Federal Register / Vol. 72, No. 182 / Thursday, September 20, 2007 / Proposed Rules 53711 

safety in air commerce. This regulation 

is within the scope of that authority 

because it addresses an unsafe condition 

that is likely to exist or develop on 

products identified in this rulemaking 

action. 

Regulatory Findings 

We determined that this proposed AD 

would not have federalism implications 

under Executive Order 13132. This 

proposed AD would not have a 

substantial direct effect on the States, on 

the relationship between the national 

Government and the States, or on the 

distribution of power and 

responsibilities among the various 

levels of government. 

For the reasons discussed above, I 

certify this proposed regulation: 

1. Is not a ‘‘significant regulatory 

action’’ under Executive Order 12866; 

2. Is not a ‘‘significant rule’’ under the 

DOT Regulatory Policies and Procedures 

(44 FR 11034, February 26, 1979); and 

3. Will not have a significant 

economic impact, positive or negative, 

on a substantial number of small entities 

under the criteria of the Regulatory 

Flexibility Act. 

We prepared a regulatory evaluation 

of the estimated costs to comply with 

this proposed AD and placed it in the 

AD docket. 

List of Subjects in 14 CFR Part 39 

Air transportation, Aircraft, Aviation 

safety, Safety. 

The Proposed Amendment 

Accordingly, under the authority 

delegated to me by the Administrator, 

the FAA proposes to amend 14 CFR part 

39 as follows: 

PART 39—AIRWORTHINESS 

DIRECTIVES 

1. The authority citation for part 39 

continues to read as follows: 

Authority: 49 U.S.C. 106(g), 40113, 44701. 

§ 39.13 [Amended] 

2. The FAA amends § 39.13 by adding 

the following new AD: 

Fokker Services B.V.: Docket No. FAA–

2007–29256; Directorate Identifier 2007–

NM–137–AD. 

Comments Due Date 

(a) We must receive comments by October 

22, 2007. 

Affected ADs 

(b) None. 

Applicability 

(c) This AD applies to Fokker Model F.28 

Mark 0070 and 0100 airplanes, certificated in 

any category, all serial numbers. 

Subject 

(d) Air Transport Association (ATA) of 

America Code 32: Landing gear. 

Reason 

(e) The mandatory continuing 

airworthiness information (MCAI) states: 

Two events have been reported of Fokker 

100 (F.28 Mk.0100) aircraft, where the Nose 

Landing Gear (NLG) failed to extend in the 

normal mode and problems were 

experienced to open the NLG doors, almost 

preventing extension of the NLG in the 

emergency (alternate) mode. Subsequent 

investigation and tests have shown that the 

friction of the bearing in the roller of the NLG 

Door Uplock Bracket Assembly is high, 

causing increased resistance in the 

mechanical system that unlocks the NLG 

doors. This condition, if not corrected, may 

result in a NLG up landing, which is 

considered a hazardous event. Since a 

potentially unsafe condition has been 

identified that may exist or develop on 

aircraft of the same type design, this 

Airworthiness Directive requires the 

introduction of an improved roller in the 

NLG Door Uplock Bracket Assembly. 

Actions and Compliance 

(f) Unless already done, do the following 

actions. 

(1) Within 4,000 flight hours after the 

effective date of this AD, modify the NLG 

Door Uplock Bracket Assembly, in 

accordance with the Accomplishment 

Instructions of Fokker Service Bulletin 

SBF100–32–143, dated February 15, 2006. 

(2) As of 18 months after the effective date 

of this AD, no spare NLG Door Uplock 

Bracket Assembly may be installed as a 

replacement part unless it has been modified 

in accordance with the Accomplishment 

Instructions of Fokker Component Service 

Bulletin D76501–32–17, dated February 15, 

2006. 

FAA AD Differences 

Note: This AD differs from the MCAI and/ 

or service information as follows: No 

difference. 

Other FAA AD Provisions 

(g) The following provisions also apply to 

this AD: 

(1) Alternative Methods of Compliance 

(AMOCs): The Manager, International 

Branch, ANM–116, FAA, has the authority to 

approve AMOCs for this AD, if requested 

using the procedures found in 14 CFR 39.19. 

Send information to ATTN: Tom Rodriguez, 

Aerospace Engineer, 1601 Lind Avenue, SW., 

Renton, Washington 98057–3356; telephone 

(425) 227–1137; fax (425) 227–1149. Before 

using any approved AMOC on any airplane 

to which the AMOC applies, notify your 

appropriate principal inspector (PI) in the 

FAA Flight Standards District Office (FSDO), 

or lacking a PI, your local FSDO. 

(2) Airworthy Product: For any requirement 

in this AD to obtain corrective actions from 

a manufacturer or other source, use these 

actions if they are FAA-approved. Corrective 

actions are considered FAA-approved if they 

are approved by the State of Design Authority 

(or their delegated agent). You are required 

to assure the product is airworthy before it 

is returned to service. 

(3) Reporting Requirements: For any 

reporting requirement in this AD, under the 

provisions of the Paperwork Reduction Act, 

the Office of Management and Budget (OMB) 

has approved the information collection 

requirements and has assigned OMB Control 

Number 2120–0056. 

Related Information 

(h) Refer to MCAI Dutch Airworthiness 

Directive NL–2006–004, dated February 28, 

2006, Fokker Service Bulletin SBF100–32–

143, dated February 15, 2006, and Fokker 

Component Service Bulletin D76501–32–17, 

dated February 15, 2006, for related 

information. 

Issued in Renton, Washington, on 

September 12, 2007. 

Ali Bahrami, 

Manager, Transport Airplane Directorate, 

Aircraft Certification Service. 

[FR Doc. E7–18553 Filed 9–19–07; 8:45 am] 

BILLING CODE 4910–13–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 2 

[Docket No. 2007N–0262] 

RIN 0910–AF92 

Use of Ozone-Depleting Substances; 

Removal of Essential-Use Designation 

(Epinephrine) 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA), after 

consultation with the Environmental 

Protection Agency (EPA), is proposing 

to amend FDA’s regulation on the use of 

ozone-depleting substances (ODSs) in 

self-pressurized containers to remove 

the essential-use designation for 

epinephrine used in oral pressurized 

metered-dose inhalers (MDIs). FDA has 

tentatively concluded that there are no 

substantial technical barriers to 

formulating epinephrine as a product 

that does not release ODSs, and 

therefore epinephrine would no longer 

be an essential use of ODSs. If the 

essential-use designation is removed, 

epinephrine MDIs containing an ODS 

could not be marketed after a suitable 

transition period. We will hold an open 

public meeting on the essential use of 

epinephrine on a date to be announced 

later. 

DATES: Submit written or electronic 

comments by November 19, 2007. 


pwalker on PROD1PC71 with PROPOSALS
53712 Federal Register / Vol. 72, No. 182 / Thursday, September 20, 2007 / Proposed Rules 

ADDRESSES: You may submit comments, 

identified by Docket No. 2007N–0262 

and/or RIN number 0910–AF92, by any 

of the following methods: 

Electronic Submissions 

Submit electronic comments in the 

following ways: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

• Agency Web site: http:// 

www.fda.gov/dockets/ecomments. 

Follow the instructions for submitting 

comments on the agency Web site. 

Written Submissions 

Submit written submissions in the 

following ways: 

• FAX: 301–827–6870. 

• Mail/Hand delivery/Courier [For 

paper, disk, or CD–ROM submissions]: 

Division of Dockets Management (HFA–

305), Food and Drug Administration, 

5630 Fishers Lane, rm. 1061, Rockville, 

MD 20852. 

To ensure more timely processing of 

comments, FDA is no longer accepting 

comments submitted to the agency by email. FDA encourages you to continue 

to submit electronic comments by using 

the Federal eRulemaking Portal or the 

agency Web site, as described 

previously in the ADDRESSES portion of 

this document under Electronic 

Submissions. 

Instructions: All submissions received 

must include the agency name and 

Docket No(s). and Regulatory 

Information Number (RIN) (if a RIN 

number has been assigned) for this 

rulemaking. All comments received may 

be posted without change to http:// 

www.fda.gov/ohrms/dockets/ 

default.htm, including any personal 

information provided. For additional 

information on submitting comments, 

see the ‘‘Comments’’ heading of the 

SUPPLEMENTARY INFORMATION section of 

this document. 

Docket: For access to the docket to 

read background documents, comments, 

a transcript of, and material submitted 

for, the joint meeting of the 

Nonprescription Drugs and PulmonaryAllergy Drugs Advisory Committee held 

on January 24, 2006, go to http:// 

www.fda.gov/ohrms/dockets/ 

default.htm and insert the docket 

number(s), found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Division of Dockets 

Management, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852. 

FOR FURTHER INFORMATION CONTACT: 

Wayne H. Mitchell or Martha Nguyen, 

Center for Drug Evaluation and Research 

(HFD–7), Food and Drug 

Administration, 5600 Fishers Lane, 

Rockville, MD 20857, 301–594–2041. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Background 

A. CFCs 

B. Regulation of ODSs 

1. The 1978 Rules 

2. The Montreal Protocol 

3. The 1990 Amendments to the Clean Air 

Act 

4. EPA’s Implementing Regulations 

5. FDA’s 2002 Regulation 

II. Criteria 

III. Effective Date 

IV. 2006 NDAC/PADAC Meeting 

V. Epinephrine 

A. Do Substantial Technical Barriers Exist 

to Formulating Epinephrine Products 

Without ODSs? 

B. Do OTC Epinephrine MDIs Provide an 

Otherwise Unavailable Public Health 

Benefit? 

1. Does Epinephrine Provide a Greater 

Therapeutic Benefit Than Similar 

Adrenergic Bronchodilators? 

2. Does OTC Marketing of Epinephrine 

MDIs Provide an Important Public 

Health Benefit? 

3. Conclusions on the Public Health 

Benefits of OTC Epinephrine MDIs 

C. Does Use of OTC Epinephrine MDIs 

Release Cumulatively Significant 

Amounts of ODSs Into the Atmosphere 

or is the Release Warranted in View of 

the Otherwise Unavailable Important 

Public Health Benefit? 

D. Conclusions 

VI. Environmental Impact 

VII. Analysis of Impacts 

A. Introduction 

B. Need for Regulation and the Objective 

of This Rule 

C. Background 

1. CFCs and Stratospheric Ozone 

2. The Montreal Protocol 

3. Benefits of the Montreal Protocol 

4. Characteristics of Asthma 

5. Current U.S. Market for OTC 

Epinephrine MDIs 

D. Benefits and Costs of the Proposed Rule 

1. Baseline Conditions 

2. Benefits of the Proposed Rule 

3. Costs of the Proposed Rule and 

Alternatives 

4. Effects on Medicaid and Medicare 

E. Alternative Phase-Out Dates 

F. Sensitivity Analyses 

G. Conclusion 

VIII. Regulatory Flexibility Analysis 

IX. The Paperwork Reduction Act of 1995 

X. Federalism 

XI. Request for Comments 

XII. References 

I. Background 

A. CFCs 

Chlorofluorocarbons (CFCs) are 

organic compounds that contain carbon, 

chlorine, and fluorine atoms. CFCs were 

first used commercially in the early 

1930s as a replacement for hazardous 

materials then used in refrigeration, 

such as sulfur dioxide and ammonia. 

Subsequently, CFCs were found to have 

a large number of uses, including as 

solvents and as propellants in selfpressurized aerosol products, such as 

MDIs. 

CFCs are very stable in the 

troposphere, the lowest part of the 

atmosphere. They move to the 

stratosphere, a region that begins about 

10 to 16 kilometers (km) (6 to 10 miles) 

above Earth’s surface and extends up to 

about 50 km (31 miles) altitude. Within 

the stratosphere, there is a zone about 

15 to 40 km (10 to 25 miles) above the 

Earth’s surface in which ozone is 

relatively highly concentrated. This 

zone in the stratosphere is generally 

called the ozone layer. Once in the 

stratosphere, CFCs are gradually broken 

down by strong ultraviolet light, 

releasing chlorine atoms that then 

deplete stratospheric ozone. Depletion 

of stratospheric ozone by CFCs and 

other ODSs allows more ultraviolet-B 

(UV-B) radiation to reach the Earth’s 

surface, where it increases skin cancers 

and cataracts, and damages some marine 

organisms, plants, and plastics. 

B. Regulation of ODSs 

The link between CFCs and the 

depletion of stratospheric ozone was 

discovered in the mid-1970s. Since 

1978, the U.S. Government has pursued 

a vigorous and consistent policy, 

through the enactment of laws and 

regulations, of limiting the production, 

use, and importation of ODSs, including 

CFCs. 

1. The 1978 Rules 

In the Federal Register of March 17, 

1978 (43 FR 11301 at 11318), FDA and 

EPA published rules banning, with a 

few exceptions, the use of CFCs as 

propellants in aerosol containers. These 

rules were issued under authority of the 

Federal Food, Drug, and Cosmetic Act 

(the act) (21 U.S.C. 321 et seq.) and the 

Toxic Substances Control Act (15 U.S.C. 

2601 et seq.), respectively. FDA’s rule 

(the 1978 rule) was codified as § 2.125 

(21 CFR 2.125). These rules issued by 

FDA and EPA had been preceded by 

rules issued by FDA and the Consumer 

Product Safety Commission requiring 

products that contain CFC propellants 

to bear environmental warning 

statements on their labeling (42 FR 

22018, April 29, 1977; 42 FR 42780, 

August 24, 1977). 

The 1978 rule prohibited the use of 

CFCs as propellants in self-pressurized 

containers in any food, drug, medical 

device, or cosmetic. As originally 

published, the rule listed five essential 

uses exempt from the ban. The third 

listed essential use was for ‘‘[m]etereddose adrenergic bronchodilator human 


pwalker on PROD1PC71 with PROPOSALS
Federal Register / Vol. 72, No. 182 / Thursday, September 20, 2007 / Proposed Rules 53713 

1FDA has verified all Web site addresses cited in 

this document, but FDA is not responsible for any 

subsequent changes to the Web sites after this 

document has published in the Federal Register. 

2The summary descriptions of the Montreal 

Protocol and decisions of Parties to the Montreal 

Protocol contained in this document are presented 

here to help you understand the background of the 

action we are taking. These descriptions are not 

intended to be formal statements of policy regarding 

the Montreal Protocol. Decisions by the Parties to 

the Montreal Protocol are cited in this document in 

the conventional format of ‘‘Decision IV/2,’’ which 

refers to the second decision recorded in the Report 

of the Fourth Meeting of the Parties to the Montreal 

Protocol on Substances That Deplete the Ozone 

Layer. Reports of Meetings of the Parties to the 

Montreal Protocol may be found on the United 

Nations Environment Programme’s Web site at 

http://ozone.unep.org/Meeting_Documents/mop/ 

index.shtml. 

3Production of CFCs in economically lessdeveloped countries is being phased out and is 

scheduled to end by January 1, 2010. See Article 

2A of the Montreal Protocol. 

4Our obligation under XV/5 was met by our final 

rule eliminating the essential use status of albuterol 

(70 FR 17168, April 4, 2005). 5The Ozone Secretariat is the Secretariat for the 

Montreal Protocol and the Vienna Convention for 

the Protection of the Ozone Layer (the Vienna 

Convention) (March 22, 1985, 26 I.L.M. 1529 

(1985)), available at http://hq.unep.org/ozone/pdfs/ 

viennaconvention2002.pdf. Based at the United 

Nations Environment Programme (UNEP) offices in 

Nairobi, Kenya, the Secretariat functions in 

accordance with Article 7 of the Vienna Convention 

and Article 12 of the Montreal Protocol. 

The main duties of the Secretariat include the 

following: 

• Arranging for and servicing the Conference of 

the Parties, Meetings of the Parties, their 

Committees, the Bureaux, Working Groups, and 

Assessment Panels; 

• Arranging for the implementation of decisions 

resulting from these meetings; 

• Monitoring the implementation of the Vienna 

Convention and the Montreal Protocol; 

• Reporting to the Meetings of the Parties and to 

the Implementation Committee; 

Continued 

drugs for oral inhalation.’’ This use 

describes epinephrine MDIs. 

The 1978 rule provided criteria for 

adding new essential uses, and several 

uses were added to the list, the last one 

in 1996. The 1978 rule did not provide 

any mechanism for removing essential 

uses from the list as alternative products 

were developed or CFC-containing 

products were removed from the 

market. The absence of a removal 

procedure came to be viewed as a 

deficiency in the 1978 rule, and was 

addressed in a later rulemaking, 

discussed in section I.B.5 of this 

document. 

2. The Montreal Protocol 

On January 1, 1989, the United States 

became a Party to the Montreal Protocol 

on Substances that Deplete the Ozone 

Layer (Montreal Protocol) (September 

16, 1987, 26 I.L.M. 1541 (1987)), 

available at http://www.unep.org/ozone/ 

pdfs/Montreal-Protocol2000.pdf.1 The 

United States played a leading role in 

the negotiation of the Montreal Protocol, 

believing that internationally 

coordinated control of ODSs would best 

protect both the U.S. and global public 

health and the environment from 

potential adverse effects of depletion of 

stratospheric ozone. Currently, there are 

191 Parties to this treaty.2 When it 

joined the treaty, the United States 

committed to reducing production and 

consumption of certain CFCs to 50 

percent of 1986 levels by 1998 (Article 

2(4) of the Montreal Protocol). It also 

agreed to accept an ‘‘adjustment’’

procedure, by which, following 

assessment of the existing control 

measures, the Parties could adjust the 

scope, amount, and timing of those 

control measures for substances already 

subject to the Montreal Protocol. As the 

evidence regarding the impact of ODSs 

on the ozone layer became stronger, the 

Parties used this adjustment procedure 

to accelerate the phase-out of ODSs. At 

the fourth Meeting of the Parties to the 

Montreal Protocol, held at Copenhagen 

in November 1992, the Parties adjusted 

Article 2 of the Montreal Protocol to 

eliminate the production and 

importation of CFCs by January 1, 1996, 

by Parties that are developed countries 

(Decision IV/2).3 The adjustment also 

indicated that it would apply, ‘‘save to 

the extent that the Parties decide to 

permit the level of production or 

consumption that is necessary to satisfy 

uses agreed by them to be essential’’

(Article 2A(4)). 

One of the most important essential 

uses of CFCs under the Montreal 

Protocol is their use in MDIs for the 

treatment of asthma and chronic 

obstructive pulmonary disease (COPD). 

The decision on whether the use of 

CFCs in MDIs is ‘‘essential’’ for 

purposes of the Montreal Protocol turns 

on whether ‘‘(1) It is necessary for the 

health, safety, or is critical for the 

functioning of society (encompassing 

cultural and intellectual aspects) and (2) 

there are no available technically and 

economically feasible alternatives or 

substitutes that are acceptable from the 

standpoint of environment and health’’

(Decision IV/25). 

Each request and any subsequent 

exemption is for only 1 year’s duration 

(Decision V/18). Since 1994, the United 

States and some other Parties to the 

Montreal Protocol have annually 

requested, and been granted, essentialuse exemptions for the production or 

importation of CFCs for their use in 

MDIs for the treatment of asthma and 

COPD (see, among others, Decisions VI/ 

9 and VII/28). The exemptions have 

been consistent with the criteria 

established by the Parties, which make 

the grant of an exemption contingent on 

a finding that the use for which the 

exemption is being requested is 

essential for health, safety, or the 

functioning of society, and that there are 

no available technically and 

economically feasible alternatives or 

substitutes that are acceptable from the 

standpoint of health or the environment 

(Decision IV/25). 

Phasing out the use of CFCs in MDIs 

for the treatment of asthma and COPD 

has been an issue of particular interest 

to the Parties to the Montreal Protocol. 

Several decisions of the Parties have 

dealt with the transition to CFC-free 

MDIs, including the following 

decisions: 

• Decision VIII/10 stated that the 

Parties that are developed countries 

would take various actions to promote 

industry’s participation in a smooth and 

efficient transition away from CFCbased MDIs (San Jose, Costa Rica, 1996). 

• Decision IX/19 required the Parties 

that are developed countries to present 

an initial national or regional transition 

strategy by January 31, 1999 (Montreal, 

Canada, 1997). 

• Decision XII/2 elaborated on the 

content of national or regional transition 

strategies required under Decision IX/19 

and indicated that any MDI for the 

treatment of asthma or COPD approved 

for marketing after 2000 would not be 

an ‘‘essential use’’ unless it met the 

criteria laid out by the Parties for 

essential uses (Ouagadougou, Burkina 

Faso, 2000). 

