[Federal Register Volume 76, Number 143 (Tuesday, July 26, 2011)]
[Rules and Regulations]
[Pages 44475-44489]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-18347]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 341

[Docket No. FDA-1995-N-0031 (Formerly Docket No. 1995N-0205)]
RIN 0910-AF32


Labeling for Bronchodilators To Treat Asthma; Cold, Cough, 
Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-
Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the final 
monograph (FM) for over-the-counter (OTC) bronchodilator drug products 
to add additional warnings (e.g., an ``Asthma alert'') and to revise 
the indications, warnings, and directions in the labeling of products 
containing the ingredients ephedrine, ephedrine hydrochloride, 
ephedrine sulfate, epinephrine, epinephrine bitartrate, racephedrine 
hydrochloride, and racepinephrine hydrochloride. FDA is issuing this 
final rule after considering data and information submitted in response 
to the Agency's proposed labeling revisions for these products. This 
final rule is part of FDA's ongoing review of OTC drug products.

DATES: Effective Date: This regulation is effective January 23, 2012.
    Compliance Date: The compliance date for all products, regardless 
of annual sales, is January 23, 2012.

FOR FURTHER INFORMATION CONTACT: Elaine Abraham, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 5410, Silver Spring, MD 20993, 301-796-
2090.

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Changes to the Labeling of OTC Drug Products Used To Treat Asthma
II. History of the Development of the 1986 Final Monograph
III. Amendments to the 1986 Final Monograph Proposed by FDA
IV. FDA's Response to Comments Received About the Proposed Labeling 
Changes
V. Additional Consumer-Friendly Changes FDA Made to the Labeling
VI. FDA's Final Conclusions on Warnings and Other Labeling 
Information for OTC Bronchodilator Drug Products
    A. Implementation Date for New Labeling
    B. Statement About Warnings
VII. Analysis of Impacts
    A. Introduction and Summary
    1. Introduction
    2. Summary
    B. Need for Regulation
    C. Benefits
    D. Costs
    1. Relabeling Costs
    2. Switching Costs
    3. Estimated Total Costs
    E. Summary of Costs and Benefits
    F. Analysis of Regulatory Alternatives to the Final Rule
    G. Regulatory Flexibility Analysis
    1. Description and Number of Affected Small Entities
    2. Economic Effect on Small Entities
    3. Additional Flexibility Considered
VIII. Paperwork Reduction Act of 1995
IX. Environmental Impact
X. Federalism
XI. References

I. Changes to the Labeling of OTC Drug Products Used To Treat Asthma

    This rulemaking amends the FM for OTC bronchodilator drug products 
used to treat asthma. The ``Indications,'' ``Warnings'' and 
``Directions'' portions of the Drug Facts label are being changed to 
help consumers better understand how to use these products and when it 
is appropriate to seek treatment from a doctor for their asthma. The 
``Indications'' section now recommends use only for temporary relief of 
mild symptoms of intermittent asthma. Changes to both the ``Warnings'' 
and ``Directions'' sections emphasize that consumers should not exceed 
the recommended dose or duration of use with these drug products. The 
``Warnings'' section is being changed to make it clearer that consumers 
whose symptoms worsen or do not improve should see a doctor. The 
``Indications,'' ``Warnings'' and ``Directions'' portions of the Drug 
Facts label have also been revised to use language that is more readily 
understood by the average consumer.

II. History of the Development of the 1986 Final Monograph

    In the Federal Register of September 9, 1976 (41 FR 38312), FDA 
published an advance notice of proposed rulemaking (ANPR) under 21 CFR 
330.10(a)(6) to establish a monograph for OTC cold, cough, allergy, 
bronchodilator, and antiasthmatic drug products. The ANPR included the 
recommendations of the Advisory Review Panel on OTC Cold, Cough, 
Allergy, Bronchodilator, and Antiasthmatic Drug Products (the Panel), 
the advisory review panel responsible for evaluating data on the active 
ingredients in this drug class. The Panel recommended that ephedrine 
and epinephrine preparations be placed in Category I (generally 
recognized as safe and effective or GRASE) for OTC bronchodilator use 
(41 FR 38312 at 38370 through 38372).
    FDA concurred with the Panel's recommendations and subsequently 
published the proposed rule in the Federal Register of October 26, 
1982, (47 FR 47520) and the FM for OTC bronchodilator drug products in 
the Federal Register of October 2, 1986, (51 FR 35326). FDA included 
the following active ingredients in the FM:

 ``Ephedrine ingredients'' (i.e., ephedrine, ephedrine 
hydrochloride, ephedrine sulfate, and racephedrine hydrochloride)
 ``Epinephrine ingredients'' (i.e., epinephrine, epinephrine 
bitartrate, and racepinephrine hydrochloride)
In subsequent rulemaking documents for this category, including this 
final rule, the term ``ephedrine ingredients'' refers to the four 
active ephedrine ingredients, the term ``epinephrine ingredients'' 
refers to the three active epinephrine ingredients, and the term ``OTC 
bronchodilator drug products''

[[Page 44476]]

refers to products containing any of these seven active ingredients.

III. Amendments to the 1986 Final Monograph Proposed by FDA

    In the Federal Register of July 27, 1995, (60 FR 38643), FDA 
published a proposed rule to amend the FM to remove ephedrine 
ingredients and to classify them as not GRASE for OTC use. At that 
time, FDA had reassessed the risks and the benefits of OTC ephedrine 
drug products based on additional safety data and proposed their 
removal because of safety concerns. After reviewing the comments 
received in response to this proposed rule, FDA concluded that 
ephedrine ingredients should remain in the FM for self-treatment of 
mild bronchial asthma, and FDA withdrew its proposal to remove 
ephedrine ingredients from the OTC drug monograph in the Federal 
Register of July 13, 2005, (70 FR 40237).
    Also, in the Federal Register of July 13, 2005, (70 FR 40237), FDA 
proposed to amend the FM for OTC bronchodilator drug products with 
revised labeling for products containing ephedrine and epinephrine 
ingredients. FDA proposed changes to the Indications, Warnings, and 
Directions sections of the labeling in 21 CFR 341.76. FDA stated that 
it considered the labeling revisions to be important for the safe and 
effective use of OTC bronchodilator drug products by providing better 
instructions to asthmatics about how to use the product correctly and 
to minimize risks. The proposed changes were:
    1. Indications: Revise the indications in Sec.  341.76(b)(1) and 
(b)(2) to a single indication using the OTC ``Drug Facts'' labeling 
format in Sec.  201.66 (21 CFR 201.66). The labeling recommends use 
only for the ``temporary relief of occasional symptoms of mild 
asthma.''
    2. Warnings: Revise the entire warnings section into ``Drug Facts'' 
labeling as follows:
     Add an ``Asthma alert'' section. This proposed section 
lists specific criteria consumers can use to identify when to seek 
treatment from a doctor for their asthma (e.g., failure of the product 
to improve symptoms, need for excessive dosing). The ``Asthma alert'' 
should appear as the first statement under the heading ``Warnings'' and 
certain parts of the ``Asthma Alert'' should be in bold type. This new 
warning replaces the warning previously found in Sec.  341.76(c)(5)(i) 
for ephedrine ingredients and in Sec.  341.76(c)(6)(ii) for epinephrine 
ingredients.
     List a number of statements that follow the subheading 
``Do not use.'' These statements include the warnings previously found 
in Sec.  341.76(c)(1), (c)(4), and (c)(6)(iii), where applicable, for 
products intended for use in a hand-held rubber bulb nebulizer.
     List a number of conditions for which consumers should 
consult a doctor before using these products under the subheading ``Ask 
a doctor before use if you have.'' This list includes the conditions 
previously stated in Sec.  341.76(c)(2), plus several additional 
conditions.
     Advise consumers to consult a doctor before using the OTC 
bronchodilator drug product with other specified drugs. This 
information appears under the subheading ``Ask a doctor or pharmacist 
before use if you are.'' The list of other specified drugs includes 
prescription drugs for asthma previously stated in Sec.  341.76(c)(3) 
as well as a new list of other drugs that could cause side effects when 
used concurrently with ephedrine or epinephrine ingredients.
     List information that consumers need to know under the 
heading ``When using this product.'' This information includes the 
following:
    a. Direct consumers' attention to information about the risks 
associated with increased blood pressure or heart rate by requiring 
that this information appear in bold type as the first bulleted 
statement.
    b. Side effects that may occur (including side effects currently 
listed in Sec.  341.76(c)(5)(ii)).
    c. Information about risks associated with taking the drug more 
often than recommended or at higher-than-recommended doses. This 
information is currently in Sec.  341.76(c)(6)(i) for products 
containing epinephrine ingredients. FDA proposed to include the 
information for all products containing either ephedrine or epinephrine 
ingredients.
    d. New information about avoiding certain foods and dietary 
supplements while using an OTC bronchodilator drug product.
    3. Directions: Revise the directions in Sec.  341.76(d)(1) and 
(d)(2) to include the statement ``do not exceed dosage'' [in bold type] 
as the first bulleted statement under the heading ``Directions.''

