Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use; Proposed Amendment of Monograph for Over-the-Counter Bronchodilator Drug Products, 40237-40249 [05-13709]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 70, Number 133 (Wednesday, July 13, 2005)]
[Proposed Rules]
[Pages 40237-40249]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-13709]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 341

[Docket No. 1995N-0205] (formerly Docket No. 95N-0205)
RIN 0910-AF32


Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug 
Products for Over-the-Counter Human Use; Proposed Amendment of 
Monograph for Over-the-Counter Bronchodilator Drug Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule; withdrawal of previous proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
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

[[Page 40238]]

sulfate, epinephrine, epinephrine bitartrate, racephedrine 
hydrochloride, and racepinephrine hydrochloride. This proposed rule is 
part of FDA's ongoing review of OTC drug products. FDA is also 
withdrawing the proposed rule (see the Federal Register of July 27, 
1995 (60 FR 38643)) to remove the ephedrine ingredients from the FM.

DATES: Submit written or electronic comments on the proposed monograph 
amendment and on FDA's economic impact determinations by November 10, 
2005. The date of withdrawal of the July 27, 1995, proposed rule is 
July 13, 2005. Please see section XI of this document for the proposed 
effective date of any final rule that may publish based on this 
proposal.

ADDRESSES: You may submit comments, identified by Docket No. 1995N-0205 
and/or RIN number 0910-AF32, by any of the following methods:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://www.fda.gov/dockets/ecomments. 
Follow instructions for submitting comments on the agency Web site.
     E-mail: fdadockets@oc.fda.gov. Include Docket No. 1995N-
0205 and/or RIN number 0910-AF32 in the subject line of your e-mail 
message.
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier (for paper, disk, or CD-ROM 
submissions): Division of Dockets Management, 5630 Fishers Lane, rm. 
1061, Rockville, MD 20852.
    Instructions: All submissions received must include the agency name 
and Docket No. or Regulatory Information Number (RIN) for this 
rulemaking. All comments received will be posted without change to 
https://www.fda.gov/ohrms/dockets/default.htm, including any personal 
information provided. For detailed instructions on submitting comments 
and additional information on the rulemaking process, see the 
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
comments received, go to https://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number, found in brackets in the heading of this 
document, into the ``Search'' box and follow the prompts and/or go to 
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Cazemiro R. Martin or Gerald M. 
Rachanow, Center for Drug Evaluation and Research (HFD-560), Food and 
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-
2222.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
    A. Advance Notice of Proposed Rulemaking (ANPRM)
    B. Tentative Final Monograph (TFM) and FM
    C. Proposal to Remove Ephedrine Ingredients From the OTC 
Bronchodilator FM
II. Comments Received in Response to the 1995 Proposal to Remove 
Ephedrine Ingredients From the OTC Bronchodilator FM
    A. Number of Comments Received
    B. Summary of Comments Received
III. FDA's Response to the Comments
    A. Asthma and Its Treatment With Ephedrine
    B. Benefit-Risk Assessment
    C. Labeling for OTC Bronchodilator Drug Products
    D. Related FDA Regulatory Actions
    E. Related DEA Regulatory Actions
IV. FDA's Tentative Conclusions
    A. Summary of Major Labeling Changes
    B. Statement About Warnings
V. Proposed Implementation
VI. Analysis of Impacts
    A. Relabeling Costs
    B. Regulatory Alternatives Considered
VII. Paperwork Reduction Act of 1995
VIII. Environmental Impact
IX. Federalism
X. Request for Comments
XI. Proposed Effective Date
XII. References

I. Background

A. Advance Notice of Proposed Rulemaking (ANPRM)

    In the Federal Register of September 9, 1976 (41 FR 38312), FDA 
published, under Sec.  330.10(a)(6) (21 CFR 330.10(a)(6)), an ANPRM to 
establish a monograph for OTC cold, cough, allergy, bronchodilator, and 
antiasthmatic drug products, together with the recommendations of the 
Advisory Review Panel on OTC Cold, Cough, Allergy, Bronchodilator, and 
Antiasthmatic Drug Products (the Panel), which was 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 category I (generally recognized as safe and effective) 
for OTC bronchodilator use (41 FR 38312 at 38370 through 38372).

B. Tentative Final Monograph (TFM) and FM

    FDA concurred with the Panel in the bronchodilator TFM (47 FR 47520 
at 47527, October 26, 1982). FDA included the following active 
ingredients in the FM for OTC bronchodilator drug products: Ephedrine 
ingredients (ephedrine, ephedrine hydrochloride, ephedrine sulfate, and 
racephedrine hydrochloride) and epinephrine ingredients (epinephrine, 
epinephrine bitartrate, and racepinephrine hydrochloride) (51 FR 35326 
at 35339, October 2, 1986). In this current proposed rule, the term 
``ephedrine ingredients'' includes the four active ingredients included 
in the FM; the term ``epinephrine ingredients'' includes the three 
active ingredients included in the FM; and the term ``OTC 
bronchodilator drug products'' includes products containing any of 
these seven active ingredients.

C. Proposal to Remove Ephedrine Ingredients From the OTC Bronchodilator 
FM

    In the Federal Register of July 27, 1995 (60 FR 38643), FDA 
published a proposed rule (the 1995 proposal) to amend the FM for OTC 
bronchodilator drug products. It proposed to remove the ephedrine 
ingredients (ephedrine, ephedrine hydrochloride, ephedrine sulfate, and 
racephedrine hydrochloride) and to classify those ingredients as not 
generally recognized as safe and effective for OTC use. At that time, 
FDA reassessed the benefit/risk of OTC ephedrine drug products and 
proposed their removal because of safety concerns, including the 
potential for these products to cause harm as a result of misuse and 
abuse. Interested persons were invited to submit written comments or 
objections to the 1995 proposal and FDA's economic impact determination 
by August 28, 1995.

II. Comments Received in Response to the 1995 Proposal to Remove 
Ephedrine Ingredients From the OTC Bronchodilator FM

A. Number of Comments Received

    FDA received comments from 56 consumers, 37 health professionals, 8 
manufacturers of OTC bronchodilator drug products, 5 Federal and State 
government agencies, 5 national associations, 4 boards of pharmacy, 2 
distributors of dietary supplements, 1 consulting firm, and 1 member of 
Congress. Several comments addressed FDA's economic impact 
determination. Copies of the comments and additional information that 
have come to FDA's attention since publication of the 1995

[[Page 40239]]

proposal are on public display in the Division of Dockets Management 
(see ADDRESSES).

