[Federal Register Volume 70, Number 133 (Wednesday, July 13, 2005)]
[Proposed Rules]
[Pages 40237-40249]
From the Federal Register Online via the Government Publishing 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: http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://www.fda.gov/dockets/ecomments.
Follow instructions for submitting comments on the agency Web site.
E-mail: [email protected]. 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
http://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 http://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 expanded discussion of case
law supporting FDA's authority to require such warnings, see the final
rule on Labeling of Diphenhydramine-Containing Drug Products for Over-
the-Counter Human Use (67 FR 72555, December 6, 2002).
V. Proposed Implementation
FDA proposes that the requirements of a final rule based on this
proposed rule be effective within 6 months after publication in the
Federal Register 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 OTC bronchodilator drug
products. Therefore, on or after 6 months after the date of publication
in the Federal Register of a final rule based on this proposed rule,
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 a 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 cannot
be repackaged or relabeled with the prior monograph labeling for these
products after the effective date of a final rule based on this
proposed rule. Manufacturers are encouraged to comply voluntarily with
this proposed rule at the earliest possible date.
VI. Analysis of Impacts
FDA has examined the impacts of this proposed rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Under the Regulatory
Flexibility Act, if a rule has a significant economic impact on a
substantial number of small entities, an agency must analyze regulatory
options that would minimize any significant impact of the rule on small
entities. Section 202(a) of the Unfunded Mandates Reform Act of 1995
requires that agencies prepare a written statement, which includes an
assessment of anticipated costs and benefits, before proposing ``any
rule that includes any Federal mandate that may result in the
expenditure by State, local, and tribal governments, in the aggregate,
or by the private sector, of $100,000,000 or more (adjusted annually
for inflation) in any one year.'' The current threshold after
adjustment for inflation is $115 million, using the most current (2003)
Implicit Price Deflator for the Gross Domestic Product. FDA does not
expect this proposed rule to result in any 1-year expenditure that
would meet or exceed this amount.
FDA believes that this proposed rule is consistent with the
principles set out in Executive Order 12866 and in these two statutes.
OMB has determined this rule is a significant regulatory action under
the Executive order. The purpose
[[Page 40247]]
of this proposed rule is to revise and improve the labeling (add
additional warning statements, change the directions, and change the
format for the indications) for OTC bronchodilator drug products. The
revised labeling is intended to provide consumers more and better
information to help ensure the safe and effective use of all OTC
bronchodilator drug products that contain these ingredients. This
proposed rule amends the FM for OTC bronchodilator drug products and
requires relabeling of all products covered by the FM. Potential
benefits include safer use of these products by consumers.
FDA's Drug Listing System (DLS) identifies approximately 25
manufacturers/distributors of approximately 40 to 50 OTC bronchodilator
drug products. Approximately half of the manufacturers/distributors
market single-ingredient ephedrine drug products, and the other half
market combination ephedrine/guaifenesin drug products. There appears
to be a very limited number of manufacturers/distributors marketing OTC
epinephrine solution products. There may be some additional marketers
and combination products sold via magazines and the Internet, which are
not in the DLS.
A. Relabeling Costs
FDA believes that the proposed relabeling costs of the type set
forth in this document generally average about $3,000 to $4,000 per
stock keeping unit (SKU) (individual products, packages, and sizes).
Assuming that there are about 50 affected OTC drug products in the
marketplace, total one-time costs of relabeling would be $150,000
($3,000 per SKU x 50 SKUs) to $200,000 ($4,000 per SKU x 50 SKUs). Even
if there are 20 additional products that FDA is not aware of, total
one-time costs of relabeling should not exceed $280,000 ($4,000 per SKU
x 70 SKUs). FDA believes that actual costs would be lower for several
reasons. First, it is FDA's understanding that most of the label
changes will be made by private label manufacturers that tend to use
relatively simple and less expensive labeling. Second, FDA has revised
the labeling format in this proposed rule based on the OTC drug product
labeling format in Sec. 201.66. Therefore, manufacturers will not
incur expenses determining how to state the new information in product
labeling. Manufacturers, however, may incur some expense to redesign
product labeling.
Most of the manufacturers who produce affected products are small
entities, using the U.S. Small Business Administration designations for
this industry (750 employees). FDA believes that any other unidentified
manufacturer of these products is also a small entity. Those
manufacturers who must relabel a large number of their products or
manufacture a new smaller size package will incur the greatest economic
impact.
