[Federal Register Volume 65, Number 64 (Monday, April 3, 2000)]
[Proposed Rules]
[Pages 17474-17477]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-8109]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 111

[Docket No. 95N-0304]


Dietary Supplements Containing Ephedrine Alkaloids; Withdrawal in 
Part

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule; withdrawal in part.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that it 
is withdrawing certain provisions of a proposed rule that published in 
the Federal Register of June 4, 1997 (62 FR 30678), relating to dietary 
supplements containing ephedrine alkaloids. FDA is taking this action 
because of concerns regarding the agency's basis for proposing a 
certain dietary ingredient level and a duration of use limit for these 
products. Elsewhere in this issue of the Federal Register, FDA is 
announcing the availability of new adverse event reports and related 
information associated with these products and its plans to participate 
in a public forum to discuss this new information at some future date. 
In addition, FDA is announcing elsewhere in this issue of the Federal 
Register the availability of additional documentation associated with 
certain adverse events referenced in the 1997 proposed rule.

DATES: The proposed rule that published on June 4, 1997 (62 FR 30678) 
is withdrawn in part for Sec. 111.100(a), (b), (c), (e), and (f) as of 
April 3, 2000.

ADDRESSES: Copies of the proposed rule and related comments are 
available for public examination in the Dockets Management Branch (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Marquita B. Steadman, Center for Food 
Safety and Applied Nutrition (HFS-007), Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20852, 301-827-6733.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of June 4, 1997 (62 FR 30678), FDA 
published a proposed rule (hereinafter referred to as the ``ephedrine 
alkaloids proposal'') to establish 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 an intake of 8 mg or more within 
a 6-hour period or a total daily intake of 24 mg or more of ephedrine 
alkaloids (hereinafter referred to as ``dosing level'' or ``dietary 
ingredient level''), and to require that the label of such supplement 
state that the product is not to be used for more than 7 days 
(hereinafter referred to as ``duration of use limit''). The agency also 
proposed to prohibit the use of ephedrine alkaloids in dietary 
supplements with ingredients, or with ingredients that contain 
substances, that have a known stimulant effect, such as caffeine, which 
may interact with ephedrine alkaloids; and to prohibit labeling claims, 
such as weight loss or body building, that require long-term intake to 
achieve the purported effect. In addition, the agency proposed to 
require a statement to accompany claims that encourage short-term 
excessive intake to enhance a purported effect, such as an increase in 
energy, that taking more than the recommended serving may result in 
serious adverse health effects; and to require specific warning 
statements to appear on product labels.
    The agency proposed these actions in response to reports of serious 
illnesses and injuries, including a number of deaths, associated with 
the use of dietary supplement products containing ephedrine alkaloids 
and the agency's investigations and assessment of these illnesses and 
injuries. This action was also supported by many of the recommendations 
made during the October 1995 meeting of an ad hoc Working Group of the 
FDA Advisory Committee (Working Group) and the August 1996 meeting of 
the Food Advisory Committee (FAC) and the Working Group concerning the 
potential public health problems associated with the use of dietary 
supplements containing ephedrine alkaloids and the recommended steps 
FDA should take to address the serious health concerns associated with 
their use (see Refs. 25 and 27 of the ephedrine alkaloids proposal 
(Docket No. 95N-0304)).
    The comment period for the June 4, 1997 (62 FR 30678), proposed 
rule closed on August 18, 1997. In a notice in the Federal Register of 
August 20, 1997 (62 FR 44247), FDA announced its intent to reopen the 
comment period after the agency corrected a number of inadvertent 
omissions in the administrative record. Subsequently on September 18, 
1997 (62 FR 48968), the agency reopened the comment period for an 
additional 75 days until December 2, 1997.
    The agency received approximately 350 letters regarding the use of 
ephedrine alkaloid-containing dietary supplements prior to publication 
of the ephedrine alkaloids proposal. These comments have been 
considered by the agency along with those commenting in response to the 
proposal. The agency received approximately 14,775 comments on the 
ephedrine alkaloids proposal. Individual consumers who use ephedrine 
alkaloid-containing dietary supplements and independent distributors of 
these products submitted most of the comments. Other comments were 
received from persons who had, or who knew persons who had, suffered 
adverse events or who were reporting adverse events associated with the 
use of an ephedrine alkaloid-containing dietary supplement. The 
remaining comments included those submitted by medical professionals, 
scientists, a scientific association, State and local health 
departments, medical associations, government agencies, dietary 
supplement manufacturers, Chinese medicine practitioners and 
associations, dietary supplement industry trade associations, public 
health associations, and consumer groups.
    The House Committee on Science requested that the Government 
Accounting Office (GAO) examine the scientific bases for the ephedrine 
alkaloids proposal and the agency's adherence to the regulatory 
flexibility analysis requirements for Federal rulemaking. On August 4, 
1999, GAO released its report entitled ``Dietary Supplements: 
Uncertainties in Analyses Underlying FDA's Proposed Rule on Ephedrine 
Alkaloids.'' A copy of this

