Longacting 2Agonist Therapy in the Management of COPD

1
Long-acting ?2-Agonist Therapyin the Management
of COPD
FR0621 7/05
2
Definition of Chronic ObstructivePulmonary
Disease (COPD)

• COPD is a disease state characterized by airflow
  limitation that is not fully reversible
• Airflow limitation is usually progressive and may
  be accompanied by airway hyperreactivity
• COPD is an umbrella term used to describe
  irreversible airflow obstruction associated
  primarily with
• Chronic bronchitis (20)
• Emphysema (80)
• Or a combination of chronic bronchitis and
  emphysema

Pauwels RA et al, on behalf of the GOLD
Scientific Committee. Am J Respir Crit Care Med.
20011631256-1276. Petty TL. American Lung
Association. State of the Air 2002. Available at
www.lungusa.org/press/lung_dis/asn_copd.html.
Accessed March 23, 2004.
3
Risk Factors and Genetic Factorsfor COPD

• Risk factors
• Cigarette smoke
• Occupational dusts
• Indoor/outdoor air pollution
• Infections
• Genetic factors
• Alpha1 (a1)-antitrypsin deficiency

Pauwels RA et al, on behalf of the GOLD
Scientific Committee. Am J Respir Crit Care Med.
20011631256-1276.
4
Pathologic Changes in COPD

• Pathologic changes in central and peripheral
  airways, lung parenchyma, and pulmonary
  vasculature
• Chronic inflammation leads to repeated cycles of
  injury and repair of airway wall
• Narrowing of airways lumen due to increasing
  collagen content and scar tissue formation
• Eventual fixed airways obstruction

Pauwels RA et al, on behalf of the GOLD
Scientific Committee. Am J Respir Crit Care Med.
20011631256-1276.
5
Pathologic Changes in COPD (cont'd)
6
Pathologic Changes in COPD (cont'd)

• Destruction of lung parenchyma emphysema
• Ranges from lesions limited to upper lung regions
  to diffuse lesions
• May also involve destruction of pulmonary
  capillary bed
• Initial thickening of intima of pulmonary
  vessels, then increasing amounts of smooth muscle
  and inflammatory cell infiltration as disease
  worsens

Pauwels RA et al, on behalf of the GOLD
Scientific Committee. Am J Respir Crit Care Med.
20011631256-1276.
7
Sequential Physiologic Changesin COPD

• Mucus hypersecretion
• Ciliary dysfunction
• Expiratory airflow limitation ? key to diagnosis
• Peripheral airways obstruction
• Parenchymal destruction
• Pulmonary vascular abnormalities
• Cor pulmonale ? associated with poor prognosis

Chronic cough Chronic sputum production
Produce hypoxemia, then hypercapnia
Pauwels RA et al, on behalf of the GOLD
Scientific Committee. Am J Respir Crit Care Med.
20011631256-1276.
8
Epidemiology and Impact of COPD

• Fourth leading cause of death in the world1
• Overall prevalence 30 to 35 million cases in
  United States2
• 16,000,000 diagnosed
• Approximately as many cases undiagnosed2
• Chronic bronchitis gt14,000,0003
• Emphysema gt1,800,0003

1. Pauwels RA et al, on behalf of the GOLD
Scientific Committee. Am J Respir Crit Care Med.
20011631256-1276. 2. Petty TL. American Lung
Association. State of the Air 2002. Available at
www.lungusa.org/press/lung_dis/asn_copd.html.
Accessed March 23, 2004. 3. American Lung
Association. Epidemiology Statistics Unit
March 2001. Available at http//www.lungusa.org/d
ata/copd/copd1.pdf. Accessed February 22, 2002.
9
Epidemiology and Impact of COPD (cont'd)

• Fourth leading cause of mortality in United
  States
• More than 119,000 deaths annually
• 42 increase in age-adjusted death rate from 1979
  to 1998
• COPD accounted for
• 13.2 million office visits to doctors in 1997
• 668,362 hospitalizations
• Annual estimated cost of COPD 31.9 billion

American Lung Association. Epidemiology
Statistics Unit March 2001. Available at
http//www.lungusa.org/data/copd/copd1.pdf.
Accessed February 22, 2002.
10
Natural History of COPD(Fletcher and Peto)
Never smoked or not susceptible to smoke
Forced Expiratory Volume in1 Second (FEV1) (
of Value at Age 25)
Smoke regularly and susceptible to its effects
Stopped at age 45
Disability
Stopped at age 65
Death

