PUBLIC MEETING ON THE SAFETY OF DIETARY SUPPLEMENTS CONTAINING EPHEDRINE ALKALOIDS VOLUME I of II [DHHS Office on Women's Health does

not guarantee the accuracy of the transcript.]

Tuesday, August 8, 2000 U.S. Public Health Service Cohen Building Auditorium Washington, D.C.

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The meeting in the above-entitled matter was convened, pursuant to notice, at 9:00 a.m.

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A G E N D A Public Meeting: Safety of Dietary Supplements Containing Ephedrine Alkaloids Tuesday, August 8, 2000 8:00 am 9:00 am Registration OPENING Wanda K. Jones, DrPH, Director Office of Women's Health 9:10 am Ephedra-containing Compounds: and Pharmacologic Context Harry H.S. Fong, Phased, University of Illinois, Chicago 9:50 am 10:05 am BREAK Adverse Event Reports: Clinical Studies Lori A. Love, MD, PhD, FDA Julie G. Bietz, MD, FDA George Ricaurte, MD, PhD, Johns Hopkins University School of Medicine MOFFITT REPORTING ASSOCIATES (301) 390-5150 Database and Historical

Raymond L. Woosley, MD, PhD, Georgetown University School of Medicine Cynthia Culmo, Texas Department of Health 11:50 am 12:10 pm 1:10 pm Q&A LUNCH (on your own) Adverse Event Reports: Panel of Experts Review Steven E. Kimmell, MD, MSCE, University of Pennsylvania Theodore M. Farber, PhD, DABT, Toxichemica International Norbert P. Page, DVM, MS, Toxichemica International Grover M. Huchins, MD, Johns Hopkins University School of Medicine Steven B. Karch, MD, City of San Francisco John W. Olney, MD, Washington University Medical School Edgar H. Adams, MS, SCD, Harris Interactive 2:55 pm 3:15 pm Q&A BREAK Ephedra Education

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Public Meeting: Safety of Dietary Supplements Containing Ephedrine Alkaloids 3:30 3:30 3:45 3:50 4:05 4:10 4:25 4:30 4:45 4:50 5:05 5:10 Abstract Session I Barbara J. Michael, HEAT Q&A James S. Turner, Swankin & Turner Q&A Linda Golodner [Brett Kay], National Consumers League Q&A Col. Esther F. Myers, PhD. RD, FADA U.S. Air Force Q&A Adraine Fugh-Berman, MD National Women's Health Network Q&A Michael McGuffin, President, American Herbal Products Association

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5:25 5:30 5:45 5:50 5:50 5:53 5:56 5:59 6:02 p.m.

Q&A Robert M. Stark, MD, FACP, Yale University Q&A Public Comment Session A 1. 2. 3. 4. Samieh Wood, Private Citizen Hanna K. Zewchzer, Private Citizen David Molony, American Association of Oriental Medicine Pablo Francisco Semiao, Private Citizen Adjourn

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LISTENING PANEL Chair: Wanda Jones, Dr. P. H.

Deputy Assistant Secretary for Health (Women's Health) Director of the Office of Women's Health U.S. Department of Health and Human Services Aaron H. Burnstein, PharmD Clinical Pharmacokinetics Research Laboratory Clinical Center Pharmacy Department Building 10, Room IN-257 Bethesda, MD Paul Coates, PhD Director Office of Dietary Supplements NIH Harris Lieberman, PhD Supervisor Research Psychologist US Army Research Institute of Environment Medicine 42 Kansas Street Natik, MA 01760-5007

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Rossanne M. Philen, M.D., MS Health Studies Branch National Center for Environmental Health Centers for Disease Control and Prevention 1600 Clifton Road, NE Mailstop E-23 Atlanta, GA 30333 Mary Ann Richardson, Dr.P.H. Program Officer National Center for Complementary and Alternative Medicine National Institutes of Health Marcel Salive, MD, MPH Prevention Scientific Research Group Division of Epidemiology and Clinical Applications National Heart, Lung and Blood Institute National Institutes of Health Berne Schwetz, DVM, PhD Acting Deputy Commission for Food and Drugs Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857

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P R O C E E D I N G S [Time noted: DR. JONES: is Wanda Jones. Women's Health. Good morning, everyone. 9:00 a.m.] My name

I am the Director of the Office on We are here to address the available

scientific information on the safety of dietary supplements containing ephedrine alkaloids. During the course of this two-day public scientific meeting, we hope to have four specific questions addressed by the many individuals and organizations who have come to provide information. These questions are: First, what positive and adverse

physiologic actions would be expected of ephedra based

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on its known constituents?

Does the available

information show an association between the use of dietary supplements containing ephedrine alkaloids and adverse events, that is cardiovascular, center nervous system, psychotropic, or other events when used as directed. Second, are there any circumstances for which there are well-established indications for the use of dietary supplements containing ephedrine alkaloids? What does and duration of use are needed

for those indications and what is the quality of any data to support such use? Third, how would one characterize the

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seriousness and/or severity of the risks of ephedrine alkaloids labeled for weight loss and exercise enhancement taking into account issues such as user demographics, age, sex, or race ethnicity, the amount consumed across the population, use with other natural or synthetic stimulants, such as caffeine, synephrine, yohimbine, or the added stress of exercise and individual sensitivity to these types products? And, fourth, are the outcomes associated with these products affected by dosage, by user characteristics such as age or predisposing health conditions, or behaviors such as combining use with other stimulants or other compounds? Is it affected

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by the duration of exposure or by others means? Well, you may be wondering why we in the Office of Women's Health, at the Public Health Service, Office of Public Health and Science is convening this forum. Well, many women take these

products as dietary supplements which makes this issue central to the immediate and broader public health concerns of the Office on Women's Health. In addition, since the purpose of the meeting is informational and not regulatory, it is more appropriate for this meeting to be held outside of a regulatory context. Of course any data obtained during our

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discussions over the next two days will help the Food and Drug Administration in it's ongoing assessment of ephedra. And so we'll deposit a record of this

meeting in the FDA docket. As we begin our discussion today, it may be helpful to provide a brief historical overview of the key events that have brought us here. In 1997, FDA

published a proposed rule that addressed the safety of dietary supplements containing ephedrine alkaloids. This proposal mainly suggested limits on dosage and use. A copy of this Federal Register proposal is

provided on the information table in the registration area.

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In response to the Federal Register announcement, FDA received numerous comments from the public. In addition the General Accounting Office

audited the agency's procedures in developing its proposed rulemaking. The audit raised a number of

issues about how the FDA had arrived at its proposed dose limits and about the openness of the process. In addition to the audit, new information collected by FDA, and the interest expressed by consumers, manufacturers, and health care providers led FDA to withdraw a large part of the 1997 proposal this past spring. The agency reopened the comment period to

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provide an opportunity for discussion and assessment of the information related to the safety of these products. And that has let to this public forum. The purpose of our forum is not regulatory management, but rather an effort to obtain and assess all available information related to the safety of these products used for weight loss and energy. And

to that end, the Office on Women's Health has brought together a panel of federal experts in pharmacokinetic, epidemiology, toxicology, nutrition, and behavior, preventive medicine, and clinical pharmacology to assist us. The role of this panel is to listen, to

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guide the discussion within the context of the four specific questions we have asked and to seek clarity where needed. Let me take a moment to briefly describe the format and logistics for the meeting. This morning and right after lunch presentation will focus on issues concerning the safety assessment of dietary supplements containing ephedrine alkaloids. Then we will have our first

abstract session followed by a few minutes of public comment. Tomorrow morning opens with public comment

then there are abstract sessions, before and after lunch, followed by more public comment.

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The speakers during public comment are numbered in your agenda. Tomorrow particularly, where

there are a lot of you, there are numbered seats toward the front of the middle section and it will help move things along if you find the number that corresponds with the number that is preceding your name in the agenda and have a seat in that chair so that we can help move you forward as the public comment period proceeds. It is my goal to start and the meeting and all presentations including the public comment as scheduled. We will be timing presentations, we have

lights and signs that will be visible to the audience

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and the speakers to queue them about their remaining time. We will try to flash the green light or show the sign when there are approximately two minutes left and give you a warning so you can wrap up, and the end on time. And a flashing red will mean stop. We want

to be sure that everyone who has registered for time to speak has that some available to present his or her views. All speaker shown in the agenda should state for the record -- all speakers, no matter where you're from -- state for the record their name, affiliation source of funding for their activities, as well as

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source of funding for their travel here.

Please be

ready to come to the podium as your time approaches. Because we had limited time for additional open comments, I would like to remind you that FDA welcomes your written comments and has reopened the public docket as of August 10th, 2000 through September 30th. This docket will display all of the

information that the Agency has received including the information presented at this meeting. We have also requested this meeting be transcribed. The meeting transcripts will be We

available to the docket as quickly as possible. expect within 15 working days.

Information about how

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to access the

public docket and submit your comments

is included with registration materials and certainly is on the table ins at the registration area. Before we begin, I would like to extend a very special thank you in advance to everyone who has come to share their views with us. so many of you here this morning. I am glad to see I think I've talked It

to virtually every one of you on the telephone.

has really been one of the most exciting things I've done in recent years. We have attempted to assemble an agenda with a full spectrum of interested parties, and everyone, no doubt, has very strongly held views and very useful

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information for all us to consider. We have relied in part on umbrella organizations including consumer organizations, professional societies, and trade groups to represent their members and to identify for us, panelists and speakers for this meeting. for your cooperation. I would also like to extend my thanks to all of the other people within the Department of Health and Human Services an the Public Health Services agencies, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, and the staff of my office who And we are very grateful

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have contributed a great deal of time and energy to planning and making this forum possible. And, now, a little housekeeping. No food

and beverages are allowed in this auditorium, and I'm sorry, that's the bad news of the meeting. restrooms are in the long corridors. The

If you exit the

auditorium, turn right, and go to that main cross area, turn right or left, and you'll see signs directing you to restrooms. And then for lunch, we have a map available of places where you can grab a quick bite for lunch the are very close by. You'll need to wear you name

badge at all times in the building, and to enter the

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auditorium. For the deaf and hard of hearing we have interpreters with us today, Yvonne Robison, here in front of me, and Lisa Beth Schaefer, who will be providing sign language interpretation. So, if you do

need interpretation please feel free to move forward so you can see them better because the lighting will not always be this strong. If you have a medical emergency please let staff know. attendance. They are around and we can get you There is a very close by a clinic that we

can be sure that your needs are taken care of. And finally, I would ask that you turn off

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cell phones and beepers, or at least set them on silent alert for the duration of the meeting. So let me underscore, we are here to listen, to guide the discussion within context of the four questions described earlier, and to clarify. So, now, let me introduce the members of the expert panel who are with me here on stage. Starting

at the far end, Dr. Paul Coates from the Office of Dietary Supplements at the National Institutes of Health; Dr. Harris Lieberman from the U.S. Army Institute of Environmental Medicine at Natik, Massachusetts. Next to him, Dr. Aaron Burstein from

the Clinical Center at the National Institutes of

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Health; Dr. Mary Ann Richardson from the National Center on Complementary and Alternative Medicines at the National Institutes of Health; Dr. Berne Schwetz from the Office of the Commissioner and the Office of Science Administration from the Food and Drug Administration. And I am hiding here, Dr. Marcel

Salive from the National Heart, Lung and Blood Institute at the National Institutes of Health. Now, we do expect one other Panel member to join us but we will proceed until she arrives. Without further adieu, I know that you're waiting for our first speaker this morning. microphone work now? Is that

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Good. It's my pleasure to Invite Dr. Harry S. Fong now to open the meeting with a background presentation on Ephedra-Containing Compounds or their Historical and Pharmacological Context. And we've asked him to

do all of this in about 30 minutes so that we can ask him questions if need be following his presentation. So it is a Herculean task. Dr. Fong, welcome and thank you. DR. FONG: Jones. Thank you very much Secretary

I know this is politically incorrect, I was

going to say my inspiration for public speaking is Elizabeth Dole the way she walks around. But this may

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not be politically correct and I guess -- well, I'll try to stand up. I really appreciate being asked to come and talk to you. As Dr. Jones said we look at the

historical perspective in pharmacology and I would like to point out that I come from a very unique place, the University of Illinois in Chicago and NIH Center for Botanical Dietary Supplement Research. think we are one of two and Dr. Coates up there has something to do with us getting some funds. make my public thanks and advertisement. When Dr. Jones asked me to speak, she was under the impression that I am some kind of an expert. So let me I

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I will not disagree with her that I am some kind of expert, but at this point I think I should tell Dr. Jones what kind of an expert that I am. And expert by

definition is a person from out of town who is willing and able to say, "Have Slides Will Travel." [Laughter.] DR. FONG: With that out of the way, let me Is this mike working?

get down to my presentation. Good.

Let's define what is ephedra.

Ephedra is

the dry area part of ephedra seneca or other related ephedra species. Ephedra has many names, vernacular

names, the most famous of which is ma huang, a Chinese

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name.

As you know it literally means -- the "ma"

means the astringent action on the tongue; "huang" is the yellow color of the drug. Here is a stem of the

ephedra seneca for the few of you who might not know what it looks like. the plant looks like. In terms of geographical distribution there were more than 30 species distributed throughout the world particularly in Asia and even some in North and Central America; there are about 10 species in the Americas. Try to give you a slight brief history. As I'm sure everyone here knows what

we all know ma huang has been used for more than 5000

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years in China as traditionally China's medicine for the treatment of asthma, congestion, colds, and so on and so forth. And ephedrine itself was isolated binding guide in Japan in 1887 and five years later or six years later Merck isolated pseudoephedrine from the same species in Europe. So you've got a world apart

with the two alkaloids the two major alkaloids being isolated from the same plant. In my opinion the classical and pioneering work which leads to the use of ephedrine was conducted by Dr. Kay K. Chen at the Peking Union College back in the early 20s and the introduction of this particular

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drug into Western medicine was followed the work publication in 1924 and 1930 by Chen and Schmidt. In an effort to look for a more active or less toxic compound amphetamine was synthesized using ephedrine as the model in 1927. Then we jumped ahead

to the early 1990s, significant to me is the promotion of ephedra and ephedrine for use as a weight reduction dietary supplements or as alternative street drugs. Twenty-five years ago we had the pleasure of Dr. Kay K. Chin visiting us and giving us a very, very detailed recapitulation of his work in this area so I thought I would share a pitcher with you. Chemically

speaking ephedra contains more -- could be up to more

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than 2 percent of alkaloids and the major alkaloids are three stereoisomeric pairs, Ephedrine, pseudoephedrine, Norephedrine, Methylephedrine and Methylpseudoephedrine with ephedrine being 40 to 90 percent of the total alkaloid. Let's look at the structure so that we are all in sync of what we are talking about. Ephedrine

differs from pseudoephedrine by the stereo chemical configuration of the hydroxy group at a carbon 3 and a sci chain, and no ephedrine and no pseudoephedrine again the same difference as methylephedrine and methylpseudoephedrine and one note that the difference between ephedrine and norephedrine is the lack of the

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methyl group in norephedrine methylephedrine has a two methyl group so one look at the basic skeleton there it is all the same. So one would expect that the biological activity or pharmacological effect are basically similar. There may be differences in the degree and

the specific effects. The occurrence of the different alkaloids vary from species to species. example. And this is just some

I don't expect you to read this slide from I just want to emphasize in

way back in the room.

ephedra seneca, ephedrine account for about 60 percent of the total alkaloids and 65 percent of

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pseudoephedrine being the second largest.

In this

particular slide the only species that has more pseudoephedrine than ephedrine is ephedra intermedia. Now, what are the primary uses for ephedra, and it is proven effective as a nasal decongestant and treatment of various types of associated ailments and is a very good broncho dilator in the treatment of asthma. And a secondarily one can use it for

treatment of -- narcolepsy and partial hypertension. But the primary use, I would like to stress as a nasal decongestion bronchial dilation. Looking at an overview of the pharmacology of this type of compound, ephedrine and

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pseudoephedrine are major constituents, as I said before, and they along with the related compounds of potent sympathomimetic that act directly by stimulating the Alpha Beta 1 and Beta 2 receptors of athonergic receptors and more commonly by indirect stimulating the release of norepinephrine from neuron stores. And so it primarily acts like release of

norepinephrine and then have some direct effect. If one looks at the structure of epinephrine and norepinephrine compared its structures to ephedrine and pseudoephedrine one sees the basic carbon skeleton and the amino group being the same. The difference being the hydroxy group in a side chain

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and the extra methyl group.

So it's not surprising

that they do act directly on the same receptors and a like we said, ephedrine and pseudoephedrine act primarily to induce the release of norepinephrine. Now, I would like to emphasize that pseudoephedrine and ephedrine have the same spectrum of activity except that pseudoephedrine is a weaker compound when it comes to its hypertensive effect and the CNS stimulant effect. Either compound on repeated dosing can lessen the biological effect because of the depletion of norepinephrine from the stores. So continuing use

does not necessarily mean you will have the same

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effect. In terms of women's health, the reason I think I was invited to women's health, ephedrine does effect the uterine muscle and consequently is being used to relieve the pain of dysmenorrhea. Every

professor is allowed one slide where people can read. Dysmenorrhea unlike the red color to emphasize the condition, by you can't really see the red. sorry about that. Ephedrine also stimulate the alpha adrenergic receptor in the bladder, small muscles, and one does increase the resistance to the outflow of urine so this would be good in the management of So I'm

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incontinence or aneurin.

But, unfortunately, for the

few of us male in the audience one experience BPH and for those of us in that category one should refrain from using this type of compounds; it is tough enough as it is. In the terms of cardiovascular effects they have the same action as epinephrine but ephedrine the action persists ten times longer than that of epinephrine and it is orally effective. The

activities mediated by the release of norephedrine and the activation of both the alpha and beta receptors. The alkaloid will stimulate the cardiac rate output and increase the peripheral vascular resistance

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and that produce a blood pressure rise.

Elevate both

this systolic and diastolic pressures and the pulse pressure as well. Most importantly is stimulates the

systemic razor restrictions and one gets hypertension from overdose or excessive use. Broncho dilation effect. The compounds

ephedrine especially as a very potent branchial dilator because of its activation of the Beta adrenergic receptor in the lungs. The effect is less

pronounced than epinephrine but it's so much to sustain longer both ephedrine and pseudoephedrine are useful as nasal decongestants, and due to the alpha adrenergic receptor mediated razor constriction

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effect. However, continued use of this type of material, let's say after more than three days continued use one can have a rebound effect. And if

one relies on nasal decongestants as a medical aid, I don't know of too many nasal decongestants that do not call rebound effect. So one must use it judiciously.

In terms of the central nervous system effect ephedrine is already active as I said earlier. The important thing of ephedrine and related compounds stimulate the release of dopamine from the nucleus eccubens area of the brain. As the dopamine is

released it then binds with the D1 and D2 receptors

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which then gives us the feeling of a well being and give us a high. The ephedrine compound also activates the adrenergic receptors located in the CNS which also contributes to our feeling of well being. Now, another CNS effect is with anuretic or weight and appetite suppression. product like that. Now, as I said earlier, the promotion of ephedrine and ephedra for weight loss was in the early 1990s. In terms of efficacy I have a question mark Of Hence one has also a

because I haven't read too many clinical reports.

the ones I could get hold of the effective weight loss

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is somewhere between four to ten pounds used over two to six months and some of the clinical studies also include a restricted diet, and so, make one wonder, is it the ephedrine or is it from the diet. But it

definitely had some effect; how long it last I don't know. Theoretically the ephedra type alkaloids is effective in that it has two actions. It has central

enuretic effects suppressed to appetite which is one of the side effects of this kind of medication, it also has the peripheral thermogenic effect to burn up the fats, -- the triglycerides and so on and so forth. I would like to make note that caffeine is a

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more potent thermogenic agent and perhaps that's the reason why they are put together. I would like to

digress a little bit and look at the relative strength of the DCNS stimulant effect of various amines. said methamphetamine and dextroamphetamine will synthesize for a better drug. And methamphetamine is greater then the ephedrine and pseudoephedrine and norephedrine in terms of the CNS effect. And, coincidentally, all of As we

these compounds have been used as in weight reduction formulas one way or another. I would like to point out that methamphetamine and amphetamine was really prescribed

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in the 1950s and '60s as an anoretic agent and they act primarily as to appetite suppression but the tolerance to appetite suppression develop very quickly. In the '50s and '60s I was a student at that

time, a lot of us was overweight, so a lot of us did take the amphetamine but a lot of us also did not lose weight, a lot of us ate just as well as before. naming names or anything like that. And phenylpropanolamine is another compound obtained from ephedra and it's been used since the 1980s as weight reduction with or without caffeine. Again, the effectiveness come in a question, in my opinion, because after three months of use they may Not

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not work anymore. In terms of ephedrine and caffeine formulation the theoretical mechanism of action have scientific base because the ephedrine has the central anoretic effect, whereas, caffeine has the greater peripheral thermogenic effect so the combination should work. However I would like to point out that

this type of combination product also have potentially a lot of adverse events of CNS and other anomic peripheral system events and it may have been synergistic CNS stimulation between the two. There's a study on the content of alkaloids and various diet products and one of the things that

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intrigued me was that there is a great variation of the content of alkaloids from one product to another even within the same product -- I don't know whether this product, herbal ecstasy, is still available or not, but you get two lots. One has a total different

profile than the other and the contents of the ephedrine alkaloids are also quite different. draw your own inclusion what this means. Adverse events the principal adverse event to us is the CNS stimulation particularly the therapeutic index is very low. one can have adverse events. At two times the does Most of the adverse You

conditions are mild, particularly dosages 30, 60

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milligram or whatnot one can have nervousness like I am having now even though I didn't take ephedrine this morning; one can have headaches, insomnia, dizziness, palpitation, skin flushing, tingling, tremors and urinary retention, so on and so forth. Personally I If I take

can't take decongestion of this of product.

and pseudoephedrine or ephedrine, my heart will be pumping a mile a minute. reactions. The most severe reaction is hypertension. That is the most important event caused by high dose or prolonged use. Arrhythmia and tachycardia also So there are idiosyncratic

results and in the case of tachycardia and potentially

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death these events in our opinion used to be associated with the concomitant administration of other drugs like caffeine and antihistamine, and particularly then you dump in phenylpropanolamine along with ephedrine or so on and so forth. have an adverse event. Now, the potential drug interactions of this drug ephedra, ephedrine is a drug. stimulant. It's a CNS One can

Of course it should be not coadministered

cardiacthycal like digitalis heart patients should not be taking this kind of stuff, people on sympathomimetic agents or among amino oxidase inhibitors among others totally contraindicated for

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that sort of thing. Now, in conclusion, I would like to make a couple observations. Ephedra and ephedrine alkaloids

are useful and can be very useful short-term sympathomimetic agents particularly in bronchial asthma as decongestants. The effectiveness as a

weight reduction agent, I keep saying that it's a question mark because I have to see more clinical papers to convince me in terms of the risk to benefit ratio. It does work; people have lost a few pounds,

but is that loss worth it. In terms of mild/severe reactions it can be manifested as I said from both individual sensitivity

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or prolonged use or overdose. One thing I absolutely do not recommend is the use or production of this product as street drugs. Thank you very much for your attention. [Applause.] DR. JONES: Thank you Dr. Fong.

Let me turn first to panel members, if you have questions for Dr. Fong. [No response.] DR. JONES: Let me turn to the floor. If

you have questions for Dr. Fong there are microphones. If you would proceed to a microphone and ask your question, brevity is the should of wit for all of us.

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Please proceed.

Yes sir.

Identify yourself

if you would please the record. MR. REINHART: Pure Foods. Dr. Fong, would you comment or clarify on the stereo specificity difference between phenylpropanolamine and the plan of ephedrine? DR. FONG: This high-tech stuff is good if Some of it just Jeffrey Reinhart, People for

you know how to do these things.

doesn't work the way I want it to work. Phenylpropanolamine is low ephedrine, okay. The phenylpropanolamine and ephedrine has the same stereo chemistry. Is that what you are asking?

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MR. REINHART:

I was asking about the My

racemic situation with phenylpropanolamine.

understanding is that phenylpropanolamine used in commerce is plus/minus racemic mixture whereas in the plant it is minus. DR. FONG: Yeah, okay. And you think that

is a tremendous difference in pharmacological effect? MR. REINHART: I think it needs to be elucidated, given the thalidomide issue. DR. FONG: I'm sorry, I really can't at this

particular moment in time I don't have the answer to be able to differentiate the difference between minus norephenephrine or the racemic phenylpropanolamine.

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But, you know, my conviction is that the difference of activity in terms of the at least the CNS stimulation and the cardiac effect will be not that great in terms of one look at the adverse effect and whatnot. Now, I am not saying that phenylpropanolamine is not safe. I'm just cautioning

not to use those things over a prolonged period of time or overdose. Jerry, can you comment on the racemic versus minus? I have a colleague who used to be a professor

then he decided to go make money. DR. McLAUGHLIN: Yes, I'm Jerry McLaughlin

from Nature Sunshine products, now it's an herb

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company. go.

See if my pointer will work here, here we

So look at here, there are two asymmetric carbon Okay? Now, we

atoms in the structure of ephedrine.

can make different structures if we just switch one of those bonds around. Okay. So the ephedrine series

are what we call erythrol, that is, both of these substitutions are going off in different -- actually in the same direction if we put all the carbons in a line. T pseudoephedrine have them going three out, or Okay.

they go in different directions.

Now, one can go one way, and one the other so that makes four possible isomers of ephedrine if look at that. Now, we further complicate the

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structure by taking the methyl off, you see it's gone over here. Nor means that the methyl is gone. Okay?

So, we end up with the nor servers.

Remember, Harry

also talked about the methylephedrines which puts another methyl on the structure of ephedrine here. So

we end up with a huge mixture of all these compounds; and the plant doesn't just make one compound. makes all these guys; okay. So I think actually the structure of phenylpropanolamine which is essentially this structure, but without defining the stereo chemistries in here giving us not only a racemic mixture of one carbon, but, you know, potentially more isomers all It

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right; so you have at least four potential compounds in phenylpropanolamine. So I'm not really sure what

phenylpropanolamine is; but if it does have a mixture of materials -- being synthetic it probably does -it's probably going to somewhat mimic the plant because the plant makes a mixture of materials. DR. JONES: Other questions either from the

floor or from the panel? [No response.] DR. JONES: DR. BRAY: Seeing none. Yes, good morning, I'm George

Bray from Baton Rouge, Louisiana, interested in the problem of weight. My reading of the ephedrine

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caffeine studies that Arne Astrup, has published from Denmark would suggest that there is a statistically and clinically significant effect of the combination in his randomized, placebo, double-blind trial. I

wondered if you comment why you put so many question marks because I thought that trial was about as nicely designed and executed as you could ask for in a clinical trial. DR. FONG: Okay. That study that you're

talking about, yes, I have the question mark as a personal thing. is a valid study. The study that you're talking about My only question was that I think

that be total weight loss was about five or seven

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kilogram of body weight lost as compared to the placebo. Now in the 33.5 kilo as compared to be My My

placebo group there is statistics significance.

question mark isn't whether it does reduce weight.

question mark is how long the patients weight is taken off and maintained; and is five or six pounds worth the risk of adverse events over prolonged periods of time. Okay? So I know I'm getting into a hornet's nest in this discussion. But it's just that for those of

you in the audience, I was a member of the FDA ad hoc meeting about five years ago on regulatory aspect and my position was even ephedra and ephedrine are good

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medication and should not be banned from regulatory status. But on the other hand as a pharmacist and as

a professor in pharmacochemistry I questioned that using an agent that has a low therapeutic index of two to three, usually I like to see an agent with therapeutic index of at least 10 to 1, this is my question mark not the statistical significance of the study. DR. JONES: Further questions?

[No response.] DR. JONES: concluded on time. I would note then that we are

Dr. Fong it does appear that you

have done the impossible and laid out a nice

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background for us for the day.

I would send this now It will give

we're scheduled for a 15-minute break.

you a chance to get acquainted with the lay of the facility, to pick up the lunch map and everything. When we come back after the break we will hear from our first panel that will look at adverse evening reports the database and the clinical studies as they appear in the docket that FDA has made available. Thank you very much for your attention. will see you in 15 minutes. time at 10:05 a.m. We will be starting on We

Thank you.

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[Brief recess at 9:45 a.m] DR. JONES: Dr. Julie Bietz, Dr. George

Ricaurte, Dr. Ray Woosley, and Cynthia Culmo, shown in your agenda with discussion of the database and clinical studies and adverse event reports. you. DR. LOVE: Dr. Jones, panel members, and Thank

guests, this morning I will present an overview on the ephedrine alkaloid containing dietary supplements including new information in FDA's recent assessment of the public health risk associated with the use of ephedrine alkaloid-containing products. The complete documents from this assessment

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are available publicly in FDA docket No. 0091200. As you can see from the slide, FDA concerns about the safety of dietary supplements goes back a long time. We first became aware of this issue

because we received a report of a death in a young man who had been using a number of products for enhancement purposes, for athletic enhancement purposes. In trying to evaluate the significance of this report, we noted that among the products he took, there were ones whose ingredients we were unfamiliar with. Ingredients like ma huang, for which we now

know is a Chinese name for ephedra and contains

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alkaloids which were refer to as ephedrine alkaloids that are very potent sympathomimetic in means, as Dr. Fong has just explain for all of us. Besides becoming aware that these ingredients were in these products, we reviewed the scientific literature which also raised our level of concern; and the other thing that we did was to look in available databases to see if there were other adverse events with this same product or with other products that contained this ingredient and we found cases of these. how to use this. 1993 was when FDA first indicated its So in 1993, I'm not sure if I know

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concerns about the safety of these products.

In 1994

we held a formal health hazard evaluation board that examined the safety of a particular product for which we had received a large number of adverse events. This was ephedrine alkaloid caffeine containing combination which was felt to represent a significant health hazard. As Dr. Jones mentioned this morning, we have had a number of public meetings where we have discussed the data that are available on these. 1995 we had a public meeting where we convened a special ad hoc working group of scientific experts that served as a working group to our Food Advisory In

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Committee which is the general scientific advisory committee that we have in FDA. And at this time we There

really evaluated all available information.

really was almost a virtual absence of information at that time and I think still today that would indicate the safe use of these types products. And it was the members' feeling at this working group that they agreed the use of certain dietary supplements known to contain or suspected to contain ephedrine alkaloids may cause consumers to experience serious adverse events. In the following year, in 1996, because of new information which included an increasing number of

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adverse events and product analyses indicating that the levels of ephedrine alkaloids were below the 25 milligram limits that had been suggested by certain members of the working group. Committee was convened. The full Food Advisory

And, again, they reviewed all

but available data information and provided their opinion on, and a rationale for specific ways that FDA could attempt to address the public health concerns with these products. Over half the Food Advisory Committee members stated that, based on the available data, no safe levels of ephedrine alkaloid could be identified for use in dietary supplements and consequently they

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recommended removal of these products from the market. Other members of the Food Advisory Committee suggested that the agency establish conditions of use that would reduce the risk of adverse events including establishing reasonable safes, per serving, and daily use levels for both ephedrine alkaloids and ephedrine as well as other requirements. Out of these public meetings came FDA's proposed rule in 1997, June 4th, 1997, and this proposed rule had a number of features including a limitation on the does which was less than 8 milligrams of ephedrine alkaloid per serving and it required certain label warning statements and

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conditions of use. Considerable amounts of data and other information were presented at these public meetings and were placed in our public docket. This included

information about products containing ephedrine alkaloids, the sources of the alkaloids, as you heard this morning, the known physiological and pharmacological effects of ephedrine alkaloids and finally the adverse effects of ephedrine alkaloids as derived both from the scientific literature as well as adverse event reporting. What are the products that we are talking about today? There are a wide variety of ephedrine

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alkaloid-containing products.

As you've heard from

Dr. Fong, there are traditional medicines that use these, they are primarily for respiratory conditions and under the direct use health-care practitioner there are drugs both prescriptions and OTCs mainly for allergy, cough and cold preparations, as well as asthma. You have heard about the street drug

alternative, but we're not talking about any of these type of products today. We are only talking about

dietary supplements that contain ephedrine alkaloids. These products are widely sold in the United States. Almost all the products contain multiple They are usually combined with other

ingredients.

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stimulants including caffeine.

Sometimes yohimbine as

well as vitamins and minerals, et cetera. The primary uses that we see they are marketed for are weight loss and energy, fitness and bodybuilding, and a general category of other which may include four lung purposes et cetera. This is just a picture showing the wider variety of products. We estimate that there are

somewhere between 3 and 400 different types of products that are now on the market and again they fall into groups for weight loss and energy and ergogenic bodybuilding type products. The sources of ephedrine alkaloid can be

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ephedra species or Ma Huang as Dr. Fong said, but other botanical sources are also possible. These

include seta cordifolia, pinoyella; however, it is most common that extracts from botanicals are listed as the source of ephedrine alkaloids, and finally there can be synthetic sources of a these alkaloids. The major alkaloids as you have heard from Dr. Fong are ephedra, pseudoephedrine, norephedrine, methylephedrine, norpseudoephedrine and methylpseudoephedrine. The L forms are what occurs in

nature in you don't see racemic mixtures or salts in nature. The sources of our information come from a

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wide variety of areas. practice.

