# Presentation: 685464

## Epinephrine Metered Dose Inhaler: An Essential OTC Asthma Medicine

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

- <footer>

## Epinephrine MDI Meets All Three Elements for Essential Use Exemption

**Essential Use Exemption**

** ****21**** ****CFR 2.125**

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

## 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?**

## Contextual Points to Remember

**Available data  **
**The role of an OTC asthma treatment**
**Wyeth’s commitment to developing alternative to CFC propellants**

## 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**

## 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**

## Contributing Experts

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

## Epinephrine MDI: An Asthma Reliever

**Controller**
- Corticosteroids
- Leukotriene modifiers
- Cromones
- Long-acting -agonists
**Reliever **
- Short-acting -agonists (epinephrine MDI)

## 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

## OTC Epinephrine MDI Labeling:Uses - Indication

- OTC Epinephrine MDI Labeling:Uses - Indication

***Uses***
**■** for temporary relief of occasional symptoms of mild asthma:
-      **■ **wheezing
**     ■ **tightness of chest
-      **■ **shortness of breath

## OTC Epinephrine MDI Labeling:Use

- OTC Epinephrine MDI Labeling:Use

***Do not use***
**■** unless a doctor said you have asthma

## OTC Epinephrine MDI Labeling:Warnings 

- OTC Epinephrine MDI Labeling:Warnings

***Warnings***
**Asthma alert: Because asthma can be life threatening, see a doctor if you**
- ■ have more than 2 asthma attacks in a week

## OTC Epinephrine MDI Labeling:Use in Children

***Directions***
- ■ Children under 4 years of age: consult a doctor
- ■ Supervise children using this product

## Primatene Mist

## Primatene Website:Directions for Use

## Primatene Website:Learning Center

***Controlling Asthma***
- Asthma is a serious disease that affects the way you breathe and should be diagnosed by a physician

## Primatene Website:Learning Center

***Asthma Triggers***
- Learn what triggers asthma

## OTC Epinephrine MDI Label is Consistent With NAEPP Guidelines

| Mild Intermittent Asthma |  |
| --- | --- |
| Day Symptoms | Night Symptoms |
|  2 days/week |  2 nights/month |

| All Asthma Patients |  |
| --- | --- |
| Quick Relief | Short-acting bronchodilator:  
2-4 puffs short-acting inhaled beta2-agonists as needed for symptoms |

## 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**

## Epinephrine MDI Meets the First Element for Essential Use Exemption

**Essential Use Exemption**

**21**** ****CFR 2.125**

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

## 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**

## Users of OTC Epinephrine MDIs Fall Into Two Populations

**Sole OTC users**
**Dual Rx and OTC users**

## Epinephrine MDI Users Tend toHave Mild, Intermittent Asthma

| Subject Characteristics | SoleOTCn=15 (%) | Dual Rx/OTC n=13
(%) | Sole Rx n=22
(%) |
| --- | --- | --- | --- |
| Asthma diagnosed by physician | 93 | 92 | 100 |
| Ever hospitalized for asthma | 7 | 38 | 36 |
| Ever visited ER for asthma | 53 | 69 | 64 |
| Mean FEV1 | 90 | 86 | 92 |
| PEFR variability | 10 | 9 | 10 |

**Kuschner, et al;  Chest, 1997**

## Sole OTC Users Meet NAEPP PFT Definition of Mild Intermittent Asthma

**NAEPP Expert Panel Report, 2002**
**Kuschner, et al;  Chest, 1997**

| Subject Characteristics | SoleOTCn=15 (%) | Dual Rx/OTC n=13
(%) | Sole Rx n=22
(%) |
| --- | --- | --- | --- |
| Asthma Diagnosed by Physician | 93 | 92 | 100 |
| Ever hospitalized for asthma | 7 | 38 | 36 |
| Ever visited ER for asthma | 53 | 69 | 64 |
| Mean FEV1 | 90 | 86 | 92 |
| PEFR variability | 10 | 9 | 10 |

## 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**

## FDA-Approved OTC Asthma Medication Not Associated With Increased ER Visits or Hospitalization

**Blanc, et al; J Allergy Clin Immunology, 1997**

| 
Risk Factor | 
% Users |  2 ER Visits |  | Hospitalization |  |
| --- | --- | --- | --- | --- | --- |
|  |  | OR | 95% CI | OR | 95% CI |
| OTC asthma medication | 6 | 0.5 | 0.2-1.5 | 0.8 | 0.3-2.5 |

## Herbal Teas/Medications and Coffee/ Black Tea Associated With Increased Risk  for ER Visits or Hospitalization

| 
Risk Factor | 
% Users |  2 ER Visits |  | Hospitalization |  |
| --- | --- | --- | --- | --- | --- |
|  |  | OR | 95% CI | OR | 95% CI |
| Herbal teas and medications | 7.7 | 1.2 | 0.5-2.7 | 2.5* | 1.1-5.6 |
| Coffee or black tea | 6.0 | 3.1* | 1.3-7.1 | 3.1* | 1.2-7.8 |