B. Regulatory Alternatives Considered
Although FDA has rejected this alternative, FDA had proposed in
1995 to amend the FM for OTC bronchodilator drug products to remove the
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. In this
proposed rulemaking, FDA considered but rejected several other labeling
and packaging alternatives: (1) A longer implementation period, (2) an
exemption from coverage for small entities, and (3) less labeling
information. FDA does not consider these alternatives acceptable
because they do not assure that consumers will have the most recent
needed information for safe and effective use of these OTC
bronchodilator drug products in a timely manner.
This proposed rule does not require any new reporting and
recordkeeping activities. Therefore, no additional professional skills
are needed.
There is one other Federal rule that overlaps, but does not
conflict with, this proposed rule. DEA regulations (discussed in
section III.E of this document) control the distribution of single-
entity OTC ephedrine drug products.
This analysis shows that this proposed rule is not economically
significant under Executive Order 12866 and that FDA has analyzed
regulatory options that would minimize any significant impact of the
proposed rule on small entities. Nevertheless, some small entities,
especially those private label manufacturers that provide a number of
the affected products, may incur significant impacts. Thus, this
economic analysis, together with other relevant sections of this
document, serves as FDA's initial regulatory flexibility analysis, as
required under the Regulatory Flexibility Act.
VII. Paperwork Reduction Act of 1995
FDA tentatively concludes that the labeling requirements proposed
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 proposed 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)).
VIII. 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.
IX. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule does not contain policies that have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
FDA tentatively concludes that the proposed rule does not contain
policies that have federalism implications as defined in the Executive
order and, consequently, a federalism summary impact statement has not
been prepared.
X. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this proposed
rule and the agency's economic impact determination. Submit a single
copy of electronic comments or three paper copies of any mailed
comments, except that individuals may submit one paper copy. Comments
are to be identified with the docket number found in brackets in the
heading of this document and may be accompanied by a supporting
memorandum or brief. Received comments may be seen in the Division of
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
XI. Proposed Effective Date
FDA is proposing that any final rule that may issue based on this
proposed rule be effective 6 months after its date of publication in
the Federal Register.
XII. References
The following references are on display in the Division of Dockets
Management (see ADDRESSES) under
[[Page 40248]]
Docket No. 1995N-0205, unless otherwise indicated, and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. Goodman & Gilman's The Pharmacologic Basis of Therapeutics,
10th ed., edited by J.G. Hardman and L.E. Limbird, McGraw-Hill Co.,
New York, NY, p. 237, 2001.
2. Chua, S.S. and S.I. Benrimoj, ``Non-Prescription
Sympathomimetic Agents and Hypertension,'' Medical Toxicology,
3:387-417, 1988.
3. Morgan, P., ``The Role of Vasopressors in the Management of
Hypotension Induced by Spinal and Epidural Anesthesia,'' Canadian
Journal of Anesthesiology, 41(5 Pt 1):404-413, 1994.
4. Boozer, C.N. et al., ``Herbal Ephedra/Caffeine for Weight
Loss; A 6-Month Randomized Safety and Efficacy Trial,''
International Journal of Obesity and Related Metabolic Disorders,
26:593-604, 2002.
5. ``Guidelines for the Diagnosis and Management of Asthma.
National Asthma Education and Prevention Program (NAEPP) Expert
Panel Report,'' National Institutes of Health Publication, Update on
Selected Topics 2002, pp. 3-125, 2002.
6. Naureckas, E.T., and J. Solway, ``Mild Asthma,'' The New
England Journal of Medicine, 345(17):1257-1262, 2002.
7. The United States Pharmacopeia 28/The National Formulary 23,
United States Pharmacopeial Convention, Inc., Rockville, MD, p. 736,
2004.
8. Hoffman, B.B., ``Catecholamines, Sympathomimetic Drugs, and
Adrenergic Receptor Antagonists,'' Goodman & Gilman's The
Pharmacologic Basis of Therapeutics, 10th ed., edited by J.G.
Hardman and L.E. Limbird, McGraw-Hill Co., New York, NY, pp. 215-
220, 2001.
9. ``Final Report of The Hemorrhagic Stroke Project,'' Comment
No. C230, Docket No. 1976N-0052N.
10. Memorandum from Division of Drug Risk Assessment I to
Division of OTC Drug Products, dated October 31, 2000.
11. Goodman & Gilman's The Pharmacologic Basis of Therapeutics,
10th ed., edited by J.G. Hardman and L.E. Limbird, McGraw-Hill Co.,
New York, NY, pp. 215-241, 2001.
12. ``Ephedrine (hydrochloride),'' Therapeutic Drugs, edited by
C. Dollery, Churchill Livingston, New York, NY, pp. 26-29, 1991.
13. Goodman & Gilman's The Pharmacologic Basis of Therapeutics,
10th ed., edited by J.G. Hardman and L.E. Limbird, McGraw-Hill Co.,
New York, NY, pp. 193-253, 2001.
