Download Breathe in, Breathe out, How to Pick `em Out: Selecting Inhalers for

Breathe in, Breathe out,
How to Pick ’em Out:
Selecting Inhalers for Patients and Institutions
Nune Zadikian, PharmD
Jeff Endicott, PharmD
University of Vermont Medical Center
April 14, 2016
Objectives
• Differentiate between the mechanisms of
action of common inhaled medications
• Compare and contrast the characteristics of
available inhaled products for prescribing
• Identify key elements involved in selecting
medications for formulary addition
Asthma
• Affects ~7% of Americans
• ~300 million worldwide
• Improved outcomes in recent decades
– More widespread preventive use of ICS
– Introduction of other effective medications
• Airway obstruction caused by airway smoothmuscle constriction and inflammation of the
bronchi
– Cough, SOB, chest tightness, wheezing
New Engl J Med 2009;360:1002-14
http://www.nhlbi.nih.gov/health/health-topics/topics/asthma
Pathophysiology of Asthma
Nature Reviews Drug Discovery 2004;3:831-44
Classifying Asthma Severity
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007
Components of Asthma Management
• Measures of assessment and monitoring
• Education
• Control of environmental and comorbid
conditions
• Pharmacologic therapy
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007
Stepped-Care Approach to Asthma
Treatment
New Engl J Med 2009;360:1002-14
Medications For Asthma
• Categorized into two general classes
– Quick-relief  PRN
• Anticholinergics
• SABAs
• Systemic corticosteroids
– Long-term control  Taken daily
• Inhaled corticosteroids
• Cromolyn sodium and nedocromil
• Immunomodulators
– Omalizumab
• Leukotriene modifiers
• LABAs
• Methylxanthines
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007
Inhaled Medications
Drug Class
Medications
Short Acting Beta-2 agonists
Albuterol, levalbuterol
Long Acting Beta-2 agonists
Formoterol, salmeterol,
indacaterol, vilanterol
(combination)
Inhaled Corticosteroids
Ciclesonide, flunisolide,
mometasone, fluticasone,
beclomethasone,
budesonide
Anticholinergic
Ipratropium
Long-Acting Anticholinergics
tiotropium, aclidinium,
umeclidinium
(combination)
INHALED CORTICOSTEROIDS
(ICS)
Cellular Effects of Corticosteroids
Annals of Internal Medicine 2003;139:359-70
Inhaled Corticosteroids
• Most effective long-term therapy in asthma
• Preventative therapy
– Multiplicity of anti-inflammatory activities
• Suppress generation of cytokines, recruit airway eosinophils and other
inflammatory mediators
• Clinical outcomes
–
–
–
–
Fewer asthmatic symptoms
Increased lung function
Improved asthma specific QOL
Fewer asthmatic exacerbations
• Suppress but do not cure asthmatic inflammation
– Airway inflammation returns to baseline 2 weeks after stopping
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007
Safety of ICS
•
Well tolerated and safe
– Only small amount available for systemic absorption
•
<20% of delivered dose deposited onto airways
– Undergo extensive first-pass metabolic inactivation
– HPA function affected with doses of 88 mcg/day of fluticasone,
•
Not clinically important, long term adverse systemic effects observed with low to medium doses
– At high doses (>1000 mcg/day of beclomethasone or equivalent), risk of skin bruising,
cataracts, elevated intraocular pressure and accelerated loss of bone mass increase
•
Growth retardation in children?
