Docket Management
Docket: 95N-0304 - Dietary Supplements Containing Ephedrine Alkaloids
Comment Number: EC -1400

Accepted - Volume 326

Comment Record
Commentor Dr. Eric Yarnell Date/Time 2003-04-05 21:45:28
Organization American Association of Naturopathic Physicians
Category Association

Comments for FDA General
Questions
1. General Comments Docket 95N-0304 Dietary Supplements Containing Ephedrine Alkaloids Comments to the Food and Drug Administration From the American Association of Naturopathic Physicians Submitted by: Eric Yarnell, ND, RH Assistant Professor, Bastyr University, Kenmore, WA President, Botanical Medicine Academy, Seattle, WA and Michael Traub, ND President, AANP, Washington, DC 2 April 2003 It is the position of the American Association of Naturopathic Physicians that: 1. The new evidence received by the FDA regarding the safety of isolated ephedrine alkaloids supports previous evidence that these alkaloids can have adverse effects (nausea, vomiting, anxiety, change in mood, autonomic hyperactivity, and palpitations). 2. A causal link between ephedrine alkaloids and severe adverse effects (myocardial infarction, hemorrhagic stroke, seizure, fetal harm, or death) has not been rigorously established. 3. The new evidence fails to address the differences between isolated ephedrine alkaloids and whole herb Ephedra sinica (ma huang) or related species, or complex, whole-herb extracts from these herbs, particularly for uses other than weight loss. Any regulatory action must explicitly exempt whole herb Ephedra spp. or whole herb extracts that have no added ephedrine alkaloids. Ephedrine-alkaloid-free species of Ephedra should also be explicitly exempted. 4. A warning label is appropriate for products containing ephedrine alkaloids, though the exact wording of the proposed label is not appropriate. 5. Dietary supplements containing ephedrine alkaloids do not present a “significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling, or if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use.” The prevalence and incidence of adverse effects from even egregious misuse of ephedrine alkaloids is comparable to the prevalence and incidence of adverse effects of other widely available other-the-counter drugs. The prevalence and incidence of adverse effects of whole Ephedra spp. or whole herb extracts of Ephedra spp. are far lower than many pharmaceutical drugs, all when taken as directed. 6. The use of ephedrine alkaloids for weight loss should be conducted under supervision of a knowledgeable health care professional. Discussion 1. The new evidence received by the FDA regarding the safety of ephedrine and related alkaloids supports previous evidence in that use of these alkaloids does increase the risk of nausea, vomiting, anxiety, change in mood, autonomic hyperactivity, and palpitations (ref 1). While these may be significant, they are manageable in most cases and not life threatening. Adding mandatory labels to products containing ephedrine alkaloids to warn patients of these issues is entirely reasonable. 2. Causality in medicine can only be definitively proven in rigorous, sufficiently powerful, randomized, double blind, controlled, clinical trials. No such trial has been conducted specifically on the safety of ephedrine alkaloids or Ephedra spp. Existing clinical trials on the efficacy of ephedrine alkaloids for weight loss have not reported any severe adverse effects, defined as myocardial infarction, hemorrhagic stroke, fetal harm, seizure, or death (ref 1). Some reviewers have used other criteria to determine the likelihood of causal association between case reports of severe adverse effects and exposure to ephedrine alkaloids (ref 2). However, these authors note that the apparent causal role of ephedrine alkaloids in severe adverse effects could also be related to “individual susceptibility, the additive stimulant effects of caffeine, the variability in the contents of pharmacologically active chemicals in the products, or preexisting medical conditions.” The RAND report on ephedrine alkaloids also concludes that, “The majority of case reports are insufficiently documented to make an informed judgment about a relationship between the use of ephedrine or ephedra-containing dietary supplements and the adverse event in question” (ref 1). 3. Existing pharmacological reports show a distinct difference between ingestion of ephedrine and ingestion of crude Ephedra sinica or whole plant extracts from Ephedra sinica, including but not limited to differences in pharmacokinetics and pharmacodynamics (ref 3). Unfortunately much adverse event reporting on ephedrine alkaloids has failed to distinguish the exact form of product implicated, or failed to assess the exact quantity of ephedrine alkaloids in the product each person ingested. However, the vast majority of cases of serious adverse effects involve use of ephedrine alkaloids and not whole herb or whole herb extracts of Ephedra spp (ref 2). Any regulatory action taken by FDA must take into account the differences between isolated ephedrine alkaloids and whole herb or whole herb extracts of Ephedra spp.