switched to once-daily ciclesonide, according to the results of a randomized, double-blind, 12-week trial in patients who received
ciclesonide 160 g once daily (n = 58 ITT patients)
or fluticasone propionate 220 g twice daily
(n = 53).[86] The two agents showed similar efficacy
in terms of the median percentage of days with
asthma control (97% with ciclesonide vs 98% with
fluticasone propionate) or free from asthma symptoms (both 98%), rescue medication use (both
100%) or night-time awakenings (both 100%) [all
primary endpoints]. Furthermore, the treatments did
not significantly differ with regard to maintaining
lung function, according to secondary measures of
efficacy including FEV1, FVC and morning PEF.[86]
Ciclesonide was no less effective than beclometasone in improving mean morning PEF (primary endpoint) after 8 weeks of treatment in patients with moderate to severe asthma (table VII).[88]
Noninferiority criteria were met for both ciclesonide
320 g/day (16 vs 6 L/min; 95% CI 1.02, 21.24)
and 640 g/day (24 vs 6 L/min; 95% CI 6.97,
29.17), with the highest ciclesonide dosage demon 2008 Adis Data Information BV. All rights reserved.

1757

strating superiority (p = 0.001) versus beclometasone 800 g/day (ExV). Ciclesonide was also as
effective as beclometasone with regard to maintaining other measures of lung function, including FEV1
and FVC (table VII).[88]
In addition, ciclesonide 640 g/day was more
effective than beclometasone 800 g/day (ExV) in
improving mean asthma symptom scores from baseline (0.9 reduction [i.e. improvement] vs 0.1 increase; p = 0.008 for the between-group difference),
although such superiority was not seen with ciclesonide 320 g/day versus beclometasone (0.2 vs
+0.1) [all data estimated from a graph].[88] Moreover, the mean reduction from baseline in rescue
medication use with ciclesonide 640 g/day was
greater than that with beclometasone (0.44 vs
+0.07 times/day; p = 0.007) and ciclesonide 320 g/
day (0.44 vs 0.01 times/day; p = 0.029).
4.1.3 Effects on Health-Related Quality of
Life (HR-QOL)

Data from five studies,[11,91,93,100,101] (two available as abstracts)[100,101] suggest that ciclesonide
may improve HR-QOL in patients with asthma.
Where reported, ciclesonide 320 or 640 g/day produced significant (p < 0.0005) improvements from
baseline in HR-QOL after 12[11,91] or 24[93] weeks,
according to overall AQLQ scores in adults and
adolescents with moderate[91] or moderate to severe[93] asthma, and overall PAQLQ scores in adolescents with severe asthma.[11]
In two randomized, placebo-controlled, 12-week
trials (section 4.1.1),[17,87] mean overall AQLQ
scores were improved from baseline to a significantly (p < 0.0001) greater extent with once-daily
ciclesonide 80, 160 and 320 g (0.36, 0.47 and
0.55)[101] and twice-daily ciclesonide 160 and
320 g (0.61 and 0.65)[100] than with placebo (data
are placebo-subtracted values).
Clinically meaningful changes (0.5) in overall
AQLQ scores were experienced by 47%, 50%,
50.6% and 31% of ciclesonide 80, 160 or 320 g/
day and placebo recipients, respectively, in one
study,[101] and by 42.5%, 43% and 26.8% of patients
treated with ciclesonide 320 or 640 g/day or placebo in another study.[100]
In a 12-week, active comparator-controlled trial
in adults and adolescents (section 4.1.2),[91] the improvement from baseline in overall AQLQ score in
Drugs 2008; 68 (12)

1758

Deeks & Perry

ciclesonide 320 g once daily recipients was not


significantly different from that in fluticasone propionate 200 g (ExV) twice daily recipients, according to per-protocol analyses (quantitative data not
reported). However, a significant between-group
difference was reported in favour of ciclesonide
with regard to the improvement from baseline in this
parameter in the modified ITT patient population
(0.29 vs 0.11; p = 0.005).[91] Non-inferiority analyses were not reported for overall AQLQ score, although ciclesonide was stated to be noninferior to
fluticasone propionate with regard to individual domain scores (quantitative data not reported).
Longer term, ciclesonide 320 g twice daily was
no less effective than fluticasone propionate 330 g
Table VIII. Inclusion and exclusion criteria, and primary and secondary efficacy outcomes in randomized, comparative, clinical trials of
ciclesonide in the treatment of persistent asthma in children and
adolescents
Inclusion criteria
6-Month duration of persistent asthma[16,37,38]
Demonstration of effective use of the MDI device[16,38] and
reproducible pulmonary function tests[16]
Exclusion criteria
Treatment with systemic[16,37,38] or oral[16] corticosteroids within
30 days of screening[16] or baseline,[37] or for >60 days in the
2 years prior to the study[37,38]
Treatment with high-dose beclometasone (>400 g) or equivalent
within 30 days prior to baseline or 8 puffs of salbutamol per day
on 3 consecutive days before randomization[38]
Primary efficacy outcomes

Secondary efficacy outcomes

FEV1[37,38]a

FEV1[16]

FEV1 percent predicted

[16]b

FEV1 percent predicted[16]c

Morning PEF[38]a

Morning PEF[16,37]

Evening PEF[38]a

Evening PEF[16]

Asthma symptom score[37]a

Asthma symptom score[38]


Rescue medication use[38]
Days free of symptoms[38]
Days free of rescue medication
use[38]
Days free of night-time
awakenings[38]

24-Hour urinary cortisol[37]d


Change from baseline to end of trial or last visit,[37] or from
randomization to end of treatment.[38]

Change from baseline to end of trial.

