Dietary Supplements Containing Ephedrine Alkaloids
FederalRegulations
Ask Donna
How this section applies to your facts.
Federal Register › Vol. 62 › 62 FR 30678
Text
Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Part 111
Dietary Supplements Containing Ephedrine Alkaloids; Proposed Rule
Proposed Rules
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 111
[Docket No. 95N-0304]
RIN 0901-AA59
Dietary Supplements Containing Ephedrine Alkaloids
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is proposing to make a
finding, which will have the force and effect of law, that a dietary
supplement is adulterated if it contains 8 milligrams (mg) or more of
ephedrine alkaloids per serving, or if its labeling suggests or
recommends conditions of use that would result in intake of 8 mg or
more in a 6-hour period or a total daily intake of 24 mg or more of
ephedrine alkaloids; require that the label of dietary supplements that
contain ephedrine alkaloids state ``Do not use this product for more
than 7 days''; prohibit the use of ephedrine alkaloids with
ingredients, or with ingredients that contain substances, that have a
known stimulant effect (e.g., sources of caffeine or yohimbine), which
may interact with ephedrine alkaloids; prohibit labeling claims that
require long-term intake to achieve the purported effect (e.g., weight
loss and body building); require a statement in conjunction with claims
that encourage short-term excessive intake to enhance the purported
effect (e.g., energy) that ``Taking more than the recommended serving
may result in heart attack, stroke, seizure or death''; and require
specific warning statements to appear on product labels
ong-term intake to achieve the purported effect (e.g., weight
loss and body building); require a statement in conjunction with claims
that encourage short-term excessive intake to enhance the purported
effect (e.g., energy) that ``Taking more than the recommended serving
may result in heart attack, stroke, seizure or death''; and require
specific warning statements to appear on product labels. FDA is
proposing these actions in response to serious illnesses and injuries,
including multiple deaths, associated with the use of dietary
supplement products that contain ephedrine alkaloids and the agency's
investigations and analyses of these illnesses and injuries. FDA is
also incorporating by reference its Laboratory Information Bulletin
(LIB) No. 4053, that FDA will use in determining the level of ephedrine
alkaloids in a dietary supplement.
DATES: Written comments by August 18, 1997. The agency proposes that
any final rule that may issue based on this proposal become effective
180 days after date of publication of the final rule.
ADDRESSES: Submit written requests for single copies of the analytical
method LIB No. 4053 to the Director, Office of Constituent Operations,
Industry Activities Staff (HFS-565), Food and Drug Administration, 200
C St. SW., rm. 5827, Washington, DC 20204. Send two self-addressed
adhesive labels to assist that office in processing your requests.
Submit written comments to the Dockets Management Branch (HFA-305),
Food and Drug Administration, 12410 Parklawn Dr., rm. 1-23, Rockville,
MD 20857. Requests and comments should be identified with the docket
number found in brackets in the heading of this document. A copy of the
analytical method LIB No. 4053, redacted adverse event reports (AER's)
associated with the use of dietary supplements containing ephedrine
alkaloids as well as copies of any accompanying medical records, and
received comments are available for public examination in the Dockets
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.
ts in the heading of this document. A copy of the
analytical method LIB No. 4053, redacted adverse event reports (AER's)
associated with the use of dietary supplements containing ephedrine
alkaloids as well as copies of any accompanying medical records, and
received comments are available for public examination in the Dockets
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.
FOR FURTHER INFORMATION CONTACT: Margaret C. Binzer, Center for Food
Safety and Applied Nutrition (HFS-456), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-401-9859, FAX 202-260-8957, or
E-mail [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
A. Characteristics of Ephedrine Alkaloids
Dietary supplements containing ephedrine alkaloids are widely sold
in the United States (Refs. 1 through 3). The ingredient sources of the
ephedrine alkaloids include raw botanicals and extracts from botanical
sources. Ma huang, Ephedra, Chinese Ephedra, and epitonin are several
names used for botanical products, primarily from Ephedra sinica Stapf,
E. equistestina Bunge, E. intermedia var. tibetica Stapf and E.
distachya L. (the Ephedras), that are sources of ephedrine alkaloids.
These alkaloids, ephedrine, pseudoephedrine, norpseudoephedrine,
norephedrine, methylephedrine, methylpseudoephedrine, and related
alkaloids, are naturally occurring chemical stimulants (Refs. 4 through
8). Although the proportions of the various ephedrine alkaloids in
botanical species vary from one species to another, in most species
used commercially, ephedrine is the most predominant alkaloid.
The ephedrine and related alkaloids are amphetamine-like compounds.
They exhibit some common types of effects but vary in the relative
intensity of these effects (Table 1) (Refs. 5, 6, and 9 through 15).
For example, ephedrine is a cardiovascular system (CVS) and nervous
system (NS) stimulant. Pseudoephedrine has some CVS and NS stimulatory
effects but is less potent than ephedrine
alkaloid.
The ephedrine and related alkaloids are amphetamine-like compounds.
They exhibit some common types of effects but vary in the relative
intensity of these effects (Table 1) (Refs. 5, 6, and 9 through 15).
For example, ephedrine is a cardiovascular system (CVS) and nervous
system (NS) stimulant. Pseudoephedrine has some CVS and NS stimulatory
effects but is less potent than ephedrine. Norephedrine (also called
phenylpropanolamine) is similar to ephedrine in its NS stimulant
effects but has fewer CVS stimulant effects than ephedrine (Refs. 12
and 16 through 18). Although norephedrine is often a minor ephedrine
alkaloid constituent, in humans it can be produced from ingested
ephedrine through normal metabolic processes (Refs. 9, 19, and 20).
Thus, its presence in body tissues and fluids may be detected, and its
physiological effects can occur, even if norephedrine is not contained
in meaningful amounts in the original supplement product. Data on the
other ephedrine alkaloids and related alkaloids are limited, and thus
their physiological and pharmacological effects are largely unknown
(Ref. 15).
Table 1.--Patterns of Signs and Symptoms Associated With Dietary Supplements Containing Ephedrine Alkaloids
----------------------------------------------------------------------------------------------------------------
Organ/system involved Clinical significance Signs and symptoms
----------------------------------------------------------------------------------------------------------------
Cardiovascular system................... Serious.................... Dysrhythmias, severe hypertension,
cardiac arrest, angina, myocardial
infarction, and stroke \1\
Less clinically significant Tachycardia, mild hypertension,
palpitations.
Nervous system.......................... Serious.................... Psychosis, suicidal, altered or loss of
consciousness (including disorientation
or confusion), and seizures
........... Serious.................... Dysrhythmias, severe hypertension,
cardiac arrest, angina, myocardial
infarction, and stroke \1\
Less clinically significant Tachycardia, mild hypertension,
palpitations.
Nervous system.......................... Serious.................... Psychosis, suicidal, altered or loss of
consciousness (including disorientation
or confusion), and seizures.
Less clinically significant Anxiety, nervousness, tremor,
hyperactivity, insomnia, altered
behavior, memory changes.
Gastrointestinal (GI)................... Serious.................... Altered serum enzymes, hepatitis.
Less clinically significant GI distress (nausea, vomiting, diarrhea,
constipation).
Dermatologic............................ Serious.................... Exfoliative dermatitis.
Less clinically significant Nonspecific rashes.
General manifestations.................. ........................... Numbness, tingling, dizziness, fatigue,
lethargy, weakness.
----------------------------------------------------------------------------------------------------------------
\1\ For the purposes of this document, strokes (i.e., cerebrovascular accidents) are considered to be related to
the cardiovascular system, because predisposing or inciting factors include hypertension, dysrhythmias and
ischemia, although it is recognized that the consequences affect the central nervous system.
B. The Availability of Ephedrine Alkaloids
---------------------------------------
\1\ For the purposes of this document, strokes (i.e., cerebrovascular accidents) are considered to be related to
the cardiovascular system, because predisposing or inciting factors include hypertension, dysrhythmias and
ischemia, although it is recognized that the consequences affect the central nervous system.
B. The Availability of Ephedrine Alkaloids
To determine the types of ephedrine alkaloid-containing dietary
supplements available in the marketplace, the agency has collected over
125 dietary supplement products labeled as containing a known source of
ephedrine alkaloids during the past 2 years (Refs. 1 and 2). These
products show that ephedrine alkaloid-containing-dietary supplements
are marketed in a variety of forms, including capsules, tablets,
powders, and liquids. The source of the ephedrine alkaloids in these
supplements vary from the raw botanical to powdered plant material and
concentrated extracts; however, most of the products contain
concentrated extracts. Although FDA is aware that some companies have
changed their labeling and formulation since the market review, this
review of the marketplace reflects the general contours of products
currently sold in the United States.
Ephedrine alkaloids are present in some products as a single
ingredient, but more commonly, they are combined with other
ingredients, including vitamins, minerals, amino acids, and other
botanicals (Refs. 1, 2, and 21). Most of the dietary supplements that
contain an ingredient source of the ephedrine alkaloids also contain
between 6 and 20 other ingredients. Some of these other ingredients
have known or suspected physiological and pharmacological activities
that have the potential for interacting with the ephedrine alkaloids so
as to increase their effects
acids, and other
botanicals (Refs. 1, 2, and 21). Most of the dietary supplements that
contain an ingredient source of the ephedrine alkaloids also contain
between 6 and 20 other ingredients. Some of these other ingredients
have known or suspected physiological and pharmacological activities
that have the potential for interacting with the ephedrine alkaloids so
as to increase their effects. For example, the majority of dietary
supplements containing ephedrine alkaloids also contain a source of
xanthine alkaloids (e.g., caffeine), another stimulant substance that
is known to increase the effects of ephedrine alkaloids (Refs. 7, 16,
22, and 23).
Because product labels do not usually provide information on
product composition (Ref. 24), and there are no data bases containing
such data, FDA laboratories analyzed the products collected to quantify
the levels of ephedrine alkaloids (Refs. 1, 2, 21, and 25). Results of
the analyses show that these products, taking into account the labeled
recommended serving instructions, are likely to provide intakes of
ephedrine alkaloids that range from below the detectible limits of
FDA's analytical method to 110 mg per serving (i.e., per single use)
(Refs. 1, 2, 21, 25, and 26). Most of the products, regardless of their
promoted use, had ephedrine alkaloid levels at or above 10 mg per
serving.
Many of the dietary supplement products that FDA collected were
promoted for uses such as weight loss, body building, increased energy,
increased mental concentration, increased sexual sensations, or
euphoria or as alternatives to illicit street drugs (Refs. 1, 2, and
25). The majority of the products collected also bore warning
statements on their labels (Refs. 1, 2, and 27). The warning statements
varied from general precautions, suggesting that the consumer check
with a health care professional before beginning any diet or exercise
program, to more specific warning statements
ions, or
euphoria or as alternatives to illicit street drugs (Refs. 1, 2, and
25). The majority of the products collected also bore warning
statements on their labels (Refs. 1, 2, and 27). The warning statements
varied from general precautions, suggesting that the consumer check
with a health care professional before beginning any diet or exercise
program, to more specific warning statements. The more specific warning
statements contained several elements, including cautions that the
consumer not use the product if they have certain diseases or health
conditions or are using certain drugs, and to stop the use of the
product if they develop certain symptoms (Refs. 1, 2, 25, and 27).
C. Adverse Events Associated With Ephedrine Alkaloids
Since 1993, FDA has received more than 800 reports of illnesses and
injuries (AER's) associated with the use of more than 100 different
dietary supplement products that contained, or were suspected to
contain, ephedrine alkaloids. These adverse events tended to involve
CVS effects and NS effects. FDA evaluated the AER's showing CVS and NS
effects and found that the single most common element was that the
products contained, or were thought to contain, a source of ephedrine
alkaloids. Approximately 50 to 60 percent of the AER's associated with
use of dietary supplements were for such products.
The AER's associated with the ephedrine alkaloid-containing
products included consistent patterns of signs and symptoms among both
otherwise healthy individuals and those with underlying diseases or
conditions. These signs and symptoms included rapid and irregular heart
rhythms, increased blood pressure, chest pain, anxiety, nervousness,
tremor, hyperactivity, and insomnia (i.e., inability or difficulty in
sleeping) and were associated with clinically significant conditions,
including heart attack, stroke, psychoses, seizure, and, in a few
cases, death
those with underlying diseases or
conditions. These signs and symptoms included rapid and irregular heart
rhythms, increased blood pressure, chest pain, anxiety, nervousness,
tremor, hyperactivity, and insomnia (i.e., inability or difficulty in
sleeping) and were associated with clinically significant conditions,
including heart attack, stroke, psychoses, seizure, and, in a few
cases, death. Many of these signs and symptoms occurred in young adults
who generally would not have been expected to be at high risk for such
conditions (e.g., heart attack and stroke). Many adverse events were
reported to occur with the first use or within the first 2 weeks of
use. Although the majority occurred in women, men also reported
experiencing adverse events.
The nature and patterns of these AER's are consistent with the
known physiological and pharmacological effects of ephedrine alkaloids
as described in: (1) Pharmacology texts for single ephedrine alkaloid
products, (2) case reports of adverse effects from the scientific
literature related to the pharmaceutical use of ephedrine alkaloids,
(3) adverse events reported in controlled clinical trials using
ephedrine in the treatment of obesity, and (4) known safety concerns
with traditional medical uses of botanicals that contain ephedrine
alkaloids. As a result, FDA focused its investigation on ephedrine
alkaloids as a likely factor in the rapidly increasing number of
serious AER's associated with the use of dietary supplement products.
D. Review Activities
The growing number and consistency of reports of serious adverse
events associated with a wide variety of ephedrine alkaloid-containing
dietary supplements, and the virtual absence of publicly available
safety data on these supplements, prompted FDA to convene an ad hoc
Working Group of its Food
r of
serious AER's associated with the use of dietary supplement products.
D. Review Activities
The growing number and consistency of reports of serious adverse
events associated with a wide variety of ephedrine alkaloid-containing
dietary supplements, and the virtual absence of publicly available
safety data on these supplements, prompted FDA to convene an ad hoc
Working Group of its Food
Advisory Committee (the Working Group) (Refs. 27 through 29).
1. The Food Advisory Committee Working Group Meeting on Dietary
Supplements Containing Ephedrine Alkaloids
On October 11 and 12, 1995, the Working Group, which consisted of
medical and other scientific experts from outside FDA as well as
industry and consumer representatives, considered the potential public
health problems associated with the use of dietary supplements and
other food products containing ephedrine alkaloids.
The Working Group reviewed the evidence on the occurrence of
adverse events associated with the use of ephedrine alkaloids. This
evidence included the known pharmacology of ephedrine alkaloids,
numerous case reports published in the scientific literature, and
published findings from clinical studies investigating the use of
ephedrine in the treatment of obesity (Ref. 30). The evidence also
included over 325 AER's that had been received by FDA that were
associated with the consumption of dietary supplements known to
contain, or suspected of containing, ephedrine alkaloids (Refs. 29 and
31). The Working Group also considered public comments made during the
meeting (Ref. 27).
Following their review of this evidence, the members of the Working
Group agreed that the use of certain dietary supplements containing
ephedrine alkaloids may cause consumers to experience serious adverse
events
upplements known to
contain, or suspected of containing, ephedrine alkaloids (Refs. 29 and
31). The Working Group also considered public comments made during the
meeting (Ref. 27).
Following their review of this evidence, the members of the Working
Group agreed that the use of certain dietary supplements containing
ephedrine alkaloids may cause consumers to experience serious adverse
events. On this basis, the Working Group recommended that FDA: (1)
Establish single serving and daily total use limits for ephedrine and
total ephedrine alkaloids; (2) require warning or cautionary statements
on the labels of these products; and (3) establish good manufacturing
practice (GMP) requirements, including proper botanical identification
and standardization of the ephedrine alkaloid and ephedrine content in
concentrated extracts. Several members of the Working Group suggested
that ephedrine alkaloids be limited to 25 mg per single serving and 100
mg total daily use. Other members suggested a variety of lower levels
of ephedrine alkaloids per serving. The Working Group also discussed
specific warning label statements but failed to agree on the wording of
the warning statements.
