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EDUCATIONAL SLIDE SET NYC/DAXAS/12/002 Date of information: July 2012 Takeda Pharmaceuticals International GmbH Thurgauerstrasse 130, 8152 Glattpark - Opfikon (Zurich), Switzerland CONTENTS INTRODUCTION 3 WHAT IS COPD? 4 WHAT IS THE ROLE OF INFLAMMATION IN COPD? 10 WHAT ARE EXACERBATIONS? 14 HOW IS COPD DIAGNOSED AND MANAGED? 25 WHAT IS DAXAS® (ROFLUMILAST) AND HOW DOES IT TREAT COPD? 34 EFFICACY OF ROFLUMILAST IN THE PIVOTAL CLINICAL TRIALS 41 EFFICACY OF ROFLUMILAST IN 44 PATIENTS AT RISK OF EXACERBATIONS ADDITIVE EFFICACY OF ROFLUMILAST IN CLINICAL TRIALS 47 SAFETY OF ROFLUMILAST IN CLINICAL STUDIES 52 REFERENCES 58 DAXAS® EUROPEAN SUMMARY OF PRODUCT CHARACTERISTICS (EXTRACT) 61 INTRODUCTION TO THE SLIDE KIT This slide kit provides detailed information on COPD, the role of chronic inflammation, and current approaches to treatment The last sections include data on roflumilast (Daxas®), a once-daily, oral anti-inflammatory drug, indicated in EU for maintenance treatment of severe COPD associated with chronic bronchitis, in adult patients with a history of frequent exacerbations, as an add-on to bronchodilator treatment The slides are fully referenced and include talking points in the slide notes The Daxas® EU SmPC (extract) is available at the end of this slide kit WHAT IS COPD? WHAT IS COPD? Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines COPD as: “a common preventable and treatable disease, characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients” Key points: COPD is preventable and treatable Airway limitation is not fully reversible, usually progressive, and associated with chronic inflammation Exacerbations and comorbidities contribute to the overall severity From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from www.goldcopd.org RISK FACTORS FOR COPD Adapted from Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from www.goldcopd.org COPD HAS PULMONARY AND SYSTEMIC COMPONENTS Inhaled substances + Genetic susceptibility Airway inflammation Mucociliary dysfunction Structural changes Systemic inflammation Airway limitation Breathlessness Bronchitis: coughing, sputum production Emphysema: hyperinflation, wheezing Skeletal muscle wasting & Cachexia Comorbidities (e.g. diabetes, cardiovascular disease, osteoporosis) Adapted from Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from www.goldcopd.org COPD IS A MAJOR BURDEN ON HEALTHCARE RESOURCES AND THE ECONOMY COPD affects 210 million people worldwide1 and causes 3 million deaths annually (5% of all deaths worldwide)2 It is predicted to become the third leading cause of global mortality by 20303 The economic burden of COPD is high, with costs increasing as the disease progresses Costs associated with severe COPD are up to 17 times higher than those associated with mild COPD4 High costs are associated with treatment of exacerbations, such as hospitalization4 Indirect costs include loss of productivity in the workplace owing to symptoms4 1. Diette GB, Orr P, McCormack MC et al. Population Health Management 2010;13:21-26. 2. WHO. COPD Fact Sheet No 315. 2011. Available from www.who.int/mediacentre/factsheets/fs315/en/index.html 3. WHO. Chronic respiratory diseases. Accessed 2011. http://www.who.int/respiratory/copd/burden/en/index.html 4. Wouters EFM. Respir Med 2003;97:S3-S14. SUMMARY The major risk factor for developing COPD is tobacco smoking COPD is associated with both chronic pulmonary and systemic inflammation The symptoms of COPD include breathlessness, chronic cough and sputum production Exacerbations and comorbidities contribute to the overall severity COPD is a debilitating disease that presents a huge healthcare and economic burden around the world WHAT IS THE ROLE OF INFLAMMATION IN COPD? CHRONIC INFLAMMATION PLAYS A CENTRAL ROLE IN COPD Smoke Pollutants Key inflammatory cells Neutrophils Inflammation CD8+ T-lymphocytes Macrophages Chronic inflammation Structural changes Systemic inflammation Bronchoconstriction, oedema, mucus, emphysema Acute exacerbation Airflow limitation Adapted from Barnes PJ. From: Stockley RA, Rennard SI, Rabe K et al (Editors). Chronic Obstructive Pulmonary Disease. Oxford, England: Blackwell Publishing; 2007:860. AIRWAY INFLAMMATION OCCURS FROM COPD ONSET AND INCREASES WITH DISEASE SEVERITY GOLD Stage I Airways with measurable