DAXAS - DAXAS - CT 11681 - English version

DAXAS - DAXAS - CT 11681 - English version

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Introduction DAXAS 500 µg, film-coated tablets B/10 (CIP code: 497 170-0) B/30 (CIP code: 493 347-3) B/90 (CIP code: 578 055-7) Posted on Mar 19 2013 Active substance (DCI) roflumilast Pneumologie - Nouveau médicament Avis défavorable au remboursement en raison d’un intérêt clinique insuffisant dans le traitement de la BPCO DAXAS a l’AMM en traitement continu de la broncho-pneumopathie chronique obstructive (BPCO) sévère (VEMS post-bronchodilatateur < 50 % de la valeur théorique) associée à une bronchite chronique chez les adultes ayant des antécédents d’exacerbations répétées, en complément d’un traitement bronchodilatateur.En raison :d’une efficacité cliniquement peu pertinente en termes de réduction des exacerbations modérées à sévères, sans données sur la dyspnée et la qualité de vie ;d’incertitudes sur les risques associés à la perte de poids, la dépression et les idées suicidaires dans une population fragile ;d’une place mal définie dans la stratégie thérapeutique ;ce médicament n’a pas d’intérêt clinique démontré dans la prise en charge de la BPCO.Pour en savoir plus, téléchargez la synthèse ou l'avis complet DAXAS. ATC Code R03DX07 Laboratory / Manufacturer NYCOMED FRANCE DAXAS 500 µg, film-coated tablets B/10 (CIP code: 497 170-0) B/30 (CIP code: 493 347-3) B/90 (CIP code: 578 055-7) Posted on Mar 19 2013

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The legally binding text is the original French ve  TRANSPARENCY COMMITTEE  OPINION  9 May 2012    DAXAS 500 µg, film-coated tablets B/10 (CIP code: 497 170-0) B/30 (CIP code: 493 347-3) B/90 (CIP code: 578 055-7)   Applicant: NYCOMED FRANCE  roflumilast  ATC code: R03DX07  List I  Date of Marketing Authorisation (centralised procedure): 5 July 2010    Reason for request: Inclusion on the list Insurance and approved for hospital use.                  Medical, Economic and Public Health Assessment Division
 
of medicines refundable by National Health
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1
CHARACTERISTICS OF THE MEDICINAL PRODUCT
1.1. Active ingredient roflumilast 
1.2. Background Roflumilast is the first drug in the class of selective phosphodiesterase-4 inhibitors, which target systemic inflammation and pulmonary inflammation associated with chronic obstructive pulmonary disease. These are intended for a particular population of patients with severe COPD associated with chronic bronchitis (see indication below).
1.3. Indication “DAXAS is indicated for maintenance treatment of severe chronic obstructive pulmonary disease (COPD) (FEV1 post-bronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment.”
1.4. Dosage “Posology The recommended dose is one tablet of 500 micrograms roflumilast once daily. DAXAS may need to be taken for several weeks to achieve its effect. DAXAS has been studied in clinical trials for up to one year.  Special populations Elderly (65 years and older) No dose adjustment is necessary.  Renal impairment No dose adjustment is necessary.  Hepatic impairment The clinical data with DAXAS in patients with mild hepatic impairment classified as Child-Pugh A are insufficient to recommend a dose adjustment (see section 5.2) and therefore DAXAS should be used with caution in these patients. Patients with moderate or severe hepatic impairment classified as Child-Pugh B or C should not take DAXAS.”   
 
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2
SIMILAR MEDICINAL PRODUCTS
2.1. ATC Classification (2010) R: Respiratory system R03: Drugs for obstructive airway diseases R03D: Other systemic drugs for obstructive airway diseases R03DX: Other systemic drugs for obstructive airway diseases R03DX07: roflumilast
2.2.
Medicines in the same therapeutic category 2.2.1. Strictly comparator medicines
DAXAS is the only phosphodiesterase-4 inhibitor indicated in COPD.
 2.2.2. Not strictly comparator medicines Not applicable.
2.3. Medicines with a similar therapeutic aim Inhalants combining a corticosteroid with a long-acting beta-2 agonist are also indicated as symptomatic treatment of severe forms of COPD. These proprietary medicinal products may therefore be considered to be the closest comparators: - budesonide + formoterol: SYMBICORT TURBUHALER 200/6 and 400/12 µg/dose - fluticasone + salmeterol: SERETIDE DISKUS 500/50 µg/dose  Other treatments for COPD: short-acting beta-2 agonists and anticholinergic bronchodilators, long-acting beta-2 agonists (formoterol, indacaterol and salmeterol) and anticholinergic bronchodilators (tiotropium), theophylline and derivatives.    
 