**Blanc, et al. J Allergy Clin Immunol 1997**

- *p<0.05

## Nationally Representative Consumer Surveys Characterize OTC Users

| Study |  | Number of Asthmatics | Number of OTC Users |
| --- | --- | --- | --- |
| 1993 Nielsen Health Study |  | 2713 | 557 |
| 1994 Nielsen Household Panel  |  | 575 | 575 |
| 1994 OTC Usage |  | 525 | 525 |
| 1994 Primatene Usage |  | 123 | 123 |
| 2005 Survey of Asthmatics  |  | 396 | 164 |
|  | Totals | 4332 | 1944 |

## Studies on Epinephrine MDI Consumers

| 1993 Nielsen Health Study |  |  |
| --- | --- | --- |
| Mail questionnaire, sample of 61,000 adults | 2,713 past 12 month asthmatics
557 OTC asthma medication users | Ailments 
How treated
Reasons for treatment choices |
| 1994 Nielsen Household Panel |  |  |
| 40,000 households, regular reporters of UPC-coded purchases | 575 purchasers of OTC asthma medication over 12-month period | Purchase incidence and frequency
 |

## Studies on Epinephrine MDI Consumers

| 1994 OTC Usage Study |  |  |
| --- | --- | --- |
| Telephone interviews of adult asthmatics | 827 asthmatics ever treated with OTC 
525 past year users | Symptom profile
Brands/products used
Physician involvement |
| 1994 Primatene Usage Study |  |  |
| Telephone interviews | 123 past year users  | Symptom profile
Physician involvement |
| 2005 Survey of Asthmatics |  |  |
| Internet survey to ID asthmatics, sample balanced to reflect US Census | 390 asthmatics who had an attack in the past year  | Symptom profile
Brands/products used
Physician involvement
Medical/Rx coverage |

## EPI MDI Users are Representative of the US Population

|  | Nielsen Survey 1993 | Nielsen Panel 1994 | OTC Usage 1994 | Primatene Usage 1994 | Asthmatics
 2005 |
| --- | --- | --- | --- | --- | --- |
| Age (%)     Average | -- | -- | 45 | 39 | 39 |
| 18-34 | 39 | 25 | 26 | 46 | 41 |
| 35-54 | 36 | 42 | 46 | 38 | 33 (35-49) |
| 55+ | 25 | 33 | 28 | 16 | 26 (50+) |
| Race (%)  White | -- | 84 | 90 | 73 | 86 |
| Non-White | -- | 16 | 10 | 27 | 14 |
| Income <$20K (%) | 32 | 33 | 27 | 29 | 20 (<$25K) |
| No Medical Ins. (%) | -- | -- | -- | -- | 22 |
| No Rx Ins. (%) | -- | -- | -- | -- | 27 |

## Who Uses OTC Epinephrine MDIs? 

**13.6 million current adult asthma patients****1**** **
**2-3 million (15-20%) are users of OTC asthma medications****2**
- ~2/3 use OTC in addition to Rx medication
- ~1/3 use OTC medications exclusively
**4.5 million canisters of EPI MDI sold annually****3**
**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**

## Who Uses OTC Epinephrine MDI?

**2005 Survey of Asthmatics**

| Question | Sole OTCn=85
(%) | Dual Rx/OTC n=64
(%)  | Sole Rx n=221
(%) |
| --- | --- | --- | --- |
| “Has a doctor ever diagnosed you as suffering from asthma?”  	(% yes) | 92 | 100 | 98 |
| “Have you visited a doctor’s office in the past year for treatment of your asthma?”                              				(% yes) | 28 | 88 | 78 |
| “Do you have medical insurance to cover doctor’s visits?”          		(% yes) | 66 | 84 | 87 |
| “Do you have a prescription medication coverage plan?”			(% yes) | 60 | 81 | 81 |

## A Perspective on Access to Medical Care and Prescription Drugs

**40 million (25%) Americans went without healthcare when sick due to costs****1**
**91% of uninsured and 44% of insured who delayed or did not obtain care did so due to cost****2**
**59 million (47%) working Americans have no paid sick leave****3**
**Asthma medication use decreased 32%  when co-pay doubled****4**

**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**

## Access is Why Consumers Use OTC Epinephrine MDI

| Most Frequent Reasons Cited by Sole OTC Users |  |
| --- | --- |
| “Easier and quicker to obtain” | 55% |
| “More reasonably priced” | 41% |
| “I don’t have health insurance” | 25% |
| “I don’t want to go to the doctor” | 25% |
| “I don’t have a doctor” | 21% |
| “OTC drugs work better for my asthma” | 11% |

