[Federal Register Volume 68, Number 43 (Wednesday, March 5, 2003)]
[Proposed Rules]
[Pages 10417-10420]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-5072]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 111

[Docket No. 95N-0304]
RIN 0910-AC51


Dietary Supplements Containing Ephedrine Alkaloids; Reopening of 
the Comment Period

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule; reopening of the comment period.

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SUMMARY: The Food and Drug Administration (FDA) is reopening for 30 
days the comment period for a proposed rule entitled ``Dietary 
Supplements Containing Ephedrine Alkaloids'' that published in the 
Federal Register of June 4, 1997 (62 FR 30678) (the June 1997 
proposal). In that document, FDA proposed a number of requirements 
relating to dietary supplements containing ephedrine alkaloids, 
including a requirement for a warning statement on the product label. 
Since publication of the June 1997 proposal, new scientific evidence 
has come to light concerning health risks associated with the use of 
dietary supplements containing ephedrine alkaloids. FDA is reopening 
the comment period to receive comment on this new evidence, as well as 
on the warning statement it is now considering for dietary supplements 
containing ephedrine alkaloids. FDA also intends to consider, to the 
extent possible, whether in light of current information FDA should 
determine that dietary supplements containing ephedrine alkaloids 
present a ``significant or unreasonable risk of illness or injury under 
conditions of use recommended or suggested in labeling, or if no 
conditions of use are suggested or recommended in the labeling, under 
ordinary conditions of use.''

DATES: Submit written or electronic comments April 4, 2003.

[[Page 10418]]


ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Anthony Curry, Center for Food Safety 
and Applied Nutrition (HFS-306), Food and Drug Administration, 5100 
Paint Branch Pkwy., College Park, MD 20740, 301-436-2071.

SUPPLEMENTARY INFORMATION:

I. Reopening of Comment Period

    In the Federal Register of June 4, 1997 (62 FR 30678) (the June 
1997 proposal), FDA (``we'' or ``the agency'') proposed to amend our 
regulations to require the label of dietary supplements containing 
ephedrine alkaloids to bear a warning statement. The proposed warning 
statement 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 that they stop using the product if 
they develop certain signs or symptoms. FDA also proposed restrictions 
on the potency and composition of dietary supplements containing 
ephedrine alkaloids, including a prohibition on 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. In addition, the agency proposed several requirements and 
restrictions relating to labeling claims and directions for use.
    We proposed these actions in response to reports of serious 
illnesses and injuries, including a number of deaths, associated with 
the use of dietary supplements containing ephedrine alkaloids and the 
agency's investigations and assessment of these illnesses and injuries.
    The comment period for the proposed rule closed on August 18, 1997. 
On September 18, 1997, FDA reopened the comment period for 75 days 
until December 2, 1997 (62 FR 48968).
    In the Federal Register of April 3, 2000 (65 FR 17474), we withdrew 
the proposed requirements and restrictions concerning potency, labeling 
claims, and directions for use, but not the proposed warning statement 
or the proposed prohibition on dietary supplements that combine 
ephedrine alkaloids with other stimulant ingredients. In the same issue 
of the Federal Register (65 FR 17510), we also announced the 
availability of adverse event reports and related information that had 
become available since the June 1997 proposal; we reopened the comment 
period until May 18, 2000, to receive comments on this new information 
(Docket No. 00N-1200).
    Recently, more scientific evidence has come to light concerning the 
risks posed by ephedrine alkaloids, including approximately 17,000 
adverse event reports received overall by FDA. For example, one study 
compared the risks of adverse events attributable to ephedra and other 
herbal products through a comparative case series investigation based 
upon poison control center reporting (Ref. 1). Another study, a case-
controlled investigation, examined the association between the use of 
ephedra and the risk for hemorrhagic stroke (Ref. 2). One study 
evaluated the adverse cardiovascular events from the FDA database that 
were temporally associated with the use of ephedra (Ref. 3). Another 
study evaluated the pharmacology of ephedrine alkaloids and caffeine 
after a single dose in humans (Ref. 4). Two studies were double-blind 
controlled clinical trials that evaluated the efficacy of ephedra in 
combination with caffeine for weight loss, with treatment durations of 
6 weeks (Ref. 5) or 6 months (Ref. 6). Further, the RAND Corporation, 
under contract with the U.S. Department of Health and Human Services, 
has conducted an evidence based review of all available sources of 
information on ephedrine alkaloid containing dietary supplements (Ref. 
7).
    Comments to the June 1997 proposal stressed the importance of 
ensuring that consumers were aware of the risks of consuming dietary 
supplements containing ephedrine alkaloids. Therefore, in light of the 
new scientific evidence as well as the comments received in response to 
the June 1997 proposal, FDA is considering the following warning 
statement for dietary supplements containing ephedrine alkaloids. This 
statement is consistent with the recent scientific reports referenced 
in this document.