[[Page 17475]]

report is available in Docket No. 95N-0304.
    Generally, GAO concluded that FDA was justified in determining that 
the number of adverse event reports relating to dietary supplements 
containing ephedrine alkaloids warranted the agency's attention and 
consideration of steps to address safety issues. However, GAO expressed 
concerns about the use of the reported adverse events in supporting the 
proposed dosing level and duration of use limit, and concluded that the 
agency needed additional evidence to support these restrictions.
    GAO also concluded that FDA's economic analysis contained the basic 
elements expected in a Federal agency's cost-benefit analysis, and the 
ephedrine alkaloids proposal complied with regulatory flexibility 
analysis requirements under the Regulatory Flexibility Act. GAO noted, 
however, that FDA's cost-benefit analysis was not always transparent 
regarding why certain key assumptions were made, the degree of 
uncertainty involved in those assumptions, or the effect that 
alternative assumptions would have had on the agency's estimates of the 
costs and benefits of the proposed action.
    GAO recommended that FDA ``provide stronger evidence on the 
relationship between the intake of dietary supplements containing 
ephedrine alkaloids and the occurrence of adverse reactions that 
support the proposed dosing level and duration of use limits.'' In 
addition, GAO recommended that FDA improve the transparency of its 
cost-benefit analysis in its final rulemaking.
    In light of GAO's conclusions, comments from others on the 
ephedrine alkaloids proposal, and having further considered issues 
related to the proposed dietary ingredient level and the duration of 
use limit, FDA believes that these aspects of its proposed approach to 
regulating these products should be reassessed. Whether there are 
appropriate alternative approaches to these aspects of the proposal for 
regulating dietary supplements containing ephedrine alkaloids will 
require evaluation of additional information not available to the 
agency when it issued the proposal. Accordingly, FDA is withdrawing the 
provisions of the ephedrine alkaloids proposal relating to the dietary 
ingredient level and duration of use limit for these products. This 
action will allow FDA to reconsider, with public input, whether any 
dietary ingredient level or duration of use limit for these products is 
appropriate or whether alternative measures should be considered. The 
withdrawn provisions are described briefly below.

II. Withdrawn Provisions of the Ephedrine Alkaloids Proposal

A. Dietary Ingredient Limit for Ephedrine Alkaloids: Per Serving Basis 
Sec. 111.100(a)(1)) and Frequency and Per Total Daily Intake Basis 
(Sec. 111.100(b))

    As stated above, the agency tentatively concluded in the ephedrine 
alkaloids proposal that a dietary supplement is adulterated if it 
contains 8 mg) or more of ephedrine alkaloids per serving 
(Sec. 111.100(a)(1)), or if the labeling suggests or recommends 
conditions of use that would result in an intake of 8 mg or more within 
a 6-hour period or a total daily intake of 24 mg or more of ephedrine 
alkaloids (Sec. 111.100(b)). Having reconsidered the basis for these 
limits, including comments on that basis by GAO and others to the 
proposal, FDA believes that it should consider additional information 
not available to the agency when it issued the ephedrine alkaloids 
proposal to determine whether a dietary ingredient limit, or some 
alternative approach, would be appropriate to regulate these dietary 
ingredients. Therefore, FDA is withdrawing these provisions of the 
ephedrine alkaloids proposal.
    FDA continues to be concerned about the potential risk for 
individuals who are particularly sensitive to the effects of ephedrine 
alkaloids, or whose sensitivity or likelihood for adverse effects may 
be increased through chronic use of these products or other means 
(e.g., physical exercise). FDA expressed this concern in the proposal, 
and noted that many members of the FAC agreed.

