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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 Registration

9:00 am OPENING

Wanda K. Jones, DrPH, Director

Office of Women's Health

9:10 am Ephedra-containing Compounds: Historical

and Pharmacologic Context

Harry H.S. Fong, Phased, University of

Illinois, Chicago

9:50 am BREAK

10:05 am Adverse Event Reports: Database and

Clinical Studies

Lori A. Love, MD, PhD, FDA

Julie G. Bietz, MD, FDA

George Ricaurte, MD, PhD, Johns Hopkins

University School of Medicine

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Raymond L. Woosley, MD, PhD, Georgetown

University School of Medicine

Cynthia Culmo, Texas Department of Health

11:50 am Q&A

12:10 pm LUNCH (on your own)

1:10 pm Adverse Event Reports: Ephedra Education

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 Q&A

3:15 pm BREAK

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Public Meeting: Safety of Dietary Supplements Containing

Ephedrine Alkaloids

3:30 Abstract Session I

3:30 Barbara J. Michael, HEAT

3:45 Q&A

3:50 James S. Turner, Swankin & Turner

4:05 Q&A

4:10 Linda Golodner [Brett Kay], National Consumers

League

4:25 Q&A

4:30 Col. Esther F. Myers, PhD. RD, FADA

U.S. Air Force

4:45 Q&A

4:50 Adraine Fugh-Berman, MD National Women's Health

Network

5:05 Q&A

5:10 Michael McGuffin, President, American Herbal

Products Association

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5:25 Q&A

5:30 Robert M. Stark, MD, FACP, Yale University

5:45 Q&A

5:50 Public Comment Session A

5:50 1. Samieh Wood, Private Citizen

5:53 2. Hanna K. Zewchzer, Private Citizen

5:56 3. David Molony, American Association of

Oriental Medicine

5:59 4. Pablo Francisco Semiao, Private Citizen

6:02 p.m. 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: 9:00 a.m.]

DR. JONES: Good morning, everyone. My name

is Wanda Jones. I am the Director of the Office on

Women's Health. 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

available to the docket as quickly as possible. We

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. I am glad to see

so many of you here this morning. I think I've talked

to virtually every one of you on the telephone. It

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. And we are very grateful

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

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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. The

restrooms are in the long corridors. 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. They are around and we can get you

attendance. 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. Is that

microphone work now?

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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: Thank you very much Secretary

Jones. 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. I

think we are one of two and Dr. Coates up there has

something to do with us getting some funds. So let me

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.

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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

get down to my presentation. Is this mike working?

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. I'm sure everyone here knows what

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

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. And this is just some

example. I don't expect you to read this slide from

way back in the room. I just want to emphasize in

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. So I'm

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

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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. Hence one has also a

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

because I haven't read too many clinical reports. Of

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. As we

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

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. Not

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

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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. You

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. At two times the does

one can have adverse events. Most of the adverse

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

can't take decongestion of this of product. If I take

and pseudoephedrine or ephedrine, my heart will be

pumping a mile a minute. So there are idiosyncratic

reactions.

The most severe reaction is hypertension.

That is the most important event caused by high dose

or prolonged use. Arrhythmia and tachycardia also

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. One can

have an adverse event.

Now, the potential drug interactions of this

drug ephedra, ephedrine is a drug. It's a CNS

stimulant. 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: Jeffrey Reinhart, People for

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

you know how to do these things. Some of it just

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

racemic situation with phenylpropanolamine. My

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. See if my pointer will work here, here we

go. So look at here, there are two asymmetric carbon

atoms in the structure of ephedrine. Okay? Now, we

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

they go in different directions. Okay.

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. It

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

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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: Seeing none.

DR. BRAY: 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. The study that you're talking about

is a valid study. 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

placebo group there is statistics significance. My

question mark isn't whether it does reduce weight. My

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: I would note then that we are

concluded on time. 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

we're scheduled for a 15-minute break. It will give

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. We

will see you in 15 minutes. We will be starting on

time at 10:05 a.m. 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. Thank

you.

DR. LOVE: Dr. Jones, panel members, and

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. So in 1993, I'm not sure if I know

how to use this.