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3
ANALYSIS OF AVAILABLE DATA
  In support of their application, the pharmaceutical company has submitted: - two main placebo-controlled studies (studies 124 and 125) with identical protocols (randomised double-blind studies) in patients with severe to very severe COPD associated with chronic bronchitis with a history of exacerbations; - supplementary data froma posteriori analysis in two pilot trials of a subgroup of patients with severe COPD associated with chronic bronchitis; - a Cochrane meta-analysis evaluating the efficacy of phosphodiesterase-4 inhibitors in reducing exacerbations;1 - an indirect comparison by network meta-analysis of different treatments for COPD, including roflumilast, as monotherapy or in combination.2 The two meta-analyses are not described below because the studies included concerned patients with moderate to severe COPD, with the exception of studies 124 and 125 of roflumilast. 
3.1.
Efficacy
 Studies 124 and 125  Comparators: Roflumilast 500 µg once daily Placebo
Method:
Study process:
Inclusion criteria:
Comparative, randomised, double-blind study.
-Pre-inclusion period of 4 weeks with placebo treatment -Double-blind treatment for 1 year -Long-term adverse effects follow-up
 40 years -- COPD for at least 12 months (ATS/ERS consensus classification), associated with chronic bronchitis defined as a productive cough lasting for at least 3 months in the 2 years preceding the study pre-inclusion visit - FEV1/FVC Post-bronchodilator70% - Post-bronchodilator FEV150% of predicated value - FEV1 reversibility12% or200 ml after 400 µg of salbutamol - 1 documented exacerbation in the year preceding the pre-inclusion visit - current smoker or ex-smoker20 pack years  Patients randomised after the pre-inclusion period if: - and spitting score calculated over the 7 days preceding the coughing randomisation visit14 - no exacerbation during the pre-inclusion period - positive blood culture during this period no - compliance of at least 80% treatment
                                            1 Chong J, Poole P, Leung B, Black PN. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2011, Issue 5. Art. No.: CD002309. DOI: 10.1002/14651858.CD002309.pub3. 2MA. Pharmacotherapies for chronic obstructive pulmonary disease: a Mills EJ, Druyts E, Ghement I, Puhan multiple treatment comparison meta-analysis. Clin Epidemiol 2011; 3:107-29.  
 
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Treatments not permitted during the study:
Treatments permitted during the study:
-inhaled corticosteroids or combinations of corticosteroid + long-acting beta-2  agonist - short-acting bronchodilators other than as the rescue therapy provided -oral beta-2 agonists  - tiotropium - ipratropium in patients treated with long-acting beta-2 agonists during the study - combinations of short-acting anticholinergic + short-acting beta-2 agonist - theophylline and antileukotriene agents - corticosteroid treatment other than as treatment of an exacerbation systemic occurring during the double-blind phase of the study   cting beta-2 agonists at a stable dose if the patient was treated with a -long-a long-acting bronchodilator during the 12 months preceding the study - or albuterol nebuliser at a stable dose if the patient was treated salbutamol previously, which could be combined with a long-acting beta-2 agonist
Total number of Study 124: 1525 patients rpaantideontmsi sedStudy 125: 1571 patients : Primary efficacy- change in pre-bronchodilator FEV1 mean endpoints:- annual frequency of moderate to severe exacerbations per patient, mean defined as those requiring oral or parenteral corticosteroid treatment, and/or leading to hospitalisation or death “Key” secondary- in post-bronchodilator FEV1 change - time to occurrence of a death of any cause endpoints included:- mean change in transition dyspnoea index (TDI) Statistical analysis:Hierarchical analysis of the different primary and then secondary endpoints.
  Results:  characteristics Patient Following the pre-inclusion period, 1525 patients were randomised in study 124 comprising 766 in the roflumilast group and 759 in the placebo group, and 1571 were randomised in study 125 comprising 773 in the roflumilast group and 798 in the placebo group.  In both studies, 30% to 35% of patients left the study early, mainly due to withdrawal of patient consent and adverse events. The occurrence of exacerbations was the most common adverse event that led to withdrawal from the study (see table 1).   Table 1:Reasons for withdrawal from the study (studies 124 and 125) Study 124 Study 125 n (%) Roflumilast Placebo Roflumilast Placebo (n=773) (n=798) 246 (31.8%) 248 (31.1%)
(n=766) (n=759) Number of patients withdrawn from the 264 (34.5%) 234 (30.8%) trial Total number of reasons* 335 295 Adverse event 119 (15.5%) 78 (10.3%) Patient’s request 120 (15.7%) 100 (13.2%) Exacerbation 43 (5.6%) 69 (9.1%) Protocol criterion for withdrawal met 7 (0.9%) 4 (0.5%) Lost to follow-up 17 (2.2%) 16 (2.1%) Other reason 29 (3.8%) 28 (3.7%) *: more than one reason may be attributed to the same patient   
 
