[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]]

_______________________________________________________________________

Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 111



Dietary Supplements Containing Ephedrine Alkaloids; Proposed Rule

  Federal Register / Vol. 62, No. 107 / Wednesday, June 4, 1997 / 
Proposed Rules  

[[Page 30678]]


=======================================================================
-----------------------------------------------------------------------


DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 111

[Docket No. 95N-0304]
RIN 0901-AA59


Dietary Supplements Containing Ephedrine Alkaloids

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to make a 
finding, which will have the force and effect of law, that a dietary 
supplement is adulterated if it contains 8 milligrams (mg) or more of 
ephedrine alkaloids per serving, or if its labeling suggests or 
recommends conditions of use that would result in intake of 8 mg or 
more in a 6-hour period or a total daily intake of 24 mg or more of 
ephedrine alkaloids; require that the label of dietary supplements that 
contain ephedrine alkaloids state ``Do not use this product for more 
than 7 days''; prohibit the use of ephedrine alkaloids with 
ingredients, or with ingredients that contain substances, that have a 
known stimulant effect (e.g., sources of caffeine or yohimbine), which 
may interact with ephedrine alkaloids; prohibit labeling claims that 
require long-term intake to achieve the purported effect (e.g., weight 
loss and body building); require a statement in conjunction with claims 
that encourage short-term excessive intake to enhance the purported 
effect (e.g., energy) that ``Taking more than the recommended serving 
may result in heart attack, stroke, seizure or death''; and require 
specific warning statements to appear on product labels. 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  
----------------------------------------------------------------------------------------------------------------
          Organ/system involved              Clinical significance                 Signs and symptoms           
----------------------------------------------------------------------------------------------------------------
Cardiovascular system...................  Serious....................  Dysrhythmias, severe hypertension,       
                                                                        cardiac arrest, angina, myocardial      
                                                                        infarction, and stroke \1\              
                                          Less clinically significant  Tachycardia, mild hypertension,          
                                                                        palpitations.                           
Nervous system..........................  Serious....................  Psychosis, suicidal, altered or loss of  
                                                                        consciousness (including disorientation 
                                                                        or confusion), and seizures.            
                                          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.                     
----------------------------------------------------------------------------------------------------------------
\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.

BILLING CODE 4160-01-P

[[Page 30681]]

[GRAPHIC] [TIFF OMITTED] TP04JN97.000


BILLING CODE 4160-01-C

[[Page 30682]]

    Many of these reports have been for clinically significant events 
(e.g., heart attack, stroke, seizures) that were observed most often in 
young adults for whom the risk of these types of events are generally 
low (see Figure 2, which summarizes data from the AER's relative to the 
age and gender of individuals experiencing an adverse event). When FDA 
examined the products reported to be associated with the CVS and NS 
effects, the most common element among them was that they involved 
products that contained or were believed to contain an ingredient 
source of ephedrine alkaloids. Thus, FDA focused its investigation on 
the ephedrine alkaloids in dietary supplement products.

BILLING CODE 4160-01-P
[GRAPHIC] [TIFF OMITTED] TP04JN97.001


BILLING CODE 4160-01-C
    However, many of the ephedrine alkaloid-containing products also 
contained other ingredients (e.g., amino acids, vitamins and minerals, 
other botanicals) whose possible influence on the observed AER's could 
not be ignored. Upon examination of the types of other ingredients, FDA 
tentatively concluded that these other ingredients should not be the 
primary focus of its evaluation because these ingredients, unlike the 
ephedrine alkaloids, did not have a history (in the amounts likely to 
be found in dietary supplements) of being able to produce the types of 
serious adverse events being observed. For example, many ephedrine 
alkaloid-containing dietary supplements also contain known stimulants 
(e.g., sources of caffeine). While caffeine is known to stimulate the 
NS, in the amounts likely to be found in dietary supplements it is not 
expected to produce effects such as stroke, heart attack, and seizure. 
Nonetheless, FDA remained aware of the possibility that other 
ingredients in these dietary supplement products contributed to the 
adverse events reported. For example, other stimulants in the 
ephedrine-containing dietary supplements could enhance the known 
stimulant effects of ephedrine alkaloids. Likewise, substances that 
affect kidney function (e.g., sources of salicin, concentrated amino 
acids) could influence the body's ability to ``clear'' or rid itself of 
ingested ephedrine alkaloids.
    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

[[Page 30683]]

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).

BILLING CODE 4160-01-P
[GRAPHIC] [TIFF OMITTED] TP04JN97.002


BILLING CODE 4160-01-C

    Adverse events appear to reflect different inherent types of 
individual sensitivities relative to dose levels, frequency or duration 
of use, and subsequent results of sympathomimetic stimulation. In some 
cases, particular events appear to occur as the result of increased 
individual susceptibility to the effects of sympathetic stimulation 
(Refs. 39 through 42). For example, in one report (ARMS No. 10862 in 
the Appendix to this document), three young adult males consumed 
similar amounts of a dietary supplement containing ephedrine alkaloids, 
yet only one male experienced serious adverse effects, which resulted 
in his death (see Police and Medical Examiner's Reports in ARMS No. 
10862 in public docket number 95N-0304). 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

[[Page 30685]]

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

[[Page 30694]]

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

[[Page 30695]]

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.

[[Page 30696]]

    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

[[Page 30697]]

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

[[Page 30698]]