Change from baseline at each study visit.

Data relating to this endpoint are discussed in section 2.4.

FEV1 = forced expiratory volume in 1 second; MDI = metered-dose


inhaler; PEF = peak expiratory flow.

2008 Adis Data Information BV. All rights reserved.

(ExA) twice daily with regard to overall AQLQ


score improvements from baseline after 6 months in
adults and adolescents, according to both the perprotocol (0.22 vs 0.16; 95% CI 0.09, 0.20 for the
between-group difference) and modified ITT (0.18
vs 0.15; 95% CI 0.10, 0.16) analyses (least squares
mean values).[93]
Furthermore, in adolescents with severe asthma,
ciclesonide 320 g once daily was no less effective
than budesonide 800 g (ExV) once daily in improving overall PAQLQ score from baseline after
12 weeks, according to both per-protocol (0.19 for
both treatment groups) and modified ITT (0.19 vs
0.18) analyses (least squares mean values).[11] The
95% CI for the difference between treatment groups
was reported as having a lower limit above the
noninferiority acceptance limit (i.e. noninferiority
criteria were met) [95% CIs not reported]. The overall PAQLQ score at baseline in each of the treatment
groups was 5.99 and 5.97 in the per-protocol and
ITT patient populations, respectively (least squares
mean values).
4.2 Paediatric Patients

Randomized, double-blind,[16,37,38,94,95] multicentre[16,37,38] trials have compared the efficacy of


12 weeks of ciclesonide treatment with placebo,[16]
fluticasone propionate[38,94,95] and budesonide[37] in
children and adolescents (n = 5121031) aged
415 years with asthma of all severities (persistent
where stated[16,37,38,95]). Trials included patients previously treated with inhaled corticosteroids, where
reported.[16,37,38] The combined results of two identical placebo-controlled trials are reported by Gelfand
et al.[16] Some data are available only from abstracts.[94,95]
Patient inclusion and exclusion criteria are summarized in table VIII. Patients initially received
placebo for a run-in period of 521 days[16] or used
rescue medication during a baseline period of
24 weeks.[37,38,94,95] Patient eligibility criteria for
randomization included an FEV1 predicted value of
4090%[16] or 5090%[37,38] after 4[37,38] or 6[16]
hours without use of a 2-agonist; and reversibility
of FEV1[16,37] or FEV1 predicted[38] of 12% in
response to a 2-agonist. Those using only bronchodilators were eligible for randomization if, in the
previous week, one or more criteria had been met on
Drugs 2008; 68 (12)

Ciclesonide: A Review

1759

Table IX. Efficacy of ciclesonide (CIC) in the treatment of persistent asthma of all severities in paediatric patients (pts) aged 411 years.
Results shown are the combined results from two identical randomized, double-blind, placebo (PL)-controlled, multicentre, 12-week trials in
pts receiving CIC or PL. Modified intent-to-treat analyses and ex-actuator doses are reported. Data are mean values
Study
[treatment duration; wk]

Gelfand et al.[16] [12]

Treatment No. of
regimen
pts

FEV1 (percent
predicted) [%]a

FEV1
(L)

(g od)

baseline

change
from
baseline

baseline

Morning PEF
(L/min)

Evening PEF
(L/min)

change
from
baseline

baseline

change
from
baseline

baseline

change
from
baseline

CIC 40

252

68.48

11.97

1.29

0.25

207

15*b

NR

12

CIC 80

259

68.25

13.58*

1.29

0.28*

208

19#b

NR

18***

CIC 160

253

68.19

14.17**

1.30

0.29**

212

16**b

NR

16***

PL

254

68.54

10.69

1.32

0.22

209

8b

NR

Primary endpoint.

Values estimated from a graph.

FEV1 = forced expiratory volume in 1 second; NR = not reported; od = once daily; PEF = peak expiratory flow; * p < 0.05, ** p < 0.01,
*** p < 0.005, # p < 0.001 vs PL.

3 days, including a 24-hour asthma symptom score


of 3, >20% variability in PEF or salbutamol
2 puffs/day.[16]
Treatment regimens used in fully published studies are shown in tables IX[16] and X.[37,38] In other
trials, patients received ciclesonide 80[95] or
160[94,95] g once daily or fluticasone propionate
88 g twice daily.[94,95] Fluticasone propionate was
administered via a MDI[38,94,95] (specified as an HFA
-MDI in some studies[38,95]), whereas budesonide
was delivered via a DPI (ExV dose reported).[37]
Primary and secondary efficacy outcomes, where
reported, are summarized in table VIII. Efficacy
assessments were based on the modified ITT population[16] or the per-protocol population with subsequent confirmatory analyses performed in the ITT
population.[37,38] Analyses were stated as last-observation-carried-forward for lung function variables in
one trial.[16]
Patient diary card measurements included morning and evening PEF,[16,37,38] asthma symptom
scores (ranging from 0 [no symptoms] to 4 [asthma
symptoms preventing sleep or daily activities]),[16,37,38] use of rescue medication[16,37,38] and
night-time awakenings.[16]
The noninferiority of ciclesonide compared with
budesonide[37] and fluticasone propionate[38] was
examined in some studies. Noninferiority was based
on the lower limit of the 95% CIs for differences
between groups using noninferiority acceptance
limits of 0.10 L for FEV1[37,38] and 12.5 L/min for
both morning[37,38] and evening[38] PEF. A noninferi 2008 Adis Data Information BV. All rights reserved.