—an explicit exemption for these products, particularly species of Ephedra that contain no ephedrine alkaloids, is mandatory. Further research is warranted to confirm the safety of whole herb or whole herb extracts of Ephedra spp, but existing data support their safety as currently provided and used. 4. Warning labels should be mandatory for products containing ephedrine alkaloids. The proposed FDA warning label, however, extrapolates too far from highly flawed reporting to suggest the risk of serious adverse effects is higher than is real. The American Herbal Product Association’s current warning label text with slight modifications is proposed as an alternative: “May cause severe heart problems, seizures, or stroke. Do not use if you are pregnant or nursing, are under 18 years of age, or if you have high blood pressure, heart or thyroid disease, diabetes, difficulty in urination due to prostate enlargement, or if taking an MAO inhibitor. Consult with a health care practitioner prior to use with any other prescription drug. Reduce or discontinue use and consult with a health care practitioners if nervousness, tremor, sleeplessness, loss of appetite, or nausea occur. Keep out of reach of children.” We support the additional labeling requirement as currently worded by FDA. 5. Dietary supplements containing ephedrine alkaloids do not present a “significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling, or if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use.” Though many cases of relatively mild adverse effects have been reported, this is not sufficient basis to consider ephedrine alkaloids a significant or unreasonable risk. As discussed above, reports of more severe adverse effects are still not definitive and thus cannot be a basis for considering ephedrine alkaloids a significant or unreasonable risk. Ephedrine alkaloids must be compared to other agents to determine relative risk. As has become eminently clear, the rate of severe adverse reactions to prescription drugs taken appropriately are so high as to rank as the fourth to sixth leading cause of death in the United States (ref 4). These figures do not necessarily include misuse of prescription drugs and also exclude community drug use. In other words, the incidence of iatrogenic severe adverse effects is very large. Compared to these standards, ephedrine alkaloids do not carry a significant or unreasonable risk of harm. It must also be pointed out again that the existing data largely ignore the fact that isolated ephedrine alkaloids are the principle putative cause of the problems, and not whole herb or whole herb extracts of Ephedra spp. There is little information about the safety of whole herb products, but no existing data suggest they are significant or unreasonable risks. 6. The use of ephedrine alkaloids for weight loss should be conducted under supervision of a knowledgeable health care professional. Given the potential for problems in rare individuals, the safest approach to use of ephedrine alkaloids as weight loss supplements would be to direct patients to consult a knowledgeable healthcare professional. This does not necessarily mean that ephedrine alkaloids should be made available by prescription only, as they have other legitimate non-weight loss uses, particularly treating allergic and bronchospastic conditions. Summary The American Association of Naturopathic Physicians, the national professional organization for licensed naturopathic physicians, supports the continued availability of Ephedra spp.-derived products that possess numerous important medicinal uses. The AANP supports the FDA’s move to increase public knowledge about the potential hazards of isolated ephedrine alkaloids, including in the form of a modified warning label and additional product labeling. Until a causal link is proven between ephedrine alkaloids and severe adverse effects, these products should remain available and do not constitute a significant or unreasonable risk of causing harm to those who take them. Whole herb and whole herb extracts of Ephedra spp. should be exempted from regulations applying to isolated ephedrine alkaloids as these are definitely not bioequivalent. Companies that sell ephedrine alkaloids should be held to these standards and should not be allowed to make false or misleading claims about ephedrine alkaloids. References 1. Shekelle P, Morton, S., Maglione M, et al. Ephedra and ephedrine for weight loss and athletic performance enhancement: Clinical efficacy and side effects. Evidence Report/Technology Assessment No. 76 (Prepared by Southern California Evidence-based Practice Center, RAND, under Contract No 290-97-0001, Task Order No. 9). AHRQ Publication No. 03-E022. Rockville, MD: Agency for Healthcare Research and Quality. February 2003. 2. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000;343:1833-8. 3. White LM, Gardner SF, Gurley BJ, et al. Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra sinica) in normotensive adults. J Clin Pharmacol 1997;37:116-21 4. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients. A meta-analysis of prospective studies. JAMA 1998;279:1200-6.




EC -1400