IV. FDA's Response to Comments Received About the Proposed Labeling 
Changes

    In response to the amendment to the FM proposed in the Federal 
Register of July 13, 2005, FDA received comments from two consumers, 
one manufacturer of OTC bronchodilator drug products, and three 
national associations. One consumer comment discussed dextromethorphan. 
This comment is not addressed further in this final rule because this 
ingredient is a cough suppressant rather than a bronchodilator.
    (Comment 1) A comment submitted by an asthma patient supported the 
proposed rule and the continued availability of asthma drugs over the 
counter (Ref. 1). The comment stated that the proposed rule provides 
adequate warnings to address both the ``realistic dangers'' (e.g., 
increased heart rate) and ``remote dangers'' (e.g., seizure) to users. 
FDA agrees with the comment.
    (Comment 2) One comment, from an association of respiratory 
therapists, stated that patients who suffer from asthma must have 
adequate instructions and education about drug administration (Ref. 2). 
The comment also stated that this information should be included with 
OTC or prescription medication to ensure that consumers receive the 
full benefits from their drugs and to prevent life-threatening 
conditions associated with improper use. The comment supported FDA's 
revisions to the warnings for OTC bronchodilator drug products to 
enhance labeling for existing products, but urged FDA to reconsider 
permitting bronchodilator products to remain OTC.
    FDA does not plan to remove bronchodilator products from the OTC 
marketplace. FDA has found that the standards for safety, 
effectiveness, and labeling for OTC bronchodilator drug products have 
been met. Safety means a low incidence of adverse reactions or 
significant side effects under adequate directions for use and warnings 
against unsafe use as well as low potential for harm which may result 
from abuse under conditions of widespread availability (21 CFR 
330.10(a)(4)(i)). Effectiveness means a reasonable expectation that, in 
a significant proportion of the target population, the pharmacological 
effect of the drug, when used under adequate directions for use and 
warnings against unsafe use, will provide clinically significant relief 
of the type claimed (21 CFR 330.10(a)(4)(ii)). OTC drug product 
labeling must be clear and truthful and must state the intended uses 
and results of the product; adequate directions for proper use; and 
warnings against unsafe use, side effects, and adverse reactions in 
such terms as to render them likely to be read and understood by the 
ordinary individual, including individuals of low comprehension, under 
customary conditions of purchase and use (21 CFR 330.10(a)(4)(v)). FDA 
has a reasonable expectation that these drugs provide a clinically 
meaningful

[[Page 44477]]

benefit in the treatment of mild symptoms of intermittent asthma when 
they are used according to labeled instructions for the temporary 
relief of wheezing, tightness of chest, and shortness of breath.
    In this final rule, FDA has revised the indication to provide the 
consumer with a better understanding of the use of these drug products. 
In the July 13, 2005, proposed rule (70 FR 40237), FDA proposed changes 
to the ``Indications'' section of the labeling in Sec.  341.76(b) (21 
CFR 341.76(b)). The indication proposed in that proposed rule was for 
the ``temporary relief of occasional symptoms of mild asthma: wheezing, 
tightness of chest, shortness of breath'' (70 FR 40237 at 40248). This 
indication was based on the National Asthma Education and Prevention 
Program (NAEPP) Guidelines of 2002, which defined mild intermittent 
asthma as having symptoms no more than twice a week during the day or 
twice a month at night. FDA determined that people with mild 
intermittent asthma were the only category of asthmatics who should be 
candidates for OTC bronchodilators and stated that asthmatics with more 
severe asthma disease (i.e., persistent asthma) should be under the 
care of a physician for consideration of additional therapy to control 
the disease (70 FR 40237 at 40240).
    Newer NAEPP guidelines on the treatment of asthma published in 2007 
(Ref. 3) state that ``mild asthma'' is a persistent form of asthma with 
symptoms occurring two or more times per week, but not daily. What was 
previously called ``mild intermittent asthma'' is now classified as 
``intermittent asthma'' and is defined as having symptoms no more than 
twice a week during the day or twice a month at night. Between 
asthmatic episodes, these asthmatics have no symptoms and can maintain 
a normal level of activity. FDA is revising the indication for OTC 
bronchodilators to be consistent with this change in terminology for 
classifying asthma severity. The revised indication is as follows: 
``For temporary relief of mild symptoms of intermittent asthma e.g., 
wheezing, tightness of chest, and shortness of breath.'' This revised 
indication conveys the same important information to the consumer as 
proposed in 2005; that these products should be used on a temporary 
basis and only for mild symptoms of intermittent asthma, while 
including a better description of the type of asthma by current 
guidelines for which OTC products should be used.
    (Comment 3) One comment agreed with FDA's proposed labeling changes 
with one exception (Ref. 4). The comment disagreed with the following 
warning, contending that the data did not support this statement:

    When using this product * * * increased blood pressure or heart 
rate can occur, which could lead to more serious problems such as 
heart attack, stroke, and death. Your risk can increase if you take 
more frequently or more than the recommended dose.

    The comment stated that FDA's proposed warning fails to acknowledge 
that while the available data on ephedrine and epinephrine show that 
both may increase blood pressure or heart rate, the effect of the 
increase varies based on the individual's risk factors. Further, the 
magnitude of the warning is not supported by the literature or adverse 
event data, and this warning is unnecessarily alarming.
    The comment further objected to FDA's warning because it implies 
that all consumers are at equal risk for complications resulting from 
increases in heart rate or blood pressure. The comment noted that 
sympathomimetic drugs (such as ephedrine) may cause modest increases in 
heart rate and blood pressure, but individual outcomes vary from person 
to person based on underlying risk factors. Because FDA described 
adverse event reports associated with taking ephedrine-containing 
bronchodilator drug products more frequently, or in higher amounts, 
than the labeled dose in the 2005 proposed rule (70 FR 40237 at 40243), 
the comment contended that no evidence was presented to link normal use 
of OTC bronchodilators with any of the events listed in the proposed 
warning. The comment recommended the following language as being more 
representative of the data:

    When using this product * * * increased blood pressure or heart 
rate may occur, which could increase your risk of more serious 
problems, especially if you have risk factors such as a history of 
high blood pressure or heart disease. Your risk may increase if you 
take more frequently or more than the recommended dose.

    FDA does not agree. FDA stated in the proposed rule (70 FR 40237 at 
40243) that based on reports it has received, the risk of adverse 
events from ephedrine can occur at any dosage and may increase when 
taking a higher dose or taking more frequent doses than at the 
recommended dose. In the July 27, 1995, proposed rule to exclude OTC 
ephedrine drug products from the FM for OTC bronchodilator drug 
products (60 FR 38643 at 38644), FDA discussed a number of reports of 
young people abusing OTC ephedrine drug products. In one case, 9 junior 
high school students took 3 to 8 ephedrine 25 milligram (mg) tablets 
and experienced rapid heart beats. One female who took 8 tablets had 
200 heart beats per minute 2 hours after taking the tablets. In another 
case, a 22-year-old female took OTC ephedrine tablets (number not 
reported) and presented to a hospital emergency room with blood 
pressure of 170/110 millimeters mercury.
    FDA also discussed three deaths that occurred. One report involved 
a 17-year-old male who died after ingesting a toxic or lethal amount of 
ephedrine. In another case, a 24-year-old male who died of an overdose 
had a blood level of ephedrine over 30 times the usual therapeutic 
range. In another case, a 52-year-old-male took 10 to 15 ephedrine 
tablets (believed to be 50 mg) over the previous 24 hours before he 
died.
    Based on these cases, we disagree with the comment that the risk of 
adverse reactions is limited mostly to people with risk factors such as 
a history of high blood pressure or heart disease. As stated in the 
July 13, 2005, proposed rule (70 FR 40237 at 40243), the risk of 
adverse events from ephedrine can occur at any dosage, even in healthy 
individuals who did not take excessive amounts. However, we agree with 
the comment that those individuals with certain risk factors are at a 
greater risk. As discussed in the proposed rule, cardiovascular side 
effects from OTC bronchodilator drug products can include an increase 
in blood pressure and heart rate, which could lead to more serious 
problems such as heart attack, stroke, and death (70 FR 40237 at 40242 
to 40243). The intent of this warning is to alert all potential users 
of these products that there are serious risks, even potential death, 
associated with the use of OTC bronchodilator drug products and that 
these risks may increase if they take the product more frequently or 
take more than the recommended dose. We are revising the warning to 
better convey risk information in clear language to people who have a 
history of high blood pressure or heart disease. See the language set 
out in Sec.  341.76(c)(4) in this rule.
    (Comment 4) One comment noted FDA's statement in the 2005 proposed 
rule that, based on differences in composition between OTC ephedrine 
drug products and dietary supplements containing botanical sources of 
ephedrine alkaloids, ``adverse event data for dietary supplements 
containing ephedrine alkaloids may not be completely applicable to 
ephedrine drug products'' (70 FR 40237 at 40241) (Ref. 4). Emphasizing 
that FDA's 2004 final rule declaring dietary supplements containing 
ephedrine alkaloids

[[Page 44478]]