•
Pharyngeal and laryngeal side effects
– Sore throat, coughing, weak/horse voice, candidiasis
•
High-dose ICS effective for severe persistent asthma
– However, dose-response curve for treatment begins to flatten at low to medium doses,
whereas dose-systemic absorption curve is linear
New Engl J Med 2009;360:1002-14
BRONCHODILATORS:
BETA-AGONISTS
Molecular Mechanism of Action of
Bronchodilators
Nature Reviews Drug Discovery 2004;3:831-44
Inhaled Long Acting Beta-Agonists
• Sustained relaxation of airway smooth muscles
– Stimulating β2-receptors  increase cAMP and
antagonize bronchoconstriction
• Lipophilic molecules
– Prolonged retention in lung tissue
– Duration of bronchodilation ~12 h after a dose
• BID administration
• No anti-inflammatory activity
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007
New Engl J Med 2009;360:1002-14
Inhaled Long Acting Beta-Agonists
• Used as adjunct to ICS for providing long-term control of
symptoms
• Reduce daytime and night-time symptoms, improve lung
function, reduce risk of exacerbations, minimize required
dose of ICS
• Not recommended as monotherapy for long-term control
of persistent asthma
– Discontinuation of ICS following LABA initiation results in an
increase in asthma exacerbation
• Use not recommended for acute symptoms or
exacerbations
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007
New Engl J Med 2009;360:1002-14
Chemical Structures
Albuterol
Indacaterol
Salmeterol
Formoterol
Inhaled B2-Agonists
Salmeterol vs Formoterol
• Salmeterol
– Partial agonist
– Onset: 15 min
– Peak effect: 3 h
– Duration: 12 h
• Formoterol
– Full agonist
– More rapid onset
• 3-5 minutes
• Similar to albuterol
– Peak effect: 15 min
– Duration: 12 h
– Less lipophilic
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007.
LABA Adverse Effects
• Cardiovascular effects seen at doses 4-5 times
those recommended
– Tachycardia
– QTc prolongation
– Hypokalemia
• Tremor
• Hyperglycemia
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007.
Safety of LABAs in Asthma
• FDA Black Box Warning
– CT comparing salmeterol vs placebo added to usual
asthma therapy
• Increased risk of asthma-related deaths in patients treated
with salmeterol
– 13/13176 vs 3/13179 treated for 28 weeks
• LABA should not be used as monotherapy as
long-term control in persistent asthma
– Daily use should not exceed 100 mcg salmeterol or 24
mcg formoterol
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007
SABA
• Relax airway smooth muscle
– Onset of action ≤ 5 min
– Peak effect in 30-60 min
– Duration of action of 4-5 hrs
• With regular use ≥ 4 X per day, potency not affected, duration of
action slightly shortened
• Drug of choice
– Acute asthma symptoms and exacerbations
– Exercise induced asthma
• Exist chemically as racemic mixtures
– Therapeutic activity resides in the (R)-enantiomer
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007
SABA
• In mild to moderate asthma, regularly scheduled
albuterol vs PRN albuterol
– No difference in level of asthma control
– No difference in efficacy or side effects
• Regularly scheduled, daily, long-term use not
recommended
• Administering SABA before ICS to improve delivery to
lower airways is unnecessary
• Use not contraindicated in patients on beta-blockers
– Effectiveness may be somewhat diminished
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007
New Engl J Med 2009;360:1002-14
SABA
• Albuterol (salbutamol), levalbuterol
• Decision largely based on cost and patient’s or
physician’s preference
– Levalbuterol
• Only active enantiomer
• When delivered by MDI, has efficacy and side-effect
profile indistinguishable from racemic albuterol
New Engl J Med 2009;360:1002-14
BRONCHODILATORS:
ANTICHOLINERGICS
Mechanism of Action of
Anticholinergics
Anticholinergics
Anticholinergics
• Mechanism of Action
– Block the action of acetylcholine at parasympathetic sites in
bronchial smooth muscle causing bronchodilation
• Ipratropium bromide
– Short acting
– Not FDA approved for asthma
– Has not demonstrated to be effective in
long-term management of asthma
• Tiotropium bromide
– Long acting, once daily for COPD
– Tiotropium Respimat: Has approval
for asthma
Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007
Ipratropium
• Not recommended routinely for quick relief of
asthmatic symptoms
• Takes longer to start working (15-20 min) and
causes less bronchodilation than SABA
• May be used in patients with SABA intolerance
• May be used in treatment of severe asthma
attacks or attacks induced by beta-blockers
New Engl J Med 2009;360:1002-14
CHRONIC OBSTRUCTIVE
PULMONARY DISEASE (COPD)
COPD
• Preventable and treatable disease
• Characterized by progressive airflow limitation caused
by chronic inflammation in the airways and lung
parenchyma
– Main cause: smoking
• ~25% of adults > 40 years have mild airflow obstruction
• Fourth leading cause of death
• 60-85% with mild to moderate disease remain
undiagnosed
Lancet 2012;379:1341-51
Pathophysiology of COPD
NEJM 2010;362:1407-16
Lancet 2012;379:1341-51
Algorithm for Treatment of COPD
NEJM 2004; 350:2689-97
COPD Assessments
• Symptoms
– Modified British Medical Research Council
(mMRC) Questionnaire
• Measure of breathlessness
– COPD Assessment Test (CAT)
• 8-item unidimensional measure of health status
impairment
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global
Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. Available from:
http://www.goldcopd.org/.