ority limit of 0.3 for asthma symptom score was


used in one study.[37]
HR-QOL was evaluated in two of the trials[16,37]
using the PAQLQ. Results from the paediatric Asthma Caregivers Quality of Life Questionnaire
(PACQLQ) were also reported in one study;[37]
noninferiority acceptance limits for PAQLQ and
PACQLQ were not reported.[37]
4.2.1 Versus Placebo

Ciclesonide was generally effective in improving


lung function in children with persistent asthma of
all severities in a large placebo-controlled study of
12 weeks duration.[16] Patients receiving ciclesonide 80 or 160 g/day exhibited significantly greater
mean increases from baseline in FEV1 percent predicted at study endpoint than those receiving placebo (primary endpoint; table IX). The improvements
in FEV1 percent predicted were sustained throughout weeks 112 of therapy with the highest ciclesonide dosage (160 g/day) [p < 0.05 vs placebo at all
timepoints; quantitative data not reported].[16]
The two higher doses of ciclesonide (80 and
160 g/day) were also significantly better than placebo at improving other measures of lung function
from baseline, including absolute FEV1 and evening
PEF (table IX).[16] Mean morning PEF was significantly improved from baseline with ciclesonide
compared with placebo regardless of dose (79% vs
4%; table IX).
In general, ciclesonide also had significant
(p < 0.01) beneficial effects in terms of improving
24-hour asthma symptom scores and reducing resDrugs 2008; 68 (12)

1760

Deeks & Perry

Table X. Efficacy of ciclesonide (CIC) vs fluticasone propionate (FP) or budesonide (BUD) in the treatment of persistent asthma in
paediatric patients (pts) aged 415 years. Results of randomized, double-blind, 12-week trials in pts receiving CIC or FP administered via a
hydrofluoroalkane-propelled metered-dose inhaler or BUD via a dry powder inhaler (Turbuhaler). Per-protocol analyses and mean values
are reported; ex-actuator doses are reported unless otherwise noted
Study [treatment

Treatment regimen

FEV1 (L)

Morning PEF (L/min)

Evening PEF (L/min)

duration; wk]

(g) [no. of pts]

baseline change from


baseline (95% CIa)

baseline change from


baseline (95% CIa)

baseline change
from
baseline

Pedersen et al.[38] [12]

CIC 80 bid [254]

1.68

0.3*b,c (0.044, 0.046)d

257

31*b,c (12.0, 5.4)d

NR

NRb,e

FP 88 bid [257]

1.67

0.3*b,c

256

34*b,c

NR

NRb

1.53

0.22*b,c

199

23*c

211

15*c

201

217

15*c

von Berg et

al.[37]

[12]

CIC 160 od [340]


f

(0.075,

BUD 400 od [173]


1.56
0.25*
95% CI for the difference between CIC and comparator.

Primary endpoint.

b ,c

0.01)d

26*

(10.9,

3.4)d

Least squares mean values.

CIC was noninferior to comparator.

The least squares mean difference between CIC 80 bid and FP 88 bid was 0.2 L/min (95% CI 8.3, 8.6 [per-protocol analysis]; i.e.
noninferiority criteria were met).

Ex-valve dose.

bid = twice daily; FEV1 = forced expiratory volume in 1 second; NR = not reported; od = once daily; PEF = peak expiratory flow; * p < 0.0001
vs baseline.

cue medication use compared with placebo.[16]


However, there were no marked differences between treatment groups with regard to night-time
awakenings (quantitative data not reported).
4.2.2 Versus Active Comparators

Ciclesonide 160 g/day, administered in one[37]


or two[38] daily doses, significantly improved lung
function (in terms of FEV1 and morning and evening PEF) compared with baseline in paediatric patients with persistent asthma in randomized, doubleblind, 12-week studies (table X). These findings are
generally supported by limited preliminary data
from two other large, randomized, double-blind
trials of 12 weeks duration (n = 512[94] and 744[95])
in paediatric patients with moderate to severe[94] or
persistent[95] asthma who received ciclesonide 80[95]
or 160[94,95] g once daily or fluticasone propionate
88 g (ExA) twice daily.[94,95] FEV1[37,38] and morning[38] and evening[38] PEF were primary endpoints,
where stated.
With regard to improving lung function parameters, once-daily ciclesonide 160 g was no less
effective than once-daily budesonide 400 g
(ExV),[37] and twice-daily ciclesonide 80 g was
noninferior to twice-daily fluticasone propionate
88 g in this regard[38] (table X). In addition, limited
data from a 12-week study[94] suggested that once 2008 Adis Data Information BV. All rights reserved.

daily ciclesonide 160 g (n = 254) and twice-daily


fluticasone propionate 88 g (n = 258) were not
significantly different in terms of improving FEV1
and morning PEF from baseline in patients with
moderate to severe asthma (quantitative data not
reported). Furthermore, in patients with persistent
asthma, improvements from baseline in FEV1 of
0.22, 0.25 and 0.28 L have been reported after
12 weeks of treatment with once-daily ciclesonide
80 or 160 g or twice-daily fluticasone propionate
88 g, with corresponding changes in morning PEF
of 23, 29 and 25 L/min, respectively (data from an
abstract; between-group statistical analyses not reported).[95]
Ciclesonide administered once[37] or twice[38]
daily also significantly (p < 0.0001) improved (i.e.
reduced) total asthma symptom scores from baseline
in paediatric patients, demonstrating an efficacy not
significantly different from that of fluticasone propionate twice daily (1.43 for both treatments)[38]
and noninferior to that of budesonide once daily
(1.21 for both treatments; 95% CI 0.20, 0.25 for
the between-group difference)[37] [coprimary endpoint;[37] median values where specified[38]].
Ciclesonide also produced reductions (p < 0.0001)
from baseline in rescue medication use similar to
those seen with fluticasone propionate (1.14 vs
Drugs 2008; 68 (12)

