| Comment Record|
Mr. Richard Hamburg ||
2003-04-03 12:48:37 |
American Heart Association |
| Comments for FDA General |
1. General Comments
THE AMERICAN HEART ASSOCIATION COMMENTS TO THE FDA ON DIETARY SUPPLEMENTS CONTAINING EPHEDRINE ALKALOIDS
April 3, 2003
RE: (Docket No. 95N-0304)
21 CFR Part 111
The American Heart Association is the nation’s largest voluntary health organization dedicated to the reduction of disability and death from heart disease and stroke, the nation’s number one and number three leading killers. Our 30,000 Scientific Council members and our four million volunteers are committed to ensuring that Americans lead “heart healthy” lifestyles through proper nutrition and physical activity, and they include the nation’s thought leaders in heart disease and stroke. These leaders are also specifically knowledgeable about heart rhythm abnormalities and high blood pressure, and the effects of exogenous agents on these conditions. Therefore, the American Heart Association is grateful to the Food and Drug Administration (FDA) for publishing this proposal to place stringent limits on the manufacturing and marketing of ephedrine-based dietary supplements and for its stepped up enforcement actions against firms marketing for “recreational purposes.”
These actions represent the recognition by the FDA of the growing concern about the health hazards of ephedrine, a sympathomimetic agent and potent stimulant found in many products, and often combined with caffeine. Ephedrine does have legitimate medical uses, notably in the treatment of the rare disorder of orthostatic hypotension due to autonomic failure, and has been included as a component of a number of prescription cough and cold preparations, used for bronchodilation. Our comments do not apply to the prescription use of ephedrine, but rather to the availability without prescription of compounds containing ephedrine, notably “ephedra” or “ma huang”, the herbal product from which ephedrine was originally isolated.
The Association is aware that the FDA’s current proposal would ban the marketing of any capsules containing more than 8 mg of ephedrine and would limit the maximum intake to 24 mg/day. The intended effect is to protect the public from the health hazards of ephedra, which many manufacturers promote as a “dietary supplement” to be used for weight loss or muscle building. Ephedra has been documented to increase the metabolic rate, possibly via the sympathomimetic effects of its component ephedrine on specific forms of adipose tissue. There are, however, no long-term studies of its safety or efficacy in humans. While these studies are not required for the manufacturing and marketing of dietary supplements, their lack for such a potent agent represents a gap in the safety net needed for the public.
In evidence of this problem, the use of ephedra has been associated with a remarkable risk profile. The recent death of a young baseball player using ephedra has been highly publicized, but is only an anecdote. More impressive is the growing literature on the adverse events associated with ephedra use. This includes multiple reports of adverse events, including ischemic stroke in an ephedra user (1), the sudden appearance of hypertension in a body-builder (2) a case-control study suggesting, though not definitively proving, an increased risk of hemorrhagic stroke at higher doses of ephedra (3), a further review of FDA data on adverse events related to ma huang use, suggesting a temporal relation of use and stroke, myocardial infarction and death, with events occurring even in individuals without underlying cardiovascular disease (4), myocardial infarction after ephedra in a young man with normal coronary arteries but slow flow suggesting an abnormality in microcirculatory function (5), and general reviews of adverse events including deaths, cerebrovascular accidents and myocardial infarctions associated with the use of ephedra alkaloids (6,7,8,9), including a review of those reported in Denmark and Canada, leading to the market recall of several ephedrine-containing products in Canada after a large number of adverse events, including stroke, myocardial infarction, cardiac arrhythmias, seizures and psychiatric disorders (8). A review of he FDA’s data on 140 events reported between June 1997 and March 1999 included hypertension as the most frequent side effect, but also included 10 deaths, 13 cases of permanent impairment, with other reports of tachycardia, myocardial infarction, stroke, and seizure (10), and this surely represents the tip of the iceberg.
A recent report from RAND investigators included these data and other reports, and included from FDA records more than 1,500 adverse event reports related to products containing herbal ephedra and 125 adverse events related to products containing synthetic ephedrine, as well as 70 adverse events from the medical literature and 18,000 adverse event reports recorded by Metabolife, a manufacturer of ephedra products (11). There was a 2.2-3.6-fold increased likelihood of headache, tachycardia, palpitations, GI, psychiatric or autonomic side effects. In the case of case reports, while the investigators were unable to definitively demonstrate that ephedrine was causal in the majority of these serious adverse events, they identified 10 “sentinel events” i.e., adverse events in the presence of ephedra or ephedrine without an identifiable alternative cause, including 2 deaths, 2 myocardial infarctions, 2 cerebrovascular accidents, 1 seizure and 3 psychiatric cases. They also identified an additional 50 possible sentinel events. Approximately half of the sentinel events occurred in individuals under the age of 30. The likelihood of adverse events occurring at a rate of less than 1 per thousand could not be evaluated. It has recently bee suggested that the likelihood of an adverse reaction to ephedra-containing products is 200 times that seen with other supplements (7).
