[Federal Register Volume 62, Number 107 (Wednesday, June 4, 1997)]
[Proposed Rules]
[Pages 30678-30724]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-14393]
[[Page 30677]]
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Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
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21 CFR Part 111
Dietary Supplements Containing Ephedrine Alkaloids; Proposed Rule
Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 /
Proposed Rules
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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.
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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. 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.
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. 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
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Organ/system involved Clinical significance Signs and symptoms
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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.
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).
[[Page 30679]]
Dermatologic............................ Serious.................... Exfoliative dermatitis.
Less clinically significant Nonspecific rashes.
General manifestations.................. ........................... Numbness, tingling, dizziness, fatigue,
lethargy, weakness.
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\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. 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. 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. 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
[[Page 30680]]
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. 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.
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. 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.
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.
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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.
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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.
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
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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)?
(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). 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.
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). 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
[[Page 30684]]
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).
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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). 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
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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.
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. 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
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. 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
[[Page 30686]]
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. 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.
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.
----------------------------------------------------------------------------------------------------------------
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
[[Page 30687]]
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. 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. 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. 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.--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.
------------------------------------------------------------------------
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
[[Page 30688]]
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). 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. 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. These results were
statistically significant (p<0.05) (ref.="" 105).="" this="" study="" showed="" that="" there="" was="" a="" possibility="" of="" rebound="" symptoms="" (symptoms="" occurring="" as="" a="" consequence="" of="" withdrawal="" of="" an="" agent,="" especially="" headache="" and="" fatigue)="" once="" the="" treatment="" was="" stopped.="" rebound="" symptoms="" were="" seen="" most="" in="" the="" ephedrine="" and="" caffeine="" treatment="" group="" but="" also="" occurred="" in="" the="" ephedrine="" alone="" group="" (refs.="" 105="" and="" 106).="" astrup="" et="" al.="" enrolled="" 127="" of="" the="" subjects="" completing="" the="" above="" clinical="" trial="" into="" an="" open="" label="" study="" where="" all="" subjects="" received="" the="" same="" treatment="" (diet="" and="" ephedrine="" plus="" caffeine)="" for="" 24="" weeks="" (refs.="" 106="" through="" 108).="" five="" of="" the="" 38="" subjects="" that="" withdrew="" or="" dropped="" out="" of="" this="" study="" did="" so="" because="" they="" experienced="" adverse="" drug="" reactions="" (ns="" and="" cvs="" effects).="" adverse="" drug="" reactions="" occurred="" in="" 102="" subjects="" during="" weeks="" 1="" through="" 24="" of="" the="" open="" trial.="" most="" symptoms="" (75="" percent)="" started="" during="" the="" first="" 4="" weeks="" of="" treatment="" and="" lasted="" about="" 4="" weeks.="" symptoms="" related="" to="" the="" cvs="" were="" primarily="" palpitations="" and="" tachycardia.="" the="" most="" frequent="" ns="" symptoms="" were="" tremor,="" agitation,="" insomnia,="" increased="" sweating,="" and="" nervousness.="" breum="" et="" al.,="" in="" another="" clinical="" trial="" in="" which="" the="" effects="" of="" ephedrine="" plus="" caffeine="" (ec)="" were="" evaluated,="" conducted="" a="" randomized,="" double="" blind,="" controlled="" 15="" week="" clinical="" trial="" comparing="" the="" effects="" of="" ec="" to="" that="" of="" dexfenfluramine="" (df),="" a="" serotoninergic="" agonist,="" in="" the="" treatment="" of="" obesity="" (ref.="" 113).="" fifty="" four="" percent="" of="" the="" subjects="" in="" the="" ec="" group="" compared="" to="" 43="" percent="" of="" the="" df="" group="" experienced="" adverse="" reactions.="" the="" majority="" of="" these="" occurred="" within="" the="" first="" 4="" weeks.="" at="" week="" one,="" 38="" percent="" of="" the="" ec="" group="" subjects="" experienced="" adverse="" drug="" reactions="" compared="" to="" 30="" percent="" in="" the="" df="" group.="" ns="" effects="" (particularly="" insomnia="" and="" agitation)="" were="" statistically="" increased="" (p="">< 0.05)="" in="" the="" ec="" treatment="" group="" (46="" percent)="" compared="" to="" the="" df="" group="" (26="" percent),="" whereas="" gastrointestinal="" adverse="" effects="" were="" significantly="" increased="" in="" the="" df="" group.="" eight="" percent="" of="" the="" ec="" group="" reported="" cardiovascular="" symptoms.="" all="" symptoms="" remitted="" after="" cessation="" of="" the="" trial="" drugs.="" the="" above="" studies="" demonstrate="" that="" adverse="" effects="" can="" occur="" with="" the="" use="" of="" ephedrine="" in="" the="" treatment="" of="" obesity="" even="" in="" carefully="" designed="" and="" conducted,="" physician-monitored="" clinical="" trials="" and="" even="" in="" persons="" prescreened="" to="" be="" in="" good="" health,="" free="" of="" known="" risk="" factors,="" and="" not="" using="" medications="" or="" other="" products="" known="" to="" adversely="" interact="" with="" ephedrine-like="" drugs.="" furthermore,="" the="" study="" population="" of="" obese="" individuals="" is="" recognized="" to="" be="" less="" sensitive="" to="" the="" effects="" of="" sympathomimetic="" agents="" than="" the="" general="" population="" (ref.="" 120).="" certain="" of="" these="" studies="" also="" evidence="" that="" there="" is="" an="" increased="" frequency="" of="" adverse="" effects="" occurring="" in="" lean="" subjects,="" secondary="" to="" sympathetic="" stimulation,="" compared="" to="" obese="" subjects="" that="" is="" unrelated="" to="" dose="" per="" body="" weight="" (ref.="" 119).="" thus,="" these="" studies="" suggest="" that="" the="" general="" population="" may="" be="" more="" sensitive="" to="" the="" effects="" of="" ephedrine="" alkaloids="" than="" the="" obese="" population.="" there="" are="" a="" number="" of="" recognized="" limitations="" inherent="" in="" these="" published="" trials,="" including="" those="" associated="" with="" study="" design,="" methods,="" and="" conduct="" (e.g.,="" small="" number="" of="" subjects="" enrolled="" in="" these="" trials,="" narrow="" targeted="" populations,="" short="" evaluation="" periods,="" and="" selective="" presentation="" of="" data="" are="" among="" the="" concerns)="" as="" are="" the="" multiple="" publications="" of="" the="" same="" data.="" yet="" despite="" these="" factors,="" the="" adverse="" effects="" observed="" in="" these="" studies="" remain="" a="" cause="" for="" concern,="" although="" these="" factors="" make="" it="" difficult="" to="" identify="" subpopulations="" that="" may="" be="" particularly="" sensitive="" to="" the="" effects="" of="" ephedrine="" or="" to="" identify="" adverse="" effects="" that="" occur="" infrequently.="" these="" studies="" were="" carefully="" monitored,="" so="" that="" subjects="" were="" withdrawn="" from="" the="" study="" when="" adverse="" effects="" became="" evident.="" therefore,="" although="" the="" observed="" adverse="" effects="" in="" these="" studies="" were="" not="" as="" severe="" or="" as="" serious="" as="" some="" observed="" with="" dietary="" supplement="" use="" (e.g.,="" heart="" attacks,="" seizures,="" strokes),="" they="" are="" indicative="" of="" the="" potential="" for="" [[page="" 30689]]="" greater="" risk="" with="" continued="" use.="" moreover,="" their="" occurrence="" is="" remarkable="" given="" the="" careful="" prescreening="" of="" study="" subjects="" such="" that="" high="" risk="" persons="" were="" not="" included="" in="" the="" study.="" the="" greatest="" limitation,="" however,="" is="" that="" these="" studies="" were="" designed="" to="" evaluate="" the="" effectiveness="" of="" ephedrine="" in="" the="" treatment="" of="" obesity.="" they="" were="" not="" designed="" to="" test="" the="" safety="" of="" the="" use="" of="" ephedrine="" in="" the="" obese,="" or="" any="" other="" population="" (ref.="" 121),="" or="" to="" test="" its="" safety="" under="" the="" conditions="" under="" which="" marketed="" dietary="" supplements="" containing="" sources="" of="" ephedrine="" alkaloids="" are="" used.="" therefore,="" these="" study="" results="" cannot="" be="" used="" to="" definitively="" demonstrate="" safety,="" or="" the="" lack="" of="" safety,="" of="" ephedrine="" alkaloid-="" containing="" supplements="" for="" use="" by="" the="" general="" population.="" nonetheless,="" despite="" the="" shortcomings="" of="" these="" studies,="" the="" results="" raise="" serious="" concerns="" about="" the="" safety="" of="" using="" ephedrine,="" from="" any="" source,="" including="" dietary="" supplements,="" in="" both="" obese="" individuals="" and="" the="" general="" public="" in="" nonmedically="" monitored="" situations.="" e.="" other="" physiologic="" and="" pharmacologic="" effects.="" some="" of="" the="" adverse="" events="" reported="" to="" fda="" that="" were="" unrelated="" to="" the="" cvs="" and="" ns="" also="" bear="" a="" recognized="" relationship="" to="" the="" known="" physiologic="" and="" pharmacologic="" effects="" of="" ephedrine="" alkaloids.="" for="" example,="" urinary="" retention,="" particularly="" in="" males="" with="" no="" history="" of="" prostatic="" hypertrophy="" (enlargement="" of="" the="" prostate="" gland),="" has="" been="" associated="" with="" the="" use="" of="" ephedrine="" (refs.="" 102,="" 103,="" and="" 122="" through="" 124).="" urinary="" retention="" has="" a="" well="" recognized="" relationship="" with="" urinary="" tract="" infections,="" which="" have="" been="" reported="" to="" fda="" with="" the="" use="" of="" products="" containing="" ephedrine="" alkaloids.="" myopathy="" (disease="" of="" muscle),="" besides="" being="" reported="" for="" the="" heart="" (refs.="" 62="" and="" 66="" through="" 68),="" is="" also="" recognized="" to="" involve="" skeletal="" muscles="" and="" may="" result="" in="" acute="" renal="" failure="" (ref.="" 125).="" certain="" gastrointestinal="" adverse="" effects,="" including="" impaired="" colonic="" motility="" and="" ischemic="" colitis,="" have="" been="" associated="" with="" the="" usage="" of="" amphetamines="" (refs.="" 102="" and="" 126).="" similarly,="" ischemic="" colitis="" has="" also="" been="" reported="" with="" the="" usage="" of="" a="" long-acting="" decongestant="" containing="" pseudoephedrine="" (ref.="" 127).="" additionally,="" acute="" hepatitis="" (inflammation="" in="" the="" liver)="" has="" been="" associated="" with="" the="" use="" of="" a="" chinese="" medicinal="" product="" containing="" ma="" huang="" (ref.="" 128).="" other="" types="" of="" adverse="" effects,="" such="" as="" the="" reports="" of="" dermatologic="" reactions,="" while="" not="" known="" to="" be="" related="" to="" the="" recognized="" physiologic="" or="" pharmacologic="" effects="" of="" ephedrine="" alkaloids,="" are="" consistent="" with="" adverse="" effects="" reported="" in="" published="" case="" reports.="" for="" example,="" there="" are="" more="" than="" 11="" published="" case="" reports,="" at="" least="" 12="" patients,="" of="" systemic="" dermatologic="" reactions,="" including="" rashes="" occurring="" in="" a="" particular="" distribution="" on="" the="" body,="" contact="" dermatitis="" (inflammation="" of="" the="" skin="" resulting="" usually="" from="" local="" contact="" with="" a="" substance),="" a="" toxic="" shock-like="" syndrome,="" angioedema="" (extreme="" swelling="" of="" tissues="" and="" structures="" of="" the="" body="" secondary="" to="" leaking="" of="" fluids="" from="" capillaries="" (small="" blood="" vessels)),="" and="" erythematous="" (reddish)="" rash="" and="" subsequent="" desquamation="" (loss="" of="" part="" of="" the="" skin="" surface)="" that="" occurred="" with="" the="" use="" of="" ephedrine="" or="" pseudoephedrine="" (refs.="" 114="" and="" 129="" through="" 138).="" concerns="" about="" toxicity="" to="" the="" fetus="" with="" maternal="" exposure="" to="" ephedrine="" alkaloids="" during="" pregnancy="" remain="" unresolved.="" increased="" fetal="" heart="" rate="" has="" been="" associated="" with="" maternal="" use="" of="" pseudoephedrine="" (ref.="" 139).="" in="" addition,="" the="" administration="" of="" intramuscular="" ephedrine="" to="" treat="" maternal="" hypotension="" has="" been="" associated="" with="" increases="" in="" fetal="" heart="" rate="" and="" beat-to-beat="" variability="" (cited="" in="" ref.="" 139).="" certain="" animal="" studies="" also="" raise="" concern="" about="" potential="" teratogenic="" effects="" that="" may="" be="" caused="" by="" the="" use="" of="" ephedrine="" during="" pregnancy="" (refs.="" 140="" through="" 143).="" potential="" toxicity="" for="" a="" breast-fed="" infant="" whose="" mother="" is="" using="" a="" dietary="" supplement="" containing="" ephedrine="" alkaloids="" is="" unknown,="" but="" toxicity="" has="" been="" reported="" in="" a="" breast-fed="" infant="" whose="" mother="" had="" been="" taking="" a="" long-acting="" oral="" decongestant="" containing="" d-isoephedrine="" for="" the="" relief="" of="" allergy="" symptoms="" (ref.="" 144).="" little="" is="" known="" about="" the="" potential="" consequences="" of="" long="" term="" use="" of="" ephedrine="" alkaloids,="" other="" than="" the="" risk="" of="" cardiomyopathy="" as="" stated="" above.="" park="" et="" al.,="" however,="" recently="" implicated="">-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. 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. 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
[[Page 30690]]
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. 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.
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
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).
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).
----------------------------------------------------------------------------------------------------------------
[[Page 30691]]
(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).
(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. 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
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. 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.
[[Page 30692]]
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. 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)).
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).
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
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)). 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
[[Page 30693]]
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. 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). 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.
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. 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.
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
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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.
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. 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. 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.
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
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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. 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. 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).
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. 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.
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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. 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). 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. The
caffeine-containing dietary supplements are often promoted as
``boosters'' or ``enhancers'' for the ephedrine alkaloid-containing
product. Under these conditions of use, both the caffeine-containing
and the ephedrine alkaloid-containing dietary supplement products
present a significant and unreasonable risk of illness and injury under
their labeled conditions of use and consequently are adulterated under
section 402(f)(1)(A) of the act.
The agency is concerned that many of the dietary supplements
implicated in the AER's contained substances that are known to have
physiological or pharmacological effects that could increase the risk
of adverse events when taken in combination with ephedrine alkaloids.
For example, substances that reduce renal clearance interfere with the
elimination of ephedrine alkaloids from the body by the kidneys (i.e.,
renal excretion) (Refs. 180 and 181) and thus may increase the risk of
adverse effects when consumed in combination with ephedrine alkaloids.
These substances include salicin, which is found in the botanical
commonly known as willow bark, and amino acids in high 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
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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. 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.
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.
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 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
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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. 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. 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 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.
FDA wants to provide an approach to placement of this information
that will give it a prominence that will ensure that it will be read
and understood by consumers but that will result in its presentation
only once on the label panel or on each page of the labeling. Because
the consequences of excessive use of ephedrine alkaloids can be
serious, the agency tentatively concludes that this information should
be on the same label panel or on the same page of the labeling (i.e.,
the same field of vision) as the claim. However, FDA is proposing to
provide for the use of one disclaimer on the label panel or on each
page of labeling in situations in which multiple claims appear on the
label panel or page of labeling where repetitive presentation of the
disclaimer could be burdensome. FDA tentatively concludes that where
the label panel or page of labeling contains multiple claims, and the
relationship between each of those statements and the disclaimer can be
made obvious, the disclaimer need only appear once on each label panel
or in each page of labeling.
FDA experience has been that one of the most effective ways of
tying two label statements that are physically separate on the same
panel is through the use of a symbol such as an asterisk. Symbols have
been used within nutrition labeling since its inception in 1973 and
have proven to be an effective way of relating labeling information to
explanatory footnotes. For example, asterisks have been used adjacent
to names of vitamins and minerals present at very low levels to refer
the consumer to a footnote stating ``Contains less than
[[Page 30699]]
2 percent of the Daily Value (formerly the U.S. Recommended Daily
Allowance).'' FDA is unaware of any data indicating consumer
difficulties with such use of symbols. The use of symbols would also
help differentiate between the label statements to which the disclaimer
is referring and the other label claims to which the disclaimer does
not apply (e.g., authorized health claims or nutrient content claims).
The agency points out that the proposed requirements for the
disclaimer also extend to labeling: There are potentially many vehicles
(e.g., placards, pamphlets, catalogs, books) that would have to bear
the disclaimer. The agency is concerned that the disclaimer be
prominent in these forms of labeling. Even with the flexibility of the
use of an asterisk to tie the claim and the disclaimer to a single
claim, the disclaimer could be obscured in pages of text of a package
insert, pamphlet, or book if it did not appear on the same page or
panel (i.e., in the same field of vision) as the claim itself. Because
of the variety of possibilities for the presentation of the disclaimer,
the agency tentatively concludes that for labeling, as for labels, it
is important that the disclaimer appear within the same field of
vision, that is, on each package panel or page where a claim is made.
