UNITED STATES OF AMERICA

    	FOOD AND DRUG ADMINISTRATION

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    	CENTER FOR DRUG EVALUATION AND RESEARCH

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    	NONPRESCRIPTION DRUGS ADVISORY COMMITTEE

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    	SAFETY ISSUES RELATED TO

    	ACETAMINOPHEN

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    	MEETING

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    	THURSDAY,

    	SEPTEMBER 19, 2002

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The Advisory Committee meeting was held in the Maryland Ballroom, Hilton
Silver spring Hotel, 8727 Colesville Road, Silver Spring, Maryland, at
8:00 a.m., Louis Cantilena, M.D., Ph.D., Chairman, presiding.

[PRESENT]{.underline}:

LOUIS CANTILENA, M.D., Ph.D., Chairman

SANDRA TITUS, Ph.D., Executive Secretary

LESLIE CLAPP, M.D., Member

[PRESENT (Continued)]{.underline}:

FRANK F. DAVIDOFF, M.D., Member

JULIE A. JOHNSON, Pharm.D., Member

Y.W. FRANCIS LAM, Pharm.D., Member

SONIA PATTEN, Ph.D., Member/Consumer Representative

DONALD L. UDEN, Pharm.D., Member

HENRY W. WILLIAMS, JR., M.D., Member

ALASTAIR WOOD, M.D., Member/Consumer Representative

[SGEs PRESENT]{.underline}:

ERIC BRASS, M.D., Ph.D.

MICHAEL COHEN, R.Ph., M.S., D.SC.

STEPHANIE Y. CRAWFORD, Ph.D.

BYRON CRYER, M.D.

JOHN CUSH, M.D.

RALPH D\'AGOSTINO, Ph.D.

RUTH S. DAY, Ph.D.

JANET ELASHOFF, Ph.D.

CURT DANIEL FURBERG, M.D., Ph.D.

NATHANIEL KATZ, M.D.

LOREN LAINE, M.D.

RICHARD NEILL, M.D.

PAUL B. WATKINS, M.D.

H. JAMES WILLIAMS, M.D.

MICHAEL C. ALFANO, D.M.D., Ph.D. (Non-voting)

WILLIAM LEE, M.D. (Non-voting)

[FDA MEMBERS PRESENT]{.underline}:

RIZWAN AHMAN, M.D., M.P.H.

JULIE BEITZ, M.D.

JONCA BULL, M.D.

STEVE GALSON

CHARLES GANLEY, M.D.

WILLIAM GILBERTSON, Pharm.D.

JOHN JENKINS

DEBBIE LUMPKINS

PARIVASH NOURJAH, Ph.D.

JOHN SENIOR, M.D.

[ALSO PRESENT]{.underline}:

DEBRA BOWEN, M.D.

SHERYL JENKINS

RAYMOND S. KOFF, M.D.

JOHN SLATTERY, Ph.D.

ANTHONY R. TEMPLE, M.D.

STEPHEN COOPER, M.D.

JOHN DENT, M.D.

ALLEN HELLER, M.D.

RAY BULLMAN

PAUL DAUGHIN, M.D.

SARAH ERUSH, Pharm. D.

MS. KATE

LOUIS LASAGNA, M.D.

[ALSO PRESENT (Continued)]{.underline}:

PETER LURIE, M.D., M.P.H.

CAROLINE RIELY, M.D.

SUSAN WINCKLER

C-O-N-T-E-N-T-S

Introductions 6

Conflict of Interest Statement 9

Introduction to Topic, Dr. Charles Ganley 11

Overview of Acetaminophen Labeled Warnings,

Dr. William Gilbertson 18

FDA Presentations:

Acetaminophen Overview, Dr. John Senior 26

Acute Liver Failure in the USA, Dr.

William Lee 34

Epidemiology and Public Health Impact,

Dr. Parivash Nourjah 49

Literature Review and Poison Control Data,

Dr. Rizwan Ahman 55

FDA Adverse Event Reports, Dr. Claudia

Karwoski 60

Public Comment:

[McNeil]{.underline}

Dr. Debra Bowen 94

Dr. John Slattery 100

Dr. Richard Charles Dart 114

Dr. Raymond S. Koff 126

Dr. Anthony R. Temple 130

[Wyeth]{.underline}

Dr. Stephen Cooper 139

[Bayer]{.underline}

Dr. Allen H. Heller 144

[GlaxoSmithKline]{.underline}

Dr. John Dent 149

Dr. Sarah Erush 177

Susan Winckler 186

Ray Bullman 193

Ms. Kate 199

Dr. Caroline Riely 204

Dr. Peter Lurie 209

Dr. Louis Lasagna 216

FDA Presentation of Labeling Regulations

for Over-the-counter Drugs 222

Committee Discussion 248

    	P-R-O-C-E-E-D-I-N-G-S

(8:04 a.m.)

CHAIRMAN CANTILENA: Welcome to the September 19th meeting of the
Nonprescription Drugs Advisory Committee, here to discuss issues
concerning acetaminophen safety.

My name is Dr. Lou Cantilena. I\'m the head of clinical pharmacology at
the Uniformed Services University, and I\'ll be chairing this session
today.

What we\'d like to do is to go around the table and have everyone
introduce themselves, and we\'ll start over on this side, please. Sir,
if you can introduce yourself.

DR. FURBERG: Curt Furberg, Wake Forest University.

DR. CRAWFORD: Stephanie Crawford, University of Illinois, College
Pharmacy.

DR. CUSH: Jack Cush. I\'m a rheumatologist from Presbyterian Hospital,
Dallas.

DR. ELASHOFF: Janet Elashoff, biostatistics, UCLA and Cedars-Sinai.

DR. WATKINS: Paul Watkins, hepatologist, University of North Carolina at
Chapel Hill.

DR. BRASS: Eric Brass, Harbor UCLA Medical Center.

DR. DAVIDOFF: Frank Davidoff, the editor emeritus of [Annals of Internal
Medicine]{.underline}.

DR. LAM: Francis Lam, University of Texas, Health Science Center in San
Antonio.

DR. CRYER: Byron Cryer, gastroenterologist, University of Texas,
Southwestern, in Dallas.

DR. LAINE: Loren Laine, gastroenterologist, University of Southern
California, Los Angeles.

DR. D\'AGOSTINO: Ralph D\'Agostino, biostatistician from Boston
University and the Framingham study.

DR. ALFANO: Mike Alfano, New York University.

DR. CLAPP: Leslie Clapp, pediatrician, Main Pediatrics and Clinical
Associate Professor, State University of Buffalo.

DR. TITUS: Sandy Titus, FDA. I\'m the Administrator for the
Nonprescription Drugs Advisory Committee.

DR. JOHNSON: Julie Johnson, University of Florida.

DR. JAMES WILLIAMS: Jim Williams, rheumatologist at the University of
Utah.

DR. UDEN: Don Uden, University of Minnesota.

DR. HENRY WILLIAMS: Henry Williams, family practice, Howard University,
Washington, D.C.

DR. NEILL: Richard Neill, family practice, University of Pennsylvania.

DR. PATTEN: Sonia Patten. I\'m an anthropologist from Minneapolis,
Minnesota, and I\'m one of the consumer representatives.

DR. WOOD: I\'m Alastair Wood, and I\'m a clinical pharmacologist from
Vanderbilt.

DR. DAY: Ruth Day. I do research on medical cognition. I\'m at Duke
University.

DR. COHEN: Mike Cohen from the Institute for Safe Medication Practices.

DR. BEITZ: Julie Beitz, Director, Division of Drug Risk Evaluation in
CDER, FDA.

DR. GANLEY: Charlie Ganley, Director of OTC Drugs, FDA.

DR. BULL: Jonca Bull, Director, Office of Drug Evaluation V, and the
Center for Drug Evaluation and Research.

DR. JENKINS: John Jenkins, Director of the Office of New Drugs in CDER.

MR. GALSON: Steve Galson, Deputy Director of the Center for Drug
Evaluation and Research.

CHAIRMAN CANTILENA: Okay. Thank you, everyone.

We will now hear the conflict of interest statement from Sandy Titus.

DR. TITUS: The following announcement addresses the issue of conflict of
interest with respect to this meeting and is made a part of the record
to preclude even the appearance of such at this meeting.

The Food and Drug Administration has granted waivers to the following
special government employees, which permits them to participate in
today\'s discussion. This includes: Drs. Byron Cryer, John Cush, Sonia
Patten, Eric Brass, Ralph D\'Agostino, Ruth Day, Curt Furberg, and Paul
Watkins.

A copy of the waiver statements may be obtained by submitting a written
request to the agency\'s Freedom of Information Office, Room 12A30 of
the Parklawn Building.

The topics of today\'s meetings are issues of broad applicability.
Unlike issues before committee in which a particular product is
discussed, issues of broad applicability involve many industrial
sponsors and academic institutions.

The committee members and consultants and invited guests have been
screened for their financial interests as they may apply to the general
topic at hand. Because general topics impact so many institutions, it is
not prudent to recite all potential conflicts of interest as they apply
to each participant.

We would also like to note for the record that Dr. Michael Alfano is
participating in this meeting as an industry representative acting on
behalf of regulated industry. As such, he has not been screened for any
conflicts of interest.

FDA acknowledges that there may be potential conflicts of interest, but
because of the general nature of the discussion before the committee,
these potential conflicts are mitigated.

In the event that the discussions involve any other products or firms
not already on the agenda for which FDA participants have a financial
interest, the participants\' involvement and their exclusion will be
noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose products they may wish to comment upon.

Thank you.

CHAIRMAN CANTILENA: Thank you, Dr. Titus.

I will now ask Dr. Charles Ganley to start us off.

DR. GANLEY: Good morning. I would like to start by taking the
opportunity to thank all of the members of the Advisory Committee and
the consultants to the committee who are taking time from their busy
schedules to participate in today\'s meeting.

There are four things that I\'m going to touch on this morning to
introduce the discussion over the next two days.

First, many members of today\'s committee have not previously been
involved with Advisory Committees addressing OTC drug issues. So I\'m
going to give a brief overview of how over-the-counter drug products are
regulated and a brief history of the OTC drug review.

Second, I hope to explain why I bring these issues today and tomorrow.

Third, I\'m going to make some comments about safety and efficacy of
internal analgesic drug products.

And last, I want to give some brief comments on today\'s topic for
discussion: unintentional acetaminophen overdose.

Over-the-counter drug products can be marketed under two different
regulatory mechanisms, either through drug monographs under the OTC drug
review or under new drug applications.

When marketing under a drug monograph, the manufacturer follows the
condition of views provided for in the monograph. The drug monographs
are categorized by the indication\'s pharmacologic effect and body
system affected.

There are no regulatory requirements mandating that manufacturers
provide information on a specific product, such as manufacturing process
or adverse event reports to the FDA. The FDA can, however, expect
manufacturers to obtain information or the manufacturer can voluntarily
provide information if asked.

Drugs marketed OTC under new drug applications generally involve
ingredients that had a long marketing history as prescription products.
The history of marketing in the prescription setting is important in
providing safety information to support OTC marketing. When marketing
under a new drug application, the same regulations for reporting
requirements that apply to prescription products also apply to OTC drug
products.

There is one other subtle point that also differentiates the two paths.
Individual products that are marketed under NDAs receive FDA approval.
For those marketed under monographs, the individual products are not
approved, but are generally recognized as safe and effective if they
follow the conditions outlined in the monograph.

The OTC drug review was initiated in the 1970s to review the efficacy
and safety of the OTC drug products marketed at that time. Rather than
review each product individually, a review process was set up to review
categories of products. Data on safety and efficacy was collected
through public notice and comment for ingredients and their conditions
of use.

The data was reviewed by an independent drug review panel and a panel
report was published in the [Federal Register]{.underline}. In the
report, the panel makes specific recommendations on the efficacy and
safety of ingredients for a particular category of product.

A comment period followed the publication of the report.

The FDA takes the report and public comments to the report to develop a
tentative final monograph, also known as a proposed rule. This proposed
rule is published in the [Federal Register]{.underline} for public
comment. The comments are reviewed by FDA and a final monograph is
written and published.

After the final monograph is published and the effective date specified,
only ingredients that are found to be generally recognized as safe and
effective can continue to be marketed for the conditions of use
described in the monograph.

Why now? The monograph for internal analgesic antipyretic and
anti-inflammatory drug products is in the proposed rule stage. The
proposed rule was published in 1988. The agency is attempting to
finalize this rulemaking as part of the ongoing review, and as part of
that review, we are looking at the most recent information available for
several safety issues related to the ingredients in this monograph.

The category of products to be discussed today and tomorrow account for
one of the largest segments of products used by consumers in the
over-the-counter drug market in the United States. I suspect that the
majority of folks in this room today have at least one of these products
in their home right now.

Ingredients marketed under the monograph include acetaminophen, aspirin,
non-aspirin salicylates, and adjuvants, such as caffeine. Ingredients
marketed under new drug applications include ibuprofen, ketoprofen,
naproxen sodium, and acetaminophen for extended released products and
suppositories.

I would like to make some important points regarding this category of
products. Consumers can self-diagnose and treat intermittent minor aches
and pain without the need for a health care provider. Serious adverse
events are rare. The majority of consumers use these products safely.

The benefit of these therapies outweigh the risk associated with their
use. The availability of these ingredients in OTC drug products is not
an issue. The agency believes that these products remain available as
over-the-counter drug products.

The subject for discussion today is unintentional acetaminophen overdose
leading to hepatotoxicity. In February of 2001, the FDA and the
Pharmaceutical Research and Manufacturers Association jointly sponsored
a workshop to discuss drug induced liver toxicity.

During that workshop, Dr. Will Lee presented information on acute liver
failure using a registry of patients on liver transplant lists. He found
that 60 percent of acetaminophen related cases were due to unintentional
overdose.

Dr. Lee will be presenting some of his data this morning.

I would just like to note that the FDA does not have access to Dr.
Lee\'s data and, consequently, has not validated it. We do, however,
believe that the data is important and should be part of today\'s
discussion.

Dr. Lee\'s data prompted FDA to conduct a review of cases of
hepatotoxicity reported with acetaminophen in the FDA adverse event
reports database. Understanding that there are limitations in assessing
causality with this database, there are cases that may be characterized
as unintentional overdose, for example, when a consumer uses more than
one product containing acetaminophen.

There are also cases of unintentional overdose reported in the
literature. Acetaminophen hepatotoxicity can occur with the ingestion of
a single large dose of acetaminophen as a means of committing suicide or
with an accidental ingestion by a child who gains access to a bottle of
acetaminophen.

There are many products available over the counter, not just drug
products, that can be used as a means to commit suicide. The issues
related to the prevention of suicide are complex and extend outside of
the discussion of acetaminophen.

For accidental ingestion by children there are already requirements for
childproof packaging. Failures of childproof packaging is applicable to
any OTC product and not just acetaminophen.

Consequently these nontherapeutic ingestions are not part of the
discussion today.

The actual number of cases of unintentional overdose per year will be
difficult to ascertain for a variety of reasons. Whether it is 25 cases,
50 cases or more is not the issue. The issue is can reasonable measures
be implemented to prevent these events.

Even if there were only 25 cases per year leading to serious injury or
death, if they are preventable with reasonable interventions, we have an
obligation to attempt to reduce the risk of occurrence.

As part of your deliberations today, the committee will consider the
following issues:

Are there identifiable circumstances or factors that contribute to these
events?

Do we understand consumer or health provider behaviors that may
influence the circumstances or factors?

Can the circumstances or factors be influenced by interventions?

Are there interventions that may prevent events or decrease the severity
of events, or is additional research needed to address some of these
issues?

That concludes my introductory comments. I would like now to introduce
Dr. Bill Gilbertson from the Division of Over-the-counter Drug Products.

DR. GILBERTSON: I\'m going to get to it. Left click. I\'m not doing too
well.

My opening remarks are going to be that I\'m going to be very brief.

(Laughter.)

DR. GILBERTSON: There we go. Thank you.

Again, my comments will be very brief this morning. Actually I\'m going
to be talking about, specifically about the acetaminophen warnings that
are limited in the rulemaking to the liver and to when it\'s used with
alcohol.

Now, my task was to go back through the 25 years of rulemaking of the
ingredient and to pick out those sections of the [Federal
Register]{.underline} that are most relevant to today\'s discussion.

What I did was I selected them out, and then I simplified them for
purposes of this presentation. So here we go.

Back in 1977, the internal analgesic report was published and the
advisory panel concluded that acetaminophen was safe and effective for
OTC use at the doses described here, and in that report, it is stated
that this ingredient is relatively free of adverse effects in most age
groups, even in the presence of a variety of disease states.

Now, this action allowed this ingredient to be included into the
monograph system. At that time, acetaminophen was marketed under a new
drug application.

It was first approved in 1960, and it now had 17 years of marketing
experience OTC. And it\'s important to note as I speak that the panel
data and information was from the 1960s and early 1970s.

Now, the report included studies of patients with various forms of liver
disease, and they found that several types of liver disease may prolong
the half-life of the drug, but they could not conclude that this
increase would also increase the risk of hepatotoxicity, and they were
unable to conclude whether it was safe for use in patients with
preexisting liver disease. And they recommended that studies be
performed to resolve this issue.

Now, there is a discussion in the report of cases of acute overdose with
doses above 15 grams. They concluded that single doses of less than 15
grams are not usually associated with serious liver disease.

Now, there was a recognition that severe liver damage can occur if
acetaminophen is used above the recommended dose, that is, four grams
daily. And the panel recommended a warning, this warning: \"do not
exceed recommended dosage because severe liver damage may occur.\"

Now, following publication in the [Federal Register]{.underline}, the
agency received numerous comments obviously on this label. Some were
opposed to the warning that made any reference to an organ or to be
organ specific because it places the responsibility of recognizing organ
damage on the consumer. It may be misunderstood or may alarm. It may
encourage suicidal persons to abuse the drug. And it\'s inappropriate
for children\'s products because there is a lack of documented
fatalities in children from acute overdose.

Incidentally, that comment did not provide any data to support that
contention.

There were also comments in favor of a liver warning, arguing that there
are no unique signs of toxicity like we have with aspirin, such as
ringing in the ears, and that the symptoms of toxicity to acetaminophen
do not appear until a few days after overdose.

And there is increased use of the drug. Fatalities and liver damage have
occurred in children, and this warning may discourage consumers from
exceeding the recommended daily dose.

In 1988, the agency published the tentative final monograph and
broadened the adult dosage schedule providing for this 500 milligram
dose. So we have a 500 milligram every three hours or 1,000 milligrams
every six hours in addition to what was there before, but they still
limited the maximum daily dose to four grams.

Now, the agency concluded that the data were insufficient to support the
panel\'s recommended warning. The warning need to specify toxic effects
to particular organs of the body caused by acute overdose, and at that
time we had no labeling in any products that I\'m aware of that made
specific reference like that to an organ.

However, liver damage can occur from overdosage and a warning statement
is warranted. These are actual statements out of the [Federal
Register]{.underline}.

Now, the warning should emphasize the need for prompt medical attention
since following overdosage there is a 24 to 48 hour period of relative
well-being when symptoms of hepatotoxicity do not appear, despite the
occurrence of liver damage.

So the agency recommended this warning. Actually the agency proposed the
warning statement to immediately follow the required warning that\'s
there now for \"keep out of reach of children,\" and I\'ve just
highlighted that to show you where it would be placed in labeling.
Prompt medical attention is critical for adults, as well as for
children, even if you do not notice any signs or symptoms.

Now, even though an alcohol warning had not been proposed in the
tentative final, many comments were received in favor of also including
such a warning. Human and animal studies were cited contending that
alcohol abusers us the drug within the labeled dose.

And one comment even proposed that we label for alcoholic abusers a dose
of a maximum two grams daily. Now, these comments are on public display
in the Dockets Management Branch here in the Parklawn Building, and as a
result, additional comments were received or I would call them reply
comments opposed to such a warning, and these comments argued that the
data were not rational; that the majority of the reports involved
subjects with a history of alcohol abuse and use far in excess of the
maximum daily dose; and that other studies were cited that disagreed
with the animal human data that had been in the previous comments.

Now, in June of 1993, the agency presented this issue to this committee,
this joint committee actually, in June of 1993. And the reason why I say
June is because tomorrow I\'ll be talking about another meeting they had
in September of that year for the salicylates and the NSAIDs.

The data that was reviewed by the committee were the issues that were in
the tentative final that I\'ve just discussed. The published reports of
acetaminophen induced liver toxicity in alcohol abusers at various
doses, phrarmacokinetic data on acetaminophen metabolism in alcohol
abusers, microsomal enzyme induction studies in subjects with liver
disease, effects of alcohol abuse on acetaminophen overdose, and some
animal data on the effects of ethanol in diet on metabolism and on
glutathione levels.

The questions asked of this committee were: does the data support a
warning for alcohol abusers?

What populations are at risk? Those that drink rarely, socially, and so
forth?

And they asked such benefit-risk questions as: will alcohol abusers
switch to other ingredients that have equivalent or greater risk?

What information should be included? Should we make specific reference
to the liver and so forth?

And are the data sufficient to support a reduced maximum daily dose, two
grams, for alcohol abusers? And if so, what should it be?

This committee concluded in June of 1993 that a warning was justified
and should refer to possible liver damage. However, there was concern by
this committee that the warning could cause alcohol abusers to switch to
other products with equivalent or greater risks and that it should not
be implemented until the committee had an opportunity to look at the
other analgesic ingredients.

And they also found that there was insufficient data to support a
reduced maximum daily dose for alcohol abusers.

So the FDA concluded in 1997 that chronic heavy alcohol use or abuse has
a significant effect on the metabolism and etoxification of the
metabolite NAPQI; that alcohol abusers are at increased risk and a
warning is warranted for adult products.

Organ specific warnings are more effective than general warnings, and we
agree that there is insufficient data to support that lower dose, and
labeling should recommend contact with a physician.

Now, these conclusions were included in a 1997 proposed rule. Comments
were received, and they were pretty well equally divided in favor for
and against the particular terms in that rule.

However, in 1998, the FDA published a final rule, alcohol warning. If
you consume three or more alcoholic drinks every day, ask your doctor
whether you should take acetaminophen or other pain reliever/fever
reducers. Acetaminophen may cause liver damage.

Now, all OTC acetaminophen containing products are required now to
include this warning whether marketed under the monograph system or
under a new drug application. So today we have this final rule in place,
and we also have the yet to be finalized 1988 tentative final proposed
warning about seeking prompt medical attention.

Thank you.

CHAIRMAN CANTILENA: Okay. Thank you, Dr. Gilbertson.

Now we have Dr. Senior also from the FDA, who will start the section of
the program by the FDA that\'s scheduled for one hour.

Dr. Senior.

DR. SENIOR: Good morning. I\'m John Senior, a hepatologist at the
agency.

We are going to have a series of presentations from the Office of Drug
Safety. Some of us will refer to acetaminophen. Some will use the
abbreviation APAP. That\'s acetyl-para-amino-phenol, APAP. So both of
these mean the same thing.

For eons of time, since pre-history, our ancestors have been making
infusion of willow bark teas to relieve aches and pains. The active
compound in that was identified in the early 1800s as salycilin.

And then the German chemists in the late part of that century developed
a series of compounds, including salicylic acids, some of which is still
used as salicylates, and the common acetylsalicylic acid, which acquired
the name aspirin just at the turn of the century.

At the same time, there were a number of other compounds that were found
to be effective in reducing fever and pain, including acetanilide and
phenacetin, which were used for a while, but turned out to be too toxic.

And it was found by Brody at the NIH in 1948-49 that both of these
compounds were metabolized to a nontoxic compound that was N-acetyl
para-aminophenol, acetaminophen, paracetamol in Britain, and APAP, the
abbreviation.

However, it took a while before it became widely used. Aspirin was
considered a wonder drug for the first half of the past century, but was
found to cause a number of problems that you\'ll be discussing tomorrow.

Acetaminophen was approved shortly after Brody\'s work at the NIH was
approved by the FDA in 1950, and then it was allowed to go over the
counter for consumer self-prescription and use in 1959.

Bear in mind that was before the amendment to the law that required the
FDA to have proof of efficacy for drug products.

So acetaminophen came in as a nontoxic alternative to what was
available, but in the [British Medical Journal]{.underline} in 1966
Davidson and Easthan reported from Edinburgh two cases of fatal
overdoses of acetaminophen in psychiatric patients.

Interesting and ironically, one had learned about the other one and went
ahead and copied.

There was also another paper by Thompson and Prescott, another death
from liver damage, another big paracetanol or acetamin overdosage and an
editorial.

Now, the way this happens in the patients is insidious. The acute
ingestion may produce some immediate nausea and vomiting and discomfort,
but it all subsides and goes away for a day, two, three, and then on
comes the bad stuff, the nausea, anorexia, vomiting, big, tender swollen
liver.

The serum transaminases may go into the thousands, tens of thousands.
The prothrombin time is elevated, liver failure, encephalopathy. The
whole deterioration process ensues, as Dr. Lee will tell you shortly.

Now, acetaminophen, the compound that was identified as this nontoxic
derivative of the coal-tar compounds, is cleared out pretty quickly by
glucuronidation on this phenolic group or by sulfation. The glucuronides
and sulfates are made by really a \-- catalyzed by a series, families of
enzymes. There\'s a whole family now of these glucuronal transferases,
and it has been recently stated that the glucuronal transferase isoform
1A9 is the one that particularly glucuronidizes acetaminophen.

Now, there was, in Brody\'s lab again, a number of really brilliant
studies that were done and published in a series of four papers in 1973
that really opened up the understanding of what was going on in the
toxicity.

Gary Mitchell and his colleagues working in Brody\'s lab described what
was going on, and what they found in mice and rats, that the damage was
related to the metabolism, not to the plasma level; that the damage was
caused by covalent bonding of some metabolite, not the original
compound, but something that was produced; then the enzymes in the liver
called Cytochrome P450s catalyzed this reaction to form this injurious
metabolite.

And the glutathione depletion worsened it, and glutathione addition
prevented the damage. That was pivotal because it suggested treatment.

Now, here\'s the metabolite that was found. The original compound,
acetaminophen, is oxidized by this Cytochrome 3E1, the principal one,
with minor contributions by some other cytochromes, to this oxidized,
reactive intermediate called N-acetyl-benzoquinonamine, and we
abbreviate it NAPQI.

This position or these other position equivalent is very reactive, very
electrophyllic and wants to grab onto something. It loves to grab onto
sulfur groups.

And there is another family of enzymes called glutathione transferases
that catalyze the transfer of glutathione onto that group, again
rendering it harmless for excretion.

If, however, all of those previous steps don\'t occur, this reactive
intermediate may attach to cell proteins, to membrane proteins and cause
cell death as a result.

Now, here\'s glutathione. This is as protective compound, and that
sulfur group will attach here. It was suggested by the Brody and
Mitchell studies that you could use other substances and now we are
using this drug, which we call Mucomyst in the trade name, but it\'s
N-acetylcysteine, and that will attach also and protect from the
deleterious consequences of the oxidized metabolite.

So we have inherently four lines of defense against overdoses or over
amounts of this compound, as we have against many other things. A small
amount is excreted unchanged, as unchanged drug.

Glucuronide conjugation is the principal way of getting rid of it.
Fifty-five, 60 percent on average.

Conjugation with sulfate is another third or so, and then what\'s
oxidized may be mocked up by glutathione and gets rid of most of the
rest of it. So there\'s very, very little of the reactive intermediate
left.

And if there still is some, you can still protect the patients with
treatment, with Mucomyst, N-acetylcysteine, if you get there in time.

Now, when we have moderate chronic overdose as occurs in the
unintentional patients, we don\'t know the moment they took the
overdose. In this country, somewhere between a third and a half of the
patients may be unintentional. The rest may be depressed, suicidal
patients.

In Britain, this number is even lower.

However, they may have none of those prodromal symptoms, and a question
remains as to whether doses somewhat over the recommended dose may be
dangerous if the enzyme systems are induced.

Data are really not sufficient yet to conclude on this.

On the other hand, people who take acetaminophen chronically may become
tolerant, and Martin Black, a friend and colleague in Philadelphia who
had worked with Mitchell and Brody at NIH, had a patient come to him who
was taking as much as 65 grams of acetaminophen a day without liver
injury, without significant liver injury.

He was addicted to percodan, and he was taking the combination percodan
and acetaminophen together.

The plasma levels may not always be helpful in these unintentional cases
because you don\'t know when they took the overdose or whether it was
accumulation, and it may be too late for effective treatment.

So there are a zillion factors affecting the absorption and metabolism.
The National Medical Library PUBMED system discloses literally hundreds
of papers on these subjects. There\'s variation and dissolution, gastric
emptying, all the rest of it. Every one of these steps is highly
variable, and some of the factors are known.

There are also a lot of drugs, a lot of compounds that induce the enzyme
systems. The liver has to handle simultaneously not only drugs,
over-the-counter remedies such as acetaminophen, alcohol, dietary
supplements, compounds from the environment, internal compounds, all at
once, and they all interact with each other and affect the metabolism

So we have then at the end of the day a huge problem of enormous
variability in the amount of the toxic compound that we worry about that
injures the cells and kills the patients.

The paper by Kritchley (phonetic) and Prescott, Prescott has really made
a life study of the metabolism and pharmacology of acetaminophen. A
60-fold variation from one person to another. Now, that cannot be dealt
with by taking the average for the group.

It is very clear that the average dose for the average person is safe,
but we are not all average people, and a dose that is safe for most
people may not be safe to some people. And consequently, larger doses
that are not tolerated by most people may be tolerated if you develop
\-- you have become tolerant to long ingestion.

So there are many, many interactions, and we\'re just beginning to learn
about many of these things. This is really an update of the previous
work that was just summarized recently.

So I offer these considerations for you to think about as you hear the
arguments pro and con about the studies that have been reported. Bear in
mind the physicians are concerned about individual patients who are
really statistical outliers. They are not concerned about the median
number, the average person in a group that is normal and not affected.

So we have to bear those in mind as we consider these issues further.

Thank you.

CHAIRMAN CANTILENA: Thank you, Dr. Senior.

Dr. Lee, please.

DR. LEE: Thank you, John.

My brief here is to talk about the acute liver failure study group and
specifically about cases of acetaminophen which I\'ve termed in the past
accidental, and maybe I need to change it over to unintentional, but if
you see the word accidental, we don\'t mean children taking overdoses
accidentally, but rather the so-called unintentional cases.

Now, this is the picture at autopsy of a liver, of actually a halothane
case, but it just introduces the topic of acute liver failure. What
we\'re talking about here is a severe hepatotoxic injury to virtually
all of the hepatocytes as seen in this low power photomicrograph.

The clinical features that are characteristic of it and mark the
severity of the injury are highlighted by the alteration in mentation.
No patients in the acute liver failure study group that I\'m going to
show you were admitted to the study without having this cardinal feature
and without having some degree of coagulopathy.

Now, again, we\'re not talking about patients with chronic liver
disease, with cirrhosis. They have to have had an acute illness, and
varying definitions have been used: less than eight weeks, less than 26
weeks.

But in most instances the acetaminophen insult is less than a week in
duration, with previously normal presumed at least hepatic function.

The interesting thing about acute liver failure is that you have a
common clinical syndrome which applies to virtually all cases, and the
feature, again, are the altermentation, but also in many, if not most of
them, some degree of brain swelling or cerebral edema.

The background for this is that its actually fortunately a very rare
disease. There are probably somewhere around 1,000 to 2,000 cases per
year. This is a guesstimate, not based on our data, but from previous
NIH consensus conferences related to this.

And as a result, we formed the acute liver failure study group on the
premise that most series prior to our coming on line in 1998, most
series were single center reports over ten or 14 years, as I\'ll show
you in a moment, and certainly most centers, even a major transplant
center, will only see a handful of cases of acute liver failure each
year.

Similarly, there\'s no viable treatment for all patients. We deliver
pregnant women who have acute liver failure. There is an antidote for
mushroom poisoning, and there\'s certainly use of N-acetylcysteine for
acetaminophen poisoning, but other than that, there\'s no treatment.

So we were looking to develop a consortium to do a treatment trial for
perhaps the non-acetaminophen cases, and I\'ll talk about that
momentarily.

The early trials or the early registries or series that were published
had mortality rates over 90 percent even in these small, single center
studies. We now, since about 1981, do transplantation. These are the
patients that have the highest listing in the UNOS transplant list, but
the question is how often do they get transplanted and how effective is
it.

So this is a group that I began setting up in 1996 and 1997 initially
with 14 academic medical centers, all of whom preform transplants except
one, and we began collecting prospective data in 1998.

We now have 25 centers, and since the year 2000 began, a pediatric
collaborative study of similar fashion employing 23 sites around the
U.S.

We have two or three missions. One is to collect detailed prospective
data and serum samples on cases meeting the criteria that I outlined
before.

We are also doing an N-acetylcysteine trial for non-acetaminophen cases,
not the topic today, and we do numerous ancillary studies relating to
etiology of the indeterminate group and various other aspects.

We have been funded initially by NIDDK with an RO3 grant; then
subsequently for the NAC trial by the FDA Orphan Products Program, and
we now have an NIH RO1 grant, which we are now starting the third year
thereof.

We collect data once informed consent is obtained from next of kin since
the patient is always mentally altered. We collect prospective data on
five page case report forms shown here on admission, and then a
subsequent case report form at the outcome, that is, hospital discharge,
transplant or death.

We are doing long-term follow-ups, but that\'s just in process now. But
anyhow, when I talk about outcomes, such as transplantation and death,
we\'ll be talking about relatively short-term outcomes.

Now, just to backtrack for a moment, I mentioned some of the earlier
studies prior to our own. Here\'s a listing of five different studies
prior to 1998, and you notice that this study, which was U.T.
Southwestern in really the pre-transplant ear, had no acetaminophen
cases, mostly Hepatitis A and B, although they weren\'t called that at
the time. It was infectious and serum.

In Rakela\'s study, which was a multi-center study, again, in the \'70s,
no acetaminophen cases. In Rakela\'s later Mayo Clinic study, again,
over approximately nine years non acetaminophen cases.

And then the first appearance of acetaminophen cases in a registry is
the study of Shakil from the University of Pittsburgh, at that time the
biggest transplant center in the U.S.

And, again, note that this is over a 12-year period, and the total n of
all cases was 177. But in any event, 20 percent or 19 percent of the
cases were thought to be due to acetaminophen toxicity.

Now, again, we haven\'t specified accidental or suicidal in that study.

This was a retrospective study that my group did in trying to get
funding, frankly, for that first RO3 study. So I asked the 14 sites that
were invited to participate to collect two years of their transplant
database registry regarding several things, just very basic data: age,
gender, presumed etiology, and outcome, and coma grade on admission.

And in that study there was 20 percent acetaminophen toxicity listed as
the primary cause by the site investigator.

Now, this is the overall data from the prospective study, the going
forward study from 1998. Currently we are over 450 cases, but this is a
snapshot when we were at 395 cases, and you see that \-- and these are
the numbers here \-- that in the current study roughly 40 percent or 160
out of 395 appear to be related to acetaminophen toxicity.

