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 Regarding Safety Concerns Related to the Use of Botanical Products Containing Aristolochic Acid

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 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 [see http://vm.cfsan.fda.gov/~dms/ds-bot.html].

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).

Attachments A-C: Listing of Botanical Ingredients of Concern Updated April 9, 2001

Attachment D: Botanical Products Determined by FDA to Contain Aristolochic Acids

Consolidated Information on Aristolochic Acid: FDA Concerned About Botanical Products, Including Dietary Supplements, Containing Aristolochic Acid

Hypertext updated by cjm/kwg/dms 2001-AUG-03