U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Office of Nutritional Products, Labeling, and Dietary Supplements
May 31, 2000

Letter to Health Care Professionals -
FDA Concerned About Botanical Products, Including Dietary Supplements, Containing Aristolochic Acid

Dear Health Care Professional:

We want to bring to your attention important safety information relative to nephrotoxicity associated with botanical products found to contain aristolochic acid.

FDA is concerned about botanical-containing products known or suspected of containing aristolochic acid and will be pursuing appropriate regulatory actions regarding these products. Some of these botanicals include: Aristolochia spp., Asarum spp., Bragantia spp., Stephania spp., Clematis spp., Akebia spp., Cocculus spp., Diploclisia spp., Menispernum spp., Sinomenium spp., Mu tong, Fang ji, Guang fang ji, Fang chi, Kan-Mokutsu (Japanese), and Mokutsu (Japanese). In addition, practitioners who prescribe botanical remedies are urged to discard any products with the above listed ingredients. For a more complete list of botanicals, Chinese names, and common names, see attachments A through C.

The term Aristolochia species (spp.) refers to several botanical species most often found in traditional Chinese medicines. Cases of nephropathy and end-stage renal disease associated with their use have been reported in the medical literature; in some instances, dialysis or transplant was necessary. Moreover, because of the similarity of Chinese names for several herbs and because of the Chinese tradition of interchangeability of similarly named herbs, there is a great propensity for many innocuous herbs to be inadvertently substituted with Aristolochia spp. not only in traditional medicines but also in dietary supplements.

The FDA has not received any adverse event reports to date of a similar nature. However, with the increasing use of dietary supplements and traditional forms of botanical remedies, a thorough history of use of dietary supplements as well as traditional medicines, including Chinese and Ayurvedic (Indian), should be routinely sought as part of the medical history, particularly in cases of unexplained interstitial renal fibrosis. Adverse events suspected to be associated with dietary supplements or other botanical-containing products, i.e. traditional medicines, may be reported to FDA's MedWatch program (1-800-332-1088) or through FDA's website (www.fda.gov).

Background: In July 1999, two new cases of nephropathy, associated with the use of Chinese botanical preparations, were reported from the United Kingdom. Both of these patients had ingested botanical preparations, for the treatment of "eczema." These botanical preparations were shown to contain aristolochic acid, a known nephrotoxin which can be found in Aristolochia spp., Bragantia spp. or Asarum spp. Biopsy samples from both patients showed extensive loss of cortical tubules with interstitial fibrosis, features typical of a nephrophathy sometimes referred to as “Chinese herbs nephropathy.” One patient has already undergone renal transplant and the other is on hemodialysis while awaiting transplant.

Previously, a series of end-stage renal disease cases had been reported from Belgium in which the affected patients had ingested a "slimming pill” containing botanical ingredients, that had been prescribed by the same clinic as part of a weight loss regimen. It was hypothesized that the botanical ingredient Stephania tetrandra, a botanical not known to contain aristolochic acid, had been inadvertently substituted with the botanical Aristolochia fangchi, which contains aristolochic acid as a normal constituent. This was thought to have occurred because of the similarity of the Chinese names for these 2 botanicals. Aristolochic acid, either solely or in conjunction with other medications/botanicals administered during the weight loss regimen, was suspected to have caused the nephropathy observed in these patients. To date, more than 100 patients in Belgium have been identified with this unusual type of nephropathy following the ingestion of this botanical preparation from the same clinic from 1990 to 1992. Of these, at least 70 patients have required renal transplant or dialysis.

Of further concern is the carcinogenic potential of aristolochic acid. Rodents administered aristolochic acid developed lymphoma, as well as cancers in the kidney, bladder, stomach, and lung. Moreover, urothelial carcinomas have been reported in some of the patients who had been diagnosed as having “Chinese herbs nephropathy.” Based on these studies, patients taking aristolochic acid may be at increased risk of developing malignancies.

We ask that you share this information with your colleagues and other interested parties. Thank you.

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

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

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