B. Proposed Compliance Procedures (Sec. 111.100(a)(2))

    In the ephedrine alkaloids proposal, FDA stated that it would use a 
high performance liquid chromatography method as specified in 
Laboratory Information Bulletin No. 4053 to determine the level of 
ephedrine alkaloids in a dietary supplement. Without a requirement that 
would establish an unacceptable dietary ingredient level for dietary 
supplements containing ephedrine alkaloids, this provision, alone, is 
no longer necessary. Accordingly, the agency has determined that this 
provision should also be withdrawn.

C. Proposed Limitations on Duration of Use (Sec. 111.100(c))

    FDA proposed in Sec. 111.100(c) to require that the label of 
dietary supplements that contain ephedrine alkaloids state ``Do not use 
this product for more than 7 days.'' FDA intended to require this 
provision in conjunction with the 8 mg per serving dietary ingredient 
limit proposed in Sec. 111.100(a)(1). FDA noted in the ephedrine 
alkaloids proposal that concern about serious adverse events with the 
long-term use of ephedrine alkaloids led several members of the Working 
Group (see Ref. 27 of the ephedrine alkaloids proposal) and of the FAC 
(see Ref. 25 of the ephedrine alkaloids proposal (Docket No. 95N-0304)) 
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. FDA also cited evidence from the 
scientific literature about the adverse effects of long-term use of 
ephedrine alkaloids (62 FR 30678 at 30695).
    FDA remains concerned with the long-term use of such products and 
the potential adverse effects such use has in combination with the use 
of other ingredients that have a stimulant effect. However, having 
reconsidered the basis for the proposed duration of use limit, 
including the comments on that basis by GAO and others to the proposal, 
FDA believes that it should consider additional information not 
available to the agency when it issued the ephedrine alkaloids proposal 
to determine whether any duration of use limit, or some alternative 
approach, is appropriate to regulate these products. In addition, the 
agency is also withdrawing the proposed 8-mg dietary ingredient limit. 
Therefore, the agency has determined that the proposed labeling 
requirement concerning duration of use should also be withdrawn.

D. Prohibition on Claims (Sec. 111.100(e) and (f))

    FDA stated in the proposal that restrictions on claims are 
necessary to maintain the integrity of the limit on the level of 
ephedrine alkaloids in dietary supplements that it proposed and of the 
other proposed restrictions on the conditions of use of these dietary 
supplements. For example, because safe and significant weight loss and 
body building cannot be achieved in a 7-day period, FDA tentatively 
concluded that claims that promote these uses promote long-term use of 
ephedrine alkaloid-containing dietary supplements, which have been 
associated with serious adverse events. For this reason, FDA 
tentatively concluded that any claims that promote long-term use of 
ephedrine

[[Page 17476]]

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. Consequently, FDA proposed in 
Sec. 111.100(e) to require that 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.
    Similarly, 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. 
Consequently, FDA tentatively concluded that claims that promote 
excessive consumption are inconsistent with the dietary ingredient 
limit for these products. Accordingly, FDA proposed 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.'' FDA proposed in 
Sec. 111.100(f)(2) certain requirements on the size, type, and 
placement of this statement on the label. Because FDA is withdrawing 
the proposed dietary ingredient limit and duration of use limit, FDA 
has determined that the proposed provisions in Sec. 11.100(e) and (f) 
should also be withdrawn. FDA believes that it should consider 
additional information not available to the agency when it issued the 
ephedrine alkaloids proposal before finally determining whether such 
provisions with respect to claims, or some alternative approach, is 
appropriate to regulate these products. Nonetheless, FDA remains 
concerned that adverse effects are associated with long-term 
consumption of such products and with consumption of such products in 
excess of labeled serving sizes.

