1. Optimizing the Management of Chronic Obstructive Pulmonary Disease (COPD)
Note to the Speaker: All bold underlined statements must be read aloud to the audience. The slides must be used in sequence and the presentation must be used in its entirety. Any changes to this slide set must be preapproved through the AstraZeneca Approval Process (AZAP).
Please note that this is a promotional presentation sponsored directly by
AstraZeneca. There are no continuing medical education (CME) credits
associated with this activity.
©AstraZeneca LP. All rights reserved.
/09

2. Top 5 Causes of Death: COPD on the Rise
120%
Heart disease
Cancer
Stroke
COPD
Accidents
103%
100%
80%
60%
40%
% Change,
20% 0%
-3%
-20%
Top 5 Causes of Death: COPD on the Rise
Key Point: COPD is increasingly prevalent and is associated with substantial morbidity
and mortality1
In the US, an estimated 126,005 people died in 2005 due to COPD, making it the fourth leading cause of death2,3
Of the 5 leading causes of death in the US, COPD is the only cause with increasing mortality4
In 2005, there were an estimated 721,000 hospital discharges with COPD as the first-listed and primary diagnosis. COPD was defined as chronic bronchitis, emphysema, and other lower chronic obstructive pulmonary diseases, including bronchiectasis5
Approximately 65% of these hospital discharges in 2005 were in subjects 65 years of age and older. This age group had a COPD hospitalization rate that was substantially higher than any other age group5
In 2006, 12.1 million US adults (≥18 years of age) were estimated to have COPD. This estimate is based on the estimated number of subjects with chronic bronchitis (9.5 million) and emphysema (4.1 million), taking into account the overlap of people who have both conditions5
The true numbers are probably higher, since COPD is underdiagnosed1,6
-40%
-41%
-60%
-52%
-63%
-80%
Jemal A et al. JAMA. 2005;294:
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Available at Accessed November 21, 2008.
2. Deaths from chronic obstructive pulmonary disease--United States, MMWR Morb Mortal Wkly Rep. 2008;57:
3. Kung H-C, Hoyert DL, Xu J, Murphy SL. Deaths: final data for Natl Vital Stat Rep. 2008;56:1-10.
4. Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States, JAMA. 2005;294:
5. American Lung Association Epidemiology & Statistics Unit Research and Program Services. Trends in COPD (chronic bronchitis and emphysema): morbidity and mortality. December Available at: atf/cf/%7B7a8d42c2-fcca ade-7f5d5e762256%7D/COPD_DEC07.PDF. Accessed November 19, 2008.
6. Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance -- United States MMWR Surveillance Summaries. 2002;51:1-16.

3. Overall Health Care Costs Are Higher in Patients With COPD
30000
Other health-care-related costs*
25000
5888
Outpatient costs
Hospitalization costs
20000
2498
Mean Health Care Cost per Person (US dollars)
15000
10000
19270
2720
Overall Health Care Costs Are Higher in Patients With COPD
Key Point: Patients with COPD incur substantially higher health care costs, compared to
patients with unrelated conditions.1 Exacerbations are responsible for most of the excess
cost2
A cross-sectional study of Medicare managed care patients over age 65 compared the health care costs in 2004 for patients with COPD to health care costs for patients with other conditions1
Patients in the COPD cohort had at least 1 inpatient claim or at least 2 outpatient claims with a listed diagnosis of COPD. Data from over 8300 patients who met these criteria were used in this study1
Patients in the comparison cohort had no claims with a listed diagnosis of COPD, but at least 1 claim with a valid diagnosis code. Data from over 25,000 patients who met these criteria were used in this study1
Each patient from the COPD cohort was matched with 3 patients from the comparison cohort based on age, sex, and length and type of Medicare enrollment1
Mean total health care costs for COPD were over $20,000 higher than for the comparison cohort1
A majority of this excess cost was for inpatient services including hospitalizations.1 Patients with COPD also had higher outpatient costs (including hospital outpatient visits, home health care services, medical equipment and laboratory tests and procedures). Additional health care costs, including emergency room and physician visits and pharmacy costs, were also higher for COPD vs the comparison cohort1
After adjusting for the cost of comorbidities and duration of Medicare eligibility, costs for COPD were over $11,000 higher than for the comparison cohort1
Exacerbations account for a majority of the health care costs associated with COPD2
5000
969
3436
COPD cohort
(n=8370)
Comparison cohort
(n=8370)
*Included emergency room visits, physician visits, and pharmacy costs. †Each comparator was based on the mean of 3 controls from a data set including 25,110 patients.
Menzin J et al. Respir Med. 2008;102:
1. Menzin J, Boulanger L, Marton J, et al. The economic burden of chronic obstructive pulmonary disease (COPD) in a US Medicare population. Respir Med. 2008;102:
2. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated &intId=989. Accessed November 21, 2008.

4. Where Can We Improve COPD Management?
COPD remains underdiagnosed1
Awareness of COPD guidelines suboptimal2
Spirometry used inconsistently2
Mortality increasing among women3
Present in the fifth decade of life,4 though early symptoms may be missed2
Early diagnosis and treatment may lead to better outcomes5
Diagnosis and treatment may prevent or delay progression of lung function
decline and symptoms5
Spirometry is key to the diagnosis of COPD5
Education represents an opportunity to improve outcomes for COPD patients2,5
Where Can We Improve COPD Management?
Key Point: Many primary care health care professionals have limited awareness of the most recent
information regarding COPD guidelines, epidemiology, pathophysiology, and the potential benefits of
available treatments.1 These factors may contribute to the underdiagnosis of COPD2
COPD remains underdiagnosed2
Awareness of COPD guidelines is low. In a survey of nearly 300 family physicians and NP/PAs attending educational programs on topics including COPD, fewer than half (47%) used the GOLD and/or ATS/ERS guidelines for COPD1
The realities of the typical COPD patient are changing. While most primary care health care professionals feel that COPD is primarily a disease of men, more women than men die each year of COPD.3 Prevailing wisdom is that COPD generally starts after age 60 years, yet COPD can begin in the fifth decade of life,4 although early symptoms may be missed1
A majority of primary care health care professionals use spirometry to diagnose COPD at least some of the time, although the GOLD Guidelines recommend spirometry for all patients with suspected COPD5
Early diagnosis and treatment of COPD, including nonpharmacological treatment such as smoking cessation, pulmonary rehabilitation, and oxygen therapy, can prevent or delay progression of airflow limitation5
Spirometry is a key component in the diagnosis of COPD5
Once COPD has been diagnosed, treatment should be aimed at meeting short-term and long-term goals, including the prevention of disease progression5
Education of both physicians and patients with COPD represents a major opportunity to improve outcomes for these patients1,5
1. Mannino DM et al. MMWR Surveillance Summary. 2002;51: Yawn BP, Wollan PC. Int J COPD. 2008;3: Deaths from chronic obstructive pulmonary disease—United States, MMWR Morb Mortal Wkly Rep. 2008;57: American Association for Respiratory Care. Accessed February 11, Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Accessed November 21, 2008.
1. Yawn BP, Wollan PC. Knowledge and attitudes of family physicians coming to COPD continuing medical education. Int J COPD. 2008;3:
2. Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance—United States, MMWR Surveillance Summary. 2002;51:1-16.
3. Deaths from chronic obstructive pulmonary disease—United States, MMWR Morb Mortal Wkly Rep. 2008;57:
4. American Association for Respiratory Care. Confronting COPD in America: Executive Summary. resources/confronting_copd/exesum.pdf. Accessed February 11, 2009.
5. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Accessed November 21, 2008.

