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April 4, 2003

Dockets Management Branch (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, Maryland 20852

Re: Docket No. 95N-0304

Dear Sir/Madam:

The American Pharmacists Association (APhA) is pleased to provide the
Food and Drug Administration (FDA) with comments on the Agency's
proposed rule regarding Dietary Supplements Containing Ephedrine
Alkaloids. APhA, founded in 1852 as the American Pharmaceutical
Association, represents the nations' 210,000 practicing pharmacists,
pharmaceutical scientists, student pharmacists and pharmacy technicians.

As published in the March 5, 2003 *Federal Register*, the FDA reopened
the comment period for the June 4, 1997 proposed rule entitled "Dietary
Supplements Containing Ephedrine Alkaloids"[^1] to receive public
comment on new evidence regarding health risks associated with the use
of dietary supplements containing ephedrine alkaloids, as well as public
comment on a warning statement under consideration. In addition, FDA is
considering whether the Agency should determine that dietary supplements
containing ephedrine alkaloids present a "significant or unreasonable
risk of illness or injury"[^2] and thus propose restrictions on the sale
and use of these products. APhA's comments focus on the labeling
proposal, as supported by policy of the Association, and on the
pharmacists' role in helping patients navigate the selection and use of
dietary supplements, including those containing ephedrine alkaloids.

APhA respects the constraints on the Agency to regulate dietary
supplements (including those with ephedrine alkaloids) "differently"
from over-the-counter medications. While changes to this regulatory
structure for [all]{.underline} dietary supplements is essential, APhA
applauds the Agency's proposal to use its limited authority to reduce
the potential for harm from ephedrine alkaloid products and encourages
Congress to grant the Agency additional authority to address the broader
problems with dietary supplements. Such action is very important, as
these products appear on the shelves of pharmacies and many other
outlets---right next to categories of traditionally-regulated products.

Pharmacists have a responsibility to assist consumers with decisions
about effectiveness, proper use, indications, safety and potential
interactions between complementary and alternative medicine and
traditional therapies. Their ability to carry out this responsibility
depends on the availability of credible, evidence-based information to
supplement their professional education and experience. Pharmacists,
especially those practicing in community pharmacy settings, are a highly
accessible resource for the public for guidance about selection and use
of dietary supplements and other alternative medicines. As outlined in
the following policy statements (adopted in 2000), pharmacists are
concerned about the regulation of dietary supplements.

1.  APhA shall work with Congress to modify the Dietary Supplement
    Health and Education Act or enact other legislation to require that
    dietary supplement manufacturers provide evidence of efficacy and
    safety for all products, including products currently in the
    marketplace.

2.  APhA supports the establishment and implementation of clear and
    effective enforcement policies to remove promptly unsafe or
    ineffective dietary supplement products from the marketplace.

3.  APhA shall work with the FDA to improve dietary supplement product
    labeling to ensure full disclosure of all product components and
    their source with associated strengths and recommendations for use
    in specific patient populations.

4.  APhA supports the development and enforcement of dietary supplement
    good manufacturing practices (GMPs) and compliance with USP/NF
    standards to assure quality, safe, contaminant-free products.

5.  APhA encourages health care professionals, manufacturers, and
    consumers to report adverse health events associated with dietary
    supplements. APhA encourages the FDA to create a database with this
    information and make it available to all interested parties.

This policy supports the Agency's proposals.

[Proposed new labeling:]{.underline} In its proposed rule, the Agency
suggests new labeling requirements to inform consumers of potential
risks associated with the use of dietary supplements containing
ephedrine and warnings against the use of these products with other
stimulant containing products or by consumers with specific health
conditions. APhA policy supports the Agency's proposed labeling,
particularly with regard to interactions with prescription medications
and patient populations at risk for potentially dangerous effects on the
heart and central nervous system. Clear, comprehensive labeling is vital
to proper and safe medication use. The Association encourages the Agency
to consider including a statement on the label that patients should
contact a doctor [or pharmacist]{.underline} should they experience side
effects or have questions regarding use of an ephedrine-containing
product with prescription or over-the-counter medications. Many
ephedrine products are purchased in areas where there is no access to a
health care professional, such as gas stations and convenience stores.
Patients who self-select these products must have access to better
labeling to support them in their decision making regarding the
selection and use of these products.