mMRC Questionnaire
Grade
Degree of breathlessness related to activities
1
Not troubled by breathlessness except on strenuous exercise
2
Short of breath when hurrying on the level or walking up a slight hill
3
Walks slower than most people on the level, stops after a mile or so, or
stops after 15 minutes walking at own pace
4
Stops for breath after walking about 100 yards or after a few minutes on
level ground
5
Too breathless to leave the house, or breathless when undressing
Stenton C. Occup Med. 2008; 58:226-227
COPD Assessment Test
http://www.catestonline.org/images/pdfs/CATest.pdf. Accessed 2/12/2016.
COPD Assessments
• Spirometric assessment
– Classification of Severity of Airflow Limitation in
COPD
Classification
Spirometric Assessment
GOLD 1: Mild
FEV1 ≥ 80% predicted
GOLD 2: Moderate
50% ≤ FEV1 < 80% predicted
GOLD 3: Severe
30% ≤ FEV1 < 50% predicted
GOLD 4: Very severe
FEV1 < 30% predicted
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global
Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. Available from:
http://www.goldcopd.org/.
4
(C)
(D)
3
2
(A)
(B)
CAT < 10
CAT ≥ 10
≥2
Or ≥ 1 leading to
hospital admission
Risk
(Exacerbation History)
Risk
(GOLD Classification of Airflow
Limitation)
Combined COPD Assessment
1 not leading to
hospital admission
1
Symptoms
mMRC 0-1
mMRC ≥ 2
Breathlessness
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global
Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. Available from:
http://www.goldcopd.org/.
GOLD Initial Pharmacologic Treatment
Patient
Group
Recommended First Choice
Alternative Choice
A
•
•
Short-acting anticholinergic prn or
Short-acting beta 2-agonist prn
•
•
•
Long-acting anticholinergic or
Long-acting beta 2-agonist or
Short-acting beta 2-agonist and short-acting
anticholinergic
B
•
•
Long-acting anticholinergic or
Long-acting beta 2-agonist
•
Long-acting anticholinergic and long-acting beta 2agonist
C
•
Inhaled corticosteroid + long-acting beta 2-agonist
or
Long-acting anticholinergic
•
Long-acting anticholinergic and long-acting beta 2agonist or
Long-acting anticholinergic and phosphodiesterase4 inhibitor or
Long-acting beta 2-agonist and phosphodiesterase4 inhibitor
•
•
•
D
•
•
Inhaled corticosteroid + long-acting beta 2-agonist
and/or
Long-acting anticholinergic
•
•
•
•
Inhaled corticosteroid + long-acting beta 2-agonist
and long-acting anticholinergic or
Inhaled corticosteroid + long-acting beta 2-agonist
and phosphodiesterase-4 inhibitor or
Long-acting anticholinergic and long-acting beta 2agonist or
Long-acting anticholinergic and phosphodiesterase4 inhibitor
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global
Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. Available from:
http://www.goldcopd.org/.
