U.S. Food and Drug Administration

 FDA - Feb 6, 2004

Dietary Supplements Containing Ephedrine Alkaloids
Final Rule Summary

The Food and Drug Administration (FDA) is issuing a final regulation declaring dietary supplements containing ephedrine alkaloids adulterated under the Federal Food, Drug, and Cosmetic Act (the FD&C Act) because these dietary supplements present an unreasonable risk of illness or injury under the conditions of use recommended or suggested in labeling, or if no conditions of use are suggested or recommended in labeling, under ordinary conditions of use. Most dietary supplements containing ephedrine alkaloids are used for weight loss or enhancement of athletic performance.

We have concluded that dietary supplements containing ephedrine alkaloids pose a risk of serious adverse events, including heart attack, stroke, and death, and that these risks are unreasonable in light of any benefits that may result from the use of these products. This action is taken under the Dietary Supplement Health and Education Act of 1994 (DSHEA) which amended the FD&C Act.

DSHEA grants FDA the authority to take action against a dietary supplement under certain circumstances, including when the product presents a significant risk, an unreasonable risk, or an imminent hazard, does not comply with good manufacturing practices, or makes an unsubstantiated structure-function claim. The final regulation that FDA is issuing today applies the unreasonable risk standard to dietary supplements containing ephedrine alkaloids.

• Section 402(f)(1)(A)of the FD&C Act requires evidence of "significant or unreasonable risk" of illness or injury. There is no requirement that there be evidence that the product has caused actual harm to specific individuals, only that scientific evidence supports the existence of sufficient risk.
• FDA's burden of proof for "unreasonable risk" is met when a product's risks outweigh its benefits in light of the claims and directions for use in the product's labeling or, if the labeling is silent, under ordinary conditions of use.
• "Unreasonable risk," represents a relative weighing of the product's known and reasonably likely risks against its known and reasonably likely benefits.
• In considering whether dietary supplements containing ephedrine alkaloids present an unreasonable risk, FDA considered evidence from three principal sources: (1) The well-known, scientifically established pharmacology of ephedrine alkaloids; (2) peer-reviewed scientific literature on the effects of ephedrine alkaloids; and (3) the adverse events (including published case reports) reported to have occurred following consumption of dietary supplements containing ephedrine alkaloids.
• In evaluating whether dietary supplements containing ephedrine alkaloids present an unreasonable risk, we looked at the seriousness of the risks and the quality and persuasiveness of the totality of the evidence to support the presence of those risks. We then weighed the risks against the importance of the benefits and the quality and persuasiveness of the totality of the evidence to support the existence of those benefits. We gave more weight to benefits that improve health outcomes, especially in the long term, than to benefits that are temporary or rely on subjective measures such as feeling or looking better.

• FDA considered studies using closely related products, as it is appropriate to consider the safety of closely related products, such as those with the same active ingredient (e.g., synthetic ephedrine products) or closely related ingredients (such as other sympathomimetics). We would expect that dietary supplements containing ephedrine alkaloids will exhibit pharmacological effects similar to those other products and, therefore, pose similar risks.
• Based on the best available scientific data and the known pharmacology of ephedrine alkaloids and other sympathomimetics, dietary supplements containing ephedrine alkaloids pose short-term and long-term risks.
• This is clearest in long-term use, where increased blood pressure in any population will clearly increase the risk of serious adverse events, such as stroke, heart attack, and death. There is also evidence of increased risk of serious adverse events from shorter term use in patients with heart failure or underlying coronary artery disease.
• Ephedrine alkaloids are members of a large family of sympathomimetic compounds. These compounds increase blood pressure and heart rate.
• Such sympathomimetic effects raise three concerns:
  • they can induce cardiac arrhythmias in susceptible people, such as those with underlying coronary artery disease
  • increased mortality has been observed in patients with congestive heart failure who were treated with sympathomimetic drugs; studies that showed these adverse effects occurred in about 3 months of product use.
  • Elevated blood pressure.