Ciclesonide: A Review

1.07 puffs/day; median values)[38] or budesonide


(1.58 vs 1.64 puffs/day).[37]
In addition, there were generally no marked differences between ciclesonide and fluticasone propionate[38] or budesonide[37] in terms of the proportion of days free of asthma symptoms (76% vs 76%
with fluticasone propionate),[38] rescue medication
use (90% vs 88% with fluticasone propionate)[38] or
night-time awakenings (100% vs 100% with fluticasone propionate;[38] 98.5% vs 98.5% with budesonide[37]) during 12 weeks of treatment (ITT analyses;[37,38] values are medians, where stated,[38] with
some values estimated from a graph[38]).
4.2.3 Effects on HR-QOL

HR-QOL benefits have been reported in paediatric patients receiving once-daily ciclesonide 40,[16]
80[16] or 160[16,37] g in placebo-controlled (section
4.2.1)[16] and active-comparator (section 4.2.2)[37]
studies of 12 weeks duration.
Recipients of ciclesonide 40, 80 or 160 g/day
experienced significant (p < 0.05) mean improvements from baseline in overall PAQLQ score compared with placebo recipients after 12 weeks (0.52,
0.54 and 0.56 vs 0.27).[16] Clinically relevant improvements from baseline in overall PAQLQ score
were exhibited by a proportion of each of the respective treatment groups (46.1%, 50.0%, 52.5% and
36.5% of patients; p = 0.0194 across treatment
arms); between-group statistical analyses were not
reported.
Ciclesonide 160 g once daily was no less effective than budesonide 400 g (ExV) once daily with
regard to significantly (p < 0.0001) improving from
baseline overall PAQLQ (0.69 vs 0.70; 95% CI
0.12, 0.10 for the between-group difference) and
PACQLQ (0.88 vs 0.96; 95% CI 0.27, 0.13) scores
(ITT analyses).[37] Furthermore, both ciclesonide
and budesonide recipients experienced clinically
relevant improvements from baseline in PAQLQ(56.6% vs 53.4% of patients) and PACQLQ-determined (60.5% vs 60.8%) HR-QOL.[37]
5. Tolerability
Inhaled ciclesonide, administered via an HFAMDI, was generally well tolerated by adult and
paediatric patients with asthma of all severities participating in the randomized, clinical trials discussed
2008 Adis Data Information BV. All rights reserved.

1761

in section 4. Tolerability data from these trials are


reviewed in this section together with data from the
prescribing information.[21,102] Relevant data from
other sources,[22,25,28,103,104] some available only as
abstracts,[22,28,103,104] are also reviewed. In general,
only descriptive analyses were reported.
5.1 General Profile

Adverse events in ciclesonide recipients were


generally mild to moderate in severity[4,5,11,16,37,38,40,41,84,86,88-93] and most were considered unrelated to the study drug by the investigators.[4,5,11,16,17,25,37,38,40,41,84,86,88-93] Discontinuation
rates because of adverse events were generally low
with ciclesonide treatment in both adult and paediatric patients in clinical trials discussed in section 4.
Where stated, ciclesonide was generally not associated with any clinically significant changes in
laboratory[5,11,17,39-42,84,89-92] or ECG[4,5,11,40] measurements, vital signs,[4,5,11,39,40,42,86,89-93] clinical chemical or haematology parameters,[4,86,93] or physical
examination findings[39,93] in adults and adolescents.
Serious treatment-emergent adverse events in
adults and adolescents, where reported, occurred in
8.5% (4 of 47 patients) and 4.1% (2 of 49 patients)
of ciclesonide 640 and 1280 g/day recipients compared with 4.4% (2 of 45 patients) of placebo recipients in one study,[39] with two such adverse events
reported in both ciclesonide (160 and 320 g/day
groups each had one event) and placebo recipients in
a separate trial.[85] In another study,[4] 7%, 6% and
5% of the treatment-emergent adverse events were
considered serious in recipients of ciclesonide
160 g/day, ciclesonide 640 g/day and placebo,
respectively. These adverse events were not considered study drug related, where stated.[39,85]
In active comparator-controlled trials in adults
and adolescents, where stated, the incidence of serious treatment-emergent adverse events was generally low (ranging from 0.4% to 3.4% of patients in any
given treatment group, where specified[84,86,89-92]);
these events were not considered[11,40,41,84,86,88,91-93]
or stated[90] as being related to the study drug. For
example, in the largest of these trials,[92] serious
adverse events were reported in a total of ten patients: three ciclesonide 80 g/day recipients
(n = 278; modified ITT population); four ciclesonide
Drugs 2008; 68 (12)

1762

160 g/day recipients (n = 270); and three fluticasone propionate 176 g/day recipients (n = 259).
In paediatric patients with asthma, ciclesonide
had no clinically relevant effect on bodyweight,[16,25]
height,[16] physical examination measurements,[16,25]
laboratory variables[16,38] or vital signs.[16,25,38] Serious treatment-emergent adverse events occurred in
1% (4 of 416 patients) of paediatric patients treated
with ciclesonide 160 g/day and 2% (4 of 205
patients) of those treated with budesonide 400 g/
day, where stated; none were considered drug related.[37]
5.2 Versus Placebo

