CICLESONIDE REVIEW.pdf

Drugs 2008; 68 (12): 1741-1770ADIS DRUG EVALUATION 0012-6667/08/0012-1741/$53.45/0 2008 Adis Data Information BV. All rights reserved.

CiclesonideA Review of its Use in the Management of Asthma

Emma D. Deeks and Caroline M. PerryWolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters KluwerHealth, 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,Klinik fur Pneumologie, Bremen, Germany; M. Zitt, Queens Long Island Medical Group, State University ofNew York, New York, New York, USA.

Data SelectionSources: Medical literature published in any language since 1980 on ciclesonide, identified using MEDLINE and EMBASE, supplementedby AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists ofpublished articles. Bibliographical information, including contributory unpublished data, was also requested from the company developingthe drug.Search strategy: MEDLINE, EMBASE and AdisBase search terms were ciclesonide.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 thetrials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic andpharmacokinetic data are also included.Index terms: Ciclesonide, asthma, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

ContentsSummary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17421. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17432. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1744

2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17442.2 Anti-Inflammatory Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1744

2.2.1 Effects on Markers of Airway Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17462.3 Pulmonary Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17462.4 Systemic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1746

3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17483.1 Deposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17483.2 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17483.3 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17493.4 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1749

4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17494.1 Adults and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1750

4.1.1 Versus Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17524.1.2 Versus Active Comparators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17544.1.3 Effects on Health-Related Quality of Life (HR-QOL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1757

4.2 Paediatric Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17584.2.1 Versus Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17594.2.2 Versus Active Comparators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17604.2.3 Effects on HR-QOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1761

5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1761

1742 Deeks & Perry

5.1 General Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17615.2 Versus Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17625.3 Versus Active Comparators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1762

6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17647. Place of Ciclesonide in the Management of Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1764

SummaryCiclesonide (Alvesco) is an inhaled corticosteroid used in the preventativeAbstracttreatment of persistent bronchial asthma in adults, adolescents and, in somecountries, children. The drug is delivered by a non-chlorofluorocarbon hydro-fluoroalkane (HFA) metered-dose inhaler (MDI). In the lungs, ciclesonide isconverted to an active metabolite, which is responsible for the beneficial effects ofthe drug in patients with asthma. Ciclesonide and its active metabolite have lowsystemic bioavailability and therefore have a low potential to produce systemicadverse events. Inhaled ciclesonide delivered by HFA-MDI is effective in theprophylactic treatment of persistent asthma in adults, adolescents and children,and is generally well tolerated.

In general, ciclesonide improves lung function and reduces asthma symptomsand rescue medication use in adults and adolescents with asthma of varyingseverity. The drug is generally no less effective than other inhaled corticosteroidswith regard to maintaining or improving lung function and may have a morefavourable tolerability profile than some other agents in this class. Ciclesonide hasalso shown efficacy in paediatric patients with asthma. Data on its long-termeffects on other clinical outcomes, such as asthma exacerbations, would be ofinterest. Further comparative and long-term studies would also be beneficial inorder to definitively position ciclesonide with respect to other inhaled corticoster-oids. In the meantime, ciclesonide offers an effective and well tolerated first-linepreventative treatment option for persistent asthma.Ciclesonide is a corticosteroid prodrug that is converted to its active metabolite,Pharmacologicaldesisobutyryl-ciclesonide (des-CIC), primarily in the lung. Compared withPropertiesciclesonide, des-CIC exhibits greater glucocorticoid receptor binding affinity andgenerally has greater anti-inflammatory effects in vitro. Ciclesonide reducesairway hyper-responsiveness to various stimuli and attenuates bronchoconstric-tion induced by allergens and exercise. The drug is also associated with theinhibition of, or reduction in, levels of pro-inflammatory mediators, such ascytokines and eosinophils. Short- and long-term treatment with inhaled cicleso-nide at therapeutic dosages was associated with negligible systemic effects inadults, 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 ofbudesonide and fluticasone propionate administered via chlorofluorocarbon-MDIand HFA-MDI devices, respectively. After inhalation, the oral bioavailability ofciclesonide and des-CIC is negligible and systemic exposure to non-plasmaprotein bound ciclesonide and des-CIC is low (12% of the dose absorbed by thelung). Pulmonary retention of ciclesonide may be facilitated by the formation ofreversible des-CIC fatty acid conjugates in lung tissue. Systemic ciclesonideappears to be extensively metabolized by the liver, primarily via the cytochromeP450 (CYP) isoenzyme CYP3A4, to inactive metabolites. At steady state, themean 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 1743

In well designed, placebo-controlled, short-term trials, inhaled ciclesonide wasTherapeutic Efficacyeffective in maintaining or improving lung function in adult and adolescentpatients with asthma of varying severity, most of whom had previously receivedcorticosteroid treatment. Ciclesonide also generally produced significant benefitsin these patients in terms of asthma symptom scores and rescue medication usecompared with placebo. Moreover, in two 12-week studies in adult patients withpersistent asthma, significantly fewer ciclesonide recipients experienced lack ofefficacy compared with placebo recipients. Longer term, the beneficial effects ofciclesonide at individualized dosages on lung function were maintained up to52 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 propion-ate, budesonide or beclometasone with regard to improving or maintaining lungfunction in adults and adolescents with asthma in clinical trials of 824 weeksduration. Ciclesonide 320 and 640 g/day was significantly more effective thanbudesonide 400 g/day and beclometasone 800 g/day, respectively, in improv-ing some lung function parameters in two recent, well designed trials. Recipientsof ciclesonide also generally experienced improvements from baseline in asthmasymptom scores and rescue medication use, with ciclesonide 640 g/day demon-strating significantly greater efficacy than beclometasone in this regard in onestudy.

Ciclesonide also showed beneficial effects as a prophylactic treatment inpaediatric patients with persistent asthma. In a large, well designed, 12-week trial,ciclesonide generally produced significant improvements in lung function, asthmasymptom scores and rescue medication use compared with placebo in childrenwith persistent asthma of varying severity. Furthermore, in additional short-termtrials, ciclesonide 160 g/day was noninferior to, or generally as effective as,fluticasone propionate or budesonide, in improving lung function in paediatricpatients with persistent or moderate to severe asthma. Ciclesonide was alsononinferior to, or as effective as, these inhaled corticosteroids in improvingasthma symptom scores and rescue medication use.

In addition, treatment with inhaled ciclesonide for 12 weeks was effective inimproving the health-related quality of life of adult and paediatric patients withasthma in placebo-controlled studies. Moreover, the drug was generally no lesseffective than fluticasone propionate or budesonide in this regard in studies of 12or 24 weeks duration.Inhaled ciclesonide was generally well tolerated in adults and adolescents withTolerabilityasthma in clinical trials, with adverse events generally being mild to moderate inseverity. Ciclesonide was also well tolerated in paediatric patients with asthma.The tolerability profile of ciclesonide may be more favourable than that of otherinhaled corticosteroids (fluticasone propionate, budesonide and beclometasone)in terms of local oropharyngeal adverse events, such as oral candidiasis andhoarseness.

1. Introduction and systemic adverse events associated with theseagents and their frequency of administration hasInhaled corticosteroids are currently the goldprompted the development of new agents with morestandard preventative treatment for persistent asth-

ma.[1,2] However, concerns about the potential local favourable safety and tolerability profiles.


1744 Deeks & Perry

Ciclesonide (Alvesco)1 is a synthetic cortico- are sourced from the manufacturers prescribing in-steroid formulated for oral inhalation via an hydro- formation;[21] some data are only available as ab-fluoroalkane (HFA) metered-dose inhaler (MDI) for stracts.[9,10,22,24,28,30,36,42,44,46,47,50]use in the treatment of persistent asthma in adults,

2.1 Mechanism of Actionadolescents and, in some countries, children. Thisarticle reviews the pharmacological properties of

Ciclesonide is a nonhalogenated, inhaled cortico-ciclesonide and its efficacy and tolerability in thesteroid prodrug that is converted by esterases in thetreatment of adult and paediatric patients with asth-lung (see section 3) to its clinically active metabolitema.desisobutyryl-ciclesonide (des-CIC; also known asThroughout this review, ex-actuator doses (ExA;R-M1, ciclesonide active principal and ciclesonidethe dose delivered from the mouthpiece) are report-active metabolite).[21] Corticosteroids exert anti-in-ed where available. Ex-valve doses (i.e. the meteredflammatory effects by binding to glucocorticoid re-dose within the inhaler) are referred to as ExV. Theceptors with subsequent transrepression or transac-ciclesonide HFA-MDI delivers an ExV dose oftivation of genes involved in inflammatory and anti-50 g from the valve with a corresponding ExAinflammatory processes.[52]dose of 40 g from the actuator, an ExV dose of

Ex vivo studies in rats suggest a marked affinity100 g from the valve with a corresponding ExAof ciclesonide for lung tissue following intratrachealdose of 80 g from the actuator or an ExV dose ofadministration.[50] The relative binding affinity of200 g from the valve with a corresponding ExAdes-CIC to the glucocorticoid receptor is high and isdose of 160 g from the actuator. Thus, ciclesonide100-fold greater than that of ciclesonide, accordingHFA-MDI ExA doses of 40, 80, 160, 320 andto in vitro binding assays.[48,49]640 g are equivalent to 50, 100, 200, 400 and