cells (%) 100 GOLD Stage II and III GOLD Stage IV 80 60 40 20 0 Neutrophils Adapted from Hogg JC, Chu F, Utokaparch S et al. N Engl J Med 2004;350:2645-2653. Macrophages CD8+ cells SUMMARY Chronic inflammation in the airways and systemic circulation contributes to the pathology of COPD COPD-specific inflammation is characterized by increased neutrophils, CD8+ T-lymphocytes and macrophages, as well as cytokines and other inflammatory mediators Chronic inflammation is present from the onset of COPD and increases with disease progression. Airway inflammation increases during exacerbations Effective COPD management should include agents that target the chronic inflammation underlying the disease WHAT ARE EXACERBATIONS? WHAT ARE EXACERBATIONS? Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines an exacerbation as: “an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication”1 Commonly caused by bacterial/viral infections1 Associated with increases in markers of inflammation2,3 Frequent exacerbations have been associated with increased disease progression4 Lower quality of life Accelerate the rate of lung function decline Increase the risk of hospitalization and mortality 1. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from www.goldcopd.org 2. Perera W, Hurst JR, Wilkinson TM et al. Eur Respir J 2007;29:527-534. 3. Papi A, Bellettato CM, Braccioni F et al. Am J Respir Crit Care Med 2006;173:1114–1121. 4. Wedzicha JA & Seemungal TA. Lancet 2007;370:786-796. EXACERBATIONS ARE ASSOCIATED WITH INCREASES IN INFLAMMATORY CELLS Adapted from Saetta M, Di Stefano A, Maestrelli P et al. Am J Respir Crit Care Med 1994;150:1646-1652. * p<0.01 versus stable disease INFLAMMATORY MARKERS ARE INCREASED AT BASELINE IN FREQUENT EXACERBATORS Reproduced from Bhowmik A, Seemungal TA, Sapsford RJ et al. Thorax 2000;55:114-120, with permission from BMJ Publishing Group Ltd COUGH AND SPUTUM PRODUCTION INDICATE AN INCREASED RISK OF EXACERBATIONS Adapted from Burgel PR, Nesme-Meyer P, Chanez P et al. Chest 2009;135:975-982. COUGH AND SPUTUM PRODUCTION INDICATE AN INCREASED RISK OF EXACERBATIONS Total exacerbation rate Adapted from Kim V , Han MK, Vance GB, et al. Chest 2011;140:626-633. History of severe exacerbations FREQUENT EXACERBATIONS ARE ASSOCIATED WITH INCREASED FUTURE RISK Patients with frequent exacerbations Lower quality of life Increased inflammation Faster disease progression Adapted from: 1. Wedzicha JA & Seemungal TA. Lancet 2007;370:786-796. 2. Donaldson GC & Wedzicha JA. Thorax 2006;61:164-168. Increased mortality rate Increased risk of recurrent exacerbations Increased likelihood of hospitalisation FREQUENT EXACERBATORS ARE FOUND AT ALL STAGES OF COPD SEVERITY Adapted from Hurst JR, Vestbo J, Anzueto A, et al. N Engl J Med 2010;363:1128-1138. HALF OF EXACERBATIONS ARE NOT REPORTED BY PATIENTS Adapted from Seemungal TAR, Donaldson GC, Paul EA, et al. Am J Respir Crit Care Med 1998;157:1418-1422. PATIENTS AT INCREASED RISK CAN BE IDENTIFIED BASED ON PATIENT RECALL OF PREVIOUS EVENTS Ask your patients for any exacerbation (flare-up) treated with antibiotics and / or oral steroids in the previous year Ask your patients about any hospitalizations due to exacerbations in the previous year If your patient answers YES to either of these questions the risk is 5.72 times higher that this patient will experience 2 or more exacerbations within the next year, compared with if the patient answers NO (p<0.001) Adapted from Hurst JR, Vestbo J, Anzueto A et al. N Engl J Med 2010;363:1128-1138. SUMMARY Exacerbations are worsening episodes in which symptoms increase beyond daily variations and leads to a change in medication Patients with frequent exacerbations have increased inflammation in the stable state Chronic cough and sputum production are associated with an increased risk of exacerbations Frequent exacerbations are associated with an increased future risk The ‘frequent exacerbator’ is a distinct phenotype that is important to identify and target with specific exacerbation prevention strategies Exacerbations are underreported, however frequent exacerbators can be identified based on patient recall of treated events HOW IS COPD DIAGNOSED AND MANAGED? COPD IS DIAGNOSED BASED ON SYMPTOMS, RISK FACTORS AND SPIROMETRY Adapted from Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from www.goldcopd.org