• Decision XIV/5 requested that each 

Party report annually the quantities of 

CFC and non-CFC MDIs and dry-powder 

inhalers (DPIs) sold or distributed 

within its borders and the approval and 

marketing status of non-CFC MDIs and 

DPIs. Decision XIV/5 also noted ‘‘with 

concern the slow transition to CFC-free 

metered-dose inhalers in some Parties’’

(Rome, Italy, 2002). 

• Decision XV/5 stated that, at the 

17th Meeting of the Parties (in 

December 2005) or thereafter, no 

essential uses of CFCs will be 

authorized for Parties that are developed 

countries, unless the Party requesting 

the essential-use allocation has 

submitted an action plan for MDIs for 

which the sole active ingredient is 

albuterol. Among other items, the action 

plan should include a specific date by 

which the Party plans to cease 

requesting essential-use allocations of 

CFCs for albuterol MDIs to be sold or 

distributed in developed countries4

(Nairobi, Kenya, 2003). 

• Decision XVII/5 stated that Parties 

that are developed counties should 

provide a date to the Ozone Secretariat5


pwalker on PROD1PC71 with PROPOSALS
53714 Federal Register / Vol. 72, No. 182 / Thursday, September 20, 2007 / Proposed Rules 

• Representing the Convention and the Protocol; 

and 

• Receiving and analyzing data and information 

from the Parties on the production and 

consumption of ODSs. 6In conformance with Decision IV/2, EPA issued 

regulations accelerating the complete phase-out of 

CFCs, with exceptions for essential uses, to January 

1, 1996 (58 FR 65018, December 10, 1993). 

7Section 314.108(a) (21 CFR 314.108(a)) defines 

‘‘active moiety’’ as the molecule or ion, excluding 

those appended portions of the molecule that cause 

the drug to be an ester, salt (including a salt with 

hydrogen or coordination bonds), or other 

noncovalent derivative (such as a complex, chelate, 

or clathrate) of the molecule, responsible for the 

physiological or pharmacological action of the drug 

substance. When describing the various essential 

uses, we will generally refer to the active moiety, 

for example, albuterol, as opposed to the active 

ingredient, which, using the same example, would 

be albuterol sulfate. When discussing particular 

indications and other material from the approved 

labeling of a drug product, we will generally use the 

brand name of the product, which, using the same 

example would be PROVENTIL HFA (among 

others). In describing material from treatises, 

journals, and other non-FDA approved 

publications, we will generally follow the usage in 

the original publication. 

before the 18th Meeting of the Parties 

(October 30 to November 3, 2006) by 

which time a regulation or regulations 

will have been proposed to determine 

whether MDIs, other than those that 

have albuterol as the only active 

ingredient, are nonessential (Dakar, 

Senegal, 2005). 

3. The 1990 Amendments to the Clean 

Air Act 

In 1990, Congress amended the Clean 

Air Act to, among other things, better 

protect stratospheric ozone (Public Law 

No. 101–549, November 15, 1990) (the 

1990 amendments). The 1990 

amendments were drafted to 

complement, and be consistent with, 

our obligations under the Montreal 

Protocol (see section 614 of the Clean 

Air Act (42 U.S.C. 7671m)). Section 

614(b) of the Clean Air Act provides 

that, in the case of a conflict between 

any provision of the Clean Air Act and 

any provision of the Montreal Protocol, 

the more stringent provision will 

govern. Section 604 of the Clean Air Act 

requires the phase-out of the production 

of CFCs by 2000 (42 U.S.C. 7671c),6

while section 610 of the Clean Air Act 

(42 U.S.C. 7671i) required EPA to issue 

regulations banning the sale or 

distribution in interstate commerce of 

nonessential products containing CFCs. 

Sections 604 and 610 provide 

exceptions for ‘‘medical devices.’’

Section 601(8) (42 U.S.C. 7671(8)) of the 

Clean Air Act defines ‘‘medical device’’

as: 

any device (as defined in the Federal 

Food, Drug, and Cosmetic Act (21 U.S.C. 

321)), diagnostic product, drug (as 

defined in the Federal Food, Drug, and 

Cosmetic Act), or drug delivery system- 

(A) if such device, product, drug, or 

drug delivery system utilizes a class I or 

class II substance for which no safe and 

effective alternative has been developed, 

and where necessary, approved by the 

Commissioner [of Food and Drugs]; and 

(B) if such device, product, drug, or 

drug delivery system, has, after notice 

and opportunity for public comment, 

been approved and determined to be 

essential by the Commissioner [of Food 

and Drugs] in consultation with the 

Administrator [of EPA]. 

4. EPA’s Implementing Regulations 

EPA regulations implementing the 

Montreal Protocol and the stratospheric 

ozone protection provisions of the 1990 

amendments are codified in part 82 of 

title 40 of the Code of Federal 

Regulations (40 CFR part 82). (See 40 

CFR 82.1 for a statement of intent.) Like 

the 1990 amendments, EPA’s 

implementing regulations contain two 

separate prohibitions, one on the 

production and import of CFCs (subpart 

A of 40 CFR part 82) and the other on 

the sale or distribution of products 

containing CFCs (40 CFR 82.66). 

The prohibition on production and 

import of CFCs contains an exception 

for essential uses and, more specifically, 

for essential MDIs. The definition of 

essential MDI at 40 CFR 82.3 requires 

that the MDI be intended for the 

treatment of asthma or COPD, be 

essential under the Montreal Protocol, 

and if the MDI is for sale in the United 

States, be approved by FDA and listed 

as essential in FDA’s regulations at 

§ 2.125 (21 CFR 2.125). 

The prohibition on the sale of 

products containing CFCs includes a 

specific prohibition on aerosol products 

and other pressurized dispensers. The 

aerosol product ban contains an 

exception for medical devices listed in 

§ 2.125(e). The term ‘‘medical device’’ is 

used with the same meaning it was 

given in the 1990 amendments and 

includes drugs as well as medical 

devices. 

5. FDA’s 2002 Regulation 

In the 1990s, we decided that § 2.125 

required revision to better reflect our 

obligations under the Montreal Protocol, 

the 1990 amendments, and EPA’s 

regulations, and to encourage the 

development of ozone-friendly 

alternatives to medical products 

containing CFCs. In particular, as 

acceptable alternatives that did not 

contain CFCs or other ODSs came on the 

market, there was a need to provide a 

mechanism for removing essential uses 

from the list in § 2.125(e). In the Federal 

Register of March 6, 1997 (62 FR 

10242), we published an advance notice 

of proposed rulemaking (the 1997 

ANPRM) in which we outlined our 

then-current thinking on the content of 

an appropriate rule regarding ODSs in 

products FDA regulates. We received 

almost 10,000 comments on the 1997 

ANPRM. In response to the comments, 

we revised our approach and drafted a 

proposed rule published in the Federal 

Register of September 1, 1999 (64 FR 

47719) (the 1999 proposed rule). We 

received 22 comments on the 1999 

proposed rule. After minor revisions in 

response to these comments, we 

published a final rule in the Federal 

Register of July 24, 2002 (67 FR 48370) 

(the 2002 final rule) (corrected in 67 FR 

49396, July 30, 2002, and 67 FR 58678, 

September 17, 2002). The 2002 final 

rule listed as a separate essential use 

each active moiety7 marketed under the 

1978 rule as essential uses for metereddose steroid human drugs for oral 

inhalation and metered-dose adrenergic 

bronchodilator human drugs for oral 

inhalation; eliminated the essential-use 

designations in § 2.125(e) for metereddose steroid human drugs for nasal 

inhalation and for products that were no 

longer marketed; set new standards to 

determine when a new essential-use 

designation should be added to § 2.125; 

and set standards to determine whether 

the use of an ODS in a medical product 

remains essential. 

II. Criteria 

Among other changes, the 2002 final 

rule, in revised § 2.125(g)(2), establishes 

a standard for removing an essential-use 

designation for any drug after January 1, 

2005, that would apply to a drug for 

which there is no acceptable non-ODS 

alternative with the same active moiety. 

The process for removing the essentialuse designation for such a drug must 

include a consultation with a relevant 

advisory committee and an open public 

meeting, in addition to a proposed rule 

and a final rule. The criterion 

established for removing the essential 

use in such circumstances is that it no 

longer meets the criteria specified in 

revised § 2.125(f) for adding a new 

essential use (§ 2.125(g)(2)). The criteria 

in § 2.125(f) are: ‘‘(i) Substantial 

technical barriers exist to formulating 

the product without ODSs; (ii) The 

product will provide an unavailable 

important public health benefit; and (iii) 

Use of the product does not release 

cumulatively significant amounts of 

ODSs into the atmosphere or the release 

is warranted in view of the unavailable 

important public health benefit.’’

The three criteria in § 2.25(f)(1) are 

linked by the word ‘‘and’’. Because the 

three criteria are linked by ‘‘and’’ (as 


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opposed to ‘‘or’’), failure to meet any 

single criterion satisfies the threshold 

under the regulation for determining 

that the use is not essential. 

We discussed these criteria in the 

preamble to the 1999 proposed rule. A 

key point in our discussion of technical 

barriers was: Generally, FDA intends the 

term ‘‘technical barriers’’ to refer to 

difficulties encountered in chemistry 

and manufacturing. A petitioner would 

have to establish that it evaluated all 

available alternative technologies and 

explain in detail why each alternative 

was unusable to demonstrate that 

substantial technical barriers exist (1999 

proposed rule at 47721). 

In applying the ‘‘technical barriers’’

criterion, we will be looking at the 

results of reformulation efforts for 

similar products, as well as statements 

made about the manufacturer’s 

particular efforts to reformulate their 

product or products. 

Similarly, in discussing what is ‘‘an 

unavailable important public health 

benefit,’’ we said: The agency intends to 

give the phrase ‘‘unavailable important 

public health benefit’’ a markedly 

different construction from the [phrase 

used in the 1978 rule] ‘‘substantial 

health benefit.’’ A petitioner should 

show that the use of an ODS would save 

lives, significantly reduce or prevent an 

important morbidity, or significantly 

increase patient quality of life to 

support a claim of important public 

health benefit (1999 proposed rule at 

47722). 

In determining whether a drug 

product provides an otherwise 

unavailable important public health 

benefit, our primary focus is on the 

availability of non-ODS products that 

provide equivalent therapeutic benefits 

for patients who are currently using the 

CFC MDIs. If therapeutic alternatives 

exist for everyone using the CFC MDI, 

we would then determine that the CFC 

MDI does not provide an otherwise 

unavailable important public health 

benefit. In the case of epinephrine MDIs, 

the fact that they are marketed over-thecounter (OTC), while the therapeutic 

alternatives for epinephrine MDIs are 

prescription drugs, makes the analysis 

of whether everyone is adequately 

served by the therapeutic alternatives 

more complicated. 

Under the third criterion, the 

threshold for removing the essential use 

designation is satisfied unless we find 

either: (1) The use of the product does 

not release cumulatively significant 

amounts of ODSs into the atmosphere; 

or (2) the release, although cumulatively 

significant, is warranted in view of the 

otherwise unavailable important public 

health benefit that the use of the drug 

product provides. In evaluating whether 

continuing the essential-use designation 

of an MDI would result in the product 

releasing significant quantities of ODSs, 

in light of past policy statements (2002 

final rule p. 48380) and the current state 

of the phase-out of ODSs, the release of 

CFCs from epinephrine MDIs is 

currently significant and as the phaseout of ODSs continues throughout the 

world, the significance of the quantities 

of CFCs released by epinephrine MDIs 

will increase. 

In applying the first part of the third 

criterion, we are guided by previous 

policy statements. The United States 

evaluated the environmental effect of 

eliminating the use of all CFCs in an 

environmental impact statement in the 

1970s (see 43 FR 11301, March 17, 

1978). As part of that evaluation, FDA 

concluded that the continued use of 

CFCs in medical products posed an 

unreasonable risk of long-term 

biological and climatic impacts (see 

Docket No. 1996N–0057 formerly 96N–

0057). Congress later enacted provisions 

of the Clean Air Act that codified the 

decision to fully phase out the use of 

CFCs over time (see 42 U.S.C. 7671 et 

seq. (enacted November 15, 1990)). We 

note that the environmental impact of 

individual uses of nonessential CFCs 

must not be evaluated independently, 

but rather must be evaluated in the 

context of the overall use of CFCs. 

Cumulative impacts can result from 

individually minor, but collectively 

significant, actions that take place over 

a period of time (40 CFR 1508.7). 

Significance cannot be avoided by 

breaking an action down into small 

components (40 CFR 1508.27(b)(7)). 

Currently, MDIs for the treatment of 

asthma and COPD are the only legal use 

for newly produced or imported CFCs 

(see 71 FR 58504 (October 4, 2006)). 

Although it may appear to some that the 

CFCs released from MDIs represent 

insignificant quantities of ODSs, and 

therefore should be exempt, the 

elimination of CFC use in MDIs is one 

of the final steps in the overall phaseout of CFC use. The release of ODSs 

from some of the MDIs may be relatively 

small compared to total quantities that 

were released 2 or 3 decades ago, but if 

each use that resulted in the release of 

relatively small quantities of ODSs were 

provided an exemption, the cumulative 

effect would be to prevent the 

elimination of ODS releasing products. 

This would prevent the full phase-out 

envisioned by the Clean Air Act and the 

Montreal Protocol. Therefore, we 

tentatively conclude that the release of 

ODSs from epinephrine MDIs is 

cumulatively significant. 

Given this proposed finding that the 

first part of the third criterion is not 

satisfied, the threshold for the removal 

of the essential-use designation for 

epinephrine under § 2.125(f)(1)(iii) is 

met if we also find that the second part 

of the third criterion is not satisfied: it 

provides an otherwise unavailable 

important public health benefit which 

warrants the cumulatively significant 

release of the ODS. 

As noted previously, because the 

three criteria in § 2.125(f)(1) are linked 

by the word ‘‘and,’’ failure to meet any 

single criterion may result in a 

determination that the use is not 

essential. Accordingly, if we find that 

the product fails to provide an 

otherwise unavailable important health 

benefit (criterion two), this would meet 

the threshold under the regulation for a 

finding that the use of the product is not 

essential, and we would not necessarily 

need to reach the last step under the 

third criterion (balancing the important 

health benefit against the release of the 

ODS to determine if the release is 

warranted). Assuming, however that we 

do analyze the third criterion, then, 

because of our tentative conclusion that 

the release of ODSs from epinephrine 

MDIs is cumulatively significant, we 

would need to conduct the balancing 

inquiry under the second part of the 

third criterion. We will discuss our 

tentative conclusions on how the 

second part of the third criterion applies 

to OTC epinephrine MDIs in section V.C 

of this document. 

The criteria in § 2.125(g)(2) (which 

refers to those found in § 2.125(f)(1)) 

that we are using in this rulemaking are 

different from those in § 2.125(g)(3) and 

(g)(4). Section 2.125(g)(2) specifically 

addresses the situation where there is 

no marketed non-ODS product 

containing the active moiety listed as an 

essential use, while § 2.125(g)(3) and 

(g)(4) apply to situations where there is 

at least one marketed non-ODS product 

with the listed active moiety. Section 

2.125(g)(2) permits FDA to remove an 

essential use even if a current essentialuse active moiety is not reformulated, 

provided that sufficient alternative 

products exist to meet the needs of 

patients, because the essential use 

would no longer provide an otherwise 

unavailable important health benefit. 

Therefore, the analysis we use here is 

not identical to the analysis we used 

under § 2.125(g)(4) in the recent 

rulemaking to remove the essential use 

for albuterol (70 FR 17168, April 4, 

2005). However, the basic concern of 

protecting the public health underlies 

all of the criteria. Therefore, our 

analyses are similar, and we have found 

it useful to borrow concepts from the 


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8Neither HFA MDIs nor DPIs release ODSs. HFA 

MDIs and DPIs are generally considered to be the 

non-ODS drug products that are most comparable 

to CFC MDIs in terms of portability and ease of use. 

9Current information indicates that production of 

albuterol HFA MDIs will be adequate to meet the 

current demand for albuterol MDIs much earlier 

than December 31, 2008. 

more specific provisions of § 2.125(g)(3) 

and (g)(4) to help give more structure to 

our analysis under the broader language 

of § 2.125(f)(1). 

III. Effective Date 

We are proposing that any rule 

finalizing the removal of the essential 

use for OTC epinephrine MDIs have an 

effective date of December 31, 2010. 

Because there are therapeutic 

alternatives which are marketed as 

prescription drugs, in determining the 

appropriate effective date for this 

rulemaking, we will consider both: (1) 

Whether adequate time exists to provide 

patient education for users of OTC 

epinephrine MDIs, particularly those 

who do not consult doctors, 

pharmacists, and other health care 

professionals; and (2) whether adequate 

production capacity and supplies are 

available to meet the new, presumably 

increased, demand for the therapeutic 

alternatives once OTC epinephrine 

MDIs are no longer sold. 

Patient education for any transition 

away from OTC epinephrine MDIs 

presents unique concerns. Much of the 

thinking about patient education on the 

transition from CFC MDIs has focused 

on the dissemination of information 

through physicians, pharmacists, and 

other health care professionals. This 

information could be given orally by 

health care professionals, or the 

information could be available in the 

professionals’ offices or pharmacies for 

patients to read. Because epinephrine 

MDIs are sold OTC, many purchasers 

will not interact with a health care 

provider. New avenues of 

communication will have to be opened 

to reach all OTC epinephrine MDI users. 

Many OTC epinephrine MDI users may 

need to be provided information to help 

them select a physician. Some OTC 

epinephrine MDI users who face 

economic barriers to appropriate health 

care may need even more time to find 

and avail themselves of free or low-cost 

health care and prescription drug 

programs (see section V.B.2.b of this 

document). These factors have led us to 

believe that a transition away from OTC 

epinephrine MDIs may be more difficult 

than transitions in which patients 

change from one prescription drug to 

another prescription drug, and 

accordingly that any effective date for 

such a rulemaking should provide for a 

longer transition period than the 

transition period for the recently 

published proposed rule to eliminate 

the essential-use designation for MDIs 

containing flunisolide, triamcinolone, 

metaproterenol, pirbuterol, albuterol 

and ipratropium in combination, 

cromolyn, and nedocromil (72 FR 

32030, June 11, 2007). We have, 

therefore, tentatively concluded that the 

December 31, 2010, effective date would 

be appropriate for a final rule removing 

the essential-use designation for OTC 

epinephrine MDIs. We invite comment 

on the proposed effective date of 

December 31, 2010, as well as possible 

alternative effective dates, such as 

December 31, 2011 or 2012. 

In determining an appropriate 

effective date, we have kept in mind 

that albuterol MDIs that use the 

hydrofluoroalkane HFA–134a (HFA) as 

a propellant are a primary therapeutic 

alternative to OTC epinephrine MDIs, 

because both drugs are in the same 

therapeutic class (short-acting inhaled 

beta-agonist bronchodilators), albuterol 

is the only member of the class available 

in an HFA MDI, and no members of the 

class are available as a DPI.8 Sales of 

OTC epinephrine MDIs have totaled 

approximately 4.5 million MDIs a year. 

We are confident that there will be 

adequate supplies of albuterol HFA 

MDIs to meet the needs of all users of 

albuterol CFC MDIs by December 31, 

2008 (the date on which albuterol MDIs 

will no longer be designated an essential 

use).9 Although we have limited data on 

production increases above current 

demand for 2009, 2010, and later, we 

believe that by December 31, 2010, 

albuterol HFA production will be able 

to meet any increased demand caused 

by this rulemaking. This proposed 

effective date is 1 year later than the 

effective date that we proposed in the 

recently published proposed rule to 

eliminate the essential-use designation 

for MDIs containing flunisolide, 

triamcinolone, metaproterenol, 

pirbuterol, albuterol and ipratropium in 

combination, cromolyn, and nedocromil 

(72 FR 32030, June 11, 2007). As we 

said in that proposed rule, many of the 

patients using some of those drugs 

would switch to albuterol HFA inhalers. 

We believe that the additional time 

required for the needed patient 

education on alternatives to OTC 

epinephrine MDIs will also provide 

additional time to scale up production 

of albuterol HFA MDIs. This additional 

time should provide greater assurance 

that there will be adequate supplies of 

albuterol HFA MDIs for all patients who 

use them. We specifically invite 

comments from manufacturers of 

albuterol HFA MDIs on this issue. 

In proposing a December 31, 2010, 

effective date, we expect that 2010 

would be a transition year characterized 

by declining production of OTC 

epinephrine MDIs. If a December 31, 

2010, effective date is established by 

this rulemaking, we anticipate that other 

administrative actions taken by EPA and 

FDA would reflect the concept of 2010 

being a transition year. 