By comparison, 49, or something like 12 percent, are related to all
other idiosyncratic drugs; Hepatitis B down to about eight percent;
Hepatitis B, something like four or five percent, and so forth; with a
still indeterminate group of somewhere around 18 percent.

Again, the snapshots have been take at various times. The largest series
that we\'ve examined intensively has a smaller n of 308, and I\'ll show
most of the data that you\'ll see, such as this slide here, reflects the
n of 308, which was just slightly earlier in our data collection.

Now, this slide shows the retrospective study in orange that I mentioned
a moment ago, the 1994-96 transplant registry study compared to our
prospective study in the light blue here. And you see there are some
differences.

In gender the earlier study appeared to have only 54 percent women,
whereas the current study has something around 73 percent female
preponderance.

In the earlier study there was 20 percent acetaminophen. In the current
prospective study, there\'s 40 percent, and so forth.

There are minor differences here. There\'s few numbers transplanted
overall in the prospective study, and greater spontaneous survivors.

The differences here, we believe, are due to the differences in data
collection. That is that if you simply collect from a transplant
database, you may exclude a lot of the acetaminophen cases. So to
collect all of the cases that have acute liver failure, including ones
that may not be considered for transplant or listed for transplant, you
will have a larger number of cases, and a number of the acetaminophen
cases will fall into that group.

There are a number of reasons why acetaminophen patients don\'t get
listed for transplantation. One is their general good outcome, but
another is the psychosocial milieu surrounding each case.

Now, this is a busy slide, but if you concentrate just on the two
left-hand columns, you see what the clinical picture is for a group of
120 cases. This is, again, out of the overall n of 308. Again, for the
acetaminophen cases, a high preponderance of women, but note that there
are more women in the idiosyncratic drugs and basically in all of the
categories of acute liver failure, and we don\'t understand that, why
that should be.

Notice the differences in these cases. The length of illness is very
short. One day of jaundice preceding onset of encephalopathy versus
typically in the idiosyncratic drugs 12 days. The degree of coma, the
severity of the disease, if you will, on hospital entry is equivalent
between all ranges, but note the very high aminotransferases, which Dr.
Senior alluded to earlier versus lower aminotransferases in the
idiosyncratic group.

But notice also with a very short duration of illness, low bilirubin
here, much higher bilirubin again indicating a much longer disease
duration.

Notice also the differences in the percent transplanted. Only six
percent of the acetaminophen cases got transplanted, 6.8 percent
spontaneous survival, for an overall survival of 73 percent. Still a
quarter of the patients with this condition do die.

By contrast, more than half of the idiosyncratic drug cases need to be
transplanted, and very low spontaneous survival, and this, again,
reflects the overall picture prior to the transplant era when most
patients with this condition went on to die.

Now, just to digress for one second, around the world there\'s quite a
difference in the cases. Dr. Senior alluded to the United Kingdom where
in one study from King\'s College Hospital in the \'90s there was 73
percent acetaminophen or, as they say it, paracetamol overdoses.

And, again, these they claim are virtually entirely suicidal overdoses.

Now, again, I\'ve used the term \"accidental,\" and I\'ll correct it to
\"unintentional\" versus \"suicidal.\" When we talk about the cases that
I\'m going to now show you two or three slides on, the suicidal cases we
define as having a history of a single time point ingestion \-- I think
that\'s key \-- with suicidal intent, whereas the unintentional cases
are multiple time point ingestions, typically have a cause for pain
identified, and deny suicidal intent.

Now, let me digress one more moment and remind you that this is, again,
not the total universe of patients that get admitted to the hospital
with acetaminophen hepatotoxicity. We outlined this, and others have,
Madre and Sief and Zimmerman, through the \'80s, and we did this study
of a 40 month examination of all the cases coming into Parkland Hospital
that had this as their main diagnosis.

And we came up with, as it shows here, a total of 71 cases admitted over
40 months with accidental or suicidal ingestions leading to potential or
accomplished hepatotoxicity. Now, again, this is not all getting to
acute liver failure. Only a small fraction of them would have reached
that endpoint.

But clinically these cases are very different in that the accidental
cases typically present late, after 24 hours, whereas virtually all of
these suicidal cases are in the emergency room within four hours of the
ingestion. They announced that they\'ve taken an overdose, and they\'re
brought in, and they get N-acetylcysteine quite early.

In that study, we saw a lot of alcohol abuse, particularly in the
accidental or unintentional group. Again, because they come in late,
they have low acetaminophen levels versus the early presenting suicidal
cases.

The late presenting cases tended to have higher aminotransferase levels,
again, when you consider all people entering, because as it shows here,
only one in five of the suicidal cases ever got an aminotransferase
level greater than 1,000. This should be greater than.

Most patients in all categories receive N-acetylcysteine or at least at
Parkland Hospital they do, but the outcomes are worse for these
so-called accidental cases.

So more of the accidental cases on a percentage basis at least get to
the threshold of acute liver failure.

Now, back to the current data. When we had the 120 cases, to analyze
this cohort separately, we actually deleted at 12 because in each of the
12 there might have been a concomitant issue, Herpes Simplex infection,
possible idiosyncratic drug reaction, and so forth.

So the 108 cases was our analysis of ones that appeared to be purely
related to acetaminophen hepatotoxicity. Once again, you\'ve seen some
of the numbers, 79 percent women. Alcohol use was 57 percent. Again,
alcohol abuse in this group was only 19 percent.

What\'s new to us at least was that nearly 40 percent were ingesting
narcotic combinations, that is, vicodan, percocet, and so forth, largely
vicodan, by the way, and that these people were ingesting these drugs
for as long as two or three months, typically in doses above those on
the package labels.

And, again, somehow the computer has changed these symbols. It\'s Mac
versus PC here. This should be dose greater than four grams per day, 69
percent; dose greater than ten grams per day, 32 percent. Again,
acetaminophen level detectable on admission, 82 percent, greater than 50
milligram per liter acetaminophen level would be 42 percent.

Aminotransferase greater than 7,000 international units more than half
of the cases, and greater than 3,500 92 percent of the cases, and again,
this is creatinine greater than two, 52 percent; and pH less than 7.3,
17 percent. So not very many of the cases become acidotic.

Now, again, we use this same criteria for dividing the so-called
accidental from the suicidal cases. This does not add up to 108 because
there were five cases where we could not determine intent. If you
examine the suicidal and the accident cases, they actually look quite
similar in terms of the dosing; a little bit different in age in the
accidental cases being older.

Interestingly they both have roughly the same degree of antidepressant
use reported, roughly the same degree of alcohol use. This, again, is
not abuse but use.

A use of more than one acetaminophen compound at the same time was quite
common in the unintentional overdoses. Again, the narcotic acetaminophen
use was more common in the unintentional overdoses.

The aminotransferase levels on the whole in this study, again, remember
this is different from the Parkland study. This is only people who reach
the threshold of hepatic coma, some degree. The aminotransferase level
was low, suggesting it\'s a little bit more subacute than these cases.
The creatinine was higher, and the overall survival is similar.

So I think once you reach the threshold of acute liver failure, the
cases, whether they\'re unintentional or intentional, are quite similar
in their characteristics.

What\'s the outcome? Basically for the overall study, again, the 308
patients I described, 43 percent survived without transplant. Only 29
percent get transplanted, and this has partly to do with the organ
shortage in the U.S., and only 84 percent of them have short-term
survival.

Twenty-eight percent die before transplantation, some of them being
listed, some of them not being listed, and still the most common cause
of death in those who died without a graft was acetaminophen
hepatotoxicity, representing about ten percent of the overall group and
about 25 percent, again, of the acetaminophen group.

So in summary, acetaminophen still accounts for about a third of all the
deaths in this series. It seems to be the most common cause by far, and
possibly growing in the U.S. This estimate is just a ballpark estimate
of the number of cases, not number of deaths. It\'s very hard to get
this data.

In our most recent studies, the relationship to alcohol abuse may be
present in some cases, but it\'s a relatively small number. Clinically
the accidental and suicidal cases look similar to each other once they
reach the threshold of encephalopathy.

And we still have relatively low mortality in these cases, but many of
them are not listed for transplant.

What I think is interesting perhaps is the role of antidepressants, the
role of narcotics particularly as John alluded to, the build-up of
dosing of six to 12 grams per day of narcotic plus acetaminophen, and in
these cases, we honestly don\'t know what\'s going on.

If they could tolerate, let\'s say, six or eight grams per day of
acetaminophen, then why did they get sick on the day or two that they
came in?

Again, repeated daily dosing and use of multiple preparations is a
problem in a small fraction of cases, and in our pediatric series, about
20 percent of these cases are apparently acetaminophen related.

Thank you very much.

CHAIRMAN CANTILENA: Thank you, Dr. Lee.

Our next three speakers are also from FDA, Dr. Nourjah, Dr. Ahmad, and
Dr. Karwoski.

DR. NOURJAH: Good morning. My name is Parivash Nourjah, and I\'m from
Office of Drug Safety.

I\'m the first of three speakers today who will talk about the safety
analysis of acetaminophen associated hepatotoxicity.

This is an overview of our presentations. I will present the national
estimates of acetaminophen associated overdose. Dr. Ahmad will follow
with a review of the literature and poison control data. And Dr.
Karwoski will conclude with a summary of FDA spontaneous reports of APAP
associated hepatotoxicity.

APAP associated hepatotoxicity has been reported with intentional
overdose, unintentional overdose, or rarely as recommended doses.

The objective of my talk is to present the estimated number of overdoses
associated with APAP, particularly related to unintentional overdoses.

Source of data. For my analysis I used four national databases. First,
the national hospital ambulatory care survey, the emergency department
component of this survey.

This is a probability survey sampling of visits made to emergency
department of non-federal, general, and short stay hospitals in the U.S.

Second, the national electronic injury surveillance system, all injury
program. This survey collects information on concealment product related
injuries treated in emergency departments of 60 selected hospitals.

Third, the national hospital discharge survey. This is a probability
survey sampling of in-patients\' discharges from non-federal, short stay
hospitals in the U.S.

And fourth, multiple cause of death files, a data file that contains
information from death certificates.

These four files provide national estimates.

This slide summarizes my findings from analyzing the mentioned
databases. These groupings are independent of each other and represent
annual averages in the U.S.

Let me remind you that these numbers represent overdoses without any
mention of hepatotoxicity. Annually there were over 56,000 emergency
department visits, more than 26,000 hospitalizations, and 458 deaths
associated with APAP.

These numbers represent both intentional and unintentional overdoses.
The definition for intentionality that are used for our analysis depend
on the data source. For the hospital discharge and mortality data, I
used ICD-9 code. APOP overdoses were classified as intentional cases
when they were codes for suicides or overdoses due to other substances,
while unintentional cases were defined as those with a code for
accidental overdoses by APAP, and there was no indication of suicide,
overdose to other substances, or depressive disorder.

For the emergency department data, I review comments field and classify
intentional cases as those with mentions of suicide or suicide ideation,
and unintentional cases as those with mentions of accidental ingestion
or therapeutic misuse.

Children less than six classified as accidental ingestion unless it is
stated otherwise.

This slide represents the number of estimated cases of unintentional
overdoses. Again, these groupings are independent from each other and
represent annual averages.

There were over 13,000 emergency department visits, more than 2,000
hospitalization, and 100 deaths associated with APAP.

I attempted to examine possible risk factors associated with
unintentional overdoses. My analysis was limited because certain
variables were under reported or simply not reported at all.

Additionally, the sample size was too small for exploring certain
variables.

I was interested in exploring the age distribution for APAP overdoses
since it is known that the medication utilization varies by age and
different APAPs are available for different ages. I examined the age
distribution for cases in three databases to see if there were
differences for the age groups. I find that the age distribution varies
by settings.

Young people were the highest percentage of cases in the emergency
department and accounted for 23 percent of hospitalized cases and less
than two percent of deaths.

Chronic liver disease has been postulated to be one of the factors that
increases the risk of hepatotoxicity from APAP. Using the multiple cause
of death database, I examined the presence of non-IQ liver disease among
those with unintentional and intentional overdoses. I found that among
the unintentional cases, 13 percent have chronic alcohol liver disease,
and 42 percent had some other chronic liver disease.

This finding suggests that chronic liver disease may be a risk factor
for developing or increasing severity of hepatotoxicity among patients
experiencing unintentional overdose.

This analysis may be limited because the diagnostic information may be
misclassified. First, if alcohol is not mentioned on the death
certificate, alcohol related liver disease may be misclassified as other
chronic liver disease.

Also, some diseases may be acute, but identify as chronic.

Second, suicidal cases may be misclassified as unintentional overdose to
protect the patient\'s family from a stigma.

There may also be detection bias because the contributing cause of death
may be investigated more with unintentional APAP overdoses than when the
cause of death is known to be suicide. Thus, liver diseases may be
reported more often.

Finally, and potentially most importantly, death certificate
information, such as the circumstances that led to death, for example,
whether it was an accidental overdose or the body system injured, such
an acute liver injury may not be consistently reported, and thus there
may be underestimated of these variables.

In conclusion, in this review of the number of cases of APAP associated
overdoses, I found that children account for at least 22 percent of the
hospitalized cases of unintentional overdoses.

Additionally, the observed association of chronic liver disease with
unintentional APAP overdoses suggests that preexisting liver disease,
both in the presence and absence of alcohol, may increase the risk of
severity of APAP associated overdoses.

This is the end of my talk, and I introduce Dr. Ahmad.

DR. AHMAD: Good morning. The objectives of my presentation this morning
are to identify case trees (phonetic) of APAP associated hepatotoxicity
in published literature and to study the extent of APAP associated
fatalities reported to poison control database.

A MEDLINE search was done to identify APAP associated hepatotoxicity
literature. The review was restricted to USK series, which at least ten
cases published in the U.S. literature in the last ten years. Eight
publications were identified and four of which cases were collected
exclusively of review of hospital medical charts and two case series,
cases that were obtained from hospital medical charts plus published
cases.

And in one case series from a registry of cases contributed by
hepatologists and other practitioners, and one exclusively from a
consortium of liver transplant centers.

The number of cases per series ranged from 47 to 73. Two were pediatric
case series and the remaining six slightly adult case series.

Gender was reported in six case series, and there was a preponderance of
females.

Of the eight case series intentionality was mentioned in five. This
slide gives the dose range in these five studies. In three of these
studies, there were cases where APAP was ingested at recommended dose,
that is, four grams per day or less.

In the Johnson case series, there were nine, or 17 percent of cases, who
ingested APAP at four grams per day or less. The mean dose ingested
ranged from 1.3 to four grams per day. All of these nine cases had a
history of alcohol use. The age range, from 27 to 58 years. There were
six males and three females. Days of use ranged from one to seven days.

Now, let me say a few words about the one case which ingested a mean
dose of 1.3 grams per day of APAP. This was a 47 year old male who
ingested a mean dose of 1.3 grams per day for two days to treat alcohol
withdrawal symptoms and died.

In the Schiodt case series, there were three of 14 person cases in the
unintentional group who ingested four grams per day or less of APAP. All
of these cases were possibly related to fasting and/or alcohol use.

In the Zimmerman case series there were 27 of 40 person cases who took
APAP at recommended dose. In addition, there were 13 of 20 person cases
who took APAP between 4.1 to six grams per day. All of these were
regular alcohol users.

In the Whitcomb case study, there were three cases who ingested APAP at
or slightly above the recommended dose. APAP dose was ingested between
3.5 to five grams per day in one case and four to six grams per day in
two cases. One case had a history of recent fasting, and the other two
had a history of both fasting and alcohol use.

In the Broughan case study, there were no cases that ingested APAP at
recommended dose.

This slide compares these outcomes and deaths in the unintentional and
intentional groups. These outcomes were defined as hepatic coma, acute
liver failure, and liver transplant. You will notice that there were a
high number of deaths and serious outcomes reported in the unintentional
group.

In other words, in two case series where intentionality was noted more
severe hepatotoxicity evidence by severe liver injury, higher
transaminase levels, longer lengths of hospital stay, and more deaths
were seen among unintentional cases compared to intentional group.

Now I would like to search case and describe data from Poison Control
Centers. Tests or toxic exposure surveillance system is the poisoning
database of American association of Poison Control Centers, and
currently has a repository of over 27 million human poison exposures
reported by over 60 participating Poison Control Centers covering over
90 percent of U.S. population.

We reviewed annual reports from 1995 to 1999 and included only cases
that listed APAP as the primary first agent. APAP is the leading cause
of poisoning in tests. In 1999, APAP related calls represented ten
percent of all calls to Poison Control Centers.

There was a slight decrease in calls from 111,000 in 1995 to 108,000 in
1999. In 1999, nearly 50 percent of calls were treatment and health care
facilities and two percent of calls had major effect, that is, the signs
or symptoms occurring as a result of APAP exposure were life threatening
or resulted in significant disability, and more than half the calls
involved children and adolescents.

Of all APAP related calls in children under six years of age which
represented about 40,000 calls, 22 percent of these occurred in children
who ingested adult formulations of APAP.

In 1995, overall APAP related fatalities were at least 76, and this
increased dramatically to 141 in 1991. APAP is the leading
pharmaceutical agent associated with deaths in tests and represented
about 60 percent of all deaths that were reported to tests in 1999.

This slide gives a breakdown of the intentionality among 141 APAP
related fatalities in 1999. Sixty-five percent of the cases were
suicidal and 30 percent of the cases were unintentional.

We included therapeutic error, unintentional, unknown, intentional
misuse, and adverse drug reaction in the unintentional group.

We included intentional misuse since these were not classified as
suicides and assumed likely to represent individuals who ingested
excessive APAP with therapeutic intent.

This slide describes the number and types of APAP formulations that were
associated in unintentional fatalities. Sixty-five percent of deaths
occurred in individuals who took single ingredient APAP product which
are available over the counter. Nine percent deaths occurred in
individuals who took prescription APAP product, and 26 percent occurred
in individuals who took multiple APAP products simultaneously, which
included an OTC plus prescription, two prescription products, two
prescriptions and an OTC, and two OTC products.

The current limitations of tests. Under reporting may be extensive.
Serious cases may go directly to emergency department and may not be
captured by poison control centers. Chronic users may not be captured by
poison control centers.

In conclusion, there are a small number of published cases of APAP
related toxicity at recommended dose, some of which occurred in the
setting of alcohol use and of fasting. Unintentional cases are
associated with more serious outcomes, including death, compared with
intentional cases.

Use of adult formulations of APAP in children under six years of age
accounted for 22 percent of APAP related calls.

And finally, among unintentional fatalities, 26 percent were due to use
of more than one APAP product simultaneously.

Now, let me introduce you to Dr. Karwoski, who will summarize
spontaneous reports of APAP associated hepatotoxicity seen in AERs.

Thank you.

DR. KARWOSKI: Good morning. My objective is to describe the
circumstances that led to hepatotoxicity in individuals who ingested one
or more APAP containing products.

The review was of spontaneous reports in the adverse event reporting
system, and our focus was on cases without apparent suicidal intent.

Our criteria included U.S. cases received by the FDA between January
1998 to July of 2001. Cases reported at least one APAP containing
product as suspect resulting in hepatotoxicity. Cases without apparent
suicidal intent were included in our review.

Of 633 reports, 43 were duplicates and 283 were excluded for various
reasons, primarily for suicidal ingestion.

We ultimately reviewed 307 cases of which 25 were pediatric and 282 were
adults greater than 12 years of age. These will be summarized
separately.

Among pediatric patients, the ages range from less than one day old to
eight years. Males represented about 70 percent of the cases that
reported gender information.

Fifteen of the 25 cases were categorized with severe life threatening
liver injury. Of these, ten died. Twenty-one of the 25 children were
hospitalized, and two were seen in an emergency department.

The milligram per kilogram per day dose was estimated based on reported
daily doses and weight, and ranged from 106 to 375 milligrams per
kilogram per day. This information could only be estimated in ten cases.

The recommended pediatric dose is 75 milligrams per kilogram per day.

Most of the children were receiving only one OTC APAP containing
product. Single ingredient or an unspecified APAP product was most
commonly reported. Of the single ingredient products, the concentrated
drops were reportedly used in seven cases.

Medication errors leading to overdose and hepatotoxicity was noted in 20
cases. In some cases, more than one error was possible. Errors related
to product confusion include use of the wrong formulation, such as the
use of the concentrated drops instead of the children\'s APAP
formulation.

The concentrated drops are three times as concentrated as the
children\'s APAP.

In four cases they described the use of an incorrect measuring device,
such as using teaspoonfuls instead of dropper fulls.

Five cases reported misinterpretation of dosing guidelines on the label
or instruction provided by a health care provider. Use of more than one
APAP containing product may have been a factor in three cases, and there
were other cases that could not easily be categorized.

Factors leading to hepatotoxicity were unknown in five cases.

Additional possible contributing factors were noted in ten cases.
Co-suspect medication use was reported in six, and possible underlying
liver disease was reported in four cases.

Of the adult patients, the ages ranged from 15 to 85 years. Females
represented just over 60 percent of the cases reviewed. One hundred
sixty-nine cases were categorized with severe life threatening liver
injury. Of these 124 died, and seven required liver transplant. Two
hundred and twenty-nine patients were hospitalized.

We used the indication for use or diagnosis for use as a surrogate for
intentionality. One hundred and ninety-nine cases, or 71 percent of the
adult cases, reported using an APAP product for a therapeutic
indication, primarily analgesia. In 74 cases, the indication for use was
unknown, and nine cases reported abuse of an APAP product containing a
narcotic.

One hundred and 38 cases listed an unspecified APAP product. It is
unknown whether these were single ingredient or combination products
that were either OTC or Rx. One hundred and twenty-two, or 33 percent of
all cases, reported the use of an Rx combination product with a
narcotic, and an OTC single ingredient product was listed in 76 cases.

Where the dosage strength was known, 500 milligrams was reported most
often. Approximately 25 percent of all individuals took more than one
APAP product, and if more than one product was reported, it more often
included the use of an Rx product with a narcotic in combination with an
OTC product.

The daily dose was estimated in 132 cases. If a dose range was provided,
the midpoint was used, and if the strength was unknown, a 500 milligram
dose was used.

Of all cases in which the dose was estimated, the mean and median dose
was six and a half and five grams, respectively, but ranged from 650
milligrams to 30 grams per day. This was across all levels of severity
of hepatotoxicity.

Sixty-five of the 132 had severe liver injury, and their mean and median
dose was slightly higher, at 7.1 and six grams, respectively.
Twenty-three of these reported using less than or equal to four grams
per day, which is the recommended dose.

Individuals that use more than one APAP product also reported higher
doses. In 43 cases, there was qualitative dosing information provided,
wording such as excessive use or excessive doses. Of these, two thirds
suggested that greater than recommended doses were used, and in 107
cases, there was no dosing information.

Alcohol use is not a standard field that is collected in the AER system.
So conclusions about this variable must be made with caution since the
information may vary with reporter.

Alcohol use was reported in 116 cases. These were broadly described as
alcoholism or alcohol abuse in 64 cases, regular, daily, or moderate use
in 23 cases, occasional use in ten cases, previous use in six, and 13
did not provide a description.

Eighty-six of the 116 alcohol users developed severe liver injury. For
those that provided dose information, the mean dose was lower for users
versus those that did not report alcohol use.

In the table, the first row shows the mean dose of patients with an
alcohol history versus those with no history. This is among all cases
that reported dosing information.

The second row shows these doses in patients that develop severe liver
injury.

A history of liver disease or possible underlying liver disease was
reported in 70 cases. At least 20 were reportedly due to alcohol.
Twenty-three reported a history of possible viral hepatitis. Forty-nine
of the 70 cases developed severe liver injury.

And, again, the mean and median dose for those patients with liver
disease was lower compared to those that did not report liver disease.

The table that\'s similar to the previous slide with the first dose
shows the mean dose of patients with liver disease versus those with no
disease, and this is among all cases that reported dosing information.

And the second row, again, shows these doses in patients with severe
liver disease.

Co-suspect medication use was reported in 93 cases. Sixty-three of these
were labeled for hepatotoxicity. Information regarding fasting or
malnutrition is often not captured, but we did note a small number of
cases that reported malnutrition or decreased PO intake.

I\'m going to go back to the 23 cases of severe liver injury that
reported doses of less than or equal to four grams. Among these 23
cases, 18 reported risk factors. Eleven reported more than one risk
factor. Fifteen had a history of alcohol use. In ten they were described
as alcoholism or alcohol abuse.

However, there were five that reported regular or occasional use.
Thirteen reported liver problems, including alcoholic liver disease and
four viral hepatitis in four case and five others reported other
abnormalities. Three reported poor nutritional status.

The circumstances were unclear in five cases with no reported risk
factors. Other possible contributors in two of the five cases were
concomitant use of phenytoin and possible sepsis in two.

There are some limitations to the data I\'ve presented today. Dosing
information may be unreliable. APAP products are generally taken on an
as needed basis, and so the actual dose ingested can be difficult to
ascertain.

There is no certainty that all of the adult cases were unintentional.
There may be a stigma associated with reporting suicide and, thus, cases
may be reported as unintentional when they are actually intentional.

For all spontaneous reporting systems there is no certainty that the
drug caused the event. We lack an accurate numerator and denominator.
Therefore, incidence rates cannot be determined, and spontaneous reports
are subject to under reporting with only one to ten percent of adverse
events reported to the FDA. This may be more significant for OTC
products.

In conclusion, our review of the AERs cases identified circumstances
that likely let to hepatotoxicity. Errors related to product confusion
were mostly observed in pediatric cases, and these errors primarily
relate to confusion over varying product formulations and strengths and
use of inappropriate measuring devices.

Many adults were taking too much APAP, and in some cases, use of
multiple APAP containing products likely contributed to hepatotoxicity.

Risk factors such as alcohol use or liver disease were also identified
and may lower an individual\'s threshold for APAP hepatotoxicity.

Questions remain that were not answered by my analysis. Do user lack
knowledge of the potential for hepatotoxicity when using an APAP
containing product?

Do users lack knowledge of the symptoms of hepatotoxicity? A lack of
knowledge may lead to a delay in medical treatment.

What is the role of malnutrition and fasting?

What is the contribution of concomitant hepatotoxic medication?

And finally, what additional factors place a small number of individuals
at risk for severe hepatotoxicity at or slightly greater recommended
doses?

The Office of Drug Safety Analyses from all three presentations have
shown that unintentional APAP associated overdoses have been associated
with a large number of emergency department and hospital admissions and
an estimated 100 deaths each year. Unintentional APAP associated
overdoses are preventable.

Using a number of data sources, our analyses have shown that
circumstances leading to APAP hepatotoxicity are multi-factorial. APAP
is present in multiple prescription and OTC products.

Additionally, these products are available in numerous strengths.

Given the observation that a number of cases have occurred from multiple
product use and overuse, there is likely to be a lack of knowledge about
the safe use of APAP.

Our review of the multiple data sources presented today identify
alcohol, underlying liver disease, and fasting as risk factors that may
lower the potential for hepatotoxicity with APAP.

We believe that a variety of risk management and communication
interventions should be considered to address unintentional APAP
associated overdoses leading to hepatotoxicity.

Thank you.

CHAIRMAN CANTILENA: Okay. Thank you, speakers from the FDA.

We now have an opportunity to question the speakers from the FDA, and
while you\'re getting ready with your questions, I would actually like
to ask the first one to Dr. Lee, and actually it\'s really asking for a
comment or even to get you to speculate for us why four fifths of the
individuals are female, you know, in your group.

DR. LEE: The question was why are so many of the cases that we see
women. I don\'t think we have an idea whether it\'s more frequently
turning to a pain reliever, and I think there is some NHANES data that
suggest that women more commonly will use pain relievers than men
overall in the U.S.

But you notice that there was a higher incidence of women in all the
categories. So there may be some intrinsic difference in dosing or in
metabolism in women. I honestly don\'t know.

CHAIRMAN CANTILENA: Okay, and then if I could just perhaps ask Dr.
Watkins to comment on the issue of, you know, gender effects with the
SIP enzymes.

DR. WATKINS: There are well recognized sex differences in drug
metabolism in rodents, but consensus, I believe, is in man that
differences are very small if they exist at all.

There are certain examples of enzymes where you can make a good argument
that there are differences in metabolism, but in the enzymes that are
relevant to acetaminophen metabolism, to my knowledge, there is no data
suggesting sex differences, for instance, in Cytochrome P450-2E1, for
instance.

Now, there are other people, such as Alastair Wood who have considerable
experience in this area and might also have a comment.

DR. WOOD: No, I think that\'s right. Paul summarized it reasonably.

CHAIRMAN CANTILENA: Okay. Dr. Katz, do you have a question for Dr. Lee?

DR. KATZ: yes, thank you, and this could equally well go to any of the
FDA folks.

I\'m struggling with the issue of association versus causality and the
acute liver failure data and in the other data as well, and obviously
acetaminophen exposure is ubiquitous in our society. Exposure to
combination opioid products containing acetaminophen is also ubiquitous
in our society.

And I\'m wondering how you dealt with the issue of association versus
causation with acetaminophen and liver failure.

DR. LEE: Sure. I think this is a hard problem, and I should point out I
didn\'t have a limitation slide, as most of the FDA speakers did, but
you have to remember that these patients are all altered mentally when
they enter our study.

Now, we\'re getting historical information. It is a prospective study.
So our investigators are usually on the scene, but there may be other
information that could have been garnered from the referring hospital,
and many of our cases are \-- something like 82 percent are referred in
from another hospital.

So the primary data, in part, is from family and part is from patient if
they\'re still awake, and then part is from referring hospitals.

I would say we have three main criteria. One is history of an ingestion
of more than four grams per day, and that was fulfilled by, I think,
something like 92 percent of the cases.

Presence of an acetaminophen level clearly doesn\'t necessarily imply
hepatotoxicity, but if there is hepatotoxicity and there is any
acetaminophen in the system, that is certainly suggestive, and
acetaminophen levels being absent doesn\'t exclude it, but something
like 69 percent of our cases had an acetaminophen level, and 52 percent
had I think it was \-- had greater than 50 grams.

So actually documenting acetaminophen in the system is number two, but
number three is the presence of very high amino transferase levels, and
this, although it\'s not exclusively limited to acetaminophen, it\'s
very characteristic as I think you could see.

Certainly there is some overlap with viral hepatitis, but in virtually
all of the cases, there was screening out, you know, by routine
hepatitis serologies.

So high amino transferase levels, presence of acetaminophen, presence of
history of more than four grams is the best we can do. Most of our
cases, by the way, would have all three; not necessarily all of them
though.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. Uden.

DR. UDEN: For Dr. Lee also.

In one of your slides, you had that there\'s a 68 percent spontaneous
survival without treatment. Does that mean that those people survived
without liver transplants or how many of those individuals received
N-acetylcysteine and were real spontaneous?

DR. LEE: Yeah. Maybe that\'s a poor word. We mean survival without
transplantation, but again, all of them would have reached the threshold
of having hepatic encephalopathy and coagulopathy and then recovered.
And something like 80 percent or so would have received NAC, but not all
of them.

DR. UDEN: Okay. And excuse me, Mr. Chairman.

And on your summary slide you said 35 percent were receiving
antidepressants and 38 percent were receiving narcotics in your series.
How many were receiving both, and how many were receiving either one
individually?

DR. LEE: I can probe into that, but I don\'t have it right available.

DR. UDEN: Thank you.

DR. LEE: Thanks.

CHAIRMAN CANTILENA: Dr. Brass.

DR. BRASS: Okay. I have a question for Dr. Senior.

As I think about the basis for risk associated with the ingestion of a
given dose of acetaminophen, it seems that two major host determinates
would be what percentage of the ingested dose will be metabolized by 2E1
and to the stoichiometric availability of glutathione to deal with the
generated metabolites.

And it\'s the second that I\'d like to probe just a little bit with you.
Specifically, are there any data in man as to the variability in the
glutathione content of the liver per gram of liver?

And how predictable is that, as well as the relationship between liver
weight and body weight and, therefore, the glutathione content for an
individual?

So we do not dose acetaminophen per kilogram. So the effective dose in a
50 kilogram person versus a 100 kilogram person might be very different
if the amount of glutathione available for detoxification scales by body
weight.

So could you just comment a little bit on glutathione content in human
liver?

DR. SENIOR: Yeah. These are excellent questions and very pertinent to
the problem and really deals with a lot of the previous questions.

What data are available in man? Very, very few on these points that you
raise so pertinently. In searching the literature, there are hundreds of
papers on acetaminophen metabolism, on acetaminophen absorption. There
are scores of papers on glucuronidation, on sulfation, on glutathione
conjugation, but very few, very, very few of those papers, only a
handful, give data on individual people.

What they give is means of groups, and what we\'re concerned about is
that some people may lack glutathione stores in the liver, but we don\'t
know it. How would you find out?

Well, you\'d have to do an awful lot of liver biopsies or something in
order to find out, and that just hasn\'t been done.

Recall that this drug, acetaminophen, was approved before there was even
a requirement to show efficacy so that there were never any really
properly dose ranging studies done for safety purposes. And the methods
and techniques available in 1950 were very limited.

Now, there are some new techniques coming available now, something
called metabonomics, which is an analysis of metabolites, which can be
done on very small samples of urine and serum and blood or plasma. And
we hope that we can find out something to answer some of your questions.

The key question is how much of the reactive intermediate is formed and
is not conjugated to a harmless glutathione mercaptide. It\'s the
unconjugated, freely reactable NAPQI, this reactive intermediate, that
does the damage, and the best estimates that were made by Kritchley and
Prescott were that there\'s a huge interindividual variation, but we
don\'t really have good data in humans.

DR. BRASS: Well, for example, it\'s often said that the issue with
alcoholics is both induction of 2E1 and depletion of glutathione stores.
Do we know in man; are there any data as to how much alcohol it takes to
lower glutathione and how much it lowers it?

DR. SENIOR: Only anecdotally. We don\'t have any really systematic
studies in man unfortunately. There are some studies. Dr. Watkins and
Dr. Slattery, I think, did some studies on giving a rather large single
dose of alcohol to naive subjects and showed that there was a modest
induction of about 20 percent.

But that isn\'t the way most people drink. Most people may take two or
three drinks a day over a long period of time and thereby may be
inducing over a long period of time rather than just over one six-hour
period of administration.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. D\'Agostino.

DR. D\'AGOSTINO: I have a couple of questions I think are directed to
Dr. Lee and some of the FDA individuals.

You all admit quite readily the weaknesses of the databases. So I have
two questions that I\'m trying to grapple that might give me some more
insight.

A number of you mentioned or showed comparisons between the suicidal and
the unintentional. Is there some insight I\'m supposed to gather by
those type of comparisons, number one?

And, number two, on the different databases, could you just review again
how you get your final data from those who die in terms of what they
actually did take?

DR. LEE: Yeah, I\'m not sure I can answer the second one. I\'m not sure
what you\'re driving at.