2. The Food Advisory Committee Meeting
In the 6 months that followed the Working Group meeting, the number
of reports of adverse events associated with the use of dietary
supplements thought to contain ephedrine alkaloids doubled. In
addition, FDA received information on two deaths of young adult males
in which the medical examiners specifically attributed the cause of
death to use of ephedrine alkaloid-containing dietary supplements (see
medical examiners' reports in Adverse Reaction Monitoring System (ARMS)
No. 10862 and 11134). FDA analyzed samples of products that consumers
claimed that they had consumed and suffered an adverse event and found
that the ephedrine alkaloid levels in many of these products were below
the 25-mg limit suggested by certain members of the Working Group
alkaloid-containing dietary supplements (see
medical examiners' reports in Adverse Reaction Monitoring System (ARMS)
No. 10862 and 11134). FDA analyzed samples of products that consumers
claimed that they had consumed and suffered an adverse event and found
that the ephedrine alkaloid levels in many of these products were below
the 25-mg limit suggested by certain members of the Working Group.
In light of the rapidly increasing numbers of adverse events as
well as of the new analytical information on AER-related intakes of
ephedrine alkaloids, FDA recognized that a determination on how to deal
with dietary supplements that contained these substances could not be
further delayed. Thus, FDA convened its Food Advisory Committee in
conjunction with the Working Group to review and provide final
recommendations on what to do with ephedrine alkaloid-containing
dietary supplements.
The Food Advisory Committee met on August 27 and 28, 1996. The
meeting included all members from the Working Group who were available
to attend the meeting, as well as additional experts to replace those
experts unable to attend or to fill out the range of expertise needed
to appropriately evaluate the subject. FDA asked the Food Advisory
Committee to consider the safety of using dietary supplements
containing ephedrine alkaloids and to make specific recommendations on
how to resolve the public health concerns surrounding their use (Ref.
25). The Food Advisory Committee reviewed the evidence that had been
presented to the Working Group as well as new data and information that
had become available since the October 1995 Working Group meeting.
Following a review of the totality of the available evidence, the
October 1995 recommendations of the Working Group, public comments, and
considerable discussion, the Food Advisory Committee agreed that FDA
should take action to address the rapidly evolving and serious public
health concerns associated with the use of ephedrine alkaloid-
containing dietary supplements (Ref
king Group meeting.
Following a review of the totality of the available evidence, the
October 1995 recommendations of the Working Group, public comments, and
considerable discussion, the Food Advisory Committee agreed that FDA
should take action to address the rapidly evolving and serious public
health concerns associated with the use of ephedrine alkaloid-
containing dietary supplements (Ref. 25). The Food Advisory Committee
could not, however, come to consensus on a specific approach to the
public health concerns. Over half of the Food Advisory Committee
members stated that, based on the available data, no safe level of
ephedrine alkaloids could be identified for use in dietary supplements
(Ref. 25). Many of these members expressed concern that many
individuals who would be at risk if they were to use products were
unaware of that risk because many of the conditions that increase the
risk of adverse events may not be self-evident (Ref. 25). Consequently,
they recommended removing dietary supplements containing ephedrine
alkaloids from the market (Ref. 25). Other members of the Food Advisory
Committee suggested that the agency establish conditions of use that
would reduce the risk of adverse events, including establishing
``reasonably'' safe per serving and daily use levels for both ephedrine
alkaloids and ephedrine as well as other requirements (Ref. 25).
II. FDA's Response
Following the August 1996 meeting of the Food Advisory Committee,
the agency completed its review of the majority of the AER's associated
with these products and reviewed the discussions and the
recommendations of the Food Advisory Committee, the scientific
literature, the views expressed in public comments, and other data.
Based on this information, the agency has tentatively concluded that
use of ephedrine alkaloids raises important public health concerns,
that the risks these substances create are potentially very serious,
and that action must be taken to protect the public health.
ecommendations of the Food Advisory Committee, the scientific
literature, the views expressed in public comments, and other data.
Based on this information, the agency has tentatively concluded that
use of ephedrine alkaloids raises important public health concerns,
that the risks these substances create are potentially very serious,
and that action must be taken to protect the public health.
A. Summary of Initial Considerations
Between 1993 and 1996, FDA received a rapidly escalating number of
AER's associated with the use of dietary supplements, some that
contained ephedrine alkaloids, some that did not (Refs. 32 through 34).
Figure 1 shows that in the 3 years since the initiation of an adverse
event monitoring system for special nutritional products, the number of
AER's received by the agency on dietary supplements has quadrupled.
BILLING CODE 4160-01-P
[GRAPHIC] [TIFF OMITTED] TP04JN97.000
BILLING CODE 4160-01-C
Many of these reports have been for clinically significant events
(e.g., heart attack, stroke, seizures) that were observed most often in
young adults for whom the risk of these types of events are generally
low (see Figure 2, which summarizes data from the AER's relative to the
age and gender of individuals experiencing an adverse event). When FDA
examined the products reported to be associated with the CVS and NS
effects, the most common element among them was that they involved
products that contained or were believed to contain an ingredient
source of ephedrine alkaloids. Thus, FDA focused its investigation on
the ephedrine alkaloids in dietary supplement products.
BILLING CODE 4160-01-P
[GRAPHIC] [TIFF OMITTED] TP04JN97.001
en FDA
examined the products reported to be associated with the CVS and NS
effects, the most common element among them was that they involved
products that contained or were believed to contain an ingredient
source of ephedrine alkaloids. Thus, FDA focused its investigation on
the ephedrine alkaloids in dietary supplement products.
BILLING CODE 4160-01-P
[GRAPHIC] [TIFF OMITTED] TP04JN97.001
BILLING CODE 4160-01-C
However, many of the ephedrine alkaloid-containing products also
contained other ingredients (e.g., amino acids, vitamins and minerals,
other botanicals) whose possible influence on the observed AER's could
not be ignored. Upon examination of the types of other ingredients, FDA
tentatively concluded that these other ingredients should not be the
primary focus of its evaluation because these ingredients, unlike the
ephedrine alkaloids, did not have a history (in the amounts likely to
be found in dietary supplements) of being able to produce the types of
serious adverse events being observed. For example, many ephedrine
alkaloid-containing dietary supplements also contain known stimulants
(e.g., sources of caffeine). While caffeine is known to stimulate the
NS, in the amounts likely to be found in dietary supplements it is not
expected to produce effects such as stroke, heart attack, and seizure.
Nonetheless, FDA remained aware of the possibility that other
ingredients in these dietary supplement products contributed to the
adverse events reported. For example, other stimulants in the
ephedrine-containing dietary supplements could enhance the known
stimulant effects of ephedrine alkaloids. Likewise, substances that
affect kidney function (e.g., sources of salicin, concentrated amino
acids) could influence the body's ability to ``clear'' or rid itself of
ingested ephedrine alkaloids
t products contributed to the
adverse events reported. For example, other stimulants in the
ephedrine-containing dietary supplements could enhance the known
stimulant effects of ephedrine alkaloids. Likewise, substances that
affect kidney function (e.g., sources of salicin, concentrated amino
acids) could influence the body's ability to ``clear'' or rid itself of
ingested ephedrine alkaloids.
The agency also considered in its evaluation the fact that
botanical sources contain mixtures of ephedrine alkaloids that may have
slightly different effects (e.g., additive or interactive effects) than
those from a single ephedrine alkaloid, as found in over-the-counter
(OTC) products. The agency compared the observed effects of supplement
products with the known physiological and pharmacological effects of
single sources of the alkaloids that are used as ingredients in several
drugs (e.g., ephedrine in OTC bronchodilator products, pseudoephedrine
in cough and cold preparations, and phenylpropanolamine in anoretic
products). However, the agency was not able to find definitive evidence
to evaluate whether ephedrine alkaloids from botanical sources are
metabolized differently than those from pharmaceutical sources, and in
the absence of more directly relevant data for dietary supplement
products, the agency considered it appropriate to rely on evidence from
pharmaceutical sources of single ephedrine alkaloids in assessing the
effects of botanical sources (see section II.C.2. of this document).
B. FDA's Strategy for Evaluation
FDA considered five questions in evaluating the reports of adverse
events involving ephedrine alkaloids that it
relevant data for dietary supplement
products, the agency considered it appropriate to rely on evidence from
pharmaceutical sources of single ephedrine alkaloids in assessing the
effects of botanical sources (see section II.C.2. of this document).
B. FDA's Strategy for Evaluation
FDA considered five questions in evaluating the reports of adverse
events involving ephedrine alkaloids that it
had received. These questions were designed to help the agency discern
relationships among AER's where direct and readily interpretable
clinical studies were not available, and where multiple host or product
factors may have affected any association (Refs. 35 through 37). The
questions focused the evaluation on whether there was a likely
association between the ephedrine alkaloids and the adverse events that
had been reported and on the strength, nature, and biological
plausibility of any association. These questions were:
(1) Using the AER's on marketed ephedrine alkaloid-containing
dietary supplements from FDA's passive surveillance system, are there
consistent patterns of signs and symptoms associated with the use of a
number of different ephedrine alkaloid-containing dietary supplement
products?
(2) Are the patterns of the signs and symptoms consistent with the
available scientific evidence and known physiologic and pharmacologic
effects of ephedrine alkaloids?
(3) Is there sufficient evidence that the relationships are
temporally correct, that is, does exposure occur temporally before the
onset of the observed patterns of signs and symptoms?
(4) Is there other evidence of causality, even in the absence of
controlled trials, e.g., evidence of dechallenge (improvement or
resolution of the signs and symptoms when use of the product is
discontinued) or positive rechallenge (reoccurrence of the signs and
symptoms when reexposed to ephedrine alkaloids)?
occur temporally before the
onset of the observed patterns of signs and symptoms?
(4) Is there other evidence of causality, even in the absence of
controlled trials, e.g., evidence of dechallenge (improvement or
resolution of the signs and symptoms when use of the product is
discontinued) or positive rechallenge (reoccurrence of the signs and
symptoms when reexposed to ephedrine alkaloids)?
(5) Considering the totality of the available information, is there
a biologically plausible explanation for the adverse events?
Finally, in fully evaluating the public health concerns associated
with these products, the agency evaluated the potential impact of other
factors that could influence final decisions on the best approach to
addressing the public health concerns.
C. Evaluation and Tentative Conclusions of the Agency
1. Using the AER's From FDA's Passive Surveillance System for Dietary
Supplements, FDA Has Tentatively Concluded That There Are Consistent
Patterns of Signs and Symptoms Associated With the Use of a Number of
Different Ephedrine Alkaloid-Containing Dietary Supplement Products
In preparation for its August 27 and 28, 1996, Food Advisory
Meeting, FDA reviewed each of the approximately 600 AER's that it had
received before June 7, 1996 (Refs. 31 and 38). The adverse events
associated with ephedrine alkaloid-containing dietary supplement
products ranged from those with clinically serious sequelae (such as
abnormal heart rhythms, chest pain, heart attack, stroke, significant
elevations in blood pressure, seizure, hepatitis, coma, psychosis, and
death) to those with less clinically significant signs and symptoms
(such as nervousness, dizziness, tremor, minor alterations in blood
pressure or heart rate, headache, and gastrointestinal distress) (see
Table 1)
h clinically serious sequelae (such as
abnormal heart rhythms, chest pain, heart attack, stroke, significant
elevations in blood pressure, seizure, hepatitis, coma, psychosis, and
death) to those with less clinically significant signs and symptoms
(such as nervousness, dizziness, tremor, minor alterations in blood
pressure or heart rate, headache, and gastrointestinal distress) (see
Table 1). Although many of the AER's crossed clinical categories,
approximately 15 percent of the reports described serious
cardiovascular effects, including abnormal heart rhythms, stroke, heart
attack, and cardiomyopathy (disease of the heart muscle). Approximately
16 percent of the reports mentioned serious NS effects, including
seizure, psychosis, mania, severe depression, vestibular (inner ear)
disturbances, and loss of consciousness. Other clinically serious or
potentially serious adverse effects reported to be associated with the
use of these products included elevations of liver function tests or
overt hepatitis (4 percent), myopathies (disease of muscle,
particularly skeletal muscle) (3 percent), disturbances of the
genitourinary system (e.g., urinary retention, urinary infection,
prostatitis (inflammation of the prostate gland), and epididymitis
(inflammation of the epididymis, part of the male genitourinary tract))
(3 percent), and dermatologic manifestations (including systemic rashes
which appear to be immune mediated or allergic in nature) (6 percent).
Approximately 30 percent of the reports mentioned other effects,
including gastrointestinal distress, abnormal blood sugar levels or
diabetes, blood disorders (including increased bleeding tendencies and
abnormal blood cell counts), thyroid disorders, and addiction to the
product. Finally, approximately 60 percent of the adverse events were
characterized by general stimulant effects on the CVS and NS of a
``less clinically serious'' nature, including anxiety, nervousness,
hyperactivity, tremor, insomnia, and altered heart rate or rhythms
disorders (including increased bleeding tendencies and
abnormal blood cell counts), thyroid disorders, and addiction to the
product. Finally, approximately 60 percent of the adverse events were
characterized by general stimulant effects on the CVS and NS of a
``less clinically serious'' nature, including anxiety, nervousness,
hyperactivity, tremor, insomnia, and altered heart rate or rhythms.
However, FDA recognized that these reports of less clinically
significant effects could be indicative of early warnings of serious
cardiovascular or nervous system risks if product use were to continue.
Serious adverse events were reported for a number of different
products promoted for a variety of uses and marketed in a variety of
formulations (Refs. 27, 31, and 38). Of these, where there was
sufficient information to evaluate how the product was marketed or
used, approximately 92 percent of the adverse events were related to
the use of products marketed for weight loss and energy purposes, and 5
percent were related to products promoted for enhancing athletic
performance or body building, although there was overlap among these
uses. Approximately 2 percent of the adverse events were related to
products marketed as alternatives to illicit street drugs or for
euphoric purposes. (This distribution of types of products parallels
the observations made from FDA's market review, which found that most
of the dietary supplements containing ephedrine alkaloids bear weight
loss and energy claims on their labels or in their labeling (Refs. 1
and 2).) Moreover, specific types of adverse events did not appear to
be limited to products promoted for any single use, such as weight
loss, energy, or euphoria.
The adverse events were reported to occur in both healthy
individuals and in individuals with underlying diseases or conditions
that may have influenced the frequency, pattern, or severity of the
adverse event (Refs. 25, 27, 31, and 38)
.) Moreover, specific types of adverse events did not appear to
be limited to products promoted for any single use, such as weight
loss, energy, or euphoria.
The adverse events were reported to occur in both healthy
individuals and in individuals with underlying diseases or conditions
that may have influenced the frequency, pattern, or severity of the
adverse event (Refs. 25, 27, 31, and 38). Of great concern to the
agency are the heart attacks, strokes, seizures, and other clinically
serious illnesses and injuries reported to occur in young adults
(Figure 2). In approximately 56 percent of the reported adverse events,
the injured party was less than 40 years of age, and approximately 25
percent of injuries occurred in those between 40 and 49 years of age.
Generally, significant CVS or NS risk factors are not expected in these
age groups. Almost 75 percent of the adverse events were reported to
occur in females, often using products promoted for weight loss. The
higher frequency of adverse events in women most likely reflects a
difference in product use (i.e., women predominantly use products
marketed for weight loss and energy purposes). However, gender
predominance in these ratios may also occur because of gender-related
differences in metabolism of ephedrine alkaloids, or gender-related
differences in the numbers and types of tissue receptors interacting
with ephedrine alkaloids (Refs. 39 through 41).
Data on duration of use of ephedrine alkaloid-containing dietary
supplements relative to the occurrence of AER's can also be used to
examine the similarity of patterns of adverse events across different
types of exposures and individual sensitivities. Figure 3 summarizes
the duration of use data collected from the AER's associated
s interacting
with ephedrine alkaloids (Refs. 39 through 41).
Data on duration of use of ephedrine alkaloid-containing dietary
supplements relative to the occurrence of AER's can also be used to
examine the similarity of patterns of adverse events across different
types of exposures and individual sensitivities. Figure 3 summarizes
the duration of use data collected from the AER's associated
with products containing ephedrine alkaloids. As shown in Figure 3,
this information reveals that about 59 percent of the adverse events
were reported to occur within 4 weeks of starting to use the product.
About 14 percent of the reported adverse events occurred on the first
day of using the dietary supplement (Ref. 38) (see ARMS No. 10009 and
11619 in the Appendix to this document) and, in a few cases, on the
initial use (Ref. 38) (ARMS No. 11401 in the Appendix to this
document). Of equal concern to the agency are reports of serious
adverse events occurring within a relatively short time period after
consumers began to use the products or consumers began to start using
the products after having stopped use for a period of time (ARMS No.
