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Posted March 4, 2003
U.S. Warns of Ephedra Risks and Proposes Warning Label for Supplements
The results of a RAND Corporation study commissioned by the National Institutes of Health, as well as other recent studies, provide additional evidence that ephedra may be associated with important health risks. The Rand report also finds only limited evidence of health benefits resulting from ephedra use.
On the basis of new evidence in the medical literature and in adverse event reports, there are reasons for heightened concern that dietary supplements containing ephedra may present a significant and unreasonable risk of illness and injury.
To protect Americans from the potentially serious risks of these dietary supplements, HHS and FDA are going to:
--Seek rapid public comment on the new evidence on health risks associated with ephedra to establish an up-to-date record as quickly as possible to support new restrictions on ephedra-containing products.
--Seek rapid public comment on whether the currently available evidence and medical literature present a "significant or unreasonable risk of illness or injury" from dietary supplements containing ephedra.
--Seek rapid comment on a strong new warning label on any ephedra products that continue to be marketed.
--Immediately execute a series of actions against ephedra products making unsubstantiated claims about sports performance enhancement.
In addition, the nation's top public health officials issued strong statements cautioning about the use of ephedra-containing products, especially under conditions of strenuous exercise and in combination with other stimulants, including caffeine.
Ephedra is a naturally occurring substance derived from the Chinese herbal Ma Huang. Its principal active ingredient is ephedrine, which when chemically synthesized is regulated as a drug. While products containing natural ephedrine alkaloids have long been used to treat certain respiratory symptoms in traditional Chinese medicine, in recent years they been extensively promoted and used with the goals of aiding weight loss, enhancing sports performance, and increasing energy.
Many of today's proposed actions involve a Federal Register notice, which went on display today, reopening for 30 days the comment period on a draft regulation FDA first proposed in 1997 and modified in 2000.
FDA's concerns about dietary supplements containing ephedra arise in part from ephedra's mechanism of action in the body. Ephedra is an adrenaline-like stimulant that can have potentially dangerous effects on the nervous system and heart.
In addition, evidence is accumulating about potentially serious safety problems following the use of ephedra-containing products. The RAND study has concluded that ephedra is associated with higher risks of mild to moderate side effects such as heart palpitations, psychiatric and upper gastrointestinal effects, and symptoms of autonomic hyperactivity such as tremor and insomnia, especially when it is taken with other stimulants.
Moreover, its review of some 16,000 adverse event reports revealed two deaths, four heart attacks, nine strokes, one seizure, and five psychiatric cases involving ephedra in which the records appeared thorough and no other contributing factors were identified. RAND called such cases "sentinel events," because they may indicate a safety problem but do not prove that ephedra caused the adverse event. The study recognized that such case studies are a weak form of scientific evidence. Other unmeasured factors may have contributed, and such serious adverse events are likely to happen (albeit at very low rates) among the millions of users of ephedra anyway. The study also identified other such events potentially associated with ephedra, in which other factors may have contributed to the adverse events or in which records were inadequate.
Two recent studies of ephedra's safety were published too late to be included in the RAND Corporation's review, and each raises further concerns about ephedra. One, published this month in the Annals of Internal Medicine, found that although ephedra-products make up less than one percent of all dietary supplement sales, these products account for 64 percent of adverse events associated with dietary supplements.
Another "case-control" study, published in the journal Neurology, concluded that the rate of hemorrhagic (bleeding) strokes among ephedra users was statistically significantly higher than among non-users, for people who take doses above 32 milligrams a day. Many ephedra dietary supplement labels recommend that users take up to approximately 100 mg of ephedra daily.
Additional relevant evidence on whether the current system of regulating ephedra's safety is adequate comes from results under FDA's more extensive regulation of synthetic ephedrine, which is identical to the main active ingredient in ephedra. Ephedrine has long been available in some FDA-approved over-the-counter and prescription drugs. It appears that the more controlled availability of synthetic ephedrine products, which are available primarily for approved uses for respiratory symptoms and carry mandatory warning labels, has not been associated with the same kind of severe adverse events as have occurred with dietary supplements containing ephedra. This long experience with synthetic ephedrine (in over-the-counter drug products, not in dietary supplements) suggests that significant restrictions on labeling, marketing, and/or access to ephedrine might effectively address unreasonable risks associated with certain forms of ephedra today.