But the answer to the first one is \-- could you rephrase the question?
I got stuck on the second.

DR. D\'AGOSTINO: You gave comparisons between the suicidal \--

DR. LEE: Okay.

DR. D\'AGOSTINO: \-- and the unintentional.

DR. LEE: Right, right.

DR. D\'AGOSTINO: And I\'m trying to grapple with the notion.

DR. LEE: Right.

DR. D\'AGOSTINO: What am I to gain from those comparisons?

DR. LEE: Okay. I think the difference from, let\'s say, the Parkland
study, for example, is that the unintentional cases, not realizing
they\'ve done something in error, do not come in in a timely fashion
and, therefore, don\'t get NAC early and tend to have more severe
injury. That is, they tend to have a worse outcome overall, in the
overall universe of these kind of patients.

There\'s many, many more patients that come in very early, suicidal
intent, don\'t even raise their aminotransferase levels. However, of the
suicidal cases that reach the level of acute liver failure, they look
identical to the accidental cases.

But I think the point is the disease sneaks up on the so-called
unintentional or accidental cases.

DR. D\'AGOSTINO: Yeah, I\'m not sure I know how to make great inferences
about the comparisons. I just wonder if all of the suicidals are very
successful. You don\'t see many of them, and you don\'t know what they
took.

The other question about the mortality, I mean, there is the causality
that\'s going on that we\'re trying to grapple with. If a person dies,
you might list everything that they ever have in their drug chest and
every other thing. So could you just go over again how we tied the
actual drug intake to the mortality to get that information?

DR. NOURJAH: The mortality data, I go with the coding, whatever the
death slide tells me. They coded for acetaminophen. There is a code
specifically. I forgot the name. I have it in my document, which when we
look at it, that drug, that code primarily exclusively includes
acetaminophen, not other drugs.

But for other classifications, for other ICD-9 or E codes I have, they
are very general. They include so many different drugs into one class.
So I don\'t know exactly what specific medication they use for overdose,
but I know they have overdoses with other class of drugs.

DR. D\'AGOSTINO: But on these spontaneous, is it they get the
information upon arrival? I mean, is there later review?

You know, if they run to the emergency department, is that where the
information is gathered?

DR. NOURJAH: For?

DR. D\'AGOSTINO: For any of the databases.

DR. NOURJAH: For any of the database \--

DR. D\'AGOSTINO: I just don\'t have a sense of how extensive especially
with the mortality cases, how extensive and complete, over complete the
data gathering is.

DR. NOURJAH: Well, we know that certificate is not very complete.
Whatever the certifier put on the death certificate, we go with that.
They may not put all the medication or not at all in some cases.

Now, whatever the list of the medications was and how they do coding I
do not know exactly, but I know they have overdose to other medications
besides acetaminophen. That\'s the only thing I know.

And you asked why we did comparison. The reason I compared, to look at,
to see what risk factors that these intentional \-- the accidental have
compared to intentional because we know that intentional or associated
deaths, it\'s related to major overdose. They take so many medications,
so many dose of acetaminophen. We know that.

But for unintentional we don\'t know anything, and we want to know what
leads to that hepatotoxicity or death. We don\'t really know they\'ve
got hepatotoxicity or not. What we know, it is on death certificate a
mention of accidental overdose to APAP. And we wanted to know what leads
them to death. What other risk factors was mentioned on death that led
them to death?

DR. D\'AGOSTINO: Thank you.

CHAIRMAN CANTILENA: Dr. Cryer, please.

DR. CRYER: This question is also for Dr. Lee.

In the database review by several of the FDA reviewers, underlying
chronic liver disease surfaced as a potential risk factor for
acetaminophen related hepatotoxicity, and this certainly caught my
attention because my assessment of the previous literature was that
chronic liver disease \-- it certainly wasn\'t conclusive that that was
related to acetaminophen hepatotoxicity.

So my question is: based upon your database review or based upon your
studies, did that surface chronic liver disease as a risk factor and
what\'s your assessment of chronic liver disease as being a potential
risk factor?

DR. LEE: We have very little data about that, Byron, because we
basically exclude those cases from further consideration. In other
words, we try to eliminate acute, nonchronic cirrhosis with superimposed
acetaminophen toxicity. That\'s kind of our basic criteria.

Not to say that there might not be some cases that didn\'t have
cirrhosis, where they didn\'t know \-- the patient didn\'t know they had
Hepatitis C beforehand, and we certainly do screening, and we will
occasionally pick up Hepatitis C antibody, but I would say it\'s a very
low number because our site investigators are already excluding these
people from the beginning.

DR. CRYER: Well, can you give me your assessment then just about the
possibility or the feasibility of that association, not specifically
based on your experience?

DR. LEE: I\'m not sure I can. I think it\'s possible that there\'s an
effect, but every one of the hepatologists in the room is probably still
using acetaminophen in chronic Hepatitis C patients for symptoms related
to interferon therapy. So I don\'t think we\'re excluding people with
chronic liver disease from using any acetaminophen at this point
certainly.

I hadn\'t focused in on that, again, because we\'ve tried to separate
out and only consider the people that have an acute problem.

CHAIRMAN CANTILENA: Dr. Cush.

DR. CUSH: Dr. Lee, I also have a question. In one of your slides where
you looked at acute liver failure patients, you showed antidepressants
as a risk factor in about a third of the patients.

DR. LEE: Yes.

DR. CUSH: Can you explain that or do you think that\'s a surrogate
marker for maybe some other behaviors that may have put them on your
list?

And did you see a use as a predictive factor in the Parkland study?

DR. LEE: Yes. There seemed to be less in the Parkland study in our
unintentional or accidental group, although I don\'t have the number
right available. We were surprised by that, but I think if you reflect
on the group of individuals, many of them again having chronic pain, low
back pain, they are often seen in a pain management clinic and would be
given antidepressants as adjunctive therapy. That\'s my assumption.

But to exclude the likelihood that a few of them or some of them even
have occult suicide ingestions I can\'t say. And, again, this group may
be having a chronic pain problem and then take a suicidal overdose,
which might explain, you know, the abrupt onset of a problem when they
seem to have been tolerating four grams or six or eight or ten grams a
day.

CHAIRMAN CANTILENA: Dr. Wood.

DR. WOOD: Yeah, this is both a question, I guess, back to Eric\'s
comment from earlier. It seems to me there are three major factors
associated with acetaminophen hepatotoxicity. One is the dose or
concentration that the patient is exposed to. A second one is the amount
of drug going down the potentially toxic pathway, which is mediated by
2E1, and the third factor, I guess, is the extent of the glutathione
stores that the individual has.

And part of the question about the intentional/nonintentional is an
attempt to convert, I suppose, the continuous variable of dose into some
discontinuous variable which may or may not be appropriate.

It seems to me, however, that we all got very comfortable extrapolating
from other situations in which we induce or inhibit drug metabolizing
enzyme. You know, we label drugs if they\'re metabolized by a CYP3A as
being lightly to be interfered with by other agents that inhibit or
induce 3A, and we do that in a fairly confident fashion.

We know a lot about the things that induce 2E1, and all of the animal
data points to induction of 2E1 as being an important risk factor for
toxicity. It seems extraordinarily improbable that induction of 2E1 in
people, given all the information we have, would not also be a risk
factor for toxicity.

So I don\'t see there\'s a major distinction between labeling for
induction of 2E1 for toxicity as acetaminophen as being any different
from labeling from inhibition of 3A, which do every day of the week
almost.

Going to the glutathione stores is harder. Intuitively, in animal
studies there\'s plenty of data to show that depletion of glutathione
increases toxicity of drugs, such as acetaminophen, that are normally
detoxified by binding to glutathione.

It\'s probably also reasonable and relatively low risk in terms of
labeling to say that individuals whose glutathione stores were in some
way depleted are at increased risk. I don\'t have data to support that,
I guess, but doing that experiment would be hard to do. But it seems an
extraordinary low risk labeling issue.

But the focus I think, the major focus, should be on deciding whether
we\'re going to label for factors that induce 2E1 and identifying in a
broad fashion what these are. There may be other enzymes that also
contribute, but 2E1 certainly seems a major contributor.

CHAIRMAN CANTILENA: Dr. Clapp.

DR. CLAPP: My question is for Dr. Karwoski.

I\'d like to ask whether in your review of the pediatric literature on
acetaminophen toxicity, whether or not you were able to ascertain if
there were any cases of mortality or morbidity along the lines of
children over 12 taking adult doses of acetaminophen, at a four gram per
day maximum who are less than 40 kilograms. If you had lightweight 12
year old children taking appropriate doses along the labeling that could
result in toxicity of 130 milligrams a day or more.

DR. KARWOSKI: We didn\'t have any of those specific cases today. The
oldest among the pediatric was eight years old. There was one case that
was actually summarized in the adults of a 19 year old who was only 26
kilograms and received a dose of 600 milligrams Q six hours and
developed hepatotoxicity. This particular woman was also on tegretol,
which they thought there might have been some sort of drug interaction
there that resulted in her having an increased susceptibility to APAP
toxicity.

But, no, our medication error staff have actually reviewed other
databases or data sources where there wasn\'t necessarily hepatotoxicity
associated with it, and they did find a number of times where adult
formulations were given to children, but in many of those cases there
wasn\'t a toxicity associated with it.

CHAIRMAN CANTILENA: Dr. Johnson.

DR. JOHNSON: I have a question for Dr. Lee.

In one of your slides you describe that 38 percent of the unintentional
patients were taking a narcotic combination, and I\'m wondering if you
have data on whether the high doses of acetaminophen were the result of
taking the combination product plus over-the-counter acetaminophen or
was really sort of a side consequence of abuse of the narcotic product.

DR. LEE: I don\'t have that specific data. I think the majority of them
were more abuse of the product, in other words, taking a daily dose that
was in excess of four grams, but there may have been \-- I just don\'t
remember offhand how many were actually double use individuals.

CHAIRMAN CANTILENA: Dr. Day.

DR. DAY: I have a question for Dr. Karwoski.

In the overall summary from the Office of Drug Safety, three broad
classes of factors were cited, factors concerned with the product
itself, with knowledge, and with risk factors, and we\'ve heard a lot
this morning about the product and about the risk factors.

And can you comment on the knowledge component, specifically the
availability of research studies on prior knowledge about potential
toxicity and also any label comprehension studies which speak to this
issue, and in both consumers and health care providers?

DR. KARWOSKI: I\'m not going to be able to comment on that. I\'m not
aware of that. I\'m not sure. Somebody else from the OTC Division might
be aware.

CHAIRMAN CANTILENA: Yeah, I think we\'ll have an opportunity this
afternoon to talk about that a little bit.

Okay, and Dr. Alfano.

DR. ALFANO: My questions is for Dr. Lee.

Dr. Lee, you\'ve assembled an admirable network of study sites and are
doing prospective work in this area. I think it\'s the only such
database we\'ve heard from, and it may explain why the bulk of the
questions have been directed to you today.

In his introductory remarks, Dr. Ganley indicated that the FDA has not
had access to this data. Since your studies are ongoing and since this
problem clearly will need to be evaluated on an ongoing basis, my
question is: is it your intention to make this data available, raw data
available?

DR. LEE: Yes.

CHAIRMAN CANTILENA: Okay. Thank you.

Two more questions. Dr. Katz, did you have one? And then Dr. Uden, and
then we\'ll close.

DR. KATZ: Thanks.

I just wanted to follow up on the issue of causality for anybody who\'d
care to answer. It seems like from a fundamental epidemiological
standpoint we\'re a long way from deducing causality from the data that
we\'ve seen, which was just really associations. And one would normally
think of doing at least a case control study where you try to get around
the issue of that when people get sick, they start to take whatever is
in their medicine chest.

And one could easily see that if you developed any painful illness,
meningitis or what have you, they\'d start to take whatever was in your
cabinet.

So I wonder if anybody is aware of any case control data where people
were hospitalized for other serious illnesses or looked at for how much
acetaminophen they were taking, whether they were taking multiple
formulations, whether they were taking high doses to see whether, in
deed, there is any strong reference for causality in some of the cases
we\'ve seen, especially with the levels of therapeutic dosage of
acetaminophen.

CHAIRMAN CANTILENA: Who from FDA would like to answer that?

DR. BEITZ: We\'re not aware of such studies.

CHAIRMAN CANTILENA: Okay, and then our final question for this part of
the program, Dr. Uden.

DR. UDEN: Yeah, I\'d like to nail down the pediatric mortality
information. In the presentation by Nourjah, Ahmad and Karwoski, they
talked about age. Some of you alluded to it, and Karwoski, you had
information about pediatric deaths.

I remember back in the late \'70s, early \'80s. I don\'t know how
commonly this was held that it was children less than six or infants.
Really if they took an overdose of acetaminophen, there weren\'t really
any published deaths at that point in time, and that for some reason
that they were able to metabolize a drug more efficiently better didn\'t
have the toxic intermediate.

So what do we know about pediatric patients less than six years of age
and their risk for mortality as compared to risk of mortality of the
group who are in their 30s, 40s, and 50s?

DR. NOURJAH: From my observation from these databases, if you look at
the pyramid, I mean, I didn\'t create the pyramid for children less than
six. However, we have a lot of observation visits for children less than
six to come to emergency department, and then less so go to hospital,
and for mortality data, they\'re a very small number, very, very small
number. Like it\'s like suggesting their children, although they get
overdose to APAP, but the severity is not that much.

That I can tell from the data I see.

DR. UDEN: And that\'s all we know about that? It would seem that we
would know a lot more about pediatric mortality related to acetaminophen
than that. I mean, I\'m just surprised at that.

DR. KARWOSKI: I don\'t think the spontaneous reports are going to give
us that answer. I mean, we certainly have a smaller number of reports in
pediatric which may give you some indication that they seem to run into
trouble less often, but we can\'t make any comparisons as to the
mortality in those versus adults.

CHAIRMAN CANTILENA: Okay. Thank you.

I think what we\'ll do, I first of all want to again thank the speakers
from the FDA for their presentation. We\'ll now take a 20 minute break.

(Whereupon, the foregoing matter went off the record at 10:07 a.m. and
went back on the record at 10:34 a.m.)

CHAIRMAN CANTILENA: We\'re going to begin the open public hearing
session, and the first group that will be presenting will be led by Dr.
Bowen. Dr. Bowen? And this group has five, zero minutes, five, zero
minutes for their presentation.

DR. BOWEN: Good morning. Mr. Chairman, Dr. Galson, Dr. Ganley, advisors
and consultants and FDA, I\'m Dr. Debra Bowen, Vice President of
Research and Development at McNeil. We are the primary researcher and
manufacturer of acetaminophen, which is the most widely used analgesic
in the United States.

McNeil also markets ibuprofen and aspirin products. It\'s a pleasure to
be with you this morning discussing the science of the safety of our
products.

As you know, McNeil\'s overriding commitment is to our consumers who use
our products and to the health care professionals who recommend them.

Today our objective is to provide a context for the committee\'s
consideration around questions raised by FDA. We\'ll provide the
scientific evidence that acetaminophen is safe and effective as it is
currently marketed and formulated, and we\'ll also review the data and
the databases that underscore acetaminophen\'s safety and use.

We\'ll share information about some actions that we\'ve taken to insure
that acetaminophen in actual use continues to be one of the safest drugs
available when taken as directed.

Let me begin by providing a brief background on acetaminophen. In the
United States, acetaminophen has been marketed since the \'50s, and
it\'s used by more than 100 million people each year. It\'s also used in
culturally and racially diverse populations around the world.

Instances of serious harm are rare, although we are the first to say
that we must insure its safety and use.

As you know, all drugs have risks as well as benefits. In massive
overdose, 15 grams over a few hours, acetaminophen may cause hepatic
damage if N-acetylcysteine, NAC, isn\'t administered early.

In adults, most of these episode are suicidal. In children, most are
accidental ingestion. Our review of the 307 AERs cases suggest that rare
serious adverse events may occur in American consumers who inadvertently
overuse acetaminophen containing products.

That is the issue that we\'re here today to discuss with you. The
precise incidence of harmful, in advertent overuse can\'t be accurately
determined from the databases that we currently have. It is clear,
however, that given the fact that 48 million American adults use
acetaminophen containing products in any single week, it is a rare
event.

The reasons for inadvertent overuse are even harder to uncover. We\'ve
reviewed the case reports containing incomplete or inaccurate
descriptive information, and we\'ve coupled this with our understanding
of reported consumer analgesic use patterns to reveal actionable
insights.

To reach actionable conclusions, we reviewed and discussed with
scientific experts the science of analgesics, acetaminophen and the
NSAIDs. We initiated a new multiple dose pharmacology study to gain
additional insight.

This study provides new data that you\'ll be hearing later, underscoring
this drug\'s wide safety end use margin.

We also conducted a modern dose ranging efficacy study to confirm
findings in old studies that the optimal single adult analgesic dose is
one gram.

In addition, we looked at consumer attitudes and behavior. In cases
where consumers report product overuse or misuse, we set out to better
understand the attitudes about medicating that may underlie their
reported usage.

Now, McNeil\'s interventions fall into two categories. First,
interventions intended to prevent serious adverse events from drug
overdose.

Second, interventions to optimize appropriate use. McNeil has always
taken the leadership role to insure the safety and use of acetaminophen
containing products for all consumers, not just those who buy Tylenol.

To prevent serious adverse events in the case of large drug overdoses,
McNeil initiated the IND for the antidote, NAC, funded the support of
its development, provides continuing support for Poison Control Centers
to answer overdose inquiries, and introduced a child resistant and error
resistant concentrated drop device for infants.

These are all examples of our longstanding commitment to prevention of
drug overdose and safety end use for American consumers.

FDA has focused today\'s dialogue on unintentional misuse. We have
implemented labeling changes that build in the strength of FDA\'s Drug
Facts label to further minimize the inadvertent overuse of analgesics
and today we are recommending an organ specific overdose warning.

These labeling and education initiatives are equally relevant to the
other over-the-counter drugs that we market, including ibuprofen and
aspirin and all multi-symptom analgesics.

In addition, we continue to emphasize the importance of our citizens\'
petition to allow dosing directions for children under two years old on
infant\'s products. We believe with you that the American consumer is
smart, responsible, and can self-manage medications.

Because our time is limited, we\'ll use the remainder of our time to
review the science of acetaminophen. We strongly encourage the committee
members to come by and review our intervention programs in more detail
down the hall in the Potomac Room.

We look forward to the discussion this afternoon.

Today my colleagues will review the longstanding science, new data, and
provide their own points of view for your consideration. Dr. John
Slattery from the University of Washington will discuss the
pharmacokinetics and metabolism of acetaminophen and will present the
recent multi-dose data.

Dr. Richard Dart, Professor from the University of Colorado will review
clinical toxicity overdose and case analyses.

And Dr. Raymond Koff from the University of Massachusetts will discuss
issues in special populations focusing on underlying liver disease.

And finally, Tony Temple, Vice President of Medical Sciences at McNeil
will complete our presentation and direct the question and answer
session.

Our review supports key conclusions, namely, that acetaminophen has been
marketed for over half a century worldwide and in many populations.
Review of science and consumer usage continues to underscore its safety.
Harm is rare and is caused by overdose.

Serious harm, caused by inadvertent misuse, is very rare. As
manufacturers of acetaminophen, ibuprofen, and aspirin, proper consumer
use of the entire class of pain reliever fever reducers is our
objective. Any change in effectiveness due to lower a dose, changes in
access, or risk emphasis for one ingredient in the entire analgesic
class will affect consumer choice and health outcomes.

Today we welcome the opportunity to share what we know and to learn from
you. Making the right changes, affecting consumers\' health in an
overall positive direction is a goal that we share with you.

Thank you.

Dr. Slattery.

DR. SLATTERY: Thanks very much. It\'s a pleasure to be here today to
talk with you about a compound that I\'ve been working with for 20-some
years.

You\'ve already seen a review of the metabolism of acetaminophen, but
that\'s actually what I\'m going to be talking about in relation to
hepatotoxicity, and as you\'ve heard, the majority of the dose of
acetaminophen is actually eliminated by nontoxic routes to the formation
of a glucuronide conjugate and a sulfate. There\'s a relatively small
fraction of the dose, a few percent, on the order of five to ten percent
of the drug that\'s converted primarily by Cytochrome P450 2E1 by two
reactive quinonimine called NAPQI, and this exerts toxicity by binding
covalently to macro molecules and also initiated processes, such as
oxidative stress.

Under normal circumstances this, of course, is conjugated by
glutathionate transferase enzyme with glutathione to form the
glutathione conjugate, which is eventually eliminated in the urine and
cysteine mercaptor (phonetic) acid conjugates and other thiol ethers.

It\'s important to realize, and as you\'ve heard today, as the dose of
acetaminophen is increased a couple of things happen. One is that the
co-factor for this process becomes depleted and you have less going out
by this route.

And another thing that happens, of course, is the glutathione stores
within the liver become depleted, and we end up with more of this
reactive intermediate being available to covalently bind and eventually
cause toxicity in the liver.

So the important things to remember from this is that there is something
of a threshold phenomenon here and that you have to deplete those
co-factors. When we look at glutathione stores, we have to have
substantial depletion of glutathione stores before we get appreciable
hepatotoxicity.

And, of course, we\'ll remember here that acetaminophen is nontoxic at
recommended doses.

Now, there is a little bit of controversy in the literature regarding
the enzymes that are responsible for the oxidation of acetaminophen to
the reactive species NAPQI, and those enzymes in the human that have
most often been talked about are 2E1, 3A4, and 1A2.

And the evidence for this largely comes from studies in human liver
microsomes, and this is just some data from our own laboratory, and the
way that this works is that it\'s called reaction phenotyping, and one
uses various chemical inhibitors very often that are specific for
certain isoforms, and you look at the degree of inhibition.

Here we had just 35 percent inhibition in this human \-- the microsomes
from this human liver at a dose or at a concentration of acetaminophen
of 0.1 micromolar.

And I won\'t go through the rest of this in any detail, but as you know,
those of you particularly who have dealt in this area of drug metabolism
with Cytochromes P450, [in vivo]{.underline} or [in vitro]{.underline}
to [in vivo]{.underline} correlations are not always perfect.

So a few years ago we started some studies, and we were particularly
interested in probing the contribution of 1A2, and the way that we
approached that was through a drug interaction study using omeprazole,
which in slow metabolizers of mephenytoin \-- those are deficients in
2C19 activity ‑- achieve high levels when maximum daily doses are used.

One of the things that we included in this study as a positive control
was caffeine. Caffeine, as you know, is a probe substrate for Cytochrome
P450 1A2. The important data to look at is over here with the slow
metabolizers, and what you can see is that in the presence of
omeprazole, the caffeine clearance was almost doubled.

By contrast, when we look at the formation clearance of these thiol
ether conjugates, this is actually a measure of the ability of the
individual or the body to form NAPQI. You can see that that formation
clearance actually didn\'t change, and this then suggests, it shows us
that P450 1A2 is not important in human beings in making this
intermediate.

This is important when one thinks about risk factors. Smoking can kind
of be rules out at this point and other compounds that would induce 1A2.

When we saw this, we thought that we\'d better continue with this
series, and we conducted a study of rifampin again on the disposition of
acetaminophen. Now this study was conducted very much the same way.
Rifampin is recognized as a very potent inducer of 3A4.

And what we did here, again, it\'s a relatively small study. We
administered rifampin, 600 milligrams per day for seven day, again
looking at this measure of the ability to form the reactive
intermediate.

We can see between the minus rifampin case and the plus rifampin case
there was really no difference in the ability to form that. So that [in
vivo]{.underline} in human beings, 3A4 seems not to be important in the
formation or NAPQI.

This then also rules out another potential set of drug interactions. So
we thought we had better continue on this line, and the next approach
that we took was we used disulfiram, which is a very potent inhibitor of
Cytochrome P450 2E1, and here we gave disulfiram 500 milligrams the
evening before the individual received acetaminophen, and again we have
this same measure of the inability to form the reactive intermediate.

And what you can see is that this actually declines substantially. It
actually declines by about 75 percent. So only 25 percent residual
activity to form NAPQI was left.

And so what this has told us and my thinking has been from that time
that P-450s 1A2 and 3A4 are not important in human beings, live human
beings in forming the reactive intermediate from acetaminophen, but the
2E1 is by far the principal enzyme in that process.

So as I said, it has important implications with regards to drug
interactions. The issue of drug interactions and particularly inducers
of 2E1 has been brought up earlier this morning, and one thing I would
like you to know is that the mechanism of induction of 2E1 is kind of
different than with most other P450s, at least one particular facet that
is important.

One of the ways that this \-- this is 2E1, in case you can\'t recognize
the shape of this protein here \-- present in this little cartoon, had
what we\'re considering here is a substrate. We can think of the
substrate being acetaminophen, and we have an inhibitor inducer and
probe inhibitor inducers that we\'ve done studies with are isonized in
ethanol.

And the way that this works is when this inhibitor inducer \-- and
you\'ll see in a minute why I call it both \-- is present, it can bind
the active site. Okay? It\'s just \-- all it needs to do is be a ligand
for 2E1. It bind the active site, and when it does that, it protects the
enzyme from degradation.

So what you see here in the cartoon is now two molecules of this enzyme,
but the important thing to realize is that while it\'s been induced,
protein levels are up. The active site is occupied so that the substrate
can\'t get in there.

While the enzyme levels are up during this phase of induction, what we
actually see in terms of activity is inhibition because of the
occupation of the active site. It switches to enhanced activity when we
can see the evidence of induction once the inhibitor inducer is actually
eliminated and the substrate can gain access to that active site.

Now, we\'ve done a few studies that have actually looked at this in
humans, and this is a study that was done with Kent Mole and Paul
Watkins, who is here today, and in this case what was done was to give
ethanol by constant rate, constant IV infusion to maintain
concentrations of 100 milligrams per deciliter for a period of six
hours, and what we\'re really trying to simulate here is the folks, you
know, who goes out Saturday night, puts the elbows on a bar and has a
few drinks, and gets legally drunk and hopefully calls a taxicab and
goes home.

What happens during the period that they are drinking, this is the ratio
of the ability to form NAPQI at any particular time along this axis,
divided by the ability to form that at time zero before any ethanol was
initiated.

While ethanol is on board, actually enzyme levels are rising a bit, but
what we see is inhibition of the ability to form this toxic
intermediate. Once you remove, you stop administering the ethanol, and
we see the same sort of thing for isoniazid. The ethanol is eliminated,
and as you administer acetaminophen again after ethanol is eliminated
from the body, that\'s the time at which you can actually pick up the
enhanced activity.

There\'s a thing that\'s important to realize about this interaction,
and that is kind of the window of vulnerability is actually kind of
relatively short and requires that the inducer-inhibitor administration
actually be stopped.

There were some questions about what goes on with hepatocellular
glutathione during this period. We\'ve recently completed some studies
that have been accepted for publication, and I can talk about that in
the question and answer period, but actually what\'s going on there in
terms of risk of this interaction runs opposite to what\'s actually
going on with the enzyme.

This is a very intricate drug interaction and one that I\'ve been
pondering for quite some time.

Another thing that has come up recently in the discussion about risk
factors for toxicity following ingestion of administration is Gilbert\'s
Syndrome, and this is a genetic deficiency in a particular glucuronal
transferase. The enzyme that\'s involved in making this nontoxic
glucuronide metabolite or conjugate. This is actually a deficiency in
UGT 1A1.

Work by Court, [et al]{.underline}., published in JPET a year or so ago
actually demonstrated that UGT 1A6 is the predominant form in making
acetaminophen glucuronide. It has a Km of about 2.2 millimolar, and if
we transfer this Km into body burden so that we give it an amount sort
of measurement, that really corresponds to a body burden of about 20
grams. So this has a very high Km.

They also identified that 1A1 and 1A9 are minor contributors. So the
question come ups really if UGT 1A1 is gone, what is the effect on
actually the formation as was identified this morning.

One of the important things in terms of toxicity is the flux of
acetaminophen through the NAPQI pathway and how much NAPQI is made. So
we can actually calculate that from data that they\'ve presented in this
paper.

They did some incubations at half millimolar acetaminophen, which really
corresponds to about a five gram body load, and if we calculate that UGT
1A1 actually was not present or its activity was zero, the formation of
NAPQI increases to where it would count on average in individuals from
about six and a half percent of dose to only about 7.3 percent of dose.

Now, these are studies in human liver microsomes. In these same sets, 56
sets of human liver microsomes, each prepared from a different
individual. The overall variability and formation of acetaminophen
glucuronide was about 15-fold.

Let me tell you that these conclusions about UGT 1A1 and 1A6 are
consistent with [in vivo]{.underline} data in people with Gilbert\'s
Syndrome. There have been two studies done, neither has demonstrated
that there\'s any difference in the ability to form acetaminophen
glucuronide. So I think this is a strong conclusion.

McNeil has recently conducted some multiple dose studies looking at the
super therapeutic range and what the focus of these actually was, is the
dose dependence at steady state after the drug has been given for three
days.

These studies had 12 individuals per group in the active arm, and they
included a placebo arm so that they could follow liver enzymes, and over
the period of administration of acetaminophen and three days after the
period of administration, there was no evidence. None of the liver
enzymes were increased beyond the normal limits.

This is just the acetaminophen concentration time course, and there\'s
not too much to point out here, except that you\'ll see really an
absence of accumulation of acetaminophen over the period of
administration, and we\'re going to be looking at data as a function of
dose really from the last dosing interval of administration.

And so here we have the four gram, the six gram, the eight gram dose,
and what we\'re looking at first is just the fraction of dose excreted
in urine, and you\'re of course interested in this because the fraction
of dose excreted in urine as the thiol ether conjugates \-- that\'s what
the T is here in each one of these things \-- is actually giving you the
information about flux through the NAPQI pathway.

These data, these are actually kind of the raw data here, and what\'s
easier to look at for the relatively \-- changes compared to what you
would see at the four gram is actually these. So these are just these
different data sets expressed relative to what happens at four grams.

And what you see at six grams and eight grams is a modest increase in
the ability or in the urinary recovery of the glucuronide conjugate. You
see a decrease in the recovery of the sulfate conjugate, and that\'s
really expected because we know that the co-factor for sulfation is
being depleted as we encounter doses in this range.

The actual recovery of the thiol ether conjugates that are formed
through the NAPQI pathway is decreasing. We have variable results with
regards to the recovery of acetaminophen in urine, which is not
surprising. The poor solubility of acetaminophen in water makes it renal
clearance urine flow dependent. So that finding isn\'t surprising.

To get a little bit of mechanistic information from this and
interpretation, we need to look at what\'s going on with formation
clearances. Formation clearances being the measure with each one of
these different steps, the glucuronide, the sulfate, the thiol ether or
NAPQI, and acetaminophen renal clearance. This is really a measure of
directly kind of what\'s going on with the activity in those different
pathways.

We see something of an increase in the ability to form the glucuronide
conjugate, and this is really something of a surprise to me, and I
don\'t have much to speculate on mechanism of that right now.

A decrease in the ability to form the sulfate conjugate, which again is
not surprising, and a decrease in the ability to form the thiol ether
conjugates.

There are potentially two explanations, I think, for this mechanism. One
is that we know as larger doses of acetaminophen are ingested we deplete
glutathione, and that\'s one potential reason for the decreased recovery
of these kind of daughters of NAPQI.

The other is that, of course, we\'re forming this reactive electrophile
that likes to bind proteins, and we know from studies in animals, some
conducted in our laboratories and some elsewhere, that NAPQI is actually
good at destroying the enzyme 2E1 that makes it, and so there are
probably two mechanisms underlying that, one being chronic
administration resulting in destruction of the enzyme that actually
makes NAPQI.

These interpretations have to be regarded as hypothetical because they
haven\'t yet been directly investigated, and they amenable to
experimental investigation.

In summary, NAPQI is formed by Cytochrome P-450 2E1 and modulation of
other Cytochrome P-450s is unimportant, in my view, as risk factors in
the toxicity of the compound.

Toxicity follows substantial glutathione depletion, and the
mitochondrial pool is \-- I didn\'t have a chance to discuss this very
much \-- but it\'s very important in terms of this toxicity.

Absence of UGT 1A1 in Gilbert\'s disease is not a significant risk
factor. We saw that acetaminophen does not accumulate on multiple doses
up to about eight grams, and I just mention the changes that actually go
on in metabolism.

Thank you very much.

DR. DART: Good morning. I\'ll be talking about the safety of
acetaminophen from several different perspectives. First we\'re going to
talk a little bit about acute substantial acetaminophen overdose. We\'ll
talk a little bit about the AERs data sets and evaluation of those;
chronic alcohol use, where we\'ve done some research at Rocky Mountain;
and finally, we\'ll be talking about repeated \-- and this is new data
on repeated supertherapeutic ingestion also from our poison center.

Well, you just heard that you can give multiple doses of eight grams a
day to patients and not have accumulation or liver injury. So you won\'t
be surprised to hear that there are prospective data about acute single
ingestion of acetaminophen up to 9.1 grams that show the same results,
and because that data is now available, I\'m going to skip over the rest
of the slide.

Now, in the clinical situation, we deal with this. This is a tool that
we use called the Rumac NAC Nomogram, and what you see here are two
lines. One is called the possible liver toxicity line, and the other is
called the probable liver toxicity line.

And in the United States, if your serum level after a single acute
ingestion falls above the dotted line here, then you will be treated
with NAC, N-acetylcysteine.

In the U.K., they use the higher line. So there\'s a little bit of
difference, but the main point of this slide is to show what happens at
a therapeutic dose, such as 15 milligrams per kilogram, a common
therapeutic dose, and you can see that levels top at about just under
20.

If you take five times that much or 75 milligrams per kilogram, then you
can peak out in the range of 90 micrograms per mL, but still far below.
So it takes a really remarkable ingestion to get up over the nomogram
line.

Now, moving to the AERs data set, this has already been described. I
won\'t go into detail. We know that it\'s hepatic events that we\'re
being assessed. There was 307 reports, and we\'re going to focus on the
281 adult reports. There were also 25 pediatrics and actually one that
doesn\'t mention acetaminophen.

Some limitations like this were already mentioned, but I just want to
remind everyone that there are limitations to case reports. We sometimes
have to use them in medicine, but really we need to understand that
causality cannot be ascertained using retrospective data, especially
case reports, for several different reasons, one being the history of
dose is often inaccurate.

There\'s a very strong \-- and as a practicing person who takes
histories from these patients \-- there\'s a very strong emphasis or
pressure on the patient to minimize the dose they have taken. They\'re
in your emergency department. You are seeing them. They very
consistently under estimate the dose that they have taken.

The other option is they don\'t know at all because they\'re unconscious
or intoxicated, and you\'re just not sure what that history is.

Another concern I have with the case report data is that \-- and this is
often unrecognized \-- that in today\'s world \-- this wasn\'t true when
I trained, but it is certainly true today \-- is that there is very
strong pressure from training programs and from hospitals to not put
information about suicide in the medical record.