Age (Years)
Death due to irreversible chronic obstructive
lung disease. Reprinted with permission from
Fletcher C, Peto R. Br Med J. 197711645-1648.
11
Percentage Change in Age-adjusted Death Rates,
United States, 1965-1998
CVD cardiovascular disease. Global Initiative
for Chronic Obstructive Lung Disease. Chronic
obstructive pulmonary disease (COPD). Available
at http//www.goldcopd.com/slides/download.ppt.
Accessed February 7, 2003.
12
Increasing Awareness of COPD

• 70 of individuals affected by COPD (15.2
  million) are unaware they have the disease
• Simple everyday tasks become difficult
• May be suffering more than necessary
• The key to disease management education,
  diagnosis, and proper treatment
• National COPD Awareness Month
• Raises awareness about COPD
• Encourages people with symptoms to seek help and
  learn about COPD and treatment options

American Lung Association. President Bush
declares November National COPD Awareness Month.
November 2001. Available at http//www.lungusa.or
g. Accessed December 17, 2002.
13
Signs and Symptoms of COPD

• Chronic cough
• Present intermittently or every day
• Often present throughout the day
• Seldom only nocturnal
• Chronic sputum production
• Any pattern may indicate COPD

Pauwels RA et al, on behalf of the GOLD
Scientific Committee. Am J Respir Crit Care Med.
20011631256-1276.
14
Signs and Symptoms of COPD (cont'd)

• Dyspnea that is
• Progressive
• Persistent
• Described by patient as increased effort to
  breathe, heaviness, gasping
• Worse on exercise or during respiratory infection
• History of risk factors, especially
• Tobacco smoke
• Occupational dusts and chemicals
• Smoke from home cooking or heating fuels
• Chest x-ray seldom diagnostic, but
  high-resolution computed tomography (CT) may aid
  in differential diagnosis

Pauwels RA et al, on behalf of the GOLD
Scientific Committee. Am J Respir Crit Care Med.
20011631256-1276.
15
SpirometryMeasurement of Airflow Limitation

• Helps identify patients in early course of
  disease
• Should be performed for patients with chronic
  cough, sputum production, and risk factors
• Measure forced vital capacity (FVC) and FEV1 and
  calculate FVC/ FEV1 ratio
• Assess severity

Pauwels RA et al, on behalf of the GOLD
Scientific Committee. Am J Respir Crit Care Med.
20011631256-1276.
16
Classification of COPD by Severity

• Stage Characteristics
• Stage 0 At Risk Chronic symptoms, exposure to
  risk factors, normal spirometry
• Stage I Mild FEV1/FVC lt70, FEV1 gt80, with or
  without symptoms
• Stage II Moderate FEV1/FVC lt70, 50 lt FEV1
  lt80, with or without symptoms
• Stage III Severe FEV1/FVC lt70, 30 lt FEV1 lt50,
  with or without symptoms
• Stage IV Very Severe FEV1/FVC lt70, FEV1 lt30 or
  FEV1 lt50 predicted plus chronic respiratory
  failure

National Heart, Lung, and Blood Institute. Global
Strategy for the Diagnosis, Management, and
Prevention of Chronic Obstructive Pulmonary
Disease NHLBI/WHO Workshop - UPDATED 20031-100.
17
Differential Diagnosis of COPD
COPD
ASTHMA

• Onset early in life
• Day-to-day variations in symptoms
• Symptoms at night/early morning
• Allergy, rhinitis, and/or eczema also present
• Family history of asthma
• Largely reversible airflow limitation

• Onset in midlife
• Symptoms slowly progressive
• Long smoking history
• Dyspnea during exercise
• Largely irreversible airflow limitation

National Heart, Lung, and Blood Institute. Global
Strategy for the Diagnosis, Management, and
Prevention of Chronic Obstructive Pulmonary
Disease NHLBI/WHO Workshop - UPDATED 20031-100.
18
COPD Management

• Management Plan
• Assess and monitor disease
• Reduce risk factors
• Manage stable COPD
• Manage exacerbations

• Goals of Effective Management
• Prevent disease progression
• Relieve symptoms
• Improve exercise tolerance
• Improve health status
• Prevent and treat complications
• Prevent and treat exacerbations
• Reduce mortality