5. Overview of COPD Pathophysiology
Cigarette Smoke
Susceptibility Genes
Gender
Proteinases/ Cell Mediators
Oxidative Stress
Environmental Irritants
Respiratory Infections
Lung
Inflammation,
Hyperinflation, Airway Obstruction, Elastic Recoil Loss
Overview of COPD Pathophysiology
Key Point: Chronic obstructive pulmonary disease (COPD) can be caused by a
variety of factors, leading to a number of pulmonary and systemic effects
While cigarette smoke is the main cause of COPD, other factors are involved in the development and progression of this disease
Susceptibility genes play a role in the development of COPD, as do gender, oxidative stress, and the activities of proteinases and cell mediators
Environmental irritants and respiratory infections may also contribute to COPD
These factors may combine to cause the lung inflammation, hyperinflation, airway obstruction, and elastic recoil loss seen in COPD
While COPD was classically characterized by chronic bronchitis and emphysema, the physiological changes in the lung may also lead to systemic and extrapulmonary effects, mucociliary dysfunction, and structural changes. Exacerbations may cause further inflammation, hyperinflation, and airway obstruction
Exacerbations
Chronic Bronchitis
Emphysema
Systemic/ Extrapulmonary Effects
Mucociliary Dysfunction
Structural Changes
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Available at: Accessed November 21, 2008.
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Accessed November 21, 2008.

6. Inflammation Is Present Even in Early Stages of COPD
GOLD Stage 0
GOLD Stage I
GOLD Stages II and III
GOLD Stage IV
120
100 98
100 92 94 87 85 88 84 80 77 80 73 67 66
Airways With Measurable Cells (%) 63 60 55 54 45 40 37 33 32 29 25 20
Inflammation Is Present Even in Early Stages of COPD
Key Point: Progression of COPD is associated with an increase in the
percentage of airways infiltrated by inflammatory cells, though inflammatory
cells are found in the earliest stages of COPD1
A study of 40 patients encompassing all stages of COPD evaluated the relationship between COPD progression and pathological findings in the airways1
High numbers of airways containing polymorphonuclear neutrophils, macrophages, and CD8 cells were seen in the lungs of these patients. Lower percentages of eosinophils and B cells were present in these samples1
The absolute numbers of each cell type were relatively constant irrespective of COPD stage, and did not increase as COPD progressed1
These results indicate inflammation occurs at all stages of COPD1
Inflammation in COPD can be caused by a number of factors including respiratory infections2
It has been hypothesized that persistent intracellular pathogens, such as adenovirus, can promote inflammation3
Patients with mild emphysema had a 5-fold increase in adenovirus protein (E1A)-containing epithelial cells compared to controls, and patients with severe emphysema had a 41-fold increase in E1A-containing epithelial cells compared to controls. This was paralleled by an increase in inflammatory cells3
The results indicate that an adaptive immune response to viral infection can influence the inflammatory process seen in COPD3 7 8
PMNs
Macrophages
Eosinophils
CD4 Cells
CD8 Cells
B Cells
Inflammatory Cells
Adapted from Hogg JC et al. N Engl J Med. 2004;350:
1. 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:
2. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Available at Accessed November 21, 2008.
3. Retamales I, Elliott WM, Meshi B, et al. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med. 2001;164:

7. Airflow Obstruction in COPD Is Partially Reversible15
Degree of Reversibility * 10
*65.6% showed a ≥15% increase in FEV1
Patients, % 5
Airflow Obstruction in COPD Is Partially Reversible
Key Point: Although COPD has been defined as mainly irreversible airflow
limitation, reversibility varies widely in COPD. Bronchodilator responsiveness
in COPD is variable
Nearly 6000 patients with moderate to very severe COPD were evaluated to determine bronchodilator responsiveness
Postbronchodilator spirometry was performed 30 minutes after administration of 80 µg ipratropium and 400 µg albuterol to ensure at least near-maximal bronchodilation. Responsiveness was assessed using 3 different criteria
≥12% and ≥200 mL FEV1 improvement over baseline
≥15% increase in FEV1 over baseline
≥10% absolute increase in the FEV1 percent predicted value
The magnitude of bronchodilator responsiveness was greater than expected
The findings indicate that patients with moderate to very severe COPD in this trial were responsive to near-maximal doses of 2 different bronchodilators, ipratropium and albuterol
Over 50% of patients met the criteria for acute bronchodilator responsiveness
-30
-25
-20
-15
-10 -5 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95
100
Change in FEV1 %
Postbronchodilator FEV1 measured after administration of 80 µg ipratropium and 400 µg albuterol.
Adapted with permission from Tashkin DP et al. Eur Resp J. 2008;31:
Tashkin DP, Celli B, Decramer M, et al. Bronchodilator responsiveness in patients with COPD. Eur Resp J. 2008;31: This figure has been reproduced with the permission of the European Respiratory Society. The slide kit has not been reviewed by European Respiratory Society prior to release, therefore the European Respiratory Society may not be responsible for any errors, omissions or inaccuracies, or for any consequences arising there from, in the content.

8. Spirometry Is Essential for Diagnosing COPD
If . . .
Chronic symptoms = cough, sputum, and/or shortness of breath
And . . .
Exposure to risk factors = tobacco, occupational irritants, and/or indoor/outdoor pollution
Then . . .
Spirometry Is Essential for Diagnosing COPD
Key Point: The diagnosis of COPD is suspected based on symptoms and a history of
exposure to risk factors, and confirmed by the presence of airflow limitation that is
not fully reversible1
According to both the GOLD and ATS/ERS guidelines, a clinical diagnosis of COPD should be considered in any patient over 40 years of age who has dyspnea, chronic cough, or chronic sputum production, and a history of exposure to risk factors for COPD1,2
Risk factors for COPD include exposure to tobacco smoke and/or occupational or environmental pollutants1,2
Diagnosis of COPD requires confirmation by spirometry. Postbronchodilator FEV1/FVC <0.70 and a FEV1 <80% of predicted value confirm the presence of airflow limitation that is not fully reversible1,2
FEV1 values can aid in staging patients with COPD1
Patients with mild COPD (stage I) may have FEV1 ≥80% predicted. These patients should be counseled to avoid risk factors for COPD, including smoking cessation1
A physical examination is rarely diagnostic in COPD. Many physical signs do not appear until the disease has progressed to more advanced stages1,2
A chest x-ray is seldom diagnostic in COPD, but can help exclude alternative diagnoses1,2
Spirometry* to confirm COPD diagnosis
• FEV1/FVC < • FEV1 determines staging
*Additional testing: chest x-ray, echocardiogram, arterial blood gas, sputum analysis, computed tomography (CT) scan.
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Accessed November 21, 2008.
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated &intId=989. Accessed November 21, 2008.
2. American Thoracic Society, European Respiratory Society. Standards for the diagnosis and management of patients with COPD. Accessed November 19, 2008.