The only time we \-- in fact, we counsel our residents: do not put that
information in the medical record unless it is extremely clear that this
happened because you are going to deprive that person of medical
insurance in the future possibly. You may deny payment for their health
expenses in the future of any kind. So there\'s huge implications for
the patient to write that in the record, and unless you\'re sure, then
you\'re not going to put it in there.

Now, we formed an expert review panel that was supported by McNeil. I
was the chairman, and these are the individuals that were included in
that panel. Several are in the room today, and you can see that they
represented emergency medicine, toxicology, hepatatology and pediatrics.

What we did was took the AERs database for adults, 281 adults, met, went
through our own self-created panel training and creation of a
standardized data collection instrument by the panel.

The panel then reviewed each of these cases individually and came to
their own clinical judgment. In other words, they were asked to look at
the AERs report, and based on that data, and obviously there is no other
data besides what\'s in the AERs report, to make a clinical judgment of
causality related to the liver injury of that patient, if liver injury
was present.

So the panel then met to undergo an iterative consensus process where
the group assigned probability of association with acetaminophen. So
each person made their individual judgment. Then we met and put these
into definitely acetaminophen related probably, which meant greater than
51 percent clinical probability that the liver injury was acetaminophen
related; possible, which was less than 50 percent and basically meant
that there was another cause that was as or more likely than
acetaminophen; unlikely meant \-- I\'m sorry. I got carried away.

Possible meant less than 50 percent. Unlikely meant that there was
another cause more likely than acetaminophen. And definitely not meant
there was no possibility in the panel\'s mind that this was a
acetaminophen case. And then the category of insufficient information.

This shows the results of the panel\'s deliberations. As you can see,
there were three cases that the panel thought were definitely
acetaminophen, but if you add those to the probables, then about 25
percent of all cases were considered related. Acetaminophen was
considered to be causally related to the liver injury that the patient
experienced.

At the other end of the graph, we have the insufficient data, and here
we see that about another quarter of the patients, there just wasn\'t
information to be able to make that determination.

Twenty-seven cases were judged definitely not and 53 unlikely. These
mean that there was either very good evidence that it was not
acetaminophen or another cause, and that accounts for about another
quarter of the cases.

And then finally there\'s this somewhat gray zone of the possibles,
where the probability was just judged clinically, and this is somewhat
subjective, to be less than 50 percent

If you look at these in a little more detail, what you see is that most
of the definite or probable cases were associated with substantial
overdoses. That\'s not surprising at all.

Also, most of the definite or probable cases were also associated with
alcohol or alcohol abuse, although as the FDA also noted from theirs as
well, this is spontaneously reported. So we really don\'t know what the
incidence of alcohol abuse was in the groups.

Finally, I\'ll just mention the 25 pediatric reports. Four were
unintentional single ingestion. There involved a maternal overdose, and
18 involved administration. Most reported children under the age of two
years, which is one of the reasons that that would be nice to have on
the label.

Now, out of this information the packaging or the materials for this
meeting lists putative risk subsets, especially history of liver
disease, coingestion of hepatotoxic medications and ethanol use.

Now, there\'s several concerns here, the primary being that this is all
based on essentially case report data, and so this is very soft.

The other problem is that acetaminophen, as we\'ve heard, is used in
about 23 percent of people in an given week or 100 million individual
users per year. So there\'s a huge confounder here in that if I\'m going
to die of something and I happen to have taken acetaminophen, the
presence of acetaminophen in the blood in a person who is dying does not
indicate that it was \-- or even in liver injury \-- does not indicate
that the acetaminophen was the cause of that liver injury.

There\'s over 100 substances just on a short list that are known to
cause hepatotoxicity to levels greater than 1,000 on AST. So there\'s a
huge confounder here.

And then finally, on the ethanol use, I\'d just like to present some
data that we\'ve generated in Denver. We performed a randomized, double
blind, placebo controlled trial in hard core alcoholic patients. These
patients received acetaminophen, one gram, or placebo four times daily
for two consecutive days. These were all currently drinking alcoholics
by history. Over 50 percent of them had been doing this for over 20
years, and nearly all of them had been doing it for at least five years.

One third of the patients had a low body mass defined as less than 21.
Standing here, my body mass is 26.

We found that there was no statistically significant difference in the
mean AST, ALT, or INR at two and four days for the acetaminophen group,
and we\'re doing another study that\'s similar. We\'ve enrolled 80
patients and have the same results.

Now, I want to point out that if you remember Dr. Slattery\'s slide
where you saw the biphasic effect of alcohol, what we do in these cases
is the patient comes in intoxicated. We wait until the alcohol wears
off, get informed consent, draw their blood, administer the
acetaminophen.

So we\'re administering the acetaminophen at the time of maximal
vulnerability for that patient.

Jumping quickly, and I\'m sorry to switch gears so fast, I\'d like to
talk about repeated super therapeutic ingestion. What do I mean by that?

Well, that\'s our term for the patients who take multiple doses
throughout a day or usually more than a day that amount to more than
four grams in a day. So they\'re taking more than the recommended, but
they\'re doing it split up, not as an acute single ingestion.

We see a lot of acetaminophen. We had in this 16 month period 7,300
cases of acetaminophen. That\'s because we are well known nationally for
this and get a lot of phone calls about it.

Of those 277, we had a documented history of repeated super therapeutic
ingestion as I just defined. Two hundred forty-nine patients agreed to
be enrolled in the study, and in those patients we measured their
acetaminophen level and their AST level or recommended that to the
physician calling, I should say.

If either of those was positive, greater than ten or greater than 50,
that patient was treated for at least 12 hours with acetylcysteine. If
not, they were discharged.

But the important point here is that we then followed them up over the
subsequent 72 hours, and here\'s the results of that study.

For patients who had no liver injury, and that means upper limits of
normal; so they were underneath the upper limits of normal for the
person\'s lab that was calling. There was a mean ingestion of 10.6 grams
with 95 percent confidence intervals of 9.4 to 11.7.

There were 126 of these patients. One hundred nine were completely well
at follow-up. Seventeen were lost to telephone follow-up. However, they
were well when they were discharged from the hospital.

In the group that achieved AST levels of 50 to 1,000 international units
per liter, the mean ingestion was 11.7; confidence intervals of 9.6 to
13.8. There were 40 of these patients. Thirty-seven did well, and three
were lost to follow-up.

Among patients \-- and this is probably the most interesting group \--
that achieved ASTs greater than 1,000, sort of the traditional
definition of acetaminophen induced hepatic injury, 12.6 grams was the
mean dose, 10.3 to 14.9, and I want to point out this relationship here
where there was a striking increase in the duration of the ingestion as
the enzyme levels went up.

There were 44 patients in this group.

Still 37 of them did well. However, seven of them \-- actually six died
and one was transplanted for a total of seven patients.

The not done group means that this is where the physician did not draw
the laboratory test that we recommended, and as you can see, they tended
to be \-- basically they weren\'t ones he expected to get toxic. They
were lower doses, and they did \-- every one we followed up did well.

They probably belong in this group, but we separated them out because we
don\'t have that AST level.

Looking at this data graphically, you can see that we see a dose
response relationship for \-- there\'s no toxicity in this column. Mild
to moderate I guess I would call this, and then greater than 1,000 in
this column.

And especially I think the time is something that we \-- it\'s very
striking to us in handling these cases, is this isn\'t something that
happens in one day. This takes kind of a committed effort. I\'m not
saying they\'d necessarily do it intentionally, but there\'s really \--
it takes some time to be able to develop this.

Switching gears again, I\'m going to talk about the data from the
submission about acetaminophen associated. It was called acetaminophen
related in the packet. I\'ve called it associated because I felt that
was a better term, and they\'re talking about a total of 458 deaths from
acetaminophen each year. This is an annual figure.

Now, something that\'s worrisome about this data is, as Dr. Lee
mentioned, this is \-- you know, patients who have acetaminophen
toxicity have some very characteristic things, which is they always have
liver injury if they\'re going to die during that acute event.

And yet on these discharge summaries, even though these patients should
have had severe liver injury, no liver disease was reported.

So we\'re not sure what to do with that section of the data. This
includes hepatitides and things like that. This is the chronic liver
disease, and then there were 58 patients out of that that were acute
liver toxicity.

If you look at those 58, 28 were stated to be unintentional, 30
intentional. Even this number concerns me because of the fact in medical
records that it\'s so common to not write down intentionality or
suicidality at least because of the ramifications for the patient.

And that\'s not one we\'re going to cover for time.

Conclusions. Prospective studies to date indicate no toxicity at or near
the recommended dose of acetaminophen. Serious hepatotoxicity does
occur. The single does estimate, as we\'ve heard before, is 15 grams or,
as emerging evidence is showing, it appears to be about 12 grams a day
for repeated dosing.

Our alcoholic data suggests that alcoholics may safely take the current
recommended doses of acetaminophen, and therefore, I see no need for any
dose reduction.

Thank you.

DR. KOFF: Good morning. My name is Ray Koff. I\'m a hepatologist.

I want to address some of the questions that came up this morning with
regard to the safety of acetaminophen in patients with chronic liver
disease.

Acetaminophen at currently recommended doses, up to four grams per day,
is safe to use in patients with chronic liver disease. And the
supporting evidence from this comes from prospective, single dose, and
multiple dose studies in a variety of liver diseases: chronic hepatitis,
cirrhosis, alcoholic liver disease, metabolic liver disease.

And finally, there is a large clinical experience over the last ten
years in the use of acetaminophen in patients with chronic liver
disease.

In contrast, as you\'ve heard this morning, the concerns for increased
hepatotoxicity at therapeutic doses of acetaminophen is largely based on
anecdotal case reports which may be inaccurate, may be unreliable, and
it\'s very hard, I think, to use them.

Now, this is not a new subject. Studies of acetaminophen metabolism in
patients with chronic liver disease go back more than 20 years. Here\'s
a study by Forest and colleagues, 1979, looking at patients without
liver disease, patients with mild liver disease, patients with severe
liver disease, based on synthetic liver function.

These were given a single dose, 1.5 grams of acetaminophen. Urinary
metabolites were looked at, and although plasma half-lives were, in
fact, prolonged in the patients only with severe disease, urinary
metabolites did not change, suggesting that at least that dose given in
a single time period had no effect on hepatic metabolism of
acetaminophen.

I\'ll skip that one.

Gordon Benson, who\'s sitting in this audience did what is a landmark
study also almost 20 years ago. He took a group of stable patients with
liver disease, most of them who were biopsy proved, some with cirrhosis,
some without cirrhosis, and gave them four grams of acetaminophen or
placebo in a double blind crossover study.

And what he showed is that the typical markers that we look for for
hepatotoxicity, bilirubins, bilirubin fractionation, AST and ALT, did
not change with almost two weeks of therapy.

Now, the most common use today for hepatologists in 2002 is the use of
acetaminophen in the management of patients with chronic Hepatitis C.
This is what we do day in and day out.

Dr. Dargere and colleagues in France, realizing this and understanding
the bits of controversy about this, decided to use three grams, which
was the recommended threshold in France \-- it\'s now four grams, by the
way \-- in a study of 17 patients who received placebo, 17
acetaminophen, for a period of one week.

And as you can see, looking at ALT as the most sensitive marker, there
were no changes either at the end of the therapy and three days later in
the placebo versus the acetaminophen group.

Because these patients did not get interferon, there was no change in
antiviral \-- in viral levels, and one would not expect changes in viral
levels with an oral analgesic.

Now, we\'ve had, as I mentioned in the beginning, over a decade of
experience using acetaminophen to manage the side effects of interferon.

In February of 1991, the FDA approved for non-A, non-B
Hepatitis/Hepatitis C interferon alpha 2B. The starter packages that
Shering sent out to treating physicians contained not only interferon
alpha 2B, but acetaminophen.

Today we are now using pegylated interferons, and Dr. Lee and myself,
Dr. Riley in the back, and every hepatologist who is in practice today
continues to use acetaminophen to manage the side effect of the
pegylated interferons.

We monitor these patients exceedingly carefully. We bring them back at
week one, week two, week four, week eight, week 12. Every month we see
them, and they are on extended therapy for upwards of a year and
sometimes longer. We see no evidence of hepatotoxicity.

Finally, if you\'re a physician dealing with patients with liver
disease, you understand that thrombocytopenia is an important problem in
those with hypersplenism and cirrhosis, and this agent has no impact
either on platelet number or platelet function.

So at recommended doses, acetaminophen for hepatologists remains the
analgesic of choice, and I think no dosage adjustments are necessary in
patients with liver disease or those who have liver dysfunction.

Thank you.

DR. TEMPLE: No, I\'m not Dr. Carr. We\'re going to pass through is
presentation.

Good morning. I\'m Dr. Anthony temple. I\'m pediatrician, medical
toxicologist. I know quite a few of you. I wish I knew more. That\'s
sincere.

I\'m pleased to be here. This process has been a great opportunity to
review the wide array of medical literature, case reports, and new
research about acetaminophen.

And what I would like to do very quickly, and just provide you a summary
of the data we\'ve talked about. You got a huge submission from us. I
hope you got a chance to read it.

What we think are the implications of that data, and then maybe ask some
questions that we also think need to be considered in this process.

There\'s no question but what acetaminophen has been extensively
investigated. Thirty thousand research articles have been published on
acetaminophen, 30,000 research articles since 1970, but sometimes the
science is not always fully understood, and that\'s why we have
discussions like this.

And there are a couple of things that we think need to be emphasized
then. One is that the threshold effect associated with the risk of
overdose toxicity, is it really an important consideration.

You have to exceed the threshold in order to have toxicity, and it\'s a
secondary effect. It is the depletion of 70 to 80 percent of hepatic
glutathione before toxicity occurs, and data demonstrates that it takes
a substantial overdose to do that.

We have shown you studies involving administration of single, large
doses well in excess of the recommended dosage range, as high as nine
grams, but do not cause toxicity; a dose escalation PK study with doses
of four grams per day \-- that\'s the recommended dose \-- plus six
grams per day, plus eight grams per day, given for three days without
any adverse events or alteration of metabolism of acetaminophen or the
events of liver toxicity.

And, in addition, even though the data are still case reports and have
some or all of the difficulties that case reports have, Dr. Dart\'s
prospective case series of repeated supertherapeutic ingestions, where
an added effort has been made to quantitate the doses in which it gives
us probably the best picture, I think, of risk from repeated
supertherapeutic ingestion, and that suggests that it takes doses in the
range of 12 grams per day over several days to produce significant
toxicity.

Now, much has been said about individual case reports, and we believe
it\'s very important that those case reports be scrutinized carefully.
And you\'ve heard that we made an attempt to try to do that with an
expert panel.

It\'s not that we\'re not familiar with these. McNeil submitted more
than half of these cases to FDA. So we saw them long before this process
went along, and even with our best efforts, such cases often remain
sketchy and often have lack of detailed information.

As a result, it\'s very important that we understand that there are
difficulties, extreme difficulties, in determining causal relationships
between the fact that acetaminophen as reported in association with an
hepatic event, but more importantly, that the cases lacked reliability
of dosing information.

And as a result, these cases can be used to indicate that people misuse
OTC and prescription products. FDA has said that. We agree with that.
They do indicate that people misuse these products, but the data cannot
be used to assess the risk of a specific dose level or to use doses to
assess special populations as FDA did their analyses. And it is the
dosing data that is the basis for much of their assessment.

Now, let\'s go on. We want to tell you what we think we ought to do. You
all know that management of everyday aches and pains is an important
consumer benefit. We think that the data continue to say that
acetaminophen remains the safest OTC pain reliever when used at
recommended doses, and the very things that we talked about suggest that
there are not very many potential interactions in spite of all of the
theoretical ones postulated.

No substantial evidence to suggest an interaction with anticonvulsants
or with Gilbert\'s disease, and certainly the data don\'t suggest even
with alcohol a need to reduce the dose for consumers of alcohol.

Obviously, consumers deserve the right dose. We spent no time talking
about the right doses. We gave you lots of data. The right dose of
acetaminophen is 1,000 milligrams four times a day.

What we think is important to this whole process is consumer attitudes
and some of the behaviors that we\'ve talked about. And through this
process we\'ve gained some insights into consumer medication use
behaviors that we think are very important to think about.

And we\'ve already begun the process of implementing new label changes
and initiated education efforts to focus consumers on the proper use of
medications.

Consumers need to know product ingredients, and they need to be able to
find that information on their package. They need to know proper dosing
and proper use of medications. They need to know that they should avoid
taking more than the recommended dose of any product, especially
acetaminophen, not use two products containing the same ingredients
during the same period of time, and recognition that all medications
have risks when taken inappropriately or an overdose.

As we\'ve said before, we\'re committed to try to do the right thing. To
this end, we\'ve initiated what we think are some appropriate
modifications to the label of our products.

On the front panel, the ingredient names appear more prominently on all
of our products than they ever have before, and that is included on the
cough-cold combination products. We believe this is important for all
products in the category, and we have brought industry support for this.

On the back panel we have already modified the overdose warning to
include specific language not only to react quickly and not wait, which
we\'ve done for years, but language that says taking an overdose may
cause serious health consequences, and we\'re stating here today that we
will modify it further so that it says taking an overdose may cause
liver damage.

We think others in the industry should follow and put similar types of
warnings on all of their pain relievers, and as we will demonstrate if
you go to the other room, we\'re committed to a broad range of consumer
and health professional education programs.

Now, we wish we \--

CHAIRMAN CANTILENA: Excuse me, Dr. Temple. If you can just hold your
comments for just a couple of more minutes, please, that will give you
five minutes over.

DR. TEMPLE: Okay.

CHAIRMAN CANTILENA: Thanks.

DR. TEMPLE: We thought you might be interested to know that there also
are some other ongoing research looking at long term use of
acetaminophen because this sometimes comes up. We have two additional
ongoing trials looking at long term use, four grams a day, one a placebo
controlled trial of three months\' duration and the other an active
control trial of 12 months\' duration.

There have been previous trials looking at long term use of
acetaminophen. We think these will help add to that database.

And now we\'ll speed through these, but we do have some issues that we
wanted to raise. As you\'ve heard, a lot of comments have been made
about the AERs data system or case reports in general, and we\'re
concerned whether AERs is an appropriate surveillance system for an old
drug with a well known safety profile and whether AERs reported doses
are accurate or inaccurate.

If AERs reported doses are inaccurate instead of accurate as you\'re
asked to say, what conclusions can be drawn? And are the assumptions
inherent in a system like AERs applicable to acetaminophen, which is
most often associated with an intentional overdose when it is designed
to work best with drugs that are taken at recommended doses?

We think that we would like to hear from the committee if they have some
ideas about ways to do prospective data capture, some type of
surveillance system targeted at specific issues, such as the outcome of
exposures to OTC pain relievers that might give us better ideas about
the future.

Clinical studies do address specific issues, still have to be done, and
can prospective clinical trials \-- should prospective clinical trials
using large overdoses of acetaminophen be conducted?

In addition to our labeling proposals, you\'ve heard that a large part
of the problem involves also prescription combination products or use of
prescription products in combination with OTC products, and we\'re
interested in your thoughts on what can be done to improve FDA oversight
of prescription consumer labeling.

You\'ll see we have made a lot of accomplishments we can talk about in
the question and answer session.

And lastly, even though FDA didn\'t mention that most of the medication
errors occurred in the under two age group, we\'re really concerned
about what we can do now to establish consensus on pediatric labeling
for children under age two.

Thank you.

CHAIRMAN CANTILENA: Okay. Thank you, Dr. Temple and the rest of your
team.

We\'ll actually now hear two five minute presentations from other
sponsors, and so then if you can hold your questions, and we\'ll have
questions at the end of the next session.

The next speaker from Wyeth is Dr. Steven Cooper.

DR. COOPER: Good morning. Yes, I am not Dr. Temple.

My name is Stephen Cooper, and I am the Senior Vice President for
Global, Clinical and Medical Affairs at Wyeth Consumer Health Care.

First, let me apologize for being a late entry on the list of speakers,
but unforeseen circumstances have made it necessary for me to make this
presentation.

At this point, let me emphatically state that all over-the-counter
analgesics, including ibuprofen, naproxen sodium, quitoprofen, aspirin,
and acetaminophen, meet the criteria set by the FDA for safe
over-the-counter use. For all of these over-the-counter drugs, serious
adverse events are very rare.

My purpose here today is to clarify some misleading information
repeatedly presented by one sponsor in their background package on the
increased number of adverse events and deaths if consumers switched form
acetaminophen to over-the-counter NSAIDs.

These clarifications are critically important for the public and the
committee to hear because of the misleading premise on which the
extrapolations of data were based. Unfortunately, the authors of the
document chose to blur the issue by using patients taking high dose,
chronically administered prescription NSAIDs as the basis for
calculating risk.

These patients are more susceptible to adverse events as a result of
their underlying diseases. It should be no surprise that under these
conditions of high dose NSAID drugs and extended duration of drug use,
the extrapolated data favored acetaminophen.

The fair and appropriate comparison would be between OTC dosage regimens
of NSAIDs and acetaminophen. This more objective approach comparing
apples to apples would show minimal, if any, increased risk in
gastrointestinal bleeding from OTC doses of ibuprofen.

Based on my comprehensive review of the data, I would like to make the
following observations starting with the acetaminophen issues.

Point one, in overdose situations, acetaminophen can result in serious
and irreversible liver toxicity. In any given year, the number of deaths
for acetaminophen reported by the American Association for Poison
Control Centers is approximately 20 times that for ibuprofen.

Point two, there are over 400 single entity and combination
acetaminophen products in the over-the-counter marketplace in addition
to the prescription combination products. Given this, it is not
surprising that some consumers unknowingly take multiple products
containing acetaminophen, leading to unintentional overdose.

This potentially can put consumers in a life threatening situation due
to the delayed onset of clinical symptoms of acetaminophen toxicity.

Point three, acetaminophen is predominantly used in over-the-counter,
single entity products and combination products, both over-the-counter
and prescription, at its maximum allowable 1,000 milligram dose.
Obviously this results in a narrowing of the therapeutic window between
the safe and the toxic dose.

This may be justified if the efficacy data support the use of the
highest dose. However, there are scant data from well controlled
clinical trials to support the use of acetaminophen, 1,000 milligrams,
or for that matter, any dose in over-the-counter combination products.

Point four, in the sponsor\'s document, they strongly defend the use of
1,000 milligrams because they claim 650 milligrams does not even reach
effective plasma levels. Given this, it is a curious contradiction that
they also present efficacy data on their newest combination prescription
product, which contains 650 milligrams of acetaminophen.

Their own data clearly shows 650 milligrams of acetaminophen is
effective.

Point five, another important aspect of the issue being debated today
relates to the safety image of acetaminophen that is portrayed in most
consumer advertising. The image of a totally safe ingredient may
exacerbate excessive use and contribute to the silent danger resulting
from overdose.

And now for the NSAID issues.

Point one, for OTC ibuprofen, its regimen is 1,200 milligrams a day
versus 24 to 3,200 milligrams a day for prescription use. Unlike
acetaminophen, the OTC directions for use clearly specify that the
consumer should take one tablet of 200 milligrams and only if necessary,
a second tablet may be taken.

In addition, OTC use of NSAIDs is limited to a maximum of ten days,
whereas prescription use is chronic.

Point two, and the final point, gastrointestinal bleeding from NSAIDs is
a real phenomenon, but there is no question that it is dose related, and
OTC regimens of ibuprofen have a very low relative risk approaching one.

This is because of the low dose, short term use and wide margin between
the OTC and prescription dose. Independent investigators, like Dr.
Michael Langdon (phonetic) and David Henry, have documented the low
relative risk of ibuprofen.

In fact, Dr. Langdon has stated that for gastrointestinal bleeding, the
incremental number of deaths above the background rate due to low dose
ibuprofen is very low and may be nil.

In conclusion, the inference made in the background material that if
acetaminophen users switch to OTC NSAIDs there would be many more deaths
is completely erroneous and unsubstantiated. OTC ibuprofen is as safe as
acetaminophen when used as directed, and in overdose situations, unlike
acetaminophen, ibuprofen rarely is life threatening.

Thank you for your time and your consideration.

CHAIRMAN CANTILENA: Okay. Thank you, Dr. Cooper.

The next speaker from Bayer is Dr. Heller, and the FDA has allocated
one, zero minutes, ten minutes for Dr. Heller.

DR. HELLER: Thank you.

So you now have the real Dr. Heller.

(Laughter.)

DR. HELLER: Mr. Chairman, members of the committee, officers of FDA,
I\'m Allen Heller, Vice President of Global R&D of Bayer Consumer Care.
I appreciate the opportunity and Bayer appreciates the opportunity to
address the committee and to be here today in these proceedings which we
believe can only benefit the consumer.

As you may know, Bayer is a leader in the field of analgesics, in the
development and marketing of analgesics, and has 100 years\' experience
in this area. While we are perhaps best known for Bayer aspirin, we also
have in our portfolio a variety of products and some products that
contain acetaminophen. Examples are Alka-Seltzer Plus for
cold-cough-allergy symptoms, Midol for menstrual symptoms.

Importantly, we do not market any single ingredient acetaminophen
product. Also, we do not market any pediatric analgesic product.

All of our acetaminophen containing products are combination products.
These products offer the consumer meaningful benefit by providing
multi-symptom relief and the convenient dosing.

Our experience is consistent with the spontaneous reports as reviewed by
FDA in indicating that our acetaminophen OTC combination products are
not associated with significant adverse events, including liver failure,
and we\'ll go into that in a bit more detail.

Nevertheless, Bayer has made voluntary changes in its labeling
consistent with recommendations from the CHPA in order to better educate
the consumer about the potential risk of simultaneous use of multiple
products containing acetaminophen, which has been alluded to.

In thinking of your deliberations today, Bayer values the importance of
clear, concise, and ingredient specific labeling. We support and we have
adopted and we have implemented the labeling proposed by the Consumer
Health Care Product Association regarding the risk of use of multiple
products containing acetaminophen, and based on our experience and the
experience with respect to FDA\'s record of spontaneous reports, we
submit that additional regulatory intervention beyond appropriate
labeling on OTC combination products is probably not warranted.

Just reviewing the FDA database very briefly, this experience suggests a
low hepatic risk potential for combination products which amounted to
only 12 percent of the cases overall, but we do recognize, and it has
been mentioned, that spontaneous reports have limitations in their
interpretation.

Also keeping that in mind, we have received at Bayer no reports of
adverse hepatic events, whether serious or non-serious, and in terms of
overall \-- for our combination products \-- and in terms of overall
adverse events for our OTC \-- our only acetaminophen combination
products, you can see that adverse events of all types, and this is over
a six year period, are relatively rare, as are serious adverse events,
which constituted only one percent of those adverse events that have
been reported to us.

We think that we know the reason for this apparently favorable safety
profile for combination products. This relates to the use pattern of
these products. These products are typically used for a short period.
They are used for well defined self-limiting symptoms, and these
combination products contain other active ingredients which because of
their effects tend to limit dose.

We believe that these factors enhance the benefit-risk relationship
relatively for these combination products.

We further believe that the enhanced warning that we have adopted and
already implemented will further educate consumers regarding the
potential risk, simultaneous risk of multiple products containing
acetaminophen.

Regarding labeling and considerations of labeling actions, labeling
should be based on substantial evidence. Individual ingredients should
be labeled and regulated based on their unique pharmacology.

We also believe that labeled and used appropriately, that all of the OTC
analgesic ingredients are safe.

A few more before I go to the conclusions. A couple more comments on
labeling.

Labeling decisions should be based on appropriate risk assessments that
make fair comparisons across equivalent dose paradigms and indications.

There have been public discussions of estimates of the public health
effects relating to hypothetical switching scenarios. We have seen \--
and the committee has seen in its briefing materials \-- estimates
related to hypothetical switching scenarios that are incorrectly based
on data from prescription use that are not relevant to OTC use.

We would caution the committee to view these hypothetical scenarios with
skepticism, these hypothetical switching scenarios. In fact, there are
recent findings that demonstrate that there\'s comparable GI risk across
all of the OTC analgesics when they\'re properly compared, and we will
present and discuss those data tomorrow.

Moving quickly to my conclusions, Bayer concurs with the FDA that all
OTC analgesic ingredients are safe and effective. Regulatory action with
acetaminophen should be independent of other ingredients and should be
based on sound, scientific principles.

The proposed labeling on simultaneous use of acetaminophen containing
products, the strengthened warning we believe is appropriate, and we
submit that further interventions for acetaminophen containing OTC
combination products are probably not warranted.

I thank you all for your attention, and once again express Bayer\'s
appreciation for participating in this process, which we believe can
only benefit the American consumer.

Thank you.

CHAIRMAN CANTILENA: Thank you, Dr. Heller.

We have actually one additional speaker for this portion of the program,
a late entry into the agenda, Dr. John Dent from GlaxoSmithKline. Five
minutes for Dr. Dent.

DR. DENT: Thank you very much, Mr. Chairman. I promise I won\'t take
more than two.

I\'m John Dent, Senior Vice President, Consumer Health Care at
GlaxoSmithKline.

GlaxoSmithKline is the second largest consumer health care company in
the world and part of the second largest pharmaceutical company in the
world. We\'re global manufacturers and marketers of products containing
aspirin, ibuprofen, and acetaminophen, or as it\'s called in Europe,
paracetamol.

These ingredients, when used as recommended, have for decades relieved
pain and fever in hundreds of millions of people safely and effectively.
As with any medicine, if the directions for use are not followed, there
is a risk of adverse events, and in extremely rare circumstances with
each of the ingredients, adverse events do occur.

However rare these events are, it is incumbent on the agency and the
industry, working with health care professionals, to insure the U.S.
consumer understands how to take these medicines safely. We believe this
can be achieved through labeling, enhanced consumer and health care
professional education.

Insuring that consumers continue to have direct access to these
important medicines at effective doses will safeguard against massively
overburdening the emergency and primary health care system.

As the FDA have stated, these medicines are effective when used as
directed at the doses approved. The challenge is to insure everyone
understands how to use these important medicines safely.

Thank you very much.

CHAIRMAN CANTILENA: Okay. Thank you. Thank you very much.

We\'ll now have the opportunity to ask questions of the panel to all of
the speakers, and what I\'d like you to do is to signal. I owe Dr. Brass
a question from the earlier session. So we\'ll start with Dr. Brass, and
then I\'ll be looking for hands.

DR. BRASS: Thank you.

As I reflect on this issue, it seems to me that the data from the
epidemiologic studies and the information from the databases are
actually consistent with a number of hypotheses and inconsistent with
very few.

So I would like to take a giant step backwards and again start with Dr.
Temple\'s conclusion that hepatotoxicity results when doses of
acetaminophen exceed a threshold amount, and I would like to pose a
hypothetical question to him and other members of his team.

Specifically if \-- and I emphasize the \"if\" \-- there was a
population whose glutathione stores were substantially lower than the
average population, would not that population have a substantially lower
threshold for the dose that would induce hepatotoxicity?

DR. TEMPLE: Well, the answer is if that were theoretically the case \--
can we turn that off so we \-- yeah. I\'ll try to find the right
function. Got it. Thank you.

But you know what? I think it would be helpful for Dr. Slattery to talk
a little bit about this issue of glutathione source because it\'s a
hypothetical issue, and the clinical data don\'t \--

DR. BRASS: I didn\'t ask for clinical data. I asked at this point, given
the absence of data, to help us think about the problem. If there was
such a population identified by any means, would it be at increased
risk?

DR. TEMPLE: Yes. I haven\'t seen a population, such a population.

DR. BRASS: And similarly, a population or individuals with substantially
increased 2E1 activity for any reason would similarly be at risk.

DR. TEMPLE: But the alcohol data \--

DR. BRASS: I didn\'t say anything about alcohol.

DR. TEMPLE: \-- shows that there is increase, but it\'s a very small
amount.

DR. BRASS: Well, okay. Again, I want to start with the principles
because then if we agree that those concepts have validity \--

DR. TEMPLE: I\'m not sure they do. You said substantial increased risk.

DR. BRASS: Okay. Well, that\'s why if you don\'t think they\'re
legitimate, then tell me why they\'re not legitimate.

DR. TEMPLE: Okay. The data on alcohol. Come on up here, John.

(Laughter.)

DR. TEMPLE: The data on alcohol demonstrate that with alcohol induction
you get a small amount, not a substantial amount, of 2E1 induction.

DR. BRASS: Okay. Again, my question didn\'t include alcohol, and that
there was no control \-- no measurement of actually the degree of 2E1
induction in those experiments, and we saw only mean data. So we didn\'t
know if there were individuals that had larger increases.

So my background question remains if there were individuals as I
described, would they be at increased risk?

DR. SLATTERY: You wouldn\'t be disappointed if I was a little bit less
argumentative.

(Laughter.)

DR. SLATTERY: And that is that there are lots of studies in animals,
right? And we know that if we treat animals with butionine, sulfoxamine,
diethylmaleate, we substantially deplete glutathione, and this has to go
down very low to where you\'re at 25 percent of total, you know,
hepatocellular stores that you start to see toxicity due to NAPQI.

I think when you try to translate some of this into the human
population, one of the things really is to, you know, think about the
safety margin and whether or not, you know, when you\'re talking about a
one gram dose four times a day, whether or not populations that people
point to, you know, those that have not eaten for some period that might
be fasting or something are actually kind of safely covered by that
current dosage recommendation.

And my gestalt is really \-- and I can\'t site data \-- you know, from
just kind of what we know about the incidence of acetaminophen
poisoning, is that the current recommended dose is safe even in those
populations.

And I would make the same sort of comment about 2E1 induction.

DR. BRASS: Yeah, okay. I\'m comfortable with that because I think the
bottom line is a challenge to those who hypothesize risk \--

DR. SLATTERY: Yes.

DR. BRASS: \-- to present data that there are populations with the
characteristics that I describe.

DR. SLATTERY: Yes.

DR. BRASS: So that, for example, if there was a population of chronic
alcohol abusers, a subset of that population that had substantial
glutathione depletion for some reason, that might be of concern to us.

DR. SLATTERY: Yeah. If I could comment on, you know, alcoholics and
alcohol abusers for just a moment, I have been puzzling over this for 20
years, and I presented some of our data here, and one of the things that
I always come back on this is the NIAAA Web page will state that there
are 18 million alcoholics and chronic abusers of alcohol in the United
States, and I\'ve seen data produced by McNeil that says 23 percent of
the U.S. adult population has used acetaminophen in the last week.

And if we put those numbers together, there are four million people who
have been exposed to the combination, and I really have to ask the
question as to whether or not if you identify a chronic abuser of
alcohol, you know, as a person at risk whether or not that risk category
has really been adequately and specifically identified.

And those numbers to me, which I think are very simplistic, say no. I
feel a little bit like Richard Feinman, you know, taking the ring and
the ice water and kind of smashing it on the desk, but I do think
there\'s some evidence that we should look at there.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. Johnson next.