NEW MODEL FOR ASSESSING SYMPTOMS AND RISK LEVELS IN PATIENTS WITH COPD When assessing risk, choose the highest risk according to airflow limitation or exacerbation history Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from www.goldcopd.org GOALS FOR TREATMENT OF STABLE COPD • Relieve symptoms • Improve exercise tolerance • Improve health status REDUCE SYMPTOMS and • Prevent disease progression • Prevent and treat exacerbations • Reduce mortality REDUCE RISK Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from www.goldcopd.org MANAGEMENT OF STABLE COPD: NON-PHARMACOLOGIC Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from www.goldcopd.org MANAGEMENT OF STABLE COPD: PHARMACOLOGIC THERAPY Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from www.goldcopd.org PHARMACOLOGIC THERAPY: KEY POINTS In Group B patients long-acting bronchodilators are preferred over the short-acting formulations recommended for patients in Group A In Group C and D patients, treatment with an ICS/LABA combination or a LAMA is recommended as first choice The PDE4 inhibitor roflumilast is recommended as a second choice to reduce exacerbations for Group D patients with chronic bronchitis as well as an alternative choice in Group C patients with chronic bronchitis Long-term monotherapy with oral or inhaled corticosteroids is not recommended in COPD Treatment with theophylline is only recommended as an alternative choice if other long-acting bronchodilators are unavailable or unaffordable Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from www.goldcopd.org IDENTIFY AND MANAGE COMORBIDITIES COPD often coexists with other diseases (comorbidities) that may have a significant impact on prognosis In general, presence of comorbidities should not alter COPD treatment and comorbidities should be treated as if the patient did not have COPD Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from www.goldcopd.org SUMMARY COPD is diagnosed based on spirometry (required), symptoms and risk factors In previous versions of the GOLD report, the assessment of COPD was based on spirometry only. As FEV1 alone is a poor predictor of disease status, the assessment of COPD also should consider current symptoms and risk of exacerbations A combined assessment of symptoms and risk of exacerbations is the basis for non-pharmacologic and pharmacologic management of COPD Routine follow-up is essential in COPD and should include monitoring of lung function, symptoms, as well as exacerbation frequency WHAT IS DAXAS® (ROFLUMILAST) AND HOW DOES IT TREAT COPD? WHAT IS DAXAS®? What? Daxas® (roflumilast) is the first oral COPD-specific anti-inflammatory therapy for patients with severe COPD who have symptoms of chronic cough and sputum, a history of frequent exacerbations, and are on bronchodilator therapy How? A potent and selective inhibitor of the PDE4 enzyme, Daxas® has a unique mode of action that targets the chronic inflammation underlying COPD Daxas® EU SmPC. Available at www.ema.europa.eu PDE4 PLAYS AN IMPORTANT ROLE IN INFLAMMATION PDE4 inhibition P P P PDE4 P Adapted from Rabe KF. Expert Rev Resp Med 2010;4: 543–555. THE PDE4 ENZYME IS EXPRESSED IN KEY INFLAMMATORY CELLS INVOLVED IN COPD STRUCTURAL CELLS Adapted from: Giembycz MA. Monaldi Arch Chest Dis 2002;57:48-64. PDE ISOFORM THE ANTI-INFLAMMATORY EFFECTS OF ROFLUMILAST WERE EVALUATED IN A 4-WEEK CROSSOVER STUDY Reproduced from Grootendorst DC, Gauw SA, Verhoosel RM et al. Thorax 2007;62;1081-1087, with permission from BMJ Publishing Group Ltd. ROFLUMILAST REDUCED LEVELS OF INFLAMMATORY MARKERS IN SPUTUM SAMPLES Total leukocyte count IL-8 Neutrophil elastase Reproduced from Grootendorst DC, Gauw SA, Verhoosel RM et al. Thorax 2007;62;1081-1087, with permission from BMJ Publishing Group Ltd. WHAT IS DAXAS®? Who? Daxas® is indicated in EU for maintenance treatment of severe COPD associated with chronic bronchitis in adult patients with a history of frequent exacerbations, as add-on to bronchodilator treatment When? Daxas® is taken orally once-a-day, either with or without food Why? Daxas® reduces exacerbations and improves lung function in the target patient population, when added to maintenance therapy with bronchodilators Daxas® EU SmPC. Available at www.ema.europa.eu EFFICACY OF ROFLUMILAST IN THE PIVOTAL CLINICAL TRIALS ROFLUMILAST SIGNIFICANTLY REDUCED THE RATE