III. Current Provisions of the Ephedrine Alkaloids Proposal

    Despite this action to withdraw the proposed dietary ingredient 
level and duration of use limit, and related provisions of the 
ephedrine alkaloids proposal, there remain provisions that the agency 
is not withdrawing in this notice. These provisions concern FDA's 
proposed prohibition on the use of ingredients with stimulant effects 
with dietary supplements containing ephedrine alkaloids 
(Sec. 111.100(d)) and the proposed warning statement (Sec. 111.100(g)).
    FDA proposed in Sec. 111.100(d) to require 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. FDA proposed this 
provision in response to the many adverse events that had been reported 
to the agency. These adverse events 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 (see Ref. 
164 of the proposed rule (Docket No. 95N-0304)). These adverse events 
suggested 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 ephedrine alkaloids alone.
    In the ephedrine alkaloids proposal, FDA also tentatively concluded 
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 that 
document, to protect the public health. The warning statements proposed 
in Sec. 111.100(g) contained several elements, including cautions that 
consumers 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 signs or symptoms. As noted in the 
preamble to the ephedrine alkaloids proposal, 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. 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. In addition, many consumers who are 
unaware that they are sensitive to the effect 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 (62 FR 30678 at 30700).
    The agency has not at this time concluded that it will finalize the 
provisions in Sec. 111.100(d) and (g). Rather, the agency intends to 
consider whether to finalize these provisions, or take additional or 
alternative regulatory action, after it receives public input on the 
significance of new information collected by the agency about the 
safety of dietary supplements containing ephedrine alkaloids.

IV. Continued Monitoring and Followup

    Although FDA is withdrawing certain provisions of the ephedrine 
alkaloids proposal, FDA continues to have a public health concern with 
respect to the use of dietary supplements containing ephedrine 
alkaloids. The agency will continue to monitor and provide appropriate 
followup on adverse events associated with the use of these products. 
In a notice of availability published elsewhere in this issue of the 
Federal Register, FDA is seeking public input about the significance of 
new information collected by the agency about the safety of dietary 
supplements containing ephedrine alkaloids. The agency is also 
requesting the submission of any other information that the submitters 
believe is relevant to such a safety assessment. Should additional 
information suggest that additional action is necessary, FDA will 
consider what action is appropriate, and take appropriate steps to 
protect consumers and the public health.

V. Enforcement

    Withdrawal of certain provisions of the ephedrine alkaloids 
proposal does not limit the agency's discretion to initiate enforcement 
actions with respect to ephedrine alkaloids containing dietary 
supplements. For example, circumstances may warrant enforcement action 
against a dietary supplement containing ephedrine alkaloids if an 
evaluation of the relevant facts show a health hazard or that the 
product is otherwise adulterated or misbranded.
    FDA maintains its street drug alternative policy, as articulated in 
the preamble to the ephedrine alkaloids proposal, which states that 
because alternatives to illicit street drugs are not intended to 
supplement the diet, products that purport to be or that are 
represented, either expressly or implicitly, for use as alternatives to 
street drugs are not dietary supplements within the meaning of section 
201(ff) of

[[Page 17477]]

the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(ff)). 
(See 62 FR 30678 at 30699 and 30700). FDA is publishing elsewhere in 
this issue of the Federal Register a notice announcing the availability 
of a guidance entitled ``Street Drug Alternatives.'' The guidance is 
intended to inform industry and the public that FDA considers any 
product that is promoted as a street drug alternative to be an 
unapproved new drug and a misbranded drug in violation of the act. To 
date, the agency has taken action against several products marketed as 
alternatives to illicit street drugs, and it may do so in the future, 
as well.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, the proposed 
rule published on June 4, 1997 (62 FR 30678), is withdrawn in part for 
Sec. 111.100(a), (b), (c), (e), and (f).

    Dated: March 28, 2000.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-8109 Filed 3-31-00; 8:45 am]
BILLING CODE 4160-01-F