318 101 (13.1%) 108 (14.0%) 49 (6.3%) 9 (1.2%) 22 (2.8%) 29 (3.8%)
314 83 (10.4%) 107 (13.4%) 66 (8.3%) 4 (0.5%) 24 (3.0%) 30 (3.8%)
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Patient characteristics were homogeneous from one group to the other and from one study to the other. Across both studies, patients had a mean age of 64 years, were primarily male (75%) and had a mean weight of 74 kg. Their COPD was severe in around 63% of cases and very severe in around 29% of cases. Ex-smokers accounted for around 52% of patients in study 124 and 65% in study 125. The mean tobacco consumption was 48 pack years. Mean pre-bronchodilator FEV1 on inclusion was 1.01 L and mean post-bronchodilator FEV1 was 1.11 L. Mean FEV1 reversibility after administration of a bronchodilator was 10.6%. It should be noted that patients included could no longer receive treatment besides roflumilast, other than short- or long-acting beta-2 agonists in patients already taking these. This constitutes minimal care in patients with severe to very severe COPD, particularly for the placebo group, and does not reflect actual practice, especially since half of patients included were treated with long-acting beta-2 agonists (48.7% in the roflumilast group and 51.0% in the placebo group across both trials).   efficacy endpoint results (ITT population) Primary Pre-bronchodilator FEV1:  In both studies, after 1 year of treatment, pre-bronchodilator FEV1 showed a statistically significant increase on roflumilast versus placebo, with an observed difference of 39 ml in study 124, 58 ml in study 125, and 48 ml in the combined analysis of both studies (see table 2). These differences are below the threshold of 100 ml normally used for the COPD indication to consider a difference in FEV1 as clinically relevant.  Frequency of moderate to severe exacerbations: In both studies, the annual frequency of moderate to severe exacerbations per patient showed a statistically significant decrease in comparison with placebo, with an observed difference of -0.189 in study 124, -0.275 in study 125, and -0.232 in the combined analysis of both studies (see table 3). This result is of little clinical relevance. It should be noted that half of patients included were not treated with long-acting beta-2 agonists, contrary to the treatment strategy recommended in patients with severe to very severe COPD. In the subgroup of patients treated with long-acting beta-2 agonists (n = 1542), the annual frequency of moderate to severe exacerbations was 1.23 on roflumilast and 1.55 on placebo, i.e. a difference of -0.320 (p = 0.0011). In the subgroup of patients who had had at least two exacerbations in the year preceding the study (n = 763,a posteriori analysis), the annual frequency of moderate to severe exacerbations was 1.53 on roflumilast and 1.94 on placebo, i.e. a difference of -0.415 (p = 0.0037).   Table 2:Results for change in pre-bronchodilator FEV1 (studies 124 and 125) Studies 124 and 125 combined Roflumilast Placebo (n=1475) (n=1511)
 Study 124 Study 125 Roflumilast Placebo Roflumilast Placebo (n=745) (n=745) (n=730) (n=766) FEV1 on randomisation 1.071 1.061 0.955 0.985 (I) Change (I) Mean* 0 046 0.008 0.033 -0.025  . 95% CI [0.030; 0.062] [-0.008; 0.023] [0.019; 0.048] [-0.039; -0.011] Difference vs. placebo (I) Mean* 0.039 0.058 95% CI [0.018; 0.060] [0.041; 0.075] p 0.0003 <0.0001 *: Method of least squares    
 
1.014
 0.04 [0.029; 0.050]  0.048 [0.035; 0.062] <0.0001
1.023
 -0.009 [-0.019; 0.002]     
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Table 3:Annual frequency of exacerbations per patient (studies 124 and 125)
 
