| Comment Record|
Ms. Pamela Hayden ||
2003-04-02 13:28:27 |
North American Spine Society |
| Comments for FDA General |
1. General Comments
March 14, 2003
Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852
SUBJECT:Comment on Dietary Supplements Containing Ephedrine Alkaloids
Docket No. 95N-0304
Recently, the Department of Health and Human Services and the Food and Drug Administration (FDA) began building a scientific and legal record on the dangers of ephedra. In addition to announcing its own initiatives, FDA also has reopened the comment period for a proposed rule on ephedrine alkaloids, originally issued in 1997. In response to the FDA request for medical community guidance on this issue, the North American Spine Society would like to submit the following comments.
The North American Spine Society (NASS) is the leading multidisciplinary organization that advances quality spine care through education, research and advocacy. NASS has just under 3,500 members; primarily orthopedic surgeons, neurosurgeons and physiatrists. NASS has made a strong commitment to patient safety and has an established Patient Safety Task Force. One of the projects this task force has undertaken was the examination of herbal supplements and a “’Natural’ Doesn’t Always Mean Safe” series of documents on herbal supplement usage. These documents include a patient history checklist, a patient education brochure and a guide for health care professionals. This guide provides information on herbal usage, regulation and ways to help patients avoid adverse events. Tables provide various herbs with their uses/effects, potential side effects and potential interactions with references. NASS is interested in this topic because alternative medicines are commonly used for chronic conditions, including back pain.
Comment 1: The New Evidence on Ephedrine Alkaloids Found in the RAND Report1
In light of gaps in current research regarding safety and efficacy of ephedra and considering RAND’s examination of the limited numbers of quality controlled trials, in combination with the 1000+ FDA adverse event reports, 70 case reports from literature and 15,951 reports from a manufacturer of ephedra products, the results of the RAND Report are one more brick in the wall of suggestive evidence which question the efficacy and safety of ephedrine. Evaluated in two of its most common uses, weight loss and enhanced athletic performance, ephedrine/ephedra produced short-term weight loss (with modest increases when combined with caffeine) and moderate increases in athletic performance when combined with caffeine over the very short term. There is no research on long-term effects of ephedrine/ephedra-containing products for either of these uses and the study does not necessarily apply to the general population. The lack of evidence of applicability to the general population is important when you consider that the dietary supplement industry estimates that approximately 12 million people were using ephedra in 1999.2 It is of even more interest when you also consider the potential for additive effects of caffeine (and other stimulants) commonly ingested by a general population preoccupied by physical fitness.
The safety portion of the study found that ephedrine and/or ephedra-containing dietary supplements or ephedrine plus caffeine increased two to three times the risk of nausea, vomiting, psychiatric symptoms, autonomic hyperactivity and palpitations. It also examined the rate of more severe adverse events: death, MI, CVA, seizures and psychiatric cases. Although the evidence presented relative to the more severe adverse events cannot provide a secure causal link, the rate of discovery of those found does raise concern for a number of reasons:
-We believe that adverse events related to dietary supplements are underreported. The FDA estimates that for each report it receives, there are 100 more unreported.3
-These events are affecting primarily individuals 30 years or younger--typically a fairly healthy population.
-The 30 and under age set are also one of the most interested/involved in strenuous exercise and weight loss.
-For the number of individuals who undergo surgery each year, ephedra presents an additional danger of prolonged bleeding, which many patients may not be aware of or are unlikely to tell their surgeon of their ephedra usage.
In addition the safety conclusions reached in this study do agree, for the most part, with those reached by NASS in its review document for health care providers, 'Natural' ≠ Safe: The Spine Care Provider’s Guide to Herbal Supplements (see below).
Common Names: Chinese Joint Fir, Ephedrine, Ma-Huang, Mormon Tea, Pseudo-ephedrine, Squaw Tea
Uses/Effects: Weight loss (common in herbal and over-the-counter weight loss products), increased energy, enhance athletic performance, asthma, bacteriostatic, antitussive
Potential Side Effects (Referenced):
Discontinue use at least 24 hours prior to surgery.
Prolonged bleeding time. Long-term use depletes endogenous catecholamines and may cause intraoperative hemodynamic instability.
Adverse cardiovascular events (palpitations, tachycardia, arrhythmia, myocardial infarction, cardiac arrest or sudden death).
Adverse central nervous system events (stroke, seizures, transient ischemic attack).
Dose-dependent increases in blood pressure and heart rate.
Rare cause of radiolucent kidney stones (with heavy usage).
Nervousness, dizziness, headache, insomnia, tremor.
Avoid in patients with hypertension, hyperthyroidism, diabetes mellitus, psychiatric conditions, glaucoma, prostate enlargement, seizure disorders and cardiovascular disease.
Potential Interactions (Referenced):
Epinephrine-Adds to cardiac stress.
Guanethedine-Enhanced sympathomimetic effects.
Heart glycosides or halothane-Arrhythmias
Monoamine oxidase inhibitor (MAOIs) (eg, phenelzine)-Enhanced sympathomimetic effects. Insomnia, headache and tremors. Life-threatening hyperpyrexia, hypertension, coma.
Stimulants (eg, caffeine, Actifed®, Sinutab®, Sudafed®) are likely to enhance ephedrine effects and increase risk of adverse effects.”