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.
    15. Kalix, P., ``The Pharmacology of Psychoactive Alkaloids from 
Ephedra and Catha,'' Journal of Ethnopharmacology, 32:201-208, 1991.
    16. Karch, S. B., ``Synthetic Stimulants,'' In ``The Pathology 
of Drug Abuse,'' edited by Karch, S. B., Boca Raton: CRC Press, 199-
240, 1996.
    17. ``Over-the-counter Products: Phenylpropanolamine,'' In 
``Medical Toxicology,'' edited by Ellenhorn, M. J., and D. G. 
Barceloux, New York: Elsevier, 514-520, 1988.
    18. Sawyer, D. R., C. S. Conner, and B. H. Rumack, ``Managing 
Acute Toxicity from Nonprescription Stimulants,'' Clinical Pharmacy, 
1:529-533, 1982.
    19. Brater, D. C., S. Kaojarern, L. Z. Benet, E. T. Lin, T. 
Lockwood, R. C. Morris, E. J. McSherry, and K. L. Melmon, ``Renal 
Excretion of Pseudoephedrine,'' Clinical Pharmacology and 
Therapeutics, 28:690-694, 1980.
    20. Kanfer, I., R. Dowse, and V. Vuma, ``Pharmacokinetics of 
Oral Decongestants,'' Pharmacotherapy, 13:116S-128S, discussion 
143S-146S, 1993.
    21. Tab J: Appendices, Briefing Materials for Food Advisory 
Committee Special Working Group on Foods Containing Ephedrine 
Alkaloids, Appendix 2, 1995.
    22. Lake, C. R., D. B. Rosenberg, S. Gallant, G. Zaloga, and B. 
Chernow, ``Phenylpropanolamine Increases Plasma Caffeine Levels,'' 
Clinical Pharmacology and Therapeutics, 47:675-685, 1990.
    23. ``Caffeine-Phenylpropanolamine,'' Drug Interaction Facts, 
Facts and Comparisons, p. 168a, 1996.
    24. Brown, D., ``Energy Pills, Ma Huang and Media,'' Herbal 
Update and Natural Health Care Quarterly, NPRC, Inc., p. 51-53, Fall 
Quarter, 1993.
    25. Meeting Transcript, Food Advisory Committee on Dietary 
Supplements Containing Ephedrine Alkaloids, August 27-28, 1996.
    26. Tab H: Market Review. Briefing Materials for Food Advisory 
Committee Special Working Group on Foods Containing Ephedrine 
Alkaloids, p. 3, 1995.
    27. Meeting Transcript, Food Advisory Committee, Special Working 
Group on Foods Containing Ephedrine Alkaloids, October 11-12, 1995.
    28-29. Tab D: Minutes of the Special Working Group on Food 
Products Containing Ephedrine Alkaloids of the FDA Food Advisory 
Committee. Briefing Materials for Food Advisory Committee on Dietary 
Supplements Containing Ephedrine Alkaloids, pp. 1-8, August 27-28, 
1996.
    30. Briefing Materials for Food Advisory Committee Special 
Working Group on Foods Containing Ephedrine Alkaloids, October 11-
12, 1995.
    31. Love, L. A.: Tab E: Evaluation of the Safety of Food 
Products Containing Sources of Ephedrine Alkaloids. Briefing 
Materials for Food Advisory Committee Special Working Group on Foods 
Containing Ephedrine Alkaloids, pp. 1-51, 1995.
    32. ``Illnesses and Injuries Associated with the Use of Selected 
Dietary Supplements. In Unsubstantiated Claims and Documented Health 
Hazards in the Dietary Supplement Marketplace,'' Department of 
Health and Human Services (DHHS), FDA, 100-105, 1993.
    33. ``Adverse Events with Ephedra and Other Botanical Dietary 
Supplements,'' FDA Medical Bulletin, 24:3, 1994.
    34. ``Adverse Events Associated with Ephedrine-containing 
Products--Texas, December 1993-September 1995,'' Morbidity and 
Mortality Weekly Report, 45:689-693, 1996.
    35. Jones, J. K., ``Approaches to Evaluating Causation of 
Suspected Drug Reactions,'' In ``Drug Epidemiology and Post-
Marketing Surveillance,'' edited by Strom, B. L., and G. Velo, New 
York: Plenum Press, 103-113, 1992.
    36. Stephens, M. D. B., Detection of new adverse drug reactions, 
Houndsmills, Macmillan, 1992.
    37. Fletcher, A. P., and J. P. Griffin, ``An Appraisal of 
Spontaneous Adverse Event Reporting,'' Adverse Drug Reactions 
Toxicological Reviews, 11:213-227, 1992.
    38. Briefing Materials for Food Advisory Committee on Dietary 
Supplements Containing Ephedrine Alkaloids, August 27-28, 1996.
    39. Insel, P. A., and H. J. Motuksky, ``Physiologic and 
Pharmacologic Regulation of Adrenergic Receptors,'' In ``Adrenergic 
Receptors in Man,'' edited by Insel, P. A., New York: Marcel Dekker, 
Inc., 201-236, 1987.
    40. Stiles, G. L., ``Drug and Hormonal Regulation of the Beta-
adrenergic Receptor-adenylate Cyclase System,'' In ``The Beta-
Adrenergic Receptors,'' edited by Perkins, J. P., Clifton: Humana 
Press Inc., 345-387, 1991.
    41. Insel, P. A., ``Beta-Adrenergic Receptors in 
Pathophysiologic States and in Clinical Medicine'' In ``The Beta-
Adrenergic Receptors,'' edited by Perkins, J. P., Clifton, NJ: 
Humana Press, 295-343, 1991.
    42. Bravo, E. L., ``Metabolic Factors and the Sympathetic 
Nervous System,'' American Journal of Hypertension, 2:339S-344S, 
1989.
    43. Weil, A., ``Preventative Maintenance'' In ``Natural Health, 
Natural Medicine,'' New York: Houghton Mifflin Co., 3-151, 1995.
    44. Pentel, P., ``Toxicity of Over-the-Counter Stimulants,'' 
Journal of the American Medical Association, 252:1898-1903, 1984.
    45. Cho, A. K., and Y. Kumagai, ``Metabolism of Amphetamine and 
Other Arylisopropylamines'' In ``Amphetamine and its Analogs. 
Psychopharmacology, Toxicology, and Abuse,'' edited by Cho, A. K., and 
D. S. Segal, London: Academic Press, Inc., 43-77, 1994.
    46. ``Over-the-counter Products'' In ``Medical Toxicology,'' edited 
by Ellenhorn, M. J., and D. G. Barceloux, New York: Elsevier, 501-559, 
1988.
    47. Hoffman, B. B., and R. J. Lefkowitz, ``Catecholamines and 
Sympathomimetic Drugs'' In ``Goodman and Gilman's The Pharmacological 
Basis of Therapeutics,'' edited by

[[Page 30714]]