11076 in the Appendix to this document).
BILLING CODE 4160-01-P
[GRAPHIC] [TIFF OMITTED] TP04JN97.002
BILLING CODE 4160-01-C
Adverse events appear to reflect different inherent types of
individual sensitivities relative to dose levels, frequency or duration
of use, and subsequent results of sympathomimetic stimulation. In some
cases, particular events appear to occur as the result of increased
individual susceptibility to the effects of sympathetic stimulation
(Refs. 39 through 42). For example, in one report (ARMS No. 10862 in
the Appendix to this document), three young adult males consumed
similar amounts of a dietary supplement containing ephedrine alkaloids,
yet only one male experienced serious adverse effects, which resulted
in his death (see Police and Medical Examiner's Reports in ARMS No.
10862 in public docket number 95N-0304)
timulation
(Refs. 39 through 42). For example, in one report (ARMS No. 10862 in
the Appendix to this document), three young adult males consumed
similar amounts of a dietary supplement containing ephedrine alkaloids,
yet only one male experienced serious adverse effects, which resulted
in his death (see Police and Medical Examiner's Reports in ARMS No.
10862 in public docket number 95N-0304). This report is illustrative of
numerous AER's suggesting an unpredictable pattern and severity of
adverse events when consuming ephedrine alkaloid-containing dietary
supplements, even when used according to package directions or under
ordinary conditions of use. In other cases, some of the adverse events
were associated with consumption of relatively low levels of ephedrine
alkaloids (e.g., approximately 10 mg or less total ephedrine alkaloids
per serving), some occurring shortly after onset of use.
These variations in the occurrence of adverse events relative to
duration, frequency, and levels of exposure are suggestive that
multiple factors influence sensitivity to ephedrine alkaloid intakes
and could be indicative that some of the adverse effects are the result
of increased individual susceptibility to the acute or chronic effects
of ephedrine alkaloids.
In summary, in reviewing the AER's associated with ephedrine
alkaloid-containing dietary supplements, the agency noted a consistency
of signs and symptoms across a large number of products, across a range
of products with a variety of intended uses, across products with many
different formulations, and across a heterogeneous group of individuals
with respect to gender, age, and health condition. Generally, the
overall pattern of observed results was consistent with stimulant CVS
and NS effects, even though not every product showed the same effect or
the same seriousness of effect, not every case involved CVS or NS
effects, and not all reports were complete or uncomplicated. The
patterns of duration of use and dosage
p of individuals
with respect to gender, age, and health condition. Generally, the
overall pattern of observed results was consistent with stimulant CVS
and NS effects, even though not every product showed the same effect or
the same seriousness of effect, not every case involved CVS or NS
effects, and not all reports were complete or uncomplicated. The
patterns of duration of use and dosage
levels suggest patterns of adverse events that are influenced by
variations in individual sensitivities. Overall, however, there was a
remarkable consistency in the types of signs and symptoms of adverse
effects reported. This consistency was recognized by the Working Group
(Ref. 27).
The foregoing discussion summarizes the AER's from a descriptive
statistical perspective. Many of these reports are summarized in the
Appendix to this document. An abbreviated description of all reports is
in public docket number 95N-0304. A few examples of experiences of
particular individuals are given below.
ARMS No. 11134--A 23-year-old male college student used an
ephedrine alkaloid-containing ergogenic product for approximately 2
years, along with several other dietary supplement products. He was
previously healthy and was known to have a healthy life style. He was
found dead by his sister in the apartment that they shared. The Medical
Examiner's report stated that the cause of death was due to ``patchy
myocardial necrosis associated with ephedrine toxicity from protein
drink containing Ma huang extract.''
ARMS No. 9552--A 35-year-old female, who was on no medications and
who had a negative past medical history, developed a non-Q wave
myocardial infarction (heart attack) while using an ephedrine alkaloid-
containing dietary supplement within the dosage recommended on the
label. She used the product for approximately 30 days, stopped for 1
week while on vacation, and then reinitiated the use of the product
552--A 35-year-old female, who was on no medications and
who had a negative past medical history, developed a non-Q wave
myocardial infarction (heart attack) while using an ephedrine alkaloid-
containing dietary supplement within the dosage recommended on the
label. She used the product for approximately 30 days, stopped for 1
week while on vacation, and then reinitiated the use of the product.
About 11 days after restarting the product, she developed acute
throbbing, anterior chest pain at rest, with radiation to the left
shoulder, numbness of the left arm and hand, diaphoresis (sweating),
and shortness of breath. In the hospital, clinical evaluations
(electrocardiogram and cardiac enzymes) indicated an acute non-Q wave
myocardial infarction, thought to be secondary to coronary artery
spasm. Cardiac catheterization showed normal coronary arteries.
ARMS No. 10009--A 35-year-old male took an ephedrine alkaloid-
containing dietary supplement (2 capsules at noon, 3 capsules at 4:30
pm). He worked out from 5:30 to 6:30 pm, developing chest pain at 7:30
pm. He was admitted to the hospital with an acute myocardial infarction
(by electrocardiogram and cardiac enzymes) and was treated medically.
Subsequent cardiac catheterization demonstrated normal coronary
arteries.
ARMS No. 11144--A 28-year-old man used an ephedrine alkaloid-
containing product for 10 months (1 capsule per day) for energy. His
father found him bloody and responding inappropriately. In the
emergency department, his blood pressure was 168/90, with a pulse of
116. Results of extensive clinical and laboratory evaluations were all
within normal limits. He was diagnosed with syncope and a closed head
injury. His neurologist concluded that ``most likely he had a seizure
secondary to ephedrine'' from the health food substance he was taking.
He was advised to avoid the product and dispose of it. This man was on
no other medications and had no significant past medical history
ive clinical and laboratory evaluations were all
within normal limits. He was diagnosed with syncope and a closed head
injury. His neurologist concluded that ``most likely he had a seizure
secondary to ephedrine'' from the health food substance he was taking.
He was advised to avoid the product and dispose of it. This man was on
no other medications and had no significant past medical history. In
particular, he never had problems with dizziness or passing out.
ARMS No. 10974--A 19-year-old woman took an ephedrine alkaloid-
containing product, one before each meal, three times per day (\1/2\ of
recommended amount) for 1 month, for weight loss. Her family witnessed
seizure activity at mealtime and took her to the emergency room.
Evaluations there were essentially normal (CT scan of the head and
electroencephalogram or EEG). The neurologist's evaluation found no
other risk factors for seizure. No other products had been used, and
there was no significant past medical history.
ARMS No. 10088--A 38-year-old female took two products containing
ephedrine alkaloids for 4 days, and she developed syncope (light-
headedness) and an extremely elevated blood pressure, measured at 180/
110. She was seen in the emergency department with severe headache,
nausea, and sweating. The consumer had been seen every 3 to 4 months
for the 5 years before this event and had no history of high blood
pressure. After stopping the products, her blood pressure returned to
normal.
ARMS No. 10919--A 49-year-old woman used an ephedrine alkaloid-
containing product, 3 capsules three times daily for 3 weeks for weight
loss. She developed weakness, dizziness, nausea, vomiting, and
palpitations and went to the emergency room, where she was found to
have vertigo (type of dizziness), serous otitis media (middle ear
inflammation) bilaterally, hypertension (150/102), and elevated liver
enzymes. The consumer reported that when she stopped the product, her
blood pressure returned to normal without any medical treatment
She developed weakness, dizziness, nausea, vomiting, and
palpitations and went to the emergency room, where she was found to
have vertigo (type of dizziness), serous otitis media (middle ear
inflammation) bilaterally, hypertension (150/102), and elevated liver
enzymes. The consumer reported that when she stopped the product, her
blood pressure returned to normal without any medical treatment. She
did not have a history of high blood pressure.
ARMS No. 10946--A 42-year-old female used an ephedrine alkaloid-
containing product, 1 capsule twice daily for 3 days for weight loss.
She was also taking vitamin B12 and an antioxidant
supplement. She developed a rash over her entire body and stopped all
three products. She restarted the ephedrine alkaloid-containing product
3 days after the onset of her rash. Three days later, on a visit to her
doctor for a nonproductive cough and congestion, she was found to be
seriously hypertensive (170/114). She had no history of hypertension
and had been seen by her gynecologist 1 week before starting the
ephedrine alkaloid-containing product, where a normal blood pressure
(120/78) was documented.
2. The Patterns of the Signs and Symptoms of Adverse Events Associated
With Ephedrine Alkaloid-Containing Dietary Supplements Are Consistent
With the Available Scientific Evidence and Known Physiologic and
Pharmacologic Effects of Ephedrine Alkaloids
The observed CVS and NS effects associated with use of ephedrine
alkaloid-containing dietary supplements are consistent with the known
pharmacologic and physiologic effects of ephedrine alkaloids. Because
there is a general paucity of scientific data or other information on
the physiologic or pharmacologic properties of ephedrine alkaloids from
botanical sources, and particularly from marketed dietary supplement
products, FDA reviewed other available evidence on ephedrine and other
ephedrine alkaloids for information on their effects
ogic and physiologic effects of ephedrine alkaloids. Because
there is a general paucity of scientific data or other information on
the physiologic or pharmacologic properties of ephedrine alkaloids from
botanical sources, and particularly from marketed dietary supplement
products, FDA reviewed other available evidence on ephedrine and other
ephedrine alkaloids for information on their effects. This evidence
included data from clinical and animal studies in support of drugs
containing a single, synthetic ephedrine alkaloid in a well-defined and
characterized product, case reports from the literature of adverse
events with ephedrine alkaloid-containing products, and traditional
medical uses of ephedrine alkaloid-containing botanicals.
Although there may be some differences in the pharmacokinetic
properties of synthetic ephedrine alkaloids used in drug products as
compared to the botanical sources of these alkaloids as used in dietary
supplements (e.g., differences in enantiomer forms, dissolution,
absorption, and bioavailability or differences that result from
interactions with other components of the botanical), given that once
absorbed, the botanical and synthetic sources of ephedrine alkaloids
undergo similar metabolic processes (Refs. 24 and 43), the agency
considered it appropriate to rely on evidence from pharmaceutical
sources of single ephedrine alkaloids in assessing the effects of
botanical sources. This judgment is supported by
ult from
interactions with other components of the botanical), given that once
absorbed, the botanical and synthetic sources of ephedrine alkaloids
undergo similar metabolic processes (Refs. 24 and 43), the agency
considered it appropriate to rely on evidence from pharmaceutical
sources of single ephedrine alkaloids in assessing the effects of
botanical sources. This judgment is supported by
the fact that adverse events reported for dietary supplements
containing ephedrine alkaloids from botanical sources are similar to
those that are reported in the literature for drugs containing an
ephedrine alkaloid from synthetic sources. FDA's Working Group agreed
that evidence on synthetic sources of ephedrine alkaloids could be
considered in evaluating botanical sources (Ref. 27).
Ephedrine and its related alkaloids are known to elicit
physiological responses similar to catecholamines (i.e., groups of
chemically related neurotransmitters, such as epinephrine,
norepinephrine, and dopamine) that have stimulant effects on the
sympathetic nervous system and thus are classified as sympathomimetic
agents (i.e., agents stimulating the sympathetic nervous system) (Refs.
7, 9 through 13, and 44 through 48). Ephedrine, pseudoephedrine, and
norephedrine are naturally occurring sympathomimetic amines in some
botanicals. Ephedrine, pseudoephedrine, and norephedrine each have
varying effects because of interaction with specific receptors in the
human body (i.e., alpha, beta-1, and beta-2 adrenergic receptors)
(Refs. 9 through 13). (Table 2 summarizes some of the major receptor
effects, and Table 3 summarizes the adrenergic activity of ephedrine,
pseudoephedrine, phenylpropanolamine (dl-norephedrine), and
norepinephrine.) Some of the physiological roles of alpha receptors are
central NS stimulation, vasoconstriction (i.e., narrowing of blood
vessels), uterine contraction, centrally mediated cardiovascular
depression, and decreased insulin secretion
e major receptor
effects, and Table 3 summarizes the adrenergic activity of ephedrine,
pseudoephedrine, phenylpropanolamine (dl-norephedrine), and
norepinephrine.) Some of the physiological roles of alpha receptors are
central NS stimulation, vasoconstriction (i.e., narrowing of blood
vessels), uterine contraction, centrally mediated cardiovascular
depression, and decreased insulin secretion. Alpha receptors also have
an effect on the urinary bladder, which can result in urinary
retention. The major physiological roles of beta receptors include
cardiac (i.e., heart) stimulation and bronchodilation (enlargement of
the bronchial or breathing tube secondary to relaxation of bronchial
smooth muscle).
Table 2.--Adrenergic Activity of Sympathomimetic Agents (Modified From Ref. 9)
----------------------------------------------------------------------------------------------------------------
Type of effects adrenergic receptors
Organ/system ------------------------------------------------------------ Other effects
1 2
----------------------------------------------------------------------------------------------------------------
Nervous system (NS)............. Central NS .................. .................. Indirect Effects
Stimulation. on
Neurotransmitters
Result in NS
Stimulation.
Cardiovascular system........... Vasoconstriction.. Cardiac Cardiac
stimulation:. stimulation:.
contracti heart
lity (force & rate.
velocity). arterio
heart lar tone.
rate. periphe
impulse ral resistance.
conduction. diastol
cardiac ic pressure.
output. cardiac
O2 afterload.
consumption. vasodilation......
stroke
volume.
diastol
ic coronary
perfusion time.
ventric
ular filling.
residua
l (end-systolic)
volume.
Other........................... uterine lypolytic activity bronchodilation...
contraction. renin insulin
ureter secretion. secretion.
motility & tone. muscle & liver
pupillary dilation glycogenolysis.
GI GI
motility & tone. motility & tone
. vasodilation......
stroke
volume.
diastol
ic coronary
perfusion time.
ventric
ular filling.
residua
l (end-systolic)
volume.
Other........................... uterine lypolytic activity bronchodilation...
contraction. renin insulin
ureter secretion. secretion.
motility & tone. muscle & liver
pupillary dilation glycogenolysis.
GI GI
motility & tone. motility & tone.
pancrea urinary bladder--
tic secretion relaxation of
(islets/acini). detrusor muscle.
contraction, relaxation of
urinary, bladder, uterus
sphincter & cerebellum--
trigone. synaptic
remodeling.
----------------------------------------------------------------------------------------------------------------
Table 3.--Adrenergic Activity of Sympathomimetic Agents (Modified From Ref. 9)
----------------------------------------------------------------------------------------------------------------
-Receptor 1- 2-
Sympathomimetic agent effects Receptor effects Receptor effects CNS effects
----------------------------------------------------------------------------------------------------------------
Ephedrine........................ moderate.......... strong............ strong strong.
Pseudoephedrine.................. moderate.......... moderate.......... moderate moderate.
Phenylpropanolamine (dl- strong............ very little....... very little strong.
norephedrine).
Norepinephrine................... very strong....... very little....... none none.
----------------------------------------------------------------------------------------------------------------
g strong.
Pseudoephedrine.................. moderate.......... moderate.......... moderate moderate.
Phenylpropanolamine (dl- strong............ very little....... very little strong.
norephedrine).
Norepinephrine................... very strong....... very little....... none none.
