| U.S. Food and Drug Administration |
CFSAN, May 16, 2000
U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Office of Nutritional Products, Labeling, and Dietary Supplements
May 16, 2000
Letter to Industry -
FDA Concerned About Botanical
Products, Including Dietary Supplements, Containing Aristolochic Acid
American Botanical Council,
American Herbal Products Association
Council for Responsible Nutrition
Consumer Healthcare Products Association
National Nutritional Foods Association, and,
Utah Natural Products Alliance.
The Food and Drug Administration (FDA) is issuing this letter to communicate
to you our concern about the marketing of dietary supplements that may contain
aristolochic acid. We also wish to communicate to you actions that manufacturers
and distributors of dietary supplements containing certain botanical ingredients
should consider in light of reports that aristolochic acid has been found in
some dietary supplements or other products that may be marketed as traditional
herbal medicines. FDA asks that you share this information with your members.
In the past several months, public warnings have been issued by Health Canada
and the Medicine Controls Agency (United Kingdom) because of findings of
aristolochic acid in several botanical products marketed as traditional
medicines. The use of products containing aristolochic acid has resulted in
several life-threatening adverse incidents. Aristolochic acids are potent
carcinogens and nephrotoxins that are present, primarily, in plants of the
family Aristolochiaceae. There are at least 14 aristolochic acids known. In
recent years, there have been several reported instances of severe nephropathy
in consumers consuming products containing aristolochic acid. The incidents
range from a few cases to, in one incident in Belgium, over 100 cases of
nephropathy linked to the use of an herbal product containing aristolochic
acids. In each incident the source of the aristolochic acids was determined to
be from an ingredient in the herbal product which is a member of this plant
family. The plant material used in the suspect products was either mis-
identified or the name of the plant ingredient was confused with that of another
plant.
Attached to this letter are lists of plants known to contain aristolochic
acid and of plants which may become adulterated with Aristolochia spp. These
lists, however, should not be considered a comprehensive listing of all plants
which may contain aristolochic acid; the family Aristolochiaceae has about 600
species.
In light of known association between products containing these plants and
incidents of nephropathy, the FDA believes that manufacturers need to take steps
to positively confirm that botanical ingredients are not inadvertently
contaminated with plant material which contains aristolochic acid. As you know,
under the Federal Food, Drug, and Cosmetic Act (the Act), as amended by the
Dietary Supplement Health and Education Act of 1994, the manufacturer bears the
primary responsibility for ensuring that its dietary supplement products are
safe. FDA believes that manufacturers can do several things to ensure that their
products are not inadvertently adulterated.
First, FDA advises manufacturers to review their current manufacturing
practices. Their manufacturing practices should include procedures that ensure
comprehensive and rigorous testing of ingredients and finished products to
prevent the sale to consumers of products that contain potentially harmful
impurities. At a minimum, we believe that it is absolutely necessary that
manufacturers who produce products that contain ingredients that may be
contaminated with aristolochic acid test their products to confirm the absence
of aristolochic acids.
Second, FDA believes that manufacturers need to take adequate steps to
identify and report adverse events, especially adverse events that may include
renal system disorders, associated with any product that contains an ingredient
on the enclosed list of ingredients. FDA recommends that firms promptly notify
FDA's MEDWATCH program of reports of adverse events associated with the use of
products containing any of the listed botanicals.
Regardless of the reason for the presence of aristolochic acid in different
products, it is important that products that contain aristolochic acid not be
allowed to enter the U.S. marketplace. Aristolochic acid is a potent carcinogen
and nephrotoxin. While a product that contains a large amount of it may result
in the rapid onset of acute toxicity symptoms in a consumer using the product, a
product containing a small amount could be used for years with no apparent
adverse effects, until serious, irreversible effects, such as renal failure, has
occurred. Because there is evidence that aristolochic acid-containing products
are in international commerce, FDA intends to issue, in the very near future, an
import alert that will provide for the automatic detention without physical
examination of any product containing a plant listed in the enclosure to this
letter. Detained product will be released when the responsible party can provide
direct analytical evidence that it is free of aristolochic acid. FDA considers
any FDA-regulated product containing aristolochic acid to be unsafe and to be
adulterated.
In conclusion, FDA urges manufacturers and distributors of dietary
supplements and other botanical-containing products containing any ingredient
identified in the attachment to this letter, if they plan to continue marketing
these products, to: (1) review their current manufacturing practices to ensure
that they do not contain aristolochic acid; and (2) ensure that adequate
procedures are in place to collect and report to FDA adverse events that may be
associated with the use of products.
FDA is available and prepared to assist the industry on these matters. Firms
are encouraged to contact FDA if they have any questions or concerns about this
important public health issue. Inquiries should be directed to Dr. Robert Moore
in the Office of Nutritional Products, Labeling, and Dietary Supplements
(202-205-4605; email rmoore2@cfsan.fda.gov).
Sincerely yours,
Christine J. Lewis, Ph.D.
Director
Office of Nutritional Products, Labeling, and Dietary Supplements
April 9, 2001 Updated attachments: Listing of Botanical Ingredients of Concern