They come from medical

You heard Dr. Fong state that in

traditional medicine there's been a these five centuries of use. In allopathic medicine the

ephedrine alkaloids have been used at least 75 years now. There is a ever-growing medical scientific

literature based on research done in the area and there is postmarketing surveillance. And in the case

of dietary supplements containing ephedrine alkaloids this is voluntary reporting. Along with the sources of evidence there are different types of evidence. These include the

preclinical which are usually animal and in vitro and

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give us a mechanistic type of information to observational, epidemiological, and clinical trials. And clinical trials have kind of been the gold standard. But these are usually probably are usually A well-controlled clinical trial

the most infrequent.

usually has only several hundred patients in it, and is usually for a relatively short duration. So the

most information that we learned on possible adverse events occur in the postmarketing period where we use adverse event monitoring which would be considered a type of case reports. And just for an example, a clinical trial to detect a relatively common adverse event, one

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occurring at 1 percent rate would require at least three to 500 patients to be able to reliably detect that. The clinical trials that are in the published

literature now on ephedrine alkaloids for the most part do not have this many subjects in any of them. As Dr. Fong mentioned we know a lot about the characteristics of ephedrine alkaloids. These are

amphetamine-like sympathomimetic amines, they have direct and indirect effects, they primarily affect the cardiovascular and nervous system. The exact effects

depend upon the alkaloid and I've already talked about the L forms. The pharmacology and mechanism of action he

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also spoke about, but I am just going to quickly review. In the cardiovascular system it can cause

basal constriction and cardiac stimulation, including increased contractility, increased heart rate, and increased stroke volume, central nervous system stimulation, and other effects including bronchodilation and effects on skeletal and smooth muscle and various organs and glands. From these known effects derived most of the adverse effects that we see associated with ephedrine alkaloids. So the adverse effects that we see affect

predominantly the cardiovascular and the nervous system and in the cardiovascular system we have

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hypertension, angina, cardiac ischemia and infarction cardiomyopathy and cerebral vascular events including hemorrhage any infarction. In the nervous system we have central stimulant effects as well as mania and psychosis seizures and I have drug abuse here but it should just be abuse, dependence, and addiction. And finally there have been reports of myopathies, uropathies, including urinary retention, effects on the GI system, including vascular effects and dermatologic reactions. This slide is a reminder just in what context do we evaluate dietary supplements? And it is

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really no different than other products that we look at. The considerations for use including the

population, the pattern of use, and the type of products and ingredients. The population for these

dietary supplements includes both the general population but special subpopulations. The pattern of

use include the amount, frequency, and duration, as well as particular conditions of use in which it may be used, including hard, physical exercise, caloric restriction, et cetera, and finally the type of products and ingredients. These are sympathomimetic

amines that have known effects. Further they are often combined with other

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stimulants ingredients which can cause an interactive or synergistic affect. This is just to again compare and contrast what we know traditionally about ephedra to what we know in dietary supplements today. Historically It with

ephedra was only considered a medicine.

health-care practitioner prescribed, used predominantly for respiratory disorders; the formulation of herbs with health-care practitioner selected they were very defined herbal combinations that are different than the combinations that are used today, and the duration of use very short term. The

current use of dietary supplements products in the

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U.S. is that these are dietary supplements; the consumer selects the products; they used for different purposes than had been previously used, including weight loss, energy, bodybuilding; the manufacturer selects the ingredients and the combinations that are used which are again different than what had been used previously; and, finally the duration of use is undefined but can be prolonged. Just to get us back to where we were on our little evolution of safety, from the proposed rule, GAO actually did a study and evaluated our use of the data for this proposed rule. And I'm sure that all of There were many

you have heard what has been said.

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criticisms about the use of the data; but, what isn't heard is that GAO really did support FDA's use of the data for its reason. And I just want to quote for you

"FDA based its proposed rule on numerous reports of adverse events associated with products thought to contain ephedrine alkaloids. It also used evidence

from scientific literature indicating that ingestion of ephedra alkaloids adversely impacts some individuals. The number and types of errors warranted FDA's consideration and steps to address safety issue. However," and there's their 'however' "we have concerns about the strength of some of the information

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FDA used to support to aspects of the proposed rule, the dosing level and the duration of use limits." Besides this, they also indicated that we had not performed a causal analysis of individual adverse events; that many of the cases lacked documentation; and that we did not have criteria to determine which event should be considered serious. And believe me, we have heard these criticisms. So we are now to the point of this public

meeting and we really want to talk about what has happened since the proposed rule. number of efforts. There have been a

Certain states and industries have

taken efforts concerning the dosage and instructions

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for use; there have been new articles in the medical scientific literature that impact on the safety these products; FDA has commissioned a number of outside expert scientific reviews to answer some of the questions with that were considered deficiencies by GAO; and, finally, we have had a continuing receipt and evaluation of spontaneous or voluntarily reported adverse events. And these too we have sought outside

experts reviews besides the in-house review. In the medical scientific literature there are many more articles, abstracts, monographs on the effects of ephedrine alkaloids available in this time frame. And this time the information is specific in

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some cases to the effects of dietary supplements or pseudoephedrine or alkaloids. We are seeing that

other patterns of injury are emerging besides cardiovascular and nervous system stimulant-related effects. And there is information on potential

pathogenic mechanisms. For these last two bullets, one of the things that have been of interest is the thought of abuse potential of these as well as the suggestion that there may be direct neurotoxicity in the central nervous system from use of these products. There have been a number of published clinical investigations on ephedrine alkaloids. The

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first of these is the Yale PPA study which was a casecontrolled study of persons 18 to 49 looking at the end point of hemorrhagic stroke in PPA. And this was

a very large study that showed that there was any increased risk, particularly in products used for weight loss. This has been put in an FDA docket and

will be the subject of a public meeting to address the issues that are specific to PPA. In the ephedra botanical dietary supplement area, in 1999, in FASEB there was publication of an abstract from Columbia St. Luke's on a double-blind, randomized, placebo-controlled 8-week efficacy trial of a ma huang guarana containing-product in obesity.

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Sixty-seven people were randomized, only 48 completed. In this trial indicated while there appeared to be some efficacy there also were adverse effects including hypertension and palpitations seen. And, finally, recently Calman, et. al, in 2000 have published a study another double-blind, randomized, placebo-controlled eight-week trial of effect in obesity of an ephedrine, synepherin caffeine salicin product, but with only 30 test subjects and 30 controls. I mentioned that we had commissioned a number of outside scientific and clinical reviews. One of these was by Dr. Enchiosa, that looked at the

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pharmacokinetics, pharmacodynamics properties in relative toxicities of botanical ephedra versus ephedrine alkaloids. The question has always been that somehow the botanical sources are not as potent or don't cause the problems that the synthetic sources cause. And

Dr. Enchiosa was able to look, because of the number of new publications that have addressed the issue directly of pharmacokinetics and pharmacodynamics of the dietary supplement product is that there really are no differences in these properties when you compare botanical sources or dietary supplements sources to synthetic products.

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There was a study by Dr. Quib Ray, looking at the use of ephedra in traditional Chinese medicine; and, again, it was commonly used short term under a health-care practitioner's practice, but, not used for the purposes of weight loss and energy. And, finally, by Dr. Walker we had an assessment of the likely reporting rates of adverse events and dietary supplements containing ephedrine alkaloids. And from this review the conclusion was is

that these were very much underreported and the reporting rate was probably far less than 1 percent. In the interim of this time FDA has continued to receive adverse events. If you look at

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this cumulative events, his is by report day, these are all the other dietary supplements, these are ephedrine alkaloids containing dietary supplements. We have had a fairly consistent proportion about a 40 percent proportion of all our adverse events in dietary supplements have been due to those that are associated with ephedrine alkaloids. This is looking at the data little bit differently, from 1997 to the current time, you can see the number of adverse events reported for ephedrine alkaloids containing dietary supplement year 2000. It is just through the first part of August,

but if you calculated this out based on receipt today

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this number would be somewhere in here.

So, we are

continuing to receive serious adverse events. What's different about these adverse events? Well, we heard what GAO and others have said about the documentation, et cetera of these adverse events, so we have made very concerted efforts to get better documentation on these cases including additional FDA investigations that can give us information about how the consumer used the product, medical records, product labeling, and labeling. And then we have

performed a number of in-depth clinical evaluations including in-house for the clinical research and review staff in the Center for Food Safety and Applied

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Nutrition, from our colleagues in the Center for Drug Evaluation and Research, and by a number of outside experts. These include Dr. Woosley, Dr. Benowitz, Dr.

Ricaurte and Dr. Stolle. And you will hear some of this, this morning. What we did is say what was different about So we

these cases and how should we study them.

picked a time frame, and we picked June 1st, 1997, I have a typo there, 07. Which is very close to the and we took

time that we published the proposed rule.

it through a 22-month period so that we would have time to actually look at these so the cut off was March 31st, 1999, with any follow-up that could be

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received in-house by the end of December 1999. Typically it takes us anywhere from three to six months or longer to be able to investigate these adverse events and to get information that we need for evaluation. There were at least 140 adverse events reported in this time on at least 143 consumers and we evaluated from demographic information, product use, clinical course, diagnoses, outcome, classification of adverse events, amount of documentation, and reason for using product. This is our cut on these reports. Of the

140 reports we considered that eight were unevaluable.

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These were cases of multiple unidentified patients, cases where the event being reported we decided was not an adverse event, cases where we couldn't tell it the product with the dietary supplement or if it was a drug. In one case there was an incorrect temporal

relationship and there was in one case there was confounding by the co-ingested product which was GBL. The other cases we did an in-depth evaluation as I stated, and then screened these into not supporting of a causal relationship including those that had insufficient information to make assessments. They were 48 where the signs and

symptoms were not consistent with ephedrine alkaloids;

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there were nine cases where so many products had been used that it was impossible to ascribe any of the effects ephedrine alkaloids, there were two cases. Cases where there were too many confounding or complicating factors, 11; or cases of intentional misuse or abuse, there were two. So this was 55 percent of our population. The other 45 percent we used a formal structured attribution analysis scheme that we could look at them and we divided these into attributable and supporting of a causal relationship. Now, we've been asked many times what is the difference between association and attribution or

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causality?

Well, association means there is really

some link there and I'm using this quote from Dr. Hill from 1965, which is nine viewpoints as to whether association means causation. It doesn't mean

causation automatically, and that's the strength of the association, the consistency of the association, the specificity of the association, temporality, the biological gradient, plausibility, coherence, experiment, and analogy. I should mention also that there are many such schemes and there's really no consensus or no gold standards on what is the best schema to use for adverse event monitoring whether its for spontaneous

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reports, voluntary reports, or that associated with clinical trials. This is what we did though, for

attribution analysis, we checked the temporal relationship between the products use and the adverse event. We wanted to know if medical care had been

sought for the adverse event and whether there was health-care professional attribution of the adverse event, whether there was evidence of dechallenge, i.e., the consumer got better when the product was discontinued, and if the symptoms -- signs ad symptoms came back when the person again took the product. How the product was used. Was it used per direction or was it used, misused or abused? Were

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other products used at the time of the adverse event? What was the reason that they were using these products; were they weight loss, energy products, or were they bodybuilding products or were they others? Were the underlying conditions or product use a more likely explanation of the adverse event? This is

looking at alternatives or alternates explanations, and finally, is the event consistent with the known affects of ephedrine alkaloids or likely extensions of the known physiological or pharmacological effects of ephedrine alkaloids. This was all done, as I said, with a very structured data form which is available in the docket

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as well as the individual results on each case.

And

these are the results that we see and this is from the full case series. Overall more adverse events are

reported for women which could be expected since more of the products that we see all the weight loss and energy product. Although we are seen more adverse

events being reported for men; 39.8 percent than we saw in our previous serious. The age range again is mostly young adults; 64 percent of the injured persons were under 39 years of age; and 16 percent of the injured persons were 19 or younger. When we evaluated consumer characteristics

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that may have impacted on the adverse event, we noted that most consumers reported that they use the product according to the directions on the label and labeling and most of them saw a health-care practitioner and the majority of them were temporally related closely temporally related to the use of the product. In looking at duration of use there was a wide duration of use it ranged from under one day, or even on the first time of use on up to very chronic use, and you see the spread; approximate 30 percent are associated with short-term use which we defined as less than or equal to one week meaning that 70 percent were longer-term use.

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When we looked at the amounts of documentation that we have, a lot of adverse events are reported by consumers. And in fact if you look at

just the flow of how they come into the center, you know, about a third of them come through our field investigators, a third come through Medwatch which are predominantly health-care professionals reporting, and a third come directly to the center. So,

approximately 36 percent overall are from health-care professionals. In looking at all of the cases that we

have evaluated, over 50 percent has some kind of additional information including medical records and many of them had copies of label and labeling.

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We clinically classified the adverse events as we've done previously into serious cardiovascular, serious nervous system, and other adverse events. We

also class them according to not serious or in cases that we couldn't tell as being unclear. The

overwhelming majority of adverse events that we saw in this new case series were four serious adverse events. And this probably reflects a bias in reporting more serious adverse events than less serious. Cardiovascular system adverse events included myocardial infarction, ischemia, stroke, dysrhythmias and severe hypertension. And in this

slide, the first slide that I am just showing the

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differences between the total group for serious cardiovascular adverse events and what I'm calling the attributable supporting; both groups would be attributable or supporting attribution; the group that had insufficient data to be able to further assess. The serious nervous system effects included seizure, depression, psychoses, and addiction was also reported as an adverse event and was seen across all of these groups. Other serious adverse events that weren't cardiovascular or nervous system included neuropathies, gastritis, hepatitis, rebnomyallises, and a case of nephrogenic diabetes insipidus.

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We also evaluated whether certain product use factors could impact on the adverse event. One of

the first things we noticed is that men and women use the products for different reported uses. And I think

this could be expected, but many more of the women use it for weight loss and the men use it for fitness bodybuilding purposes. However, when you look at the classification of adverse events by gender you also note that there's a different pattern based on gender. In women you

have many more cardiovascular adverse events, whereas in mean you have more nervous system adverse events. And if you further subset this, looking at

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serious adverse events just in the men, but by use, in looking at the weight loss category it's really very similar to what you see in women, in that the cardiovascular system is what is predominantly involved. But in the fitness group you have a very

high proportion of nervous system type of facts. It appeared that strenuous exercise besides possibly being involved with this group also impacted on a cardiovascular adverse events in that we had at least seven reports of serious cardiovascular adverse events that were associated with strenuous exercise. In addition to looking at all of the other information, we in the interminable and supporting

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cases, looked at all the information that was available on the product label and labeling, and all of these contained information on how to use the product including the dose frequency and durations. Almost all of them contained warnings or precautionary statements. Many stated the actions that consumers

should take in the event of an adverse event, and all were multi-ingredient products. The overwhelming

majority of these had caffeine and other sources of stimulants in them. Again I said that we specifically looked at the likelihood of association in the subset where we could evaluate that; and all of them are temporally

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related because that was, of course, a criteria, and in a very high proportion of them there is health-care attribution that the adverse event was caused or contributed to from the use of the ephedrine alkaloid containing products. The majority of these were for weight loss purposes. And almost all of the consumers improve

when the product was discontinued indicating positive dechallenge. In much smaller proportion of them there

was evidence of positive rechallenge. Looking at other alternative explanations for the adverse event, you know, a very high proportion of these consumers used other dietary

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supplements and other medications at the same time that they were using a dietary supplement product containing ephedrine alkaloids. Furthermore, many of them had certain types of underlying health conditions. However, it was the

opinion of the clinical reviewers that these other factors, the usr of dietary supplements other medication use or the underlying health condition was not a more likely explanation of the adverse event. And the dietary supplements containing ephedrine alkaloids were thought clinically to have caused or contributed to the adverse event in all these cases. And, finally, we evaluated whether the

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observed signs and symptoms were consistent with the effects of ephedrine alkaloids and/or were likely extension of their pharmacological activity. again we had a very high rate where there was agreement. So just to briefly summarize, the current FDA data are consistent with the scientific literature concerning the effects of ephedrine alkaloids, and previous information from adverse events. These And

adverse events can be predicted from the known physiological and pharmacological actions of ephedrine alkaloids and, therefore, should be anticipated if consumers are going to be using these products.

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FDA believes that the current availability and use of dietary supplements containing ephedrine alkaloids continues to be a serious public health concern, but we are here in a listening mode. All

along in all of our evaluations and presentations at public meetings we have been very open in soliciting any information that could be available to impact on our evaluation and assessment of safety. hoping we hear some today, thank you. [Applause.] DR. BIETZ: Dr. Jones, panel members and And we're

guests, this morning I will present an analysis of adverse event reports for ephedrine alkaloid

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containing dietary supplements. DR. JONES: identify yourself. DR. BIETZ: DR. JONES: I'm sorry? Give your name -- just for the F the record, Julie, please

record, for the recorded record. DR. BIETZ: Oh, certainly. My name is Julie

Bietz, I'm with FDA CEDER, Office of Postmarketing Drug Risk Assessment. I will present an analysis of the adverse events that were conducted by CEDER's office of postmarketing drug risk assessments this past February and the complete review document that we prepared is

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available for public inspection under Docket No. 00N 1200. CFSAN provided our office with the following materials for review; adverse event reports that were received by CFSAN on 139 cases from June of 1997 through March of 1999. As you've heard CFSAN

conducted extensive follow-up investigations to obtain additional information on many of these cases, and this information was made available to us for our review. In addition, CFSAN provided us with summary tabulations of 1,176 adverse event reports that they received from 1990 through November 1999. These

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tabulations included some demographic information, but only limited clinical information. The

above-mentioned 139 cases are included among these reports. The remainder of the presentation will focus on the clinical review of the 139 cases. Thirty-one

cases were excluded from further review for the following reasons: 11 cases were confounded by the

concurrent use of other products that may have attributed to the event. In nine cases it was not

possible to ascertain whether an EADS product had been used. There were six consumer reports of events that Three cases were

were not readily evaluable.

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confounded by an underlying disease, and in two reports several individuals were named but no unique consumer could be identified. This left 108 cases.

The median age of these 108 remaining cases was 35 years with a range of six days to 67 years. More cases involved women than men. Most cases

involved the cardiovascular system or central nervous system. There were 49 hospitalizations or emergency

room visits reported and there were nine deaths. At least 45 different EADS products were identified among the 108 cases. Most were combination

products that also contained caffeine from a variety of sources. Most individuals reported taking the EADS

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product as directed without apparent misuse or overuse. Given the amount of information contained in the reports, it was not possible to estimate either a daily EADS dose or the ephedrine alkaloid content of the products that we found in these reports. Forty-six cases reported cardiovascular events. The median age of these cases was 39 years More cases occurred

with a range of 15 to 64 years. in women than in men.

All cases were reported to have Seventeen

occurred during the use of an EADS product.

cases were report within one week of product use with the range of one does to over one year of product use.

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In 30 cases the EADS product was being used weight reduction. Hospitalization occurred in roughly

two-thirds of cases and there were seven deaths reported from cardiothoracic arrest, sudden cardiac death, or stroke. Both health-care providers and

consumers reported these events in roughly equal numbers. Cardiovascular events included cardiac arrest, cerebral vascular events including stroke, cardiac ischemia, hypertensive events, and cardiac rhythm disturbances. This table shows how the 46

cardiovascular events were categorized and the number of cases within each category that appear to have no

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known risk factors.

Overall one-half of cases had no

known risk factors such as an underlying illness or concurrent use of another product that could have contributed to the event. The age range for the 41 central nervous system cases was 15, I'm sorry -- central nervous system conditions included central stimulant events, psychiatric events with or without central stimulant effects and seizures. This table shows how the 41

central nervous system events were categorized and the number of cases within each category that appear to have no known risk factors. Again, overall one-half of cases had no

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known risk factors such as underlying illness or concurrent use of another product that could have contributed to the event. The age range for the 41 central nervous system cases was 15 to 51 years. in women than in men. More cases occurred

The onset of central stimulant

effects were shortest with longer durations of use reported for psychiatric events and for seizures. The

EADS products were predominantly used for weight lost or as enhancers for bodybuilding. Unlike

cardiovascular events hospitalization was reported less frequently and there were no deaths reported. More central nervous system events were reported by

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consumers than health-care providers. The remaining events included gastrointestinal, musculoskeletal, renal and hematologic events. This table shows how these events

were categorized and the number of cases within each category that appear to have no known risk factors. Roughly 40 percent of these cases had no known risk factors such as an underlying illness or concurrent use of another product that could have contributed to the event. So in summary then, CEDER conducted an indepth review of 139 cases that had been reported to CFSAN between June of 1997 and March of 1999. In

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general, these cases describe young adults, particularly women, who were using EADS product for weight loss. Cardiovascular and central nervous Based on

system adverse events were most common.

information available roughly one-half of the cases had no known risk factors such as underlying illness or concurrent use of other products. An association with EADS products with these adverse events as strongly suggested, given the presence of ephedrine alkaloids in all products evaluated in this review. The similarity between

these events and the known pharmacological events of ephedrine alkaloids, the close temporal proximity of

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EADS product use and adverse events that were reported, and the absence of known risk factors in half the cases. In addition pre-existing risk factors may have played a role such as hypertension, such as a prior history of hypertension or cardiac arrhythmia; may have played a role in some of the more series events the were reported; and a voluntary nature of adverse event reporting implies that the actual number of events occurring in the general population would be higher. DR. JONES: Is Dr. Ricaurte here? Dr. Jones, members of the

DR. RICAURTE:

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panel, ladies and gentlemen, good morning. George Ricaurte.

My name is

I am an associate professor of

neurology at the Johns Hopkins University School of Medicine where I direct movement disorders clinics on the Bayview campus and where I also direct a research laboratory on neurotoxicology. I am a board certified neurologist and I hold a Ph.D. in pharmacology. I have conducted

research on the neurotoxicity of amphetamine and related substances for greater than 15 years. Today I will be address points one, two, and four of the ephedra questions predefined by the Office of Public Health and Science of the U.S. Department of

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Health and Human Services for today's discussion. To avoid confusion, I would like to begin with a definition of terms. As shown on the first

slide, ephedra as I will be using the term today is meant to refer to plant derive material containing ephedrine and related alkaloids. These include

ephedrine, pseudoephedrine, norephedrine and methylephedrine. As I believe has been discussed previously by Dr. Fong, ephedrine is generally regarded as the main active ingredient in ephedra, although there are also other active substances. Ephedrine, as has been

mentioned, is known to exist in four stereo isomeric

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forms in two corresponding racemic mixtures. Structurally and pharmacologically ephedrine is best characterized as a sympathomimetic amine. Other sympathomimetic amines shown on this slide include dopamine, norepinephrine, epinephrine, phenylpropanolamine, and ephedra. Like those of other

sympathomimetic amines the effects of ephedra are those that would be predicted to occur following stimulation of the central and sympathetic nervous systems, either directly or indirectly. To varying

degrees sympathomimetic amines typically produce increased mental arousal, increased sense of well-being, increased heart rate and blood pressure,

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vasoconstriction, cardiac stimulation, bronchial dilatation, and decreased appetite. Depending on the particular circumstances a number of these effects might be considered positive and indeed have been exploited medically over a number of years, but usually with due regard for adverse effects. Adverse effects of ephedrine alkaloids generally, although not always, represent an exaggeration of their milder pharmacological effects and may include sleep disturbance and anxiety, agitation, mania, psychoses, drug dependence, hypertension, stroke, seizures, cardiac arrhythmia,

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myocardial infarction, and excessive weight loss or anorexia. These adverse effects are typically seen in individuals who take excessive doses of ephedra, but can also occur in some individuals who use ephedracontaining products as directed. Clearly adverse effects of ephedra alkaloids can be serious and indeed fatal. While very little is

known about the potential influence of gender, race, or ethnicity, and the risk of developing serious complications of ephedra-containing compounds there are several population that appear to be at increased risk. These shown on this slide and include

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populations with certain neuropsychiatric disorders and those with significant cardiovascular disease. The latter would include people with -- individuals with hypertension, coronary arteries disease, occult or known aneurysms, or arterial venous malformations, and possibly obese subjects since these individuals are more likely to suffer from atherosclerotic vascular disease. Persons with a family, or family history of anxiety mood disorder may also be at higher risk for developing neuropsychiatric complications of ephedra. Finally, it is possible that individuals with a history of drug dependence are more likely to abuse

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ephedra-containing products. Ironically, the very same group of individuals that are targeted for use of ephedracontaining products are often those at highest risk for developing serious complications. For example,

deconditioned, overweight individuals would be expected to be more most susceptible to the cardio and cerebral vascular complications of ephedra. This may

also may be true for individuals who are engaged in vigorous activity since exercise itself increases sympathetic tone. Unfortunately, very little controlled research has been conducted regarding risk associated

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with long-term use of ephedra by these groups of individuals. Similarly little is known about the

propensity for individuals to develop tolerance to the effects of ephedra. This too is unfortunate because

with the development of tolerance escalating doses are the rule, and high doses are more likely to lead to more serious complications. Thus far I have detailed some of the adverse cardiovascular and neuropsychiatric effects of ephedra that can potentially occur. I will now devote the

remainder of my time to a less well-known and more insidious potential adverse effect of ephedrine, CNS neuro injury or neurotoxicity.

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As indicated previously ephedrine is the most abundant and the main active ingredient in ephedra. As shown on the next slide, ephedrine is

closely related and structured to another sympathomimetic amine, methamphetamine shown on the right. As you know, methamphetamine is a well-known

drug of abuse. In addition to the remarkable similarities and structure ephedrine and methamphetamine have two other similarities and I would like to bring to your attention. First, and I must confess, contrary to my

initial expectation when I first considered the structure of ephedrine which unlike methamphetamine

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has a hydroxyl group which is somewhat difficult to see, but it's a hydroxyl group that's located on the beta carbon of the molecule, a moiety that one might anticipate would interfere with the crossing of ephedrine through the blood brain barrier. Based on that structural difference, it was my initial impression that in ephedrine would be largely devoid of central effects. As I alluded to

earlier this expectation of mine -- initial expectation of mine proved incorrect. This is perhaps

best illustrated in an early study of Martin and colleagues where they looked at the physiologic and subjective and behavioral effects of a number of

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amphetamines derivatives including ephedrine and methamphetamine. Somewhat to my surprise, what these investigators showed in this early study which, as you can see, was published in 1971 what these investigators found is that -- an I'm afraid you don't see the upper portion of the panel, but methamphetamine is shown here in the open circles, ephedrine are the open squares. And having to find

this slide if you could move down just a tad I'd appreciate it. Because what this is intended to show

you it is that once you account for the difference in potency between methamphetamine and ephedrine by

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simply increasing the dose, the efficacy of these two sympathomimetic amine's in this case in raising blood pressure is nearly equal. The second interesting and important observation from this early study was that as was the case with the sympathomimetic effect of ephedrine with regard to the psycho stimulant affect once you adjusted for differences and potency, again by increasing the dose of ephedra, the psycho stimulant effect of ephedrine was indeed comparable to that of methamphetamine. The other similarities between ephedrine and methamphetamine that I would like to bring to your

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attention today has to do with potential of these two compounds to produce brain dopaminergic neurotoxicity. Research carried out in various laboratories over the last two decades or so has yielded very strong evidence that methamphetamine has the potential to damage brain dopamine neurons. Dopamine neurons as

you may be aware are neurons that originate in the substantial nigra shows schematically here at the level of the brain stem, and from there these nerve cells send axon projections to primarily to the striatum, a region of the brain involved with estral paramedial mobile function. These are the nerve cells that degenerate in

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Parkinson's disease indeed is the degeneration of these nerve cells in Parkinson's disease that accounts for the movement disturbance that patients with Parkinson's disease experiences. Before presenting to you some recent data that we collected on the neurotoxic potential of ephedrine I would like to briefly summarize for you what we already know about the neurotoxic potential of methamphetamine. Hopefully this will help place the

ephedrine neurotoxicity data in its proper context. As shown on this slide there are a number of indicators that methamphetamine has the potential to damage brain dopamine neurons. In summary the

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evidence for methamphetamine neurotoxicity comes from both chemical and anatomic studies. The chemical

studies indicate that a number of unique markers for brain dopamine axon terminals are markedly reduced in animals with previously administered doses of methamphetamine. The anatomical evidence or structural evidence indicates that the loss of these dopamine axonal markers, the long-term loss of these dopamine axonal markers is due to degeneration of dopamine axon and axons terminals. Notably the toxic effect of methamphetamine is highly selective since it does not involve

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noradonergic, cholinergic neurons, gabaergic neurons, or other neurons thus far analyzed. With the single

exception certain of seratononic neurons which are affected in some species. The next few slides depict representative data on methamphetamine induced dopamine neurotoxicity in animals collected in my laboratory. In these

studies baboons were given various doses of methamphetamine ranging from .5 milligrams per kilogram up to 2 milligrams per kilogram. These doses

were given systemically at two-hour intervals, a total four doses were given. The animals were then allowed

a two-week drug-free period so that we might measure

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long-term toxic effects of methamphetamine as opposed to acute pharmacological effects of the drug. Two weeks after treatment we measured a number using postmortem tissue from these animals; specifically striatae tissue, we measured dopamine, dopa, as well as the dopamine transporter here labeled with a compound called Win35428 and the vesicular monoamine transporter here labeled with a dihydro -attriated dyhydrotetabenazine. Regardless of which

are these dopamine axonal markers we measured, as you can see here in the data before you, what you can see is that there is a dose-related reduction in each of these axonal markers that's produced by

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methamphetamine in the baboons striatum.

Notably,

even the lowest dose that we tested produced significant effects. Collectively the chemical, an as I will show you in a second, the anatomic data that we and other laboratories have collected, collectively that data strongly indicates that methamphetamine has the potential to damage dopamine axons and axon terminal is shown schematically here. And it is that damage or

destruction of these terminals that leads to loss of dopamine in the various other dopaminergic axonal markers. The toxicity of methamphetamine can be

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detected with imaging techniques as well.

Shown here

are the results of two different types of imaging studies carried out in the same baboons that I just showed you the neurochemical data from. In other words, after -- bear with me here for a minute because this is a somewhat complicated but important slide. There are three panels, the top, Just focus on the middle

the middle, an the bottom. and the top.

The middle simply represents a

postmortem quantitative autoradiographic study where we are now using tritiated label when to label the dopamine transporter the control animal is shown on the left, the methamphetamine treated animal is shown

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on the right, and you can see essentially what you saw with the chemical data. And that is, that there is a

profound loss of dopamine transporters in the striatum of the methamphetamine treated animal. Now, please focus on the top panel. What's

important and I think interesting about this panel is that these are the results of a study carried out with carbon 11 labeled Win35428. As you may know carbon 11

emits positrons and thus permits the execution of positron emission tomographic studies. These are

elegant studies that allow for direct visualization of dopamine terminals at the levels of the striatum. DR. JONES: Dr. Ricaurte, you have about 30

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seconds.

So if you would move towards a summary and

conclusion. DR. RICAURTE: Very good. And what you see

simply here is that during life this animal shows loss of dopamine transporters that is confirmed in postmortem studies. Armed with that information with

PET imaging, what we've done is conducted a study of human methamphetamine users, compared them to controls, and to patients with Parkinson's disease and you can see that the human subjects previously exposed to methamphetamine shows evidence of loss of dopamine transporters. What does this have to do with ephedra? To

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directly compare the neurotoxic potential of ephedrine with that of methamphetamine, we have recently done some studies in squirrel monkeys, where monkeys are given fivefold higher doses of ephedrine to accommodate for the difference and potency. And what

this slide simply shows you is that ephedrine like methamphetamine produces a loss of dopamine transporters -- of dopamine and dopamine transporters. In summary, what I've covered today are, I've discussed the cardiovascular and neuropsychiatric complications of ephedrine-containing products, their abuse liability, I've touched upon, and I've also discussed the potential for neurotoxicity. Due to

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limitations of time, I cannot address some of the limitations that I recognize are in our animal studies. But the reason for presenting them today is

to simply highlight for you the neurotoxic potential that ephedrine has for dopamine neurons in the brain. Thank you. DR. JONES: Thank you, Dr. Ricaurte. We

would invite you to put the into the record.

full text of your remarks

We would welcome full text.

[Applause.] DR. RICAURTE: I will. I will then submit a

complete record of the written remarks, thank you. DR. JONES: Very good, thank you.

