Alvesco: a once-daily steroid for asthma prophylaxis

Transcription

1 Alvesco: a once-daily steroid for asthma prophylaxis Dermot Ryan BAO, MRCGP, MICGP, DCH PRODUCT PROFILE Proprietary name: Alvesco Constituents: ciclesonide Indication: treatment to control persistent asthma in adults (18 years and older) Dosage and method of administration: 160µg once daily; dose reduction to 80µg once daily may be an effective maintenance dose for some patients Contraindications: hypersensitivity to ciclesonide or any of its excipients; status asthmaticus; acute episodes of asthma Precautions: active or quiescent pulmonary tuberculosis (only use if patients are adequately treated); fungal, viral or bacterial infections (only use if patients are adequately treated); severe hepatic impairment; transfer from oral steroids to inhaled ciclesonide; pregnancy; lactation Interactions: cytochrome P450 3A4 system inhibitors such as ketoconazole, itraconazole and ritonavir or nelfinavir Side-effects: common: paradoxical bronchospasm Presentation/cost: 80µg, 160µg per dose (inhaled); 80µg 120 doses, 28.56; 160µg 120 doses, Ciclesonide is a novel inhaled steroid with high lung deposition and a oncedaily dosage. Dr Ryan considers its properties and its potential role in asthma prophylaxis. Ciclesonide (Alvesco) is a newly licensed inhaled corticosteroid indicated for prophylaxis of asthma in sufferers from the age of 18 and above. It is available in two strengths, 80µg and 160µg, that need to be taken once per day. Studies have demonstrated equivalence whether the dose is taken in the morning or in the evening. 1 Once-daily dosing may improve compliance. 2,3 Mechanism of action Ciclesonide is an inactive prodrug that only becomes activated after esterification to the active metabolite (desisobutyryl-ciclesonide) in the lung. The active compound is highly bound to the lung tissue. Due to its mode of activation and high serum protein-binding (see Figure 1), there is minimal systemic activity. Free ciclesonide is rapidly eliminated from the systemic circulation by hepatic metabolisation with inactive metabolites being excreted in the faeces. These properties make it a very safe medication in standard doses. 4 The retention time of ciclesonide in the lung is explained by its lipophilicity; this long retention period in turn is responsible for the long duration of action, translating clinically into once-daily dosing. Asthma is increasingly viewed as a small airways disease. 5 Recent studies have demonstrated that although the central airways may exhibit reduced inflammation, the process smoulders on in the periphery. 6 Ciclesonide is formulated as a solution in an HFA (hydrofluoroalkane) propellant generating a small particle size, achieving approximately 52 per cent pulmonary deposition and permitting a uniform distribution throughout both lungs. 7,8 Clinical trials Ciclesonide has been used in a variety of clinical trials with doses ranging from µg per day. Most of the data to date has been on trials performed to fulfil regulatory requirements. Much of the data is available only as abstracts but an increasing number of papers are being published in peer-reviewed journals. Prescriber 5 March