National Heart, Lung, and Blood Institute. Global
Strategy for the Diagnosis, Management, and
Prevention of Chronic Obstructive Pulmonary
Disease NHLBI/WHO Workshop - UPDATED 20031-100.
19
Goals of Pharmacologic Therapyfor COPD

• To prevent and control symptoms
• To reduce frequency and severity of exacerbations
• To improve health status
• To improve exercise tolerance

National Heart, Lung, and Blood Institute. Global
Strategy for the Diagnosis, Management, and
Prevention of Chronic Obstructive Pulmonary
Disease NHLBI/WHO Workshop - UPDATED 20031-100.
20
Recommended PharmacologicTherapy for COPD

• Inhaled corticosteroids for moderate-to-severe
  COPD with frequent exacerbations
• Trial with inhaled corticosteroids (6 wk-3 mo) to
  identify candidates for long-term treatment
• Combination of ?2 agonist, anticholinergic, or
  theophylline may produce additional improvements
  in lung function and health status
• No evidence to support use of leukotriene
  antagonists

• Mild (Stage I)
• Short-acting inhaled bronchodilator as needed
• Moderate (Stage II)
• Add regular treatment with one or more
  long-acting inhaled bronchodilators
• Severe (Stage III)
• Add inhaled corticosteroids if repeated
  exacerbations
• Very Severe (Stage IV)
• Add long-term oxygen if chronic respiratory
  failure
• Consider surgical treatments

National Heart, Lung, and Blood Institute. Global
Strategy for the Diagnosis, Management, and
Prevention of Chronic Obstructive Pulmonary
Disease NHLBI/WHO Workshop - UPDATED 20031-100.
21
Pharmacologic Treatment Optionsfor COPD

• Bronchodilators
• ?2 agonists
• Short acting
• Long acting
• Formoterol fumarate inhalation powder
• Salmeterol
• Salmeterol fluticasone dipropionate
• Anticholinergics
• Ipratropium, tiotropium
• Methylxanthines
• Aminophylline, theophylline
• Inhaled glucocorticosteroids

National Heart, Lung, and Blood Institute. Global
Strategy for the Diagnosis, Management, and
Prevention of Chronic Obstructive Pulmonary
Disease NHLBI/WHO Workshop - UPDATED 20031-100.
22
Bronchodilators in Stable COPD

• Central to symptom management
• Inhaled therapy preferred
• Prescribed on as-needed or regular basis to
  prevent or reduce symptoms
• Long-acting bronchodilators more convenient
• Combinations of bronchodilators may improve
  efficacy and reduce risk of side effects versus
  increasing dose of a single agent

National Heart, Lung, and Blood Institute. Global
Strategy for the Diagnosis, Management, and
Prevention of Chronic Obstructive Pulmonary
Disease NHLBI/WHO Workshop - UPDATED 20031-100.
23
Recent Pharmacologic Optionsfor COPD

• SPIRIVA (tiotropium bromide inhalation powder)
• Inhaled anticholinergic agent
• Indicated for long-term, once-daily, maintenance
  treatment of COPD-related bronchospasm
• Mean 28 to 31 peak improvement in FEV1 after 1
  week and maintained consistently in 12-month
  studies
• ADVAIR DISKUS (salmeterol fluticasone
  dipropionate)
• Single-product combination inhalation agent
• Bronchodilatory (?2 agonist) and
  anti-inflammatory (corticosteroid) mechanisms of
  action
• Indicated for twice-daily maintenance therapy of
  airflow obstruction in COPD due to chronic
  bronchitis
• Has not been evaluated in COPD for longer than 6
  months
• Not to be used for treatment of acute symptoms of
  shortness of breath
• Should not be used concomitantly with a
  long-acting ?2 agonist

SPIRIVA product information, Boehringer
Ingelheim, Inc. ADVAIR DISKUS product
information, GlaxoSmithKline.
24
Corticosteroid Usein Stable COPD

• Use of corticosteroids in management of stable
  COPD is limited
• Oral corticosteroids
• Long-term treatment with oral corticosteroids not
  recommended
• Lack of evidence of long-term benefit
• Associated with steroid myopathy (associated with
  muscle weakness, decreased functionality,
  respiratory failure)
• Inhaled corticosteroids
• Do not modify the long-term decline of FEV1
• Added to bronchodilator for severe COPD with
  frequent exacerbations

