Epinephrine Metered Dose Inhaler: An Essential OTC Asthma Medicine

1
Epinephrine Metered Dose Inhaler An Essential
OTC Asthma Medicine

• Roger G. Berlin, MD, FACP, FACG
• President, Global Scientific Affairs
• Wyeth Consumer Healthcare

FINAL VERSION A 11/12/2009 354 AM
2
Epinephrine MDI Meets All Three Elements for
Essential Use Exemption

• Otherwise unavailable important public health
  benefit
• Small amount of CFCs released
• Significant technical hurdles to reformulation

• Essential Use Exemption

21 CFR 2.125
3
FDA Questions in the Federal Register Meeting
Notice

• Who currently uses OTC epinephrine MDIs?
• How many of these MDIs are used annually?
• What are the alternatives if these products are
  no longer available?
• From literature sources, what is the value of use
  of the product to the users, and why do they use
  it?
• What established treatment guidelines recommend
  the use of OTC epinephrine?
• How many people with asthma do not have ready
  access to prescription medication through health
  care professionals?

4
Contextual Points to Remember

• Available data
• The role of an OTC asthma treatment
• Wyeths commitment to developing alternative to
  CFC propellants

5
Wyeth is Committed to Developing a Non-CFC
Epinephrine MDI

• Actively developing an HFA alternative
• Working expeditiously to develop a replacement
• Requesting product remain available throughout
  transition

6
Agenda

• Epinephrine MDI description, indication, label,
  asthma guidelines
• Public health need
• Published consumer data
• Safety efficacy data
• Amount of CFC emission
• Technical barriers to reformulation
• Summary conclusion

7
Contributing Experts

• Stephen Campbell, JD, MBA
• Senior Vice President, Regulatory
  AffairsAmphastar Pharmaceuticals
• Kenneth Dretchen, PhD
• Professor ChairmanDepartment of
  PharmacologyGeorgetown University Medical
  CenterWashington, DC

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Epinephrine MDI An Asthma Reliever

• Controller
• Corticosteroids
• Leukotriene modifiers
• Cromones
• Long-acting ?-agonists
• Reliever
• Short-acting ?-agonists (epinephrine MDI)

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Epinephrine MDI A Short-Acting Drug With Rapid
Onset

• Non-selective ?-adrenergic agonist with
  ?-agonist activity
• Onset of effect 15 seconds
• Duration of action 30 minutes
• Rapidly metabolized by COMT and MAO
• ?-agonist causes local vasoconstriction
• decreases systemic absorption

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OTC Epinephrine MDI LabelingUses - Indication
Uses for temporary relief of occasional
symptoms of mild asthma wheezing
tightness of chest shortness of breath
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OTC Epinephrine MDI LabelingUse
Do not use unless a doctor said you have asthma
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OTC Epinephrine MDI LabelingWarnings
Warnings Asthma alert Because asthma can be life
threatening, see a doctor if you have more than
2 asthma attacks in a week
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OTC Epinephrine MDI LabelingUse in Children
Directions Children under 4 years of age
consult a doctor Supervise children using this
product
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Primatene Mist
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Primatene WebsiteDirections for Use
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Primatene WebsiteLearning Center
Controlling Asthma Asthma is a serious disease
that affects the way you breathe and should be
diagnosed by a physician
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Primatene WebsiteLearning Center
Asthma Triggers Learn what triggers asthma
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OTC Epinephrine MDI Label is Consistent With
NAEPP Guidelines
19
Epinephrine MDI Long History of Safe and
Effective OTC Use

• NDA approved in 1956
• 183 million canisters sold
• 25 billion dosing episodes
• 4.5 million canisters sold/year
• Used by 2-3 million consumers/year

Translates to 15-20 of U.S. asthmatics
20
Epinephrine MDI Meets the First Element for
Essential Use Exemption

• Otherwise unavailable important public health
  benefit
• Small amount of CFCs released
• Significant technical hurdles to reformulation

• Essential Use Exemption

21 CFR 2.125
21
Epinephrine MDI Provides an Otherwise Unavailable
Important Health Benefit

• Need for rescue medication
• No other FDA-approved OTC MDI reliever
  medication
• Alternatives possibly unsafe/ineffective
• Consumers using OTC MDI in accordance with label
  and consistent with Guidelines

