| U.S. Food and Drug Administration |
CFSAN, April 4, 2001
U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Office of Nutritional Products, Labeling, and Dietary Supplements
April 4, 2001
Letter to Health Professionals -
Safety Concerns Related to the Use of Botanical Products Containing Aristolochic Acid
Dear Health Professional Colleague:
We would like to bring to your attention important safety information about
botanical products containing aristolochic acid, which are sold as dietary
supplements and "traditional herbal medicines." We urge you to review your cases
of unexplained renal disease, particularly interstitial fibrosis associated with
end-stage renal disease, as well as cases of urothelial tract tumors, in order
to determine the use of dietary supplements or "traditional medicines" in these
patients.
On May 31, 2000, the FDA issued a letter to health care professionals
concerning the nephrotoxicity and carcinogenicity of botanical products
containing aristolochic acid. During this time period, FDA also issued a letter
to representatives of the dietary supplement trade associations urging that
their members review their manufacturing procedures to ensure that botanical
products are free of aristolochic acid. In addition, FDA issued an import alert
providing for the detention of any botanical ingredients that were either
labeled as containing the plant Aristolochia or may be confused with it.
These actions were the result of several factors, including:
- In Belgium, there have been approximately 100 cases of renal disease in
patients who had participated in a "slimming regimen" from 1990-1992
consisting, in part, of a weight-reducing pill containing powdered herbs. The
major pathological lesion consisted of extensive renal interstitial fibrosis
with atrophy and loss of tubules. At least 70 of these patients have required
either dialysis or transplantation. It was concluded that one of the
botanicals (Stephania tetrandra) had been inadvertently substituted
with Aristolochia fangchi, a botanical known to contain aristolochic
acid, because of the close similarity of the Chinese names.
- In 1996, it was reported that aristolochic acid-related DNA adducts had
been detected in renal tissue from 5 of the original Belgian patients.
(Schmeiser HH et al. Detection of DNA adducts formed by aristolochic acid in
renal tissue from patients with Chinese herbs nephropathy. Cancer Res
1996;56:2025-8)
- In August 1999, 2 new cases of interstitial fibrosis were reported from
the UK in which the patients had consumed botanical preparations containing
aristolochic acid. Both patients have developed end-stage renal failure; one
has already been transplanted and the other is awaiting transplant. (Lord GM
et al. Nephropathy caused by Chinese herbs in the UK. Lancet 1999;354:481-2)
Since this time, the following new information is available:
- 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 (46%) 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]
- 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. A second case of urothelial
carcinoma is suspected and in a third patient, lymphoma on a graft was
detected. (Communication from the French Medical Products Safety Agency;
October 27, 2000)
- Laboratory analyses by the FDA of certain botanical products sold in the
United States have revealed the presence of aristolochic acid. These include
single-ingredient products labeled as Aristolochia (sometimes called
Virginia snakeroot) and botanicals that are likely to be substituted with
Aristolochia (e.g., Stephania tetrandra, Clematis
armandii, and Akebia extract). In addition, aristolochic acid was detected
in several finished products sold as dietary supplements. Warning letters and
requests for recalls have been issued to the various manufacturers or
distributors involved.
- Two patients in the U.S. have been recently reported who developed
end-stage renal disease in association with the use of botanical preparations
containing aristolochic acid.
- The first patient began using herbal "medicines" in 1994. She progressed
to end-stage renal disease within 8 months. A renal biopsy showed extensive
interstitial fibrosis with focal lymphocytic infiltration. A renal transplant
was performed in 1996. Laboratory analyses of the patient's botanical
products, conducted in Belgium, indicated the presence of aristolochic acid in
2 of the 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" for approximately 2 years, until 1994. She was recently diagnosed
with end-stage renal disease and is awaiting a renal transplant. Laboratory
analysis by the California Department of Health Services showed the botanical
product to contain aristolochic acid. Although the product was labeled as
containing the herb Stephania tetrandra, it is likely that
Aristolochia fangchi had been substituted for it, thereby accounting
for the presence of aristolochic acid in the product.
We bring to your attention the association of end-stage nephropathy due to
exposure to aristolochic acid and the risk of the development of malignancies,
particularly urothelial carcinoma. Cases of renal disease or malignancies
associated with the use of botanical preparations should be reported as soon as
possible to FDA's MedWatch program by telephone (800-332-1088).
Thank you for your efforts and cooperation in addressing this potentially
serious public health issue.
Sincerely,
Christine J. Lewis, Ph.D.
Director
Office of Nutritional
Products, Labeling, and Dietary Supplements
Center for Food Safety and
Applied Nutrition