GOLD Committee, Executive Summary 2004.
25
FORADIL AEROLIZER (formoterol fumarate
inhalation powder)in the Management of COPD
26
Formoterol Fumarate Inhalation Powder

• Capsule dosage form containing a dry powder
  formulation of formoterol fumarate intended for
  oral inhalation only, and only with the
  AEROLIZER inhaler
• Clear, hard gelatin capsule
• 12 mcg formoterol fumarate 25 mg lactose as a
  carrier

FORADIL AEROLIZER prescribing information.
27
Formoterol Fumarate Inhalation Powder Mechanism
of Action

• FORADIL AEROLIZER is a long-acting selective
  ?2-adrenergic receptor agonist (?2 agonist).
  Inhaled formoterol fumarate acts locally in the
  lung as a bronchodilator
• The pharmacologic effects of FORADIL AEROLIZER
  are at least in part attributable to stimulation
  of intracellular adenyl cyclase, the enzyme that
  catalyzes the conversion of adenosine
  triphosphate (ATP) to cyclic-3', 5'-adenosine
  monophosphate (cyclic AMP)
• Increased cyclic AMP levels cause relaxation of
  bronchial smooth muscle and inhibition of release
  of mediators of immediate hypersensitivity from
  cells, especially from mast cells

FORADIL AEROLIZER prescribing information.
28
Formoterol Fumarate Inhalation PowderLong-acting
?2 Agonist

• Formoterol fumarate long-acting ?2 agonist
• Onset of action similar to albuterol
• Indicated for the maintenance treatment of asthma
  and COPD, and prevention of EIB
• Not indicated for acute symptoms of asthma

FORADIL AEROLIZER prescribing information.
29
Salmeterol Xinafoate Long-acting ?2 Agonist

• Salmeterol long-acting ?2 agonist
• Indicated for maintenance treatment of asthma and
  COPD, and prevention of EIB
• Not indicated for acute symptoms of asthma

Serevent prescribing information.
30
Formoterol Fumarate Inhalation PowderChemical
Structures of ?2 Agonists
Drawn from prescribing information for 1.
PROVENTIL HFA (Schering Corporation) 2.
Serevent DISKUS (GlaxoSmithKline) 3. FORADIL
AEROLIZER (Schering Corporation)
31
Formoterol Fumarate Inhalation PowderHydrophilic/
Lipophilic Properties

• Albuterol Hydrophilic
• Reaches receptor through aqueous extracellular
  compartment
• Is easily washed away
• Salmeterol Highly lipophilic
• Binding to the ?2 receptor is delayed
• Prolonged retention at lipophilic receptor
• Formoterol Amphiphilic
• Both hydrophilic and lipophilic properties
• Available in aqueous compartment

Anderson GP. Life Sci. 1993522145-2160.
32
Formoterol Fumarate Inhalation PowderPharmacokine
tic Properties

• Absorption
• Rapidly absorbed into plasma, reaching a maximum
  drug concentration of 92 pg/mL within 5 minutes
  of dosing
• Distribution
• Binding to human plasma proteins in vitro was 61
  to 64
• Metabolism
• Formoterol is metabolized primarily by direct
  glucuronidation at either the phenolic or
  aliphatic hydroxyl group and O-demethylation
  followed by glucuronide conjugation at either
  phenolic hydroxyl groups
• Four cytochrome P450 isozymes (CYP2D6, CYP2C19,
  CYP2C9, and CYP2A6) are involved in the
  O-demethylation of formoterol
• Formoterol did not inhibit CYP450 enzymes at
  therapeutically relevant concentrations
• Excretion
• Systemically absorbed formoterol is eliminated in
  the urine and in the feces over a period of 104
  hours. Unchanged formoterol and the glucuronide
  conjugates are eliminated renally
• The mean terminal elimination half-life was
  determined to be 10 hours

FORADIL AEROLIZER prescribing information.
33
Formoterol Fumarate Inhalation PowderPharmacodyna
mic Properties

• Tolerance to the bronchoprotective effects of
  formoterol was observed as evidenced by a
  diminished bronchoprotective effect on FEV1 after
  2 weeks of dosing, with loss of protection at the
  end of the 12-hour dosing period
• Rebound bronchial hyperresponsiveness after
  cessation of chronic formoterol therapy has not
  been observed