The sale of remaining stocks of CFC 

MDIs by manufacturers, wholesalers, 

and retailers was a consideration in 

setting the effective date of the albuterol 

rule (70 FR 17168, 17179, April 4, 

2005). We believe that this 

consideration is appropriate for this 

rulemaking also. In evaluating the 

period of time needed to sell remaining 

stocks of OTC epinephrine MDIs, a 

factor that must be considered is the 

expiration dating for the relevant 

products. Both PRIMATENE MIST and 

the OTC epinephrine MDIs made by 

Armstrong Pharmaceuticals, Inc. 

(Armstrong) have expiration dates set at 

24 months after manufacture. Drug 

products are not generally sold right up 

to the expiration date. Drugs are 

generally sold well before the expiration 

date, allowing the purchasers a 

significant amount of time to use the 

drug before it reaches its expiration 

date; therefore, we believe that all OTC 

epinephrine MDIs manufactured prior 

to publication of a final rule based on 

this proposal should be sold by 

December 31, 2010. 

We are tentatively proposing a 

December 31, 2010, effective date based 

on our preliminary assumption that 

there will not be an inhaled epinephrine 

OTC drug product that does not contain 

ODSs on the market in the foreseeable 

future. We strongly urge interested 

individuals to submit detailed 

information on whether inhaledepinephrine will be available in a nonODS formulation and when a non-ODS 

inhaled epinephrine product can 

reasonably be expected to be on the 

market. We also specifically request 

comment on whether publishing a final 

rule or the effective date of any such 

rule should be affected by the additional 

information that we receive concerning 

the availability of an inhaled 

epinephrine OTC drug product that 

does not contain ODSs. 

IV. 2006 NDAC/PADAC Meeting 

Section 2.125(g)(2) requires that we 

consult an advisory committee before 

we remove an essential-use designation 

when there is no non-ODS product with 

the same active moiety. We consulted 

the Nonprescription Drug Advisory 


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10The transcript of the NCPAC/PADAC meeting, 

slides used in presentations made at the joint 

meeting, and written material presented to the 

committees for the meeting may be found at http:// 

www.fda.gov/ohrms/dockets/ac/cder06.html. 11The OTC monograph for Cold, Cough, Allergy, 

Bronchodilator, and Antiasthmatic Drug Products 

permits OTC marketing of epinephrine in a handheld rubber nebulizer for use in the treatment of 

asthma (21 CFR part 341). While this product did 

not use CFCs, all of the information available to us 

shows that such products are no longer marketed. 

The OTC monograph for Cold, Cough, Allergy, 

Bronchodilator, and Antiashtmatic Drug Products 

permits OTC marketing of oral dosage forms of 

ephedrine. Ephedrine is not available in an MDI. In 

addition, OTC ephedrine products have a slower 

onset of action than epinephrine MDIs, and 

therefore they cannot be considered a suitable 

alternative to OTC epinephrine MDIs. 

12The U.S. Census’ estimate of the U.S. 

Population was 299,948,296 as of October 10, 2006, 

1804 GMT, with an estimated net increase in the 

population of 1 person every 11 seconds. See http:// 

www.census.gov/population/www/popclockus.html. 

13The nine moieties formulated as HFA MDIs are 

albuterol, beclomethasone, budesonide, fenoterol, 

fluticasone, flunisolide, formoterol, ipratropium, 

and salmeterol. While a salmeterol DPI 

(SEREVENT) has been approved in the United 

States, salmeterol HFA MDIs have only been 

approved overseas. There are no approved fenoterol 

or formoterol products in the United States, but 

fenoterol HFA MDIs and formoterol HFA MDIs have 

been approved in several foreign countries. 

14PRIMATENE MIST contains 35 percent alcohol 

and other MDIs also contain alcohol. Wyeth did not 

reveal the amount of alcohol in their prototype or 

explain why the amount of alcohol could not be 

reduced or the taste otherwise minimized. 

Committee (NDAC) and the PulmonaryAllergy Drugs Advisory Committee 

(PADAC) on the essential-use status of 

OTC MDIs containing epinephrine at a 

joint committee meeting held on 

January 24, 2006 (NDAC/PADAC 

meeting).10 Presentations were made by 

representatives of Wyeth Consumer 

Health (Wyeth), two patient advocacy 

and public policy groups, and physician 

organizations. Seven of the joint 

committee members recommended that 

epinephrine be retained as an essential 

use, while eleven members 

recommended that the essential-use 

designation be removed. The opinions 

expressed by the NDAC and PADAC 

(NDAC/PADAC) members and other 

participants in the NDAC/PADAC 

meeting will be discussed below. 

This NDAC/PADAC meeting should 

not be confused with the open public 

meeting on the essential-use status of 

OTC MDIs containing epinephrine we 

will be holding in the near future. We 

will publish a notice for that meeting in 

the Federal Register shortly. 

V. Epinephrine 

Epinephrine is a short-acting 

adrenergic bronchodilator used in the 

treatment of asthma. A new drug 

application (NDA) for OTC epinephrine 

MDIs was approved in 1956. 

Epinephrine was included in the 1978 

rule under the provision designating 

‘‘[m]etered-dose adrenergic 

bronchodilator human drugs for oral 

inhalation’’ as an essential use. 

Approved NDAs for OTC epinephrine 

MDIs are currently held by Wyeth and 

Armstrong, (a subsidiary of Amphastar 

Pharmaceuticals, Inc.). Wyeth markets 

their OTC epinephrine MDIs as 

PRIMATENE MIST, while Armstrong 

labels their product as ‘‘house brands’’

for certain retail pharmacies. 

Epinephrine MDIs are the only MDIs for 

treatment of asthma (or any other 

disease) that are approved for OTC 

use.11 Customers do not need a 

prescription from a health care provider 

to purchase OTC epinephrine MDIs. 

Wyeth presented data at the NDAC/ 

PADAC meeting estimating that 2 to 3 

million people with asthma use OTC 

epinephrine MDIs (meeting transcript p. 

51, Wyeth slide 19). Based on the 2005 

National Health Interview Survey 

(NHIS), the Centers for Disease Control 

and Prevention’s National Center for 

Health Statistics (NCHS) has estimated 

that 7.7 percent of the U.S. population 

currently has asthma (Ref. 1). Using an 

estimate of the U.S. population of 300 

million,12 we can estimate that 

approximately 23 million people in the 

United States currently have asthma. 

Epinephrine is also an active 

ingredient in many other drug products. 

It is used in a self-injectable dosage form 

for treatment of severe allergic reactions. 

EPIPEN is an example of epinephrine in 

this dosage form. Epinephrine is also 

available OTC as a solution for use in an 

electrically powered nebulizer for the 

treatment of asthma. This rulemaking 

will not affect the availability of these 

non-MDI drug products. 

A. Do Substantial Technical Barriers 

Exist to Formulating Epinephrine 

Products Without ODSs? 

As we said in the 2002 final rule, we 

intend the term ‘‘technical barriers’’ to 

refer to difficulties encountered in 

chemistry and manufacturing. To 

demonstrate that substantial technical 

barriers exist, it will have to be 

established that all available alternative 

technologies have been evaluated and 

why each alternative is unusable (2002 

final rule at 48373). Wyeth did not 

present any significant data on technical 

barriers to formulating an inhaled 

epinephrine product without ODSs at 

the NDAC/PADAC meeting. At the 

NDAC/PADAC meeting, Wyeth said that 

they had been trying to reformulate or 

outsource their product for over a 

decade and mentioned unacceptable 

prototypes, but they mentioned that a 

significant difficulty in reformulation 

was avoiding designs that would 

infringe patents held by 3M Co. (3M) 

and GlaxoSmithKline (GSK) (meeting 

transcript, pp. 86–88). It should be kept 

in mind that patent licenses and 

contract manufacturing by patent 

holders have been very frequently used 

during the current transition away from 

CFC MDIs. An example of this is 3M’s 

manufacture of, and patent licensing for, 

albuterol HFA MDIs. 3M holds patents 

on HFA MDI technology and it also 

manufactures PROVENTIL HFA 

(albuterol) MDIs for sale by Schering 

Corporation (Schering). Ivax Corp. has 

licensed HFA MDI technology patents 

from 3M and manufactures PROAIR 

HFA (albuterol) MDIs. We have not been 

presented with any evidence that Wyeth 

could not obtain patent licenses or 

arrange for contract manufacturing by a 

patent holder. 

At least nine different active moieties 

have been formulated as HFA MDIs for 

the treatment of asthma and COPD in 

the United States and abroad.13 HFA 

MDIs have been formulated with both 

suspensions and solutions. Albuterol 

and levalbuterol are close chemical 

analogs of epinephrine. Given the 

chemical similarity between them and 

the success with reformulating albuterol 

(as albuterol sulfate in PROAIR HFA, 

PROVENTIL HFA, and VENTOLIN 

HFA) and levalbuterol (as levalbuterol 

tartrate in XOPENEX), there appears to 

be no technical reason why epinephrine 

cannot be successfully reformulated into 

an HFA MDI. Wyeth said at the NDAC/ 

PADAC meeting that early attempts to 

formulate an epinephrine HFA MDI 

were characterized by higher pressures 

and quantities of alcohol that provided 

unacceptable sensations to users of the 

product, including an unpleasant taste 

of alcohol14 (Wyeth briefing material, p. 

1–7; meeting transcript, p. 87). These do 

not seem to represent technical barriers; 

rather they seem to be the type of 

problems routinely encountered in the 

development of a new product that 

require prototypes to be reengineered. 

Indeed, Wyeth did not seem to truly 

believe that there were technical 

barriers to development of an 

epinephrine HFA MDI, predicting that 

they would have a product developed 

and clinically tested by 2011, and 

attributing their earlier difficulties to a 

lack of in-house expertise (Wyeth 

briefing material, p. 1–7). FDA has had 

experience with several firms 

reformulating products from ODS 

containing MDIs to non-ODS products. 

Based on our experience with those 

reformulation efforts, it seems highly 

unlikely that a non-ODS inhaled 

epinephrine drug product will be 


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15The nine moieties formulated as DPIs are 

albuterol, beclomethasone, budesonide, fluticasone, 

formoterol, mometasone, salmeterol, terbutaline, 

and tiotropium. While albuterol HFA MDIs have 

been approved in the United States, albuterol DPIs 

are not currently marketed in the United States, but 

are approved overseas. A terbutaline CFC MDI and 

other terbutaline products have been approved in 

the United States, but terbutaline DPIs have only 

been approved overseas. There are no approved 

formoterol products in the United States, but 

formoterol DPIs have been approved in several 

foreign countries. 

16PROAIR HFA is indicated for adults and 

children 12 years of age and older. 

17The author of the study report did not appear 

to view the study as supporting the OTC use of 

epinephrine MDIs, stating that the results of the 

study do not imply that it is safe for people with 

asthma to self-medicate without physician 

intervention and that results of the study indicate 

that nonprescription epinephrine presents the same 

risk of delaying patients from seeking medical care 

as other beta-agonists. The report concluded with 

a statement that a larger study is required before 

epinephrine can be recommended as rescue therapy 

when a prescription beta2-agonist MDI is not 

accessible (Ref. 3). 

18The author of the study report recognized that 

the large number of actuations might be impractical 

(Ref. 43). 

19The Guidelines represent best practices and are 

recognized as the clinical standard of care for 

treatment of asthma. See, e.g., http:// 

www.asthmanow.net/care.html; http:// 

www.colorado.gov/bestpractices/index.html; http:// 

www.doh.wa.gov/CFH/asthma/publications/plan/ 

health-care.pdf. 

developed and clinically tested until 

well after 2011. As we mentioned 

before, we are particularly interested in 

receiving comment on current efforts on 

developing non-ODS inhaled 

epinephrine drug products that would 

be suitable for OTC sale, including any 

discernible impediments to such efforts. 

Wyeth said that an epinephrine DPI 

was not a viable alternative to the 

epinephrine MDI, but without any 

elaboration (Wyeth briefing material, p. 

1–7). The DPI has proven to be a very 

successful dosage form. At least nine 

different moieties have been formulated 

as DPIs for treatment of asthma and 

COPD in the United States or overseas.15

Alkermes, Inc., developed a large dose 

epinephrine DPI for investigations into 

using an epinephrine DPI for treatment 

of anaphylaxis. While this product has 

not been approved by FDA and it is not 

intended for the treatment of asthma, it 

does show that epinephrine can be 

formulated into a DPI (Refs. 2 and 3). 

Thus, all of the evidence before us 

indicates that epinephrine can be 

formulated into a drug product that does 

not release ODSs. The facts presented by 

Wyeth at the NDAC/PADAC meeting 

did not indicate that there are technical 

barriers to the development of a nonODS epinephrine product, despite the 

conclusions that Wyeth presented at the 

meeting. However, as noted previously, 

we are especially interested in receiving 

public comment concerning any such 

technical barriers that may exist. 

B. Do OTC Epinephrine MDIs Provide 

an Otherwise Unavailable Important 

Public Health Benefit? 

Because we have reached a tentative 

conclusion that there are no substantial 

technical barriers to formulating 

epinephrine into a non-ODS product, 

we do not believe it is necessary at this 

time to reach a conclusion on the public 

health benefits of OTC epinephrine 

MDIs. However, this issue was 

discussed at length at the NDAC/ 

PADAC meeting and we are keenly 

interested in the potential public health 

benefits of having epinephrine MDIs 

available OTC. We will evaluate and 

weigh those public health benefits 

before issuing any final rule on the 

essential-use designation for 

epinephrine. Accordingly, we will 

discuss some of the questions on which 

we would be particularly interested in 

receiving comments that would be 

relevant in reaching a conclusion on the 

public health benefits of OTC 

epinephrine MDIs. 

1. Does Epinephrine Provide a Greater 

Therapeutic Benefit Than Similar 

Adrenergic Bronchodilators? 

During the last several years, four 

prescription HFA MDIs with two 

different forms of albuterol have come 

onto the market: 

• Albuterol sulfate MDI (PROAIR 

HFA); 

• Albuterol sulfate MDI (PROVENTIL 

HFA); 

• Albuterol sulfate MDI (VENTOLIN 

HFA); and 

• Levalbuterol tartrate MDI 

(XOPENEX HFA). 

These products use HFA as a 

replacement for ODSs, which does not 

affect stratospheric ozone. Albuterol and 

epinephrine are both adrenergic 

bronchodilators. Albuterol MDIs are 

therapeutic alternatives to OTC 

epinephrine MDIs and are, by far, the 

most widely prescribed short-acting 

bronchodilators. To determine whether 

epinephrine provides an otherwise 

unavailable important public health 

benefit, we should compare OTC 

epinephrine MDIs to albuterol HFA 

MDIs. The labeled indication for the 

OTC epinephrine MDIs is ‘‘for 

temporary relief of occasional symptoms 

of mild asthma.’’ The comparable 

labeled indication for the albuterol HFA 

MDIs is ‘‘for treatment or prevention of 

bronchospasm with reversible 

obstructive airway disease.’’ OTC 

epinephrine MDIs and three of the 

albuterol HFA MDIs are indicated for 

adults and children 4 years of age and 

older.16 The labeled indications for the 

albuterol HFA MDIs cover all patients 

described in the labeled indication for 

OTC epinephrine MDIs. 

Clinical data presented by a 

representative of Wyeth at the NDAC/ 

PADAC meeting indicated that OTC 

epinephrine MDIs may be slightly 

quicker to onset of action than albuterol 

MDIs, but they have a significantly 

shorter duration of action (Wyeth 

briefing statement at p. 1–9). The 

slightly quicker onset of action may 

explain why some people with asthma 

describe OTC epinephrine MDI as 

working better than prescription drugs. 

The slightly quicker onset of action is a 

pharmacodynamic assessment, but there 

are no clinical data to support a 

conclusion that this perceived quicker 

relief provided by epinephrine leads to 

better outcomes. Therefore, we do not 

believe that this represents a ‘‘otherwise 

unavailable important public health 

benefit.’’

Wyeth presented another study of the 

treatment of nocturnal asthma that 

concluded that OTC epinephrine MDIs 

can ‘‘achieve the same benefit as 

albuterol’’ MDIs (Ref. 4, p. 533).17

However, as pointed out by NDAC/ 

PADAC members, the frequency of 

doses of epinephrine used in this study 

were several times the amount approved 

in labeling (this was also true, but to a 

smaller degree, for albuterol in this 

study).18 Further, this was a limited 

study with only eight subjects 

completing the evaluations. These 

elements made the utility of this study 

for purposes of this rulemaking very 

questionable, and even if these 

questions were ignored, the study 

shows, at best, that epinephrine is 

roughly as effective as, but not more 

effective than, albuterol. 

In the United States, the generally 

recognized standard of care for asthma 

is set forth in the National Heart, Lung, 

and Blood Institute’s Expert Panel 

Report 2: Guidelines for the Diagnosis 

and Management of Asthma (EPR–2) 

(Ref. 5).19 The National Heart, Lung, and 

Blood Institute is one of the National 

Institutes of Health. In the 2002 update 

to EPR–2 (Ref. 6), we find the latest 

updates to the standard. 

In several points in Wyeth’s written, 

oral, and visual presentation for the 

NDAC/PADAC meeting, it was stated 

that use of epinephrine was consistent 

with the National Heart, Lung and 

Blood Institute’s asthma treatment 

guidelines (Ref. 5) (frequently called the 

second Expert Panel Report or EPR–2), 

issued as part of the National Asthma 


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20EPR–2 was updated in 2002 (Ref. 6) (EPR—

Update 2002). References to outside publications or 

any other statements of fact or opinion in this 

document concerning a drug product are not 

intended to be equivalent to statements in labeling 

approved under section 505 of the act (21 U.S.C. 

355) and part 314 of FDA regulations (21 CFR part 

314). 

21The EPR–2 is very similar to other published 

standards of care (See the Australian Asthma 

Management Handbook: 2002 (Ref. 7) and the 

‘‘Canadian Asthma Consensus Report, 1999’’ (Ref. 

8). 

22The reason we say that the difference is not 

significant for purposes of this document is that so 

many of the numbers discussed represent such 

broad estimates that the difference between 14 

percent and 22 percent would not affect any 

conclusion. We are acutely aware that for the 

individuals and families involved, absence of 

health insurance is very significant. 

Education and Prevention Program.20

The EPR–2, as updated, is widely seen 

as representing the generally recognized 

standard of care for asthma in the 

United States.21 Wyeth stated in its 

written materials that epinephrine is not 

mentioned specifically in the EPR–2 

(Wyeth briefing material, p. 1–8; 

meeting transcript, pp. 50–51; Wyeth 

slide 18). FDA disagrees with these 

statements. The 2002 update to the 

EPR–2 states that ‘‘[n]onselective agents 

(i.e., epinephrine, isoproterenol, 

metaproterenol) are not recommended 

due to their potential for excessive 

cardiac stimulation, especially in high 

doses’’ (Ref. 6, p. 120). While 

recognizing the possibility that the 

concerns expressed in the EPR–2 about 

cardiovascular risk may be overstated 

(see Refs. 4 and 9), we do not need to 

reach a conclusion on the relative 

cardiovascular risk of the use of 

epinephrine compared to the use of 

albuterol. FDA is unaware of any 

evidence comparing epinephrine and 

albuterol at recommended doses 

indicating that the cardiovascular safety 

of epinephrine is better than that of 

albuterol. 

A voting consultant with NDAC 

characterized the OTC epinephrine MDI 

as an ‘‘inferior medicine’’ (meeting 

transcript, p. 181). She admitted there 

was an absence of good data on the 

safety and efficacy of OTC epinephrine 

MDIs. Her opinions were shared by 

many members of the committees. 

NDAC/PADAC members who 

recommended that the essential use for 

OTC epinephrine MDIs be retained did 

not state that epinephrine was safer or 

more effective than albuterol. The 

evidence before us indicates that 

epinephrine is not safer or more 

effective than albuterol. The EPR–2 

recommends against epinephrine’s use. 

The consensus opinion at the NDAC/ 

PADAC meeting was that OTC 

epinephrine MDIs presented no 

significant therapeutic advantage over 

albuterol MDIs. This leads us to 

tentatively conclude that OTC 

epinephrine MDIs do not provide a 

clinical benefit that is otherwise 

unavailable. If we intended to draw a 

conclusion about the public health 

benefits of OTC epinephrine MDIs, and 

if OTC epinephrine MDIs were 

prescription drugs, as albuterol HFA 

MDIs are, our analysis would be nearly 

complete. However, the epinephrine 

MDIs, PRIMATENE MIST and the 

Armstrong products, are the only MDIs 

for treatment of asthma that are 

marketed OTC. We, therefore, have to 

examine more questions on the possible 

public health benefits of the continued 

OTC marketing of epinephrine CFC 

MDIs. 