22
Users of OTC Epinephrine MDIs Fall Into Two
Populations

• Sole OTC users
• Dual Rx and OTC users

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Epinephrine MDI Users Tend toHave Mild,
Intermittent Asthma
Kuschner, et al Chest, 1997
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Sole OTC Users Meet NAEPP PFT Definition of Mild
Intermittent Asthma
NAEPP Expert Panel Report, 2002 Kuschner, et al
Chest, 1997
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OTC Use Studied in 601 Specialist Treated
Asthmatic Adults

• Subjects recruited from random sample of
  pulmonary and allergy specialists
• Interview data based on validated questionnaires
• Endpoints assessed
• 12 month prevalence of reported use
• ? 2 ER visits or hospitalization

Blanc, et al J Allergy Clin Immunology, 1997
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FDA-Approved OTC Asthma Medication Not Associated
With Increased ER Visits or Hospitalization
Blanc, et al J Allergy Clin Immunology, 1997
27
Herbal Teas/Medications and Coffee/ Black Tea
Associated With Increased Risk for ER Visits or
Hospitalization
plt0.05
Blanc, et al. J Allergy Clin Immunol 1997
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Nationally Representative Consumer Surveys
Characterize OTC Users

29
Studies on Epinephrine MDI Consumers
30
Studies on Epinephrine MDI Consumers
31
EPI MDI Users are Representative of the US
Population
32
Who Uses OTC Epinephrine MDIs?

• 13.6 million current adult asthma patients1
• 2-3 million (15-20) are users of OTC asthma
  medications2
• 2/3 use OTC in addition to Rx medication
• 1/3 use OTC medications exclusively
• 4.5 million canisters of EPI MDI sold annually3
• 1.5-2.3 canisters / year / user

1. US Centers for Disease Control, Summary
Health Statistics for US Adults 2003, July
2005 2. 1993 Nielsen Health Survey applied to
CDC estimates 3. IRI FDMX YTD 11/6/05 augmented
with WalMart estimated at 27 of FDMW
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Who Uses OTC Epinephrine MDI?
2005 Survey of Asthmatics
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A Perspective on Access to Medical Care and
Prescription Drugs

• 40 million (25) Americans went without
  healthcare when sick due to costs1
• 91 of uninsured and 44 of insured who delayed
  or did not obtain care did so due to cost2
• 59 million (47) working Americans have no paid
  sick leave3
• Asthma medication use decreased 32 when co-pay
  doubled4

1. Budetti, et al The Commonwealth Fund 1999
National Survey of Workers Health Insurance 2.
Reed, et al Issue Brief from HSC, 2002 3. US
Department of Labor, Bureau of Labor Statistics,
Employee Benefits in Private Industry, 1999 4.
Goldman, et al JAMA, 2004
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Access is Why Consumers Use OTC Epinephrine MDI
2005 Survey of Asthmatics
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Access is Why Consumers Use OTC Epinephrine MDI
2005 Survey of Asthmatics
37
Consumers Use Epinephrine MDI According to Label
and Consistent With NAEPP Guidelines
1. 1994 Primatene Usage Study 2. 1994 OTC Usage
Study 3. 1994 Nielsen Household Panel
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Sole OTC Users Tend to Medicate for Rescue
(95 CI)
2005 Survey of Asthmatics
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There is No Other FDA-approved OTC MDI Asthma
Reliever

• Epinephrine MDI is the only FDA-Approved OTC
  "reliever"
• No alternative "reliever" available without a
  prescription has been shown to be effective and
  safe

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Data Support the Important Health Benefit of OTC
Epinephrine MDI

• Epinephrine MDI is an effective bronchodilator
• Safety
• Pharmacology
• Clinical adverse events
• Few reported deaths mostly not related to
  epinephrine MDI

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Efficacy Shown in Three Trials

• Pinnas, et al
• J Clin Pharmacol, 1991
• Dauphinee, et al
• Am Rev Respir Dis, 1994
• Hendeles, et al
• Ann Allergy Asthma Immunol, 2005

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Epinephrine MDI Studied in Moderate to Severe
Asthma

• Design
• R, DB, PC, X-over
• N12 moderate to severe asthma, FEV1 55
• 2 inhalations 1 minute apart, followed by oral
  tablet at 15 minutes
• Efficacy measure
• ?15 increase in FEV1

Pinnas, et al J Clin Pharmacol, 1991
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Epinephrine MDI is Effective in Moderate to
Severe Asthma
1
1













p lt 0.05 vs placebo plt 0.05 vs metaproterenol
Pinnas, et al J Clin Pharmacol, 1991
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Epinephrine MDI Studied in Mild to Moderate
Asthma