800 g ExV doses.[3-5] The pharmacology and clin-2.2 Anti-Inflammatory Effectsical profile of ciclesonide have been reviewed pre-

viously in Drugs.[6] Several studies have demonstrated the anti-in-flammatory effects of ciclesonide in vitro.[43-48] In2. Pharmacodynamic Properties general, des-CIC appeared to confer greater anti-

Discussion here focuses on the pharmaco- inflammatory activity than ciclesonide.[46-48]dynamics of ciclesonide delivered via an HFA-MDI In vitro, ciclesonide and/or des-CIC were gener-where possible. In addition, for completeness, data ally effective in inhibiting pro-inflammatory func-from studies using the Cyclohaler dry powder in- tions, including the stimulated expression of intra-haler (DPI) are also included.[7,8] The type of inhala- cellular adhesion molecule-1[43,45] and the stimulat-tion device was reported as a MDI,[9-14] a chloro- ed release of inflammatory mediators, such asfluorocarbon (CFC)-free MDI[15] or was not speci- granulocyte-macrophage colony-stimulating fac-fied[16-20] in some studies. tor,[45,46] monocyte chemoattractant protein-1

The pharmacodynamic properties of both the R- (MCP-1),[43] interferon (IFN)-,[48] interleukin (IL)-and S-epimers of ciclesonide were evaluated in 2,[48] IL-4,[48] IL-5,[48] IL-8[45] and tumour necrosissome studies; however, this section focuses only on factor-.[47] Ciclesonide and des-CIC also inhibitedthe properties of the R-epimer (table I), which un- the induced proliferation of immune system cellsderwent development for clinical use.[21] (human peripheral blood mononuclear cells, CD4+

lymphocytes and rat spleen cells[48]) [table I] as wellData are from studies in adults, adolescents andas human airway smooth muscle cells (table I),[46]children with asthma,[7,8,12,13,15,18-20,22-35] patientsthe hyperplasia of which is characteristic in patientswith an asthma exacerbation,[36] healthy volun-with asthma.[53]teers,[14] clinical trials discussed in section

4,[4,5,9-11,16,17,37-42] and several in vitro[43-49] and in The anti-inflammatory effects of ciclesonidevivo or ex vivo animal studies.[48-51] Additional data treatment have been confirmed in patients with mild

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



Table I. Overview of the pharmacodynamic properties of ciclesonide (CIC; R-epimer) and desisobutyryl-CICAnti-inflammatory effectsGenerally 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-cellmigration 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 modelsPrevents 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 inflammationReduces percentage of eosinophils in sputum[7,15,35] and serum levels of ECP[7,15] in patients with asthmaAttenuates allergen-induced levels of eosinophils in sputum[23,31] and ECP in serum[31] in patients with asthmaAttenuates allergen-induced reductions in interferon--positive CD4+ T cells after allergen provocation at some dosages in patients withatopic asthma[23]

Reduces exhaled nitric oxide levels in patients with asthma[15,18-20,32,35]

Pulmonary effectsAttenuates airway responsiveness to AMP[7,15,18,20,34,35] and methacholine[20,32] in patients with mild to moderate asthmaImproves some, but not all, measures of airway trapping indicative of small airway obstruction in patients with mild to moderateasthma[20]

Reduces early- and/or late-phase allergen-induced bronchoconstriction in patients with atopic[13,23] or mild allergic[8,31] asthmaAttenuates exercise-induced bronchoconstriction in patients with asthma[12]

Systemic effectsNo clinically relevant HPA-axis suppression at therapeutic doses in healthy adults,[14] or adults, adolescents and children withasthma[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 growthfactor-1.

persistent asthma. In a small (n = 21), randomized, ma.[13] The drug also significantly (p < 0.05) re-double-blind, crossover trial,[18] once-daily cicleso- duced chemokine (CCL17)-induced T-cell migra-nide 320 g significantly (p < 0.05 vs placebo) tion versus placebo, both prior to, and 6 hours after,inhibited levels of IL-12 and MCP-1 in sputum allergen challenge (table I), with such migration alsowithin 4 hours of administration. Inhibition of IL-12 significantly (p < 0.05) lower after than before aller-and MCP-1 levels, as well as levels of other cyto- gen challenge in ciclesonide recipients.[13]kines, including IL-1, IL-6, IL-7 and IL-8, in spu- Potent anti-inflammatory effects of ciclesonidetum was observed within 4 hours of patients receiv- have also been demonstrated in several in vivoing twice-daily ciclesonide 640 g (all p < 0.01 vs

animal studies (table I).[48,49,51] Furthermore, in rats,placebo). In addition, levels of IFN-inducible pro-ciclesonide exhibited stronger local than systemictein-10 were significantly (p < 0.001) inhibited com-anti-inflammatory activity (no statistical analysespared with placebo after 1 week of treatment withreported)[48] and was up to 44-fold less potent thanciclesonide 640 g twice daily.[18]fluticasone propionate in producing systemic ef-Furthermore, once-daily ciclesonide 80 g atten-fects.[49]uated allergen-induced 2-fold increases in the pro-

Smooth muscle actin reduction has been shownduction of some cytokines (IL-4 and IL-5), accord-to correlate with improvements in airway function ining to data from one centre (n = 5 evaluable patients)patients with asthma.[54] Ciclesonide has demonstra-of a randomized, double-blind, placebo-controlled

crossover study in patients with mild atopic asth- ted an ability to downregulate transforming growth


1746 Deeks & Perry

factor-1-induced -smooth muscle actin expres- In general, ciclesonide was also effective in re-sion in human lung fibroblasts in vitro.[43] ducing levels of exhaled nitric oxide, a potential

marker of airway inflammation, in patients withasthma of mild to moderate severity.[15,18-20,32,35]2.2.1 Effects on Markers of Airway Inflammation

Asthma is associated with airway inflammation2.3 Pulmonary Effectsand eosinophilia, with the latter a possible determi-

nant of asthma severity.[55] In general, ciclesonide In general, treatment with ciclesonide signifi-significantly reduced the percentage of eosinophils

cantly reduced airway responsiveness to adenosinein induced sputum compared with pretreatment,[7,15]monophosphate[7,15,18,20,34,35] and methacholine chal-

run-in[35] or washout levels or placebo[35] in random- lenge[20,32] in patients with asthma of mild to moder-ized, double-blind[7,35]/double-observer,[15] placebo-ate severity (all p < 0.05 vs placebo or pretreatment,[7,35]

or active comparator-controlled,[15] crossoverwhere reported[7,15,18,20,32,34]) [table I]. Moreover, in

trials in patients with asthma (table I). terms of reducing airway responsiveness, cicleso-Ciclesonide has also demonstrated beneficial ef- nide 3201280 g/day was as effective as fluti-

fects on allergen-induced sputum eosinophil levels casone propionate 4401760 g/day,[24,32,33] andin patients with atopic[23] or mild allergic[31] asthma there was no significant difference between cicleso-in randomized, double-blind, placebo-controlled, nide 320 g/day and budesonide 400 g/daycrossover studies (n = 10[23] or 21[31]). The percent- (ExV),[15] in randomized, double-blind[24,32,33]/doub-age of induced sputum eosinophils was significantly le-observer,[15] dose-escalating[24] or cross-attenuated with low-dose ciclesonide (40 and 80 g/ over[15,32,33] trials (15103 randomized patients)day) 24 hours after allergen challenge in one with 2- to 4-week treatment periods.study,[31] with the highest ciclesonide dosage (80 g/ In addition, ciclesonide 320 g/day improvedday) also attenuating the number of induced sputum some, but not all, measures of air trapping indicativeeosinophils at this timepoint (all p < 0.025 vs place- of small airway obstruction (p < 0.05 vs placebo), inbo). In contrast, the number of allergen-induced patients with mild to moderate asthma in a random-sputum eosinophils was significantly attenuated ized, double-blind, 5-week study (n = 16).[20]with both ciclesonide 40 and 80 g/day 8 hours, but Early- and/or late-phase bronchoconstriction re-not 24 hours, after allergen challenge in the other

sponses to allergen challenge were generally alsostudy (p < 0.05 vs placebo).[23]

reduced with ciclesonide treatment in patients withIn sputum, levels of eosinophil cationic protein atopic[13,23] or mild allergic[8,31] asthma (all p < 0.05(ECP), a product released by activated eosinophils, vs placebo).

were also significantly (p < 0.05) reduced from Exercise-induced bronchoconstriction, experi-pretreatment levels with ciclesonide 400 g/day (ad- enced by 7080% of patients with asthma, wasministered via DPI[7] or CFC-free MDI[15]) in pa- attenuated to a clinically relevant extent in cicleso-tients with asthma in two studies. However, cicleso-

nide 320 g/day recipients.[12]nide 100 and 1600 g/day had no effect on thisparameter in one study.[7] Allergen-induced levels of 2.4 Systemic Effectsserum ECP were significantly (p = 0.024) attenuatedwith ciclesonide 80 g/day compared with placebo; Inhaled corticosteroids may cause hypothalamic-however, there was no significant difference be- pituitary-adrenal (HPA)-axis suppression, whichtween ciclesonide 40 g/day and placebo.[31] may manifest as cataracts, reduced bone density and

IFN- is a potential anti-inflammatory modula- retardation of growth velocity in children.[58,59]tor.[56,57] In a randomized, crossover study in ten Nevertheless, to date, no clinically relevant evi-patients with atopic asthma,[23] ciclesonide 40 g/ dence of HPA-axis suppression, as measured byday attenuated allergen-induced reductions in IFN- serum cortisol levels (morning[7] or 24-hour pro--positive CD4+ T cells 24 hours after allergen file[14]) or 24-hour urinary cortisol levels,[8] has beenprovocation (p < 0.05 vs placebo), although such observed following short-term treatment (1- toattenuation was not seen with ciclesonide 80 g/day. 2-week periods) with inhaled ciclesonide