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Dr. Woosley. DR. WOOLSEY: Dr. Jones, members the

committee, and guests, I am, as shown here, Raymond Woosley, Professor of Pharmacology and Medicine at Georgetown University where I am chair of the pharmacology department. pharmacology. I have a Ph.D. in

I am also board certified internist and

board certified clinical pharmacologist, and currently president of the American Society for Clinical Pharmacology and Therapeutics. I am a consultant for the FDA, a special government employee, working with CFSAN for the last few years, but today I appear as an unpaid volunteer

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for presenting to you this information today. I have no financial ties to any other products involved and hope that I can give you an objective analysis of the 140 cases that were presented to me about a year so ago. I will be giving you my opinion of those cases. Dr. Neil Benowitz, a clinical pharmacologist

also and colleague performed a similar analysis and came to the same results. I think though, as I have

watched the other presentations of those same cases, it is interesting that in 140 cases that were very complex it's always there are differences between the different approaches that people take. And I will

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today give you my approach based on the following background or biases however you want to look at them; but my experiences. My experience began as a clinical pharmacologist 25 years ago studying the variable factors that contributed to the response of drugs trying to identify those factors which would explain variability. Often studying drug action, many times

studying, unfortunately, drug toxicity. I was co-director of the cardiac arrhythmia suppression trial. 1988. This was a trial that ended in

It was the study of drugs intended to save

lives, but the study was stopped prematurely because

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the antiarrhythmic drugs under study actually were taking lives. toxicity. It was heightened in 1990 when I saw a case of seldane-induced sudden cardiac arrest and began a series studies often with funding from the NIH and the FDA to study the factors responsible for that fairly rare cardiac complication. So in reviewing -And that began my interest in cardiac

actually in 1995, 95 cases of medwatch reports of ephedrine products that had been reported to the FDA, and the 140 cages that I have more recently reviewed, it was heavily influenced by my experiences with the cardiac drugs in the antiarrhythmic trials and the

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cardiac actions of antihistamines and many other classes of drugs over this period of time. So I guess in those cases we were looking at the medwatch reports often of prescription drugs where we often knew some of the pharmacology, but not all of it. And in this case, it is very different. We are

looking at the pharmacology or cases where the pharmacology has been known for centuries. And we are

looking at the drug in a different use than its usual prescription use. So it is a different situation and

people come at this with different backgrounds and different approaches. But I used the following scoring system. I

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said -- I went through the cases and gave them a score of one to five. And five was used when the reaction

reported is generally accepted as a medical consequence of the sympathomimetic amines, such as ephedrine, it was temporally related to the administration of the product or the report included a dechallenge with resolution of the symptoms associated with discontinuation of the product, and the product contained the information necessary, and the report contained the information necessary for a reasonable evaluation of causation excluding other likely causes. So that would get a score of five, or would be very similar to the reactions generally expected, it was

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temporally related, but the report may have lacked dechallenge or some of the information necessary for a reasonable evaluation. So it was a slight reduction in the amount of evidence that was available in the report. And as

was said earlier, unlike the reports in 1995, these included intensive evaluation, affidavits from witnesses, family members, and sometimes victims or people injured in the report. A score of three was that it was generally accepted as a medical consequence, but there lacked a great deal of the information necessary for complete evaluation of causation.

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Two, there may have been other cases or other causes that might have explained it. And a

score of one, that the report was just too incomplete to allow one to reasonably assess the report. And causation in my case was assessed by view of copies of the medical records, affidavits of the patients and their family members, analytical chemistry reports which were often available of the biological fluids in ephedrine-containing products and postmortem reports. Well, in doing this, I was heavily influenced by many of the structures that you have already seen, and I will go quickly through these

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because you've seen this already.

But I think it is

important to repeat that in analyzing these reports you have to -- I had to take into account all that I had learned about the pharmacology of sympathomimetic amines. And the structural similarities between

ephedrine and amphetamine is shown here; the simple difference of a methyl group and hydroxyl group here. Methamphetamine was talked about a second ago. The very similar chemical structure, the fact

that phenylpropanolamine is also a metabolite of ephedrine. It's pseudoephedrine is chemically very

similar but by changing the stereochemistry to pick an isomer that has all the same properties but a

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different sensitivity, a different dose response curve. The message that I got from looking at all of this is that all of these compounds can do the same thing but at different doses and different sensitivities, different potencies, sorry. And of

course they were acting as adrenaline often does because it is a catecholamine which has the same phenelylamine backbone which allows it to interact with alpha and beta receptors and stimulate the sympathetic nervous system. And there are products on

the market like the phenylephrine which can constrict blood vessels and have medical use.

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Well, these stimulant amines will affect the heart and blood vessels, increase blood pressure, and increase cardiac work and when any of these compounds have been looked at including, ephedrine carefully over the centuries, and in more recent years in clinical reports those sympathomimetic amines are known to be associated with stroke, heart attack, arrhythmias, and sudden death. So this was known, and I used that fact in analyzing the under 140 cases. And if you look at the

104 cases of the 140 that I've scored as four five you find that the fives are shown here, the fours are shown here, there were seven cases that I felt that

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there was very strong evidence that the sudden death was caused by or associated with the use of an ephedrine-containing product. four. Three were rated as a

Arrhythmia such as atrofibulation, ventricular

tachycardia, palpitations to arrhythmias and cardiac awareness, syncope, dizziness, chest pain, and myocardial infarction were all seen. These are the

effects that you would expect with any sympathomimetic amine given to a large population of people. And the brain stimulate affect would be expected for this class of compounds to lower the seizure threshold, to cause psychoses and cause anxiety and other CNS symptoms. And when I reviewed

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the 140 cases I found that five -- that I gave a score of five to ten cases of seizures, tremors occurred in seven, personality change one of the most frequent reports that I gave a score of five, 24 cases, and a score of four was given to four cases here. Severely increased blood pressure, six were given a five, and there were 12 severe strokes that I felt were clearly associated and probably the result of the use of an ephedrine-containing product. Well, what are the factors which caused these kinds of events to occur? I think clearly

dosage can be involved, but in almost all the cases, in fact all the cases that I reviewed, dosage was not

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a factor.

These drugs were -- and I said "drugs" as

Harry Fong said earlier over and over, these are drugs and the drug dosage for these compounds was as recommended on the labeling. all of this. So dosage can't explain

And I think one of the things that we've

learned with terfenadine and many drugs now, is that there is receptor diversity. We know that there are

ion channels in the heart, for example, that a simple change of one amino acid in the protein can alter the sensitivity to a drug. And that mutation or that

polymorphism in a receptor or an ion channel can be responsible for an untoward response supersensitivity to this kind of drug.

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So, I believe that what we know about the receptor diversity and the receptor polymorphism that existed, beta receptors and ion channels are enough to explain the exaggerated cardiovascular response that are occurring in many individuals. At the same time many individuals can take these compounds and never have a serious reaction. is this receptor diversity that I believe is responsible for this disconnect, where some people can tolerate these products without any problem, but an occasional person will have a stroke or heart attack. Why is ephedrine not in use in medicine today? Well, there are more safe and effective drugs It

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that are available.

And medicine has moved past a

drug, as Harry Fong said earlier, only a two -- a therapeutic index of only two. We now have many other

products with therapeutic tendencies of 10 and 20 which can be used clinically and not cause reactions in the supersensitive population that is out there today. So I conclude that ephedrine, although safe for some healthy people, causes stroke, heart attack, seizures, sudden death, and other less serious adverse effects in susceptible individuals, or a normal people giving excessive dosages. I think the warning labels will not be

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effective in preventing the harmful effect of ephedrine because the individuals often do not know that he or she is susceptible to the adverse effects of ephedrine until they take their first few doses. And for me there is no acceptably safe dosage of ephedrine when used as a dietary supplement, because, it has no proven nutritional or even medical value using current standards of evidence to offset its known harmful effects, adverse effects, expected to occur in some people. is just unacceptable. [Applause.] MS. CULMO: My name is Cynthia Culmo. I am So to me the risk benefit ratio Thank you.

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employed by the Texas Department of Health, but I am here today on behalf of the Association of Food Drug Officials who has paid for my travel expenses to this meeting. In light of the time, and my nervousness, I'm going to speak fast so I should get through in plenty of time. I am here to present a state's I don't have a

regulatory perspective on this issue.

lot of impressive credentials, but now I have a the unsolicited long-term on-the-job knowledge and experience with this category of products. I'll give you a background on the Association of Food Drug Officials, herein referred to

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as AFDO, and I am pleased to offer comments on this important issue. AFDO is a 104-year-old organization that represents federal, state, and local government, regulatory officials, and industry associates. Many

of whom are involved in food safety efforts focusing on dietary supplements. AFDO strongly supports the

Food and Drug Administration's desire to develop strategies for achieving effective regulation of dietary supplements. AFDO wishes to comment on a few of these and more specifically on the issues of this docket. We

had consistently, through testimony and in numerous

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written comments, placed a high priority on product safety and provision of adequate label information to help educate the consumers on safe and appropriate use of dietary supplements. Although the safety of dietary supplements is often equated to conventional foods, many contained concentrated extracts of botanicals that have profound physiological and pharmacological affects that result in added health risk when compared to conventional foods and the whole unextracted botanical. AFDO continues to support fast tracking of specific good manufacturing practices, particularly those requirements that address critical safety areas

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related to consistency and purity of the ingredients and dosage. This is particularly important for all

dietary supplements. On several occasions AFDO has expressed its concern regarding deficiencies and the labeling information for safe use; including information regarding contraindications, problematic drug or product interactions, and restrictions for which safety has not been established by clinical studies or historical uses in at-risk preparations such as young people. Today's docket addresses the safety of dietary supplements containing ephedrine alkaloids.

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The traditional medical use of these products, the use of the products as dietary supplements labeled for weight loss and exercise enhancement, and the known physiologic and pharmacological actions of ephedrine alkaloids, including their use in combination with other stimulants. The following are responses to the specific questions posed for this forum with regard to additional AERs and the information that was made public by the FDA this past spring. In regards to the

first question -- and I am not going to read the questions -- the known and expected physiological actions of ephedrine are well-documented, as you have

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heard the previous speakers allude to.

The beneficial

actions include bronchial dilation and decongestant effects. Another positive action might be weight loss

and overweight or obese persons due to appetite suppression and thermogenesis. Serious adverse physiological actions are also expected and known for this potent stimulant including cardiovascular neurologic and other types of serious adverse events that have included elevated blood pressure, cardiac arrhythmias, heart attacks, seizures, stroke, psychosis and death. Not surprisingly, each of these adverse events is represented in the AERs, reported to the FDA

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and several states.

Since all the products in the

reports contain ephedrine and since all the adverse events are consistent with ephedrine toxicity, there is clearly and association between the use of dietary supplements containing ephedrine alkaloids and the adverse events. And just as in the first serious of AERs reported by FDA in 1997, this new series documents that over 90 percent of the injured consumers took the ephedrine-containing dietary supplement products as recommended, or at lesser amounts, than as directed by the manufacturer on the labeling. Not to go over each of the external

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reviewers as well as CFSAN and CEDER there was an evaluation performed by mention -- and I apologize if I mispronounce names -- an RPH and MS, Claudia Kowalski, a PharmD within the FDA's Center for Drug Evaluation and Research, CEDER, who describe the adverse events as possibly related to the use of ephedrine alkaloid-containing products. CEDER's division of Drug Risk Evaluations' more conservative evaluation may reflect its traditional frame of reference in evaluating adverse reactions from prescription drugs where wellcontrolled clinical trials have established the drug safety effectiveness, contraindications, and most

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likely tbe adverse effects.

It also reflects their

expectations that physicians familiar with the patient's medical history prescribed the drugs and report the adverse events through a well-established system. Dr. Janet Woodcock summarized CEDER's report as follows, and I quote: "we nonetheless believe it

is most likely that ephedrine alkaloid-containing dietary supplements, EADSs are causing these adverse effects. The primary reason for our belief is" -- she I'll quote three: "the

lists, one, and two.

similarity between the adverse events and the known pharmaco dynamic properties of ephedrine alkaloids."

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Additionally although many EADes may contain other ingredients the most cogent interpretation of these data focuses on the common element, the presence of ephedrine alkaloids. In other words, the fact that

the adverse events are associated with ephedrine alkaloids containing a variety of other constituents, taken with the fact that we are not at the same level of adverse events associated with the other constituents on the EADes, it supports the causal relationship between ephedrine alkaloids and the adverse events. Under question two, DSHEA, the Dietary Supplement Health and Education Act, dietary

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supplements or more regulated as foods rather than the stricter regulatory requirements of drugs. And they

are intended to supplement the diet to affect or maintain normal structure and function of the body or produced general well-being. The central nervous system stimulation of ephedrine alkaloids may play a role in suppressing appetite and increasing perceived energy levels. increased metabolism produced by ephedrine particularly in combination with caffeine, it may increase the rate of weight loss for individuals on a low-calorie diet. These effects are drug effects, and there An

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are significant risks associated with taking the products for energy or weight loss, particularly when use for long periods of time. The bronchodilation and

the cardiovascular stimulation produced by ephedrine alkaloids had no role in maintaining normal structure, function, or well-being in healthy individuals. Dr. Wei from the School of Medicine expressed that ephedra is used in its traditional Chinese medicine, TCM, for short-term treatment of medical conditions such as cough, nasal congestion, asthma, emphysema, and bronchitis. These conditions

are either diseases or characteristics of diseases in dietary supplements and are not intended to diagnose,

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treat, cure, or prevent any disease.

Ephedra is not

used in TCM to lose weight, pump iron, or to fight fatigue. Considering dose and duration studies have demonstrated that obese women on a low-calorie diet taking 20 milligrams of ephedra, three times a day, with or without 200 milligrams of caffeine for six months experienced increased weight loss compared with women taking the placebo. We are not aware of data evaluating lower doses of ephedrine for weight loss or data characterizing the effective dose and the duration of use for ephedrine for increasing energy or

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bodybuilding. safety.

The question addresses efficacy and not

The states health departments, pharmacies and agricultural departments, as well as the FDA, have long been concerned with the safety aspect of ephedrine alkaloid-containing dietary supplements. Both state programs and AFDO have testified to this concern. During comment periods in public hearings,

representatives of industries have promised to publish in peer review journals the results of on going, double-blind, placebo studies that will show that ephedrine-containing dietary supplement products were safe.

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The promises were sometimes delivered at the eleventh hour and have been instrumental in delaying passage of any restrictions to improve safety by the regulatory agencies on more than one occasion. Six years have passed and the touted safety studies still haven't been produced. What happened?

The financial cost of a large clinical trial to determine safety should not pose a burden for manufacturers that claim billion dollars in sales for ephedrine-containing diet products alone. Have the

studies suffered due to the small numbers of subjects, the short duration of the studies, or the number of subjects that dropped out or were eliminated due to

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significant side effects?

If the studies participants

were subjects that were screened in as healthy individuals to be part of a carefully controlled physician-monitored, clinical study, what were the reasons for noncompletion of those studies? It appears that the studies, to the extent that they lasted, document the pattern and the types of adverse events reported and known for sympathomimetic stimulant agents even among apparently healthy persons. Dr. Woosley so adequately summarized in his review of the adverse events a great deal of discussion and deliberation has sought to identify a

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safe dose of ephedrine in dietary supplements. However, a safe dose assumes that there is safe medical value to taking ephedra as a dietary supplement. The lack of proven medical benefit of

dietary supplements containing ephedrine alkaloids makes the risk benefit ratio these supplements unfavorable. The occurrence of serious side effects makes the use of ephedrine-containing products as a dietary supplement at dosages they can increase the blood pressure and heart rates in susceptible individuals unacceptable without medical supervision. The adverse events reported to FDA in a

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series and in a previous series on dietary supplements containing ephedrine alkaloids, represent only the tip of the iceberg of the number of adverse events occurring from these products. The evaluation by Dr. Walker, M.D. PhD of Harvard School of Public Health, concluded less than one percent of the serious adverse events caused by dietary supplements is reported to the FDA. proportion may well be smaller by an order of magnitude or more. In the 20 months from June 1, 1997, to March 31, 1999, FDA received 140 reports of adverse events; 60 of which could be clearly attributed to ephedrineThe true

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containing dietary supplements, or supported a role of ephedrine in producing these adverse events. Adverse events included deaths, permanent disabilities from cerebral vascular disruption, cardiac arrest, heart attacks, seizures and psychosis. If Dr. Walkers estimates of reporting rates are correct, 300 to 3,000 or more individuals a month may be suffering serious, and in some cases, disabling or fatal adverse events from dietary supplements containing ephedrine alkaloids. Risk from dietary

supplements containing ephedrine alkaloids are serious, and the consequence is are devastating for some affected individuals and their families.

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Are the outcomes associated with the use of these products affected by dosage? affected by dosage. Outcomes may be

Data currently available

indicates the dosage of products currently marketed for weight loss of bodybuilding and enhancing energy propose a significant risk of life-threatening adverse events. But these data do not indicate an expected

safe dose. In addition, over half of the members of an advisory expert panel convened by the FDA in 1996, the Food Advisory Committee concluded that based upon the available data, no safe level of ephedrine alkaloids could be identified for use in dietary supplements.

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The growing number and the consistency of the AERs associated with dietary supplements containing ephedrine alkaloids and the continued lack of safety data must lead one to the same conclusion today. Mario Enchioso, from Newark Medical College stated in his conclusions in his review, "I believe that these relationships are of importance in relation to whether one can identify a safe dose of ephedrine for supplements. In the absence of clinical indication that would provide some basis for risk to benefit consideration, it would not be possible to recommend a

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safe dose of ephedrine considering user characteristics. Strenuous to moderate exercise

appears to increase the risk of serious adverse effects from dietary supplements containing ephedrine alkaloids in both men and women." Dr. Benowitz commented, "several individuals in our view suffered adverse events during exercise. Exercise results in activation of the sympathic nervous system which increases blood pressure and heart rate. Ephedrine and/or caffeine could augment

the cardiovascular stress of exercise which could be another mechanism for difference in the individual's susceptibility."

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He also concluded that the three types of the adverse events reported in a AERs he reviewed were consistent with the known stimulant properties of ephedrine and caffeine. In addition, it is well-established that the combination of stimulants has a synergistic effect with increased risk for adverse events. As Dr. Love noted, it could have a potentially positive impact on thermogenesis that may also account for the increased adverse effects seen with a combination of these agents. Another negative result documented with taking ephedrine-containing dietary supplement

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products is a positive urine screen for amphetamines. This could be particularly problematic for athletes and military personnel. Most amateur collegiate, and

professional organizations now prohibit the use of ephedrine-containing products by their athletes. Serious adverse effects from dietary supplements containing ephedrine and these AERs, the last series of the AERs and the AERs reported to the states occurred from the first day of use to after months or years of use. Safety of these products cannot be assured by limiting use to days or weeks. Life-threatening

adverse events occurred in young individuals with no

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identified, preexisting medical conditions.

Label

warnings directed to individuals at increased risk because of medication or medical conditions would not protect these individuals. The states and the FDA have ample evidence why these products are being consumed for weight loss, performance enhancers, and energy boosters. This is

easily demonstrated by FDA's review of the products and other marketing advertising and labeling received by the states. An example of the consumers'

perception of these products is exemplified in petitions received during Texas Department of Health's rule-making procedures that said sign up today, save

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the Chinese speed, and please sign to keep the Chinese speed. It's virtually impossible for an individual state to bring about meaningful restrictions on sales or labeling these nationally distributed products. And many states have delayed individual action because they are expecting and waiting for FDA to provide leadership and finally act with meaningful restrictions. DR. JONES: to a conclusion? MS. CULMO: Okay. I need to wrap up here. Could you please wrap up or get

In conclusion, being a representative of

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many involved or regulatory oversight, I am compelled to address the regulation of these products. encourages the FDA to act expeditiously. There have been two included advisory committee reports, two series of external reports, scientific medical specialties have been utilized, and most have concluded that dietary supplements containing ephedrine alkaloids present significant or unreasonable risk of injury or illness under conditions recommended by the manufacturers. It's time to place to politics and the money aside and act responsibly as the public health agency relied upon by the general public to protect their AFDO

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safety.

Recent polls demonstrates that FDA is held in

high regard by the general public and is viewed as doing a good job. To continue that trust FDA must act in these needless injuries. We would like to thank the USPHS

for this opportunity to comment, and we look forward to working with all interested parties to address this important public health issue. DR. JONES: [Applause.] DR. JONES: And thank you to all panel Thank you.

Thank you, Ms. Culmo.

members for staying on time even if I needed to prod a couple times.

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We want to open for questions and answers first from the panel. I will take the prerogative,

since I have a microphone, of asking the first just of the panel, do any of you have any data whatsoever on the role of the thyroid as an underlying condition since an estimated 20 -- some say as many as 40 percent of women from about midlife to later might have an undiagnosed thyroid condition which obviously can have cardiac and other effects. Any suggestions

of the role that that might contribute as the underlying conditions and interaction with these compounds? DR. WOOSLEY: I think clearly the

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hypothyroid individuals are known to be at increased risk for sympathomimetic amine administration. don't recall in 140 cases if there were any. to call that there were, made Lori knows, but hypothyroidism is also a potential complication in that these people are at increased risk of arrhythmias as are the hyperthyroid. So, I think we don't have data that I'm aware of to quantify that group any more than we have any other group. But we would, based on the I I seem

pharmacology, based on the disease itself or the illness, I would say that those would be another group that often are unaware of their condition who might be

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at increased risk. The other aspect of it is, there were some of these cases that were taking thyroid supplements and if that dosage wasn't adjusted perfectly at the time they took the sympathomimetic amine that could be another risk factor. DR. JONES: DR. COATES: DR. JONES: state your name? DR. COATES: I'm Paul Coates, from the I have two Thank you. Dr. Coates. I have --

Thanks very much.

For the record, Paul, would you

Office of Dietary Supplements at NIH.

questions -- brief questions for Dr. Love, and one

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brief question for Dr. Ricaurte. Dr. Love would you -- maybe I missed it but would you be able to provide the references for the St. Luke's Roosevelt study and for the Calman study which you referenced on your slide? You noted that

the St. Luke's Roosevelt study was in abstract form, do you know if it's been published since? DR. LOVE: published. in 1999. DR. COATES: DR. LOVE: And the Calman study? The Calman study, I forget the I have not heard that it's been

It was published in abstract form in FASEB

journal it was just recently published in 2000.

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DR. COATES:

And then I wonder whether -I was

the number were going by fast before me.

concerned to be sure that I understood that the adverse event reporting system represented, was there a difference between the adverse event reports that occurred among those who were using the products primarily for weight loss as opposed to those who was using the products primarily for bodybuilding for want of a better term? DR. LOVE: From our data more men, of

course, appeared to be using it for the fitness bodybuilding purposes. An in that population looking

at the classification of adverse events there were

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more central nervous system type of effects. Particularly if you looked at it there were more cases of seizures in some of these individuals, but also strenuous exercise did impact on just the cardiovascular events that that you could see irrespective of what the product was used for. DR. COATES: And if you do not mind I will Dr. Ricaurte, you

ask one question of Dr. Ricaurte.

provided a tantalizing approach towards the end when you said that the methamphetamine studies on dopaminergic neurons in the baboon could be reflected in similar studies in humans and then you ended with the tantalizing brief remark about ephedrine studies

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and monkeys.

Can you give me a little bit more

insight into how you think that the studies that were done in monkeys could draw you to the same conclusion that you had about methamphetamine in the baboon and in the human? DR. RICAURTE: Well, as you know, the

closing remarks were not meant to be so tantalizing brief and I apologize. I think the data on the

neurotoxic potential of ephedrine compared to that of the methamphetamine although it is at a very early stage; there is a paucity of studies. That data clearly indicates to me that like methamphetamine, ephedrine -this is the minus

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isomer of ephedrine, that ephedrine has the potential to damage dopamine neurons in the primate central nervous system. I think that that's where we are with the current studies. What we don't know as yet is, what

are the lowest doses of ephedrine that produce the neurotoxicity in the primate brain. We don't know

whether or not the data in monkeys extrapolates to humans. With the methamphetamine subjects I can tell that when you look at issues of dosage, the doses that produce the toxicity in nonhuman primates are on the orders of those used by some humans. We don't know if

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that's also the case for ephedrine. DR. JONES: I have questions, two more

questions from the panel, Dr. Schwetz and then Dr. Lieberman. DR. SCHWETZ: Berne Schwetz from the FDA. How much of an I

have a question for Dr. Woosley.

adjustment is normally made to account for the tolerance that develops? And are these adjustments

more likely or less likely to be made by people who would have the receptor to polymorphism? DR. WOOSLEY: It is an excellent question Clearly

and one that I'm not aware of good data on.

there is tolerance to some of the cardiovascular

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effects and we know with other drugs that people titrate their dose to maintain a drug effect. And I

think that it also raises the other concern, and that is variability between products. Because if you

titrate your dose to a higher level because of the tolerance and then you change lots or you change products, and now you're taking in an ephedrine product that has two to three times higher dose, then that could be a very dangerous situation. But Dr. Ricaurte may be able to answer it better about the CNS effects. But the cardiovascular

effects of these compounds, there is tolerance that develops, but there is a sustained stimulation of the

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heart and the blood pressure if the dose is increased. And I think those are the cases where -- I mean, we all exercise and the blood pressure and the heart rate goes up, but we don't maintain that high blood pressure and high heart rate throughout the day and the hours, and the heart and the body has a chance to rest. Whereas, in this case when your ingesting the products continually for days, then I think that's putting people who might have small -- aneurysm or some other predisposing factor bringing out a problem that would not have otherwise occurred DR. JONES: Last question from the panel Dr.

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Lieberman. DR. LIEBERMAN: Dr. Lieberman, U.S. Army

Research Institute of Environmental Medicine, I have a two-part question for Dr. Woosley and Dr. Love. The

question is, given your concerns about ephedrine and ephedrine-like products in dietary supplements, do you have similar concerns about these products when they are sold as OTC decongestants? And the part of the

question is for Dr. Love is, is there any surveillance data that speaks to that particular situation issue? DR. LOVE: Well, again, as I talked about

the types of products we were talking about today, the issue of the effects in OTC products were really off

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the table because the are regulated under a different scheme than the food products. So we were trying to

focus this just specifically on the effects in these dietary supplement products. I am not from the Center

on Drugs and I don't think that I am confident to comment on anything they may have in this area. DR. LIEBERMAN: I understand that those But my

products are regulated very differently.

question had to do with the data that might be available from those products, not a generic question about your opinion on whether they should be regulated differently. DR. LOVE: We have asked them to do reviews

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in the past and there has been limited information available in their database or adverse events or these type products. Remember the products contain very

different ingredients than the dietary supplement products. DR. WOOSLEY: I would say that, yes, I do

have the same concern, but less because there is a risk benefit ratio that you can assess. I mean, there

is pharmacological effect that a drug is being used with an informed label, it's been reviewed by the FDA as a drug, and there is a medical value to it, some response, the reason a person keeps taking it and they realize that benefit. So there is a risk benefit

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ratio that can come from that. I would also say though, that if you look at pharmacology of the heart and blood vessels beta-blockers reduce death. And anything that

stimulates the sympathetic nervous system is probably the wrong dose or the wrong individual going to cause cardiovascular harm. So I think you should assume

that any central -- any cardiovascular stimulate will have some harm if used in a broad population. question is, is it being used under the proper supervision and inform the public and with some medical value. DR. JONES: Thank you. Let me turn now to The

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questions from the floor.

You have been very patient.

There are microphones on the floor, and if you would identify yourselves just for the record so that we have that, and then keep your question brief so that we can accommodate all who like to ask. McLaughlin. DR. MCLAUGHLIN: Nature Sunshine Products. Jerry McLaughlin from I have three questions. Dr.

The first relates to the therapeutic index of the ephedrine. I learned a long time ago that you can't And saying

believe everything that Harry Fong says.

that a therapeutic index of three exists for the ephedrine is way off, and then to have it reduced to

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two, and one of the later speeches was way off too. challenge you to back that up, and the University of Michigan we learned that the therapeutic index is the effective dose 50 divided by the lethal dose 50. those calculations I have my Merck index I could certainly help figure that out right now.

I

Find

The second thing is, no one is reporting on the total number of people who are using the ephedra products from which you are extracting these adverse effect reports. What is that number? I've heard it

quoted on 20/20 by someone from the American Herbal Products Association that it is approximately 2 billion doses a year, something like that. I suspect

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that's probably close relating to the amount of products that we sell. Two billion doses a year, I'm

not quite sure how many how many people are taking those 2 billion doses a year, but I suspect considering that 54 percent of Americans are obese or overweight, at least, and that a lot of those people need to take something to try and take the curb off their appetite and reduce their risk of death from the associated diseases. I suspect that we are looking at

probably a population of 20 million people that may be taking ephedra products. And what are you telling us? That there are

1,100 reports in the last ten years of adverse effects

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of 20 million people.

Let's look a some of the other

things that use all the time like polio vaccine in which there are ten people that get polio or one million people that get the vaccine. Some antibiotics like chlorophenol, one person of 200,000 dies of aplastic anemia that takes chlorophenocol. So the total instances of these

adverse effects is very small when you look at the overall population. neglected that. And all the reports today

And then finally, on the report about

the baboons getting their dopaminergic neurons damaged, I couldn't help but notice the dose. Even

the lowest dose that was given to the baboons of

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methamphetamine was 5 milligrams per kilo.

The dose

of methamphetamine itself when taken for diet is 5 milligrams per 70 kilogram person. Okay. So even Okay.

your lowest dose is like 70 times -- it was .5? So seven times then. was seven times the usual dose.

So your lowest dose Now, you said okay But

there are some people who do take more than that. I am going to point out to the audience, and the

people listening, that those are the abusers who are tolerant to methamphetamine. DR. RICAURTE: Let me address very quickly

because this was in the latter part of the -- there are two points with regard to the issue of dose. It

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wasn't 5, .5 milligrams per kilogram.

When you

consider issues of dose, there are two very important adjustments that one has to make. One is an

adjustment for difference in body mass using principles of interspecies drug scaling. Once you do

those adjustments the .5 milligram per kilogram dose becomes low on a milligram per kilogram basis for the human being. So you need to make that adjustment.

The second point I would make is that for the ephedrine, we don't as yet know, indeed for methamphetamine, we haven't fully defined the lowest dose that produces the brain dopamine or toxicity. So

at this point I just think we are at too early a stage

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to draw conclusions about -- such as have been drawn that the doses in humans are much, much lower than those that produce neurotoxic effects on animals. I just don't think at this point that we know. DR. JONES: Any other responses from this

panel to Dr. McLaughlin's questions. DR. LOVE: Well, I think his comment on

reporting rate is correct one, but it goes both ways. We do not have information where we can do incidence and prevalence. We do not have access to the Yes we have

information that we could provide that.

enumerator and we know that that is massively

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underreported, but we have no information on a denominator; and knowing the members of doses does not help us with that. DR. McLAUGHLIN: information tomorrow. DR. JONES: DR. WOOSLEY: Dr. Woosley. I would like to address the I'll give you some

therapeutic index issue, because therapeutic index implies that there's a per therapeutic value, and it's impossible to calculate a therapeutic index until someone shows a proven value of these products. We

know that there is underreporting at the Agency in the safety databases. In order to really calculate the

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incidence as Lori just alluded to, you would need another approach to do that; and one of the ways that the Agency has always evaluated these types of products is to ask them to do large enough control trials to give you a risk benefit ratio to document benefit, and then give you a careful assessment of the harm. If there are 2 or 3 billion people taking doses of these products, the society deserves a control trial to answer these questions and I don't think we should be guessing or extrapolating from animal baths and animal tissues when people are taking these drugs.

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DR. JONES: Culmo. MS. CULMO: denominator issue?

Thank you, Dr. Woosley.

Ms.

Can I quickly address the

Industry consistently relates this He just

denominator of 2 to 3 billion servings sold.

alluded to the fact that he could give her data tomorrow. It will be on servings sold. There is not We have

information on actual denominators consumed.

a number of reports where consumers have reported that they have taken the product one time and had to discontinue the product because of adverse effects. So there is not a known denominator at this time. DR. JONES: Thank you. Yes, sir.

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MR. SIEGNER:

My name is West Siegner, a

partner with the law firm of Hyman, Phelps and McNamara and I am here on behalf of industry. First I

would like to address partially the question that Dr. Lieberman raised about OTC use and side effects. I

don't, I can offer this as a quote from the record of the '96 advisory committee meeting and can provide the quote, I may not get the words exactly correct but this issue of adverse events with the OTC database came up repeatedly at that meeting and at one point someone from the Center for Drug Evaluation Research and I believe it was Dr. Wyntrob, got up and addressed that issue and stated something to the effect that we

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have no significant adverse effects in the database from labeled use of the products. be happy to provide that to panel. Another issue that I wanted to raise simply because this afternoon we'll hear more information on background risk and consumption rates, and I think this is important to put everything into perspective. The Center for Drug Evaluation and Research from FDA submitted a written evaluation of the adverse events to the docket and this is in the docket. And I think And, again, I would

it is important to have this in the record this morning and I will just read the quote conclusion from their report. It's not the only conclusion but it is

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one of conclusions.

"It is possible that the reported

serious adverse events are of coincidental background spontaneous occurrences in the population and are not necessarily causally related to ephedra products uses. The availability of additional information including product, market or usage data would be useful to the further characterization of the potential risks associated with the use of these products." And then finally this is a point, Dr. Jones, you mention at the beginning that everybody is supposed to mention any potential conflicts. I am not

questioning anybody's objectivity here, but I think it is important if the industry members are going to be

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required to divulge information on potential conflicts as I feel is appropriate, that everybody do that. I commend Cynthia Culmo for doing that. DR. JONES: Woosley did as well. We have asked people. Dr. And

I'm not sure Dr. Ricaurte did.