----------------------------------------------------------------------------------------------------------------
The different types of ephedrine alkaloids exhibit some similar
effects but vary in the intensity of these effects (Refs. 10 through
13). For example, ephedrine increases arterial blood pressure in humans
both by peripheral vasoconstriction (narrowing of the blood vessels in
the periphery of the body) and by cardiac stimulation, resulting in
increased heart rate and cardiac output. The magnitude of these
cardiovascular responses can vary on an individual basis and may be
dependent on a number of factors, including genetic characteristics, a
history of certain diseases or conditions, or the use of certain
medications. Other actions of ephedrine include stimulation of oxygen
uptake and thermogenesis (heat or energy production). Pseudoephedrine
is less potent than ephedrine both in its bronchodilatory and
vasopressor effects (i.e., effect of elevating blood pressure). It
produces about one half the
bronchodilation and one quarter of the vasopressor effects of ephedrine
(Refs. 9 and 13).
a. Physiologic and pharmacologic evidence: cardiovascular effects
of ephedrine alkaloids. The adverse events involving the CVS reported
to FDA that are associated with dietary supplements containing
ephedrine alkaloids are consistent with the known effects of
sympathomimetic agents on the CVS. Cardiovascular effects resulting
from the use of sympathomimetic agents are well documented in the
literature (Refs. 49 through 52). For example, use of ephedrine has
been reported to interfere with the regulation of serum potassium
levels (Refs
t are associated with dietary supplements containing
ephedrine alkaloids are consistent with the known effects of
sympathomimetic agents on the CVS. Cardiovascular effects resulting
from the use of sympathomimetic agents are well documented in the
literature (Refs. 49 through 52). For example, use of ephedrine has
been reported to interfere with the regulation of serum potassium
levels (Refs. 53 through 55) and thus may predispose certain
individuals to cardiac dysrhythmias (i.e., abnormal heart rhythms)
(Refs. 18 and 56); myocardial ischemia (i.e., inadequate circulation of
blood and oxygen to the heart muscle); and infarction (i.e., death or
damage of heart cells, also called heart attack) (Refs. 57 through 61).
Cardiac damage has also been reported with the use of pseudoephedrine
and phenylpropanolamine (norephedrine) (Refs. 16, 56, 60, and 62
through 64). Results of several studies on blood pressure effects with
the use of ephedrine alkaloids have indicated that individuals with
hypertension may be at greater risk of blood pressure elevations with
the use of ephedrine (reviewed in (Ref. 64)).
The signs and symptoms observed in the AER's are consistent with
the available scientific literature on the effects of ephedrine
alkaloids. Serious cardiovascular adverse events are the major cause of
death reported in the AER's with the use of ephedrine alkaloid-
containing products and primarily involve ischemia (inadequate blood
flow) which can cause heart attacks and strokes. These events have
occurred in asymptomatic, otherwise healthy young adults with normal
coronary or cerebral blood vessels (Ref. 25), a finding also noted with
pharmaceutical preparations of ephedrine alkaloids (Refs. 60, 61, and
65), where vasospasm with subsequent ischemia is a proposed mechanism
of tissue injury. Besides causing damage by affecting blood flow,
sympathomimetic agents, such as ephedrine, can damage the heart and
other tissues or organs by other mechanisms
rmal
coronary or cerebral blood vessels (Ref. 25), a finding also noted with
pharmaceutical preparations of ephedrine alkaloids (Refs. 60, 61, and
65), where vasospasm with subsequent ischemia is a proposed mechanism
of tissue injury. Besides causing damage by affecting blood flow,
sympathomimetic agents, such as ephedrine, can damage the heart and
other tissues or organs by other mechanisms. Cardiomyopathy (i.e.,
disease of the heart muscle) related to catecholamine mediated
cytotoxicity (cell damage) has been reported with chronic use of
ephedrine alkaloids (durations of use generally at or above the
recommended dose that occur over many months or years) (Refs. 62 and 66
through 68). Fatal cardiomyopathies have also been reported with
chronic use of ephedrine alkaloid-containing dietary supplements (ARMS
No. 11134 in Ref. 149a).
Ephedrine and pseudoephedrine have been implicated also in stroke
secondary to intracranial (i.e., inside the brain) and subarachnoid
(i.e., underneath the membrane that covers the brain and spinal cord)
hemorrhage and vasculitis (i.e., inflammation of blood vessels), as
well as in ischemic strokes (Refs. 9 and 69 through 71), particularly
when used in combinations with phenylpropanolamine (norephedrine) or
caffeine (Refs. 65 and 72 through 78) or in the presence of monoamine
oxidase inhibitors (MAOI) (Ref. 72). These effects are noted to be
similar to the necrotizing angiitis (severe inflammation with
destruction of the blood vessels) seen in chronic amphetamine abuse
(Refs. 16, 74, and 77 through 79).
b. Physiologic and pharmacologic evidence: NS effects of ephedrine
alkaloids. The adverse events involving the NS reported to FDA that are
associated with dietary supplements containing ephedrine alkaloids are
consistent with the known effects of sympathomimetic agents on the NS.
These effects, such as seizure (Refs. 63, 65, and 80), psychosis, and
mania (Refs. 81 through 99), have been reported with the use and the
abuse of ephedrine alkaloids
of ephedrine
alkaloids. The adverse events involving the NS reported to FDA that are
associated with dietary supplements containing ephedrine alkaloids are
consistent with the known effects of sympathomimetic agents on the NS.
These effects, such as seizure (Refs. 63, 65, and 80), psychosis, and
mania (Refs. 81 through 99), have been reported with the use and the
abuse of ephedrine alkaloids. More recently, a case report in the
scientific literature reported ephedrine-induced mania associated with
the use of a botanical dietary supplement (Ref. 100).
Neuropsychiatric effects reported in AER's related to ephedrine
alkaloid-containing dietary supplements also are consistent with the
known physiologic and pharmacologic actions of ephedrine alkaloids
documented in the scientific literature. Mania and psychosis have
occurred in individuals without identifiable risk factors who have used
these products, as well as in people who used them who had possible
predisposing factors, such as a personal history of mood disorders
(i.e., depression or manic depression), a family history of manic
depression, or concurrent use of products that increase sensitivity of
an individual to the effects of ephedrine alkaloids (see Table 4).
AER's noting neuropsychiatric adverse effects in persons using non-MAOI
antidepressant drugs concurrently with dietary supplements containing
ephedrine alkaloids are consistent with a report of the serotonin
syndrome associated with the concurrent use of serotonin reuptake
inhibitors (a new class of antidepressant drugs) and OTC cold remedies
containing pseudoephedrine (Ref. 101).
Table 4).
AER's noting neuropsychiatric adverse effects in persons using non-MAOI
antidepressant drugs concurrently with dietary supplements containing
ephedrine alkaloids are consistent with a report of the serotonin
syndrome associated with the concurrent use of serotonin reuptake
inhibitors (a new class of antidepressant drugs) and OTC cold remedies
containing pseudoephedrine (Ref. 101).
Table 4.--Factors Influencing Sensitivity to Sympathomimetic Agents
------------------------------------------------------------------------
Factor Examples
------------------------------------------------------------------------
Age.......................... Children, elderly.
Genetics..................... Metabolizer genotype; adrenergic receptor
genotype and numbers.
Physiological states......... Hyperdynamic (exercise), underweight.
Dieting practices............ Severe caloric or fluid restriction.
Medications and food......... MAOI, methyldopa, -receptor
blocking agent, caffeine or other
stimulants.
Diseases or health-related Heart disease, thyroid disease, diabetes,
conditions. renal disease, high blood pressure,
depression, psychiatric conditions,
glaucoma, prostate enlargement, seizure
disorder.
Duration of use.............. Vascular spasm; stroke and myocardial
infarction may influence the type and
severity of adverse events in the
sensitive individual.
------------------------------------------------------------------------
sease, diabetes,
conditions. renal disease, high blood pressure,
depression, psychiatric conditions,
glaucoma, prostate enlargement, seizure
disorder.
Duration of use.............. Vascular spasm; stroke and myocardial
infarction may influence the type and
severity of adverse events in the
sensitive individual.
------------------------------------------------------------------------
c. Variability in individual responses to ephedrine alkaloids. The
unpredictability of individual responses to ephedrine alkaloid-
containing dietary supplement products, as reported in AER's, is also
consistent with what is known about the physiological and
pharmacological properties of these alkaloids (Refs. 7, 10 through 12,
39 through 41, and 48). Individual variability in the effects of
ephedrine has been reported in several clinical investigations (Refs. 5
and 102 through 104). The marked sensitivity of some individuals to the
effects of ephedrine has been recognized in the Western scientific
literature almost from the time that ephedrine was introduced as a
therapeutic agent in the mid-1920's (Refs. 5 and 102). Two early
studies by different investigators recommended a 10 mg initial oral
test dose to assess the individual's sensitivity to sources of
ephedrine (Refs. 5 and 102).
Factors that appear to influence individual susceptibility to
sympathomimetic agents are diverse (see Table 4) and are not yet well
defined by biological bases. These factors include genetics,
particularly those genes controlling metabolic functions; receptor
numbers and types; gender; age; and certain physiological states or
disease conditions (reviewed in Refs. 39 through 42)
. 5 and 102).
Factors that appear to influence individual susceptibility to
sympathomimetic agents are diverse (see Table 4) and are not yet well
defined by biological bases. These factors include genetics,
particularly those genes controlling metabolic functions; receptor
numbers and types; gender; age; and certain physiological states or
disease conditions (reviewed in Refs. 39 through 42). In addition, the
dosage and duration of use may influence the effects seen with
ephedrine alkaloids, as tachyphylaxis (i.e., decrease or diminution of
some effect) is known to occur with chronic use of these agents (i.e.,
there are decreases in certain effects with chronic use that are
thought to be due to occupation of all adrenergic receptor sites;
discontinuation of ephedrines for a few days results in receptor
availability and receptor mediated effects). An example of
tachyphylaxis could be tremor or insomnia, which occurs soon after
starting ephedrine alkaloid-containing products but which may resolve
in certain individuals with continued use of ephedrine alkaloids.
d. Clinical trials using ephedrine in the treatment of obesity.
Although many dietary supplements containing ephedrine alkaloids are
marketed for weight loss or energy purposes, there is a paucity of
meaningful data on the safe use of these products for this purpose.
A number of controlled clinical trials reported in the scientific
literature evaluated the effects of pharmaceutical preparations of
ephedrine, either singly or combined with caffeine or aspirin, on
weight loss in the treatment of obesity (Refs. 105 through 119). While
the primary purpose of these trials was to evaluate efficacy of
ephedrine for purposes of weight loss in grossly obese individuals,
these clinical trials also document that clinically significant adverse
effects can occur in populations with no known risk factors with the
use of ephedrine, and that synergistic adverse effects can result when
ephedrine and caffeine are combined
gh 119). While
the primary purpose of these trials was to evaluate efficacy of
ephedrine for purposes of weight loss in grossly obese individuals,
these clinical trials also document that clinically significant adverse
effects can occur in populations with no known risk factors with the
use of ephedrine, and that synergistic adverse effects can result when
ephedrine and caffeine are combined. The patterns and types of the
adverse effects reported in these trials are consistent with the known
effects of sympathomimetic agents, that is, they mainly involved NS and
CVS effects. A summary of these studies follows. (In this document, the
agency makes no evaluation or judgment of the effectiveness of the use
of ephedrine in the treatment of obesity.)
A Danish group of researchers investigated the usefulness of
ephedrine and caffeine alone and in combination for the treatment of
obesity (Refs. 105, 106, and 112). One hundred and eighty subjects were
randomized to one of four treatment groups: (1) Ephedrine--20 mg, (2)
ephedrine--20 mg and caffeine--200 mg, (3) caffeine--200 mg, and (4)
placebo control. The treatments were administered three times a day for
24 weeks in conjunction with a defined low calorie diet. One hundred
and forty-one individuals completed the trial. Subject withdrawals were
reported to be equally distributed across the four groups with no
statistical differences among the groups. More side effects were noted
in the treatment groups compared to the placebo control group in both
those subjects continuing in, and those withdrawing from, the trial.
Study results showed that 60 percent of the ephedrine and caffeine
treatment group, 44 percent of the ephedrine treatment group, and 36
percent of the caffeine treatment group experienced side effects
compared to 24 percent of the placebo control group
ed
in the treatment groups compared to the placebo control group in both
those subjects continuing in, and those withdrawing from, the trial.
Study results showed that 60 percent of the ephedrine and caffeine
treatment group, 44 percent of the ephedrine treatment group, and 36
percent of the caffeine treatment group experienced side effects
compared to 24 percent of the placebo control group. These results were
statistically significant (p-adrenergic
agents like ephedrine in the etiology of a type of lung cancer,
particularly in persons simultaneously exposed to carcinogenic
environmental factors such as smoking (Ref. 145). This report indicates
the need for long-term followup to adequately assess the risks
associated with product use, as well as the importance of particular
group characteristics (e.g., smoking status) in evaluating risk.
f. Traditional uses of botanical sources of ephedrine alkaloids:
adverse effects. In the traditional medicinal use of Ephedra, the raw
botanical was administered, either alone or more commonly combined with
other specific botanicals, in the form of a water infusion (tea), three
times a day. Traditional treatment was prescribed by a trained health
practitioner based on the evaluation of a particular patient and was
predominately for short term use. Commonly used dosages of the raw
botanical ranged from 1.5 to 9 grams (g), generally averaging 5 to 6 g
of Ephedra per dose (Refs. 14 and 146). Tyler has estimated that a tea
made from 2 g of the raw botanical Ephedra (containing 1.25 percent
ephedrine) will yield a dose of 15 to 30 mg ephedrine (cited in Ref.
147). Thus, use of 5 to 6 g of the raw botanical Ephedra, an average
amount used in a tea could yield a dose of ephedrine ranging from
approximately 38 mg to 75 mg.
FDA has no knowledge of any systematic collection of morbidity and
mortality data on individuals treated with Ephedra in traditional
medicine
ning 1.25 percent
ephedrine) will yield a dose of 15 to 30 mg ephedrine (cited in Ref.
147). Thus, use of 5 to 6 g of the raw botanical Ephedra, an average
amount used in a tea could yield a dose of ephedrine ranging from
approximately 38 mg to 75 mg.
FDA has no knowledge of any systematic collection of morbidity and
mortality data on individuals treated with Ephedra in traditional
medicine. Ephedra was historically considered a medium or middle class
herb, meaning that recognized toxicities could be associated with its
use (Refs. 14, 146, and 148). Several reference texts, in fact, list
precautions and contraindications for the use of the botanical Ephedra
in traditional medicinal preparations (Refs. 14 and 146). Another
reference warns against overdosage (Ref. 25).
While there is a paucity of data in the scientific literature on
the safety of the use of Ephedra, several scientific references report
adverse effects associated with the use of Ephedra. One early study in
the United States reported two cases of urinary retention in men aged
56 and 65 years. These men all noted bladder pain and difficulty in
voiding which developed after one to three doses of a fluid extract of
Ephedra. The symptoms resolved after the use of the extract was
discontinued. More recently, a published case report notes the
occurrence of erythroderma associated with the use of an herbal product
containing Ma huang which was obtained from a Chinese herbalist for the
relief of cold-like symptoms (Ref. 138). The woman who was the subject
of this report had a history of similar episodes following usage of OTC
cold preparations containing ephedrine alkaloids. These references
document that adverse effects occurred with the traditional use of
Ephedra, and that these effects are consistent with effects occurring
with modern pharmaceutical preparations of synthetic ephedrine.
3
ke symptoms (Ref. 138). The woman who was the subject
of this report had a history of similar episodes following usage of OTC
cold preparations containing ephedrine alkaloids. These references
document that adverse effects occurred with the traditional use of
Ephedra, and that these effects are consistent with effects occurring
with modern pharmaceutical preparations of synthetic ephedrine.
3. The Relationship is Temporally Correct
One possible source of serious error in evaluating observational
data, such as that found in FDA's postmarketing surveillance system, is
the potential for inappropriately assuming that a cause and effect
relationship exists between a
particular exposure and a particular adverse event without evaluating
the true relationship of the adverse event to the exposure. Unless
there are data that ensure that there is the correct temporal
relationship between exposure and effect (i.e., that the adverse
effects follow exposure), there is a potential for serious
misinterpretation of data. To evaluate this potential source of serious
error, FDA evaluated the AER's to determine whether there was clear
evidence of the correct temporal sequence having occurred. FDA found
evidence of the correct relationship in the AER's that it received
(see, e.g., ARMS Nos. 10088, 8475, 9747, and 11112).
Further support that the temporal relationship is correct can be
found in clinical studies that described the pharmacological and
physiological effects of different ephedrine alkaloids and in the
clinical trials with obese subjects.