14. Chen, K.K. and C.F. Schmidt, ``Ephedrine and Related
Substances,'' Medicine, 9:1-117, 1930.
15. Clark, J.E. and W.A. Simon, ``Cardiac Arrhythmias After
Phenylpropanolamine Ingestion,'' Drug Intelligence and Clinical
Pharmacy, 17:737-738, 1983.
16. Bernstein, E. and B.M. Diskant, ``Phenylpropanolamine: A
Potentially Hazardous Drug,'' Annals of Emergency Medicine, 11:311-
315, 1982.
17. Mueller, M. and E.B. Solow, ``Seizures Associated with a New
Combination Pick-me-up Pill [Letter],'' Annals of Neurology, 11:322,
1982.
18. Koby, M., ``Disease and Disorders,'' Ferri's Clinical
Advisor, edited by F.F. Ferri et al., published by W.B. Saunders,
section 1, 2003.
19. Goodman & Gilman's The Pharmacologic Basis of Therapeutics,
10th ed., edited by J.G. Hardman and L.E. Limbird, McGraw-Hill Co.,
New York, NY, pp. 1821-1848, 2001.
20. Hari, C.K. et al., ``Acute Angle Closure Glaucoma
Precipitated by Intranasal Application of Cocaine,'' Journal of
Laryngology Otology, 113(3):250-251, 1999.
21. Sneddon, J.M. and P. Turner, ``Ephedrine Mydriasis in
Hypertension and the Response to Treatment,'' Clinical Pharmacology
and Therapeutics, 10(1):64-71, 1969.
22. Astrup, A. et al, ``The Effect of Safety of an Ephedrine/
Caffeine Compound Compared to Ephedrine, Caffeine, and Placebo in
Obese Subjects on an Energy Restricted Diet. A Double Blind Trial,''
International Journal of Obesity, 16:269-277, 1992.
23. Toubro, S. et al., ``Safety and Efficacy of Long-term
Treatment with Ephedrine, Caffeine, and an Ephedrine/Caffeine
Mixture,'' International Journal of Obesity, 17(1):S69-S72, 1993.
24. Karch, S.B., ``Other Naturally Occurring Stimulants,'' The
Pathology of Drug Abuse, edited by S.B. Karch, CRC Press, Boca
Raton, FL, pp. 177-198, 1996.
25. ``Analeptics: Caffeine,'' Drug Interaction Facts and
Comparison, pp. 230-230b, 1996.
26. ``Caffeine,'' Therapeutic Drugs, edited by C. Dollery,
Churchill Livingston, New York, NY, pp. 3-6, 1991.
27. Letter from B.W. Williams, FDA, to R. Deer, BDI
Pharmaceuticals, Division of Body Dynamics, Inc., dated February 24,
1997, coded LET3.
28. Letter from B.W. Williams, FDA, to M. Krassnof, PDK Labs,
Inc., dated February 24, 1997, coded LET2.
29. Letter from S. Shapiro, counsel to BDI Pharmaceuticals, to
R. Eshelman, FDA, dated March 14, 1997, in OTC Vol. 04BPEA2.
30. Letter from R. Spinello, PDK Labs Inc., to R. Eshelman, FDA,
dated March 14, 1997, in OTC Vol. 04BPEA2.
List of Subjects in 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, it is
proposed that 21 CFR part 341 be amended as follows:
PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC
DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
1. 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.
2. 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 occasional
symptoms of mild 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, 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 (the act)
relating to misbranding and the prohibition in section 301(d) of the
act against the introduction or delivery for introduction into
interstate commerce of unapproved new drugs in violation of section
505(a) of the 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
[[Page 40249]]
(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] 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.'' [statements shall appear in bold type as
the first statements under this subheading]
(ii) ``[Bullet] nervousness, sleeplessness, rapid heart beat,
tremor, and seizure may occur. If these symptoms persist or get worse,
consult a doctor right away.''
(iii) ``[Bullet] avoid caffeine-containing foods or beverages''.
(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 can 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 [insert total number of dosage units that
equals 150 milligrams] in any day''.
(D) ``[Bullet] use more than [insert total number of dosage units
that equals 100 milligrams] a day for more than 3 days a week''.
(E) ``[Bullet] have more than 2 asthma attacks in a week.''
(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 can 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 12 inhalations in any day''.
(D) ``[Bullet] use more than 9 inhalations a day for more than 3
days a week''.
(E) ``[Bullet] have more than 2 asthma attacks in a week.''
(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''.
(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 exceed dosage''
[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, not to exceed
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 exceed dosage'' [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. 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: June 30, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-13709 Filed 7-12-05; 8:45 am]
BILLING CODE 4160-01-S