But I am sure he would be happy to state for the record what his conflicts are. Those of us who are

public employees are public property and, you know -[Laughter.] MR. SIEGNER: DR. JONES: I understand that. Thank you.

Thank you though Mr. Siegner.

Dr. Ricaurte, do you want to state briefly any potential, you know, who has funded, where you've

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gotten funding et cetera, please record. DR. RICAURTE: I, to my knowledge, do not

have any potential conflicts interest and I have so indicated in this forum. DR. JONES: support your research? DR. RICAURTE: All of funding for my studies Funding even from government to

at John Hopkins comes directly from the NIH. DR. JONES: Very good. Okay. We are

running close to lunch time but I do see three gentleman with questions, so I will take those questions. And then would ask if you do indeed have

further questions, concerns, or comments that we can't

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get to in subsequent sessions, you know, for any of you who are here for those, we have some -- I believe there are some forms that are available for pickup you can raise those questions or express those comments to the record in writing and we would invite you to do so. This gentleman, yes, sir. MR. REINHART: People for pure foods. I

wanted to ask two questions; the first one, Dr. Woosley would you comment on the pathophysiology of the punitive cardiomyopathies that you reviewed? Was

there anything either dominant or consistent about the pathophysiology?

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DR. WOOSLEY:

The cardiomyopathies that are

in the literature are those associated with sympathomimetic amines in general. The cases that I

reviewed I don't recall any microscopic anatomy of the heart that would address your question. MR REINHART: Ricaurte. And second question for Dr.

Is the dopaminergic neurotoxicity

associated with the depletion of norepinephrine. DR. RICAURTE: No it is not. That's one of

the really quite remarkable features of the toxic effects of these amphetamine derivatives because on the one hand, as you've heard, people will argue that

the doses are high, although I'm not sure that that is

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accurate.

But a remarkable feature of the toxicity is

that it is extremely selective as evidenced by the fact that noradgeneric neurons are totally unaffected. MR. REINHART: Do you have an insight as to

what the mechanism of the toxicity is? DR. RICAURTE: It's been a tough nut to

crack, but I think the weight of the evidence right now would suggest a primary role of endogenous dopamine that perhaps dopamine mediates a cytotoxic effect of methamphetamine and related substances. MR. REINHART: DR. JONES: Thank you. Let me take the

Thank you.

second question from here since this microphone hasn't

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gotten much. MR. GREEN: I am Ralph Green. I am an

attorney, but I am not with any governmental agency or any other agency. But a quick question, I think, for What is the

Dr. Woosley, or anyone else on the panel.

percentage of gastrointestinal problems that had been exhibited by the ephedrine in your analysis of the 140 cases or any other studies that you might be aware of? DR. LOVE: I don't think there is data that can give you a percentage. There are case reports in

the published literature on the effects of ephedrine alkaloids on the GI system we have noted them in our studies as well as Dr. Bytes has noted them. There

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are a range of adverse effects they can be seen in the GI system including those that could be due to the vasculature of the GI system. MR. GREEN: Of the 140, Dr. Woosley, that

you studied, were there any gastrointestinal problems among that group of people? DR. WOOSLEY: I do recall there were some,

but I did not quantify them I focused mostly on cardiac and neurologic, but I do seem to recall that there were some. But, again, I don't think there's

any way to, with a percentage in a spontaneous system. DR. JONES: MR. LAFABI: Thank you. Yes, sir. I am a

Hi, I am Bob Lafabi.

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professor of public health for sports medicine at Armstrong State University in Savannah, and I am also a consultant for Twinlab. It was a great series of information. I

think we'll appreciate that it seems very reasonable, very sound but I got to tell you, I just keep having this question, you know, where's the beef? to hear a lot about AERs. I expected

I mean, let's face it,

there may not be 2 million dosages every year but I can tell you, in terms of number of uses we are in the hundreds of thousands, and I expected to hear hundreds if not thousands of AERs. What we've got here in this

brief review was 60 possible AERs, possible, 46 and 41

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from CFSAN and then a theory over neurotoxicity, reasonable, but a theory, an analysis of those same AERs and then opinions from another regulatory agency. When you look at -- let's take a very conservative figure, 600,000 users, very conservative. DR. JONES: please. MR. LAFABI: DR. JONES: MR. LAFABI: I'm sorry? Get to the question, please. The question is, how can anyone Thank you. Get to the question

look at providing this kind of information to the FDA in its docket that would enable it to or give it some support for limiting something where there's no data.

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By the time you take out artifact, the fact that many of these people may have been taking illegal drugs that they did not tell you about, and then they didn't know that they had risk factors that you obviously don't know about, you may have absolutely nothing left. And so the question is, where is the data, the

real data? DR. RICAURTE: Let me just answer with a I think the concluding

brief statement -- a sentence.

sentence of my presentation -- I'll get it in somehow, in this regard, I say, I find it puzzling that while on the one federal policy in the United States severely restricts access to methamphetamine and other

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related drugs.

On the other hand, current law

provides various at-risk populations unlimited access to ephedrine alkaloids. I think you can't ignore the And therein

pharmacology of the these substance.

would lie my rationale as to why a careful look at these products is in order and why some oversight is needed in order to simply not allow unlimited access to a methamphetamine analog. DR. JONES: Ray go ahead. DR. WOOSLEY: I was just going to say, I And to your question, sir -- oh,

think it was said earlier, we have been pleading with the industry to provide the safety data that we all

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need.

The pharmacology is very consistent, the

reports are very consistent, this is not an issue of whether people are being killed or harmed by this compound; the question is, is there any medical value to them being exposed to this known risk and the systems that we have available will never quantify that risk, but they have identified it and there's absolutely no doubt by reasonable people that there is harm. I think we need the data that this gentleman has called for and I hope the industry that is selling this million/billions of doses will be responsible and provide us with that data.

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DR. JONES:

And clearly that was exactly

what I was going to say, the question stands on the record, sir, and we acknowledge it indeed as a call for more data. We have voluntary adverse event

reporting system, and, you know, in God we trust all others bring data. And what we brought to you today

is what we have in the adverse event reporting system, and have recognized the imperfections that that system brings with it. need to be done. There is a lot more work that does We acknowledge your question, it is

a valid question, we would like to see more work done. I will acknowledge now, we are at lunchtime and I would indeed like to start on time at 1:10 p.m.

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Thank you all very much for your in put. [Whereupon, at 12:12 p.m. the meeting was recessed to be reconvened this same day at 1:10 p.m.]

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A F T E R N O O N

S E S S I O N [Time noted: 1:10 p.m.]

DR. JONES:

Welcome back folks.

Let me note

for our 1:10 p.m. panel, Adverse Event Reports, this ephedrine education panel of experts review. There

will be a change in order of the presenters, so if you would simply note this, Dr. Kimmel will go first then Dr. Page, then Dr. Karch, then Dr. Farber, then Dr. Hutchins, then Dr. Olney, and, finally, Dr. Adams. Thank you, Dr. Kimmel, go ahead. DR. KIMMEL: Thank you, Dr. Jones, ladies

and gentlemen of the panel, and members of the audience. My name is Steven Kimmel from the

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University of Pennsylvania, School of Medicine, Department of Medicine Cardiovascular Division. The

Center for Clinical Epidemiology and Biostatistics in the Department of Biostatistics in Epidemiology. I have been funded by the Ephedra Education Council for this meeting including travel. I will put up some relevant background and talk over it in the interest of time. I am the chair

of a multidisciplinary panel of experts sponsored by the Ephedra Education Council who were charged to review and assess the scientific information relevant to dietary supplements containing ephedrine alkaloids. The other panel members will introduce

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themselves as they step of the present. Prior to a July 27 meeting, each panel reviewed the health assessments that the FDA released on April 3rd including health assessments prepared by consultants to the FDA. The panel also reviewed the

relevant published literature, and reviewed the adverse event reports. The literature review included

the published literature on the incidence of heart attacks, strokes, and seizures in the general population of norephadra users, including young adults. And finally at our July 27th meeting the pane

reviewed some unpublished data on the effectiveness of ephedra products in weight management.

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Here is relevant background

I have a

masters in epidemiology and I do research in the cardiac affects of noncardiac drugs. So, as an overview of what I like to talk about, there are three things: one, to address

questions that ar raised for this meeting by DHHS, Office on Women's Health; second to discuss very briefly the phenylpropanolamine and hemorrhagic stroke case control study which I know was of interest to this meeting; and, third to relate other consensus statements reached by our panel. So the first questions raised by DHHS. primary question that we addressed was, does the The

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available information show an association between the use of dietary supplements containing ephedrine alkaloids -- and I'll use the term "ephedrine" just for simplicity -- and serious adverse events when used as directed? Other questions that we addressed, are there circumstances for which there are indications for dietary supplements containing ephedrine, and thirdly, are outcomes associated with user characteristics? Turning now to the first and primary question is there an association between the dietary supplements and serious adverse events? As you heard today the preexisting data

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consists almost exclusively to adverse event reports for dietary supplements. The panel also consider

other data including physiology data primarily for over-the-counter ephedrine, pharmacology data primarily for over-the-counter ephedrine, pharmacology data, similarly for over-the-counter ephedrine, pathology data and other literature, primarily again for over-the-counter ephedrine alkaloids. will address these issues as the present. I'm going to focus on the adverse event reports. In addition we had available additional data And others

which were sales data from a sample of ephedrine dietary manufacturers to use to estimate the incidence

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of serious events among ephedrine dietary supplement users. And to compare this to the background

incidence of serious events in the population that as similar as we could find compared to dietary supplements users. As you know there are many limitations to adverse event reporting. The primary one is that

causality usually cannot be proven because there is no comparison control group. associations dan be wrong. pretty straightforward. background risk. anyway. In addition, even The reason for this is

Events may simply be due to

That is, they may have happened

and even if the event is rare with enough

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users there will be events that occur that are unrelated to exposure. In addition there are other confounding issues that make interpretations difficult. The

presence of obesity, exercise as examples, which we know increase the risk of cardiovascular events are difficult to dissect from other factors including use of dietary supplements. As a result of all this, the incidence rates are unknown which is important both for comparative purposes" and for estimates of absolute risk. In addition changes in adverse event reporting are difficult to interpret for many reasons.

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An increase in adverse unit reporting can be real, a real increase in events, it could be due to publicity which may be due to no real increase event if you get an increase in minor events. I'm talking now about

serious events minor events reported for you owe you get events that were reported long ago, so in other words, your annual numbers really have not increased, y get reports of people who didn't even use the product, you get reports of people who didn't really have side effects. And the publicity as a marker for

increased reporting, particularly of minor events has been documented in the literature. And thirdly, you may have simply an increase

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in number of users.

That is, you may not have a true

increase in risk the risk being the number of events over the number of users. This is a slide of the number of adverse event reports by the year that they were reported to FDA from 1993 to 1999. And the things that we noted

here are first of all that rapid rise here in 1994, it comes down little bit, a dramatic rise in 1996 which comes down again and levels off quite dramatically after 1996. So what is the reason for this? Is this

an epidemic of ephedrine serious adverse events? Well, I mentioned one issue which is publicity. This is not meant to be a proof slide, but

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certainly we know what was happening around this time. In 1994 formula one was receiving a tremendous amount of press, right before this. In 1996 FDA had to their

press release on ephedrine dietary supplements; Montel Williams had a broadcast and there were numerous other events that certainly increased public knowledge of what was going on. So some of these increases certainly could be due to reporting; again, certainly not a definitive analysis. The other interesting thing here, as I

mentioned, was that the numbers come down the numbers of events come dramatically down here and we don't see a rise -- dramatic rise or we don't see it continue to

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rise.

This would still be concerting, of course, if

the number users decreased; if these reports scare people away from these products and decreased use, this was still be worrisome. In fact, this is actually the opposite of what we see is happening. And now superimposed on the

same yellow line is a new white line which is the estimated servings sold based on a survey I'll discuss in more detail later. But suffice it to say that the

number of millions of serving sold based on a survey of a small sample of dietary supplements manufacturers has increased dramatically in the years. If dietary supplements increased the risk of

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serious adverse events and if reporting rates didn't change, and we know that there has been continued media attention in 1997, the FDA released their report in the Federal Register and that received a fair amount of media coverage. We don't see the blip here.

So assuming that the reporting rates are the same the divergence of these curves is inconsistent at least with true association. So in summary the limitations of spontaneous reporting are that they can't prove incidence rates. Effects of publicity are difficult to discern. There

is nonspecificity of reports over reporting and, of course, underreporting, which you've heard a lot

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about, is always a concern and there's no control group. So in order to try to address some of these limitations, and using data from sales of ephedrine dietary supplements, the panel had two goals. One was

to try to estimate the risk of serious adverse events occurring among ephedrine users, and, second, to compare these with population-based estimates of risk of the same events. I'm going to focus on strokes, heart attacks, MIs, and seizures. Well, what do you need to calculate incidence rates? You need the number of events and

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the amount of exposure we're going to usee in time. Our goal was, if anything, to try to overestimate risk among users. As you'll see, all of

these calculations have a lot of assumptions associated with them. We were trying to, if anything,

overestimate risk, try to be as -- if you want to use the term -- "conservative as possible". I will point out some of those as we go along. So number of events is the first thing we need

and for this we used all events reported to FDA from June 1, 1997 through March 31, 1999. We included all

of their events, whether they were attributable, supporting, or insufficient data. We assumed that

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they all really occurred and that they occurred on exposure to ephedrine. Some specifics about these. For our MIs we

included unstable angina and all sudden death in which MI could not be excluded. This is important because

of the population-based statistics exclude these patients. They are based on hospitalized patients who So, again, if

survive to come to the hospital.

anything, I think will be overestimating risk in ephedra users relative to the population statistics. And similarly for stroke we included all subtypes of strokes, not all studies do, and TIAs which most studies do not; other studies.

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What are reporting rates? data from the literature.

These are some

These are from medications

and looking at the series of events that we'll be discussing. In one study reporting rates for MI among

a group of drugs was 2.4 percent; seizures in another group was 25 to 37 percent. Now, this was after

vaccines at time of heightened awareness of adverse events and probably is a little high. 18 percent. Cardiac arrest,

Again, in this study the physicians were

aware that there was active surveillance going on so again it may be high. But this is a range for the types of serious adverse events that we are looking at. These are

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studies of medications not dietary supplements and various medications were vaccines. The reality is, it is impossible to know for sure what the reporting rate is. Specific to ephedra,

we may see increased reporting because of mass publicity, the fact that these are severe events that are unusual in a younger population, and, therefore are less likely to be attributable to other common causes; acute and occurred in close temple relation to the exposure -- these are not latent effects that occur five years down the line. We may see decrease

reporting because of underreporting of dietary supplement events in general. This has been

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hypothesized -- some suggestions based on some surveys in the literature there's no, as far as I'm aware direct study of literature looking at dietary supplement reporting rates; and of course different reporting mechanisms to the pharmaceutical industry which reports adverse events to drugs is not available here. Now, you know, which way this is going to go is unclear. I want to make one comment though related

to Dr. Walker's statement in which heard about this one percent or less reporting rate. If you read his Number

report carefully you'll see a could of things. one, he was not talking about ephedra.

He was talking

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about all dietary supplements in general.

Number,

two, he acknowledges that all of these things might increase report rates. He acknowledges that these may But essentially, the 1

decrease reporting rates too.

percent was for all dietary supplements and it was a guess. And the basis for that guess was a guess. the only example that was given in that paper was Ltryptophan which as, you may know caused use and aphelia myalgia syndrome in which Dr. Walker was concerned that there was underreporting. If you read A

the FDA report in the Journal of the American Medical Association and follow up to that, essentially

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tragedy, they calculate the 50 percent of all serious events reported. And if you included minor events it

was 25 percent; certainly not 1 percent. So the 1 percent is a guess, I think, based on other data. we do. So for our calculation we used reporting rates of 10 percent. And we used this based on the at We may use that as a lower risk and

the time what we had which was what the FDA used in the Federal Register on ephedra alkaloids in 1997 for some calculations. We did, however, look at a range, 1 to 20 percent to see how sensitive our estimates were.

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Okay.

That's the enumerator.

What about

the denominator of exposure time?

Well, as I

mentioned, there was an independent survey which was commissioned by the American Herbal Products Association and performed by one with Arthur Andersen. This was an anonymous survey of 42 companies, of whom, only 13, that is 31 percent reported on annual sales. From the annual sales data we calculated an estimate of the number of person time exposed. We are

going to assume again to be conservative that this, these 13 companies, are the only companies that sell ephedra in the entire country. Okay. This is clearly a worst-case estimate

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in terms of exposure time which will increase our risk. We also assume that perhaps this represented 75 We could have said 60 percent. We really

percent.

were just trying to see how sensitive our estimates were to our assumptions. So we have all the members in place we have the number of events adjusted for reporting proportion and the persons years of ephedrine use in this same time frame. I want to turn now to the first event. slide. slide. We wanted to compare this to the background No, wait, I don't want to turn to the nest Next

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risk.

In order to do this we performed a

comprehension literature review of epidemiology studies of population-based statistics and tried to identify a range of risk from U.S. studies representing a similar age range a reported cases. There are some issues with this there's difficulties, I will try to point those out as I go along. Now the first event. Seizure rates.

Assuming in a 10 percent reporting rate and assume in the sales from these 13 companies that responded were all sales, we estimated 2 million person years of exposure; this is in a 22-month period. This is not

one year this is 22-month period in which the AERs

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were reported.

We calculated an estimated rate of This is below the

seizures at 3.6 per 100,000.

background rate in the population of the 20 to 60 per hundred thousand -- population statistics. I am in no way saying that ephedra reduces the risk of seizures at all. All I am saying is that

the estimated rate is certainly not consistent with the dramatic increase in rate. This slide here shows the estimate of seizure rate per 100,000 person years with changes in our estimated reporting percentage as well as changing usage of ephedra products. The yellow line here is

assuming all the companies that reported are the only

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manufacturers, the 10 percent is our baseline risk; and as you can see, as the reporting rate drops down to 1 percent obviously the estimated seizure rate goes up, but is still certainly consistent with the range of events here. The next is stroke rate. Our estimated rate

of strokes among ephedra users 7.1 per 100,000 the background rate was three to 60 depending on the study. This slide shows how those estimates have changed by reporting rates and consumption used. For

almost all of our assumptions they are within range. There's one here that's a little bit and I want to

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make two remarks here.

One, this is a wide range in

the population, I'm sorry, I didn't say in the last slide, this gray box is the population rate. goes from 5 to 60. So it

It is very hard to sort of get an

actual number; 40 percent of all strokes in AERs that we looked at occurred in women over the age of 45, The five here is from studies of women under the age of 45 who belong to HMOs. So along with the healthy

worker effect is essentially a younger population. We know that in a population of 45- to 50year-olds the strokes rate goes up dramatically, it's 50 to 100 per 100,000. We use 60 as an upper limit,

again, realizing that this is really all just

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estimates. The second point I want to point out is that we're not comparing one rate to another rate, we are really just looking at a range. say what the actual number is. It's impossible to We are looking for a

consistency with the reported range or with the population range and we're also looking for dramatic differences. And I'll give you just one example, when

Fen-Phen -- at the time Fen-Phen was removed from the market or Fenflordamine and textrafenfloamine, rather, the estimated prevalence of valve abnormalities, and this was a different situation because this was distinct pathology, but the incidence of the

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prevalence of valve abnormalities was 30 percent based on case servings. The population-based prevalence was 1 percent. So the concern was that there was 30-fold

increased risk and we're looking for that kind of dramatic risk here realizing that we have a range, and we don't see that. Turning now to myocardial infarction our estimated rate was 5.1 per 100,000, again, consistent with the lower rate in the population. same study of young women here, And again as we very our assumptions the numbers change, but, again, most of the numbers are This is that

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certainly consistent with the range.

Rhe other thing

I will mention again is that these MI studies were all from people under the age 45, and 30 percent of the MIs that we saw in the reports were over the age of 45. And if you take those out, these dots here will So it's quite hard to compare. And in fact it is hard to compare. are numerous limitations to this. There

come down.

We had to make

numerous assumptions to obtain our incidence upsets estimates. We tried to vary it over a reasonable This not a

range and we tried to be conservative.

true control group, variability in population characteristics, we're comparing this to general

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population statistics we certainly know that obesity is a risk factor for cardiovascular disease. that exercise can be a trigger for myocardial infraction and sudden death. The population You also We know

statistics don't pick out the population.

heard this morning that 50 percent of the AERs had other risk factors. The population-based statistics especially in the younger populations -- I don't think they collected that data but certainly in women under the age 45 I don't think that 50 percent of them have significant risk factors for cardiovascular disease. And, of course, we had to use a range of incidence.

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In summary, this is not an attempt to prove or disapproved an association between ephedra and adverse events. However, even under our estimates

that we believe are likely to overestimate incidents of events in ephedrine users, the estimated rates of seizure, strokes, and MIs among these users may be

consistent simply with the background rate of events expected in the absence of ephedrine use. Based on this and the other data that you will hear from our other panel members, I will read our consensus to the first question of the association. The panel feels that the available

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information does not demonstrate an association between the use of dietary supplements containing ephedrine alkaloids and serious adverse events when

used as directed, and I would define "as directed" according to the AHPA trade recommendation; which is serving limits of not more than 25 milligrams of total ephedrine alkaloids, and total daily consumption of not more than 100 mg of total ephedrine, and appropriate warnings, all we believe consistent with over-the-counter available ephedrine alkaloids products. The next question are there indications for dietary supplements containing ephedrine alkaloids?

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The panel didn't have a lot of time to review information on this but I will go through a little bit next slide. These were some multiple dose studies,

again, now, over-the-counter ephedrine looking at weight loss. is two fold. And the purpose of putting up this slide One, to show you that there are studies

that have shown weight loss, as you heard about this morning, with ephedra. They are small studies they

are limited but the certainly support the hypothesis that this is effective for weight management. We also were able to review a randomize placebo-controlled study right after Huber -- and he will be presenting this study as I understand,

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tomorrow, looking at three different dietary supplements containing ephedrine alkaloids, randomized placebo-controlled which showed significant weight loss with all three, and no significant effect on heart rate or blood pressure. So are there indications? Well, based on a

review of these data we believe the dietary supplements containing ephedrine alkaloids may be useful in weight management. The third question, are outcomes associated with user characteristics? You're going to hear some

issues about this from other panel members, but our conclusion is or our consensus is that given the

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absence of data clearly demonstrating an association between ephedrine dietary supplements and serious adverse events when used as directed, the presence or absence there was this acceptable population cannot be determined. However serious overdosing and overuse can lead to serious adverse events, minor and/of very rare idiosyncratic reactions may occur including skin reactions and allergic reactions with use at recommended serving sizes as they came with any ingested food. The PPA and hemorrhagic stroke study was we were made aware of this after our panel met for their

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consensus so the panel didn't have a chance to review the study. perspective. I reviewed the study from epidemiological I understand others are going to present I'll give you my own quick

this in great detail.

conclusions. I don't think that the study was sufficient. I think that were several severe

limitations which prevented definitive conclusions about the association between PPA hemorrhagic stroke from the study. Finally, the other consensus statements reached bt the panel, I'd like to just go through some of those. I think these are important; we thought We believe that all labeling of

about this a lot.

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dietary supplements containing ephedrine alkaloids should contain appropriate directions and warnings for the public as adopted by AHPA and similar to those approved for over-the-counter ephedrine alkaloids products. We also believe that these should be readily legible and available to the consumer for prior to purchasing the product. You'll hear pathology data by Dr. Hutchins but their consensus statement was that the pathology data available do not show a pattern that is consistent with ephedrine alkaloids containing dietary supplements as a cause of death. We believe that an

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independent multidisciplinary panel should be assembled to perform a clinical pathologic review of all death reported to FDA. We also believe that in order to provide a more comprehensive scientific database, the National Institutes of Health, The Department of Health and Human Services and industry should work together to consider further controlled studies to address unresolved issues. Our last slide, we believe that very strongly that preparations that contain ephedrine alkaloids and that are marketed without responsible label instructions, serving size limitations, or are

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marketed with claims of achieving an altered state of consciousness or euphoria including so-called street drugs should be prohibited because they promote excessive use and abuse. And with that I will end and turn it over to Dr. Page. [Applause.] DR. PAGE: have the first slide. Panel, I am Norbert Page, and I am a partner in Toxichemica International. I'm going to speak very briefly about the published literature on the adverse effects of Thank you, Dr. Kimmel. Could we

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ephedrine alkaloids containing dietary supplements. To save time I'm going to refer to these really as ephedra products. I might mention that I am a consultant at this time to the Ephedra Education Council, but as you'll see from this slide I've been allied with doing hazardous assessments and risk assessments with federal agencies for some time. I've been on the The only

staff of a number of the health agencies.

one I really haven't been on has been the Food and Drug Administration. But I'm consider myself fairly

knowledgeable in the area of the hazard assessments and risk assessments prepared quite a large number of

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criteria documents for the various agencies. I'm going to focus specifically on the FDA's literature report. Now we have done an

independent review of the published literature and we will be providing some additional references to the FDA docket. But I want to specifically address some

of the structure of the FDA report. First of all, I want to complement Dr. Love and staff. They did a pretty good job of actually

searching and retrieving the bulk of the literature. So we've go a few that we're going to add but they have done, I think, an excellent job of getting the literature.

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I have some serious problems in the interpretation. My major concern however is that they

are relying very heavily on the PPA literature to analyze the health effects of the ephedra products. In my opinion this is not scientifically appropriate. Why do I say that? First, PPA is present

only in very small amounts and it is also only in a few of the ephedra products -- going to go into that. Also there is only a very minute amount of ephedra that is metabolized to PPA. A third reason, there's substantial pharmacological and toxicological differences between PPA and both ephedra a pseudoephedrine the main

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alkaloids in ephedra products.

I won't dwell with

this third issues since we have other speakers who will. I'm going to talk now about PPA in ephedra products. I might mention that you already seen one

slide I think it was earlier by Dr. Fong and his data pretty similar to what I have here, I think he had 40 to 90 percent ephedra, whereas I came out with 30 to 90 is the generally accepted amount in ephedra products. But as you can see from here the really two major ephedra alkaloids, ephedrine and pseudoephedrine.

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There's a few others, the methylephedrine, and PPA in very small amounts and usually not existing. Let's look a PPA in the commercial ephedra products. There have been a number of studies that I'm going to show the two Dr. In the first one in 1997 they

have looked at this. Gurley and his team.

looked at six of the ephedra products, three which had no PPA and the other three had very small amounts, and this is percent of the total alkaloid content .61 .3 and 3.1. Dr. Gurley had another study, the should be down here, but in the study in recent study in the year 2000 he expanded it and actually looked at 20

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ephedra products. PPA at all.

And he found that in 14 he found no

In the other six there were very small

amounts. .16 to .25 milligrams per dose. Now, keep in mind that I think you've heard that there may be as much as 20, 30 milligrams in a dose, perhaps even more, but that's what we will -- so we we're talking about a very small amount. Lee also recently published and where he found 3 percent of the total ephedra alkaloids which are used TEA consistent of PPA. Betz in 1995 who used

to be with FDA also review that the alkaloids content and he found in his first paper about 5.1 percent but in another study more recently he looked at nine of

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ephedra products and these are popular products he took off-the-shelf, and of those nine, he did not have PPA and two head trace amounts. .2 percent and 1.8 percent. So I think you can see from here there's very little in most products there's no PPA. In those

products that do have PPA, it's extremely small amounts. Let's take up the issue of metabolism of major ephedra to PPA. Ephedrine can be demethylated

to PPA, however, the amount of demethylation is extremely small. It varies with the publisher.

Beckett and Wilkerson found about 4.3 percent

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metabolism.

Bob and et al used both methods and they Basalt and Cravey in '97 came

found 4 percent in 4.3 over 4 percent.

Now the FDA has used Dollery's report where they show 8 to 20 percent metabolism. I want to point

out that Dollery is a secondary reference and it is actually a 1975 publication that Dollery used and in that there is not much information as to the individual so we really don't know much about whether there was any underlying situation that may have promoted the metabolism. What we do know though is

that if an individual has an alkaline urine, this is a study by Wilkinson using Ph of eight, this does

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increase the metabolism of ephedra to PPA. that their study it went up to 18.2 percent.

The fact But, by

and large in normal individuals metabolism is rather minimal around 4 to 5 percent. The other issue is it appropriate to use other routes of exposure. We were talking about

ingestion of dietary supplements, is it appropriate to use products that are given by nasal spray or inhalation? appropriate. And my opinion, I think this is The alkaloids in ephedra products

according to the references I've listed, they are absorbed slower than at pure alkaloids but the basic pharmacokinetics in the metabolism is quite similar.

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So I don't ever problem with using information from other routes. I want to present one paper that I think is kind of interesting in deals with the pharmacokinetics it's also cardiovascular effects, I won't be talking about the cardiovascular effects since someone else will. But in this study, Wyden, et al, subjected 12

subjects to 25 milligram dose of ma huang twice in one day, in other words he had a total dose or 50 milligrams and they measured the blood pressure and also they sampled the blood quite frequently. And just to speed up there's no PPA in this product and it is primarily ephedra. And what they

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did they compared the pharmacokinetics for ma huang capsules which is finely powered herb to that of ephedra tables and ephedra solution. Here are the results. Basically absorption

is nearly complete for all three forms; it's readily absorbed, I don't think there's any debate about that, the elimination Kinetic is pretty straightforward, it's one compartment first-order model and that seems to be consistent across the literature. They did find

that there is slower absorption from capsules than from tablets or solutions. The main thing in the

capsules is there is a longer period of time to reach the maximum time peak level in the blood. It's

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getting close to four hours compared with less than two if it's in the tablet or solution form. In other words, you've got the absorption coming in a little bit slower, reaching the peak at a later time; whether that is significant or not in valuation I'm not sure. basically about the same. But the half time is Gurley also did a similar

study and he found a slightly slower absorption to ephedra alkaloids from pills than from gel caps. it seems like a pretty good system. Now, I want to get into the extent of the literature. There's only a few reports that actually And So

deal with the adverse effect of ephedra products.

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the FDA has concluded, however, the literature on ephedrine and pseudoephedrine in medical products; for example those used in asthmatic preparations and so on. They also included the literature on PPA medical

products. Real quickly, these are the 11 articles that have been published pertaining to the ephedra products themselves. There's a fair amount of literature on

the ephedra -- I mean, the epinephrin, ephedrine and the pseudoephedrine which has also been prepared and available in the FDA's document. But, anyway, there

are only 11 journal reports involving 12 cases. Two serious events, one is a death and that

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was an athlete with existing cardiac pathology. the pathology has been there, according to the

But

pathologist, for a couple weeks and it was a necrosis with repair. There had been no exposure to the In

ephedra products within the prior 24 hours.

addition there were other risk factors which I have mentioned. So, therefore, the association with

ephedra product I think is really questionable. Second major case is a stroke and this was an infarct. The man was engaged in intensive body

building and he's consuming excessive amounts of many products in addition to the ephedra products. He also

had a congenital heart defect, patent frame in the

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valley, but it's a clear case of overdosing with many products and there are also the other risk factors. This is a list of the other papers in the literature on the ephedra products, not as serious, and one thing that does stand out, there were three

cases out of the five where there's a previous history of psychiatric conditions, whether the ephedra product had any role or nor in these cases is open to question. It would appear though that temporal

relationship a couple of those cases may have been related to dietary product. factors involved. On the two hypertension cases these were But there are other risk

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definitely related to overdosing.

In fact one of the

cases the individual had consumed in one does more than four times the daily allowance as recommended on the label. So it was strictly overdosing. Hepatitis, one case. It is not clear the

role of ephedrine alkaloids, in fact, the author said there's something in the dietary supplement that probably triggered this not necessarily ephedrine, but it could be some other product. One thing it did look On intulethias

like it was immune mediated hepatitis.

there was long-term, high does use, you see the levels there that's extremely high doses and the individual also had a diet high in protein and calcium, and

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acolytes, very low fluid intake. The other thing is, it is certainly related to ephedrine in this case since there was ephedrine and pseudoephedrine measured in the calculi. The last case is erythroderma. This

occurred about eight hours after the individual ingested Chinese herbs. There was a history of prior

sensitization and reactions to the over-the-counter alkaloid products ephedrine and pseudoephedrine In summary it's my opinion that the PPA literature is not relevant to this analysis of ephedra products the reasons for the reasons I have stated. Also, the few reported serious adverse effects from

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the injection of ephedra products were related to excessive consumption, the overdose are due to other risk factors. Thank you.

