| U.S. Food and Drug Administration |
CFSAN, May 31, 2000
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
(800-332-1088).
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 nephropathy 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.
Christine J. Lewis, Ph.D.
Director
Office of Nutritional Products, Labeling, and Dietary Supplements
Center for Food Safety and Applied Nutrition
Susan Alpert, Ph.D., M.D.
Director, Food Safety
Center for Food Safety and Applied Nutrition
April 9, 2001 Updated attachments: Listing of Botanical Ingredients of Concern