1001600 g/day in randomized, double-blind, pla- tical analyses not reported in one study[24]). How-cebo-controlled, crossover trials in adults with mild ever, results were mixed with regard to HPA-axisto moderate asthma (aged 1846 years)[7,8] or suppression measured by 24-hour urinary cortisolhealthy volunteers (aged 2128 years)[14] [table I]. levels in trials comparing ciclesonide with budeso-

nide.[11,37,40,41] In three of the trials,[11,37,40] HPA-axisHPA-axis suppression was also negligible insuppression was significantly (p < 0.05) lower withadults and adolescents receiving low to high dosessome dosages of ciclesonide compared with budeso-of ciclesonide (801280 g/day) in active compara-nide. No significant difference in this parameter wastor-[24,26,27,32,34] and placebo-controlled[26,27,32,34]observed between ciclesonide and budesonide recip-studies of 9 days to 12 weeks duration, and inients in one study.[41]12-week clinical trials discussed in section

4.[4,5,9,11,17,39-41] In these studies, measures of HPA- Ciclesonide had a negligible effect on markers ofaxis suppression included overnight[32] or bone formation in one short-term study[9] and its24-hour[4,5,9,11,17,24,26,27,34,40,41] urinary cortisol levels,

extension phase.[10] Levels of markers of bone for-serum cortisol levels,[4,5,9,39] 24-hour serum[24,27] or

mation were significantly (p < 0.05) increased com-plasma[34] cortisol levels and stimulated plasma[32] pared with beclometasone pretreatment after 12[9]or serum[17,26,27,39] cortisol levels. (serum osteocalcin) and 52[10] (serum osteocalcin

Although data on the effects of ciclesonide on and serum alkaline phosphatase) weeks of cicleso-HPA-axis function over the longer term are limited, nide treatment in patients with moderate to severepreliminary data from noncomparative[30] and com- asthma. Furthermore, low-dose ciclesonide (40 orparative[22] multicentre extension studies in adults 160 g/day) had no effect on skeletal maturity in theand adolescents with mild to moderate[30] or se-

majority of prepubertal children with asthma in avere[22] persistent asthma showed no clinically rele- double-blind, placebo-controlled, 52-week studyvant or marked suppressive effects on low-dose (n = 661)[25] [table I].cosyntropin-stimulated serum cortisol levels or

Inhaled corticosteroids may inhibit growth veloc-24-hour urinary cortisol levels over 52 weeks inity in children, although final adult height does notpatients who received therapeutic dosages of in-

haled ciclesonide. Similar findings have been re- appear to be affected.[60] Long term, low-doseported in long-term clinical studies discussed in ciclesonide (40 or 160 g/day) was noninferior tosection 4.1.[10,42] placebo with regard to mean linear growth velocity

in prepubertal children in a large (n = 661), double-In children with asthma, HPA-axis function inblind, 52-week trial (respective differences vs place-terms of 10-[25] or 12-hour[29] overnight urinary cor-bo of 0.02 cm/year [95% CI 0.19, 0.16] andtisol levels, 24-hour urinary cortisol levels[25,28] and0.15 cm/year [95% CI 0.33, 0.03]; 0.5 cm/yearlow-dose cosyntropin-stimulated serum cortisolnoninferiority limit).[25] Moreover, there was no sig-levels[28] was not suppressed following treatmentnificant difference between ciclesonide and placebowith ciclesonide 40160 g/day in short-[29] or long-recipients in terms of mean change from baseline interm[25,28] randomized,[25,28,29] double-blind[25,29] or

nonblind[28] trials (table I). These data are supported height.[25] The mean lower-leg growth rate of chil-by the results of some,[16,38] but not all,[37] clinical dren (n = 24) aged 612 years with mild asthmatrials in children with asthma discussed in section 4. receiving ciclesonide 40160 g/day was similar to

that of placebo recipients in a double-blind, cross-Inhaled high-dose ciclesonide (640 g twiceover study with 2-week treatment periods[29] (tabledaily) had a significantly (p < 0.0001) lower sup-I). Notably, the height of children treated withpressive effect on serum cortisol levels than oralciclesonide 160 g/day (n = 58) increased signifi-prednisolone 40 mg once daily in patients with acutecantly from baseline compared with budesonideasthma exacerbation.[36] Moreover, in some in-400 g/day (ExV) recipients (n = 26) [1.18 vsstances, HPA-axis suppression was significantly0.70 cm; p = 0.0025] in a subgroup analysis of one(p < 0.05) lower with ciclesonide than with fluti-

casone propionate[24,26,27,32,34] (between-group statis- 12-week trial.[37]


1748 Deeks & Perry

3. Pharmacokinetic Properties without an AeroChamber Plus spacer in patientswith asthma.[69]

This section focuses on the pharmacokinetics of3.1 Depositionciclesonide inhaled via an HFA-MDI, unless other-

wise stated. Data are from studies in healthy volun- The mean deposition of ciclesonide in the lungteers,[3,61-66] patients with asthma[65,67-69] or undergo-

was 52%, both in patients with mild asthmaing lung surgery[70] and from a population pharma- (n = 12)[67] and in healthy volunteers (n = 8),[3] aftercokinetic study.[71] Additional data have been inhalation of a single radiolabelled dose ofobtained from the manufacturers prescribing infor- 320 g,[67] or after a single or multiple inhalations ofmation,[21] the summary of product characteris- a radiolabelled 40 g dose.[3] Deposition occurredtics[72,73] and from in vitro[43,45,74-82] and in vivo throughout the lungs, but was greater in peripheralanimal[83] studies. Some data are available only as regions containing the small airways and alveoliabstracts.[66,70,71,80] than in central regions.[3,67] The mean oropharyngeal

An overview of the pharmacokinetic properties deposition of ciclesonide was 32.9%[67] and 38.0%[3]of ciclesonide and its active metabolite des-CIC is in the respective studies.provided in table II. The pharmacokinetics of des- Oropharyngeal deposition of ciclesonide follow-CIC do not appear to be affected by asthma severity, ing inhalation via an HFA-MDI was lower than thatgender, weight or race, according to a pooled popu- of budesonide[63] and fluticasone propionate[68] in-lation pharmacokinetic/pharmacodynamic analysis haled via a CFC-[63] and HFA-[68] MDI. Followingmodel.[71] In elderly patients, des-CIC exposure may inhalation of a single dose of ciclesonide 640 g, thebe marginally increased compared with young pa- oropharyngeal molar-adjusted area under the con-tients,[21] although the changes are not clinically centration-time curve (AUC) from time zero torelevant and require no dosage adjustment.[72,73] 1 hour (AUC1) for des-CIC and total ciclesonideSimilarly, no clinically relevant changes in the phar- (des-CIC and parent drug) was 4% and 47% that of

a single dose of budesonide 800 g (ExV; bothmacokinetic profile of ciclesonide are observed inp < 0.0001) in healthy volunteers (n = 18),[63] andpatients with mild to moderate hepatic impair-8% and 53% that of a single dose of fluticasonement;[21] dosage adjustments are not recommendedpropionate 880 g (both p < 0.001) in patients within this patient population.[72,73] Furthermore, theasthma (n = 18).[68]pharmacokinetics of des-CIC after inhalation of a

single ciclesonide 320 g dose were not appreciably The amount of ciclesonide present in the oro-different when ciclesonide was delivered with or pharynx following inhalation of a 640 g dose of

ciclesonide rapidly decreased within 15 minutes inhealthy volunteers[63] and patients with asthma[68](both n = 18). Furthermore, the mean oropharyngealAUC1 for des-CIC was 8%[63] and 17%[68] that ofciclesonide (point estimates), suggesting low oro-pharyngeal activation of ciclesonide to des-CIC.[63,68]

3.2 Absorption and Distribution

The systemic absorption of ciclesonide is mini-mal, thus reducing the likelihood of systemic ad-verse events.[21] The maximum plasma concentra-tion of ciclesonide and des-CIC is approximatelydose related following single inhaled doses ofciclesonide 320 and 1280 g in patients with asth-ma.[65,67,69]

Table II. Summary of the pharmacokinetic properties of ciclesonide(CIC) and desisobutyryl-CIC (des-CIC) after oral inhalation of asingle 320 g dosea in patients with asthma aged 1952 years(n = 12[67] and 30[69]). Values are means unless specified otherwiseParameter CIC des-CICLung deposition (%) 52[67]Oropharyngeal 32.9[67]deposition (%)Cmax (g/L) 0.91.9[67,69] 0.3,[69] 0.41[67]AUC0- (g h/L) 0.50.9 [67,69] 1.3,[69] 1.87[67]tmax (h) 0.25[67,69] 0.94,[67] 1.0[69]bt1/2 (h) 0.5,[69] 0.57[67] 4.66.02[67,69]a Administered with[67,69] or without[67] a spacer.b Median value.AUC0- = area under the serum concentration-time curve from time0 to infinity; Cmax = maximum serum concentration; tmax = time toreach Cmax; t1/2 = elimination half-life.