The RAND investigators also reviewed 52 clinical trials that evaluated the use of either herbal ephedra or the synthetic ephedrine in man for either weight loss or athletic performance, and concluded that there was no long-term proof of safety or efficacy. While there have indeed been short-term studies in small numbers of patients suggesting that some ephedra compounds are safe when used in a carefully regulated setting, and may increase weight loss more than placebo (12, 13), these studies cannot be used to predict safety and/or efficacy for the population at large. They do not take into account the increased sensitivity of some individuals within the population to a potential pro-arrhythmic effect of these agents, nor the tendency of the public to disregard warning signs about the safe amount of a product to be taken. Even in these studies, use was associated with a significant increase in systolic blood pressure and heart rate. And of course, without regulation the consumer cannot safely assume the amount of ephedrine in a given product or even batch of a product. In a recent study of 20 products, using HPLC, the total alkaloid content varied from 0.0 -18.5 mg/dosage unit, with ranges for ephedrine and pseudoephedrine varying from 1.1-15.3 mg and 0.2-9.5 mg, respectively. Norpseudoephedrine, which is a Schedule IV controlled substance, was also commonly present. In addition, there was remarkable lot-to-lot variation in content, ranging from 180-1000%, and the label was often of little use in determining what one was ingesting (14). This poses an obvious risk to the consumer who takes doses from a lot with little drug at first and finds little effect, and then increases to a greater dose of a lot with greatly increased drug.
Given the national preoccupation with “slimness,” particularly but not exclusively by college age individuals, and the common use of body-building products, the concern of the American Heart Association is that a warning to limit the daily intake of these products and to avoid caffeine use with them will go unheeded. The potential health hazards associated with ephedrine are too serious to permit them to be sold on the open market, without the supervision of a physician and without regulation of content and purity.
The American Heart Association urges the FDA to strongly consider removing dietary supplements that contain ephedrine from the open market. We recognize that the increasing interest in dietary supplements will be accompanied by a demand and need for more scientific information to substantiate potential claims for approval or disapproval of the specific supplement. We agree with the RAND investigators that further study of ephedrine for weight loss should be accomplished before its use for this purpose is allowed. We see no evidence that it has a beneficial effect on athletic performance. The American Heart Association would be pleased to discuss this further and to assist the FDA in any way possible.
1. Kaberi-Otarod J, Conetta R, Kundo KK, Farkash A. Ischemic stroke in a user of thermadrene: a case study in alternative medicine. Clin Pharmacol Ther 2002 Sep;72(3):343-6
2. Wettach GE, Falvey SG. A mysterious blood pressure increase in a drilling Naval reservist. Mil Med 2002 Jun;167(6):521-3
3. Morgenstern LB, Viscoli CM, Kernan WN, Brass LM, Broderick JP, Feldmann E, Wilterdink JL, Brott T, Horwitz RI. Use of Ephedra-containing products and risk for hemorrhagic stroke. Neurology 2003 Jan 14;60(1):132-5
4. Samenuk D, Link MS, Homoud MK, Contreras R, Theohardes TC, Wang PJ, Estes NA 3rd. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin Proc 2002 Jan;77(1):12-6 Comment in: Mayo Clin Proc. 2002 Jan;77(1):7-9. Mayo Clin Proc. 2002 Jul;77(7):733.
5. Rezkalla SH, Mesa J, Sharma P, Kloner RA. Myocardial infarction temporally related to ephedra--a possible role for the coronary microcirculation. WMJ 2002;101(7):64-6.
6. Geiger JD. Adverse events associated with supplements containing ephedra alkaloids. Clin J Sport Med 2002 Jul;12(4):263
7. Bent S, Tiedt TN, Odden BS, Shlipak MG. Ann Int Med 2003 Mar; 138: http://www.acponline.org/journals/annals/ephedra.htm
8. van der Hooft CS, Stricker BH. [Ephedrine and ephedra in weight loss products and other preparations] [Article in Dutch] Ned Tijdschr Geneeskd 2002 Jul 13;146(28):1335-6
9. Samenuk D, Link MS, Homoud MK, Contreras R, Theohardes TC, Wang PJ, Estes NA 3rd. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clinic Proceedings 2002;77:12-16.
10. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. New Engl J Med 2000; 343:1833-1838
11. 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.
12. Kalman D, Incledon T, Gaunaurd I, Schwartz H, Krieger D. An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults. Int J Obes Relat Metab Disord 2002 Oct;26(10):1363-6
13. Boozer CN, Daly PA, Homel P, Solomon JL, Blanchard D, Nasser JA, Strauss R, Meredith T. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int J Obes Relat Metab Disord 2002 May;26(5):593-604
14. Gurley BJ, Gardner SF, Hubbard MA. Content versus label claims in ephedra-containing dietary supplements. Am J Health Syst Pharm 2000 May 15;57(10):963-9