Fluticasone (Flovent, Arunity)
Albuterol (ProAir, Ventolin, Proventil)
Fluticasone/Salmeterol
(Advair)
Beclomethasone (QVAR)
Levalbuterol (Xopenex)
Mometasone/Formoterol
(Dulera)
Budesonide (Pulmicort)
Budesonide/Formoterol (Symbicort)
Fluticasone/Vilanterol (Breo)
Mometasone (Asmanex)
Olodaterol (Striverdi)
Salmeterol (Serevent)
Formoterol (Foradil)
Indacaterol (Arcapta)
Ipratropium/Albuterol (Combivent)
Tiotropium/Olodaterol (Stiolto)
Umeclidinium/Vilanterol (Anoro)
Glycopyrolate/Indacaterol (Ubitron)
Ipratropium (Atrovent)
Umeclidinium (Incruse)
Tiotropium (Spiriva)
Aclidinium bromide (Turdoza)
Glycopyrolate (Seebri)
Anticholinergics
Which drug is best?
Trials
• Olodaterol vs placebo vs formoterol
Koch A. Int J Chron Obstruc Pulm Dis. 2014;9:697-714
Trials
• Olodaterol improved lung function (FEV1) over placebo
– Formoterol also improved lung function over placebo
• Olodaterol improved health-related quality of life
scores compared to placebo(Transitional Dyspnea
Index and St. George’s Respiratory Questionnaire)
– No significant difference seen when comparing formoterol
versus placebo
– No comparison given for olodaterol versus formoterol
• Safety similar between formoterol and olodaterol
Koch A. Int J Chron Obstruc Pulm Dis. 2014;9:697-714
Trials
• “The 24 Hour Lung Function Time Profile of Olodaterol Once
Daily Versus Placebo and Tiotropium in Patients with
Moderate to Very Severe Chronic Obstructive Pulmonary
Disease”
• Outcomes examined change in FEV1
– Tiotropium vs placebo (statistically significant)
– Olodaterol vs placebo (statistically significant)
– Improvements in FEV1 appeared similar between tiotropium and olodaterol
Lange P, et al. J Pulm Respir Med. 2014; 4: 196
Trials
• Umeclidinium/vilanterol (Anoro Ellipta)
– Improvement in FEV1 compared with vilanterol
alone or tiotropium alone
– Improvement in Transition Dyspnea Index
compared to placebo, not to monotherapy
• Aclidinium
– Improvement in FEV1 over placebo
– Improvement in TDI over placebo
Decramer M, et al. Lancet Resp Med. 2014; 2: 472−86
Donohue JF, et al. Resp Res. 2014; 15:78
Kerwin EM, et al. J Chronic Obstruct Pulm Dis. 2012; 9: 90–101
Jones PW, et al. Eur Resp J. 2012; 40: 830–6
Drug Selection
• Randomized, controlled trials are typically
placebo controlled
– No indicators one more efficacious than another
– FDA approval does not require a drug to be more
efficacious than another
• Combination therapies typically compare to
monotherapy
–2>1
FDA Approved Indications
• ICS/LABA
– COPD/Asthma
• Fluticasone/Salmeterol
(Advair)
• Budesonide/Formoterol
(Symbicort)
• Fluticasone/Vilanterol
(Breo)
– Asthma
• Mometasone/formoterol
(Dulera)
• Long-acting
anticholinergics
– COPD/Asthma
• Tiotropium (Spiriva)
– Different doses
– COPD
• Aclidinium bromide
(Turdoza)
• Umeclidinium (Incruse)
• Glycopyrolate (Seebri)
Frequency
• LABA
– Twice daily
• Salmeterol
• Formoterol
– Once daily
• Indacaterol
• Olodaterol
• Vilanterol/Fluticasone
• Long acting
anticholinergics
– Twice daily
• Glycopyrrolate
• Aclidinium
– Once daily
• Tiotropium
• Umeclidinium
Fluticasone (Flovent, Arunity)
Albuterol (ProAir, Ventolin, Proventil)