2. Does OTC Marketing of Epinephrine 

MDIs Provide an Important Public 

Health Benefit? 

Our discussion on the public health 

benefit of OTC marketing of epinephrine 

is largely informed by the data 

presented and the opinions expressed at 

the NDAC/PADAC meeting. 

a. Is patient convenience an important 

public health benefit? Wyeth asserted at 

the NDAC/PADAC meeting that the 

convenience of patients having an OTC 

MDI for asthma provides an ‘‘important 

public health benefit’’ (meeting 

transcript, p. 66). Having this OTC 

product available would allow patients 

who run out of their prescribed 

medication and cannot get a refill 

authorization from their physician to go 

to the local store and purchase OTC 

epinephrine MDI. Wyeth presented data 

from a survey they had conducted 

indicating that one-third of OTC 

epinephrine MDI users use it as their 

sole asthma medication, while twothirds use it in addition to prescription 

drugs. The survey indicated that 55 

percent of people with asthma who 

solely use OTC epinephrine MDIs for 

their asthma said that the OTC product 

is ‘‘easier and quicker to obtain.’’ Fiftyeight percent of asthma patients who 

use both prescription drugs and OTC 

epinephrine MDIs say they purchase the 

OTC MDI when they either ‘‘run out of 

my prescription medication’’ or ‘‘have 

an asthma attack and I don’t have my 

prescription with me’’ (Wyeth slide 36). 

Maintaining current valid 

prescriptions and supplies of prescribed 

drugs is a regular and sometimes 

onerous, but necessary, task for many 

patients with chronic diseases. It would 

certainly be more convenient for all of 

these patients if some sort of therapeutic 

alternative were available OTC. 

However, there are no OTC remedies for 

most serious diseases. Of note, patients 

with anaphylaxis to bee stings or 

peanuts can face sudden, lifethreatening attacks if exposed to their 

relevant triggers. Yet epinephrine 

autoinjectors, such as EPIPEN, are not 

OTC products because of considerations 

that include the proper evaluation and 

treatment of such patients. No evidence 

has been presented to us, in the course 

of this rulemaking, to indicate how 

asthma differs from other serious 

diseases in a way that warrants having 

an OTC treatment available. 

These facts would support a 

conclusion that any added convenience 

of OTC availability of epinephrine for 

patients who have been prescribed 

drugs for the treatment of asthma, such 

as albuterol MDIs, does not provide an 

‘‘important public health benefit.’’

b. Do OTC epinephrine MDIs provide 

an important health benefit for people 

who have poor access to adequate 

health care? Wyeth and several 

members of NDAC and PADAC have 

stated that a significant number of 

people with asthma do not have 

adequate access to health care, and a 

significant number of these people with 

asthma use OTC epinephrine MDIs. To 

examine the public health benefit of 

OTC marketing of epinephrine MDIs we 

must examine (1) The number of people 

with asthma who use epinephrine 

because of inadequate access to health 

care providers able to diagnose asthma 

and prescribe treatments other than 

epinephrine, and (2) the extent that OTC 

epinephrine benefits these people. We 

are particularly interested in the public 

health benefits that may be provided to 

this population by having epinephrine 

MDIs available OTC. Any final 

conclusion we reach on the essentialuse designation of epinephrine could be 

affected by data on the public-health 

benefit contained in comments 

submitted in response to this proposed 

rule. 

Wyeth presented information at the 

NDAC/PADAC meeting from their 2005 

survey indicating that 22 percent of 

people with asthma did not have health 

insurance (Wyeth slide 31). Statistics 

from NCHS (Ref. 10) indicate that 

slightly less than 14.1 percent of the 

general population does not have health 

insurance. While the difference between 

14.1 percent and 22 percent is not 

significant for purposes of this 

document,22 it may be true that the 

percentage of people with asthma who 

are uninsured is higher than that of the 

general population. Wyeth also 

presented data indicating that 27 

percent of people with asthma do not 

have health insurance that provides 

prescription drug benefits (Wyeth slide 


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31). However, lack of insurance does not 

necessarily equate to poverty and 

financial barriers to adequate health 

care. Approximately 18 percent of 

uninsured Americans have household 

incomes of $75,000 or more, and 

another 17 percent have household 

incomes of $50,000 to $74,999 (Ref. 11). 

Other barriers to health care exist, 

such as lack of sick leave, 

transportation, and child care. However, 

we do not have any data that would be 

useful in determining how these barriers 

affect people with asthma and their use 

of OTC epinephrine MDIs. 

There is very little data about how 

barriers to health care affect use of OTC 

epinephrine MDIs. According to data 

provided by Wyeth, roughly two-thirds 

of OTC epinephrine MDI users use the 

MDIs in addition to prescription drugs, 

while one-third solely use OTC 

epinephrine MDIs (Wyeth slide 32). As 

discussed in section V.B.2.b of this 

document, a majority of the two-thirds 

of OTC epinephrine MDI users who also 

use prescription drugs do so for reasons 

of convenience. However, because the 

two-thirds of OTC epinephrine MDI 

users who also use prescription drugs 

apparently have adequate access to 

health care, we will focus, for this part 

of the document, on the one-third of 

OTC epinephrine MDI users who solely 

use OTC epinephrine MDIs. We have 

very little data on why patients use OTC 

epinephrine MDIs instead of prescribed 

drugs. At the NDAC/PADAC meeting 

Wyeth presented data from their 2005 

Internet survey of people with asthma 

(Wyeth slide 35). The data are 

summarized in table 1 as follows: 

TABLE 1.—MOST FREQUENT REASONS CITED BY SOLE OTC EPINEPHRINE MDI USERS

‘‘Easier and quicker to obtain’’ 55 percent 

‘‘More reasonably priced’’ 41 percent 

‘‘I don’t have health insurance’’ 25 percent 

‘‘I don’t want to go to a doctor’’ 25 percent 

‘‘I don’t have a doctor’’ 21 percent 

‘‘OTC drugs work better for me’’ 11 percent 

The basis for the ‘‘more reasonably 

priced’’ response in the survey is 

unclear. While the perception of a 

percentage of the survey participants 

may have been that OTC epinephrine 

was less costly, an accurate 

determination of the relative price of the 

OTC product compared to the 

prescription substitutes would require a 

complex analysis which could not be 

embodied in an informal Internet 

opinion survey. For example, it is not 

clear how respondents calculated the 

retail price of the prescription drug 

products that they compared to OTC 

epinephrine, if they were comparing 

comparable drug products, or the degree 

to which they factored health insurance 

co-payments or the availability of 

patient assistance programs into their 

price comparison. It is also unclear if 

the respondents viewed the cost of a 

visit to a physician to obtain a 

prescription as a part of the price of a 

prescription drug. Because it is not clear 

what this response actually means, it 

contributes little to our analysis of the 

possible public health benefits of 

epinephrine. 

As discussed at length at the NDAC/ 

PADAC meeting, the response in the 

survey that ‘‘OTC drugs work better for 

my asthma’’ is not supported by 

adequate and well-controlled studies. 

The responses that may best inform 

an attempt to reach a low-end estimate 

of the percentage of people who solely 

use OTC epinephrine MDIs who do so 

because of barriers to health care are ‘‘I 

don’t have health insurance’’ (25 

percent), ‘‘I don’t want to go to a doctor’’

(25 percent), and ‘‘I don’t have a doctor’’

(21 percent). Those stating absence of 

health insurance are describing a 

potential barrier to health care. The 

other two statements are more 

ambiguous. ‘‘I don’t want to go to a 

doctor’’ may be an expression of a 

general aversion to going to doctors, it 

may be a manifestation of a desire not 

to confront a potentially serious illness, 

or it also may reflect that an asthmatic 

may not wish to go to a doctor because 

of lack of insurance or other barriers to 

health care. ‘‘I don’t have a doctor,’’ may 

be similar to ‘‘I don’t want to go to a 

doctor,’’ or it may reflect a person who 

has not yet chosen a doctor, because of 

a recent arrival in a locality or because 

the person has stopped seeing a 

previous doctor. 

The survey participants were 

permitted to select more than one 

reason for solely using an OTC 

epinephrine MDI. While we know that 

participants gave more than one answer 

(the sum of the answers is 178 percent), 

we do not know how the responses 

overlapped with each other. We will 

assume, for now, that the 25 percent 

responding ‘‘I don’t have health 

insurance’’ represents users of OTC 

epinephrine who do so because of 

barriers to health care. We realize that 

this may underrepresent those people 

with asthma whose responses of ‘‘I don’t 

want to go to a doctor,’’ and ‘‘I don’t 

have a doctor’’ also reflected a barrier to 

health care. However, any 

underestimation may be 

counterbalanced by other factors, such 

as: 

• Approximately 18 percent of 

uninsured Americans have household 

incomes of $75,000 or more, and 

another 17 percent have household 

incomes of $50,000 to $74,999 (Ref. 11). 

While uninsured, these people would 

not necessarily face barriers to health 

care. 

• According to Wyeth’s 2005 Internet 

survey, 28 percent of people with 

asthma who solely use OTC epinephrine 

MDIs have visited a doctor in the 

previous year for treatment of asthma; 

these patients presumably have access 

to health care. 

We do not know how these two points 

relate to the numbers from Wyeth’s 2005 

Internet survey giving the reasons that 

people with asthma purchase OTC 

epinephrine MDIs. As was frequently 

noted at the NDAC/PADAC meeting, the 

debate over the essential-use status of 

epinephrine is hobbled by a paucity of 

data, and we note here that we are 

especially interested in receiving public 

comments and any available data 

concerning this issue. The fact that this 

is an Internet survey, and that we know 

little about how the survey was 

conducted, raises questions about its 

reliability. However, in the absence of 

better data, we estimate that 25 percent 

of people with asthma who solely use 

OTC epinephrine MDIs for treatment of 

asthma do so because of barriers to 


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23At the NDAC/PADAC meeting Wyeth presented 

estimates that 15 to 20 percent of adults with 

asthma use OTC epinephrine (Wyeth slide 32). 

Applying these percentages to the number of adults 

who have asthma, they estimated that 2 to 3 million 

people use OTC epinephrine MDIs at any given 

time. Wyeth appears to have made a mistake. If we 

look at the 1993 ACNielsen study (Wyeth slide 29) 

where the study population was adults, it appears 

that Wyeth compared the number of respondents 

who reported using an OTC asthma drug (557) to 

the number of respondents who reported having an 

asthma incident in the previous 12 months (2,713). 

If we divide 557 by 2,713, we get 0.205 or 20 

percent. The number of adults who have asthma is 

substantially higher than the number who have had 

an asthma incident in the previous 12 months; for 

2004 the numbers are 14.4 million and 7.7 million 

respectively (Ref. 35). Applying 15 to 20 percent to 

the number of adults with asthma would result in 

a significant inflation of the number of OTC 

epinephrine MDI users. Applying 15 to 20 percent 

to the number of adults who have had an asthma 

incident in the previous 12 months gives us an 

estimate of 1.7 to 2.3 million people using OTC 

epinephrine MDIs. We believe that this estimate is 

more accurate than the 2 to 3 million estimate. 

24See Refs. 17 and 18. The various studies used 

different methods of measuring non-compliance, so 

direct numeric comparisons are not possible. 

health care. Since two-thirds of people 

who use OTC epinephrine MDIs also 

use prescription drugs to treat their 

asthma, somewhat less than 9 percent of 

all people with asthma using OTC 

epinephrine MDIs do so because of 

barriers to health care. These figures 

appear to be the best low-end estimate 

we can derive from the limited data we 

have before us. Referring to their 2005 

Internet survey, Wyeth stated that 60 

percent of people with asthma solely 

using OTC epinephrine MDIs replied 

that they had a ‘‘prescription 

medication coverage plan’’ (Wyeth slide 

33). This figure is lower than the 66 

percent who replied that they had 

insurance covering physicians visits. 

This means that approximately 40 

percent of OTC epinephrine MDI users 

who solely use the product did not have 

prescription drug coverage. This seems 

a reasonable high-end estimate of the 

percentage of people with asthma solely 

using OTC epinephrine MDIs who do so 

because of barriers to health care. This 

estimate is over-inclusive because it 

includes people with asthma whose 

income would mean that absence of 

insurance does not present a barrier to 

health care and patients with asthma 

that have access to free or low-priced 

drugs through doctor’s samples or free 

and low-priced drug programs. The fact 

that lack of insurance coverage for 

prescription drugs does not perfectly 

reflect barriers to health care is shown 

by the fact, according to Wyeth’s 2005 

survey, that 19 percent of asthma 

patients who solely use prescription 

drugs do not have insurance coverage 

for prescription drugs. While it is overinclusive for some groups, the higher 

figure may do a better job of capturing 

people who face other poorly quantified 

barriers to health care, such as lack of 

sick leave, transportation, or child care. 

We have arrived at an estimate that 

between 25 percent and 40 percent of 

people with asthma who solely use OTC 

epinephrine MDIs, and therefore 

between 9 percent and 14 percent of all 

people with asthma that use OTC 

epinephrine MDIs, do so because of 

barriers to health care. We have also 

estimated that 1.7 to 2.3 million people 

with asthma use OTC epinephrine 

MDIs. This estimate is based on data 

provided by Wyeth at the NDAC/ 

PADAC meeting, although Wyeth 

reached a different conclusion based on 

the same numbers.23 Applying our 

estimate that between 9 percent and 14 

percent of all people with asthma who 

use OTC epinephrine MDIs do so 

because of barriers to health care to our 

estimate that 1.7 to 2.3 million people 

with asthma use OTC epinephrine 

MDIs, we arrive at an estimate that 

between 150,000 and 320,000 people 

with asthma who use OTC epinephrine 

MDIs do so because of barriers to health 

care. At the NDAC/PADAC meeting, a 

representative for several HispanicAmerican health policy organizations 

presented information about the high 

incidence of asthma among HispanicAmericans and African-Americans 

(meeting transcript, pp. 162 to 169). The 

representative opposed removing 

epinephrine’s essential-use designation, 

stating that it would have a serious 

adverse impact on people with asthma 

who face barriers to health care, and 

that this impact would be 

disproportionately felt by HispanicAmericans. 

According to the 2002 NHIS (Ref. 12), 

7.2 percent of Non-Hispanic Whites in 

the United States had asthma, while the 

prevalence of asthma in Non-Hispanic 

Blacks was 9.5 percent and the 

corresponding figure for Non-Hispanic 

American Indians was 9.9 percent. The 

incidence of asthma among all 

Hispanics in the United States (4.9 

percent) was lower than the incidence 

for the general population (7.2 percent), 

but the rate for Puerto Ricans was 

markedly higher at 13.1 percent. 

The National Health Care Disparities 

Report (Ref. 13) (2005 NHCDR) (which 

was mentioned by the speaker), 

indicates that Hispanic-Americans have 

significantly worse access to health care 

in terms of numbers of uninsured 

persons (Ref. 13, p. 92) having a usual 

source of care (a facility where one 

regularly receives care) (Ref. 13, p. 94), 

and having a usual primary care 

provider (a doctor or nurse from whom 

one regularly receives care) (Ref. 13, p. 

95). Other portions of the 2005 NHCDR 

provide information about asthma 

counseling in community health centers 

(Ref. 13, p. 135) and hospital admissions 

for pediatric asthma (Ref. 13, p. 150). 

None of the data in the 2005 NHDCR 

refer directly to the use of OTC 

epinephrine MDIs, so drawing specific 

conclusions from the 2005 NHCDR is 

difficult and subjective. 

Results from the National Cooperative 

Inner City Asthma Study (NCICAS) 

were referred to at the NDAC/PADAC 

meeting. NCICAS was sponsored by the 

National Institute of Allergy and 

Infectious Diseases (NIAID). NCICAS 

studied a treatment strategy for children 

with asthma living in inner-city census 

tracts where at least 20 percent of the 

population was below federal poverty 

guidelines. The study was conducted in 

eight study units located in seven cities 

across the United States. Wyeth 

presented information from a report 

from NCICAS, showing that 53 percent 

of the participants in the study reported 

difficulties in obtaining short term care 

for their children’s asthma (Ref. 14). 

Ninety-three percent of the families 

studied in NCICAS were insured, 

largely by Medicaid, and while 50 

percent of the families studied had to 

pay for health care (presumably a copayment for most of the families), only 

8 percent reported ‘‘care costs too 

much’’ as a barrier to health care. The 

intervention studied in the NCICAS was 

described as effective by one of the lead 

investigators (Ref. 15). Failure to refill 

prescriptions for asthma drugs was 

mentioned by Wyeth at the NDAC/ 

PADAC meeting (meeting transcript, p. 

113). Another report from NCICAS 

shows that 16 percent of caregivers 

reported not having a prescription filled 

for the child with asthma for whom they 

were caring (Ref. 16). This number 

compares favorably with compliance 

rates found in the general population.24

People do not always have prescriptions 

filled or take their medicine, regardless 

of income or health insurance. 

Dr. Carolyn Kercsmar, who 

participated in the NCICAS and is a 

member of PADAC, responded to 

Wyeth’s description of the data from the 

NCICAS by saying, ‘‘* * *[the children 

with asthma and the caregiver’s] access 

were problems and didn’t prevent them, 

it just hindered their care, and it was 

not just for acute care. It was for 

problems in accessing chronic care. 

Also, in that study, the vast majority of 

the patients had medication prescribed 

including albuterol as part of that 

study.* * *’’ (meeting transcript, p. 

141). 


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The NCICAS data do not show that 

the availability of OTC epinephrine is 

needed for adequate treatment of asthma 

in poor inner-city areas. While 

recognizing that the patient population 

studied was largely insured, we believe 

that comparable health care access 

options for low-income, non-insured 

patients are widely available. Programs 

that offer free or low-cost drugs, such as 

Schering’s ‘‘SP Cares program’’ (see 

www.schering-plough.com/ 

schering_plough/corp/sp_cares.jsp), and 

organizations that provide more 

comprehensive health care free or at 

low-cost, such as Communicare in 

South Carolina or the Puget Sound 

Neighborhood Health Centers in 

Washington, should be able to help 

lower economic barriers to access for 

people with asthma who use OTC 

epinephrine MDIs. Although we do not 

believe that all of the people currently 

using OTC epinephrine MDIs due to 

economic barriers to health care can or 

will avail themselves of these programs, 

we do believe that these programs are 

widely available, and that they can 

provide adequate alternatives to OTC 

epinephrine MDIs for many people with 

asthma. This should minimize some of 

the adverse impacts that may result 

from the absence of OTC epinephrine 

MDIs. 

In looking at the issue of OTC 

epinephrine MDIs as an alternative for 

people with asthma who face barriers to 

health care, it should be kept in mind 

that the retail price of OTC epinephrine 

MDIs is also a barrier to health care. In 

comparing the price of OTC epinephrine 

to that of its alternatives, we must keep 

in mind that OTC epinephrine MDIs, 

which cost approximately $13 per 

inhaler (meeting transcript, p. 127), are 

not available through any low-cost drug 

plans. Prescription drugs obtained 

through these programs can be 

substantially less expensive than OTC 

epinephrine MDIs. To give one example, 

an eligible person obtaining VENTOLIN 

HFA (albuterol MDI) through GSK’s 

‘‘Bridges to Access’’ program would 

make a $10 co-payment for a 60-day 

supply of the drug; after 60 days no 

further co-payment is required (see 

http://bridgestoaccess.gsk.com/ 

index.html). OTC epinephrine MDIs are 

more expensive than prescription drugs 

for people who can and do avail 

themselves of low-cost drug programs 

such as ‘‘SP Cares’’ and ‘‘Bridges to 

Access.’’

A public speaker representing an 

asthma education and advocacy 

organization before the NDAC/PADAC 

meeting said that the longer duration of 

effect of albuterol and levalbuterol (and 

other newer prescription drugs that do 

not release ODSs) means that, while 

these drug are more expensive per MDI 

and per dose, they may be cheaper than 

OTC epinephrine MDIs when the price 

is calculated for each hour of relief 

(meeting transcript, pp. 159–160). While 

a drug’s duration of action can affect the 

cost to a patient (or other payor) for 

therapy with the drug, we do not have 

the comparative clinical data to confirm 

the assertion made by the speaker. 

We believe that a small population of 

people with asthma who face barriers to 

health care may derive some benefit 

from having epinephrine MDIs available 

OTC. We also believe that utilization of 

programs providing low-cost or free 

prescription drugs may reduce, but not 

eliminate, the number of people with 

asthma facing barriers to health care 

who depend on OTC epinephrine MDIs. 