B. Summary of Comments Received

    (Comment 1) Several comments contended that the 1995 proposal does 
not indicate whether FDA had analyzed whether additional labeling 
warnings (including restrictions on distribution) would address FDA's 
concerns about safer OTC use of ephedrine drug products, especially by 
young people. The comments stated that FDA should use its authority to 
amend current product labeling warnings required by the FM for OTC 
bronchodilator drug products.
    (Comment 2) The comments suggested a number of reasons for the 
potential unsafe use of OTC ephedrine drug products:
     Virtually all of the unsafe use is related to products 
with brand names that promote the unapproved pharmacological effects of 
ephedrine.
     Although these products are labeled with the required FDA 
bronchodilator labeling, they are promoted in the marketplace as 
stimulants, weight loss products, and performance enhancers.
     These products are readily available for sale in 
convenience stores, service stations, and truck stops or by magazine 
mail order.
     Little or no restrictions exist on the sale of these 
products to teenagers and children.
     FDA and the Federal Trade Commission have not utilized 
their enforcement authority to address the safety problems associated 
with improper promotion of these products, which is the main problem.
    (Comment 3) Several comments made suggestions concerning OTC sales 
of these products. These included the following recommendations:
     Proof of age should be required to reduce purchase of 
these products by children.
     Ephedrine and its salts should be placed under schedule V 
of the Controlled Substances Act to control sales, while allowing 
people who have a legitimate medical need for the products to purchase 
them.
     States could restrict OTC sale of ephedrine drug products.
    (Comment 4) Many comments supported FDA's proposal to remove 
ephedrine active ingredients from the OTC marketplace. In addition, 
these comments presented the following arguments against the sale of 
all OTC bronchodilator drug products:
     Easy access leads to self diagnosis, results in the delay 
of treatment, and may mask other symptoms.
     People who use OTC bronchodilators do not receive patient 
education about their disease, about the medication, or about the 
product's possible side effects on the heart and central nervous 
system.
     OTC availability allows the products to be sold to 
individuals of any age and implies that mild asthma is not serious, 
despite the fact that people with mild asthma can die from the disease.
     People can make deadly mistakes if they do not use these 
products properly.
     People do not, or cannot, read the product's warnings and 
do not always understand or heed what they read.
     Parents often use these products for their small children, 
even though interaction with a pediatrician is necessary for treating a 
child's asthma.
     OTC bronchodilators are often used for unintended 
purposes.
    (Comment 5) Several comments cited a number of problems occurring 
in their States as a result of the unrestricted availability of OTC 
ephedrine drug products. These included the use of higher than the 
labeled doses, prolonged use of products, use for unapproved 
indications (e.g., for weight loss and as a stimulant), and improper 
use, particularly by children.
    (Comment 6) A few comments addressed the OTC availability of 
epinephrine aerosol dosage forms\1\ and dietary supplements that 
contain ephedrine alkaloids or ephedra.\2\
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    \1\ The 1995 proposal did not involve epinephrine aerosol dosage 
forms. In the Federal Register of May 20, 1996 (61 FR 25142), FDA 
amended the bronchodilator drug products FM by removing pressurized 
metered-dose aerosol container dosage forms for the ingredients 
epinephrine, epinephrine bitartrate, and racepinephrine 
hydrochloride. The bronchodilator FM currently includes these three 
epinephrine ingredients only for use in a hand-held rubber bulb 
nebulizer (21 CFR 341.76(d)(2)). Accordingly, because these 
ingredients in pressurized metered-dose aerosol container dosage 
forms are not included in this document, FDA is not addressing the 
comments on this dosage form.
    \2\ The 1995 proposal on OTC bronchodilator drug products did 
not involve dietary supplements. FDA has addressed dietary 
supplements containing ephedrine alkaloids separately in a final 
rule that published on February 11, 2004 (69 FR 6788), under Docket 
No. 1995N-0304. The final rule declared dietary supplements 
containing ephedrine alkaloids adulterated under section 
402(f)(1)(A) of the Federal Food, Drug, and Cosmetic Act (the act) 
(21 U.S.C. 342(f)(1)(A)) because they present an unreasonable risk 
of illness or injury. Accordingly, dietary supplements containing 
ephedrine alkaloids may no longer be marketed in the United States.
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III. FDA's Response to the Comments

    After considering the comments submitted for the 1995 proposal to 
remove ephedrine and other active ingredients from the FM, FDA is 
withdrawing that proposal. The scope and coverage of this current 
proposed rule differ from the 1995 proposal. FDA has given serious 
consideration to the various arguments presented by the comments on the 
1995 proposal, has considered other information, and has determined 
that ephedrine and other bronchodilator ingredients should remain in 
the FM for self-treatment of mild bronchial asthma for several reasons:
     There are people with diagnosed mild bronchial asthma for 
whom the benefits of symptomatic treatment with OTC bronchodilators for 
temporary wheezing, shortness of breath, and tightness of chest 
outweigh the risks of use.
     Additional labeling warnings and directions in this 
current proposal provide information to promote safer use of these 
products.
     FDA has taken regulatory action against ephedrine drug 
products with misleading brand names that promoted weight loss, 
enhancement of athletic performance, or stimulant uses.
     Drug Enforcement Administration (DEA) requirements 
restricting the sale of ephedrine, its salts, optical isomers, and 
salts of optical isomers that became effective after FDA published the 
1995 proposal are in effect and, among other things, require single-
ingredient ephedrine drug products to be sold behind the counter. 
Therefore, access to these products is controlled.

A. Asthma and Its Treatment With Ephedrine

    Asthma is a chronic lung disease caused by inflammation of the 
airways, resulting in episodes of airway narrowing and obstruction. 
Asthma can be serious and should be diagnosed and treated by a 
physician. Although there is no cure for asthma, appropriate management 
most often leads to control of the condition. FDA notes that the Panel 
stated that sympathomimetic drugs (e.g., ephedrine) are used to 
overcome the spasm that causes narrowing of the bronchial air tubes, 
and the usefulness of ephedrine is limited to the milder forms of 
asthma (41 FR 38312 at 38370 through 38371).
    In assessing ephedrine, the Panel relied on data from two studies 
conducted in 1973 and 1975, respectively. The patient population 
enrolled in these studies was not only clinically stable (i.e., normal 
electrocardiogram, blood pressure, and pulse), but also had no apparent 
history of adverse events related to treatment with other stimulant 
bronchodilators used at the time. One study was a double-blind 
comparison of 24 milligrams (mg) ephedrine and a combination of 24 mg 
of ephedrine and 130 mg theophylline (41 FR 38312 at

[[Page 40240]]