[Applause.] DR. PAGE: Karch. DR. KARCH: Steven Karch. San Francisco. Good afternoon. My name is I'd like to introduce Dr. Steven

I'm an assistant medical examiner in I'm a cardiac pathologist, my

principal interest is in the investigation of drugrelated deaths, my textbook on the subject is generally considered to be the standard text and it was quoted extensively in both the 1997 iteration and

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in the parent literature review. We're going to speak -- my comments are confined to cardiovascular complications of the ephedra alkaloids. The AERs will be discussed shortly by Professor Hutchinson. Briefly, he found no consistent

pathologic changes or any evidence that the epidemic or ephedra exposure was responsible for any of the deaths reported. My own review is consistent with his findings and I've have had the opportunity to examine several of the hearts of from these individuals, and my own review is that there is no consistency of

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clinical or pathological pathologic features apparent. Part C of the FDA docket is entitled review of published literature on toxic effects of ephedrine alkaloids and it deals mainly with purported cardiovascular and neurologic complications. It

contains 94 references of which 38 or 40 percent refer not at all to the primary literature, but only to meetings and textbooks. Of the 56 citations to the primary research literature almost all are the case reports none are the prospective studies; 12 of these were to pseudoephedrine amounting to 21 percent; 19 or 34 percent just about a third related to ephedrine and

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more than half, 24, were about phenylpropanolamine. It is clear from reading this document that the FDA considers all isomers of ephedrine to be equivalent both in terms of effects exerted and toxicity produced. This clearly is not the case and there are new fairly recent in vitro studies demonstrating, for example, that a naturally occurring 1R2S isomer has much greater affinity for beta one and beta two receptors than does synthetic pseudoephedrine and that conversely phenylpropanolamine has much less affinity. In spite of all these very clear differences at the molecular level the FDA relies so heavily on the

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phenylpropanolamine data to raise questions about the safety of ephedra and I feel that is inappropriate. In addition the FDA literature review contains a number of what I feel are simply misleading and/or simply mistaken conclusions. For example, the FDA says vasculitis with ephedrine is particularly likely when used in combination with the phenylpropanolamine or caffeine. However, the two citations offered in support are about cases where ephedra or ephedrine was not even ingested. The FDA says ephedra and phenylpropanolamine are listed as commonly abused, stimulant drugs, and

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the source if you track it down, is a 1994 textbook which in itself contains no reference for the statement. At the same time the FDA has chosen to

ignore the paucity of mentions in other documents like the household survey and so forth. The FDA literature review includes data which contradict some of its own conclusions. The FDA

says a significant increase in diastolic and systolic pressures occur in normal intensive subjects with oral doses of ephedrine equal to or greater than 60 milligrams. citation 82. The sole support for this statement is This statement is a paper, it's a review

paper and it discusses seven earlier studies that were

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done normal tensive individuals; half of whom showed no change whatsoever in blood pressure At the same time the FDA fails to mention a series of studies done by exercise physiologists which have demonstrated no blood pressure effect even with maximal exercise stress testing. I've listed some of these here for you, and you'll notice that not all of them are new, so I'm not sure why they weren't picked up and included. For

instance, Bright in 1981, gave 120 milligrams of pseudoephedrine to six healthy males and subjected them to submaximal stress testing. There was no

change in recovery time, there was no change in

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systolic pressure, there is no change in diastolic pressure, and there was no change in heart rate maximal heart rate or VO2mas. Clemens in 1993 did placebo trials these were double-blind, double dummy. Ten healthy women

exercising maximal exercise and I truly mean maximal. These are VO2maxes of up to 60, treated with pseudoephedrine, had no changes a recovery time, maximal pulse rate, diastolic or systolic blood pressure. In Dr. White's study published in 1997, variable effects were noticed in 12 volunteers given 20 milligrams of ephedrine, but in the half that did

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experience an increase in blood pressure, the increase was confined to 8 millimeters. And I'm hard-pressed

to believe that eight millimeter increase in systolic pressure not in diastolic was at all significant And, finally, and more recently is the paper by Rosanne in 1999 120 milligrams of pseudoephedrine every 12 hours to a group of, I think it was a dozen volunteers, healthy males. In a simulated

weightlessness, again, had zero affect on any measurable cardiovascular parameter. At the same time that these studies have been ignored through important papers on the effects of measured exercise that have not been mentioned

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either and I think their mission is wrong.

Some of

these are very convincing studies such as the paper by Bell and Jacob which appeared in Aviation and Space Medicine last year, the study involved nine healthy male, recreational runners, these were not professional athletes, they were just fit people who did what is called the Canadian Forces Warrior Test, which is something that's a part of the Canadian Army basic training. And these people ran a 3.2 kilometer

course wearing about 25 pounds of combat gear, they ran it with placebo, and they ran it after having taken 375 milligrams of caffeine and 75 milligrams of ephedrine. There was no change in systolic pressure

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there is no change diastolic blood pressure, there was no change in maximal pulse achieved, there was no change in recovery time, the only change achieved was they exercised longer. I find this particularly difficult to accept since I have an interesting cardiomyopathy. The FDA

says cardiomyopathy has been reported with use of ephedrine, and I think I might have cited as one of the sources. In fact there only four cases in the

world literature alleging a ephedrine cardiomyopathy. And you will note that the first was a 35-year-old man taking 400 milligrams of ephedrine per day and liberal doses of prednisone for 14 years.

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The second person was a 28-year-old 321pound, cigarette-smoking-woman who was taking two grams 2000 milligrams of ephedrine per day for eight years. And the third was another woman, I believe she was also overweight taking more than 1000 milligrams a day for ten years. The only other case, and I wouldn't have cited it, bit it is cited in the FDA document, refers to 14-year-old who developed heart failure after taking 225 milligrams of phenylpropanolamine in a suicide attempt. The FDA says that myocardia ischemia and

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infarction have been reported.

Well, yes, that's true

but seven of the eight citations offered are cases that involve phenylpropanolamine. And the one case

involving an ephedrine user was an ephedrine nose drop abuser who was taking ephedrine, six milligrams an hour, every hour, every day, for many months. Ephedrine and coronary spasms. Well, again

the FDA says cardiac damage may result from coronary artery spasms induced by stimulation of adrenergic receptors. This is clearly true; however, the two

citations offered in support both involve patients who been given high spinal anesthetics. One of them was a

former cocaine user and probably was a norepeneprine

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depleted, but be that as it may.

They were given high

spinal anesthetics which means the heart was deprived of its sympathetic enervation leaving the parasympathetic unopposed, leaving the Alpha effects of ephedrine to be magnified. There have been no

other reports of coronary spasms in ephedrine users besides these two. The relevance of this observation in anesthesiologists is quite apparent, but the relevance to consumers of food supplements is not. The FDA says shifting of potassium to skeletal muscle following use adrenergic agents like a ephedrine alkaloids may predispose certain individuals

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to cardiac dysrhythmias.

Three references are cited.

The first was an attempted suicide who took an unknown amount of pseudoephedrine, theophylline, and no toxicology was performed. The second referenced citation involves an attempted suicide who took 375 milligrams of ephedrine, 3000 milligrams of caffeine, that would be roughly 50 cans of caffeinated soft drink, and 750 milligrams of phenylpropanolamine. Why the potassium

shift should be attributed to a ephedrine in this instance escapes me. Lastly it was another attempted suicide who took an unknown amount of drug, and no toxicology

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testing was performed. Ephedrine and brain hemorrhage. The FDA

says a ephedrine and pseudoephedrine have been implicated in cerebrovascular accidents secondary to intercranial hemorrhage and vasculitis. Well, only

half of the events that were reported actually involved ephedrine. Most of those were overdoses that occurred in IV drug users and the diagnoses of vasculitis was histologically proved in only two, and one was taking phenylpropanolamine, the other a combination of ephedrine, caffeine and theophylline. One of the FDA citations No. 71 is actually a letter disputing the diagnoses of cellulitis made in

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reference No. 64. When it comes to the comments of the reviewers I feel they have not been as forthcoming as they might have been, and they may have overlooked some things that are important to considering the safety of these compounds. One of the FDA consultants

goes even farther than the FDA and -- which considers all the isomers to be identical and considers all sympathomimetic drugs to be the same, there is no other reason to explain the statement that ephedrine shortens the refractory period and facilitates the development of re-entry cardiac arrhythmias. There have been no published studies of the

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effects of ephedrine on the electrophysiology of the heart. So I don't really see how the statement could

have been included. Two of the FDA consultants believe that unpredictable variations in individual sensitivity may have caused reactions. One even argues that "we do

not know which specific enzymes in the bowel and liver metabolize ephedrine. Are there individuals who have

exaggerated sensitivity to ephedrine products before because they lack a specific P450 enzyme? have two comments to that. Well, I

The first is we already

know that ephedrine is not metabolized, so I don't see how genetic variation could fail to not metabolize it.

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And this morning we were told that the pharmacology of ephedrine was thoroughly well understood. Finally when it comes to individual risk

factors, variations of metabolism is unlikely for reasons already indicated. I think individual

susceptibility may however be possible due to the presence of undiagnosed medical disorders such as coronary artery disease or even hypertension. The same considerations of course would apply to caffeine and numerous over-the-counter drugs, and in fact FDA's own consultants states that quote "millions of people use products containing ephedrine, but the number of adverse reactions reported in the

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United States is now in the hundreds." In conclusion I believe that ephedrine recommended doses has not been shown to be cardiotoxic but in extremely excessive doses it is cardiotoxic and there's every reason to suppose it would. Ephedra and its isomer exhibit such different behavior as to make comparisons among ephedrine, pseudoephedrine, and phenylpropanolamine irrelevant. And, finally, patients with severe undiagnosed coronary artery disease taking recommended doses of ephedrine may be at risk, but they may also be ar risk from other very widely marketed products.

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Thank you for your time. [Applause.] DR. FARBER: Good afternoon and thank you,

Dr. Jones, and panel members for allowing me to address you. I am Theodore Farber and I have a slide

up here that just gives you something of my relevant background Ph.D. in pharmacology in 1960; 40 years of experience as a toxicologist; board certified as a toxicologist in first class of board certification. have been recertified four times over the last 20 years. I am a principal in toxic chemica International. Dr. Page is my partner and close I

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associate. I serve almost 24 years in federal government. The last four years of my service was as

director of the Health Effects division in EPA's pesticide program. Basically I was the chief health

scientists and chief toxicologist for a staff of 120 regulatory toxicologists, probably the largest group of regulatory toxicologist in the world, and was a member of the senior executives service. I had the pleasure of serving 19 years with Food and Drug Administration in many diverse positions, the last of which was as director of the Drug and Environmental Toxicology Division, Center for

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Veterinarian Medicine responsible for the approval of all drugs given to food producing animals here in America. Can we have the next slide please? I would just like to discuss -- mention and give you an overview of the 276 adverse affect reports that were released in March if this year. The normal basis or process for making a hazard evaluation or a risk assessment is a process that takes into consideration human epidemiology data, animal bioassay studies, mechanistic studies and pharmacokinetic data. You've already heard from Dr. Page and Dr.

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Karch something about the problems that they have found in terms of the literature support used by the FDA. I'd like to just discuss some of the aspects of

the reliability of the advance adverse affect reports. I and my colleague, Dr. Page, have recently evaluated 276 of these reports on products containing ma huang which has been assembled by Food and Drug. These reports are completely unfiltered and are largely made up of anecdotic accounts of adverse effects reported by a lay public Many of the AERs are reported into the system by secondhand parties. Let me state directly

right now that these AERs contain and are inadequate

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database for the purpose of causal analysis. And that Food and Drug, by using this deficient database has violated its own caveats in regards to the use of AERs for causality analysis. It's a busy slide and it represents quite a lot. All of the AER files that we have looked at many

of them have contained errors, omissions, inaccuracies, inconsistencies regarding the age and sex of the affected parties, the identity of the product, the identity of the ingredients in the product, the dose taken, dose frequency, and dose duration, as well as the adverse effects mentioned in the files.

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Some medical records were difficult to read because of the poor handwriting connected with medical records and/or the poor reproduction of those medical records. By combining the total number of AERs

lacking medical records with the number of AERs containing medical records, but lacking information on dose amount, dose frequency, and does duration we found at a bottom line of this file to slide that there were 202 AERs, approximately 73 percent of the file that were missing information for at least one data parameter considered to be essential for any legitimate causality analysis. This was not a good database and is simply

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not scientifically appropriate to perform a causality analysis on this database, and to make any regulatory decisions based on such an inadequate database. These 276 slides really are very, very similar to the files, the AERs that were issued in the original proposed rule period back in 1997. So they

are not really any significant improvement over what we have seen before. I said FDA has violated its own caveats. portions of the proposed rule docket there were innumerable places in the docket where these caveats were mention as official policy so to say of the agency and I've underlined the last two items. These In

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caveats mention that the accumulated case reports cannot be used to calculate incidents or estimates of product risk. And occurrence or incidence rates In

cannot be derived from AERs only reporting rates. using these AERs for causal analysis FDA has once again totally ignored its own disclaimers inserted into the index files of the AERs regarding inappropriate use of the database for causality analysis.

Very similar caveats can also be found in the current FDA AER web site. In spite of the misgivings that Dr. Page and I had in regards to the performance of the causal

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analysis on this kind of information we did perform our own analysis nonetheless. I'm sure that you're

not surprised, some of you, at least, are not surprised that our results were significantly different than the results of the FDA. I've put this slide up to show you another surprising piece of information that we picked up from the reports connected with the most recent release of AERs. What is surprising is that there was a

significant lack of concordance between FDA's causality analysis and the causality analysis performed by its outside experts who have expressed their concern about the safety of ephedra products

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this morning.

This slide demonstrates the lack of

concordance for some selected but representative AERs. An excessive and unacceptable level or degree of judgment and speculation is required for the use of these AERs for any causality analysis. obvious that not only from the considerable disagreement between Toxichemicer, our firm, and FDA and the causal causality rating, but also by the considerable disagreement between FDA and its own selected outside reviewers. There is a significant considerable lack of concordance with the causality ranking for AERs analyzed by Food and Drug and its outside experts. It is

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There was lack of concordance between FDA's opinion and its outside experts of 45 percent for AERs that Food and Drug rated as attributable. For the AERs

rated by Food and Drug as supportive, there was a 66 percent lack of concordance. In addition to good case reports a denominator of that is obtained from the treated group is needed for an additional further evaluation on the causality of these reports. We have a situation here

where the agency has provided only enumerator of questionable significance and reliability, has not made any effort to determine what the denominator is in the treated group, neither has the Agency made any

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effort to determine what the nominator and the denominator is in the untreated group, has gone through a similar exercise as that performed and mention by Dr. Kimmel this afternoon. Further, it's interesting to note that when aspertane was first approved by Food and Drug many years ago, over 5,000 AERs were reported into the agency. FDA stated that the AER system was unreliable

and took no action against aspartame. Indeed the AERs compiled by FDA do not support any causal connection between consumption of ephedra products and other serious illnesses or injuries. Even assuming these reports were all

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accurate and they are clearly not, there are only approximately 1,200 reports in this file compared to a conservative estimate of consumption levels equal to many billions of servings of ephedra products since 1994. In particular there's little evidence in this AER file that alleged deaths, strokes, heart attacks, psychotic episodes, and other serious adverse effects occur more often in individuals who conceive ephedra products than those who do not. Further, any

of serious adverse effects seen in the entire AER file are more likely the result of pre-existing medical conditions, drug abuse, excessive exercise, or

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concomitant use of medications and other substances whose use was recommended against on the product labeling. Finally it is interesting to note that in an internal FDA memo from staffers in Dr. Betz's unit at Food and Drug, these staffers have concluded quote, "that it is possible that the reported serious adverse effects in all of the AERs are reflective of the coincidental background of spontaneous occurrence in the population and are not causally related to the use ephedra products." In conclusion the use of AERs to determine causality requires considerable judgmental evaluation.

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The majority -- the great majority of AERs lack a level of detail and are missing key data that are needed for an adequate scientific evaluation. experts in hazard evaluation and risk assessment cannot agree on causality due to the unreliable and incomplete data in these AERs. FDA should heed its Even

own expressed concern with the unwarranted use of AERs for causality analysis. And lastly the AERs related

to ephedrine alkaloid-containing dietary supplements, if anything, support the conclusion that they are safe; that is, there is no unreasonable risk when they are used according to label instructions. Thank you very much.

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[Applause.] DR. HUTCHINS: My name is Grover Hutchins,

I'm an anatomic pathologist and as you can see from the slide I got my a medical degree in 1961, did training in anatomic pathology at the John Hopkins Hospital. I have been on the staff of that

institution for over 30 years and I'm currently a professor of pathology on the active staff at Hopkins. My activities are primarily related to the autopsy service and I do service teaching and research work in particularly heart, lung, pediatric diseases mainly based on the autopsy pathology. I am certified in anatomic pathology and

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also in pediatric pathology. I have been asked to review 22 adverse event reports where a death had occurred thought to be in association with the consumption of ephedrine alkaloids. For each case I examined the record for

the likely cause of death and attempted to correlate the clinical and pathologic information available in the AER to determine the most probable cause of death. The determination of causes of death is a routine component of autopsy practice in our institution and I applied the same reproach here using the various levels of information that were available in the various cases.

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For the group as a whole I sought for likely consistent pathologies that could account for the death and with particularly looking for some likelihood that there was any causal role for ephedrine alkaloids in the outcome. As you'll see

from the results that I'll present here, I do not find such consistency in this information. The available information in these reports were really quite variable. Six of those that I

reviewed consisted of only of one or two pages of information. pages. length. One report was quite thorough, 230

The remainder were of some intermediate Among the 22 deaths, ten were in women, 12

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were in man; the average age 35 years with a range from five days to 59 years, most were in the third, fourth, and fifth decades of life. cases had an autopsy done. Thirteen of the

This was not the case in

seven and the information was inadequate in two to determine whether or not the autopsy had been performed. The exposure to ephedrine alkaloids was well documented in 12 of the cases; that is, and I'm referring here to exposure sometime in close proximity to the death of a patient. This information was

uncertain the in ten of the cases. Toxicology specifically for ephedrine

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alkaloids was positive in four of the cases, negative in ten, and not done in eight. The cases divided up into some general categories, and I'll show a series of slides which illustrate these. The first are four deaths that were The

to me explained by congenital cardiac problems.

first three of these were individuals who had suffered a sudden collapse and were found at autopsy to have an underlying problem which was perfectly capable of having caused their demise. These involved a disorder of the myocardium, asymmetrical hypertrophy a malformation of the coronary arteries, an abnormal origin of the left

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coronary artery and an abnormality of the mitral valve. The fourth case that I included on this list was signed out on the report as simply been congenital cardiomyopathy. interpretation. I do not know the basis for that I do not know if an autopsy was

performed, but I have included here in any case since that was the extent of information. Three of the

deaths were explain by coronary disease. In two of these patients, the first and third here, an autopsy was done demonstrated significant coronary artery arthrosclerosis obstructing the vessels. The second patient had

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symptoms in risk factors which were totally consistent with coronary artery disease, however, an autopsy was not performed. Each of these patients had taken the

ephedrine alkaloids for a varying periods, but in my view the deaths here were explained adequately by the presence of symptoms and findings of coronary artery disease. In two instances autopsy demonstrated the presence of myocarditis in the heart. This is an

inflammatory reaction in the myocardium usually of unknown cause. The one case had taken materials for

about a month and other case for one day and did have a positive toxicity, however, since myocarditis is a

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very well-recognized caused of sudden unexpected deaths, it seems more appropriate to attribute the outcome to that. Four of the cases were explained by cerebral vascular disease. autopsy performed. very unclear. None of these individuals had an The information on exposure was

Two of them, the ones at the bottom

were the 12 most probably hypertensive hemorrhages in the context of pre-existing hemorrhage. One, the

second an intercranial aneurysm and the first a carotid occlusion of unknown cause. Two of the deaths were explained by aortic dissections. This is a tearing of the wall of the

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aorta, typically occurs in the context of some abnormality in the structure of the aortic wall and is in many instances has a familial basis. The fact that in the first case the aorta was found to be dilated and the second case there was a very strong family history of aortic dissection. It

seems far more probable that this is that genetic form of weakening of the connective tissues of the aorta that predisposes to dissection. These were both discovered at autopsy, however, exposure to ephedrine alkaloids was unclear in those cases. There were to me a interesting group

of cases, unfortunate outcomes of individuals who were

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doing very strenuous fasting and exercise and exposure to high temperatures in the first two cases listed their the death in the first case was related to a hypothermia to 108 degrees, which is really phenomenally high. He had not been exposed to the

agents for at least two months prior to his death. The other two cases the deaths were due to radnomyalysis which is a breakdown of muscle in the context of extreme exercise. Again, there was one

indication of bile that was positive for the agent. Blood was negative, and in the other case there had been historical information of exposure, but no toxicology was done.

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There are two sort of odd deaths, if you will, in a sense a five-day old premature child died of necrotizing enterocolitis, this is an entity of uncertain cause associative with prematurity and with the early feeding. It probably has at least in part The exposure here was

and infectious etiology.

related to maternal intake of ephedrine alkaloids and the connection to my view is kind of unclear. The other case the clinical information was scant. I have characterized as with the flu-like The

illness because there were pulmonary symptoms.

individual also had symptoms that could have been related to cardiac problems that had been going on for

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some days.

She had stopped exposure a week before the

death and no autopsy was performed. The final category are two explained deaths despite careful autopsy it was not possible to arrive at a conclusion as to what the cause of death was in these individuals. Both have had exposure to the

agents and these, in my view, remain in that category of unexplained outcomes. In summary among the 22 AERs that I reviewed, explanations for death were found in 20 of the cases; these were all well-recognized causes of death in the general population albeit some are rather uncommon others common. In the two cases where the

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cause of death was unexplained and this is an incidence that is consistent with general experience with autopsies if you really look at your information critically you really don't understand in some cases why the individual has died. In conclusion I found no consistency of clinical or pathologic features in the group of cases, nor was there evidence to show that exposure to ephedrine alkaloids was a contributing or causative factor in the death from my perspective. It is only in the two unexplained deaths the use of ephedrine alkaloids could be a speculative explanation for that outcome.

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Thank you. [Applause.] DR. HUTCHINS: speak. DR. OLNEY: I'm John Olney, Professor of Dr. John Olney will now

Psychiatry and Neuropathology at Washington University in St. Louis. I have 30 years' clinical experience as

director of the psychiatry consultation service at Washington University and a thirty-year research program in the neuroscience funded by five different divisions of NIH as are listed there For research focusing on stroke, perinatal brain damage, epilepsy, head trauma, Alzheimer's

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disease, schizophrenia, drug addiction, and fetal alcohol syndrome. I have also conducted food toxicology research. Thirty years ago I discovered that

monosodium glutamate, MSG, a widely used flavor additive destroys nerve cells in the immature hyperthalmus or brain. Twenty years ago I discovered that the artificial sweetener NutraSweet also has the same neurotoxic properties. And I have also published

evidence potentially linking NutraSweet ingestion to an increased incidence of malignant brain tumors. I've received several awards, one of them

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listed there from NIMH, that's the National Institutes of Mental Health. career scientist. That was to perform research as a That award has been renewed every And I've received

five years for the last 30 years.

other honorary awards and elected member to the National Academy of Sciences. Why am I here? I'm serving as a consultant Specifically they

to the Ephedra Education Council.

ask me to evaluate evidence pertaining to the potential of ephedrine alkaloids to cause or contribute to neurological or psychiatric disorders. The evidence I've examined includes the adverse event reports putatively linking ephedrine

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alkaloids to nervous systems disturbances including all of the adverse event reports review for FDA by outside consultants. Drs. Ricaurte and Stoll from also have examined the world literature pertaining to the effects of ephedrine alkaloids on the nervous system of humans or experimental animals. Concerning the adverse event reports, FDA identified 28 adverse event reports pertaining to the nervous system. However, FDA disqualified 12 of these

reports because they provided insufficient information. Nevertheless FDA submitted all 28

reports to two outside consultants, Drs. Ricaurte and

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Stoll and asked them to rate each report in terms of how strongly it links of ephedrine alkaloids to an adverse event. Doctors Ricaurte and Stoll found only two cases that they agreed were strongly linked to ephedrine alkaloid ingestion. Remarkably both of

these cases were among those that FDA had already disqualified due to insufficient information. This

signifies that FDA and their two expert consultants have not identified a single adverse event report that they can agree closely links ephedrine alkaloids to adverse nervous system effects. In a cover letter to FDA, Dr. Ricaurte

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stated that ephedrine alkaloids pose a health risk. But the risk he identified pertains not to the general public, but to specific individuals who have a predisposition to certain illnesses or who ingest ephedrine alkaloids and/or other stimulants in abusive doses. This places ephedrine alkaloids in the same

category as sodium chloride, or common table salt, which poses a health risk not to the general public but to individuals who are predisposed to high blood pressure or certain kidney and heart diseases. There are many such food-related substances that FDA considers so harmless for the general public that they require and are given no regulatory

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attention. Concerning the world literature, the most reliable evidence comes from randomized, placebocontrolled, human trials that demonstrate that the industry recommended dosage of ephedrine is 25 milligrams taken not to exceed four times per day is not associated with a significantly higher incidence of adverse nervous system effects compared to placebocontrolled. Concerning animal studies, they do not demonstrate a neurotoxic action of ephedrine unless administered at doses that would be considered massively abusive in a human context.

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If one wishes to discuss the studies by Dr. Ricaurte that he referred to in squirrel monkeys we could perhaps discuss the doses used in that study later on. Concerning the FDA position, it is not clear to me what position FDA espouses, but FDA appears to believe that dietary supplements containing ephedrine alkaloids are hazardous to the public health. I will share with you my observations regarding this apparent FDA position. the FDA position is self-contradictory. It appears that For many

years ephedrine and its analogs have been marketed as over-the-counter drugs -- several decades, and FDA has

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shown no concern about the adverse effect potential or abuse potential of these agents even when consumed together with various sources of caffeine and large amounts of caffeine from coffee, tea, caffeinated soft drinks, and so forth. The logical conclusion arguing from this FDA precedent is that FDA does not really believe that ephedrine either alone or in combination with caffeine poses a public health hazard. If they did believe

that they would have already been trying to develop more stringent regulatory control for the use of overthe-counter ephedrine drugs together with these various sources and heavy intake of caffeine.

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The FDA position does not seem to be substantiated by evidence. If FDA believes that

ephedrine alkaloids when consumed in reasonable doses in reasonable doses or hazardous for the nervous system; this belief is not supported by a single adverse event report. FDA and two expert consultants

could not identify any adverse event report pertaining to the nervous system that they could agree was strongly linked to ephedrine alkaloid consumption. So

that FDA position is not supported by a single adverse event report. It's not supported by the world

literature and it's not supported by the FDA precedent. In fact it contradicts FDA precedent.

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Now, I want to say a word about health protection standards. First I will discuss AHPA

standards AHPA being the American Herbal Products Association. AHPA has developed a sound health

protection standards -- set of health protection standards including responsible label practices which is enforces upon its membership. For example, AHPA sets doses limitations for ephedra products not to exceed 25 milligrams of ephedrine per serving, four servings per day, and AHPA recommends that individuals with high blood pressure, heart disease, or various other illnesses consult with their physician before using a ephedra products.

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These are sound recommendations simply because its best to err on the side of cautiousness and on the side of consumer protection. I want to compare AHPA and FDA standards using a couple of examples. Table salt is hazardous

for individuals with high blood pressure, but FDA allows table salt to be sold in bulk or added to processed foods without warning labels. Ephedra

products if used in doses recommended by AHPA, appear to have little or no effect on blood pressure. Nevertheless, AHPA warns individuals with high blood pressure to consult their physician before using ephedra products.

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Caffeine, a known stimulant, is present in high concentrations in many products: coffee, tea,

caffeinated soft drinks, and so forth, and is ingested chronically, in large amounts, by millions, tens of millions of consumers, some of whom are in this room. There's no proof that ephedrine alkaloids are less safe than caffeine, but AHPA recommends that ephedra products be used in restricted doses, whereas, FDA does not attempt to restrict the public consumption of coffee, tea, or caffeinated soft drinks. These are very simple examples that I've used to set the stage for making the point that AHPA seems to be taking a responsible approach. So that

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you fully understand where I'm coming from, let me mention that over the years I've been critical of FDA for their failure to require adequate warning labels on foods that contain additives that have potentially toxic side effects. It has not been table salt and caffeine that have been the subject of my concern. It is substances

like monosodium glutamate substances that are toxic to the immature brain, and these are substances that FDA allows to be added to foods in any amounts and fed to infants and children without any warning labels at all. It is my belief that food products should be

regulated very carefully, and I don't care personally

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whether the regulation is done by FDA or by the industry itself. But I do want to the regulations to

be responsible from a consumer protection standpoint, and to be effective. Let me close by saying that based on all of the evidence that I have examined and based on standards that are more strict than FDA ordinarily requires, I consider it reasonably reasonable to conclude that ephedrine alkaloids contained in dietary supplements are safe if used in doses recommended by AHPA and if used in keeping with all other APHArecommended label instructions. And I might add that

if FDA and APHA or other similar organizations could

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get together and draft some regulations similar to the guidelines already being followed by AHPA it seems to me that that would be a gigantic step forward. Thank you. [Applause.] MR. ADAMS: Edgar Adams. Good afternoon. My name is

I'm a senior vice president at Harris

Interactive and I was asked to review some of the data on the abuse liability of ephedra -- products containing ephedrine alkaloids because in several of the reports by FDA and their outside consultants references have been made to abuse liability and addiction. And in one of the reports a typical

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addiction case is actually referenced. I am currently senior vice president for clinical research at Harris Interactive. Many of you

have probably not heard of us, we conduct the Harris Poll which you probably have heard of. I'm a principal investigator, I study investigated abuse liability of tramadol verses -- and hydrocodone in over 11,000 subjects. And also current

principal investigator on a study looking at the abuse liability of nicotine replacement therapies in over 1,300 subjects. Previously I spent 23 years actually 23 years five months in the United States Public Health

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Service and was director of the division of epidemiology and prevention research at the National Institute on Drug Abuse. There, among other things, I was responsible for the drug abuse warning network which is a measure of consequences and not prevalence associated with various medications and other drugs of abuse such heroine, methamphetamine, et cetera. I was also responsible for the household survey and served as an advisor to the Pompidou Group of the Council Europe as a expert in drug abuse epidemiology. As you can see, my educational background is

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pharmacy, pharmacology, and I have a degree in health policy evaluation and management. I reviewed cases that were possibly associated to what abuse independence and misuse including the two cases that were included in the insufficient data group because of intentional misuse or abuse. And to the extent possible I compared the

information in the reports to the diagnostic and statistical manual of the American Psychiatric Association for abuse and dependence. I also looked

at the data from the drug abuse warning network from 1989 through 1998. Now, before I show the data let me review

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some definition, and these are definitions of part the harmonization between the World Health Organization and tbe diagnostic and statistical manual. Misuse is usually identified as repeated use of a drug for nontherapeutic purposes. An obvious

example is the use of a nicotine replacement therapy to avoid smoking regulations such as smoking on a plane. Abuse or the WHO classification, harmful use refers to repeated misuse that causes damage to health or problems in social, occupational activities, or other legal obligations. The key here is the there is

repeated use and there is an impact on obligations or

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developments of other problems. Dependence. In both ICD10 and the DSM4

Manual focuses on the loss of control over the use of a drug including consequences. While it includes

tolerance and dependence neither is necessary or sufficient. Withdrawal refers to a time-limited syndrome that occurs in concentrations of use and which symptoms that are clinically or functionally significant. Everybody recognizes that heroin causes

withdrawal but so do many other drugs including steroids tricyclic antidepressants. The DSM4 criteria for substance abuse

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basically is one of these four criteria, and, again, as I outlined -- I'm not going to go through each one -- but you can see they all require recurrent substance abuse and either failure to make obligations which are used in situations which are haphazard, legal problems such as being arrested for substancerelated or disorderly conduct, or driving while intoxicated, and continued substance abuse despite having persistent or recurrent social or interpersonal problems such as fights with spouse. B says you cannot be an abuse if you've ever been diagnosed for dependence for this class of substance. The criteria for substance dependence

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require three of the following:

no tolerance or

withdrawal are there, basically taking larger amounts to get the same effect, withdrawal, the substance taken in larger amounts over a longer period of time that was intended, a persistent desire or unsuccessful efforts to cut down or control substance use, a great deal of time spent in activities necessary to obtain the substance, uses substance or recover from its effects, important social occupational or recreational activities given up or reduced because of substance use, and use despite continued knowledge of having persistent or recurring physical problems, such as an ulcer made worse by drinking.

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I am not going to try to discuss this slide. I realize it is busy. things. All I wanted to show is two

One, I looked at the products that were being

taken; age, sex, weight, reason for use, the dose that was taken, the duration, of use, the content, whether it had ma huang, ephedrine, caffeine, et cetera; whether or not the person was hospitalized; what the adverse events that were described were and what the outcome was. You can see a lot of missing data up there. I picked one case. This is case 11918 which is

actually the case that is cited in one of the expert reports as being a typical case of addiction. If I

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didn't note it, let me note it now, while we often refer to as drug addiction, in the clinical sense there's no such thing as addiction. You will note that the WHO and DSM criteria did not have the word "addiction." dependence. It's usually

And when people think of addiction they But the

typically think of compulsive use.

appropriate clinical term is "dependence." The product used in his case was Be Thin Again. It was a 38-year-old female taking the product She wanted to lose weight for

for weight loss. wedding.

When she bought the product she was told the

five tablets a day which was the maximum recommended

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dose would be safe.