Gilman, A. G., T. W. Rall, A. S. Nies, and P. Taylor, New York: McGraw-
Hill, Inc., 187-220, 1990.
    48. Becker, D. E., ``Clinical Implications of Autonomic Drugs,'' 
Journal of Oral Maxillofacial Surgery, 50:734-740, 1992.
    49. Lynch, J., and M. A. House, ``Cardiovascular Effects of 
Methamphetamine,'' Journal of Cardiovascular Nursing, 6:12-18, 1992.
    50. Pentel, P. R., J. Jentzen, and J. Sievert, ``Myocardial 
Necrosis Due to Intraperitoneal Administration of Phenylpropanolamine 
in Rats,'' Fundamental Applied Toxicology, 9:167-172, 1987.
    51. Karch, S. B., ``Cocaine: Cardiovascular System'' In ``The 
Pathology of Drug Abuse,'' edited by Karch, S. B., Boca Raton: CRC 
Press, 83-124, 1996.
    52. Cardiovascular Toxicity of Cocaine: Underlying Mechanisms. 
National Institute on Drug Abuse Monograph Series, DHHS, 1991.
    53. McCleave, D. J., P. J. Phillips, and A. E. Vedig, 
``Compartmental Shift of Potassium--a Result of Sympathomimetic 
Overdose,'' Australian and New Zealand Journal of Medicine, 8:180-183, 
1978.
    54. Liu, Y. L., S. Toubro, A. Astrup, and M. J. Stock, 
``Contribution of Beta 3-adrenoceptor Activation to Ephedrine-
induced Thermogenesis in Humans,'' International Journal of Obesity, 
19:678-685, 1995.
    55. Sympathomimetics, In ``Martindale The Extra Pharmacopeia,'' 
edited by Reynolds, E. F., London: The Royal Pharmaceutical Society, 
1563-1595, 1996.
    56. Weesner, K. M., M. Denison, and R. J. Roberts, ``Cardiac 
Arrhythmias in an Adolescent Following Ingestion of an Over-the-
Counter Stimulant,'' Clinical Pediatrics, 21:700-701, 1982.
    57. Menegakis, N. E., and M. S. Amstey, ``Case Report of 
Myocardial Infarction in Labor,'' American Journal of Obstetrics and 
Gynecology, 165:1383-1384, 1991.
    58. Whittet, H. B., and D. Veitch, ``Ischemic Chest Pain After 
Abuse of a Topical Nasal Vasoconstrictor,'' British Medical Journal, 
229:860, 1989.
    59. Wilson, A. F., H. S. Novey, P. Cloninger, J. Davis, and D. 
White, ``Cardiopulmonary Effects of Long-term Bronchodilator 
Administration,'' Journal of Allergy and Clinical Immunology, 
58:204-212, 1976.
    60. Wiener, I., A. G. Tilkian, and M. Palazzolo, ``Coronary 
Artery Spasm and Myocardial Infarction in a Patient with Normal 
Coronary Arteries: Temporal Relationship to Pseudoephedrine 
Ingestion,'' Catheterization and Cardiovascular Diagnosis, 20:51-53, 
1990.
    61. Hirabayashi, Y., K. Saitoh, H. Fukuda, H. Mitsuhata, and R. 
Shimizu, ``Coronary Artery Spasm after Ephedrine in a Patient with 
High Spinal Anesthesia,'' Anesthesiology, 84:221-224, 1996.
    62. Pentel, P. R., F. L. Mikell, and J. H. Zavoral, ``Myocardial 
Injury After Phenylpropanolamine Ingestion,'' British Heart Journal, 
47:51-54, 1982.
    63. Clark, J. E., and W. A. Simon, ``Cardiac Arrhythmias After 
Phenylpropanolamine Ingestion,'' Drug Intelligence and Clinical 
Pharmacy, 17:737-738, 1983.
    64. Chua, S. S., and S. I. Benrimoj, ``Non-prescription 
Sympathomimetic Agents and Hypertension,'' Medical Toxicology, 
3(Sep-Oct) pp. 387-417, 1988.
    65. Bernstein, E., and B. M. Diskant, ``Phenylpropanolamine: A 
Potentially Hazardous Drug,'' Annals of Emergency Medicine, 11:311-
315, 1982.
    66. Van Mieghem, W., E. Stevens, and J. Cosemans, ``Ephedrine-
induced Cardiopathy,'' British Medical Journal, 1:816, 1978.
    67. To, L. B., J. F. Sangster, D. Rampling, and I. Cammens, 
``Ephedrine-induced Cardiomyopathy,'' Medical Journal of Australia, 
2:35-36, 1980.
    68. Gaultieri, J., and C. Harris, ``Dilated Cardiomyopathy in a 
Heavy Ephedrine Abuser,'' Journal of Toxicology, Clinical 
Toxicology, 34:581-582 (Abstract), 1996.
    69. Wooten, M. R., M. S. Khangure, and M. J. Murphy, 
``Intracerebral Hemorrhage and Vasculitis Related to Ephedrine 
Abuse,'' Annals of Neurology, 13:337-340, 1983.
    70. Bruno, A., K. B. Nolte, and J. Chapin, ``Stroke Associated 
with Ephedrine Use,'' Neurology, 43:1313-1316, 1993.
    71. Loizou, L. A., J. G. Hamilton, and S. A. Tsementzis, 
``Intracranial Haemorrhage in Association with Pseudoephedrine 
Overdose,'' Journal of Neurology, Neurosurgery, and Psychiatry, 
45:471-472, 1982.
    72. Hirsch, M. S., R. M. Walter, and R. J. Hasterlik, 