Comment 2: The Proposed Warning Statement for Dietary Supplements Containing Ephedrine Alkaloids
The North American Spine Society finds the warning statements suggested by the FDA to be completely appropriate in content and degree. In a case, such as ephedrine, where the safety evidence is limited, difficult to obtain and points to the possibility of very severe adverse events, the interests of protecting consumer health should outweigh those of industry. These warnings could, at the very least, work to reduce likelihood of concomitant activities that increase risk of harm (eg, stimulant use, strenuous exercise with ephedra use).
Comment 3: Whether Ephedrine Presents “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 Labeling, Under Ordinary Conditions of Use.”
Based on our reviews, the evidence presented in the RAND Report and the severity of the adverse events being considered, NASS believes that ephedrine does present a significant or unreasonable risk to consumers. We believe that the proposed warning statements should be a minimum protection to provide consumers with an awareness of the potential dangers of ephedrine. Because of the lack of strong scientific evidence (the limited likelihood of any being produced in the future), the limited evidence we have to date will probably be all that will be available to refute the safety and effectiveness of supplements under DSHEA. In cases of dietary supplements where serious health issues loom, the FDA should be able to regulate these items much like drugs. After all, synthetic ephedrine is marketed and regulated as a drug. The health and welfare of the public should rise above industry business concerns. If the dietary supplement industry has the best interests of its consumers at heart and believes in its products, warning labels and increased regulation shouldn’t be objectionable; in fact, it should be welcomed as proof of the safety and efficacy of the products it produces.
The North American Spine Society would be happy to submit a copy of its herbal supplement documents to you at any time, should you be interested in reviewing them. Any questions can be addressed to Pam Hayden, Director of Research, (815) 675-0021, Fax (815) 675-3137, E-mail: email@example.com.
David A. Wong, MD
Co-Chair, Patient Safety Task Force
Stanley Herring, MD
Co-Chair, Patient Safety Task Force
1US Food and Drug Administration. Evidence Report/Technology Assessment Number 76. Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects. Available at: http://www.fda.gov/bbs/topics/NEWS/ephedra/summary.html. Accessed: March 14, 2003.
2Dietary Supplements for Weight Loss: Limited Federal Oversight Has Focused More on Marketing than on Safety (Testimony, 07/31/2002, GAO-02-985T). Cited in: US Food and Drug Administration. Evidence on the Safety and Effectiveness of Ephedra: Implications for Regulation. Available at: http://www.fda.gov/bbs/topics/NEWS/ephedra/whitepaper.html. Accessed: March 14, 2003.
3Spake A. Natural hazards. Tonic or toxic? Americans are gobbling up nature’s remedies for everything from obesity to depression. US New & World Report. 2001;130(6):42-49.
4American Society of Anesthesiologists. Considerations for anesthesiologists: what you should know about your patients’ use of herbal medicines. Park Ridge, IL: American Society of Anesthesiologists; 1999.
5Flanagan K. Preoperative assessment: safety considerations for patients taking herbal products. Journal of PeriAnesthesia Nursing. 2001;16(1):19-26.
6US Food and Drug Administration Center for Food Safety and Applied Nutrition. Illnesses and injuries assicated with the use of selected dietary supplements. In: Unsubstantiated Claims and Documented Health Hazards in the Dietary Supplement Marketplace (out of print). 1993. Available at: http://www.cfsan.fda.gov/~dms/ds-ill.html. Accessed December 20, 2001.
7Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med. 1998;158(20):2200-221.
8Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343:1833-1838.
9Powell T, Hsu FF, Turk J, Hruska K. Ma-huang strikes again: ephedrine nephrolithiasis. Am J Kidney Dis. 1998;32:153-159. Cited by: American Academy of Orthopaedic Surgeons’ Committee o Complementary and Alternative Medicine. CAM herb/drug interactions. Available at: http://www3.aaos.org/courses/cam/dhintact.htm. Accessed December 21, 2001.
10White LM, Gardner SF, Gurley BJ, Marx MA, Wang PL, Estes M. Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra sinica) in normotensive adults. J Clin Pharmacol. 1997 ;37(2) :116-122. Cited by American Academy of Orthopaedic Surgeons’ Committee on Complementary and Alternative Medicine. CAM herb/drug interactions. Available at: http://www3.aaos.org/courses/cam/dhintact.htm. Accessed December 21, 2001.
11Ang-Lee MK, Moss J, Yuan C-S. Herbal medicines and perioperative care. JAMA. 2001;286:208-216.
12Roizen MF. Anesthetic implications of concurrent diseases. In: Miller RD, ed. Anaethesia. 4th ed. New York, NY: Churchill Livingstone, Inc; 1994:903-1014. Cited by: Ang-Lee MK, Moss J, Yuan C-S. Herbal medicines and perioperative care. JAMA. 2001;286:208-216.
13Blau JJ. Ephedrine nephrolithiaisis associated with chronic ephedrine abuse. J Urol. 1998;160:825. cited by: Ang-Lee MK, Moss J, Yuan C-S, Herbal medicines and perioperative care. JAMA. 2001;286:208-216.
14Nightingale SL. From the Food and Drug Administration. JAMA. 1997;278:15. Cited by: Ang-Lee MK, Moss J, Yuan C-S. Herbal medicines and perioperative care. JAMA. 2001;286:208-216.
15Chang LK, Whitaker DC. The impact of herbal medicines on dermatologic surgery. Dermatol Surg. 2001;27:759-763.
16Cupp MJ. Clinical pharmacology. Herbal remedies: adverse effects and drug interactions. American Family Physician. 1999 Mar 1. p.1239.