38371). Measurements including specific airway resistance, vital 
capacity, and forced expiratory volume in 1 second (FEV1) 
showed that ephedrine significantly decreased the airway resistance and 
increased both capacity and FEV1 over a 2-hour period. This 
effect was enhanced and prolonged by the presence of theophylline, a 
prescription drug. The Panel cited another study comparing ephedrine 
and terbutaline (a prescription drug) in 26 asthmatics. The data 
indicated that 25 mg ephedrine resulted in significant improvement in 
the pulmonary function tests between 120 and 240 minutes after taking a 
single dose (41 FR 38312 at 38371). The results were similar to 2.5 mg 
terbutaline, but less than the effect of 5 mg terbutaline. These 
clinical studies supported improvement in pulmonary function tests 
between 2 and 4 hours after taking a single dose of 25 mg ephedrine, 
with the improvements lasting up to 4 hours. These studies support the 
use of ephedrine for patients with asthma who are otherwise clinically 
stable (i.e., not found by a physician to have high blood pressure or 
other cardiovascular risk).
    Ephedrine is an [agr] and [bgr] adrenergic agonist and also 
enhances the release of norepinephrine from sympathetic neurons. In 
addition to its bronchodilation effect, other effects of ephedrine are 
related to its pharmacodynamic actions through [agr] and [bgr] 
adrenergic receptors (Ref. 1). These include awareness of heart beat, 
rapid heart beat, and variable increases of blood pressure. The Panel 
indicated that a study by Dulfano and Glass on 26 asthmatics between 28 
and 61 years old showed that (at measured intervals of 15, 30, 60, 120, 
180, and 240 minutes) a single dose of 25 mg ephedrine had no 
significant effect on either heart rate or blood pressure (41 FR 38312 
at 38370).\3\ The Panel also cited a study by Tashkin and Simmons of 
the cardiovascular effects of 25 mg ephedrine (over a 7-hour period) in 
20 asthmatics. The Panel noted that there was only a modest increase in 
heart rate of up to 11 beats per minute as a maximum, and the systolic 
and diastolic blood pressure showed no significant change (41 FR 38312 
at 38370).\4\
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    \3\ The authors reported maximal cardiovascular effects at 180 
minutes after administration of ephedrine compared to control 
(baseline): Heart rate (beats per minute) decreased from 91.6 to 
83.1; blood pressure (millimeters of mercury (mm Hg)), systolic 
increased from 127.8 to 129.9 and diastolic increased from 81.0 to 
82.4.
    \4\ The authors reported that after ephedrine, mean heart rate 
was significantly higher than control (baseline) values (average 7.4 
to 10.9 beats per minute) at 2 to 5 hours as well as mean placebo 
values (average 7.7 to 10.6 beats per minute at 2, 4, and 5 hours). 
The authors measured blood pressure over a 7-hour period after the 
subjects took ephedrine.
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    In 1988, Chua and Benrimoj reviewed the blood pressure effects of 
OTC sympathomimetic drugs, including ephedrine (Ref. 2). They made the 
following observations:
     McLaurin et al. (1961) and Laitinen et al. (1982) found 25 
mg of ephedrine produced no significant effect on blood pressure and 
heart rate of normotensive patients.
     Tashkin et al. (1975) obtained similar results when 
comparing the cardiovascular and bronchial effects of terbutaline with 
ephedrine.
     Bye et al. (1974) demonstrated a significant rise in 
systolic blood pressure of 17 and 7 millimeters of mercury (mm Hg) with 
50 and 25 mg of ephedrine, respectively, but no effect on diastolic 
blood pressure.
     Elis et al. (1967) showed that a single oral dose of 30 mg 
ephedrine produced an average increase in mean arterial blood pressure 
of 5 mm Hg.
     Drew et al. (1978) showed that oral doses of 60 mg 
ephedrine produced significant increases in systolic and diastolic 
blood pressure in normotensive subjects.
     The discrepancy between Bye et al. and McLaurin et al. may 
be due to the different parameters analyzed and the time intervals for 
blood pressure measurement.
    Other information also supports a pressor effect (increases blood 
pressure) of ephedrine. Intravenous ephedrine is used to increase blood 
pressure in patients with hypotension during spinal and epidural 
anesthesia, particularly during obstetrical procedures (Ref. 3).
    In the recent final rule on dietary supplements containing 
ephedrine alkaloids (69 FR 6788, February 11, 2004), FDA discussed the 
results from a study by Boozer et al. (Ref. 4). That study evaluated 
the blood pressure effects of a combination of ephedrine alkaloids and 
caffeine compared to placebo over a 6-month period. Using automated 
blood pressure measurements over 24 hours at weeks 1, 2, and 4, the 
ephedrine alkaloid and caffeine group had significantly higher blood 
pressure measurements after 4 weeks of treatment. The effect reported 
in this study cannot be attributed to the caffeine because the effect 
of caffeine on blood pressure is transient, and the acute effect of 
caffeine to increase blood pressure is lost within 2 weeks of continued 
use (69 FR 6788 at 6802). FDA finds that the collective evidence 
suggests that ephedrine at doses recommended for a bronchodilator 
effect causes elevation of blood pressure. Some individuals who use 
ephedrine are at risk of experiencing adverse effects from therapy 
because of ephedrine's effect on blood pressure. Despite the results of 
the Boozer study and other evidence, FDA considers the therapeutic 
benefits of ephedrine as an OTC bronchodilator outweigh its effects in 
elevating blood pressure based on its temporary and intermittent use. 
(See also section III.B of this document.)
    According to the National Asthma Education and Prevention Program 
guidelines, mild intermittent asthma is defined as having symptoms no 
more than twice a week during the day or twice a month at night (Ref. 
5). Between asthmatic episodes, these asthmatics have no symptoms and 
can maintain a normal level of activity. FDA has determined that people 
with mild intermittent asthma are the only category of asthmatics who 
should be candidates for oral ephedrine. 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 (Ref. 6).
    The Panel noted that wide use of epinephrine aerosols for temporary 
relief of milder forms of asthma has been attended by few and mild side 
effects. The Panel cited a double-blind study in asthmatics during 
which epinephrine aerosol demonstrated a significant increase in 
bronchial air flow in 15 minutes accompanied by symptomatic relief, 
whereas the placebo gave little change (41 FR 38312 at 38372). The 
Panel concluded that epinephrine is a safe and effective OTC 
bronchodilator ingredient when used according to recommended labeling, 
and FDA included epinephrine in the FM (51 FR 35326 at 35332 through 
35333).