**2005 Survey of Asthmatics**

## Access is Why Consumers Use OTC Epinephrine MDI

| Most Frequent Reasons Cited by Dual Rx/OTC Users |  |
| --- | --- |
| Availability of Rx Inhaler 
“When I run out of my prescription medication” – 36%
“When I have an asthma attack and I don’t have my prescription with me” – 34% | 58% |
| “When I feel an OTC medication will work better” | 47% |

**2005 Survey of Asthmatics**

## Consumers Use Epinephrine MDI According to Label and Consistent With NAEPP Guidelines

| Question | Most Frequent Response |
| --- | --- |
| “About how frequently do you use Primatene Mist to treat your symptoms?”1 | 75% use the product once per week or less |
| “Again, thinking about the last time you had an attack and used Primatene Mist, how many sprays did you need to initially relieve your symptoms? (unaided)”2 | 81% indicate 1-2 sprays  |
| Household Panel:  actual purchases scanned3  | 76% purchase one to two canisters per yr |

**1. 1994 Primatene Usage Study**
**2. 1994 OTC Usage Study**
**3. 1994 Nielsen Household Panel**

## Sole OTC Users Tend to Medicate for Rescue

| Question | Sole OTC
(n=100) | Dual Rx/OTC
(n=64) | Sole  Rx
(n=221) |
| --- | --- | --- | --- |
| “How many attacks, if any, have you had in the past three months?” | 3.86
(2.98 - 4.91) | 5.39
(2.11 - 8.67) | 4.38
(3.14 - 5.62) |
| “Have you been to the emergency room in the past 12 months because of your asthma?” (% yes) | 10%
(6% - 17%) | 36%
(25% - 48%) | 21%
(16% - 27%) |
| “I take my medication ONLY when I feel an attack is coming on” (% yes) | 92%
(85% - 96%) | 48%
(40% - 63%) | 50%
(43% - 56%) |

**2005 Survey of Asthmatics**

- (95% CI)

## 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**

## 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

## 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

## Epinephrine MDI Studied in Moderate to Severe Asthma

**Design**
- R, DB, PC, X-over
- N=12; 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**

## Epinephrine MDI is Effective in Moderate to Severe Asthma

- *

- *

- *

- *

- *

- *

- *

- *

- ‡

- ‡

- ‡

- ‡

- *

** *p < 0.05 vs placebo‡ p*<* 0.05 vs metaproterenol

**1**

**Pinnas, et al; J Clin Pharmacol, 1991**

**1**

## Epinephrine MDI Studied in Mild to Moderate Asthma

**Design**
- R, DB, PC, X-over
- N=24; 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**

## Epinephrine MDI is Effective in Mild to Moderate Asthma

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

- * p<0.001

**Dauphinee, et al; Am Rev Respir Dis, 1994**

**1**

**1**

## 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**

## Epinephrine MDI is Effective in Nocturnal Asthma 

- Epinephrine MDI is Effective in Nocturnal Asthma

**2**

**4**

**8**

- *

- **

**Labeled dose**

**Exaggerated doses**

**Hendeles, et al;  Ann Allergy Asthma Immunol, 2005**

-  *p = 0.01**p = 0.002

## 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**

## 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, 7****th**** Ed 2004**

## 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/min****2**

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

## Heart Rate Not Increased After Epinephrine MDI at 4-fold Excess Dose

**Hendeles, et al; Ann Allergy Asthma Immunol, 2005**

- *

- *

- *

- 2

- 4

- 8

**Labeled dose**

**Exaggerated doses**

- *p = 0.001

## 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

## Fatalities Are Rare and Largely Unrelated to Epinephrine MDI

| Insufficient information | 21 |
| --- | --- |
| Probably not related | 7 |
| Abuse | 5 |
| Possibly related | 2 |

## 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**

## 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

## 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

## 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**

## 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"**

## Epinephrine MDI Meets the Second  Element for Essential Use Exemption

**Essential Use Exemption**

**21**** ****CFR 2.125**

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

## 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**

## Epinephrine MDI Releases Minimal CFC

**1. 70 FR 49836**
** ****2. IPCC/TEAP Special Report on Safeguarding the Ozone Layer, 2005**

## Epinephrine MDI Meets the Third Element for Essential Use Exemption

**Essential Use Exemption**

**21**** ****CFR 2.125**

- Otherwise unavailable importantpublic health benefit** **
- Small amount of CFCs released
**Significant technical hurdles****to reformulation**

## 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 **

## FDA Clinical Development Plan Guidance

**Supplies**

**PK Study**

**Dose Ranging **
**Study**

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

**Approximately 4 years****  **

**NDA **
**Preparation**

**FDA Review**

**10 mo**

**6 mo**

**15 mo**

**15 mo**

**6 mo**

**10 mo**

**FDA Guidance for Industry, Clinical Development Programs for MDI and DPI Drug Products, 1994**

## 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**

## HFA Reformulation Ongoing

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

## 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"**

## 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**

## 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

## Data Support Safe Effective Product With Appropriate Use

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

## 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**

## 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**

## 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**