9. Spirometry Is a Useful Tool to Assess COPD Severity and Progression1,2
Stage I II
III IV
FEV1/FVC <0.70
FEV1 <30% predicted or FEV1 <50% predicted plus chronic respiratory failure
FEV1/FVC <0.70
30% ≤FEV1 <50% predicted
FEV1/FVC <0.70
50% ≤ FEV1 <80% predicted
FEV1/FVC <0.70
FEV1 ≥80% predicted
Severity
Chronic cough and sputum production
Stage I symptoms + dyspnea
Progressive dyspnea
Stage III symptoms + respiratory failure, right heart failure, weight loss, arterial hypoxemia
Typical
symptoms
Spirometry Is a Useful Tool to Assess COPD Severity and Progression
Key Point: Assessment of COPD severity is based on symptoms, spirometry, and the
presence of complications. Assessment of COPD should be ongoing as disease
progresses1
The presence of postbronchodilator FEV1/FVC <0.70 is diagnostic of COPD.* The pattern of symptom development is generally well established, although it does not always correlate exactly with stage according to FEV1. The severity of the symptoms and the degree to which they affect the patient’s daily life are key determinants of health status1,2
Typically, the main symptoms of patients with stage I or mild COPD are cough and sputum production. These symptoms may be present for years and may be discounted as ‘normal’ by the patient1
Dsypnea is the hallmark symptom of COPD, and typically appears in stage II or moderate COPD. It is characteristically persistent and progressive. Initially, dyspnea is experienced with strenuous effort but gradually begins to limit even normal activities1
In severe COPD (stages III), the symptoms of cough, sputum production, and dyspnea continue and worsen. In very severe COPD (stage IV), additional complications such as respiratory failure, right heart failure, weight loss, and arterial hypoxemia may develop1
1. American Thoracic Society, European Respiratory Society. Standards for the diagnosis and management of patients with COPD Accessed November 19, 2008.
2. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for diagnosis, management, and prevention of chronic obstructive pulmonary disease Updated Accessed November 21, 2008.
*Based on the spirometric values (FEV1%), COPD had been classified into four different severity stages – mild, moderate,
severe, and very severe. This classification can help predict health status and mortality.
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated &intId=989. Accessed November 21, 2008.
2. American Thoracic Society, European Respiratory Society. Standards for the diagnosis and management of patients with COPD. Accessed November 19, 2008.

10. Goals of COPD Management
Relieve symptoms
Minimize side effects
Improve exercise tolerance
Prevent and treat exacerbations and complications
Improve health status
Prevent disease progression
Reduce mortality
Short Term
and
Long Term
Goals of COPD Management
Key Points:
Although disease prevention is the ultimate goal of COPD management, once COPD is diagnosed, effective management should focus on short-term and long-term goals
Effective management includes both pharmacologic and nonpharmacologic treatment
The short-term goals of therapy for COPD are to relieve symptoms, prevent and treat complications and exacerbations, and improve health status and exercise tolerance
Long-term goals are to prevent disease progression and reduce mortality
These goals should be achieved with minimal side effects from treatment
An effective management plan for COPD includes 4 components
Assess and monitor disease
Reduce risk factors
Manage stable COPD
Manage exacerbations
COPD management includes both pharmacologic and nonpharmacologic treatment.
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Accessed November 21, 2008.
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Accessed November 21, 2008.

11. Nonpharmacologic Therapy to Manage COPD
Smoking Cessation
Patient Education
Vaccination
Pulmonary Rehabilitation
Surgical and Non-surgical Alternatives
Oxygen Therapy
Nonpharmacologic Therapy to Manage COPD
Key Point: The approach to the management of stable COPD should be individualized to control symptoms and
exacerbations and improve quality of life1
Patients with COPD should be educated about their disease, including basic information about pathophysiology, risk factors for progression, the approach to therapy, and what they can do to minimize symptoms and manage their disease1
The single most important step to the prevention and treatment of COPD is smoking cessation, which can reduce declines in lung function and mortality1,2
Individuals with moderate COPD (FEV1 75% predicted) who quit smoking had smaller declines in lung function over 5 years compared to those who continued to smoke3
Respiratory infections also present a risk for subjects with COPD. Vaccination against common pathogens can reduce morbidity and mortality in patients with COPD, particularly the elderly and those with severe airflow limitation1
Influenza vaccination of nearly 1300 elderly COPD patients from 2000 to 2005 led to a 24% reduction in the risk of all-cause winter mortality during influenza season. This difference in risk was not statistically significant4
Nonpharmacologic therapy includes pulmonary rehabilitation, which can improve exercise capacity, reduce symptoms, and improve quality of life1
Pulmonary rehabilitation in over 125 patients with COPD resulted in significant decreases in hospitalizations (P=.017), and mean health care costs (P=.0002) in the year after rehabilitation5
Oxygen therapy is a main treatment for very severe COPD1
Surgical options include lung volume reduction surgery, bullectomy, and lung transplantation. These procedures may have benefits for carefully selected patients1
Mortality risk decreased and exercise capacity and quality of life increased over a 5-year period in over 600 patients who underwent lung volume reduction surgery6
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Accessed November 21, 2008.
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Available at Accessed November 21, 2008.
2. Anthonisen NR, Skeans MA, Wise RA, et al. The effects of a smoking cessation intervention on 14.5-year mortality. Ann Intern Med. 2005;142:
3. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. JAMA. 1994;272:
4. Vila-Córcoles A, Ochoa O, de Deigo C, et al. Effects of annual influenza vaccination on winter mortality in elderly people with chronic pulmonary disease. Int J Clin Pract. 2008;62:10-17.
5. Raskin J, Spiegler P, McCusker C et al. The effect of pulmonary rehabilitation on health care utilization in chronic obstructive pulmonary disease. J Cardiopulm Rehab. 2006;26;
6. Naunheim KS, Wood DE, Mohsenifar Z, et al. Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the National Emphysema Treatment Trial Research Group. Ann Thorac Surg. 2006;82:

12. Pharmacologic Therapy to Manage COPD
Stage I II
III IV
FEV1/FVC <0.70
FEV1 <30% predicted or FEV1 <50% predicted plus chronic respiratory failure
FEV1/FVC <0.70
30% ≤FEV1 <50% predicted
FEV1/FVC <0.70
50% ≤FEV1 <80% predicted
FEV1/FVC <0.70
FEV1 ≥80% predicted
Severity
Active reduction of risk factor(s); influenza vaccination
Add short-acting bronchodilator (when needed)
Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation
Pharmacologic Therapy to Manage COPD
Key Point: The goal of pharmacologic therapy for COPD is to control symptoms and reduce
exacerbations; none of the existing medications can modify the long-term decline in lung function1
Therapy for COPD depends on severity. Because COPD is progressive, treatment tends to be cumulative, with more therapies added as the disease worsens1
While severity of airflow limitation is a general guide to therapeutic options, the selection of therapy is mainly determined by patient symptoms and clinical presentation1
In mild COPD, treatment consists of reducing risk factors, including smoking cessation, and influenza vaccinations. Short-acting bronchodilators are added if the patient is symptomatic1
In moderate COPD, the guidelines recommend treatment with one or more long-acting bronchodilators such as anticholinergics or long-acting β2 agonists (LABAs) as needed. Pulmonary rehabilitation may be added as necessary1
Combining different agents improves spirometric values and symptoms more than using single agents alone2
In severe COPD, inhaled corticosteroids can be added to existing therapy if the patient experiences repeated exacerbations. The use of ICS and LABAs in patients with COPD demonstrated improved symptoms and lung function and reduced exacerbations, and are also effective when used as combination therapy1
ICS/LABA combination therapy is more effective than the monocomponents in reducing exacerbations and improving lung function and health status in patients with COPD1
Combination therapy should be considered in all patients hospitalized for COPD exacerbations requiring antibiotics1
In very severe COPD, patients may experience chronic respiratory failure requiring long-term oxygen therapy. Surgery may be considered in selected patients1
Add inhaled glucocorticosteroids if repeated exacerbations
Add long-term oxygen if chronic respiratory failure; Consider surgery
Adapted from Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Accessed November 21, 2008.
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated Accessed November 21, 2008.
2. American Thoracic Society, European Respiratory Society. Standards for the diagnosis and management of patients with COPD. Accessed November 19, 2008.