2 52% in lung absorption from lung 32% in oropharynx mainly inactive long retention due to gradual conversion to active drug and depot formation high protein binding, <1%* free, active drug 50-90% swallowed absorption from gut orally bioavailable fraction <1% rapid clearance to inactive metabolites first-pass inactivation *clinical significance has not yet been demonstrated Figure 1. Absorption and metabolism of ciclesonide Against placebo, doses of either 160µg or 640µg per day maintained asthma control vs placebo. Interestingly, in this study 160µg was as effective as 640µg with neither dose demonstrating any effect on the HPA axis and both having a similar side-effect profile to placebo. 9 Formal dose-ranging studies have fluticasone DPI 12 MDI budesonide MDI DPI mometasone HFA MDI 14 ciclesonide HFA MDI 52 beclometasone HFA-MDI CFC-MDI 4-7 DPI 19 DPI = dry powder inhaler MDI = metered-dose inhaler Per cent Table 1. Lung deposition of inhaled corticosteroids not been performed but there is evidence that there is a doseresponse curve in terms of reducing airway inflammation as measured by airway responsiveness to adenosine monophosphate in doses up to 1280µg daily, when given by dry powder inhaler. 10, 20 In mild to moderate asthma a large randomised trial (n=451) demonstrated equivalence between ciclesonide 160µg one puff daily and fluticasone (Flixotide) 100µg one puff twice daily (88µg ex valve) in terms of reduction of asthma symptoms and need for rescue medication and improvement in lung function (see Figure 2). 11, 21 Similarly in patients on step two medication, whose asthma had been stabilised in the run-in phase on budesonide 200µg twice daily, a trial of ciclesonide 160µg (either in the morning or evening) vs budesonide 200µg twice daily demonstrated equivalence in all asthma outcomes between all dosage regimens. 12 In a trial of ciclesonide 320µg once daily vs fluticasone 250µg twice daily, equivalent effect was observed in terms of reduced bronchial hyper-responsiveness. This study did not run for a sufficiently long period of time to gauge whether there was an appreciable reduction in exacerbations between either group. 13 In patients with more severe asthma, previously uncontrolled on beclometasone equivalent doses of µg per day, daily doses of 640µg and 1280µg per day demonstrated comparable efficacy, with both doses achieving a significant improvement in asthma control compared to the run-in baseline period when patients were on beclomethasone 1600µg per day. In common with many new medications, full publication of 24 Prescriber 5 March

3 Asthma-controlled days* (per cent) Nights without awakening (per cent) Mild Moderate Mild Moderate ciclesonide 160µg once daily fluticasone 100µg twice daily *days without symptoms and rescue medication use Figure 2. Once-daily ciclesonide vs twice-daily fluticasone showing equal efficacy 11 published results in peer-reviewed journals is a long process. In particular, studies performed in children as young as four years of age have been performed with promising results both in providing good asthma control and specifically, in children age 6-12, demonstrating no slowing in lower leg growth, suggesting no adverse effect on bone development. 14,17 Side-effects and interactions In all clinical trials to date the side-effect profile has been similar to that seen in the placebo arm. At higher doses (800µg ciclesonide vs 1000µg fluticasone), compared to higher doses of fluticasone there is a 50 per cent marked reduction in oropharyngeal deposition. 15 In a randomised, double-blind, double-dummy, cross-over trial involving patients with moderately severe asthma treated with either fluticasone 2000µg daily or ciclesonide 1600µg daily, there was a significant suppression of HPA axis measures after taking fluticasone for four weeks compared to taking ciclesonide for four weeks. 16 When should I use ciclesonide? Ciclesonide may be useful in the patient at step two, ie a patient who needs to be on an inhaled steroid. Its once-daily dosing lends itself to improved compliance. It is possible that instead of switching patients who are uncontrolled on an inhaled corticosteroid to a combination treatment, switching to ciclesonide may prove to be beneficial. Further studies need to be performed to confirm this hypothesis. The benefits of this treatment are beginning to be realised in clinical trials. Early studies indicate that there is a clear role to play, particularly in terms of simplicity and convenience for the patient. Further work is being carried out to demonstrate the beneficial effects of this novel inhaled steroid in longer-term studies and in patients with more severe asthma to define its 26 Prescriber 5 March