Section 403(f) of the act requires mandatory label or labeling
information to be prominently placed on the label with such
conspicuousness (compared with other words, statements, designs, or
devices, in the labeling) as to render it likely to be read and
understood by the ordinary individual under customary conditions of
use. In other instances where information must appear in a prominent
and conspicuous manner on the product label, FDA has proposed that the
information be ``in easily legible print or type in distinct contrast
to other printed or graphic matter'' (e.g., Sec. 101.13(d)(2)).
Therefore, to be consistent with previous actions and to ensure that
the information is presented in a way that makes it likely to be read,
FDA tentatively concludes that the information be presented in easily
legible print or type in distinct contrast to other printed or graphic
matter.
FDA has long held that accompanying information should be in a size
reasonably related to that of the information it modifies (e.g.,
Secs. 101.22(i)(2) and 102.5(b)(2)(ii)). More recently, this relative
prominence has been expressed as a size no less than that required by
Sec. 101.105(i) for the net quantity of contents statement, except
where the size of the claim is less than two times the required size of
the net quantity of contents statement, in which case the accompanying
information can be no less than one-half the type size of the
information modified, but no smaller than one-sixteenth of an inch (see
e.g., Sec. 101.13(g) (1) and (i)(2)). The agency also has long held
that one-sixteenth of an inch is the minimum type size for disclaimer
statements, unless the package complies with Sec. 101.2(c)(5) (see
e.g., Sec. 101.13(g)(1) and (i)(2)). One-sixteenth of an inch is
specified in Sec. 101.2(c) as the minimum type size for most other
mandatory information on the principal display panel or information
panel, e.g., designation of ingredients, name and place of business,
and quantitative information for relative claims. Consequently, the
agency tentatively concludes that the minimum type size for such
information should be one-sixteenth of an inch.
Accordingly, FDA is proposing to provide for the disclaimer, as
outlined above, in Sec. 111.100(f)(2). If FDA adopts
Sec. 111.100(f)(2), the labeling of a dietary supplement that contains
ephedrine alkaloids and that purports to be, or that is represented as,
useful for short-term effects, such as increased energy, increased
mental concentration, or enhanced well-being, would be misleading, and
thus misbranded, if it does not include the disclaimer set out in
Sec. 111.100(f)(1).
The agency recognizes that most of the claims that will require the
use of the disclaimer, if this proposal is adopted, will be statements
that are made subject to section 403(r)(6) of the act. That provision
also requires that a disclaimer accompany the statements. In the
Federal Register of December 28, 1995 (60 FR 67176), FDA proposed
requirements for the disclaimer that is required to accompany
statements made under section 403(r)(6) of the act. FDA requests
comments on how best to place the disclaimer proposed in this document
in conjunction with the disclaimer required under section 403(r)(6) of
the act on the label or in labeling of dietary supplements so that both
disclaimers will be read and understood by consumers.
c. Claims that suggest that the product is intended to be used as a
substitute for an illicit street drug. FDA is aware that some ephedrine
alkaloid-containing products are being promoted as alternatives or
substitutes for such illicit street drugs as MDMA (4-methyl-2,
dimethoxyamphetamine), a methamphetamine analogue. MDMA is also known
as ``ecstasy,'' ``XTC,'' and ``X.'' The precursor of MDMA is MDA (3,4
methylene dioxyamphetamine), an amphetamine whose use results in
destruction of serotonin-producing neurons that play a direct role in
regulating aggression, mood, sexual activity, and tolerance to pain
(Ref. 16). Many products claiming to be herbal alternatives to MDMA
bear claims on their label or in the labeling that highlight these
mood-or mind-altering effects.
Such street drug alternative claims do not fall within the scope of
the claims that Congress intended to permit on the labels or in the
labeling of dietary supplements. The Dietary Supplement Health and
Education Act of 1994 (the DSHEA) added section 201(ff) to the act (21
U.S.C. 321(ff)), which provides, in part, that the term dietary
supplement means a product ``intended to supplement the diet'' that
bears or contains one or more dietary ingredients. While Congress did
not elaborate in the legislative history on what it intended the phrase
``intended to supplement the diet'' to mean, many of the congressional
findings set forth in the DSHEA suggest that Congress intended dietary
supplements to augment the diet to promote health and reduce the risk
of disease.
In using the term ``diet'' in section 201(ff) of the act, Congress
did not define this term in either the act or the legislative history.
The term ``diet'' is defined in Webster's Dictionary as ``an organism's
usual food and drink'' (Ref. 200). Dorland's Medical Dictionary defines
``diet'' as ``the customary allowance of food and drink taken by any
person from day-to-day, particularly one especially planned to meet
specific requirements of the individual, and including or excluding
certain items of food'' (Ref. 201). These definitions suggest that the
diet is composed of usual food and drink that may be designed to meet
specific nutritional requirements. Under section 201(ff) of the act,
dietary supplements are food except for purposes of section 201(g) of
the act and thus may be part of, or augment, the diet. These common
sense definitions for the term ``diet'' do not encompass alternatives
to illicit street drugs.
Products promoted to be an alternative to or substitute for an
illicit street drug are intended to be used for recreational purposes
to effect psychological states (e.g., to ``get high'' or to promote
feelings of euphoria). Illicit street drugs are not food or drink and
thus, cannot supplement the diet. In addition, use of products claiming
to be alternatives to illicit street drugs does not promote health or
reduce the risk of disease, the intended use for dietary supplements
suggested in the
[[Page 30700]]
congressional findings listed in the DSHEA. In fact, serious adverse
events, including cardiac arrhythmia that resulted in death, are
associated with the use and abuse of products promoted for use as an
alternative to MDMA (see ARMS No. 10862 in Ref. 149a).
Because alternatives to illicit street drugs are not intended to be
used to supplement the diet, products that purport to be or that are
represented, either expressly or implicitly, for use as an alternative
to a street drug are not dietary supplements within the meaning of
section 201(ff) of the act. Therefore, manufacturers, packers, and
distributors cannot take advantage of the exemption for structure
function claims from the drug definition in section 403(r)(6) of the
act. Because these products are intended to be used to affect the
structure and function of the body, they are drugs within the meaning
of section 201(g)(1)(C) of the act.
7. Warning Label Statements
Several members of the Working Group and of the Food Advisory
Committee recommended that specific information be conveyed in a
warning or cautionary statement for ephedrine alkaloid-containing
dietary supplements (Refs. 25 and 27). Persons having certain diseases
or taking specific medications known to interact with ephedrine
alkaloids are at risk of suffering adverse events with the use of
dietary supplements containing ephedrine alkaloids. Generally, use of
ephedrine alkaloids at any intake level by these persons is
contraindicated (Refs. 10 through 12, and 55). For these persons, a
warning label statement can be a useful means of alerting them to
potential consequences that can result from the use of the product.
Table 5 identifies groups that are at risk if they use ephedrine
alkaloids. In addition, many consumers who are unaware that they are
sensitive to the effects of ephedrine alkaloids may not recognize the
significance of early warning signs and symptoms as potential
indicators of more serious side effects (e.g., dizziness or severe
headache may be early symptoms of hypertension or stroke). Under these
circumstances, a warning statement could provide information on what
actions the consumer should take if certain symptoms occur.
FDA has received several AER's, some clinically significant, that
were associated with the use of dietary supplements containing
ephedrine alkaloids at levels below the level proposed in
Sec. 111.100(a)(1) where signs and symptoms including high blood
pressure, chest pain, increased heart rate, severe headache, and nausea
were observed (Ref. 149a). Although these AER's are not sufficient to
support a lower per serving limit, they do provide cause for concern
for lower per serving levels. To reduce the potential for adverse
events to occur at these lower per serving levels, FDA tentatively
concludes that a warning statement on the labels of dietary supplements
containing ephedrine alkaloids is necessary, in conjunction with
dietary ingredient limitations and other requirements proposed in this
document, to protect the public health.
FDA is therefore proposing in Sec. 111.100(g) to require that a
specific warning statement appear on the labels of dietary supplements
containing ephedrine alkaloids. FDA's authority to require label
warning statements on dietary supplement products derives from sections
201(n), 403(a)(1), and 701(a) of the act. These statutory provisions
authorize FDA to issue a regulation designed to ensure that persons
using dietary supplements will receive information that is material
with respect to consequences that may result from the use of a product
under its labeled conditions.
a. Caution statement suggested by industry. Several dietary
supplement industry trade groups met with FDA on November 30, 1995, and
suggested that dietary supplements containing ephedrine alkaloids bear
a specific warning statement (Ref. 199). Representatives from the
National Nutritional Foods Association (NNFA), the American Herbal
Products Association (AHPA), the Nonprescription Drug Manufacturers
Association (NDMA), and the Utah Natural Products Alliance (UNPA)
(hereinafter referred to as the dietary supplement industry
2) recommended the following statement:
---------------------------------------------------------------------------
\2\ FDA is using this shorthand for convenience. It does not
intend to imply that these groups represent the entire dietary
supplement industry.
---------------------------------------------------------------------------
CAUTION: Taking more than the recommended amount will not
necessarily increase benefits. Begin use with one-half or less the
recommended dose to assess your tolerance. (If Pertinent) Please note:
This product contains caffeine and should not be taken by those wishing
to eliminate caffeine from their diet. Seek advice from a health care
practitioner if you are pregnant or nursing or if you are at risk or
are being treated for high blood pressure, heart, thyroid or
psychiatric disease, diabetes, depression, seizure disorder, stroke or
difficulty in urination due to prostate enlargement. Consult your
health care professional before use if you are taking an MAO inhibitor
or any other prescription drug. Discontinue use and consult your health
care professional if dizziness, nausea, sleeplessness, tremors,
nervousness, headache, heart palpitations or tingling sensations occur.
NOT INTENDED FOR SALE TO OR USE BY PERSONS UNDER THE AGE OF 18. KEEP
OUT OF REACH OF CHILDREN. DO NOT EXCEED RECOMMENDED DOSE.
FDA has carefully considered proposing adoption of the statement
suggested by industry. While the agency considers the industry
suggestion to be a good starting point, FDA tentatively concludes that
some changes are necessary in the statement if it is to fulfill its
purpose of fairly warning consumers about the special risks attendant
to use of dietary supplements that contain ephedrine alkaloids.
b. Tentative conclusions. The dietary supplement industry suggested
that the warning statement begin with the term ``caution.'' FDA,
however, questions whether this term is adequate to convey the severity
of the harm that can result from the use of the product. Because use of
ephedrine alkaloid-containing dietary supplements has the potential to
cause serious injury to certain subgroups of the population, the agency
tentatively concludes that the use of the term ``WARNING'' is
warranted. The term ``WARNING'' is commonly used to denote danger, and,
therefore, the use of this term will communicate to consumers the harm
that could result to the special populations that are the subject of
the warning.
The dietary supplement industry suggested that the statement
include the instruction ``Seek advice from a health care provider if
you are pregnant or nursing or if you are at risk or are being treated
for high blood pressure, heart or thyroid disease, diabetes, difficulty
in urination due to prostate enlargement.'' Several members of the
Working Group and of the Food Advisory Committee recommended that a
warning statement direct consumers who have certain diseases or
conditions that increase the risk of adverse events not to use the
product or to see a health care provider prior to using the product
(Refs. 25 and 27). The feeling of these members was that a health care
provider could assess the potential risks for the individual consumer
if he or she uses the product.
FDA concurs with this portion of the industry's labeling
recommendation. As discussed in section II.C. of this document, based
on the scientific literature and the known physiological and
pharmacologic effects of ephedrine alkaloids, an individual who is
pregnant or nursing, has high blood pressure, heart or thyroid disease,
or difficulty in
[[Page 30701]]
urination because of prostate enlargement has an increased risk for
experiencing serious adverse effects with the use of ephedrine
alkaloids. However, FDA also tentatively finds that the warning
statement should be broadened to address other individuals who may
place themselves at particular risk if they consume the product. The
relevant scientific literature, case reports and AER's suggest that
persons suffering from depression or other psychiatric conditions,
glaucoma, or seizure disorders are also at increased risk of
experiencing an adverse event if they consume ephedrine alkaloid-
containing products.
Use of ephedrine alkaloids during pregnancy or while nursing can
cause adverse effects in the fetus or the infant. Ephedrine alkaloids
can cross the placental wall and can be absorbed by the fetus when
taken by a pregnant woman (Refs. 10 through 12 and 55). Similarly,
ephedrine is excreted in the breast milk and can be consumed by the
nursing infant. The fetus, infants, and children are sensitive to the
effects of ephedrine alkaloids and thus are more likely to experience
adverse events (Refs. 39 and 41).
Use of ephedrine alkaloids by persons with high blood pressure can
result in blood pressure elevations or loss of adequate medical control
of hypertension (Ref. 64) which increases the risk of serious
consequences (e.g., stroke and heart attack) (Refs. 62 and 70). Because
ephedrine alkaloids also interfere with the regulation of serum
potassium levels (Refs. 53 through 55), individuals with heart disease
who use ephedrine alkaloids are at greater risk of 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).
With respect to thyroid disease, individuals with hyperthyroidism
(resulting from increased secretion of thyroid hormone) show increased
sensitivity to adrenergic agents, such as ephedrine alkaloids, which
can result in thyroid storm with dire consequences (e.g., cardiac
dysrhythmias, congestive heart failure, coma, and death) (Refs. 39, 41,
55, and 202).
For persons with diabetes, use of sympathomimetics can result in an
increase in blood sugar and loss of diabetic control (Refs. 29, 41, and
51). In addition, ephedrine can cause constriction of the urinary
bladder sphincter and ultimately lead to dysuria (increased, painful,
or difficulty in urination). This condition is not only associated with
prostate enlargement or only seen in men. Published case reports and
AER's received by the agency document the finding that urinary
retention following the use of ephedrine alkaloid-containing products
can occur in both females and males, including young boys without any
history of prostate enlargement (see ARMS No. 10298 and 11164 in Ref.
149a and Refs. 102, 103, 123, and 124).
Use of ephedrine alkaloids by persons suffering from depression or
other psychiatric conditions increases the risk for the occurrence of
serious adverse events, including psychosis and mania (Refs. 81 through
96, 98, 99, 109, and 220). Because ephedrine can cause an increase in
intraocular pressure (i.e., pressure inside the eyeball), use of
ephedrine alkaloids by persons with glaucoma will worsen this disease,
which over time, can result in blindness (Refs. 39 and 41). Finally,
persons with seizure disorders who use ephedrine alkaloids have an
increased risk for experiencing a seizure (Refs. 63, 65, and 80).
Because the nature of the risks associated with the use of ephedrine
alkaloids for persons who have the diseases and health-related
conditions listed above, it is important that these consumers be
advised to consult a health care provider before using ephedrine
alkaloid-containing dietary supplements.
With regard to the statement in industry's suggested statement ``if
you are at risk or are being treated for high blood pressure * * *,''
the agency considers it unlikely that consumers will be able to
adequately evaluate their risk for developing the conditions listed in
this statement. Most of these conditions are not self-diagnoseable. In
addition, individuals who have a disease or condition listed in this
statement, but who are not currently being treated, may believe that
they are not at risk of experiencing an adverse event. Consequently,
the agency tentatively concludes that the warning statement needs to
include an instruction to consult a health care provider before using
an ephedrine alkaloid-containing dietary supplement.
The dietary supplement industry statement only instructs the
consumer to consult his or her health care professional before use if
he or she is taking an MAOI or any other prescription drug. FDA
tentatively concludes that this statement should be broader because of
the need for professional help in assessing the risks of ephedrine
alkaloid intake with a range of conditions.
However, people using MAOI drugs should not use ephedrine alkaloid-
containing products at all. Several members of the Working Group and of
the Food Advisory Committee recommended that the warning statement
advise consumers not to use the dietary supplements containing
ephedrine alkaloids if they are taking these types of drugs (Refs. 25
and 27). Because the use of MAOI drugs in combination with ephedrine
alkaloids results in blood pressure elevations and increases the risk
of serious consequences (e.g., stroke and heart attack), FDA is
proposing to warn against use of ephedrine alkaloid-containing products
in this circumstance (Refs. 10 through 12, 39, 41, and 55). Because
persons remain at risk while the MAOI drug remains in the body, FDA
tentatively concludes that consumers need to be informed that it may
take up to 2 weeks for the MAOI drug to clear the body (Refs. 203 and
204).
Because MAOI drugs increase the effects of sympathomimetic agents,
and consequently will increase the frequency and severity of adverse
effects, persons taking such drugs should be given as much information
as possible. The agency is concerned that some patients may not be
fully informed about MAOI drugs, may not fully understand or remember
all the information given to them, or with the passage of time, may
forget or lose information that has been provided. Thus, the warning
statement needs to be as informative as possible.
Rather than include general language, such as ``any prescription
drug'' in the warning statement, FDA tentatively finds that it is
important to identify specific types of prescription and OTC drugs that
contain ingredients that in combination with ephedrine alkaloids are
known or expected to increase the likelihood, frequency, or severity of
adverse effects. Therefore, FDA tentatively concludes that consumers
need to be warned not to use ephedrine alkaloid-containing dietary
supplement in combination with specific drugs, such as drugs for
depression, psychiatric or emotional conditions (Refs. 10 through 12,
55, and 205); drugs for Parkinson's disease (Ref. 55); methyldopa (Ref.
