| U.S. Food and Drug Administration |
CFSAN, April 9, 2001
U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Office of Nutritional Products, Labeling, and Dietary Supplements
April 9, 2001
Letter to Industry Associations -
Safety Concerns Related to the Use of Botanical Products Containing Aristolochic Acid
To:
American Botanical Council,
American Herbal Products Association,
Council for Responsible Nutrition,
Consumer Healthcare Products Association,
National Nutritional Foods Association,
Utah Natural Products Alliance,
American Association of Oriental Medicine, and the
American College of Acupuncturists and Traditional Medicine.
On May 16, 2000, the Food and Drug Administration (FDA) issued a letter to
communicate to manufacturers and distributors of dietary supplements the
agency's concerns about the marketing of dietary supplements that may contain
aristolochic acid. That letter urged manufacturers and distributors to review
their manufacturing procedures to ensure that botanical products are free of
aristolochic acid. During this time period, FDA also issued an import alert
providing for the automatic detention without physical examination of any
botanical dietary ingredients that were either labeled as Aristolochia
or may be confused with it.
Since the issuance of our previous letter, new information is available that
reinforces our concern about the marketing of dietary supplements and other
botanical products that may contain aristolochic acid. We are, therefore,
issuing this letter to re-emphasize the actions we believe that manufacturers
and distributors of dietary supplements containing certain botanical ingredients
should consider in light of reports that aristolochic acid has been found in
products that may be marketed as dietary supplements and to bring to your
attention new information about the serious health hazards associated with the
use of botanical products that contain aristolochic acid. FDA asks that you
share this information with your members.
Concerns about the marketing of dietary supplements containing aristolochic
acid were prompted last year by public warnings issued by Health Canada and the
Medicine Controls Agency (United Kingdom) because of findings of aristolochic
acid in several botanical products marketed in those countries 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.
Since our last letter, information has become available that further defines
the health risks associated with oral exposure to aristolochic acids. This
information comes from new reports from other countries of adverse health
consequences in consumers who used products that contained aristolochic acids,
recent reports of adverse effects in consumers in the United States, and our
finding of aristolochic acids in a range of products purchased in the United
States. We discuss each of the issues below.
A study conducted in Belgium reported that among 39 patients with end-stage
renal failure from the original Belgian cohort, who had agreed to undergo
prophylactic surgery, there were 18 cases of urothelial carcinoma. All tissue
samples analyzed contained aristolochic acid-related DNA adducts. The authors
concluded that "our data suggest that aristolochia toxins (aristolochic acids
and also possibly other derivatives) cause renal disease and urothelial cancer."
[Nortier, JL et al. Urothelial carcinoma associated with the use of a Chinese
herb (Aristolochia fangchi). N Engl J Med 2000; 342:1686-92]
A new report of seven cases similar to the Belgian cases were identified in
France, corresponding to exposure to botanical preparations contaminated with
Aristolochia fangchi from 1989-1992. In May 2000, a case of urothelial
carcinoma was diagnosed in one of these patients, and another case is suspected
in a second patient. In a third patient, a lymphoma on a graft was detected.
[Communication from the French Medical Products Safety Agency; October 27,
2000]
Two patients in the United States have recently been reported with end-stage
renal disease in association with the use of botanical preparations containing
aristolochic acids. In one case, the patient began using herbal products in 1994
and progressed to end-stage renal disease within 8 months. The patient required
a renal transplant in 1996. Subsequent laboratory analysis of the patient's
botanical products indicated the presence of aristolochic acid in 2 of the 6
products that she had been using [Meyer MM et al. Chinese herb nephropathy.
Baylor Univ Med Center Proc 2000; 13-334-7]. The second patient had consumed a
botanical product called "Stephania tablets (Han Fang Ji Pian)" for
approximately 2 years, until 1994. She was recently diagnosed with end-stage
renal disease and is awaiting a renal transplant. Although labeled as containing
the herb Stephania tetrandra, analysis of the product by the California
Department of Health Services found it to contain aristolochic acid.
In 2000, FDA purchased a limited sample of herbal products marketed in the
United States and analyzed them for aristolochic acids. We purchased 34 products
that were labeled to contain Aristolochia spp. or that contained an
ingredient which might be mis-identified as, or substituted with, an
Aristolochia spp. Of the 34 products we evaluated, 18 were found to
contain aristolochic acids. FDA is working with the firms whose products
contained aristolochic acid in order to ensure that these products are removed
from the marketplace and that consumers who may have purchased them are alerted.
A table summarizing the results of our sample is attached.
In light of the known association between products containing aristolochic
acids and the occurrence of nephropathy and urothelial cancer, and our findings
that some botanical products containing these substances are being marketed in
the United States, the FDA believes that it is imperative that manufacturers
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. FDA has validated an analytical method for the
determination of aristolochic acids in plant material.
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 many of the products that are, or that contain, plants that
contain aristolochic acids or that may be inadvertently contaminated with an
Aristolochia spp. are imported into the United States, FDA has issued
an import alert that provides 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 any aristolochic acid to be unsafe and to
be adulterated under the Act.
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,
Christine J. Lewis, Ph.D.
Director
Office of Nutritional
Products, Labeling and Dietary Supplements
Center for Food Safety and
Applied Nutrition
Attachments A-C:
Listing
of Botanical Ingredients of Concern Updated April 9, 2001
Attachment D:
Botanical
Products Determined by FDA to Contain Aristolochic Acids