adulterated (69 FR 6788) was specific to dietary supplements, the 
comment expressed concern that the labeling for OTC bronchodilator drug 
products was being revised based on data from botanically derived 
ephedrine alkaloids in dietary supplements, which are different from 
the ephedrine or epinephrine ingredients in OTC bronchodilator drugs. 
For example, the active ingredients in OTC bronchodilator drugs must 
meet United States Pharmacopeia standards of identity, strength, 
quality, and purity, but dietary supplements contain varying amounts 
and proportions of ephedrine and other ephedrine alkaloids (such as 
norephedrine, pseudoephedrine, and methylephedrine), depending on the 
plant species used (70 FR 40237 at 40241).
    Although dietary supplements contain ephedrine alkaloids that are 
not present in OTC ephedrine drug products, ephedrine is the ingredient 
that was common to both dietary supplements and OTC drug products. As 
mentioned in the proposed rule, botanically-derived ephedrine alkaloids 
and the OTC bronchodilator drug product ingredients are related 
sympathomimetic chemicals that have similar pharmacologic actions. The 
adverse events associated with dietary supplements that used to contain 
ephedrine alkaloids may also occur in susceptible individuals taking an 
OTC bronchodilator drug product containing ephedrine covered by this 
monograph. FDA considers the known risks associated with dietary 
supplements that contained ephedrine alkaloids to be important for 
consideration as part of our analysis in the development of labeling 
warnings for bronchodilator drug products containing ephedrine, and 
thus includes those risks in its analysis.
    (Comment 5) A comment objected to the inclusion of a warning about 
``death'' in the labeling for OTC bronchodilator drug products (Ref. 
4). It said that this warning should be reserved for the ``most 
exceptional circumstances'' and that the existing data did not support 
the warning. The comment noted that there is no reference to the word 
``death'' in the current electronic Physician's Desk Reference labeling 
for OTC products, but cited 51 patient leaflets for prescription 
products that warn patients specifically about the possibility of death 
when taking a particular product.
    FDA agrees that the term ``death'' in a warning should be used only 
when it is an accurate representation of existing data. As discussed in 
comment 3, we have reports of death resulting from taking too much 
ephedrine. We conclude that the warning is important for safe use of 
these OTC drug products to alert consumers to the potential 
consequences of inadequate treatment of asthma and the potential for 
serious adverse events, such as heart attack, stroke, and death, 
associated with these products.
    (Comment 6) A comment questioned the meaning of the term 
``temporary'' in the ``Indication'' statement in Sec.  341.76(b)(1) of 
the 1995 OTC bronchodilator FM, ``for temporary relief of shortness of 
breath, tightness of chest, and wheezing due to bronchial asthma'' 
(Ref. 5). The comment asked what the time period associated with 
``temporary'' was intended to be and whether these drugs provide 
temporary relief for all levels of asthma severity.
    For bronchodilator drug products, ``temporary'' is defined by the 
dosing intervals that appear in the directions for use. The temporary 
effect of ephedrine is expected to be 4 hours and the temporary effect 
of epinephrine is expected to be 3 hours. If relief is not achieved 
after taking a dose of the product, consumers should seek the advice of 
a health professional. FDA notes that the term ``temporary'' is 
commonly used in OTC drug product labeling to imply short-term rather 
than permanent relief and to discourage consumers from prolonged use.
    To better explain proper use of these products, FDA is revising the 
``indication'' statement in this final rule as follows: ``for temporary 
relief of mild symptoms of intermittent asthma: [bullet] wheezing 
[bullet] tightness of chest [bullet] shortness of breath'' (see comment 
2). People with more severe asthma should consult a physician and ask 
about other types of asthma relief products.
    (Comment 7) One comment addressed the additional ``Indications'' in 
Sec.  341.76(b)(1)(i) and (b)(ii) of the OTC bronchodilator FM, ``for 
the temporary relief of bronchial asthma'' and ``eases breathing for 
asthma patients by reducing spasms of bronchial muscles'' (Ref. 5). The 
comment stated that this language does not differentiate OTC 
bronchodilators from other bronchodilators that ``do the job better.'' 
It was the comment's view that patients may assume that the OTC drug 
product works the same as prescription products.
    FDA's labeling for OTC bronchodilator drug products is intended to 
help consumers use products safely and effectively in the OTC setting. 
It is not intended to compare OTC bronchodilators to prescription 
products. Although OTC labeling is generally not intended to compare or 
differentiate among various available products, the revised ``Asthma 
alert'' warning for oral ephedrine does advise the consumer that 
bronchodilators that have a different route of administration may be 
advantageous, i.e., inhaled products provide faster asthma relief than 
oral products (see Comment 10). The indications to which the comment 
objected in the FM were revised in the proposed rule to amend the FM 
(70 FR 40237 at 40242). FDA is finalizing the indication in Sec.  
341.76(b) to a single statement as follows: ``for temporary relief of 
mild symptoms of intermittent asthma: [bullet] wheezing [bullet] 
tightness of chest [bullet] shortness of breath.'' Therefore, the 
revised indication and ``Asthma alert'' should help consumers to better 
understand how to use these products.
    (Comment 8) A comment addressed the ``Warning'' in Sec.  
341.76(c)(1) of the OTC bronchodilator FM, ``do not use this product 
unless a diagnosis of asthma has been made by a doctor'' (Ref. 5). The 
comment stated that this warning implies that a diagnosis makes the 
patient an expert at self-prescribing asthma treatments, but that such 
a diagnosis offers no information of value to the consumer when using 
an OTC bronchodilator drug product.
    FDA maintains that there is a role for OTC bronchodilator drug 
products in the treatment of asthma. As conveyed in the labeling, these 
products are appropriate for consumers for whom a doctor has confirmed 
the diagnosis of intermittent asthma.
    (Comment 9) A comment addressed the ``Warning'' in Sec.  
341.76(c)(3) of the OTC bronchodilator FM, ``Do not use this product if 
you have ever been hospitalized for asthma or if you are taking any 
prescription drug for asthma unless directed by a doctor'' (Ref. 5). 
The comment stated that a potential user does not know how 
hospitalization or prescription drug use will change the effectiveness 
of an OTC bronchodilator drug product.
    FDA designed this warning to address safety concerns; a prior 
hospitalization or prescription drug use will not change the 
effectiveness of an OTC bronchodilator drug product. In addition, FDA 
revised the warnings from the 1995 FM for OTC bronchodilator drug 
products in the 2005 proposed rule (70 FR 40237 at 40248). The purpose 
of the warnings is to clearly convey to potential users of OTC 
bronchodilators that they should seek the advice of a doctor before 
using any bronchodilator products. The revised two part warning advises

[[Page 44479]]

consumers not to use the OTC bronchodilator drug product unless 
directed by a doctor. Asthmatics who have previously needed hospital 
care, or are taking a prescription drug to treat asthma, need to 
consult a doctor before using an OTC bronchodilator.
    The warnings in this final rule have been broadened and revised. 
See the language set out in Sec.  341.76(c)(2) and Sec.  341.76(c)(3) 
in this rule.
    (Comment 10) The same comment also addressed the ``Warning'' in 
Sec.  341.76(c)(5)(i) of the OTC bronchodilator FM for ephedrine 
products, ``do not continue to use this product, but seek medical 
assistance immediately if symptoms are not relieved within 1 hour or 
become worse'' (Ref. 5). The comment stated that if consumers' symptoms 
do not improve or become worse at any time during treatment, the 
labeling should advise them to seek immediate medical attention.
    FDA agrees and is providing broader labeling information on this 
issue in the revised ``Asthma alert.'' The new information is intended 
to help asthmatics understand whether the drug is not working as 
intended or whether a consumer's condition may be worsening.
    The 60-minute timeframe after which a consumer should seek medical 
attention is specific to ephedrine oral drug products and reflects the 
time that is needed for the drug to be absorbed from the 
gastrointestinal tract and to reach therapeutic blood levels. The time 
is modified to 20 minutes for inhaled drug products.
    FDA's new ``Asthma alert'' for ephedrine-containing products is set 
out in Sec.  341.76(c)(5) in this rule.
    FDA has modified the ``Asthma alert'' warning from the warning 
proposed in the 2005 proposed rule. For ephedrine containing products, 
the statement, ``this product will not give you asthma relief as 
quickly as an inhaled bronchodilator'' has been added as the final 
bulleted statement. Although there are many factors involved, inhaled 
drugs in general show a faster onset of action than oral drugs (Ref. 
6). As discussed previously, oral ephedrine can take 60 minutes to 
reach therapeutic levels. This statement has been added to the warning 
to inform the consumer that there are other options for asthma 
treatment available that can be used in place of oral ephedrine if oral 
ephedrine does not provide rapid enough symptom relief.
    In the ``Asthma alert'' section, two bulleted statements were 
revised that follow the statement, ``because asthma may be life 
threatening, see a doctor if you.'' For ephedrine, the statement 
``[Bullet] need [insert total number of dosage units that equals 150 
milligrams] in any day'' was changed to ``[Bullet] need more than 
[insert total number of dosage units that equals 150 milligrams] in 24 
hours.'' Since 150 mg is the maximum dose of ephedrine that should be 
used in 24 hours (i.e., one day, see directions), consumers who need 
more to relieve their symptoms should see a doctor. The terminology 
``one day'' may not be clear to consumers as to the exact time frame, 
so this has been changed to ``24 hours'' to specify the time frame. 
Also, the statement ``[Bullet] use more than [insert total number of 
dosage units that equals 100 milligrams] a day for more than 3 days a 
week'' has been changed to ``[Bullet] use more than [insert total 
number of dosage units that equals 100 milligrams] in 24 hours for 3 or 
more days a week.'' The ``day'' time frame is changed to ``24 hours'' 
and ``for more than 3 days a week'' is changed to ``for 3 or more days 
a week.'' These changes are made for clarity and do not alter the 
proposed content of the alert.
    Similar changes were made to the ``Asthma alert'' for epinephrine-
containing products which is revised to read as set out in Sec.  
341.76(c)(6) in this rule.
    The ``Asthma alert'' is the type of warning identified in 21 CFR 
201.66(c)(5)(ii) [the Drug Facts rule] that has an appropriate 
subheading that is highlighted in bold type. FDA is amending Sec.  
201.66(c)(5)(ii)(B) to cross-reference this new warning.
    (Comment 11) One comment addressed the ``Warning'' in Sec.  
341.76(c)(6)(ii) of the OTC bronchodilator FM for epinephrine products, 
``do not continue to use this product, but seek medical assistance 
immediately if symptoms are not relieved within 20 minutes or become 
worse'' (Ref. 5). The comment noted that while inhaled epinephrine 
works quickly, the duration of symptom relief is very short. The 
comment stated that patients are told not to use the drug more 
frequently than instructed, but not given a reason to comply with the 
instruction. The comment stated that labeling should explain that an 
increasing need for medication is a sign of airway swelling that must 
be treated by a physician. The labeling should tell users that the 
bronchodilator effect wears off before the next dose may be taken 
safely and to seek immediate treatment if symptoms are not completely 
relieved or if they worsen. The labeling should also warn against using 
inhaled epinephrine in place of, or in addition to, prescription 
bronchodilators.
    In this rule, FDA is requiring new labeling that addresses the 
concerns expressed in the comment. Consumers are told not to use the 
drug more frequently than instructed because of an increased risk of 
serious adverse events. Specifically, the new required labeling will 
read as set out in Sec.  341.76(c)(4) in this rule.
    The labeling also warns to ask a doctor or pharmacist before using 
any OTC bronchodilator if taking prescription drugs for asthma. In 
addition, FDA's new labeling addresses the comment's concern that an 
increasing need for medication is a sign of airway swelling that must 
be treated by a physician. As discussed in comment 10, FDA's new 
``Asthma alert'' for epinephrine-containing products will read as set 
out in Sec.  341.76(c)(6) in this rule.
    FDA believes that the revised Asthma alert as well as the revised 
warning on the potential for serious adverse events if bronchodilators 
are not used according to labeled instructions respond to the comment's 
concern regarding adequate warnings for epinephrine.

