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.
Standard for Determination
- 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.
Evaluation
Ephedra Pharmacology
- 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.
Peer-reviewed scientific literature on ephedra's safety and effectiveness
- 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.
Adverse Event Reports
- 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.
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Questions and
Answers about FDA's Actions on Dietary Supplements Containing Ephedrine Alkaloids
Further Information