13. Symbicort® (budesonide/formoterol fumarate dihydrate) Inhalation Aerosol for COPD
SYMBICORT 160/4.5 μg is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema
Does not replace fast-acting inhalers and should not be used to treat acute symptoms of COPD
Symbicort® (budesonide/formoterol fumarate dihydrate) Inhalation Aerosol
for COPD
Note to the Speaker: All bold underlined statements must be read aloud to
the audience. The slides must be used in sequence, and the presentation
must be used in its entirety. Any changes to this slide set must be
preapproved through the AstraZeneca Approval Process (AZAP).
Please note that this is a promotional presentation sponsored directly by
AstraZeneca. There are no continuing medical education (CME) credits
associated with this activity.
SYMBICORT HFA* pMDI† 160/4.5 μg is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with COPD including chronic bronchitis and emphysema
SYMBICORT is not a rescue medication and does NOT replace fast-acting inhalers
©AstraZeneca LP. All rights reserved.
/09
*HFA = hydrofluoroalkane. †pMDI = pressurized metered dose inhaler.
SYMBICORT [package insert]. Wilmington, DE: AstraZeneca LP.

14. SYMBICORT Has Been Extensively Studied in Patients With Moderate to Very Severe COPD
Overview of Key Phase III Studies
Study
Duration (weeks) N
Purpose Was to Compare the Efficacy and Safety of...
SUN1 52
1964
SYMBICORT pMDI 160/4.5 μg × 2 inhalations BID and SYMBICORT pMDI 80/4.5 μg × 2 inhalations BID versus formoterol* and placebo*
SHINE2 26
1704
SYMBICORT pMDI 160/4.5 μg × 2 inhalations BID and SYMBICORT pMDI 80/4.5 μg × 2 inhalations BID versus its monocomponents† and placebo*
SYMBICORT Has Been Extensively Studied in Patients With Moderate to Very Severe COPD
Key Points:
The efficacy and safety of SYMBICORT in the treatment of COPD was evaluated in two double-blind, double-dummy, placebo-controlled, parallel-group multicenter studies1,2
The SUN study evaluated the efficacy and safety of SYMBICORT in 1964 patients with moderate to very severe COPD over a period of a year1
The SHINE study evaluated the efficacy and tolerability of SYMBICORT in 1704 patients with moderate to very severe COPD over a period of 6 months2
This presentation will focus on results from the SUN trial (specifically, the results from the SYMBICORT 160/4.5 µg x 2 inhalations BID arm, consistent with the approved labeling for COPD)
Eligible patients for these studies included men and nonpregnant women aged ≥40 years with a diagnosis of COPD for >2 years who met the following inclusion criteria1,2
Prebronchodilator FEV1 ≤50% and prebronchodilator FEV1/FVC <70%
History of ≥1 COPD exacerbation that required treatment with a course of oral corticosteroids and/or antibacterials within the year before screening
Current or previous smoker with a smoking history of ≥10 pack-years
Modified Medical Research Council dyspnea scale score of ≥2
Documented use of an inhaled SABA as rescue medication
Breathlessness, Cough, and Sputum Score (BCSS) ≥2 per day during >50% of the 2-week run-in period2
*Administered as 2 inhalations BID.
†Monocomponents refers to administration of budesonide monotherapy, formoterol monotherapy, and budesonide + formoterol administered in separate devices, all administered as 2 inhalations BID.
1. Rennard SI et al. Drugs. 2009;69: Tashkin DP et al. Drugs. 2008;68:
1. Rennard SI, Tashkin DP, McElhattan J, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs. 2009;69:
2. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008;68:

15. SUN and SHINE Study Design Features
Patients receiving concomitant medications prior to study initiation1,2
Allowed to remain on ICS during run-in
Long-acting anticholinergics were changed to stable doses of ipratropium during run-in and throughout the study
Long-acting β2-agonists (LABAs) were changed to short-acting
β2-agonists (SABAs) as needed
Subjects with underlying comorbidities were included1,2
Hypertension (42%)
Dyslipidemia (22%-24%)
Cardiac disease (18%)
Diabetes (10%-11%)
SUN and SHINE Study Design Features
Key Point: The design of the SUN and SHINE studies allowed for inclusion
of a real-world study population, as evidenced by concomitant medications
and patient comorbidities1,2
During the 2-week run-in period, patients already on ICS alone or in combination, were allowed to continue on ICS monotherapy, and patients who were previously receiving anticholinergics were placed on stable doses of ipratropium bromide. LABAs were discontinued, but as-needed SABAs were allowed1,2
Patients enrolled in the studies were well represented by populations of subjects sharing comorbid conditions, such as hypertension, dyslipidemia, cardiac disease, diabetes, among others1,2
Specifically, about 42% of the patients had hypertension, 22%-24% had abnormal lipid profiles, about 18% had cardiac disease (ie, coronary artery disease, myocardial infarction, and angina pectoris), and 10%-11% had diabetes1,2
1. Rennard SI et al. Drugs. 2009;69: Tashkin DP et al. Drugs. 2008;68:
1. Rennard SI, Tashkin DP, McElhattan J, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs. 2009;69:
2. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008;68:

16. SUN Assessed the Efficacy and Safety of SYMBICORT Over 12 Months in Patients With COPD1,2
SYMBICORT pMDI
(n=494)
(n=494)
160/4.5 µg  2 Inhalations BID
R A N D O M I Z A T
SYMBICORT pMDI
80/4.5 µg  2 Inhalations BID
Run-in
Follow-up
Formoterol DPI
(n=495)
4.5 µg  2 Inhalations BID
Placebo  2 Inhalations BID
(n=481)
SUN Assessed the Efficacy and Safety of SYMBICORT Over 12 Months in Patients With COPD
Key Point: The SUN study was a 12-month, randomized, double-blind, double-dummy, parallel-group,
placebo-controlled study that assessed the efficacy and safety of SYMBICORT in 1964 patients with
COPD1
During a 2-week run-in period, patients previously receiving ICS alone or in combination continued ICS monotherapy, and patients previously receiving anticholinergic therapies were placed on stable doses of ipratropium bromide. LABAs were discontinued but as-needed short-acting β2-agonists (SABAs) were allowed1
After the 2-week run-in period, ICS treatment was discontinued, and eligible patients were randomized to one of the following 4 treatments, all of which were dosed BID for 12 months1
SYMBICORT pMDI 160/4.5 μg × 2 inhalations
SYMBICORT pMDI 80/4.5 μg × 2 inhalations
Formoterol DPI 4.5 μg × 2 inhalations
Placebo × 2 inhalations
Please note that for patients with COPD, the only approved dose is SYMBICORT 160/4.5 µg x 2 inhalations BID2
Study rescue medication (albuterol) for as-needed use throughout the randomized treatment period was allowed in all patients, as was ipratropium bromide pMDI for only those patients that had been on anticholinergic treatment before study enrollment. In addition, temporary treatment with systemic corticosteroids, antibiotics, xanthines, nebulized SABAs and anticholinergic agents were allowed for COPD exacerbations1,3
Long-acting anticholinergics, inhaled LABAs, inhaled SABAs other than study rescue medication, oral β2-adrenergic agonists, ephedrine-containing formulations, leukotriene receptor antagonists (LTRAs), xanthine-containing derivatives, disodium cromoglycates, noncardioselective β-blockers, and ICSs were not allowed during the course of the study1
The design of the SHINE study was similar to that of the SUN trial, with the major differences being the SHINE study’s shorter duration (6 months) and the addition of 2 arms: (1) budesonide 160 μg plus formoterol 4.5 μg monocomponents, administered in separate devices, and (2) budesonide 160 µg administered alone.4 Should you choose to present the SHINE study schema, please click the information icon in the lower right-hand corner. After presenting this slide, you will then proceed with the remaining slides
Double-blind
Visit 1 2 3 4 5 6 7 8 FU
Month
-0.5 1 2 4 6 9 12 13
1. Nelson HS et al. Poster 302 presented at: Chest 2008; October 25-30, 2008; Philadelphia, PA. 2. Rennard SI et al. Drugs. 2009;69:
1. Rennard SI, Tashkin DP, McElhattan J, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs. 2009;69:
2. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca LP.
3. Rennard SI, Tashkin DP, McElhattan J, et al. Long-term efficacy of budesonide/formoterol administered in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease. Poster presented at: Chest 2008; October 25-30, 2008; Philadelphia, PA
4. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008;68:

17. SHINE Assessed Efficacy and Tolerability of SYMBICORT Over 6 Months in Patients With COPD
SYMBICORT pMDI
(n=277)
160/4.5 µg  2 Inhalations BID
R A N D O M I Z A T
SYMBICORT pMDI
(n=281)
80/4.5 µg  2 Inhalations BID
Budesonide pMDI 160 µg  2 Inhalations BID +
(n=287)
Run-in
Formoterol DPI 4.5 µg 2  Inhalations BID
Follow-up
Budesonide pMDI
(n=275)
160 µg  2 Inhalations BID
Formoterol DPI
(n=284)
4.5 µg  2 Inhalations BID
SHINE Assessed Efficacy and Tolerability of SYMBICORT Over 6 Months in Patients With COPD
Key Points:
The SHINE study was a 6-month, randomized, double-blind, double-dummy, parallel-group, placebo controlled study that assessed the efficacy and tolerability of SYMBICORT in 1704 patients with COPD1
The design of this study was similar to that of the SUN trial, with the major differences being the shorter duration (6 months) and the addition of 2 arms: (1) budesonide 160 μg plus formoterol 4.5 μg monocomponents, administered in separate devices, and (2) budesonide 160 µg administered alone1
During a 2-week run-in period, patients previously receiving ICS alone or in combination continued with ICS monotherapy, patients previously receiving anticholinergic therapies were placed on stable doses of ipratropium bromide, LABAs were discontinued but as-needed SABAs were allowed1
After the 2-week run-in period, ICS treatment was discontinued, and eligible patients were randomized to one of the following 6 treatments, all of which were dosed BID for 6 months1
SYMBICORT pMDI 160/4.5 μg × 2 inhalations
SYMBICORT pMDI 80/4.5 μg × 2 inhalations
Budesonide pMDI 160 μg × 2 inhalations plus formoterol DPI 4.5 μg × 2 inhalations
Budesonide pMDI 160 μg × 2 inhalations
Formoterol DPI 4.5 μg × 2 inhalations
Placebo × 2 inhalations
Please note that for patients with COPD, the only approved dose is SYMBICORT 160/4.5 µg x 2 inhalations BID2
Study rescue medication (albuterol) for as-needed use throughout the randomized treatment period was allowed in all patients, as was ipratropium bromide pMDI for only those patients that had been on anticholinergic treatment before study enrollment. In addition, temporary treatment with systemic corticosteroids, antibiotics, xanthines, nebulized SABAs and anticholinergic agents were allowed for COPD exacerbations. Other allowed medications included ephedrine- and bronchodilator-free antitussives and mucolytics, nasal corticosteroids, oral or ophthalmic cardioselective β-blockers1
Long-acting anticholinergics, inhaled LABAs and SABAs other than study rescue medication, oral β2-adrenergic agonists, ephedrine-containing formulations, leukotriene receptor antagonists (LTRAs) and 5-lipoxygenase inhibitors, xanthine-containing derivatives (except as allowed for exacerbations), disodium cromoglycates, noncardioselective β-blockers, and ICSs other than the study medication were not allowed during the course of the study1
Placebo  2 Inhalations BID
(n=300)
Double-blind FU
Visit 1 2 3 4 5 6
Month
-0.5 1 2 4 6 7
Adapted from Tashkin DP et al. Drugs. 2008;68:
1. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008;68:
2. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca LP.

18. COPD Efficacy Variables Included Measures of Stabilization and Bronchodilation1-3
Comparison
Demonstrated
SYMBICORT
Versus
Predose FEV1
160/4.5 µg x 2 inhalations BID
and
80/4.5 µg x 2 inhalations BID
Formoterol 4.5 µg x 2 inhalations BID (SUN and SHINE)
Stabilizing, anti-inflammatory effect, largely contributed by budesonide
1-hour Postdose FEV1
Budesonide 160 µg x 2 inhalations BID (SHINE) and Placebo (SUN)
Bronchodilatory effect, largely contributed by formoterol
COPD Efficacy Variables Included Measures of Stabilization and Bronchodilation
Key Points:
Primary efficacy variables were predose FEV1 and 1-hour postdose FEV1 values1-3
Predose FEV1 was measured to demonstrate the stabilizing, anti-inflammatory effects of budesonide, and 1-hour postdose FEV1 was measured to demonstrate the bronchodilatory effects of formoterol1-3
Predose FEV1 and 1-hour postdose FEV1 were assessed on the day of randomization, and at months 1, 2, 4, 6, 9, and 121,3
For both variables, the change from baseline to the average over the treatment period was assessed1,3
For predose FEV1, SYMBICORT 160/4.5 µg x 2 inhalations BID and SYMBICORT 80/4.5 µg x 2 inhalations BID were compared with formoterol 4.5 µg x 2 inhalations BID1-3
For 1-hour postdose FEV1, SYMBICORT 160/4.5 µg x 2 inhalations BID and SYMBICORT 80/4.5 µg x 2 inhalations BID were compared with budesonide (in the SHINE study)3 and placebo (in the SUN study)1
1. Rennard SI et al. Drugs. 2009;69: Data on File, , AZPLP. 3. Tashkin DP et al. Drugs. 2008;68:
1. Rennard SI, Tashkin DP, McElhattan J, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs. 2009;69:
2. Data on File, , AZPLP.
3. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008;68:

19. SUN Patient Demographic and Baseline Clinical Characteristics1,2
Treatment Group, Mean
SYMBICORT 160/4.5 µg (n=494)
SYMBICORT 80/4.5 µg (n=494)
Formoterol 4.5 µg (n=495)
Placebo (n=481)
Total (N=1964)
FEV1, L (SD)
1.02 (0.39)
1.04 (0.39)
1.03 (0.40)
1.08 (0.42)
1.04 (0.40)
Predicted FEV1, % (SD)
33.8 (11.4)
34.5 (11.5)
33.7 (11.3)
35.5 (11.9)
34.4 (11.6)
Reversibility ≥12% + D in FEV1 ≥0.2L, n (%)
150 (30.4)
144 (29.1)
158 (31.9)
153 (31.8)
605 (30.8)
Postbronchodilator† Predicted FEV1, n (%)
<30%
120 (24.3)
94 (19.0)
119 (24.0)
90 (18.7)
423 (21.5)
≥30% to <50%
290 (58.7)
314 (63.6)
285 (57.6)
298 (62.0)
1187 (60.4)
≥50% to <80%
84 (17.0)
85 (17.2)
89 (18.0)
91 (18.9)
349 (17.8)
≥80%
1 (0.2)
2 (0.1)
SUN Patient Demographic and Baseline Clinical Characteristics
Key Points:
Demographic and baseline characteristics of patients were similar between treatment groups in the SUN study1,2
Note that the degree of reversibility at baseline was low (only 30.8% of patients had ≥12% reversibility with ≥0.2L change in FEV1)1
In addition, >80% of the study population had postbronchodilator predicted FEV1 <50%1
Patient demographics and baseline clinical characteristics were similar for the SHINE study3
The study included patients aged 40 to >80 years, with a mean age of 63 years2
The median smoking history of all patients was 40 pack-years2
Please note that the efficacy slides that follow are based on results of the SUN trial
Note: mean age was ~63 years and ~64% of subjects were male. *Safety analysis set. †Data were missing for 3 subjects.
1. Rennard SI et al. Drugs. 2009;69: Data on File, AZPLP.
1. Data on File, , AZPLP.
2. Rennard SI, Tashkin DP, McElhattan J, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs. 2009;69:
3. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008;68:

20. SYMBICORT Significantly Improved Lung Function as Early as Day 1, Which Was Sustained Over 12 Months1,2
Predose FEV1
140
120
SYMBICORT 160/4.5 µg (n=471) *
100 80
Adjusted Mean Change From Baseline (mL) 60
Formoterol 4.5 µg (n=465) 40 20
Placebo (n=436)
SYMBICORT Significantly Improved Lung Function as Early as Day 1, Which
Was Sustained Over 12 Months
Key Points:
SYMBICORT provided improvement in predose FEV1 (average over the treatment period) for a sustained maintenance effect over 12 months1,2
Other measures of lung function included 1-hour postdose FEV1 (primary variable) and AM PEF (secondary variable)1,2
As early as day 1, SYMBICORT significantly improved 1-hour postdose FEV1 and AM PEF (P<.001 vs placebo, data not shown)1,2
Improvements in predose FEV1 were observed in patients treated with SYMBICORT 160/4.5 µg x 2 inhalations BID1,2
When compared with formoterol, this increase was statistically significant (P=.008)1,2
This graph shows the adjusted mean change from baseline in predose FEV1. This graph demonstrates improvements in predose FEV1 after the first month for both SYMBICORT 160/4.5 µg and formoterol, while it worsened in patients taking placebo1,2
Consistent with the approved labeling for COPD, this presentation will focus on efficacy data for the SYMBICORT 160/4.5 µg x 2 inhalations BID arm (specifically, data from the year-long SUN study)
-20 1 2 3 4 5 6 7 8 9 10 11 12
AOT
Month
SUN: A 12-month Efficacy and Safety Study
*P<.008 vs FM. (P value based on ANCOVA analysis) AOT = average of the randomized treatment period.
1. Rennard SI et al. Drugs. 2009;69: Data on File, , AZPLP.
1. Rennard SI, Tashkin DP, McElhattan J, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs. 2009;69:
2. Data on File, , AZPLP

21. SYMBICORT Rapidly Improved Lung Function Within 5 Minutes of the First and Subsequent Doses
Improvement in Serial FEV1 Within 5 Minutes
SYMBICORT 160/4.5 µg x 2 Inhalations BID (n=121)
Mean Percent Change From Baseline in FEV1
Baseline 0 5 10 15 20 35 25 30
Maintenance Effect
First Dose (day of randomization)
Last Dose (end of month 12, LOCF)
SYMBICORT Rapidly Improved Lung Function Within 5 Minutes of the First
and Subsequent Doses
Key Points:
SYMBICORT improved lung function within 5 minutes, peaked in 2 hours, and continued to work over the 12-hour dosing cycle1
Within 5 minutes of the first dose, SYMBICORT provided significant bronchodilation (17.7% [150 mL] improvement in FEV1 over baseline)1
After 12 months of treatment, SYMBICORT continued to provide significant bronchodilation within 5 minutes (21.8% [200 mL] improvement in FEV1 over baseline)1
SYMBICORT is not a rescue medication and does NOT replace fast-acting inhalers2
In interpreting these data, please note that1
Baseline is defined as the predose FEV1 on the day of randomization
Maintenance effect is defined as an 8.7% mean improvement in FEV1 prior to last dose
Should you choose to present comparator arm data, please click the information icon in the lower right-hand corner. After presenting these data, you will then proceed with the remaining slides
Within 5 Min Postdose 2 4 6 8 10 12
Hours 15 3 30
Minutes 1
LOCF = last observation carried forward.
Data on File, , AZPLP.
SUN: A 12-month Efficacy and Safety Study
1. Data on File, , AZPLP.
2. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca LP. 21

22. SYMBICORT Rapidly Improved Lung Function Within 5 Minutes of the First and Subsequent Doses
Improvement in Serial FEV1 Within 5 Minutes
SYMBICORT 160/4.5 µg x 2 Inhalations BID (n=121) 35 30
First Dose (day of randomization)
Last Dose (end of month 12, LOCF) 25
Mean Percent Change From Baseline in FEV1 20 15 10
Maintenance Effect
Comparator Arms
Mean Percent Improvement in 5 Minutes
Day of Randomization
SYM 160/4.5 µg: 17.7%
FM: 16.5%
Placebo: 1.7%
End of Treatment
SYM 160/4.5 µg: 21.8%
FM: 15%
Placebo: 1.9%
SYMBICORT Rapidly Improved Lung Function Within 5 Minutes of the First
and Subsequent Doses
Key Point: SYMBICORT improved lung function within 5 minutes, peaked in
2 hours, and continued to work over the 12-hour dosing cycle
This slide shows the improvement in postdose FEV1 within 5 minutes of the first dose and at the end of the 12 months of treatment for each of the comparator arms
Patients taking SYMBICORT 160/4.5 µg had a 17.7% (150 mL) improvement in FEV1 within 5 minutes of the first dose. In comparison, on the first day, patients in the formoterol and placebo arms experienced 16.5% (140 mL) and 1.7% (10 mL) improvements in mean postdose FEV1 respectively
At the end of 12 months, patients in the SYMBICORT 160/4.5 µg arm had a 21.8% (200 mL) improvement in FEV1 within 5 minutes, while patients in the formoterol and placebo arms experienced 15% (130 mL) and 1.9% improvements in mean postdose FEV1 respectively
In interpreting these data, please note that
Baseline is defined as the predose FEV1 on the day of randomization
Maintenance effect is defined as an 8.7% (90 mL) mean improvement in FEV1 prior to last dose 5
Baseline 0
Within 5 Min Postdose 15 30 1 2 3 4 6 8 10 12
Minutes
Hours
Data on File, , AZPLP.
SUN: A 12-month Efficacy and Safety Study
Data on File, , AZPLP. 22