B. Benefit-Risk Assessment

    FDA has done a benefit-risk assessment of the different uses of 
ephedrine ingredients. FDA has determined, based on its review of the 
available information, that the benefits of single-dose ephedrine 
ingredients for the temporary relief of mild asthma outweigh the risks. 
In contrast, FDA determined for dietary supplements containing 
ephedrine alkaloids that the risks of use outweigh any benefits.
    In the Federal Register of February 11, 2004, FDA declared dietary 
supplements containing ephedrine alkaloids adulterated under the act 
because they present an unreasonable risk of illness or injury based on 
a risk-benefit analysis (69 FR 6788 at 6824). After reviewing the 
available data on weight loss, enhancement of athletic

[[Page 40241]]

performance, eased breathing in healthy individuals, and other uses, 
FDA concluded that the data do not indicate that these dietary 
supplement products containing ephedrine alkaloids provide a benefit 
sufficient to outweigh the risks. FDA stated that there is sufficient 
evidence to conclude that ephedrine alkaloids can increase blood 
pressure and heart rate. FDA also stated that dietary supplements 
containing ephedrine alkaloids ``expose users to several risks, 
including the consequences of a sustained increase in blood pressure 
(e.g., serious illnesses or injuries that include stroke and heart 
attack that can result in death) and increased morbidity and mortality 
from worsened heart failure and proarrhythmic effects'' (69 FR 6788 at 
6827). FDA also stated that although the proarrhythmic effects of 
dietary supplements containing ephedrine alkaloids typically occur only 
in susceptible individuals, the long-term risks from elevated blood 
pressure can occur even in nonsusceptible, healthy individuals (69 FR 
6788 at 6827). FDA concluded that dietary supplements containing 
ephedrine alkaloids are adulterated because they present an 
unreasonable risk of illness or injury under the conditions of use 
recommended or suggested in labeling or, if no conditions of use are 
suggested or recommended in labeling, under ordinary conditions of use. 
FDA does not consider its decision on the use of ephedrine alkaloids in 
dietary supplements as precluding the use of sympathomimetic 
ingredients in other regulated products for appropriate populations. 
The benefits compared to risks should be analyzed in each instance.
    In the clinical studies discussed in section III.A of this 
document, ephedrine demonstrated a bronchodilator effect in subjects 
with mild asthma. This bronchodilator effect provides temporary relief 
of shortness of breath, tightness of the chest, and wheezing due to 
bronchial asthma. These OTC ephedrine drug products provide health 
benefits when used by appropriate populations (i.e., mild asthmatics) 
for a limited period of time by relieving the symptoms of an asthma 
attack and possibly reducing symptom progression. Relieving symptoms of 
a mild asthma attack is an important benefit. The relief of symptoms 
enables an asthmatic to perform normal everyday activities without 
restrictions brought on by shortness of breath. The finding that OTC 
single-ingredient ephedrine drug products provide a health benefit for 
mild asthmathics justifies the continued marketing of such products 
despite the risks. This favorable benefit-risk assessment distinguishes 
ephedrine as a drug from FDA's unfavorable benefit-risk assessment for 
dietary supplements containing ephedrine alkaloids.
    FDA's decision in this proposed rule to have a different position 
for OTC drug products that contain ephedrine compared to dietary 
supplements that contain ephedrine alkaloids is not arbitrary or 
capricious. The decision is based on differences in the intended uses 
of these products, as well as differences in the scientific evidence 
available to support the risk-benefit ratio for the products. The risk-
benefit ratio is dependent on several factors, including the product's 
intended use, the product's benefits, if any, and the availability of 
adequate measures to control risk.
    FDA recognizes the risks associated with ephedrine containing drug 
products. However, there are several differences between OTC drug 
products containing ephedrine and dietary supplements that contain 
ephedrine alkaloids that may be relevant to the differing risk-benefit 
profiles of these products.
     Ephedrine used in a drug product in the treatment of 
asthma needs to meet the United States Pharmacopeia (USP) standards of 
identity, strength, quality, and purity. The USP ingredients contain 
not less than 98 or 98.5 percent and not more than 100.5 or 101 percent 
of the declared amount of ephedrine, ephedrine hydrochloride, or 
ephedrine sulfate (Ref. 7). The botanical sources of ephedrine that 
were used in dietary supplement products did not have to meet USP 
standards and contained varying amounts of ephedrine and other 
ephedrine alkaloids depending upon the botanical species that were 
used. Although the proportions of the various ephedrine alkaloids in 
botanical species vary from one species to another, in most species 
used commercially, ephedrine was typically the predominant alkaloid in 
the raw material (69 FR 6788 at 6789).
     Botanical sources of ephedrine alkaloids contain ephedrine 
and other sympathomimetics, including norephedrine, pseudoephedrine, 
and methylephedrine. All of these compounds are pharmacologically 
active and have variable effects on adrenergic receptors. These 
variable effects depend on several factors including dosages, route of 
administration, and individual susceptibility (Ref. 8). For example, in 
the Hemorrhagic Stroke Project Study, the use of phenylpropanolamine (a 
sympathomimetic drug) was associated with a statistically significant 
increased risk for hemorrhagic stroke (Ref. 9) whereas pseudoephedrine 
was not (Ref. 10). The combination of sympathomimetic compounds may 
have additional pharmacological effects on the cardiovascular system 
compared to ephedrine alone and, as a consequence, may have additive 
risks.
     In previous Federal Register notices (47 FR 35344, August 
13, 1982; 48 FR 52513, November 18, 1983; and 49 FR 26814, June 29, 
1984), FDA recognized the negative consequences of combining multiple 
sympathomimetic ingredients or a sympathomimetic plus caffeine in the 
same drug product. In these notices, FDA defined any drug product 
containing ephedrine in combination with phenylpropanolamine or 
caffeine as a new drug requiring a new drug application for marketing. 
At the time, FDA was concerned about the additive effects of the 
combination of two or more sympathomimetic ingredients without any 
demonstrated enhanced benefit. FDA has not permitted marketing of OTC 
drug products containing more than one sympathomimetic drug because of 
safety concerns.
    FDA has received and evaluated adverse reaction reports on both 
drug products containing ephedrine and dietary supplements containing 
ephedrine alkaloids. Based on the differences in composition described 
in the previous paragraphs between the drug products and dietary 
supplements, adverse event data for dietary supplements containing 
ephedrine alkaloids may not be completely applicable to OTC ephedrine 
drug products.
    FDA acknowledges that OTC drug products containing ephedrine 
ingredients may be used by consumers who are obese or have high blood 
pressure and that these products can cause adverse events. Because 
sympathomimetic ingredients may pose risks for adverse events, even 
after a single dose, FDA has considered the benefits and risks 
associated with the use of these products by these consumers. While OTC 
ephedrine drug products are not without risk, they have demonstrated 
benefit for asthmatics in the intermittent and temporary treatment of 
the symptoms associated with mild asthma. FDA concludes that the 
benefit from lessening the severity of an asthma attack outweighs the 
risk of an increase in blood pressure when OTC ephedrine drug products 
are taken in accordance with a warning to ask a doctor before use if 
you have heart

[[Page 40242]]

disease or high blood pressure and with the recommended dosage.
    After reviewing the safety and effectiveness information on 
ephedrine in OTC drug products, FDA has determined that the benefits of 
OTC drug products containing single ingredient ephedrine outweigh the 
risk when the product is used according to labeled instructions. In 
determining that the benefit outweighs the risk for the marketing of 
ephedrine in OTC drug products, FDA finds that there continues to be a 
clinically meaningful benefit derived by asthmatics using these 
products on an intermittent basis for the temporary relief of 
bronchospasm. FDA continues to believe that OTC drug products 
containing single ingredient ephedrine are generally recognized as safe 
and effective and are not misbranded under the conditions of use in the 
bronchodilator FM and with the labeling in this proposed rule.