Ciclesonide exhibits a tolerability profile generally similar to that of placebo, according to data
from several pooled analyses[21,102] of placebo-controlled trials conducted in adult and adolescent patients, where specified.[102] The incidence of adverse
events considered possibly related to the study drug
was broadly similar in ciclesonide and placebo recipients (6.6% and 6.5% of patients),[21] as was the
proportion of patients who reported at least one
treatment-emergent adverse event (52.359.8% of
ciclesonide 160640 g/day recipients vs 58.0% of
placebo recipients; total n = 624).[102]
The tolerability profile of ciclesonide was also
generally similar to placebo in paediatric patients
aged 411 years with asthma, with treatment-emergent adverse events potentially related to the
study drug reported in 0.04.3% of ciclesonide
40160 g/day recipients[16,25] compared with
0.5%[25] and 1.2%[16] of placebo recipients.
The most common adverse event considered to
be potentially study drug related in one pooled analysis[21] was paradoxical bronchospasm (including
chest discomfort, asthma, bronchospasm, chest pain,
dyspnoea, cough, wheezing and obstructive airway
disorder), which occurred with a generally similar
incidence in ciclesonide (n = 1850) and placebo
(n = 934) recipients (1.8% vs 1.9% of patients)
[statistical analyses not reported]. In another pooled
analysis (n = 1131),[102] treatment-emergent adverse
events that occurred in 5% of patients (aged
12 years) in any treatment group and with at least
3% greater incidence in any ciclesonide treatment
group (160, 320 or 640 g/day) versus placebo
2008 Adis Data Information BV. All rights reserved.

Deeks & Perry

included headache (4.911.0% vs 7.3% of patients),


nasopharyngitis (7.010.5% vs 7.5%) and nasal congestion (1.85.5% vs 1.6%).
Adverse events that occurred in 3% of patients
in any treatment group and in at least twice as many
patients receiving some ciclesonide dosages as opposed to placebo in individual 12-week trials in
adults and adolescents included headache (5% and
7% of ciclesonide 80 and 320 g/day recipients vs
3% of placebo recipients),[5] as well as back pain
(3% and 5% vs 2%),[5] sore throat (3% and 5% vs
0%)[5] and upper respiratory tract infection (8% and
13% of ciclesonide 160 and 640 g/day recipients vs
6% of placebo recipients).[4]
In general, the incidence of local oropharyngeal
adverse events was low with both ciclesonide and
placebo treatment in adults, adolescents and children, where stated.[4,5,16,17,25,42,104] These data are
supported by a large pooled analysis of trials in
patients with asthma, in which ciclesonide
401280 g/day (n = 7706) and placebo (n = 1215)
recipients exhibited a low incidence of oropharyngeal adverse events per patient-year, specifically candidiasis (both 0.02) and hoarseness (both
0.03).[103] These local oropharyngeal adverse events,
and others, including pharyngitis, dry throat and
dysgeusia, were considered possibly drug related in
another large (n = 2784) pooled analysis, but occurred with a low incidence in both ciclesonide
(0.10.9% of patients) and placebo (0.00.4%) recipients.[21]
However, in one clinical trial,[39] oral candidiasis
occurred in 6.4% (3 of 47 patients) and 8.2% (4 of
49 patients) of ciclesonide 640 and 1280 g/day
recipients compared with no placebo recipients.[39]
Furthermore, although hoarseness did not occur in
recipients of ciclesonide 1280 g/day, almost three
times more ciclesonide 640 g/day (6.4%; 3 of 47
patients) than placebo (2.2%; 1 of 45 patients) recipients reported hoarseness.
5.3 Versus Active Comparators

In 12- to 24-week clinical trials in adults and


adolescents discussed in section 4.1, where reported, treatment-emergent adverse events occurred
in
1761%
of
ciclesonide
recipients,[11,40,41,84,86,89,90,92,93] 1852% of budesonide reDrugs 2008; 68 (12)

Ciclesonide: A Review

cipients[11,40,41,89,90] and 2763% of fluticasone propionate recipients.[84,86,92,93] In a longer-term safety


trial of 52 weeks duration in adults and adolescents,[22] 74.1% and 79.2% of ciclesonide 640 g/
day and beclometasone 640 g/day recipients reported treatment-emergent adverse events.
In 12-week studies comparing ciclesonide with
budesonide in adult and adolescent patients, where
reported, treatment-emergent adverse events with an
incidence of 5% in any treatment group included
upper respiratory tract infection (5.112% of
ciclesonide recipients vs 7.9%[40] and 19%[90] of
budesonide recipients), pharyngitis (5.9% vs
3.8%),[11] asthma (4.49.9% vs 4.012%),[40,89,90] flu
syndrome (4% vs 7%)[90] and bronchitis (3.8% and
6.1% vs 4.0%).[40] Where reported, treatment-emergent adverse events that occurred with an incidence
of 5% in either ciclesonide or fluticasone propionate recipients in 12- to 24-week clinical trials included nasopharyngitis (2.211.8% vs 5.78.8% of patients),[86,91-93] upper respiratory tract infection
(3.48.2% vs 7.39.4%),[84,86,93] hoarseness (3.1%
vs 9.2%)[93] and asthma (3.9%[93] and 6.9%[86] vs
5.5%[93] and 5.7%[86]). Between-group statistical
analyses not reported.
Longer term, pharyngitis was reported in 3.5%
and 5.2% of ciclesonide 640 g/day and beclometasone 640 g/day recipients in a randomized, doubleblind, multicentre, 52-week study in adult and adolescent patients (n = 297).[22] In the same trial, oral
candidiasis occurred in 4.1% of ciclesonide and
10.4% of beclometasone recipients (statistical analyses were not reported).
In paediatric patients, where reported, the incidence of treatment-emergent adverse events was
38% in both ciclesonide 160 g/day and budesonide
400 g/day (ExV) recipients in the 12-week trial
discussed in section 4.2.[37] The most common treatment-emergent respiratory-related adverse events
that occurred with a 5% incidence in either of the
treatment groups, included pharyngitis (6.0% of
ciclesonide recipients vs 6.8% of budesonide recipients), nasopharyngitis (4.1% vs 5.4%) and upper
respiratory tract infection (3.6% vs 6.3%).[37] Furthermore, where stated, only rhinitis (7.9% vs 8.2%
of patients) and upper respiratory tract infection
2008 Adis Data Information BV. All rights reserved.

