Dear Colleague:
We are writing to provide you with important information about a strong association between the consumption of L-tryptophan and a cluster of symptoms called Eosinophilia-Myalgia Syndrome (EMS). Analysis by the Food and Drug Administration (FDA) and the Centers for Disease Control (CDC) of case reports received over recent months has shown a virtually unequivocal link between the consumption of L-tryptophan tablets or capsules and EMS.
FDA has, therefore, instituted a nationwide recall of all over-the-counter dietary supplements in capsule or tablet form providing for 100 milligrams (mg) or more of L-tryptophan in a daily dose. Dietary supplements providing for less than 100 mg. will remain on the market pending further evaluation.
As explained below, the scientific explanation for the risk with L-tryptophan use is not yet fully understood, but we believe it is important to communicate to you what is currently know. Physicians and other health professionals may also find useful our background information on EMS symptoms and on the regulatory status of L-tryptophan products at this time. We will inform you of any major changes in these matters as they occur.
Background
As of January 12, 1990, state health departments had reported 1,070 EMS cases to CDC. In at least one case, a patient with L-tryptophan-induced EMS died of an ascending polyneuropathy. L-tryptophan-induced EMS may have played a role in six other deaths; this is under investigation.
Although CDC, FDA and state health officials are virtually certain there is a causal relationship between EMS and use of L-tryptophan, at this time it has not been possible to link the illness to any specific lot, brand, manufacturer, or supplier of L-tryptophan, nor have extensive laboratory investigations yet identified a specific chemical or microbial contaminant responsible for the cases of EMS.
All patients with EMS but two have reported the consumption of L-tryptophan, either as a single ingredient or as a major ingredient in capsule or tablet form dietary supplements. Consumption has ranged from 150 to 17,000 mg. Of L-tryptophan per day, except that one cases of consumption of 28 mg. daily has now been identified and confirmed. Mean intake has been approximately 2.6 grams per day.
Symptoms of EMS typically develop over several weeks. Myalgia (often incapacitating) and fatigue are the most characteristic symptoms. Patients may also complain of shortness of breath, a maculopapular, vesicular or urticarial rash, and swelling of the extremities (peripheral edema). In addition to the rash, physical findings may include signs of congestive heart failure, or, in the later stages of the syndrome, skin changes typical of scleroderma. Laboratory findings include a significant eosinophilia (absolute count greater than 1,000/cu mm, possibly as high as 10,000 to 30,000/cu mm). Liver function tests, CPK, and aldolase are normal in most patients, but may be occasionally mildly evaluated. Arterial blood gases may show moderate hypoxia.
The course of the illness has not been completely defined; it may progress to a scleroderma-like syndrome or to an ascending polyneuropathy. Most patients have shown an improvement after the L-tryptophan supplements were discontinued, while in other patients, the disease continued unchanged or progressed.
Legal Status of Products and FDA Recommendations
Based on what is currently known about the potential for risk with L-tryptophan, FDA has asked for the withdrawal from the market of all over-the-counter L-tryptophan dietary supplements that provide for the intake of 100 mg. or more daily. The withdrawal has not at this time been extended to dietary products that, following the label instructions, deliver a daily dose of less than 100 mg. of L-tryptophan. We are continuing to evaluate the safety of those products and will take further actions as appropriate.
At the current time, the only other lawfully marketed products with L-tryptophan are infant formulas, enteral nutrition products, approved parenteral products, and food products using L-tryptophan in accordance with the Code of Federal Regulations' provision (21 CFR 172.320) regarding Special Dietary and Nutritional Additives. These may be recommended or prescribed by physicians for any use in the course of their routine practice of medicine without special authorization. In assessing the risk that may be associated with these products, the physician should consider that although none of the cases of EMS reported to CDC or FDA have involved infant, parenteral or enteral formulas, the sources of L-tryptophan in these products may be the same as those in over-the-counter dietary supplements that have been associated with EMS. For each patient, the physician must consider the essential need of the patient for the product balanced against the potential risk.
FDA is aware that oral dosage forms of L-tryptophan, marketed as food supplements, have been used to treat a variety of medical problems, including insomnia, premenstrual tension, stress, and depression. There is, however, no approved marketing application for any oral dosage form of L-tryptophan for the treatment of any illness, disease, sign, or symptoms, and no condition (other than nutritional replacement) for which L-tryptophan is generally recognized as safe and effective. Therefore, the agency would like to clarify that use of L-tryptophan tablets or capsules for any of the non-nutritional conditions listed above must be considered as an investigational use of an unapproved new drug, and carried out under the investigational provisions of the Federal Food, Drug, and Cosmetic Act.
The FDA does not wish to interfere with the conduct of legitimate research with L-tryptophan; indeed we encourage such investigation. Physicians may apply for an Investigational New Drug Application (IND) to carry out such research. In light of the adverse findings reported, investigators should consider that informal use of L-tryptophan in uncontrolled studies is not appropriate. Proposals for study of L-tryptophan should include protocols to study the drug for a well-defined use in a well-established patient population, and in a well-controlled clinical trial. This policy is intended to balanced the right to conduct research and the need for good scientific information with the obligation to protect participants in clinical studies.
For more information, see the November 17, November 24 and December 8, 1989, editions of CDC's Morbidity and Mortality Weekly Report. Also, CDC's guidelines, "Interim Information and Guidance for Physicians on Eosinophilia-Myalgia Syndrome," are available from state health departments.
Dr. Douglas Archer (202-245-1057) or Dr. Richard Calvert (202-245-7862) (see updated contact information below) of FDA's Center for Food Safety and Applied Nutrition may be contacted for questions concerning L-tryptophan for non-drug use.
Mr. Patrick Savino (301-295-8012) of FDA's Center for Drug Evaluation and Research may be contacted for questions regarding drug use of L-tryptophan.
Sincerely yours,
/S/
Stuart L. Nightingale, M.D.
Associate Commissioner
For Health Affairs
Updated contact information: Dr. Nancy Slifman (202 205-5056)
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