C. Labeling for OTC Bronchodilator Drug Products

    Product labeling (indications, warnings, and directions) is 
important for the safe and effective use of ephedrine OTC drug 
products. The current and new proposed labeling instructs asthmatics 
how to use the product correctly in order to minimize risks. Labeling 
recommends use only for the intermittent treatment of mild symptoms of 
asthma. Labeling also alerts certain populations with conditions that 
increase the risk of adverse events to seek advice from a health care 
provider before using the product. Any deviation from the labeling may 
put an asthmatic at increased risk for an adverse event and prevent 
maximum benefit from the drug. For example, if an asthmatic uses an OTC 
ephedrine drug product on a daily basis over a prolonged period of time 
because of recurrent symptoms, there are increased risks associated 
with the long-term use of ephedrine and with inadequate treatment of 
the asthma condition. The indications, warnings, and directions 
(including dosage directions) define the conditions of use of the 
ingredient. If the drug is not used as labeled, the risks may outweigh 
the benefits of the drug. The proposed new labeling for OTC 
bronchodilator drug products is intended to inform asthmatics about the 
safe and effective use of these drug products. The labeling is also 
intended to inform asthmatics that if their asthma condition worsens, 
with more frequent or more severe symptoms, they should immediately 
consult a physician to reassess the management of the asthmatic 
condition and to consider an alternative drug therapy.
    FDA stated in the dietary supplement rule that warning statements 
cannot adequately protect consumers from the risks associated with 
dietary supplements containing ephedrine alkaloids (69 FR 6788 at 
6828). In this proposed rule, FDA is proposing new warning statements 
and labeling to minimize the risks associated with taking OTC drug 
products containing ephedrine ingredients. The difference is based on 
the favorable benefit-risk ratio associated with the OTC drug products 
containing ephedrine ingredients for the treatment of mild asthma. 
Unlike dietary supplements, OTC drug products have demonstrated 
benefits in the treatment and mitigation of disease. Based on 
controlled clinical investigations (see Sec.  330.10(a)(4)(ii)), FDA 
determined that the benefits associated with the use of OTC drug 
products containing ephedrine for disease indications outweigh the 
risks and justify the use of these products despite their risks. 
However, such uses for disease mitigation and treatment are beyond the 
scope of permissible dietary supplement uses (69 FR 6788 at 6810). FDA 
considers the OTC drug products containing ephedrine ingredients to be 
safe and effective and not misbranded for the treatment of physician-
diagnosed mild cases of asthma when appropriately labeled, including 
appropriate warning statements. The FM contains labeling that advises a 
user of these products:
     Not to use this drug unless a diagnosis of asthma has been 
made by a doctor,
     Not to use the drug if you have certain medical 
conditions, and
     To consult a doctor when the drug does not provide relief 
within a specific time interval or causes side effects that persist.
    FDA continues to consider the two types of currently marketed OTC 
bronchodilator sympathomimetic ingredients, ephedrine and epinephrine, 
to be safe and effective for the self-treatment of mild asthma. These 
ingredients have slightly different actions. Oral ephedrine provides 
less bronchial muscle relaxation but has a more sustained effect than 
inhaled epinephrine. FDA recognizes that use of OTC epinephrine aerosol 
drug products to relieve the symptoms of mild asthma may elicit 
sympathomimetic effects similar to those elicited by oral ephedrine 
ingredients. Consequently, because of the pharmacological similarities 
of these two sympathomimetic active ingredients, FDA considers similar 
labeling of OTC ephedrine and epinephrine drug products necessary to 
inform consumers of the safe and effective use of these OTC drug 
products. As previously stated, FDA continues to believe that people 
with mild asthma can properly use OTC bronchodilator drug products to 
self-treat occasional wheezing, shortness of breath, and tightness of 
chest after their asthma has been diagnosed by a physician. FDA has 
determined, however, that to help ensure safe and effective use and to 
minimize the risks of OTC bronchodilator drug products, additional 
labeling is needed for these products.
1. Uses
    The current indications for OTC bronchodilator use are in Sec.  
341.76(b)(1) and (b)(2). The primary indication is ``For temporary 
relief of shortness of breath, tightness of chest, and wheezing due to 
bronchial asthma'' (Sec.  341.76(b)(1)).
    The labeling of the product may also state one or both of the 
following uses (Sec.  341.76(b)(2)):
     ``For the'' (select one of the following: ``temporary 
relief'' or ``symptomatic control'') ``of bronchial asthma.''
     ``Eases breathing for asthma patients'' (which may be 
followed by: ``by reducing spasms of bronchial muscles'').
    Two of these indication statements mention temporary relief, while 
the third statement does not. Also, in the second statement 
manufacturers have the option of selecting either ``temporary relief'' 
or ``symptomatic control.'' For safe and appropriate use, these use 
statements should inform consumers that these products are to be used 
for temporary relief of occasional symptoms of mild asthma. Therefore, 
FDA is proposing to revise the indication statement in Sec.  341.76(b) 
to a single statement as follows: ``for temporary relief of occasional 
symptoms of mild asthma: [bullet] wheezing [bullet] tightness of chest 
[bullet] shortness of breath''.
2. Warnings
    a. Warnings related to effects on the cardiovascular system. Oral 
ephedrine has effects on the cardiovascular system (Refs. 11 through 
14). Cardiovascular effects include elevation of the systolic and 
diastolic blood pressure (Ref. 11). Other effects include awareness of 
heartbeat and rapid heartbeat accompanied usually by some elevation of 
blood pressure (Ref. 14). Pressor responses are due partly to 
vasoconstriction but mainly to cardiac stimulation. The force of 
myocardial contraction is enhanced by the drug,