``Subarachnoid Hemorrhage Following Ephedrine and MAO Inhibitor,'' 
Journal of the American Medical Association, 194:1259, 1965.
    73. Lake, C. R., S. Gallant, E. Masson, and P. Miller, ``Adverse 
Drug Effects Attributed to Phenylpropanolamine: A Review of 142 Case 
Reports,'' American Journal of Medicine, 89:195-208, 1990.
    74. Glick, R., J. Hoying, L. Cerullo, and S. Perlman, 
``Phenylpropanolamine: An Over-the-counter Drug Causing Central 
Nervous System Vasculitis and Intracerebral Hemorrhage. Case Report 
and Review,'' Neurosurgery, 20:969-974, 1987.
    75. Stoessl, A. J., G. B. Young, and T. E. Feasby, 
``Intracerebral Haemorrhage and Angiographic Beading Following 
Ingestion of Catecholaminergics,'' Stroke, 16:734-736, 1985.
    76. Fallis, R. J., and M. Fisher, ``Cerebral Vasculitis and 
Hemorrhage Associated with Phenylpropanolamine,'' Neurology, 35:405-
407, 1985.
    77. Forman, H. P., S. Levin, B. Stewart, M. Patel, and S. 
Feinstein, ``Cerebral Vasculitis and Hemorrhage in an Adolescent 
Taking Diet Pills Containing Phenylpropanolamine: Case Report and 
Review of Literature,'' Pediatrics, 83:737-741, 1989.
    78. Barinagarrementeria, F., A. Mendez, and F. Vega, ``Cerebral 
Hemorrhage Associated with the Use of Phenylpropanolamine,'' 
Neurologia, 5:292-295, 1990.
    79. Le Coz, P., F. Woimant, D. Rougemont, M. Sanson, D. Laplane, 
M. Haguenau, and B. Pepin, ``Benign Cerebral Angiopathies and 
Phenylpropanolamine,'' Revue Neurologique (Paris), 144:295-300, 
1988.
    80. Mueller, S. M., E. B. Solow, ``Seizures Associated with a 
New Combination Pick-me-up Pill [letter],'' Annals of Neurology, 
11:322, 1982.
    81. Lambert, M. T., ``Paranoid Psychoses After Abuse of 
Proprietary Cold Remedies,'' British Journal of Psychiatry, 151:548-
550, 1987.
    82. Roxanas, M. G., and J. Spalding, ``Ephedrine Abuse 
Psychosis,'' Medical Journal of Australia, 2:639-640, 1977.
    83. Escobar, J. I., and M. Karno, ``Chronic Hallucinosis from 
Nasal Drops,'' Journal of the American Medical Association, 
247:1859-1860, 1982.
    84. Clovis, W. L., ``Mania and Cough Syrup [letter; comment],'' 
Journal of Clinical Psychiatry, 54:200, 1993.
    85. Hall, R. C., T. P. Beresford, S. K. Stickney, C. S. Nasdahl, 
and J. H. Coleman, ``Psychiatric Reactions Produced by Respiratory 
Drugs,'' Psychosomatics, 26:605-608, 615-616, 1985.
    86. Herridge, C. F., and M. F. a'Brook, ``Ephedrine Psychosis,'' 
British Medical Journal, 2:160, 1968.
    87. Ishigooka, J., Y. Yoshida, and M. Murasaki, ``Abuse of BRON: 
A Japanese OTC Cough Suppressant Solution Containing Methlephedrine, 
Codeine, Caffeine and Chlorpheniramine,'' Progress in Neuro-
Psychopharmacology and Biological Psychiatry, 15:513-521, 1991.
    88. Kane, F. J., Jr., and R. Florenzano, ``Psychosis 
Accompanying Use of Bronchodilator Compound,'' Journal of the 
American Medical Association, 215:2116, 1971.
    89. Levine, B., R. Jones, K. Klette, M. L. Smith, and E. 
Kilbane, ``An Intoxication Involving Bron and Verapamil,'' Journal 
of Analytical Toxicology, 17:381-383, 1993.
    90. Loosmore, S., and D. Armstrong, ``Do-Do Abuse,'' British 
Journal of Psychiatry, 157:278-281, 1990.
    91-92. Shufman, N. E., E. Witztum, and A. Vass, ``[Ephedrine 
Psychosis],'' Harefuah, 127:166-167, 1994.
    93. Whitehouse, A. M., and J. M. Duncan, ``Ephedrine Psychosis 
Rediscovered,'' British Journal of Psychiatry, 150:258-261, 1987.
    94. Cobbs, L. W., ``Paranoia in a Polypharmacy Setting,'' 
Hospital Practice (Off Ed), 27:165-168, 1992.
    95. Wood, K. A., ``Nasal Decongestant and Psychiatric 
Disturbance [letter],'' British Journal of Psychiatry, 164:566-567, 
1994.
    96. Puar, H. S., ``Acute Memory Loss and Nominal Aphasia Caused 
by Phenylpropanolamine,'' Southern Medical Journal, 77:1604-1605, 
1984.
    97. Lake, C. R., E. B. Masson, and R. S. Quirk, ``Psychiatric 
Side Effects Attributed to Phenylpropanolamine,'' 
Pharmacopsychiatry, 21:171-181, 1988.
    98. Lake, C. R., R. Tenglin, B. Chernow, and H. C. Holloway, 
``Psychomotor Stimulant-Induced Mania in a Genetically Predisposed 
Patient: A Review of the Literature and Report of a Case,'' Journal 
of Clinical Psychopharmacology, 3:97-100, 1983.