OF MODERATE/SEVERE EXACERBATIONS Co-primary endpoint: Exacerbation rate Adapted from Calverley PMA, Rabe KF, Goehring UM et al. Lancet 2009;374:685–694. ROFLUMILAST SIGNIFICANTLY IMPROVED LUNG FUNCTION IN 12-MONTH CLINICAL STUDIES Adapted from Calverley PMA, Rabe,KF, Goehring, UM et al. Lancet 2009;374:685–694. EFFICACY OF ROFLUMILAST IN PATIENTS AT RISK OF EXACERBATIONS GREATEST BENEFITS OF ROFLUMILAST WERE OBSERVED IN PATIENTS WITH A HISTORY OF FREQUENT EXACERBATIONS M2-124 and M2-125 pooled post hoc analysis With permission of the European Respiratory Society. Bateman ED, Rabe KF, Calverley PMA, et al. Eur Respir J September 2011;38:553-560; doi:10.1183/09031936.00178710. THE EFFECT OF ROFLUMILAST ON EXACERBATIONS WAS GREATEST IN PATIENTS WITH CHRONIC COUGH AND SPUTUM Patients with chronic bronchitis ± emphysema Adapted from Rennard SI, Calverley PMA, Goehring UM, et al. Respiratory Research 2011; 12: 18. ADDITIVE EFFICACY OF ROFLUMILAST IN CLINICAL TRIALS ROFLUMILAST SIGNIFICANTLY REDUCED EXACERBATIONS WHEN ADDED TO LABA Pre-specified analysis of exacerbation rate in LABA subgroup Adapted from Bateman ED, Rabe KF, Calverley PMA et al. Eur Respir J 2011:38;553-560. LABA = Long-acting β2-agonist ROFLUMILAST REDUCED EXACERBATIONS WHEN ADDED TO BRONCHODILATORS Rabe KF. Br J Pharm 2011;163:53-67. LABA = Long-acting β2-agonist; SAMA = Short-acting muscarinic antagonist * Post-hoc analysis ROFLUMILAST REDUCED EXACERBATION RATE WHEN ADDED TO ICS M2-111 and M2-112 pooled post-hoc analysis Adapted from Rennard SI, Calverley PMA, Goehring UM, et al. Respiratory Research 2011; 12: 18. ICS = Inhaled corticosteroids SUMMARY OF EFFICACY Daxas® significantly reduces exacerbations – the greatest reductions were seen in patients at increased risk, i.e. Patients with a history of frequent exacerbations Patients with symptoms of chronic bronchitis Daxas® provides further reductions in exacerbations independent of concomitant therapy with bronchodilators or inhaled corticosteroids. SAFETY OF ROFLUMILAST IN CLINICAL STUDIES ROFLUMILAST WAS GENERALLY WELL TOLERATED IN CLINICAL STUDIES Data were pooled from four 1-year placebo-controlled trials and four 6-month trials for evaluation of adverse reactions Reprinted by permission from Macmillan Publishers Ltd: Clin Pharm Ther Michalski JM, Golden G, Ikari J and Rennard SI. 91:134-142. Copyright 2012. * Adverse reactions that occurred with a frequency >2% of patients tested THE MAJORITY OF GI-RELATED AES RESOLVED WITHIN 4 WEEKS Nausea Diarrhoea 69% 74% resolved resolved Roflumilast Adapted from Calverley PMA, et al. Int J Chron Obstruct Pulmon Dis 2012; 7:375-382. Placebo GI=Gastrointestinal WEIGHT DECREASE ASSOCIATED WITH ROFLUMILAST OCCURRED MAINLY IN THE FIRST 6 MONTHS OF TREATMENT Calverley PMA, Rabe,KF, Goehring, UM, et al. Lancet 2009;374:685–694. (supplementary webappendix). THE LARGEST WEIGHT DECREASE WAS OBSERVED IN OBESE PATIENTS Calverley PMA, Rabe,KF, Goehring, UM, et al. Lancet 2009;374:685–694. (supplementary webappendix). SUMMARY OF SAFETY Roflumilast was generally well tolerated in clinical studies, with the majority of side effects being mild to moderate and transient Some patients experienced a weight decrease while taking roflumilast Analyses have shown that the greatest weight decrease was experienced by patients with a high BMI Patients should be monitored for changes in body weight and neuropsychiatric events while taking roflumilast REFERENCES (FIRST AUTHOR A–G) Barnes PJ, Hansel TT. Prospects for new drugs for Chronic Obstructive Pulmonary Disease. Lancet 2004;364:985-996. Barnes PJ. Chemokines in COPD. In: Stockley RA, Rennard SI, Rabe K, Celli B, editors. Chronic Obstructive Pulmonary Disease. Oxford, England: Blackwell Publishing; 2007:860. Bateman ED, Rabe KF, Calverley PMA, et al. Roflumilast with long-acting β2-agonists for COPD: influence of exacerbation history. Eur Respir J 2011;38:553-560. Bhowmik A, Seemungal TA, Sapsford RJ, et al. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 2000;55:114-120. Boschetto P, Quintavalle S, Miotto D, et al. Chronic obstructive pulmonary disease (COPD) and occupational exposures. J Occupational Med and Toxicology 2006;1:11. Burgel PR, Nesme-Meyer P, Chanez P, et al. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest 2009;135:975-982. Calverley PMA, Martinez FJ, Fabbri LM, et al. Int J Chron Obstruct Pulmon Dis 2012;7:375-382. Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685-694. Daxas® European Summary of Product Characteristics. www.ema.europa.eu Accessed 2011. Decramer M, Celli B, Kesten S et al. Frequency of exacerbations adversely impacts the course of COPD. Am J Respir Crit Care Med 2010;181:A1526. Diette GB, Orr P, McCormack MC et al. Is pharmacologic care of chronic obstructive pulmonary disease consistent with the guidelines? Population Health Management 2010;13:21-26. Donaldson GC and Wedzicha JA. COPD exacerbations: Epidemiology. Thorax 2006;61:164-168. Ekberg-Aronsson M, Pehrsson K, Nilsson J-A, et al. Mortality in GOLD stages of COPD and its dependence on symptoms of chronic bronchitis. Respir Res 2005;6:98. Gamble E, Grootendorst DC, Hattotuwa K, et al. Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis. Eur Respir J 2007;30:467-471. Giembycz MA. Development status of second generation PDE4 inhibitors for asthma and COPD: the story so far. Monaldi Arch Chest Dis 2002;57:48-64. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of COPD. 2011. www.goldcopd.org Accessed 2011. Groenewegen KH, Schols AMWJ, Wouters EFM. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest 2003;124:459-467. REFERENCES (FIRST AUTHOR G–R) Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007;62;1081-1087. Guerra S, Sherrill DL, Venker C, et al. Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk. Thorax 2009;64:894-900. Hatzelmann A, Morcillo EJ, Lungarella G, et al. The preclinical pharmacology of roflumilast – A selective oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharm Therapeutics 2010;23:235-256. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645-2653. Hogg J. Why does airway inflammation persist after the smoking stops. Thorax 2006;61:96-97. Hurst JR, Perera WR, Wilkinson TM, et al. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173:71-78. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010;363:1128-38. Kim V, Han MK, Vance GB, et al. The chronic bronchitic phenotype of COPD: An analysis of the COPDGene Study. Chest 2011;140;626-633. Lundbäck B et al. A 20-year follow-up of a population study-based COPD cohort – report from the Obstructive Lung Disease in northern Sweden studies. J COPD 2009;6:263-271. Martinez FJ, Rabe KF, Wouters EFM, et al. Time course and reversibility of weight decrease with roflumilast, a phosphodiesterase 4 inhibitor. Am J Respir Crit Care Med 2010;181:A4441. Michalski JM, Golden G, Ikari J and Rennard SI. PDE4: A novel target in the treatment of chronic obstructive pulmonary disease. Clin Pharm Ther 2012;91:134-142. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med 2006;173:1114-1121. Pauwels R, Calverley P, Buist AS, et al. COPD exacerbations: the importance of a standard definition. Respir Med 2004;98:99-107. Perera W, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J 2007;29:527-534. Postma D, Anzueto A, Calverley P, et al. A new prospective on optimal care for patients with COPS. Prim Care Respir J 2011;20:205-209. Rabe KF. Roflumilast for the treatment of chronic obstructive pulmonary disease. Expert Rev Resp Med 2010;4:543–555. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol 2011;163:53-67. Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respir Research 2011;12:18. REFERENCES (FIRST AUTHOR S–Z) Saetta M, Di Stefano A, Maestrelli P, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med 1994;150:1646-1652. Saetta M, Turato G, Facchini FM, et al. Inflammatory cells in the bronchial glands of smokers with chronic bronchitis. Am J Respir Crit Care Med 1997;156:1633–1639. Saetta M. Airway inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:S17-S20. Salvi SS, Barnes PJ. Chronic Obstructive Pulmonary Disease in non-smokers. Lancet 2009;374;733-743. Seemungal TA, Donaldson GC, Bhowmilk A, et al. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1608-1613. Seemungal TAR, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:1418-1422. Seemungal TAR, Hurst JR and Wedzicha JA. Exacerbation rate, health status and mortality in COPD – a review of potential interventions. Int J COPD 2009;4:203-223. Silver H, Blanchette CM, Roberts M, et al. Prevalence of comorbidities in patients hospitalized for COPD exacerbations and impact on inpatient mortality and hospital expenditures. Am J Respir Crit Care Med 2010;181:A5943. Soler-Cataluna JJ, Martinez-Garcia MÁ, Román Sánchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005;60:925-931. Vestbo J, Prescott E and Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Am J Respir Crit Care Med 1996;153:15301535. Wedzicha JA and Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786-796. World Health Organization. COPD Fact Sheet No 315. 