[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.
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[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