In healthy volunteers, the absorption pharmaco- plete elimination achieved 80120 hours after ad-kinetics of des-CIC were generally similar at steady ministration.[64] The clearance of ciclesonide andstate and after a single ciclesonide 320 g dose, with des-CIC (assuming complete ciclesonide activation)no apparent accumulation of des-CIC.[21] was 152 and 228 L/h after intravenous administra-

tion.[21]Airway inflammation associated with asthma ap-In patients with asthma, the mean serum elimina-pears not to affect the distribution of ciclesonide, as

tion half-life (t1/2) of ciclesonide was rapid comparedthe pharmacokinetic profile of both ciclesonide andwith that of des-CIC after inhalation of a singledes-CIC in patients with asthma and a forced expir-320 g dose of ciclesonide (table II).[67,69] Further-atory volume in 1 second (FEV1) of 6090% ofmore, the serum t1/2 values for both ciclesonide andpredicted did not markedly differ from that seen indes-CIC following administration of a singlehealthy volunteers.[65] Evidence suggests that des-ciclesonide 320 g dose were generally similar re-CIC does not accumulate in red blood cells.[21]gardless of spacer use in patients with asthma.[69] AtThe oral bioavailability of ciclesonide and des-steady state, the mean t1/2 of des-CIC was 6.72 hoursCIC is

1750 Deeks & Perry

with respect to ciclesonide and nonblind for budeso-nide in two trials.[40,89] A nonblind, 40-week exten-sion[42] of one 12-week study[4] has also been report-ed, and the trials by Pearlman et al.[17] and Knox etal.[86] each report combined data from two identicalplacebo-[17] or active comparator-controlled[86]trials. Some of the study data are available only asabstracts.[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 a40-week continuation[10] of one trial;[9] some dataare available only as abstracts.[9,10] In the regimenstudy,[97] the efficacy of ciclesonide 160 g/day wasgenerally similar when administered in the morning

Table III. Estimated daily dose equivalence between ciclesonideand other inhaled corticosteroids in both adults and children, ac-cording to current treatment guidelines[1]

Agent Dose range (g)low medium high

AdultsCiclesonide 80160 >160320 >3201280Budesonide 200400 >400800 >8001600Fluticasone 100250 >250500 >5001000propionateBeclometasone 200500 >5001000 >10002000ChildrenCiclesonide 80160 >160320 >320Budesonide 100200 >200400 >400Fluticasone 100200 >200500 >500propionateBeclometasone 100200 >200400 >400 or the evening, although morning peak expiratory

flow (PEF) was improved to a significantlyspecified[16,17,85,87] in some trials. In active compara- (p < 0.05) greater extent with evening administra-tor-controlled studies, fluticasone propionate was tion. In one dosage comparison,[9] ciclesonidedelivered via an HFA-MDI,[38,84,86,92,93,95] MDI[94] 640 g twice daily was not superior to ciclesonideor DPI,[91] budesonide was delivered via a 320 g twice daily in treating patients with moderateDPI[11,37,40,41,90] or HFA-MDI,[89] and beclometasone to severe bronchial asthma. Moreover, patients whowas administered via a CFC inhaler.[88] ExA doses completed the dose comparison[9] and subsequentlyare reported for MDIs, whereas ExV doses are re- received ciclesonide 1280 g/day for 4 weeks, hadported for DPIs. sustained beneficial effects with individualized

ciclesonide dosages throughout a 40-week extensionperiod.[10] However, in another study,[96] twice-daily4.1 Adults and Adolescentsciclesonide 320 g was superior in efficacy to once-daily ciclesonide 160 g in patients with severeThe clinical efficacy of ciclesonide has beenasthma with regard to most parameters, includingcompared with that of placebo,[4,5,17,39,85,87] budeso-the time to first asthma exacerbation (primary end-nide,[11,40,41,89,90] fluticasone propionate[84,86,91-93] andpoint). Ciclesonide was delivered via an MDI[9,10]beclometasone[88] in randomized,[4,5,11,17,39-41,84-93] (specified as an HFA-MDI[97]), where clearly report-double-blind[4,5,11,17,39,41,84-87,90,92] or nonblind[88,91,93]ed. These studies are not discussed further withintrials of 824 weeks duration. Patients (n >100)this review.were adults and adolescents aged 12 years with

Eligibility criteria for the clinical trials in adultsmild to moderate,[4,5,17,40,84,85] moderate,[41,91] moder-and adolescents are summarized in table IV; oneate to severe,[88,93] severe[11,39,87] and stable[86] asth-study was conducted only in Japanese patients.[85]ma, where stated (reported as persistent in most

Most trials excluded patients who had receivedstudies[4,5,11,17,39,41,87-93]). In general, patients hadrecent treatment with systemic or injectable cortico-been previously treated with corticosteroids, wheresteroids,[5,11,17,40,41,84-86,88-93] with some excludingstated.[4,5,11,39-41,84-86,88-90,92,93] In some studies, pa-those who had received recent treatment with oraltients not using inhaled corticosteroids[17] (i.e. re-corticosteroids,[4,5,17,40] inhaled corticosteroids,[40]ceiving only rescue medication,[41,92] bronchodilat-long-acting 2-adrenoceptor agonists (LABAs)[5,86]ors[91] or non-steroidal controllers[91]) or those usingor an inhaled corticosteroid plus a LABA.[92]inhaled corticosteroids 30 days prior to screening[17]

were eligible. Overall, patients had an FEV1 predict- During a baseline period of up to 28 days, pa-ed of 52101% at baseline, where report- tients received placebo,[17] oral prednisone,[39] in-ed.[4,5,11,17,39-41,84-93] Treatment was double-blind haled corticosteroids,[4,5,11,39,85,86,88-91,93] rescue med-



Table IV. Eligibility criteria for the enrolment and randomization of adult and adolescent patients with asthma in randomized, comparative,clinical trials of ciclesonideTrial eligibility criteriaHistory 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 durationPrevious 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 nochange 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 studyPrevious treatment with asthma medications (at stable regimens where stated[41,91]) 2830 days preceding the study[17,41,91]Eligibility criteria for randomizationFEV1 predicted value of: 6090%,[5] 5090%,[41] 6190%,[92] 90%[86] or >50% to 69%[89] or 80%[93] after 4[84,89,93] or 6[17,39] hours without rescuemedication[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] orinhaled 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

1752 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 ofciclesonide was analysed in the intent-to-treat(ITT)[4,85] or modified ITT[5,17,39] population.Where stated, most noninferiority studies used theper-protocol population for efficacy analy-ses,[11,40,41,84,89-93] with subsequent confirmatoryanalyses performed in the ITT[84,90] or modifiedITT[40,89] population where specified. In one trial,[41]further analyses were performed in the full analysisset to test for the superiority of ciclesonide overbudesonide if noninferiority was initially demon-strated. Other active comparator-controlled stud-ies[86,88] used the ITT patient population to assess theefficacy of ciclesonide.

Four studies evaluated health-related quality oflife (HR-QOL) using the Asthma Quality of LifeQuestionnaire (AQLQ),[17,87,91,93] which consists of32 questions within four domains (symptoms, activ-ities, emotional function and environmental expo-sure). Each question is scored on a 1- to 7-pointscale; higher scores denote a better HR-QOL.[98] Inaddition, a study in adolescents (aged 1217 years)used the Paediatric Asthma Quality of Life Ques-tionnaire (PAQLQ) to evaluate HR-QOL.[11] ThePAQLQ consists of 23 items across three domains(symptoms, emotional function and activity limita-tions); questions are scored from 1 to 7, with ahigher score indicative of a better HR-QOL.[99] TheHR-QOL results of Weinstein et al.[87] are availablein a separate abstract.[100] HR-QOL data for anotherplacebo-controlled study[17] were also obtained froman abstract.[101] In active comparator-controlledtrials, the noninferiority acceptance limit for

Table V. Primary and secondary efficacy outcomes in randomized,comparative, clinical trials of ciclesonide in the treatment of asthmain adults and adolescentsPrimary efficacy outcomesFEV1[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 rescuemedication 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 outcomesFEV1[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 rescuemedication 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]

b Change from baseline to end of treatment.c Change from baseline to end of trial or termination.d Defined as a 20% decrease from baseline in FEV1 or a

50% decrease in predicted FEV1; asthma exacerbation; adaytime asthma score of 3 on 4 days within the week priorto a study visit; a night-time asthma score of 2 on 4 nightsor 3 on 2 nights within the week before a visit,[4,5] areduction from baseline of 20% in PEF[4] or another lungfunction deterioration that compromized health.[5]

FEV1 = forced expiratory volume in 1 second; FVC = forced vitalcapacity; PEF = peak expiratory flow.

AQLQ[91,93] and PAQLQ[11] scores was 0.5, basedon the lower limit of the 95% CI for the between-

morning and evening), +0.15 for night-time asthma group differences.symptom score,[92] +5% for the withdrawal rate due

4.1.1 Versus Placeboto asthma exacerbation[93] and 8% for the percent-age of days without asthma symptoms and rescue Ciclesonide 80640 g/day was effective inmedication use.[11] One study[88] evaluated the maintaining or improving lung function in adultsnoninferiority of ciclesonide compared with and adolescents with asthma in placebo-controlledbeclometasone in adults and adolescents, using a trials of 8 or 12 weeks duration (table VI).[4,5,17,85,87]predefined noninferiority margin of 22.4 L/min for Where stated, there were generally no significantmorning PEF, and tested for superiority if noninferi- differences between the various ciclesonide dosagesority was shown. Noninferiority was based on the in terms of efficacy.[4,5,17]




Tabl

e VI

. Effi

cacy

of c

icles

onid

e (C

IC) i

n the

trea

tmen

t of a

sthma

in a

dults

and

ado

lesce

nts. R

esult

s of r

ando

mize

d, do

uble-

blind

, plac

ebo

(PL)-

contr

olled

, mult

icentr

e, 8-

or12

-wee

k tri

als

in a

dult[4

,5] or

adu

lt an

d ad

oles

cent

[17,85

,87] p

atie

nts

(pts)

with

mild

to mo

derat

e[4,5,

17,85

] or

seve

re[87

] ast

hma

rece

ivin

g CI

C or

PL

once

dai

ly (od

) or t

wice

daily

(bid)

adm

inist

ered

via

a h

ydro

fluor

oalka

ne m

eter

ed-d

ose[

4,5] o

r unsp

ecifie

d[17,8

5,87]

inha

ler.