2011. www.who.int/mediacentre/factsheets/fs315/en/index.html. Accessed 2011. World Health Organization. Chronic respiratory diseases. http://www.who.int/respiratory/copd/burden/en/index.html. Accessed 2011. Wouters EFM. Economic analysis of the Confronting COPD survey: an overview of results. Respir Med 2003;97:S3-S14. DAXAS® EUROPEAN SUMMARY OF PRODUCT CHARACTERISTICS (EXTRACT) NAME OF THE MEDICINAL PRODUCT DAXAS 500 MICROGRAMS FILM-COATED TABLETS 2. QUALITATIVE AND QUANTITATIVE COMPOSITION EACH CONTAINS 500 MICROGRAMS OF ROFLUMILAST. EXCIPIENT: THIS PRODUCT CONTAINS 199 MG LACTOSE MONOHYDRATE PER FILM-COATED TABLET. FOR A FULL LIST OF EXCIPIENTS, SEE SECTION 6.1. 3. PHARMACEUTICAL FORM FILM-COATED TABLET (TABLET).YELLOW, D-SHAPED FILM-COATED TABLET, EMBOSSED WITH “D” ON ONE SIDE. 4. CLINICAL PARTICULARS 4.1 THERAPEUTIC INDICATIONS 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. 4.2 POSOLOGY AND METHOD OF ADMINISTRATION 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 (SEE SECTION 5.1). 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 (SEE SECTION 4.3). PAEDIATRIC POPULATION: THERE IS NO RELEVANT USE OF DAXAS IN THE PAEDIATRIC POPULATION (UNDER 18 YEARS). METHOD OF ADMINISTRATION: FOR ORAL USE. THE TABLET SHOULD BE SWALLOWED WITH WATER AND TAKEN AT THE SAME TIME EVERY DAY . T HE TABLET CAN BE TAKEN WITH OR WITHOUT FOOD . 4.3 CONTRAINDICATIONS HYPERSENSITIVITY TO ROFLUMILAST OR TO ANY OF THE EXCIPIENTS (SEE SECTION 6.1). MODERATE OR SEVERE HEPATIC IMPAIRMENT (CHILDPUGH B OR C). 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE ALL PATIENTS SHOULD BE INFORMED ABOUT THE RISKS OF DAXAS AND THE PRECAUTIONS FOR SAFE USE AND SHOULD BE GIVEN A PATIENT CARD BEFORE STARTING DAXAS. RESCUE MEDICINAL PRODUCTS: ROFLUMILAST IS AN ANTI-INFLAMMATORY SUBSTANCE INDICATED FOR MAINTENANCE TREATMENT OF SEVERE COPD ASSOCIATED WITH CHRONIC BRONCHITIS IN ADULT PATIENTS WITH A HISTORY OF FREQUENT EXACERBATIONS AS ADD ON TO BRONCHODILATOR TREATMENT. IT IS NOT INDICATED AS RESCUE MEDICINAL PRODUCT FOR THE RELIEF OF ACUTE BRONCHOSPASMS. WEIGHT DECREASE: IN 1-YEAR STUDIES (M2-124, M2-125), A DECREASE OF BODY WEIGHT OCCURRED MORE FREQUENTLY IN PATIENTS TREATED WITH D AXAS COMPARED TO PLACEBO-TREATED PATIENTS. AFTER DISCONTINUATION OF DAXAS, THE MAJORITY OF PATIENTS HAD REGAINED BODY WEIGHT AFTER 3 MONTHS. BODY WEIGHT OF UNDERWEIGHT PATIENTS SHOULD BE CHECKED AT EACH VISIT. PATIENTS SHOULD BE ADVISED TO CHECK THEIR BODY WEIGHT ON A REGULAR BASIS. IN THE EVENT OF AN UNEXPLAINED AND CLINICALLY CONCERNING WEIGHT DECREASE, THE INTAKE OF DAXAS SHOULD BE STOPPED AND BODY WEIGHT SHOULD BE FURTHER FOLLOWED-UP. 1. TABLET Daxas® EU SmPC. Available at www.ema.europa.eu DAXAS® EUROPEAN SUMMARY OF PRODUCT CHARACTERISTICS (EXTRACT) (CONTINUED) SPECIAL CLINICAL CONDITIONS: DUE TO LACK OF RELEVANT EXPERIENCE, TREATMENT WITH DAXAS SHOULD NOT BE INITIATED OR EXISTING TREATMENT WITH DAXAS SHOULD BE STOPPED IN PATIENTS WITH SEVERE IMMUNOLOGICAL DISEASES (E.G. HIV INFECTION, MULTIPLE SCLEROSIS, LUPUS ERYTHEMATOSUS, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY), SEVERE ACUTE INFECTIOUS DISEASES, CANCERS (EXCEPT BASAL CELL CARCINOMA), OR PATIENTS BEING TREATED WITH IMMUNOSUPPRESSIVE MEDICINAL PRODUCTS (I.E.: METHOTREXATE, AZATHIOPRINE, INFLIXIMAB, ETANERCEPT, OR ORAL CORTICOSTEROIDS TO BE TAKEN LONG-TERM; EXCEPT SHORT-TERM SYSTEMIC CORTICOSTEROIDS). EXPERIENCE IN PATIENTS WITH LATENT INFECTIONS SUCH AS TUBERCULOSIS,VIRAL HEPATITIS, HERPES VIRAL INFECTION AND HERPES ZOSTER IS LIMITED. PATIENTS WITH CONGESTIVE HEART FAILURE (NYHA GRADES 3 AND 4) HAVE NOT BEEN STUDIED AND THEREFORE TREATMENT OF THESE PATIENTS IS NOT RECOMMENDED. PSYCHIATRIC DISORDERS: DAXAS IS ASSOCIATED WITH AN INCREASED RISK OF PSYCHIATRIC DISORDERS SUCH AS INSOMNIA, ANXIETY, NERVOUSNESS AND DEPRESSION. RARE INSTANCES OF SUICIDAL IDEATION AND BEHAVIOR, INCLUDING COMPLETED SUICIDE, HAVE BEEN OBSERVED IN CLINICAL TRIALS (SEE SECTION TREATMENT WITH DAXAS 