[[Page 10419]]

[GRAPHIC] [TIFF OMITTED] TP05MR03.028

    FDA also intends to consider, to the extent possible, whether in 
light of current information FDA should determine that dietary 
supplements containing ephedrine alkaloids present a ``significant or 
unreasonable risk of illness or injury under conditions of use 
recommended or suggested in labeling, or if no conditions of use are 
suggested or recommended in the labeling, under ordinary conditions of 
use'' (see 21 U.S.C. 342(f)(1)(A)). Furthermore, FDA

[[Page 10420]]

seeks comment on what additional legislative authorities, if any, would 
be necessary or appropriate to enable FDA to address this issue most 
effectively.
    For interested parties who would like to submit comments on these 
issues or additional data from any well-conducted scientific studies, 
we are reopening the comment period of the June 1997 proposal for 30 
days. If, after evaluating the comments received on this document, FDA 
believes that a warning statement on the labels of dietary supplements 
containing ephedrine alkaloids is necessary to protect the health of 
individuals consuming such products, the agency will move quickly to 
publish a final rule requiring the appropriate warning statement and to 
take any other action we determine to be appropriate.

II. How to Submit Comments

    Interested persons may submit to the Dockets Management Branch (see 
ADDRESSES) written or electronic comments. Two copies of any mailed 
comments are to be submitted, except that individuals may submit one 
copy. Submit electronic comments to http://www.fda.gov/dockets/ecomments. Identify all comments with the docket numbers found in 
brackets in the heading of this document. You may review received 
comments in the Dockets Management Branch office between 9 a.m. and 4 
p.m., Monday through Friday.

III. References

    The following references have been placed on display in the Dockets 
Management Branch (see ADDRESSES) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Bent, S., T. N. Tiedt, M. C. Odden, and M. G. Shlipak, ``The 
Relative Safety of Ephedra Compared with Other Herbal Products,'' 
published in the Annals of Internal Medicine, March 2003, vol. 138, 
number 6.
    2. Morgenstern, L. B., C. M. Viscoli, W. N. Kernan, L. M. Brass, J. 
P. Broderick, E. Feldmann, J. L. Wilterdink, T. Brott, and R. I. 
Horwitz, ``Use of Ephedra-Containing Products and Risk for Hemorrhagic 
Stroke,'' published in the Journal of Neurology, 2003; vol. 60: pp. 
132-135.
    3. Samenuk, D., M. S. Link, M. K. Homoud, R. Contreras, T. C. 
Theohardes, P. J. Wang, Estes NA 3d., ``Adverse Cardiovascular Events 
Temporally Associated With ma huang, an Herbal Source of Ephedrine,'' 
Mayo Clinic Proceedings, 2002, vol. 77(1):12-6.
    4. C. A., Haller, P. Jacob 3rd, N. L. Benowitz, ``Pharmacology of 
Ephedra Alkaloids and Caffeine After Single-dose Dietary Supplement 
Use,'' Clinical Pharmacology and Therapeutics, 2002, June, vol. 71(6), 
pp. 421-432.
    5. Boozer, C. N., J. A. Nasser, S. B. Heymsfield, V. Wang, G. Chen, 
J. L. Solomon, ``An Herbal Supplement Containing Ma Huang-Guarana for 
Weight Loss: A Randomized, Double-blind Trial,'' International Journal 
of Obesity and Related Metabolic Disorders, 2001;25(3):316-24.
    6. Boozer, C. N., P. A. Daly, P. Homel, J. L. Solomon, D. 
Blanchard, J. A. Nasser, et. al. ``Herbal Ephedra/Caffeine for Weight 
Loss: a 6-month Randomized Safety and Efficacy Trial,'' International 
Journal of Obesity Related and Metabolic Disorders, 2002, vol. 26(5): 
pp. 593-604.
    7. Shekelle, P. G, M. L. Hardy, M. Maglione, S. C. Morton, 
``Ephedra and Ephedrine for Weight Loss and Athletic Performance 
Enhancement: Clinical Efficacy and Side Effects,'' Agency for 
Healthcare Research and Quality (in press).

    Dated: February 27, 2003.
William K. Hubbard,
Associate Commissioner for Policy and Planning.
[FR Doc. 03-5072 Filed 2-28-03; 3:30 pm]
BILLING CODE 4160-01-S