ICS are the most effective controller medications of persistent asthma.1 However, ICS over long periods of time have the potential to cause systemic adverse events, such as HPA-axis function suppression, growth retardation, osteoporosis, cataracts and skin thinning.2
Alvesco is designed to reduce the risk of these systemic adverse events. Alvesco has several favorable characteristics that lead to an improved safety profile compared with some of the other available ICS. These characteristics include:
Systemic bioavailability of ICS may cause HPA-axis suppression by decreasing endogenous cortisol production. The effect of a wide range of Alvesco doses on 24-hour urinary and serum cortisol levels in both adults and children has been shown to be minimal in numerous clinical trials.3–5, 6-10, 11, 12, 13–18, 19
Alvesco is a lung-targeted ICS that has demonstrated excellent oropharyngeal and systemic safety because it is activated within the lung by airway esterases.20 Systemic safety is further enhanced as Alvesco is highly plasma-protein bound and almost complete first–pass metabolism.20, 21,22
1. Morning serum cortisol: serum cortisol levels have a diurnal secretion pattern. The highest levels occur in the early morning, within 1 hour of awakening. Measurements are taken at a single timepoint: values >7 µg/dL indicates that suppression of HPA-axis function is unlikely.
2. Twenty-four-hour urinary cortisol excretion: approximately 95% of serum cortisol is excreted in urine. Values ≤40 nmol/L/m/24-hours suggest suppression of HPA-axis function. This method is highly reproducible and minimizes inter-individual variation.
3. Cosyntropin stimulation: serum cortisol levels can be stimulated by cosyntropin injection. A 200 nmol/L increase in serum cortisol 30 minutes post-injection is normal.
Results from the GAPP survey demonstrate that approximately 34% of patients believe they have experienced side effects such as oral thrush, pharyngitis and hoarseness from their ICS therapy. The survey also shows that this adversely affects compliance, with 21% and 35% of patients reporting that they have stopped taking medications or considered skipping doses, respectively. Furthermore, only 48% of patients report taking their asthma medication as per physician instructions 100% of the time, which is consistent with the literature on chronic disease in general. These results demonstrate the need for an ICS that is effective but better tolerated than currently available ICS medications.23
Alvesco has demonstrated, in numerous clinical trials:24, 25
Alvesco has been extensively studied in the clinical setting. Results from a pooled analysis of Phase II and III clinical trials showed that patients who had received Alvesco 80–640 µg/day (n=1102) demonstrated similar rates of oropharyngeal adverse events to those who had received placebo (n=429).152 Specifically, rates of oral candidiasis (Alvesco, 0.9%; placebo, 0.7%), hoarseness (Alvesco, 0.6%; placebo, 0.5%), pharyngitis (Alvesco, 0.5%; placebo, 0%) and pharyngolaryngeal pain (Alvesco, 4.7%; placebo, 5.1%) were low and comparable between groups.
In several placebo-controlled trials of patients with asthma of varying severity, treatment-emergent adverse events rated as ‘likely’ related to treatment were similar between Alvesco and placebo.3, 4, 8, 26, 12 Adverse events occurring with an incidence of ≥3% in controlled trials of ≤12 weeks duration are given in Table 1. Adverse events rated as ‘probably’ related to treatment occurred infrequently.