206); or any product containing ephedrine, pseudoephedrine, or
phenylpropanolamine (ingredients often found in allergy, asthma, cough/
cold and weight control products) (Refs. 180 and 207 through 209).
FDA tentatively finds that the drug methyldopa needs to be
identified on the label. It increases the pressor results of
sympathomimetic agents, such as ephedrine alkaloids, resulting in
hypertension (Ref. 206). FDA has
[[Page 30702]]
reached a similar tentative judgment with respect to ephedrine,
pseudoephedrine, and phenylpropanolamine because each of these
substances, in combination with an ephedrine alkaloid-containing
dietary supplement, could lead to an additive effect and consequently
increase the risk of serious adverse events. While many consumers may
not be familiar with the term ``ephedrine,'' ``pseudoephedrine,'' or
``phenylpropanolamine,'' they may be aware of the type of product being
taken for a specific condition or ailment, e.g., allergy, asthma,
cough/cold, and weight control products.
The agency recognizes that because of the large number of drugs for
depression, psychiatric or emotional conditions, and Parkinson's
disease that are contraindicated for use with ephedrine alkaloids and
the limited amount of space on the labels of dietary supplements, not
all of them can be listed on the label. However, the conditions for
which the consumer is taking the drug can be identified, using less
label space. If consumers are unsure whether their drug may interact
with the ephedrine alkaloids, they should be cautioned to check with
their health care professional before using the dietary supplement.
The dietary supplement industry suggested that the statement
include the instruction ``Discontinue use and consult your health care
professional if dizziness, nausea, sleeplessness, tremors, nervousness,
headache, heart palpitations or tingling sensations occur.'' Several
members of the Working Group and of the Food Advisory Committee also
recommended that any warning statement include information on what
actions the consumer should take if certain symptoms occur (Refs. 25
and 27).
Signs and symptoms, such as dizziness, severe headache, rapid or
irregular heart beat, chest pain, shortness of breath, nausea,
sleeplessness, noticeable changes in behavior, or loss of consciousness
are often early warning signs of serious illness or injury, including
heart attack, stroke, or seizure. It is important that the consumer
stop using the product if these signs or symptoms occur because
continued use of the product may aggravate the adverse effects. The
agency tentatively finds that the terms ``stop'' and ``call'' should be
used for ``discontinue'' and ``consult,'' respectively, because they
are more simple and direct terms.
The proposed warning statement instructs the consumer to call a
health care professional if any of the listed symptoms occur. A health
care professional will be able to evaluate the significance of the
signs and symptoms, determine the risks of more serious adverse events
occurring, and prescribe any treatment that may be necessary. The
effects, such as tremor, sleeplessness, and tingling sensations, that
are included in the instruction suggested by the industry are not
usually clinically serious and will likely cease once the product use
is discontinued (Refs. 210). For these reasons, FDA tentatively
concludes that the statement needs to include the instruction to ``Stop
use and call a health care professional immediately if dizziness,
severe headache, rapid or irregular heart beat, chest pain, shortness
of breath, nausea, noticeable changes in behavior, or loss of
consciousness occur.''
The dietary supplement industry suggested that the statement
include a direction for the consumer not to exceed the recommended
dose. Members of the Working Group and of the Food Advisory Committee
recommended that the warning statement include a direction for the
consumer not to exceed the recommended serving or dose (Refs. 25 and
27).
The agency concurs with the industry's suggestion. FDA tentatively
finds that this type of statement is necessary to provide information
instructing the user not to consume the product excessively. Excessive
consumption of ephedrine alkaloids is associated with adverse events,
including heart attack, stroke, seizure, and death. Therefore, the
statement is a material fact about the consequences of use of the
product. However, FDA has used the term ``serving'' rather than
``dose,'' because the agency considers the term ``serving'' to be more
appropriate for use on a food label.
The dietary supplement industry suggested that the statement
include the instruction that ``Taking more than the recommended amount
will not necessarily increase benefits.'' Similarly, the Working Group
suggested that the warning statement contain the instruction that
``Larger quantities may not be more effective.'' The agency is not
aware of any data or other information that establishes that there are
benefits from the use of dietary supplements containing ephedrine
alkaloids. Therefore, the agency would be concerned about requiring a
statement on the label that implies a judgment (that the product has
benefits) that the agency has not made. While some questions can be
raised in this regard under section 403(r)(6) of the act, the agency
considers them to be moot because the instruction for the consumer not
to exceed the recommended serving eliminates the need for the ``Taking
more than recommended * * *'' statement.
The dietary supplement industry suggested that the statement advise
the consumer to: ``Begin use with one-half or less the recommended dose
to assess your tolerance.'' The agency addressed limiting the levels of
ephedrine alkaloids contained in dietary supplements in proposed
Sec. 111.100 (a)(1) and (b). In addition, because of label space
constraints, the agency is trying to keep the warning statement as
short as possible. Therefore, FDA tentatively concludes that there is
no reason to require inclusion of this information.
The dietary supplement industry recommended the following in a
caution statement, if appropriate for the product: ``This product
contains caffeine and should not be taken by those wishing to eliminate
caffeine from their diet.'' The Food Advisory Committee also suggested
that other stimulants with their source, such as caffeine from Kola
nut, be identified on the label of a dietary supplement containing
ephedrine alkaloids. However, the agency is proposing to prohibit
stimulant substances in combination with ephedrine alkaloids in dietary
supplements. Therefore, FDA tentatively concludes that there is no
reason to require the inclusion of such a statement.
The dietary supplement industry recommended that the direction
``Not for use by persons under the age of 18'' be included in the
warning statement. Several members of the Working Group and of the Food
Advisory Committee suggested that the warning statement include a
direction that the product is not intended for use by persons under the
age of 18. The agency has received limited reports of adolescents
abusing or misusing ephedrine alkaloid-containing dietary supplements.
Moreover, the agency has stated elsewhere in this document that claims
implying usefulness of these products as alternatives to illicit street
drugs render the product an unauthorized drug. FDA considers that
removal of alternative street drug claims from the labeling of dietary
supplements will significantly reduce or eliminate the appeal of these
products to adolescents and therefore is not proposing to require that
this direction be included in the warning. However, the agency requests
comments on whether the direction ``not for persons under the age of
18'' should be included.
[[Page 30703]]
The industry group's statement included the instruction ``Keep out
of reach of children.'' Children show increased sensitivity to the
effects of sympathomimetic agents compared to adults (Refs. 39 and 41)
and are, therefore, at increased risk for experiencing adverse events
from the use of ephedrine alkaloids. The agency has limited data and
information that dietary supplements containing ephedrine alkaloids are
being given to, or are associated with accidental overdosage by,
children. FDA requests comment, particularly data, on whether this
statement is necessary to alert consumers to the fact that ephedrine
alkaloid-containing dietary supplements should not be made available to
children.
c. The agency's proposal. Based on FDA's authority under sections
201(n), 403(a)(1), and 701(a) of the act, the agency proposes to
require manufacturers to include the warning statement set out in
Sec. 111.100(g)(1) in the labeling of their ephedrine alkaloid-
containing products. The agency tentatively finds that the warning
statement is necessary to disclose material facts about the
consequences of using the product, and that it will help to reduce the
risk that some individuals will experience an adverse event from using
this type of product.
The agency solicits comments on all aspects of the warning
statement, including data to support any specific instruction. The
agency also solicits comments on approaches to shorten or simplify the
warning statement. Because substances contained in ingredients (e.g.,
ephedrine alkaloids contained in Ephedra) are not required to be listed
in the ingredient list on the label of dietary supplements, the agency
is concerned that consumers and health care providers may not be aware
that ephedrine alkaloids are contained in the product and thus may not
necessarily recognize the seriousness of the symptoms listed in the
statement, when they occur. FDA requests comments on whether the
warning statement should disclose that ephedrine alkaloids are
contained in the product. In addition, the agency is concerned that
some 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. FDA
requests comments on whether the warning statement should disclose the
possibility of increasing the risk of adverse events by a pattern of
stopping and starting use. Based on the comments received by FDA, the
warning statement proposed below may need to be modified.
In an effort to promote uniformity in labeling, FDA is proposing to
require that the warning statement appear on the labels of ephedrine
alkaloid-containing dietary supplements in the exact manner presented
in proposed Sec. 111.100(g)(1), except when the disclaimer proposed in
Sec. 111.100(f) appears on the same label panel as the warning
statement, in which case the instruction ``Do not exceed recommended
serving'' would not have to appear in the warning statement. However,
the agency recognizes that other ingredients that may be used in
ephedrine alkaloid-containing dietary supplements may have consequences
of use that need to be disclosed on the label. The agency requests
comments on how to allow for warning statements for other ingredients
in conjunction with the ephedrine alkaloid warning statement on the
label of dietary supplements. In addition, the agency solicits comments
on the format of the warning statement to improve its clarity (e.g.,
should the statement be set out in bullets).
d. Placement of warning statement on label. The agency intends to
provide an approach to the placement of the warning label statement to
give manufacturers flexibility to design their own label warning
formats, while ensuring that consumers are given adequate notice of the
information contained in the warning.
Section 403(f) of the act requires that information appearing on
the label or labeling be prominently placed and appear with such
conspicuousness (as compared with other words, statements, designs, or
devices, in the labeling) as to render it likely to be read by the
ordinary individual under customary conditions of use. In the agency's
rulemaking that mandated warning statements on certain protein
products, the agency decided not to mandate specific requirements for
type size and other format elements. However, the agency did require
that the warning statement appear ``prominently and conspicuously on
the principal display panel of the package label'' (Sec. 101.17). In
addressing the placement of the label warning, the agency noted that
the seriousness and nature of the risks associated with the use of
protein products in very low calorie diets was sufficient to require
placement of the warning statement on the principal display panel
(Sec. 101.17).
FDA tentatively concludes that the warning statement that it is
proposing must appear prominently and conspicuously on the label of
dietary supplements containing ephedrine alkaloids so that consumers
are given adequate notice of the information contained in the warning.
While the risks associated with the use of dietary supplements
containing ephedrine alkaloids are serious, the agency is not proposing
to require that the warning label statement for dietary supplements
containing ephedrine alkaloids appear on the principal display panel.
The agency recognizes that, because of the length of the required
warning statement, in many cases it may be impracticable for the
warning statement to appear on the principal display panel without
interfering with the placement of other information that is required to
appear on that panel.
The requirement in the act for prominent display means that the
warning statement must be presented on the label or labeling in a
manner that renders it as readily observable and likely to be read. In
this regard, the agency's experience with the graphic requirements for
the new nutrition label has been that a box around required label
information greatly increases the prominence of the information placed
inside the box. Moreover, focus group discussions regarding warning
labels show that messages put in a boxed area help consumers to
distinguish the message from other information as well as draw
attention to it (Ref. 210a). Therefore, FDA is proposing to require in
Sec. 111.100(g)(3) that the warning statement for ephedrine alkaloid-
containing dietary supplements be separated from other information by a
box. If FDA adopts these regulations, manufacturers will have the
flexibility to design their own label and warning label format subject
to Sec. 111.100(g)(3).
Section 201(k) of the act defines the term ``label'' as ``a display
of written, printed, or graphic matter upon the immediate container of
any article'' and further states a requirement that ``any word,
statement, or other information appear on the label shall not be
considered to be complied with unless such word, statement, or other
information also appears on the outside container or wrapper, if any
there be, of the retail package of such article * * *.'' Thus, if FDA
adopts its proposal to require that a warning statement appear on the
label of ephedrine alkaloid-containing dietary supplements, the warning
statement would also have to appear on the retail package of such a
product, if that package is not the immediate container.
FDA requests comments on these proposed requirements for placement
of the warning statement.
[[Page 30704]]
In addition to this proposed regulation, the agency has issued
proposed and final rules on dietary supplements, including premarket
notification procedures for new dietary ingredients (61 FR 50774,
September 27, 1996) and label warning statements and unit dose
packaging requirements for iron containing dietary supplements (62 FR
2218, January 15, 1997). The agency has proposed to codify each of the
proposed and final regulations in different parts of the Code of
Federal Regulations. The agency believes that it would be easier for
consumers as well as for the dietary supplement industry to find and
use regulations for dietary supplements if they were consolidated into
one part of the CFR. Accordingly, FDA is proposing to revise part 111
to consolidate the regulations for dietary supplements. FDA is
proposing to change the title of part 111 from ``Current Good
Manufacturing Practice for Dietary Supplements'' to ``Dietary
Supplements.'' This is necessary to reflect that other regulations for
dietary supplements in addition to regulations for current good
manufacturing practice will be contained in this part. FDA is proposing
to establish four subparts in part 111: Subpart A--General Provisions,
Subpart B--Current Good Manufacturing Practice for Dietary Supplements,
Subpart C--New Dietary Ingredients, and Subpart D--Restricted Dietary
Ingredients. The labeling provisions for dietary supplements will
continue to be placed in 21 CFR part 101.
D. Other Approaches Considered by the Agency
In choosing the proposed approach to limit the risks presented by
ephedrine alkaloids in dietary supplements, the agency considered, but
rejected, several other approaches. Because the act does not allow
premarket review authority for dietary supplements, FDA has no data and
information to establish conditions of use that will ensure the safe
use of ephedrine alkaloid-containing dietary supplements. Therefore,
the only viable approach available to FDA is one in which the agency
prohibits levels of a substance in, or conditions of use for, a dietary
supplement that it can prove may render the product injurious to health
or that present a significant or unreasonable risk of illness and
injury under the conditions of use suggested or recommended in the
labeling or under ordinary conditions of use.
The agency is unaware of any classical toxicological studies whose
results identify ``no adverse effect levels'' for ephedrine alkaloids
directly applicable to humans, or whose results establish intake-
response curves for ephedrine alkaloids in dietary supplements and that
could be used to establish a level of ephedrine alkaloids that are safe
for consumers to use in dietary supplements. The intake-response
relationships between ephedrine alkaloids and their effects in humans
are unknown for both botanical sources and marketed dietary supplement
products containing ephedrine alkaloids. Moreover, because there are
consumers who may be sensitive to the effects of ephedrine alkaloids
because of a variety of factors that are not readily identifiable or
predictable, a margin of safety based on classical toxicological
principles likely cannot be determined. For these reasons, the agency
tentatively finds that the use of a classical toxicological approach to
determine a safe level of ephedrine alkaloids in dietary supplements is
not a usable approach.
Several members of the Food Advisory Committee recommended that FDA
consider the risk associated with the use of dietary supplements
containing ephedrine alkaloids in the context of any benefit that the
consumer may receive from the use of these products (Ref. 25). In
applying a risk-to-benefit calculation, a certain amount of risk may be
accepted if there is a meaningful benefit to be gained by the consumer
(Ref. 25). However, the Food Advisory Committee members were unable to
identify a benefit for ephedrine alkaloids in terms of supplementing
the diet (Ref. 25). Moreover, risk-benefit analysis is something that
is done under the act for drugs, not food.
Several members of the Working Group suggested that any limitations
on the level of ephedrine alkaloids in dietary supplements be based on
the use of pharmaceutical ephedrine in OTC oral bronchodilator drugs
and the use of Ephedra in traditional herbal medicine (Ref. 27). Other
members of the Working Group and several members of the Food Advisory
Committee found difficulty in extrapolating from OTC drug data because
the products, the populations using the products, and intended use of
the products are dissimilar (Ref. 25). In addition, the latter members
were concerned about the potential for adverse events to occur,
particularly in populations sensitive to the effects of ephedrine
alkaloids, if therapeutic levels of ephedrine are used in dietary
supplements (Ref. 25). Several members of the Food Advisory Committee
were also concerned about using data from the use of Ephedra in
traditional herbal therapies to support the safety of the use of
ephedrine alkaloids in dietary supplements because the therapeutic use
of ephedrine alkaloids has traditionally not involved the same
conditions, the same populations, or the same purposes as those under
which dietary supplements are used (Ref. 25).
The agency considered the applicability of OTC drug data and
tentatively concluded that these data, which involve use in a
restricted population (physician-diagnosed mild asthmatics) under
limited directions for use (i.e., not to exceed 12.5 to 25 mg every 4
hours, not to exceed 150 mg in 24 hours) and with warnings and
contraindications for use, has no application here. The determination
of safety for drugs is based on a weighing of the proven benefits of
the use of the product against the risks. This approach may not be used
with foods under section 402(a) of the act. The only question for food
use under this section is whether it will cause harm or not. While the
concept of ``unreasonable risk'' as stated in section 402(f)(1)(A) of
the act, may imply that some evaluation of effects, including risks and
benefits, is appropriate for dietary supplements, it is not necessary
to reach that question here, because, as stated above, there are no
demonstrated benefits for ephedrine alkaloids. Moreover, the risks
attendant on consuming dietary supplements containing levels of
ephedrine permitted in oral bronchodilator drugs (12.5 to 25 mg
ephedrine per dose) are manifest.
In addition, there is no basis for extrapolating from data from a
subgroup of the population, diagnosed asthmatics, who may be less
sensitive to the effects of ephedrine (Ref. 25) than the general
population, to the general population, among which a significant number
of people are known or suspected of being very sensitive to ephedrine.