1993 was when FDA first indicated its

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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. In

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

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Committee which is the general scientific advisory

committee that we have in FDA. And at this time we

really evaluated all available information. There

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. The full Food Advisory

Committee was convened. 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

ingredients. They are usually combined with other

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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. They come from medical

practice. 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

the most infrequent. A well-controlled clinical trial

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

ephedra was only considered a medicine. It with

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

you have heard what has been said. There were many

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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. There have been a

number of efforts. 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 case-

controlled 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

these cases and how should we study them. So we

picked a time frame, and we picked June 1st, 1997, I

have a typo there, 07. Which is very close to the

time that we published the proposed rule. and we took

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. And

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

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. And we're

hoping we hear some today, thank you.

[Applause.]

DR. BIETZ: Dr. Jones, panel members and

guests, this morning I will present an analysis of

adverse event reports for ephedrine alkaloid

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containing dietary supplements.

DR. JONES: F the record, Julie, please

identify yourself.

DR. BIETZ: I'm sorry?

DR. JONES: Give your name -- just for the

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

were not readily evaluable. Three cases were

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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

with a range of 15 to 64 years. More cases occurred

in women than in men. All cases were reported to have

occurred during the use of an EADS product. Seventeen

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. More cases occurred

in women than in men. 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 in-

depth 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

system adverse events were most common. Based on

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. RICAURTE: Dr. Jones, members of the

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panel, ladies and gentlemen, good morning. My name is

George Ricaurte. 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 ephedra-

containing 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 ephedra-

containing 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,

the middle, an the bottom. Just focus on the middle

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 full text of your remarks

into the record. 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. I have a Ph.D. in

pharmacology. 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. This was a trial that ended in

1988. 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. And that began my interest in cardiac

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 --

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. Three were rated as a

four. 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. So dosage can't explain

all of this. 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. It

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

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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. So to me the risk benefit ratio

is just unacceptable. Thank you.

[Applause.]

MS. CULMO: My name is Cynthia Culmo. I am

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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

regulatory perspective on this issue. I don't have a

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 well-

controlled 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

lists, one, and two. I'll quote three: "the

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. An

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

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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. The question addresses efficacy and not

safety.

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. The true

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 ephedrine-

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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? Outcomes may be

affected by dosage. 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: Could you please wrap up or get

to a conclusion?

MS. CULMO: Okay. I need to wrap up here.

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. AFDO

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

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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. Thank you.

DR. JONES: Thank you, Ms. Culmo.

[Applause.]

DR. JONES: And thank you to all panel

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. I

don't recall in 140 cases if there were any. I seem

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

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: Thank you. Dr. Coates.

DR. COATES: Thanks very much. I have --

DR. JONES: For the record, Paul, would you

state your name?

DR. COATES: I'm Paul Coates, from the

Office of Dietary Supplements at NIH. I have two

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: I have not heard that it's been

published. It was published in abstract form in FASEB

in 1999.

DR. COATES: And the Calman study?

DR. LOVE: The Calman study, I forget the

journal it was just recently published in 2000.

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DR. COATES: And then I wonder whether --

the number were going by fast before me. I was

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

ask one question of Dr. Ricaurte. Dr. Ricaurte, you

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. I

have a question for Dr. Woosley. How much of an

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

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

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

products are regulated very differently. But my

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. The

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

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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. Dr.

McLaughlin.

DR. MCLAUGHLIN: Jerry McLaughlin from

Nature Sunshine Products. I have three questions.

The first relates to the therapeutic index of the

ephedrine. I learned a long time ago that you can't

believe everything that Harry Fong says. And saying

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. I

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. Find

those calculations I have my Merck index I could

certainly help figure that out right now.

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. And all the reports today

neglected that. 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

your lowest dose is like 70 times -- it was .5? Okay.

So seven times then. So your lowest dose

was seven times the usual dose. Now, you said okay

there are some people who do take more than that. But

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

information that we could provide that. Yes we have

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: I'll give you some

information tomorrow.

DR. JONES: Dr. Woosley.

DR. WOOSLEY: I would like to address the

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: Thank you, Dr. Woosley. Ms.

Culmo.

MS. CULMO: Can I quickly address the

denominator issue? Industry consistently relates this

denominator of 2 to 3 billion servings sold. He just

alluded to the fact that he could give her data

tomorrow. It will be on servings sold. There is not

information on actual denominators consumed. We have

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. And, again, I would

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

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. And

I commend Cynthia Culmo for doing that.

DR. JONES: We have asked people. Dr.

Woosley did as well. 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: I understand that. Thank you.

DR. JONES: 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: Funding even from government to

support your research?

DR. RICAURTE: All of funding for my studies

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: And second question for Dr.

Ricaurte. 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: Thank you.