Ex-a

ctua

tor

dose

s an

d in

tent

-to-tr

eat (

ITT) o

r mod

ified

ITT a

nalys

es a

re pre

sente

d; me

anva

lues

unl

ess

othe

rwis

e no

ted

Stud

yTr

eatm

ent r

egim

enM

orni

ng P

EFEv

enin

g PE

FFE

V 1La

ck o

fAs

thm

a sy

mpt

omR

escu

e m

edica

tion

[treatm

ent d

uratio

n;(g

) [no

. of p

tsa]

(L/mi

n)b(L/

min)

(L)b

effi

cacy

sco

reu

se (t

imes

/day)

wk]

base

line

chan

geba

selin

ech

ange

base

line

chan

ge fr

om(%

of pt

s)bba

selin

ech

ange

base

line

chan

gefro

mfro

mba

selin

efro

mfro

mba

selin

eba

selin

eba

selin

eba

selin

eAd

achi

et a

l.[85]

CIC

80 o

d [78

]36

7.31

4.23

#c37

5.25

1.58

#2.

310.

01**

*6.

490.

00d

0.57

0.

20#

[8]CI

C 16

0 od

[71]

357.

313.

75#c

362.

813.

38#

2.25

0.02

#5.

720.

04d

0.42

0.01

**CI

C 32

0 od

[83]

385.

970.

40#c

389.

812.

64#

2.32

0.

03*

5.78

0.

20**

d0.

51

0.03

#

PL o

d [79

]36

0.41

24

.95c

367.

2823

.28

2.30

0.

154.

950.

75d

0.40

0.64

Chap

man

et a

l.[4]

CIC

160

od [1

07]

NR

4.

0##c

,d

NR

3.

5**e

2.70

0.01

0**c ,

d30

##1.

00f

0.00

#d,f

NR

0.00

##d ,

f

[12]

CIC

640

od [1

12]

NR

0.

4##c

,d

NR

0.

7***

e2.

660.

003*

c ,d

31##

0.86

f0.

00#d

,f

NR

0.00

##d ,

f

PL o

d [11

0]N

R28

.0

cN

R17

.0

e2.

610.

144

c63

0.57

f0.

43

d,f

NR

0.57

d

,f

Lang

don

et a

l.[5]

CIC

80 o

d [11

3]41

3c2.

0***

c42

5c2.

0* c

2.55

c0.

13**

*c

36**

c1.

43f

0.0#

#f2.

14f

0.0*

**f

[12]

CIC

320

od [1

13]

413c

3.0#

c42

5c4.

0***

c2.

55c

0.19

##

c23

##c

1.00

f0.

0##f

1.43

f0.

0***

f

PL o

d [11

9]41

3c18

.0

c42

5c12

.0c

2.55

c0.

03c

50c

1.15

f1.

0

f1.

93f

0.5

f

Pear

lman

et a

l.[17]

CIC

80 o

d [25

7]36

2.26

10.9

3#c

379.

329.

89*c

2.42

0.28

#c2.

62

0.58

#c3.

21

0.86

##c

[12]

CIC

160

od [2

50]

354.

8021

.06#

c36

8.64

18.0

6*c

2.40

0.29

#c2.

52

0.70

#c3.

05

1.02

##c

CIC

320

od [2

55]

371.

4117

.22#

c38

8.02

14.5

9*c

2.48

0.31

#c2.

67

0.61

#c3.

20

1.04

##c

PL o

d [24

9]36

7.43

1.

70c

384.

561.

48c

2.45

0.17

c2.

70

0.15

c3.

170.

42c

Wei

nste

in e

t al.[8

7]gCI

C 16

0 bi

d +

PL b

id31

1.25

18.1

1##c

1.78

21.2

*c,i

[12]

[531h

]CI

C 32

0 bi

d +

PL b

id32

3.63

20.7

1##c

1.82

24.5

#c,i

PL b

id32

7.23

9.

69c

1.77

12.7

c

aIT

T[4,8

5] or

modi

fied

ITT[

5,17]

pts,

whe

re s

tate

d.b

Mor

ning

PEF

,[4,5,

85] F

EV1[

17] a

nd

lack

of e

ffica

cy[4,

5] w

ere

prim

ary

endp

oint

s in

som

e st

udie

s.c

Leas

t squ

ares

mea

n va

lues

.d

Valu

es e

stim

ated

from

a g

raph

.e

Aver

age

unsp

ecifie

d.f

Med

ian.

gAb

stra

ct. T

his

stud

y al

so in

clude

d a

flutic

ason

e pr

opio

nate

plu

s PL

trea

tmen

t arm

.h

Ove

rall

pt p

opul

atio

n; n

umbe

r of p

ts in

indi

vidua

l tre

atm

ent g

roup

s no

t rep

orte

d.i

Perc

enta

ge c

hang

e fro

m b

asel

ine.

FEV 1

=

fo

rced

exp

irato

ry v

olum

e in

1 s

econ

d; N

R =

not r

epor

ted;

PEF

=

pe

ak e

xpira

tory

flow

; * p

< 0

.05,

** p

< 0

.01,

*** p

< 0

.005

, # p

0.

001,

##

p

0.00

01 v

s PL

; p

< 0.0

1,

p 20% variability in PEF or salbutamol used in one study.[37]2 puffs/day.[16] HR-QOL was evaluated in two of the trials[16,37]

using the PAQLQ. Results from the paediatric Asth-Treatment regimens used in fully published stud-ma Caregivers Quality of Life Questionnaireies are shown in tables IX[16] and X.[37,38] In other(PACQLQ) were also reported in one study;[37]trials, patients received ciclesonide 80[95] ornoninferiority acceptance limits for PAQLQ and160[94,95] g once daily or fluticasone propionatePACQLQ were not reported.[37]88 g twice daily.[94,95] Fluticasone propionate was

administered via a MDI[38,94,95] (specified as an HFA 4.2.1 Versus Placebo-MDI in some studies[38,95]), whereas budesonide Ciclesonide was generally effective in improvingwas delivered via a DPI (ExV dose reported).[37] lung function in children with persistent asthma of

Primary and secondary efficacy outcomes, where all severities in a large placebo-controlled study ofreported, are summarized in table VIII. Efficacy 12 weeks duration.[16] Patients receiving cicleso-assessments were based on the modified ITT popu- nide 80 or 160 g/day exhibited significantly greaterlation[16] or the per-protocol population with subse- mean increases from baseline in FEV1 percent pre-quent confirmatory analyses performed in the ITT dicted at study endpoint than those receiving place-population.[37,38] Analyses were stated as last-obser- bo (primary endpoint; table IX). The improvementsvation-carried-forward for lung function variables in in FEV1 percent predicted were sustained through-one trial.[16] out weeks 112 of therapy with the highest cicleso-

Patient diary card measurements included morn- nide dosage (160 g/day) [p < 0.05 vs placebo at alling and evening PEF,[16,37,38] asthma symptom timepoints; quantitative data not reported].[16]scores (ranging from 0 [no symptoms] to 4 [asthma The two higher doses of ciclesonide (80 andsymptoms preventing sleep or daily activi- 160 g/day) were also significantly better than pla-ties]),[16,37,38] use of rescue medication[16,37,38] and cebo at improving other measures of lung functionnight-time awakenings.[16] from baseline, including absolute FEV1 and evening

PEF (table IX).[16] Mean morning PEF was signifi-The noninferiority of ciclesonide compared withcantly improved from baseline with ciclesonidebudesonide[37] and fluticasone propionate[38] wascompared with placebo regardless of dose (79% vsexamined in some studies. Noninferiority was based4%; table IX).on the lower limit of the 95% CIs for differences

between groups using noninferiority acceptance In general, ciclesonide also had significantlimits of 0.10 L for FEV1[37,38] and 12.5 L/min for (p < 0.01) beneficial effects in terms of improvingboth morning[37,38] and evening[38] PEF. A noninferi- 24-hour asthma symptom scores and reducing res-


1760 Deeks & Perry

Table X. Efficacy of ciclesonide (CIC) vs fluticasone propionate (FP) or budesonide (BUD) in the treatment of persistent asthma inpaediatric patients (pts) aged 415 years. Results of randomized, double-blind, 12-week trials in pts receiving CIC or FP administered via ahydrofluoroalkane-propelled metered-dose inhaler or BUD via a dry powder inhaler (Turbuhaler). Per-protocol analyses and mean valuesare reported; ex-actuator doses are reported unless otherwise notedStudy [treatment Treatment regimen FEV1 (L) Morning PEF (L/min) Evening PEF (L/min)duration; wk] (g) [no. of pts] baseline change from baseline change from baseline change

baseline (95% CIa) baseline (95% CIa) frombaseline

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,eFP 88 bid [257] 1.67 0.3*b,c 256 34*b,c NR NRb

von Berg et al.[37] [12] CIC 160 od [340] 1.53 0.22*b,c (0.075, 0.01)d 199 23*c (10.9, 3.4)d 211 15*cBUD 400f od [173] 1.56 0.25*b,c 201 26*c 217 15*c

a 95% CI for the difference between CIC and comparator.b Primary endpoint.c Least squares mean values.d CIC was noninferior to comparator.e 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).f Ex-valve dose.bid = twice daily; FEV1 = forced expiratory volume in 1 second; NR = not reported; od = once daily; PEF = peak expiratory flow; * p < 0.0001vs baseline.