DR. JOHNSON: I have a question that I think is again for Dr. Slattery
and really on related lines. Dick Winchelbaum at Mayo has done a fair
amount of work in recent years on genetic variability in the sulfur
transferases, and you talked a little bit about genetic impact relative
to the glucuronadation pathway. I\'m wondering if you can comment on the
impact of genetic polymorphisms in the sulfur transferases or the
glutathione transferase.

DR. SLATTERY: Yeah, I\'m sorry, but I haven\'t seen any specific data on
that with regards to acetaminophen disposition. He\'s actually used
different model compounds.

You have to remember that the sulfation pathway is about, you know, half
as important as the glucuronide pathway, and I think that\'s a very good
question, but I just don\'t have data to answer you with.

DR. JOHNSON: And I don\'t know the specifics off the top of my head of
the sulfur transferase polymorphisms. My recollection is it\'s not
absent enzyme or nonfunctional enzyme, but \--

DR. SLATTERY: Yes, it\'s diminished activity. It\'s diminished activity,
and I actually think it has more to do with the promoter than the coding
region. So it\'s not like a SIP 2D6 sort of polymorphism or something
like that.

So, yeah, it addresses the issue of underlying variability.

If I can continue for one more second, it raises another question. In
the morning session there was a bit \-- well, there was a statement that
the variability and kind of the formation of NAPQI across the population
might be as great as 60-fold, and I really do doubt that assertion.
I\'ve done a lot of work with a drug called Busulfan and used in marrow
transplantation that really can be viewed as a direct probe of the GST
A11, which is the GST that makes this conjugate in the glutathione
pathway.

And these are, you know, patients that are in reasonably good shape as
they come in for transplantation. Coefficient of variation and the
clearance of that compound is only about 16 percent. That goes across
data that was analyzed when we had 300 patients. We have 1,300 now, and
it seems to be about the same.

But I didn\'t mean to digress from your question on PST.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. Crawford.

DR. CRAWFORD: Thank you, Mr. Chairman.

This question is directed to Dr. Bowen and Dr. Temple.

I appreciated the summaries of the selected toxicology studies on
acetaminophen use, but I note a void of applied research data that
considers the social, behavioral and cultural factors in risk assessment
of possible acetaminophen induced hepatotoxicity.

I did hear as you described how your company has initiated labeling
changes and educational programs. As we consider potential
recommendations for risk assessment and management, I ask if you have
any data available on variables such as what Dr. Day mentioned earlier,
consumer comprehension of labeling and information, safety impact of
different packaging, the effectiveness of those different educational
programs.

And, Dr. Bowen, you had mentioned the widespread use of acetaminophen in
diverse populations and different cross-cultural populations. I ask also
do you have any data on outcomes and socio-cultural subpopulations which
could be used to determine potential higher risk.

DR. BOWEN: Gee, yes. Some. We do.

(Laughter.)

DR. BOWEN: Sheryl Hanks, who works for us at McNeil, Sheryl, do you want
to just talk to that?

MS. JENKINS: Sure. Thank you.

We have several surveys available to us. We\'re fortunate to have Dr.
Kaufman here from the Sloan Epidemiology Unit at Boston University
that\'s helped to inform us.

In addition, we have several other survey studies that have informed us.
They include the Medascope survey, NICBI (phonetic) survey, and then an
internal survey done conducted by McNeil that provides some more in
depth.

If you take them all together, we get a story, and it\'s a very
interesting one. We bandied about the 23 percent use of acetaminophen in
the past week. The vast majority of consumers appear to take their
medications, all OTC analgesics, within recommended dose.

We find that there\'s approximately one percent or less that exceed
doses during either \-- one percent or less during the past week. Some
consumers may report more having ever exceeded those doses, and then
these surveys also inform us about why that might be the case.

And I know that FDA has also had some suppositions about why that may
happen.

There are some respondents who report not being aware of the active
ingredient in their medication, and that ranges depending on \-- and
this is in single ingredient \-- that depends on what the product is and
what the active ingredient is.

And so it can range from about ten percent who are aware to about 50
percent who are aware of the active ingredient. So it would appear that
more information could be given depending on what the information that
we have from these respondents and how generalizable that really is.

Respondents in many of the surveys also report why they are exceeding
these doses, and I\'ll just rank them because it\'s very difficult.
There are different population sizes, but I can rank them.

In many cases they want faster relief. So they exceed the recommended
dose.

They have severe pain, and that will inspire them to exceed the
recommended dose.

They feel that they\'re not getting \-- they feel that OTC analgesics
may be weaker and, therefore, they\'re inspired to increase the dose, or
they\'ve taken an Rx version of the medication previously.

DR. CRAWFORD: Excuse me.

MS. JENKINS: Yes.

DR. CRAWFORD: You\'ve answered my question in terms of some survey data.
Have you tried any other assessment or evaluation methods to look at
some of these social behavioral factors?

MS. JENKINS: By manipulating and actually conducting interventions?

DR. CRAWFORD: Yes.

MS. JENKINS: No.

DR. CRAWFORD: Thank you.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. Laine.

DR. LAINE: I had a couple of questions for Dr. Dart.

First related to the \-- while he gets up there \-- the panel review of
experts. I guess if I were doing a study like that, first of all, I
assume that they were all paid by McNeil, but if I were doing a study
like that, I\'d probably want them not to know that McNeil was
sponsoring this review. I\'d probably not want them to know the issues,
i.e., that there was an FDA hearing that was going to evaluate
hepatotoxicity of acetaminophen, issues such as that, and another issue
probably is what I would do is probably mix in cases other than just the
FDA reports or else they\'d know that every single case was an FDA
report.

I was wondering if those conditions, any of those conditions were met in
your review. That\'s my first question.

DR. DART: It sounds like most of those are actually to the company and
not to me. Among the things that \--

DR. LAINE: I thought you were chair, but I\'m sorry.

DR. DART: Well, I said that it was funded by McNeil. So \--

DR. LAINE: No, but do they know that it was funded by McNeil? Do they
know that the issue related to an upcoming \--

DR. DART: Yes, of course they knew.

DR. LAINE: Okay.

DR. DART: There were cases mixed in to see whether or not there was a
lot of variability in how they rated things.

DR. LAINE: So other than the 300 cases, there were other fake cases and
things mixed in.

DR. DART: That\'s right.

DR. LAINE: So they did not know how many of those were there.

DR. DART: That\'s right. There was another \--

DR. LAINE: Do you know how many? Were there a lot of them? I\'m just
meaning were there a lot to them?

DR. DART: There were about 15 or 20, as I recall.

DR. LAINE: Out of 300 and \--

DR. DART: Out of 281, I think it is.

DR. LAINE: But they did know the issues as well, why \--

DR. DART: They did know that \--

DR. LAINE: So, again, I\'m not saying that these people aren\'t
extremely bright and, you know, noble, but obviously their potential \--

DR. DART: Well, we were very up front about that, and as I said in my
presentation, I can say that the discussion was spirited, to put it
mildly, and especially from the different backgrounds that people came
from.

DR. LAINE: And that\'s my second question. I was interest in your
comment that people under report suicide intention. Do you have data
where that is?

My anecdotal view from a large medical service at a large urban hospital
is exactly the opposite, and there are kind of both medical and legal
problems with doing that as well. So I\'m surprised that, you know,
residents are counseled not to do that.

So I was just wondering are there data to actually show that those are
or is that just an anecdotal view?

DR. DART: It\'s a widespread anecdotal view. I\'ve been in three
different programs, and that was the consistent teaching, and it\'s
logical. I mean, why would you put something in a binding record that
could prevent the patient from having insurance coverage, for example,
in the future?

And it is a recent development. I\'ll freely grant that that\'s probably
within the last five to ten years that that has evolved.

DR. LAINE: I understand, but I actually don\'t see it at our hospital. I
mean, one of the reasons you would do it is because the patient goes out
and kills himself. There are certain medical legal responsibilities to
you out in the future.

DR. DART: Well, the point is to record what happened, not to put
pejorative comments in there. So they would say if the patient said, \"I
took ten grams,\" yes, they would write down, \"Patient took 20
tablets,\" or whatever it was. They just wouldn\'t label it as suicidal.

DR. LAINE: I don\'t think we should let that go unchallenged. I mean, we
certainly teach our residents that what should go into the medical
record is the truth, and I think most other centers do that.

It\'s extraordinarily important that the next physician reading that
record knows what the truth, what the honest opinion of the loss and
record it in the record and thought.

And the idea that we would be falsifying the record or giving the
impression that it\'s widespread in this country that we falsify medical
records, I think is utterly wrong, and I think that should be corrected
before it becomes widely \--

DR. DART: Okay. Well, I think you\'re misstating what I said.

CHAIRMAN CANTILENA: Hold on just a second, please. If we can get off the
subject of that, I happen to \-- you know, like I\'m on your side, but
that\'s the same thing in our institution as well. It should be, you
know, the truth that\'s in there, but let\'s not spend any time on that.

We have four more individuals who will ask questions, and for a program
that we will actually extend the questions until 12:15, and then we\'ll
have the full hour for lunch.

So if you don\'t mind, just excuse me so that we can get back on track
and perhaps over lunch we can all chat about that issue. But, Dr. Cohen,
you\'re next.

DR. COHEN: Yes. Given that we\'re, I guess, mainly concerned about the
unintentional overdoses at this meeting and later on today we intend to
work on some risk management strategies, I guess I\'m kind of left
disappointed that there isn\'t more information about the causality, and
we haven\'t really discussed that very much at all.

In my own work, we handle a lot of anecdotal reports with mostly our
reports that come through the medication AERs reporting program, and
we\'ve seen a number of contributing factors that have been reported to
us mostly by health care professionals, misunderstanding the way that
the concentration is expressed on the label, for example; the brand name
extensions, where one brand of drug really has multiple ingredients,
when people think they\'re taking other than what\'s actually in that
package.

And maybe we can talk about some of these others a little bit later, but
I can tell you that when we receive these reports, we follow up. We ask
how did this happen, either through the health professional, who then
could contact the patient if necessary, and it doesn\'t seem like
that\'s being done here, and I don\'t understand.

I mean, there\'s thousands of these reports that have occurred over the
years. Isn\'t there that basic root cause information that we need to
\-- you know, with our decision making this afternoon, I think we were
starting to hear some of that with Dr. Crawford\'s question. The
response was excellent, and it was cut off.

Is there more information? What is causing these events to actually
occur? That\'s what we need to know. I wanted to hear about that.

CHAIRMAN CANTILENA: So are you asking that to Dr. Temple?

DR. COHEN: To the company, to any of the \-- even FDA.

CHAIRMAN CANTILENA: Okay. Well, how about if we just ask the company at
this point? And this afternoon we\'ll have an opportunity to ask others.

Dr. Temple, would you like to address that issue?

DR. TEMPLE: Let me just comment. This is really a question of adverse
event reporting since most of the data sets are adverse event reports.
And generally speaking, much of that data is extracted from things like
medical literature, other sources, and so you\'re limited in terms of
what\'s available to you.

That\'s why we are suggesting that we need a more prospective, proactive
approach to getting at the root of this problem, because that \-- it\'s
only through that route that you can really get to the next level of why
consumers behave the way they do.

DR. COHEN: Because right now I think we\'re mainly being asked to
speculate about the changes that are needed in order to reduce these
unintentional events. And I wish there was more information out there.

I know that you do as well.

DR. TEMPLE: Yeah.

DR. COHEN: But without that information, it\'s hard to make the changes
that are necessary with the labeling other than speculating what might
work. So we\'ll probably be doing that this afternoon.

CHAIRMAN CANTILENA: Well, that\'s one possibility.

Okay. Dr. Elashoff.

DR. ELASHOFF: Yes. This set of questions and comments applies to the
talks by Dr. Slattery, Dr. Dart, and Dr. Koff.

On none of the reports of the individual studies either in tabular or in
graphical form was it identified whether those plus or minuses were
standard deviations or standard errors. I\'m assuming they\'re standard
errors. Some of them are really quite large.

On some of the slides there was no indication of what the sample size
was. When it was there, they were mostly quite small.

It was implied that if the means were similar or the result was not
significantly different, then an important difference could be ruled
out. With this kind of sample size, I don\'t think that\'s true. I think
we ought to see for all of those a 95 percent confidence interval so
that we could tell what differences the results are actually consistent
with.

DR. SLATTERY: If I can respond to at least my part of that, in my case
there were standard deviations. The n\'s were small. These were small,
you know, studies done simply in my laboratory with regards to the
effect of rifampin or omeprazole. I\'d love to see those done in larger
patient groups.

It\'s kind of the standard size, you know, group size that you see in
simple drug interactions, studies of that kind. I don\'t know if there
are other specific data that you\'d like me to speak to.

DR. ELASHOFF: Well, both the talks by Dr. Dart and Dr. Koff had similar
issues, and if a study is small, it still should be demonstrated that
it\'s big enough to have the power it needs to have to detect what might
be important.

DR. SLATTERY: Yes. These were not powered as pivotal studies, but they
were prospective. If you take a look at other evidence in the
literature, for example, anticonvulsants and their effects on NAPQI
production measured the way that we did, you\'ll find an agreement on
that.

Lloyd Prescott has published the same sort of thing. So I am, you know,
rather confident in that and would welcome, you know, a larger study,
and the same with regards to 1A2. I think we\'d confirm the result.

DR. DART: In the studies that I presented, there were two, I think. The
repeated supertherapeutic ingestion did have 95 percent confidence
intervals on it. We can go back and see that if you want. That was a
total of 270 patients or so, and the largest group had about 140 and the
smaller ones had 40.

In the alcohol study, that was actually \-- we\'ve done two studies on
that for a total of 260 patients, half of which, roughly half of which
are acetaminophen and half that didn\'t, and that had a power to detect
a difference in the AST of just 13 units. So I didn\'t put that on
there.

DR. KOFF: In the study that I showed of the single dose, that was
standard errors. In the Benson study done, again, in 1983 and in the
Dargere study, standard deviations were shown.

And, again, these were obviously studies done several years ago before
epidemiologic importance of powering studies was done, and these were
\-- that\'s the data we have.

DR. ELASHOFF: That\'s why it\'s advantageous to do confidence intervals,
so that you can actually see what the study does show.

DR. KOFF: Yeah. Well, we\'re waiting for the Dargere paper to be
published in full. It\'s still just an abstract that appeared in
[Hepatology]{.underline}. The Benson paper, of course, did not have
adequate data for me to go back and do confidence limits. Maybe we can
\-- Gordon is here \-- we can get some of that old data and see if we
can get those numbers.

CHAIRMAN CANTILENA: Great. Thank you.

Dr. Davidoff, then Cryer, then Williams, and then lunch.

DR. DAVIDOFF: I had a question I guess primarily for Dr. Bowen but for
others. It regards language because the term \"rare\" or \"very rare\"
has been used, and I certainly wouldn\'t disagree that in terms of a
denominator of hundreds of millions of doses, some of the events we\'re
talking about can be seen as rare.

But that\'s looking at rates essentially. But if you start looking at
the absolute numbers, I really question the use of language like
\"rare\" and \"very rare.\"

According to the test data submitted by Proctor & Gamble, in a three
year period there were 316,000 cases of reports of acetaminophen
analgesic single medication incidence of which roughly 128,000 were
considered to be intentional, but 178,000 considered unintentional.

How reliable that is we are not certain. Anyhow, the bottom of those,
there were about 1,800 serious and of those 768 were serious or major.

So I really wonder. I mean, if we saw those numbers in connection with
other kinds of etiologies or context, I\'m not sure that we would be
using the terms \"rare\" and \"very rare.\"

As a final sort of comment related to that, the analysis of the AERs
data which suggested that only about a quarter of them, namely, about 75
out of the total cases were, in fact, definite or probable acetaminophen
related. We also know that the reporting to that database is only of the
order of between one and ten percent.

So if you multiply out, you\'re now talking about something in the range
of 750 to 7,500 cases over whatever period the AERs has been conducted.
Again, I would suggest that that\'s consistent with the serious toxicity
or death in the range of about 1,000 in three years. So I really wonder
whether we\'re talking about rare events or not.

DR. TEMPLE: Let me just comment first on the poison center, the test
data, because there is important data if you\'re going to talk about
this during the day.

Having been involved in establishing that system, the accidental cases
in this case are largely young children getting into product that
they\'re not exposed to. So you can\'t use the same ratios about
unintentional. So they\'re largely accidental ingestions in kids.

And, secondly, poison centers report exposures which simply means
somebody took a product and they called a poison center to know what to
do about it. So they can\'t give you any perspective on the size of the
serious problem.

So we tried to focus on serious cases that might cause harm. That\'s
maybe how we got from the bigger numbers down to the things that are
really, really relevant.

DR. BOWE: I think that\'s right, and perhaps the word \"rare\" should
have been \"very uncommon\" or \"uncommon\" if that\'s more comfortable
for you. Because I think that rare has a definition and a regulatory one
from the point of view of looking at the number of cases in any given
database.

I would like to comment, however, that some of the cases that were in
the adult AERs system, although they were collected over three years,
actually occurred over a 25-year period. So that should be also in your
calculation.

CHAIRMAN CANTILENA: Thank you.

Dr. Cryer.

DR. CRYER: I just wanted to follow up on Dr. Brass\' earlier question
about data from clinical experiences from [in vivo]{.underline} studies
about the effects of glutathione depletion, and this is specifically for
Dr. Dart.

I would just wonder whether or not your data set on alcohol users who
were given acetaminophen also just asked a subpopulation of patients who
were fasted. And if so, what were your observations in the fasted
subpopulation?

DR. DART: Yeah, we did determine body mass index on all of the subjects,
and so we looked at it from various different ways because if you look
in the literature, there\'s not one number that\'s used to represent
malnutrition or under nutrition. For example, some will say 21. Some
will say 20. So we did it both with 21 and 20, and there\'s basically a
third and a fifth of the patients that fell under those two categories.

Now, this is a post hoc analysis, but if you take those two groups and
compare the means of that way, then again you find no difference between
them and anyone else in the study.

DR. CRYER: Were all patients fed?

DR. DART: The patients could eat after they were in the institution,
right.

CHAIRMAN CANTILENA: Okay, and our final question from Dr. James
Williams.

DR. WILLIAMS: My question has already been addressed.

CHAIRMAN CANTILENA: Okay. Very good. All right. What we\'d like to do
now is break for lunch for one full hour. We will meet back according to
my watch about 12:15 \-- 1:15.

Thank you.

(Whereupon, at 12:17 p.m., the meeting was recessed for lunch, to
reconvene at 1:15 p.m., the same day.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(1:24 a.m.)

CHAIRMAN CANTILENA: We\'ll go ahead and begin the second portion of our
open public hearing. The first speaker, Dr. Sarah Erush, has been
granted ten minutes, ten minutes by the Food and Drug Administration.

Dr. Erush.

DR. ERUSH: Thank you.

I\'d like to present to you today a review of acetaminophen overdoses
admitted to our hospital with an emphasis on the unintentional cases to
demonstrate that these patients actually exhibit greater morbidity and
mortality than do the intentional cases and, as such, suggest that
further measures be put in place to prevent these tragedies from
occurring.

My name is Sarah Erush, and I\'m the Director of the Drug Information
Service at the hospital of the University of Pennsylvania in
Philadelphia. HUP is a 700 bed tertiary academic medical facility with
Level 1 trauma and transplant services. It serves the tri-state region
of Pennsylvania, New Jersey, and Delaware, and averages about 35,000
admissions per year.

Of note, none of these are pediatric admissions. So all of the data I\'m
going to present to you today is in adult patients.

Our adverse drug event program is run by Dr. Karen Shalaby and operated
by our Drug Information Service. It averages 600 reports per year and
obtains them through both spontaneous and targeted reporting methods.

Prior to 1998, we like many other institutions did not routinely report
acetaminophen overdoses because we did not feel that they were
preventable adverse drug reactions. Due to Dr. Shalaby\'s prompting, in
1998 we did begin to routinely report all acetaminophen overdoses, and
much to our surprise, we found a significant number of unintentional
overdoses which we feel are in all likelihood completely preventable.

Therefore, we undertook a review of all the cases that we had in our
database for the past four years and found 54 reports of acetaminophen
overdose, and of the 47 cases that we\'ve been able to review to date,
23 of those, or a full 50 percent, were unintentional overdoses.

To demonstrate our certainty that these patients are actually
unintentional, of the 23 patients identified, in 13 of those cases the
attending physician was so certain that the patient had mistakenly
overdosed on the drug no psychiatric consult was requested.

In ten cases where a psychiatric consult was requested, in all cases
psychiatry stated that these patients had no intent to harm themselves.

In looking at the patient demographics between the two groups, you\'ll
not that the patients in the unintentional group are slightly older than
the intentional group, that there\'s an even split between male and
female patients, with more female patients in both groups, and that the
intentional group was more likely to be directly admitted to the
hospital while the unintentional group was more likely to be transferred
in.

In looking at where we could accurately determine the amount of
acetaminophen ingested, it was very interesting to note in the
unintentional group that the median and average doses were between six
and eight grams per day, which while above the recommended maximum of
four grams per day, is still far below the ten to 15 gram dosage usually
considered to be toxic.

In determining whether the patient obtained the drug either through
prescription means or over the counter, again, it was evenly split
between both groups, but it was interesting to note that in the
unintentional group more patients took single entity acetaminophen
products than did combination products, making it clear that they knew
that what they were taking contained acetaminophen.

The reasons for the ingestion in the intentional group are listed here
with pain, toothache, insomnia and headache being the most common
reasons.

The primary reason for exceeding the maximum dose was a frustration with
unrelieved pain, with many patients stating they knew they were
exceeding the recommended dose and did so because they thought it was
such a safe drug.

We define an acute exposure as any exposure that occurred in less than
seven days, and as expected, in the intentional group most of these
patients were a one time overdose situation, but the unintentional
group, you\'ll note, often took their drug over a period of one to three
days and, in fact, 30 percent of these patients took the drug over a
period of greater than seven days.

Therefore, as expected, when looking at the average peak acetaminophen
levels in this group, the unintentional group has a much lower peak
acetaminophen level than does the intentional group. But unexpectedly,
when looking at the average peak levels of ALT, AST, INR, and total
bilirubin to indicate their liver function, the unintentional group had
significantly higher levels than did the intentional group, indicating
that this group had experienced significantly greater toxicity than did
the unintentionals.

In terms of length of hospital stay, the patients in the unintentional
group also stayed longer in terms of both ICU days and total days of
hospital stay, again, indicating that they had greater morbidity than
did the intentional patients.

And most distressingly, in terms of patient outcome, in the
unintentional group more patients did not have resolution of their liver
disease. More patients were evaluated for transplant. More patients were
transplanted, and more patients died as a result of their unintentional
overdoses.

We were so intrigued by the unintentional group exhibiting such greater
morbidity, considering they had taken lower doses and taken them over an
extended period of time, that we undertook a review of risk factors to
see if we could find any differences between the groups, and in fact, we
looked at hepatic disease, alcohol use, drug abuse, and concomitant
disease.

And as you\'ll note, we didn\'t find great differences between the
groups with the possible exception of more alcohol use in the
unintentional group.

And when we further reviewed this risk factor, we found that the primary
difference lies where the unintentional patients maybe had more patients
who had chronic alcohol abuse with an acute ingestion on top of that.

However, it was interesting when we looked at the number of risk factors
per patient. A full 96 percent, or 22 of the 23 patients in the
unintentional group, had at least one of the previously defined risk
factors for acetaminophen hepatotoxicity, and that was compared to only
70 percent in the intentional group.

And as these curves demonstrate, the unintentional group was more likely
to have one or more risk factors than did the intentional group, leading
us to believe that the existence of risk factors does have an impact on
toxicity in unintentional ingestions.

So I\'d like to summarize the data that I\'ve presented to you in
stating that in the 47 patients that we looked at, unintentional
overdoses accounted for a full 50 percent of those cases; that the doses
in these patients were lower and ingested over a period of one to three
days; that the unintentional cases had greater toxicity when judged by
LFTs, INR, and length of stay; that the unintentional cases also had
higher transplant and death rates than did the intentional group.

Additionally, the influence of risk factors remains present, but
unclear, though alcohol use and having more than one risk factor was
more prevalent in the unintentional group.

We also wanted to point out to you that the hospital costs for the
unintentional group were nearly double of that of the intentional group,
and that\'s interesting to note because if you\'ll remember they didn\'t
have double the length of stay. So, again, these costs are indicative of
the severity of illness of this group.

And if we take these numbers and we extrapolate this cost data to
similar institutions around the country, the cost of acetaminophen
overdoses in general to the health care industry easily runs into the
hundreds of millions of dollars.

We also wanted to note that the results that we\'re presenting to you
now are very similar to those that have been published previously, which
indicates to us that this is a significant ongoing issue in the United
States that, again, we would like to propose is preventable.

There are multiple recommendations that could be made or considered at
least to prevent this tragedy. Obviously, we don\'t advocate taking
acetaminophen off the market. However, we do think that educational
practices for both health care practitioners and consumers alike could
be significantly improved.

Of major importance would be to continue to encourage the reporting of
acetaminophen overdoses. As we mentioned before, most institutions do
not report these overdoses because they do not feel they\'re preventable
adverse drug events.

And notably, none of the cases that we presented to you today were
reported to our local poison center, which is where much of the data on
unintentional overdoses comes from, and much of that poison center data
on an unintentional overdoses is accidental ingestions in children,
while all of the data that we\'ve presented to you today is in adults.

As such, we\'d like to propose that this problem is potentially severely
underestimated, and further data is better needed to define the risk for
the unintentional patient population and to target educational practices
for them.

We also need to erase the notion with both prescribers and patients
alike that acetaminophen is such a safe drug.

Changes in labeling, packaging, and even perhaps the addition of small
amounts of antidote to acetaminophen products are all other things that
could be considered to help improve the safety of this product.

And finally, I\'d like to close with a quote from one patient that was
representative of many that we found in our chart review and clearly
demonstrates patients\' ignorance of the potential dangers of this drug.

\"If I\'d known it would make me this sick, I never would have taken
it.\"

We respectfully ask the committee to consider taking measures to improve
the safety of acetaminophen products and thereby the safety of the
American public.

And we thank you very much for allowing us the time to present this
today.

CHAIRMAN CANTILENA: Thank you very much.

Our next speaker in the public hearing is Susan Winckler, American
Pharmaceutical Association.

MS. WINCKLER: Thank you for the opportunity to present the views of the
American Pharmaceutical Association, the national professional society
of pharmacists.

I am Susan Winckler, a pharmacist and an attorney and APHA\'s Vice
President of Policy and Communications.

My comments today will focus on the pharmacist\'s perspective on the use
of acetaminophen, possible sources of problems seen with the OTC
analgesics, and the need for consumer education.

In the interest of full disclosure, APHA frequently partners with
federal agencies, consumer groups, the pharmaceutical industry and
others to develop educational tools for pharmacists and consumers. The
association did not receive funding to participate in today\'s meeting,
and the views I am presenting are solely those of the association and
its members.

APHA\'s 50,000 members include pharmacists, practitioners,
pharmaceutical scientists, student pharmacists, and pharmacy
technicians. These members provide care in all practice settings, such
as community pharmacies, hospitals, and long-term care facilities.

In those settings we help consumers manage and improve their medication
use, including the appropriate selection and monitoring of prescription
and OTC products, such as acetaminophen.

Acetaminophen is widely used in both prescription and OTC analgesics and
cold, allergy, and sinus preparations. Pharmacists, other health care
providers, and patients frequently select acetaminophen products because
of the excellent safety profile and relatively low number of side
effects and for its appropriateness in special populations, such as
pediatric patients and patients with asthma, hypertension, or
gastrointestinal disorders.

It is of significant therapeutic value for millions of patients.
However, acetaminophen, like all other drug products, is only safe and
effective when it\'s used appropriately.

Improving the public health and safety with respect to medication use is
the pharmacist\'s and APHA\'s highest priority. APHA supports the review
of adverse events to determine if a medication\'s benefits are
outweighed by its risks.

While reports of adverse events are possible indicators of problems,
many of these reports may be incomplete and do not show causality. It is
hard to determine if acetaminophen was the sole or primary cause of the
reported events, what other factors may have played a role, or if the
use of acetaminophen before the adverse event was only a coincidence.

We know, however, that patients may unintentionally exceed the
recommended dosage by taking the incorrect dose of the medication or
ingesting multiple products that contain acetaminophen. This can occur
when caregivers for pediatric patients accidentally give the wrong
dosage because they use an inaccurate measuring device; incorrectly
determine the dose based on the child\'s age rather than the child\'s
weight or are not aware of the difference between products, such as
acetaminophen suspension and concentrated drops.

In other cases, patients with multiple symptoms unknowingly ingest
multiple products that contain acetaminophen. For example, a patient on
the prescription drug percocet for significant pain may also take
nonprescription Sudafed severe cold formula to treat cold symptoms,
unaware that both products contain acetaminophen.

In other instances, patients exceed the appropriate dose by taking more
than the recommended initial dose, taking another dose before the
appropriate time interval has passed, or exceeding the maximum number of
doses in a day because they believe it will increase the medication\'s
effectiveness.

While all of these situations can result in an overdose of the
medication and enlarged doses may contribute to an adverse event, these
examples are a sign of incorrect usage by the consumer that may well be
due to not reading or reading but not following the label directions.

To combat this problem, we must work with consumers to become educated
about the importance of both reading and following label directions for
both prescription and OTC medications. The widespread use of OTC
analgesics may have led consumers to become complacent about their use.

A study by the National Council on Patient Information and Education,
NCPIE, found that while 95 percent of consumers read product labeling
when selecting and using an OTC medication, they often don\'t read the
entire label and instead select the information they view as important.

And what consumers may view as important doesn\'t necessarily match with
what health care providers and regulators view as important. As an
example, only 34 percent read the information about the active
ingredient, and only 21 percent of those consumers read the warnings
information.

Consumers must be reminded that any medication, including OTCs, has the
potential to harm if it\'s used incorrectly. A survey of caregivers
underscored this point as only 28 percent of them were aware that OTCs
could have side effects, and only 36 percent could name a possible side
effect that could occur for a given medication.

Consumers must be encouraged to read product labeling, to take the
medication as directed, to learn of possible side effects, and
understand what to avoid while taking the medication.

Consumers with questions or special needs should also be encouraged to
talk to their pharmacist or physician before taking any new medication
or combining multiple products.

APHA recommends that all prescription and OTC products containing
acetaminophen be clearly marked. Patients often identify with the brand
name of the medication they are taking, but are not aware of the
product\'s active ingredients.

For example, patients may report that they are using the product
Tylenol, but a survey found that only eight percent of those individuals
could also report using acetaminophen.

OTC products should contain verbiage, such as \"contains
acetaminophen,\" on the product\'s front panel, preferably in
combination with the drug name.

Additionally, acetaminophen containing prescription drug products could
be identified through the use of auxiliary labels placed on the
prescription vial by the pharmacist, and both products should include
warnings about therapeutic duplication.

We\'re pleased that Bayer, McNeil, and other manufacturers of OTC
products have announced revision of labeling for their acetaminophen
containing products to emphasize the active ingredient and include an
overdose warning.

APHA encourages the FDA to recognize the industry\'s efforts in this
area and to further advance their efforts by allowing important dosing
information for patients under the age of two to be added to the product
label. The inclusion of this dosing information may prevent overdoses
caused by inaccurate dose estimates.

In conclusion, acetaminophen is one of the safest and most effective OTC
and prescription drug products available for pain relief when it\'s used
correctly. It is important that the agency does not reduce access to
this valuable pain medication.

The agency should work with product manufacturers, pharmacists,
physicians, and consumer groups to educate consumers on the appropriate
selection and use of all OTC products, including acetaminophen, aspirin,
and other NSAIDs.

Consumer education activities, such as NCPIE\'s Be Med Wise public
education campaign, is a great way to educate consumers about the need
to both read and follow label directions and to ask their pharmacists if
they have any questions.

Helping consumers learn how to appropriately select and use OTC
medications is key to reducing product overdoses and related adverse
events.

Thank you for your consideration of the view of the nation\'s
pharmacists.

CHAIRMAN CANTILENA: Thank you.

Our next speaker, Mr. Ray Bullman from the National Council on Patient
Information and Education.

MR. BULLMAN: On behalf of the National Council on Patient Information
and Education, I am pleased to address the FDA\'s Nonprescription Drugs
Advisory Committee.

Found in 1982, NCPIE, as we call ourselves, is a nonprofit coalition of
135 member organization, including national consumer and patient
organizations, health care professional associations, voluntary health
associations, manufacturers, and government agencies.

The FDA is represented on an NCPIE board of directors in a nonvoting
liaison capacity.

In the interest of disclosure, neither NCPIE nor I received funding to
participate in today\'s meeting. Support for the Be Med Wise campaign,
which I\'ll describe, was developed by NCPIE, and provide an
unrestricted educational grant from McNeil Consumer and Specialty
Pharmaceuticals, and subsequent Proctor & Gamble.

The appropriate use of medicines, specifically the exchange of useful
information between consumers and health care professionals to foster
such appropriate use, has been at the heart of NCPIE\'s mission for 20
years. Our national education campaigns have featured themes such as
\"Team Up and Talk,\" \"Have Your Medicines Had a Checkup,\" and
\"Educate Before You Medicate.\"

While my comments may not necessarily reflect the opinions of each NCPIE
member, there\'s universal support among our membership for the vital
role that high quality health care provider and patient communication,
public awareness and education play in promoting safe and appropriate
use of medications.

Whether consumers are self-medicating or have a new prescription, we
urge them to ask questions, to share information about other medicines
they\'re taking, and to report any problems to their health care
professionals.

Today this is more important than ever before, with nonprescription
medicines accounting for six of the top ten medicines taken by Americans
according to the Sloan survey published in JAMA on January 16th of this
year.

Also in January of this year, NCPIE launched our Be Med Wise public
education campaign to promote the wise use of nonprescription medicines
and to raise awareness about the new Drug Facts label on
over-the-counter products.

Survey research commissioned by NCPIE last year indicated that many
consumers do not recognize the potential for harm if they take more than
the recommended dose of an OTC medicine, take more than one OTC product
containing the same active ingredient, inappropriately combined OTC and
prescription medicines, or inappropriately combine medications and
dietary supplements in some cases.

As specifically relates to OTC pain relievers, our poll found that only
34 percent of respondents taking an OTC medicine for headache could
correctly identify its active ingredient. Two thirds, 66 percent, either
incorrectly identified the active ingredient or did not know what the
active ingredient was.

We also found that one third of respondents report having taken more
than the recommended dose of an over-the-counter medicine.

Our campaign activities to date have included extensive use of
television, radio, print, and the Internet to encourage consumers to be
med. wise when selecting and using over-the-counter medicines. Message
points that relate specifically to the committee\'s deliberations today
include over-the-counter medicines are serious medicines that can cause
harm if taken incorrectly.

Many over-the-counter medicines contain the same active ingredient. So
make sure you know the active ingredient or ingredients in each of the
medicines you plan to use or to administer to others.

Compare the active ingredients if you\'re taking multiple medicines.