4.8). THEREFORE, THE RISKS AND BENEFITS OF STARTING OR CONTINUING SHOULD BE CAREFULLY ASSESSED IF PATIENTS REPORT PREVIOUS OR EXISTING PSYCHIATRIC SYMPTOMS OR IF CONCOMITANT TREATMENT WITH OTHER MEDICINAL PRODUCTS LIKELY TO CAUSE PSYCHIATRIC EVENTS IS INTENDED. PATIENTS SHOULD BE INSTRUCTED TO NOTIFY THEIR PRESCRIBER OF ANY CHANGES IN BEHAVIOR OR MOOD AND OF ANY SUICIDAL IDEATION. MOREOVER, DAXAS IS NOT RECOMMENDED IN PATIENTS WITH A HISTORY OF DEPRESSION ASSOCIATED WITH SUICIDAL IDEATION OR BEHAVIOR. PERSISTENT INTOLERABILITY: WHILE ADVERSE REACTIONS LIKE DIARRHOEA, NAUSEA, ABDOMINAL PAIN AND HEADACHE MAINLY OCCUR WITHIN THE FIRST WEEKS OF THERAPY AND MOSTLY RESOLVE ON CONTINUED TREATMENT, DAXAS TREATMENT SHOULD BE REASSESSED IN CASE OF PERSISTENT INTOLERABILITY. THIS MIGHT BE THE CASE IN SPECIAL POPULATIONS THAT MAY HAVE HIGHER EXPOSURE, SUCH AS IN BLACK, NON-SMOKING FEMALES (SEE SECTION 5.2) OR IN PATIENTS CONCOMITANTLY TREATED WITH THE CYP1A2 INHIBITOR FLUVOXAMINE OR THE DUALCYP3A4/1A2 INHIBITORS ENOXACIN AND CIMETIDINE (SEE SECTION 4.5). THEOPHYLLINE: THERE ARE NO CLINICAL DATA TO SUPPORT THE CONCOMITANT TREATMENT WITH THEOPHYLLINE FOR MAINTENANCE THERAPY. THEREFORE, THE CONCOMITANT TREATMENT WITH THEOPHYLLINE IS NOT RECOMMENDED. LACTOSE: DAXAS TABLETS CONTAIN LACTOSE. PATIENTS WITH RARE HEREDITARY PROBLEMS OF GALACTOSE INTOLERANCE, THE LAPP LACTASE DEFICIENCY OR GLUCOSE-GALACTOSE MALABSORPTION SHOULD NOT TAKE THIS MEDICINAL PRODUCT. 4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION INTERACTION STUDIES HAVE ONLY BEEN PERFORMED IN ADULTS. A MAJOR STEP IN ROFLUMILAST METABOLISM IS THE N-OXIDATION OF ROFLUMILAST TO ROFLUMILAST N-OXIDE BY CYP3A4 AND CYP1A2. BOTH ROFLUMILAST AND ROFLUMILAST N-OXIDE HAVE INTRINSIC PHOSPHODIESTERASE 4 (PDE4) INHIBITORY ACTIVITY. Daxas® EU SmPC. Available at www.ema.europa.eu DAXAS® EUROPEAN SUMMARY OF PRODUCT CHARACTERISTICS (EXTRACT) (CONTINUED) THEREFORE, FOLLOWING ADMINISTRATION OF ROFLUMILAST , THE TOTAL PDE4 INHIBITION IS CONSIDERED TO BE THE COMBINED EFFECT OF BOTH ROFLUMILAST AND ROFLUMILAST N-OXIDE. CLINICAL INTERACTION STUDIES WITH CYP 3A4 INHIBITORS ERYTHROMYCIN AND KETOCONAZOLE SHOWED INCREASES OF 9% OF THE TOTAL PDE4 INHIBITORY ACTIVITY (I.E. TOTAL EXPOSURE TO ROFLUMILAST AND ROFLUMILAST N-OXIDE). INTERACTION STUDIES WITH CYP1A2 INHIBITOR FLUVOXAMINE, AND THE DUAL CYP3A4/1A2 INHIBITORS ENOXACIN AND CIMETIDINE R ESULTED IN INCREASES OF THE TOTAL PDE4 INHIBITORY ACTIVITY OF 59%, 25% AND 47%, RESPECTIVELY . A COMBINATION OF D AXAS WITH THESE ACTIVE SUBSTANCES MIGHT LEAD TO AN INCREASE OF EXPOSURE AND PERSISTENT INTOLERABILITY . IN THIS CASE , D AXAS TREATMENT SHOULD BE REASSESSED (SEE SECTION 4.4). ADMINISTRATION OF THE CYTOCHROME P450 ENZYME INDUCER RIFAMPICIN RESULTED IN A REDUCTION IN TOTAL PDE4 INHIBITORY ACTIVITY BY ABOUT 60%. T HEREFORE , THE USE OF STRONG CYTOCHROME P450 INDUCERS ( E . G . PHENOBARBITAL , CARBAMAZEPINE ,PHENYTOIN ) MAY REDUCE THE THERAPEUTIC EFFICACY OF ROFLUMILAST . C O - ADMINISTRATION WITH THEOPHYLLINE RESULTED IN AN INCREASE OF 8% OF THE TOTAL PDE4 INHIBITORY ACTIVITY (SEE SECTION 4.4). IN AN INTERACTION STUDY WITH AN ORAL CONTRACEPTIVE CONTAINING GESTODENE AND ETHINYL OESTRADIOL , THE TOTAL PDE4 INHIBITORY ACTIVITY WAS INCREASED BY 17%. N O INTERACTIONS WERE OBSERVED WITH INHALED SALBUTAMOL , FORMOTEROL , BUDESONIDE AND ORAL MONTELUKAST , DIGOXIN , WARFARIN , SILDENAFIL AND MIDAZOLAM . C O - ADMINISTRATION WITH AN ANTACID ( COMBINATION OF ALUMINIUM HYDROXIDE AND MAGNESIUM HYDROXIDE ) DID NOT ALTER THE ABSORPTION OR PHARMACOKINETICS OF ROFLUMILAST OR ITS N-OXIDE . 4.6 FERTILITY , PREGNANCY AND LACTATION P REGNANCY: T HERE ARE LIMITED AMOUNT OF DATA FROM THE USE OF ROFLUMILAST IN PREGNANT WOMEN. STUDIES IN ANIMALS HAVE SHOWN REPRODUCTIVE TOXICITY ( SEE SECTION 5.3). D AXAS IS NOT RECOMMENDED DURING PREGNANCY AND IN WOMEN OF CHILDBEARING POTENTIAL NOT USING CONTRACEPTION . R OFLUMILAST HAS BEEN DEMONSTRATED TO CROSS THE PLACENTA IN PREGNANT RATS . BREASTFEEDING : A VAILABLE PHARMACOKINETIC DATA IN ANIMALS HAVE SHOWN EXCRETION OF ROFLUMILAST OR ITS METABOLITES IN MILK. A RISK TO THE SUCKLING CHILD CANNOT BE EXCLUDED. D AXAS SHOULD NOT BE USED DURING BREAST -FEEDING . FERTILITY : IN A HUMAN SPERMATOGENESIS STUDY , ROFLUMILAST 500 MICROGRAMS HAD NO EFFECTS ON SEMEN PARAMETERS OR REPRODUCTIVE HORMONES DURING THE 3-MONTH TREATMENT PERIOD AND THE FOLLOWING 3-MONTH OFF -TREATMENT PERIOD. 