V. Additional Consumer-Friendly Changes FDA Made to the Labeling

    To make the bronchodilator labeling more consumer friendly and to 
reach a range of consumers' literacy skills, FDA has made changes to 
the labeling that do not affect content but make the labeling more 
understandable to people of all literacy levels. FDA is making these 
changes so as not to affect the content of the labeling as proposed in 
the 2005 proposed rule, but to make the labeling clear to ordinary 
individuals including individuals of low comprehension as stated in 
Sec.  330.10(a)(4)(v). These changes are as follows:
     As described in comment 10, two bulleted statements in the 
``Asthma alert'' section were revised. These follow the statement, 
``Because asthma may be life threatening, see a doctor if you.'' For 
ephedrine, the statement ``[Bullet] need [insert total number of dosage 
units that equals 150 milligrams] in any day'' was changed to 
``[Bullet] need more than [insert total number of dosage units that 
equals 150 milligrams] in 24 hours'' to clarify the timeframe indicated 
by a ``day.'' Also, the statement ``[Bullet] use more than [insert 
total number of dosage units that equals 100 milligrams] a day for more 
than 3 days a week'' has been changed to ``[Bullet] use more than 
[insert total number of dosage units that equals 100 milligrams] in 24 
hours for 3 or more days a week.'' A similar change was

[[Page 44480]]

made to the epinephrine ``Asthma alert.''
     As discussed in comment 3, warnings about increased blood 
pressure or heart rate have been revised.
     The phrase, ``avoid caffeine-containing foods and 
beverages'' under the heading ``When using this product'' has been 
changed to ``avoid foods or beverages that contain caffeine.''
    FDA has added a ``Stop use and ask a doctor if'' section by moving 
warning statements proposed in 2005 under, ``when using this product'' 
to this new section. The section will read as set out in Sec.  
341.76(c)(7) in this rule.
    The statement ``your asthma is getting worse (see Asthma alert)'' 
is taken from the ``Asthma alert'' warning and has been moved to this 
new section to clarify what the consumer should do if the product is 
not providing the necessary relief for them. The other three bulleted 
statements were previously in the labeling section under the heading 
``When using this product.'' Moving these statements under this heading 
does not affect content and may clarify for consumers how they should 
handle any of these side effects by emphasizing that they should see a 
doctor.
     Under ``Directions'' for ephedrine and epinephrine, the 
first bulleted statement, ``do not exceed dosage'' has been changed to 
``do not take more than directed'' or ``do not use more than 
directed,'' respectively.
     The second bulleted statement under ``Directions'' for 
ephedrine contains the phrase, ``not to exceed 150 mg in 24 hours'' and 
has been revised to the sentence, ``do not take more than 150 mg in 24 
hours.'' The bulleted statement now reads as follows: ``[Bullet] adults 
and children 12 years of age and over: oral dose is 12.5 to 25 
milligrams every 4 hours as needed. Do not take more than 150 
milligrams in 24 hours.''
     The second bulleted statement under Directions for 
epinephrine states the dose as 1 to 3 inhalations not more often than 
every 3 hours. This has been revised by adding, ``do not use more than 
12 inhalations in 24 hours'' to be consistent with information provided 
in the ``Asthma alert.'' The bulleted statement now reads as follows: 
``[Bullet] adults and children 4 years of age and over: 1 to 3 
inhalations not more often than every 3 hours. Do not use more than 12 
inhalations in 24 hours. The use of this product by children should be 
supervised by an adult.''

VI. FDA's Final Conclusions on Warnings and Other Labeling Information 
for OTC Bronchodilator Drug Products

A. Implementation Date for New Labeling

    FDA has determined in order to provide for safe and effective use 
of OTC bronchodilator drug products at the earliest possible time 
because of the safety issues involved with the use of these products 
that this final rule be implemented within 180 days after its 
publication. Therefore, on or after 180 days after the date of 
publication of this final rule in the Federal Register, any OTC 
bronchodilator drug product that is subject to the final rule and that 
contains nonmonograph labeling or packaging may not be initially 
introduced or initially delivered for introduction into interstate 
commerce unless it is the subject of an approved application. Any OTC 
bronchodilator drug product that is initially introduced or initially 
delivered for introduction into interstate commerce after the effective 
date of this final rule, and is not in compliance with the regulations, 
is subject to regulatory action. Further, any OTC drug product that was 
previously initially introduced or initially delivered for introduction 
into interstate commerce may not be repackaged or relabeled with the 
prior monograph labeling for these products after the effective date of 
this final rule. Manufacturers are encouraged to comply voluntarily as 
soon as possible.

B. Statement About Warnings

    Mandating warnings in an OTC drug monograph does not require a 
finding that any or all of the OTC drug products covered by the 
regulation actually caused an adverse event, and FDA does not so find. 
Nor does FDA's requirement of warnings repudiate the prior OTC drug 
monographs and regulations under which the affected drug products have 
been lawfully marketed. Rather, as a consumer protection agency, FDA 
has determined that warnings are necessary to ensure that these OTC 
drug products continue to be safe and effective for their labeled 
indications under ordinary conditions of use as those terms are defined 
in the Federal Food, Drug, and Cosmetic Act. This judgment balances the 
benefits of these drug products against their potential risks (see 21 
CFR 330.10(a)).
    FDA's decision to act in this instance need not meet the standard 
of proof required to prevail in a private tort action (Glastetter v. 
Novartis Pharmaceuticals, Corp., 252 F.3d 986, 991 (8th Cir. 2001)). To 
mandate warnings, or take similar regulatory action, FDA need not show, 
nor do we allege, actual causation. For an expanded discussion of case 
law supporting FDA's authority to require such warnings, see the 
December 6, 2002, (67 FR 72555), final rule entitled ``Labeling of 
Diphenhydramine-Containing Drug Products for Over-the-Counter Human 
Use.''

VII. Analysis of Impacts

A. Introduction and Summary

1. Introduction
    FDA has examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct 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 final rule is not 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. Because the requirements are likely to impose a 
burden on a substantial number of affected small entities, the Agency 
projects that the final rule will have a significant economic impact on 
a substantial number of small entities and has conducted an Initial 
Regulatory Flexibility Analysis as required under the Regulatory 
Flexibility Act.
    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 $136 million, using the most current (2010) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.

[[Page 44481]]

2. Summary
    The purpose of this final rule is to revise the labeling of the 
``Indications,'' ``Warnings,'' and ``Directions'' sections for over-
the-counter (OTC) single-ingredient ephedrine and epinephrine 
bronchodilators. The required revised labeling would indicate the 
condition (mild symptoms of intermittent asthma) for which the product 
is intended and would warn consumers about when to seek medical 
assistance. The final rule would also use language that is more readily 
understood by the average consumer. The revised labeling may lead 
consumers to seek medical care and to improved asthma management. Thus, 
the estimated benefits of the final rule may come from reduced medical 
costs associated with adverse events arising from the misuse or abuse 
of the product. The estimated annual benefits range from $14.0 million 
to $69.3 million. One-time labeling costs from personnel, reallocation 
time, materials, and inventory disposal range from $0.7 million to $4.1 
million. In addition, costs may arise from increased physician and 
medication expenses paid by consumers who may switch to managed care. 
The estimated annual costs from additional medical care range from $1.3 
million to $2.5 million. Annualized over 20 years, the estimated total 
costs range from $1.3 million to $2.8 million with a 3-percent discount 
rate, and from $1.3 million to $2.9 million with a 7-percent discount 
rate. Annualized over 20 years, the estimated net benefits (estimated 
benefits minus estimated costs) from the regulation range from $11.2 
million to $68.0 million with a 3-percent discount rate and from $11.1 
million to $68.0 million with a 7-percent discount rate.

B. Need for Regulation

    The Centers for Disease Control and Prevention (CDC) reported that 
in 2009, 7.7 percent (or 17.5 million) of non-institutionalized adults 
and 9.6 percent (7.1 million) of children suffer from asthma in the 
United States. Within population subgroups, asthma prevalence is higher 
among females, children of non-Hispanic Black and Puerto Rican race or 
ethnicity, and persons with family income below the poverty level (Ref. 
7). In 2006, asthma was listed as one of the top five most costly 
conditions in the United States (Ref. 8). Asthma leads to direct health 
care costs and indirect costs such as mortality and lost productivity 
that pose a high burden on society. For example, in 2007, there were 
1.75 million asthma-related emergency department visits and 456,000 
asthma hospitalizations (Ref. 7), and in 2009, there were 3,447 persons 
who died of asthma (Ref. 9).
    A study found that 5 to 10 percent of individuals with asthma use 
nonprescription bronchodilators as monotherapy for the treatment of 
asthma (Ref. 10). Current references for managing asthma acknowledge 
that once asthma has been professionally diagnosed, patients with mild 
cases of asthma may use OTC bronchodilators and patients who have more 
frequent or serious symptoms should be referred to a prescription long-
term controller. While the Handbook of Nonprescription Drugs lists 
epinephrine and ephedrine as the nonprescription bronchodilators 
available for the treatment of asthma (Ref. 11), the National Heart, 
Lung and Blood Institute's guidelines for the diagnosis and management 
of asthma does not recommend epinephrine or ephedrine as a medication 
of choice for quick-relief of asthma (Ref. 3). (See discussion under 
IV. FDA's Response to Comments Received About the Proposed Labeling 
Changes, Comment 2.)
    There have been concerns that self-diagnosis and self-treatment of 
asthma along with illicit use or misuse of OTC single-ingredient 
ephedrine and epinephrine bronchodilators can lead to serious clinical 
consequences, which may include death. Studies indicate that 
approximately 20 percent of individuals using OTC epinephrine inhalers 
have mild-to-moderate persistent asthma, and should not be using OTC 
products but be under the supervision of a physician (Ref. 12). The 
American Association of Poison Control Centers National Poison Data 
System (NPDS), which collects data on adverse event exposure and 
information calls associated with pharmaceutical products, reported 
1,035 cases associated with exposure to non-selective beta agonists in 
2008 (Ref. 13). Although in most of these cases the reason for exposure 
was reported to be unintentional, 350 of these cases had to be treated 
in a health facility. Furthermore, other studies report abuse of 
epinephrine inhalers among high school students (Ref. 14) and fatal 
cases of asthma in which individuals were using OTC epinephrine (Ref. 
15).
    The use of OTC bronchodilators appears to be associated with 
certain demographic characteristics such as low income or educational 
attainment. For example, a study that drew participants from Northern 
California found that 60 percent of subjects who had used only OTC 
bronchodilator to treat asthma did not have any health insurance or a 
primary caregiver for the management of asthma (Ref. 16). Furthermore, 
another study reports that overuse of inhaled beta-agonists is 
associated with lower educational level (Ref. 17).
    Executive Order 12866 directs agencies to assess the need for any 
regulatory action and to provide an explanation of how the regulation 
will meet that need. FDA is responsible for protecting the public 
health and for helping the public get the accurate, science-based 
information they need to use medicines to maintain and improve their 
health. FDA concludes that current labeling of single ingredient 
ephedrine and epinephrine products available over-the-counter provide 
inadequate information. The revised labeling would provide consumers 
access to information that may enable them to better assess the risk of 
taking OTC bronchodilators and to possibly improve the management of 
asthma.