Always read the OTC drug label carefully and follow dosage instructions,
warnings, et cetera.

Tell your doctor and pharmacist the names of all the medicines you are
taking, particularly before a new prescription is introduced to the
regime or a new OTC is introduced.

When in doubt about choosing and using an over-the-counter medicine,
consult your doctor or pharmacist.

Our campaign Web site, bemedwise.org, highlights the fact that many OTC
medicines contain the same active ingredient and includes a graphic
demonstrating the number of products, both prescription and OTC that
contain acetaminophen, ibuprofen, aspirin, and naproxen sodium.

In August, NCPIE conducted a five-city media tour coinciding with the
back-to-school season to convey ten tips to parents and caregivers when
giving over-the-counter medicines to children. Working with our network
of pharmacists and pharmacy organizations, NCPIE will next develop and
disseminate Be Med Wise messages to consumers at community based
pharmacies across the country.

An initial product will be a series of brochures and Web based messages
with the working title of which will be promoting the wise use of
over-the-counter pain relievers, followed by similar titles addressing
the most widely used categories of OTC products.

I\'ve summarized the work of our Be Med Wise campaign because I feel
there are some insights that may prove helpful in the context of
today\'s meeting. As specifically relates to the Advisory Committee,
NCPIE recommends that FDA sustain its support for consumer and patient
education by continuing its collaboration with organizations like NCPIE
and other organizations.

Continue to develop and disseminate consumer directed messages about the
Drug Facts label as an educational resource, calling special attention
to knowing the active ingredient in your medicines and comparing
products when taking multiple medicines.

Regularly assessing or supporting research on consumers\' understanding
and use of the Drug Facts label. Such consumer research can help guide
collaborative efforts to inform and educate about appropriate use of
medicines.

And finally, to commit support and resources for an ongoing national
consumer medicine safety and education partnership, such an effort could
be modeled after the multi-stakeholder partnership for food safety
education with its highly visible fight BAC food safety campaign.
That\'s B-A-C, in which FDA is intricately involved. It could
incorporate timely and relevant messages about, for example, risk
recognition and management and medication error reduction.

NCPIE first proposed such a sustaining medication, education, and safety
campaign to the FDA in 1998. Broad goals for such a campaign would be to
educate consumers and health care professionals about changes and
improvements in medicine education, to promote question asking,
information seeking and information sharing as valuable tools to improve
communication and knowledge, and to better equip consumers and
caregivers to recognize and/or act on medication related errors or
problems.

NCPIE envisions the Be Med Wise campaign as a multi-year effort to
support and enhance consumer\'s informed self-care decision making when
selecting and using over-the-counter medicines. As such, it could serve
as the foundation for a broadened, multi-stakeholder, collaborative
national consumer medicine education and safety partnership.

Throughout our history, the FDA has worked closely with us on many
educational campaigns. Our partnership to promote the Be Med Wise
messages and especially the new Drug Facts label has been rewarding.

We commend NDAC for highlighting important safety issues and the role
that consumer education can play as we continue working together to
insure the public\'s wise use of medicines.

Thank you.

CHAIRMAN CANTILENA: Thank you, Mr. Bullman.

Our next speaker is Ms. Kate.

MS. KATE: I\'d like to thank you very much for allowing me to be here
today.

On April 18th, 1995, my son Marcus said to me, \"Oh, Ma, I think I\'m
going to die.\"

I told him I would never let that happen. I had no idea at that time how
serious his medical condition was or that it would continue to get
worse. A few weeks before, our son had injured his wrist. He had a
severe sprain and was prescribed acetaminophen with codeine by our
family physicians. He took the medication for the prescribed time.

When the prescription was finished, he continued to have some pain and
purchased an over-the-counter acetaminophen product. During this time,
we spoke to Marcus frequently. These calls were to check on how he was
doing, and I would always ask the usual Mommy questions.

How\'s your wrist? How do you feel? Are you eating?

He said his wrist didn\'t hurt as much, but he wasn\'t feeling well and
wasn\'t very hungry. When we spoke to him on the Friday before Easter,
Marcus said he thought he was getting the flu. He said he was nauseous,
had body aches, and a temperature.

We found out later that these are also symptoms of acetaminophen
toxicity.

At this point he purchased an over-the-counter flu remedy, also
containing acetaminophen. On Easter Sunday he felt bad enough to go to a
local hospital. After being in the first hospital for two days, Marcus
was transferred to another hospital and put on the organ donor list.

On April 24th, eight days after entering the hospital, and with no donor
liver available, we stood next to our 23 year old son\'s hospital bed
and watch and listened as he slowly slipped from our lives.

I and my husband and our other two sons watched as the color drained
from Marcus\' face when his heart stopped. Our previously healthy, happy
son was gone.

When we found out that the cause of death was liver failure due to
acetaminophen toxicity, we didn\'t know what to think. Our search for an
answer started. We found out that acetaminophen was a leading cause of
drug overdose and death in the United States and the United Kingdom. We
learned that the numbers of deaths per year were in the hundreds and
that adverse events were over 100,000 per year.

We also found out that fasting was as much a factor as alcohol when
combined with acetaminophen to cause liver failure.

If our son or my husband I had had even an inkling that acetaminophen
toxicity existed, I feel that the outcome of our story would be totally
different, perhaps no story to tell at all.

My husband and I have made contact with other families across the
country who have had family members die to acetaminophen toxicity. They
thought they were alone.

This panel knows the statistics. You know they\'re not alone. To this
day we meet people, tell them our story, and we still get the same
response: I didn\'t know that.

We continue to meet doctors who are not aware of the frequency of
acetaminophen toxicity. My husband has educated our local EMS to the
signs of toxicity. Most people know about stomach problems and bleeding
associated with NSAIDs. Why aren\'t they aware of acetaminophen liver
problems?

We\'ve taken on the project of trying to educate as many people as we
can, but it should be the responsibility of the manufacturers to educate
consumers. With yearly profits in the billions from acetaminophen
products alone, I feel that the funds are available for consumer
education.

Commercials for prescription drugs warn of possible side effects and to
consult your physician. You have the guidance of your doctor. With
over-the-counter products, you\'re on your own. If companies are
permitted to advertise their products, they should be require to inform
people that fasting, alcohol, preexisting liver problems can lead to
liver damage, liver failure, and death.

There\'s a phrase that makes me sick. The phrase is \"risk-benefit
ratio.\" It seems that it\'s acceptable that a number of people will die
if you sell a certain amount of medication. It\'s not acceptable.
There\'s no acceptable ratio when one of those people is your loved one,
and important information was withheld, information that has been known
for 20 years.

I know this panel will do what\'s right. You have to. You can\'t allow
more innocent men, women, and children to suffer from the adverse
effects cause by acetaminophen.

Seven years have passed since Marcus\' death. Don\'t let another year
pass and more families go through the unbelievable pain and sorrow that
our family has had to endure. Sometime positive has to result from such
an unnecessary death as our son\'s.

In his memory we have given out seven scholarships in his name to his
high school. Another tribute would be to stop the additional suffering
due to the greed and indifference to consumers by manufacturers of
acetaminophen products.

This is Marcus when he was three. It\'s one of our favorite pictures.
That\'s Marcus on his aunt\'s boat up in Maine. Marcus just enjoying
himself with his friends. This is Marcus\' graduation picture.

And as requested by some of the people I have been in contact with, two
families requested me to show pictures. This is Wendy. She died at 28
from acetaminophen toxicity. And this is Cindy, dressed in a gown to go
to her class reunion two months before she passed away.

And I just hope by looking at these faces that you know and hope you
know that death is not an acceptable side effect.

Thank you very much.

CHAIRMAN CANTILENA: Okay. Thank you very much.

Our next speaker is Dr. Caroline Riely.

DR. RIELY: Good afternoon. Thank you for the opportunity to provide
testimony here.

My name is Dr. Caroline Riely. I\'m a professor of medicine and
pediatrics at the University of Tennessee at Memphis.

I\'m providing testimony today on behalf of the American Liver
Foundation, the leading national voluntary health agency dedicated to
the prevention, treatment, and cure of hepatitis and other liver
diseases through research, education, and advocacy.

We are here today because we are concerned about the issue of adverse
reactions in the liver to over-the-counter medications.

As a hepatologist caring for patients with both acute and chronic liver
disease, I suggest both acetaminophen and nonsteroidal anti-inflammatory
drugs, such as ibuprofen, to my patients depending on the setting.

For example, acetaminophen is the antipyretic and analgesic of choice
for patients with chronic, non-alcohol related liver disease, despite
its well known association with hepatotoxicity.

Acetaminophen, normally a very safe drug, is an hepatotoxin under
certain conditions, and we\'ve heard a lot about that today. The
therapeutic window for this agent is quite narrow. The usual adult dose
is one gram by mouth every four hours, but a single dose of 20 grams can
cause lethal hepatotoxicity.

Many believe that four grams per day is a safe level, but some have
suggested that it may be more prudent to use two grams a day as the
maximum safe dose for those who regularly use alcohol.

Acetaminophen is a constituent of many combination medications, both
over the counter and prescribed. So a patient may take two forms of
acetaminophen without being aware of that fact.

For example, a patient may use Tylenol P.M. and percocet and may
inadvertently exceed the safe dose.

This is particularly a problem in the pediatric population. Well meaning
parents administer multiple doses, can reach toxic dose inadvertently
resulting in liver injury. In this age group, the problem is magnified
by the multiple formulations available. The parent may not be aware that
the preparation advised for infants, a concentrated form given in drops,
is much more potent than the syrup administered by teaspoon in older
children. Toddlers using the infant formula but given by the spoonful
may inadvertently develop injury to the liver.

We\'re concerned that the present marketing practices make it very
difficult to find the standard dose formulation, the 325 milligram
pills. As a result, the consumer thinks that the extra strength
preparation is the only one available.

Given the narrow therapeutic window, this failure to market the lower
dose may contribute to increased adverse events.

At the American Liver Foundation, we would like to encourage an active
approach to this problem and would like to participate in any way that
we can. There needs to be greater awareness on the part of all, the
consumer or their parents, the pharmacist, and the physician.

We would advocate an innovative educational effort to help minimize
these problems. For example, the package warning in use now are too
small, difficult to reach, and thus may appear to the consumer to be
unimportant.

An educational effort at the site of purchase would be useful. There
could be signs or brochures in Spanish as well as English available at
the display shelf or at the checkout counter. Pharmacists distributing
acetaminophen containing prescription drugs, such as percocet or
vicodan, should label the bottle to indicate that the medication
contains acetaminophen, with a warning that toxic doses may be obtained
if the patient is an alcohol user or taking OTC acetaminophen.

Public service announcements on TV would be helpful, and the
manufacturer should promote the use of the 325 milligram tablets or at
least give them equal shelf space with some informative guidelines as to
which dose is appropriate for whom.

Likewise physician education is important. Physicians need to know all
of the medications, both over the counter and prescribed, that their
patients are taking. They should be aware of the narrow therapeutic
window for acetaminophen and its interaction with alcohol. And
pediatricians and family practitioners should go over with the parents
the appropriate dosing for the various pediatric formulations.

We realize that the discussion of the NSAIDs is tomorrow\'s topic. We
would like to take this opportunity to remind the panel that NSAIDs,
such as ibuprofen, are potentially toxic in patients with chronic liver
disease, leading to renal failure at even modest doses.

Thus, in this setting acetaminophen is a better choice for the treatment
of pain or fever.

Acetaminophen is a good drug, proven so over decades. Efforts at
education of the consumer and the professional will result in an even
better safety record for this agent.

The American Liver Foundation wishes to thank the FDA for convening this
panel. We believe that these drugs represent only the tip of the
iceberg. We need a better understanding of the potential for
hepatotoxicity of all therapeutic agents.

Thus, we recommend the creation of a task force to examine the issue of
drug induced hepatotoxicity. We need better review mechanisms and
studies to address this problem. The American Liver Foundation stands
ready to assist in this initiative.

Thank you very much for allowing me this opportunity to share our views
with you today.

CHAIRMAN CANTILENA: Thank you, Dr. Riely.

Our next speaker is Dr. Peter Lurie.

DR. LURIE: Good afternoon. I\'m Peter Lurie, a physical with Public
Citizens Health Research Group in Washington, and I have no conflicts to
disclose. We take no money from government or industry.

Let\'s start with some history. In 1977, a review panel not dissimilar
to the present one recommended the following warning for acetaminophen
containing products: \"do not exceed recommended dosage because severe
liver damage may occur.\" And a second piece of advice: \"do not exceed
recommended dosage or take for more than ten days because severe liver
damage may occur.\"

The FDA chose to ignore this advice. Now, a quarter of a century later,
we\'re looking at what is literally an epidemic of fatal acetaminophen
associated poisonings, a near doubling just between 1995 and 1999, and
estimates \-- we\'ve heard data just recently suggesting it might, in
fact, be an under estimate of 458 deaths per year according to death
certificate data.

Acetaminophen is the leading cause of toxic drug ingestion in the United
States.

The FDA has estimated that at least 57 to 74 percent of ingestions are
intentional. Yet the issue before the committee is described as, quote,
unintentional acetaminophen hepatotoxicity, which is an illogical
restriction of this debate and seemingly a capitulation to the idea that
nothing can be done for those making suicide attempts.

In fact, many suicide attempts are impulsive and are, in fact, cries for
help. And many of them will turn out to be fatal despite that. Most,
however, are not fatal, and fatality rates are related to the doses
consumed.

I think writing off what is, in fact, the leading cause of death related
to acetaminophen overdose makes absolutely no sense to me, and I\'m
going to suggest a number of things that might be done that will not
only have an impact upon the intentional overdoses, but will also have a
ripple effect upon unintentional ones.

Now, one of the things that some countries have done, something not
mentioned at all in the FDA briefing packet for reasons unclear to me,
is that numerous countries have, in fact, tried to do something about
this problem. The most recent of these occurred in the United Kingdom
where in September of 1998, there was a restriction placed on the number
of acetaminophen packs, acetaminophen tablets per pack: 16 if you
purchased the drug in a supermarket, 32 if you bought it from the
pharmacy, with an overall restriction on 100 tablets that could be
bought. Otherwise you had to go and get a prescription from your doctor.

Early evaluations of the program showed decreases in total and severe
acetaminophen overdoses, as well as decreases in acetaminophen overdose
related liver transplant and death.

All of this, it seems to me, should be informative to the committee and
are the kinds of things that should be considered.

I\'m going to go through a six point plan of things that could be done,
and let me start with the first, which is consumer access to risk
information. We heard a lot about that. In fact, most of what the
committee has heard so far has been about access to information as a
consumer group.

Of course, we\'re in favor of that, but we\'d like to see it go well
beyond that.

On the matter of risk information though, what we have is woefully
inadequate. Obviously it\'s not even consistent with what the review
panel recommended a quarter of a century ago.

In addition, there should be a general warning about liver toxicity. The
label should mention the symptoms of liver toxicity and advise patients
to at least consult their medical care providers if they start to
develop any of those symptoms.

It should also warn against the simultaneous use of multiple
acetaminophen containing products, and there should be a warning on the
box the way it was done with aspirin and Reye\'s Syndrome, and there has
been an enormous impact on Reye\'s Syndrome deaths as a result of that
box warning.

We also support a patient information leaflet in each packet.
Advertising, although not regulated by the FDA, the FTC could require
the kinds of warnings that we see on direct to consumer advertising for
prescription products at this point, and they could talk about the
dangers of overdose, and so on.

I would also like to see the FDA writing articles in medical and lay
journals and running late night or any time PSAs regarding the dangers
of acetaminophen overdose. So that\'s number one.

But what can be done beyond the customary claims to education and the
need to do all of this when, in fact, very little will, in fact, be
done?

We can reduce the maximum daily doses, and that would be a good place to
start. Among unintentional adult acetaminophen related liver toxicity
cases reported to the FDA or published in the medical literature, the
median daily dose was five grams a day. Now, the total maximum dose is
set by FDA to be four grams a day. So that itself is a very small margin
for error.

Of course, for certain groups of people the medium maximum dose among
\-- sorry \-- the median daily dose among those with hepatotoxicity was
still lower: for alcohol users, 4.6 grams per day; for liver disease
patients, four grams a day, literally the maximum dose; hepatotoxicity,
patients taking other hepatotoxic meds., 3.9 grams per day.

The margin of safety for those with those underlying conditions of
particular drug use is clearly too small. There needs to be a reduction
in the maximum daily dose for them, but given that overall the total
daily dose was five grams a day, only 20 percent higher than what the
FDA says is safe as a maximum, we think you should consider lowering the
maximum dose for everybody.

Point three, reduce the per tablet doses. Because there is a practical
limit on how many pills a suicidal patient can take, it\'s only logical
that reducing the strength of the individual dosage forms to 325
milligrams per tablet would yield important benefits.

It\'s also likely to benefit pediatric patients who get into the
medicine cabinet and ingest acetaminophen containing products, as well
as those who are unknowingly taking multiple acetaminophen containing
products.

Four, standardize the liquid formulations. The FDA reports 25 cases of
pediatric hepatotoxicity. In at least four of them, teaspoonfuls of
medication were administered instead of dropper fulls. I mean, I
remember as a physician being very confused about that when patients
make the transition, you know, to toddlerhood. And obviously patients
are just as confused.

While acetaminophen suspension has 32 milligrams per mL, the drop
contain three times as much, which is obviously ample opportunity for
overdose.

All liquid forms of the drug should be required to have the same
concentration. That would really address that problem in a
straightforward and simple fashion.

Remove irrational acetaminophen containing combinations from the market.
Forty-nine percent of over-the-counter acetaminophen sales is in the
form of combination products, but most, if not all, of these
combinations are just irrational. Patients and their parents should be
encouraged to use only the medication that they need, not lapse into
this shotgun approach to drug therapy.

The use of combination products with elaborate and often misleading
brand names discourages patients from learning the generic names of
active ingredients, potentially leading to overdoses when taken with
other acetaminophen containing drugs. Approximately 25 percent of
patients with liver toxicity collected by the FDA had taken more than
one acetaminophen containing product.

Finally, more research. We\'ve heard some mention earlier of the idea of
combining acetaminophen containing products with N-acetylcysteine, a
drug that is used to treat acetaminophen overdose. We are not aware of
data that show that that\'s an efficacious approach, but certainly it
does merit further study.

Now, none of these approaches, the six things that I have mentioned will
be enough on its own to eliminate the problem of acetaminophen
overdoses. Multiple approaches clearly are necessary here, not one
simply restricted to labeling and advertising, but beyond that. If not,
we\'ll be looking back a quarter century from now and somebody else will
be able to look back and say, \"This is what the FDA panel was told or
what the FDA panel reviewed, but nothing was done,\" and we\'ll have
more cases on our hands.

Thank you.

CHAIRMAN CANTILENA: Thank you, Dr. Lurie.

Our last speaker for this section is Dr. Lou Lasagna from Tufts
University.

Dr. Lasagna.

DR. LASAGNA: Thank you.

My name is Lou Lasagna. I am Dean Emeritus of the Sackler School for
graduate biomedical studies at Tufts University, and for many years I
was Director of the Center for the Study of Drug Development, first with
the University of Rochester and then at Tufts.

My interest in analgesics harks back to a half century ago when I became
involved in clinical trial design and the search for nonaddictive
substitutes for morphone and for new pain relievers that would offer
safer and more effective analgesia.

I am here today to present my personal views. I have not received
compensation for my time, although I must say I\'ve had many satisfying
collaborations with industry, with pharmaceutical companies over the
years. And some of the research at our center is supported to this day
by unrestricted grants from industry.

My goal today is not to propose solutions to the complicated questions
before this committee, but rather to raise some issues that I believe
need to be part of your deliberations.

The remarks that I am going to make can be applied to any of the drugs
under discussion during this two-day meeting. Three issues of special
concern.

First, dose response versus benefit to risk. OTC drugs, as you know, are
by their nature expected to be generally safe in recommended dosages and
regimens. Intuitively the minimal effective dose should be utilized in
an OTC setting.

Even with generally safe drugs, excessive amounts of drug or dosages
above the ceiling dose for efficacy can increase the risk of toxicity.
The balance of benefit to risk of all OTC drugs is related to the dose
response for efficacy.

In the ideal world, the ceiling dose for efficacy is well below the
toxic levels allowing a wide therapeutic window. I think the committee
needs to determine for both single entity and combination products
whether the current dosages and regimens are, in fact, optimal based on
the available data.

Two, combination policy. A second point relates to the way OTC
combination products are approved for marketing. Under the FDA
guidelines for analgesics, for example, a combination policy clearly
states that the contribution of each ingredient must be shown in well
controlled clinical trials. This policy is applied to all new
combination drugs that seek approval under NDAs.

In contrast, under the monograph system, the monographs for analgesics
and for cough, cold, allergy products allow combinations to be marketed
based on historical data of the individual components. There are often
few data from controlled trials to justify the dosage of the analgesic
ingredient or even to indicate whether the ingredient contributes
meaningfully to the overall efficacy of the combination.

This policy has led to proliferation of a vast array of cough, cold,
allergy products that contain an analgesic. Both acetaminophen and
aspirin at their highest allowable doses are often part of these
combination products.

For newer analgesic drugs, the problem would appear to be under greater
FDA control because of their NDA status requiring clinical studies to
demonstrate both efficacy and safety.

Well, what is the optimal dose of analgesic that should be in OTC
combination products? Whenever possible, data from well controlled
clinical trials should drive this decision making process.

Third, promotion of products. Although there is fierce competition among
pharmaceutical companies, they all have a responsibility as they would
admit to be honest with the consumer. This honesty needs to be reflected
not only in the product label, but in promotion material in print, in
TV, and so forth.

OTC drugs, like all other drugs, are neither perfectly safe nor free of
drug interactions. You may remember that two to four percent of all the
new drugs approved by FDA are ultimately removed from the market,
usually because of serious toxicity rarely occurring that was not
detected prior to marketing.

This message, I would submit, needs to be clearly articulated to the
consumer. Overstating the safety image of any drug can lead to adverse
effects. Well, the big question in closing is I would submit the
following. Are there ways by labeling changes, by educational material
for parents, consumers, patients, for physicians, other ways which
without loss of therapeutic benefit can make what are generally safe OTC
products even safer.

I don\'t have the answer, but I would submit that the question is one
that deserves an answer.

Thank you.

CHAIRMAN CANTILENA: Thank you, Dr. Lasagna.

What I\'ve actually done, I\'ve asked the FDA to help to focus the
committee somewhat by reviewing if they would, you know, the regulations
that cover, you know, the labeling for the over-the-counter drugs, and I
think there\'s someone prepared with a couple of slides that they can
sort of get us all on the same page.

And then I\'ve also asked Dr. Ganley if he could scan in some images of
labels from some of the over-the-counter drugs that we\'ve been talking
about just so you have an idea of, you know, what they look like, you
know, as they\'re out there today.

So if you don\'t mind start with that.

Okay. Sandy just reminded me that that panel also has a handout that was
just given out just as we came back from lunch that has a lot of this
information and some sample labels as well.

While that\'s coming up, Dr. Ganley, perhaps you could, you know, remind
the committee in terms of jurisdiction over advertising for the
over-the-counter drugs, if you can just sort of clarify that because a
lot of the comments we\'ve heard have touched on the advertising and
marketing.

DR. GANLEY: Yeah, for OTC drugs, the FDA has jurisdiction over the
promotional labeling, which would be the label on the package, package
insert.

If there\'s a stand within a store, that\'s sort of considered
promotional labeling. What we wouldn\'t necessarily regulate, which is
regulated by FTC, would be TV advertising, magazine advertising,
newspaper advertising and things such as that.

CHAIRMAN CANTILENA: Okay. Thank you.

MS. LUMPKINS: Okay. You all are well aware of the Drug Facts format. The
Drug Facts format is FDA\'s effort to simplify the labeling for
consumers, to put information in discrete places consistently across all
labels.

So basically this is one of the regulations, and this is the outline
format that Drug Facts labeling should take. So this was our first
attempt.

Now, there are some other regulations that regulate the labeling of
these products. One of these deal with the PDP that\'s also pertinent to
this discussion today. Those are the statement of identity regs.

And what I\'m going to do is I\'m just going to briefly describe for you
what the statement of identity needs to be. The statement of identity
basically has two parts. It\'s the established name of the drug, and the
established name of the drug is usually the name that\'s in the
compendial like the USP.

Beyond that, there is the pharmacologic category of the drug. That\'s
its general purpose, its, you know, analgesic antipyretic kind of a
thing.

In combination products, the statement of identity gets to be a little
bit problematic. The regs. allow for if there is no established name of
the combination, say, acetaminophen pseudoephedrine tablets. The
manufacturer has the option of using the general pharmacologic category.
This is pertinent to today\'s discussion because that means for those
combination products, the active ingredient is not going to appear on
the PDP.

And what we\'ve done is we\'ve scanned in some of the principal display
panels of some of the commonly marketed over-the-counter drugs
containing acetaminophen both in combinations and single ingredients so
you could sort of see.

There\'s also another aspect to the statement of identity that you
should be aware of. The statement of identity is required to be printed
in a size reasonably related to the most prominent display of the trade
name. It\'s also required to be in direct conjunction with the trade
name.

Now, this works very well when you\'re dealing with a single entity
ingredient where they\'re required to have something like acetaminophen
on the front panel.

For the combination products, that gets to be a little bit more
problematic because you\'re dealing with, you know, cough-cold product
or nasal decongestant, antitussive. So you\'re not going to get that
visual message to consumers that this product may have acetaminophen in
it.

Sir?

DR. GANLEY: I just want to clarify when you\'re saying PDP you\'re
saying principal display panel.

MS. LUMPKINS: Right. Sorry about that.

Basically the PDP is described as like the panel presented for display
for sale. So that would be the thing that the consumer would see first
when they look at the products when they sit on the shelf.

Yes. So basically what you have is flu would be the trade name. We\'ve
obviously for obvious reasons blocked out most of the name. This is what
you generally see on cough-cold products. This is the general
pharmacologic category.

I just have \--

DR. GANLEY: Debbie, could you just read some of those things under there
because it\'s hard to see it back here, too?

MS. LUMPKINS: Okay. The general pharmacologic category for this product
is pain reliever, fever reducer, nasal decongestant, cough suppressant.

Nowhere on there is an active ingredient. Totally required by the
regulation.

Next one.

This is a generic product that was bought at a local Target store, and
it has a little different approach. No problem with the statement of
identity there in recognizing that product.

(Laughter.)

MS. LUMPKINS: Again, this one does actually have all of the active
ingredients on it. I\'m not even sure if I can read them. This is your
point of reference here.

Let me see. Push this? Thank you. I never worked one before.

These right here are your active ingredients. This is your trade name.
These are your pharmacologic categories.

CHAIRMAN CANTILENA: Okay. And the regulation then just really requires
the categories.

MS. LUMPKINS: For combinations that\'s all that would be \--

CHAIRMAN CANTILENA: And not the active ingredients.

MS. LUMPKINS: \-- required, yes.

CHAIRMAN CANTILENA: Okay.

DR. GANLEY: I think the other thing is that the regulation isn\'t really
clear on the type size. It says it should be reasonable, and we\'re
always struggling on the NDA side for people to increase the size
because that\'s what they really want to downsize, is the statement of
identity or the name of the active ingredient.

And you can see it on that last one where you could hardly, you know \--

MS. LUMPKINS: You could hardly read it.

DR. GANLEY: Right. You could show them where the type size in there \--
I don\'t want to pick on that product individually, but \--

MS. LUMPKINS: There are others.

DR. GANLEY: \-- they\'re not unique in that regard.

MS. LUMPKINS: Go ahead.

This one, there\'s your pharmacologic category. This is also a
combination.

Reasonably related to the most prominent ‑- it\'s a very tricky legal
definition. Some people could say, \"Well, if you can read it, that\'s
good enough.\" Other people would say, \"Well, it needs to be bigger.\"

CHAIRMAN CANTILENA: So then in that case, then the active ingredients
are on the other side of the box. They\'re on the back.

MS. LUMPKINS: Right. They would be in the Drug Facts usually for an
combination. As you saw, there were some that did try to do both, but
you know, you can understand the logistics of the combination, too,
because when you\'ve got five and six different ingredients, it gets
hard to get all of that and still have all of your trade dress.

CHAIRMAN CANTILENA: Okay. Very good. Does anyone on the panel have any
questions for FDA on this point specifically, on the labeling?

Dr. Wood, then Dr. \--

DR. WOOD: Is there a fundamental legal reason why the size of the
labeling can\'t be defined? I mean if that was one of the
recommendations that this panel was to make \--

MS. LUMPKINS: It would require amendment of the regulation, but it\'s
certainly something that could be done.

DR. WOOD: But there\'s no reason why this panel couldn\'t make such a
recommendation; is that right?

And similarly, going back to the point that\'s been made many times
today, that individuals overdose on these products because they don\'t
recognize that they\'re taking the same product in different ways,
there\'s no reason why we shouldn\'t highlight one of the ingredients to
be called out like acetaminophen, for example?

MS. LUMPKINS: Well, you know, the Drug Facts labeling has very specific
font size requirements for all of the headings for the minimum font size
that\'s acceptable for the text.

DR. WOOD: Yeah, but that\'s not what is redone at \--

MS. LUMPKINS: Something comparable could be done for statement of
identity.

DR. WOOD: Okay.

MS. LUMPKINS: And it\'s certainly within the purview of this panel to
make that recommendation.

DR. WOOD: Okay. Thank you.

CHAIRMAN CANTILENA: Dr. Neill.

DR. NEILL: When people go into the drugstore or to the grocery store and
they look on the shelf, I am used to food labels now telling me a
serving size and commonly a grocery store putting a unit price in a
common denominator format so that when I\'m comparing one bread to
another bread, I know the cost per pound.

For medications, because of the way that they are marketed, they may be
present in 24 caplet size, 12 caplet, a blister pack, many different
formats, and I have no idea whether this panel can make recommendations
about how to present cost data or dosage data in addition to that
principal ingredient.

If no other recommendation were made, I guess I had not understood,
despite being on this committee off and on for the last few years, that
the ingredient name was distinct from the category name, and that the
category pain reliever-fever reducer was required and the ingredient
not.

MS. LUMPKINS: Only in combos. With a single ingredient product, it would
be required to state acetaminophen on the principal display panel. So
it\'s just for the combinations where it gets to be a little difficult.

DR. NEILL: But while I could understand the educational value of having
the class data there, for consumers who are attempting to get what they
can get for a certain dollar amount and recognizing that combinations in
my anecdotal, nonscientific survey make up the majority of that shelf
space, and acknowledging that that shelf space is very expensive for
products you put up there, I would think that it would be useful to have
that there.

And so it is helpful for me to get guidance from staff about, you know,
gee, what is within the purview. The information about the regulations
is helpful.

CHAIRMAN CANTILENA: Any further questions for the FDA?

I\'m sorry. Dr. Cush.

DR. CUSH: Can someone at the FDA tell me why they have oversight on
matters of display, but yet have no oversight on the far more
influential and pervasive practice of direct to consumer advertising
print and media?

CHAIRMAN CANTILENA: Dr. Ganley, do you want to handle that one?

MS. LUMPKINS: Yeah, go ahead.

(Laughter.)

MS. LUMPKINS: I don\'t have an answer for that one.

DR. GANLEY: Someone from industry could probably answer it better. I
really don\'t know why that distinction.

DR. CUSH: You can\'t answer the question?

DR. GANLEY: Well, I don\'t know the history.

DR. CUSH: \-- the rule.

DR. GANLEY: Well, we don\'t set the rules necessarily. Congress sets the
rules on us and we write the regulations based on those laws, and so it
must be within laws of who provides the oversight for the advertising.

I don\'t know the historical background related to that, but we can\'t
just go out and write a regulation that\'s not within the purview of
what the law allows us to do, and so I\'m assuming that that authority
has been given to FTC.

The promotional labeling, a display in the store that has the name of a
product on it is still really pretty much labeling until you leave that
store, I think. I didn\'t write it. I just have to follow it.

CHAIRMAN CANTILENA: Just to follow up on that, obviously our panel is
advisory to the FDA. Is there a similar panel or some mechanism for
feedback for the FTC, Part 1?

Part 2 is: can the panel recommend items that are sort of under their
jurisdiction? And is there any, you know, formal exchange that that
would actually get back to them from FDA?

DR. BULL: I would mention that we do have ongoing dialogue with FTC and
could certainly explore what the options would be in terms of building
more substance into the interaction, as well as the level of oversight,
and to take these concerns to them.

CHAIRMAN CANTILENA: Yes, Dr. Clapp.

DR. CLAPP: I\'d like to know about the package itself. Once the package
is gone, on the medicine bottle is there the requirement that the
category name be on the bottle as well in the front of the label?

And if so, is this just for combinations or, I mean, is this just for
single ingredient items?

Because my concern is everyone tosses this, and if you have the Tylenol
bottle or Tylenol cold and flu and you\'re depending to read the
microscopic vision for those of us who are graduated to the presbyopic
types, I\'m sure that it\'s a great challenge to read it on the back of
the label, but perhaps on the front, that would be a more reasonable
likelihood that we could read the ingredient.

MS. LUMPKINS: Basically Drug Facts is required on the outer carton. The
principal display regulations speak to the outer container, but in
reality what manufacturers usually do is their PDP is pretty much
displayed on their inner container.

I mean absent, you know, some of the extra things that you might get on
a carton, but there aren\'t any real regulations because the PDP is
about the outermost container.

Now, if it\'s marketed without an outer container, then your PDP becomes
the bottle itself.

So sorry.

DR. CLAPP: Is it within the purview of this committee then to make a
recommendation that the container itself have an identification of the
active ingredient on the outside of the label?

MS. LUMPKINS: I would think it would be.

CHAIRMAN CANTILENA: I\'m sorry. Could you use the microphone, please?

DR. GILBERTSON: The immediate container has to have the name of the
active ingredient, and it has to have the name of the product, on the
immediate container and on the principal display panel.

The other information she\'s talking about that\'s found on the Drug
Facts is not necessarily required on the immediate container, but it
must have that plus the name of the manufacturer, the number of capsules
or tablets. And so there are certain things that are required,
especially the name and the active ingredient.

Combinations are different, as she points out.

DR. CLAPP: My question is for the front and the back of the label as
being different. When you have a bottle of Tylenol, the front of the
label has pretty much the same information as the front of the package,
and then as I recall the back has the dosages and \--

DR. GILBERTSON: That\'s not in the new Drug Facts format you\'re looking
at, I presume.

DR. CLAPP: I\'m presuming that the front does not have necessarily the
active ingredient for certain on combinations on the front of the label
of the package once you discard the box. That\'s what I\'m \--

DR. GILBERTSON: The immediate bottle container must have the active
ingredient listed and the name of the product.

DR. WOOD: Even for combinations?

DR. CLAPP: Where is my question. The location is the issue.

DR. GILBERTSON: That\'s the issue, and I just pointed out \--

DR. CLAPP: The location and whether or not it\'s single ingredient and
combination is my concern. I think in the microscopic print you\'ll find
it on the back, as I recall.