cue medication use compared with placebo.[16] daily ciclesonide 160 g (n = 254) and twice-dailyHowever, there were no marked differences be- fluticasone propionate 88 g (n = 258) were nottween treatment groups with regard to night-time significantly different in terms of improving FEV1awakenings (quantitative data not reported). and morning PEF from baseline in patients with

moderate to severe asthma (quantitative data not4.2.2 Versus Active Comparators reported). Furthermore, in patients with persistentCiclesonide 160 g/day, administered in one[37] asthma, improvements from baseline in FEV1 of

or two[38] daily doses, significantly improved lung 0.22, 0.25 and 0.28 L have been reported afterfunction (in terms of FEV1 and morning and even- 12 weeks of treatment with once-daily ciclesonideing PEF) compared with baseline in paediatric pa- 80 or 160 g or twice-daily fluticasone propionatetients with persistent asthma in randomized, double- 88 g, with corresponding changes in morning PEFblind, 12-week studies (table X). These findings are of 23, 29 and 25 L/min, respectively (data from angenerally supported by limited preliminary data abstract; between-group statistical analyses not re-from two other large, randomized, double-blind ported).[95]trials of 12 weeks duration (n = 512[94] and 744[95])

Ciclesonide administered once[37] or twice[38]in paediatric patients with moderate to severe[94] ordaily also significantly (p < 0.0001) improved (i.e.persistent[95] asthma who received ciclesonide 80[95]reduced) total asthma symptom scores from baselineor 160[94,95] g once daily or fluticasone propionatein paediatric patients, demonstrating an efficacy not88 g (ExA) twice daily.[94,95] FEV1[37,38] and morn-significantly different from that of fluticasone pro-ing[38] and evening[38] PEF were primary endpoints,pionate twice daily (1.43 for both treatments)[38]where stated.and noninferior to that of budesonide once dailyWith regard to improving lung function para-(1.21 for both treatments; 95% CI 0.20, 0.25 formeters, once-daily ciclesonide 160 g was no lessthe between-group difference)[37] [coprimary end-effective than once-daily budesonide 400 gpoint;[37] median values where specified[38]].(ExV),[37] and twice-daily ciclesonide 80 g wasCiclesonide also produced reductions (p < 0.0001)noninferior to twice-daily fluticasone propionatefrom baseline in rescue medication use similar to88 g in this regard[38] (table X). In addition, limited

data from a 12-week study[94] suggested that once- those seen with fluticasone propionate (1.14 vs



1.07 puffs/day; median values)[38] or budesonide in section 4. Tolerability data from these trials are(1.58 vs 1.64 puffs/day).[37] reviewed in this section together with data from the

prescribing information.[21,102] Relevant data fromIn addition, there were generally no marked dif-other sources,[22,25,28,103,104] some available only asferences between ciclesonide and fluticasone pro-abstracts,[22,28,103,104] are also reviewed. In general,pionate[38] or budesonide[37] in terms of the propor-only descriptive analyses were reported.tion of days free of asthma symptoms (76% vs 76%

with fluticasone propionate),[38] rescue medicationuse (90% vs 88% with fluticasone propionate)[38] or 5.1 General Profilenight-time awakenings (100% vs 100% with fluti-casone propionate;[38] 98.5% vs 98.5% with budeso- Adverse events in ciclesonide recipients werenide[37]) during 12 weeks of treatment (ITT analy- generally mild to moderate in severi-ses;[37,38] values are medians, where stated,[38] with ty[4,5,11,16,37,38,40,41,84,86,88-93] and most were consid-some values estimated from a graph[38]). ered unrelated to the study drug by the investiga-

tors.[4,5,11,16,17,25,37,38,40,41,84,86,88-93] Discontinuation4.2.3 Effects on HR-QOLrates because of adverse events were generally lowHR-QOL benefits have been reported in paedia-with ciclesonide treatment in both adult and paedia-tric patients receiving once-daily ciclesonide 40,[16]tric patients in clinical trials discussed in section 4.80[16] or 160[16,37] g in placebo-controlled (section

Where stated, ciclesonide was generally not asso-4.2.1)[16] and active-comparator (section 4.2.2)[37]ciated with any clinically significant changes instudies of 12 weeks duration.laboratory[5,11,17,39-42,84,89-92] or ECG[4,5,11,40] measure-Recipients of ciclesonide 40, 80 or 160 g/dayments, vital signs,[4,5,11,39,40,42,86,89-93] clinical chemi-experienced significant (p < 0.05) mean improve-cal or haematology parameters,[4,86,93] or physicalments from baseline in overall PAQLQ score com-examination findings[39,93] in adults and adolescents.pared with placebo recipients after 12 weeks (0.52,

Serious treatment-emergent adverse events in0.54 and 0.56 vs 0.27).[16] Clinically relevant im-adults and adolescents, where reported, occurred inprovements from baseline in overall PAQLQ score8.5% (4 of 47 patients) and 4.1% (2 of 49 patients)were exhibited by a proportion of each of the respec-of ciclesonide 640 and 1280 g/day recipients com-tive treatment groups (46.1%, 50.0%, 52.5% andpared with 4.4% (2 of 45 patients) of placebo recipi-36.5% of patients; p = 0.0194 across treatmentents in one study,[39] with two such adverse eventsarms); between-group statistical analyses were notreported in both ciclesonide (160 and 320 g/dayreported.groups each had one event) and placebo recipients inCiclesonide 160 g once daily was no less effec-a separate trial.[85] In another study,[4] 7%, 6% andtive than budesonide 400 g (ExV) once daily with5% of the treatment-emergent adverse events wereregard to significantly (p < 0.0001) improving fromconsidered serious in recipients of ciclesonidebaseline overall PAQLQ (0.69 vs 0.70; 95% CI160 g/day, ciclesonide 640 g/day and placebo,

0.12, 0.10 for the between-group difference) andrespectively. These adverse events were not consid-PACQLQ (0.88 vs 0.96; 95% CI 0.27, 0.13) scoresered study drug related, where stated.[39,85](ITT analyses).[37] Furthermore, both ciclesonide

In active comparator-controlled trials in adultsand budesonide recipients experienced clinicallyand adolescents, where stated, the incidence of seri-relevant improvements from baseline in PAQLQ-ous treatment-emergent adverse events was general-(56.6% vs 53.4% of patients) and PACQLQ-deter-ly low (ranging from 0.4% to 3.4% of patients in anymined (60.5% vs 60.8%) HR-QOL.[37]given treatment group, where specified[84,86,89-92]);these events were not considered[11,40,41,84,86,88,91-93]5. Tolerabilityor stated[90] as being related to the study drug. For

Inhaled ciclesonide, administered via an HFA- example, in the largest of these trials,[92] seriousMDI, was generally well tolerated by adult and adverse events were reported in a total of ten pa-paediatric patients with asthma of all severities par- tients: three ciclesonide 80 g/day recipientsticipating in the randomized, clinical trials discussed (n = 278; modified ITT population); four ciclesonide


1762 Deeks & Perry

160 g/day recipients (n = 270); and three fluti- included headache (4.911.0% vs 7.3% of patients),casone propionate 176 g/day recipients (n = 259). nasopharyngitis (7.010.5% vs 7.5%) and nasal con-

gestion (1.85.5% vs 1.6%).In paediatric patients with asthma, ciclesonidehad no clinically relevant effect on bodyweight,[16,25] Adverse events that occurred in 3% of patientsheight,[16] physical examination measurements,[16,25] in any treatment group and in at least twice as manylaboratory variables[16,38] or vital signs.[16,25,38] Seri- patients receiving some ciclesonide dosages as op-ous treatment-emergent adverse events occurred in posed to placebo in individual 12-week trials in1% (4 of 416 patients) of paediatric patients treated adults and adolescents included headache (5% andwith ciclesonide 160 g/day and 2% (4 of 205 7% of ciclesonide 80 and 320 g/day recipients vspatients) of those treated with budesonide 400 g/ 3% of placebo recipients),[5] as well as back painday, where stated; none were considered drug relat- (3% and 5% vs 2%),[5] sore throat (3% and 5% vsed.[37] 0%)[5] and upper respiratory tract infection (8% and

13% of ciclesonide 160 and 640 g/day recipients vs6% of placebo recipients).[4]5.2 Versus Placebo