Finally, the agency finds it inappropriate to extrapolate data from
the use of OTC ephedrine-containing drugs because dietary supplements
contain a mixture of several ephedrine alkaloids and a variety of other
ingredients, including vitamins, minerals, other botanicals, and other
physiological and pharmacologically active substances, while OTC drugs
contain only a single ephedrine alkaloid. The presence of other
alkaloids and substances in dietary supplements may act to increase the
likelihood, frequency, and severity of adverse events from the use of
these products. In fact, clinical studies show that adverse events are
more likely to occur when ephedrine is combined with other substances,
such as caffeine. Therefore, the fact that pharmaceutical ephedrine
[[Page 30705]]
has been approved by FDA for an OTC use does not provide assurance of
safety for the use of ephedrine alkaloids in dietary supplements.
The agency considered the applicability of traditional use of
botanical sources of ephedrine alkaloids in establishing dietary
ingredient levels for ephedrine alkaloids in dietary supplements. A
history of long usage of a medicinal herb in traditional therapies does
not provide an assurance of safety for a component of a dietary
supplement because these conditions of use are so different. The
history of use of Ephedra in traditional Asian medicine primarily for
the treatment or relief of respiratory symptoms provides insufficient
assurance that ephedrine alkaloids will not present a significant or an
unreasonable risk of injury to consumers who use dietary supplement
products containing ephedrine alkaloids to supplement the diet. Not
only are dietary supplements marketed for different uses than the
traditional use of Ephedra, most dietary supplements are marketed in a
form that is different than the form in which it has been traditionally
used, e.g., as a concentrated extract in capsules and tablets, in the
presence of other substances rather than the raw botanical in a tea.
FDA is not aware of any systematic collection of data related to
adverse effects occurring in individuals treated with Ephedra in
traditional medicine. However, several reference texts list precautions
and contraindications for the use of the botanical Ephedra in
traditional medicine preparations (Refs. 6, 14, and 146). Thus, FDA
tentatively concludes that use of ephedrine alkaloids in traditional
Asian medicine does not provide the basis on which to establish a safe
level of use of ephedrine alkaloids in dietary supplements.
IV. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select the regulatory approach that maximizes net benefits
(including potential economic, environmental, public health and safety,
and other advantages; distributive impacts; and equity). Executive
Order 12866 classifies a rule as significant if it meets any one of a
number of specified conditions, including having an annual effect on
the economy of $100 million or adversely affecting in a material way a
sector of the economy, competition, or jobs, or if it raises novel
legal or policy issues. If a rule has a significant economic impact on
a substantial number of small entities, the Regulatory Flexibility Act
requires agencies to analyze regulatory options that would minimize the
economic impact of that rule on small entities.
FDA finds that this proposed rule is an economically significant
rule as defined by Executive Order 12866, and finds under the
Regulatory Flexibility Act that this proposed rule will have a
significant impact on a substantial number of small entities. Finally,
FDA, in conjunction with the Administrator of the Office of Information
and Regulatory Affairs (OIRA) of the Office of Management and Budget
(OMB), finds that this proposed rule is a major rule for the purposes
of congressional review (Pub. L. 104-121).
A. Market Failure
The market failure addressed by this regulation is that some
consumers may not have sufficient information on the health risks
associated with dietary supplements containing ephedrine alkaloids to
make informed choices concerning the consumption of these products,
despite the presence of warning labels of various types on many of
these products. Ordinarily, consumers would be expected to seek out and
pay for the level of information they consider appropriate with respect
to consumption decisions. However, the level of information currently
utilized by consumers with respect to these products may be less than
optimal because of consumer perceptions that products marketed as foods
or derived from botanical sources are inherently safe, and the cost of
generating evidence to evaluate the safety of these products may be
quite high. In addition, the onset of the adverse health events
associated with these products is frequently quite unexpected or occurs
without identifiable risk factors, and consumers may have little or no
opportunity to adapt their behavior based on experience with the risks
of these products prior to suffering a severe adverse event.
B. Regulatory Options
FDA has the following primary options:
1. Take no action.
2. Take no regulatory action, but generate additional information
on which to base a future regulatory action.
3. Take proposed action.
4. Take proposed action, but with a higher potency limit.
5. Ban dietary supplements that contain ephedrine alkaloids.
6. Take proposed action, but do not require warning statement.
7. Require warning statements only.
C. Benefits and Costs
1. Option 1--Take No Action
By convention, the option of taking no action is the baseline in
comparison with which the costs and benefits of the other options are
determined. Therefore, neither additional costs nor benefits are
associated with taking no action. Although no regulatory costs or
benefits are generated if no regulatory action is taken, preventable
adverse events will continue to occur if no regulatory action is taken.
The number of such adverse events is expected to increase over time
because the marketplace for these types of products has been increasing
rapidly since the 1994 passage of the DSHEA, and the number of AER's
associated with use of these products has also been increasing sharply
over the last few years (Figure 1).
2. Option 2--Take No Regulatory Action, but Generate Additional
Information on Which To Base a Future Regulatory Action
FDA has the option of taking no regulatory action but generating
additional information on which to base future regulatory action on
this issue. The benefit of generating additional information is a
reduction in the substantial uncertainty concerning the specific nature
of the relationship of the adverse events associated with dietary
supplements containing ephedrine alkaloids and, possibly, a more
precisely targeted regulation. A more precisely targeted regulation
could imply potency limits either higher or lower than the proposed
potency limits, and either more or fewer ingredient and labeling
restrictions than those proposed. The cost of generating additional
information is the cost of whatever activity is undertaken to generate
the additional information and the health cost of any adverse events to
these products that would occur if regulatory action were delayed but
that would not occur if regulatory action were not delayed.
3. Option 3--Take Proposed Action
a. Benefits. The benefit of the proposed action is a potential
reduction in the number or severity of adverse events associated with
dietary supplements containing ephedrine alkaloids. The proposed rule
consists of the following four actions: (1) Per day and per serving
potency limits on total ephedrine alkaloids (TEA), (2) restrictions on
caffeine and other
[[Page 30706]]
stimulants, (3) mandatory warning statement, and (4) labeling
restrictions.
To estimate the benefits of these actions, a percentage decrease in
the current number of adverse events associated with dietary
supplements containing ephedrine alkaloids will be estimated for each
regulatory action listed above. The estimated effects of all proposed
actions will then be combined to obtain a total reduction in the
expected annual number of adverse events. This percentage reduction
will then be applied to an estimate of the current number of such
adverse events to obtain an estimated number of adverse events avoided
per year. The estimate of the current number of adverse events will be
based on, but not identical to, the current number of relevant AER's
because of uncertainty over a number of issues including, for example,
the degree to which the relevant adverse events are reported. These
sources of uncertainty will be discussed in greater detail later.
Each of the proposed actions may affect the number of adverse
events by reducing the number of people who consume the relevant
products or by modifying their use of these products in a manner that
reduces the risk of an adverse effect. In addition, the potency limits
and ingredient restrictions may affect the number of adverse events by
reducing the probability that those who consume these products will
suffer an adverse event. Each of these effects will be considered in
turn, beginning with the effect of the proposed actions on the number
of people who consume these products.
The proposed potency limits and other ingredient restrictions may
affect the number of people consuming these products because they may
affect the value placed by consumers on the use of these products. Some
information on the likely effect of the proposed potency limits on the
consumption of these products comes from a report from one firm that
marketed an ephedrine alkaloid-free substitute for a supplement that
previously contained ephedrine alkaloids. The sales of the substitute
product were reportedly approximately 33 percent lower than the sales
of the ephedrine alkaloid-containing product (Ref. 211). In the absence
of more specific information, it is reasonable to suppose that a given
reduction in sales is associated with a proportionate reduction in the
number of people consuming these products.
It would not be reasonable to suppose the proposed potency limits
and other ingredient restrictions would have a greater effect on the
sales of these products than complete elimination of all ephedrine
alkaloids from these products. First, the functional effect, as
perceived by consumers, of removing all ephedrine alkaloids from a
product is probably greater than the perceived functional effect of
removing some of the ephedrine alkaloids and removing some ingredients
that interact with those ephedrine alkaloids. Second, if only some
firms remove ephedrine alkaloids from their products, relatively close
substitutes will exist for the prior formulations of those products
because other firms might not remove ephedrine alkaloids from their
products. However, if all firms make the same changes in their
products, then relatively close substitutes will not exist for the
prior formulations of those products. Therefore, the proposed potency
limits and other ingredient restrictions are estimated to reduce the
number of people consuming these products by between 0 to 33 percent.
The effect of the potency limits on the probability of an adverse event
for those who continue to consume these products will be addressed
later in this section.
The proposed warning statement is also likely to reduce the number
of people consuming these products because a few of the relevant
products do not currently have warning statements, and because, in some
cases, the proposed warning statement is more comprehensive, more
focused, and more strongly worded than existing warning statements. The
only information available on the effect of warning statements on sales
concerns diet soft drinks containing saccharin. Following the
introduction of warning statements relating to saccharin, annual sales
of diet soft drinks containing saccharin were reported to be 15 percent
below what they would otherwise have been (Ref. 212). The effect of the
proposed warning statement for dietary supplements containing ephedrine
alkaloids will probably be smaller than the effect of the saccharin
warning label on diet soft drinks because most such supplements already
have some type of warning statement. Therefore, the proposed warning
statement will probably reduce the number of people consuming these
products by 0 to 15 percent.
The proposed label claim restrictions are also likely to reduce the
number of people consuming these products by making the marketing of
these products more difficult. The only information available on the
potential effects of label claims on sales concerns ready-to-eat
breakfast cereals. Following an advertising campaign relating bran
consumption to a reduced risk of developing cancer, sales of high bran
breakfast cereals were reported to have increased approximately 40
percent (Ref. 213). The effect of eliminating label claims on dietary
supplements containing ephedrine alkaloids will probably be smaller
because the claims involved are more general, and because other sources
of information on the purported effects of ephedrine alkaloids are
readily available or have been used recently enough that consumers are
familiar with them.
However, approximately 10 percent of the AER's involved supplements
labeled as alternatives to street drugs. Assuming that consumers of
these products will not purchase these products if they are not labeled
as alternatives to street drugs, the labeling restriction will reduce
expected adverse events by at least 10 percent. Therefore, the proposed
restriction on label claims will probably reduce the number of people
consuming these products by between 10 percent and 40 percent.
In addition to these consumption effects, the proposed potency
limits and ingredient restrictions will probably also decrease the
likelihood that those who continue to consume these products will
suffer an adverse event.
FDA is not aware of clinical information, particularly evidence
from well-designed and conducted human studies on the relationship
between intakes of ephedrine alkaloids from botanicals and the
probability of an adverse event. One method of approaching the
estimation of the health benefits of reduced exposure to ephedrine
alkaloids is to consider the proportion of adverse event reports that
involve products with TEA levels greater than that allowed under the
proposed potency limits. FDA was able to obtain information on the
actual exposures associated with adverse events for 13 products that
provided intakes of less than 20 mg TEA per reported use by multiplying
the consumer's reported use level against an FDA product analysis
result. These reports provided information on the lower end of the
range of estimated intakes by consumers. Among these 13 reports of
adverse events associated with intakes of less than 20 mg, 9 involved
consumer intakes of between 8 mg and 20 mg/per serving. This approach
suggests that the proposed potency limit might reduce the expected
number of adverse events by at least 80 percent, although the actual
reduction is probably higher because the 13 reports did not include the
many adverse event reports that occurred at intakes above 20 mg TEA per
serving. On the other hand, the actual reduction might also be lower
because the 13 reports did not include
[[Page 30707]]
all adverse event reports that occurred at intakes below 20 mg TEA per
serving.
This approach to estimating the impact of the proposed potency
limits assumes that the probability of an adverse event is related to
intakes of TEA. If the probability of an adverse event is not related
to TEA intake, then the potency limits may result in little or no
reduction in the expected number of adverse event reports. For example,
if individual sensitivities to ephedrine alkaloids are the major
underlying factor in the reported adverse events, then it is possible
that there may be no ``safe'' intake for these persons. Based on this
information, all that can be said concerning the proposed potency
limits is that they may reduce the expected number of adverse events by
between 0 to 80 percent.
The restriction on other stimulants, including caffeine, should
also reduce the probability of an adverse event. Combinations of
ephedrine alkaloids and caffeine, at sufficiently high doses, are
associated with an increased probability of an adverse event. For
example, one study found that 60 percent of the study subjects had an
adverse reaction to a combination of 20 mg ephedrine and 200 mg
caffeine, while only 44 percent had an adverse reaction to 20 mg
ephedrine alone (Ref. 105). Thus, in this study, the presence of 200 mg
caffeine appears to have increased the probability of an adverse event
from consumption of 20 mg ephedrine by about 50 percent. Comparable
information is not available on the effect of combinations of ephedrine
and caffeine at lower levels of either ephedrine or caffeine.
Similarly, no information is available on the effect of other
stimulants or other ephedrine alkaloids.
An informal review of 217 adverse event reports featuring dietary
supplements suspected of containing ephedrine alkaloids found that 99
reports featured products for which labeled ingredient information was
available. Of those reports, 70 percent involved products labeled as
containing a source of caffeine. The levels of caffeine and ephedrine
alkaloids in these products is not known. Assuming that these adverse
event reports are typical of all relevant adverse event reports and
that 50 percent of the reported adverse events to products labeled as
containing caffeine may have been due to the presence of caffeine in
conjunction with ephedrine alkaloids, the restriction on stimulants is
estimated to reduce the expected number of adverse events by up to 35
percent. However, the impact of the proposed stimulant restrictions may
be somewhat lower because the impact may depend on the levels of
stimulants and ephedrine alkaloids involved, and the levels of
stimulants and ephedrine alkaloids found in dietary supplements may be
lower than the levels used in the study on which this estimate is
based. In order to address this possibility, the restrictions on
stimulants will be assumed to reduce the expected number of adverse
reactions by 25 percent.
In order to use the estimated risk reductions discussed above to
derive an expected reduction in the number of adverse events, the
current number of adverse events must be estimated. There are a number
of issues involved in estimating the current number of adverse events
based on the number of reported adverse events.
The first issue is that the data base of over 600 AER's includes
all reports thought to be related to the consumption of ephedrine
alkaloid-containing dietary supplements, even though the nature of the
available evidence did not allow specific cause and effect
determinations for the majority of individual reports. FDA, therefore,
used additional information to provide assurance that the patterns of
signs and symptoms associated with the ephedrine alkaloid-containing
dietary supplements were likely due to the presence of ephedrine
alkaloids in these products. One approach to addressing this issue is
to examine the evidence for positive dechallenge and rechallenge when
product use is discontinued and reinitiated, respectively. The
relationship of the reported adverse events to the consumption of
dietary supplements categorized as containing ephedrine alkaloids has
been corroborated by dechallenge in about 27 percent of the AER's.
Positive rechallenge was reported in about 4 percent of the AER's. The
majority of AER's, however, lacked sufficient information to evaluate
the presence or absence of dechallenge or rechallenge effects.
Therefore, the number of cases in which dechallenge alone or in
combination with rechallenge was tried but did not occur is not
available; nor is there information on whether dechallenge and
rechallenge would have occurred in the large number of reports which
lack such information. It is possible that all cases might have been
associated with positive dechallenge and rechallenge results if such
information were available. On the other hand, a certain number of
false reports might also be expected. The proportion of reported
adverse events actually related to the consumption of dietary
supplements suspected of containing ephedrine alkaloids is probably
between 27 and 90 percent. Within this range, FDA believes the most
likely value is around 80 percent and, therefore, tentatively assumes
that 80 percent of the reported adverse events are actually related to
the consumption of dietary supplements. FDA requests comments on this
assumption.
The second issue is the uncertainty that all 600 AER's involved
products that actually contained ephedrine alkaloids. Confirmation of
the presence of ephedrine alkaloids in problem products is not
available in all cases. The likelihood of the presence of ephedrine
alkaloids is based on the labeling of the products involved, FDA's own
market survey (including laboratory analysis of 125 marketed products),
and the similarity of the reported adverse events to the known effects
of ephedrine alkaloids. The proportion of reported adverse events
associated with dietary supplements that involve supplements containing
ephedrine alkaloids is probably between 25 and 90 percent. Within this
range, FDA believes the most likely value is around 80 percent and,
therefore, tentatively assumes that 80 percent of the reported adverse
events associated with consumption of dietary supplements involve
supplements that contain ephedrine. FDA requests comments on this
assumption.
The third issue is that the actual number of adverse events is
likely to differ from the reported number of adverse events because all
adverse events are probably not reported. This issue is particularly
important with respect to passive reporting systems that rely on the
voluntary submission of data, such as the system used to gather the
AER's relevant to this issue.
Typical reporting rates for passive reporting systems addressed to
adverse events associated with drugs are generally assumed to be on the
order of 10 percent. Reporting rates are higher than usual if the
potential health risks associated with a particular substance are
widely publicized, if the adverse events are considered to be otherwise
unusual, and if reports are gathered from a variety of sources. On the
other hand, reporting rates would be lower than usual if consumers and
physicians assume that dietary supplements are incapable of producing
adverse events because they are not drugs or because they are
``natural.'' In order to incorporate this uncertainty, the reporting
rate for the relevant adverse events is assumed to be 10 percent.