C. Benefits

    The estimated benefits of the final rule would derive from a 
reduction in the number of adverse events, namely hospitalizations, 
emergency department (ED) visits, physician visits, and mortality, 
associated with self-medication or mismanagement of asthma medication 
that may be prevented with revised information or with the help of 
professional guidance.
    FDA estimates the number of preventable events based on the range 
of individuals with asthma that use OTC bronchodilators as monotherapy, 
which is between 5 percent (Low) and 10 percent (High) (Ref. 10). Table 
1 of this document presents the number of preventable events by 
category. The analysis assumes that the percent of ambulatory or ED 
visits related to medication adverse effects approximates the percent 
of events that may be preventable due to mismanagement or misuse of the 
medication, and that adults and children face the same incidence rates 
or likelihood of experiencing each of these events. (See Appendix A for 
a description on how these are estimated.)

[[Page 44482]]



                                      Table 1--Estimated Preventable Events
----------------------------------------------------------------------------------------------------------------
                                                                                     Number of events
               Description a                       Length of visit       ---------------------------------------
                                                                                  Low                High
----------------------------------------------------------------------------------------------------------------
Ambulatory Visits.........................  0.8 hr......................                 282                 564
Emergency Department (ED) Visits..........  3.0 hrs.....................                  67                 134
Hospital Stays:
    Inpatient.............................  3.4 days....................                   4                   7
    Emergency Department (ED).\b\           4.0 days....................                  13                  27
Statistical Lives Saved...................  ............................                   2                   9
----------------------------------------------------------------------------------------------------------------
Notes: \a\ See Appendix A for calculations.
\b\ ED hospital length of stay includes 4.93 hours of estimated ED wait time. Sources: Refs. 10-12, 15, 18-25.

    Using information of the average length of hospital stays (3.4 
days, Ref. 18), ED wait time (3.0 hours and 4.93 hours for ED visits 
that result in discharge and hospital admissions, respectively, Ref. 
19) and time spent in a physician's visit (0.8 hour, Ref. 20), the 
benefits from the estimated preventable events are valued using median 
or average costs on physician visits ($155/visit, Ref. 26), ED visits 
($569/visit, Ref. 27) and hospital stays ($1,400/day, Ref. 28). We also 
include part of the indirect benefits: namely, averted loss of work 
time, using the 2009 median hourly wage of $15.95 plus benefits (equal 
to $20.73) as reported by the Bureau of Labor Statistics (Ref. 29). 
Estimates for the loss of work time are determined assuming 8-hour work 
days, i.e., 3 days in the hospital would be considered 24 hours of lost 
work. FDA notes that an appropriate method to value the indirect costs 
of illness would be either a revealed or stated preference measure of 
willingness to pay. Because we do not have such a measure for these 
events, we used the value of lost work-time, which likely leads to a 
lower bound of the estimate of the indirect benefits. Estimated 
statistical lives saved are valued using Environmental Protection 
Agency (EPA)'s value of a statistical life (VSL) adjusted for 
inflation, $7.9 million/life (Ref. 30). The total estimated benefits 
range from $13.98 million to $69.33 million (see table 2 of this 
document).

                                          Table 2--Estimated Prevented Events and Associated Estimated Benefits
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                          Number of events         Estimated benefit a
                                                                                                     ---------------------------------------------------
               Description                             Time                          Cost                                                        High
                                                                                                          Low          High     Low  ($000)     ($000)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Ambulatory Visits........................  ............................  $155/visit.................          282          564        43.71        87.43
Emergency Department (ED) Visits.........  ............................  $569/visit.................           67          134        38.04        76.09
Hospital Stays:
    Inpatient............................  3.4 days....................  $1,400/day.................            4            7        21.04        42.08
    ED...................................  4.0 days....................  $1,400/day.................           13           27        75.19       150.38
Loss of Work Time:
    Ambulatory Visits....................  0.8 hr......................  $20.73/hr\b\...............          282          564         4.58         9.16
    ED Visits............................  3.0 hrs.....................  $20.73/hr\b\...............           67          134         3.19         6.38
Hospital Stays:
    Inpatient............................  27.2 hrs\c\.................  $20.73/hr\b\...............            4            7         2.11         4.22
    ED...................................  32.1 hrs\c\.................  $20.73/hr\b\...............           13           27         8.91        17.82
Statistical Lives Saved..................  ............................  $7.9 Mil/life..............            2            9      $13,788      $68,941
                                                                                                                               -------------------------
    Total Estimated Benefits.............  ............................  ...........................  ...........  ...........      $13,985      $69,334
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notes: \a\ Statistical Lives Saved are valued in millions of dollars.
\b\ Median hourly wage of $15.95 plus benefits.
\c\ Time estimates for loss of work related to hospital stays assume 8-hour work days.

D. Costs

    The estimated costs come from labeling costs and additional costs 
borne by those consumers who switch to prescription medication or other 
OTC products within the same therapeutic class.
1. Relabeling Costs
    Based on Universal Product Code (UPC) counts of the number of OTC 
products listed in the Red Book and where ephedrine or epinephrine is 
the single-active ingredient, the number of OTC bronchodilators has 
decreased from 19 UPCs in 2000 to 13 in 2010. While inhalers are the 
most prevalent form, OTC bronchodilators are also available in capsules 
and tablets. FDA estimates that approximately seven manufacturers and 
distributors market five different brands that are sold in 13 product-
form variations or UPCs (see table 3 of this document).

[[Page 44483]]



     Table 3--Estimated Number of Over-the-Counter Single-Ingredient
           Ephedrine and Epinephrine Brands and Manufacturers
------------------------------------------------------------------------
                                       2000         2004         2010
------------------------------------------------------------------------
No. of Brands \a\................            5            5            5
    Form: Aerosol................            3            3            3
    Form: Capsule................            1            1            1
    Form: Tablet.................            1            1            1
No. of UPCs......................           19           15           13
    Form: Aerosol................           11            8            7
    Form: Capsule................            5            4            4
    Form: Tablet.................            3            3            2
No. of Manufacturers and                     8            6            7
 Distributors \a\................
------------------------------------------------------------------------
Note: \a\ A brand, manufacturer or distributor is counted only once.
Source: Calculations based on the Red Book, Refs. 31-33.
 

    FDA estimates the costs of the required labeling change using a 
model developed by a contractor, RTI International (RTI). The labeling 
cost model was based on an earlier model developed by RTI for FDA to 
estimate the cost of food label changes (Ref. 34). The required change 
would revise the ``Indications,'' ``Warnings'' and ``Directions'' 
sections of the Drug Fact label, and would be deemed minor. (See 
discussion under IV. FDA's Response to Comments Received About the 
Proposed Labeling Changes.) The required compliance period is 6 months 
and it would affect 100 percent of the OTC single ingredient ephedrine 
and epinephrine UPCs.
    RTI's labeling cost estimates are based on the 6-digit North 
American Industry Classification System (NAICS) that corresponds to 
Pharmaceutical Preparation Manufacturing of Bronchial Remedies (NAICS 
code 325412). Labeling costs include labor, material, inventory and 
recordkeeping. Since FDA provides the design of the label, the labeling 
cost model assumes there are no costs associated with analytical tests, 
market tests or label design. The estimated one-time relabeling cost 
ranges from $0.75 million to $4.1 million (see table 4 of this 
document).

                    Table 4--Estimated Labeling Cost
------------------------------------------------------------------------
                                                  Midpoint       High
           Cost factor             Low  ($000)     ($000)       ($000)
------------------------------------------------------------------------
Labor............................          206          729        1,354
Materials........................           45          112          230
Inventory........................          486        1,015        2,481
Recordkeeping....................            9           18           22
                                  --------------------------------------
Total Labeling Cost..............          746        1,873        4,087
------------------------------------------------------------------------

2. Switching Costs
    Since the revised labeling requirement advises consumers that 
moderate and severe cases of asthma and all cases of persistent asthma 
should be under the supervision of a physician and that inhalers 
provide faster relief, this may have two possible effects on users of 
OTC ephedrine products with mild-to-severe asthma. Some individuals may 
respond to this new advice and seek medical help that gets them under a 
managed care plan. While some of these individuals may seek a physician 
and switch to prescription medicine as a result, others may substitute 
other OTC products within the same therapeutic class. FDA does not 
estimate the number of switchers within the same class and assumes that 
all switchers will seek a physician and switch to prescription 
medicine. This estimate may be considered an upper bound of the costs 
as nonprescription medicine is, on average, lower than prescription 
medicine.
    FDA uses 13 percent as the proxy for the proportion of patients 
with asthma that may respond to the labeling change and switch to 
prescription medicine, which is based on a study that reported that 13 
to 22 percent of prescription drug spending is attributable to 
purchases made by consumers who asked for the advertised drug after 
exposure to television or radio advertisements (Ref. 35). The implied 
assumption is that consumers who read the labeling would respond to the 
new ``Indications,'' ``Warnings'' and ``Directions'' sections by then 
visiting a physician to be placed under a managed care plan or by 
switching to a new OTC medication as if they were responding to 
advertisements. The estimated number of switchers is 446 to 892. The 
range of switchers is estimated by taking the population at risk 
(245,870 and 491,740 for Low and High, respectively) and weighting it 
by the percent of the physician visits from patients with asthma (1.4 
percent) and the percent of the physician visits due to advertising (13 
percent).
    The additional annual estimated costs of switching to prescription 
care is calculated using the difference in total medical expenditures 
of current asthma users without preventive prescription care ($4,721, 
Ref. 36) and with preventive prescription care ($7,586, Ref. 36), and 
the estimated number of switchers. The total estimated cost of 
switching is calculated by multiplying the additional estimated cost 
from switching to preventive prescription care ($2,865) times the 
estimated number of individuals switching to preventive care. The total 
estimated cost from switching ranges from $1,278,000 to $2,555,000.
3. Estimated Total Costs
    The estimated total costs include one-time labeling costs plus 
annual switching costs. Annualized over 20

[[Page 44484]]

years, total estimated costs range from $1.3 million to $2.8 million 
with a 3-percent discount rate and from $1.3 million to $2.9 million 
with a 7-percent discount rate (see table 5 of this document).