DR. JONES: Thank you. Let me take the

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

Dr. Woosley, or anyone else on the panel. What is the

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: Thank you. Yes, sir.

MR. LAFABI: Hi, I am Bob Lafabi. I am a

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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? I expected

to hear a lot about AERs. 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: Thank you. Get to the question

please.

MR. LAFABI: I'm sorry?

DR. JONES: Get to the question, please.

MR. LAFABI: The question is, how can anyone

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

brief statement -- a sentence. I think the concluding

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

pharmacology of the these substance. And therein

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: And to your question, sir -- oh,

Ray go ahead.

DR. WOOSLEY: I was just going to say, I

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. There is a lot more work that does

need to be done. 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. The

primary question that we addressed was, does 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. And others

will address these issues as the present.

I'm going to focus on the adverse event

reports. In addition we had available additional data

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. In addition, even

associations dan be wrong. The reason for this is

pretty straightforward. Events may simply be due to

background risk. That is, they may have happened

anyway. 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

survive to come to the hospital. So, again, if

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? These are some

data from the literature. 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. Cardiac arrest,

18 percent. 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

report carefully you'll see a could of things. Number

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

decrease reporting rates too. But essentially, the 1

percent was for all dietary supplements and it was a

guess.

And the basis for that guess was a guess. A

the only example that was given in that paper was L-

tryptophan which as, you may know caused use and

aphelia myalgia syndrome in which Dr. Walker was

concerned that there was underreporting. If you read

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 may use that as a lower risk and

we do.

So for our calculation we used reporting

rates of 10 percent. And we used this based on the at

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

percent. We could have said 60 percent. We really

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. Next

slide. No, wait, I don't want to turn to the nest

slide.

We wanted to compare this to the background

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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

seizures at 3.6 per 100,000. This is below the

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. So it

goes from 5 to 60. 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 50-

year-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. It's impossible to

say what the actual number is. 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. This is that

same study of young women here,

And again as we very our assumptions the

numbers change, but, again, most of the numbers are

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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

come down. So it's quite hard to compare.

And in fact it is hard to compare. There

are numerous limitations to this. We had to make

numerous assumptions to obtain our incidence upsets

estimates. We tried to vary it over a reasonable

range and we tried to be conservative. This not a

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. We know

that exercise can be a trigger for myocardial

infraction and sudden death. The population

statistics don't pick out the population. You also

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. And the purpose of putting up this slide

is two fold. 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. I reviewed the study from epidemiological

perspective. I understand others are going to present

this in great detail. I'll give you my own quick

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

about this a lot. We believe that all labeling of

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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: Thank you, Dr. Kimmel. Could we

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

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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

staff of a number of the health agencies. The only

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

have looked at this. I'm going to show the two Dr.

Gurley and his team. In the first one in 1997 they

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. And he found that in 14 he found no

PPA at all. 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

found 4 percent in 4.3 Basalt and Cravey in '97 came

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. The fact

that their study it went up to 18.2 percent. 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? And my opinion, I think this is

appropriate. 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. But the half time is

basically about the same. Gurley also did a similar

study and he found a slightly slower absorption to

ephedra alkaloids from pills than from gel caps. So

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

deal with the adverse effect of ephedra products. And

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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. But

the pathology has been there, according to the

pathologist, for a couple weeks and it was a necrosis

with repair. There had been no exposure to the

ephedra products within the prior 24 hours. In

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. But there are other risk

factors involved.

On the two hypertension cases these were

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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

like it was immune mediated hepatitis. On intulethias

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: I'd like to introduce Dr. Steven

Karch.

DR. KARCH: Good afternoon. My name is

Steven Karch. I'm an assistant medical examiner in

San Francisco. I'm a cardiac pathologist, my

principal interest is in the investigation of drug-

related 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. The sole support for this statement is

citation 82. 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 321-

pound, 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? Well, I

have two comments to that. 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. I

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

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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. In

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

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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

cannot be derived from AERs only reporting rates. In

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. It is

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.

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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. Even

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

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. One report was quite thorough, 230

pages. The remainder were of some intermediate

length. 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. Thirteen of the

cases had an autopsy done. 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

to me explained by congenital cardiac problems. The

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. I do not know the basis for that

interpretation. 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. None of these individuals had an

autopsy performed. The information on exposure was

very unclear. 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

and infectious etiology. The exposure here was

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

illness because there were pulmonary symptoms. The

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: Dr. John Olney will now

speak.