FORADIL AEROLIZER prescribing information.
34
Formoterol Fumarate Inhalation PowderIndications

• Bronchoconstriction in patients with COPD
• Long-term, twice-daily (morning and evening)
  administration in the maintenance treatment of
  patients with COPD, including chronic bronchitis
  and emphysema
• Maintenance treatment of asthma
• Long-term, twice-daily (morning and evening)
  administration in the prevention of bronchospasm
  in adults and children 5 years of age and older
  with reversible obstructive airways disease
  (including patients with symptoms of nocturnal
  asthma) who require regular treatment with
  inhaled, short-acting ?2 agonists
• It is not indicated for patients whose asthma can
  be managed by occasional use of inhaled,
  short-acting ?2 agonists
• Acute prevention of EIB
• Administered at least 15 minutes before exercise,
  on an occasional, as-needed basis in the
  treatment of adults and children 5 years of age
  and older

FORADIL AEROLIZER prescribing information.
35
Formoterol Fumarate Inhalation Powder
Significantly Greater Bronchodilation in COPD
versus Placebo

• Significantly Higher FEV1 With Formoterol as
  Compared With Ipratropium At Most Time Points
  Over 12 Hours After Morning Dose (P0.001)

Last Treatment Day of a 12-Week Treatment Period
(n194)
(n194)
(n200)
Mean FEV1 (L)
? Second dose of ipratropium
At time points 5 and 15 minutes and hours 1, 2,
3, 4, 5, 6, 10, 11, and 12 (P0.001)
Dahl R et al. Am J Respir Crit Care Med.
2001164778-784.
36
Formoterol Fumarate Inhalation Powder
Significant Improvement in Overall Symptom
Scoresfor COPD versus Ipratropium
Patient diary scores on a scale of 0 to 3, with a
maximum of 18 higher scores worse symptoms.
Plt0.001 vs placebo P0.009 vs ipratropium
(n194)
(n194)
(n200)
Dahl R et al. Am J Respir Crit Care Med.
2001164778-784.
37
Formoterol Fumarate Inhalation Powder
Significantly Reduces Use of Rescue Albuterolin
COPD versus Ipratropium
Plt0.001 vs placebo Plt0.014 vs ipratropium
(n194)
(n194)
(n200)
Dahl R et al. Am J Respir Crit Care Med.
2001164778-784.
38
Formoterol Fumarate Inhalation Powder Quality of
Life (QoL) Assessment in COPD

• St Georges Respiratory Questionnaire (SGRQ)
• Total score drawn from three subscores symptoms,
  activity, impacts
• Questionnaire administered at baseline and at
  conclusion of each study
• Formoterol fumarate inhalation powder
• Significantly improved total QoL scores versus
  placebo1
• Significantly reduced the need for rescue
  medicine use versus placebo1
• Effect of ipratropium bromide metered-dose
  inhaler (MDI) on QoL scores did not differ from
  placebo

1. Dahl R et al. Am J Respir Crit Care Med.
2001164 778-784.
38
39
Formoterol Fumarate Inhalation Powder
Significantly Improves QoLin COPD Patients
versus Ipratropium
12-Week Study
n194
Plt0.001 vs placebo Plt0.002 vs ipratropium
n194
SGRQ St. Georges Respiratory Questionnaire
Dahl R et al. Am J Respir Crit Care Med.
2001164778-784.
40
Formoterol Fumarate Inhalation PowderPotential
Role in Management of Acute Exacerbations of COPD

• Clinical evidence of benefits of inhaled ?2
  agonists in treatment of acute exacerbations of
  COPD1
• Greater effect on spirometry than parenterally
  administered bronchodilators
• Significant (Plt0.001), dose-dependent changes in
  FEV1, FVC, and inspiratory capacity (IC) in
  patients with acute exacerbations of COPD
  demonstrated with formoterol fumarate inhalation
  powder2

1. McCrory DC et al. Chest. 20011191190-1209.
2. Cazzola M et al. Clin Drug Invest.
200222369-376.
41
FORADIL AEROLIZERAdverse Events in COPD Trials