DR. GILBERTSON: Right.

DR. CLAPP: But if you\'re reading the front of the bottle, my question
is: is it for the single ingredient items like just acetaminophen?

DR. GILBERTSON: No, combinations are treated differently than single
ingredient \--

DR. CLAPP: I heard that. You didn\'t hear what I said.

DR. GILBERTSON: I don\'t know how to answer it than to say that there is
\-- the provision is written that you have to have the immediate
container with the name and so forth, and \--

MS. LUMPKINS: But she\'s saying on the front.

DR. GILBERTSON: The front of the immediate container \--

MS. LUMPKINS: No, no.

DR. GILBERTSON: \-- of a combination drug.

MS. LUMPKINS: No, you just have to have it.

CHAIRMAN CANTILENA: On the front of the bottle versus the back in the
small print.

DR. CLAPP: Versus the back.

MS. LUMPKINS: It just has to be there. It doesn\'t necessarily have to
go on the front.

DR. CLAPP: That\'s my question, front versus back.

MS. LUMPKINS: That\'s right.

CHAIRMAN CANTILENA: Okay.

DR. UDEN: And there are no regulations for font size for the immediate
container, correct?

MS. LUMPKINS: Not if it had an outer container. Drug Facts applies to
the outermost carton. If there is no outermost carton, then Drug Facts
would apply to the bottle and font sizes required by Drug Facts would
apply there.

CHAIRMAN CANTILENA: Yes, go ahead, Dr. Wood.

DR. WOOD: I have a question for Dr. Lurie, who looks like he\'s leaving.

When you were talking about the U.K. rules, you focused on the package
size, 16 and 32. What you didn\'t mention was the other thing that they
introduced, was that you had to dispense it in a blister pack.

And it\'s likely that that was at least as effective, given the
Australian experience, as the restriction on the package size. Would you
like to talk about that?

DR. LURIE: I\'ll take your word for it on that. I understood that not
everybody implemented blister packs, even though most people did, in
fact, do so. So I agree it would be hard to separate out those two
effects.

No. I do, again, though think it\'s a very important experience with a
number of studies now showing important benefits in, you know, all of
the realms you\'d be interested in, from hepatotoxicity, to the blood
levels, to transplants, and ultimately death.

So it\'s a very important experience and one that I think holds
important lessons here.

CHAIRMAN CANTILENA: There\'s a follow-up question on that, and then Dr.
Davidoff.

DR. WOOD: Just to follow on the U.K. experience while this discussion is
going on, I saw a paper in reading up for this meeting and that I want
to make sure I understood correctly, and I thought that paper in
reviewing the U.K. experience showed that, in fact, there was a
substantial increase in GI bleeding and associated deaths following that
restriction on the packaging of acetaminophen.

And I just wonder whether anybody knows if that\'s the case and if I
understood that correctly. And, again we have been discussing this
channeling issue, and the presumption was that that was due to
channeling of high risk patients to NSAID therapy.

Does anybody know if that was, indeed, the case?

DR. KATZ: Well, just to focus again on the packaging issue, there are
data from Australia, you know, very convincing data that actually looks
at antidepressant packaging and tricyclates (phonetic) antidepressant
packaging, and that was put into blister packs that shows a clear and
dramatic reduction in use of tricyclates in overdose.

With tricyclates, you know, it\'s harder to sort of make a dramatic
gesture that says, you know, you don\'t love me as you press out 50
tablets than it is to sort take a bottle and swig it back, and so
there\'s this sort of intuitive reasoning, I think, that seems
attractive and borne out by data, which is always reassuring, which
speaks to the issue that was talked about earlier, that we\'re not just
talking about unintentional poisoning. It\'s also important that we try
to prevent death from the intentional poisoning, too.

DR. LURIE: Absolutely. That\'s, in fact, the majority of cases, and,
again, I do think it\'s important for the committee to get away from the
sometimes stereotypical notion that nothing can be done for people who
attempt or succeed in committing suicide.

People are impulsive. People regret what they do. People often just jam
as many pills of whatever kind they can into their mouths. They don\'t
say, you know, this is the recommended FDA \-- you know, this is the
toxic dose according to the FDA. This is how many 500 milligram tablets
I\'ll take.

They take as many as they can get without knowing the dosage pool and
they stuff them in. And the more difficult you make that for them, the
bigger impact you\'re going to have.

CHAIRMAN CANTILENA: Okay. Thank you very much.

We have a question from Dr. Davidoff.

DR. TEMPLE: Mr. Chairman, could I just recommend there\'s a Dr. Daughin
right behind me from England who knows what\'s going on, and he\'s a
toxicologist if you want to know what\'s happening now in terms of \--

CHAIRMAN CANTILENA: Okay. Actually, if I could hold on that because I
think Dr. Davidoff has been waiting for quite some time, and then we\'ll
come back and answer that specific question.

Go ahead, Dr. Davidoff.

DR. DAVIDOFF: Well, I actually had two quick questions, I think. The
first was for Dr. Erush, and that was I thought her data were pretty
interesting because they seemed to be a big more solid perhaps than some
of the other, more second hand data.

My question specific was: what percent of the people of your 40-plus
patients actually took doses as near as you could tell that were within
the guideline, the therapeutic guideline for OTC use?

DR. ERUSH: That were within four grams per day?

DR. DAVIDOFF: Yes, right.

DR. ERUSH: I can\'t give you a percent. I\'d say that it was probably
two or three that were at or below the recommended dose.

DR. DAVIDOFF: And how reliable do you think that information is?

DR. ERUSH: Well, if you remember, because I think I do, from our slide,
I think in the unintentional group, it was about 34 percent where we
were 100 percent certain of what they had taken. And we had another
group where we could estimate a range, and then some we absolutely
didn\'t know.

I don\'t remember exactly which group those fell into.

DR. DAVIDOFF: But it does appear to be from what you were saying that
there were at least a few patients who reliably \--

DR. ERUSH: Yes.

DR. DAVIDOFF: \-- took four grams or less.

DR. ERUSH: Yes, I would assume that there is.

DR. DAVIDOFF: Right. The other question I had had to do with the Drug
Facts because it wasn\'t clear to me whether everything that\'s in the
Drug Facts information that was handed out to us is required to be
somewhere on the package, either the bottle or the outer package,
including the statement about acetaminophen may cause liver damage.

Is that required to be on or where is that required to be or is it
required to be anywhere?

MS. LUMPKINS: Right now it\'s not required. Right now it\'s not required
to be anywhere because we\'re still in the midst of the rulemaking. If
it were to be required, it would be included in Drug Facts at the very
least and maybe somewhere else.

DR. LAINE: So this alcohol warning is not on the package now?

MS. LUMPKINS: It\'s in the Drug Facts.

DR. LAINE: It\'s just not \--

MS. LUMPKINS: Yeah, it\'s required.

DR. LAINE: It\'s just not in this format, but it is there.

MS. LUMPKINS: He was talking about a different \-- he was talking about
an overdose liver warning, but the alcohol warning is a required part of
Drug Facts.

DR. LAINE: Oh, I thought he was talking about alcohol warning, but okay.

DR. GANLEY: Just to clarify, the alcohol warning was the proposed rule
in 1997, finalized in \'98. Okay? There was a recommendation, if you
remember, by the panel. If you take an overdose, that may lead to severe
\-- that is not required though.

MS. LUMPKINS: Right.

DR. GANLEY: So there\'s two different things. One is associating with
alcohol, and the other is associating with overdose.

MS. LUMPKINS: This is where it falls in the labeling of Drug Facts,
right here.

CHAIRMAN CANTILENA: So the Drug Facts is the current labeling by law.

MS. LUMPKINS: Yes.

CHAIRMAN CANTILENA: It\'s in the process of implementation.

MS. LUMPKINS: It\'s required.

DR. GANLEY: But the liver warning is not required.

MS. LUMPKINS: The liver warning is not.

CHAIRMAN CANTILENA: Right. The alcohol is part of Drug Facts, and that
\--

DR. GANLEY: Yeah, the alcohol liver warning is.

CHAIRMAN CANTILENA: \-- is in effect, but the liver is not.

Okay. Speaking of liver, perhaps we can talk about \-- just get that
follow-up from England, just to answer Dr. Wood\'s question, and then we
will proceed.

DR. DAUGHIN: My name is Paul Daughin, and I\'m a toxicologist from
London, and I can comment on both the British perspective in terms of
pack size and also the Australian perspective on pack size and it
happened in Australia.

In the U.K. in September \'98, there was a change to maximum sales of
paracetamol in a fan (phonetic) of 32 tablets or blister packs in
pharmacies, 16 tablets in non-pharmacy outlets, supermarkets,
street-side stores.

There have been a number of studies that have tried to look at the
impact of that. There\'s definitely been an impact on severe overdose,
about a 20 percent decrease in the number of deaths from paracetamol in
the year after the legislation was brought in, and a decrease in the
number of referrals to liver transplant units.

The problem is those are relatively small numbers, and so it\'s
difficult to know whether we\'re seeing a real effect or not.

When you look at the other end of the spectrum, the non-severe
overdoses, there\'s been a much less significant impact. There are about
70 to 80,000 overdoses per year in the U.K. There\'s perhaps been a two
or three percent decrease in the number of overdoses overall.

There\'s also been data that\'s looked at the number of sales of over
the counter analgesics. Paracetamol sales have decreased from 300
million a year to about 150 million a year. Ibuprofen sales have
increased by a factor of about 70 to 80 percent. Aspirin sales have
fallen slightly.

If we then look at Australian data, during 1999 and 2000 there were two
incidents where paracetamol had to be removed because of problems with
contamination. A poison service and a clinical toxicology service looked
at cases that were presented to them of overdose, both deliberate and
accidental. There was no overall change in the number of paracetamol
overdoses, but there was a significant increase in the number of
ibuprofen accidental poisonings that were reported to the poison service
and a significant increase in the number of aspirin poisonings in the
clinical toxicology service, suggesting that the decrease in the number
of paracetamol sales was perhaps shifting things to ibuprofen and other
nonsteroidal agents.

So data from the U.K. and the Australia just to give the wider
perspective to it, and to reiterate, in the U.K. what we\'ve seen is a
decrease in the sale of paracetamol with an increase in the sale of
alternative analgesics.

CHAIRMAN CANTILENA: Okay. Thank you.

I think Dr. Brass has a follow-up.

DR. BRASS: Yeah, just to make sure I understand. When you said there was
a 20 percent decrease in the number of severe poisonings, was that
corrected for the change in sales denominator?

DR. DAUGHIN: Yes, that was.

DR. BRASS: So the rate per \--

DR. DAUGHIN: Yeah, the rate had fallen.

DR. BRASS: Thank you.

DR. DAUGHIN: But to reiterate, there are relatively small numbers, and
we\'ve only seen two years of follow-up, and so there may be
fluctuations in the data, and we don\'t know whether we\'ve seen a real
change or not

CHAIRMAN CANTILENA: Okay. Thank you.

What I would like to do now is actually take a 12 minute break until
3:00 p.m. and give everyone a chance to stretch, and then we\'re going
to come back and change the program a little bit.

(Whereupon, the foregoing matter went off the record at 2:48 p.m. and
went back on the record at 3:10 p.m.)

CHAIRMAN CANTILENA: Thank you.

What I\'d like to do actually for the panel members is I\'m going to be
passing some packages and, you know, container bottles around which
demonstrate new packaging which I understand has been available for two
to three months, which goes over some of the things that we\'ve talked
about, and again, this is just for one of the sponsors. It isn\'t
obviously for the generics, but I think it actually addresses some of
the comments that were made, and we\'ll just pass that around. Just if
you can pass it that way and then back across.

What I thought we\'d do to avoid the possibility of being here until
midnight if we followed the prescription or the points to consider that
we were given is to change a little bit and to sort of, you know, focus
the discussion into several specific areas, and I realize there\'s a lot
of overlap between the topics, but what I would like to propose is that
we start to talk about unintentional overdoses and some of the factors,
and then get into the labeling.

And I\'ll actually ask the question: do people favor changes to the
label now or should we hold off until there are more studies done?

And if yes, what type of changes to the label? If you want to do it now,
then what type of changes should we make now?

And we have some choices that were given to us on the sheets from the
points to consider.

Then I thought we would separate out the drug-drug interactions and
subpopulation question, people with, you know, liver disease, et cetera,
alcoholics, into a separate discussion, realizing that some of that does
impact on the issues for labeling, but I would like to separate that.

And then if anyone is still breathing, we can then take up the issue of
combination for, you know, the Rx drugs and talk about that.

And then lastly, end with exactly what was requested by FDA, which is
Item 5: what additional studies are needed, if any, to evaluate the
issue?

So actually let me just start with a question, and I think for the first
question I will just do sort of a yes/no, and then we can have an open
discussion about factors. When I do the labeling question, I intend to
go around the table so that every individual will have an opportunity to
comment on the reason for their vote or specific factors that they feel
are most important for the question, or if they wish, they don\'t have
to comment and they can just vote. Either way, that\'s fine.

So we will get into the labeling as sort of the second issue, but I
guess the first question was in general by show of hands: as we sit here
after we\'ve heard, you know, everything from the sponsor, from FDA, et
cetera, et cetera, and from what we know from the packets and our own,
you know, expertise, do we feel there is a significant issue regarding
unintentional overdose that should stimulate action by FDA to try to,
you know, decrease the occurrence of unintentional overdose?

I\'m specifically using the word \"action\" because if we say change in
this or change in that, that\'s a whole separate, you know, topic. So I
would just like to get a feel for where people are.

If the vote to this is unanimously no, then you can easily make happy
hour.

(Laughter.)

CHAIRMAN CANTILENA: And we\'re probably done for the day, but if it\'s
not unanimously no, then we\'ll go on to the other issues and actually
talk about it.

So again, the question: is the issue of unintentional overdose as we
have heard it, you know, worthy of action by FDA as we sit here today?

If you are in the affirmative, if it is worthy of action, if you can
raise your hand, please, and we\'ll actually take a count.

(Show of hands.)

CHAIRMAN CANTILENA: Okay. I think we\'re unanimous. Was there anyone
voting in the negative or abstaining?

(Show of hands.)

CHAIRMAN CANTILENA: Okay. So there goes happy hour. Okay.

(Laughter.)

CHAIRMAN CANTILENA: All right. What I\'d like to do is actually open the
discussion to look and actually concentrate on some of the factors that
were, you know, listed for us in point number one for the committee
discussion, the possible factors.

And, again, we are going to specifically talk about, you know, labeling
in sort of the next section. So you can talk about it, but really
don\'t, you know, focus.

But just a general discussion of what people feel are the most important
factors that are contributing to unintentional overdose, and I\'ll just
open it up and we\'ll start around the table.

Dr. Cush.

DR. CUSH: The issue of unintentional toxicity could also be regarded as
uneducated toxicity. So I would make the proposal that all these
packages, whether it\'s single product or combined product or even
prescription product, have the bold label that this product contains
acetaminophen.

Moreover, I\'d also maybe even go so far as to say that we should take
about more of a bold, big box warning just like the Surgeon General\'s
warning for tobacco, saying the combined use of acetaminophen containing
products may be harmful to your liver.

CHAIRMAN CANTILENA: Okay. I think Dr. Brass is next.

DR. BRASS: I\'m going to preface my remarks now and actually say it for
all my subsequent remarks this afternoon, that I\'m really cognizant of
the fact that on a given answer, it\'s not going to be based on the
compelling data that has been presented. Rather, it\'s going to be based
on common sense, a gestalt of the information and my own clinical
experience and what I understand about acetaminophen hepatotoxicity.

And so that will make my ability to defend my answers somewhat more
difficult than I normally feel. Having said that, I think there are four
areas that strike me as being relevant. One is the use, unintentional
use, of multiple acetaminophen containing products.

Two, exceeding the recommended dose with under appreciation of the
consequences of exceeding the dose.

A third issue we didn\'t hear a lot about today, but we\'ve heard about
previously is misdosing of infants and the difficulty in proper dosing
of infants.

And the fourth issue is related to subgroups as yet to be defined, and
I\'ll hold off on that.

And I will also add another caveat from my perspective. As we think
about these and potential changes, I will also point out that we
actually don\'t have a lot of data that tells us about the efficacy of
risk management in the OTC setting, the effectiveness of warnings on
labels, how to modify consumer behavior in the OTC setting. So we\'ll be
making that up as we go along as well.

CHAIRMAN CANTILENA: Thank you.

Dr. Williams.

DR. WILLIAMS: Well, I would support everything Jack Cush suggested. I
think there needs to be clearly stated that acetaminophen is in these
products, and that the patients need to be educated that combinations of
acetaminophen containing products can exceed the allowable dose, and
that would be the only thing that I would add to it, is that there needs
to be a continued patient education process like that Med Be Wise or
whatever to let the patients know that acetaminophen isn\'t totally
benign.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. Elashoff.

DR. ELASHOFF: Yes. I think a major issue has to do with the efficacy
labeling of even the single product because if you buy the bottles with
the 325, it says take two every four to six hours. At least that\'s the
bottle I got.

If you get the one for 500, it says take two every four to six hours.
Those can\'t be both good advice.

In this oral surgery study, they talked about 60 percent of people took
another 1,000 milligram dose in less than four hours, and it says the
duration of a single dose was three to five hours.

So if you start taking the 1,000 milligrams every four hours, what do
you do by the time you get to the 16 hour point and you\'re not supposed
to take anymore in the 24 hours?

It leaves people hanging. So I think that whole business of the efficacy
labeling contributes to the probability of taking an overdose and needs
to be looked at.

CHAIRMAN CANTILENA: Thank you.

Dr. Katz.

DR. KATZ: Two points. The first is that although the data is really
amazingly weak in terms of understanding exactly what the magnitude of
causal connection is between acetaminophen and acute liver failure, it
still seems obvious to me that from a labeling point of view somebody
should be able to buy something in the supermarket and know what\'s in
it.

And one of my more boring hobbies is that I\'m interested in the history
of opioid therapy, and I was reminded during this conversation of the
fact that in the late 19th Century, you could go to the pharmacy and be
sold a bottle of something that contained ten percent morphine without
there being any requirement at all to put on the bottle exactly what was
in it, even if it was a treatment for opioid addiction.

And so it strikes me that we\'re talking about something very similar,
and that we may look with horror, you know, back on those days, but now
it doesn\'t really seem that different.

So I would propose, and I think that it would be relatively
straightforward to achieve consensus on this, that the name of the
medication should be on the bottle itself and not just the package, with
a list of every ingredient that\'s in it and know what it\'s for in
terms of the concentration in a size font that\'s readable.

To me that doesn\'t seem like a radical notion, and so that\'s my first
point.

My second point is that, on the other hand, lack of effective pain
management is a huge problem in this country, and I think as we were
talking about putting warnings on labels, we don\'t want to make Tylenol
look like a dangerous drug.

The person that I\'m worried about is the little old lady who is going
to say, \"Oh, now, look at this warning. I\'d better not take my, you
know, few Tylenol a day for my arthritis, and I\'d better sit home and
suffer again.\"

We certainly don\'t want people who are most vulnerable due to under
medication of pain to be adversely affected and then the balance
actually have a negative impact on public health.

CHAIRMAN CANTILENA: Thank you.

Dr. Clapp.

DR. CLAPP: I have concerns about the dosing of acetaminophen for
pediatric patients particularly, considering the milligram per kilogram
dosing that we as pediatricians recommend.

One of my concerns is that in adult strength Tylenol the recommendation
is for children 12 years and older to take two 500 milligram gelcaps
every four to six hours, along with adults, and the variation in 12 year
olds\' weight can be all across the map.

You can have a 65 pound 12 year old who\'s a petite person, as well as
200 pound 12 year old. I\'m wondering about some of the studies done,
particular the pharmacologist from the University of Pennsylvania that
said there was some identified cases that had no clear-cut etiology as
to the nature of the risk factor for toxicity.

I\'m wondering if perhaps in adults the little old lady that you
suggest, perhaps it might be that adults also have some issues
concerning weight and milligram per kilogram dosing of Tylenol.

So that in addition to putting age recommendations, that across the
board weight be a consideration for instructions in dosing
acetaminophen.

CHAIRMAN CANTILENA: Thank you.

Dr. Patten.

DR. PATTEN: Yes. I\'ll speak for little old ladies.

(Laughter.)

DR. PATTEN: I think that little old ladies are fairly heavy users of
professional health care providers, and so that is a wonderful
subpopulation for health care providers to assist then in making these
kinds of decisions.

So physicians, nurse practitioners, and so on, who are seeing little old
ladies as patients will have a wonderful opportunity to make sure that
they\'re not overlooking or rejecting acetaminophen as an effective pain
medication.

So much emphasis in medicine today is on prevention that as I\'m
starting to think about reconfiguring labels or having new information
on the labels, I\'m thinking about it in terms of a preventive measure.

And so, therefore, I\'m not quite so worried about quickly assessing
efficacy. Efficacy of other kinds of preventive measures often aren\'t
assessed until long down the road.

Thank you.

CHAIRMAN CANTILENA: Thank you.

Dr. Cohen.

DR. COHEN: Yeah, I wanted to mention a few things that we really
haven\'t discussed yet that might be contributing to some of the
confusion and unintentional overdoses.

First of all, I also obviously agree that it\'s important to have the
ingredients of all of these products clearly listed, and I think it\'s
important to understand what type of background might be needed to bring
this information out, just printing it on a white background.

I mean, I saw, you know, a modification of the label as displayed in the
other room, and it looked pretty good, but I think we could do better
than that, and I think that should be part of the requirement. The font
size, et cetera, needs to be looked at.

I know we do that with prescription drugs, for example, where the size
of the nonproprietary name has to be half the size of the brand name,
and perhaps we could look into something like that for this.

The brand extensions, as I mentioned earlier, I think they\'re important
to contain this information, and I note that quite a few of these
products actually do take space now to say that they\'re not aspirin,
the non-aspirin product or does not contain aspirin.

I think the statements in the labeling now, the dosing under two years
old, call your doctor or if you had more than three drinks or take more
than three drinks, call your doctor. At the minimum I think it should
also say your pharmacist, not just your doctor, because in many cases
they\'re going to be more accessible.

But more than that, I think it\'s really important and we haven\'t
really discussed it all that much yet, is the idea of having actual
dosing for people that are under two years old, little ones.

We need that. People need to know what to do because they\'re not
calling their doctor in some of these cases. They\'re taking it upon
themselves. If their child has a fever, they\'re not going to wait until
somebody actually calls back.

I think the extended release products need to be looked at and the
dosing of them. They\'re not always being administered as they were
intended. They are sometimes given Q four hours or Q six hours. I know
some health professionals have actually made that mistake.

I think the statements in the labeling, droppers full, are confusing
when we\'re talking about the infant concentrate product, and I don\'t
mean to just indicate that McNeil is the only manufacturer. We have seen
generic products that have that same product as well, and the term
\"droppers full\" to a lot of people means a full dropper, not the
actual measurement that\'s on the dropper itself.

The safety lock product is extremely important. we saw data in our
packets that has really helped to reduce the number of overdoses with
that concentrate. Yet the generic manufacturers do not have this
product.

And I think if it it has worked so well and we\'re going to continue to
have that product on the market \-- and I know that\'s probably
something we also should talk about, the concentration that\'s available
\-- then I think we ought to require that from all of the manufacturers,
however that\'s done.

One other thing. The way that the concentrations are expressed on the
liquid products, if you look at the label, I don\'t know if we have them
here, but you\'ll see the concentration is actually expressed as a 160
milligram per on both the concentrated product and the children\'s
product.

In other words, it\'s 160 per five mL, and the other one, I believe, is
160 per 1.6 mL. But what the consumer might see if they were looking at
them both at the same time on a shelf next to one another is that they
both are the same concentration.

I think that the way that that concentration is expressed could be a lot
clearer, and so I think that\'s something also that we should be looking
at.

Thank you.

CHAIRMAN CANTILENA: Okay. Dr. Wood and then Dr. Furberg and then Dr.
Cush.

DR. WOOD: I tried in my own mind to break this down into three sort of
subheadings, and I had the Brass sort of preamble first, I think, where
I\'m working on sort of intuitive reasoning as much as databased
reasoning.

But it seemed to me there were sort of three headings moved forward:
prevention of confusion making it harder to take an overdose, and
labeling for subgroups.

And you\'ve taken the last one off the table for now, and I\'ll respect
that.

The prevention of confusion, it seems to me that we need to certainly
include labeling for the ingredients on the front, but it seems to me we
ought to consider going further than that because for the combination
products, there\'s multiple ingredients, and they all have long names,
and certainly most of the people I know, they would just blank out on
that.

So I think there may be a need to have something that sort of calls out,
contains acetaminophen. If it\'s reasonable to say it doesn\'t contain
aspirin on the front label, it\'s probably equally reasonable to say it
contains acetaminophen because what you really want people to know is
that when they line up three bottles and they\'re about to take tables
from each of these, they need to understand that each of these contains
acetaminophen and that there\'s going to be an additive effect from
that. So I think it\'s not just listing the ingredients. It\'s calling
that out somehow.

The third thing in avoiding confusion, it seems to me, is limiting the
number of doses, the different dosage forms that are available so that
particularly in children there\'s not multiple concentrations available,
and the issues of the 350 and the 500 and so on have been talked about
before.

Then the second heading was making it harder to take an overdose, and it
seems to me, again, we have to work on somewhat intuitive reasoning, but
I think we have a duty to prevent people dying from acetaminophen
however they get there, and I think we need to address both the people
who in a gesture or whatever take too much acetaminophen or those who
get there by taking too much accidentally.

And I don\'t make as big a distinction as other people perhaps have made
of that, and I think blister packs clearly would help in that, and the
data that was presented from the U.K. which was presented, I guess, to
speak against that seemed to me to only speak more compellingly in favor
of that.

There\'s not much we\'ve managed to do as physicians that have reduced
the frequency of overdoses in any situation than the fact that we\'ve
done that.

So I think dealing with the blister packs also allows you to put the
\"contains acetaminophen\" wording right at the point of use as well.

The labeling from subgroup issues I\'ll leave for now.

CHAIRMAN CANTILENA: Thank you.

Dr. Furberg.

DR. FURBERG: Yeah, I\'d like to extend what Dr. Cohen said, that we
should rest the liquid formulation. I think we really should pursue
standardization of that and so to avoid unintentional use.

And also I agree with Dr. Wood. Blister packs, I think, is the way to
go, but in order to keep the level playing field, let\'s look into that
in a broader sense, and that could also apply to other pain killers.

CHAIRMAN CANTILENA: Okay. Thank you.

Actually I have a question for Dr. Ganley.

The issue of standardization of concentration, are there other factors
such as, you know, the volume, you know, like in a specific age group
that have, you know, resulted in the concentration issues that we\'re
discussing?

DR. GANLEY: I\'m not sure if you\'re asking standardized concentrations
or the volume allowed in a bottle.

CHAIRMAN CANTILENA: Not in a bottle. In terms of, you know, like a dose.
Is there background information as \--

DR. GANLEY: You mean the total doses in a bottle.

CHAIRMAN CANTILENA: \-- to why we have, you know, different
concentrations?

DR. GANLEY: Well, I guess the easy answer here is that\'s what the free
market is right now. You know, the only example that I can think of in
this country that has a limitation on the package size is sodium
phosphate, and that was based was based on problems with the 240 mL
bottle where people were running into problems with various metabolic
abnormalities because they would drink the whole bottle.

And that\'s been cut down in size, and it\'s still been somewhat of a
little bit of a problem for us, and we\'re going to make some changes in
that even and cut it down to 45 most likely because people are still
taking 90 and getting into problems.

But there there was something that we could specifically point to and
identify that there was a problem. It becomes more problematic for us
when we want to put limitations on package sizes and, you know, the way
these monographs are written, various dosage strengths and things like
that because we have to provide some data that would justify it for us.
Okay? We can\'t just do it on a whim.

And so, for example, if people thought there should be a package size
imitation, we really have to go into U.K. and find out really what is
the story going on there.

And we\'ve heard different opinions today of what\'s going on, but we\'d
have to go in and actually get data or go to Australia and get data and
then use that as a basis if we were going to go down that route.

But we just can\'t say that this committee thought that you should only
have 30 tablets in a package size because a lot of these \-- you know, a
rule like this would have to go through various clearances at OMB, and
if we don\'t have data to support that, you know, there would have to be
\-- it\'s very difficult to impose that on companies, I think.

DR. WOOD: That was not what I was proposing. I was proposing blister
packs, not a limit on the \--

DR. GANLEY: But my point is that we need to find out. I talked to
someone in the U.K. the other day, and I got a different impression of
how successful this has actually been from what\'s been said today.

I\'m not going to state that I really think we need to go and talk to
the regulators in the U.K. and really find out has this been a
successful program.

CHAIRMAN CANTILENA: Okay. Dr. Cush and then Dr. Brass.

DR. CUSH: To get to the pediatric issue, I think that I would support
the comments thus far made. I would actually go so far as to say that we
should really say that all of these preparations we\'re talking about
today should really have the label, and that this is a problem for adult
use only, and that if there are products to be marketed to children,
that they should go under a separate product, a separate box, and they
should be pediatric formulations to avoid children using adult doses and
getting confused in that situation.

Also, I\'d also suggest as far as education that avoidance of the
abbreviation APAP, and I think it\'s more in the prescriptive end rather
than the OTC end, would also go a long way in avoiding a lot of
confusion.

DR. GANLEY: Can I just follow up on that a second?

I can tell you one of the problems we\'re running into now with
manufacturers through the NDA side is they will have a single
formulation that they package, and it will have dosing that includes
adult dosing and children dosing, and what they want to do is take that
exact same formulation and make a children\'s package.

It\'s the exact same formulation. Everything is the same, and that\'s
the problem we\'re sort of running into. We\'ve been reluctant to try to
do that because you could actually carve out the elderly package, the
adolescent package. It\'s just innumerable how many different things you
go.

And so we\'ve sort of said, well, there\'s no difference here from this
adult package, and you\'re just throwing this children\'s package on the
market now, and that\'s going to lead potentially to some problems
because you could create five other, you know, various package groups.

DR. CUSH: I don\'t think that we heard that the LD was a particular
issue, other than that these were the main users of these drugs. We did
hear that children are a separate issue and how they get into trouble.
This is what might address that.

I think if you have separate packaging, it avoids the ability to look at
adult dosing and kid dosing and, well, my kid is kind of a big kid. So
I\'ll give him the adult dose.

And I think if you just go for a pediatric package, it just has labeling
for that child or children up to the age of 16 or it could be on a per
kilogram or per poundage weight basis.

DR. GANLEY: Well, one of the things you did say in the first comment was
that you mentioned a pediatric formulation. But again, one thing is that
if you go down that route, you have ten companies that market something
and you multiply that potentially just by four or five, and you have a
children\'s product and an adult product.

I mean, I\'m not arguing with you. I think it\'s something we need to
look into to see is that something that is a worthwhile measure, but the
potential is that, you know, you just have a reproduction of the same
product, but in a different package.

DR. CUSH: But the goal, of course, would be to prevent pediatric
accidental overuse.

DR. GANLEY: Right.

DR. CUSH: And if that\'s a measure that would work, then I think it
should be employed.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. Brass.

DR. BRASS: It seems like we\'re moving on to some of the specific
labeling suggestions, which I thought you were going to separate out.

CHAIRMAN CANTILENA: We actually are. After two more questions, we\'ll
have a vote, and then a discussion.

DR. BRASS: Okay. Then I have a question of clarification apropos of
this. Acetaminophen containing products actually are available in the
U.S. market in a variety of package sizes, forms, and I think including
some blister pack things.

Now, clearly consumers are selecting them for different reasons, but it
would be interesting to know whether or not those products are being
used preferentially in suicide attempts, et cetera, and at least
understand the data within our own system, as well as collecting that
additional data.

CHAIRMAN CANTILENA: Okay. Comments from Dr. Williams and then Dr.
Alfano.

DR. WILLIAMS: I just wanted to speak against blister packing
requirement. As a rheumatologist, several of my patients that use
acetaminophen also have disease of their hands, and blister packs would
make it even more difficult for them to use these products.

CHAIRMAN CANTILENA: Dr. Alfano.

DR. ALFANO: Yeah, my comment is sparked by I guess something Dr. Brass
said, which many people seem to share, that he feels compelled to offer
comments based primarily on sort of intuitive reasoning. I think DR.
Cook also seconded that concern.

And I think we should make those comments based upon disintuitive
reasoning. My concern is that we not take that intuitive definition of
the problem and combine it with empirical solutions that we really have
not evaluated yet. So we need to be really careful because they won\'t
cancel out the soft data on either end.

And it really leads me to comment along the lines of the way we teach
our medical students, which is first do no harm, which is not to say do
nothing, and you know, there\'s 24 billion doses of this product sold
each year, and therefore, a little change unintentionally could make a
big difference. So we really do need to be careful.

Also, we have seen some formidable changes by the manufacturer in the
readability of the label and to its credit, it\'s at the expense of the
sell on the label. It may not go far enough, but it\'s definitely moving
in the right direction, and we ought to see how that plays out, as well
as the industry-wide introduction of the Drug Facts label moving
forward.

I was intrigued that we\'re also starting to get some prospective data
now from Dr. Lee and Dr. Erush, and that type of data, I think, can go a
long way in terms of interacting with the people who have actually had
these unintentional overdoses so that we can understand the cause of
them and then on that basis design better labeling.

The other databases don\'t allow us to interact with the patient or the
consumer and, therefore, we could stumble. So clearly there\'s the need
for improved labeling, improved consumer education.

As I think back to the Reye\'s Syndrome, success where the problem was
reduced by an order of magnitude. I don\'t think it was simply the
labeling. It was the consumer education and public relations that went
with that.

Thank you.

CHAIRMAN CANTILENA: Thank you, Dr. Alfano, for your comments.

Dr. Crawford.

DR. CRAWFORD: Thank you.

Very quickly, I\'m very much in support with most of what\'s been said
in this discussion. I just want to point out the fact that we shouldn\'t
be presumptive to assume that even the majority of consumers who would
consume the product know the word acetaminophen, those six syllables. I
think it is much more known through the predominant brand name, and the
only reason I bring this up is that any efforts that this committee
might recommend to the FDA I think we should also say it\'s part of
broader educational campaigns to inform consumers what is acetaminophen.
Because most people know what aspirin is, but no by that name
\"acetaminophen.\"

CHAIRMAN CANTILENA: Okay. Thank you.

I\'d now like to shift gears slightly, although we\'ve already started
to touch on it. Oh, I\'m sorry. Dr. Johnson.

DR. JOHNSON: I had a couple of comments. One was in relation to, I
think, sort of what can be done, and one of the points that really
hasn\'t been addressed is education of professionals, and my guess is
that physicians and pharmacists would be fairly surprised, as I was, not
at the suicidal intentional overdose and the impact of that, but at the
unintentional overdose and the potential risk of that.