 
Study 124
Roflumilast
n
765
Freq.
1.077
Placebo
n
758
Freq.
1.266
Difference
-0.189
Roflumilast versus placebo
Ratio
0.851
95% CI
[0.737; 0.982]
p
0.0278
Study 125 772 1.210 796 1.485 -0.275 0.815 [0.710; 0.935] 0.0035 Studies 124 and 125 1537 1.142 1554 1.374 -0.232 0.831 [0.752; 0.918] 0.0003 combined    Secondary endpoint results  Post-bronchodilator FEV1: In study 124, mean post-bronchodilator FEV1 increased by 57 ml in patients treated with roflumilast (95% CI = [40; 73]) while it remained stable with a variation of 8 ml in those treated with placebo (95% CI = [-9; 25]). This difference of 49 ml is statistically significant (p<0.0001) but below the threshold for clinical relevance.  In study 125, mean post-bronchodilator FEV1 increased by 44 ml in patients treated with roflumilast (95% CI = [30; 59]) while it decreased with a variation of -17 ml in those treated with placebo (95% CI = [-31; -3]). This difference of 61 ml is statistically significant (p<0.0001) but not clinically relevant.  Time to occurrence of a death of any cause: In study 124, 17 patients died in each group. The mean time to death of any cause was 213.8 days (±118.9 days) in the roflumilast group and 207.5 days (±108.5 days) in the placebo group, with no statistically significant difference.  In study 125, 25 patients died in each group. The mean time to death of any cause was 201.0 days (±116.9 days) in the roflumilast group and 214.6 days (±137.3 days) in the placebo group, with no statistically significant difference. Transition dyspnoea index (TDI): As no statistically significant difference was demonstrated for the second “key” secondary endpoint, analysis of TDI has been considered as exploratory. Across both studies, the change in TDI was 0.662 points on roflumilast from an initial score of 5.950, and 0.409 on placebo from an initial score of 5.917 (clinical relevance threshold for TDI: change1 point).    Supplementary data: studies 111 and 112 These were two randomised double-blind studies comparing roflumilast to placebo for 1 year in patients with severe COPD (FEV1 < 50% of predicted value) who were smokers or ex-smokers. Associated chronic bronchitis and a history of exacerbations were not criteria required for inclusion.  Unlike studies 124 and 125, the use of inhaled corticosteroids was permitted but administration of a long-acting bronchodilator was prohibited. All patients were treated with a short-acting bronchodilator during the study at a mean dose of 5 puffs/day.  The primary efficacy endpoints were change in pre-bronchodilator FEV1 in study 111 and post-bronchodilator FEV1 in study 112, and the annual frequency of moderate to severe exacerbations per patient as defined in studies 124 and 125.
 
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A posteriori was performed  analysisby distinguishing patients who had chronic bronchitis associated with their COPD from those who did not.  Results (ITT population): A total of 2690 patients were included in the two studies, with 2686 included in the ITT analysis (1327 treated with roflumilast and 1,359 on placebo). Patients with associated chronic bronchitis made up around 62% of the total.  Pre-bronchodilator FEV1 was 1.0L on inclusion. After 1 year of treatment, the mean increase in pre-bronchodilator FEV1 was 51 ml (95% CI = [0.037; 0.065]) across the whole population in comparison with placebo. The changes in subgroups of patients with associated chronic bronchitis (46 ml) or without this condition (60 ml) were of the same order.  The difference in frequency of exacerbations after one year of treatment between roflumilast and placebo was -0.007 exacerbations/patient/year in patients with symptoms of emphysema alone and -0.610 (ratio = 0.738; 95% CI = [0.616; 0.885]) in patients with associated chronic bronchitis.  Table 1:Frequency of moderate to severe exacerbations, grouped according to the presence or absence of associated chronic bronchitis (studies 111 and 112)  Roflumilast Placebo Roflumilast versus placebo  n Freq. n Freq. Difference Ratio 95% CI Emphysema alone 352 0.579 413 0.586 -0.007 0.989 [0.780; 1.254] Chronic bronchitis 817 0.486 847 0.659 -0.610 0.738 [0.616; 0.885] All patients 1327 0.523 1359 0.610 -0.087 0.857 [0.748; 0.981]  Given these results, the development of roflumilast was continued in studies 124 and 125 in patients with severe to very severe COPD associated with chronic bronchitis.
3.2. Adverse effects In studies 124 and 125, the most frequently reported adverse effects were weight loss of the order of 2 kg (10.1% on roflumilast vs. 2.8% on placebo), diarrhoea (8.4% vs. 3.2%), nausea (4.0% vs. 1.9%) and headaches (3.3% vs. 1.6%).  Across all the drug development trials, these incidences were 6.8% vs. 1.8% for weight loss, 10.1% vs. 2.6% for diarrhoea, 5.2% vs. 1.4% for nausea and 4.6% vs. 2.0% for headaches.  The majority of these adverse effects were of mild to moderate severity. The adverse effects primarily occurred in the early weeks of treatment and the majority disappeared as treatment was continued. The weight loss stopped progressing after the first 6 months.  The administration of roflumilast was also associated with neuropsychiatric adverse effects (6.0% in total vs. 3.0%) such as insomnia (2.6% vs. 0.9% on placebo), nervous tension or anxiety (< 2%) and depression (< 2%). Five cases of suicidal ideation and behaviour were observed on roflumilast (out of 14,000 patients exposed to roflumilast), while one case was observed in the placebo group. Although analysis of these cases could not connect them to the administration of roflumilast, a causal link with roflumilast is plausible due to its pharmacological activity. Consequently, its use is not recommended in patients with a history of depression associated with suicidal ideation or behaviour.  No carcinogenic effects were demonstrated with roflumilast; however, patients with cancer were excluded from the studies. For this reason, administration of roflumilast is not recommended in these patients.  
 