It was suggested that she take

three tablets per day, which she did, then later on she began to lose weight less slowly -- or less rapidly, I'm sorry, and went up to five tablets per day again on recommendation. That recommendation, by I'm

the way, it's unclear where it came from.

assuming it came from where she bought the product She took the product for 19 months it did contain ma huang, she was not hospitalized, she did experience mood changes, became argumentative, and abusive. When she recognizes it happening, she stops

taking the medication; there's no indication in her own letter whether or not she had problems too stop

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taking this.

She did state that she felt addicted to

the drug and that's why she stopped taking it. Again, these are the cases. to go through them all. I am not going

However, it would appear that

by the criteria listed in the DSM4 that this woman, which is the third case here, was in fact abusing the drug. She did take it after she began having fights So

with her husband and abusive arguments, et cetera. it would appear that she was abusing drugs. She was

taking it for a longtime and was experiencing some of the side effects associated with long-term use of sympathomimetic. Case 12837 technically is not an abuser. He

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said that he began using the medication and resumed cocaine use. So he became a cocaine dependent, and

based on criteria he would not be considered an abuser here, The first two cases which I won't discuss other than to note that that all the no -- are the two cases that were thrown out by FDA as abuse or misuse. Essentially they were overdoses, one of which was an intentional overdose. The next thing I want to talk about is Dawn. Essentially Dawn was set up to look at the consequences associated with drug abuse, to monitor pattern of trends of new abuse entities. For example,

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in the 80s tees and blues followed using the Dawn system. In Dawn drug abuse is defined as the use of

prescription drugs in a manner inconsistent with acceptable medical practice; the use of over-thecounter drugs contrary to approve labeling. In other

words if it says take an aspirin twice, four times a day, and you take three aspirin or four aspirin then that technically meets the criteria for abuse in Dawn. And the use any of other substance, heroin, cocaine, marijuana typically abuse drugs for psychic effect, dependence, or suicide And these are the third piece there of what really Dawn is most useful for, for a variety of

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reasons.

There is one other comment.

Suicide the

intentional overdose is not a symptom of drug abuse. It is not part of any other diagnostic criteria and should be excluded from Dawn data anytime that you look at the data for abuse concerns. Other psychic effects which is part of another definition is use of a drug to improve or enhance any mental emotional or physical state, and these are actually reduced pain, stay awake, relax, help study, et cetera, from the Dawn report. Three points here. One is, you can see

that's there was an increase -- these are ephedrine episodes in Dawn, 1989 to 1998. You can see that

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there was an increase in the mid-90s and then a decrease in the last two years, basically roughly by 50 percent. You can see that in terms of all the evidence of Dawn these average around 0.2 percent; clearly less than 0.5 cents percent of all mentions, usually about a third are in combination with alcohol which could account for some problems. Essentially the Dawn data are now projected to estimate the number of cases that might occur in all the hospitals in the United States that have emergency rooms, which is between three or 4,000 with all the consolidations it's hard to know; but

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essentially you can see if you look at 1989 that the weighting factor for drugs like ephedrine and other typical over-the-counter products is somewhere between 8 and 10. So that 1,119 is based on about 120 to 150 The key

reports in the hospitals that report to Dawn.

is that despite the increase in use of the products, the consequences associated with use, at least measured by the drug abuse warning network, seemed to be decreasing. To reiterate, the number of mentions of ephedrine in Dawn have decreased substantially, by 50 percent in last two years. Reported ephedrine Dawn

cases are likely to have been attempted suicide, in

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fact, more than half are attempted suicide.

And in

comparison, other over-the-counter medications the same indication. You can see that acetaminophen

accounts 32,000 episodes, ibuprofen 17,000, et cetera. So, in conclusion on this piece the Dawn data suggested a decline in consequences associated with ephedrine. The majority of the consequences

associated with suicide attempts which were inappropriate in looking at abuse. Finally, it would appear that based on the adverse events there is not a significant -- I see the red light going off, this is last slide. There's not a significant evidence of

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widespread abuse of the product.

And in fact a

meeting held on the sole issue of abuse in 1999, reached essentially the same conclusion, and that was basically backed by the federal government's nonsupport of international scheduling and these consequences are reenforced by the millions Americans that use these products apparently without consequence. If there were significant problems you would expect to see the Dawn data and other indicators increasing substantially. Thank you. [Applause.]

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DR. JONES:

Thank you Dr. Adams, and to the

panel, again, for respecting time and keeping things concise and to the point. Let me turn to my colleagues for questions, Dr. Salive. DR. SALIVE: Marcel Salive, NIH. You reviewed all the

I have a question.

case reports and I understood the comment about possible role of coincidental effects in these cases and I wanted to ask about positive rechallenge, whether any -- there are some cases cited in the FDA report where the adverse event occurs with the use the product, the product is stopped and then product is

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readminister and the same sort of symptoms reoccur. won't ask the pathologists about this, only the clinicians but were their cases of that? I believe there were some dermatologic and possibly cardiology. DR. FARBER:

I

What you're talking about is a

fundamental set down by Coke many, many decades ago, and, yes, there were some cases but very, very few. DR. KIMMEL: I'm sure we have the number

somewhere I do not think anyone has them off the top of their head. DR. SALIVE: But would I be correct to say

those might be less likely due to chance? DR. KIMMEL: I think that certainly is a

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reasonable assumption. DR. FARBER: I the in the analysis that we

did when there was a dechallenge to rechallenge we probably gave that AER a high probability. DR. KIMMEL: DR. FARBER: them. DR. KIMMEL: It a small number. The problem The problem with -Frankly, there weren't many of

with dechallenge of course alone which was a much larger number is, for adverse events like MIs and strokes, the fact that you don't have another -- there is with dechallenge from an MI. don't think. So it's hard and I

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DR. SALIVE:

The challenge from the product

is what I was speaking of. DR. KIMMELL: Right. But if you stop the

products and then don't have another MI, does that mean that the product was the MI. I mean, in other

words, for those types of acute events that happen in isolation at a particular time, I think obviously dechallenge is not particular helpful. And I don't

know of any cases of rechallenge of recurrent MI or strokes. DR. JONES: DR. FARBER: Dr. Farber. Page points out to me that in

most of those dechallenge/rechallenge situations it

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was generally an allergic phenomena that was reported in the AER. DR. JONES: Dr. Burstein. Aaron Burstein, Clinical

DR. BURSTEIN: Center at NIH.

I have a question for Dr. Page

regarding some of the kinetic you presented, specifically the study of White and colleagues. Could

you just clarify for me the specific product that was tested because I know that some of the studies have looked at single entity products versus products that also contain herbal therapies that contain caffeine some of the kinetics may differ depending on the product.

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DR. PAGE: study. Okay.

Right.

Let me get my data on the

The White study did pertain to the use It was the

of a dietary supplement ma huang. commercial product called ma huang.

DR. BURSTEIN:

I believe that the authors in

that study refer to it as a single entity product in the same group, later goes on to study combination products with caffeine. DR. PAGE: That's correct. So, I think that is important

DR. BURSTEIN:

to point out that that slow absorption rate has only been documented for the single entity product and when

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you administer these products with caffeine the hypothesis is that the caffeine actually speeds to rate of absorption such that there's really no difference between those combination products and synthetic ephedrine. DR. PAGE: You probably are right. That's We really

the reason I didn't really emphasize it. know that much about the absorption.

So I think call

them all the same is probably a conservative approach on it.

DR. JONES: DR. SCHWETZ:

Dr. Schwetz. I have three questions, two

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quick ones for Dr. Hutchins. selected for your review?

How were the 22 deaths

And are the results of your

analysis published or reported someplace that they could be put into the record? DR. HUTCHINS: The 22 deaths were included

in that whole group of AERs that we reviewed and were selected from that. DR. KIMMEL: was in March of '97. DR. FARBER: The 22 deaths were the total I think they came from -- it

deaths in the 276 AERs reported out about Food in Drug in March of this year. They were not selected, they

were the total number of deaths in the AERS.

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DR. SCHWETZ:

Yeah, I thought I remembered

the number 7 deaths from the information this morning. Are those seven that were referred to this morning among these 22? DR. HUTCHINS: It would be my assumption

that they were, but I do not know for sure. DR. KIMMEL: It was all deaths included I don't recall

since March 1997, if I'm correct.

specific I recall seven in which the reviewer felt that they were attributable amongst all deaths. We

didn't look at just the attributable, we looked at all -- all deaths that were provided by FDA from March '97, in fact, I think it went all the way through

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1999. DR. SCHWETZ: And my other question is

whether not there is more information that can be submitted to the record regarding your evaluation of these death records? DR. HUTCHINS: I have written a brief report I haven't

on the first 11 cases that I looked at.

completed that for the next 11, but I would be happy to submit that in a few days. DR. SCHWETZ: I have one other question that Thank you Dr.

has to do with the denominator. Hutchins.

Several people have made reference to the

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fact that there are several billion servings per year but how does that translates into the denominator? DR. KIMMEL: The calculation was done on the

basis of the data in the survey which has been submitted to the docket was total number of servings plus we were able to calculate average serving sizes an average servings per day. So, we could essentially

assuming normal use, assuming use according to directions, we calculated the average person time. And I can show you details if you would like, but it's an estimate of person time from person days. DR. SCHWETZ: I don't need to know but I'd

like to see it if you have it for the record so that

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you can calculate how many people are one-time users how many people are multi-time users, what else do they use? DR. KIMMEL: at all. You can't tell that from this

This is purely an estimate of number of

person days exposed based on total exposure and total doses and amount of dose per day. It is just like you

would use prescription records for a prescription drug in doing the same type of assessment with AERs where they try to estimate the number of events or number of prescriptions written. There is no individual patient level data or person level data. There's not information on time

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and duration, so we can's assess that all.

This is

purely a one slice total amount of exposure over the 22 months as the denominator with the number of events in those 22 month periods as the numerator. DR. JONES: follow-up question? DR. PHILEN: DR. JONES: No. No? Okay. I comment AHPA Dr. Philen, did you have a

One question then from me.

for taking some effort toward labeling dosing recommendations and so forth. I wanted to know what

the basis was for the 25 milligrams, four times a day, recommendation, is that drawn from related compounds,

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has there been a controlled clinical trial, dosing studies done in that respect? AUDIENCE PARTICIPANT: If you please, I'm

council to the Ephedra Committee of AHPA, and that is actually kind of a legal question rather that a scientific question. I helped put the panel together

and I know they probably don't know the answer to that question because it was done several years ago. know that Michael McGuffin, President of AHPA, is going to talk tomorrow, and I would respectfully request we wait until he talks, he can address that issue. DR. KIMMEL: But I can give you a little I

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information from hot scientific standpoint in terms of my interpretation of this being reasonable. Over-the-

counter ephedrine is 25 milligrams up to six times a day, total dose of 150 milligrams. total ephedrine alkaloids. This is last in

In addition Dr. -- I'm Enchiosa, who wrote

sorry if I pronounce it wrong --

a report for FDA did comment that the relative potency for instance of pseudoephedrine is less than ephedrine and she actually gives an example, and I don't remember which product it was, but if you add up total ephedrine alkaloids in the product it was 34 milligrams, but the ephedrine equivalent of nd overthe-counter product would be 11.75. So at least my

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personal feeling is that this is not as high in fact essentially lower than the over-the-counter products. So for my own sort of personal clinical point I think it's total reasoning. DR. JONES: That is really my reason for

asking is, was it drawn from those sorts of data as well as evidence. Other questions from the panel? [No response.] DR. JONES: Questions from the floor?

Please come to the microphone and identify yourself please. MR. REINHART: Yes, Jeffrey Reinhart, People

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for Pure Foods.

I have a question for Dr. Schwetz. The panel that is presenting is

DR. JONES:

the panel to which you should address your questions unless Dr. Schwetz's question is not clear and you would like him to restate his question. The

information presented by the panel as part of the meeting is where we would specifically like to seek clarity. MR. REINHART: Looking for clarity, has your

group done, or do you intend to do any formal rigorous meta analysis of peer reviewed published literature? It seems that meta analysis criteria are appropriate here.

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DR. KIMMEL: meta analysis.

I can speak to the method of

Per case series I would call it a Meta

summary, there's nothing to meta analyze per se.

analysis really are applicable to randomized trials. MR. REINHART: DR. KIMMEL: So you need double blinds. We did -- one of our consensus

statements is that there should be considerations for other studies. If DHHS and NIH and others feel that

some types of summary estimates are, for lack of a better term meta analysis would be helpful I think that would be worth a trial, although I would caution that I think meta analysis for case series or essentially useless.

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MR. REINHART:

Backing up from meta analysis

could, you characterize your method of analysis within the context of the FDA's Doctor nonsignificant scientific agreement? those criteria? DR. KIMMEL: Could you restate the question? Would you say you for fulfilled

I'm not quite sure I understand it? MR. REINHART: Did your analysis fulfill or

come reasonably close to the FDA's doctrine of significant scientific agreement? DR. KIMMEL: I'm not sure which analysis and

I'm not sure what FDA says is the definition of significant scientific agreement so I can't answer

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maybe someone else on the panel can.

I was not aware

that there is a definition of "significant scientific agreement." MR. REINHART: DR. JONES: Thank you.

Next question, please. Adriane Fugh-Berman, There are a number

MS. FUGH-BERMAN:

National Women's Health Network.

of reports and in the medical literature that were not included in the analyses I have seen this afternoon. But I'm particularly curious about one case that was left out of the Dr. Karch's report on cardiomyopathies. And I was wondering, Dr. Karch, why

you left out to the case of the 23-year-old that was

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published by Thiaharates which I know you're familiar with since you wrote a letter to the editor about it. DR. KARCH: a cardiomyopathy. Well, I left it because it's not I

It is a florid myocarditis.

finally got a chance to examine the slides and to any cardiac pathologist who has seen them is pretty clear, and I've shown them to other cardiac pathologists. It's garden variety myocarditis, and that's not cardiomyopathy and that's why it's not included with the list, in spite of Dr. Theohardies paper and, of course, he's not a cardiac pathologist. MS. FUGH-BERMAN: Right, but it had been And I would like to

shown to a cardiac pathologist.

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correct the former speaker.

I believe it was Dr. Page

referring to the same case, that 23-year-old did not have a history of cardiac disease. And I have the

report with me if you care to see it. DR. PAGE: Well, I would just indicate that

I have reviewed the medical records, and a I don't think you're right, but I'd be happy to take a look at what you've got to offer. I did have that listed, by the way, as my number one case as you probably saw. DR. FARBER: aspect about that case. There's another interesting When the Food and Drug

investigator went into the young men's apartment to

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try to pick up samples, the only open bottle that he found, and we maybe sort of logically assumed that that was the bottle that he was using at or somewhat before his death that that sample was taken off by a Food and Drug investigator and analyzed and shown to only contain pseudoephedrine and not ephedrine whatsoever. And this is described as an ephedrine-

related death, calculations are made by the professor from Tufts in regards to some very almost negligible or almost insignificant levels found in the urine of ephedrine, pseudoephedrine was not found in the urine. One wonders where the ephedrine is coming from in that particular urine sample. It is an interesting case.

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MS. FUGH-BERMAN: here.

I admit to being confused

The product that was implicated was Twinlabs

Ripped Fuel which his sister said he had been taking once or twice a day in recommended dosages. the product that you're saying contains pseudoephedrine and not ephedrine? DR. FARBER: It's in the AER record. It's Is that

plain and simple, the sample was picked up and analyzed any it didn't contain any ephedrine. this analysis was done by Food and Drug. DR. PAGE: It sounds like we're talking And

about two different cases, but the one I'm thinking about there definitely was information in the records

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as to an existing cardiopathology of one to two weeks duration. DR. KIMMEL: A lot of this, as well as the

disagreements here points to the whole issue of the use of AERs for assessing causality and the lack of denominator data, and the lack of consideration of background risk you end up going in circles. And if

you truly believe that something causes an outcome and you collect cases all of whom were exposed, you will believe there's an association, and you certainly could be right, but you also can be wrong and there are plenty of those examples where the AER system has not been accurate in terms of that.

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So, I think part of the issue of the debate here is that you need other data. DR. JONES: DR. KARCH: Thank you. And the appearance of that

association is somewhat flustered by selective literature citation. The person in the audience knew

that I had responded to the case report pointing out that description of the anatomic changes was inconsistent, but that never got included in the FDA literature summary. DR. JONES: question. DR. SALIVE: Well, I wanted to ask the Dr. Salive, final comment or

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cardiologists about given the natural history of disease and subclinical disease, you know, what is the role of the proposed, I guess, from your group labeling and how would it address people who are unaware of their own risk who have, you know, subclinical cardiac disease to prevent them from taking his product? DR. KIMMEL: cardiologist. I assume that's me who is the First of all I

A couple of things.

think you have to determine whether there is in association and how strong that is and how many people it really affects? The concept of a susceptible You can

population you can postulate for anything.

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postulate it for -- as we've talked about -- salt. Number one, how big of a problem it is. Second, if you believe, as I can tell from the way that you're responding, that there it is a susceptible population who don't know, then the problem is what about all of the over-the-counter pseudoephedrine, what of the over-the-counter ephedrine, and why are they not at equal risk from those products? And I guess the issue is that we -- as you can see in our consensus statement we don't exclude the possibility that there is a susceptible population. Again, "susceptible" means what happens when

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you take the ephedra, does your blood pressure go up, and by how much? In the small trials, now granted

they're small, the heart rate goes up by 5 beats per minute. As a cardiologist I'll tell you, I wouldn't

attribute anything to that even if you have significant coronary disease. The blood pressure goes

up depending on the study or down. It is possible that there's a susceptible person who has an exaggerated blood pressure response to these products and has underlying coronary disease and therefore or an exaggerated tachycardic response and therefore has an effect. that. I totally agree with

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How many people there are, and who is at risk and, what is the risk, and is that risk different than the other products that are available, again, over-the-counter, that I can't answer. So I

don't disagree with you, I'm just not sure, (a) how big the problem is, and how different it is between dietary supplements and other products. DR. JONES: Thank you, Dr. Kimmel, and thank

you to the panel put together by the Ephedra Education Council for bringing your conclusions, your analysis to us this afternoon. We are ready for our break. reconvene at 3:30. We will

If you are presenting in the

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abstract session or in the public comment session this afternoon, please be sure you are near the front so that you can come up as your time approaches and staff will assist you if need be. Thank you very much. about 10 minutes. [Brief recess taken at 3:20 p.m.] DR. JONES: Ms. Michal, if you would, as For We will see you in

we've done with the others, identify yourself.

all the speakers today, identify yourself, and proceed now. Thank you. MS. MICHAL: My name is Barbara Michal. I

am the founder of the consumer organization Halt

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Ephedrine Abuse Today.

I am grateful for this

opportunity to come and address the panel and share information. Just a little bit about myself. The source

of funding for these efforts are my personal funds; the source of funding for my travel today was the Health and Human Services. I founded Halt Ephedrine Abuse Today in 1997 after ephedrine killed my 24-year-old son, Christopher. I want to make it very clear that it was

not a dietary supplement product that killed my son, it was a synthetic ephedrine product. But when I

started researching ephedrine the first time and I

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discovered how dangerous this drug is, whether in its botanical or its synthetic form, I started this work. The main purpose of HEAT is for consumer education. We have a survey on the Internet and the

survey results are posted up here for you to see on the overhead. iceberg. And this is just the tip of the (1)

The surveys that we are receiving are:

only those who have Internet access, and (2) those who are actively seeking information on the Internet about ephedrine. Now we have had over 800 responses in the last year and a half. For the purposes of this

public meeting I have separated out only those

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responses that we have had that specifically address dietary supplements; and we've had 355. There have

been more than that, but I have taken out those that did not have sufficient information to quantify in the survey results. So, as you can see, our total number of contacts that we've used here is 355. We have 26

percent male respondents, with 74 percent female respondents. You can see the age breakdown. The

majority of our respondents are between 16 and 30 years old or 16 and 35. Now, some of that may be due to technology, that the old respondents don't have access to

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computers or are not computer literate.

And, again,

also younger respondents don't have access to computers. The total number of people reporting addiction or dependence is 26 percent. These are

self-reported that they are dependent on these products, they experience withdrawal systems when they come off; 82 percent of the females who report addiction or dependence, 18 percent are males. The reported adverse reactions that we are asking for, you can see the percentages and they are in declining value; rapid heartbeat 64 percent of respondents. And we do also get respondents from

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people who have no adverse reactions to ephedrine.

I

want to make it clear that I do not only include those who have adverse reactions. We get surveys from

people saying, I love the stuff, it's working great, and I'm not having any adverse event reports. As you can see from the numbers there are very significant numbers of consumers who are reporting potentially very, very serious adverse events. Now, in addressing the questions that are the specific focus of this meeting, question one, the association between the use of ephedrine dietary supplements and adverse effects when used as directed.

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The majority of these reports report that they are using the products according to label directions. There is also a significant problem in the industry with even pill to pill variability in the same bottle of the active ingredients. Along with being founder of HEAT and doing this work on a voluntary basis, I am a paralegal and I work with an attorney in California and we prosecute civil litigation cases on ephedra injury, and we are handling quite a few cases right now and are in contact with attorneys across the country. So through my work in my career and through my work in my mission I'm getting significant

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information and information from experts and consumers. Question 3, the risks with the seriousness and severity as determined by age or sex, we have found that through the survey there is no specific age bracket where adverse events are more likely to occur. We are getting reports of adverse events and serious adverse events from young to old, male and female. The reporting could be a gender thing that men will not report as often as women will, it could also be because of technology and women are more often ready to share information. So this may be why we're

getting the breakdown as far as gender.

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We do not check for ethnicity.

We have no

questions on our survey relating to ethnicity, so I cannot speak to that specific issue. As far as the amount consumed across the population, the industry has been talking how many billions of servings. Initially in their testimony

they have been talking, not here, but in other testimony, they have been talking amount consumed, and they have no way to know how much is consumed. The

amount of product that has been sold, does that net out the product that's been thrown away; the product that is sitting on someone's shelf; the product that has been returned to the manufacturer for refund?

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That's a major question that needs to be addressed. They have no way to know how much of the product has been consumed compared to with how much that has been sold. In using those products in combination with other stimulants, the industry does not have a standard formula for a weight loss product, or a standard formula for a fitness enhancement product. These products run the gamut. caffeine ephedrine and aspirin. Some may be only Some products

containing a whole cocktail of stimulants with caffeine, yohimbine, citrus ceratium, which is synephrine, green tea extract and the effect of

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aspirin combined with these products. One of the adverse reactions to ephedrine can be body aches and headaches. Some of these

products add aspirin or the herbal white willow bark to their product, and it does two things. One, it

masks some of the adverse effects of ephedrine, the body aches, headaches; two, it is a blood thinner and

it speeds delivery of the stimulant to the system. Now, they have shown that caffeine, aspirin, ECA stack, ephedrine, caffeine, aspirin may be effective in weight loss, but I think it's an extremely dangerous combination. Talking about use of

these products with the stress of exercise, and one

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study was mentioned where the duration of exercise was longer, that it seemed to increase stamina; yes, but again because of these effects with the aspirin in most of these fitness products, athletes are more often prone to push past their normal level of endurance and can do structural damage, muscle damage, cardiac damage, they're pushing their systems way beyond by using these artificial stimulants. There is also the issue of individual sensitivity and people don't know, I don't know if I'm sensitive to ephedrine. I know I'll never take it,

but you don't know until you do take it and you suffer the adverse event, and they what? There's no way to

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know.

And there are so many different -With question number four, the outcomes

affected by dosage.

We're not finding that.

Again,

these reports, many of them, almost the major majority of them are taking them according to label directions, they are not abusing the drugs, they are not taking more or more often than they should be. The dosages, again, there is no industry standard. AHPA can recommend the dosage amount, but

in the ephedrine, there could the 8 milligrams per dose, there could be 12 milligrams per dose, there could be 25 milligrams per dose, or, if the industry, that particular manufacturer is not a member of AHPA

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there could be 30 or 40 milligrams per dose.

And,

again I have mentioned pill-to-pill variability in the same bottle. When you are working with botanicals

there is always the variability because of soil conditions, weather conditions, processing and harvesting methods, storage methods, whether noxious weeds are weeded out and separated out before processing. How much -- whether it is a powder or whether it's reduced to down to an extract, there are so many different variables when you are working with botanicals. Whether there are pre-disposing health

conditions, so many of the consuming public have

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undiagnosed asymptomatic health conditions that would be contraindicated to the use of ephedrine, and they don't know until it's too late. Many, many, even bipolar, we are finding that they are finding that there are latent bipolar tendencies in some people that are a asymptomatic, the people take ephedrine, go into the mania, the mania phase is then untreated and they go into full-blown psychosis. Duration of exposure, we've had people who have reported serious adverse reactions taking one pill; we've had people reporting they've had no reactions after taking it for years. There is no

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duration of use that is safe, there is no dosage amounts that is safe. My biggest question in all of this, in all the regulation, and all of the lobbying, and all of the arguments, and all of the scientific studies, how high does the body count have to go? The deaths are

continuing, the strokes are continuing, the cardiac arrests are continuing, the public has a perception, we have been well taken care of by the FDA for many years, and the public has the perception that if it's over-the-counter it's safe and FDA has approved it. This is not true with the dietary supplements. The

burden is on the FDA to go to product-by-product and

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prove that these are unsafe. The consuming public is also operating under the misconception in the myth that all natural equals safe because of the hype of the industry. Well,

cocaine is all natural, marijuana is all natural, hemlock is all natural. safe. All natural does not equal

And ephedrine is not a food, it is a drug; a

very powerful cardiovascular and central nervous system stimulant that has no place in over-the-counter products and especially no place in unregulated herbal products. There is one other issue that I have with the industry's advertising about increased energy.

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Energy comes from the efficient use of fuel which is food. What these people who are using ephedrine are

experiencing this artificial stimulation which in fact depletes natural energy reserves. And when the

ephedrine wears off, they have a down, the euphoria comes off, they have a down, they experience this, they take more to bring themselves back up again. This is not energy. This is artificial stimulation,

and it is the total fraud to call what comes the effects of ephedrine energy. As far as the adverse events reports that the industry has been studying and the clinical experts here have been studying, I want to find out

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from the industry how many adverse event reports they've had and whether they have reported them to the FDA and whether they have subjected their own adverse event reports to the kind of scrutiny that these adverse event reports have been subjected to. And

that's a major question that I think needs to be addressed. We know that there are adverse events reports being reported to the industry, to the manufacturers. And with the 30 percent of the

responding industry, people to the AHPA survey how many of them were the top three or four manufacturers and how many of them actually came across with adverse

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event reports? We have some other comments that I just want to share with you that have come from the survey from consumers. These are just comments from ordinary Joe

Q. Public and Jean Q. Public, people who find the web site, people who fill out the survey. I have been in

touch with these people some by phone, some by Internet, some I have not been in touch with. these are comments that we receive: But

"It's a shame I took I'm very

what we will try to lose a few pounds.

someone's word that it was not dangerous. shocked."

"A friend and colleague of mine died He was a weightlifter

yesterday, he just turned 40.

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and he was extremely health-conscious and seemingly very healthy. I heard secondhand the doctors found

ephedrine in his system following a massive stroke last week." "I tried" and I have deleted product names but product names are in my survey. product for two weeks. "I tried this

I've been off it for three I

weeks now and I'm still trembling and nervous.

can't concentrate at work and I'm very nervous when I drive. It has subsided considerably in the last week, I have talked to a

but it is still affecting my work.

couple of doctors who have no real remedy for getting this stuff out of my system and bringing me back to

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normalcy." "I'm very interested in your findings of using this awful drug. I have been taking this

product for over a year now and had suffered several mini strokes. Then I went to hospital for a test and I think is all because of the herb,

suffered stroke.

since the test came out that nothing was wrong with me, and now I have no feeling in my right hand, weakness on my entire right side due to the CVA I suffered. I want to make sure this stuff comes off I am mad that our government lets

the shelves fast.

this drug/herb be sold in Wal-Mart as well as on the malls across the country."

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Another one, "I've been searching the web for information on withdraw symptoms associated with ma huang. I quit taking a product -- like product, a

product named Life Product two weeks ago, one that they compare it to. After taking it for three months

as the label claimed was safe, I did lose weight but I haven't felt normal since I stopped taking the product -DR. JONES: MS. MICHAL: DR. JONES: up. MS. MICHAL: I wanted to let you know that I Please wrap up. I'm sorry. You're out of time, please wrap

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have surveys here, direct surveys, 39-year-old woman, acute kidney failure, 40-year-old woman, primary pulmonary hypertension. transplant. The only cure is lung

A 28-year-old woman, tingling sensations

that sound to me like a precursor of stroke, but, of course, I'm not a medical expert. Here is a 29-year-old male, hospitalized for irregular heart beat and high blood pressure. We are getting reports like this and the lawsuits that I have seen from other attorneys and the lawsuits that we're handling in our office show that there is a very significant public health issue here. Thank you very much.

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DR. JONES: [Applause.] DR. JONES: the panel, if any? DR. SALIVE:

Thank you, Ms. Michal.

We are open for questions from

Marcel Salive, NIH.

Do you encourage that people who respond to your Internet survey to report their adverse events and if so, to where? MS. MICHAL: Absolutely to the FDA. I

encourage every survey respondent to report to the FDA. Whether they do or not is another thing. But I

do encourage them to absolutely. My intention is with my survey we are going

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to revamp the web site and I will have a selection a button on the survey that they can select to have the surveys sent directly to the FDA. DR. JONES: Other questions from the panel?

[No response.]

DR. JONES:

Questions from the floor?

[No response.] DR. JONES: Michal. And turn now to Mr. James Turner of Swankin & Turner. MR. TURNER: Good afternoon. My name is We thank you very much, Ms.

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James Turner and I'm here in the capacity of a chairman of the board of Citizens for Health. Citizens for Health is a consumer group that has supported the passage of Douche and has been critical of the FDA's use of its resources and activities in regulating dietary supplements since the passage of Douche. We've been critical from two angles. First

we feel that the agency has been excessively focused on raising what they consider to be serious questions about the safety and efficacy of dietary supplements. Which we think is an overstated position by agency and we feel that the reports such as this GAO report and

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others on the ephedra issue have supported our view of that excessive regulatory attitude. On the other hand we feel that the FDA has underused authority it has; authority for example to create good manufacturing practice for dietary supplement and we believe that the agency does have substantially more authority to create label information and other supporting information that it has used. And, again as one of the plaintiffs in the

Pierson case we believe that that position has been supported by third-party forces that suggests that the FDA has not been as vigorous and effective in its use of authority that it actually does have.

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Our basic point then is that the FDA has been overzealous in attempting to draw an analogy between dietary supplements and prescription drugs, in particular, and also over-the-counter drugs. It has

been overzealous in that activity and underzealous in the activity of utilizing the resources and legal resources and the authority that it has to ensure that dietary supplement products are manufactured properly and carry the proper kind of information for their effective use by the consumer. These arguments that I have made are underlined by the ephedra case history but the ephedra case history I believe is just the first of many of

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these issues that are going to develop over the next few years. The FDA has given an almost impossible

task of drawing a line which says everything on the right side of the line is good for everyone, and everything on the left side of the line is bad for everyone. In attempting to draw that line and poll

products into that kind of a regulatory framework leads to serious failures on the part -- failures on behalf of the consumer, of both kinds. Over 3 billion doses of ephedrine have been sold for example. Many consumers report a positive They think

relationship with ephedrine, they like it. it's a good product.

Their interest in having that

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product on the market is as important to be addressed as the interest of making sure that people who may be susceptible to it may not understand how to use it or may receive improperly manufactured forms of it are protected. addressed. And I believe that I and Citizens for Health believe that that is the direction in which the FDA needs to move. That is to take the consideration of Our Both sides of that equation need to be

all consumers in these areas into consideration.

view about the way to do that would be to vigorously develop the good manufacturing aspects of Douche, vigorously pursue the Pierson court's guidelines, and

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how to create information for consumers that does not unduly burdened their rights, and does not unduly burdened the government and its ability to carry that out. This is the issue of warnings contraindications,

cautions, and so forth. We also believe that it's very important for the Agency to institute vigorous postmarketing survey procedures so it can more easily trigger that portion of the Act which permits the FDA to act to remove products that are unsafe once they've been -- and this is in Douche, once they've marketed. The idea then is

good manufacturing practices and all other things that tend to being sure that the products on the market are

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properly manufactured, effectively packaged, and meet the requirements that would be sound for a marketing activity. Second point is to make sure that there is effective information and we have said in other settings with the FDA and we say continuously that the Internet offers another opportunity for the FDA to create a very robust information flow. But the second

point is a robust information flow so that consumers can match their interests and their desires and their needs with the regulatory position that the FDA is taking on the ability of a product to meet those kinds of interests.