[[Page 40243]]

and cardiac output is augmented, provided venous return is adequate. 
The renal, abdominal, and intestinal blood flows are decreased; whereas 
the coronary, cerebral, and muscle blood flows are increased (Ref. 11).
    FDA is aware of reported adverse drug events on the cardiovascular 
system associated with the use of ephedrine-containing drug products. 
Similar events have been reported for dietary supplement products 
containing ephedrine alkaloids (69 FR 6788 at 6814 through 6815). The 
reported adverse events include elevations in blood pressure and/or 
heart beat, and serious adverse events include abnormal heart rhythm 
(arrhythmias), heart attack, and stroke. These adverse events are 
consistent with the known pharmacology of sympathomimetic drugs, as 
reported in the literature. The reports we have received for ephedrine 
containing bronchodilator drug products were associated with use that 
was more frequent or in higher amounts than the labeled dose. However, 
even at recommended doses, many people have an increased risk for a 
serious side effect to occur.
    Sympathomimetic drugs, including ephedrine ingredients, mimic the 
effects (stimulation of the sympathetic nervous system) of naturally 
occurring epinephrine and norepinephrine (Ref. 11). In addition to 
their direct pharmacological effects, many of these ingredients also 
stimulate the release of norepinephrine from nerve endings. The release 
of norepinephrine further increases the sympathomimetic effects of 
these drugs on the body, at least transiently. Susceptible individuals, 
who have coronary artery disease or heart failure and use 
sympathomimetic drugs, are at increased risk for serious adverse 
events, including heart attack, stroke, and death. Sympathomimetic 
drugs also can cause abnormal heart rhythms (pro-arrhythmic effect) and 
can induce cardiac arrhythmias in susceptible individuals, such as 
those with underlying coronary artery disease, heart failure, or an 
abnormal cardiac conduction system.
    Over longer periods of use, the risk for adverse health effects to 
susceptible individuals becomes greater due to a sustained elevation in 
blood pressure. Ephedrine and epinephrine ingredients are expected to, 
and evidence indicates that they do, have similar pharmacological 
effects, such as increased blood pressure and heart rate, to those of 
other sympathomimetic ingredients (Refs. 11 and 12). The 
pharmacological effects of ephedrine and epinephrine (and other 
sympathomimetics), both efficacious and adverse, will vary dependent of 
the dose, route of administration (e.g., oral versus inhaled), and 
individual susceptibility.
    Based on reports that FDA 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 
dosing interval. Therefore, FDA proposes to revise product labeling to 
inform consumers that use of an OTC bronchodilator drug product can 
cause an increase in blood pressure and heart rate, which could lead to 
more serious problems such as heart attack, stroke, and death; and the 
risks for these problems may increase if the product is taken at higher 
doses or more frequently than recommended. The labeling also warns 
consumers against the use of any OTC bronchodilator drug products 
without a physician's diagnosis of asthma, and directs consumers to 
consult with a doctor before use, if they have a diagnosis of certain 
conditions, such as heart disease and high blood pressure.
    The proposed labeling for these products has been modified from the 
labeling in the FM to follow the ``Drug Facts'' format in Sec.  201.66 
(21 CFR 201.66). This standardized format and content for product 
labeling is intended to enable consumers to better read and understand 
the labeling information and to promote the safe and effective use of 
OTC drug products. The Drug Facts labeling format provides a more 
structured, organized, and compact presentation of the proposed 
labeling information for these products. Accordingly, the proposed 
labeling should help consumers to use these OTC bronchodilator drug 
products more safely and effectively.
    Current labeling in Sec.  341.76(c)(2) states ``Do not use this 
product if you have heart disease, high blood pressure, * * *.'' In 
this proposed rule, FDA is adding the following statements under the 
heading ``When using this product'': ``[Bullet] increased blood 
pressure or heart rate can occur, which could lead to more serious 
problems such as heart attack, stroke, and death. Your risk may 
increase if you take more frequently or more than the recommended dose. 
[Bullet] * * * rapid heart beat * * * may occur. If these symptoms 
persist or get worse, consult a doctor right away.''
    b. Warnings related to effects on the nervous system (central and 
peripheral). Ephedrine is known to elicit physiological responses 
similar to catecholamines (i.e., groups of chemically related 
neurotransmitters, such as epinephrine, norepinephrine, and dopamine). 
These drugs have stimulant effects on the sympathetic nervous system 
and thus are classified as sympathomimetic agents (i.e., agents 
stimulating the sympathetic nervous system (Refs. 12 and 13)). The 
central effects of ephedrine and epinephrine ingredients include 
tenseness, nervousness, tremor, and sleeplessness. The peripheral 
effects primarily include the effects on the cardiovascular system.
    The central nervous system effects appear to limit the maximally 
tolerated dose, which varies widely among individuals as judged by 
clinical experience (Ref. 14). Overdose results in exaggeration of the 
side effects which individuals describe as disagreeable and may help to 
limit overuse or abuse.
    Reported adverse drug events and the known pharmacological data 
associated with the use of ephedrine and epinephrine ingredients 
include nervousness, tremor, and seizure. Because of these effects, FDA 
is proposing to revise product labeling to inform consumers that use of 
OTC bronchodilator drug products more frequently or at higher doses 
than recommended may cause adverse effects such as seizure and tremor. 
Current labeling in Sec.  341.76(c)(5)(ii) states ``Some users of this 
product may experience nervousness, tremor, sleeplessness * * *. If 
these symptoms persist or get worse, consult your doctor.'' In this 
proposed rule, FDA is placing these warnings under the heading ``When 
using this product'' (Sec.  341.76(c)(4)(ii)) and adding seizure to 
this warning to read as follows:
    `` nervousness, sleeplessness, * * *, tremor, and seizure 
may occur. If these symptoms persist or get worse, consult a doctor 
right away.''
    FDA is aware that persons with seizure disorders who use ephedrine 
are at increased risk for experiencing a seizure (Refs. 15, 16, and 
17). Epinephrine ingredients have similar pharmacological effects 
(Refs. 11 and 12). Therefore, in this proposed rule, FDA is amending 
the warnings to add ``seizures'' as one of the conditions for which a 
person should ask a doctor before using OTC bronchodilator drug 
products.
    c. Warnings related to effects on urination. Ephedrine and 
epinephrine ingredients may cause difficulty in urination in males, 
particularly in older males, who might have an enlarged prostate gland. 
Current labeling in Sec.  341.76(c)(2) states ``Do not use this product 
if you have * * * difficulty in urination due to enlargement of the 
prostate gland.'' In this proposed rule, FDA is simplifying this 
language under the heading ``Ask a doctor before use if you have'' to 
read ``* * * trouble