[[Page 30715]]

    99. Leighton, K. M., ``Paranoid Psychosis After Abuse of 
Actifed,'' British Medical Journal, 284:789-790, 1982.
    100. Capwell, R. R., ``Ephedrine-Induced Mania from an Herbal 
Diet Supplement [letter],'' American Journal of Psychiatry, 152:647, 
1995.
    101. Skop, B. P., J. A. Finkelstein, T. R. Mareth, M. R. Magoon, 
and T. M. Brown, ``The Serotonin Syndrome Associated with 
Paroxetine, an Over-the-Counter Cold Remedy, and Vascular Disease,'' 
American Journal of Emergency Medicine, 12:642-644, 1994.
    102. Chopra, R. N., and B. Mukherjee, ``Toxic Effects of 
Ephedrine-A Warning,'' The Indian Medical Gazette, Nov. 622-626, 
1933.
    103. Balyeat, R. M., and H. J. Rinkel, ``Clinical Notes, 
Suggestions and New Instruments: Urinary Retention Due to the Use of 
Ephedrine,'' Journal of the American Medical Association, 98:1545-
1546, 1932.
    104. Wu, S. T., and B. E. Read, ``Ephedrine, N.N.R. A Review 
with Case Reports,'' Chinese Medical Journal (Engl), xli:1010-1016, 
1927.
    105. Astrup, A., L. Breum, S. Toubro, P. Hein, and F. Quaade, 
``The Effect and Safety of an Ephedrine/Caffeine Compound Compared 
to Ephedrine, Caffeine and Placebo in Obese Subjects on an Energy 
Restricted Diet. A Double Blind Trial,'' International Journal of 
Obesity, 16:269-277, 1992.
    106. Toubro, S., A. V. Astrup, L. Breum, and F. Quaade, ``Safety 
and Efficacy of Long-term Treatment with Ephedrine, Caffeine and an 
Ephedrine/Caffeine Mixture,'' International Journal of Obesity, 17 
Suppl 1:S69-S72, 1993.
    107. Quaade, F., A. Astrup, L. Breum, S. Toubro, and P. Hein, 
``[The Effect of an Ephedrine/caffeine Combination as a Supplement 
to a Weight-reducing Diet. A Randomized, Placebo-controlled, Double-
blind Trial],'' Ugeskrift For Laeger, 154:1258-1263, 1992.
    108. Toubro, S., A. Astrup, L. Breum, and F. Quaade, ``The Acute 
and Chronic Effects of Ephedrine/Caffeine Mixtures on Energy 
Expenditure and Glucose Metabolism in Humans,'' International 
Journal of Obesity, 17 Suppl 3:S73-7, 1993.
    109. Astrup, A., C. Lundsgaard, J. Madsen, and N. J. 
Christensen, ``Enhanced Thermogenic Responsiveness During Chronic 
Ephedrine Treatment in Man,'' American Journal of Clinical 
Nutrition, 42:83-94, 1985.
    110. Astrup, A., and S. Toubro, ``Thermogenic, Metabolic, and 
Cardiovascular Responses to Ephedrine and Caffeine in Man,'' 
International Journal of Obesity, 17 Suppl 1:S41-S43, 1993.
    111. Astrup, A., S. Toubro, S. Cannon, P. Hein, L. Breum, and J. 
Madsen, ``Caffeine: A Double-blind, Placebo-controlled Study of its 
Thermogenic, Metabolic, and Cardiovascular Effects in Healthy 
Volunteers,'' American Journal of Clinical Nutrition, 51:759-767, 
1990.
    112. Astrup, A., S. Toubro, S. Cannon, P. Hein, and J. Madsen, 
``Thermogenic Synergism Between Ephedrine and Caffeine in Healthy 
Volunteers: A Double-Blind, Placebo-Controlled Study,'' Metabolism, 
40:323-329, 1991.
    113. Breum, L., J. K. Pedersen, F. Ahlstrom, and J. Frimodt-
Moller, ``Comparison of an Ephedrine/Caffeine Combination and 
Dexfenfluramine in the Treatment of Obesity. A Double-Blind Multi-
Centre Trial in General Practice,'' International Journal of 
Obesity, 18:99-103, 1994.
    114. Pasquali, R., G. Baraldi, M. P. Cesari, N. Melchionda, M. 
Zamboni, C. Stefanini, and A. Raitano, ``A Controlled Trial Using 
Ephedrine in the Treatment of Obesity,'' International Journal of 
Obesity, 9:93-98, 1985.
    115. Pasquali, R., M. P. Cesari, N. Melchionda, C. Stefanini, A. 
Raitano, and G. Labo, ``Does Ephedrine Promote Weight Loss in Low-
Energy-Adapted Obese Women?,'' International Journal of Obesity, 
11:163-168, 1987.
    116. Pasquali, R., F. Casimirri, N. Melchionda, G. Grossi, L. 
Bortoluzzi, A. M. Morselli Labate, C. Stefanini, and A. Raitano, 
``Effects of Chronic Administration of Ephedrine During Very-Low-
Calorie Diets on Energy Expenditure, Protein Metabolism and Hormone 
Levels in Obese Subjects,'' Clinical Science (Colch), 82:85-92, 
1992.
    117. Krieger, D. R., P. A. Daly, A. G. Dulloo, B. J. Ransil, J. 
B. Young, and L. Landsberg, ``Ephedrine, Caffeine and Aspirin 
Promote Weight Loss in Obese Subjects,'' Transactions of the 
Association of American Physicians, 103:307-312, 1990.
    118. P. A. Daly, D. R. Krieger, A. G. Dulloo, J. B. Young, and 
L. Landsberg, ``Ephedrine, Caffeine and Aspirin: Safety and Efficacy 
for Treatment of Human Obesity,'' International Journal of Obesity, 