                      Table 5--Total Estimated Cost
------------------------------------------------------------------------
                  Description                    Low ($000)  High ($000)
------------------------------------------------------------------------
Annual Cost:
    Switching Cost............................     1,278.00     2,555.00
One-Time Cost:
    Labeling Cost.............................       745.57     4,086.83
Annualized Cost
    3 Percent.................................     1,326.65     2,821.70
    7 Percent.................................     1,343.77     2,915.53
------------------------------------------------------------------------

E. Summary of Costs and Benefits

    The net benefits are determined based on the various combinations 
(Low and High) of costs and benefits and annualizing over 20 years 
assuming a 3 and 7 percent discount rate, separately. Annualized over 
20 years, the minimum and maximum estimated net benefits range from 
$11.2 million to $68.0 million with a 3 percent discount rate, and from 
$11.1 million to $68.0 million with a 7 percent discount rate (see 
table 6 of this document).

                                   Table 6--Estimated Annualized Net Benefits
----------------------------------------------------------------------------------------------------------------
                                                                        Cost                  Net benefits
                          Benefits                           ---------------------------------------------------
                                                                  Low          High         Low          High
----------------------------------------------------------------------------------------------------------------
                                                                        Annualized at 3% over 20 years
----------------------------------------------------------------------------------------------------------------
$13,985.....................................................       $1,327       $2,822      $12,658      $11,163
69,334......................................................        1,327        2,822       68,008       58,171
----------------------------------------------------------------------------------------------------------------
                                                                        Annualized at 7% over 20 years
----------------------------------------------------------------------------------------------------------------
13,985......................................................        1,344        2,916       12,641       11,069
69,334......................................................        1,344        2,916       67,991       58,265
----------------------------------------------------------------------------------------------------------------
Notes: Estimates are in $000s. Net Benefits are benefits minus costs.
 

    Current asthma prevalence rates (percents of the population 
affected shown in parentheses) between population subgroups show that 
females (9.3) have higher current asthma prevalence than males (7.0), 
and that children (9.6) have higher asthma prevalence than adults 
(7.7). Compared with white persons (7.8), the prevalence is higher 
among black (11.1) and lower among Asians (5.3). Moreover, those with 
family income below the Federal poverty level have higher asthma 
prevalence (11.6) than those with incomes in the near poor (8.5), and 
not poor (7.3) categories (Ref. 7). While the estimated benefits are 
calculated based on average characteristics of an asthma individual, it 
is likely that those sub-groups, e.g., children and the poor, with high 
prevalence rates may benefit the most from the regulation.
    Several factors such as growing asthma prevalence and educational 
programs geared to improving asthma management and care may impact the 
market for OTC epinephrine and ephedrine bronchodilators. Current 
asthma treatment and management guidelines (Ref. 3) do not recommend 
OTC ephedrine and epinephrine as the standard of care and this may 
impact the demand for epinephrine and ephedrine bronchodilators and 
their substitutes, e.g., other OTC bronchodilators or prescription 
medication within the same therapeutic class. Moreover, the expected 
withdrawal of chlorofluorocarbon (CFC) inhalers may affect the sale of 
OTC epinephrine and ephedrine bronchodilators. FDA is uncertain on the 
impact of these effects on the overall market for OTC bronchodilators 
in the coming years, but at best, the benefits from preventable adverse 
events or improved asthma management due to the revised labeling may 
offset the additional cost of switching to prescription medication and 
managed care.

F. Analysis of Regulatory Alternatives to the Final Rule

    The final rule seeks to change the labeling to make it more 
understandable to the average reader and to warn users when to seek 
medical assistance. Changes would also include information that 
alternative medication may provide faster relief. The final rule 
establishes an implementation period of 180 days from publication.
    The following alternatives were identified: (1) Extend the 
compliance period, and (2) require more labeling. The compliance 
periods were 12 and 18 months. Another alternative would be to require 
additional labeling changes that would be considered ``Major.'' This 
type of labeling change would involve multiple color changes that would 
require a label redesign such as substantial changes or elimination of 
a claim, caution statement or disclaimer. Table 7 of this document 
presents the relabeling costs associated with these alternatives. 
Extending the implementation period would lower the costs under both 
minor and major labeling changes. Extending the period, however, would 
also postpone the period in which benefits may be observed.

[[Page 44485]]



                       Table 7--Estimated Labeling Costs Under Alternatives to Final Rule
----------------------------------------------------------------------------------------------------------------
                                                                   Labeling change
                                   -----------------------------------------------------------------------------
                                                    Minor                                  Major
    Compliance period  (months)    -----------------------------------------------------------------------------
                                                   Midpoint       High                    Midpoint       High
                                    Low  ($000)     ($000)       ($000)    Low  ($000)     ($000)       ($000)
----------------------------------------------------------------------------------------------------------------
6.................................          746        1,873        4,087        1,200        2,813        5,851
12................................          429        1,063        1,840          870        1,974        3,550
18................................          244          656        1,164          540        1,267        2,308
----------------------------------------------------------------------------------------------------------------

G. Regulatory Flexibility Analysis

    FDA has examined the economic implications of the final rule as 
required by the Regulatory Flexibility Act. If a rule will have a 
significant economic impact on a substantial number of small entities, 
the Regulatory Flexibility Act requires agencies to analyze regulatory 
options that would lessen the economic effect of the rule on small 
entities. This analysis serves as the Initial Regulatory Flexibility 
Analysis as required under the Regulatory Flexibility Act.
1. Description and Number of Affected Small Entities
    The Small Business Administration (SBA) uses different definitions 
of what a small entity is for different industries. Using 2009 SBA size 
standard definitions, a firm categorized in NAICS code 315412 
(Pharmaceutical Preparations) is considered small if it employs fewer 
than 750 persons (Ref. 37). Using the most currently available data on 
the number of establishments by employee size from the 2007 Economic 
Census (Ref. 38) shows that the majority of the establishments have 
employee sizes by which they would be considered small (see table 7). 
Using data at the establishment level implicitly assumes that the 
typical manufacturing establishment is roughly equivalent to the 
typical small manufacturing firm.
2. Economic Effect on Small Entities
    FDA uses data on the total value of shipments by employment size 
from the 2007 Economic Census (Ref. 38) to determine the unit labeling 
cost as a percent of the total value of shipments for a typical 
manufacturer. The average value of shipments is presented for all 
establishments in NAICS code 325412 and for establishments employing 1-
10, 11-499 and over 500 employees, separately. The average value of 
shipments for entities that employ up to 10 workers is $1,433,000 while 
for entities with more than 500 employees it is over $1,160 million. It 
is estimated that the average one-time labeling cost per UPC as a 
percent of average value of shipments for small entities may be between 
0 and 22 percent (see table 8 of this document). The Agency tentatively 
concludes that this rule would have a significant impact on a 
substantial number of small entities, but the impact is uncertain.

                                                             Table 8--Estimated Impact of the Final Rule on Small Business Entities
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                  Establishments  (NAICS 325412)                                      Value of shipments  ($000)       Percent cost per UPC of average value of
-----------------------------------------------------------------------------------------------------------------------------------                    shipment
                                                                                                                                   -----------------------------------------------
                             Employees                                   Count          Percent          Total          Average           Low          Midpoint          High
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
0-10..............................................................             408              41        $584,656           1,433            4.00           10.05           21.94
11-499............................................................             508              51      55,256,380         108,772            0.05            0.13            0.29
500+..............................................................              75               8      87,035,221       1,160,470            0.00            0.01            0.03
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Source: Pharmaceutical Preparations (NAICS 325412), 2007 Economic Census (Ref. 38).

3. Additional Flexibility Considered
    In this section, we discuss alternatives that would present 
reductions in costs which would be channeled through small entities.
    a. Alternative 1: Exempt small-sized manufacturers from labeling 
requirement. Exempting small-sized manufacturers from the labeling 
requirement would result in a one-time saving of 10 to 22 percent of 
the value of shipments (see table 8 of this document). However, 
assuming that the majority of the consumers purchase from small-size 
firms, it is uncertain that the estimated public health benefits 
discussed above would be observed.
    b. Alternative 2: Expand the compliance period for small 
businesses. FDA considers expanding the compliance period to 12 and 18 
months for manufacturers employing up to 10 workers. Table 9 of this 
document shows that the longer the compliance period, the lower the 
costs, and that costs may be reduced to 1 and 6 percent under the 18-
month compliance period. The longer the compliance period, however, the 
longer it may take to observe benefits.

                      Table 9--Percent Cost of Average Value of Shipment for Small Entities
----------------------------------------------------------------------------------------------------------------
                                                   Average Value     Percent cost of average value of shipment
   Compliance period  (months)       Number of     of shipments  -----------------------------------------------
                                     employees        ($000)            Low          Midpoint          High
----------------------------------------------------------------------------------------------------------------
6...............................            0-10          $1,433             4.0            10.1            21.9
12..............................            0-10           1,433             2.3             5.7             9.9
18..............................            0-10           1,433             1.3             3.5             6.2
----------------------------------------------------------------------------------------------------------------


[[Page 44486]]

VIII. Paperwork Reduction Act of 1995

    FDA concludes that the labeling requirements in this document are 
not subject to review by the Office of Management and Budget because 
they do not constitute a ``collection of information'' under the 
Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the 
labeling statements are a ``public disclosure of information originally 
supplied by the Federal Government to the recipient for the purpose of 
disclosure to the public'' (5 CFR 1320.3(c)(2)).

IX. Environmental Impact

    FDA has determined under 21 CFR 25.31(a) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

X. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. Section 4(a) of the Executive order 
requires agencies to ``construe * * * a Federal statute to preempt 
State law only where the statute contains an express preemption 
provision or there is some other clear evidence that the Congress 
intended preemption of State law, or where the exercise of State 
authority conflicts with the exercise of Federal authority under the 
Federal statute.'' The sole statutory provision giving preemptive 
effect to the final rule is section 751 of the act (21 U.S.C. 379r). We 
believe that we have complied with all of the applicable requirements 
under the Executive order and have determined that the preemptive 
effects of this rule are consistent with Executive Order 13132.