| Body system | Alvesco (n=672) | Placebo (n=446) |
|---|---|---|
| Body as a whole | ||
| Abdominal pain | 5 (0.74%) | 3 (0.67%) |
| Accidental injury | 12 (1.8%) | 8 (1.8%) |
| Allergic reaction | 3 (0.44%) | 0 |
| Asthenia | 2 (0.30%) | 4 (0.90%) |
| Back pain | 12 (1.8%) | 7 (1.6%) |
| Fever | 2 (0.30%) | 4 (0.90%) |
| Flu syndrome | 12 (1.8%) | 11 (2.5%) |
| Infection | 8 (1.2%) | 10 (2.2%) |
| Pain | 4 (0.60%) | 0 |
| Pain in extremity | 3 (0.44%) | 6 (1.3%) |
| Surgery | 6 (0.90%) | 6 (1.3%) |
| Cardiovascular system | ||
| Chest pain | 6 (0.90%) | 1 (0.22%) |
| Hypertension | 4 (0.60%) | 1 (0.22%) |
| Digestive system | ||
| Diarrhoea | 7 (1.0%) | 3 (0.67%) |
| Dyspepsia | 1 (0.15%) | 3 (0.67%) |
| Gastroenteritis | 5 (0.74%) | 1 (0.22%) |
| Mouth ulceration | 1 (0.15%) | 3 (0.67%) |
| Nausea | 11 (1.6%) | 6 (1.3%) |
| Sore throat | 16 (2.4%) | 10 (2.4%) |
| Vomiting | 2 (0.30%) | 7 (1.6%) |
| Musculoskeletal system | ||
| Arthralgia | 5 (0.74%) | 1 (0.22%) |
| Joint disorder |
1 (.15%) | 3 (0.67%) |
| Nervous system | ||
| Depression | 2 (0.30%) | 4 (0.90%) |
| Dizziness | 5 (0.74%) | 3 (0.67%) |
| Headache | 42 (6.3%) | 33 (7.4%) |
| Respiratory system | ||
| Asthma | 40 (6.0%) | 107 (24.0%) |
| Bronchitis | 13 (1.9%) | 14 (3.1%) |
| Increased cough | 13 (1.9%) | 13 (2.9%) |
| Dyspnea | 8 (1.2%) | 7 (1.6%) |
| Pharyngitis | 3 (0.44%) | 6 (1.3%) |
| Rhinitis | 34 (5.1%) | 38 (8.5%) |
| Sinusitis | 13 (1.9%) | 3 (0.67%) |
| Upper respiratory tract infection | 53 (7.9%) | 43 (9.6%) |
| Voice alteration | 7 (1.0%) | 4 (0.90%) |
For Alvesco prescribing information please refer to full Summary of Product Characteristics
Disclaimer: For exclusive use at EPG Asthma Knowledge Centre, July 2008. Local regulation may apply. Please check your local SmPC.
References:
1. GINA. Global Initiative for Asthma. www.ginasthma.com. 2006.
2. Dahl R. Systemic side effects of inhaled corticosteroids in patients with asthma. Respir Med 2006;100:1307–1317.
3. Chapman KR, Patel P, D’Urzo AD, Alexander M, Mehra S, Oedekoven C, et al. Maintenance of asthma control by once-daily inhaled ciclesonide in adults with persistent asthma. Allergy 2005;60:330–337.
4. Langdon CG, Adler M, Mehra S, Alexander M, Drollmann A. Once-daily ciclesonide 80 or 320 μg for 12 weeks is safe and effective in patients with persistent asthma. Respir Med 2005;99:1275–1285.
5. Postma DS, Sevette C, Martinat Y, Schlosser N, Aumann J, Kafe H. Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or evening. Eur Respir J 2001;17:1083–1088.
6. Szefler S, Rohatagi S, Williams J, Lloyd M, Kundu S, Banerji D. Ciclesonide, a novel inhaled steroid, does not affect HPA-axis function in patients with moderate-to-severe persistent asthma. Chest 2005;128:1104–1114.
7. Derom E, van De Velde V, Marissens S, Engelstätter R, Vincken W, Pauwels R. Effects of inhaled ciclesonide and fluticasone propionate on cortisol secretion and airway responsiveness to adenosine 5’monophosphate in asthmatic patients. Pulm Pharmacol Ther 2005;18:328–336.
8. Lipworth BJ, Kaliner MA, LaForce CF, Baker JW, Kaiser HB, Amin D, et al. Effect of ciclesonide and fluticasone on hypothalamic-pituitary-adrenal axis function in adults with mild-to-moderate persistent asthma. Ann Allergy Asthma Immunol 2005;94:465–472.
9. Lee DK, Fardon TC, Bates CE, Haggart K, McFarlane LC, Lipworth BJ. Airway and systemic effects of hydrofluoroalkane formulations of high-dose ciclesonide and fluticasone in moderate persistent asthma. Chest 2005;127:851–860.