17 Suppl 1:S73-S78, 1993.
    119. Horton, T. J., and C. A. Geissler, ``Aspirin Potentiates 
the Effect of Ephedrine on the Thermogenic Response to a Meal in 
Obese but Not Lean Women,'' International Journal of Obesity, 
15:359-366, 1991.
    120. Chappel, C. I., G. Rona, T. Balazs, and R. Gaudry, 
``Comparison of Cardiotoxic Actions of Certain Sympathomimetic 
Amines,'' Canadian Journal of Biochemistry, Physiology, 37:35-42, 
1959.
    121. Bray, G. A., ``Use and Abuse of Appetite-suppressant Drugs 
in the Treatment of Obesity,'' Annals of Internal Medicine, 119:707-
713, 1993.
    122. Beck, R. A., D. L. Mercado, S. M. Seguin, W. P. Andrade, 
and H. M. Cushner, ``Cardiovascular Effects of Pseudoephedrine in 
Medically Controlled Hypertensive Patients,'' Archives of Internal 
Medicine, 152:1242-1245, 1992.
    123. Glidden, R. S., and F. J. DiBona, ``Urinary Retention 
Associated with Ephedrine,'' Journal of Pediatrics, 90:1013-1014, 
1977.
    124. Boston, L. N., ``Dysuria Following Ephedrine Therapy,'' 
Medical Times, lvi:94-95, 1928.
    125. Swenson, R. D., T. A. Golper, and W. M. Bennett, ``Acute 
Renal Failure and Rhabdomyolysis After Ingestion of 
Phenylpropanolamine-Containing Diet Pills,'' Journal of the American 
Medical Association, 248:1216, 1982.
    126. Sequeira, R. P., ``Central Nervous System Stimulants and 
Anoretic Agents'' In ``Side Effects of Drugs Annual 16,'' edited by 
Dukes, M. N. G., and J. K. Aronson, Amsterdam: Elsevier, 1-6, 1993.
    127. Schneider, R. P., ``Ischemic Colitis Caused by 
Decongestant?,'' Journal of Clinical Gastroenterology, 21:335-336, 
1995.
    128. Nadir, A., S. Agrawal, P. D. King, and J. B. Marshall, 
``Acute Hepatitis Associated with the Use of a Chinese Herbal 
Product, Ma-Huang,'' American Journal of Gastroenterology, 91:1436-
1438, 1996.
    129. Taylor, B. J., and M. B. Duffill, ``Recurrent Pseudo-
scarlatina and Allergy to Pseudoephedrine Hydrochloride,'' British 
Journal of Dermatology, 118:827-829, 1988.
    130. Serup, J., ``Exfoliative Erythroderma after Taking the 
Elsinore Pill and Accidental Induction with Ephedrine Nose Drops,'' 
Ugeskrift For Laeger, 143:1660-1662, 1981.
    131. Tomb, R. R., ``Systemic Contact Dermatitis from 
Pseudoephedrine,'' Contact Dermatitis, 24:86-88, 1991.
    132. Cavanah, D. K., and Z. K. Ballas, ``Pseudoephedrine 
Reaction Presenting as Recurrent Toxic Shock Syndrome,'' Annals of 
Internal Medicine, 119:302-303, 1993.
    133. Villas Martinez, F., A. J. Badas, J. F. Garmendia Goitia, 
and I. Aguirre, ``Generalized Dermatitis Due to Oral Ephedrine,'' 
Contact Dermatitis, 29:215-216, 1993.
    134. Hauken, M., ``Fixed Drug Eruption and Pseudoephedrine,'' 
Annals of Internal Medicine, 120:442, 1994.
    135. Heydon, J., and P. Pillans, ``Allergic Reaction to 
Pseudoephedrine [letter],'' New Zealand Medical Journal, 108:112-
113, 1995.
    136. Camisa, C., ``Fixed Drug Eruption Due to Pseudoephedrine,'' 
Cutis,  41:339-340, 1988.
    137. Shelley, W. B., and E. D. Shelley, ``Nonpigmenting Fixed 
Drug Eruption as a Distinctive Reaction Pattern: Examples Caused by 
Sensitivity to Pseudoephedrine Hydrochloride and Tetrahydrozoline,'' 
Journal of the American Academy of Dermatology, 17:403-407, 1987.
    138. Krivda, S. J., and P. M. Benson, ``Nonpigmenting Fixed Drug 
Eruption,'' Journal of the American Academy of Dermatology, 31:291-
292, 1994.
    139. Anastasio, G. D., and P. Harston, ``Fetal Tachycardia 
Associated with Maternal Use of Pseudoephedrine, and Over-the-
Counter Oral Decongestant,'' Journal of the American Board of Family 
Practice, 5:527-528, 1992.
    140. Nishikawa, T., H. J. Bruyere, E. F. Gilbert, and Y. Takagi, 
``Potentiating Effects of Caffeine on the Cardiovascular 
Teratogenicity of Ephedrine in Chick Embryos,'' Toxicology Letters, 
29:65-68, 1985.
    141. Kanai, T., T. Nishikawa, A. Satoh, and A. Kajita, 
``Cardiovascular Teratogenicity of Ephedrine in Rats,'' Teratology, 
34:469, 1986.
    142. Nishikawa, T., H. J. Bruyere, Y. Takagi, E. F. Gilbert, and 
H. Uno, ``Cardiovascular Teratogenicity of Ephedrine in Chick 
Embryos,'' Toxicology Letters, 29:59-63, 1985.
    143. Matsuoka, R., E. F. Gilbert, H. Bruyers, J. M. Optiz, ``An 
Aborted Human Fetus with Truncus Arteriosus Communis--Possible 
Teratogenic Effect of Tedral,'' Heart and Vessels, 1:176-178, 1985.
    144. Mortimer, E. A., ``Drug Toxicity from Breast Milk? 
[letter],'' Pediatrics, 60:780-781, 1977.