1763

(6.9% vs 6.5%) occurred with an incidence of 5%


in paediatric patients treated with either ciclesonide
160 g/day or fluticasone propionate 176 g/day
(ExA).[38] Between-group statistical analyses were
not reported.[37,38]
During longer-term therapy, the incidence of
pharyngitis was 14.7% and 13.5% in paediatric patients receiving ciclesonide 40160 g/day or fluticasone propionate 100200 g/day (via DPI) in
three identical nonblind, multicentre, 52-week trials
(n = 615) [combined results available as an abstract].[28]
Where statistical analyses were performed,[91,93]
the incidence of some oropharyngeal adverse
events, such as oral candidiasis and hoarseness, was
generally significantly (p < 0.01) lower with ciclesonide than with fluticasone propionate. These findings are generally supported by data from a large
pooled analysis of trials in patients with asthma (age
range not reported),[103] in which the incidence per
patient-year of oral candidiasis and hoarseness was
0.02 and 0.03 in ciclesonide 401280 g/day
(n = 7706) recipients compared with 0.07 for both
adverse events in recipients of other inhaled corticosteroids, including budesonide 400 g/day (ExV),
beclometasone 400 g/day (ExV) or fluticasone
propionate 176880 g/day (ExA; n = 3330). Moreover, in a subanalysis of this study (n = 2169), the
combined incidence of candidiasis and hoarseness
was significantly lower in ciclesonide 320 g/day
than fluticasone propionate 440 g/day recipients
(0.5% vs 4.5%; p = 0.0013). A significantly lower
combined incidence of candidiasis and hoarseness
was also exhibited by ciclesonide 640 g/day recipients compared with fluticasone propionate 880 g/
day recipients (2.8% vs 7.7%; p < 0.0001).[103] The
incidences of candidiasis in the ciclesonide 320 g/
day, ciclesonide 640 g/day, fluticasone propionate
440 g/day and fluticasone propionate 880 g/day
groups were 0%, 0.6%, 1.5% and 3.5%, respectively; the corresponding incidences of hoarseness were
0.5%, 2.2%, 3.0% and 4.2%.
The differences between ciclesonide and other
inhaled corticosteroids in the effects on markers of
systemic glucocorticoid activity are discussed in
section 2.4.
Drugs 2008; 68 (12)

1764

6. Dosage and Administration


Inhaled ciclesonide administered via an HFAMDI is approved in the EU for use in adults and
adolescents aged 12 years for the prophylactic
treatment of persistent asthma.[72,73] Ciclesonide,
dispensed via the HFA-MDI, is also approved for
the prophylactic treatment of asthma[102] and corticosteroid-responsive bronchial asthma[21] in adults
and adolescents aged 12 years in the US[102] and
Canada,[21] and for similar indications in several
other countries worldwide. Ciclesonide is also approved for the long-term treatment of asthma in
paediatric patients in some countries, including
Switzerland (patients aged 6 years).[105]
In the EU,[72,73] the recommended initial dosage
is ciclesonide 160 g once daily, preferably administered in the evening, with subsequent titration to
the minimum dosage required to maintain effective
asthma control. Ciclesonide may also be administered via an HFA-MDI using an AeroChamber
Plus spacer device in patients who have difficulty
in synchronizing inhaler actuation with inhalation.
In the US,[102] the recommended starting dosage
of ciclesonide is 80 g twice daily in patients receiving bronchodilators alone (maximum recommended
dosage 160 g twice daily), 80 g twice daily in
patients receiving inhaled corticosteroids (maximum recommended dosage 320 g twice daily) and
320 g twice daily in patients receiving oral corticosteroids (maximum recommended dosage 320 g
twice daily).
In Canada,[21] the recommended initial dosage is
ciclesonide 320 g once daily in patients previously
maintained with inhaled corticosteroids or only
bronchodilators, and ciclesonide 320 g twice daily
in patients with severe asthma. The dosage may be
adjusted based on individual patient response; the
recommended daily ciclesonide dose range is
80640 g.
In paediatric patients aged 6 years with mild to
moderate asthma, ciclesonide 80160 g once daily
or 80 g twice daily is recommended in Switzerland,[105] with ciclesonide 640 g twice daily recommended in those with severe persistent oral prednisone-dependent asthma (reduction of the prednisone
dosage is recommended after the first 10 days use in
combination with ciclesonide).
2008 Adis Data Information BV. All rights reserved.