4. There is Other Evidence, Even in the Absence of Controlled Trials,
Such as Evidence of Dechallenge That Suggests a Causal Relationship
Between the Use of Ephedrine Alkaloid-Containing Dietary Supplements
and Adverse Events
Causality is most readily demonstrated in well-designed and
conducted clinical trials, in which the multiple factors that may
influence study results and interpretations can be controlled
vidence, Even in the Absence of Controlled Trials,
Such as Evidence of Dechallenge That Suggests a Causal Relationship
Between the Use of Ephedrine Alkaloid-Containing Dietary Supplements
and Adverse Events
Causality is most readily demonstrated in well-designed and
conducted clinical trials, in which the multiple factors that may
influence study results and interpretations can be controlled. However,
evidence of causality can be inferred from observational studies,
including individual case reports, particularly where there is evidence
of positive dechallenge and rechallenge, that is, where, when the
consumer stopped using the product, the signs and symptoms resolved or
improved, and when the consumer began using the product again, the
symptoms reoccurred. Although many of the AER's did not provide enough
information to adequately evaluate these questions, over 26 percent of
AER's provided information suggesting successful dechallenge, and 4
percent of reports provided information of rechallenge, suggesting that
the product was the direct cause of the adverse event. A number of the
previously described cases are particularly good examples of positive
dechallenge in that symptoms resolved spontaneously on cessation of use
of the product without medical treatment (see Arms Nos. 10088, 11065,
and 11112 in the Appendix to this document).
Furthermore, some specific AER's suggest that a pattern of starting
and stopping use of dietary supplements containing ephedrine alkaloids
may increase an individual's susceptibility to experiencing adverse
events as has been suggested in reviews of adverse events occurring
with the use of phenylpropanolamine (Ref. 73). One case described
above, ARMS No. 9552, in which a woman suffered a heart attack soon
after she restarted using an ephedrine alkaloid-containing product, may
be an example of such increased sensitivity
lkaloids
may increase an individual's susceptibility to experiencing adverse
events as has been suggested in reviews of adverse events occurring
with the use of phenylpropanolamine (Ref. 73). One case described
above, ARMS No. 9552, in which a woman suffered a heart attack soon
after she restarted using an ephedrine alkaloid-containing product, may
be an example of such increased sensitivity.
Thus, FDA tentatively concludes that there is evidence of
dechallenge and rechallenge from the AER's that supports a causal
relationship between the ingestion of ephedrine alkaloids and the types
of CVS and NS and other effects observed with use of the ephedrine
alkaloid-containing dietary supplement products. Additional support for
this conclusion is also provided in the published clinical trials in
the treatment of obesity described above.
5. A Biologically Plausible Explanation for the Adverse Events
Considering the totality of the available information, FDA
tentatively concludes that the available evidence strongly supports
that the adverse effects that are occurring with the use of dietary
supplements containing ephedrine alkaloids are caused by the ephedrine
alkaloids. This tentative conclusion derives from the previous
discussions in this document. The observed adverse effects
predominately involve the CVS and NS and are consistent with the known
physiological and pharmacological effects of ephedrine alkaloids noted
in medical/pharmacological texts. Furthermore, similar patterns of CVS
and NS effects have been documented both in anecdotal reports in the
scientific literature and in the published results of controlled
clinical trials using pharmaceutical preparations of various ephedrine
alkaloids. The available data further suggest that these types of
adverse events should be anticipated and expected with the use of
ephedrine alkaloid-containing products by the general population.
D. Additional Concerns
nted both in anecdotal reports in the
scientific literature and in the published results of controlled
clinical trials using pharmaceutical preparations of various ephedrine
alkaloids. The available data further suggest that these types of
adverse events should be anticipated and expected with the use of
ephedrine alkaloid-containing products by the general population.
D. Additional Concerns
The agency is aware of a number of factors related to currently
marketed dietary supplements that may contribute to the likelihood of
adverse events but that the available data are inadequate to evaluate
fully. These factors weighed heavily on the minds of many members of
the Food Advisory Committee as they discussed the public health
concerns associated with the use of these products. These factors
include:
(1) The size of the population that is susceptible to experiencing
adverse events with the use of ephedrine alkaloids, because there are
neither good data on the number and pattern of supplement users in the
United States nor good data on the full range of characteristics that
cause or increase risk. Nonetheless, the potential population at risk
is quite large if one considers the following likely risk factors:
(a) The large number of persons who have diseases or conditions, or
who are at risk for such conditions, for whom the use of ephedrine
alkaloid-containing dietary supplements is inappropriate (Table 5).
nor good data on the full range of characteristics that
cause or increase risk. Nonetheless, the potential population at risk
is quite large if one considers the following likely risk factors:
(a) The large number of persons who have diseases or conditions, or
who are at risk for such conditions, for whom the use of ephedrine
alkaloid-containing dietary supplements is inappropriate (Table 5).
Table 5.--Identifiable At Risk Population With Use of Ephedrine Alkaloids
----------------------------------------------------------------------------------------------------------------
Estimated number of affected persons in the United States (in
Disease or condition millions)
----------------------------------------------------------------------------------------------------------------
Cardiovascular disease...................... 50 (Ref. 158).
Hypertension................................ 50 (Ref. 158).
Kidney trouble.............................. 3.5 (Ref. 159).
Prostate disease............................ 2.6 (Ref. 159).
Glaucoma.................................... 2.4 (Ref. 160).
Diabetes.................................... 16 (8 million undiagnosed) (Ref. 161).
Depressive, anxiety or schizophrenic 42.3 (Ref. 162).
disorders.
Thyroid disease............................. 11 (6 million undiagnosed) (Ref. 163).
Pregnancy................................... 4 (each year) (Ref. 179).
----------------------------------------------------------------------------------------------------------------
...................... 16 (8 million undiagnosed) (Ref. 161).
Depressive, anxiety or schizophrenic 42.3 (Ref. 162).
disorders.
Thyroid disease............................. 11 (6 million undiagnosed) (Ref. 163).
Pregnancy................................... 4 (each year) (Ref. 179).
----------------------------------------------------------------------------------------------------------------
(b) The large number of factors that may increase susceptibility or
sensitivity to the effects of ephedrine alkaloids and other
sympathomimetic agents (Table 4). These variables include gender, age,
genetics, certain physiologic states, and the use of certain products
(e.g., foods and drugs) (Ref. 25).
(2) The potential for interactive and unpredictable effects from
the mixture of ephedrine alkaloids found in botanical sources, which
may serve to increase the likelihood, frequency, or severity of an
adverse event. Unlike drugs which contain only a single, well-
characterized ephedrine alkaloid, botanical sources contain a mixture
of these alkaloids. The potential for interactive effects among these
alkaloids is likely but largely unknown (Ref. 25).
(3) The potential for other ingredients in the dietary supplement
products to interact with the ephedrine alkaloids to increase the
likelihood or severity of an adverse event (Ref. 25).
(4) The natural or formulation variations in levels and relative
proportions of the ephedrine alkaloids in marketed dietary supplement
products and the resultant risk for persons who can tolerate one level
or mixture but who unknowingly are exposed to different levels or
mixtures because they change brands, or because the composition of the
brand that they typically use is altered (Ref. 25).
(4) The natural or formulation variations in levels and relative
proportions of the ephedrine alkaloids in marketed dietary supplement
products and the resultant risk for persons who can tolerate one level
or mixture but who unknowingly are exposed to different levels or
mixtures because they change brands, or because the composition of the
brand that they typically use is altered (Ref. 25).
(5) The formulations of the products themselves (including the
numbers, types, and forms of ingredients used in the product and the
form of the final product) may influence the likelihood, frequency, or
severity of adverse effects because product characteristics may
influence dissolution, absorption, bioavailability, and metabolism of
active and inactive ingredients in the product and thus influence the
effects of the product (Ref. 25).
E. General Summary and Tentative Conclusions
FDA has received more than 800 AER's involving more than 100
dietary supplement products. Among these products the most common and
consistent finding is the presence of ephedrine alkaloids. The products
associated with these adverse events are marketed in diverse
formulations and for a variety of uses.
Sympathetic nervous system and cardiovascular system stimulant
effects account for the majority of the reported adverse events
associated with dietary supplements containing ephedrine alkaloids.
These effects include heart attack, stroke, seizure, chest pain,
psychosis, anxiety, nervousness, tremor, and hyperactivity (Refs. 25
and 27). The type and patterns of these adverse effects are consistent
with the CVS and NS effects known and expected to occur with the use of
sympathomimetic agents, such as the ephedrine alkaloids. The known
physiological and pharmacological activities of ephedrine alkaloids and
the adverse events that have occurred in controlled clinical trials
using ephedrine corroborate this conclusion
and 27). The type and patterns of these adverse effects are consistent
with the CVS and NS effects known and expected to occur with the use of
sympathomimetic agents, such as the ephedrine alkaloids. The known
physiological and pharmacological activities of ephedrine alkaloids and
the adverse events that have occurred in controlled clinical trials
using ephedrine corroborate this conclusion. The biological
plausibility of these types of adverse events occurring with the use of
ephedrine alkaloids, the temporal relationship between the use of the
dietary supplements and the onset of the adverse events, and the
evidence of dechallenge and rechallenge also support a causal
relationship between the use of ephedrine alkaloid-containing products
and subsequent adverse events.
Both the Working Group and the Food Advisory Committee reviewed the
available data and information on the occurrence of adverse events
associated with the use of dietary supplements containing ephedrine
alkaloids in certain individuals. The Working Group was specifically
asked whether the available information contains sufficient evidence to
demonstrate that the use of dietary supplements containing ephedrine
alkaloids may cause consumers to experience serious adverse events. The
Working Group concluded that it was. Although not asked this question,
those members of the Food Advisory Committee who addressed the question
agreed with the Working Groups's conclusion.
Thus, FDA tentatively concludes that there is a consistent, large,
and growing body of evidence that establishes a causal association
between the use of ephedrine alkaloids and subsequent adverse events.
The agency also tentatively concludes that the use of ephedrine
alkaloid-containing dietary supplements is associated with a serious
and significant public health concern because of the nature of the
adverse events and the size of the population at risk.
III. The Proposed Regulation
A. The Scope of This Proposal
sociation
between the use of ephedrine alkaloids and subsequent adverse events.
The agency also tentatively concludes that the use of ephedrine
alkaloid-containing dietary supplements is associated with a serious
and significant public health concern because of the nature of the
adverse events and the size of the population at risk.
III. The Proposed Regulation
A. The Scope of This Proposal
This proposal applies to dietary supplements containing one or more
ephedrine alkaloids and related alkaloids, including those from the
botanical species Ephedra sinica Stapf, Ephedra equistestina Bunge,
Ephedra intermedia var., tibetica Stapf, Ephedra distachya L., and Sida
cordifolia or their extracts.
Conventional food products that contain ephedrine alkaloids,
including snack bars, cookies, and beverages, are not covered by this
proposal. Conventional food products are subject to section 409 of the
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 348) and,
given the adverse events associated with the use of ephedrine
alkaloids, these substances are unapproved food additives when used in
conventional foods.
Use of botanical sources of ephedrine alkaloids in traditional
herbal therapies is beyond the scope of this proposal. Although several
Ephedra species (including those considered as Ma huang) have been
reported to have a long history of use in traditional Asian medicine
for the treatment of the symptoms of colds, to relieve respiratory
symptoms, and to regulate water metabolism (Refs. 4, 6, 14, and 146),
products bearing claims evidencing that they are intended for
therapeutic use are regulated as drugs under the act.
This proposal also does not cover OTC or prescription drugs that
contain ephedrine alkaloids. Ephedrine is approved as an active
ingredient in oral OTC bronchodilator drugs for use in the treatment of
medically diagnosed mild asthma (21 CFR 341.76). However, in the
Federal Register of July 27, 1995 (60 F.R
ncing that they are intended for
therapeutic use are regulated as drugs under the act.
This proposal also does not cover OTC or prescription drugs that
contain ephedrine alkaloids. Ephedrine is approved as an active
ingredient in oral OTC bronchodilator drugs for use in the treatment of
medically diagnosed mild asthma (21 CFR 341.76). However, in the
Federal Register of July 27, 1995 (60 F.R. 38643), FDA proposed to
amend the final monograph for OTC bronchodilator drug products to
remove the ingredients ephedrine, ephedrine hydrochloride, ephedrine
sulfate, and racephedrine hydrochloride and to classify these
ingredients as not generally recognized as safe and effective for OTC
use.
FDA issued the proposal to amend the final monograph for OTC
bronchodilator products in response to a request from the U.S.
Department of Justice, Drug Enforcement Administration (DEA), to
restrict OTC availability of ephedrine because of its illicit use as
the primary precursor in the synthesis of the controlled substances
methamphetamine and methylcathinone. The agency also issued the
proposal because of new information that showed that misuse and abuse
of OTC ephedrine drug products can cause potential harm, and because of
comments made by FDA's Pulmonary-Allergy Drugs Advisory Committee and
the Nonprescription Drugs Advisory Committee. FDA is currently
evaluating public comments to that proposal and will be addressing this
subject in a future issue of the Federal Register.
B. Rationale for the Proposal
on that showed that misuse and abuse
of OTC ephedrine drug products can cause potential harm, and because of
comments made by FDA's Pulmonary-Allergy Drugs Advisory Committee and
the Nonprescription Drugs Advisory Committee. FDA is currently
evaluating public comments to that proposal and will be addressing this
subject in a future issue of the Federal Register.
B. Rationale for the Proposal
It is incumbent upon the agency to respond to the concerns raised
by the number, seriousness, and pattern of adverse events associated
with the use of ephedrine alkaloid-containing dietary supplements.
Given the AER's, the case reports in the scientific literature,
controlled clinical trials, published reports of adverse effects with
traditional uses of ephedrine alkaloid-containing botanicals, and other
data, it is apparent that there are serious and well-documented public
health risks attendant to the use of ephedrine alkaloids in marketed
dietary supplement products, and that the agency needs to propose
actions to address these risks.
Over the years, FDA has employed a variety of strategies in
addressing food ingredients that created significant public health
risks. In cases where small subpopulations have faced serious, even
potentially deadly, risks because of ingredients with allergic
potential (e.g., nuts and shellfish), FDA has required that the
presence of the allergen be declared on the food label so that
consumers who are at risk can avoid products that contain the problem
ingredient (Sec. 101.4 (21 CFR 101.4)). In other cases where a food or
food ingredient has presented special health risks to consumers under
certain use conditions, the agency has required warning label
statements to ensure that consumers are alerted to the potential health
hazards associated with use of the product
o that
consumers who are at risk can avoid products that contain the problem
ingredient (Sec. 101.4 (21 CFR 101.4)). In other cases where a food or
food ingredient has presented special health risks to consumers under
certain use conditions, the agency has required warning label
statements to ensure that consumers are alerted to the potential health
hazards associated with use of the product. For example, FDA has
required a special warning statement to appear on the label of protein
products intended for use in weight reduction, stating in part that
very low calorie protein diets may cause serious illness or death
(Sec. 101.17(d) (21 CFR 101.17(d))). In other cases, e.g., the proposed
regulations for poisonings in young children because of high intakes of
iron-containing dietary supplements, the agency was concerned that, for
high potency products, warning labels alone would not be effective in
preventing serious harm. Therefore, the agency has decided to require,
at least in some cases, warning labels plus special packaging
requirements to reduce the risk of serious harm (Ref. 150).
In other cases, where a substance contained in a food may be
harmful to health, it has been the agency's policy to define a level at
which the harmful substance may render the food adulterated. For
example, to address the public health problem of histamine poisoning
associated with the consumption of certain fish, the agency issued
guidance on the level of histamine at which FDA is likely to take
action against the fish because it is adulterated (Ref. 151). Moreover,
in Sec. 109.4(b) (21 CFR 109.4(b)), the agency has said that it will
establish regulatory limits that represent the level at which an added
poisonous or deleterious substance adulterates a food within the
meaning of section 402(a)(1) of the act (21 U.S.C. 342(a)(1))
on the level of histamine at which FDA is likely to take
action against the fish because it is adulterated (Ref. 151). Moreover,
in Sec. 109.4(b) (21 CFR 109.4(b)), the agency has said that it will
establish regulatory limits that represent the level at which an added
poisonous or deleterious substance adulterates a food within the
meaning of section 402(a)(1) of the act (21 U.S.C. 342(a)(1)).