We are keenly interested in, and request 

comments on, the public health effect 

and costs that may result from the 

removal of OTC epinephrine MDIs from 

the market and how these programs may 

reduce any adverse impact on the public 

health. We will take under 

consideration and weigh carefully the 

potential consequences identified in 

public comments before issuing any 

final rule. In assessing the public health 

benefits of OTC epinephrine MDIs, the 

benefits of having the drug available 

OTC must be balanced against the 

potential risks, if any. 

c. Do risks of self-treatment of asthma 

outweigh the public health benefits that 

OTC epinephrine MDIs may provide? 

Much of the discussion at the NDAC/ 

PADAC meeting focused on the issue of 

whether the risks of self-treatment of 

asthma outweigh the public health 

benefits that OTC epinephrine MDIs 

may provide. This issue could affect any 

decision we make on the essential-use 

status of OTC epinephrine MDIs. 

Accordingly, we will discuss some of 

the points raised at the NDAC/PADAC 

meeting and other information we feel 

may be relevant, and request comment 

on these issues to the extent that they 

apply to OTC epinephrine MDIs as an 

essential use of ODSs. 

i. Misdiagnosis of asthma. OTC 

epinephrine MDIs are only indicated for 

mild intermittent asthma. The approved 

labeling for OTC epinephrine MDIs 

states that the drug should only be used 

after a doctor has diagnosed asthma. 

This is because asthma can be a difficult 

disease to diagnose, even for physicians 

(Ref. 19). COPD, vocal chord 

dysfunction, heart disease, and many 

other illnesses can be misdiagnosed as 

asthma (see Ref. 5, p. 22). 

The results of a study presented by 

Wyeth at the NDAC/PADAC meeting 

indicated that 92 percent of those 

surveyed who solely use OTC 

epinephrine MDI stated that they had 

been diagnosed with asthma by a doctor 

(Wyeth slide 23, citing Ref. 20). We do 

not have data on how recently the 

diagnoses were made or on the current 

accuracy of the diagnoses. The study 

did state that only 47 percent of those 

who solely use OTC epinephrine MDIs 

currently had a primary caregiver for 

management of asthma (Ref. 20, p. 989), 

which would seem to indicate that at 

least some of the diagnoses were not 

particularly recent. The Internet survey 

presented by Wyeth at the NDAC/ 

PADAC meeting indicates that 8 percent 

of purchasers of OTC epinephrine MDIs 

have not been diagnosed with asthma by 

a physician, and 28 percent of those 

who solely use OTC epinephrine MDI 

reported that they visited a doctor’s 

office in the past year for treatment of 

their asthma (Wyeth slide 33). This 

would imply that 72 percent of people 

who solely use OTC epinephrine MDI 

had not seen a doctor in the past year 

for diagnosis and treatment of their 

asthma. 

Asthma is a variable disease that can 

either lessen or worsen in severity over 

time. A person previously diagnosed 

with asthma may be asymptomatic for 

long periods of time. A diagnosis of 

asthma and, more important, an 

evaluation of its severity made at some 

point in the past may no longer be 

accurate. Currently, follow-up visits are 

recommended at 1- to 6-month intervals 

after an initial diagnosis of asthma 

(EPR–2, Ref. 5, p. 87). A previous 

diagnosis of asthma does not necessarily 

mean that an individual’s current 

asthma-like symptoms are caused by 

asthma, or that the individual’s asthma 

is of the same severity as originally 

diagnosed. The likelihood of the 

previous diagnosis accurately reflecting 

the patient’s current status would 

seemingly have to decrease the older the 

diagnosis and evaluation is. A study 

referred to by Wyeth at the NDAC/ 

PADAC meeting said that ‘‘self 

assessment of asthma severity may not 

be ‘on target,’ especially among 

individuals who self-medicate their 

illness with nonprescription 

bronchodilators’’ (Ref. 20, p. 992). It 

should be kept in mind that this was 

said about a group in which 92 percent 

had reported having been diagnosed by 

a physician as having asthma. This 

study was relatively small and, while 

potentially informative, it cannot be 

viewed as conclusive at this time. 

There are some additional data 

available on the potential misdiagnosis 

of the severity of asthma by purchasers 

of OTC epinephrine MDIs. Wyeth 

presented data at the NDAC/PADAC 


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meeting that 76 percent of OTC 

epinephrine MDI purchasers bought one 

or two OTC epinephrine MDIs a year. 

This indicates that 24 percent of 

purchasers bought three or more OTC 

epinephrine MDIs each year. A Wyeth 

web page (http://www.primatene.com/ 

faq/answers.asp#puffs) says that each 

15 milliliters (mL) vial should deliver 

270 puffs and the 22.5 mL of 

PRIMATENE MIST vial should deliver 

405 puffs. The 15 ml vial is the most 

popular size of PRIMATENE MIST 

(meeting transcript, p. 127). The 15 mL 

size is also the size manufactured for 

sale as house brands by Armstrong. If 

we look at three 15 mL MDIs used over 

a year-long period, we see that they 

would provide 16 puffs a week, a level 

of use that would indicate asthma 

incidents that are so frequent or severe 

that it no longer should be characterized 

mild intermittent asthma. We realize 

that some of the 24 percent of people 

who solely use OTC epinephrine MDIs 

and purchase three or more MDIs in a 

year may not be using all of the contents 

of the OTC epinephrine MDIs they 

purchase. They may be replacing lost 

MDIs or purchasing extra MDIs to keep 

at work or in a gym bag. It also should 

be noted that the use of two 22.5 mL 

vials a year also provides 16 puffs a 

week, again indicating a level of use that 

would not be associated with mild 

intermittent asthma. 

There is other evidence that 

purchasers of OTC bronchodilators were 

unable to correctly diagnose the severity 

of their asthma. A study was conducted 

in Australia of purchasers of albuterol 

(or salbutamol, as it is known in 

Australia and most of the rest of the 

world), a bronchodilator that was 

available both with and without a 

prescription in the State of New South 

Wales (Ref. 21). In that study, 95 percent 

of the surveyed purchasers who usually 

or always purchased albuterol without a 

prescription were undertreated for their 

asthma according to a relevant standard 

of care. We have not formed an opinion 

on the applicability of the study to the 

questions involved in this rulemaking. 

We realize that the study involved a 

different drug (albuterol), in a different 

country (Australia), and that the study 

is over 13 years old. However, we also 

recognize that the study may represent 

some of the better data currently 

available on the question of selfdiagnosis of asthma by the purchasers of 

OTC bronchodilators. 

The evidence seems to suggest that 

many OTC epinephrine MDI purchasers 

are buying the drug based either on selfdiagnosis or on an out-of-date 

physician’s diagnosis. 

The issue of the accuracy of the 

diagnosis of asthma upon which a 

purchase of an OTC epinephrine MDI is 

made is very important in reaching a 

determination on the public health 

benefits of having the drug available 

OTC. While some evidence suggests that 

many purchasers of OTC epinephrine 

MDIs are doing so based on an 

inaccurate diagnosis of the severity of 

their asthma, we have not reached a 

conclusion on that evidence’s weight 

and significance. 

ii. Undertreatment of asthma. 

Undertreatment of asthma can cause 

more frequent symptoms and attacks, 

missed work and school, activity 

limitations, a decline in lung health and 

function and, possibly, death (Ref. 9). 

As mentioned earlier, in the United 

States, the generally recognized 

standard of care for asthma is set forth 

in the EPR–2 (Ref. 5). In the 2002 update 

to EPR–2 (Ref. 6) we find the latest 

updates to the standard. Asthma is 

divided into four classes of severity, 

which correspond to treatment ‘‘steps.’’

More severe classes of asthma are 

defined by greater frequency of 

symptoms during the day and night, 

lower peak expiratory flow (PEF) and 

forced expiratory volume in 1 second 

(FEV1) (both are measurements of how 

well a patient can exhale using the 

greatest effort), and higher variability in 

PEF measurements over the course of a 

day. 

As the severity of a patient’s asthma 

increases, treatment becomes more 

aggressive: For mild persistent asthma, 

daily use of an inhaled corticosteroid 

(available only by prescription) is 

recommended; if the patient has 

moderate persistent asthma, higher 

doses of inhaled corticosteroids and/or 

inhaled corticosteroids with a longacting beta-agonist are recommended; 

and for severe persistent asthma, still 

higher doses of inhaled corticosteroids 

are recommended in conjunction with a 

long-acting bronchodilator (available 

only by prescription). 

If a patient’s asthma becomes more 

severe, treatment should become more 

aggressive, and if the asthma is well 

controlled, a physician should generally 

try to reduce the quantity of drugs being 

taken in order to provide good control 

with the minimum quantity of drugs. 

This approach is characterized as a 

‘‘stepwise approach for managing 

asthma’’ (EPR 2002 Update, Ref. 6, 

Appendix A–1). 

No daily medication is recommended 

for mild intermittent asthma, but the 

EPR–2 recommends the use of a shortacting inhaled beta2-agonist 

bronchodilator, as needed to treat the 

occasional bronchospasm. Albuterol is a 

short-acting inhaled beta2-agonist 

bronchodilator and albuterol MDIs are 

the most widely prescribed ‘‘rescue 

inhalers’’ in the United States. The 

EPR–2 does not recommend 

nonselective short-acting beta-agonist 

bronchodilators as rescue inhalers, but 

rather they recommend use of an 

inhaled short-acting beta2 selective 

agonist. Beta-receptors are adrenergic 

sites in the autonomic nervous system 

in which physiological responses occur 

when agents, in this case beta-agonists, 

are bound to the receptor. Activation of 

beta-receptors causes various reactions, 

including relaxation of the bronchial 

muscles and an increase in the rate and 

force of cardiac contraction. The betareceptors are subdivided into beta1, 

located primarily in the heart and 

intestinal smooth muscle, and beta2, 

more localized to bronchial, vascular, 

and uterine smooth muscles. 

Epinephrine is a non-selective betaagonist which affects both the beta1 and 

beta2-receptors so that it affects both 

heart and bronchial smooth muscles (as 

well as the intestinal, vascular, and 

uterine smooth muscles). Beta2 selective 

agonists, such as albuterol, have less of 

an effect on the heart than beta1 and 

non-selective beta-agonists have. 

Epinephrine’s lack of selectivity has 

caused concerns about its effect on the 

heart, but the limited data we have 

before us do not indicate that use of 

OTC epinephrine MDIs is associated 

with a greater risk of significant adverse 

cardiovascular events. 

The question of undertreatment of 

asthma for purchasers of OTC 

epinephrine MDIs is not confined to 

people with asthma who solely or 

primarily use OTC epinephrine MDIs. 

The level of usage of short-acting beta2- 

agonists is a factor that should be 

monitored by physicians treating 

asthma patients (EPR–2, Ref. 6, p. 35). 

Increased usage may often indicate the 

need for treatment being stepped up, 

while decreased usage may indicate that 

treatment could be stepped down. The 

availability of OTC epinephrine MDIs 

allows patients to purchase a shortacting beta-agonist without a 

prescription. It seems possible that this 

may deny important information to the 

health care provider as to the accurate 

assessment of a patient’s use of rescue 

inhalers. We are unaware of any data 

that directly address this issue. 

iii. Patient education. Patient 

education is generally regarded as a key 

component to successful asthma 

treatment. The EPR–2 says, ‘‘[E]ducation 

for an active partnership with patients 

remains the cornerstone of asthma 

management and should be carried out 

by health care providers delivering 


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asthma care. Education should start at 

the time of asthma diagnosis and be 

integrated into every step of clinical 

asthma care’’ (Ref. 5, p. 5). 

Elements of patient education can 

include providing information about 

how asthma affects the lungs, the 

difference between short-acting rescue 

medications and control medications, 

the importance of using control 

medication as prescribed, important 

environmental control measures that 

may need to be considered, such as 

removing asthma triggers from the 

patient’s home, the tracking of severity 

of the patient’s asthma, and proper use 

of an MDI. 

The proper use of an MDI is an 

important factor in proper treatment of 

asthma. This issue was mentioned but 

not discussed at the NDAC/PADAC 

meeting (meeting transcript, p. 139). 

Improper use of an MDI can result in a 

reduction of the dose delivery by 50 

percent or more (Ref. 22). A study in 

children and adolescents showed less 

than 25 percent used their MDIs 

correctly (Ref. 23), and a study in adults 

showed similar results (Ref. 24). 

Further, the last study showed that 

inadequate English language literacy is 

associated with poor use of MDIs. 

The importance of patient education 

may be a significant issue in any 

discussion of the risks and benefits of 

self-treatment of asthma. 

iv. Effects of undertreatment. While 

the cost of treatment for poor and 

medically underserved populations was 

frequently mentioned at the NDAC/ 

PADAC meeting, much less was said 

about the effects and costs of 

undertreatment. A recent study of urban 

pediatric patients, who were 

predominantly from poor and minority 

households, showed that an increased 

use of corticosteroids in pediatric 

patients (in accordance with the 

guidelines in EPR–2) resulted in fewer 

hospitalizations, emergency department 

visits, and outpatient visits (Ref. 25). 

The importance of prompt 

appropriate treatment of asthma is 

reinforced by studies suggesting that 

delaying treatment with inhaled 

corticosteroids decreases the 

effectiveness of the inhaled 

corticosteroids once treatment begins 

(Refs. 26 and 27). 

Studies also indicate that regular use 

of beta-agonist bronchodilators may 

reduce the person with asthma’s 

response to subsequent beta-agonist 

administration (Ref. 28). This tolerance 

could mean that patients who regularly 

use OTC epinephrine MDIs may be 

placed in a position where their 

occasional use of a beta2-agonist, as part 

of a course of treatment using inhaled 

corticosteroids as a control medication, 

may not be as effective for these patients 

as might otherwise be possible. The 

effects of undertreatment of asthma may 

be a key issue in any discussion of the 

risks and benefits of self-treatment of 

asthma. 

One public speaker did say that ‘‘a 

delay in the early introduction of 

prescription anti-inflammatory asthma 

therapy could lead to the development 

of irreversible lung damage’’ (meeting 

transcript, p. 171). We do not find his 

statement to be persuasive. The use of 

inhaled steroids was not shown to 

prevent damage to the lungs in several 

studies (Refs. 29, 30, and 31), and the 

evidence supporting the speaker’s 

statement about ‘‘irreversible lung 

damage’’ is limited and not conclusive 

(Ref. 32). Any disagreement on the issue 

of permanent lung damage should not 

be allowed to obscure the fact that 

proper use of inhaled steroids 

significantly reduces asthma morbidity. 

3. Conclusions on the Public Health 

Benefits of OTC Epinephrine MDIs 

We believe that epinephrine does not 

have any clinical advantages over 

albuterol HFA MDIs and that patient 

convenience for patients that have not 

kept their asthma drugs prescriptions 

current or do not have the prescribed 

drug product with them is not an 

important public health benefit. We 

have not reached a conclusion on the 

risks and benefits of continuing to have 

epinephrine available OTC for people 

with asthma who face barriers to 

obtaining appropriate health care, and 

therefore we cannot reach a conclusion 

on whether the use of OTC epinephrine 

MDIs provides an important health 

benefit. We specifically request 

comments on the expected costs and 

public health effects to individuals with 

asthma if OTC epinephrine MDIs were 

removed from the market without a 

similar product being available OTC. 

While our tentative conclusion that 

epinephrine is no longer an essential 

use is based primarily on the conclusion 

we have drawn regarding technical 

barriers to producing the epinephrine in 

a non-ODS formulation, we will 

evaluate the public-health effects of 

removal of OTC epinephrine from the 

market, and any final conclusions we 

reach on the essential-use designation of 

epinephrine may be significantly 

influenced by data received in 

comments on the public-health issues 

raised by this proposal. 

C. Does Use of OTC Epinephrine MDIs 

Release Cumulatively Significant 

Amounts of ODSs Into the Atmosphere 

or is the Release Warranted in View Of 

The Otherwise Unavailable Important 

Public Health Benefit? 

The use of CFCs in MDIs for the 

treatment of asthma and COPD is the 

only legal use in the United States of 

newly manufactured CFCs. The quantity 

of CFCs used in OTC epinephrine MDIs 

is a significant portion of the total 

quantity of newly manufactured CFCs 

used, and therefore eventually released, 

in the United States. The size of the 

portion will increase as other MDIs 

containing CFCs are removed from the 

market. As we discussed in part II of 

this document, the release of CFCs from 

MDIs is cumulatively significant. 

Because we have not reached a 

conclusion on the public health benefits 

of OTC epinephrine MDIs, we cannot 

reach a conclusion on whether the 

release of CFC ODSs is warranted in 

view of the public health benefits. 

D. Conclusions 

We have tentatively concluded the 

following: 

• The pharmaceutical industry has 

had success in formulating similar 

moieties without ODSs. In particular, 

HFA MDIs containing albuterol, a close 

chemical analog of epinephrine, have 

been approved by FDA. We have no 

evidence to suggest that formulating 

epinephrine in a product that does not 

release ODSs poses unique technical 

challenges. Therefore, we tentatively 

conclude that no substantial technical 

barriers exist to formulating an 

epinephrine inhaler without ODSs. 

• The release of ODSs into the 

atmosphere from OTC epinephrine 

MDIs is cumulatively significant. 

We have not reached a conclusion on 

whether the use of OTC epinephrine 

MDIs provides an unavailable important 

public health benefit or whether the 

release of ODSs from OTC epinephrine 

MDIs is warranted in view of the 

otherwise unavailable public health 

benefit. However, as we discussed in 

part II of this document, if a use fails to 

meet any one of the three criteria in 

§ 2.125(f), FDA may elect to go through 

rulemaking to remove its essential-use 

designation. 

We have therefore tentatively 

concluded that oral pressurized MDIs 

containing epinephrine are no longer an 

essential use of ODSs and should be 

removed from the list of essential uses 

in § 2.125(e). As noted throughout the 

preamble, we are keenly interested in 

receiving public comments and any 

available data concerning technical 


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barriers to developing an epinephrine 

inhaler without ODSs, the status of any 

ongoing efforts to develop such a 

product, and the public health effects 

and costs of removing epinephrine MDIs 

from the market prior to a similar 

product being available OTC. Any final 

conclusions that we reach on the 

essential-use designation of epinephrine 

may be significantly influenced by such 

comments. 

VI. Environmental Impact 

We have carefully considered the 

potential environmental effects of this 

action. We have tentatively concluded 

that the action will not have a 

significant adverse impact on the 

human environment, and that an 

environmental impact statement is not 

required. Our initial finding of no 

significant impact and the evidence 

supporting that finding, contained in a 

draft environmental assessment, may be 

seen in the Division of Dockets 

Management (see ADDRESSES) between 9 

a.m. and 4 p.m., Monday through 

Friday. We invite comments on the draft 

environmental assessment. Comments 

on the draft environmental assessment 

may be submitted in the same way as 

comments on this document (see 

DATES). 

VII. Analysis of Impacts 

A. Introduction 

FDA has examined the impacts of the 

proposed rule under Executive Order 

12866 the Regulatory Flexibility Act (5 

U.S.C. 601–612), and the Unfunded 

Mandates Reform Act of 1995 (Public 

Law No. 104–4). Executive Order 12866 

directs agencies to assess all costs and 

benefits of available regulatory 

alternatives and, when regulation is 

necessary, to select regulatory 

approaches that maximize net benefits 

(including potential economic, 

environmental, public health and safety, 

and other advantages; distributive 

impacts; and equity). The agency 

believes that this proposed rule is a 

significant regulatory action as defined 

by the Executive order. 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. The agency does not believe 

that the proposed rule would have a 

significant economic impact on a 

substantial number of small entities. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $122 

million, using the most current (2005) 

Implicit Price Deflator for the Gross 

Domestic Product. This proposed rule 

may result in a 1-year expenditure that 

would meet or exceed this amount. 

The Congressional Review Act 

requires that regulations that have been 

identified as being major must be 

submitted to Congress before taking 

effect. This rule is major under the 

Congressional Review Act. 

This proposed rule would prohibit 

sales of OTC epinephrine CFC MDIs in 

interstate commerce after December 31, 

2010, forcing users to either selfmedicate with less effective therapies 

(see section VII.D.3.a), or to visit a 

physician and get a prescription for an 

alternative drug product such as 

albuterol. Because OTC epinephrine 

CFC MDIs are widely regarded by 

physicians and people with asthma as 

the most effective relief medication for 

asthma available OTC, if users of these 

MDIs choose to self-medicate, they will 

be more likely to require hospitalization 

or an emergency department visit. 