While the Association supports the Agency's proposed new labeling, we
have concerns that the proposed labeling may imply that the FDA has
approved these products, and therefore be seen as endorsing these
products as "safe and effective". APhA encourages the Agency to require
that the label include a statement clarifying that the product has
[not]{.underline} been reviewed for safety and efficacy by the FDA.

[New evidence:]{.underline} APhA policy supports FDA efforts to require
that dietary supplement manufacturers provide evidence of **efficacy and
safety** for all products, including products currently in the
marketplace. Recent studies suggest that products containing ephedrine
do pose risks to certain patient populations and under certain
conditions (such as use in conjunction with other stimulant containing
products, increased frequency, dose or duration). There has been
sufficient new scientific evidence to warrant further study into the
incidence and mechanism of clinical toxicities associated with the use
of ephedrine alkaloids in combination with other stimulant substances
and strenuous activity. Ephedra (active constituent ephedrine) is a
relatively potent herb with nonselective adrenergic agonist activity in
the human body. Historically, ephedra has been used in traditional
Chinese medicine (TCM) for bronchial asthma and related congestive
conditions under the supervision of TCM practitioners. Studies
documenting the pharmacological activity of ephedra have been available
since the 1920s. In fact, the principal active ingredient is ephedrine,
which when the chemically identical active is synthesized, is regulated
as a [drug]{.underline}.

The recent promotion of ephedra as a natural weight loss and
performance-enhancing herb greatly increases the risk of exposure to
this nonselective adrenergic stimulant. The FDA and the Department of
Health and Human Services have both cautioned consumers, particularly
athletes and those who engage in strenuous activities, about using
dietary supplements that contain ephedra. APhA supports presenting this
information in an urgent time frame to prevent further associated
morbidity and mortality. This is particularly pressing in light of the
common practice of individuals to utilize other stimulants and exercise
to promote weight loss and performance in addition to ephedra containing
products.

The toxicities of ephedra are well documented, with focused concern
regarding cardiotoxic and nervous system manifestations when used as a
single agent. It is reasonable to suggest the potential for harmful
interactions with other stimulant drugs and strenuous physical activity.
Therefore, caution in the use of ephedra containing products should be
exercised, in addition to further study validating the potential adverse
effects associated with this chemical.

APhA supports efforts to require dietary supplement manufacturers to
provide evidence of **efficacy and safety** for their products, as well
as Agency efforts to remove unsafe or ineffective products from the
marketplace. In addition, APhA supports the development and
implementation of good manufacturing practices for dietary supplements
to ensure quality, safe and contaminant-free products.

APhA appreciates this opportunity to comment to the FDA on this
important consumer health issue. Dietary supplements containing
ephedrine alkaloids are an example of an area where the Agency's limited
authority must be used in order to ensure patient access to **quality,
safe and effective** products. APhA strongly supports FDA's efforts and
looks forward to working with the Agency and others to ensure that
consumers have access to high quality products which are appropriate for
that individual.

Sincerely,

![](media/image2.png){width="1.625in" height="0.7527777777777778in"}

John A. Gans, PharmD

Executive Vice President & CEO

cc: The Honorable W.J. "Billy" Tauzin, Chairman, House Energy & Commerce
Committee

> Arthur H. Kibbe, Immediate Past President, APhA Academy of
> Pharmaceutical Research and Science

Susan C. Winckler, RPh, JD, Vice President, Policy & Communications and
Staff

Counsel

Susan K. Bishop, Senior Manager, Regulatory Affairs & Political Action

[^1]: 62 FR 30678

[^2]: 68 FR 10417

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