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Across all the trials, 84 deaths were observed in patients treated with roflumilast 500 µg, 7 in those treated with 250 µg and 86 in those on placebo. COPD exacerbations were the most common cause of death. No causal link between roflumilast and the deaths was established.  Weight loss and psychiatric adverse effects (depression, suicidal ideation) will be subject to particular surveillance in the risk management plan. These effects could be very harmful in a fragile population where they already constitute comorbidities and risk factors linked to COPD.
3.3. Conclusion This assessment of the efficacy and tolerance of roflumilast is based primarily on two randomised, double-blind, placebo-controlled studies in patients with severe to very severe COPD (post-bronchodilator FEV1/FVC and post-bronchodilator FEV1 70% of 50% predicted value) dating back at least 12 months and associated with chronic bronchitis with 1 documented exacerbation in the year preceding the pre-inclusion visit. After 1 year of treatment, the difference in pre-bronchodilator FEV1 increase (primary efficacy endpoint) between the roflumilast and placebo groups was statistically significant in favour of roflumilast, but the differences observed (39 ml and 58 ml in each study respectively and 48 ml in the combined analysis of both studies) are below the clinical relevance threshold of 100 ml. The annual frequency of moderate to severe exacerbations per patient (co-primary efficacy endpoint) was significantly reduced in the roflumilast group in comparison with placebo: -0.189 and -0.275 in each study respectively and -0.232 in the combined analysis of both studies. This result is of little clinical relevance. In the subgroup of patients treated with long-acting beta-2 agonists (n = 1542,a posteriorianalysis), which corresponds to the recommended management of patients with severe to very severe COPD, the annual frequency of moderate to severe exacerbations was 1.23 on roflumilast and 1.55 on placebo, i.e. a difference of -0.320 (p = 0.0011). In the subgroup of patients with a history of frequent exacerbations (2 exacerbations in the year preceding the trial; n = 763;a posteriorianalysis), the annual frequency of moderate to severe exacerbations was 1.53 on roflumilast and 1.94 on placebo, i.e. a difference of -0.415 (p = 0.0037).  The most frequently reported adverse effects on roflumilast were weight loss of the order of 2 kg (10.1% on roflumilast vs. 2.8% on placebo), diarrhoea (8.4% vs. 3.2%), nausea (4.0% vs. 1.9%), headaches (3.3% vs. 1.6%) and neuropsychiatric effects (6% vs. 3%, including insomnia, anxiety, nervous tension, depression, suicidal ideation and suicidal behaviour). Particular attention should be paid to weight loss and to the risk of neuropsychiatric adverse effects, which could be very harmful in a fragile population where these already constitute comorbidities and risk factors linked to COPD.
 