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And third we are arguing that there should be a more vigorous postmarketing monitoring process by the FDA to systematically look at products as they have reached the market so that they can have in early warning system that means that things can be dealt with effectively. One of the things that an early

warning system created by postmarketing surveillance, I believe could be organized to do, is avoid the kind of problems that turned up in the ephedra adverse events reporting system. If a system has been organized systematically and scientifically to review who is using the products and what their effects, what their

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experience is and what the effects of the products are, if a system like that is organized prior to the product reaching the market, when the information is collected and I think it should be proactive and I had been critical for years, and the Citizens for Health has been critical for years about the passive adverse reporting system. We need an active system where the

FDA is actually soliciting information in a systematic scientific way. That kind of information can be a very effective tool in providing the kind of information that would allow the FDA to act in a regulatory way that could sort through the process protecting the rights and the safety and the well-being and the

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health of both those people for whom these products are proper and effective and useful products, and those people for whom they pose a danger. That is a very sparse presentation of what can be a very active regulatory approach, but it suggests what we believe, from our point of view, an approach that is more suited to the kind of world in which we have millions of people using products safety safely and effectively, which are helpful to them, which are not excessively expensive to them, and which they have good experiences with protecting them while at the same time protecting those people who have either because of their own individual framework an

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adverse reaction potential or, more importantly, making sure that the products that are manufactured are done so in the way that protects individuals without having to remove the ability of people to have the products that will be useful to them. That's the sum of my statement, and I am happy take questions at this point. DR. JONES: Thank you, Mr. Turner.

For the record, will you state whether Citizens for Health is a consultant to or has any potential or real -MR. TURNER: No, we have not been involved We have paid our own --

with the ephedra industry.

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I've arrived here by cab.

We have paid our own way on

this issue on all of the work that we've done to put this together is by the people in our office. DR. JONES: record. Questions from the panel? DR. COATES: Dr. Coates. Thank you, Mr. Turner, for the

For the record, Mr. Turner,

what questions of the four were you answering with this discussion? For me it sounded much more oriented

toward the regulatory components of FDA, issues which as I understood it were not really on the table for discussion today. MR. TURNER: Well, the framework first of

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all, we are concerned about the way that the adverse information has been collected, and I was addressing that point. The information that the FDA has about

the seriousness of this problem is very skewed information. I did decide and believe it was

important to suggest an alternative way of dealing with that problem. To that extent that may very well

be a regulatory issue. But each of the points that I argued about how we should proceed are addressed at a specific issue that is considered to be a problem in the ephedra case and I did want to add that I believe that that these are generic problems. They were not

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specific to ephedra.

That is the issue of adverse

reaction reporting on others is very similar in its failure as in the ephedra situation. In fact we have been very critical of that entire system. So I am saying that the adverse

reaction reporting piece has suggested that there's a problem here I believe has failed to create that. to support that. DR. JONES: Other questions from the panel? Or

[No response.] DR. JONES: Questions from the floor?

[No response.] DR. JONES: Very good. Thank you, Mr.

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Turner. [Applause.] DR. JONES: Linda Golodner of Brett Kay,

from the National Consumers Leagues. Is someone to do the overheads up here yet? Could come up and again. Sorry the old technology

used to be more reliable it looks like it's the opposite in this meeting. Hello staff in the back of the room. They're booting up the system. MR. KAY: They're at the end anyway.

I could go through the first part which is pretty brief any then go through them.

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DR. JONES:

Thank you.

And if you would,

state your name for the record and who supports your work, et cetera. MR. KAY: My name is Brett Kay I am a health

policy associate for the National Consumers League. We are a private nonprofit consumer advocacy organization. We're funded through various means

mostly membership and through grants and from foundations, and unions, and various other methods. But we're not taking it -- we don't have any money from the dietary supplement industry and no one has paid our way to do any of the speaking today or testimony.

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As I said, the National Consumers League is one of America's oldest nonprofit consumer advocacy organization and we've represented consumers and workers in the marketplace for over 100 years in assuring that consumers can purchase safe and effective products is of primary concern to our organization. We have a long history of working with the Food and Drug Administration and its predecessors to require that manufacturers produce safe and effective products with truthful and not misleading label claims. The league support the FDA's efforts to

reduce the risks associated with dietary supplements

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containing ephedrine alkaloids.

This product has

clearly demonstrated that it has safety concerns with numerous adverse events reported to FDA. In 1997, in NCL submitted comments to the FDA regarding products containing ephedrine alkaloids urging the FDA to move in a timely manner to adopt then proposed regulations which included limiting the amount of ephedrine in these products to 8 milligrams per serving and 24 milligrams per day and requiring warning labels regarding recommended length of use. Unfortunately, the proposed regulations were never finalized and the dosage and duration recommendations were withdrawn.

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Since that time in June 1997, hundreds of new complaints added to the already numerous documented complaints up to that point have been filed. It seems clear that ephedra products pose a

serious health threat and consumers are at risk. Dietary supplements containing ephedra as we've heard many times, are currently sold for a variety of purposes including weight loss, increased energy, and body building. And because they are

marketed to such a diverse population many of whom are vulnerable to the often tantalizing claims these products are ripe for abuse. Dieters seeking quick

weight loss or young men looking to pump up quickly

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are often desperate for fast results and may take more than the recommended dose for longer periods than recommended. Because these products are often portrayed as a natural, most consumers assume they are safe. more consumers turn to dietary supplements to selfmedicate and improve their health, the safety these products must be ensured. Further, as consumer take As

more responsibility for the health they need to proper tools to make safe and effective decisions. Without adequate labeling consumers are deprived of important and necessary information to make the proper decisions. Currently dietary

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supplements containing ephedra do not contain adequate labeling. As a result reports of seizures, heart

attack, stroke, an even death are too common. NCL supports the FDA's previously proposed rule as a necessary step to ensure that consumers are provided appropriate instructions and warnings about these products. Most of the adverse events reported

occurred in otherwise healthy young to middle aged adults who used to products for weight control, body building, or increased energy. Again, without proper labeling instructions and warnings consumers cannot be educated or how to use these products safely. We are also concerned

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about the abuse of these products by adolescents. Teenagers and young adults are particularly conscious of their physical appearance and products promoting weight loss or bodybuilding could be subject to misuse by this population. Further, the inclusion of ephedrine in products marketed as natural alternatives to illicit drugs such as ecstasy contribute to possible misuse and abuse by a vulnerable and impressionable population, one that often sees itself as invincible, and is all too often not the case. I would like to talk about the issue of labels and consumer behavior. NCL recently conducted

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a survey of consumers attitudes and behaviors with over-the-counter drugs. While OTCs and dietary supplements are very different products with drastically different regulatory requirements to consumers they are not so different. The line between dietary supplements and OTCs has been blurring in recent years and many consumers do not differentiate the two products. They

are next to each other on the shelves at pharmacies, supermarkets, and convenience stores and are often advertised in similar magazines in similar ways. According to the confusion is the fact that

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many well-known pharmaceutical manufacturers offer dietary supplements with the same brand name as their OTC products. Because of the similarities I feel it

is relevant to provide some data about OTC use to gain perspective on dietary supplements. And since

labeling is the most direct method of communication to consumers about a product it is important to see how consumers use the labels. Please keep in mind that this was a telephone survey and there is often a disconnect between what people say they do and what they actually do. So these results sort of represent a best-case

scenario and may be conservative estimates

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specifically for the dietary supplements. This is the first just sort of to give you who it was done by, random sampling phone survey, plus or minus 3 percent margin of error, respondents were at least 18 years old, and it was conducted May 15th through the 31st, 2000. survey data. We asked a series of questions about how consumers view OTC products and view the labels and also their own health care, and how they're making decisions. And, as you can see, compared to five So these are pretty new

years ago, making decisions on their own, more consumers are making health care decisions on their

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own; 58 percent represent or claim that they're making more decisions now than they were five years ago with only 9 percent making less decisions. We asked a question about what you do when facing my health ailments. help decide which OTC take. information on the label. We asked what resources to The number one response, So what you see here is

that a label plays a vital role in consumer information. Additionally word-of-mouth from friends and relatives and ads also have a great deal of influence. I think this is even more so for dietary supplements, particularly for teenagers and young adults concerning

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weight loss or bodybuilding.

I think friends and

relatives and the advertisements and promotions probably have a great deal of influence. The Internet as you can see also is a growing influence on consumer choice and again, for younger populations probably even more so. How often do you generally read the label? The good news is that 66 percent or two-thirds of the population, is reading the label almost all nearly every time. The bad news of course is that one-third

of them are not reading the label on a consistent basis. That can pose a serious problem especially for

the products where there are potential help risks,

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contraindications, or other warnings if a third of the population is not even looking for those in the first place. And if you're talking about dietary supplements where they assume they are safe and natural, they may not look at the label even less. How easy are the labels to read and understand? telling. I think this is a very important and

And this is for OTCs, first of all, so the

labeling requirements are very distinct and clear; 25 percent still feel that it is somewhat or very difficult. That's one quarter of the population. For dietary supplements, I think, which have

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different labeling requirements than the OTCs may be even more confusing. Now, do you take more than a recommended dose? And 32 percent are saying that almost always,

or most, or some of the time they are taking more than the recommended dose. For product like ephedra, this

can have serious health implications. And then the other question which is of issue, do you take them for long than recommended? Again one-fifth, a larger than acceptable number of consumers, is saying that they take OTC products longer than recommended. We can extrapolate this out to them taking for

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dietary supplements in similar ways and also misbehavior may lead to serious health problems for people using products containing ephedrine alkaloids. So while the league supports the previously proposed rule, we also urge the FDA to continue to evaluate the safety of these products. Because many

of the health conditions that increase the risk of adverse events are not self-evident such as hypertension, diabetes, and other cardiovascular conditions. People with such conditions who use these

products are unaware of the health risks. Further, more and more people are turning to dietary supplements and there is increased attention

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on body image by adolescents and young adults in the population that often leased inappropriate behaviors. Thus, if the scientific data shows there is no safe level of ephedrine alkaloids that can be used, an adequate labeling regime cannot be implemented, then we feel that dietary supplements containing ephedrine alkaloids should be removed marketplace. Thank you for this opportunity. accept any questions. DR. JONES: Thank you, Mr. Kay. This I will

presentation is now open for questions. any questions? Dr. Philen.

Panelists,

DR. PHILEN:

Rossanne Philen from the

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Centers for Disease Control. DR. JONES: DR. PHILEN: We can't hear you. I'm Rossanne Philen from the I believe

Centers for Disease Control and Prevention.

I heard you say that you collect adverse event reports; could you tell us more? MR. KAY: No. No?

DR. PHILEN: MR. KAY: reports.

We do not collect adverse event

I was talking about the ones collected and

documented from the FDA. DR. PHILEN: MR. KAY: From the FDA?

Yes.

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DR. PHILEN:

Okay.

All right.

So you don't

collect an of that information? MR. KAY: No, unfortunately, we do not. Okay.

DR. PHILEN: MR. KAY:

We receive anecdotal things from

time-to-time on a series of consumer and health issues, but nothing systematic in any way. DR. PHILEN: Do people ask you where or what

they can report or to whom? MR. KAY: Yes, we have promoted FDA's

Medwatch program in the past and have I put it on brochures and other educational materials that we've used, and if people call today, if they have problems,

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I tell them to report to FDA Medwatch program. DR. PHILEN: DR. JONES: Thank you. Other questions from the panel?

One question I have, Mr. Kay, is do you have any information on what consumers -- you indicated for your OTC-related survey that they looked at the label, most of them do read the labels, a lot still don't, and that they're easy to understand and so forth, but do you have any indication where consumers go for other information, not just on use of the product, per se, like you suggested, that, you know, the literature, friends, or whatever -MR. KAY: Right.

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DR. JONES: sources.

But what they consider reliable

And it goes to reliability of information

that consumers might -MR. KAY: Yes, I do. Actually, one of the

-- I didn't have it on these slides, but part of -the most reliable that people usually use is the doctors from this survey and from others consistently for health information people are still relying -something around 65 percent or so talk to their doctor. Another 50 percent consider the pharmacist,

especially for something for minor ailments, will talk to the pharmacist; nurses, probably about 30 percent or so. That's what they consider. It's health care

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professionals, generally. DR. JONES: floor? [No response.] DR. JONES: No. Mr. Kay, there might have Okay. Questions, from the

been a paper that dropped from your sheaf there. MR. KAY: DR. JONES: [Applause.] DR. JONES: Let me now call Col. Ester Myers Thank you. Thank you very much, Mr. Kay.

from the U.S. Air Force for presentation. COL MYERS: members. Good afternoon, Dr. Jones, panel

I'd like to share a just a few comments with

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you this afternoon addressing the nutritional supplements and some unique military concerns as your deliberate the answers to your questions and ask you to particularly addressed concerns that we might have. DR. JONES: And you will state your name for

the record and any potential conflicts of interest. COL. MYERS: I'm Col. Ester Myers, the

Surgeon General's consultant for nutritional and dietetics for the Air Force. no conflict of interest. As you so mentioned the government owns us. [Laughter.] COL. MYERS: The unique military concerns As far as I know I have

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will surround three different possible issues.

One of

them is what happens during deployment and assignments oversees? Another one has to do with our special

flying population aviators and then the personnel reliability program. about each of those. Now, to address the issue of ephedra for us, we kind of put it in the whole issue of herbals and dietary supplements. It is one of those that need to And I'll mention And let me explain a little bit

be addressed in each of these issue.

specifically who may talk about ephedra. In terms of deployment and being located overseas there are many varying supplements available

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when a person deploys.

You'll find that the product

certainly that are available in Europe and Asia vary from what are available in the United States and they may be thinking that they are taking the same type of product when it in fact may be very different. labeling requirements differ. Right now the The

dietitians that are assigned in Usaf are having the challenge of coming out with a listing of products that are comparable to the American product so that our servicemen can make reliable decisions about what to take. And the second one in terms of taking sometimes that they are limited by what they can take

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along with their baggage so that they may take issue a supply supplements when they leave. It may not be

sufficient for the entire time that they are there. Probably the major concern though is what happens in that environment during deployment. In

many cases that heat is very high, especially if they go to the Middle East, that's coupled with a very high level of activity, and at the same time a very high level of stress. Several of the presentation this morning have mentioned the fact that ephedra may be affected by all three of those issues. In addition, to that, there may be

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unfamiliar fluid and electrolyte beverages and there may be limited availability and ephedra and dehydration is also a major concern for us. Of particular concern in the Air Force is what happens to our flying population and aviators. And we have addressed different types of products that they need to be very careful about, certainly anything that's a cardiovascular agent, one of which is ephedra, a sedative, hallucinogen, and anything that will promote dehydration since that's critical to our flying personnel. The third type of issue confronted by the military is what we call the PRP, that's our personnel

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reliability program. that deals with that.

There is a an entire regulation Personnel reliability, the goal

of that particular program is to screen and select anyone who has the capability or will be handling nuclear weapons. And then to remove anyone that might

have any reason why they could not -- or have questionable reliability. In particular you are looking for anything that would have mood alterations that would cause changes in mood. We have submitted changes to the Air

Force instruction which is pending release of the DOD instruction that we would like for the military members to consider that herbal and dietary

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supplements be treated the same as over-the-counter. What that means is, that they need to talk with their physician about self-medication so the positions could then evaluate to be whether or not they could continue in their status as PRPs. In 1998, we did form a working group in the Air Force that was dealing with nutritional supplements in particularly addressing aviators and personnel on PRP program. The people in the working

group were consultants, dietitians, pharmacists flight surgeons. We also had members of external agencies,

NIH from the Office of Dietary Supplements, ASMA, which is the association that sets and regulations for

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commercial airline pilots as well as representatives from USARF. We were targeted to

address the guidelines for the military members who were aviators and PRP. We wanted to look at an

educational approach so that people could make reliable decisions instead of coming out with a magic list of those that could they could and could not take. We were very concerned about labeling and the issue about how much active ingredient were in the various products so that the personnel again could make reliable decisions. And then we wanted to

address the marketing of products on military

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installations. There are three major venues of products of ways that products can be sold on military installations. One of them is through AAFES, which is

the Army Air Force exchange service they have a contract with a company that produces and sells dietary supplements. Another venue is in DECA, which And a third

is our commissary, our grocery store. venue is in the fitness centers.

And in the fitness

centers often what they would come up with is the juice bars and so the items that are being made do not have labels that are readily available to for the consumer to look at.

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Our major concern about this was that it was implied consent. Just as people had indicated that if

a product is available on the market there is an implied assumption that it is completely safe. The same thing is probably true about issues about products that are sold on military installations. You take the young, 18-year-old

airman, soldier, or Marine Corps man, put them on the base and then sell a product, and they're going to assume that that's safe for them to use and also allowable. And as I showed you earlier, there are some cases when it is not allowable for them to take

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different products.

And then we come up with the

legal dilemma of the commander says I don't want this sold on my base, but it's legally available on the market; then there's a whole lot of legal issues about whether the commander wants to ban it on his particular base to protect his soldiers. In terms of the policy guidance that came out of that working group one was the recommendation and PRPs that herbal and dietary supplements be treated as over-the-counter which means they must in fact report them to their physician and get official approval to use them. There was an Air Force Surgeon General

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policy to that effect indicating that they should be treated as over-the-counter for the two categories of people were talking about, anyone who is on PRP or on flying safety. Special tactics and Madge COMS issued several policy letters. The services agencies which

is the agency over the fitness centers has also issued a policy letter indicating for those people who on flying status or PRP that the products needs to be tagged so that they can know what products they can safely take and still maintain their flying status or their PRPs status. And ephedra is one of the products

that we recommend they do not take.

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And then there is an ATHEs information paper that indicates they must have a precautionary label on those items. And I know that you can't read this

label but it is a five-by-seven precautionary notice that is supposed to be placed anywhere they sell the dietary supplements. The content of that notice. First of all,

it says the "follow instructions," you don't take more than is on the label. specifically." It says "more is not better

It addresses that you must consult

your health care provider, it identifies what are common symptoms and then it indicates to stop immediately if you feel those symptoms. It defines

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dietary supplements in the context of health care. other words contact your provider before you take these items.

In

A special warning for pregnant mothers and children and then tells you again how to report the adverse side effects. Other existing guidance. If you're on

flying status, you are already limited to one multivitamin a day and any supplements that are approved by the flight surgeon. The drug testing

program again outlaws certain dietary supplements and then for flying status if your own and anorectic drug that's medically disqualified for flying.

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In terms of looking at implementing these policies we said there was a lot of education that would required, both for the consumer as well as for So we did create a trifold

the health-care providers.

brochure, then again ephedra is one of the products that's listed on the page that says specific supplements to avoid that you need to contact your health care provider and it is listed under a cardiovascular effector agent. There is a web site that has this brochure on it as well as a list of papers for military members that specifically addresses issues for us. We've created a videotape for health-care

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providers to make sure that the flight surgeons when the fliers or people on PRP came in and asked questions they were familiar with all the different names the products might have and how to address those. And then a series of news articles. The dietary supplement brochure includes definitions of policy summary, guidelines for use, types of supplements to avoid, and sources of information, and web sites. This is the web site if you want to look on you can look it up at any point and log on to see what kind of information is available to military members. There is a reading room section that's for both the

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provider or the physician. The videotape is basically a primer on herbs and supplements with some common names that tells the provider how to address that in their conversations with the patients. These are the types of news releases that are targeted for the military members. Other initiatives, we are focusing on looking at ephedra. We have had two deaths in the

military that are associated with ephedra, so it has got our attention. We are looking for examples about

the reporting incidents we were talking about underreporting today and I think that that is

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absolutely true. that.

We are looking at how to enhance

The Army policy letter again is reinforcing for

people to make sure that they're reporting those up through the system to make sure that those are adequately reported. In one week at Travis alone we had three ER admissions due to dehydration secondary to taking products with ephedra. In looking at the health behavior survey, Captain Gortney from the Navy was successful in adding three questions to the supplement to the questionnaire that will be administered in the year 2003 that specifically asked basically your question about the

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denominator.

How many people are taking them, and how

often they're taking them in the military population. So when we look at those two pieces of data now we will hopefully have a good nominator and denominator for us. And we are collaborating with the FDA discussing underreporting, what kinds of things we can do to reduce the underreporting and get an accurate member as well as a potential for data sharing so we can look to see what is the real issue and what do we need to do to maintain the safety of our military members. We are exploring the possibility of a DOD

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policy on ephedra rather than service specific.

The

Navy is very concerned, had a working group about a month ago, or two months ago now, specifically addressing supplement use in the training environment; again, where they're under heavy exercise and lots of stress. Looking at finding out whether or not we can get precautionary labels similar to what's in AAFES, in the Navy exchange, which is the NEX, or the DECA and the Commissary. the AAFES. Bottom line, in the military we are very concerned. We need to make sure that we safeguard Right now we only have them in

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the health of the military members.

We do have some

unique concerns particularly in cases of deployment what should happen in supplement use during deployment for our aviators and for people on the personnel reliability program. And we're looking for governing

guidance and specific studies that will show us whether or not these products are safe for our military members. Thank you very much. [Applause.] DR. JONES: from the panel? Thank you Col. Myers. Questions

Dr. Schwetz. You mentioned a special

DR. SCHWETZ:

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warning for pregnant women and children, can you say more of what that warning says? copy for the record? COL. MYERS: I can give you a copy for the If you would supply a

record, I certainly can. I think that is says specifically, consult your physician. But I can get that for you. Dr. Philen. Col. Myers, does the Air Force

DR. JONES: DR. PHILEN:

have any systematic recordkeeping regarding adverse events related to this ephedra or other supplements? COL. MYERS: Not outside of the FDA system.

Our reporting system is who -- we do have each

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hospital obviously has a committee that looks at the different effects and so forth. But our method right

now in terms of collecting it throughout is through the FDA. There has been some discussion of whether or not we need to set something similar. When we went

back to look under flying safety, in particular, we wanted to go back to say, tell us the results of the flying safety; how many flying mishaps have been attributed to something like this? And the data isn't

stored in the way that we can use it. DR. JONES: DR. COATES: Dr. Coates. Col. Myers, given the

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discussion that occurred earlier today about -- the word isn't "discrepancy" but differences of interpretation about autopsy findings. Would there be

any possibility of submitting records of the deaths that you referred to that could be attributed to ephedra to some independent evaluation to determine as some of the ones this morning were submitted -- raise the question about how closely associated with ephedra use they were. COL. MYERS: If you forward the request I One was a

can see how it goes through channels.

different service -- both were from different services than mine, so I would have to -- if you wanted to

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submit the request.

Or get with me afterwards and I

can tell you how to find out the answer to that question. DR. JONES: obtained theoretically? me put it that way? COL. MYERS: DR. JONES: [Laughter.] DR. JONES: Other questions from the panel? The could be requested. We can ask for anything. But those data could be They could be requested, let

[No response.] DR. JONES: Questions from the floor?

[No response.]

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DR. JONES:

I will note Col. Myers, thank

you very much, you offered to provide for the record the warning for women who are pregnant or may become pregnant. COL. MYERS: yes. DR. JONES: Yes, the precautionary notice. The precautionary labeling,

As well, you held up a trifold brochure, if you would provide that for the record as well we would appreciate that. COL. MYERS: DR. JONES: I certainly will. Thank you very much, Col. Myers.

Dr. Fugh-Berman.

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DR. FUGH-BERMAN: Adraine Fugh-Berman.

Good afternoon, I am

I am a physician and vice chair

of the National Women's Health Network which is a consumer advocacy group that's independent, membersupported, we take no money from pharmaceutical companies, medical device manufacturers, or dietary supplement companies. I do not personally take money

from any of these entities and put this together on my own time and paid for my own farecard. Ephedra is -- I want to go back to a point that Dr. Fong made this morning which is that ephedra has a long history of use in both western and eastern herbalism. But that it's traditionally used for

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respiratory ailments, asthma, usually, and there is no reported cases of adverse events that are associated with traditional use of this herb. And this might be

because the side effects of increased metabolism are actually something that one tries to avoid in asthma treatment. Asthmatics just what to breathe, we don't want to stay up all night. And we adjust dosages to

avoid side effects like rapid heartbeat or insomnia which are actually common to a lot of asthma medications. But a speeded up metabolism is the goal

if you're trying to lose weight, if you're a bodybuilder or if you're trying to get high. And the

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use of ephedra for weight loss, bodybuilding, energy, or recreational use has no traditional precedent, and it can't be considered safe. Any range in which weight loss occurs is an overdose. Ephedra has been associated not only with

strokes, heart attacks, kidney stones, and chest pain in adolescence, but ephedra effects in everyone. does not cause side

Clearly there is susceptible

populations and populations that are less susceptible, but we don't know what the difference is between these two populations. Our response to the first question that has been given the panel is that ephedra contains -- well

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I'm not going to go into what it is, we have already really heard that. We've heard about systemic

affects, bronchodilation, increased peripheral resistance, increased heart rate, increased blood pressure. Now, bronchodilation can be helpful in those with asthma and over-the-counter oral asthma medications including Primateen, and Bronchaid do include ephedrine and many unconventional and conventional treatments for asthma can increase heart rate and blood pressure and they can be dangerous in people with underlying cardiovascular disease or cerebral vascular abnormalities, sympathomimetic

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agents are contraindicated in people MAOIs, in people with prosthetic hypertrophy, in people with thyroid disorders. But it least -- and this is in response to Dr. Lieberman's comment this morning -- at least the labels on the ephedrine-containing asthma drugs they had decent warning labels; and I've included some Xerox's of them in my testimony which I will make available to the panel. Primateen, for example states "intentional abuse of this product can be harmful or fatal." recommended dosages on these OTC drugs is up 150 milligrams a day. And I would say that in an ideal Still

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world, I would want none of these sympathomimetic other than the methyzanthenes, don't mess with my coffee and chocolate, these other sympathomimetic should only be given to people under the supervision of a health-care practitioner who is knowledgeable in their use. And the National Women's Health Network recommends that both warnings and dosage information on ephedrine-containing dietary supplements and ephedrine- containing from OTC drugs be standardized. Consumers assume that products that are available OTC safe, but there should be a higher standard of safety for over-the-counter products and

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for prescription drugs and there should be a higher standard of safety for products that are used for cosmetic concerns rather than medical conditions. energy and wanting well-defined muscles are not medical conditions. And while obesity is associated Low

with several health problems, it's very difficult to separate the risk of obesity from the risk of dieting. And we would certainly want any products that are available for weight loss that are over-the-counter to be safe. Ephedra is not safe. It was very

interesting hearing Dr. Love's excellent report this morning that it was quite striking that 40 percent of

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adverse events related to dietary supplements are associated with ephedra-containing products. But it

really struck me about 64 percent, she said 64 percent occurred in people under 39 and 16 percent of these adverse events in people under 19. You know it's tough to hurt young people. You know, think back about the ways we used to abuse our bodies when we were teenagers. You know, it's

pretty hard to cause an adverse event in a teenager. Ephedra has done so. So not only has it been

associated with many medical problems, but also psychiatric problems, ephedrine-induced psychosis and episodes of mania are quite well-documented.

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And it's been associated with the chest pains in adolescence, this is the study that has not been mentioned today, but it was the case controlled study 28 adolescents with chest pain versus 26 adolescence with other complaints that found ephedrine in 17.8 percent of the cases of chest pains and 0 percent of the controls. None of the kids in whom ephedrine was found admitted use of ephedrine-containing products. And

routine urine screens won't pick it up, these were not picked up by tox lab or EMED, they were picked up on GC Maspec. Ephedra is also associated with kidney

stones and a kidney stone database has analyzed over

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200 stones that contain ephedrine, norephedrine, and pseudoephedrine. I have already mentioned the case of this 23-year-old who was taking an ephedra caffeine product, a fatality. There was another product that

was used successfully for suicide, ephedrine/caffeine combination. There has been a case of a severe MAOI

interaction that was reported a between phenelzine and ephedrine product that contained caffeine and also theophylline. Now, there's been a number of trials of ephedrine for weight loss and increased heart rate has been seen in most of these. The increases in blood

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pressure are less consistent and they're probably more likely to occur early on in use. In studies that have

looked blood pressure within a few hours of taking ephedrine they found increased blood pressure in at least some percentage of the participants. In most of the trials of weight loss, what they've done it to not take the first blood pressure reading after baseline until a week or usually four weeks after the trial has started and people get habituated by that. So in those trials you do not see an increase in blood pressure over the long-term. And

the reason that I'm pointing that out is that, okay,

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maybe people do habituate to the ephedrine's cardiovascular affects after while, but if you have an underlying cardiovascular or cerebral vascular problem you don't need to have your blood pressure high for more than a couple of days to have a problem. So that immediate effects of tachycardia or hypertension can still be important and that actually has been looked at very carefully. Additionally very

few these trials have actually included hypertensive patients. There have been a number of statements made here today about the efficacy of this herb for weight loss. I've made a chart of weight loss trials that I

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could find.

It omits four Danish studies that there

are no English abstracts for and I don't have translation resources for. But I've identify eight

weight loss trials not counting the one that Lori Love mentioned this morning. And only three out of these

eight trials showed a beneficial effect on weight loss. Five out of eight in these trials show no difference in weight loss between a placebo group and ephedrine or an ephedrine/caffeine combination, in one case caffeine ephedra aspirin. A couple of trials have included hypertensive. There is one trial of the ephedrine

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caffeine combination that included treated hypertensive and did not find more hypertension in a group that was already on treatment. In the answer to question two, we would say there's no well-established indications for the use of dietary supplements containing ephedrine alkaloids. Ephedra increases for thermogenesis as do many sympathomimetic agents, but these trials have not shown a consistent or a dramatic effect on weight loss and they have shown significant adverse affects. Not only are most of these weight loss trials quite small, but there's a strikingly high drop-out rate. And a number of those drop-out are due

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to adverse side effects.

Sometimes the re not perhaps

what we would consider serious side effects, but they aer insomnia, they are palpations, there's nausea and vomiting that sort of thing. somebody to drop out. The use of ephedra for the treatment of respiratory conditions is probably not dangers and giving the bronchiodialating affects of ephedrine, it's probably effective, but there's been no methodologically acceptable clinical trials of efficacy of ephedra preparations for respiratory conditions that I they could identify. There is some evidence that a Good reasons for

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caffeine/ephedrine combination can improve aerobic exercise performance, and you saw one of those studies mentioned today, the Bell study. Well, what wasn't

mentioned was that not only does the treatment increase heart rate, but the incidence of nausea and vomiting in that study was 25 percent. In answer to question three about whether there are differences in individual sensitivity; individual sensitivity can only be established retrospectively, after an adverse event has occurred. Certainly some are more susceptible than others. is the same with cocaine, the majority of cases of stroke that are associated with ephedrine have This

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occurred in people with cerebral vascular abnormalities. However, cerebral vascular

abnormalities are not very uncommon; they affect about 1 percent of the population, and, you know, most of us don't have a prescreening MRI before we go to buy our dietary supplements. Ephedra is certainly associated with more adverse reactions when combined with other sympathomimetic. Okay, we don't know what, for which

subpopulations ephedra may be more dangerous, but we do know that virtually all of the adverse effects the associated with use ephedra alkaloids have had been when it was used for weight loss, recreational use, or

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bodybuilding. Asthmatics are apparently the only population who are responsibly using this herb. And

so I say there's no safe doses, but there are safe indications. For number four, are the outcomes associated with use of these products affected by dosage or other factors? Maybe, but we don't have enough information

to date to take the answer these questions and there's high variability in products which has already been mentioned. Ephedra should not be available in products that are labeled for weight loss, labeled for

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bodybuilding, fitness, energy enhancement, or recreational use. The only indications for which

ephedra products should be labeled are respiratory conditions. The National Women's Health Network would oppose taking ephedra off the market; for traditional use in traditional forms it is not hazardous. But

it's use for weight loss, exercise enhancement, or as an energizer are not traditional uses and any dose at which these effects occurs in overdose. [Applause.] DR. JONES: Thank you, Dr. Fugh-Berman. Thank you.

Questions from the panel?

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[No response.] DR. JONES: Questions from the floor?

[No response.] DR. JONES: Berman. Next Michael MGuffin, President of the American Herbal Products association. MR. McGUFFIN: Good evening, Dr. Jones, And thank Thank you very much, Dr. Fugh-

esteemed panel, members of the audience.

you for the opportunity to present an industry perspective on the safety of dietary supplements containing ephedrine alkaloids. My name is Michael McGuffin and I am

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President of the American Herbal Products Association or AHPA. AHPA is the national trade association and

voice of the herbal products industry comprised of companies doing business as growers, importers, manufacturers, and marketers of herbs in herbal products. AHPA serves its members by promoting the

responsible commerce of products that contain herbs. As some AHPA members sell products that contain botanical ephedra and extracts of ephedra we have an interest in the regulation and safety of such products. My presentation here will primarily summarize an ephedra survey undertaken by AHPA earlier

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this year.