Based on the current number of reported adverse events and the
assumptions discussed above
[[Page 30708]]
concerning the relationship between the number of reported adverse
events and the underlying number of adverse events, the expected annual
number of adverse events involving these products is approximately
1,100 cases. Applying the risk reductions discussed previously for the
proposed actions implies a reduction in the health risks from these
products such that the expected number of adverse events involving
these products will be reduced by between approximately 400 cases and
1,100 cases per year. Based on published estimates of the value
consumers might place on reducing the risk of the general types of
adverse events involved, these benefits are valued at between $240
million and $670 million per year (Ref. 215).
Table 6 summarizes these results. The first column is the type of
adverse event. ``Serious CVS'' refers to serious cardiovascular system
events, including myocardial infarctions, dysrhythmias, strokes, and
cardiomyopathies. ``Serious NS'' refers to serious nervous system
events, including seizures, loss of consciousness, vestibular events,
and psychiatric events. ``Less clinically significant'' events may
include certain types of dermatological events and gastrointestinal
events. The second column is the average annual number of AER's from
January 1993 to June 1996. Because the sales of these products is
increasing rapidly, and the reports of adverse events are also
increasing rapidly (see Figure 1), FDA believes that this is a
conservative estimate of benefits. The 3-year average has been used
rather than the growth trend because extrapolating short-term growth
trends into the future can result in large errors. The third column is
the estimated average annual number of adverse events over this time
period based on what FDA believes are the most likely values for the
relevant assumptions. The fourth column is the estimated reduction in
adverse events from all proposed actions, given as a range from low to
high. These estimated reductions are based on adding the effects of the
proposed actions as summarized in Table 7. The low end of this range
represents a 35 percent reduction in the estimated annual adverse
events and the high end represents a 100 percent reduction. The
estimates have been rounded to the nearest ten. The fifth column is the
value of reducing the risk of particular adverse events such that one
expected adverse event is avoided per year across the at-risk
population, in thousands of dollars. The sixth column is the estimated
value of the annual risk reductions for the various adverse events in
millions of dollars, given as a range from low to high, rounded to the
nearest million.
Table 6.--Estimated Value of Annual Risk Reduction From Proposed Actions
----------------------------------------------------------------------------------------------------------------
Value of Value of
Reduction in estimated estimated
Annual Estimated estimated risk risk
Type of event reported annual annual cases reduction reduction
cases 1 cases 2 3 per case ($ ($ millions)
thousands) 4 5
----------------------------------------------------------------------------------------------------------------
Death....................................... 6 40 10-40 5,000 70-190
Serious CVS................................. 27 170 60-170 837 50-140
Serious NS.................................. 29 190 70-190 1,483 100-280
Ab. liver function.......................... 7 50 20-50 3 0
Other serious............................... 12 80 30-80 775 20-60
Less serious................................ 93 600 210-600 0.4 0
-------------------------------------------------------------------
Total................................. 174 1,110 390-1,110 NA 240-670
----------------------------------------------------------------------------------------------------------------
1 Annual reported cases are based on the average number of adverse event reports per year between January 1993
and June 1996. Trends in the data were not extrapolated because of the short timeframe involved.
2 Estimated annual cases are based on the following assumptions: (1) 80 percent of the reported adverse events
involving the consumption of dietary supplements suspected of containing ephedrine alkaloids are actually
related to the consumption of dietary supplements, (2) 80 percent of the supplements involved in the reported
adverse events that are related to the consumption of supplements actually contain ephedrine alkaloids, and
(3) 10 percent of adverse events to the dietary supplements containing ephedrine alkaloids are reported. Thus,
the estimated number of annual cases is 0.8 x 0.8 x 10 times the number of annual reported cases.
Considerable uncertainty exists with respect to the validity of the assumptions on which this estimate is
based and the actual number of annual cases may be higher or lower than the estimate.
3 The low end of the range of the reduction in estimated annual cases represents a 35 percent reduction in
estimated annual cases. The high end of this range represents a 100 percent reduction in estimated annual
cases. The 35 percent and 100 percent estimates are based on adding up the estimated effects of the proposed
actions, as indicated in Table 7.
4 The value of the risk reduction per case is based on published estimates of the value consumers place on
reducing the risk of the general types of adverse events involved (Ref. 215).
5 The value of the estimated risk reduction is based on multiplying the risk reduction per case times the
reduction in the estimated annual cases.
Table 7.--Combined Effect of Proposed Actions
------------------------------------------------------------------------
Estimated
reduction in
Proposed action adverse events
(in percent)
------------------------------------------------------------------------
Actions reducing consumption of supplements containing
ephedrine alkaloids:
Potency limits and ingredient restrictions.......... 0-33
Warning statement................................... 0-15
Label claim restrictions........................... 10-40
Combined effect.................................... 10-88
Actions reducing probability of adverse event given
consumption:
Potency limits...................................... 0-80
Ingredient restrictions............................ 25
Combined effect..................................... 25-100
[[Page 30709]]
Combined effect of all proposed actions................. 35-100
------------------------------------------------------------------------
b. Costs. The primary social costs of the proposed actions are the
compliance costs, which include the one-time costs associated with
relabeling and reformulating the affected supplements and the recurring
costs associated with testing for the level of ephedrine alkaloids in
conjunction with future product reformulations or changes in
ingredients, and the value of the utility losses to any consumers who
do not value the reformulated supplements as highly as supplements
currently found on the market. This cost must be considered somewhat
paradoxical because the cause of this loss of value, the reduction or
removal of ephedrine alkaloids, would also reduce or eliminate the
risks associated with using these products. In addition, indirect
social costs in the form of capital losses and temporary unemployment
may arise from the distributive effects of the proposed action, which
are discussed below. Some portion of the compliance costs will be borne
by manufacturers and distributors of these products, and some portion
will be passed on to consumers of these products. Costs borne by
manufactures and distributors will be borne by the owners,
stockholders, and employees of those firms.
In addition to the potential impact of compliance costs,
manufacturers and distributors of the dietary supplements containing
ephedrine alkaloids will be adversely affected by the reduction in
consumption of these products caused by the proposed actions. Also,
manufacturers, distributors, and importers of raw or bulk Ma huang and
other affected ingredients may be affected by these consumption
effects. These effects are distributive effects rather than social
costs because they do not involve the loss of productive resources, and
because a loss of business in one sector of the economy is generally
associated with an increase in business in competing sectors. However,
as indicated above, social costs may be involved to the extent that
otherwise productive capital investment is lost and temporary
unemployment is generated. In addition, distributive effects are
obviously very significant to the affected parties.
FDA has previously estimated the cost of relabeling all dietary
supplements in the economic impact analysis for the proposal on
nutrition labeling of dietary supplements that was published in the
Federal Register of December 28, 1995 (60 FR 67184) (the December 1995
proposal). Total discounted labeling costs based on an 18 month
compliance period were estimated to be between $52 and $85 million.
This cost included recurring testing or analytical costs based on
testing the nutrient content of each product an average of once every 5
years. Based on comments to the December 1995 proposal, these estimates
were revised in the economic impact analysis of the final rule. The
revised estimate was $194 million, with $91 million of these costs
occurring in the first 18 months and the remainder being a discounted
sum of future analytical costs. In order to use this estimate as a
basis for estimating labeling costs for the current proposal, the
previous estimate must be adjusted to account for the compliance period
associated with this rule and the fact that not all dietary supplements
contain ephedrine alkaloids.
The proposed effective date of any regulation based on this
proposal will be 180 days after the date of publication of the final
rule. If the nutritional labeling rule had a compliance period of 180
days rather than 18 months, the total estimated labeling costs would
have been $334 million, with $286 million of these costs occurring in
the first 6 months.
Adjusting the previous estimate to account for the fact that not
all dietary supplements contain ephedrine alkaloids requires
information on the proportion of dietary supplements that contain
ephedrine alkaloids. The market surveys identified 125 dietary
supplements suspected of containing ephedrine alkaloids. A public
comment submitted to the Special Working Group of the Food Advisory
Committee suggested the number of such products is at least 200 (Ref.
216). In the December 1995 proposal, the total number of dietary
supplement products was estimated to be between 4,000 and 25,000. In
the final rule entitled ``Iron-Containing Supplements and Drugs: Label
Warning Statements and Unit-Dose Packaging Requirements'' that
published in the Federal Register of January 15, 1997 (62 FR 2218),
this estimate was revised to 29,000. If 200 dietary supplements contain
ephedrine alkaloids, then about 1 percent of the estimated total number
of dietary supplements contain ephedrine alkaloids and the cost of
changing the labels on dietary supplements containing ephedrine
alkaloids would be about 1 percent of the costs estimated for changing
the labels on all dietary supplements.
Another method of estimating the proportion of dietary supplements
that contain ephedrine alkaloids is to use sales data. This method is
complicated by the fact that sales might not be evenly distributed
across dietary supplements, implying that the proportion of dietary
supplement sales accounted for by supplements that contain ephedrine
alkaloids may not be the same as the proportion of dietary supplement
products that contain ephedrine alkaloids.
Ma huang and other ephedra products have been reported to represent
3.5 percent of individual botanical sales in selected health food
stores, while individual sales of products containing single botanicals
are estimated to make up about 53 percent of total botanical supplement
use (Ref. 3). Information is not available on the proportion of
products with multiple botanical ingredients that contain ephedrine
alkaloids. Botanical supplement retail sales have been estimated to
have accounted for approximately 26 percent of total dietary supplement
retail sales in 1995 (Ref. 217). However, this estimate includes a
number of product categories under dietary supplements that would not
be considered dietary supplements under the legal definition of a
dietary supplement. After adjusting for the definition of dietary
supplements, supplements containing botanicals accounted for
approximately 35 percent of dietary supplement retail sales in 1995.
The definition of dietary supplement used in this estimate includes
vitamins, minerals, and botanical (including herbal) supplements.
If all supplements containing ephedrine alkaloids are characterized
as
[[Page 30710]]
botanical supplements, this information suggests that between 1 and 17
percent of dietary supplement use involves products that contain
ephedrine alkaloids. If the proportion of dietary supplement products
containing ephedrine alkaloids reflects the proportion of dietary
supplement sales accounted for by products containing ephedrine
alkaloids, then between 1 and 17 percent of the total number of dietary
supplement products contain ephedrine alkaloids, or between 200 and
5,000 products.
Based on the preceding information, labeling costs for this
proposal are estimated to be between 1 and 17 percent of the costs
previously estimated for changing the labels on all dietary
supplements, after adjusting those costs for the length of the
compliance period. Thus, total discounted labeling costs for this
proposal are estimated to be between $3 million and $60 million, with
between approximately $3 million and $50 million of these costs
occurring in the first year and between a minimal amount and
approximately $0.5 million in every year after the first year.
If the proposed 180 day compliance period for making the proposed
label changes coincided with some portion of the 18-month compliance
period of the final rule requiring nutritional labeling of dietary
supplements, then some portion of the combined labeling costs of the
two regulations would be eliminated because some firms would be able to
make both labeling changes during normally scheduled labeling changes.
The degree of overlap of the compliance periods of these regulations
depends on the date on which the final rule is published. If
appropriate, this consideration will be addressed in the economic
analyses of the final rule.
Information is not available on the cost of reformulating the
affected products. Reformulation may simply involve reducing the amount
of the ingredient source of the ephedrine alkaloids and removing the
restricted ingredients. One method of approaching this issue is to
consider the types of personnel and the amount of effort that might be
required for reformulation. A reasonable assumption is that it might
take a scientist from 1 to 4 weeks to develop an acceptable
reformulation. In this case, the cost of reformulating a product would
be between $1,000 and $5,000, based on median weekly earnings data for
1994 and 50 percent overhead (Ref. 218).
Many dietary supplements containing ephedrine alkaloids probably
contain restricted ingredients or do not meet the proposed potency
limits on TEA and will either have to be reformulated or removed from
the market. The number of dietary supplements containing ephedrine
alkaloids has been estimated, above, to be between 200 and 5,000. Under
this assumption, if all products were reformulated, the one-time cost
of reformulating the affected products would be between $0.2 million
and $25 million. The recurring costs associated with testing for
ephedrine alkaloid levels in conjunction with future product
reformulations was addressed in the labeling costs.
Another cost associated with product reformulation is the cost of
any inventory losses involving products produced prior to the
publication of a final rule based on this proposal that cannot be sold
by the date that final rule goes into effect. The proposed effective
date of any final rule on this issue is 180 days after publication of
the final rule. FDA has no information on the amount of inventory
typically carried for these products, but tentatively assumes that 180
days will provide sufficient time to utilize existing stock.
In addition to the compliance costs discussed above, the proposed
action will also lead to utility losses for some consumers because it
removes products with certain characteristics from the marketplace.
Theoretically, the value of this utility loss is the difference in the
value consumers placed on the eliminated products and the value of the
products purchased in place of the eliminated products. Estimating this
loss requires estimating demand curves for the eliminated products and
for the products substituted for the eliminated products.
Identifying likely substitutes for dietary supplements as currently
formulated is complicated by the fact that a wide range of effects are
attributed to these supplements, for example, energy, weight loss, body
building, and increased mental concentration. However, little reliable
information is available on the actual effects produced by these
supplements. In addition, various other botanical substances exist that
might be used in supplements to replace either some portion of the
ephedrine alkaloids or the restricted ingredients and might produce
effects that consumers may perceive to be similar to the effects that
consumers attributed to these supplements as currently formulated.
Finally, FDA has insufficient information to estimate demand curves for
dietary supplements containing ephedrine alkaloids or potential
substitutes for these products.
Based on these considerations, FDA cannot place bounds on the value
of the consumer utility losses that may be associated with this action.
However, if substitute products could be identified, then the absolute
price difference between the affected products and the substitute
products would represent a lower bound on consumer utility losses. No
comparable argument is available for the upper bound of the utility
loss.
In addition to compliance costs and utility losses, the proposed
action will also generate distributive effects. The total reduction in
the consumption of dietary supplements containing ephedrine alkaloids
from all proposed actions including the potency limits, ingredient
restrictions, labeling restrictions, and mandatory warning statement
was estimated in the analysis of the benefits of this option to be
between 10 percent and 33 percent. Total annual sales of supplements
containing Ma huang have been estimated to be between $600 million and
$700 million (Ref. 219). Therefore, sales of these products may be
reduced by between $60 million and $230 million per year. Information
is not available on the total annual sales of supplements containing
sources of ephedrine alkaloids other than Ma huang.
Countervailing effects may also take place which may reduce the
impact of these negative distributive effects on affected firms. For
example, the proposed rule may reduce the number of product liability
lawsuits brought against manufacturers of dietary supplements
containing ephedrine alkaloids. FDA has insufficient information on the
current incidence or cost of these lawsuits to estimate the effect of
this reduction, if any, on the negative distributive effects generated
by consumption changes. Of course, distributive effects that are
negative with respect to a given industry will be positive with respect
to some other industry.
Finally, social costs may be associated with these distributive
effects. For example, some portion of the value of the capital invested
in the production of these supplements may be lost and that loss might
not be offset by other effects, such as an augmentation to the value of
the capital invested in the production of substitutes. However, FDA has
insufficient information to estimate the social costs that might be
associated with these distributive effects.
Under these assumptions, the proposed action will generate total
compliance costs of between $3 million and $80 million, plus
unquantifiable utility losses to consumers of these products. Between
$3 million and $70 million of these costs will occur in the
[[Page 30711]]
first 6 months after publication of the final rule. In addition, the
proposed action will produce distributive effects of between $60
million and $230 million per year and social costs might be associated
with those distributive effects. Because the sales of these products
are increasing rapidly, FDA believes that this is a conservative
estimate of cost and distributive effects. Again, extrapolations have
not been made on the growth trend because extrapolating short-term
trends into the future can result in large errors. Costs and sales
reductions of this magnitude may threaten the viability of many firms
in this industry. If some of these firms go out of business, temporary
unemployment of labor and permanent loss of capital resources may
result. FDA has insufficient information to estimate these costs.
4. Option 4--Take Proposed Action, but With a Higher Potency Limit
Another option is to take all proposed actions but adopt potency
limits higher than the proposed potency limits. For example, some trade
associations representing the dietary supplement industry have
previously expressed support for potency limits of 12 mg/serving and 50
mg/day TEA (Ref. 220). With respect to benefits arising from
consumption effects (i.e., the likelihood of reducing the number or
seriousness of adverse events), FDA has some information to estimate
the effect of variations between the proposed potency limits and higher
potency limits on the consumption effects associated with those limits.
That is, of the 13 reports of adverse events for which exposure data
for intakes less than 20 mg per serving were also available, 5 were in
the range between 8 and 12 mg per serving intake.
If consumption is sensitive to small changes in the potency limits,
then higher potency limits would reduce the benefits resulting from
consumption effects because higher potency limits would presumably have
a smaller effect on the effects of these products than the proposed
potency limits. Therefore, the effect of raising the potency limits on
benefits arising from shifts in consumption will be to reduce those
benefits below those generated under Option 3.
Raising the proposed potency limits will not affect the one-time
compliance costs but might reduce utility losses to consumers of these
products and the distributive effects produced by consumption shifts.
