Download Treating chronic inflammation in COPD with Daxas

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
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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.
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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.
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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
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