XI. References

    The following references are on display in the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, under Docket No. FDA-1995-N-0031 
(formerly Docket No. 1995N-0205), 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 FDA is not responsible for any subsequent 
changes to the Web sites after this document publishes in the Federal 
Register.)
1. Comment No. EMC3, Docket No. 1995N-0205, Division of Dockets 
Management.
2. Comment No. C127, Docket No. 1995N-0205, Division of Dockets 
Management.
3. National Heart, Lung, and Blood Institute, ``National Asthma 
Education and Prevention Program. Expert Panel Report 3: Guidelines 
for the Diagnosis and Management of Asthma, Full Report 2007,'' 
National Institute of Health Publication No. 07-4051, (NAEPP), 
August 2007, http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf, accessed January 2011.
4. Comment No. EMC1, Docket No. 1995N-0205, Division of Dockets 
Management.
5. Comment No. EMC2, Docket No. 1995N-0205, Division of Dockets 
Management.
6. Sciarra, J. J. and C. J. Sciarra, ``Aerosols,'' in ``Remington: 
The Science and Practice of Pharmacy,'' 21st Ed., Edited by Troy, D. 
B. et al., Lippincott Williams and Wilkins, Baltimore, MD, p. 1001, 
2006.
7. Akinbami, L. J., J. E. Moorman, and X. Liu, ``Asthma Prevalence, 
Health Care Use, and Mortality: United States, 2005-2009,'' National 
Health Statistics Reports, No. 32, National Center for Health 
Statistics, Hyattsville, MD,  http://www.cdc.gov/nchs/data/nhsr/nhsr032.pdf, accessed January 2011.
8. Soni, A., ``The Five Most Costly Conditions, 1996 and 2006: 
Estimates for the U.S. Civilian Noninstitutionalized Population,'' 
Agency for Healthcare Research and Quality Statistical Brief #248, 
http://www.meps.ahrq.gov/mepsweb/data_files/publications/st248/stat248.pdf, accessed January 2011.
9. Xu, J. et al., ``Deaths: Final Data for 2007,'' National Vital 
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Statistics, Hyattsville, MD. http://www.cdc.gov/nchs/data/nvsr/nvsr58/nvsr58_19.pdf, accessed December 2010.
10. Smith, J., ``Nonprescription Asthma Treatment Trends,'' U.S. 
Pharmacist, 33(3):4-7, 2008, http://www.uspharmacist.com, accessed 
December 2010.
11. Bollmeier, S. G. and T. R. Prosser, ``Chapter 13: Asthma'' in 
Handbook of Nonprescription Drugs: An Interactive Approach to Self-
Care, 16th Ed., Edited by R. R. Berardi et al., American 
Pharmaceutical Association, Washington, DC, pp. 213-228, 2009.
12. Dickinson, B. D. et al., ``Safety of Over-the-Counter Inhalers 
for Asthma: Report of the Council on Scientific Affairs,'' Chest, 
118(2): 522-526, 2000, http://chestjournal.chestpubs.org/content/118/2/522.long, accessed December 2010.
13. Bronstein, A. C., et al., ``2008 Annual Report of the American 
Association of Poison Control Centers' National Poison Data System 
(NPDC): 26th Annual Report,'' Clinical Toxicology, 47: 911-1084, 
2009, http://www.aapcc.org/dnn/Portals/0/2008annualreport.pdf, 
accessed December 2010.
14. Boyd, C. J., C. J. Teter, and S. E. McCabe, ``Pilot Study of 
Abuse of Asthma Inhalers by Middle and High School Students,'' 
Journal of Adolescent Health, 34(6):531-4, 2004.
15. Levenson, T. et al., ``Asthma Deaths Confounded by Substance 
Abuse: An Assessment of Fatal Asthma,'' Chest, 110: 604-610, 1996, 
http://chestjournal.chestpubs.org/content/110/3/604, accessed 
January 2011.
16. Kuschner, W. G. et al.,``Nonprescription Bronchodilator 
Medication Use in Asthma,'' Chest, 112(4):987-993, 1997, http://chestjournal.chestpubs.org/content/112/4/987.full.pdf, accessed 
January 2011.
17. Janson, S.L. et al., ``Predictors of Asthma Medication 
Nonadherence,'' Heart and Lung, 37(3):211-218, 2008, http://www.heartandlung.org, accessed January 2011.
18. Hall, M. J. et al., ``National Hospital Discharge Survey: 2007 
Summary,'' National Health Statistics Reports, Number 29, October 
26, 2010, National Center for Health Statistics, http://www.cdc.gov/nchs/data/nhsr/nhsr029.pdf, accessed January 2011.
19. Kravitz, R. L. et al., ``Comparing the Use of Physician Time and 
Health Care Resources Among Patients Speaking English, Spanish, and 
Russian,'' Medical Care, 38(7):728-738, 2000.
20. Horwitz, L. I., J. Green, and E. H. Bradley, ``US Emergency 
Department Performance on Wait Time and Length of Visit,'' Annals of 
Emergency Medicine, 55(2):133-141, 2010.
21. Camargo C. A, C. Spooner, and B. H. Rowe, ``Continuous Versus 
Intermittent Beta-Agonists for Acute Asthma,'' Cochrane Database of 
Systematic Reviews, Issue 4. Art. No.: CD001115. DOI: 10.1002/
14651858.CD001115.  http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD001115/frame.html, accessed January 2011.
22. National Center for Health Statistics, ``Summary Health 
Statistics for U.S. Adults: National Health Interview Survey, 
2009,'' Vital and Health Statistics, Series 10, Number 249,  http://www.cdc.gov/nchs/data/series/sr_10/sr10_249.pdf, accessed January 
2011.
23. National Center for Health Statistics, ``Summary Health 
Statistics for U.S. Children: National Health Interview Survey, 
2009,'' Vital and Health Statistics, Series 10, Number 247,  http://www.cdc.gov/nchs/data/series/sr_10/sr10_247.pdf, accessed January 
2011.
24. Hsiao, C. et al., ``National Ambulatory Medical Care Survey: 
2007 Summary,'' Number 27, November 3, 2010, National Center for 
Health Statistics, http://www.cdc.gov/nchs/data/nhsr/nhsr027.pdf, 
accessed January 2011.
25. Niska, R., F. Bhuiya and J. Xu, ``National Hospital Ambulatory 
Medical Care Survey: 2007 Emergency Department Summary,'' Number 26, 
August 6, 2010, National Center for Health Statistics, http://www.cdc.gov/nchs/data/nhsr/nhsr026.pdf, accessed January 2011.
26. Machlin, S. R. and K. Carper, ``Expenses for Office-Based 
Physician Visits by Specialty, 2004,'' Statistical Brief  
166, March 2007, Agency for Healthcare Research and Quality, 
Rockville, MD, http://www.meps.ahrq.gov/mepsweb/data_files/publications/st166/stat166.pdf, accessed January 2011.
27. Agency for Healthcare Research and Quality, ``Table 6: Emergency 
Room

[[Page 44487]]

Services--Median and Mean Expenses per Person with Expense and 
Distribution of Expenses by Source of Payment: United States, 
2008,'' Medical Expenditure Panel Survey Household Component Data, 
Generated interactively on January 2011.
28. Merrill, C. T., E. Stranges and C. Steiner, ``Hospital Stays 
Related to Asthma for Adults, 2005,'' Statistical Brief #54, June 
2008, Healthcare Cost and Utilization Project, Agency for Healthcare 
Research and Quality, http://www.hcup-us.ahrq.gov/reports/statbriefs/sb54.pdf, accessed January 25, 2011.
29. Bureau of Labor Statistics, ``May 2009 National Occupation 
Employment and Wage Estimates United States,'' http://www.bls.gov/oes/current/oes_nat.htm, accessed January, 2011.
30. Environmental Protection Agency, ``Guidelines for Preparing 
Economic Analyses,'' EPA 240-R-10-001, December 2010, http://
yosemite.epa.gov/ee/epa/eed.nsf/pages/Guidelines.html/$file/
Guidelines.pdf, accessed January 2011.
31. 2000 Drug Topics Red Book, Thomson, pp. 581-584, 612, 629, 678-
9, 789, 2000.
32. 2004 Red Book, Thomson, pp. 621-622, 646, 659--60, 690, 763, 
2004.
33. 2010 Red Book, Thomson Reuters, pp. 829-830, 849, 865, 900, 987, 
2010.
34. Muth, M. K, E.C. Gledhill and S. A. Karns, ``FDA Labeling Cost 
Model, Final Report,'' RTI International, RTI Project Number 
06673.010, January 2003.
35. Rosenthal, M. B. et al., ``Demand Effects of Recent Changes in 
Prescription Drug Promotion,'' Forum for Health Economics & Policy: 
Vol. 6: (Frontiers in Health Policy Research), Article 2,  http://www.bepress.com/fhep/6/2, accessed January 2011.
36. Chevarley, F. M., ``Total Medical and Prescription Expenditures 
by Current Asthma Status and Whether Asthma Daily Preventive 
Medicine is Being Taken, United States, 2006,'' Agency for 
Healthcare Research and Quality Statistical Brief #241, April 2009,  
http://www.meps.ahrq.gov/mepsweb/data_files/publications/st241/stat241.pdf, accessed January 2011.
37. U.S. Small Business Administration, ``Table of Small Business 
Size Standards Matched to North American Industry Classification 
System Codes,'' http://www.sba.gov/sites/default/files/Size_Standards_Table.pdf, accessed January 2011.
38. U.S. Census Bureau American FactFinder, ``Sector 31: EC0731SG3: 
Manufacturing: Summary Series: General Summary: Industry Statistics 
for Subsectors and Industries by Employment Size: 2007,'' http://factfinder.census.gov/servlet/IBQTable?_bm=y&-geo_id=&-ds_name=EC0731SG3&-_lang=en, accessed January 2011.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 341

    Labeling, Over-the-counter drugs.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
201 and 341 are amended as follows:

PART 201--LABELING

0
1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.


0
2. Section 201.66 is amended by revising paragraph (c)(5)(ii)(B) to 
read as follows:


Sec.  201.66  Format and content requirements for over-the-counter 
(OTC) drug product labeling.

* * * * *
    (c) * * *
    (5) * * *
    (ii) * * *
    (B) Allergic reaction and asthma alert warnings. Allergic reaction 
warnings set forth in any applicable OTC drug monograph or approved 
drug application for any product that requires a separate allergy 
warning. This warning shall follow the subheading ``Allergy alert:'' 
The asthma alert warning set forth in Sec. Sec.  341.76(c)(5) and 
341.76(c)(6) of this chapter. This warning shall follow the subheading 
``Asthma alert:''
* * * * *

PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC 
DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

0
3. The authority citation for 21 CFR part 341 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.