[[Page 30716]]

    145. Park, P. G., J. Merryman, M. Orloff, and H. M. Schuller, 
``Beta-Adrenergic Mitogenic Signal Transduction in Peripheral Lung 
Adenocarcinoma: Implications for Individuals with Preexisting 
Chronic Lung Disease,'' Cancer Research, 55:3504-3508, 1995.
    146. Hsu, H. Y., Y. P. Chen, S. J. Shen, C. S. Hsu, C. C. Chen, 
and H. C. Chang, ``7. Ephedrae Herba (Ephedra, Ma-Huang)'' In 
``Oriental Materica Medica: A Concise Guide,'' Long Beach, CA: 
Oriental Healing Arts Institute, 52-53, 1986.
    147. Blumenthal, M., and P. King, ``A Review of the Botany, 
Chemistry, Medicinal Uses, Safety Concerns, and Legal Status of 
Ephedra and its Alkaloids,'' HerbalGram, 34:22-26, 43, 56, and 57, 
1995.
    148. Leung, A., ``Chinese Medicinals,'' HerbalGram, 23:21-31, 
1990.
    149. Memorandum to the Record from FDA Research Chemists, re: 
Summary of FDA Analyses of Consumer Samples Associated with Adverse 
Events, January 9, 1997.
    149a. Table: AER's Associated With Specific Consumer Intakes of 
Ephedrine Alkaloids.
    150. Iron-Containing Supplements and Drugs; Label Warning 
Statements and Unit-Dose Packaging Requirements; Final Rule (62 FR 
2218, January 15, 1997).
    151. Decomposition and Histamine Raw, Frozen Tuna and Mahi-Maji; 
Canned Tuna; and Related Species (CPG 7108.240). Compliance Policy 
Guides, Cpt 5, Sec. 540.525, 10/30, 1989.
    152. Bressler, R., ``Adverse Drug Reactions,'' In ``Geriatric 
Pharmacology,'' edited by Bressler, R., and M. D. Katz, McGraw-Hill, 
41-61, 1993.
    153. Jensen, E. W., and N. J. Christensen, ``Sympathetic 
Activity Increases with Age. Relationship to Blood Flow Volume and 
Longterm Smoking,'' International Journal of Obesity, 17 Suppl 
3:S112-4; discussion S115, 1993.
    154. Pi-Sunyer, F. X., ``Short-Term Medical Benefits and Adverse 
Effects of Weight Loss,'' Annals of Internal Medicine, 119:722-726, 
1993.
    155. Landsberg, L., and D. R. Krieger, ``Obesity, Metabolism, 
and the Sympathetic Nervous System,'' American Journal of 
Hypertension, 2:125S-132S, 1989.
    156. Stokholm, K. H., L. Breum, and A. Astrup, ``Cardiac 
Contractility, Central Haemodynamics and Blood Pressure Regulation 
During Semistarvation,'' Clinical Physiology, 11:513-523, 1991.
    157. Association of Analytical Chemists (AOAC) Official Method 
980.35 Ephedrine in Solid Dosage Drugs: Spectrophotometric Method. 
In ``Official Methods of Analysis,'' edited by AOAC International, 
Arlington, VA: AOAC International, 9-10, 1995.
    158. Fact Book Fiscal Year 1995, Chapter 2 Program Overview, pp. 
9, 27-28, National Heart, Lung and Blood Institutes, National 
Institutes of Health (NIH), Public Health Service (PHS), DHHS, March 
1996.
    159. Table 62. Number of Selected Reported Chronic Conditions, 
by Age: United States, 1994, Current Estimates From the National 
Health Interview Survey, 1994, Vital and Health Statistics, from the 
Centers for Disease Control and Prevention/National Center for 
Health Statistics, Series 10, No. 193, December 1995.
    160. Table 22. Annual Average of Impairments and Chronic 
Conditions 1990-1992, to be published in Prevalence of Selected 
Chronic Conditions: United States 1990-1992, National Center for 
Health Statistics, Vital and Health Statistics 10 [194] 1995.
    161. Diabetes Statistics, p. 1, NIH Publication No. 96-3873, 
National Diabetes Information Clearinghouse, National Institute of 
Diabetes and Digestive and Kidney Diseases, NIH, PHS, DHHS, October 
1995.
    162. Number of U.S. Adults (in millions) with Mental Disorders, 
1990, National Institute of Mental Health UPDATE, OM-00-4097, Office 
of Scientific Information, National Institute of Mental Health, NIH, 
PHS, DHHS, August 1994.
    163. Wood, L. C., D. S. Cooper, and E. C. Ridgway, ``Your 
Thyroid A Home Reference,'' pp. 216-219, Ballantine Books, New York, 
1995.
    164. Tab F: Additional Clinical Summaries of Adverse Event 
Reports. Briefing Materials for Food Advisory Committee on Dietary 
Supplements Containing Ephedrine Alkaloids, August 27-28, 1996.
    165. ``Analeptics: Caffeine,'' Drug Interaction Facts, Facts and 
Comparisons, pp. 230-230b, 1996.
    166. ``Caffeine'' In ``Therapeutic Drugs,'' edited by Dollery, 
C., Edinburgh; New York: Churchill Livingstone, C3-C6, 1991.
    167. Herbal Diuretics (Monograph). The Lawrence Review of 
Natural Products, Facts and Comparisons, pp. 1-2, May 1989.
    168. Guarana (Monograph). The Lawrence Review of Natural 
Products, Facts and Comparisons, pp. 1-2, May 1991.
    169. Mate (Monograph). The Lawrence Review of Natural Products, 
Facts and Comparisons, pp. 1-2, April 1988.
    170. Unknown: Mate. IARC Monographs, Edition 51:pp. 273-287, 
1996.
    171. Belliardo, F., A. Martelli, and M. G. Valle, HPLC 
Determination of Caffeine and Theophylline in Paullinia Cupana Kunth 
(guarana) and Cola spp. samples, Zeitschrift Fur Lebensmittel-
Unterschung Und-Forschung, 180:398-401, 1985.
    172. Herb Research Foundation: Herbal Stimulants Fact Sheet, 
1995.
    173. Dulloo, A. G., ``Ephedrine, Xanthines and Prostaglandin-
inhibitors: Actions and Interactions in the Stimulation of 
Thermogenesis,'' International Journal of Obesity, 17 Suppl 1:S35-
S40, 1993.
    174. Dulloo, A. G., J. Seydoux, and L. Girardier, ``Potentiation 
of the Thermogenic Antiobesity Effects of Ephedrine by Dietary 
Methylxanthines: Adenosine Antagonism or Phosphodiesterase 
Inhibition?,'' Metabolism, 41:1233-1241, 1992.
    175. Astrup, A., S. Toubro, N. J. Christensen, and F. Quaade, 
``Pharmacology of Thermogenic Drugs,'' American Journal of Clinical 
Nutrition, 55:246S-248S, 1992.
    176. Yohimbe (Monograph), The Lawrence Review of Natural 
Products, Facts and Comparisons, pp. 1-2, May 1993.
    177. ``Agents for Impotence, Yohimbine HCl,'' Drug Interaction 
Facts, Facts and Comparisons, p. 731m, 1996.
    178. Wilkerson, R. D., ``Cardiovascular Effects of Cocaine: 
Enhancement by Yohimbine and Atropine,'' Journal of Pharmacology and 
Experimental Therapeutics, 248:57-61, 1989.
    179. Folic Acid Proposed Rule (58 FR 53269, October 14, 1993).
    180. ``Nasal Decongestants,'' Drug Interaction Facts, Facts and 
Comparisons, pp. 183i-184d, 1996.
    181. ``Salicylates: Sallicyclic Acid Derivatives,'' Drug 
Interaction Facts, Facts and Comparisons, pp. 248a-248d, 1996.
    182. Weiner, M., ``White Willow'' In ``Weiner's Herbal--The 
Guide to Herb Medicine,'' Mill Valley, CA: A Quantum Book, 260-261, 
1990.
    183. Herbal Diuretics (Monograph). The Lawrence Review of 
Natural Products, Facts and Comparisons, pp. 1-2, May 1989.
    184. Uva ursi (Monograph). The Lawrence Review of Natural 
Products, Facts and Comparisons, pp. 1-2, September 1987.
    185. Cascara (Monograph). The Lawrence Review of Natural 
Products, Facts and Comparisons, pp. 1-3, May 1996.
    186. Senna (Monograph). The Lawrence Review of Natural Products, 
Facts and Comparisons, pp. 1-2, January 1991.
    187. De Witte, P., J. Cuveele, and J. Lemli, ``Bicascarosides in 
Fluid Extracts of Cascara,'' Planta Medica, 57:440-443, 1991.
    188. Meeting Transcript, Food Advisory Committee, Special 
Working Group on Food Products Containing Stimulant Laxatives, June 
1995.
    189. Hardy, C., memorandum to file, November 5, 1996.
    190. Hardy, C., memorandum to file, November 6, 1996.
    191. O'Donnell, J. T., ``Diets and Obesity Drug Treatment,'' 
Journal of Pharmacy Practice, IX, 5:330-341, 1996.
    192-193. ``Weight Management and Eating Disorders'' In 
``Krause's Food, Nutrition, & Diet Therapy,'' edited by Mahan, L. 
K., and S. Escott-Stump, Philadelphia: W.B. Saunders, 451-488, 1996.
    194. ``Nutrition and Your Health: Dietary Guidelines for 
Americans,'' U.S. Department of Agriculture, DHHS, 1995.
    195. National Task Force on the Prevention and Treatment of 
Obesity: Long-term Pharmacotherapy in the Management of Obesity, 
Journal of the American Medical Association, 276:1907-1915, 1996.
    196. Levy, A. S., and A. W. Heaton, ``Weight Control Practices 
of U.S. Adults Trying to Lose Weight,'' Annals of Internal Medicine, 
116:661-666, 1992.
    197. Lowenthal, D. T., and Y. Karni, ``The Nutritional Needs of 
Athletes'' In ``Total Nutrition. The Only Guide You'll Ever Need,'' 
edited by Herbert, V., G. J. Subak-Sharpe, and T. S. Kasdan, New 
York: St. Martin's Press, 403-421, 1996. 197a. Salemi, J., and J. T. 
O'Donnell, ``Performance Enhancing Drug Use in Athletes,'' Journal 
of Pharmacy Practice, IX, 5:386-395, 1996.
    198. Cybergenics, Phase I, Anabolic Muscle Building Cycle, 
distributed by L&S Research Corp., 1990.
    199. Memorandum of November 30, 1995 Industry Meeting, Executive 
Secretary, January 4, 1997.
    200. ``Webster's New Riverside University Dictionary,'' edited 
by Soukhanov, A. H., and K. Ellis, The Riverside Publishing Co., 
1984.