4 future role in the management of asthma. References 1. Postma DS, Sevette C, Martinat Y, et al. Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or evening. Eur Resp J 2001;17: Casale TB, Nelson HS, Kemp J, et al. Budesonide turbuhaler delivered once daily improves health-related quality of life and maintains improvements with a stepped-down dose in adults with mild to moderate asthma. Ann Allergy Asthma Immunol 2003; 90(3): Guest J, Davie A, Ruiz F, et al. Switching asthma patients to a oncedaily inhaled steroid improves compliance and reduces health care costs. Primary Care Respiratory Journal 2005; 14: Szefler S, Rohatagi S, Williams J, et al. Ciclesonide, a novel inhaled steroid, does not affect hypothalamicpituitary-adrenal axis function in patients with moderate-to-severe persistent asthma. Chest 2005;128(3): Bjermer L. History and future perspectives of treating asthma as a systemic and small airways disease. Resp Med 2001;95: Key points ciclesonide is a novel inhaled steroid its small particle size leads to high pulmonary deposition ciclesonide is an inactive prodrug converted to the active form in the lungs the mode of activation and high serum binding result in low systemic bioavailability its long duration of action achieves once-daily dosing 6. Berry M, Hargadon B, Morgan A, et al. Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma. Eur Resp J 2005;25: Newman S, Salmon A, Nave R, et al. High lung deposition of 99mTclabelled ciclesonide administered via HFA-MDI to patients with asthma. Eur Resp J 2004;24(suppl 48):583s. 8. Bethke T, Boudreau RJ, Hasselquist BE, et al. High lung deposition of ciclesonide in 2D and 3D imaging. Eur Resp J 2002;20(suppl 38): Chapman KR, Patel P, D'Urzo AD, et al. Maintenance of asthma control by once-daily inhaled ciclesonide in adults with persistent asthma. Allergy 2005;60(3): Taylor DA, Jensen, MW, Kanabar K, et al. A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5'-monophosphate in asthmatic patients. Am J Resp Crit Care Med 160: Buhl R, Vinkler I, Magyar P, et al. Once-daily ciclesonide and twice-daily fluticasone proprionate are equally effective in the treatment of patients. Eur Resp J 2004;48:346s. 12. Gagdil DA, Niphadkar P, Jagganath KT, et al. Once-daily ciclesonide is as effective as twice daily budesonide in maintaining lung function and asthma control in patients with asthma. J Allergy Clin Immunol 2005;115:2 p 13. Lee DK, Haggart K, Currie GP, et al. Effects of hydrofluoroalkane formulations of ciclesonide 400µg once daily vs fluticasone 250µg twice daily on methacholine hyper-responsiveness in mild-to-moderate persistent asthma. Br J Clin Pharmacol 2004; 58(1): Agertoft L, Pedersen S. Short-term lower-leg growth rate and urine cortisol excretion in children treated with ciclesonide. J Allergy Clin Immunol 2005;115(5): Richter K, Kanniess F, Biberger C, et al. Comparison of the oropharyngeal deposition of inhaled ciclesonide

5 and fluticasone proprionate in patients with asthma. J Clin Pharmacol 2005;45: Lee DK, Fardon TC, Bates CE, et al. Airway and systemic effects of hydrofluoroalkane formulations of high-dose ciclesonide and fluticasone in moderate persistent asthma. Chest 2005;127: Georgitis JW, Galant S, Lloyd BK, et al. Once-daily ciclesonide does not cause HPA-axis suppression in pediatric asthma patients. Am Acad Paediatrics San Francisco 2004 (October 9-13). 18. Engelstatter R, Banerji D, Steinijans VW, et al. Low incidence of oropharyngeal adverse events in asthma patients treated with ciclesonide: results from a pooled analysis. Am J Resp Crit Care Med 2004;169(7):abstract A O Connor B, Sips P, Engelstatter R, et al. Management of moderate-tosevere bronchial asthma by ciclesonide: a twelve week trial. Am J Resp Crit Care Med 2002;165:abstract G Magnussen H, Hofman J, Novakova B, et al. Once daily ciclesonide 80µg or 160µg is comparable to twice daily fluticasone propionate 88µg in the treatment of persistent asthma. Altana, Niphadkar P, Jagannath KT, Joshi M, et al. Efficacy of ciclesonide 160µg once daily is comparable to budesonide 200µg twice daily in treating patients with asthma. Altana, Dr Ryan is a general practitioner in Loughborough, Leicestershire, and a clinical research fellow at the University of Aberdeen Prescriber 5 March