• Design
• R, DB, PC, X-over
• N24 mild to moderate asthma, FEV1 65
• Dose
• 2 inhalations epinephrine or placebo
• Second inhalation given 1 minute after first

Dauphinee, et al Am Rev Respir Dis, 1994
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Epinephrine MDI is Effective in Mild to Moderate
Asthma














1
1
plt0.001
Dauphinee, et al Am Rev Respir Dis, 1994
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Epinephrine MDI Studied in Nocturnal Asthma

• Design
• R, X-over, inpatient CRC
• 8 inpatients (aged 20-46 years) with nocturnal
  asthma
• FEV1 on awakening 45 pre-Epi, 44
  pre-albuterol
• Dose
• 2, 4 and 8 inhalations epi or albuterol
• at 17 minute intervals

Hendeles, et al Ann Allergy Asthma Immunol, 2005
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Epinephrine MDI is Effective in Nocturnal Asthma

Labeled dose

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Exaggerated doses
4
2
p 0.01p 0.002
Hendeles, et al Ann Allergy Asthma Immunol, 2005
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Pharmacologic Basis for Safety of Epinephrine MDI

• Extremely low systemic bioavailability
• 5-10 of inhaled dose absorbed
• Rapidly metabolized by
• COMT airways systemic
• MAO systemic
• Plasma levels only elevated with exaggerated
  dosing

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45 Puffs Required to Equal Plasma Levels Seen
With Vigorous Exercise
1. Dahlof, et al Allergy, 1987 2. Warren, et al
Clin Pharmacol Ther, 1986 3. Basic Clinical
Pharmacology, 7th Ed 2004
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Limited Increases in Plasma Levels and Cardiac
Effects with Large Doses

• Large doses (20-45 actuations) required to
  materially increase plasma epinephrine levels
  1,2,3
• Even after 45 actuations mean heart rate
  increased by only 9 beats/min2

• Simons, et al Pediatrics, 2000
• Warren, et al Clin Pharmacol Ther, 1986
• Dahlof, et al Allergy, 1987

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Heart Rate Not Increased After Epinephrine MDI at
4-fold Excess Dose
Labeled dose
Exaggerated doses



8
4
2
p 0.001
Hendeles, et al Ann Allergy Asthma Immunol, 2005
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Examining the 40-Year History of Epinephrine MDI
OTC Use

• 183 million canisters sold
• 25 billion dosing episodes
• Data obtained from
• Wyeth 1964-2005
• AAPCC 1983-2005
• FDA 1969-2005
• Few deaths reported
• 35 fatal cases reported to Wyeth
• 15 fatal cases reported to FDA

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Fatalities Are Rare and Largely Unrelated to
Epinephrine MDI
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Expert Reviews Have Acknowledged Epinephrine MDI
Safety Profile

• Advisory Review Panel on OTC Cold, Cough,
  Allergy, Bronchodilator and Antiasthmatic Drug
  Products
• 1976 FDA Advance Notice of Proposed Rulemaking
• 1986 FDA Final Rule on Bronchodilator Drug
  Products
• 1994 - NDAC on Benefit/Risk of Epinephrine
• 2005 FDA Proposed Amendment of Monograph for
  Over-the-Counter Bronchodilator Drug Products

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AMA Acknowledged a Need for an OTC Asthma Reliever

• the availability of at least one OTC asthma
  quick relief medication allows individuals with
  mild asthma and those who do not have access to
  the health-care delivery system to
  self-medicate.

Council on Scientific Affairs American Medical
Association Chest, 2000
56
FDA Reaffirms Need for OTC Bronchodilator Drugs
in 2005

• FDA continues to believe that people with mild
  asthma can properly use OTC bronchodilator drug
  products to self-treat occasional wheezing,
  shortness of breath, and tightness of chest after
  their asthma has been diagnosed by a physician. .
  .