• The evidence shows that there is an increase in blood pressure attributable to ephedrine alkaloids. A relative increase in blood pressure in any population, even individuals with "normal" blood pressure, will increase the risk of heart attack, stroke, and death in that population. Many individuals are unaware that they have coronary artery disease or early heart failure because these conditions may not cause prominent symptoms until later in the course of these conditions.
• Approximately one in four adults has high blood pressure. Of those with high blood pressure, 31 percent are unaware that they have it. The extremely high prevalence of diagnosed and undiagnosed hypertension in the United States population, and the likelihood that blood pressure in obese patients is already elevated, make the effects of great concern.
• The published controlled studies of the use of ephedrine alkaloid products for weight loss cannot establish the safety profile of dietary supplements containing ephedrine alkaloids because many of the most serious risks, such as strokes or heart attacks (consequences of elevated blood pressure), arrhythmias, or worsened heart failure would not have been detected in the trials because of the design limitations of these trials. These limitations also impact certain conclusions attributed to these trials.
• Based on clinical data, the ephedrine alkaloids present in dietary supplements would be expected to have the same or similar effects as other sympathomimetics on heart rate and blood pressure. Controlled clinical trials using products containing ephedrine alkaloids confirm their typical sympathomimetic effects. These studies show a blood pressure effect from ephedrine itself, independent of any additional effect from caffeine.
• There is evidence from peer-reviewed scientific literature that a wide range of drugs with sympathomimetic activity have adverse effects (increased mortality due to heart failure and sudden death) in patients studied with congestive heart failure. These effects have been seen in relatively short-term studies. Similarly, there are studies that document that people with coronary artery disease are more susceptible to the well-known pro-arrhythmic effects of sympathomimetics. The occurrence of such an arrhythmic event is not one that requires prolonged exposure but would represent a risk associated with each use, including the first.

• The adverse event reports are not dispositive of a determination of unreasonable risk and our determination did not depend on them. However, the types of adverse events reported are consistent with the risks expected from the known pharmacology of these products and the findings described in clinical studies.
• AERs may raise concerns about a product, as well as buttress a finding that a particular dietary supplement represents an unreasonable risk based on other types of evidence. This is particularly true with dietary supplements containing ephedrine alkaloids because of the disproportionate number of adverse event reports we have received for these supplements as compared to other supplement products. The importance of the AERs for dietary supplements containing ephedrine alkaloids is that they support the clinical and scientific evidence of the risks of these products.
• Although there is no required reporting of AERs to us for dietary supplements, including those containing ephedrine alkaloids, FDA, and others, have reviewed and analyzed thousands of AERs in depth to ensure that all relevant evidence has been considered.
• Despite the limitations of such AERs, a detailed review of the AERs submitted to us for dietary supplements containing ephedrine alkaloids and comparison of those AERs to scientific data about the pharmacology of these substances establishes that the AERs are consistent with the known and expected pharmacological effects of these products considered. FDA has received approximately 2,200 AERs submitted directly to us and was provided approximately 16,000 reports from call records submitted by Metabolife International, one of the largest distributors of dietary supplements containing ephedrine alkaloids.

Conclusion

Multiple studies demonstrate that dietary supplements containing ephedrine alkaloids, like other sympathomimetics, raise blood pressure and increase heart rate. These products expose users to several risks, including the consequences of a sustained increase in blood pressure (e.g. serious illnesses or injuries including stroke and heart attack that can result in death). There is also a risk of increased morbidity and mortality from worsened heart failure and pro-arrhythmic effects. Although the pro-arrhythmic effects of these products typically occur only in susceptible individuals, the long-term risks from elevated blood pressure can occur even in nonsusceptible, healthy individuals.

These risks are not outweighed by the known or reasonable likely benefits of dietary supplements containing ephedrine alkaloids. These products do not provide a meaningful health benefit. The best clinical evidence for a benefit is for weight loss, but even there the evidence supports only a modest short-term weight loss insufficient to positively affect cardiovascular risk factors or health conditions associated with being overweight or obese. Other possible benefits, such as enhanced athletic performance, enhanced energy, or a feeling of alertness, lack scientific support and/or they would provide only temporary benefits that are trivial in comparison to the risks.

This advisory was prepared by the FDA Office of Public Affairs.