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0012-6667/08/0012-1741/$53.45/0
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 Bibliographical information, including contributory unpublished data, was also requested from the company developing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
Summary
Abstract
Pharmacological
Properties
Ciclesonide: A Review
Therapeutic Efficacy
Tolerability
1743
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.
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
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
The use of trade names is for product identification purposes only and does not imply endorsement.
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.
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
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
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
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
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.
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
1750
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
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.
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
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.
Median.
Abstract. This study also included a fluticasone propionate plus PL treatment arm.
Average unspecified.
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
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
367.43
PL od [249]
311.25
371.41
354.80
362.26
PL od [119]
CIC 80 od [257]
425c
18.0c
413c
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
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]
385.97
Chapman et
357.31
[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
1754
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)
a
b
c
d
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
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]
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
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
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
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
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.
Ex-valve dose.
k
m ITT[41] or modified ITT[89,92] analyses; quantitative data from per-protocol analyses not reported.
95% CI for the difference between CIC and comparator. In one study,[40] a 97.5% CI for the difference between treatments is reported.
1756
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
FEV1[37,38]a
FEV1[16]
[16]b
Morning PEF[38]a
Morning PEF[16,37]
Evening PEF[38]a
Evening PEF[16]
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]
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.
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.
1760
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)
duration; wk]
baseline change
from
baseline
1.68
257
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]
(0.075,
Primary endpoint.
b ,c
0.01)d
26*
(10.9,
3.4)d
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.
Ciclesonide: A Review
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
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.
Ciclesonide: A Review
1763
1764
Ciclesonide: A Review
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
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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