4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES D AXAS HAS NO INFLUENCE ON THE ABILITY TO DRIVE AND USE MACHINES . 4.8 U NDESIRABLE EFFECTS I N CLINICAL COPD STUDIES , APPROXIMATELY 16% OF PATIENTS EXPERIENCED ADVERSE REACTIONS WITH ROFLUMILAST ( COMPARED TO 5% IN PLACEBO ). T HE MOST COMMONLY REPORTED ADVERSE REACTIONS WERE DIARRHOEA (5.9%), WEIGHT DECREASED (3.4%), NAUSEA (2.9%), ABDOMINAL PAIN (1.9%) AND HEADACHE (1.7%). T HE MAJORITY OF THESE ADVERSE REACTIONS WERE MILD OR MODERATE . T HESE ADVERSE REACTIONS MAINLY OCCURRED WITHIN THE FIRST WEEKS OF THERAPY AND MOSTLY RESOLVED ON CONTINUED TREATMENT. WITHIN THE FOLLOWING TABLE, ADVERSE REACTIONS ARE RANKED UNDER THE MEDDRA FREQUENCY CLASSIFICATION: VERY COMMON (≥1/10); COMMON (≥1/100 TO <1/10); UNCOMMON (≥1/1,000 TO <1/100); RARE (≥1/10,000 TO <1/1,000); VERY RARE (<1/10,000), NOT KNOWN (CANNOT BE ESTIMATED FROM THE AVAILABLE DATA). WITHIN EACH FREQUENCY GROUPING, ADVERSE REACTIONS ARE PRESENTED IN ORDER OF DECREASING SERIOUSNESS. Daxas® EU SmPC. Available at www.ema.europa.eu DAXAS® EUROPEAN SUMMARY OF PRODUCT CHARACTERISTICS (EXTRACT) (CONTINUED) ADVERSE REACTIONS WITH ROFLUMILAST IN CLINICAL COPD STUDIES: IMMUNE SYSTEM DISORDERS: HYPERSENSITIVITY (UNCOMMON). ENDOCRINE DISORDERS: GYNAECOMASTIA (RARE). METABOLISM AND NUTRITION DISORDERS: WEIGHT DECREASED, DECREASED APPETITE (COMMON). PSYCHIATRIC DISORDERS: INSOMNIA (COMMON), ANXIETY (UNCOMMON), DEPRESSION, NERVOUSNESS (RARE). NERVOUS SYSTEM DISORDERS: HEADACHE (COMMON), TREMOR, VERTIGO, DIZZINESS (UNCOMMON), DYSGEUSIA (RARE). CARDIAC DISORDERS: PALPITATIONS (UNCOMMON). RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: RESPIRATORY TRACT INFECTIONS - EXCLUDING PNEUMONIA (RARE). GASTROINTESTINAL DISORDERS: DIARRHOEA, NAUSEA, ABDOMINAL PAIN (COMMON), GASTRITIS, VOMITING, GASTRO-ESOPHAGEAL REFLUX DISEASE, DYSPEPSIA (UNCOMMON), H AEMATOCHEZIA , C ONSTIPATION (R ARE ). H EPATOBILIARY DISORDERS : G AMMA -GT INCREASED , A SPARTATE AMINOTRANSFERASE (AST) INCREASED (R ARE ). SKIN AND SUBCUTANEOUS TISSUE DISORDERS: RASH (UNCOMMON), URTICARIA (RARE). MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: MUSCLE SPASMS A N D WE A K NE S S , M Y A L G IA , B A C K P A I N (U N C O M M O N ), B L O O D CRE A T INE PH O S P H O K I N A S E (CPK) I NC RE AS E D (R A RE ). G ENERA L D IS O RDERS A N D ADMINISTRATION SITE CONDITIONS : M ALAISE , ASTHENIA , FATIGUE (UNCOMMON ). IN CLINICAL STUDIES , RARE INSTANCES OF SUICIDAL THINKING AND BEHAVIOR (INCLUDING COMPLETED SUICIDE) WERE REPORTED. PATIENTS SHOULD BE INSTRUCTED TO NOTIFY THEIR PRESCRIBER OF ANY SUICIDAL IDEATION (SEE ALSO SECTION 4.4) 4.9 O VERDOSE I N P HASE I STUDIES , THE FOLLOWING SYMPTOMS WERE OBSERVED AT AN INCREASED RATE AFTER SINGLE ORAL DOSES OF 2,500 MICROGRAMS AND ONE SINGLE DOSE OF 5,000 MICROGRAMS ( TEN TIMES THE RECOMMENDED DOSE ): HEADACHE , GASTROINTESTINAL DISORDERS , DIZZINESS , PALPITATIONS , LIGHT - HEADEDNESS , CLAMMINESS AND ARTERIAL HYPOTENSION . IN CASE OF OVERDOSE , IT IS RECOMMENDED THAT THE APPROPRIATE SUPPORTIVE MEDICAL CARE IS PROVIDED. SINCE ROFLUMILAST IS HIGHLY PROTEIN BOUND, HAEMODIALYSIS IS NOT LIKELY TO BE AN EFFICIENT METHOD OF ITS REMOVAL. IT IS NOT KNOWN WHETHER ROFLUMILAST IS DIALYSABLE BY PERITONEAL DIALYSIS . 6. PHARMACEUTICAL PARTICULARS 6.1 L IST OF EXCIPIENTS C ORE : L ACTOSE MONOHYDRATE, MAIZE STARCH, POVIDONE (K90), MAGNESIUM STEARATE. COATING: HYPROMELLOSE 2910, MACROGOL 4000, TITANIUM DIOXIDE (E171), IRON OXIDE YELLOW (E172). 6.2 I NCOMPATIBILITIES N OT APPLICABLE . 6.3 S HELF LIFE 3 YEARS . 6.4 S PECIAL PRECAUTIONS FOR STORAGE T HIS MEDICINAL PRODUCT DOES NOT REQUIRE ANY SPECIAL STORAGE CONDITIONS . 6.5 NATURE AND CONTENTS OF CONTAINER PVC/PVDC ALUMINIUM BLISTERS IN PACKS OF 10, 14, 28, 30, 84, 90 OR 98 FILM-COATED TABLETS. NOT ALL PACK SIZES MAY BE MARKETED. 6.6 SPECIAL PRECAUTIONS FOR DISPOSAL NO SPECIAL REQUIREMENTS. 7. MARKETING AUTHORISATION HOLDER NYCOMED GMBH, BYK-GULDEN-STRAßE 2, D-78467 KONSTANZ, GERMANY 8. MARKETING AUTHORISATION NUMBEREU/1/10/636/001-007. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 05/07/2010 DETAILED INFORMATION ON THIS MEDICINAL PRODUCT IS AVAILABLE ON THE WEBSITE OF THE EUROPEAN MEDICINES AGENCY HTTP:// DATE OF INFORMATION: MAY 2011 Daxas® EU SmPC. Available at www.ema.europa.eu