Proposed Amendment of Monograph for
Over-the-Counter Bronchodilator Drug
ProductsFederal Register, July 13, 2005
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Alternatives For Users of OTC Epinephrine MDIs

• Emergency room visit
• Wait times
• Proximity
• Charge semi-urgent 312, urgent 621
• Alternative medicines or unproven therapies
• Refill through channels
• Physician care

Williams N Engl J Med, 1996
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Epinephrine MDI Provides an Otherwise
Unavailable Important Health Benefit

• Used by approximately 15-20 of US asthmatics
• Effective bronchodilator with favorable safety
  profile and therapeutic index
• Use consistent with NAEPP definitions of mild,
  intermittent asthma
• Access is key -- no other FDA-approved OTC
  "reliever"

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Epinephrine MDI Meets the Second Element for
Essential Use Exemption

• Otherwise unavailable important public health
  benefit
• Small amount of CFCs released
• Significant technical hurdles to reformulation

• Essential Use Exemption

21 CFR 2.125
60
Data Show Ozone Layer is Improving

• A notable result of the analysis is that for
  latitude zones of 40 and above in both
  hemispheres, large positive and significant
  estimates of a change in trend are obtained 1
• Consistent with data from Intergovernmental Panel
  on Climate Change 2
• Established by World Meterological Organization
  and UN Environment Programme

• Reinsel, et al J Geophysical Res, 2004
• IPCC/TEAP Special Report on Safeguarding the
  Ozone Layer, 2005

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Epinephrine MDI Releases Minimal CFC
1. 70 FR 49836 2. IPCC/TEAP Special Report on
Safeguarding the Ozone Layer, 2005
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Epinephrine MDI Meets the Third Element for
Essential Use Exemption

• Otherwise unavailable importantpublic health
  benefit
• Small amount of CFCs released
• Significant technical hurdlesto reformulation

• Essential Use Exemption

21 CFR 2.125
63
HFA Reformulation is a Lengthy and Complex Process

• Challenging formulation development
• Must deliver right amount of drug to right place
  in lung
• Extensive clinical testing to meet FDA
  requirements

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FDA Clinical Development Plan Guidance
Approximately 4 years
15 mo
Clinical Supplies
6 mo
10 mo
PK Study
Dose Ranging Study
15 mo

• Clinical Safety and Efficacy
• Phase III Efficacy
• Phase III Safety
• Exercise-Induced Asthma
• Pediatric

6 mo
NDA Preparation
10 mo
FDA Review
FDA Guidance for Industry, Clinical Development
Programs for MDI and DPI Drug Products, 1994
65
Wyeth 10-Year Efforts to Develop a Non-CFC
Alternative

• Significant technical hurdles
• Highly specialized area of expertise
• Existing HFA formulation patents
• Levels of alcohol and delivery pressure
• Limited commercial opportunity for potential
  partners
• Epinephrine HFA development partner - Amphastar

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HFA Reformulation Ongoing

• Development partner identified
• Amphastar
• Epi HFA prototype development ongoing
• 2 formulations
• Suspension
• Solution
• 6 months stability data

67
Answers to FDA Questions in the Federal Register
Meeting Notice

• 1. Who currently uses OTC epinephrine MDIs?2-3
  million asthmatics currently use OTC epinephrine
  MDIs
• How many of these MDIs are used annually?4.5
  million canisters are used annually
• 3. What are the alternatives if these products
  are no longer available?There are no alternative
  OTC asthma "relievers"

68
Answers to FDA Questions in the Federal Register
Meeting Notice

• From literature sources, what is the value of use
  of the product to the users, and why do they use
  it?The literature and survey data suggest that
  consumers depend on the product due to lack of
  access to Rx medicine or medical care
• 5. What established treatment guidelines
  recommend the use of OTC epinephrine?Epinephrine
  MDI use is consistent with NAEPP guidelines

69
Answers to FDA Questions in the Federal Register
Meeting Notice

• How many people with asthma do not have ready
  access to prescription medication through health
  care professionals?Sole users are less likely to
  have medical and/or prescription coverage
• 1/3 do not have medical coverage
• 40 do not have prescription coverage

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Data Support Safe Effective Product With
Appropriate Use

• Safe and effective
• Appropriate use by consumer
• No other safe and effective OTC alternative

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If Epinephrine MDI Loses Essential Use Exemption.
. .

• 1 million sole OTC users may have no
  FDA-approved safe and effective OTC alternative
• 2 million dual Rx/OTC users may have no backup
  if they run out of, or do not have access to,
  their prescription
• US asthmatics will be without an FDA-approved OTC
  MDI option

72
Epinephrine MDI Meets All Three Elements for
Essential Use Exemption

• Otherwise unavailable important public health
  benefit
• Small amount of CFCs released
• Significant technical hurdles to reformulation

73
The Essential Use Exemption Should Be Maintained

• Epinephrine MDI meets all 3 criteria for
  maintaining the essential use exemption
• Wyeth is developing an HFA alternative to meet
  the needs of the environment and consumers
• Exemption should be maintained