[[Page 40244]]

urinating due to an enlarged prostate gland''.
    d. Warnings related to glaucoma. Current warnings in the monograph 
for OTC bronchodilator drug products do not include any information 
about glaucoma. Glaucoma is a group of diseases that are distinguished 
by an increase in pressure inside the eye. There are two major types of 
glaucoma: (1) Chronic or primary open-angle glaucoma and (2) acute 
closed-angle glaucoma (also known as narrow angle glaucoma). 
Approximately 90 to 95 percent of people with glaucoma have the open-
angle variety, while 5 to 10 percent have closed-angle glaucoma (Ref. 
18). Normally, aqueous humor (a clear fluid produced within the eye) 
drains out of the eye through a drainage site. However, in people with 
narrow angle glaucoma, sympathomimetic drugs (e.g., ephedrine) cause 
pupil dilatation (mydrasis) that may result in blockage of the normal 
drainage site (Refs. 18 through 21). Because the fluid within the eye 
cannot drain properly in these predisposed individuals, the fluid 
pressure inside the eyeball increases quickly, leading to the symptoms 
of narrow angle glaucoma (Ref. 19). Therefore, in this proposed rule, 
FDA is proposing to add ``narrow angle glaucoma'' as one of the 
conditions under the warning subheading ``Ask a doctor before use if 
you have''.
    FDA considers it beneficial for consumers to know this information 
and encourages them to ask their physician in order to be fully 
informed. FDA has previously included this type of information in the 
labeling of OTC ophthalmic vasoconstrictor drug products containing 
topically applied ephedrine (21 CFR 349.75(c)(2)).
    e. Warnings related to nausea and loss of appetite. Ephedrine may 
cause nausea and loss of appetite in some people. Current labeling in 
Sec.  341.76(c)(5)(ii) states ``Some users of this product may 
experience * * * nausea and loss of appetite. If these symptoms persist 
or get worse, consult your doctor.'' In this proposed rule, FDA is 
deleting ``nausea'' and ``loss of appetite'' as side effects because 
they are minor in comparison to other side effects included in product 
labeling.
    f. Warnings related to interactions with drugs used for psychiatric 
or emotional conditions. Current labeling in Sec.  341.76(c)(4) 
contains a drug interaction precaution not to use an OTC bronchodilator 
drug product ``if you are now taking a prescription monoamine oxidase 
inhibitor (MAOI) (certain drugs for depression, psychiatric, or 
emotional conditions * * *).'' In this proposed rule, to be consistent 
with the Drug Facts labeling format in Sec.  201.66, FDA is deleting 
the words ``Drug interaction precaution.'' FDA believes that the 
information about MAOIs in the labeling may be ineffective because some 
users of OTC bronchodilator drug products may not know that a drug they 
are taking is an MAOI. In this proposed rule, FDA is including 
information about the use of prescription drugs for depression or 
psychiatric or emotional conditions under the subheading ``Ask a doctor 
or pharmacist before use if you are''. Therefore, in this proposed 
rule, FDA is including an additional warning:
    `` Ask a doctor or pharmacist before use if you are taking 
prescription drugs for * * * depression, or psychiatric or emotional 
conditions''.
    g. Warnings related to interactions with other drugs, foods, and 
beverages. FDA is aware that certain other drugs, foods, and beverages 
can interact with OTC ephedrine and epinephrine ingredients and cause 
an increased stimulant effect. The drugs include other sympathomimetic 
agents such as pseudoephedrine, phenylephrine, phenylpropanolamine, and 
caffeine. Some foods and beverages contain caffeine, and some dietary 
supplements contain other ingredients reported or claimed to have a 
stimulant effect.
    FDA previously determined that certain combinations of these 
ingredients presented a potential hazard to health. In the Federal 
Register of August 13, 1982 (47 FR 35344), FDA announced that it had 
determined that combination drug products consisting of caffeine, 
phenylpropanolamine, and ephedrine are new drugs and are required to be 
the subject of an approved new drug application.
    A number of sympathomimetic amines have been marketed as 
prescription drugs used for the treatment of obesity. These include 
benzphetamine hydrochloride, dextroamphetamine sulfate, diethylpropion 
hydrochloride, methamphetamine hydrochloride, phendimetrazine tartrate, 
phentermine hydrochloride and phentermine resin, and sibutramine 
hydrochloride monohydrate. These sympathomimetic drugs can interact 
with OTC ephedrine and epinephrine bronchodilator drug products (also 
sympathomimetics) and cause an increased stimulant effect. Current 
labeling in Sec.  341.76(c)(3) states ``Do not use this product * * * 
if you are taking any prescription drug for asthma unless directed by a 
doctor.'' In this proposed rule, FDA is adding ``obesity'' and ``weight 
control'' to this warning, which now appears under the subheading ``Ask 
a doctor or pharmacist before use if you are,'' to read as follows:
    `` taking prescription drugs for * * * obesity, weight 
control * * *''.
    Two studies indicate that the stimulant effects of ephedrine 
increase when combined with caffeine (Refs. 22 and 23). Caffeine is a 
nervous system stimulant that can induce nervousness, insomnia, and 
tachycardia (rapid heart rate) (Refs. 24, 25, and 26). FDA is concerned 
that taking caffeine and ephedrine at the same time may increase 
sympathetic stimulation of the cardiovascular system and nervous 
system, e.g., increased heart rate, insomnia, and nervousness. In the 
Federal Register of September 27, 2001 (66 FR 49276), FDA issued a 
final rule establishing that any oral OTC bronchodilator active 
ingredient in combination with certain pharmacological drug categories, 
including any stimulant active ingredient, is not generally recognized 
as safe and effective and is misbranded for OTC use. FDA stated that it 
did not believe that any such combination drug products are currently 
marketed OTC.
    Although OTC bronchodilator drug products containing ephedrine 
ingredients in combination with caffeine are not allowed and are not 
currently marketed, current labeling of OTC ephedrine drug products 
does not contain a warning about the concurrent use of products 
containing caffeine or other ingredients that may have a stimulant 
effect. FDA considers it essential to warn consumers of the risk of 
excessive use of ephedrine and epinephrine ingredients from any source 
or use in combination with other products that have stimulant effects. 
These products include other sympathomimetic drugs, foods or beverages 
containing caffeine, and dietary supplements containing ingredients 
reported or claimed to have a stimulant effect.
    In this proposed rule, FDA is proposing to add the following 
warnings to the FM to address concurrent use of different stimulant 
products:
     Under the subheading ``Ask a doctor or pharmacist before 
use if you are'', the statement ``taking any drug that contains 
phenylephrine, pseudoephedrine, ephedrine, or caffeine (such as for 
allergy, cough-cold, or pain)''.
     Under the subheading ``When using this product'', the 
statements ``avoid caffeine-containing foods or beverages'' and ``avoid 
dietary supplements containing ingredients reported or claimed to have 
a stimulant effect''.
    h. Other additional warnings. The FM for OTC bronchodilator drug 
products contains seven active ingredients (see