Alternatively, if they choose to see a 

physician to obtain a prescription for 

albuterol, the OTC epinephrine CFC 

MDI users, or their insurers, will have 

to pay more, not only for visits to the 

physician, but also for more expensive 

drugs. More physician visits, however, 

may lead current OTC epinephrine MDI 

users to increase their use of 

prescription control medication, such as 

inhaled corticosteroids, which should 

decrease their likelihood of both asthma 

attacks and hospital visits. We have no 

data suggesting whether current OTC 

epinephrine MDI users are more likely 

to self-medicate or to visit a physician 

and get an albuterol MDI prescription 

once OTC epinephrine MDIs are no 

longer available. We therefore focus on 

scenarios where, if OTC epinephrine 

MDIs are no longer available, all current 

OTC epinephrine MDI users either selfmedicate with other products such as 

herbal supplements, caffeine, and OTC 

ephedrine or visit a physician to obtain, 

and fill, prescriptions for albuterol 

MDIs. These extreme scenarios offer 

plausible bounds for estimating the 

costs and benefits resulting from this 

proposed rule and regulatory 

alternatives. 

CFCs available for production of OTC 

epinephrine MDIs may be exhausted 

prior to the effective date of this 

proposed rule if the United States was 

unable to obtain an essential-use 

allocation for CFCs under the Montreal 

Protocol for use in OTC epinephrine 

MDIs for 2010 (see Ref. 33, p. 59). If so, 

this proposed rule may not have any 

significant impacts. To the extent that 

CFCs for production of OTC 

epinephrine MDIs remain available, we 

estimate this proposed rule will have 

the impacts summarized in the 

following table. 

TABLE 2.—SUMMARY OF ANNUAL QUANTIFIABLE EFFECTS OF THE PROPOSED RULE, ASSUMING CFCS FOR PRODUCTION

OF OTC EPINEPHRINE MDIS REMAIN AVAILABLE

Increased Health 

care Expenditure, 

in 2006 Dollars 

Increased 

Emergency 

Department 

Visits for 

Asthma 

Increased 

Hospitalizationsfor 

Asthma 

Reduced CFC 

Emissions 

from PhaseOut (tonnes) 

If current OTC epinephrine MDI users self-medicate $360 million to 

$1.0 billion 

0 to 

440,000 

40,000 to 120,000 70 

If current OTC epinephrine MDI users visit their physician for prescription albuterol (excluding controller medication) $170 million to 

$340 million 

70 

We are unable to estimate 

quantitatively the reductions in skin 

cancers, cataracts, and environmental 

harm that may result from the reduction 

in CFC emissions by roughly 70 tonnes 

during these years. Although we cannot 


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estimate quantitatively the public health 

effects of the phase-out, based on a 

qualitative assessment, the agency 

concludes that the benefits of this 

regulation justify its costs. 

We state the need for the regulation 

and its objective in section VII.B of this 

document. Section VII.C of this 

document provides background on CFC 

depletion of stratospheric ozone, the 

Montreal Protocol, the OTC epinephrine 

MDI market, and the health conditions 

that epinephrine is used to treat. We 

analyze the benefits and costs of the 

rule, including effects on government 

outlays, in section VII.D of this 

document. We assess alternative dates 

in section VII.E of this document, and 

discuss sensitivity analysis in section 

VII.F of this document. We present an 

analysis of the effects on small business 

in a regulatory flexibility analysis in 

section VIII of this document. We 

discuss our conclusions in section VII.H 

of this document. 

B. Need for Regulation and the 

Objective of This Rule 

This proposed regulation responds to 

U.S. obligations under the Montreal 

Protocol, as well as the requirements of 

the Clean Air Act. The Montreal 

Protocol itself recognizes that the 

regulation of ODSs is necessary because 

private markets are very unlikely to 

preserve levels of stratospheric ozone 

sufficient to protect the public health. In 

private markets, individual users of CFC 

MDIs have no significant private 

incentive to switch to non-ozonedepleting products because under 

current regulations the environmental 

and health costs of ozone-depleting 

products are external to users. 

Moreover, should MDI users voluntarily 

internalize these costs by switching to 

alternative products, they would not 

receive the benefits of their actions. 

Each user would bear all of the costs 

and virtually none of the benefits of 

such a switch, as the environmental and 

health benefits would tend to be 

distributed globally and occur decades 

in the future. Thus, the outcome of an 

unregulated private market would be 

the continued use of CFC MDIs, even if 

the social value of reducing emissions 

were clearly much greater than the price 

premium for non-ozone-depleting 

therapies. 

One of the objectives of this proposed 

rule is to respond to the obligations 

under the Montreal Protocol requiring 

the United States to reduce atmospheric 

emissions of ODSs, specifically CFCs. 

CFCs and other ODSs deplete the 

stratospheric ozone that protects the 

Earth from ultraviolet solar radiation. 

We are proposing to end the essentialuse designation for ODSs used in MDIs 

containing epinephrine because we 

have tentatively concluded that no 

substantial technical barriers exist to 

formulating epinephrine in a product 

that does not release ODSs (see section 

V.A of this document). Removing this 

essential-use designation will reduce 

emissions that deplete stratospheric 

ozone. 

C. Background 

1. CFCs and Stratospheric Ozone 

During the 1970s, scientists became 

aware of a relationship between the 

level of stratospheric ozone and 

industrial use of CFCs. Ozone (O3), 

which causes respiratory problems 

when it occurs in elevated 

concentrations near the ground, shields 

the Earth from potentially harmful solar 

radiation when it is in the stratosphere. 

Excessive exposure to solar radiation is 

associated with adverse health effects, 

such as skin cancer and cataracts, as 

well as adverse environmental effects. 

Emissions of CFCs and other ODSs 

reduce stratospheric ozone 

concentrations through a catalytic 

reaction, thereby allowing more solar 

radiation to reach the Earth’s surface. 

Because of this effect and its 

consequences, environmental scientists 

from the United States and other 

countries advocate ending all uses of 

these chemicals. 

2. The Montreal Protocol 

The international effort to craft a 

coordinated response to the global 

environmental problem of stratospheric 

ozone depletion culminated in the 

Montreal Protocol, an international 

agreement to regulate and reduce 

production of ODSs. The Montreal 

Protocol is described in section I.B.2 of 

this document. One hundred and 

ninety-one countries have now ratified 

the Montreal Protocol, and the overall 

usage of CFCs has been dramatically 

reduced. In 1986, global consumption of 

CFCs totaled about 1.1 million tonnes, 

and by 2004, total annual production 

had been reduced to 70,000 tonnes (Ref. 

34). This decline amounts to more than 

a 90-percent decrease in production and 

is a key measure of the success of the 

Montreal Protocol. Within the United 

States, use of ODSs, and CFCs in 

particular, has fallen sharply—

production and importation of CFCs is 

less than 1 percent of 1989 production 

and importation (Ref. 34). 

A relevant aspect of the Montreal 

Protocol is that production of CFCs in 

any year by any country is generally 

banned after the phase-out date unless 

the Parties to the Montreal Protocol 

agree to designate the use for which the 

CFCs are produced as ‘‘essential’’ and 

approve a quantity for that use. 

Each year, each Party nominates the 

amount of CFCs needed for each 

essential use and provides the reason 

such use is essential. Agreement on both 

the essentiality and the amount of CFCs 

needed for each nominated use has been 

reached by consensus at the annual 

Meeting of the Parties. 

3. Benefits of the Montreal Protocol 

EPA has generated a series of 

estimates of the environmental and 

public health benefits of the Montreal 

Protocol (Ref. 35). The benefits include 

reductions of hundreds of millions of 

nonfatal skin cancers, 6 million fewer 

fatalities due to skin cancer, and 27.5 

million cataracts avoided between 1990 

and 2165 if the Montreal Protocol were 

fully implemented. EPA estimates the 

value of these and related benefits to 

equal $4.3 trillion in present value 

when discounted at 2 percent over the 

period of 175 years. This amount is 

equivalent to about $6 trillion after 

adjusting for inflation between 1990 and 

2004. This estimate includes all benefits 

of total global ODS emission reductions 

expected from the Montreal Protocol 

and is based on reductions from a 

baseline scenario in which ODS 

emissions would continue to grow for 

decades but for the Montreal Protocol. 

4. Characteristics of Asthma 

OTC epinephrine MDIs are used to 

treat asthma, a chronic respiratory 

disease characterized by episodes or 

attacks of bronchospasm on top of 

chronic airway inflammation. These 

attacks can vary from mild to lifethreatening and involve shortness of 

breath, wheezing, cough, or a 

combination of symptoms. Many 

factors, including allergens, exercise, 

and viral infections may trigger an 

asthma attack. 

Early release data from the first 6 

months of the 2006 NHIS indicate that 

8.0 percent of people in the United 

States have asthma (Ref. 36, fig. 15.5). 

The prevalence of asthma decreases 

with age, with the prevalence being 9.5 

percent for children ages 0 to 14, 

compared to 7.8 percent for persons 

ages 15 to 34, and 7.4 percent for adults 

ages 35 and over (Ref. 36, fig. 15.5). 

The early release data from the first 6 

months of the 2006 NHIS also indicate 

4.2 percent of Americans had an asthma 

episode in the previous 12 months, with 

5.5 percent of children under age 14, 3.6 

percent of persons ages 15 to 34, and 4.0 

percent of adults over age 35 reporting 

episodes (Ref. 36, fig. 15.2). 


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25The 15 to 20 percent figures were derived, in 

part, from comparing the number of purchasers of 

OTC epinephrine MDIs to the number of adults 

suffering an asthma incident in the previous 12 

months. 

26Retail sales data from drug stores and 

supermarkets provided by ACNielsen do not 

include retail sales data from Wal-Mart because 

Wal-Mart does not participate in ACNielsen 

surveys. 

27Even if there is no essential-use allocation 

under the Montreal Protocol for the year 2010, 

production of epinephrine CFC MDIs would likely 

continue well into the year with manufacturers 

using preexisting stocks of CFCs. 

According to data from the National 

Ambulatory Medical Care Survey, in 

2004 there were about 15 million 

outpatient asthma visits to physician 

offices and hospital clinics and 1.8 

million emergency department visits 

(Ref. 37, table 19). According to data 

from the National Center for Health 

Statistics: National Hospital Discharge 

Survey, there were 497,000 hospital 

admissions for asthma in 2004 (Ref. 37, 

table 12) and 4,099 mortalities in 2003 

(Ref. 37, table 1). The estimated direct 

medical cost of asthma (hospital 

services, physician care, and 

medications) was $11.5 billion in 2004 

(Ref. 37, table 20). 

We estimate that OTC epinephrine 

MDI users make roughly 280,000 to 

370,000 visits to emergency 

departments and require roughly 75,000 

to 100,000 hospitalizations annually. 

We know of no data or study suggesting 

OTC epinephrine MDI users differ from 

other people with asthma in their risk 

of requiring emergency department 

visits or hospitalizations. In a published 

study of 601 people with asthma (Ref. 

38), the authors did not find any 

evidence that epinephrine users are 

more likely to visit emergency 

departments or to require 

hospitalization than people with asthma 

who do not use epinephrine. On the 

other hand, we know of no data 

suggesting that OTC epinephrine MDI 

users are less likely to visit emergency 

departments or require hospitalization. 

As described in section V.B.2.b of this 

document, we estimate that 1.7 to 2.3 

million people with asthma use OTC 

epinephrine MDIs. Assuming 1.7 to 2.3 

million people with asthma are OTC 

epinephrine MDI users, and that they 

require emergency department visits 

and hospitalization in proportion to 

their share of the population, OTC 

epinephrine MDI users account for 

roughly 280,000 to 370,000 emergency 

department visits annually [15 percent 

of 1.8 million = 280,000; 20 percent of 

1.8 million = 370,000] and 75,000 to 

100,000 hospitalizations annually [15 

percent of 497,000 = 75,000; 20 percent 

of 497,000 = 100,000].25

While the prevalence of asthma (the 

percent of the population diagnosed 

with asthma) has been increasing in 

recent years, CDC reports that the 

incidence of asthma (the rate of new 

diagnoses) has remained fairly constant 

since 1997 (Ref. 39). Non-Hispanic 

Blacks, children under 17 years old, and 

females have higher incidence rates 

than the general population and also are 

more likely to have had an attack of 

asthma in the previous 12 months. The 

CDC notes that although increases have 

occurred in the numbers and rates of 

physician office visits, hospital 

outpatient visits, and emergency 

department visits, these increases are 

accounted for by the increase in 

prevalence. The CDC also notes that 

asthma mortality and asthma 

hospitalization rates were declining and 

stated that these downward trends 

might indicate early successes by 

asthma intervention programs. 

5. Current U.S. Market for OTC 

Epinephrine MDIs 

We estimate that 1.7 million to 2.3 

million consumers purchase roughly 4.5 

million OTC epinephrine MDIs in the 

United States each year, at an average 

price of $13.29 per MDI. 

Based on data from ACNielsen for the 

52 weeks ending September 9, 2006 

(Ref. 40), we estimate 3.5 million OTC 

epinephrine MDIs are sold in the United 

States annually, excluding sales through 

Wal-Mart Stores, Inc. (Wal-Mart).26

Wyeth estimates roughly 25 percent of 

OTC medications such as PRIMATENE 

MIST, a branded OTC epinephrine MDI 

product, are sold through Wal-Mart 

annually (Wyeth slide 32), implying a 

total market of roughly 4.5 million OTC 

epinephrine MDIs sold annually. This is 

equivalent to 1.3 billion inhalations per 

year, or 146 million days of therapy (at 

9 inhalations per day, the highest 

recommended long-term dose). 

Based on ACNielsen data (Ref. 40) for 

the 52 weeks ending September 9, 2006, 

adjusted for sales through Wal-Mart, we 

estimate OTC epinephrine MDI sales 

amount to roughly $60 million in the 

United States annually and the average 

U.S. retail price of OTC epinephrine 

MDIs is $13.29, equivalent to roughly 

$0.41 per day of therapy. 

According to American Lung 

Association reports derived from the 

National Center for Health Statistics’

2004 NHIS (Ref. 37, table 10), 11.6 

million individuals reported having had 

an asthma attack in the last 12 months. 

According to Wyeth Pharmaceuticals 

(Wyeth slide 32), 15 to 20 percent of 

adults with asthma that have had an 

asthma attack in the previous 12 months 

use OTC epinephrine MDIs. As we 

discussed in section V.B.2.b of this 

document, we estimate that 1.7 to 2.3 

million people with asthma use OTC 

epinephrine MDIs. Each of these users, 

on average, purchases roughly 1.9 to 2.6 

OTC epinephrine MDIs each year [4.5 

million MDIs ÷ 1.7 million users = 2.6 

MDIs per user per year; 4.5 million 

MDIs ÷ 2.3 million users = 1.9 MDIs per 

user per year]. 

We estimate 600,000 to 1.3 million 

OTC epinephrine MDI users do not 

regularly use prescription asthma 

products. According to Wyeth 

Pharmaceuticals, somewhere between 

43 percent (Wyeth slide 33) and twothirds (Wyeth slide 32) of OTC 

epinephrine MDI users also use 

prescription drugs for treatment of their 

asthma. This implies that 600,000 to 1.3 

million OTC epinephrine MDI users do 

not use prescription asthma medicine 

[1,752,653 x .33 = 578,375; 2,336,871 x 

.57 = 1,332,016]. 

D. Benefits and Costs of the Proposed 

Rule 

We estimate the benefits and costs of 

government action relative to a baseline 

scenario that, in this case, is a 

description of the production, use, and 

access to OTC epinephrine MDIs in the 

absence of a final rule based on this 

proposed rule. In this section we first 

describe such a baseline, and then 

present our analysis of the benefits of 

the rulemaking. We also present an 

analysis of the most plausible regulatory 

alternatives, given the Montreal 

Protocol. Next, we turn to the costs of 

the rulemaking and to an analysis of the 

effects on the Medicare and Medicaid 

programs. 

1. Baseline Conditions 

We developed baseline estimates of 

future conditions to assess the economic 

effects of prohibiting marketing of OTC 

epinephrine MDIs after December 31, 

2010. It is standard practice to use, as 

a baseline, the state of the world 

without the rulemaking in question, or 

where the rulemaking implements a 

legislative requirement, the world 

without the statute. For this proposed 

rule, we make the baseline assumption 

that it is questionable if the United 

States would be able to obtain an 

essential-use allocation for CFCs for the 

manufacture of OTC epinephrine MDIs 

under the Montreal Protocol for 2010.27

To the extent that new CFCs for 

production of OTC epinephrine MDIs 

remain available past that date, we 

estimate this rulemaking will have 

quantifiable impacts as summarized in 

table 2. If CFCs for the production of 

OTC epinephrine MDIs are no longer 


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available by the end of 2010, this rule 

will have no impact. 

2. Benefits of the Proposed Rule 

The benefits of a final rule based on 

this proposed rule include 

environmental and public health 

improvements from protecting 

stratospheric ozone by reducing CFC 

emissions by roughly 70 tonnes 

annually. Benefits also include 

expectations of increased returns on 

investments in environmentally friendly 

technology, reduced risk of unexpected 

disruption of supply of OTC 

epinephrine MDIs, and continued 

international cooperation to comply 

with the spirit of the Montreal Protocol, 

thereby potentially reducing future 

emissions of ODSs throughout the 

world. 

Failure to finalize this proposed rule 

may lead the Parties to the Montreal 

Protocol to consider restrictions on 

access to the CFCs required to 

manufacture these OTC epinephrine 

MDIs products, which could create the 

risk of removal of these products from 

the market. 

a. Reduced CFC emissions. 

Withdrawal of OTC epinephrine MDIs 

from the market will reduce CFC 

emissions by approximately 70 tonnes 

per year. Current CFC inventories are 

substantial. Nominations for new CFC 

production are generally approved by 

the Parties to the Montreal Protocol 2 

years in advance. The proposed rule 

would ban marketing of OTC 

epinephrine CFC MDIs after December 

31, 2010. There is some uncertainty 

with respect to the amount of inventory 

that will be available in the future, but 

the United States’ ability to obtain an 

essential-use allocation for CFCs for the 

manufacture of OTC epinephrine MDIs 

in 2010 is questionable. 

In an evaluation of its program to 

administer the Clean Air Act, EPA has 

estimated that the benefits of controlling 

ODSs under the Montreal Protocol are 

the equivalent of $6 trillion in 2004 

dollars. However, EPA’s report provides 

no information on the total quantities of 

reduced emissions or the incremental 

value per tonne of reduced emissions. 

EPA derived its benefits estimates from 

a baseline that included continued 

increases in emissions in the absence of 

the Montreal Protocol. We have 

searched for authoritative scientific 

research that quantifies the marginal 

economic benefit of incremental 

emission reductions under the Montreal 

Protocol, but have found none 

conducted during the last 10 years. As 

a result, we are unable to quantify the 

environmental and human health 

benefits of reduced emissions from this 

regulation. Such benefits, in any event, 

were included in EPA’s earlier estimate 

of benefits. 

The reduction of CFC emissions 

associated with removing OTC 

epinephrine CFC MDIs from the U.S. 

market represents only a fraction of 1 

percent of total global CFC emissions. 

Current allocations of CFCs for OTC 

epinephrine MDIs account for less than 

0.1 percent of the total 1986 global 

production of CFCs (Ref. 41). 

Furthermore, current U.S. CFC 

emissions from MDIs represent a much 

smaller, but unknown share of the total 

emissions reduction associated with 

EPA’s estimate of $6 trillion in benefits, 

because that estimate reflects future 

emissions growth that has not occurred. 

If a final rule removing the essentialuse designation of OTC epinephrine 

MDIs takes effect before CFCs cease to 

be available, the proposed rule may 

account for some small part of the 

benefits estimated by EPA. However, we 

are unable to assess or quantify specific 

reductions in future skin cancers and 

cataracts associated with the reduced 

emissions that might be associated with 

this proposed rule or the regulatory 

alternatives. 

b. Returns on investment in 

environmentally-friendly technology. 

Establishing a phase-out date prior to 

the expiration of patents on HFA MDI 

technology and other aerosolized drug 

technology that does not use ODSs 

rewards the developers of the ozone-safe 

technologies. In particular, such a 

phase-out date would validate 

expectations that the government will 

protect incentives to research and 

develop ozone-safe technologies. 

Newly developed technologies to 

avoid ODS emissions have resulted in 

more environmentally ‘‘friendly’’ air 

conditioners, refrigerants, solvents, and 

propellants, but only after significant 

investments. Several manufacturers 

have claimed development costs that 

total between $250 million and $400 

million to develop HFA MDIs and new 

propellant-free devices for the global 

market (Ref. 42). 