The agency has attempted to be flexible and practical in tailoring
its strategy for dealing with public health risks, taking into account
the nature and type of the risk and the potential effectiveness of
various alternative approaches. In the case of ephedrine alkaloids in
dietary supplements, there are many factors and underlying etiologies
that can influence individual sensitivity to these substances. Some of
these factors are easily identified or readily controlled; many are
not. Factors that are known to influence the likelihood, frequency, and
severity of adverse events associated with the use of sympathomimetic
agents, including ephedrine alkaloids, include genetics, age (e.g.,
children and the elderly are at increased risk), preexisting conditions
(e.g., kidney disease, heart disease, hypertension, diabetes, thyroid
disease, glaucoma, and enlarged prostate), pregnancy, concurrent use of
medications (e.g., MAOI, methyldopa), or excessive consumption (see
Table 4) (Refs. 39 through 42, 152, and 153). Other factors that may
increase an individual's susceptibility to experience adverse events
with the use of ephedrine alkaloids include exercise, body size (i.e.,
lean and normal weight individuals appear to be more susceptible than
obese individuals), and dietary intake (i.e., severe caloric and fluid
restrictions increase the likelihood of adverse events) (Refs. 39, 42,
119, and 154 through 156)
factors that may
increase an individual's susceptibility to experience adverse events
with the use of ephedrine alkaloids include exercise, body size (i.e.,
lean and normal weight individuals appear to be more susceptible than
obese individuals), and dietary intake (i.e., severe caloric and fluid
restrictions increase the likelihood of adverse events) (Refs. 39, 42,
119, and 154 through 156).
Significantly, however, many adverse events associated with
ephedrine alkaloid-containing dietary supplements occur in individuals
who have no apparent risk factors, or who are unaware that they are at
risk. Additionally, approximately 40 percent of the reported adverse
events occur with the first use or within 1 week of first use,
providing little or no warning to consumers of potential risk (see
Figure 3). The agency tentatively concludes, therefore, that neither
disclosure of the presence of ephedrine alkaloids on the product label
nor the use of a warning statement, alone, will be sufficient to
protect consumers because many individuals are not aware, and are
unable to determine, that they are at risk from consuming ephedrine
alkaloids, and serious adverse events may occur on the first use or
with very short-term use.
Therefore, the agency has tentatively determined that several
measures are needed if the observed adverse events associated with the
use of ephedrine alkaloid-containing dietary supplements are to be
effectively addressed. These measures are discussed below.
C. Proposal for Dietary Supplements Containing Ephedrine Alkaloids
verse events may occur on the first use or
with very short-term use.
Therefore, the agency has tentatively determined that several
measures are needed if the observed adverse events associated with the
use of ephedrine alkaloid-containing dietary supplements are to be
effectively addressed. These measures are discussed below.
C. Proposal for Dietary Supplements Containing Ephedrine Alkaloids
1. Dietary Ingredient Limit for Ephedrine Alkaloids: Per Serving Basis
One possible strategy for addressing the significant number of
adverse effects associated with ephedrine alkaloids in dietary
supplements is to restrict the level of the ephedrine alkaloids in
these products. In considering this possibility, FDA evaluated two
issues: (a) Is there a level at which ephedrine alkaloids cause safety
concerns; and (b) if there is, will restricting dietary supplements
from containing ephedrine alkaloids at or above that level be adequate,
alone, to protect the public health, or will additional steps be
necessary.
In considering these questions, FDA evaluated the evidence that
provides information on the adverse effects of ephedrine alkaloids that
is most relevant to the uses and formulations of marketed dietary
supplement products: (a) The published findings from the clinical
studies investigating the use of ephedrine for weight loss for the
treatment of obesity, and (b) the numerous AER's associated with the
consumption of dietary supplements containing ephedrine alkaloids.
First, the agency reviewed clinical trials that have been performed
to explore therapeutic uses for ephedrine alone and in combination with
other pharmaceutical substances (see earlier discussion in section
II.C.2.d. of this document (Refs. 105 through 119))
treatment of obesity, and (b) the numerous AER's associated with the
consumption of dietary supplements containing ephedrine alkaloids.
First, the agency reviewed clinical trials that have been performed
to explore therapeutic uses for ephedrine alone and in combination with
other pharmaceutical substances (see earlier discussion in section
II.C.2.d. of this document (Refs. 105 through 119)). Information from
these trials show that 20 mg ephedrine per dose can cause adverse
events to occur in a significant percentage of obese persons (up to 60
percent) prescreened to be free of known risk factors while using these
products for a relatively short time (i.e., most adverse events
occurred during the first 4 weeks of use). Thus, these studies
establish that 20 mg per serving of ephedrine presents potential risks
for a subpopulation of morbidly obese persons but provide no
information on risk at levels below 20 mg per serving for obese
persons. These studies also provide no information on risk at levels
below 20 mg per serving for use by persons in the general population
(e.g., lean or moderately overweight persons), who are known to be more
sensitive to
sympathomimetic substances like ephedrine alkaloids than are the
morbidly obese persons who constituted the study population (see
section II.C.2.d. of this document). FDA is not aware of any well-
designed and conducted studies that evaluate the risks of intakes of
ephedrine levels below 20 mg per serving in any population group.
Second, FDA, through its postmarketing surveillance program, has
found consistent patterns of adverse events across a broad range of
marketed dietary supplement products that contain a variety of
ephedrine alkaloid levels per serving
is not aware of any well-
designed and conducted studies that evaluate the risks of intakes of
ephedrine levels below 20 mg per serving in any population group.
Second, FDA, through its postmarketing surveillance program, has
found consistent patterns of adverse events across a broad range of
marketed dietary supplement products that contain a variety of
ephedrine alkaloid levels per serving. FDA's laboratory analyses of the
ephedrine alkaloid levels in the small number of available dietary
supplement products that consumers who suffered adverse events turned
over to the agency showed that these adverse events were related to
ephedrine alkaloid levels from approximately 1 to over 50 mg per
serving (Ref. 149). These data, as well as analytical data from samples
collected from the marketplace after FDA received AER's from consumers
who no longer possessed the product, show a pattern of clinically
significant adverse events, including neuropsychiatric effects (e.g.,
severe depression, seizure), malignant (i.e., extremely high) blood
pressure, and myocardial necrosis (i.e., death of the heart muscle)
with subsequent cardiac arrest and death, with the use of ephedrine
alkaloids at levels approaching and above 10 mg per serving (e.g.,
seven reports of clinically serious adverse events were associated with
products that contained 10 to 15 mg per serving) (Ref. 149a).
Clinically significant adverse events were also reported with the use
of ephedrine alkaloids at levels that exceeded this range.
FDA has also received a few reports of adverse events, some
clinically significant, including tremor, extremely high blood
pressure, severe headache, nausea, chest pain, increased heart rate,
and insomnia, associated with the use of ephedrine alkaloids at levels
below 8 mg (e.g., 2 to 8 mg ephedrine alkaloids per serving) (Ref.
149a)
of ephedrine alkaloids at levels that exceeded this range.
FDA has also received a few reports of adverse events, some
clinically significant, including tremor, extremely high blood
pressure, severe headache, nausea, chest pain, increased heart rate,
and insomnia, associated with the use of ephedrine alkaloids at levels
below 8 mg (e.g., 2 to 8 mg ephedrine alkaloids per serving) (Ref.
149a). The true clinical significance of these levels of ephedrine
alkaloids is difficult to interpret because of the lack of the data
(e.g., too few reports with analysis to identify a pattern of
clinically serious adverse events at any specific level). Thus, the
available information from the AER's and the scientific literature does
not provide sufficient data to adequately evaluate risk below
approximately 10 mg per serving.
Given the available evidence, it is difficult to ascertain whether
there is a threshold level of ephedrine alkaloids below which the
general population and susceptible individuals will not experience
serious adverse events. The shape of an intake-response curve for any
particular adverse effect related to ephedrine alkaloid intakes is not
known. In the absence of data that allow a systematic evaluation of
intakes of ephedrine and other related alkaloids below 10 mg per
serving, it is not possible to adequately define or describe the
potential risks and at-risk groups from ephedrine alkaloids. However,
the available data, including the AER's and the known physiological and
pharmacological effects of ephedrine, provide convincing evidence that
clinically serious adverse events will occur at intake levels above 10
mg ephedrine alkaloids per serving
10 mg per
serving, it is not possible to adequately define or describe the
potential risks and at-risk groups from ephedrine alkaloids. However,
the available data, including the AER's and the known physiological and
pharmacological effects of ephedrine, provide convincing evidence that
clinically serious adverse events will occur at intake levels above 10
mg ephedrine alkaloids per serving.
FDA recognizes, however, that this 10-mg level is also subject to
some uncertainty because of such factors as intra-assay variabilities
(i.e., difference in analytical results from one run to the next with
the same method), natural variabilities in the alkaloid content of
botanical ingredients, variations in formulation levels from batch to
batch, and inaccuracies in the amounts reported to be taken by
consumers. When these sources of variability are considered, given that
they are likely to be additive, the range around the 10 mg per serving
estimated intake can be expected to deviate by 10 to 20
percent. Thus, FDA tentatively concludes that the life-threatening
adverse events associated with the use of ephedrine alkaloids can
reasonably be expected to occur at intake levels as low as 8 to 9 mg
ephedrine alkaloids per serving. However, given the limitations in the
available data, the agency requests comments on whether it is more
appropriate to focus on the 10 mg level.
Based on the available evidence and the likely sources of
measurement error around estimated intake levels, the agency
tentatively concludes that the use of dietary supplements containing 8
mg or more ephedrine alkaloids per serving may render the dietary
supplement injurious to health
available data, the agency requests comments on whether it is more
appropriate to focus on the 10 mg level.
Based on the available evidence and the likely sources of
measurement error around estimated intake levels, the agency
tentatively concludes that the use of dietary supplements containing 8
mg or more ephedrine alkaloids per serving may render the dietary
supplement injurious to health. The agency also tentatively concludes
that consumption of dietary supplements that contain this level or more
of ephedrine alkaloids presents a significant and unreasonable risk of
illness or injury under the conditions of use recommended or suggested
in the labeling or under ordinary conditions of use, and that,
therefore, products that contain this or higher levels of ephedrine
alkaloids are adulterated. \1\
---------------------------------------------------------------------------
\1\ FDA has limited information on which ingredients dietary
supplement manufacturers are likely to substitute for ephedrine
alkaloids. Given this uncertainty, FDA cannot comment on the safety
of potential substitutes. FDA notes that manufacturers bear the
burden of ensuring that any ingredients that they may substitute for
sources of ephedrine alkaloids meet all safety standards for dietary
supplements.
---------------------------------------------------------------------------
To reflect this tentative conclusion, FDA is proposing to adopt
Sec. 111.100(a)(1) which states that dietary supplements that contain 8
mg or more ephedrine alkaloids (the total of ephedrine,
pseudoephedrine, norpseudoephedrine, norephedrine, methylephedrine,
methylpseudoephedrine and related alkaloids) per single serving shall
be deemed to be adulterated under section 402(a)(1) and (f)(1)(A) of
the act. FDA is proposing to adopt this provision under sections
402(a)(1), (f)(1)(A), and 701(a) (21 U.S.C. 371(a)) of the act
n 8
mg or more ephedrine alkaloids (the total of ephedrine,
pseudoephedrine, norpseudoephedrine, norephedrine, methylephedrine,
methylpseudoephedrine and related alkaloids) per single serving shall
be deemed to be adulterated under section 402(a)(1) and (f)(1)(A) of
the act. FDA is proposing to adopt this provision under sections
402(a)(1), (f)(1)(A), and 701(a) (21 U.S.C. 371(a)) of the act.
Under section 402(a)(1) of the act, a food, including a dietary
supplement, is adulterated if it bears or contains any added poisonous
or deleterious substance that may render it injurious to health.
Section 402(f)(1)(A) of the act provides that a dietary supplement is
adulterated if it, or one of its ingredients, poses a significant or
unreasonable risk of injury or illness when used as directed or under
ordinary conditions of use. Under section 701(a) of the act, FDA has
authority to issue regulations for the efficient enforcement of the
act. These sections authorize FDA to issue a regulation that
establishes a level of ephedrine alkaloids that, the available evidence
makes clear, will render a dietary supplement adulterated as a matter
of law.
FDA tentatively concludes that such a regulation will advance the
purposes of the act in two significant ways. First, it will provide
guidance to the dietary supplement industry as to a level of ephedrine
alkaloids that can be used in their products with some confidence that
such products will not be subject to regulatory action. Second, it will
make clear that if products that contain higher levels of ephedrine
alkaloids are marketed; such products will be considered unsafe and
adulterated and will be subject to all the relevant sanctions under the
act.
Eight mg per serving and above represent levels at which the
presence of ephedrine alkaloids in a dietary supplement may render the
product injurious to health and presents a significant and unreasonable
risk. FDA cannot say that it is a safe level, nor has
s are marketed; such products will be considered unsafe and
adulterated and will be subject to all the relevant sanctions under the
act.
Eight mg per serving and above represent levels at which the
presence of ephedrine alkaloids in a dietary supplement may render the
product injurious to health and presents a significant and unreasonable
risk. FDA cannot say that it is a safe level, nor has
it been arrived at in a way that factored in some margin of safety. The
evidence does not exist to establish a safe level. FDA notes that many
members of the Food Advisory Committee stated that they were unaware of
a basis for determining a safe level (Ref. 25). Thus, the agency is
concerned about the potential for risk at levels below 8 mg per serving
for individuals who are particularly sensitive to the effects of
ephedrine alkaloids, or whose sensitivity could be increased through
chronic use of these products or other processes (e.g., physical
exercise).
Given the seriousness of the public health concerns and the
uncertainty surrounding the risks attendant upon consumption of
ephedrine alkaloids below 8 mg per serving, the agency solicits
comments, and asks that they include data, particularly clinical data,
on the safety of the use of less than 8 mg of ephedrine alkaloids per
serving in dietary supplements. Should data and information become
available that demonstrate that the use of less than 8 mg of ephedrine
alkaloids per serving in dietary supplements poses a hazard to the
public health, or that the level of ephedrine alkaloids that will
render a product adulterated is higher than 8 mg per serving, the
agency will consider modifying Sec. 111.100 accordingly
r
serving in dietary supplements. Should data and information become
available that demonstrate that the use of less than 8 mg of ephedrine
alkaloids per serving in dietary supplements poses a hazard to the
public health, or that the level of ephedrine alkaloids that will
render a product adulterated is higher than 8 mg per serving, the
agency will consider modifying Sec. 111.100 accordingly.
At this time, the agency is not proposing a level at which
ephedrine, as opposed to the mixture of ephedrine alkaloids found in
products containing botanicals, may render a product adulterated, even
though some members of FDA's Working Group and of the Food Advisory
Committee recommended that the agency establish a separate level for
ephedrine (Refs. 25 and 27). There is some reason to believe that
ephedrine may be particularly significant in contributing to the
occurrence of many of the cardiovascular effects seen in the reports of
adverse events because ephedrine is often the predominant alkaloid in
botanical sources. In addition, ephedrine is known to exhibit more
intense cardiovascular effects relative to the other ephedrine
alkaloids (Refs. 5 and 9 through 13). For example, serious adverse
events have been reported with the use of dietary supplements
containing less than 5 mg ephedrine. However, the available data are
difficult to interpret because of the uncertainties about the
potentially interactive effects of the other ephedrine alkaloids in the
raw botanical or botanical extract and the presence of other
physiologically and pharmacologically active ingredients in the dietary
supplement products that may act to potentiate the overall NS and CVS
stimulatory effects of ephedrine and thus exacerbate the adverse
effect. The agency requests comments on whether a separate dietary
ingredient limit should be established for ephedrine in addition to
ephedrine alkaloids, and if so, what that limit should be.
2. Proposed Compliance Procedures
In proposed Sec
in the dietary
supplement products that may act to potentiate the overall NS and CVS
stimulatory effects of ephedrine and thus exacerbate the adverse
effect. The agency requests comments on whether a separate dietary
ingredient limit should be established for ephedrine in addition to
ephedrine alkaloids, and if so, what that limit should be.
2. Proposed Compliance Procedures
In proposed Sec. 111.100(a)(2), the agency states that it will use
the high performance liquid chromatography (HPLC) method as specified
in LIB No. 4053 to determine the level of ephedrine alkaloids in a
dietary supplement. The agency developed this HPLC analytical method to
identify and quantify ephedrine alkaloids from botanical sources. It
was necessary for the agency to develop an analytical method because
the official analytical methods used for the determination of ephedrine
alkaloids in pharmaceutical dosage forms are unsuitable for botanical
products. Current official analytical methods do not discriminate
between ephedrine alkaloids and other alkaloids that may be in the
botanicals (e.g., ephedroxane and methylbenzylamine) (Ref. 157). This
HPLC method has made possible the resolution and quantification of the
several different ephedrine alkaloids known to occur in the Ephedras
and other botanicals, including ephedrine, pseudoephedrine,
norephedrine, methylephedrine, methylpsuedoephedrine,
norpseudoephedrine, and related alkaloids. This method is currently
undergoing collaborative evaluation and testing.