Again, these changes may occur because higher potency limits might have
a somewhat smaller impact on the perceived benefits of these products
than the proposed potency limits. However, as indicated above, FDA has
insufficient information to estimate the effect of small changes in the
potency limits on the consumption effects produced by those limits and
cannot estimate the utility losses associated with various potency
limits.
5. Option 5--Ban Dietary Supplements That Contain Ephedrine Alkaloids
Based on the framework used earlier, banning dietary supplements
that contain ephedrine alkaloids would lead to a somewhat higher lower
bound on estimated benefits. In particular, banning these products
would reduce the health risks from these products such that the
expected number of adverse events are reduced by between approximately
120 cases and 1,400 cases per year.
Banning dietary supplements that contain ephedrine alkaloids will
not change the one time compliance costs estimated under Option 3
because all affected products were subject to reformulation and
relabeling costs under Option 3. However, banning these products would
decrease access to these products by consumers who may perceive
benefits, thus substantially increasing the potential utility losses to
consumers. With respect to distributive effects generated by
consumption changes, the total reduction in the consumption of dietary
supplements that now contain ephedrine would probably be approximately
33 percent under this option, that is, at the high end of the range of
10 to 33 percent estimated under Option 3. Therefore, sales of these
products would be reduced by between $200 million and $230 million per
year. Costs and sales reductions of this magnitude may threaten the
viability of many of the firms producing these products. However,
countervailing distributive effects are also possible in that some
firms that currently produce dietary supplements containing ephedrine
alkaloids may also produce or be able to produce substitute products.
In that case, those firms would avoid some or all of the costs
associated with producing dietary supplements containing ephedrine
alkaloids.
6. Option 6--Take Proposed Action, but Do Not Require Warning Statement
The purpose of the proposed warning statement is to focus existing
warnings more precisely on the health risks posed by these products,
particularly in cases where any use of these products may be
contraindicated, and to add warnings to those products which do not
already have warning statements. Even with the proposed potency limits
and ingredient restrictions, some consumers may be at high risk of
suffering an adverse event from consuming these products because of
high individual sensitivity to these products, because of an increase
in risk associated with simultaneous consumption of drug products, or
because of an underlying health condition. Thus, the proposed warning
statement is expected to have some benefit independent of the other
proposed requirements. Eliminating the proposed mandatory warning
statement will affect estimated labeling costs because, under this
option, only those labels affected by the claims restrictions would
have to be changed. However, the vast majority of the affected products
have labels that would be affected by the claims restrictions. Among
the products in the market surveys, 94 percent of the products
investigated had one or more claims that would be restricted under this
option. Thus, labeling costs under this option will be only
approximately 6 percent lower than the labeling costs estimated for
Option 3.
Finally, under the framework developed earlier, this option will
have little effect on the other costs and distributive effects
estimated for the proposed action under Option 3 because of the
influence of the other factors involved.
7. Option 7--Require Warning Statements Only
Estimating the benefit of eliminating all proposed actions except
the required warning statement involves a controversial value judgment
concerning the evaluation of risks that are voluntarily accepted in the
presence of the amount of information on those risks provided on the
proposed warning statement.
Under the assumption that any adverse events that may occur due to
such behavior cannot represent net social costs, warning statements
will eliminate all net social costs associated with these adverse
events. This assumption is based on the notion that the proposed
warning statement provides adequate information on the risks of
consuming these products and the notion that if those consuming these
products have adequate information on the risks involved, then their
consumption decisions reflect their personal judgments concerning the
relative value of the benefits and risks of consuming these products.
If no existing warning statements provide adequate information
while the proposed warning statement will
[[Page 30712]]
provide adequate information, then the social benefits of this option
would be at least as great as the value of banning dietary supplements
containing ephedrine alkaloids. On the other hand, if some existing
warning statements already provide adequate information, then the
benefits of this option would still be at least as great as the value
of banning dietary supplements containing ephedrine alkaloids; however,
the benefits of both options would be lower.
Under the assumption that any adverse events that may occur due to
such behavior represent social costs, eliminating all actions other
than the proposed warning statement will substantially reduce the
benefits from those estimated for Option 3. This assumption is based
either on the notion that the level of information provided on the
proposed warning statement is inadequate to ensure that consumers can
make informed consumption decisions, or on the notion that public
health risks require intervention even if those risks are voluntarily
undertaken in the presence of adequate information on the benefits and
risks of the relevant activity. Under this assumption, this option will
reduce the health risks from these products such that the expected
number of adverse events will be reduced by between 0 cases and
approximately 210 cases per year.
With respect to compliance costs, eliminating all actions except
the warning statement would eliminate the costs associated with product
reformulation and consumer utility losses.
Finally, this option would substantially reduce the distributive
effects of this action. Under this option, the estimated total
reduction in the consumption of dietary supplements containing
ephedrine alkaloids would be between 0 and 15 percent. Therefore, sales
of these products would be reduced by between $0 and $110 million per
year. A reduction in sales of this magnitude would threaten the
viability of fewer firms than the proposed action, as estimated under
Option 3.
V. Regulatory Flexibility Analysis
In the economic impact analysis for the December 1995 proposal, FDA
estimated the number of dietary supplement manufacturers to be between
150 and 600, with the majority of those firms being small businesses.
Based on additional information, these estimates were revised in the
economic impact analysis of the final rule on nutritional labeling. The
revised estimate was 500 to 850 firms, with 95 percent of those firms
classified as small businesses.
The proportion of dietary supplement manufacturers producing
products containing ephedrine alkaloids is unknown. The two market
surveys identified 85 manufacturers and distributors of dietary
supplements suspected of containing ephedrine alkaloids. Assuming that
the proportion of these firms that are small businesses is the same as
the proportion of firms in the dietary supplement industry that are
small businesses, 95 percent of these firms, or approximately 80 firms,
are small businesses.
Total compliance costs incurred by small businesses will be
virtually equal to total compliance costs incurred by all businesses
estimated earlier because the vast majority of the firms affected by
the proposed action are small businesses. Relabeling, reformulation,
and testing costs are fixed costs on a per product basis and will
disproportionately affect small businesses. Total compliance costs of
the proposed action were estimated to be between $3 million and $80
million, with between $3 million and $70 million of these costs
occurring in the first 6 months after publication of the final rule.
However, FDA has insufficient information to estimate the portion of
these costs that will be borne by the owners, stockholders, and
employees of these firms and the portion that will be passed on to
consumers of these products through price increases. In addition, the
proposed action will generate consumption shifts that were previously
estimated to produce negative distributive effects of between $60
million and $230 million per year. Countervailing distributive effects
are also possible. For example, the proposed rule may reduce the number
of product liability lawsuits brought against manufacturers of dietary
supplements containing ephedrine alkaloids. Based on reported annual
retail sales of between $600 million and $700 million for products
containing Ma huang, these costs and distributive effects may be
significant.
Most of the regulatory alternatives discussed earlier would reduce
the impact of this rule on small businesses. The options of taking no
action and taking no action other than generating additional
information both reduce the impact on small businesses to zero.
Requiring only warning statements would substantially reduce compliance
costs to between $3 million and $60 million, with between $3 million
and $50 million of these costs occurring in the first 6 months, and
also substantially reduce negative distributive effects generated by
consumption shifts to between $0 and $110 million per year. Taking the
proposed action without requiring the warning statement would slightly
reduce compliance costs to between $3 million and $80 million, with
between $3 million and $70 million of these costs occurring in the
first 6 months, but would not affect distributive effects because of
the other factors influencing those effects. Taking the proposed action
but raising the proposed potency limit to the level suggested by a
trade group representing the dietary supplement industry would probably
not significantly alter the impact of this rule on small businesses.
Finally, banning dietary supplements containing ephedrine would not
change reformulation or relabeling costs and would lead to distributive
effects from consumption shifts in the range of $200 million to $230
million per year. This action would have the greatest negative impact
on small businesses.
VI. Conclusions
The estimated benefits of Option 3, take the proposed action, are
between $240 million and $670 million per year. The estimated
quantifiable costs are between approximately $3 and $70 million in the
first year, and between a minimal amount and about $0.5 million in
every year after the first year. Thus, notwithstanding the considerable
uncertainty concerning the marginal effectiveness of the individual
requirements of the proposed rule, FDA is confident that it would
generate benefits that far exceed the quantifiable costs. In addition
to the quantifiable costs, however, the proposed action will also
generate non-quantifiable utility losses for some consumers and
distributive effects from consumption shifts with an estimated value of
between approximately $60 million and $230 million per year, with
possible countervailing distributive effects from a reduction of
liability lawsuits. Social costs might be associated with these
distributive effects.
VII. Environmental Impact
The agency has carefully considered the potential environmental
effects of this action. Based on the available information, FDA has
concluded that the action will not have a significant impact on the
human environment, and that an environmental impact statement is not
required. The agency's finding of no significant impact and the
evidence supporting that finding, contained in an environmental
assessment, may be seen in the Dockets Management Branch (address
above) between 9 a.m. and 4 p.m., Monday through Friday (Ref. 221).
[[Page 30713]]
The agency will reevaluate its environmental decision if new
information is received suggesting that the action would have
significant environmental effects.
VIII. Paperwork Reduction Act
This proposed rule contains no information collection or
recordkeeping requirements under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501 et seq.).
IX. References
The following references have been placed on display at the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Office of Special Nutritionals: Market Review of Dietary
Supplements Containing Ephedrine Alkaloids, October 11, 1995.
2. Office of Special Nutritionals: Market Review of Dietary
Supplements Containing Ephedrine Alkaloids, August 27, 1996.
3. Brevoort, P., ``The U.S. Botanical Market--An Overview,''
HerbalGram, 36:49-57, 1996.
4. The Ephedras (Monograph). The Lawrence Review of Natural
Products, Facts and Comparisons, 1989.
5. Chen, K. K., and C. F. Schmidt, ``Ephedrine and Related
Substances,'' Medicine, 9:1-117, 1930.
6. Ma huang (Appendix: Mahuanggen). In ``Pharmacology and
Applications of Chinese Materia Medica,'' edited by Chang, H., and
P. P. But, Singapore: World Scientific Publishing Co. Pte. Ltd.,
1119-1124, 1987.
7. Karch, S. B., ``Other Naturally Occurring Stimulants,'' In
``The Pathology of Drug Abuse,'' edited by Karch, S. B., Boca Raton:
CRC Press, 177-198, 1996.
8. ``Phenethylamines,'' In ``Pharmaocognosy, Phytochemistry,
Medicinal Plants,'' edited by Bruneton, J., New York: Laviosier
Publishing, 711-715, 1995.
9. Cetaruk, E. W., C. K. Aaron, ``Hazards of Nonprescription
Medications,'' Emergency Medicine Clinics of North America, 12:483-
510, 1994.
10. ``Ephedrine (hydrochloride),'' In ``Therapeutic Drugs,''
edited by Dollery, C., Edinburgh; New York: Churchill Livingstone,
E26-E29, 1991.
11. ``Pseudoephedrine Hydrochloride,'' In ``Therapeutic Drugs,''
edited by Dollery, C., Edinburgh: Churchill Livingstone, P297-P299,
1991.
12. ``Phenylpropanolamine (Hydrochloride),'' In ``Therapeutic
Drugs,'' edited by Dollery, C., Edinburgh: Churchill Livingstone,
P91-P93, 1991.
13. Hanna, P. E., ``Adrenergic Agents,'' In ``Wilson and
Gisvold's Textbook of Organic Medicinal and Pharmaceutical
Chemistry,'' edited by Delgado, J. N., and W. A. Remers, J. B.
Lippincott, 413-427, 1996.
14. Huang, K. C., ``Antiasthmatic Herbs,'' In ``The Pharmacology
of Chinese Herbs,'' Boca Raton: CRC Press, 229-232, 1993.
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[[Page 30717]]
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Dietary Supplements, December 20, 1996.
List of Subjects in 21 CFR Part 111
Drugs, Packaging and containers, Incorporation by reference,
Labeling.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 111 be revised as follows:
PART 111--RESTRICTIONS FOR SUBSTANCES USED IN DIETARY SUPPLEMENTS
Subpart A--General Provisions--[Reserved]
Subpart B--Current Good Manufacturing Practice for Dietary Supplements
Sec.
111.50 Packaging for iron-containing dietary supplements.
Subpart C--New Dietary Ingredients--[Reserved]
Subpart D--Restricted Dietary Ingredients
111.100 Dietary supplements that contain ephedrine alkaloids.
Authority: Secs. 201, 402, 403, 701 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321, 342, 343, 371).
PART 111--RESTRICTIONS FOR SUBSTANCES USED IN DIETARY SUPPLEMENTS
Subpart A--General Provisions--[Reserved]
Subpart B--Current Good Manufacturing Practice for Dietary
Supplements
Sec. 111.50 Packaging of iron-containing dietary supplements.
(a) The use of iron and iron salts as iron sources in dietary
supplements offered in solid oral dosage form (e.g., tablets or
capsules), and containing 30 milligrams or more of iron per dosage
unit, is safe and in accordance with current good manufacturing
practice only when such supplements are packaged in unit-dose
packaging. ``Unit-dose packaging'' means a method of packaging a
product into a nonreusable container designed to hold a single dosage
unit intended for administration directly from that container,
irrespective of whether the recommended dose is one or more than one of
these units. The term ``dosage unit'' means the individual physical
unit of the product (e.g., tablets or capsules). Iron-containing
dietary supplements that are subject to this regulation are also
subject to child-resistant special packaging requirements codified in
16 CFR parts 1700, 1701, and 1702.
(b)(1) Dietary supplements offered in solid oral dosage form (e.g.,
tablets or capsules), and containing 30 milligrams or more of iron per
dosage unit, are exempt from the provisions of paragraph (a) of this
section until January 15, 1998, if the sole source of iron in the
dietary supplement is carbonyl iron that meets the specifications of
Sec. 184.1375 of this chapter.
(2) If the temporary exemption is not extended or made permanent,
such dietary supplements shall be in compliance with the provisions of
paragraph (a) of this section on or before July 15, 1998.
Subpart C--New Dietary Ingredients--[Reserved]
Subpart D--Restricted Dietary Ingredients
Sec. 111.100 Dietary supplements that contain ephedrine alkaloids.
The ephedrine alkaloids include ephedrine, pseudoephedrine,
norpseudoephedrine, norephedrine, methylephedrine,
methylpseudoephedrine, and related alkaloids. These substances are
chemical stimulants contained in
[[Page 30718]]
particular botanical products, 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.
(a)(1) Dietary supplements that contain 8 milligrams (mg) or more
of ephedrine alkaloids (the total of ephedrine, pseudoephedrine,
norpseudoephedrine, norephedrine, methylephedrine,
methylpseudoephedrine, and related alkaloids) per single serving shall
be deemed to be adulterated under sections 402(a)(1) and 402(f)(1)(A)
of the Federal Food, Drug, and Cosmetic Act.
(2) The Food and Drug Administration will use high performance
liquid chromatography (HPLC) to determine the level of ephedrine
alkaloids in a dietary supplement as specified in its Laboratory
Information Bulletin (LIB) No. 4053, which is incorporated by reference
in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies may be
obtained from the Director, Office of Constituent Operations, Industry
Activities Staff (HFS-565), Center for Food Safety and Applied
Nutrition, Food and Drug Administration, 200 C St. SW., rm. 5827,
Washington, DC 20204, or may be examined at the Center for Food Safety
and Applied Nutrition's Library, Food and Drug Administration, 200 C
St. SW., rm. 3321, Washington, DC, or at the Office of the Federal
Register, 800 North Capitol St. NW., suite 700, Washington, DC.
(b) The labeling of dietary supplements that contain ephedrine
alkaloids shall not suggest or recommend conditions of use that would
result in an 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.
(c) The label of dietary supplements that contain ephedrine
alkaloids shall state ``Do not use this product for more than 7 days.''
(d) 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.
(e) No dietary supplement that contains ephedrine alkaloids may
purport to be, or be represented as, either expressly or implicitly,
for use for long-term effects, such as weight loss or body building.
(f)(1) 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, shall state ``Taking more than the recommended serving may cause
heart attack, stroke, seizure, or death.''
(2) This information shall appear on the same label panel or same
page of labeling as the claim and shall be connected to the claim by
use of an asterisk. This information shall appear in easily legible
print or type, in distinct contrast to other printed or graphic matter,
and in a type size no less than is required by Sec. 101.105(i) of this
chapter for the net quantity of contents statement, except where the
size of the claim is less than two times the required size of the net
quantity of contents statement, in which case the information shall be
no less than one-half the size of the claim, but no smaller than one-
sixteenth of an inch. Where the label or labeling contains multiple
claims, the information shall appear once on each label panel or on
each page of labeling.
(g)(1) The labeling of any dietary supplement that contains
ephedrine alkaloids shall bear the following warning:
WARNING: If you are pregnant or nursing, or if you have heart
disease, thyroid disease, diabetes, high blood pressure, depression or
other psychiatric condition, glaucoma, difficulty in urinating,
prostate enlargement, or seizure disorder consult a health care
provider before using this product. Do not use if you are using
monoamine oxidase inhibitors (MAOI) or for 2 weeks after stopping a
MAOI drug; certain drugs for depression, psychiatric or emotional
conditions; drugs for Parkinson's disease; methyldopa; or any product
containing ephedrine, pseudoephedrine or phenylpropanolamine
(ingredients found in allergy, asthma, cough/cold and weight control
products). Stop use and call a health care professional immediately if
dizziness, severe headache, rapid and/or irregular heart beat, chest
pain, shortness of breath, nausea, noticeable changes in behavior, or
loss of consciousness occur. Do not exceed recommended serving.