[[Page 40245]]

section I.B of this document). FDA believes that additional warnings 
are necessary to inform mild asthmatics of the need to carefully follow 
the warnings and directions for OTC bronchodilator drug products 
containing any of these active ingredients. FDA is also concerned that 
possible serious consequences could develop from excessive use of OTC 
bronchodilator drug products, or continued use of these products by an 
asthmatic who needs professional medical attention. Therefore, in this 
proposed rule, FDA is including additional warnings in Sec.  341.76 for 
OTC bronchodilator drug products.
    FDA considers it necessary to inform mild asthmatics that asthma, 
if not treated appropriately, can worsen and be life-threatening. To 
emphasize this concern in this proposed rule, FDA is including the 
following ``Asthma alert'' warning in Sec.  341.76(c)(5)(i) for 
ephedrine products:
    Asthma alert: Because asthma can be life threatening, see a doctor 
if you [in bold type]:
     are not better in 60 minutes
     get worse
     need [insert total number of dosage units that equals 150 
milligrams] in any day
     use more than [insert total number of dosage units that 
equals 100 milligrams] a day for more than 3 days a week
     have more than 2 asthma attacks in a week
    In this proposed rule, FDA is including the following similar 
``Asthma alert'' warning in Sec.  341.76(c)(6)(i) for epinephrine 
products for use in a hand-held rubber bulb nebulizer, which states:
    Asthma alert: Because asthma can be life threatening, see a doctor 
if you [in bold type]
     are not better in 20 minutes
     get worse
     need 12 inhalations in any day
     use more than 9 inhalations a day for more than 3 days a 
week
     have more than 2 asthma attacks in a week
    i. New labeling format. In order to make OTC drug product labeling 
easier to read and understand, and to help ensure the safe and 
effective use of all OTC drug products, FDA is revising the current 
labeling in the OTC bronchodilator FM to conform to the standardized 
OTC drug product labeling format in Sec.  201.66. This labeling format 
is included in this proposed rule and requires the use of specific 
language in the labeling of OTC bronchodilator drug products.
3. Directions
    FDA is proposing to 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''. This 
revision is intended to more prominently inform users of these products 
not to exceed the recommended dosage.

D. Related FDA Regulatory Actions

    FDA has exercised its authority under the act to take regulatory 
action against OTC bronchodilator drug products containing ephedrine 
ingredients being marketed directly or indirectly for unapproved uses 
(e.g., stimulant, weight control, and athletic performance enhancement) 
via a product name that suggested one of these uses. Since the 1995 
proposal, FDA issued warning letters to companies whose products have 
been linked to significant adverse reactions.
    One letter was for a product that contained ephedrine and another 
ingredient (an expectorant) (Ref. 27). FDA noted that the ``statement 
of identity'' and ``indications'' portion of the product label state 
the correct uses. However, the trade name of this product suggested it 
was intended to aid in weight loss, an unapproved use for these 
ingredients. FDA stated its belief that because there are serious 
health risks inherent in the promotion of ephedrine for weight loss, 
the trade name of the product must be changed in order to ensure that 
the product is not promoted for the unacceptable weight loss use.
    FDA stated in another letter that the product's trade name suggests 
it is intended for stimulant and recreational use (Ref. 28). FDA had 
received reports of adverse reactions linked to the use of this product 
as a stimulant.
    FDA requested that these manufacturers take action immediately to 
correct these violations and stated that failure to do so may result in 
regulatory action (e.g., seizure and/or injunction). In response to 
these warning letters, the manufacturers agreed to revise their 
ephedrine-containing drug product trade names (Refs. 29 and 30).

E. Related DEA Regulatory Actions

    In the Federal Register of October 11, 1994 (59 FR 51365), DEA 
issued a final rule eliminating the threshold for single-entity 
ephedrine drug products. The threshold is an amount of a listed 
chemical that determines if a transaction such as receipt or sale of 
the chemical is a regulated transaction under 21 CFR part 1310. The 
final rule subjected all transactions involving bulk ephedrine and 
single-entity ephedrine drug products, regardless of size, to the 
requirements for regulated transactions for listed chemicals under the 
applicable provisions of the Controlled Substances Act (see 21 U.S.C. 
802(39)(A)), which includes recordkeeping, reporting, and notification.
    DEA regulations require that in retail settings open to the public 
where single-entity ephedrine products are sold, such drugs must be 
stocked behind a counter where only employees have access (21 CFR 
1309.71(a)(2)). In addition, each person who sells these products must 
identify the other party to the transaction by having the other party 
present documents that would verify the identity (i.e., a driver's 
license and one other form of identification) and address of the other 
party (21 CFR 1310.06 and 1310.07(d)). The required recordkeeping 
includes the date of the transaction, quantity, form of packaging of 
the ephedrine product, method of transfer (company truck, picked up by 
customer, etc.), and type of identification used by the purchaser to 
the regulated person at the time the order is placed (21 CFR 1310.06).

IV. FDA's Tentative Conclusions

A. Summary of Major Labeling Changes

    Over the past 28 years since the Panel report was published, 
updated guidelines for the treatment of asthma have been issued, e.g., 
``Guidelines for the Diagnosis and Management of Asthma'' (Ref. 5). The 
benefits of bronchodilator drug products containing ephedrine or 
epinephrine as a treatment for mild bronchospasms continue to outweigh 
their risks. FDA recognizes that some people with asthma have used such 
products intermittently for many years and obtain a benefit from 
continued availability. FDA is proposing to update the labeling for 
these products to provide for safer and more effective use. Based on 
the available evidence, FDA is proposing to amend the FM for OTC 
bronchodilator drug products to make the changes set forth in the 
following paragraphs (sections IV.A.1 through IV.A.3 of this document).
1. Indications
    FDA is proposing to revise the indications in Sec.  341.76(b)(1) 
and (b)(2) to a single indication in the new OTC drug labeling format.

[[Page 40246]]

2. Warnings
    FDA is proposing to revise the entire warnings section as follows:
     Add an ``Asthma alert'' section that lists four conditions 
in which the user of the product should see a doctor. This ``Asthma 
alert'' shall appear as the first statement under the heading 
``Warnings'' and parts of the alert shall 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.
     List a number of other drugs that people might also be 
taking at the same time and thus should consult a doctor before using 
the OTC bronchodilator drug product. This information appears under the 
subheading ``Ask a doctor or pharmacist before use if you are.'' This 
list includes prescription drugs for asthma previously stated in Sec.  
341.76(c)(3) plus a new list of other drugs that could cause side 
effects when used in conjunction with ephedrine or epinephrine 
ingredients.
     List certain information that consumers need to know under 
the heading ``When using this product.'' This information includes the 
following:
    [ctrcir] Side effects that may occur (including side effects 
currently listed in Sec.  341.76(c)(5)(ii)),
    [ctrcir] Information about problems that may occur if the drug is 
taken more frequently or at a higher than recommended dosage (currently 
in Sec.  341.76(c)(6)(i) for products containing epinephrine 
ingredients, and which FDA is now proposing to include for both 
products containing ephedrine or epinephrine ingredients), and
    [ctrcir] New information about avoiding certain foods and dietary 
supplements while using an OTC bronchodilator drug product.
FDA considers the new information about the risks associated with an 
increase in blood pressure and heart rate to be the most important of 
this information and that consumers' attention should be specifically 
directed to this information. Accordingly, FDA is proposing that this 
information appear in bold type as the first statement in this section.
3. Directions
    FDA is proposing to 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''.

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 
monograph 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 monograph rulemakings 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 act. This judgment balances the benefits of these drug 
products against their potential risks (see Sec.  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