Fluticasone/Salmeterol
(Advair)
Beclomethasone (QVAR)
Levalbuterol (Xopenex)
Mometasone/Formoterol
(Dulera)
Budesonide (Pulmicort)
Budesonide/Formoterol (Symbicort)
Fluticasone/Vilanterol (Breo)
Mometasone (Asmanex)
Olodaterol (Striverdi)
Salmeterol (Serevent)
Formoterol (Foradil)
Indacaterol (Arcapta)
Ipratropium/Albuterol (Combivent)
Tiotropium/Olodaterol (Stiolto)
Umeclidinium/Vilanterol (Anoro)
Glycopyrolate/Indacaterol (Ubitron)
Ipratropium (Atrovent)
Umeclidinium (Incruse)
Tiotropium (Spiriva)
Aclidinium bromide (Turdoza)
Glycopyrolate (Seebri)
Anticholinergics
Types of Inhalers
• Metered-Dose Inhalers (MDI)
• Soft-Mist Inhalers (Respimat)
• Dry-Powder Inhalers (DPI)
– Single-Dose
• Aerolizer
• HandiHaler
• Neohaler
– Multidose
•
•
•
•
•
•
Diskus
Ellipta
Flexhaler
Pressair
RespiClick
Twisthaler
Device Considerations
Device
Advantages
Disadvantages
Pressurized metered-dose
inhalers (pMDI’s)
• Portable and compact
• Independent of
inspiratory flow
• Reproducible dosing
• Low cost
• Coordination between
actuation and
inspiration
• High oropharyngeal
deposition
Dry powder inhalers (DPI’s) • Portable and compact
• Do not require
coordination (no spacer
needed)
Soft-mist inhalers
• Slow velocity aerosol
• Do not require
coordination (no spacer
needed)
• Inspiratory flow
dependent (less in new
devices)
• Poor dose
reproducibility
• Affected by
environmental factors
• Dose loading into device
Survey
• Recent survey of healthcare providers and
patients examined what influences their
preferences for inhaler devices
• 245 patients with COPD from USA, UK, France,
and Germany
• 504 HCPs from US, UK, France, Italy, and Japan
Molimard M. J Aerosol Med Pulm Drug Deliv. 2015;28:219-28
Survey
Ease of use
Size of inhaler
Dose
recording
Disposable or
recyclable
Doses carried
Dose
confirmation
Once vs twice
daily dosing
Molimard M. J Aerosol Med Pulm Drug Deliv. 2015;28:219-28
Survey
Molimard M. J Aerosol Med Pulm Drug Deliv. 2015;28:219-28
Patient Preference
Molimard M. J Aerosol Med Pulm Drug Deliv. 2015;28:219-28
Provider Preference
Molimard M. J Aerosol Med Pulm Drug Deliv. 2015;28:219-28
Inhalational
flow
Drug
deposition
Aerosol
velocity
Inhaled
drug
particle size
Bonini M, et al.COPD Res and Prac. 2015; 1:9
Deposition
• Inhalation flow
– Failure to inhale slow and deep leads to failure with
pMDI
• Greater impaction of drug
– DPI’s require greater inhalation flows
• Flows > 60 L/min may be necessary for de-aggregation and
dispersion
• Particle size
– 2-5 micron have greatest deposition in bronchial tree
• Aerosol velocity
– Slow-moving velocity achieves greater deposition
Deposition
Before training
After training
Respimat
pMDI
Brand P, et al. Int J of COPD. 2008; 3:763-70
Deposition
• Device selection impacts drug deposition
– All devices (when used appropriately) should be effective
and achieve appropriate clinical response
Drug
formulation
Degree of
airway
obstruction
Inspiratory
flow
Lung
Deposition
Device
usability
Particle size
Patient
ability
Scichilone N, et al. Pulm Pharmacol Ther. 2015; 31:63-7
Feedback
Seebri Prescribing Information. InspiraChamber
prescribing Information. Turdoza Prescribing
Information.