DR. OLNEY: I'm John Olney, Professor of

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. That was to perform research as a

career scientist. That award has been renewed every

five years for the last 30 years. And I've received

other honorary awards and elected member to the

National Academy of Sciences.

Why am I here? I'm serving as a consultant

to the Ephedra Education Council. Specifically they

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, placebo-

controlled, 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 placebo-

controlled.

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. It appears that

the FDA position is self-contradictory. 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 over-

the-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 APHA-

recommended 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: Good afternoon. My name is

Edgar Adams. 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 substance-

related 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. All I wanted to show is two

things. 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." It's usually

dependence. And when people think of addiction they

typically think of compulsive use. But the

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

for weight loss. She wanted to lose weight for

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

the way, it's unclear where it came from. I'm

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. I am not going

to go through them all. 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

with her husband and abusive arguments, et cetera. So

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-the-

counter 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

reports in the hospitals that report to Dawn. The key

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.

I have a question. You reviewed all the

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. I

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: 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: The problem with --

DR. FARBER: Frankly, there weren't many of

them.

DR. KIMMEL: It a small number. The problem

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. So it's hard and I

don't think.

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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.

DR. BURSTEIN: Aaron Burstein, Clinical

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: Right. Let me get my data on the

study. Okay. The White study did pertain to the use

of a dietary supplement ma huang. It was the

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.

DR. BURSTEIN: So, I think that is important

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

the reason I didn't really emphasize it. We really

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. How were the 22 deaths

selected for your review? 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: I think they came from -- it

was in March of '97.

DR. FARBER: The 22 deaths were the total

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

since March 1997, if I'm correct. I don't recall

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

on the first 11 cases that I looked at. I haven't

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

has to do with the denominator. Thank you Dr.

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: You can't tell that from this

at all. 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: Dr. Philen, did you have a

follow-up question?

DR. PHILEN: No.

DR. JONES: No? Okay.

One question then from me. I comment AHPA

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. I

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

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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. This is last in

total ephedrine alkaloids. In addition Dr. -- I'm

sorry if I pronounce it wrong -- Enchiosa, who wrote

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 over-

the-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.

DR. JONES: The panel that is presenting is

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: I can speak to the method of

meta analysis. Per case series I would call it a

summary, there's nothing to meta analyze per se. Meta

analysis really are applicable to randomized trials.

MR. REINHART: So you need double blinds.

DR. KIMMEL: 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? Would you say you for fulfilled

those criteria?

DR. KIMMEL: Could you restate the question?

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: Thank you.

DR. JONES: Next question, please.

MS. FUGH-BERMAN: Adriane Fugh-Berman,

National Women's Health Network. There are a number

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: Well, I left it because it's not

a cardiomyopathy. It is a florid myocarditis. I

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

shown to a cardiac pathologist. And I would like to

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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: There's another interesting

aspect about that case. 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: I admit to being confused

here. 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. Is that

the product that you're saying contains

pseudoephedrine and not ephedrine?

DR. FARBER: It's in the AER record. It's

plain and simple, the sample was picked up and

analyzed any it didn't contain any ephedrine. And

this analysis was done by Food and Drug.

DR. PAGE: It sounds like we're talking

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: Thank you.

DR. KARCH: 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: Dr. Salive, final comment or

question.

DR. SALIVE: Well, I wanted to ask the

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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: I assume that's me who is the

cardiologist. A couple of things. First of all I

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

population you can postulate for anything. You can

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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. I totally agree with

that.

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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. We will

reconvene at 3:30. 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. We will see you in

about 10 minutes.

[Brief recess taken at 3:20 p.m.]

DR. JONES: Ms. Michal, if you would, as

we've done with the others, identify yourself. For

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. And this is just the tip of the

iceberg. The surveys that we are receiving are: (1)

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. Some may be only

caffeine ephedrine and aspirin. 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. All natural does not equal

safe. 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. But

these are comments that we receive: "It's a shame

what we will try to lose a few pounds. I took

someone's word that it was not dangerous. I'm very

shocked." "A friend and colleague of mine died

yesterday, he just turned 40. He was a weightlifter

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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. "I tried this

product for two weeks. I've been off it for three

weeks now and I'm still trembling and nervous. I

can't concentrate at work and I'm very nervous when I

drive. It has subsided considerably in the last week,

but it is still affecting my work. I have talked to a

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

suffered stroke. I think is all because of the herb,

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

the shelves fast. I am mad that our government lets

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: Please wrap up.