These investments have resulted in 

several innovative products in addition 

to HFA MDIs. For example, breathactivated delivery systems, dose 

counters, DPIs, and mini-nebulizers 

have also been successfully marketed. 

c. International cooperation. The 

advantages of selecting a date that 

maintains international cooperation are 

substantial because the Montreal 

Protocol, like most international 

environmental treaties, relies primarily 

on a system of national selfenforcement, although it also includes a 

mechanism to address noncompliance. 

In addition, compliance with the 

Montreal Protocol’s directives is subject 

to differences in national 

implementation procedures. 

Economically less-developed nations, 

which have slower phase-out schedules 

than developed nations, have 

emphasized that progress in eliminating 

ODSs in developing nations is affected 

by observed progress of developed 

nations, such as the United States. If we 

had adopted a later phase-out date, 

other Parties could attempt to delay 

their own control measures. 

3. Costs of the Proposed Rule and 

Alternatives 

The costs of removing OTC 

epinephrine MDIs from the market 

include the costs of increased physician 

visits, increased use of more expensive 

reliever MDIs, and potential increases in 

the use of controller medications, visits 

to emergency departments, and 

hospitalizations. Because we cannot 

predict whether OTC epinephrine MDI 

users will self-medicate or go to a 

physician for a prescription reliever 

once OTC epinephrine MDIs are 

removed from the market, we quantify 

the costs for two extreme cases. In the 

first case, OTC epinephrine MDI users 

not already seeing a physician selfmedicate, while those who already see 

a physician switch from OTC 

epinephrine MDIs to albuterol HFA 

MDIs. In the second case, all OTC 

epinephrine MDI users visit their 

physician and switch to albuterol HFA 

MDIs. We propose these two cases as 

reasonable bounds for the expected cost 

of removing OTC epinephrine MDIs 

from the market. 

a. Self-medication. If all OTC 

epinephrine MDI users who do not 

already see a physician for asthma were 

to self-medicate once OTC epinephrine 

MDIs were no longer available, and 

those who do see a physician were to 

increase their albuterol use, we estimate 

this rulemaking would result in $360 

million to $1.0 billion in increased 

spending annually. This spending 

includes $280 million to $1.0 billion 

resulting from increased 

hospitalizations and emergency 

department visits, and roughly $30 

million to $80 million in increased 

spending on more expensive medicines. 

Under the assumption of selfmedication, we estimate that removing 

OTC epinephrine MDIs from the market 

would result in 40,000 to 120,000 more 

hospitalizations for asthma annually, 

and up to 440,000 more asthma-related 

emergency department visits each year. 

These estimates, based on calculations 

throughout this section, do not capture 

the decreased quality of life of OTC 


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epinephrine MDI users, lost 

productivity, or the cost of alternative 

therapies, such as herbal remedies, 

caffeine and OTC ephedrine. 

The authors of a published study 

found that people with asthma who selfmedicate with herbal products and 

caffeine, the most common forms of self 

medication, are at increased risk of 

requiring an emergency department visit 

or hospitalization (Ref. 38). They found 

that those using herbal treatments are 

2.5 times as likely to require 

hospitalization, and that those who use 

caffeine to treat asthma are 3.1 times as 

likely as other people with asthma to 

require both an emergency department 

visit and hospitalization. 

We estimate that OTC epinephrine 

MDI users who do not use prescription 

medicine for their asthma make roughly 

100,000 to 200,000 emergency 

department visits and require roughly 

25,000 to 50,000 hospitalizations. We 

estimate OTC epinephrine MDI users 

make roughly 280,000 to 370,000 

emergency department visits and 

require about 75,000 to 100,000 

hospitalizations annually, as described 

in section VII.C.4 of this document. We 

estimate somewhere between 43 percent 

and two-thirds of OTC epinephrine MDI 

users do not use prescription medicine 

for their asthma, as discussed in section 

6. Assuming that OTC epinephrine MDI 

users who do not use prescription 

medicine for asthma do not differ in 

their rates of hospitalization and 

emergency department visits from those 

who do use prescription medicine for 

asthma, we estimate that OTC 

epinephrine MDI users who do not use 

prescription medicine for asthma make 

100,000 to 200,000 emergency 

department visits and require 25,000 to 

55,000 hospitalizations annually 

[275,700 emergency department visits x 

1/3 = 91,900 emergency department 

visits; 367,600 emergency department 

visits x (1 - .43) = 209,532 emergency 

department visits; 74,550 

hospitalizations x 1/3 = 24,850 

hospitalizations; 99,400 hospitalizations 

x (1 - .43) = 56,658 hospitalizations]. 

If current OTC epinephrine MDI users 

who do not use prescription medicine 

for asthma were to self-medicate with 

herbal treatments, and those selfmedicating with herbal treatments face 

2.5 times the risk of a hospitalization, 

this would imply a lower bound 

increase of roughly 40,000 

hospitalizations [24,850 hospitalizations 

x (2.5 - 1) = 37,275]. As an upper bound, 

if all OTC epinephrine MDI users were 

to self-medicate with caffeine, 

emergency department visits would 

increase by roughly 440,000 [209,532 

emergency department visits x (3.1 - 1) 

= 440,017] and hospitalizations would 

increase by roughly 120,000 [56,658 

hospitalizations x (3.1 - 1) = 118,983]. 

We do not have data that will allow us 

to estimate increases in hospitalizations 

and emergency department visits for 

patients using other forms of selfmedication, such as OTC ephedrine. We 

request comments that would provide 

information allowing us to address this 

issue. 

We estimate the 2006 cost of an 

emergency department visit for asthma 

at roughly $300 and the cost of 

hospitalization for asthma at roughly 

$7500. Based on data from the 2004 

National Hospital Discharge Survey, the 

American Lung Association estimates 

the 497,000 hospitalizations for asthma 

cost roughly $3.6 billion in inpatient 

care and physician services, equivalent 

to roughly $7,300 per hospitalization 

(Ref. 37). The 1.8 million emergency 

department visits for asthma cost about 

$518 million, equivalent to roughly 

$280 per visit. Adjusting these figures 

for inflation according to the CPI for 

medical care, we estimate that the 

average hospitalization for asthma 

would cost roughly $7,500 and the 

average emergency department visit for 

asthma would cost roughly $300 in 

2006. 

Based on these estimates, if current 

OTC epinephrine MDI users who do not 

currently use prescription medicine 

were to self-medicate, the result would 

be costs of roughly $280 million [37,275 

hospitalizations x $7,565.84 = 

$282,016,770] to $1.0 billion annually 

[(118,982 hospitalizations x $7,565.84) + 

(440,017 emergency department visits x 

$294.17) = $1,029,639,003]. 

Assuming current OTC epinephrine 

MDI users who do use prescription 

medicine for asthma increase their use 

of albuterol HFA MDIs without 

requiring more frequent physician 

visits, we estimate that they will pay 

roughly $30 million to $80 million more 

for medicine each year. As discussed in 

section 6, somewhere between 43 

percent and two-thirds of OTC 

epinephrine MDI users also use 

prescription medicine for their asthma. 

Assuming current OTC epinephrine 

MDI users who also use prescription 

medicines for their asthma use roughly 

the same number of OTC epinephrine 

MDIs per year as those who do not, we 

estimate dual users use roughly 2 

million to 3 million OTC epinephrine 

MDIs annually [4,486,104 MDIs x 0.43 

= 1,929,025; 4,486,104 MDIs x 2/3 = 

2,990,736 MDIs]. As discussed in the 

following section, we estimate an 

albuterol HFA MDI will cost between 

$16 and $25 more than an OTC 

epinephrine MDI, and that one albuterol 

MDI is roughly equivalent to one OTC 

epinephrine MDI. The lower priced 

albuterol MDIs are currently being 

withdrawn from the market, and will 

not be available at the time of the 

proposed effective date of this rule (see 

70 FR 71685). The higher price for 

albuterol HFA MDIs implies that if OTC 

epinephrine MDI users who also use 

prescription medicine for their asthma 

were to increase their use of albuterol 

HFA MDIs when OTC epinephrine 

MDIs are no longer available, they and 

their insurers would spend roughly $30 

million to $80 million more per year for 

medicine [1,929,025 MDIs x $16.08 per 

MDI = $31,022,023; 2,990,736 MDIs x 

$25.15 per MDI = $76,418,426]. 

In total, self-medication by OTC 

epinephrine-only MDI users and 

increased albuterol use by those already 

using prescription medicine would 

result in increased spending of $360 

million to $1.0 billion annually 

[$282,016,770 + $76,418,426 = 

$358,435,196; $1,029,639,003 + 

$31,022,023 = $1,060,661,026]. 

b. Increased physician visits and 

albuterol use. If, as a result of the 

removal of OTC epinephrine MDIs from 

the market, all current OTC epinephrine 

MDI users were to seek out prescription 

albuterol HFA MDIs through increasing 

the frequency of physician visits, we 

estimate that this scenario would result 

in roughly $170 million to $340 million 

in increased health care spending, 

including $100 million to $225 million 

in economic costs through an increase 

in visits to physicians and $72 million 

to $114 million in increased spending 

on prescription albuterol. 

We estimate that if current 

epinephrine users who do not use 

prescription medicine for their asthma 

make one additional physician visit per 

year to enable them to switch from OTC 

epinephrine MDIs to albuterol MDIs, the 

result would be roughly 600,000 to 1.3 

million additional physician visits 

annually. This estimate stems directly 

from the estimate presented in section 6 

that there are roughly 600,000 to 1.3 

million epinephrine users who do not 

use prescription medicine for their 

asthma. These estimates assume that 

OTC epinephrine MDI users who do use 

prescription medicine for their asthma, 

and therefore already make regular 

physician visits, are able to increase 

their albuterol use without increasing 

the frequency of those visits. 

We estimate the 2006 cost of a 

physician visit for asthma to be roughly 

$170. Based on 2004 data from the 

National Ambulatory Medical Care 

Survey, the American Lung Association 

estimates that 1.5 million physician 

visits and non-emergency outpatient 


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53730 Federal Register / Vol. 72, No. 182 / Thursday, September 20, 2007 / Proposed Rules 

28Analysis completed by FDA based on 

information provided by IMS Health, IMS National 

Sales Perspective (TM), 2005, extracted March 

2006. 

hospital visits for asthma cost roughly 

$2.4 billion, equivalent to roughly $160 

per physician visit. Adjusting these 

figures for inflation according to the CPI 

for medical care, we estimate that a 

physician visit for asthma would cost 

roughly $170 per visit in 2006. An 

increase of 600,000 to 1.3 million 

physician visits each year would 

therefore cost roughly $100 million to 

$225 million annually [584,217.75 visits 

x $168.966 per visit = $98,712,936; 

1,332,016.47 visits x $168.966 per visit 

= $225,065,495]. These estimates do not 

take into account the value of the time 

patients spend visiting their physicians. 

If all current OTC epinephrine MDI 

users were to switch to prescription 

albuterol HFA MDIs, we estimate the 

result to be roughly $70 million to $115 

million in increased spending on 

medicine. We estimate that it will take 

roughly one albuterol HFA MDI to 

replace each OTC epinephrine MDI 

removed from the market. OTC 

epinephrine MDIs contain roughly 270, 

405, or 540 inhalations, depending on 

the size of the MDI. Based on ACNielsen 

data for the 52 weeks ending September 

9, 2006 (Ref. 40), we estimate that the 

average OTC epinephrine MDI 

contained 293 inhalations, equivalent to 

32.6 days of therapy, assuming OTC 

epinephrine MDI users use, but do not 

exceed, the long term maximum 

recommended dose of 9 inhalations per 

day. The usual dosage of albuterol HFA 

MDIs is 8 to 12 inhalations per day, and 

albuterol HFA MDIs contain 200 

inhalations, implying that each MDI 

contains 17 to 25 days of therapy per 

MDI. Allowing for the greater 

therapeutic effectiveness of albuterol 

compared to epinephrine, we estimate it 

will take roughly one albuterol HFA 

MDI to replace each OTC epinephrine 

MDI removed from the market. 

Based on ACNielsen data from the 52 

weeks ending September 9, 2006 (Ref. 

40), we estimate the average retail price 

of an OTC epinephrine MDI to be 

$13.29. Based on average retail sales 

prices across all payer types for the first 

half of 2004, the average albuterol HFA 

MDI cost $39.42 (Ref. 43). This estimate 

does not reflect less expensive albuterol 

HFA MDIs introduced to the market 

since that time. Some market analysts 

also predict that albuterol HFA MDI 

prices will decline up to 20 percent as 

the market switches away from albuterol 

CFC MDIs and large payers use their 

market power to drive down prices (Ref. 

44). Taking these factors into 

consideration, we estimate the average 

retail price of an albuterol HFA MDI is 

$30 or more, a price increase of roughly 

$16 to $25 per MDI. If current OTC 

epinephrine MDI users must purchase 

one albuterol MDI for each OTC 

epinephrine MDI they currently 

purchase, total expenditures by current 

OTC epinephrine MDI users and their 

insurers would increase roughly $70 

million to $115 million [4,486,104 MDIs 

x $16.08 per MDI = $72,134,239; 

4,486,104 MDIs x $25.55per MDI = 

$114,627,640]. 

If, instead of self-medicating, OTC 

epinephrine MDI users go to the 

physician and increase their use of 

albuterol HFA MDIs, we estimate 

increased spending of roughly $170 

million to $340 million dollars annually 

[$98,712,936 for physician visits + 

$72,134,239 for medicine (albuterol) = 

$170,857,175; $225,065,495 in 

physician visits + $114,627,640 in 

medicines = $339,693,135]. 

These estimated expenditures would 

decrease dramatically if generic 

albuterol HFA MDIs were to be 

introduced to the market. Patents listed 

in ‘‘Approved Drug Products with 

Therapeutic Equivalence Evaluations’’

(Orange Book) for albuterol HFA MDIs 

expire in 2010 and 2017, making those 

possible dates for generic entry. Of 

course, unforeseen introduction of 

alternative therapies could reduce these 

expected increases in expenditures. 

These increased expenditures 

represent, to some extent, transfers from 

consumers and third-party payers, 

including the Federal Government and 

State governments, to pharmaceutical 

manufacturers, patent holders, and 

other residual claimants. However, to 

some extent, these increased 

expenditures represent purchases of 

products that are more costly to 

manufacture and bring to market, and, 

therefore, would be social costs. We are 

unable to estimate the fraction of those 

increased expenditures on drugs that 

constitute social costs. 

c. Controller medication. We estimate 

that the cost to current OTC epinephrine 

MDI users of filling additional 

prescriptions for controller medications 

would, on average, exceed the potential 

direct cost savings from reducing 

hospitalizations and emergency 

department visits by more than $280 per 

current OTC epinephrine MDI user. 

In a study of almost 50,000 asthma 

patients (Ref. 45), the authors found that 

patients with low adherence to 

controller medication have significantly 

higher risk (odds ratio of 1.72) of 

emergency department visits or of 

hospitalization relative to patients with 

moderate or high adherence. The study 

found that patients receiving high daily 

doses of controller medication had the 

lowest risk (odds ratio of .37) of 

emergency department visits or of 

hospitalization. As discussed in section 

VII.D.3.a of this document, we estimate 

OTC epinephrine MDI users who do not 

use prescription medicines make 

roughly 100,000 to 200,000 emergency 

department visits and require about 

25,000 to 55,000 hospitalizations 

annually. If they all were to visit their 

physicians, receive prescriptions for a 

controller medication, fill them, and use 

the medication, based on the results of 

the study of almost 50,000 asthma 

patients, we estimate 20 to 40 percent of 

these emergency department visits and 

hospitalizations could be avoided, 

equivalent to roughly 20,000 to 80,000 

fewer emergency department visits [20 

percent of 91,900 is 18,380; 40 percent 

of 209,532 is 83,813] and 5,000 to 

10,000 fewer hospitalizations [20 

percent of 24,850 is 4,970; 40 percent of 

56,658 is 11,332]. Assuming the average 

cost for an emergency department visit 

for asthma is about $300 and the average 

cost of a hospitalization for asthma is 

roughly $7,500, as discussed in section 

D.3.a of this document, this would 

reduce health care costs by roughly $40 

million to $100 million annually 

[($294.17 per visit x 18,380) + ($7565.84 

per hospitalization x 4,970) = 

$41,236,000; ($294.14 per visit x 83,813) 

+ ($7565.84 per hospitalization x 

11,332) = $105,837,600]. This cost is 

roughly $70 to $80 per current OTC 

epinephrine MDI user per year 

[$41,236,000 / 584,218 OTC 

epinephrine only MDI users = $70.58; 

$105,837,600 / 1,332,016 OTC 

epinephrine only MDI users = $79.46]. 

We looked at a range of CFC-free 

controller medications such as 

FLOVENT HFA, ASMANEX 

TWISTHALER, PULMICORT 

TURBOHALER, and QVAR, and found 

the wholesale price of the smallest dose 

of the least expensive medication to be 

roughly $1.00 per day of therapy,28

equivalent to roughly $370 per patient 

year of therapy. On average, the cost of 

increasing the use of controller 

medication among current OTC 

epinephrine MDI users who do not 

currently use prescription medicine 

would exceed the benefits, in terms of 

decreased emergency department visits 

and hospitalizations, by over $280 per 

person per year. This number would be 

lower if a greater fraction of people with 

asthma at high risk of emergency 

department visits were to begin using 

controller medication on a regular basis, 

and higher if a greater fraction of low 

risk people with asthma were to begin 

using controller medication on a regular 


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basis. These estimates do not take into 

account the impact of asthma attacks on 

individuals’ quality of life and 

productivity. 

4. Effects on Medicaid and Medicare 

As a result of the removal of OTC 

epinephrine CFC MDIs from the market, 

we estimate State and Federal Medicaid 

spending will increase $35 million to 

$250 million annually and that Federal 

Medicare spending, together with 

private spending by Medicare 

beneficiaries, will increase $20 million 

to $250 million annually. Some OTC 

epinephrine MDI users may be eligible 

for both Medicare and Medicaid. To the 

extent this population is large, these 

estimates overstate potential spending 

increases from this proposed rule by 

counting these individuals twice: once 

in Medicaid estimates and once in 

Medicare estimates. We are unable to 

estimate the size of the population of 

OTC epinephrine MDI users eligible for 

both programs. 

a. Medicaid. We estimate that 20 to 25 

percent of the costs of the removal of 

OTC epinephrine MDIs from the market 

will be born by State and Federal 

Medicaid programs, equivalent to $70 

million to $250 million annually if 

Medicaid-eligible OTC epinephrine MDI 

users who do not use prescription 

medicine for their asthma were to selfmedicate upon implementation of this 

proposed rule, and equivalent to $35 

million to $85 million annually if 

Medicaid-eligible OTC epinephrine MDI 

users were to visit their physicians to 

obtain and fill prescriptions to enable 

them to switch to albuterol. Assuming 

epinephrine users with insurance, 

including Medicaid, are more likely to 

visit a doctor, and less likely to selfmedicate, the costs of this proposed rule 

are more likely to fall in the $35 million 

to $85 million range. 

According to proprietary surveys 

conducted by or for Wyeth between 

1993 and 1994 (Wyeth slide 31), 27 

percent to 33 percent of OTC 

epinephrine MDI users had incomes of 

less than $20,000 at the time the surveys 

were conducted. A 2005 Internet survey 

conducted by Wyeth found that 20 

percent of OTC epinephrine MDI users 

had incomes of less than $25,000. 

Eligibility for Medicaid varies by State 

but is generally tied to the Federal 

poverty guidelines (Ref. 46). The 2006 

Federal poverty guidelines establish a 

poverty threshold of $20,000 in annual 

income for a family of four (Ref. 47). 

Accordingly, if we assume 20 percent to 

25 percent of OTC epinephrine MDI 

users are eligible for Medicaid, if 

Medicaid-eligible OTC epinephrine MDI 

users who do not use prescription 

medicine were to self-medicate, and if 

those who do self-medicate were to 

switch to albuterol, Federal Medicaid 

spending would increase roughly $70 

million to $250 million annually [20 

percent of $360 million = $72 million; 

25 percent of 1 billion = $250 million]. 

If all current epinephrine users eligible 

for Medicaid were to instead visit their 

physicians and use prescription 

albuterol, we estimate that Federal 

Medicaid spending would increase by 

$35 million to $85 million dollars 

annually [20 percent of $170,857,175 = 

$34,171,435; 25 percent of $339,693,135 

= $84,923,284]. These estimates exclude 

costs that may result from increased 

prescribing of controller medications, 

and do not take into account the impact 

of asthma attacks on individuals’ quality 

of life and productivity. 

b. Medicare. We estimate 10 percent 

to 25 percent of the costs of the removal 

of OTC epinephrine MDIs from the 

market will be paid by Federal Medicare 

spending and by Medicare beneficiaries. 