• Similar to those reported with other selective ?2
  agonists, such as
• Angina, hypertension or hypotension,
  tachycardia, arrhythmias, nervousness, headache,
  tremor, dry mouth, palpitation, muscle cramps,
  nausea, dizziness, fatigue, malaise, hypokalemia,
  hyperglycemia, metabolic acidosis, and insomnia
• FORADIL AEROLIZER should not be used to treat
  acute symptoms of asthma or used more than twice
  daily. Acute symptoms should be treated with
  inhaled, short-acting selective ?2 agonists
• FORADIL AEROLIZER should be used with caution
  in patients with cardiovascular disorders
• FORADIL AEROLIZER is not a substitute for
  inhaled or oral corticosteroids and in the
  treatment of asthma, they should not be stopped
  or reduced

FORADIL AEROLIZER prescribing information.
42
FORADIL AEROLIZERAdverse Events in COPD Trials
(cont'd)

• Of the 1634 patients in two pivotal
  multiple-dose, controlled trials in COPD, 405
  were treated with FORADIL AEROLIZER 12 mcg
  twice daily. The numbers and percentage of
  patients who reported adverse events were
  comparable in the 12- mcg twice-daily and placebo
  groups. Adverse events experienced were similar
  to those seen in asthmatic patients, but with a
  higher incidence of COPD-related adverse events
  in both placebo- and formoterol- treated patients
• The following slide shows adverse events where
  the frequency of an adverse event was gt1 in the
  FORADIL AEROLIZER group and exceeded placebo.
  The two clinical trials included doses of 12 mcg
  and 24 mcg, administered twice daily
• Seven adverse events showed dose ordering among
  tested doses of 12 and 24 mcg administered twice
  daily pharyngitis, fever, muscle cramps,
  increased sputum, dysphonia, myalgia, and tremor
• Overall, the frequency of all cardiovascular
  adverse events in the two pivotal studies was low
  and comparable to placebo (6.4 for FORADIL
  AEROLIZER 12 mcg twice daily, and 6.0 for
  placebo)
• There were no frequently occurring specific
  cardiovascular adverse events for FORADIL
  AEROLIZER (frequency greater than or equal to 1
  and greater than placebo)

FORADIL AEROLIZER prescribing information.
43
FORADIL AEROLIZEROverall Incidence of Adverse
Events in COPD TrialsSimilar to Placebo

• Number and Frequency of Adverse Events Occurring
  in gt1 of Adult COPD Patients Treated in
  Multiple-Dose Controlled Clinical Trials
• FORADIL? AEROLIZER?, Placebo,
  
• Adverse Event 12 mcg bid (n405)
  (n420)
• Upper respiratory infection 7.4 5.7
• Back pain 4.2 4.0
• Pharyngitis 3.5 2.4
• Chest pain 3.2 2.1
• Sinusitis 2.7 1.7
• Fever 2.2 1.4
• Leg cramps 1.7 0.5
• Muscle cramps 1.7 0
• Anxiety 1.5 1.2
• Pruritus 1.5 1.0
• Increased sputum 1.5 1.2
• Dry mouth 1.2 1.0
• Trauma 1.2 0

43
FORADIL AEROLIZER prescribing information.
44
FORADIL AEROLIZER
AEROLIZER Inhaler
45
FORADIL AEROLIZER Benefits

• Provides feedback confirming that the full dose
  was taken. The patient can

Hear the capsule spin in the inhaler during
inhalation
Feel a mildly sweet taste on the back of the
throat
See that the medication has been inhaled

• Eliminates the need for hand-breath coordination
• 98 of patients were able to use the AEROLIZER
  inhaler correctly in a randomized study of 98
  adult asthma patients

Eliraz A et al. Int J Clin Pract.
200155164-170.
46
FORADIL AEROLIZER Follow the 4 Ps

• Peel paper backing from blister card, and push
  capsule through remaining foil immediately before
  use
• Put capsule in AEROLIZER inhaler chamber and
  twist mouthpiece closed. Never place capsule
  directly into mouthpiece
• Press both side buttons once and release, with
  AEROLIZER inhaler held upright
• Place mouth on mouthpiece and inhale, with
  AEROLIZER inhaler held with blue buttons
  pointing sideways

47
FORADIL AEROLIZER Summary in the Management of
COPD

• Worldwide use for more than a decade
• Significant bronchodilation within 5 minutes and
  duration 12 hours
• Improves pulmonary function tests, symptoms, and
  QoL in COPD patients
• Reduces use of rescue medication versus placebo
• Safe and well tolerated

47