(2) The phrase ``Do not exceed recommended serving'' is not
required to appear in the warning statement when the disclaimer
required in paragraph (f)(1) of this section appears on the same label
panel as the warning statement.
(3) The warning statement required by paragraph (g)(1) of this
section shall appear prominently and conspicuously on the product label
and shall be set off in a box by use of hairlines.
Dated: April 22, 1997.
Michael A. Friedman,
Deputy Commissioner for Operations.
Donna E. Shalala,
Secretary of Health and Human Services.
Note: The following Appendix will not appear in the annual Code
of Federal Regulations.
Appendix--AER's Associated With Ephedrine Alkaloid-Containing
Dietary Supplements
----------------------------------------------------------------------------------------------------------------
ARMS No. Product manufacturer Clinical summary
----------------------------------------------------------------------------------------------------------------
9101...................... Thermojetics Herbal Tablets- 33 yo F used product (bid, ?dose) in 11/93 until
Green--Herbalife International. 1st week in 1/94, when she started having dizzy
spells that progressed to involve numbness of L
arm & forehead, weakness of both legs, SOB, and
shaky feelings. 1/30/94 seen in ER for dizziness &
tachycardia, Dx labyrinthitis, Tx Valium, d/c on
Antivert. 2/2/94 episodes worsened, including
dizziness, severe tachycardia, and SOB. She was
transported to hospital & admitted w/extensive w/u
(CAT, XR echo, doppler, halter, labs). D/c on 2/8
on Tenormin and Ativan w/Dx of SVT. Normal PE in
10/93. No h/o allergies or CV disease. Mother
(insomnia) & husband (blood in stool) using
product w/various SSx. Sister took product w/o
problems.
9316...................... E'OLA AMP II Pro Drops--E'OLA 23 yo F hospitalized w/ cardiac arrest, CPR, then
Bio-genics, Inc. ICU. Dx inferolat MI. CK > 2000 (MB+), EKG: sinus
tachy & ST inf leads; angio: lacerated
coronary (partial dissection) & hematoma at
bifurcation of circumflex artery. Used AMP II 3-4
drops in beverage night before arrest, also noted
to be using other `diet pills' (?dose/durations).
Drug screen negative, doing well off product.
[[Page 30719]]
9552...................... Nature's Nutrition Formula One-- 35 yo F good health, no risk factors for CAD used
Affiliated Consultants Inter./ product 04/94--05/94 (30 days) for WL&E, as much
Alliance U.S.A. Inc. as 1-2 caps bid 30 days. She stopped for a week
but resumed again at 3 caps qd. On 6/25/94,
developed acute onset of throbbing, ant. CP at
rest, w/ pain radiation to the left shoulder,
numbness of left arm & hand, diaphoresis and SOB.
The pain persisted, and she was taken to the ER.
The pain decreased with subl nitro and was
completely relieved with morphine and nitro. On
admission, BP: 140/100, EKG: minor ST depressions
V1, V2, and minor ST elevation in INF leads,
elevated cardiac enzymes. Dx: Acute non-Q wave MI
probably secondary to coronary spasm. Cardiac cath
6/27/94 LV angiogram very mild posterior basilar
hypokinesis, normal LV function w/ good ejection
fraction. Normal coronary arteries. Discharged
after 4 days on Cardizem, aspirin, nitro prn, & f/
u for a limited stress test.
9747...................... Ripped Fuel--Twin Laboratories, 40 yo F reported by physician to suffer a grand mal
Inc. seizure after using product for 3 days (2 bid) as
directed. Her husband stated she stopped breathing
and he had to administer mouth to mouth
resuscitation. She was on no medication and had no
personal nor family history of seizures. She had
no symptoms until she felt dizzy immediately
before her seizure. CT head--no abnormalities.
9751...................... Slim NRG--Momentum Marketing... 28 yo F (weighing 95 lb) reported by MD. Used
product, 1 tid for 6 months for weight loss (30
lb). Stopped product abruptly, became despondent
over 10 days ending w/attempted suicide--gunshot
wound to chest. No other products used. Past
mental history negative for mental illness, use of
drugs/alcohol. Drug/ETOH screen neg. Tx: w/
antidepressants. Positive dechallenge.
9754...................... Shape-Fast--Shaperite Concepts 44 yo F reported by physician's assistant to be
Ltd. taking product (400 mg bid) when she developed
heat stroke, chest and back pain, hyperthermia and
tachycardia while exercising.
9818...................... Power Trim--Enrich 43 yo M who used product (details not given) over a
International. 6 wk period and lost 30 lb., developed new onset
insomnia and atrial fibrillation. Seen by health
care provider and given Lanoxin, hospitalized next
day when light headedness developed. Extensive w/u
(EKG, CXR, echo-cardiogram, smac, myocardial
enzymes), compatible with AF. Dx: ``new onset
atrial fibrillation, possibly due to the stimulant
effect of his dietary supplement.'' Tx: Lanoxin,
Betapace, Verapamil, and Coumadin.
9864...................... Nature's Nutrition--Formula 44 yo M, active swimmer and tennis player, with no
One--Affiliated Consultants known cardiovascular risks as documented by
Intl/Alliance U.S.A. medical history, originally obtained a sample of
product during a routine physical from his health
care provider when he requested some substitute
for his daily coffee and cocoa use. He used this
product as directed, and was able to eliminate his
afternoon coffee/cocoa use. On 12/18/93 (3 weeks
after starting product), after playing his routine
weekly game of tennis, he came home, laid down and
was found dead about noon. Resuscitative efforts
were unsuccessful. Autopsy revealed an acute
thrombus, 1.5 cm from the origin of the left
anterior descending coronary artery, resulting in
occlusion. All lumina were otherwise patent,
although calcification of the coronary arteries
resulting in focal narrowing to about 50 percent
was noted. A drug screen performed at the time of
autopsy was reportedly negative for amines.
10009..................... MetaboLift Thermogenic--Twin 35 yo M w/acute MI (inferoapical). Took product
Laboratories, Inc. (two capsules at noon and 3 capsules at 4:30 PM)
Worked out 5:30 PM--6:30 PM and developed chest
pain around 7:30 PM. Consumer admitted, treated w/
TPA, subsequent cardiac catheterization
demonstrated normal coronaries. CPK elevated, EKG
diagnostic for MI.
10026..................... Formula One--Affiliated 48 yo F took product (3 caps qd) for 6-7 months
Consultants Intl./Alliance when developed weakness, syncopal episode,
U.S.A. increased BP, increased HR, tightness in chest.
Seen in ER w/EKG which showed nonspecific STT wave
abnormality, and increased cardiac enzymes. BP-120/
99. Saw MD next day, complained of right sided
weakness and speech difficulty. Meds:
antihypertensives, hormones. Dx: ``conversion
reaction'', thought to be stress related. Sxs
improved over next month. MD later told about use
of product, which he states could aggravate
nervousness.
10063..................... Super Diet Max--KAL, Inc....... 22 yo F had been using product several months at 1
tab bid for WL. On day of adverse event she had
taken 2 caps (1 q AM, 1 q PM), and experienced
increased BP, pounding heart, n/v, lasting 1.5-2
hr. Event abated after product discontinued. Saw
health care provider. Started on Prozac 2 wks
prior to adverse event.
10088..................... Nature's Sunshine SN-X 100 38 yo F took product for 4 days and developed
Vegitabs--Nature's Sunshine. syncope, blood pressure = 180/110. Seen in ER with
severe HA, nausea, diaphoresis. The consumer had
been seen every 3-4 months for 5 years prior to
this event and no history of high blood pressure.
After stopping the product her blood pressure
returned to normal.
10275..................... Nature's Nutrition Formula One-- 63 yo F reports using product for 3 weeks at
Affiliated Consultants recommended dose, never used maximum recommended
International/Alliance U.S.A. dose, when she developed hives. The next day she
had difficulty walking across room, difficulty
breathing and swallowing, and vomited. She
suffered ventricular fibrillation, a small non Q-
wave infarct by enzymes criteria and was
hospitalized 5 days where evaluation (cardiac
catheterization, electrophysiology study) failed
to find any sort of heart problem or heart disease
to explain her arrest. She has chronic obstructive
pulmonary disease secondary to cigarette smoking.
Previous to arrest no medicine and only vitamin
and occasional aspirin.
[[Page 30720]]
10437..................... Thermojetics Herbal Tablets-- 55 yo F reports grand mal seizure after 3 days on
Beige, Thermojetics Herbal product per directions. No significant past
Tablets--Green, Formula 1, history, normal CT and EEG. No meds or other
Formula 2, Formula 3-- dietary supplement products.
Herbalife International.
10862..................... Ultimate Xphoria--Alternative 20 yo M took 8 tabs @ 4 pm (directions: Take 4
Health Research. tablets, on an empty stomach; do not exceed 4
tablets in 24 hours). Within 30 minutes,
complained of being hot, w/ sweating & HA. Found
dead by friends 8 hr later. Coroner's report notes
toxic levels of ephedrines.
10919..................... Power Trim--Enriched 49 yo F used Power Trim, 3 capsules three times
International. daily for 3 weeks for weight loss. She developed
weakness, dizziness, nausea, vomiting, and
palpitations and went to the ER where she was
found to have vertigo, serous otitis media
bilaterally, hypertension (150/102) and elevated
liver enzymes. The consumer reports stopping the
product and her blood pressure has returned to
normal without any medical treatment. She has no
history of high blood pressure.
10943..................... Multi DS--(1) Omnitrim Tea & 37 yo F used for 1 week, Omnitrim Tea, 2 teaspoons
(2) Omni 4--Omnitrition three times per day, and Omni 4 (a vitamin) one
International, Inc. daily, both as directed, for weight loss. She
stopped due to the development of shakes, sweats,
dizziness, racing heart, and loss of hearing in R
ear. Symptoms abated after stopping product. No
other products in use and no significant medical
history.
10946..................... Multi DS--(1) ThermoChrome 42 yo F used Thermochrome 5000, 1 capsule twice
5000, (2) Isotonic Vitamin daily for 3 days for weight loss. She was also
B12, & (3) Isotonic OPC3 (1) taking B12 and an antioxidant supplement. She
Health Power Products Inc./ developed a rash over her entire body and stopped
Market America; (2) & (3)-- all three products. She restarted the Thermochrome
Labels unavailable. 5000 after 3 days and 3 days after that, on a
visit to her doctor for a nonproductive cough and
congestion, was found to be hypertensive (170/
114). She has no history of hypertension and was
seen by her gynecologist 1 week before starting
the Thermochrome with a normal blood pressure (120/
78).
10957..................... E'Ola Amp II Pro Drops--E'OLA 34 yo F used E'Ola AMP II Pro Drops according to
Bio-genics, Inc. label directions, off and on over a 2 year period
for weight loss. She developed ``triple vision''
which lasted a few moments and recurred 3 days
later accompanied by vertigo. She was initially
seen in an ER, where examination and CT were
normal and she was diagnosed with dehydration. She
spent 3 days in bed with severe vertigo, nausea,
and vomiting. She was unable to reach out and pick
up a drinking glass. An MRI showed multiple
bilateral cerebellar infarcts. No source of
embolization was identified. Cardiovascular,
autoimmune, and coagulopathy workups were
unremarkable.
10960..................... Blast and Burn--Vita Labs Inc.. 16 yo F used Blast and Burn as directed on the
package for several weeks for performance as a
high school athlete. Within the first week of use
she was taken to the ER with a racing heart. She
had several similar episodes. She couldn't afford
to buy a second bottle of the product and noticed
her symptoms resolved once she stopped using the
product.
10974..................... ShapeFast--Shaperite Concepts 19 yo F took Shaperite, one before each meal, three
Ltd. 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
ER. CT and EEG were normal. Neurologist's
evaluation found no other risk factors for
seizure. No other products used, no significant
past history noted.
10977..................... Emphora Ecstasy--Label 18 yo F took Emphora Ecstasy, 4 pills at once, to
unavailable. get high. About 2 hours later she noted dizziness,
racing heart and felt she would pass out if she
stood up. She was unable to sleep for most of that
night. The next morning she passed out in the
shower, injuring her neck and back. She went to
the ER where the only abnormality noted was a low
potassium of 3.1 meq/L (normal 3.6-5.2). She has
had dizziness in the past but no previous loss of
consciousness. The product was not used again and
her symptoms resolved.
10989..................... Herbal Ecstasy--Label 18 yo F used Herbal Ecstasy, 5 pills at once, one
unavailable. time as directed to get high at a Lolapalooza
concert. She felt ``numb, weird'' and fell
backwards. She was unable to sleep for 3 nights in
a row. Over the next 8 months, she had difficulty
sleeping, refused to leave the house unless her
parents insisted and did not attend college as
planned in the fall. She has been diagnosed with
panic attacks and depression and is currently
under psychiatric treatment. She has also been
diagnosed with a ``weak heart valve.''
10990..................... Tri-Chromaleane--Achievers 58 yo M used Tri-Chromaleane, 3 pills once daily
Unlimited. for 6 weeks for weight loss. He developed memory
problems. He couldn't remember his son's middle
name, his office phone number or how to get home
from a local store. He would start work and be
unable to remember why he had started the task or
what to do next. He stopped the product and his
symptoms resolved over the next 2 weeks. At the
same time he had been participating in a clinical
trial of Proscar for the prevention of prostate
cancer and does not know whether he had been
taking Proscar or placebo. The Proscar study
coordinator reported that it was unlikely that the
consumer's complaints were related to Proscar. Of
note, he never had prostate cancer.
[[Page 30721]]
10991..................... Tri-Chromaleane--Achievers 54 yo F used Tri-Chromaleane, at less than the
Unlimited. recommended amount, once daily for a number of
weeks. She was under treatment for hypertension
and was told by the distributor that the product
would lower her blood pressure. After starting the
product her blood pressure increased and her
doctor added a second medication and her blood
pressure improved. She was unable to pass an
insurance physical due to her inadequately
controlled high blood pressure. She stopped the
Tri-Chromaleane and her blood pressure has
improved to the point that her doctor is planning
to stop the second blood pressure medication to
see if she can be controlled on a single
medication (as she was before using the Tri-
Chromaleane).
11050..................... ThermoChrome 5000--Health Power 63 yo F took 2-3 pills bid, for 2 months for weight
Products. loss. She was taking Lescol for
hypercholesterolemia, Zantac for esophageal reflux
and Vasotec for hypertension. She developed
worsening of her hypertension (174/93) and
episodes of palpitations. She sought medical
assistance from a neighbor who is a physician
after an especially severe episode of
palpitations. After stopping products BP
normalized (140/80) and palpitations resolved.
11062..................... Power Trim--Enrich 42 yo F used 2-3 caps before meals tid as directed
International. for 3 months for weight loss. She was taken to
hospital by ambulance after family members found
her seizing. She had another seizure while being
examined by neurologist. She complained of
increased headaches and slow thinking in the days
preceding her stroke and was taking penicillin for
a dental abscess. CT and MRI showed a small R-
sided intracerebral hemorrhage. MRI and
angiography revealed no evidence of any vascular
abnormality. She was treated with Dilantin.
11065..................... Thermo Slim--Weight Loss 23 yo F used product, 1 tab before meals 3 times
Specialist. per day with The Accelerator Guarana, 1 tab before
AM and noon meals, for 8 days. On the 9th day she
forgot to take her noontime dose. At first she
thought she might be going into withdrawal, took
another dose and vomited shortly afterwards. She
was taken to the ER with complaints of a racing
heart, dizziness, numbness of face and arms, and
disorientation. The doctor advised her to stop the
products and over the next week her symptoms
resolved.
11078..................... Formula One with Quick Start-- 36 yo F used Formula One for 2 yrs, stopped that
Alliance U.S.A. product and then took Quick Start 2 caps which she
used once. The next morning she experienced grand
mal seizures. She was taking 2 iron tablets,
Ionamin 30 (a dietary supplement) and B12 liquid;
also had switched to the night shift. CT, MRI, and
EEG were normal.
11081..................... Herbal Ecstacy--Label M used Herbal Ecstacy, 10 pills once, to get high.
unavailable. He states he became ``psycho,'' very active,
developed a ``bad mood'' and assaulted a friend.
His symptoms resolved and he did not try the
product again.
11105..................... Trim Easy--TeamUp International 31 yo F used Trim Easy for about 1 year for weight
Inc. loss. She originally used 2 capsules three times
daily for 1 month and then increased to 3 capsules
three times daily (9 total). The directions
advised beginning at 2 capsules three times per
day and increasing if tolerated to 3 capsules
three times per day, the maximum recommended dose.
At times she would forget one of the 3 doses and
double up the next time she took the product (6
capsules at once). She continued to take a total
of 9 capsules this way daily for about 3 months
and then decreased to a total of 6 capsules taken
all at once each day for about 8 months. She
developed dizzy spells which increased over 1
month's time to twice daily and eventually
suffered a stroke--an intracerebral hemorrhage
with Lft hemiparesis and aphasia. CT and MRI
documented the bleed, showing midline shift.