10. Hansel TT, Benezet O, Kafe H, Ponitz HH, Cheung D, Engelstatter R, et al. A multinational, 12-week, randomized study comparing the efficacy and tolerability of ciclesonide and budesonide in patients with asthma. Clin Ther 2006;28:906–920.
11. Ukena D, Biberger C, Steinijans V, von Behren V, Malek R, Weber HH, et al. Ciclesonide is more effective than budesonide in the treatment of persistent asthma. Pulm Pharmacol Ther 2006, July 11;[Epub ahead of print].
12. Bateman E, Karpel J, Casale T, Wenzel S, Banerji D. Ciclesonide reduces the need for oral steroid use in adult patients with severe, persistent asthma. Chest 2006;129:1176–1187.
13. Agertoft L, Pedersen S. Short-term lower-leg growth rate and urine cortisol excretion in children treated with ciclesonide. J Allergy Clin Immunol 2005;115:940–945.
14. Von Berg A, Engelstaetter R, Minic P, Sréckovic M, Garcia Garcia ML, Lato T, et al. Comparison of the efficacy and safety of ciclesonide 160 μg once daily versus budesonide 400 μg once daily in children with asthma. Pediatr Allergy Immunol
2007;18:391–400.
15. Gelfand EW, Georgitis JW, Noonan M, Ruff ME. Once-daily ciclesonide in children: efficacy and safety in asthma. J Pediatr 2006;148:377–383.
16. Weinbrenner A, Huneke D, Zschiesche M, Engel G, Timmer W, Steinijans VW, et al. Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide. J Clin Endocrinol Metab 2002;87:2160–2163.
17. Postma DS, Ind PW, Magnussen H, van den Berge M. A double-blind, randomized, controlled study comparing the efficacy and safety of inhaled ciclesonide with oral prednisolone in patients with an asthma exacerbation. Proc Am Thoracic Soc 2006:A74.
18. Pedersen S, Garcia Garcia ML, Manjra A, Theron I, Engelstatter R. A comparative study of inhaled ciclesonide 160 microg/day and fluticasone propionate 176 microg/day in children with asthma. Pediatr Pulmonol 2006;41:954–961.
19. Chapman K, Patel P, Boulet L, D’Urzo A, Alexander M, Mehra S, et al. Efficacy and long-term safety of ciclesonide in asthmatic patients as demonstrated in a 52-week long study. Eur Respir J 2002;20:373s–374s: Abs. 2328.
20. Nave R, Fisher R, Zech K. In vitro metabolism of ciclesonide in human lung and liver precision-cut tissue slices. Biopharm Drug Dispos 2006;27:197–207.
21. Rohatagi S, Luo Y, Shen L, Guo Z, Schemm C, Huang Y, et al. Protein binding and its potential for eliciting minimal systemic side effects with a novel inhaled corticosteroid, ciclesonide. Am J Ther 2005;12:201–209.
22. Nave R, Bethke T, Marle SV, Zech K. Pharmacokinetics of [14C] ciclesonide after oral and intravenous administration to healthy subjects. Clin Pharmacokinet 2004;43:479–486.
23. Global asthma physician and patient (GAPP) survey www.gappsurvey.org. 2006.
24. Engelstätter R, Escher A, Haefner D. Low incidence of oropharyngeal adverse events in asthma patients treated with ciclesonide. Eur Respir J 2005;26(Suppl 49):255s.
25. Banerji D, Szwarcberg J, Fish J, Kundu S, Williams J, Hamedani P. The incidence of oropharyngeal adverse events in adolescent/adults and pediatric asthma patients is similar for ciclesonide and placebo: results from pooled analyses. Allergy Asthma Proc 2004;25:P206.
26. Pearlman D, Berger W, Kerwin E, LaForce C, Kundu S, Banerjee D. Once-daily ciclesonide improves lung function and is well tolerated by patients with mild-to-moderate persistent asthma. J Allergy Clin Immunol 2005;116:1206–1212.
27. Bernstein DI, Allen DB. Evaluation of tests of hypothalamic-pituitary-adrenal axis function used to measure effects of inhaled corticosteroids. Ann Allergy Asthma Immunol 2007;98:118–127.