Patient Considerations
• Age, physical, and cognitive ability
–
–
–
–
Coordination of breath and actuation (pMDI)
Dose loading into device (Respimat)
Once vs twice daily dosing
Inspiratory flow dependent (DPI)
• Convenience
– Single vs multi dose
– Need for a spacer
• Cost
• Adherence
– Dose counters
Patient Preference
Formulary
• Continually updated list of medications and
related information
• Includes
– List of medications
– Medication-associated products and devices
– Medication-use policies
– Decision support tools
– Organizational guidelines
American Society of Health-System Pharmacists. ASHP guidelines on the pharmacy and
therapeutics committee and the formulary system. Am J Health-Syst Pharm. 2008; 65:1272–83
Formulary System
• Ongoing process through which an
organization establishes policies
– Use of drug therapies
– Drug-related products
– Identify most medically appropriate and costeffective
• Overseen by Pharmacy & Therapeutics
Committee (P&T)
American Society of Health-System Pharmacists. ASHP guidelines on the pharmacy and
therapeutics committee and the formulary system. Am J Health-Syst Pharm. 2008; 65:1272–83
Formulary System
• Evaluating medications for inclusion on
formulary
– Using evidence-based decision making
• Review, evaluate, and apply the relevant biomedical
literature
– Create a Drug-Evaluation Document or P&T Drug
Monograph
American Society of Health-System Pharmacists. ASHP guidelines on the pharmacy and
therapeutics committee and the formulary system. Am J Health-Syst Pharm. 2008; 65:1272–83
Monograph
• Brand/generic
• FDA approval info
• FDA approved
indications
• Potential non-FDA
approved indications
• Pharmacology/MOA
• Recommended dosage
• PK/PD
• Special populations
• Pregnancy category
• Evidence
– Compare vs alternatives
– Clinical trials (critique)
• Medication safety
assessment
• Pharmacoeconomic
assessment
American Society of Health-System Pharmacists. ASHP guidelines on the pharmacy and
therapeutics committee and the formulary system. Am J Health-Syst Pharm. 2008; 65:1272–83
Need for the drug?
• Prevalence and importance of condition to be
treated
• Does this drug overcome problems with
existing therapies?
• FDA approved indications?
Schiff GD, Galanter WL, Duhig J, et al. PLoS Med. 2012; 9:1-7
Efficacy
• Quality and strength of evidence
• Design of studies
• Patient population
• Conflicting evidence
Schiff GD, Galanter WL, Duhig J, et al. PLoS Med. 2012; 9:1-7
Safety
• Look-alike, sound-alike drugs
• Administration or preparation requirements
• Long term experience with the drug
• Patient monitoring or special precautions
Schiff GD, Galanter WL, Duhig J, et al. PLoS Med. 2012; 9:1-7
Misuse potential
• Existing marketing to consumers/prescribers
for off-label indications
• Difficulty in accurately diagnosing conditions
which the drug is indicated for
• Experience with similar drugs that may be
misused
Schiff GD, Galanter WL, Duhig J, et al. PLoS Med. 2012; 9:1-7
Cost
• Product cost
• Preparation, storage, administration,
monitoring
• Comparative costs/generics available
• Insurance coverage
Schiff GD, Galanter WL, Duhig J, et al. PLoS Med. 2012; 9:1-7
Therapeutic interchange
Safety
• Safe to
change
between
products
Efficacy
• Equally
efficacious
Cost
• Save some
money for
the patient
Therapeutic interchange
• Several ICS/LABA combinations available
– Some have different approvals by the FDA
• Safety
– No major concerns switching between ICS/LABAs
• Efficacy
– One combination product has not been shown to be
superior when inhaler used correctly
• Cost
– Inhaler A = $65.70/15 days
– Inhaler B = $91.40/15 days
– Inhaler C = $59.52/15 days
> $140,000/year
Conclusion
• Inhaled therapies utilize various mechanisms of action to
help control asthma and COPD
– Minor differences between agents exist that afford them their
unique characteristics
• Despite these differences, no drug in the same class has
proven to be more efficacious than another in clinical trials
• Patient and inhaler characteristics need to be considered to
appropriately select products for patients
• Formulary system is in place to ensure the safest, most
efficacious and cost effective treatments for our patients in
the health care system