FDA strongly recommends that manufacturers also use this or other
methods that the agency adopts, although manufacturers will be free to
use any alternative method that they find appropriate. However, FDA
will use whatever method it adopts in this proceeding as the basis for
its enforcement actions, and this method will be the legally
established method
collaborative evaluation and testing.
FDA strongly recommends that manufacturers also use this or other
methods that the agency adopts, although manufacturers will be free to
use any alternative method that they find appropriate. However, FDA
will use whatever method it adopts in this proceeding as the basis for
its enforcement actions, and this method will be the legally
established method. Therefore, manufacturers would be advised to
compare their method of choice to the HPLC method to ensure that the
alternative method produces similar results.
3. Proposed Limit for Ephedrine Alkaloids: Frequency and Per Total
Daily Intake Basis
In addition to proposing a level for ephedrine alkaloids in dietary
supplements at or above which their presence will render the product
adulterated, the agency is proposing to address its concern that
products containing ephedrine alkaloids below the dietary ingredient
limit may be used in a manner that increases the likelihood, frequency,
and severity of adverse events. Intake of multiple servings of
ephedrine alkaloid-containing dietary supplements, particularly when
such intake occurs within a relatively short timeframe (e.g., hours or
within a day), can result in an excessive level of ephedrine alkaloids
in the body that will increase the likelihood of an acute adverse event
and the severity of the event that occurs. Concern over the hazards of
taking several servings of ephedrine alkaloid-containing dietary
supplements in a short period of time led several members of the
Working Group and of the Food Advisory Committee to recommend that FDA
limit the intake of dietary supplements containing ephedrine alkaloids
to no more than four to five times per day and establish daily use
limits, e.g., the amount of ephedrine alkaloids the consumer should not
exceed in a day. In light of this, FDA evaluated the risks associated
with different patterns of daily intake of ephedrine alkaloid-
containing dietary supplements
to recommend that FDA
limit the intake of dietary supplements containing ephedrine alkaloids
to no more than four to five times per day and establish daily use
limits, e.g., the amount of ephedrine alkaloids the consumer should not
exceed in a day. In light of this, FDA evaluated the risks associated
with different patterns of daily intake of ephedrine alkaloid-
containing dietary supplements.
The average plasma half-lives for pharmaceutical ephedrine,
pseudoephedrine, and phenylpropanolamine are approximately 6 hours
(range 3 to 11 hours), 6 hours, and 4 hours, respectively (Refs. 10
through 12, 20, and 46). Generally, this means that after one half-life
(e.g., 4 to 6 hours) half of the ephedrine alkaloids still remain in
the blood. More than 24 hours are needed for complete clearance of a
single serving of ephedrine alkaloids from the body. Because ephedrine
alkaloids remain in the body for hours, when additional servings of an
ephedrine alkaloid-containing dietary supplement are consumed, the
ingested alkaloids are additive to those already in the body. This
process will result in an increase in blood and tissue concentrations
of ephedrine alkaloids. Generally, the higher the blood and other body
tissue levels of ephedrine alkaloids, the greater the likelihood and
severity of adverse events (Ref. 46).
Given the pharmacological evidence that average plasma half-lives
of ephedrine alkaloids are approximately 4 to 6 hours, elevated blood
levels of ephedrine alkaloids will be maintained if a serving is
consumed every 4 to 6 hours. Because ephedrine alkaloids are stimulant
substances, they can cause insomnia if taken close to sleeping hours.
Thus, if 6 to 8 hours in a day are typically used for sleeping, there
is a period of 16 to 18 hours per day in which consumers of ephedrine-
containing dietary supplements would
vated blood
levels of ephedrine alkaloids will be maintained if a serving is
consumed every 4 to 6 hours. Because ephedrine alkaloids are stimulant
substances, they can cause insomnia if taken close to sleeping hours.
Thus, if 6 to 8 hours in a day are typically used for sleeping, there
is a period of 16 to 18 hours per day in which consumers of ephedrine-
containing dietary supplements would
have interest in consuming this substance. By dividing the 16 to 18
waking hours in a day by the largest average half-life for ephedrine
alkaloids (i.e., 6 hours), the results reveal the possibility of taking
a maximum of three servings per day.
Three servings of a dietary supplement that contains the proposed
maximum per serving amount of ephedrine alkaloids (less than 8 mg)
would yield a daily intake level of less than 24 mg ephedrine
alkaloids. Thus, a dietary supplement product that contains ephedrine
alkaloids and whose label or labeling instructs consumers to take 24 mg
or more per day would present a significant and unreasonable risk of
injury and illness under the conditions of use suggested or recommended
in the labeling and thus would render the product adulterated under
section 402(f)(1)(A) of the act. Similarly, an ephedrine alkaloid-
containing product whose label or labeling instructs consumers to take
8 mg or more during a 6-hour period would instruct consumers to consume
an amount of ephedrine alkaloids that has been shown to cause injury.
This labeling also would present a significant and unreasonable risk
and render the product adulterated under section 402(f)(1)(A) of the
act.
FDA tentatively concludes that without a daily use limit, the per
serving limit cannot be effective in reducing the potential for adverse
events because consumers may unknowingly consume an excessive amount of
ephedrine alkaloids by taking several servings of dietary supplements
in a relatively short period of time. Therefore, FDA is proposing in
Sec
d under section 402(f)(1)(A) of the
act.
FDA tentatively concludes that without a daily use limit, the per
serving limit cannot be effective in reducing the potential for adverse
events because consumers may unknowingly consume an excessive amount of
ephedrine alkaloids by taking several servings of dietary supplements
in a relatively short period of time. Therefore, FDA is proposing in
Sec. 111.100(b) that the labeling of dietary supplements that contain
ephedrine alkaloids shall not suggest or recommend conditions of use
that would result in intake of 8 mg or more ephedrine alkaloids within
a 6-hour period or a total daily intake of 24 mg or more of ephedrine
alkaloids. FDA is proposing this regulation under sections 402(f)(1)(A)
and 701(a) of the act to ensure that ephedrine alkaloid-containing
dietary supplements do not bear directions for use that will create a
significant and unreasonable risk.
In some cases, the label directions for use of dietary supplements
containing ephedrine alkaloids can cause consumers to exceed the per
serving limit or to consume servings more frequently than every 6
hours. For example, FDA would consider the following label instructions
to increase the risk of adverse events: ``take what your body needs''
or ``take 1 tablet (containing 7 mg ephedrine alkaloids) per serving,
not to exceed 3 tablets per day.'' In the later example, the consumer
may believe that it is safe to consume 3 tablets (21 mg ephedrine
alkaloids) at one serving or servings separated by less than 6 hours.
Examples where the agency would not consider that the directions for
use would cause consumers to exceed the per serving limit or take
serving more frequently than every 6 hours include ``take 1 tablet per
day,'' ``take 1 tablet every 6 hours, do not take more than 3 tablets
per day,'' or ``take 1 tablet not more than every 8 hours, do not take
more than 2 tablets per day.''
4
than 6 hours.
Examples where the agency would not consider that the directions for
use would cause consumers to exceed the per serving limit or take
serving more frequently than every 6 hours include ``take 1 tablet per
day,'' ``take 1 tablet every 6 hours, do not take more than 3 tablets
per day,'' or ``take 1 tablet not more than every 8 hours, do not take
more than 2 tablets per day.''
4. Proposed Limitation on Duration of Use
The available data suggest that some types of adverse events may be
related to the duration of using ephedrine alkaloids. Long-term use of
sympathomimetic agents, such as ephedrine alkaloids, even at relatively
low levels, is related to serious adverse events, including
cardiomyopathy (i.e., disease of the heart muscle) and myocardial
necrosis (death of heart cells and tissue), that can result in death
(Refs. 7, 16, 49, 51, and 52). The scientific literature establishes
that use of ephedrine alkaloids for a period of several months or years
can result in cardiomyopathy (Refs. 66 through 68). Similarly, fatal
cardiomyopathies have been seen in the AER's associated with chronic
use of ephedrine alkaloid-containing dietary supplements at serving
levels close to the dietary ingredient limit the agency proposed above
(ARMS No. 11134 in Refs. 29 and 149a).
Concern about these types of adverse events with the long-term use
of ephedrine alkaloids led several members of the Working Group (Ref.
27) and of the Food Advisory Committee (Ref. 25) to recommend that, in
conjunction with a per serving dietary ingredient limit, FDA require a
statement on the label of ephedrine alkaloid-containing dietary
supplements to warn consumers not to use the product for a period
longer than 7 days. These members stated that a 7-day use limit is
standard guidance for the use of pharmacoactive drug substances,
including ephedrine alkaloids, and may reduce the occurrence of adverse
events related to long-term use of ephedrine alkaloids (Ref. 25)
tement on the label of ephedrine alkaloid-containing dietary
supplements to warn consumers not to use the product for a period
longer than 7 days. These members stated that a 7-day use limit is
standard guidance for the use of pharmacoactive drug substances,
including ephedrine alkaloids, and may reduce the occurrence of adverse
events related to long-term use of ephedrine alkaloids (Ref. 25).
Moreover, a 7-day limit on the use of ephedrine alkaloids is supported
by the AER's data, which show that over 60 percent of the adverse
events occurred when ephedrine alkaloid-containing dietary supplements
were used for more than 7 days.
For these reasons, FDA tentatively concludes that ephedrine
alkaloid-containing dietary supplements that do not bear the statement
``Do not use this product for more than 7 days'' present a significant
and unreasonable risk of injury and illness under the recommended or
suggested conditions of use. Therefore, under sections 402(f)(1)(A) and
701(a) of the act, to reduce the potential for adverse events occurring
as a result of consumers using ephedrine alkaloids for more than a
period of 7 days, FDA is proposing to require in Sec. 111.100(c) that
the label of dietary supplements that contain ephedrine alkaloids state
``Do not use this product for more than 7 days.''
The agency notes that this warning focuses on duration of use, not
on when reinstitution of use of ephedrine alkaloids is appropriate. FDA
is not aware of definitive data on whether there is a period of time
when the reinstitution of use of ephedrine alkaloids will not present a
risk of adverse events. FDA solicits comments, particularly data, on
this matter. In addition, FDA solicits comments on how consumers will
interpret this label statement in terms of reintroducing dietary
supplements containing ephedrine alkaloids in their diets.
5
re of definitive data on whether there is a period of time
when the reinstitution of use of ephedrine alkaloids will not present a
risk of adverse events. FDA solicits comments, particularly data, on
this matter. In addition, FDA solicits comments on how consumers will
interpret this label statement in terms of reintroducing dietary
supplements containing ephedrine alkaloids in their diets.
5. Proposed Prohibition of Ingredients With Stimulant Effects
As previously discussed, because the nature and patterns of adverse
events observed in the AER's were consistent with the known
physiological and pharmacological effects of the ephedrine alkaloids,
the agency focused its evaluation on the ephedrine alkaloids. However,
the majority of the adverse events that have been reported to FDA have
involved the use of dietary supplements that contain ephedrine
alkaloids in combination with other ingredients, some with known
physiological or pharmacological effects, including kola nut, yohimbe,
willow bark, senna, and Uva ursi (Ref. 164). In many cases, the AER's
showed that more severe adverse effects (e.g., heart attack, stroke,
seizure) occurred with the use of dietary supplements that contained
ephedrine alkaloids at levels below 20 mg together with other
ingredients than were noted in the scientific literature with the use
of ephedrine at 20 mg (Ref. 149a). These observations suggest that the
other ingredients may act, in combination with the ephedrine alkaloids,
to produce more frequent, more severe, or potentially different
patterns of adverse effects than those noted with the use of an
ephedrine alkaloid alone.
w 20 mg together with other
ingredients than were noted in the scientific literature with the use
of ephedrine at 20 mg (Ref. 149a). These observations suggest that the
other ingredients may act, in combination with the ephedrine alkaloids,
to produce more frequent, more severe, or potentially different
patterns of adverse effects than those noted with the use of an
ephedrine alkaloid alone.
Moreover, the clinically significant adverse events that occurred
with amounts of ephedrine alkaloids below the 8 mg per serving limit
may have been related to the compounding effects of ephedrine alkaloids
in combination with other ingredients. Because of the known additive
effects that occur when ephedrine alkaloids are combined with certain
types of other ingredients, such as stimulants, proposed
Sec. 111.100(a)(1), by itself, will likely not be effective in reducing
the potential for adverse events. Certain types of other substances
interact with the ephedrine alkaloids to increase the effects of the
ephedrine alkaloids, thereby acting like more ephedrine alkaloids were
contained in the product.
For example, caffeine is a nervous system stimulant that can induce
nervousness, insomnia, and tachycardia (increased heart rate) (Refs. 7,
165, and 166). Intake of toxic levels of caffeine can cause death
resulting from CV stimulatory effects (Ref. 46). Various botanicals are
known to be sources of caffeine, including green tea, guarana, yerba
mate (also known as Ilex paraguariensis), and kola nut (Refs. 167
through 172).
The scientific literature reveals that the frequency and severity
of adverse effects increase when ephedrine alkaloids and caffeine are
combined (Refs. 22, 73, 105, and 106). Recent clinical trials have
focused on whether a combination of ephedrine and caffeine would be
more effective in the treatment of obesity than ephedrine alone. The
usual dosage of ephedrine and caffeine was 20 mg and 200 mg,
respectively, given three times a day before meals
severity
of adverse effects increase when ephedrine alkaloids and caffeine are
combined (Refs. 22, 73, 105, and 106). Recent clinical trials have
focused on whether a combination of ephedrine and caffeine would be
more effective in the treatment of obesity than ephedrine alone. The
usual dosage of ephedrine and caffeine was 20 mg and 200 mg,
respectively, given three times a day before meals. The results of
these trials, certain of which were carefully designed and conducted to
eliminate potential confounders to the interpretation of study results
(e.g., concurrent medication usage, underlying diseases and conditions
or other risk factors), indicate that the effects, including adverse
effects, of combining ephedrine and caffeine are synergistic (Refs.
105, 173, and 174).
Caffeine and ephedrine also appear to be synergistic in
thermogenesis, i.e., they increase the rate of thermogenesis by
influencing different parts of the metabolic pathways (Refs. 173 and
175). While the resulting effects of combining ephedrine and caffeine
could have a potentially positive impact on thermogenesis because of
their effects on metabolic pathways, it may also account for increased
adverse effects seen with combinations of these agents because of
increased sympathetic stimulation of other organ-systems (e.g., CVS and
NS). The synergistic adverse effects include an increased frequency of
certain signs and symptoms, e.g., increased heart rate, insomnia,
nervousness, and increased blood pressure, that are considered
characteristic of sympathomimetic stimulation.
Other substances with stimulant effects in combination with
ephedrine alkaloids may act to increase the likelihood of an adverse
event. Yohimbine from the botanical yohimbe, in small doses, is
reported to stimulate part of the nervous system and to cause elevated
blood pressure, increased heart rate, tremor, and anxiety (Refs. 176
through 178)
characteristic of sympathomimetic stimulation.
Other substances with stimulant effects in combination with
ephedrine alkaloids may act to increase the likelihood of an adverse
event. Yohimbine from the botanical yohimbe, in small doses, is
reported to stimulate part of the nervous system and to cause elevated
blood pressure, increased heart rate, tremor, and anxiety (Refs. 176
through 178). Because of their stimulant effects on the nervous system,
combining sources of yohimbine with the ephedrine alkaloids may
increase the likelihood, frequency, and severity of adverse events.
Therefore, the agency tentatively concludes that, based on the
available evidence, adverse events may be related to the interactive or
additive effects of stimulant substances in combination with ephedrine
alkaloids in dietary supplements. This tentative conclusion is
supported by statements made by several members of the Food Advisory
Committee at the August 27 and 28, 1996, meeting (Ref. 25). For these
reasons, the agency tentatively concludes that any dietary supplement
that contains ephedrine alkaloids in combination with ingredients that
produce the aforementioned effects presents a significant or
unreasonable risk of injury or illness under the conditions of use
suggested in the labeling or under ordinary conditions of use and are
adulterated. To eliminate this risk, under sections 402(f)(1)(A) and
701(a) of the act, FDA is proposing Sec. 111.100(d), which states that
no ingredient, or ingredient that contains a substance, that has a
known stimulant effect (e.g., sources of caffeine, yohimbine) may be
included in a dietary supplement that contains ephedrine alkaloids.