I will provide quantitative information

tabulated in this survey on the total consumption or actually total sale of supplements containing ephedrine alkaloids and also on serious adverse events reported by consumers to manufacturers and marketers of these products. I will also discuss some of the manufacturing, marketing, and labeling practices that were observed in this survey. As other speakers have

acknowledged, AHPA has taken a lead on establishing industry guidance on the responsible sale of products containing ephedra since 1994 when a trade recommendation for such products was first approved by

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our board. This formal industry position has been revised from time-to-time and is currently supported by other trade associations including the National Nutritional Foods Association, the Utah Natural Products Alliance, and the Consumer Health Care Products Association. The policy which serves as a

condition of membership for all AHPA members who sells supplements containing ephedra consist of several elements. These include serving limits of 25

milligrams of total ephedrine alkaloids per serving and a 100 milligrams per day, a requirement to state the amount of ephedrine alkaloids on the product's

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label, a cautionary label statement that limits use to persons over the age of 18 that cautions against consumption of any amount in excess of the recommended serving size and against unsupervised used by persons with certain pre-existing conditions. It also

recommends against use in pregnancy, and it also recommends discontinuation in the event that specifically described side effects are experience. The industry position also prohibits the use of synthetics of ephedrine alkaloids and prohibits the marketing of any ephedra product as an alternative to an illegal street drug. AHPA and the others associations that I

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mentioned earlier recommended in May 1999 that FDA adopt these policies for all supplements that contain ephedrine alkaloids. Our organizations and others

have also worked to establish these guidelines as regulations in several states including Ohio, Missouri, and Hawaii. At the beginning of this year I APHA, through it's ephedra committee, sponsored a survey of companies that sell supplements containing ephedra or extracts of ephedra. The survey was administered by The

the accounting firm of Arthur Andersen, LLP. target companies were 42 manufacturers and/or

marketers including both AHPA and non-AHPA members,

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whose products were listed in the FDA's initial adverse event report as reported in the proposed rule published by FDA, June 4th, 1997. The survey consisted of a series of general questions regarding each company's overall business as well as specific questions related to current manufacturing, labeling, and marketing of supplement products containing ephedrine alkaloids. The survey

also requested quantitative sales information for each of the last five years. Of the four to 42 companies solicited Arthur Andersen received responses from 14, eight of the 14 respondents were AHPA members; all responses to the

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survey were confidential.

So the report received by

AHPA consisted of summarized aggregates of individual responses. The compiled results of the survey included the following data: the survey asked for information

regarding the principal purposes for which these products are marketed; 12 of the 14 respondents replied to these questions and reported such uses as we've heard here today; weight loss, energy, increased athletic performance, and for a few products, four products, for use for colds and asthma. A significant portion of the survey was designed to measure the degree to which these products

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are in conformity with the industry's trade recommendations. The maximum amount of total

ephedrine alkaloids recommended in each serving was reported to be less than 25 milligrams, the industry recommended maximum for all but one of the respondents' products. And this was a total of about

120 products between the 14 companies. The maximum amount recommended to be consumed within a 24-hour period was less than 100 milligrams, the industry-recommended maximum for all of the respondents' products. All respondents

reported that they use a cautionary statement substantially similar to the statement recommended by

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the industry standard, except that one of the 14 companies reported that it does not include the recommendation against use by persons under 18 years of age as is recommended by industry. All of the respondents reported that they state on their product's label the amount of ephedrine alkaloids contained in the products as recommended in our standard. All but one reported to their

manufacturing practice include testing of each lot of finished product to determine the labeled amount. Twelve of the 12 respondents who sell products that all so include xanthene alkaloids caffeine reported the quantity of these alkaloids is

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also disclosed on the label. All respondents reported that they do not use synthetic ephedrine in any of their products consistent with the industry's long-standing prohibition against use of such ingredients. One of

our primary interests in conducting the survey was to determine the breath of consumption of these products. We were only able to ask sales as we didn't have access to information about how many consumers that represents, or how many doses each of them took. The total number of servings sold by the 14 responding companies defined as the maximum amount to be consumed each use per the directions on the label

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was reported with each of the past five years.

The

total serving sod were reported to be 425 million in 1995; 585 in 1996; 976 in 1997; 1.75 billion in '98 and over 3 billion servings last year. This significant, ongoing, increase represents a more than sevenfold increase in sales in 1999 compared to 1995, and the average annual growth in sales volume of 64 percent in each of the intervening five years, and total sales of 6.8 billion servings over the five-year period. The final portion from the survey was designed to determine whether companies that sell these products are prepared to receive consumer

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complaints and to quantify any serious adverse events reported. For purposes of the survey a serious

adverse event was defined as quote, "any report of a person suffering a heart attack, stroke, seizure, death or other injury that resulted in hospitalization or treatment by a physician." The survey found that

all 14 respondents reported that they do have systems in place for collecting reports of serious adverse events, a total of 25 serious adverse events were reported to the 14 respondents in 1999 which can be calculated at just over 8 such reports with each billion serving sold A total of 66 serious adverse events was

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reported to the 14 respondents of the five-year period from '95 to '99 compared to the more than 6.8 billion servings sold in the same five-year period. This

total represents a reporting rate of less than 10 such reports per billion servings sold. Because the responses to the survey were confidential no follow-up was done to assess the legitimacy of any of these reports of serious adverse events; nor did the survey attempt to evaluate individual companies' procedures for collecting reports or establish any degree of probability between any report and any actual adverse event. All reports identified here should therefore

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be considered to be just that, reports filed by consumers. It is also valuable to note that although

the recorded, reported sales of supplements containing ephedrine alkaloids has increased more than sevenfold in the last five years. There has been no

commensurate increase in reports of adverse events gathered by FDA. In summary the AHPA ephedra survey estimated the total sales of products containing ephedrine alkaloids to have been over 3 billion servings in 1999 with a combined total of 6.8 billion servings sold in the past five years and an average annual increase in sales of 64 percent.

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The survey also found that in almost all of the ephedra products marketed by the survey's respondents are in full conformity with the industryestablish standards. Finally, the survey recorded that consumers of these products are reporting very few serious adverse events to the companies that market these products. AHPA has taken to position since 1994 that

acknowledges the use by persons over the age 18 of supplements that contain ephedrine alkaloids as a legitimate self-care option. Our association's trade

recommendations regarding the formulation, labeling, and marketing of such products now adopted broadly

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through the industry and by some state governments also acknowledges that such products must be treated with respect both by the companies that market them and by the consumers who use them. The survey sponsored by AHPA's Ephedra Committee provides for the first time some information toward the creation of a denominator against which all reports of adverse events could be measured. The

conclusion that should be drawn from this compiled data is the supplement products containing ephedrine alkaloids are safe when responsibly manufactured, labeled, and marketed in conformity with the industryestablish policies and responsibly used by consumers.

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It is my sincere hope that the information provided here today from the AHPA ephedra survey will assist the process of determining a national regulatory policy that protects consumers health as well as their access to supplements containing ephedrine alkaloids. Thank you. [Applause.] DR. JONES: Thank you, Mr. McGuffin. Dr. Salive.

Questions from the panel? DR. SALIVE:

Can you explain why you only

had a 33 percent response rate to the survey? MR. McGUFFIN: According to our Arthur We've hired Arthur

Andersen that's quite good.

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Andersen to do other surveys for us in the past primarily with regard to tonnage, how many pounds of different herbs are we using. percent in those. So with Arthur Andersen tells us, and this is a business, that if they get one-third response from a targeted audience, they considered that a quite successful response rate. DR. SALIVE: Out of those 42 companies what We're lucky to get 20

percentage are members of your association? MR. McGUFFIN: See, because the information

is blinded I did not actually see the list, although actually our committee did.

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DR. SALIVE: MR. McGUFFIN: saw that list.

Who they sent it out to? That's right, our committee

What we don't know is which responded.

Of those who -- I actually don't have that information, which portion were our members of the whole list. I do know that, as I said, eight of the

14 respondents were AHPA members, but I don't know of the 42 how many were. Again, we selected it from that group that FDA had already identified as possibly products of concern through their adverse event system. DR. JONES: Dr. Lieberman. Thank you. The question has

DR. LIEBERMAN:

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already come up today, how you established your daily dose and your single-dose levels and the issue it was suggested that that might be a scientific question. But I'm asking purely from a scientific perspective, can you give us the scientific criteria that would be used that were used to establish those levels? MR. McGUFFIN: We borrowed both the dosages

numbers and the cautionary language from the models of the OTC products. And also from the historical use

and extrapolation, as Dr. Fong said, you expect 2 percent alkaloids; the standard dose is six to nine grams, that's 120 and 180 milligrams and then tbe OTC maximum dose is 150 and we just went conservative from

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that.

But that's, as I recall, how it was It was some years ago. the cautionary statement looks

established.

And, again,

remarkably similar to that that is on the over-thecounter products. DR. LIEBERMAN: DR. JONES: DR. PHILEN: Thank you.

Dr. Philen. You mentioned that you do have

some adverse events reported; can you tell me sort of the type of personnel at the companies that would be collecting this information and then what they do with this information? MR. McGUFFIN: We did not ask those

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questions. DR. PHILEN: So you don't even have a wild

guess who is collecting this, if it's a clerk or a scientist? MR. McGUFFIN: We didn't and, you know, I'm

not here to present that I have all of the perfect answers in these few sheets of paper or in our first survey, but we really worked hard to get this survey undertaken, and some of what we felt like we had to do is get people used to the fact that it's really valuable to gather this information. I think that's a

fine idea to next time not only ask them, do you but ask for a description of it. Because we'd like to

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know.

You know the responsible industry really does

want good systems in place that captures this information and that does something with it if it is in fact indicative of concern. We really do want to

have such systems and support such systems; so I think that's a good idea going forward. DR. PHILEN: Well, you need to know how it's

handled and if it's reported to the appropriate people afterwards. MR. McGUFFIN: Right. this time. DR. PHILEN: DR. JONES: Thank you. Questions from the floor? Ms. We did not ask that

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Culmo. MS. CULMO: Cynthia Culmo, Association of Mr. McGuffin, do you know if

Food and Drug Officials.

those 25 adverse events were reported to the FDA? MR. McGUFFIN: MS. CULMO: We don't know.

And of your responders versus

your nonresponders, do you know the percentages that were your small companies versus your billion dollar sales companies? MR. McGUFFIN: companies. We asked mostly larger

We didn't really -- there was one idea

that we should poll all AHPA companies which includes about two-thirds of our members or quite small

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companies.

We did get some data on the sizes of the

companies though, and they tended to be -- I've got the study here and I could give your copy -- they tended to be large companies who responded. Better

than half of them were sales with sales above $50 million total sales including ephedra products. MS. CULMO: And was there a reason you

didn't inquire as to whether or not the reports had been forwarded to the FDA? MR. McGUFFIN: I don't believe there was a

decision not to as much as that we didn't consider that at the time. MS. CULMO: Thank you.

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DR. JONES:

Thank you.

Other questions from either the panel or the floor? [No response.] DR. JONES: much. MR. McGUFFIN: [Applause.] DR. JONES: The last of the abstract Thank you very much. Mr. McGuffin, thank you very

session, Dr. Robert Stark, Yale University. MR. RUBIN: Good afternoon my name is Paul

Rubin, an attorney in the Washington, D.C. office of Patton Boggs was. I'm actually scheduled to speak

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tomorrow on behalf of Metabolife, when I will introduce our expert panel. One of our distinguished

experts is speaking today, and I would now like to introduce him. Dr. Robert Stark is a graduate of Harvard Medical School. He did his residency in internal

medicine at the University of Pennsylvania and a fellowship in cardiology at the National Institutes of Health. Dr. Stark currently practices internal medicine and cariology in Greenwich, Connecticut and is a clinical assistant professor of medicine at Yale University School of Medicine. Since 1997 he has

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researched the safety and efficacy of dietary supplements used for weight loss and has been involved in evaluating FDA's adverse event reports for ephedrine. Dr. Stark will be discussing the safety profile of ephedra and ephedra caffeine combinations in dietary supplements including his assessment of the adverse event reports compiled by FDA. DR. STARK: having me here. Dr. Stark.

Thank you and thank you for

My participation today was funded by I'm here as a clinician.

Metabolife International.

I see internal medicine and cardiology patients in my office and in the hospital daily. And

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I mention that in part to explain why it is that I don't have attractive slides or a zipping PowerPoint presentation to back up my talk. I also mention it because I want you to have some understanding of the mindset and the context in which a clinician considers the issue of dietary supplements. On the one hand in favor of dietary

supplements are the centuries of experience in using them, are the scientific studies which I'll go into today, and also the satisfied experiences of current users. On the other hand weighing against the use of dietary supplements are the anecdotal adverse

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reports that randomly circulate.

There are also the

studies, many of which use primates which show some adverse effects. And finally tbe well-organized

collections of adverse events reports that are collected and analyzed by professionals and then are disseminated. To a clinician it's these latter

adverse event reports that carry an awful lot of weight. And I reviewed hundreds of reports three

years ago and a little over 100 early this year when the new set of AERs came out. And I'd like to share with you some of them that I analyzed that are exemplary of the majority, and then go on to talk about the research studies that

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were suggested by them. The first report may speak to what Dr. Marcel Salive, from an NIH asked about earlier today, and that is the existence of any positive rechallenge studies for adverse effects. This is a 29-year-old

woman who reported two separate adverse event occurring in 1996 and 1998. She unexpectedly became

pregnant twice while using depoprovera contraceptive and while taking Metabolife dietary supplement. She

indicated that she had seen a television special about women who take Metabolife and who get pregnant while they're on birth control. And she wrote to the FDA.

"I was on Metabolife when I became pregnant,

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both times.

I thought maybe this would be an example

of positive rechallenge but a subsequent FDA memo from an analyst, Dr. Morefski stated that this woman was found to have a uterine fibroid by her physician and so she was taken off of Depoprovera. Both pregnancies

occurred while she was off oral contraceptive. The Depoprovera was stopped and the woman became pregnant. Nevertheless this case remains one of the FDA collections of adverse event reports related to the use of ephedra and it's counted as among the 800 or now 1,100-some adverse events that have been collected. A second involved a 24-year-old man who was

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undergoing chemotherapy for acute limpoitic leukemia. He developed signs of both liver failure and chromium toxicity. In addition to receiving potentially hepatotoxic chemotherapy. He was also taking ephedra

and a nutritional supplement that contain greater than 1,400 micrograms of chromium. His serum chromium

level was measured at over 300 times the toxic level and he eventually had to have had to have a liver transplant due to chromium toxicity. Nevertheless his

case is listed by the FDA as been one of their adverse events related to ephedra alkaloids. as ARMS No. 13464 This is listed

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A last report, a similar report, involves a suspicious pelvic mass in a young middle-aged woman. This was a 40-year-old who noticed tennis balls size mass in her left lower abdomen. She had an ultrasound This was removed

and it showed a left ovarian cyst.

and was found to be an ordinary benign adenoma. Because she had been taking an ephedra supplement for the previous three weeks, she retained a lawyer to represent her. She actually had a history

15 years before work of having severe gynecological problems. She had a coloscopy and conization biopsy and then in the ensuing 15 years never went back to the doctor, never sought gynecological care, never had

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a Pap smear, and now presents with this mass.

There's

no known cause and effect relationship between ovarian cyst and the ingredients in ephedra supplements. This

ovarian cyst is probably just another incident in this patient's long history. Yet it is still listed as

being indicative of an ephedra-related problem Now, the accepted methodology for evaluating a suspected adverse drug reaction is usually to demonstrate actual exposure to drug or the agent and to demonstrate proximity of exposure, not to four months ago, or two years ago, but a reasonable time before the event to demonstrate production of a reaction or a response that has been previously

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recognized to be a response for that substance and then to prove the absence of significant contributing or other underlying medical conditions. In many of the cases that I reviewed that are now on permanent record with the FDA, there are major flaws in these specific areas. These reports

as such really don't form a sufficient basis to suggest or confirm a danger to health from a ephedra. In addition to these numerous AERs compiled by the FDA, I also reviewed relevant literature on ephedra use on the pharmacology and epidemiology of ephedra use, and looked at the reports, analysis reports authored by the expert reviewers who were

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retained by the FDA to evaluate the FDA's adverse event reports. I really didn't find sufficient

evidence to support a significant risk from ephedra or ephedra/caffeine containing combinations when taken in accordance with product labeling. And I based my conclusions on the following: the literature is in agreement that there is a legitimate role for single agent like ephedra or combination agent like ephedra and caffeine regimens in appropriate patients for promoting weight loss. Several studies by Astrup and by others have shown that there is a synergistic effect between ephedrine and caffeine in causing weight loss.

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Studies at the University of London and the Harvard Medical School also show that the combined regimen of ephedrine and caffeine was generally well tolerated, however, some patients did experience dry mouth, tremors, dizziness and insomnia and these were the drop-outs that were mentioned earlier. Also some patients had a four or five beat per minute increase in their heart rate. Another

study from the University of Copenhagen showed the most of these side effects declined over time back down to placebo levels usually by six or eight weeks of treatment. The ephedrine and caffeine dose ranges that

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were looked at in all of these studies which generally 72 milligrams per day of ephedrine and 240 milligrams per day of caffeine. These doses are identical to, or

even exceed, the doses that are currently recommended by dietary supplement manufacturers. And there

doesn't seem to be any causal link between these doses and serious adverse events. In addition, these are the same or similar doses that are already contained in common asthma and decongestant medications. The ephedrine contained in

Marax of the caffeine contained in extra-strength Excedrin, dwarf those levels that are found in the herbal supplements that we're discussing today.

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Even one of the FDA experts who reviewed this issue concluded that quote, "the ephedra doses in herbal products is similar to or less than that in bronchodilators or decongestants." For my review of the FDA adverse event reports and the literature and the reports of the experts reviewers, I don't find a sufficient evidence to support a significant health risk from ephedra/caffeine combinations when taken in accordance with recommendations and product labeling. The risk of experiencing adverse effects events presented by ephedra dietary supplements is no greater in magnitude than the new risk presented by

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over-the-counter drugs that contains synthetic ephedrine and the potential adverse events are similar to those associated with caffeine. The overall health risk associated with the ephedra/caffeine supplements is far less, for example, than that associated with the ingestion of peanut products by the general population because a small proportion of our population have peanut allergies. The same is true for shellfish products or certain additives like MSG. Ephedra supplements appear to be effective and safe in normal healthy populations, but they do present some risk when taken by certain people with

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pre-existing conditions which we've mentioned earlier. For people with no such predisposition, these supplements did not appear to increase the likelihood of cardiac events. Ingestion of ephedra can increase the heart rate as I mentioned before by for or five beats per minute, but this does not appear to be associated with adverse events in the absence of underlying pathology. I hope that when future AERs are collected by the FDA that they will be shared together with full accompanying clinical information with multidisciplinary panels of reviewers in order to accurately access the risk posed by these dietary

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supplements. I'd be happy to take questions. [Applause.] DR. JONES: Thank you, Dr. Stark. Dr. Philen.

Questions from the panel? DR. PHILEN:

Dr. Stark, I believe I heard

you say right at the beginning of your comments that you had, had a lot of reports of favorable experiences from using ephedra in your patients, but that the adverse reports were simply anecdotal. Now, if these favorable experience reports are to be, you know, accurately reported I guess I can say, then are you collecting these in a systematic

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fashion?

Do you plan to report these out as any kind

of a paper or technical thing? DR. STARK: I don't want to in anyway

suggest that I've collected favorable reports from patients. I merely said that in determining the

benefits versus the drawbacks one has to consider the long history of use, the favorable reports by current users. I'm not collecting adverse events or positive events. DR. PHILEN: anecdotal? DR. STARK: They are. So then are favorable reports

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DR. JONES: panel?

Any other questions from the

[No response.] DR. JONES: Questions from the floor?

[No response.] DR. JONES: very much. DR. STARK: [Applause.] DR. JONES: This concludes our abstract Thank you. Very good. Dr. Stark, thank you

session and we now move to Public Comment Session A. I just want to say a word of thanks to all of our speakers today that I've not had to be the

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strict disciplinarian that I've got this terrible reputation for an have had for about 30 years for keeping things on track and on time. I'm very much

appreciate everyone sticking to time limits and keeping their remarks to the point. We would now invite -- we have four commenters registered for this particular public comments session Samieh Wood, Hanna Zechzer, and I'm sorry if I have abused the name, David Molony and Pablo Francisco Semiao. If you would be a prepared

pleased to approach the podium, you will each have three minutes. And we will not be questioning you

about your remarks.

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We very much appreciate your coming.

My

personal opinion about science in the public interest is that science that we do in government is better served when the public has a role, so we very much welcome your comments. MS. WOOD: here from California. My name is Samieh Wood and I am I just want to say this, that

what every one of the little me the grass-roots level that everyday citizen out there, for every one of me there's hundreds or thousands of people whose voices will not be heard today. I also would like to make a comment that I sat there today and I heard the distinguish panel of

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the regulatory group who provided their research and I as a citizen, as a consumer, was very, very offended when one industry representative stood here and said "where is to beef?" Even though I've been a vegetarian for 25 years, I think I have some beef for the gentleman right now. In 1995, following a complete hysterectomy You know, we the ladies here the And I gained 25 to 30 That was

I was put on HRT.

boomers this is our turns now. pounds.

I went from size four to size nine.

very unacceptable for me. I went to the nearest health food store. said, "I need a diet pill." I

The lady who is there to

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this day gave me this ephedra drop and she said, "Samieh, this is a miracle pill. thank before this." Well, it was the miracle pill. lost the weight and also lost my mind. para -- psychosis. I took it. I You're going to

I suffered a

I entered the horrible dark zone

of my life that I've never ever want any woman to experience. I had to dropout of master's degree I was I

going for my second master's in family counseling. would sit there and I was blank. After three hours of lecture I couldn't comprehend, I couldn't retain anything that was said to me.

I would lock myself in the bedroom and my two

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teenage kids lost their mother.

It was a horrible,

horrible experience for any human being to have to go through. I also must say that I am the epitome of goods health. I've been a very vegetarian for 25

years I have never tasted a drop of alcohol in my life, I have never smoked a cigarette, I am antitobacco, antialcohol, antidrug. So when I took

that pill it went into a pure brain, right here, and it hit me right there. I would get in the car I would drive 80 miles in a 45 mile zone, and I would say, "what is happening to me, God? Why am I so abnormal?" but I

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couldn't stop myself. happening to me. citizen.

I didn't know what was

I became an abnormal dangerous

I was dangerous to myself, I was dangerous

to my family, I was dangerous to the road when I got on the road. That pill is a silent weapon, ladies and gentlemen. I cannot help but to remember 25 years ago

when I told my dad, "when you smoke, I can't breath. I wheeze in my chest." And he told me to shut up.

Twenty-five years later my dad died from lung cancer and everybody in this room now agrees that secondhand smoke can kill. And I think maybe it shouldn't take 25 years

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from now for the government to stop this silent dangerous pill called ephedra. Please let's that stop Thank

it before we have many people in the graveyard. you. DR. JONES: [Applause.] DR. JONES: Ms. Zechzer. Thank you, Ms. Wood.

And, oh, I'm sorry, Ms. Wood, for the record, would you please state the source of support for your travel here today? We do want our commenters

-- please to the microphone so we have this on the record. And just remind all our commenters to please

do so as well.

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MS. WOOD:

I found out about HEAT through

the newspaper article that was sent to me by an 83year-old Chinese friend of mine, my former professor from the University of Hawaii. I contacted Ms.

Barbara Michals on the Internet, and I said to her, "You have -- here is my credit card, I will pay for all my expenses, and I am devoted into fighting this ephedra pill." This is a crusade for me from now

until whenever I can. DR. JONES: The source of travel support to

be here at this meeting today, please? MS. WOOD: I provided my -- I don't know. I

provided my credit card.

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DR. JONES:

Ms. Michal -- no, just for the

record, my office supported your travel to come to the meeting today. MS. WOOD: I'm very grateful for that. I

didn't know that, but I'm very grateful for that. DR. JONES: MS. WOOD: DR. JONES: MS. ZECHZER: Thank you. Thank you. Ms. Zechzer. Dr. Jones and panel members, I

am Hanna Zechzer, here as a consumer at my own expense. My case was one of those reported to the FDA in 1998, through a Medwatch report by my health care provider.

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I am addressing question number one of an adverse reaction of heart and respiratory failure due to a dietary supplement containing ephedra with caffeine. At the time of my reaction I was 42 years old with no predisposing health conditions. The only

stimulant I was taking would've been an occasional cup of coffee or caffeinated soft drink. Two years ago I was taking an herbal supplement for weight loss as prescribed on the bottle. I had received a pamphlet in the mail and A doctor's claim in the enclosed

ordered the product.

literature said this was not a drug, but all

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ingredients were organic and natural.

The selling

factor for me was that it was all natural, so I thought it was safe. The label stated that the ingredients were ma huang and guarana. After taking the pills for

seven days I began experiencing a severe headache and felt very jittery. I then develop the chills, chest My A two-

pressure and a tingly feeling in my left arm. blood pressure was elevated at 150 over 100.

hour grand mall seizure followed which was eventually controlled and I was then intubated. My problems

worsened as doctors tried to figure out the reason for my decline, thinking it was neurologically related.

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A drug screen tested positive amphetamines of which I was not taking. I was transferred to a Upon

larger hospital with greater capabilities.

admission there I had a diagnosis of one seizure, etiology unknown; two, altered mental status; three, respiratory insufficiency despite ventilator treatment; four, hypotension requiring dopamine drip. An echocardiogram revealed severe cardiomyopathy with an ejection fraction of less than 15 percent. A cardiac catheterization revealed a

dilated hyperkinetic ventricle with reduction in ejection fraction. Hemodynamics, coronary arteries,

and aortic root were all normal.

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Another echocardiogram three days later still revealed severe myopathic left ventricle with five ventricle dysfunction. A repeat echocardiogram

seven days later revealed persistent severe diffuse hypokinesis with markedly depressed ejection fraction. The following day another echocardiogram revealed a normal left ventricle function with borderline concentric hypertrophy. The discharge summary states the principal diagnoses as multiple system -- excuse me, multisystem failure secondary to obesity drugs. Secondary

diagnoses are sepsis, respiratory failure,cardiogenic shock, congestive heart failure, rhabdomyolysis,

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tonoclonic seizure, obesity, urinary tract infraction, pneumonia. I was in the hospital for a total of 14,

ten of which was on life support. My children were faced with the possibility of losing their mother, my parents their daughter, my sisters their little sister. DR. JONES: minutes are -MS. ZECHZER: All because of my reaction to I was an unsuspecting Please wrap up. Your three

the dietary supplement ephedra.

victim because I did not know of the dangers of this ingredient. By the grace of God, I physically

recovered from this reaction with no permanent heart

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damage.

I am now being treated for post traumatic

stress disorder to deal with the emotional side to this. Thank you. DR. JONES: [Applause.] DR. JONES: Mr. Molony, the American Thank you, Ms. Zechzer.

Association of Oriental Medicine. MR. MOLONY: I'm the Executive Director of

the American Association of Oriental Medicine. The American Association of Oriental Medicine is the oldest and largest association of acupuncture and Oriental medicine practitioners and the United States with herbal medicine falling within

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our practice in many states and predominantly in our training nationally. Our profession is the only rigorous national certification examination for herbal medicine and there are diplomants of that exam in every state with over 5,000 licensed practitioners using herbal medicine in California alone. As licensed health care professionals we applaud the FDA efforts to protect the public from mislabeled products. Yet due to the potential

negative impact in of overregulation or outright removal of the availability of the herb on our privilege to provide such herbs to our patients we

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would like to see a clarification to proposed regulations of ephedrine-containing products that recognize a difference between the effects of ephedrine and ephedra. Many of the reports state first that the illness or death was related to ephedrine-containing diet and stimulant product then state that the most common source of ephedrine is the herb ephedra. We would like to point out that ma huang, ephedra sinensis is the first herb to be taught in the traditional Chinese system of herbology. Herbs are

classified in more than two dozen categories and always starts with ma huang as the first herb in the

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first category. To take away access to this herb would show disrespect to the well-educated practitioners of historical, traditional, and validated system of medicine that has licensed practitioners in most every state and would be similar to restricting use of the scalpel by surgeons. Interestingly enough, there are no traditional indications for the use of ephedra for either weight loss or stimulant use although there is recognition of its stimulant effect. that out. For more information on the use of ephedra I want to point

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we would like for you to refer to any of the many Chinese herbal textbooks on the subject. There is in

each book information on dosage, indications, and contraindications that have been in existence for hundreds if not thousands of years. I also want to note that almost every herb is historical used in formulation which accentuates the effectiveness of the herb while minimizing any untoward effects even with long-term usage, if that formulation is indicated for long-term usage. To summarize the regulation of ephedra needs further discussion from all parties. Use of ephedrine

for its thermogenic dietary stimulant stimulant

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properties is not a traditional indication in herbology and thus the herb needs for observation and understanding by both traditional herbal providers and conventional regulatory agencies working together. To severely restrict ephedra the herb from the public and especially from the armamentarium of qualified herbal practitioners because of the abuse of its alkaloid cousin ephedrine, or even for ephedrine's abuse by unscrupulous manufacturing should be avoided and its regulation dealt with in a rational manner. The development of dosage schedules should take into consideration age, weight, and even constitution should be developed with the input of

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classically trained herbalist as well as conventional scientists and regulatory staff. The American Association of Oriental Medicine would like to see continued availability and use of ephedra for its members and its profession and its profession and hopes that his forum is a stepping stone to continue discussion on the issue. As a

result we offer expertise of our educated and experienced herbalist to confer with issues around the usage of safety and control of all herbal products. Thank you. DR. JONES: [Applause] Thank you, Mr. Molony.

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MR. MOLONY: DR. JONES: Mr. Semiao. MR. SEMIAO:

And I paid my own way. Thank you. Thank you.

My name is Pablo Francisco

Semiao, I also paid for my own farecard to get down here and I represent a portion of the fitness industry. I'm a public health graduate student and I also or have been a certified personal trainer since 1994 by the American Council on Exercise. My concern over the sales of these dietary supplements comes from what I've heard and seen. the gym I hear: take these first thing in the In

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morning with some coffee and you'll be ready for workout. At a fitness seminar I hear: carbs are bad

for you if you're trying to slim down; so how do you get the energy to workout, fat burners. It's not really ephedrine it's only Ma Huang, instead in the bottle. For some time now I've

noticed personal trainers at fitness center and private studios prescribe and sell supplements containing ephedrine alkaloids without any regard for the safety of the consumer. Yet these trainers are

not registered dietitians or have credentials that will allow them to determine if the supplements would have any adverse side effects.

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They also do not pay attention is to warnings by the FDA or any other reputable journal studies. Their sources of information are usually muscle magazines.

off-the-rack

After supplying gym and studio managers and owners information from the FDA studies and articles about ailments, deaths, and side effects attributed to ingestion of these pills, they dismissed them with the belief that there is still need for long-term studies or for those who are actually educated say, they are within statistical variance Meanwhile, the risks to the consumer of dangerous side effects and even death will continue to

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exist until the marketers of these supplements choose to heed the warnings and stop their just to any person or until this product becomes controlled. The definition of the drug from Webster's dictionary is a substance other than food intended to affect the structure or function of the body. The

reality is that these supplements are drugs even though they are sold with warning labels and estimated safe dosages. Yet there should be some control of their distribution due to those unqualified marketers who have access to them and for the sake of marketing and for the sake of making a profit off the consumer

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without any concern for their health, especially to those women who are eager to lose weight to meet today's in vogue, slim physiques, or those who have coronary heart disease dangers. I would also like to emphasize that American Council on Exercise in its journal reminds its certified professionals to be mindful of professional limitations when working with clients. And their

chief exercise physiologist Richard Carlton also reminds that recommending supplements is beyond the scope of practice off all certified professionals. Most dietitians will not even recommend them especially the stimulants.

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In 1994, Congress passed and President Clinton signed the Dietary Supplement Health and Education Act. This legislation eliminated FDA's

authority to regulate the safety of nutritional supplements before they are on the market. Now, the

FDA can intervene only after an illness or injury occurs. The FDA can still restrict the sale of unsafe dietary supplements when there is evidence of the product which presents a significant or unreasonable safety concern. But now the agency must

wait for complaints about a product before acting. As a responsible certified trainer and

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health professional, I submit my complaint and recommend that the FDA make an effort to control or regulate the marketing of dietary supplements containing ephedrine alkaloids for the protection of the consumer. This is not as much as for the product Thank

itself but for its availability to just anyone. you. [Applause] DR. JONES: Thank you, Mr. Semiao.

That concludes our scheduled day. In terms of tomorrow, we will open at 9 a.m. with just a brief recap of logistics and introductions. And then we will start a public common

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session.

We have had one change in the agenda.

Scheduled a 10:01 a.m., Dr. Jerry McLaughlin will speak. We apparently lost an abstract somewhere in

the submission there and we are plugging him into the end of the public comment session, and apologize to Dr. McLaughlin. Otherwise we will see you back here at nine o'clock. Please turn in your badges, they will be here in the morning you can check-in. If you are scheduled for public comment, please see your number in the agenda, if you choose to sit in the chair with a number on it our staff will

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facilitate your getting up here and be ready for all that. Thank you very much. Have a nice evening.

[Whereupon, at 5:25 p.m. the meeting adjourned to reconvened on August 9, 2000, at 9:00 a.m.]

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C E R T I F I C A T E This is to certify that the foregoing public meeting on The Safety of Dietary Supplements Containing Ephedrine Alkaloids, held on Tuesday, August 8, 2000, was transcribed as herein appears, and this is the original transcript thereof.

____________________ Gerald Brooks Court Reporter

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