Deeks & Perry

Local prescribing information for ciclesonide


should be consulted for comprehensive information
regarding contraindications, drug interactions and
other precautions.
7. Place of Ciclesonide in the
Management of Asthma
The focus of asthma therapy is the management
of airway inflammation, with the aim of achieving
and maintaining clinical control, avoiding drug-related adverse events and preventing asthma-related
mortality.[1,2,106] Recommendations in current treatment guidelines approach asthma therapy in a stepwise manner, with therapy commencing at the most
suitable step of treatment options for the initial
disease severity.[1,2]
Inhaled corticosteroids (e.g. ciclesonide, budesonide, fluticasone propionate, beclometasone and
mometasone) are the mainstay preventative therapy
for all patients with persistent asthma.[1,2,107] In patients with persistent asthma or whose intermittent
asthma is poorly controlled by as-needed symptomatic treatment, inhaled corticosteroids at low dosages are the initial treatment of choice. If asthma
control remains inadequate, low-dose inhaled corticosteroids in combination with an inhaled LABA, or
medium-dose inhaled corticosteroids, are generally
recommended.
Medium- or high-dose inhaled corticosteroids in
combination with LABA use is a treatment option
for patients whose asthma control continues to be
inadequate.[1,2,107] Once asthma control is achieved,
the current treatment guidelines recommend reducing the dose of inhaled corticosteroid to the lowest
dose required to effectively maintain control.[1,2,107]
Despite being considered the most effective treatment currently available for the prevention of asthma,[1,107] inhaled corticosteroids may produce local
and systemic adverse effects, especially at high dosages and with long-term treatment.[108,109] As a result, these agents are often under-prescribed by physicians and safety concerns may affect patient compliance to therapy, resulting in suboptimal asthma
control, especially in children.[60,110,111] Complex
treatment regimens, difficult-to-use inhalation devices, financial limitations and carelessness/forgetDrugs 2008; 68 (12)

Ciclesonide: A Review

fulness may also reduce patient compliance to inhaled corticosteroid therapy.[108,112]


Ciclesonide is a relatively new corticosteroid
with certain features that may be advantageous in
patients with asthma. Ciclesonide addresses the underlying airway inflammation of asthma and helps
attenuate airway hyper-responsiveness, exercise-induced bronchoconstriction and early- and late-phase
allergen-induced bronchoconstriction (section 2).
Unlike some other inhaled corticosteroids that are
delivered via a CFC-containing MDI, ciclesonide is
delivered via an HFA-MDI (non-CFC) device.
Ciclesonide exists as an HFA solution, as does
beclometasone, in contrast to other corticosteroids
currently available as HFA/CFC suspensions or dry
powder formulations. HFA solutions are often delivered by MDI devices as extra fine aerosols consisting of particles generally smaller than those produced by MDI HFA and CFC suspensions and
DPIs.[59,113,114] The particle size delivered is important in determining the deposition of corticosteroid
in the lungs relative to the oropharyngeal cavity,
with smaller particles more likely to be deposited in
the lungs.[59,114]
The HFA-MDI device produces ciclesonide particles of 12 m in diameter, which enables efficient and widespread deposition of ciclesonide within the lungs. The areas of deposition include peripheral regions consisting of the small airways
(<2 mm in diameter) and alveoli, which can contribute significantly to asthma pathogenesis.[59,115] In
general, the lung deposition of ciclesonide appears
to be greater than that produced by a number of
other inhaled corticosteroid formulations,[59,113] although direct comparisons have not been performed.
Ciclesonide inhalation via HFA-MDI also results
in minimal oropharyngeal deposition that is significantly less than that of budesonide (CFC-MDI) and
fluticasone propionate (HFA-MDI) [section 3].
Ciclesonide therapy may therefore have a lower
propensity to cause local adverse events than some
other inhaled corticosteroid formulations, at least
partly because of more efficient drug delivery to the
lungs.
Unlike most other inhaled corticosteroids (e.g.
budesonide, fluticasone propionate and mometasone), which are inhaled as pharmacologically active compounds, ciclesonide is inhaled in the form
2008 Adis Data Information BV. All rights reserved.

1765

of a prodrug and is converted to its active metabolite, des-CIC, primarily on-site in the lung, thus
potentially minimizing potential systemic adverse
effects. Moreover, only limited activation of
ciclesonide occurs upon oropharyngeal deposition,
resulting in significantly lower amounts of active
agent in the oropharynx compared with budesonide
and fluticasone propionate (section 3), thereby reducing the potential for local adverse events.
The targeted activity of ciclesonide is prolonged
as a result of pulmonary retention of the drug due to
its high lipophilicity and ability to form reversible
fatty-acid esters in the lung (section 3) enabling
once-daily administration. The fact that ciclesonide
is administered once daily may confer an advantage
in terms of patient therapy adherence compared with
some other currently available agents (e.g. fluticasone propionate, beclometasone and flunisolide),
which require more frequent administration. However, at present, no studies have been undertaken
comparing ciclesonide with other inhaled corticosteroids with regard to patient therapy adherence.
Both ciclesonide and des-CIC exhibit low (<1%)
oral bioavailability following ciclesonide inhalation
(section 3.2), whereas oral bioavailability of up to
26% has been reported for some other inhaled corticosteroids.[59] Furthermore, plasma-protein binding
of ciclesonide and des-CIC appears to be greater
than that of a number of other inhaled corticosteroids, as does the clearance of ciclesonide and the
apparent clearance of des-CIC (assuming complete
conversion of the prodrug).[59,114] However, studies
directly comparing these agents with regard to these
parameters are not available. Such pharmacokinetic
properties minimize the likelihood of systemic exposure to des-CIC and thus the potential for systemic effects (section 2).
Ciclesonide, administered via HFA-MDI, is effective in the treatment of persistent asthma in adults
and adolescents (section 4.1) and paediatric patients
(section 4.2). Importantly, the beneficial effects of
inhaled ciclesonide do not appear to be accompanied
by the detrimental systemic effects associated with
inhaled corticosteroids, such as HPA-axis suppression and its clinical manifestations, at least over a
12-week treatment period (section 2). However, further long-term studies are required to confirm the
Drugs 2008; 68 (12)