In general, the incidence of local oropharyngealadverse events was low with both ciclesonide andCiclesonide exhibits a tolerability profile gener-placebo treatment in adults, adolescents and chil-ally similar to that of placebo, according to datadren, where stated.[4,5,16,17,25,42,104] These data arefrom several pooled analyses[21,102] of placebo-con-supported by a large pooled analysis of trials introlled trials conducted in adult and adolescent pa-patients with asthma, in which ciclesonidetients, where specified.[102] The incidence of adverse401280 g/day (n = 7706) and placebo (n = 1215)events considered possibly related to the study drugrecipients exhibited a low incidence of oro-was broadly similar in ciclesonide and placebo re-pharyngeal adverse events per patient-year, specifi-cipients (6.6% and 6.5% of patients),[21] as was thecally candidiasis (both 0.02) and hoarseness (bothproportion of patients who reported at least one0.03).[103] These local oropharyngeal adverse events,treatment-emergent adverse event (52.359.8% ofand others, including pharyngitis, dry throat andciclesonide 160640 g/day recipients vs 58.0% ofdysgeusia, were considered possibly drug related inplacebo recipients; total n = 624).[102]another large (n = 2784) pooled analysis, but oc-The tolerability profile of ciclesonide was alsocurred with a low incidence in both ciclesonidegenerally similar to placebo in paediatric patients (0.10.9% of patients) and placebo (0.00.4%) re-aged 411 years with asthma, with treatment-emer-cipients.[21]gent adverse events potentially related to the

However, in one clinical trial,[39] oral candidiasisstudy drug reported in 0.04.3% of ciclesonideoccurred in 6.4% (3 of 47 patients) and 8.2% (4 of40160 g/day recipients[16,25] compared with49 patients) of ciclesonide 640 and 1280 g/day0.5%[25] and 1.2%[16] of placebo recipients.recipients compared with no placebo recipients.[39]The most common adverse event considered toFurthermore, although hoarseness did not occur inbe potentially study drug related in one pooled ana-recipients of ciclesonide 1280 g/day, almost threelysis[21] was paradoxical bronchospasm (includingtimes more ciclesonide 640 g/day (6.4%; 3 of 47chest discomfort, asthma, bronchospasm, chest pain,patients) than placebo (2.2%; 1 of 45 patients) recip-dyspnoea, cough, wheezing and obstructive airwayients reported hoarseness.disorder), which occurred with a generally similar

incidence in ciclesonide (n = 1850) and placebo5.3 Versus Active Comparators(n = 934) recipients (1.8% vs 1.9% of patients)

[statistical analyses not reported]. In another pooledanalysis (n = 1131),[102] treatment-emergent adverse In 12- to 24-week clinical trials in adults andevents that occurred in 5% of patients (aged adolescents discussed in section 4.1, where report-12 years) in any treatment group and with at least ed, treatment-emergent adverse events occurred3% greater incidence in any ciclesonide treatment in 1761% of ciclesonide recipi-group (160, 320 or 640 g/day) versus placebo ents,[11,40,41,84,86,89,90,92,93] 1852% of budesonide re-



cipients[11,40,41,89,90] and 2763% of fluticasone pro- (6.9% vs 6.5%) occurred with an incidence of 5%pionate recipients.[84,86,92,93] In a longer-term safety in paediatric patients treated with either ciclesonidetrial of 52 weeks duration in adults and adoles- 160 g/day or fluticasone propionate 176 g/daycents,[22] 74.1% and 79.2% of ciclesonide 640 g/ (ExA).[38] Between-group statistical analyses wereday and beclometasone 640 g/day recipients re- not reported.[37,38]ported treatment-emergent adverse events. During longer-term therapy, the incidence of

In 12-week studies comparing ciclesonide with pharyngitis was 14.7% and 13.5% in paediatric pa-budesonide in adult and adolescent patients, where tients receiving ciclesonide 40160 g/day or fluti-reported, treatment-emergent adverse events with an casone propionate 100200 g/day (via DPI) inincidence of 5% in any treatment group included three identical nonblind, multicentre, 52-week trialsupper respiratory tract infection (5.112% of (n = 615) [combined results available as an ab-ciclesonide recipients vs 7.9%[40] and 19%[90] of stract].[28]budesonide recipients), pharyngitis (5.9% vs Where statistical analyses were performed,[91,93]3.8%),[11] asthma (4.49.9% vs 4.012%),[40,89,90] flu the incidence of some oropharyngeal adversesyndrome (4% vs 7%)[90] and bronchitis (3.8% and events, such as oral candidiasis and hoarseness, was6.1% vs 4.0%).[40] Where reported, treatment-emer- generally significantly (p < 0.01) lower with cicleso-gent adverse events that occurred with an incidence

nide than with fluticasone propionate. These find-of 5% in either ciclesonide or fluticasone propion- ings are generally supported by data from a largeate recipients in 12- to 24-week clinical trials includ- pooled analysis of trials in patients with asthma (ageed nasopharyngitis (2.211.8% vs 5.78.8% of pa-

range not reported),[103] in which the incidence pertients),[86,91-93] upper respiratory tract infection patient-year of oral candidiasis and hoarseness was(3.48.2% vs 7.39.4%),[84,86,93] hoarseness (3.1% 0.02 and 0.03 in ciclesonide 401280 g/dayvs 9.2%)[93] and asthma (3.9%[93] and 6.9%[86] vs (n = 7706) recipients compared with 0.07 for both5.5%[93] and 5.7%[86]). Between-group statistical adverse events in recipients of other inhaled cortico-analyses not reported. steroids, including budesonide 400 g/day (ExV),

Longer term, pharyngitis was reported in 3.5% beclometasone 400 g/day (ExV) or fluticasoneand 5.2% of ciclesonide 640 g/day and beclometa- propionate 176880 g/day (ExA; n = 3330). More-sone 640 g/day recipients in a randomized, double- over, in a subanalysis of this study (n = 2169), theblind, multicentre, 52-week study in adult and ado- combined incidence of candidiasis and hoarsenesslescent patients (n = 297).[22] In the same trial, oral was significantly lower in ciclesonide 320 g/daycandidiasis occurred in 4.1% of ciclesonide and than fluticasone propionate 440 g/day recipients10.4% of beclometasone recipients (statistical anal- (0.5% vs 4.5%; p = 0.0013). A significantly loweryses were not reported). combined incidence of candidiasis and hoarseness

was also exhibited by ciclesonide 640 g/day recipi-In paediatric patients, where reported, the inci-ents compared with fluticasone propionate 880 g/dence of treatment-emergent adverse events wasday recipients (2.8% vs 7.7%; p < 0.0001).[103] The38% in both ciclesonide 160 g/day and budesonideincidences of candidiasis in the ciclesonide 320 g/400 g/day (ExV) recipients in the 12-week trialday, ciclesonide 640 g/day, fluticasone propionatediscussed in section 4.2.[37] The most common treat-440 g/day and fluticasone propionate 880 g/day

ment-emergent respiratory-related adverse eventsgroups were 0%, 0.6%, 1.5% and 3.5%, respective-that occurred with a 5% incidence in either of thely; the corresponding incidences of hoarseness weretreatment groups, included pharyngitis (6.0% of0.5%, 2.2%, 3.0% and 4.2%.ciclesonide recipients vs 6.8% of budesonide recipi-

ents), nasopharyngitis (4.1% vs 5.4%) and upper The differences between ciclesonide and otherrespiratory tract infection (3.6% vs 6.3%).[37] Fur- inhaled corticosteroids in the effects on markers ofthermore, where stated, only rhinitis (7.9% vs 8.2% systemic glucocorticoid activity are discussed inof patients) and upper respiratory tract infection section 2.4.


1764 Deeks & Perry

6. Dosage and Administration Local prescribing information for ciclesonideshould be consulted for comprehensive informationregarding contraindications, drug interactions andInhaled ciclesonide administered via an HFA-other precautions.MDI is approved in the EU for use in adults and

adolescents aged 12 years for the prophylactictreatment of persistent asthma.[72,73] Ciclesonide, 7. Place of Ciclesonide in thedispensed via the HFA-MDI, is also approved for Management of Asthmathe prophylactic treatment of asthma[102] and corti-costeroid-responsive bronchial asthma[21] in adults

The focus of asthma therapy is the managementand adolescents aged 12 years in the US[102] andof airway inflammation, with the aim of achievingCanada,[21] and for similar indications in severaland maintaining clinical control, avoiding drug-re-other countries worldwide. Ciclesonide is also ap-lated adverse events and preventing asthma-relatedproved for the long-term treatment of asthma inmortality.[1,2,106] Recommendations in current treat-paediatric patients in some countries, includingment guidelines approach asthma therapy in a step-Switzerland (patients aged 6 years).[105]wise manner, with therapy commencing at the mostIn the EU,[72,73] the recommended initial dosagesuitable step of treatment options for the initialis ciclesonide 160 g once daily, preferably admin- disease severity.[1,2]istered in the evening, with subsequent titration to

Inhaled corticosteroids (e.g. ciclesonide, budeso-the minimum dosage required to maintain effectivenide, fluticasone propionate, beclometasone andasthma control. Ciclesonide may also be adminis-mometasone) are the mainstay preventative therapytered via an HFA-MDI using an AeroChamberfor all patients with persistent asthma.[1,2,107] In pa-Plus spacer device in patients who have difficultytients with persistent asthma or whose intermittentin synchronizing inhaler actuation with inhalation.asthma is poorly controlled by as-needed sympto-In the US,[102] the recommended starting dosagematic treatment, inhaled corticosteroids at low dos-of ciclesonide is 80 g twice daily in patients receiv-ages are the initial treatment of choice. If asthmaing bronchodilators alone (maximum recommendedcontrol remains inadequate, low-dose inhaled corti-dosage 160 g twice daily), 80 g twice daily incosteroids in combination with an inhaled LABA, orpatients receiving inhaled corticosteroids (maxi-medium-dose inhaled corticosteroids, are generallymum recommended dosage 320 g twice daily) andrecommended.320 g twice daily in patients receiving oral cortico-