The agency is aware that several manufacturers and distributors of
ephedrine alkaloid-containing dietary supplements also market caffeine-
containing dietary supplements that are intended to be used with a
``companion'' ephedrine alkaloid-containing dietary supplement
concentrations
(Refs. 181 and 182). By reducing renal clearance, higher levels of
ephedrine alkaloids are maintained in the blood for longer periods of
time, thus prolonging the effects of ephedrine alkaloids. The
maintenance of high blood levels of ephedrine alkaloids increases the
likelihood of adverse events, particularly in those who may be
sensitive to the effects of ephedrine alkaloids. In addition, consumers
may experience adverse events if more ephedrine alkaloids are consumed
while blood levels are maintained because the absorption of additional
ephedrine alkaloids into the bloodstream will result in even higher
blood and tissue concentrations of ephedrine alkaloids and in any
effects that may follow. Generally, the higher the blood levels of
ephedrine alkaloids, the greater the risk of adverse events and the
greater the likelihood that the adverse effects that do occur will be
severe (Ref. 46).
Diuretics and laxative substances in an ephedrine-alkaloid-
containing dietary supplement may also increase the likelihood,
frequency, and severity of adverse events (Refs. 182 through 186). Uva
ursi is a botanical diuretic contained in many ephedrine alkaloid
products (Ref. 184). The compounds ursolic acid and isoquercetin found
in Uva ursi are mild diuretics. The ephedrine alkaloids also exhibit
diuretic effects (Ref. 4). For example, ephedrine has a mild diuretic
effect, and pseudoephedrine has a marked diuretic effect. The use of a
product that contains ephedrine alkaloids in combination with other
substances with diuretic effects increases the likelihood and severity
of consequent fluid and electrolyte imbalances, both of which could
affect CVS and NS risks.
Senna and Cascara are examples of botanicals that contain potent
stimulant laxative substances called
d pseudoephedrine has a marked diuretic effect. The use of a
product that contains ephedrine alkaloids in combination with other
substances with diuretic effects increases the likelihood and severity
of consequent fluid and electrolyte imbalances, both of which could
affect CVS and NS risks.
Senna and Cascara are examples of botanicals that contain potent
stimulant laxative substances called
anthraquinone glucosides (Refs. 185 through 187). Use of excessive
amounts of stimulant laxatives can cause stomach cramps, nausea,
vomiting, and diarrhea. Chronic use may lead to laxative dependence,
diarrhea, and, in severe cases, dehydration and electrolyte disorders
(Ref. 188). Ephedrine is known to influence cellular potassium (an
electrolyte) concentrations (Refs. 53 and 54). Use of laxative
substances in combination with ephedrine alkaloids may act to increase
the likelihood, frequency, and severity of adverse events. The agency
requests comments, particularly data, on the interactive effects of
other ingredients and the ephedrine alkaloids in dietary supplements.
Based on the comments and data received by FDA, the agency may prohibit
the use of ingredients that produce the aforementioned effects in a
dietary supplement that contain ephedrine alkaloids.
6. Proposed Prohibitions on Claims
As described previously in section II.C.1. of this document, FDA
has received numerous reports of adverse events associated with
ephedrine alkaloid-containing dietary supplements promoted for use for
weight loss, increased energy, body building, enhanced athletic
performance, increased mental concentration, and enhanced well-being
and with products promoted to be used as an alternative to illicit
street drugs. While many of the products that were associated with
adverse events contained more than one type of claim or representation
on their label or in their labeling, the majority of adverse events
reported to FDA are related to the use of products promoted or used for
weight loss or energy purposes
nhanced well-being
and with products promoted to be used as an alternative to illicit
street drugs. While many of the products that were associated with
adverse events contained more than one type of claim or representation
on their label or in their labeling, the majority of adverse events
reported to FDA are related to the use of products promoted or used for
weight loss or energy purposes. Although fewer of the AER's were
associated with products promoted for body building and enhanced well-
being, clinically serious adverse events, including seizure, heart
attack, and death, have been reported to FDA that were associated with
the use of products represented for these purposes. At least one death
in a young man has been reported with the use of a product promoted as
an alternative to an illicit street drug.
In reviewing the AER's, it was evident that specific types of
claims contained in the labeling of dietary supplements containing
ephedrine alkaloids promoted different patterns of use. Claims such as
weight loss and body building encouraged long-term use to achieve the
product's purported effect (Ref. 189). In addition, claims of increased
energy, increased mental concentration, or enhanced well-being, in a
number of cases, encouraged short-term excessive consumption to achieve
more of the product's purported effect (Ref. 190). Finally, the agency
found that claims that suggest that the product is intended to be used
as a substitute for an illicit street drug fostered abuse. Because
claims in product labeling may influence how a consumer uses the
product, claims in product labeling are a condition of use for dietary
supplements
term excessive consumption to achieve
more of the product's purported effect (Ref. 190). Finally, the agency
found that claims that suggest that the product is intended to be used
as a substitute for an illicit street drug fostered abuse. Because
claims in product labeling may influence how a consumer uses the
product, claims in product labeling are a condition of use for dietary
supplements.
Several Food Advisory Committee members identified a number of
significant risks attendant to using dietary supplements containing
ephedrine alkaloids for purposes such as weight loss, energy, or as an
illicit street drug alternative, including adverse events that are
associated with long-term use, excessive consumption, and abuse of
ephedrine alkaloids (Ref. 25). Because the identified types of claims
promote use patterns that are associated with adverse events, the
agency has tentatively concluded that claim restrictions are necessary
to maintain the integrity of the limit on the level of ephedrine
alkaloids in dietary supplements that it is proposing in
Sec. 111.100(a)(1) and of the other proposed restrictions on the
conditions of use of these dietary supplements.
a. Claims that promote long-term use. Claims in the labeling of
dietary supplements that use of a product may result in effects such as
weight loss or body building promote long-term use of the product
because these effects cannot be achieved in a short period of time.
Weight loss occurs when caloric intake is reduced or energy expenditure
(e.g., exercise) is increased. To lose 1 pound (lb), approximately
3,500 kilocalories (kcal) must be expended by reducing caloric intake
or by increasing energy expenditures (e.g., physical activity) or both
(Ref. 191). Rapid weight loss is associated with health risks,
including increased protein loss from the body stores and increased
risk of gallstone formation (Ref. 27). In fasting, over 50 percent of
rapid weight reduction is attributable to the loss of body fluids
lories (kcal) must be expended by reducing caloric intake
or by increasing energy expenditures (e.g., physical activity) or both
(Ref. 191). Rapid weight loss is associated with health risks,
including increased protein loss from the body stores and increased
risk of gallstone formation (Ref. 27). In fasting, over 50 percent of
rapid weight reduction is attributable to the loss of body fluids.
Risks associated with rapid loss of fluids from the body include
hypotension (i.e., reduction in blood pressure) and electrolyte
disturbances. Steady weight loss over a longer period of time results
in a true weight loss with a reduction of fat stores (Ref. 193).
Guidelines recommend that a safe rate of weight loss is \1/2\ to 1 lb
per week (Ref. 194). Therefore, depending upon the amount of weight
loss that the individual desires to achieve, weight loss programs may
extend from weeks to months (Ref. 195).
Long-term weight loss practices have been documented in the
scientific literature. A survey of weight control practices among 1,431
adults indicated that the average respondent participating in the
survey had a weight loss attempt lasting from 5 to 6 months and had
averaged one attempt a year for the past 2 years (Ref. 196). In
addition, approximately 30 percent of persons trying to lose weight
were chronic dieters and had been on weight loss plans at least 1 year
(Ref. 196). Thus, this survey indicates that common weight loss
practices can be characterized as long-term in duration and recurrent
in nature.
Conversely, body building involves the building of lean muscle mass
by strength and endurance training. The addition of muscle mass can be
accomplished only through regular muscle work (weight training or
similar conditions) coupled with a caloric increase (Ref. 197). To
increase size and strength, a muscle must be exercised at 60 to 80
percent of its capacity several times a week
in nature.
Conversely, body building involves the building of lean muscle mass
by strength and endurance training. The addition of muscle mass can be
accomplished only through regular muscle work (weight training or
similar conditions) coupled with a caloric increase (Ref. 197). To
increase size and strength, a muscle must be exercised at 60 to 80
percent of its capacity several times a week. In addition, a gain of 1
lb of muscle requires about 2,500 extra calories, in addition to the
calories needed for the training (Ref. 197). An increase of 700 to
1,000 calories (cal) to the daily diet should support a gain of 1 to 2
lb of lean muscle in 7 days (Ref. 197). Body building systems that
include intensive physical training programs, controlled diet, and
dietary supplementation purport to achieve results in 6 weeks (Ref.
198), and the individual must continue a training program to maintain
or increase the muscle mass.
As previously mentioned in section III.C.4. of this document, long-
term use of ephedrine alkaloids, even at relatively low levels, is
related to serious adverse events, including cardiomyopathy (i.e.,
disease of the heart muscle) and myocardial necrosis (death of heart
cells and tissue), that can result in death. After reviewing the
scientific literature and the AER's as well as recommendations by the
Working Group and by the Food Advisory Committee, FDA has tentatively
concluded that ephedrine alkaloid-containing dietary supplements must
bear the statement ``Do not use this product for more than 7 days,''
and that those that do not present a significant and unreasonable risk
of injury and illness under the recommended or suggested conditions of
use.
Significant and safe results from weight loss or body building
should not and cannot be achieved within a period of 7 days. An
individual could lose approximately 4 lb of body fat in 7 days under
complete fasting conditions if the normal energy requirements are 2,000
cal per day. (This assumption is based
nable risk
of injury and illness under the recommended or suggested conditions of
use.
Significant and safe results from weight loss or body building
should not and cannot be achieved within a period of 7 days. An
individual could lose approximately 4 lb of body fat in 7 days under
complete fasting conditions if the normal energy requirements are 2,000
cal per day. (This assumption is based
on the fact that 3,500 kcal must be expended to achieve 1 lb of weight
loss.) As discussed above, however, this rate of weight loss is not
safe or recommended.
Regarding body building, lean muscle mass cannot be built in 7 days
(Ref. 197). Moreover, the scientific literature evidences that the use
of ephedrine alkaloids during intense physical activity, such as body
building, increases the risks of serious adverse events. Use of
ephedrine alkaloids during periods of intense physical activity results
in enhanced or synergistic actions on the sympathetic nervous system.
It is through such enhanced physiological processes that chronic
effects on the heart, such as myocardial necrosis (i.e., death of heart
cells and tissue), can occur with prolonged use of ephedrine alkaloids
(Refs. 16 and 197a).
Because safe and significant weight loss and body building cannot
be achieved in a 7-day period, claims that promote these uses promote
long-term use of ephedrine alkaloid-containing dietary supplements,
which has been associated with serious adverse events. For this reason,
FDA tentatively concludes that any claims that promote long-term use of
ephedrine alkaloid dietary supplements, such as those for weight loss
and body building, promote conditions of use that present a significant
and unreasonable risk of illness and injury. Therefore, under sections
402(f)(1)(A) and 701(a) of the act, the agency is proposing in
Sec
h serious adverse events. For this reason,
FDA tentatively concludes that any claims that promote long-term use of
ephedrine alkaloid dietary supplements, such as those for weight loss
and body building, promote conditions of use that present a significant
and unreasonable risk of illness and injury. Therefore, under sections
402(f)(1)(A) and 701(a) of the act, the agency is proposing in
Sec. 111.100(e) to prohibit dietary supplements that contain ephedrine
alkaloids from being represented, either expressly or implicitly, for
use for long-term effects such as weight loss or body building.
b. Claims that promote short-term excessive consumption. Many
claims found on the labels of, or in the labeling for, ephedrine
alkaloid-containing dietary supplements, including increased energy,
increased mental concentration, and enhanced well-being, encourage the
consumer to take more of the product than is indicated on the label to
achieve more of the purported effect. Several members of the Food
Advisory Committee stated that when a product is promoted to increase
these types of effects, the claim encourages the consumer to exceed the
labeled directions for use to gain more of the desired effects (Ref.
25). For example, if a product is promoted for energy, the consumer is
encouraged to take more to gain greater energy.
Many of the AER's received by the agency were associated with
dietary supplements containing ephedrine alkaloids that were promoted
for one or more of these purposes. In a number of instances, the
consumer took more than directed on the product label and experienced
an adverse event (Ref. 190). Claims that promote excessive consumption,
even for one or a very limited number of uses, are inconsistent with
proposed Sec. 111.100 (a)(1) and (b), because they encourage the
consumer to take more than directed in the conditions of use set out on
the label so that the consumer can achieve the purported effect.
In section II.C.2.a. and II.C.2.b
l and experienced
an adverse event (Ref. 190). Claims that promote excessive consumption,
even for one or a very limited number of uses, are inconsistent with
proposed Sec. 111.100 (a)(1) and (b), because they encourage the
consumer to take more than directed in the conditions of use set out on
the label so that the consumer can achieve the purported effect.
In section II.C.2.a. and II.C.2.b. of this document, FDA described
data from the clinical literature and AER's that show that consumption
of an excessive amount of ephedrine alkaloids in a relatively short
period of time is associated with serious adverse events, including
seizure, psychosis, mania, heart attack, and death. The agency
tentatively concludes that the potential for these serious adverse
events to occur with excessive consumption of ephedrine alkaloids is a
material fact with respect to consequences that may result from the use
of a dietary supplement promoted for short-term effects that encourage
excessive consumption, and therefore a material fact that must be
disclosed on the label.
FDA's authority to require disclosure statements in the labeling of
dietary supplement products derives from sections 201(n), 403(a)(1),
and 701(a) of the act. Section 201(n) of the act states, ``If an
article (e.g., a food or dietary supplement product) is alleged to be
misbranded because the labeling or advertising is misleading, then in
determining whether the labeling or advertising is misleading there
shall be taken into account (among other things) not only
representations made or suggested by statement, word, design, device,
or any combination thereof, but also the extent to which the labeling
or advertising fails to reveal facts material in light of such
representations or material with respect to consequences that may
result from the use of the article to which the labeling or advertising
thereof or under such conditions of use prescribed in the labeling or
advertising thereof or under such conditions of use as are customary o
on thereof, but also the extent to which the labeling
or advertising fails to reveal facts material in light of such
representations or material with respect to consequences that may
result from the use of the article to which the labeling or advertising
thereof or under such conditions of use prescribed in the labeling or
advertising thereof or under such conditions of use as are customary or
usual.'' Under section 403(a)(1) of the act, a food is misbranded if
its labeling is false or misleading in any particular. Thus, the
omission of a material fact from the label or labeling would misbrand a
product. These statutory provisions, combined with section 701(a) of
the act, authorize FDA to issue a regulation designed to ensure that
persons using ephedrine alkaloid-containing dietary supplements will
receive information that is material with respect to consequences that
may result from the use of the supplement under its labeled conditions.
Therefore, FDA is proposing in Sec. 111.100(f)(1) that the label or
labeling for dietary supplements that contain ephedrine alkaloids that
purport to be or are represented, either expressly or implicitly, to be
used for short-term effects, such as increased energy, increased mental
concentration, or enhanced well-being, must state ``Taking more than
the recommended serving may cause heart attack, stroke, seizure, or
death.'' However, given the significance and the potentially life-
threatening nature of the adverse events that may occur when
individuals consume excessive amounts of ephedrine alkaloids, the
agency requests comments on whether this statement should appear on the
label of dietary supplements containing ephedrine alkaloids, regardless
of any claims appearing on the label or in labeling
e, or
death.'' However, given the significance and the potentially life-
threatening nature of the adverse events that may occur when
individuals consume excessive amounts of ephedrine alkaloids, the
agency requests comments on whether this statement should appear on the
label of dietary supplements containing ephedrine alkaloids, regardless
of any claims appearing on the label or in labeling.
FDA wants to provide an approach to placement of this information
that will give it a prominence that will ensure that it wi
This text is long and has been trimmed here. Open the source document for the complete record.
This is a copy of a public record, reproduced as it was published. It is not legal advice, and it may not be the version a court would rely on. Check the official source before you cite it.