If all Medicare-eligible OTC epinephrine 

MDI users were to self-medicate upon 

implementation of this proposed rule, 

Federal Medicare spending and 

spending by Medicare beneficiaries 

would increase roughly $40 million to 

$250 million dollars annually. 

Alternatively, if all Medicare-eligible 

OTC epinephrine MDI users were to 

visit their doctors to obtain and fill 

prescriptions for albuterol, Federal 

Medicare spending and spending by 

Medicare beneficiaries would increase 

roughly $20 to $85 million annually. 

Assuming epinephrine users with 

insurance, including Medicare, are more 

likely to visit a doctor, and less likely 

to self-medicate, the costs of this 

proposed rule are more likely to fall in 

the $20 million to $85 million range. 

According to proprietary surveys 

conducted by or for Wyeth between 

1993 and 2005 (Wyeth slide 31), 16 

percent to 33 percent of OTC 

epinephrine MDI users are over the age 

of 55, implying the percentage of 

epinephrine users over the age of 65, 

and therefore eligible for Medicare, 

must be lower. Accordingly, if we 

assume 10 percent to 25 percent of OTC 

epinephrine MDI users are over the age 

of 65, Medicare spending and private 

spending by Medicare beneficiaries 

would increase $40 million to $250 

million annually if all Medicare-eligible 

OTC epinephrine MDI users were to 

self-medicate [10 percent of $360 

million = $36 million; 25 percent of $1.0 

billion = $250 million], and by $20 

million to $85 million annually if they 

were all to visit their physicians for 

prescription albuterol [10 percent of 

$170,857,125 = $17 million; 25 percent 

of $339,693,135 = 84,923,284]. These 

estimates exclude costs that may result 

from increased prescribing of controller 

medications, and do not take into 

account the impact of asthma attacks on 

individuals’ quality of life and 

productivity. 

E. Alternative Phase-Out Dates 

The alternatives we considered 

included the following phase-out dates: 

1. December 31, 2008; 

2. December 31, 2009; 

3. December 31, 2010 (the proposed 

rule). 

Spending per year does not differ 

among the regulatory alternatives. The 

only difference among the alternatives is 

how long the estimated costs shown in 

table 2 of this document would accrue. 

At some time in the near future, the 

unavailability of CFCs—not the 

proposed rule or an alternative—may 

lead to removal of OTC epinephrine 

from the marketplace. Our current belief 

is that bulk CFCs are likely to be 

unavailable in 2010 (see section VII.A), 

so the costs for the first alternative 

would be the present value of the 

annual costs for 2 years, 2008–2009, and 

the cost for the second alternative 

would be the present value of the costs 

for 1 year, 2009. The third alternative, 

which is the proposed rule, would have 

no quantifiable costs or benefits. We 

invite comments on these projections 

and on the costs and benefits of any 

other possible alternative effective 

dates, such as December 31, 2011 or 

2012. 

F. Sensitivity Analyses 

The estimated costs summarized in 

table 2 incorporate a range of estimates 

about the price increases consumers and 

other payers will face, the size of the 

affected market, and the consequences 

of consumers’ response to the removal 

of OTC epinephrine MDIs from the 

market. This represents the full range of 

uncertainty for the estimated effects of 

this proposed rule. The full range 

incorporates the ranges of estimates for 

the individual uncertain variables in the 

analysis. 

In each section of the document, we 

show the ranges associated with each 

major uncertain variable, taking into 

account the possibility that in response 

to the removal of OTC epinephrine 

MDIs from the market, OTC epinephrine 

MDI users who do not currently use 

prescription medicines will either selfmedicate or visit a physician to get an 

albuterol prescription. The estimated 

increases in emergency department 

visits and hospitalizations depend upon 

a range of estimates of the percentage of 

people with asthma that use OTC 


pwalker on PROD1PC71 with PROPOSALS
53732 Federal Register / Vol. 72, No. 182 / Thursday, September 20, 2007 / Proposed Rules 

29FDA has verified all Web site addresses cited 

in this document, but FDA is not responsible for 

any subsequent changes to the Web sites after this 

document has published in the Federal Register. 

epinephrine MDIs (15 to 20 percent) and 

the fraction of OTC epinephrine MDI 

users that do not use prescription 

medicines and are therefore more likely 

to self-medicate (somewhere between 33 

and 57 percent), as well as the rate we 

estimate hospitalizations and emergency 

department visits will increase among 

this population (2.5 to 3.1 times). 

Similarly, estimates of the impact of 

the removal of OTC epinephrine MDIs 

from the market on public and private 

spending depends on whether or not 

OTC epinephrine MDI users selfmedicate, the above estimates on 

increased hospitalizations and 

emergency department visits, and the 

cost of those visits. A range of estimates 

of the percentage of adults with asthma 

that use OTC epinephrine MDIs (15 to 

20 percent) and the fraction of OTC 

epinephrine MDI users that do not use 

prescription medicine for their asthma 

(somewhere between 33 and 57 

percent), in addition to the overall size 

of the OTC epinephrine MDI market, 

determines the number of additional 

physician visits these users will require 

to switch from OTC epinephrine MDIs 

to albuterol MDIs. Estimated increases 

in spending on medicine depend on the 

size of the OTC epinephrine MDI 

market, and the price premium current 

OTC epinephrine MDI users can expect 

to pay for their medicine, roughly $16 

to $25 per MDI. 

G. Conclusion 

Limits in available data prevent us 

from quantifying the costs and benefits 

of the proposed rule and weighing them 

in comparable terms. The benefits of 

international cooperation to reduce ODS 

emissions are potentially enormous but 

difficult to attribute to any of the small 

steps, such as this rulemaking, that 

make such cooperation effective. As 

discussed above in detail, the benefits of 

the removal of OTC epinephrine MDIs 

from the market include environmental 

and public health improvements from 

protecting stratospheric ozone by 

reducing CFC emissions. Benefits also 

include expectations of increased 

returns on investments in 

environmentally friendly technology, 

reduced risk of unexpected disruption 

of supply of CFC MDIs, and continued 

international cooperation to comply 

with the spirit of the Montreal Protocol, 

thereby potentially reducing future 

emissions of ODSs throughout the 

world. The removal of OTC epinephrine 

MDIs from the market could potentially 

cost public and private consumers of 

OTC epinephrine MDIs hundreds of 

millions of dollars annually, and 

increase hospitalizations and emergency 

department visits for asthma 

significantly. If CFCs cease to be 

available for OTC epinephrine MDIs 

before the effective date of a final rule 

removing the essential-use designation 

of OTC epinephrine MDIs, however, this 

proposed rule would have no benefits or 

costs. We specifically request comments 

on the costs and benefits of this 

proposed rule. 

VIII. Regulatory Flexibility Analysis 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Because known current 

producers are not small entities and the 

likelihood that the proposed rule will 

not impose compliance costs, the 

agency does not believe that this 

proposed rule would have a significant 

economic impact on a substantial 

number of small entities. FDA requests 

comment on this issue. 

IX. The Paperwork Reduction Act of 

1995 

We have tentatively concluded that 

this proposed rule contains no 

collection of information. Therefore, 

clearance by the Office of Management 

and Budget under the Paperwork 

Reduction Act of 1995 is not required. 

X. Federalism 

We have analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. We 

have tentatively determined that the 

rule does not contain policies that have 

substantial direct effects on the States, 

on the relationship between the 

National Government and the States, or 

on the distribution of power and 

responsibilities among the various 

levels of government. Consequently, we 

do not currently plan to prepare a 

federalism summary impact statement 

for this rulemaking procedure. We 

invite comments on the federalism 

implications of this proposed rule. 

XI. Request for Comments 

Interested persons may submit to the 

Division of Dockets Management (see 

ADDRESSES) written comments regarding 

this proposal. Submit a single copy of 

electronic comments or two copies of 

any mailed comments, except that 

individuals may submit one paper copy. 

Comments are to be identified with the 

docket number found in brackets in the 

heading of this document. Received 

comments may be seen in the Division 

of Dockets Management between 9 a.m. 

and 4 p.m., Monday through Friday. 

An upcoming public meeting on the 

essential-use status of OTC MDIs 

containing epinephrine will provide an 

additional opportunity for public 

comment. We will provide details on 

the meeting in a notice published in the 

Federal Register in the near future. 

XII. References 

The following references have been 

placed on display in the Division of 

Dockets Management, 5630 Fishers 

Lane, rm. 1061, Rockville, MD 20852, 

and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday. FDA has verified the 

Web site addresses, but we are not 

responsible for subsequent changes to 

the Web site after this document 

publishes in the Federal Register.29

1. National Center for Health Statistics, 

‘‘Early Release of Selected Estimates Based 

on Data From the 2005 National Health 

Interview Survey,’’ figure 15.4, available at 

http://www.cdc.gov/nchs/data/nhis/ 

earlyrelease/200606_15.pdf. 

2. Alkermes, Inc., press release, dated 

March 22, 2004, available at http:// 

www.alkermes.com/newsroom/ 

showArticle.aspx?id=267. 

3. Fu, K. et al., ‘‘Air-Epinephrine: 

Inhalation Therapy for the Emergency SelfTreatment of Anaphylaxis,’’ Journal of 

Aerosol Medicine, Vol. 16(2):190, June 2003. 

4. Hendeles, L. et al., ‘‘Response to 

Nonprescription Epinephrine Inhaler During 

Nocturnal Asthma,’’ Annals of Allergy, 

Asthma, and Immunology, 95:530, December 

2005. 

5. National Heart, Lung, and Blood 

Institute, ‘‘Expert Panel Report 2: Guidelines 

for the Diagnosis and Management of 

Asthma,’’ NIH publication No. 97–4051, July 

1997. 

6. National Heart, Lung, and Blood 

Institute, ‘‘Expert Panel Report: Update on 

Selected Topics 2002: Guidelines for the 

Diagnosis and Management of Asthma,’’ NIH 

publication No. 02–5074, June 2003. 

7. National Asthma Council Australia Ltd., 

‘‘Asthma Management Handbook: 2002,’’

Melbourne:2002. 

8. Boulet, J. P. et al., ‘‘Canadian Asthma 

Consensus Report, 1999,’’ Canadian Medical 

Association Journal, 161(11 Supp.):S1, 

November 30, 1999. 

9. Dickinson, B. D. et al., ‘‘Safety of Overthe-Counter Inhalers for Asthma: Report of 

the Council on Scientific Affairs,’’ Chest, 

118(2):522, August 2000. 

10. Cohen, R. A. and M. E. Martinez, 

‘‘Health Insurance Coverage: Estimates from 

the National Health Interview Survey, 2005,’’

National Center for Health Statistics, June 

2006, available at http://www.cdc.gov/nchs/ 

data/nhis/earlyrelease/insur200606.pdf. 

11. U.S. Census Bureau, ‘‘Table HI01. 

Health Insurance Coverage Status and Type 

of Coverage by Selected Characteristics: 2004: 

All Races,’’ available at http:// 

pubdb3.census.gov/macro/032005/health/ 

h01_001.htm. 


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12. National Center for Health Statistics, 

‘‘Asthma Prevalence, Health Care Use and 

Mortality, 2002,’’ fig. 1, available at http:// 

www.cdc.gov/nchs/products/pubs/pubd/ 

hestats/asthma/asthma.htm. 

13. Agency for Health Quality and 

Research, 2005 National Healthcare 

Disparities Report, AHQR publication 06–

0017, December 2005, available at http:// 

www.ahrq.gov/qual/nhdr05/nhdr05.htm. 

14. Crain, E. F. et al., ‘‘Reported Difficulties 

in Access to Quality Care for Children with 

Asthma in the Inner City,’’ Archives of 

Pediatric and Adolescent Medicine,’’

152:333, April 1998. 

15. Evans, R. et al., ‘‘A Randomized 

Clinical Trial to Reduce Asthma Morbidity 

Among Inner-City Children: Results of the 

National Cooperative Inner-City Asthma 

Study,’’ Journal of Pediatrics, 135(3):332, 

September 1999. 

16. Bauman, L. J. et al., ‘‘Relationship of 

Adherence to Pediatric Asthma Morbidity 

Among Inner-City Children,’’ Pediatrics, 

110(1):1, June 2006. 

17. Bender, B. et al. ‘‘Measurement of 

Children’s Asthma Medication Adherence by 

Self Report, Mother Report, Canister Weight, 

and Doser CT,’’ Annals of Allergy, Asthma, 

and Immunology, 85:416, November 2000. 

18. Erickson S. R. et al., ‘‘Compliance From 

Self-Reported versus Pharmacy Claims Data 

With Metered-Dose Inhalers,’’ The Annals of 

Pharmacotherapy, 35(9): 997, September 

2001. 

19. Joyce, D. P., K. R. Chapman, and S. 

Kesten, ‘‘Prior Diagnosis and Treatment of 

Patients with Normal Results of 

Methocholine Challenge and Unexplained 

Respiratory Symptoms,’’ Chest, 109(3):697, 

March 1996. 

20. Kuschner, W. G. et al. 

‘‘Nonprescription Bronchodilator Medication 

Use in Asthma,’’ Chest, 112(4):987, October 

1997. 

21. Gibson, P., ‘‘Association Between 

Availability of Non-Prescription b2 Agonist 

Inhalers and Undertreatment of Asthma,’’

British Medical Journal, 306:1514, June 5, 

1993. 

22. Giraud, V., and N. Roche, ‘‘Misuse of 

Corticosteroid Metered-Dose Inhaler Is 

Associated With Decreased Asthma 

Stability,’’ European Respiratory Journal, 

19:246, 2002. 

23. Scarfone, R. J. et al., ‘‘Demonstrated 

Use of Metered-Dose Inhalers and Peak Flow 

Meters by Children and Adolescents with 

Acute Exacerbations,’’ Archives of Pediatric 

and Adolescent Medicine,’’ 156:378, April 

2002. 

24. Williams, M. V., ‘‘Inadequate Literacy 

Is a Barrier to Asthma Knowledge and SelfCare,’’ Chest, 114(4):1008, October 1998. 

25. Cloutier, M. et al., ‘‘Use of Asthma 

Guidelines by Primary Care Providers to 

Reduce Hospitalizations and Emergency 

Department Visits in Poor, Minority, Urban 

Children,’’ Journal of Pediatrics, 146:591, 

May 2005. 

26. Overbeek, S. E. et al., ‘‘Is Delayed 

Introduction of Inhaled Corticosteroids 

Harmful in Patients With Obstructive 

Airways Disease (Asthma and COPD)?’’

Chest, 110(1):35, July 1996. 

27. Selroos, O. et al., ‘‘Effect of Early vs 

Late Intervention With Inhaled 

Corticosteroids in Asthma,’’ Chest, 

108(5):1228, November 1995. 

28. Salpeter, S. R., T. M. Ormiston, and E. 

E. Salpeter, ‘‘Meta-Analysis: Respiratory 

Tolerance to Regular b2 Agonist Use in 

Patients with Asthma,’’ Annals of Internal 

Medicine, 140(10):802, May 18, 2004. 

29. Szefler, S. et al., ‘‘Long-Term Effects of 

Budesonide or Nedocromil in Children With 

Asthma,’’ New England Journal of Medicine, 

343:1054, October 12, 2000. 

30. Guilbert, T. et al., ‘‘Long-Term Inhaled 

Corticosteroids in Pre-School Children at 

High Risk for Asthma,’’ New England Journal 

of Medicine, 354:1985, May 11, 2006. 

31. Bisgard, H. et al., ‘‘Intermittent Inhaled 

Corticosteroids in Infants with Episodic 

Wheezing,’’ New England Journal of 

Medicine, 354:1998, May 11, 2006. 

32. Bousquet, J. et al., ‘‘Asthma: From 

Bronchoconstriction to Airways 

Inflammation and Remodeling,’’ American 

Journal of Respiratory and Critical Care 

Medicine, 161:1720, 2000. 

33. United Nations Environmental 

Programme, 2006 Assessment Report of the 

Technology and Economic Assessment Panel, 

2006. 

34. United Nations Environmental 

Programme, Production and Consumption of 

Ozone-Depleting Substances: 1986–2004, 

2005. 

35. U.S. Environmental Protection Agency, 

‘‘The Benefits and Costs of the Clean Air Act: 

1990–2010,’’ (http://www.epa.gov/air/ 

sect812/copy99.html) November 1999. 

36. National Center for Health Statistics, 

‘‘Early Release of Selected Estimates Based 

on Data From the January-September 2006 

National Health Interview Survey’’ March 28, 

2007, available at http://www.cdc.gov/nchs/ 

about/major/nhis/released200703.htm#15. 

37. American Lung Association, ‘‘Trends in 

Asthma Morbidity and Mortality,’’

Epidemiology & Statistics Unit, Research and 

Scientific Affairs, July 2006. 

38. Blanc, P. D. et al., ‘‘Use of Herbal 

Products, Coffee or Black Tea, and Over-theCounter Medications as Self-Treatments 

Among Adults with Asthma,’’ Journal of 

Allergy and Clinical Immunology, 100:(6\1) 

789, December 1997. 

39. Mannino, D. M. et al., ‘‘Surveillance for 

Asthma—United States, 1980–1999,’’

Morbidity and Mortality Weekly Report, 

51(SS01):1–13, March 29, 2002. 

40. Analysis completed by FDA based on 

retail sales data from drug stores and 

supermarkets provided by ACNielsen for the 

52 weeks ending September 9, 2006. 

41. U.S. Environmental Protection Agency, 

final rule, ‘‘Protection of Stratospheric 

Ozone: Allocation of Essential Use 

Allowances for Calendar Year 2006,’’ 71 FR 

58504, October 4, 2006. 

42. Rozek, R. P., and E. R. Bishko, 

‘‘Economics Issues Raised in the FDA’s 

Proposed Rule on Removing the EssentialUse Designation for Albuterol MDIs,’’

National Economic Research Associates, 

August 13, 2004 (FDA Docket No. 2003P–

0029/C25). 

43. Analysis completed by FDA based on 

prescription data provided by IMS Health, 

National Prescription Audit, 2004; IMS 

Health, IMS MIDAS (TM), Q1/2004–Q2/2004. 

44. Gal, A., and N. R. Chari, ‘‘TEVA, SEPR: 

SGP to Phase Out CFC Albuterol Production 

by Early 2007; TEVA and SEPR Likely to 

Benefit,’’ report prepared for Sanford C. 

Bernstein & Co., LLC (New York), October 17, 

2006. 

45. Berger, W. E. et al., ‘‘The Utility of the 

Health Plan Employer Data and Information 

Set (HEDIS) Asthma Measure to Predict 

Asthma-Related Outcomes,’’ Annals of 

Allergy, Asthma and Immunology, 93:538, 

December 2004. 

46. Centers for Medicare and Medicaid 

Services, Medicaid at-a-Glance 2005: A 

Medicaid Information Source, available at 

http://www.cms.hhs.gov/MedicaidEligibility/ 

downloads/MedGlance05.pdf. 

47. Department of Health and Human 

Services, notice, ‘‘Annual Update of the HHS 

Poverty Guidelines,’’ 71 FR 3848, January 24, 

2006. 

List of Subjects in 21 CFR Part 2 

Administrative practice and 

procedure, Cosmetics, Devices, Drugs, 

Foods. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act, the Clean Air 

Act, and under authority delegated to 

the Commissioner of Food and Drugs, 

after consultation with the 

Administrator of the Environmental 

Protection Agency, it is proposed that 

21 CFR part 2 be amended as follows: 

PART 2—GENERAL ADMINISTRATIVE 

RULINGS AND DECISIONS 

1. The authority citation for 21 CFR 

part 2 continues to read as follows: 

Authority: 15 U.S.C. 402, 409; 21 U.S.C. 

321, 331, 335, 342, 343, 346a, 348, 351, 352, 

355, 360b, 361, 362, 371, 372, 374; 42 U.S.C. 

7671 et seq. 

§ 2.125 [Amended] 

2. In § 2.125, remove and reserve 

paragraph (e)(2)(v). 

Dated: February 5, 2007. 

Jeffrey Shuren, 

Assistant Commissioner for Policy. 

Editorial note: This document was 

received at the Office of the Federal Register 

on September 17, 2007. 

[FR Doc. 07–4663 Filed 9–17–07; 12:01 pm] 

BILLING CODE 4160–01–S 


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