23. SYMBICORT Significantly Reduced Overall Daily COPD Symptoms by 35% Versus Formoterol Over 12 Months
Overall Symptoms*
Breathlessness*
Cough†
Sputum‡
35%
28%
33%
42% 10
Adjusted Mean Change From Baseline (% Improvement Versus Formoterol) 20 30 40
SYMBICORT Significantly Reduced Overall Daily COPD Symptoms by 35% Versus
Formoterol Over 12 Months
Key Points:
SYMBICORT significantly reduced daily overall COPD symptoms by 35% versus formoterol over 12 months (P=.03)
COPD symptoms included breathlessness, cough, and sputum, which were all reduced over 12 months versus formoterol
Breathlessness scores were assessed and recorded in patients’ Breathlessness Diaries. These data are based on the Breathlessness, Cough, and Sputum Scale (BCSS), which is a validated 3-item questionnaire designed to assess patients’ daily respiratory symptoms. Patients were asked one question each about the severity of their breathlessness, cough, and sputum. Symptoms were evaluated on a 5-point Likert scale from 0 to 4, where higher scores indicate more severe symptoms
The overall BCSS measurement is a secondary variable, with the primary comparison being SYMBICORT vs placebo
The first bar on the left indicates improvement in the composite BCSS versus formoterol, while the 3 bars on the right indicate improvement in the individual parameters that make up the BCSS
Compared to placebo, SYMBICORT reduced overall BCSS by 124%, breathlessness by 118%, cough by 88%, and sputum by 183%
Should you wish to present more information about the BCSS and its validation, please click the information icon in the lower right-hand corner. After presenting that information, you will then proceed with the remaining slides 50
Symptoms
SUN: A 12-month Efficacy and Safety Study
Comparison is SYMBICORT 160/4.5 µg x 2 inhalations BID (n=489) versus formoterol 4.5 µg x 2 inhalations BID (n=489).
*P=.03. †P=.04. ‡P=.15.
Data on File, , AZPLP.
Data on File, , AZPLP.

24. BCSS: A Validated Measure of Common COPD Symptoms
The BCSS is a reliable and validated 3-item questionnaire
Designed to assess patients’ daily respiratory symptoms
Underwent a rigorous validation process designed by AstraZeneca
Patients are asked to record the severity of three common COPD symptoms:
Breathlessness
Cough
Sputum
Symptoms are evaluated on a 5-point Likert-type scale ranging from 0 to 4, with higher scores indicating more severe symptoms
BCSS: A Validated Measure of Common COPD Symptoms
Key Point: BCSS is a reliable and validated patient-reported measure for evaluating
the severity of three of the most common symptoms associated with COPD
BCSS is a novel questionnaire for assessing three of the most common COPD symptoms, breathlessness, cough and sputum production. Although there are other instruments used in clinical practice and research settings, such as the BDI/TDI (Baseline Dyspnea Index/Transition Dyspnea Index), the MRC (Medical Research Council) Dyspnea Scale, the Oxygen Cost Diagram and the Borg Scale, they only assess breathlessness and do not assess cough or sputum production
Patients are asked to record responses to three questions on a daily basis:
How much difficulty did you have breathing today?
How was your cough today?
How much trouble was your sputum today?
Each of the three symptoms is evaluated on a 5-point Likert-type scale ranging from 0 to 4, where a higher score indicates a more severe symptom. The total score, which is the composite of these individual symptom scores, can therefore range from 0 to 12
The BCSS has been validated in a study with patients with COPD. BCSS scores significantly correlated with lung volume functions (percent predicted FEV1 and PEF), sputum volumes, modified Borg scale and indicators of HRQL (health-related quality of life), such as the SGRQ (St. George’s Respiratory Questionnaire) and the SF-36 (Short-form 36) Health Survey
Leidy NK et al. Respir Med. 2003;97(suppl A):S59-S70.
Leidy NK, Schmier JK, Jones MKC, et al. Evaluating symptoms in chronic obstructive pulmonary disease: validation of the Breathlessness, Cough, and Sputum Scale©. Respir Med. 2003;97(suppl A):S59-S70.

25. SYMBICORT Reduced Total Daily Rescue Medication Use Over 12 Months
SYMBICORT 160/4.5 µg x 2 Inhalations BID
Formoterol 4.5 µg x 2 Inhalations BID
-0.2
-0.4
LS Mean Change From Baseline (inhalations/day)
-0.6
-0.8
SYMBICORT Reduced Total Daily Rescue Medication Use Over 12 Months
Key Point: SYMBICORT significantly reduced total daily rescue medication
use by 56% (P=.019) over 12 months versus formoterol1
SYMBICORT is not a rescue medication and does NOT replace fast-acting inhalers2
This graph demonstrates that a reduction in total daily rescue medication use was observed in patients treated with SYMBICORT pMDI 160/4.5 µg x 2 inhalations BID compared with formoterol 4.5 µg x 2 inhalations BID (P=.019)1
The LS mean reduction in total daily rescue medication use was 1.0 inhalations/day for SYMBICORT compared to 0.64 inhalations/day with formoterol1
-1.0 *
-1.2
(n=490)
(n=489)
SUN: A 12-month Efficacy and Safety Study
*P=.019.
Data on File, , AZPLP.
1. Data on File, , AZPLP.
2. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca LP.

26. Adverse Event Profile for SYMBICORT
Adverse Events Reported by ≥3% of Subjects in Any Treatment Group
SYMBICORT 160/4.5 µg (n=771) %
Budesonide 160 µg (n=275) %
Formoterol 4.5 µg (n=779) %
Placebo (n=781) %
COPD-related respiratory events
13.4
12.4
17.1
14.3
Nasopharyngitis
7.3
3.3
5.8
4.9
Oral candidiasis
6.0
4.4
1.2
1.8
Bronchitis
5.4
4.7
4.5
3.5
Sinusitis
1.5
3.1
Viral upper respiratory tract infection
3.6
2.7
Pneumonia
2.3
2.6
Adverse Event Profile for SYMBICORT
Key Points:
The percentage of patients with drug-related adverse events was low and similar across treatment groups
The adverse event profile for SYMBICORT was comparable to placebo
The chart on this slide shows adverse events reported by >3% of subjects in any treatment group and includes pooled safety data from both SUN and SHINE
It is important to note that the greater and earlier discontinuation rate for the monoproduct and placebo groups could be translated into fewer opportunities for these discontinued subjects to report adverse events
“COPD-Related Respiratory Events” included bronchitis, cough, increased sputum, breathlessness, and wheezing. The sign/symptom qualified as an adverse event if it was serious, the subject discontinued the study due to the sign or symptom, and/or the sign or symptom was new or not consistent with the subject’s preexisting COPD history, and the subject was not treated with oral steroids or hospitalized for these symptoms
Represents pooled data from both SUN and SHINE studies, at a dose of 2 inhalations BID.
Data on File, , AZPLP.
Data on File, , AZPLP.