0
4. Section 341.76 is amended by revising paragraphs (b), (c), and (d) 
to read as follows:


Sec.  341.76  Labeling of bronchodilator drug products.

    (b) Indication. The labeling of the product states the following 
under the heading ``Use'': ``for temporary relief of mild symptoms of 
intermittent asthma: [bullet] \1\ wheezing [bullet] tightness of chest 
[bullet] shortness of breath''. Other truthful and nonmisleading 
statements, describing only the indication for use that has been 
established and listed in this paragraph (b) may also be used, as 
provided in Sec.  330.1(c)(2) of this chapter, subject to the 
provisions of section 502 of the Federal Food, Drug, and Cosmetic Act 
relating to misbranding and the prohibition in section 301(d) of the 
Federal Food, Drug, and Cosmetic Act against the introduction or 
delivery for introduction into interstate commerce of unapproved new 
drugs in violation of section 505(a) of the Federal Food, Drug, and 
Cosmetic Act.
---------------------------------------------------------------------------

    \1\ See Sec.  201.66(b)(4) of this chapter for the definition of 
``bullet.''
---------------------------------------------------------------------------

    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) The following statements shall appear after the subheading ``Do 
not use'' [in bold type]:
    (i) ``[Bullet] unless a doctor said you have asthma''.
    (ii) ``[Bullet] if you are now taking a prescription monoamine 
oxidase inhibitor (MAOI) (certain drugs taken for depression, 
psychiatric or emotional conditions, or Parkinson's disease), or for 2 
weeks after stopping the MAOI drug. If you do not know if your 
prescription drug contains an MAOI, ask a doctor or pharmacist before 
taking this product.''
    (2) The following information shall appear after the subheading 
``Ask a doctor before use if you have'' [in bold type]: ``[bullet] ever 
been hospitalized for asthma [bullet] heart disease [bullet] high blood 
pressure [bullet] diabetes [bullet] thyroid disease [bullet] seizures 
[bullet] narrow angle glaucoma [bullet] a psychiatric or emotional 
condition [bullet] trouble urinating due to an enlarged prostate 
gland''.
    (3) The following information shall appear after the subheading 
``Ask a doctor or pharmacist before use if you are'' [in bold type]:
    (i) ``[Bullet] taking prescription drugs for asthma, obesity, 
weight control, depression, or psychiatric or emotional conditions''.
    (ii) ``[Bullet] taking any drug that contains phenylephrine, 
pseudoephedrine, ephedrine, or caffeine (such as for allergy, cough-
cold, or pain)''.
    (4) The following information shall appear after the subheading 
``When using this product'' [in bold type]:
    (i) ``[Bullet] your blood pressure or heart rate may go up. This 
could increase your risk of heart attack or stroke, which may cause 
death.'' [in bold type]
    (ii) ``[Bullet] your risk of heart attack or stroke increases if 
you: [Bullet] have a history of high blood pressure or heart disease 
[Bullet] take this product more frequently or take more than the 
recommended dose''. [in bold type]
    (iii) ``[Bullet] avoid foods or beverages that contain caffeine''.

[[Page 44488]]

    (iv) ``[Bullet] avoid dietary supplements containing ingredients 
reported or claimed to have a stimulant effect''.
    (5) For products containing ephedrine, ephedrine hydrochloride, 
ephedrine sulfate, or racephedrine hydrochloride identified in Sec.  
341.16(a), (b), (c), and (f).--(i) The following information shall 
appear after the subheading ``Asthma alert: Because asthma may be life 
threatening, see a doctor if you'' [in bold type]:
    (A) ``[Bullet] are not better in 60 minutes''.
    (B) ``[Bullet] get worse''.
    (C) ``[Bullet] need more than [insert total number of dosage units 
that equals 150 milligrams] in 24 hours''.
    (D) ``[Bullet] use more than [insert total number of dosage units 
that equals 100 milligrams] in 24 hours for 3 or more days a week''.
    (E) ``[Bullet] have more than 2 asthma attacks in a week''.
    (F) ``These may be signs that your asthma is getting worse.''
    (G) ``[Bullet] This product will not give you asthma relief as 
quickly as an inhaled bronchodilator.''
    (ii) This ``Asthma alert'' shall appear on any labeling that 
contains warnings and shall be the first warning statement under the 
heading ``Warnings''.
    (6) For products containing epinephrine, epinephrine bitartrate, or 
racepinephrine hydrochloride identified in Sec.  341.16(d), (e), and 
(g).--(i) The following information shall appear after the subheading 
``Asthma alert: Because asthma may be life threatening, see a doctor if 
you'' [in bold type]:
    (A) ``[Bullet] are not better in 20 minutes''.
    (B) ``[Bullet] get worse''.
    (C) ``[Bullet] need more than 12 inhalations in 24 hours''.
    (D) ``[Bullet] use more than 9 inhalations in 24 hours for 3 or 
more days a week''.
    (E) ``[Bullet] have more than 2 asthma attacks in a week''.
    (F) ``These may be signs that your asthma is getting worse.''
    (ii) This ``Asthma alert'' shall appear on any labeling that 
contains warnings and shall be the first warning statement under the 
heading ``Warnings.''
    (iii) For products intended for use in a hand-held rubber bulb 
nebulizer. The following statement shall also appear after the 
subheading ``Do not use'' along with the other information in paragraph 
(c)(1) of this section: ``[bullet] if product is brown in color or 
cloudy''.
    (7) The following information shall appear after the subheading 
``Stop use and ask a doctor if'' [in bold type]:
    (i) ``[Bullet] your asthma is getting worse (see Asthma alert)''.
    (ii) ``[Bullet] you have difficulty sleeping''.
    (iii) ``[Bullet] you have a rapid heart beat''.
    (iv) ``[Bullet] you have tremors, nervousness, or seizure''.
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) For products containing ephedrine, ephedrine hydrochloride, 
ephedrine sulfate, or racephedrine hydrochloride identified in Sec.  
341.16(a), (b), (c), and (f): (i) ``[Bullet] do not take more than 
directed'' [sentence appears as first bulleted statement under 
``Directions'' and in bold type]
    (ii) ``[Bullet] adults and children 12 years of age and over: oral 
dose is 12.5 to 25 milligrams every 4 hours as needed. Do not take more 
than 150 milligrams in 24 hours''.
    (iii) ``[Bullet] children under 12 years of age: ask a doctor''.
    (2) For products containing epinephrine, epinephrine bitartrate, 
and racepinephrine hydrochloride identified in Sec.  341.16(d), (e), 
and (g) for use in a hand-held rubber bulb nebulizer. The ingredient is 
used in an aqueous solution at a concentration equivalent to 1-percent 
epinephrine:
    (i) ``[Bullet] do not use more than directed'' [appears as first 
bulleted statement under ``Directions'' and in bold type].
    (ii) ``[Bullet] adults and children 4 years of age and over: 1 to 3 
inhalations not more often than every 3 hours. Do not use more than 12 
inhalations in 24 hours. The use of this product by children should be 
supervised by an adult.''
    (iii) ``[Bullet] children under 4 years of age: ask a doctor''.
* * * * *

    Dated: July 15, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.

    Note: The following appendices will not appear in the Code of 
Federal Regulations.

Appendices

Appendix A. Definitions

    Population at Risk: Population with asthma x percent of individuals 
with asthma using OTC bronchodilators as monotherapy x percent of 
individuals with mild-to-moderate asthma using OTC epinephrine inhalers
    Physician visits: Population at risk x percent of total ambulatory 
visits related to asthma x percent of ambulatory visits due to 
medication adverse effects
    Emergency Department (ED) Visits: Population at risk x percent of 
ED visits related to asthma x percent of ED visits related to 
medication adverse effects x percent of ED visits of patients with 
acute asthma that were discharged
    Inpatient Hospital Stays: Population at risk x percent of total 
ambulatory visits related to asthma x percent of hospital discharges 
due to asthma x percent of adverse effects related to medication
    ED Hospital Stays: Population at risk x percent of ED visits 
related to all asthma conditions that resulted in hospitalizations x 
percent of ED visits related to medication adverse effects x percent of 
ED visits of patients with acute asthma that were admitted
    Lives Saved: Mortality due to asthma x percent of individuals with 
mild-to-moderate asthma using non-prescription OTC ephedrine x percent 
of fatal asthma deaths where patient used was using epinephrine.
    Note: See Appendix B for values and sources.

Appendix B. Values and Sources Used for Estimated Benefits Calculations

------------------------------------------------------------------------
                                       Value               Source
------------------------------------------------------------------------
Individuals with Asthma that                5-10%  Ref. 10
 use OTC Bronchodilators as
 Monotherapy.
Individuals with Mild-to-                     20%  Ref. 12
 moderate Asthma Using OTC
 Epinephrine Inhalers.
Individuals with Acute Asthma              20-30%  Ref. 21
 Visiting the ED and Requiring
 Admission.
Fatal Asthma Cases and Use of                  5%  Ref. 15
 OTC Epinephrine.
Population with Asthma (Adults         24,587,000  Refs. 22, 23
 and Children).
Total Ambulatory Visits........       994,321,000  Ref. 24
Total Ambulatory Visits, Asthma        13,872,000  Ref. 24
Total Visits, Injury-related...       106,451,000  Ref. 24
Total Visits, Injury-related            8,752,000  Ref. 24
 due to Medication Adverse
 Effects.
Total ED Visits................       116,802,000  Ref. 25
Total ED Visits, Asthma........         1,750,000  Ref. 25

[[Page 44489]]

 
Total ED Visits, Injury-related        39,395,000  Ref. 25
Total ED Visits, Injury-related           716,000  Ref. 25
 due to Medication Adverse
 Effects.
Total ED Visits, Admitted......        14,641,000  Ref. 25
Total ED Visits, Admitted with            158,000  Ref. 25
 Asthma.
Total Hospital Discharges......        34,369,000  Ref. 18
Total Hospital Discharges,                456,000  Ref. 18
 Asthma.
Mortality, Asthma..............             3,447  Ref. 11
------------------------------------------------------------------------

[FR Doc. 2011-18347 Filed 7-25-11; 8:45 am]
BILLING CODE 4160-01-P