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4 TRANSPARENCY COMMITTEE CONCLUSIONS
4.1. Actual benefit COPD leads to disability and a marked deterioration in quality of life, and can be life-threatening. This proprietary medicinal product is intended as anti-inflammatory maintenance treatment of COPD. Public health benefit: The public health burden of COPD is substantial. The subpopulation of patients who could receive treatment with DAXAS 500 µg represents a significant burden. Improvement in the treatment of COPD is a public health need which is an established priority (GTNDO,3French Law on Public Health4). In view of the data from clinical trials and taking into account the alternatives available, no impact on the population in terms of morbidity, mortality or quality of life is expected from this proprietary medicinal product. Furthermore, it is not clear whether the results of the clinical studies are transferable to actual practice, particularly as the profile of patients treated in actual practice may differ from that of patients in the studies (in terms of frequency of bronchial exacerbations and associated therapeutic management). The medicinal product DAXAS 500 µg may therefore not be capable of delivering an additional response to the identified need. Consequently, DAXAS is not expected to have an impact on public health.  For the following reasons: - efficacy that is not clinically relevant in terms of change in pre-bronchodilator FEV1 (increase of 48 ml vs. placebo) and of little clinical relevance in terms of frequency of moderate to severe exacerbations (reduction of 0.23 exacerbations/patient/year vs. placebo); - the absence of relevant data on dyspnoea and quality of life that could demonstrate real benefit for patients; - doubts as to whether the efficacy results are transferable to real life; - uncertainty about the risks associated with weight loss, depression and suicidal ideation following administration of roflumilast in a fragile population where these symptoms are already comorbidities and risk factors linked to COPD; - a poorly defined place in the treatment strategy, given the absence of any comparative study with another active treatment or in combination with the other available treatments, in particular inhaled corticosteroid/long-acting beta-2 agonist combinations; the actual benefit of DAXAS 500 µg film-coated tablets is insufficient to justify its reimbursement by National Health Insurance.  
                                            3Groupe Technique National de Définition des Objectifs [National technical group for setting of public-health objectives] (DGS-2003) 4No. 2004-806 of 9 August 2004 on public health policy: on Public Health 2004: Law  Lawobjective no. 75 on COPD [rapport DREES indicateurs - July 2005] _ _
 
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4.2. Reminder of treatment strategy The diagnosis and management of patients with COPD should include an assessment of the stage of severity of the COPD, based on an examination of symptoms (chronic cough, exertional dyspnoea, production of purulent sputum, exacerbations) and pulmonary function testing. No drug can prevent COPD from progressing to chronic respiratory failure. Stopping smoking is the only measure that may restore a normal rate of decline in FEV1. Influenza vaccination is indicated. Exercise training and respiratory physiotherapy help to improve symptoms, quality of life and participation in activities of daily living. The drug treatment of COPD (outside exacerbations) is stepped according to the stage of severity and response to treatment. The drugs used are intended to diminish symptoms and reduce the frequency and severity of exacerbations.  Bronchodilators, beta-2 antagonists and anticholinergics in inhalant form are the main symptomatic treatment of COPD. Inhaled short-acting bronchodilators (beta-2 agonists or anticholinergics), taken on demand, are recommended as first-line therapy. Long-acting bronchodilators are recommended when ongoing symptomatic treatment is necessary, i.e. when dyspnoea persists despite the use of a short-acting bronchodilator several times a day. Three long-acting beta-2 agonists (formoterol, indacaterol and salmeterol) and a long-acting anticholinergic (tiotropium) are available. There is no difference in their efficacy.  Extended-release theophylline may be administered if the patient has difficulty using inhaled bronchodilators or if the latter do not improve dyspnoea sufficiently; its use is limited by its narrow therapeutic margin.  Inhaled corticosteroids may only be used in conjunction with a long-acting bronchodilator in patients with severe COPD with a FEV1 < 50% of the predicted value and repeated exacerbations. They have demonstrated no effect on mortality (from any cause) and increase the risk of lower respiratory tract infections, particularly pneumonia.  Treatment with a long-acting bronchodilator or a combination of long-acting bronchodilator and inhaled corticosteroid should only be continued if a beneficial effect on symptoms is observed. Systemic corticosteroids are not recommended.  Oxygen therapy is restricted to patients with diurnal hypoxaemia (PaO2 55 mmHg) outside an acute episode and despite optimal treatment.
4.3. Transparency Committee recommendations The transparency Committee does not recommend inclusion on the list of medicines refundable by National Health Insurance, nor on the list of medicines approved for hospital use and various public services.  
 
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