Cerebral angiogram did not show any additional
abnormality such as an arteriovenous malformation.
11106..................... Therma Slim--Great American 47 yo F used 1 pill at breakfast and 1 at lunch for
Products. 2 months. She developed profuse sweating,
trembling and HTN, and menstrual bleeding which
lasted 6 wks. She was treated first with
Megesterol and then with Premarin and Provera, by
gynecologist. It was also noted that her BP had
risen from 110/70 (3/18/96) to 156/98 (4/10/96).
She complained to radio station where she
originally heard about product and received a
letter telling her side effects she was
experiencing were normal and would quickly
subside. 4/11/96--Consumer contacted her HMO after
seeing broadcast on ephedra and was advised to
stop using product. 6/1/96--This consumer later
suffered a pontine stroke and requires an
endotracheal tube and feeding tube for long-term
ventilatory and nutritional support, respectively.
Estrogen use was implicated as a possible
contributing factor by health care provider.
11107..................... Diet Fuel--Twin Laboratories, 42 yo M used Diet Fuel, 3 pills daily for 9 months.
Inc. He became dizzy, nauseated, developed left sided
chest pain, passed out in a meeting. Paramedics
noted his pulse to be in the 30's and he was
hospitalized. After cardiology evaluation and
electrophysiologic studies it was concluded that
the consumer had an abnormal vasodepressor
response to tilt plus catecholamine administration
and was placed on Tenormin. The consumer reports a
similar episode many years prior and as a young
man treated with Dilantin for what was diagnosed
as epilepsy.
11109..................... Unspecified E'OLA product-- 46 yo F used two E'OLA products, an energy product,
E'OLA Bio-genics, Inc. 2 drops twice daily, and a metabolism booster, 4-5
drops twice daily, both for 1\1/2\ weeks, for
energy and weight loss. She developed a heart rate
of 200 beats per minute and sought medical
attention. Medical records describe evaluation for
recurrent paroxysmal palpitations for 20 years. No
mention of the use of E'Ola products. Blood
pressure, pulse, EKG, echocardiogram, exercise
stress test failed to reveal an underlying cardiac
disorder.
[[Page 30722]]
11112..................... Thinner Jizer--Quiet Storm..... 34 yo F used Thinner Jizer 1 pill for 1 day, 1 pill
twice daily, then 2 pills in AM and 1 pill in PM,
increasing as directed. After 3 days on the
highest amount (2 pills AM and 1 pill PM) she
developed jitters and was advised by the
distributor to cut back the dose as this response
was normal. She used 1 pill AM and 1 pill PM for
an additional 3 days when she developed acute
visual changes in her right eye lasting 25
minutes. She sought medical care and was advised
that her symptoms were likely due to vascular
spasm, possibly related to her use of ephedra. She
stopped the product, took aspirin for 1 week and
has had no further episodes of acute visual
changes. She was taking no other products and has
no significant prior history.
11114..................... Herbal Ecstacy--Label 16 yo M used Herbal Ecstacy, 2 pills one time. Half
unavailable. an hour later he found himself driving down the
wrong side of a road and didn't realize it until
he saw a car headed towards him. He described
feeling ``a major rush, tingly, hyper.'' He denies
taking other products including drugs, alcohol, or
street-type drugs at the time. He occasionally
uses ginkgo biloba, but had not taken any that
day.
11131..................... Multi DS--(1) Herbal Ecstacy & 20 yo M used Herbal Ecstacy, 5 pills one time as
(2) Nirvana--(1) Global World directed, for recreational purposes. He also took
Media & (2) Label unavailable. 6 Nirvana pills one time (directions recommend 7
pills) also for recreational purposes. He went to
a club and began to feel dizzy, lightheaded and
nauseous. He noted stomach cramps, thirst, and a
``real bad headache.'' His symptoms forced him to
leave the dance floor, feeling he was going to
pass out. He fell on his knees, started ``seeing
things'' and felt his seeing and hearing were
distorted. He noted shortness of breath,
sleeplessness, and hives. His symptoms resolved by
the next day. He denies alcohol, other drug or
product use that night.
11134..................... Multi DS--(1) Ripped Fuel, (2) 23 yo M college student who used multiple dietary
The Ultimate Whey Designer supplements for approximately 2 years with
Protein, (3) Super Amino 2000, observed daily use during the year prior to being
(4) Super Once-A-Day Timed found dead at home by his sister. There was no
Release Multiple Vitamins and previous medical history and no evidence of trauma
Chelated Minerals--(1) Twin or substance abuse. Toxicology screens were
Laboratories, Inc. (2) Next negative for alcohol, barbiturates, cocaine,
Nutrition Inc. (3) Ultimate methamphetamine, morphine, and salicylate but
Nutrition Products Inc. (4) indicated the presence of ephedrine alkaloids in
Quest Vitamins LTD. the urine. The Medical Examiner's reports states
the cause of death as, ``patchy necrosis
associated with ephedrine toxicity from protein
drink containing ma huang extract.'' Review of
health examination reports from the University
Health Service indicate the consumer was in
excellent health with normal weight, height, blood
pressure, and laboratory measurements.
11137..................... Natural Trim--Starlight 39 yo F used product for 6.5 months, 1 thermogenic
International. pill, 1 vitamin and 1 booster pill at 10 AM, and 1
thermogenic pill at 4 PM, as directed. While on
antibiotics for a sore throat, she developed upset
stomach and stopped the products. She became
shaky, weak, and exhausted, and felt as if she
were about to pass out if she tilted her head. She
was diagnosed with hyperthyroidism. She also
reports her supplier has stopped selling the
product as the seller has suffered seizures.
11140..................... Power Trim--Enrich 59 yo F used Power Trim and later Power Prime and
International. has had a total of 3 vertigo attacks: 2/96, 4/96,
and the third at an unspecified time. She has been
to the ER and seen her physician.
11144..................... Metabolift--Twin Laboratories, 28 yo M used Metabolift for 10 months, 1 cap 1-2
Inc.. times daily for energy. While visiting a rental
property with his father's truck, his father had
found him bloody, walking away from the garage,
and responding inappropriately. He has transient
retrograde amnesia. In the emergency room his
blood pressure was 168/90, and pulse was 116. CT
head EKG were normal. He was diagnosed with
syncope and a closed head injury. The next week
the consumer had an EEG, echocardiogram, and MRI
of the head--all normal. His neurologist stated
``most likely he had a seizure secondary to the
ephedrine'' from the health food substance he was
taking. He was advised to avoid the product and
dispose of it. He was on no other medication, has
no significant past medical history and has never
had problems with dizziness or passing out.
11180..................... Nature's Nutrition Formula One-- 41 yo F used Nature's Nutrition Formula One
Alliance U.S.A. Inc. (Alliance) 1-2 pills in AM and 1-2 pills PM for
about 6 months for energy. One morning she took 2
pills, skipped breakfast and drank a diet Pepsi.
Soon after she developed hives while visiting a
nursing home and was given benadryl tablets. Two
hours after taking the Formula One she was found
unconscious in a stairwell by nursing personnel
who described seizure activity. She was taken to
an ER where the evaluation including EEG and CT
scan was normal. She has not used the product
again and has had no further episodes.
11181..................... Multi DS--(1) Ripped Fuel & (2) 19 yo M used Ripped Fuel 2 pills 2-3 times daily,
Unspecified chromium according to label directions, for 2 days for
picolinate with caffeine weight-loss and body-building. He was found by
product--(1) Twin family members on the morning of the third day, in
Laboratories, Inc., (2) GNC. his bed with seizure activity and afterward
complained of dizziness and a headache. He was
taken to the ER and given IV Dilantin. CT and MRI
were normal and EEG was nonparoxysmal. He had also
been taking chromium picolinate, 1 pill daily as
directed for 3-4 months; Phosphagen, 1 teaspoon
with meals, three times per day as directed for 3-
4 months; and B2G vanadyl sulfate, 2 capsules with
meals, three times per day, as directed for 1
month at the time of the event. Based upon the
test results and history of use of the Ripped
Fuel, his neurologist felt the patient did not
need to be treated with Dilantin. The neurologist
advised the patient to stop use of all ``over-the-
counter medications''. The patient suffered a
second witnessed seizure 1 month later and was
started on Dilantin. His past history is
significant for a concussion as a child with a
normal CT at the time.
[[Page 30723]]
11215..................... Multi DS--Ripped Fuel and 24 yo M used Ripped Fuel, 2 tablets three times
Ripped Force--Label daily for 2 years and Ripped Force, 1 bottle daily
unavailable. for 2 months. He used both products for body
building. He went on vacation, stopped the
products and within 3 days experienced 2 grand mal
seizures. The second seizure was witnessed by the
ambulance crew while en route to the ER. MRI of
head and EEG were both reportedly normal. He was
also using `vanadyl', creatine, and amino acids as
part of his body building regimen. He denied use
of recreational drugs, medications, or other
products.
11248..................... (1) Formula One, (2) Equilizer, 37 yo M used products 2 yr (and had used other
(3) Protein Plus Chromium products containing ephedrine prior to use of
Picolinate, (4) Fast Start-- Formula One). (Formula One use: 1-2 cap mid AM &
(1) Alliance U.S.A., Inc, (2), PM, per label instructions). Also known to consume
(3), (4) Equinox Intl. large amount of diet cola. Experienced apparent
sudden cardiac arrest, with no details known
surrounding death. Coroner's report notes:
cardiomegaly w/mild LVH, focal interstitial
fibrosis & mild medial hypertrophy. PMH: neg for
HTN. Tox screen noted pseudoephedrine in urine.
11249..................... Victory Turbo Pump--Joe Wider 20 yo M took product for 3 months (once or twice
Nutrition. per week), experienced grand mal seizure. Neg.
past history and family history for seizure
disorders. He was treated with Dilantin.
11286..................... Breathe Easy Herbal Tea-- 36 yo F used Breathe Easy Herbal Tea on one
Traditional Medicinals. occasion at less than recommended dose. She
steeped tea for 1 minute and drank \1/3\ cup
instead of steeping tea for 5 min as indicated on
the instructions. She used product along with 2
Advil to relieve cold/congestion symptoms.
Approximately 15 min after drinking tea she
experienced rapid, pounding heartbeat. Following
advice of friend who is a nurse, she drank large
amounts of water in effort to ``flush tea out of
her system.'' She felt so bad she could hardly get
out of bed, but did not seek medical care
secondary to anxiety about hospitals. Symptoms
resolved completely within 5 hours. Routine
medical visit approx 1 month after event was
unremarkable. Past medical history is significant
for occasional palpitations. Consumer's husband
used product on several occasions prior to event
with no report of negative side effects.
11298..................... (1) Fast Start-The Equilizer, 41 yo M used 3 herbal products as directed on
(2) Nigh Time, (3) Protein labels in an attempt to lose weight. He
Plus, Chromemate--Equinox experienced a ``rush'', and blurred vision which
International. influenced his ability to operate heavy equipment.
On 5th day of using the product, his underwear was
noted to be stained red. A physician visit
confirmed hematuria, and noted BP of 136/102, and
labs: SGPT 72, cholesterol 208, triglycerides 401.
He stopped the product, with recovery, including
normalization of BP.
11401..................... Ultra Energy Now--Phoenix 42 yo M used Energy Now tablets on 2 separate
Health Products. occasions. He took 3 tablets as instructed on
label on both occasions. First occasion was
without incident. 2 weeks later when he used
product for second time, he experienced severe
diaphoresis, blurred vision, SOB, lightheadedness,
and pounding chest pain within 1 hour of taking
product. Symptoms lasted approx 15 min and had
resolved completely by the time he was seen in
emergency room. He was admitted to hospital
overnight for evaluation including EKG, CBC, & SMA-
18 which was all within normal limits. Of note, he
was not using any other products. History is
significant only for positive tobacco history=1.5
pack of cigarettes per day.
11417..................... Thermojetics Herbal Tablets-- 34 yo F died following diagnosis of primary
Green--Herbalife International. pulmonary hypertension (PPH). Mother of deceased
found bottles of Herbalife Green & Beige tablets
in home of the deceased. Duration and detail of
use are unknown. Deceased appeared to be in
excellent health until approx. 3 months prior to
her death when she developed SOB & n/v while
skiing in Colorado despite numerous previous ski
trips in same location which were uneventful. She
was diagnosed with ``high altitude sickness.''
Symptoms persisted and she subsequently underwent
cardiac catheterization 3 months after onset of
sxs. Results of cath were apparently consistent
with PPH and indicated that she would need heart/
lung transplant in 3-5 years. She died 3 days
later in August 94. Past medical history is
significant only for hospital admission 1 year
prior to death for CP, SOB, and possible
pneumonia.
11441..................... Ripped Fuel--Twin Laboratories, 27 yo M died secondary to injuries sustained in
Inc. motor vehicle accident. Wife of deceased reports
he had been taking Ripped Fuel 2 tabs bid as
instructed on label for approx. 3 years prior to
death. No autopsy was performed. Post mortem blood
analysis indicate: 0.05 percent ethyl alcohol &
0.31 percent mg/L phentermine. Post mortem urine
analysis: Positive for phentermine, negative for
cocaine, opiates, benzodiazepine, cannabinoids.
11442..................... Thermojetics Herbal Tablets-- 39 yo F used Herbalife Diet Plan which consisted of
Green--Herbalife International. the following 5 products: Formula 1 Protein Drink
Mix (2 tablespoon bid); Formula 2 Multivitamin-
Mineral Tablet (1 tablet tid); Formula 3 Cell
Activator Capsules (2 capsule bid); Herbal Beige
Tablet (1 tablet bid); Herbal Green Tablet (3
tablet bid) all taken as directed on label. No
other products were being used at the time she
developed the adverse events. 3-4 months after
starting plan, she began experiencing blurred
vision and headache. 2 weeks later she began
experiencing dizziness, lightheadedness, slurred
speech, and numbness on right side of her body.
Evaluation by neurologist indicated patchy sensory
deficit in right leg, most pronounced in foot. MRI
of brain showed findings consistent with recent
hemorrhage associated with cavernous malformation.
Evaluation by internist indicated negative w/u for
Lyme disease and no additional significant
findings. Symptoms improved after consumer
discontined use of products.
[[Page 30724]]
11619..................... AMP II Drops--E'OLA Bio-genics, 35 yo F used Liquithin & AMP II Pro (both 7 drops
Inc. bid) and Citrin Trim (2 tablet/day) for 1 day and
developed migraine headache which she typically
experiences every month. She awoke at 3 AM on
morning after using products with notable right
sided facial weakness, CP, palpitations, right arm
weakness and numbness, photophobia, and unsteady
gait. She was seen by doctor and admitted to
hospital. Symptoms improved during hospitalization
which was uneventful. All test results were within
normal limits except cerebral arteriogram findings
which suggested mycotic aneurysmal change or
possible changes secondary to an unusual drug
induced vasculitis or collagen vascular disease.
Discharge dxs included: right facial and arm
weakness, cause uncertain; improving right eye
irritation; resolving headache; resolved chest
pain & palpitations with neg w/u; and history of
right C5-6 cervical radiculopathy, carpal tunnel
syndrome. Sxs continued to improve in month
following discharge. History is significant for:
Classical migraine headache associated with right
jaw tingling; cardiac murmur with prior
evaluation; allergy to iodine dye (tachycardia);
and habit of drinking 1.5 quart of caffeinated
soda daily.
----------------------------------------------------------------------------------------------------------------
Abbreviations Used in Clinical Summaries in the Appendix
abn = abnormal
angio = angiography
ant = anterior
AF = atrial fibrillation
bid = twice a day
BP = blood pressure
CAD = coronary artery disease
Cap/caps = capsule(s)
cath = catheterization
CBC = complete blood count
CK (CPK) = creatine kinase
cm = centimeter
CP = chest pain
CPR = cardiopulmonary resuscitation
CT = computerized tomography
CV = cardiovascular
CXR = chest X-ray
d/c = discontinue or discharge
DTR = deep tendon reflexes
Dx(s) = diagnosis(es)
EEG = electroencephalogram
EKG = echocardiogram
EMG = electromyography
ER = emergency room
ETOH = ethanol
F = female
f/u = followup
fxn = function
GPT = alanine aminotransferase
h/o = history of
HA = headache
HTN = hypertension
ICU = intensive care unit
IEP = immunoelectrophoresis
inf = inferior
L = left or liter
LFT = left
lb = pound
LV = left ventricle
M = male
MB+ = MB positive
MD = medical doctor
meq = milliequivalents
MI = myocardial infarction
min = minutes
MRI = magnetic resonance imaging
neg = negative
nitro = nitroglycerin
n/v = nausea and vomiting
PE = physical examination
PMH = past medical history
q = every
qd = everyday
R = right
SGPT = serum GPT
SOB = shortness of breath
SSx = signs & symptoms
ST/STT = ST-T waves
subl = sublingual
SVT = supraventricular tachycardia
tab(s) = tablet(s)
tach(y) = tachycardia
tid = 3 times a day
tox = toxicological
TPA = tissue plasminogen activator
Tx = treatment
w/ = with
w/o = without
w/u = workup
WL&E = weight loss & energy
wnl = within normal limits
yo = years old
yr = year
[FR Doc. 97-14393 Filed 6-2-97; 8:45 am]
BILLING CODE 4160-01-P