MS. MICHAL: I'm sorry.

DR. JONES: You're out of time, please wrap

up.

MS. MICHAL: I wanted to let you know that I

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have surveys here, direct surveys, 39-year-old woman,

acute kidney failure, 40-year-old woman, primary

pulmonary hypertension. The only cure is lung

transplant. 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: Thank you, Ms. Michal.

[Applause.]

DR. JONES: We are open for questions from

the panel, if any?

DR. SALIVE: 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: We thank you very much, Ms.

Michal.

And turn now to Mr. James Turner of Swankin

& Turner.

MR. TURNER: Good afternoon. My name is

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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

relationship with ephedrine, they like it. They think

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. Both sides of that equation need to be

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

all consumers in these areas into consideration. Our

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

with the ephedra industry. We have paid our own --

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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: Thank you, Mr. Turner, for the

record.

Questions from the panel? Dr. Coates.

DR. COATES: 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. Or

to support that.

DR. JONES: Other questions from the panel?

[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. As

more consumers turn to dietary supplements to self-

medicate and improve their health, the safety these

products must be ensured. Further, as consumer take

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. So these are pretty new

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

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. We asked what resources to

help decide which OTC take. The number one response,

information on the label. 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? I think this is a very important and

telling. 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 for

longer than recommended.

We can extrapolate this out to them taking

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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. I will

accept any questions.

DR. JONES: Thank you, Mr. Kay. This

presentation is now open for questions. Panelists,

any questions? Dr. Philen.

DR. PHILEN: Rossanne Philen from the

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Centers for Disease Control.

DR. JONES: We can't hear you.

DR. PHILEN: I'm Rossanne Philen from the

Centers for Disease Control and Prevention. I believe

I heard you say that you collect adverse event

reports; could you tell us more?

MR. KAY: No.

DR. PHILEN: No?

MR. KAY: We do not collect adverse event

reports. I was talking about the ones collected and

documented from the FDA.

DR. PHILEN: From the FDA?

MR. KAY: 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.

DR. PHILEN: Okay.

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: Thank you.

DR. JONES: 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: But what they consider reliable

sources. 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: Okay. Questions, from the

floor?

[No response.]

DR. JONES: No. Mr. Kay, there might have

been a paper that dropped from your sheaf there.

MR. KAY: Thank you.

DR. JONES: Thank you very much, Mr. Kay.

[Applause.]

DR. JONES: Let me now call Col. Ester Myers

from the U.S. Air Force for presentation.

COL MYERS: Good afternoon, Dr. Jones, panel

members. 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. As far as I know I have

no conflict of interest.

As you so mentioned the government owns us.

[Laughter.]

COL. MYERS: The unique military concerns

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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. And let me explain a little bit

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

be addressed in each of these issue. And I'll mention

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. The

labeling requirements differ. Right now 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. There is a an entire regulation

that deals with that. 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

is our commissary, our grocery store. And a third

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. It says "more is not better

specifically." 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. In

other words contact your provider before you take

these items.

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

the health-care providers. So we did create a trifold

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. We are looking at how to enhance

that. 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. Right now we only have them in

the AAFES.

Bottom line, in the military we are very

concerned. We need to make sure that we safeguard

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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: Thank you Col. Myers. Questions

from the panel? Dr. Schwetz.

DR. SCHWETZ: You mentioned a special

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warning for pregnant women and children, can you say

more of what that warning says? If you would supply a

copy for the record?

COL. MYERS: I can give you a copy for the

record, I certainly can.

I think that is says specifically, consult

your physician. But I can get that for you.

DR. JONES: Dr. Philen.

DR. PHILEN: Col. Myers, does the Air Force

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

can see how it goes through channels. One was a

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: But those data could be

obtained theoretically? They could be requested, let

me put it that way?

COL. MYERS: The could be requested.

DR. JONES: We can ask for anything.

[Laughter.]

DR. JONES: Other questions from the panel?

[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: The precautionary labeling,

yes.

DR. JONES: Yes, the precautionary notice.

As well, you held up a trifold brochure, if you would

provide that for the record as well we would

appreciate that.

COL. MYERS: I certainly will.

DR. JONES: Thank you very much, Col. Myers.

Dr. Fugh-Berman.