27. Other Safety Findings for SYMBICORT in COPD
No Clinically Important Differences Between SYMBICORT pMDI 160/4.5 µg and Placebo Were Observed in the Following Parameters1-3
Vital signs
Physical examination
ECG
24-hour urinary cortisol
Bone mineral density*
Lenticular opacities and intraocular pressure*
Other Safety Findings for SYMBICORT in COPD
Key Point: No clinically important changes in vital signs, or other physical
examination, laboratory, or ECG measures, were observed in patients taking
SYMBICORT pMDI 160/4.5 µg x 2 inhalations BID1-3
In addition to the adverse events described earlier, investigators looked at several other important safety parameters, including vital signs, cardiovascular assessments, ophthalmologic examinations, and laboratory data1-3
No clinically important abnormalities were observed in ECG variables, including QT prolongation, with similar proportions of patients across all treatment groups experiencing QTc intervals ≥450 msec1
24-hour urinary cortisol changes were not considered clinically important, and clinically significant changes were not seen in physical examinations1,2
In the SUN study, clinically significant changes in ophthalmologic assessments were infrequent with no clinically important differences between groups1
Additionally, BMD was stable over the SUN study’s 12-month treatment period3
*As reported in SUN only.
1. Rennard SI et al. Poster 308 presented at: Chest 2008; October 25-30, 2008; Philadelphia, PA.. 2. Tashkin DP et al. Drugs. 2008;68: Rennard SI et al. Drugs. 2009;69:
1. Rennard SI, Tashkin DP, McElhattan J, et al. Long-term efficacy of budesonide/formoterol administered in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease. Poster presented at: Chest 2008; October 25-30, 2008; Philadelphia, PA.
2. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008;68:
3. Rennard SI, Tashkin DP, McElhattan J, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs. 2009;69:

28. SYMBICORT: Important Safety Information
Particular care is needed for patients being transferred from systemically active corticosteroids to inhaled corticosteroids
Patients who are receiving SYMBICORT should not use additional formoterol or other long-acting inhaled beta2-agonists for any reason
Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids, including budesonide, a component of SYMBICORT
Long-term use of orally inhaled corticosteroids, such as budesonide, a component of SYMBICORT, may affect normal bone metabolism resulting in a loss of bone mineral density
Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of inhaled corticosteroids, including budesonide, a component of SYMBICORT
Caution should be exercised when considering the coadministration of SYMBICORT with long-term ketoconazole and other known potent CYP3A4 inhibitors
SYMBICORT should be administered with caution in patients being treated with MAO inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents
WARNING: Long-acting beta2-adrenergic agonists may increase the risk of asthma-related death. Therefore, when treating patients with asthma, SYMBICORT should only be used for patients with asthma not adequately controlled on other asthma-controller medications (eg, low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies. Data from a large placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol may apply to formoterol (a long-acting beta2-adrenergic agonist), one of the active ingredients in SYMBICORT (see WARNINGS in full Prescribing Information)
SYMBICORT: Important Safety Information
Key Point: To help ensure patient safety, some additional considerations should be made when
prescribing SYMBICORT
Particular care is needed for patients being transferred from systemically active corticosteroids to inhaled corticosteroids
Patients who are receiving SYMBICORT should not use additional formoterol or other long-acting inhaled beta2-agonists for any reason
Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids, including budesonide, a component of SYMBICORT
In 2 placebo-controlled SYMBICORT COPD clinical studies, pneumonia did not occur with greater incidence in the SYMBICORT 160/4.5 group compared with placebo, while the incidence of lung infections other than pneumonia (eg, bronchitis) was slightly higher for SYMBICORT than placebo
Long-term use of orally inhaled corticosteroids, such as budesonide, a component of SYMBICORT, may affect normal bone metabolism resulting in a loss of bone mineral density
Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of inhaled corticosteroids, including budesonide, a component of SYMBICORT
Caution should be exercised when considering the coadministration of SYMBICORT with long-term ketoconazole and other known potent CYP3A4 inhibitors
SYMBICORT should be administered with caution in patients being treated with MAO inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents
WARNING: Long-acting beta2-adrenergic agonists may increase the risk of asthma-related death. Therefore, when treating patients with asthma, SYMBICORT should only be used for patients with asthma not adequately controlled on other asthma-controller medications (eg, low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies. Data from a large placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol may apply to formoterol (a long-acting beta2-adrenergic agonist), one of the active ingredients in SYMBICORT (see WARNINGS in full Prescribing Information)

29. Approved Dosage for Patients With COPD
160/4.5 µg, 2 inhalations twice daily*
Approved Dosage for Patients With COPD
Key Points:
The approved COPD maintenance dosage is SYMBICORT 160/4.5 µg, 2 inhalations twice daily, administered in the morning and in the evening
To further simplify dosing, SYMBICORT has an actuation counter
The actuation counter is attached to the top of the metal canister and indicates the number of inhalations (puffs) remaining
The counter counts down toward zero each time an actuation is released. When the arrow approaches 20, it enters a yellow-colored zone which reminds patients that it is time to refill the medication
SYMBICORT should be discarded after the counter reaches zero, indicating that the patient has used the number of inhalations on the product label and box
To remove any excess medication, patients should rinse their mouth with water after each dose
SYMBICORT 160/4.5 μg is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with COPD including chronic bronchitis and emphysema
SYMBICORT is not a rescue medication and does NOT replace fast-acting inhalers
SYMBICORT 160/4.5 μg is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema
SYMBICORT is not a rescue medication and does NOT replace fast-acting inhalers
*Administered in the morning and in the evening.
SYMBICORT [package insert]. Wilmington, DE: AstraZeneca LP.
SYMBICORT [package insert]. Wilmington, DE: AstraZeneca LP.

30. Rapid Improvement in Lung Function and Long-lasting Control
Rapid Improvement in Lung Function and Long-lasting Control* With SYMBICORT Can Help Patients Do More
SYMBICORT significantly improved lung function as early as day 1, which was sustained over 12 months1
SYMBICORT rapidly improved lung function within 5 minutes† of the first and subsequent doses2
SYMBICORT significantly reduced overall daily COPD symptoms by 35% vs formoterol over 12 months3
Rapid Improvement in Lung Function and Long-lasting Control* With SYMBICORT Can Help
Patients Do More
Key Points:
SYMBICORT significantly improved lung function as early as day 1, which was sustained over 12 months1
SYMBICORT rapidly improved lung function within 5 minutes† of the first and subsequent doses2
SYMBICORT significantly reduced overall daily COPD symptoms by 35% vs formoterol over 12 months3
SYMBICORT 160/4.5 μg is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with COPD including chronic bronchitis and emphysema4
SYMBICORT is not a rescue medication and does NOT replace fast-acting inhalers4
Some important notes regarding formulary/managed care coverage for SYMBICORT
Nationwide, over 80% of patients with prescription drug coverage for SYMBICORT pay a Tier 1 or Tier 2 copay‡5
Please ask participants to defer all managed care questions to the AstraZeneca pharmaceuticals sales specialist (PSS) at the conclusion of the meeting
*In a 12-month clinical study, SYMBICORT improved predose FEV1, 1-hour postdose FEV1, serial FEV1 (to measure onset of effect), AM and PM peak expiratory flow (PEF), and reduced COPD symptoms and rescue albuterol use. †Significant bronchodilation (>15% improvement in FEV1) occurred within 5 minutes.
1. Data on File, , AZPLP. 2. Data on File, , AZPLP Data on File, , AZPLP.
*In a 12-month clinical study, SYMBICORT improved predose FEV1, 1-hour postdose FEV1, serial FEV1 (to measure onset of effect), AM and PM peak expiratory flow (PEF), and reduced COPD symptoms and rescue albuterol use. †Significant bronchodilation (>15% improvement in FEV1) occurred within 5 minutes.
‡Individual costs may vary by plan.
1. Data on File, , AZPLP.
2. Data on File, , AZPLP.
3. Data on File, , AZPLP.
4. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca LP.
5. Source: “Patients” means covered lives as calculated by Fingertip Formulary® as of April

31. Comments to AstraZeneca
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