1766

findings of such relatively short-term measures of


HPA-axis suppression.
Inhaled ciclesonide was generally effective in
maintaining and improving lung function in adults,
adolescents and children in well designed, placebocontrolled, short-term trials of 8 or 12 weeks duration (sections 4.1.1 and 4.2.1). Ciclesonide also generally produced beneficial effects with regard to
asthma symptom scores and reduced rescue medication use in these patient populations. Furthermore, significantly fewer adult patients experienced
lack of efficacy with ciclesonide than with placebo
in well designed, 12-week studies (section 4.1.1).
Limited data from one nonblind, 40-week extension
study in adult patients suggest that the beneficial
effects of inhaled ciclesonide in terms of lung function are maintained during long-term treatment (section 4.1.1). However, further long-term studies in
adult and paediatric patients are warranted.
In terms of improving or maintaining lung function, ciclesonide was generally no less effective than
fluticasone propionate, budesonide or beclometasone (at equipotent dosages according to current
treatment guidelines[1]) in adults and adolescents, in
trials of 824 weeks duration (section 4.1.2). However, ciclesonide, at relatively higher dosages of 320
and 640 g/day, has been shown to confer beneficial
effects in some lung function parameters compared
with budesonide 400 g/day and beclometasone
800 g/day. Notably, the effectiveness of ciclesonide administered once daily is generally no less
than that of twice-daily fluticasone propionate,
budesonide or beclometasone in adults and adolescents, according to some 8- or 12-week trials (section 4.1.2).
In general, ciclesonide therapy also improved
asthma symptom scores and reduced the need for
rescue medication use, with an efficacy generally
similar to that of fluticasone propionate and budesonide in adults and adolescents. However, high-dose
ciclesonide 640 g/day was more effective than
beclometasone in improving such parameters in this
patient population (section 4.1.2).
Ciclesonide is an effective prophylactic treatment for persistent asthma in paediatric patients.
Head-to-head, well designed, short-term trials in
paediatric patients aged 415 years with asthma
have shown ciclesonide 160 g/day to be noninferi 2008 Adis Data Information BV. All rights reserved.

Deeks & Perry

or to, or generally as effective as, fluticasone propionate or budesonide in terms of improving lung
function (section 4.2.2). Ciclesonide was also
noninferior to, or as effective as, these inhaled corticosteroids with regard to reducing rescue medication use and improving asthma symptom scores
in this patient population.
Moreover, preliminary data suggest that inhaled
ciclesonide may be as effective as oral prednisolone
in the treatment of patients with an acute asthma
exacerbation;[36] however, ciclesonide is currently
not approved for such an indication.
The limited clinical data currently available generally indicate a lack of dose-response for inhaled
ciclesonide in terms of therapeutic effect, which
may have implications in its use for the treatment of
more severe asthma (section 4). However, it is currently difficult to compare ciclesonide with other
inhaled corticosteroids in terms of therapeutic doseresponse, as data from other inhaled corticosteroid
dose-response studies are variable and have been
inconsistent in demonstrating an unambiguous relationship between the dose and the therapeutic efficacy of these agents, partly because of study heterogeneity.[116,117]
Ciclesonide is generally well tolerated by adult
and paediatric patients and may have a more favourable tolerability profile than other inhaled corticosteroids with regard to local adverse events, such as
oral candidiasis and hoarseness (section 5). Ciclesonide may also have less of a propensity to produce
systemic adverse events than other inhaled corticosteroids (section 2.4), although additional long-term
comparative and high-dose studies are required to
fully determine the potential benefits of ciclesonide
in this regard. Further long-term studies are required
in order to confirm the tolerability profile of ciclesonide in relation to other available corticosteroids.
Asthma can be a distressing disease, especially in
children, placing limitations on the physical capability, social lives and emotional well-being of patients.[118] Data from short-term, well designed studies in adult (section 4.1.3), adolescent (section 4.1.3)
and paediatric patients (section 4.2.3) indicate that
inhaled ciclesonide is effective in improving the
HR-QOL of patients with asthma, and has an efficacy generally no less than that of fluticasone propionate or budesonide in this regard.
Drugs 2008; 68 (12)

Ciclesonide: A Review

At present, no robust studies have been undertaken to evaluate the efficacy of ciclesonide in comparison with other inhaled corticosteroids in terms
of asthma exacerbations during long-term treatment
and hospitalizations, and pharmacoeconomic data
for ciclesonide are not yet available. There are currently no recommendations regarding the severity of
persistent asthma for which ciclesonide treatment
may be used, although the present lack of data of
ciclesonide in combination with LABA therapy may
limit the use of ciclesonide to the treatment of patients who do not require add-on therapy to achieve
asthma control. However, the potential use of
ciclesonide in combination with LABAs may be
defined with the results of ongoing trials evaluating
this combination therapy.
In conclusion, ciclesonide delivered by HFAMDI generally improves lung function and reduces
asthma symptoms and rescue medication use in
adults and adolescents with asthma of varying severity. The drug is generally no less effective than other
inhaled corticosteroids in terms of maintaining or
improving lung function and may have a more favourable tolerability profile than some other agents
in this class. Ciclesonide has also shown efficacy in
paediatric patients with asthma. Data on its longterm effects on other clinical outcomes, such as
asthma exacerbations, would be of interest. Further
long-term and comparative studies would also be
beneficial, as would pharmacoeconomic data, in
order to definitively position ciclesonide with respect to other inhaled corticosteroids. In the
meantime, ciclesonide offers an effective and generally well tolerated first-line preventative treatment
option for persistent asthma.
Disclosure
The preparation of this review was not supported by any
external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity
to comment on this article. Changes resulting from any comments received were made on the basis of scientific and
editorial merit.

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Correspondence: Emma D. Deeks, Wolters Kluwer


Health | Adis, 41 Centorian Drive, Private Bag 65901,
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Drugs 2008; 68 (12)