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DR. FUGH-BERMAN: Good afternoon, I am

Adraine Fugh-Berman. I am a physician and vice chair

of the National Women's Health Network which is a

consumer advocacy group that's independent, member-

supported, 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 does not cause side

effects in everyone. 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." Still

recommended dosages on these OTC drugs is up 150

milligrams a day. And I would say that in an ideal

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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. Low

energy and wanting well-defined muscles are not

medical conditions. And while obesity is associated

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. Good reasons for

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

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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. This

is the same with cocaine, the majority of cases of

stroke that are associated with ephedrine have

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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. Thank you.

[Applause.]

DR. JONES: Thank you, Dr. Fugh-Berman.

Questions from the panel?

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[No response.]

DR. JONES: Questions from the floor?

[No response.]

DR. JONES: Thank you very much, Dr. Fugh-

Berman.

Next Michael MGuffin, President of the

American Herbal Products association.

MR. McGUFFIN: Good evening, Dr. Jones,

esteemed panel, members of the audience. And thank

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 accounting firm of Arthur Andersen, LLP. The

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 industry-

establish 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 industry-

establish 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.

Questions from the panel? Dr. Salive.

DR. SALIVE: Can you explain why you only

had a 33 percent response rate to the survey?

MR. McGUFFIN: According to our Arthur

Andersen that's quite good. We've hired Arthur

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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. We're lucky to get 20

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

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: Who they sent it out to?

MR. McGUFFIN: That's right, our committee

saw that list. 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.

DR. LIEBERMAN: Thank you. The question has

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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

established. It was some years ago.

And, again, the cautionary statement looks

remarkably similar to that that is on the over-the-

counter products.

DR. LIEBERMAN: Thank you.

DR. JONES: Dr. Philen.

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. We did not ask that

this time.

DR. PHILEN: Thank you.

DR. JONES: Questions from the floor? Ms.

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Culmo.

MS. CULMO: Cynthia Culmo, Association of

Food and Drug Officials. Mr. McGuffin, do you know if

those 25 adverse events were reported to the FDA?

MR. McGUFFIN: We don't know.

MS. CULMO: 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: We asked mostly larger

companies. 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: Mr. McGuffin, thank you very

much.

MR. McGUFFIN: Thank you very much.

[Applause.]

DR. JONES: The last of the abstract

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.

DR. STARK: Thank you and thank you for

having me here. My participation today was funded by

Metabolife International. I'm here as a clinician.

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. This is listed

as ARMS No. 13464

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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

and it showed a left ovarian cyst. This was removed

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.

Questions from the panel? Dr. Philen.

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: So then are favorable reports

anecdotal?

DR. STARK: They are.

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DR. JONES: Any other questions from the

panel?

[No response.]

DR. JONES: Questions from the floor?

[No response.]

DR. JONES: Very good. Dr. Stark, thank you

very much.

DR. STARK: Thank you.

[Applause.]

DR. JONES: This concludes our abstract

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: My name is Samieh Wood and I am

here from California. 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

I was put on HRT. You know, we the ladies here the

boomers this is our turns now. And I gained 25 to 30

pounds. I went from size four to size nine. That was

very unacceptable for me.

I went to the nearest health food store. I

said, "I need a diet pill." 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. You're going to

thank before this."

Well, it was the miracle pill. I took it. I

lost the weight and also lost my mind. I suffered a

para -- psychosis. 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

going for my second master's in family counseling. I

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. I didn't know what was

happening to me. I became an abnormal dangerous

citizen. 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

it before we have many people in the graveyard. Thank

you.

DR. JONES: Thank you, Ms. Wood.

[Applause.]

DR. JONES: Ms. Zechzer.

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 83-

year-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: Thank you.

MS. WOOD: Thank you.

DR. JONES: Ms. Zechzer.

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

ordered the product. A doctor's claim in the enclosed

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

pressure and a tingly feeling in my left arm. My

blood pressure was elevated at 150 over 100. A two-

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

larger hospital with greater capabilities. Upon

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: Please wrap up. Your three

minutes are --

MS. ZECHZER: All because of my reaction to

the dietary supplement ephedra. I was an unsuspecting

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: Thank you, Ms. Zechzer.

[Applause.]

DR. JONES: Mr. Molony, the American

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. I want to point

that out.

For more information on the use of ephedra

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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: Thank you, Mr. Molony.

[Applause]

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MR. MOLONY: And I paid my own way.

DR. JONES: Thank you. Thank you.

Mr. Semiao.

MR. SEMIAO: 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. In

the gym I hear: take these first thing in the

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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

off-the-rack muscle magazines.

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

itself but for its availability to just anyone. Thank

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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