[[Page 30717]]

    201. Dorland's Illustrated Medical Dictionary, Philadelphia, W. 
B. Saunders, 1988.
    202. Wilson, B. E., and W. N. Hobbs, ``Case Report: 
Pseudoephedrine-Associated Thyroid Storm: Thyroid Hormone-
Catecholamine Interactions,'' American Journal of the Medical 
Sciences, 306:317-319, 1993.
    203. Elis, J., D. R. Laurence, H. Mattie, and B. N. C. Prichard, 
``Modification by Monoamine Oxidase Inhibitors of the Effect of Some 
Sympathomimetics on Blood Pressure,'' British Medical Journal, 2:75-
78, 1967.
    204. Dawson, J. K., S. M. Earnshaw, and C. S. Graham, 
``Dangerous Monoamine Oxidase Inhibitor Interactions Are Still 
Occurring in The 1990s,'' Journal of Accident and Emergency 
Medicine, 12:49-51, 1995.
    205. Grahame-Smith, D. G., and J. K. Aronson, ``Drug 
Interactions'' In ``Oxford Textbook of Clinical Pharmacology and 
Drug Therapy,'' Oxford: Oxford University Press, 122-136, 1992.
    206. ``Sympathomimetics--Methyldopa,'' Drug Interaction Facts, 
Facts and Comparisons, p. 679, 1996.
    207. ``Bronchodilators: Sympathomimetics,'' Drug Interaction 
Facts, Facts and Comparisons, pp. 173a-173h, 1996.
    208. ``Nonprescription Diet Aids: Phenylpropanolamine HCl,'' 
Drug Interaction Facts, Facts and Comparisons, pp. 240b-241, 1996.
    209. ``Anorexiants,'' Drug Interaction Facts, Facts and 
Comparisons, pp. 236-239, 1996.
    210. Lefkowitz, R. J., B. B. Hoffman, and P. Taylor, 
``Neurohumoral Transmission: The Autonomic and Somatic Motor Nervous 
Systems'' In ``Goodman and Gilman's The Pharmacological Basis of 
Therapeutics,'' edited by Gilman, A. G., T. W. Rall, A. S. Nies, and 
P. Taylor, New York: McGraw-Hill, Inc., 84-121, 1990.
    210a. Proposed Warning Labels for Iron-Containing Products; FDA 
Report on Consumer Research; Availability (60 F.R. 27321, May 23, 
1995).
    211. FDC Reports, pp. 11-12, September 16, 1996.
    212 Schucker, R., R. Stokes, M. Stewart, and D. Henderson, ``The 
Impact of the Saccharin Warning Label on the Sales of Diet Soft 
Drinks in Supermarkets,'' Journal of Public Policy and Marketing, 
2:46-56, 1983.
    213. Freimuth, V., S. Hammond, and J. Stein, ``Health 
Advertising: Prevention for Profit,'' American Journal of Public 
Health, 78:557-561, 1988.
    214. Scott, H., and S. Rosenbaum, ``Rhode Island Physician's 
Recognition and Reporting of Adverse Drug Reactions,'' Rhode Island 
Medical Journal, 70:311-316, 1987.
    215. Estimating the value of consumer's loss from foods 
violating the FD&C Act, vol. II, Final Report, pp. G1-G40, September 
1988. (The valuation of particular adverse event categories is based 
on the values presented for acute CNS and liver or kidney changes, 
chronic CNS system impairment, heart disease, and stroke. The 
reported values are the averages of the values generated by the 
three health indices presented and, where appropriate, weighted by 
the proportion of adverse events in an adverse event category that 
are of the type for which values are reported. The dollar figures 
were converted to 1996 dollars based on the relative consumer price 
indices for 1988 and 1996.)
    216. Submission by D. Jones, Information Relevant to the 
Assessment of the Safety of Dietary Supplements Containing Ephedrine 
Alkaloids, FDA Advisory Committee on Food Products Containing 
Ephedrine Alkaloids, pp. 1-20, October 9, 1995.
    217. Nutrition Business Journal, vol. 1, No. 1, pp. 1-5, August 
1996.
    218. Median Weekly Earning of Wage and Salary Workers Who 
Usually Work Full Time by Detailed (3-Digit Census Code) Occupation 
and Sex, 1994 Annual Averages, U.S. Department of Labor, Bureau of 
Statistics.
    219. Food Labeling and Nutrition News, pp. 14-15, July 18, 1996.
    220. Safe and Appropriate Marketing of Ephedra-Containing 
Products, August 22, 1996.
    221. Memorandum to Office of Special Nutritionals from 
Environmental Scientist, re: Agency Action on Ephedra Alkaloids in 
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