"Although the overall evidence suggests that serious adverse events from ephedra appear to be infrequent," said Dr. McClellan, "we know that such events can be very serious and possibly fatal. We believe that the current scientific evidence strongly suggests that at least some ephedra products present an unreasonable risk. We also believe that FDA's system for regulating synthetic versions of the chemicals in ephedra appears to have a much better track record of safety. To give us the strongest possible basis for further regulatory action, we are asking for quick comments on whether these dietary supplements present an unreasonable risk of harm, and whether it makes sense for FDA to seek new authority in this area."
Under the Dietary Supplement Health and Education Act of 1994, FDA does not review dietary supplements for safety and effectiveness before they are marketed. Rather, the law allows FDA to prohibit sale of a dietary supplement if it "presents a significant or unreasonable risk of injury." This legal standard of "significant or unreasonable risk" implies a risk-benefit calculation based on the best available scientific evidence. It strongly suggests that the agency must determine if a product's known or supposed risks outweigh any known or suspected benefits, based on the available scientific evidence, in light of the claims the product makes and in light of the product's being sold directly to consumers without medical supervision.
In seeking comment on these issues, FDA is reopening a proposed rule entitled "Dietary Supplements Containing Ephedrine Alkaloids." That proposal would have required a warning statement for these products, as well as restrictions on their potency and composition. FDA later withdrew parts of this proposed rule because of concerns about the specific scientific evidence in the proposal, expressed by the General Accounting Office.
In a broad action against potentially dangerous products, FDA today sent more than two dozen warning letters to firms marketing dietary supplements that contain ephedrine alkaloids. The letters, targeted particularly at products making claims for athletic performance, explain that any claims their products make about effects on the structure and function of the human body must be truthful and not misleading. They outline FDA's view in light of the RAND report that the claims being made are not adequately substantiated by scientific data, and they direct the companies to submit any data supporting the claims within 15 days.
The letters also warn firms that they must not make claims about their products' ability to treat or cure a disease or condition such as obesity. Under the Federal Food, Drug and Cosmetic Act, unapproved products making these "disease claims" are unapproved new drugs and therefore subject to other prompt regulatory actions, including injunctions against firms and seizures of their products.
FDA will also continue to work closely with the Federal Trade Commission to ensure that dietary supplement products containing ephedra do not make false and misleading claims. "If an ad says a product is 'safe,' the advertiser's must have competent and reliable evidence to prove the claim," said Timothy J. Muris, Chairman of the Federal Trade Commission. "Consumers depend on advertising for factual information and deceptive ad claims can put a consumer's health at risk. That's why the FTC is currently investigating a number of weight loss products containing ephedra and we will continue to pursue aggressively marketers making unsubstantiated claims about product safety or effectiveness."
In addition, FDA today proposed a warning label for all ephedra-containing dietary supplements. The proposed label warns about the risks of serious adverse events, including heart attack, seizure, stroke, and death; cautions that the risk can increase with the dose, with strenuous exercise, and with other stimulants such as caffeine; specifies certain groups (such as women who are pregnant or breast feeding) who should never use these products; and lists other conditions, such as diseases and the use of certain medications, that rule out the use of ephedrine alkaloids.
"The steps being announced today demonstrate FDA's commitment to taking the most effective actions possible under current law, given the state of the scientific evidence," said Dr. McClellan. "It may be possible to use ephedra safely, in small doses, for some purposes. But in the face of continued serious adverse events following the use of ephedra, there is a problem. It is a problem we are determined to fix."
Once the 30-day comment period has ended, FDA will analyze the comments and publish its conclusions about the most appropriate approach to reducing the risk of using dietary supplement products containing ephedrine alkaloids.
Additional materials about the risks of products containing ephedrine alkaloids, including a more technical FDA "white paper," may be found on FDA's Web site:
--Sample Warning Letter
--List of Warning Letters
--"Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects" (Rand Report)
--Summary of the Rand Report on Ephedra
--Additional Background on Ephedra