Medium- or high-dose inhaled corticosteroids insteroids (maximum recommended dosage 320 gcombination with LABA use is a treatment optiontwice daily).for patients whose asthma control continues to beIn Canada,[21] the recommended initial dosage isinadequate.[1,2,107] Once asthma control is achieved,ciclesonide 320 g once daily in patients previouslythe current treatment guidelines recommend reduc-maintained with inhaled corticosteroids or onlying the dose of inhaled corticosteroid to the lowestbronchodilators, and ciclesonide 320 g twice dailydose required to effectively maintain control.[1,2,107]in patients with severe asthma. The dosage may be

adjusted based on individual patient response; the Despite being considered the most effective treat-recommended daily ciclesonide dose range is ment currently available for the prevention of asth-80640 g. ma,[1,107] inhaled corticosteroids may produce local

In paediatric patients aged 6 years with mild to and systemic adverse effects, especially at high dos-moderate asthma, ciclesonide 80160 g once daily ages and with long-term treatment.[108,109] As a re-or 80 g twice daily is recommended in Switzer- sult, these agents are often under-prescribed by phy-land,[105] with ciclesonide 640 g twice daily recom- sicians and safety concerns may affect patient com-mended in those with severe persistent oral predni- pliance to therapy, resulting in suboptimal asthmasone-dependent asthma (reduction of the prednisone control, especially in children.[60,110,111] Complexdosage is recommended after the first 10 days use in treatment regimens, difficult-to-use inhalation de-combination with ciclesonide). vices, financial limitations and carelessness/forget-



fulness may also reduce patient compliance to inof a prodrug and is converted to its active metabo-haled corticosteroid therapy.[108,112] lite, des-CIC, primarily on-site in the lung, thus

potentially minimizing potential systemic adverseCiclesonide is a relatively new corticosteroideffects. Moreover, only limited activation ofwith certain features that may be advantageous inciclesonide occurs upon oropharyngeal deposition,patients with asthma. Ciclesonide addresses the un-resulting in significantly lower amounts of activederlying airway inflammation of asthma and helps

attenuate airway hyper-responsiveness, exercise-in- agent in the oropharynx compared with budesonideduced bronchoconstriction and early- and late-phase and fluticasone propionate (section 3), thereby re-allergen-induced bronchoconstriction (section 2). ducing the potential for local adverse events.Unlike some other inhaled corticosteroids that are The targeted activity of ciclesonide is prolongeddelivered via a CFC-containing MDI, ciclesonide is as a result of pulmonary retention of the drug due todelivered via an HFA-MDI (non-CFC) device. its high lipophilicity and ability to form reversibleCiclesonide exists as an HFA solution, as does fatty-acid esters in the lung (section 3) enablingbeclometasone, in contrast to other corticosteroids once-daily administration. The fact that ciclesonidecurrently available as HFA/CFC suspensions or dry is administered once daily may confer an advantagepowder formulations. HFA solutions are often deliv- in terms of patient therapy adherence compared withered by MDI devices as extra fine aerosols consist-

some other currently available agents (e.g. fluti-ing of particles generally smaller than those pro-casone propionate, beclometasone and flunisolide),duced by MDI HFA and CFC suspensions andwhich require more frequent administration. How-DPIs.[59,113,114] The particle size delivered is impor-ever, at present, no studies have been undertaken

tant in determining the deposition of corticosteroidcomparing ciclesonide with other inhaled cortico-in the lungs relative to the oropharyngeal cavity,steroids with regard to patient therapy adherence.

with smaller particles more likely to be deposited inBoth ciclesonide and des-CIC exhibit low (

1766 Deeks & Perry

findings of such relatively short-term measures of or to, or generally as effective as, fluticasone pro-HPA-axis suppression. pionate or budesonide in terms of improving lung

function (section 4.2.2). Ciclesonide was alsoInhaled ciclesonide was generally effective innoninferior to, or as effective as, these inhaled corti-maintaining and improving lung function in adults,costeroids with regard to reducing rescue med-adolescents and children in well designed, placebo-ication use and improving asthma symptom scorescontrolled, short-term trials of 8 or 12 weeks dura-in this patient population.tion (sections 4.1.1 and 4.2.1). Ciclesonide also gen-

erally produced beneficial effects with regard to Moreover, preliminary data suggest that inhaledasthma symptom scores and reduced rescue med- ciclesonide may be as effective as oral prednisoloneication use in these patient populations. Further- in the treatment of patients with an acute asthmamore, significantly fewer adult patients experienced exacerbation;[36] however, ciclesonide is currentlylack of efficacy with ciclesonide than with placebo not approved for such an indication.in well designed, 12-week studies (section 4.1.1). The limited clinical data currently available gen-Limited data from one nonblind, 40-week extension erally indicate a lack of dose-response for inhaledstudy in adult patients suggest that the beneficial ciclesonide in terms of therapeutic effect, whicheffects of inhaled ciclesonide in terms of lung func- may have implications in its use for the treatment oftion are maintained during long-term treatment (sec- more severe asthma (section 4). However, it is cur-tion 4.1.1). However, further long-term studies in rently difficult to compare ciclesonide with otheradult and paediatric patients are warranted. inhaled corticosteroids in terms of therapeutic dose-

In terms of improving or maintaining lung func- response, as data from other inhaled corticosteroidtion, ciclesonide was generally no less effective than dose-response studies are variable and have beenfluticasone propionate, budesonide or beclometa- inconsistent in demonstrating an unambiguous rela-sone (at equipotent dosages according to current tionship between the dose and the therapeutic effi-treatment guidelines[1]) in adults and adolescents, in cacy of these agents, partly because of study hetero-trials of 824 weeks duration (section 4.1.2). How- geneity.[116,117]ever, ciclesonide, at relatively higher dosages of 320 Ciclesonide is generally well tolerated by adultand 640 g/day, has been shown to confer beneficial and paediatric patients and may have a more favou-effects in some lung function parameters compared rable tolerability profile than other inhaled cortico-with budesonide 400 g/day and beclometasone steroids with regard to local adverse events, such as800 g/day. Notably, the effectiveness of cicleso- oral candidiasis and hoarseness (section 5). Cicleso-nide administered once daily is generally no less nide may also have less of a propensity to producethan that of twice-daily fluticasone propionate, systemic adverse events than other inhaled cortico-budesonide or beclometasone in adults and adoles- steroids (section 2.4), although additional long-termcents, according to some 8- or 12-week trials (sec- comparative and high-dose studies are required totion 4.1.2). fully determine the potential benefits of ciclesonide

In general, ciclesonide therapy also improved in this regard. Further long-term studies are requiredasthma symptom scores and reduced the need for in order to confirm the tolerability profile of cicleso-rescue medication use, with an efficacy generally nide in relation to other available corticosteroids.similar to that of fluticasone propionate and budeso- Asthma can be a distressing disease, especially innide in adults and adolescents. However, high-dose children, placing limitations on the physical capabil-ciclesonide 640 g/day was more effective than ity, social lives and emotional well-being of pa-beclometasone in improving such parameters in this tients.[118] Data from short-term, well designed stud-patient population (section 4.1.2). ies in adult (section 4.1.3), adolescent (section 4.1.3)

Ciclesonide is an effective prophylactic treat- and paediatric patients (section 4.2.3) indicate thatment for persistent asthma in paediatric patients. inhaled ciclesonide is effective in improving theHead-to-head, well designed, short-term trials in HR-QOL of patients with asthma, and has an effi-paediatric patients aged 415 years with asthma cacy generally no less than that of fluticasone pro-have shown ciclesonide 160 g/day to be noninferi- pionate or budesonide in this regard.



2. British Thoracic Society. British guideline on the managementAt present, no robust studies have been under-of asthma: a national clinical guideline (revised 2007) [online].

taken to evaluate the efficacy of ciclesonide in com- Available from URL: http://www.sign.ac.uk/pdf/sign63.pdf[Accessed 2008 Apr 28]parison with other inhaled corticosteroids in terms

3. Leach CL, Bethke TD, Boudreau RJ, et al. Two-dimensionalof asthma exacerbations during long-term treatment and three-dimensional imaging show ciclesonide has high lungdeposition and peripheral distribution: a nonrandomized studyand hospitalizations, and pharmacoeconomic datain healthy volunteers. J Aerosol Med 2006; 19 (2): 117-26for ciclesonide are not yet available. There are cur-

4. Chapman KR, Patel P, DUrzo AD, et al. Maintenance ofrently no recommendations regarding the severity of asthma control by once-daily inhaled ciclesonide in adults with

persistent asthma. Allergy 2005 Mar; 60 (3): 330-7persistent asthma for which ciclesonide treatment5. Langdon CG, Adler M, Mehra S, et al. Once-daily ciclesonidemay be used, although the present lack of data of 80 or 320g for 12 weeks is safe and effective in patients with

ciclesonide in combination with LABA therapy may persistent asthma. Respir Med 2005 Oct; 99 (10): 1275-856. Reynolds NA, Scott LJ. Ciclesonide. Drugs 2004; 64 (5): 511-9limit the use of ciclesonide to the treatment of pa-7. Taylor DA, Jensen MW, Kanabar V, et al. A dose-dependenttients who do not require add-on therapy to achieve

effect of the novel inhaled corticosteroid ciclesonide on airwayasthma control. However, the potential use o

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