And so I think that along with consumer education, it\'s really
important that there\'s also professional education to really heighten
people\'s awareness that smaller than perceived risk doses may be risky
for certain populations.

And I\'ll save my other comments for later.

CHAIRMAN CANTILENA: Okay. Thank you.

One more comment on this from Dr. Davidoff.

DR. DAVIDOFF: Yes. Aside from generally supporting the intuitive or you
might say Bayesian notion that it makes sense to let people know exactly
what they\'re taking, I think that there is this issue of are there high
risk populations in some sense. It\'s quite important because a lot of
the thinking about what to do seems to hinge around the question of
whether they\'re are potentially identifiable.

Having heard all of this through all of this information, my sense is
that there appear to be some higher risk patients. The problem is that
we haven\'t figured out \-- I really don\'t think we\'ve figured out how
to identify them, and part of the clue may be in some of the data that
was presented from the University of Pennsylvania study.

Because it\'s beginning to me to look like it may not just be a factor,
an additional risk factor per patient. It may be a multiplicity of
additional risk factors that really begins to matter.

That being the case, it\'s going to be really difficult to pin that
down, but I think at this point it is reasonable to say that there are
some patients who are at increased risk, and I don\'t see any reason why
that kind of a statement couldn\'t be captured and not be distorting the
information that we do have.

One of the concerns I have about the way the alcohol warning is now
written is that the statement about potential liver toxicity is tucked
in under the alcohol warning, making it look as though it\'s the
patients who drink who are at risk.

But from PEN data and lots of other information, it looks like that
isn\'t the only additional risk factor. So I would urge that
consideration be given to having a liver toxicity statement separate
from the alcohol warning.

CHAIRMAN CANTILENA: Okay. Thank you.

If we can now sort of continue our conversation about the labeling, what
I\'d like to get is a yes/no from the panel on whether or not you favor
changes to the label now versus waiting for further studies to be
completed.

And let me just, you know, define by th regulatory definition of now.
Dr. Ganley, perhaps you can tell us \--

(Laughter.)

CHAIRMAN CANTILENA: \-- how long it took to change the label after the
panel voted in June of \'93 for the alcohol warning.

DR. GANLEY: I think you could have subtracted from the slides, Lou. It
was \'98 that the final came out. \'97 was when the proposal went out.
So it was a four-year period.

I think we\'ll act a little more promptly now because really this, you
know, is an important monograph to get done, and we\'re committed, I
think. The whole agency is committed to get it done, and so I think any
recommendations that you make will, you know, encourage us to get it
through the regulatory process as quickly as possible.

CHAIRMAN CANTILENA: Okay. So the initial question is, you know: do you
favor changes to the label for all acetaminophen products now, or should
those changes be held until studies are completed and analyzed and we
have more information to go on?

And if you vote yes, perhaps in your comments if you wish, can you
specifically highlight some of the things that you would like to change
now in the label versus perhaps, you know, something that we can hold
off on for however may years the studies will take, et cetera, et
cetera?

So what I\'d like to do this time is start at the end of the table here
with Dr. Furberg. If you can first vote, you know, yes or no, and then
if yes, highlight, you know, specifically the information that you\'d
like to see in the label.

DR. FURBERG: My vote is yes, and I would like to see the ingredients on
the container readable, in bold.

CHAIRMAN CANTILENA: Okay, and then we were passing around these bottles,
which are relatively new to the market. So I guess maybe if you can
recall, is something like that, you know, what you were talking about
or, you know, something else?

DR. FURBERG: Something like that.

CHAIRMAN CANTILENA: Dr. Crawford.

DR. CRAWFORD: Thank you.

My vote is no, not right now. Ultimately yes for changes in labeling. I
would like to see more empirical studies on issues such as
comprehension, understanding, readability for consumers, literacy levels
and how that might affect it both for the labeling and possibly for the
packaging.

CHAIRMAN CANTILENA: Dr. Cush.

DR. CUSH: I vote for a change now, and any product that contains
acetaminophen should say \"contains acetaminophen\" in a font and size
that is at least 50 percent of the major label of the brand name on the
box or bottle and that there also be even another box. It may take up
the whole side of the outside package that says \"warning: combined use
could be associated with increased toxicity.\"

CHAIRMAN CANTILENA: Thank you.

Dr. Elashoff.

DR. ELASHOFF: Yeah. I essentially agree with that, although I would like
to see the actual dose more prominent. One of those you have to keep
turning and turning around the box to find where the dose is. It took me
a couple of minutes to see that the dose was actually there. It was tiny
print on an end of the box that you wouldn\'t even think of looking at.

So I think the dose needs to be more prominent, especially since there
are two different strengths on the market.

CHAIRMAN CANTILENA: Thank you.

Dr. Watkins.

DR. WATKINS: I think the labeling change should be now, and I think the
key thing is that acetaminophen be clearly noted on the front of the box
and on the bottle, and then definitely education efforts to be made to
get people to understand what acetaminophen is and the danger of
combining products.

I get a little concerned about the equivalent of a black box warning
just because I think it may scare people away from the product
unnecessarily, but the idea of the education, I think, is the important
thing and exactly how to do that I\'m not sure.

CHAIRMAN CANTILENA: Dr. Brass.

DR. BRASS: I\'m going to vote now with an asterisk, and that \--

CHAIRMAN CANTILENA: Why am I not surprised, Dr. Brass.

(Laughter.)

DR. BRASS: Because I\'m a little concerned and actually agree with some
of the other comments that I\'m very clear in my mind what the problems
are that need to be addressed in the label. I\'m less clear what the
best way to address the problem is.

And, therefore, I would like to see some fast track validation that
whatever change is implemented really addresses the problem.

So, therefore, my first problem is to insure the consumer knows that the
product contains acetaminophen and not to combine it. So I do agree that
the front of the package must say \"contains acetaminophen,\" and I
would also add a warning that says \"do not use with other products that
contain acetaminophen\" so that that is crystal clear. So somehow
that\'s message one.

Message two is that this is not a benign product, and that the
recommended dose is a recommended dose. So under the directions I would
try to convey something like \"do not exceed the recommended dose unless
directed by a doctor. Exceeding the recommended dose may cause liver
damage,\" or something that makes it clear that it shouldn\'t be done,
and it\'s not a benign thing.

Again, whether that\'s the best way to do that I don\'t know, but
something like that.

And then the third issue, which I actually don\'t even have
recommendations on because I don\'t know how to do it, is the dosing of
infants and children that minimizes the incorrect dosing, whether
that\'s standardization of preparations, reexpressing the label. I
don\'t know how to do that, but something has to be done now to minimize
those incorrect dosing regimens.

CHAIRMAN CANTILENA: Thank you.

Dr. Davidoff.

DR. DAVIDOFF: I would endorse going ahead now. I really don\'t have a
whole lot to add to the recommendations that Dr. Brass brought up.

I also agree, however, that some sort of education in the broad sense is
really quite important. I think the NCPIE data and other data do
indicate that consumers tend not to read labels, not to read them
terribly carefully. They don\'t tend to understand them well.

Labeling is all very well, and certainly saying that every product that
contains acetaminophen contains is potentially valuable, but only
potentially. And I think that as with the Reye\'s Syndrome experience,
that a good deal of the benefit seems to have accrued from things that
went beyond labeling.

So I would strongly urge that there be the changes, but that that
education be somehow built in.

CHAIRMAN CANTILENA: Dr. Lam.

DR. LAM: I would vote for changes right now, and to me there are two
issues that concern. Number one is the lack of appreciation of toxicity
and the lack of appreciation of what would be the reasonable and
appropriate use.

And as I look at the label given to us by the FDA and think about what I
would do, normally if I pick up a package, the first thing I would do is
to go for how to take the medicine, the directions, and under the
direction it said do not exceed 12 caplets in 24 hours. And I would
think that would be the place to actually tell them what would happen if
you take more than the recommended dose.

During the experience on dealing with kids, telling them don\'t do that
is less effective as telling them don\'t do that and explain to them why
you don\'t want to do that.

So I presume that do not exceed the recommended dose or the maximum
recommended dose with an explanation, which really doesn\'t take that
much wording in there should be the way to do it.

CHAIRMAN CANTILENA: Thank you.

Dr. Cryer.

DR. CRYER: Without repeating several of the comments that have been
made, I agree with many of the things. I personally see the issue of
education being more important than these issues of labeling because
without the education the labeling really has minimal impact.

To emphasize some comments that maybe haven\'t been emphasized, I think
it\'s equally important to make sure that whatever is implemented with
respect to OTC dosing of acetaminophen or all analgesics should also
equally be applied to prescribed products because in the acetaminophen
case, the issue as I heard it, about a quarter of the issue was of the
problems were combining the OTC products with the prescribed products.
So you\'re really not accomplishing anything if you focus all of your
efforts in the OTC arena without applying the same proposals to the
prescribed issues. So I think you need to make that parallel.

And the other thing that I really want to focus on is that you should
have changes now, but ultimately there has to be some sort of
validation. We\'re all educated, sitting around making proposals as to
what we think should be the best thing for the consumer and the lay
population, but we don\'t really know.

I would propose that ultimately the FDA might want to consider as a
stipulation for approval of OTC products that there needs to be some
threshold level of consumer comprehension as the validation for ultimate
acceptance of that OTC product because I really haven\'t gotten since
that that is part of the requirements.

I mean, we\'re kind of working in a vacuum in terms of the knowledge.

CHAIRMAN CANTILENA: Yeah. Actually, you know, for the drugs that are
switched from Rx to OTC, that\'s always, you know, part of the
information, you know, that we get, you know, actual use studies and
things like that. But I hear what you\'re saying in terms of this
specific area where, you know, these have been on the market for a long
time and, you know, we don\'t have that information. Very good.

Dr. Laine.

DR. LAINE: I agree with everything. All of the good ideas are taken.

I would say yes, now. Just to emphasize a couple of things, what I am
struck by when I look at this label is the fact that what we\'re all
here talking about isn\'t listed anywhere, that is, liver disease. As
Dr. Davidoff mentioned, it implies only if you drink alcohol do you get
liver disease.

So, I mean, to reiterate what was said, I mean, somewhere on this label
we should have a warning that liver damage can occur.

I think the harder decision is I agree with the way Dr. Brass worded it,
that if you exceed the dose, the question we have to grapple with
frankly is that actually ignores the unintentional or, you know, the
just minimally \-- the four to six to eight gram dose, and I think
that\'s what we have to grapple with. How shall we deal with that now or
should we not?

But I definitely at a minimum would at least mention that damage can
occur. Use is important, and perhaps under directions we should somehow
try to get across it\'s not only do not exceed 12 caps in 24 hours, but
get across, again, the idea as people have mentioned that don\'t exceed
a total of X amount of acetaminophen in the directions. Because just to
try to make it very clear that people need to keep in mind that they may
be taking multiple acetaminophen containing components.

So I\'ll stop there, but those two are important to me.

CHAIRMAN CANTILENA: Thank you.

Dr. D\'Agostino.

DR. D\'AGOSTINO: I obviously agree with so much that\'s gone ahead. If I
didn\'t, people would say it\'s insane. But I\'d just to just throw out
a couple of points here.

We\'re not really dealing with the zero database. I mean, the
relationship between the particular overdose and the sort of latency
period and then coming back and having a terrible condition, I mean,
even though we don\'t have careful, well controlled studies, Dr. Lee\'s
data, the AERs data, and so forth, even when the McNeil panel reviewed
that, there were a number of cases that were, as far as they were
concerned and as far as everyone else was concerned, clearly has a
relation.

And we know the causality, and we see the problems that can develop. So
I don\'t think we\'re working from, say, a zero database.

I think also that the idea of the combination not containing the product
ingredients in the front is just something that has to be addressed, and
that we can do.

And just to go back, I kept writing over and over again as we were
talking what does the consumer do with what we\'ve done. The point that
was just raised by Dr. Cryer is that I\'m concerned. We\'ve gone through
a lot of these things in these meetings here. You can put things on the
label, but do the consumers understand them?

And what\'s going on in my mind is how do we get those labeled
comprehension studies as we load up the box with all of these new
warnings and what have you. How do we know the consumer is going to
understand them?

And I think we will come back to that, but I just want to mention that.

CHAIRMAN CANTILENA: Thank you.

Dr. Alfano.

DR. ALFANO: Well, as you know, I don\'t vote, but I have a perspective
that changes in the label along the line of what we saw passed around, I
think are clearly in the right direction.

As far as whether there should be a specific liver warning or not, this
is one of those areas where I would actually like to see what the
consumer tells us. The new label actually has a warning, has an overdose
warning that warns that serious health problems in the event of overdose
and basically advises people to get to the Poison Control Center and
physician right away.

I would be concerned that to a layman maybe liver means, once again, oh,
that\'s for people who drink. That\'s not me, and you could actually
make a case it might not be helpful. And here\'s where we need to be
careful.

Is it is more helpful or not? If it is, then we ought to say liver. If
not, we ought to simply say serious health problems.

CHAIRMAN CANTILENA: Thank you.

Dr. Clapp.

DR. CLAPP: first, I\'d like to say I\'ve seen tremendous improvement on
the new and improved bottle of Tylenol as compared to the box that we
have here, but there are some ambiguities that I remain concerned about
in the dosing on the basis of weight.

For example, with the children\'s Tylenol elixir or liquid form or
tablets, and actually the concentration of Tylenol or acetaminophen is
typically 100 \-- well, is always to my knowledge 160 milligrams in one
teaspoonful or per five mL, and the droppers, it\'s 80 milligrams in .8
milligrams \-- milliliters. I\'m sorry.

And intuitive reasoning that I can presume as a pediatrician is that you
will have to wrestle a small baby to drink a teaspoonful of vile tasting
medicine, and it\'s much easier to get them to drink .8 milliliters than
five milliliters.

And I don\'t know if the drug company \-- that\'s their intention, but
the reality is it\'s much easier dosing.

But in the Tylenol, children\'s Tylenol, it says 96 pounds and over four
tablets, which is equal to 650 milligrams, but on the gelcaps, it says
12 years and older, 500 milligrams. You can take two tablets.

So there\'s a little bit of ambiguity here that we haven\'t addressed,
and I\'m not sure if we are then focusing on weight is the issue or age
is the issue. The confusion that we are leading people to believe.

If children swallow pills, believe me, as a pediatrician they do not
want to chew things that taste terrible. They don\'t want to drink four
to six teaspoons full of something. The younger they are in swallowing
pills, the happier they are.

So we need to make sure that there\'s some consistency that we are
giving the public with dosing. I don\'t know if I can request
information from the FDA as to toxicity in adults related to weight only
as the indication because I wonder if the 96 pounds is a magic number
that we see these unidentified etiologies of liver toxicity as the cause
may be based on weight alone. So that\'s one thing.

Secondly, in reading this label it says take two caplets every four to
six hours as needed, and then the next bullet is, \"Do not take more
than eight caplets in 24 hours.\"

Well, this is intuitive, and this is where the pharmacologist is letting
us know that studies are useful, but it seems like once you find out the
information of how much you need to take, you\'re through with the
bottle.

And I\'m concerned that without having that information, every four to
six hours leads us into the toxicity range of acetaminophen, and that\'s
the six grams if you do 100 grams every four hours. Should we embolden
that?

I think it might be something to embolden so that at least if they\'re
not interested in reading, they see there\'s something to pay attention.

Lastly, the issue of toxicity is addressed with liver damage. What does
it say? Oh, yeah, \"acetaminophen may cause liver damage.\" I think
separating that from the alcohol warning is critical because the point
that\'s been made in a very clear and very tragic way today is that
alcohol is not the only risk factor. Toxicity can be related to dosing,
and that\'s it.

So I think it would be more prudent to say overdosage of acetaminophen
can cause liver damage in a separate area from the alcohol warning so
that we don\'t distract from those who are not drinkers, are not
drinking three drinks a day and they say, well, this is just for those
who are drinkers.

The last point has been made multiple times about font size. I think
that it\'s crucial to have the font size so that you actually pay
attention to the active ingredient on the front of the bottle, but as
well, I notice in the active ingredient label which is really much
improved because it\'s highlighted though, I have to hold the bottle
over here to see that that active ingredient is actually \-- thank you.
I\'m going to use those today.

(Laughter.)

DR. CLAPP: \-- is actually acetaminophen.

And so although the active ingredient is labeled, it\'s not emboldened,
and so it\'s interesting to see the highlight, but I think embolding it
will help us who are over 40.

Thank you.

CHAIRMAN CANTILENA: Thank you.

Dr. Katz.

DR. KATZ: Thank you.

I also agree with much that\'s been said, but at the risk of being
repetitious, I\'d like to be very specific so that the record is clear.

Number one, I would reiterate that all ingredients need to be on the
front, including on the combination products and including the
concentration per dose. For example, it should say acetaminophen, 500
milligrams per tablet, or phenylpropanolamine, X milligrams per tablet,
as opposed to just acetaminophen, and then you have to dig in the back
to find out how much it has.

Number two, I think that the class should also be in the front. So it
should say acetaminophen, pain reliever; phenylpropanolamine,
decongestant, and then the amount, all in the front.

Number four is that it has to be on the bottle itself, not just on the
box because everyone throws their boxes always, as has been pointed out
already, and nobody can remember anything until they actually have to go
to the bottle and take what\'s in it.

I was sitting in the airport on the way here, and a guy was giving one
of his friends some Aleve from a bottle of Aleve that he had and was
telling him, \"Yeah, my doctor told me that you\'re not supposed to take
that with something else, but I can\'t remember now what he said and
what a great doctor I have for telling me that.\"

And you know, if it\'s not on the bottles, you can refresh your memory
every time, you know, whatever the issue is. Then you can pretend that
it has never been mentioned.

Then I agree with having a warning on the bottle that there are other
products that also contain acetaminophen and that you need to only
combine them with a doctor\'s supervision. And I agree with there being
the specific mention of liver damage as the potential consequence.

The issues of dosing under age two have to be dealt with right away, and
again, I was happy to hear Byron suggest earlier that the same things
need to happen with prescription combination products that contain
acetaminophen. What\'s good for the goose is good for the gander.
Otherwise, you know, we\'re not really accomplishing our objectives.

I would argue against any kind of black box or Surgeon General\'s type
of warning that says that can cause liver damage or something because I
feel that that would cause more harm than good from a public health
standpoint.

And I would also recommend that while I think all of these things should
be done right now, there should also be implemented immediately a period
of study with specific mentions of what exactly needs to be studied with
regard to consumer behavior such that this can be an iterative process
since, as has been pointed out, we really don\'t know exactly how these
changes will impact on consumer behavior.

And that period of study and revision needs to be incorporated as part
of the plan.

In terms of the dosing by weight issue, you know, I share the concerns
that the dosagings are very confusing and inconsistent. I would
recommend that those issues be sorted out during that period of study
that follows implementation of label changes because I feel that those
are thorny issues; that if one had to make those decisions now before
implementing changes, those changes may never get implemented.

CHAIRMAN CANTILENA: Thank you.

Dr. Johnson.

DR. JOHNSON: I vote in favor of changes and, again, will be a little bit
reiterative. I think that a liver warning should be added, and it should
clearly be separate from the alcohol warning.

For drugs that are presented in blister packs, nd one of the examples
that went around was, I think that\'s usually going to be combination
products. I have a concern that people throw away the box even in the
blister packs, although maybe less often than with bottled drugs, and
often the blister packs have almost no information on them.

And so I think it\'s important as the example is shown there that it
does say \"contains acetaminophen,\" at a minimum, and preferably would
have all of the drug names, not just the brand name of the product.\"

For combination drugs, I think that it\'s actually quite unacceptable
that the rules are different and that the drug names don\'t have to
appear on the front, and I applaud McNeil for their efforts to change
that, and the examples provided has a statement, \"This product contains
X number of drugs,\" and I think most consumers have no idea how many
drugs are in those combination products, and then lists those all by
name.

And I think that that\'s something that should be considered as a
requirement as opposed to a voluntary step.

I think the prescription acetaminophen containing products are also
important, and I think auxiliary labeling for Rx products is going to be
really critical to getting the message across in a sort of complete way,
and therefore, education of pharmacists who are the ones who have to
stick those labels on the prescription bottles is going to be really
critical.

In terms of the warning, I think that it\'s important that the message
is not just overdose and instead says \"exceeding the recommended dose\"
because, again, if you say overdose, then people who aren\'t attempting
suicide will assume that that doesn\'t apply to them.

And so it has to be very clear either that it\'s both overdose and
exceeding recommended dose or just exceeding recommended dose.

And then finally, I think that we all sort of have to admit that the
information on the product probably doesn\'t do as much to educate
consumers as we\'d like, and so I think particularly TV advertisements
is probably really the way to educate.

And a couple of months ago I saw the NCPIE advertisement about my drug
has two products, and I was really impressed. And I will admit I\'m
probably not the average consumer in this regard, but I found it to be a
very, very effective commercial.

And I think if people saw that kind of commercial, it wasn\'t focused on
any specific product, but it gets a very, very important message. And so
I think that kind of approach is very important, and I think all of
industry who has these kind of products should support such efforts.

CHAIRMAN CANTILENA: Thank you.

Dr. Williams.

DR. WILLIAMS: I\'ll defer.

CHAIRMAN CANTILENA: We\'ll come back to Dr. Williams.

Dr. Uden.

DR. UDEN: The other Dr. Williams has left us.

I agree that we \--

CHAIRMAN CANTILENA: How do you mean?

DR. UDEN: I have his chair. That\'s all I know. I don\'t have to worry
about my wheels falling off anymore.

I agree with voting that you have to have label changes immediately. I
remember back in the early \'80s when I was managing many Tylenol
overdoses in pediatric patients and knew the literature very well to
read \-- and I\'ve been out of that gig for a while \-- but to read that
the unintentional overdoses could occur at median doses of around five
to six grams a day was very surprising to me.

Therefore, I agree with everything that\'s been said, that the names
have to be on the front with the concentration of the drug.

And I also am a very big fan of label comprehension studies, which are
multi-cultural, multi-literacy that would go along with this because I
don\'t think this OTC product has been \-- that that has happened with
this.

CHAIRMAN CANTILENA: Thank you.

Dr. Williams.

DR. HENRY WILLIAMS: I agree with the previously stated package labeling,
as well as the concerns about the various overdosing, as well as the
utilization of the alcohol warning as separate from the liver warning.

The concern that I have is a little bit on the other side of the
consumer. The concern that I have is associated with the labeling. It
says stop taking; ask your doctor.

The question I have is whether or not our doctors are informed with the
proper information about the product and whether or not we as
individuals in education should propose that this also have a health
care educational \-- health professional education component to it, as
well as the consumer education.

I hate to have a patient come to a doctor\'s office who has not been
sophisticated in the knowledge about the Tylenol risk and not being able
to identify it or even able to attribute other satisfactory marks to it.

So mine is education plus the yes.

CHAIRMAN CANTILENA: Okay. So your vote was that changes should be now.

DR. HENRY WILLIAMS: Right.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. Neill.

DR. NEILL: Yes, changes now. Put the name on the front of the pack.
Prescription drug should be subject to this as well.

The only substantive addition that I\'d want to make has to do with the
concentrations. In counting up the dosage forms for acetaminophen
available, I count eight, which include within them 24 different
concentrations or strengths.

The majority of that variation occurs in the pediatric forms. Some of
those are so close together as to be meaningless. And while it\'s true
the most commonly found strengths over the counter are going to be 100
milligrams per mL for the dropper, which isn\'t expressed that way;
it\'s expressed as 80 per .8 because the dropper is .8. I don\'t know
why, but it is.

And then there are solutions and liquids for older children which vary
in concentration, but can be had when expressed in the same per
milliliter concentration as the drops are in your 12 milligrams per
milliliter, 24, 32, 33.3, 33.4, 65 milligrams per mL. There\'s a 48
milligram per mL as well.

Why all of those are available, why they are \-- and I had to do a lot
of calculations to put those all in a common denominator because some
are expressed in per 15 mL. Some are \-- which is a tablespoon \-- some
are expressed as per teaspoon, which is five mLs.

I would have to remember that as a doctor, which I don\'t, and I\'ve
been doing this for 20 years now, why I would have to convert from .8
into mLs or mLs to five mLs or to 15 mLs is just beyond me. And you
know, if I can be confused, anybody is going to be confused.

The fact that I cannot reliably tell a parent over the phone, \"Go in
for your six kilogram child and give ten milligrams per kilogram,\" and
know what dosage form they are going to find in the shelf makes it
impossible for me over the phone to give a useful recommendation.

I may say, \"Go and get X brand,\" but if that costs twice as much and
there\'s a concentration which is similar, there\'s no good reason not
to use the other, but there are five different forms that are there.

So we need to reduce that variation in what the consumer sees on the
shelf and what I have to try and remember in the middle of the night.

CHAIRMAN CANTILENA: Dr. Patten.

DR. PATTEN: I will support making changes immediately. I certainly think
that all active ingredients should be listed on the front of the label,
the label of the package, and it should be on the label on the actual
container, including on the back side of the bubble packs.

I think that the size of the letters of the ingredients becomes an
issue. It needs to be easy for people to read, and I noticed something
in one of the packages going around, a very subtle kind of a thing.
It\'s the package that does list the ingredients on the front, but it
first lists the category and I think maybe that\'s it in cobalt blue,
and then you get an arrow that takes you to acetaminophen in a pale
orange against a pale yellow background.

And the human eye will be drawn to the cobalt blue and perhaps will go
no further. I think there\'s a good body of literature probably coming
out of the discipline of psychology taking a look at color and the way
the human eye works and is drawn. And I think maybe that there should be
greater attention paid to that so that the consumer will pay as much
attention to the active ingredient listed on the front of that label as
to the category that the ingredient addresses.

Another question I would ask, we see here in the Drug Facts over and
over \"do not exceed\" such-and-such a dose. \"Do not exceed,\" \"do not
exceed.\" And I\'m just wondering why instead the label doesn\'t say,
\"Do not take more than.\"

I think \"exceed\" is not a word that everyone uses as part of their
common vocabulary, but if you tell people not to take more than so many
tablets in a given period, it might be more useful.

And then since my job is to represent consumers, I\'ll just remind
everyone that not every consumer of OTC drugs has a doctor or has access
to a doctor, and I\'m not sure how labels can address that problem, but
certainly when all labels say \"or ask a doctor,\" \"see a doctor,\"
\"ask a doctor before this, that or the other,\" we have to take into
consideration all of those folks in this country that don\'t have access
to a doctor.

CHAIRMAN CANTILENA: Thank you.

Dr. Wood.

DR. WOOD: Well, I always worry about these signs at the side of the road
that say \"beware of falling rocks,\" you know. I\'m never quite sure
what to about that.

(Laughter.)

CHAIRMAN CANTILENA: You\'re supposed to drive faster, Al.

DR. WOOD: Right. You know, or when you pull down the thing on your SUV
and it says, \"This SUV may roll over.\" You know, I\'m not sure that
makes me feel much safer.

But seriously, I think there is a need for labeling changes right now,
and I think most of it has been covered. We should have a stick on label
for Rx preparations that looks the same. Somebody said they should all
be in the same color.

I think we should also though, given what we\'ve all articulated about
our concerns about lack of data go further than that, and I don\'t see
why the agency shouldn\'t, along with the manufacturer set a target for
risk reduction.

Why don\'t we set a target that says the number of overdoses from
acetaminophen should fall by a certain percentage by a certain period of
time, and that will encourage everybody to come up with a plan that
reduces risk.

I mean, you know, just think of the Resulin experience. We went through
all sorts of attempts to reduce the hepatotoxicity produced by that, and
they were not notably successful, and we were only addressing physicians
with that.

So I would like us to go further than just, you know, putting up signs
that say \"beware of falling rocks\" and encourage the agency to come up
with a risk reduction plan with the manufacturer that is testable and
that demonstrates some sort of results within some period of time. And
if the first situation doesn\'t work, then get back to the drawing board
and do it again, guys.

But we certainly have better data here on the number of people who are
getting hepatic failure from overdoses from acetaminophen than we\'ve
probably had with any other risk that we\'ve dealt with in prescription
drugs certainly, and we ought to be able to reduce this number lickety
split.

And the fact that we\'ve gone on for 25 years just kind of dickering
around, putting out more road signs doesn\'t seem to me a very
satisfactory outcome.

CHAIRMAN CANTILENA: Thank you.

Dr. Day.

DR. DAY: Well, I\'m in favor of labor changes now, especially about
dosing, and I\'m not so concerned about getting these things on. I think
we\'re going to vote for them, but I\'m very concerned about how we put
them on.

Yes, we can increase legibility and font size. Those are very standard,
human factors, principles that are well known, and we can rely on those.

Yes, we can enhance readability so the frequency of words in the
language and the sentence length or the bullet length can be adjusted.
We know about that.

However, we can do all of that and the information still may not be
cognitively accessible, and what I mean by that is the ease with which
people can find, understand, remember, and use the information. People
on this side of the table have already pulled out one good example of
how it might not work in some cases by subsuming the liver damage under
the alcohol warning.

So the principle there is chunking. You\'ve got to chunk together
different types of information and separate it out from information it
doesn\'t go with, and so I\'m very in favor a big supporter of the Drug
Facts format. However, it gets to be a bit repetitive, and I\'m not sure
that it will enable us to enhance some of the messages we want to
enhance unless we think outside of this box. It\'s a wonderful box, but
think outside of it for a moment and consider another cognitive
principle, and that is if you have the same information in two ways,
that increases the chances that people are going to get it.

And two effective ways are text and pictorial, and I\'ve made a little
pictorial diagram of dosing. So it\'s sort of a thermometer type thing,
and you can have number of tablets per unit of time going up like this,
and you have kids here, adults here, and a big cross-out here that says
you never take that much, and so on.

So whether it\'s this pictogram or some other pictogram, having both a
linguistic and a pictorial representation of the same information could
be to the advantage of the consumers.

Now, I know that industry will sometimes come back and say, \"Well, but
you know,\" and then you have to have these other pictograms. If you
enhance one part and then the other part might fall away and so on and
so forth.

So instead of having to put something out, try it and see what happens,
we develop alternative representations for the same information now,
test them quickly in a laboratory situation in a labeled comprehension
study where you test for multiple cognitive processes, such as finding,
understanding, remembering, and using; see which ones win; see if they
work across different populations with different literacy skills so that
people who don\'t read might understand the pictogram or people with
multiple language backgrounds. All of this can be found out in the order
of months.

This could be a study within one month, a set of them within six months,
and so then we know how to do it.

So I hope that today as we vote for things to be on the label, that we
will take into account that we really need to think hard and develop
alternative ways to do that and test them before they then go out into
the real world, and we can do actual use tests as well once the
laboratory tests are completed.

One final comment, and that\'s for the prescription medications. It\'s
great to have the pharmacist put on the auxiliary label. We\'ve done
research where we have the same patient, same drug, same pharmacy,
having gotten refills five or six times. Every single time there\'s
different labels on there.

DR. COHEN: Just let me just comment on that because you can standardize
very easily the way those labels are printed out if it\'s in the
computer system itself. In some of the pharmacies the chains are already
doing that.

So if you\'re using a combination ingredient, it automatically will
print out on the label in a standard way. So I just wanted to mention
that.

I would definitely vote yes. I think that the label changes are needed
immediately on the packages. I think it\'s really important that FDA
spend a little time looking at the best way to do this.

I think there needs to be a standardization. There needs to be a
standard font size. There might need to be a standard background, as I
said, to call out that information. You might need to use all upper case
text or something like that. I don\'t know exactly the best way to go
here, but it certainly can make a difference, and we\'ve seen that with
some other products recently where contrast was given. So that\'s
important that it be done and it be done in a standard way.

As I said earlier, and I agree with my colleague down at the other end
of the table about the statement \"call your doctor,\" it\'s just not
enough. It should also say \"call your pharmacist,\" as many of the
other products do that are over the counter now.

And I realize that some of these drugs are only available in
supermarkets and that\'s where they\'re purchased, but if people need
guidance and they need it in a hurry, the pharmacists are readily
accessible, and I know they\'re willing to help.

That said, I have to agree with Julie Johnson. We do need to educate the
health care practitioners. They are not all as cognizant as they should
be of the appropriate dosing.

I mentioned earlier the term droppers full being confused, and I think
that needs to be addressed with the dosing if we\'re going to have the
concentrated form with the dropper. Whether it\'s a color line or some
other mechanism, that needs to be addressed.

The idea of the safety lock, and they showed some evidence of its
effectiveness with the infant\'s concentrate Tylenol product, that not
being available with other manufacturers or with other products, I know
that this manufacturer McNeil does have a cough and cold product. It\'s
not available now, but they explained in our packet that it\'s because
it\'s not available in a suspension form. And it was my understanding
they might be reformulating it so that it\'s in a suspension form.

That\'s great, but I think any highly concentrated form should be
available in that packaging, and I think that should be part of it.

And then finally, again, I think this is ‑- I\'m sorry to repeat, but
this idea of expressing the concentration of the liquid formulations on
a volumetric basis rather than a metric weight basis is important per mL
or whatever the standard is so that you would be able to compare 32
milligram versus 100 milligram per milliliter, for example.

We\'ve had health professionals \-- at least one case I remember that
was reported to us \-- where an RN actually used the concentrated liquid
in a teaspoonful amount because of confusion with the amount of drug in
there. So I think that\'s important as well.

Thank you.

CHAIRMAN CANTILENA: Okay. Thank you.

And I vote yes for now, changes, and I will not, you know, reiterate a
lot of the things that have been said. I would like to compliment, you
know, McNeil on this new packaging. I think it\'s an excellent first
step and all of the comments that were made to improve I think, you
know, should be considered, but I think certainly an excellent first
step. That is very good.

Just one other thing to emphasize. If at all possible, standardize the
concentrations in an age group so that you don\'t have all of these, you
know, concentrations which are very confusing.

In my own household we have at least four different concentrations, and
I have to use a calculator when I dose my kid. Fortunately she doesn\'t
get sick that often. So good for her.

Anyway, Dr. Jenkins, I think, has a comment about, you know, dosing, or
Dr. Ganley.

DR. GANLEY: Yeah. I think it\'s worthwhile for us to just make some
comments on one of the issues as has been raised regarding the
citizens\' petition to include dosing for children under two years of
age.

We\'ve been working on this petition for the last two and a half years
or so, and it\'s not as straightforward as people think, and originally
the petition has to go down to two months of age, and after we research
the literature and prescribing practices and such, it turns out there\'s
a significant amount of bacteremia and serious infections in a
population of children with fever from two to six months of age.

And so that was one of the issues that we had to address, and you know,
again, that\'s based on our going out and collecting that information.

The other thing is that the proposal was to base it on weight or the
dosing on weight or age, and it turns out that the charts that would
have been proposed in that, there\'s no correlation and weight. And we
actually went to the CDC age-weight tables, and it\'s very difficult to
dose by age in that age group because the children are growing so
quickly.

And so those have been some of the things that we\'ve been struggling
with. There is actually a proposed rule written that\'s going through
endorsement clearance, and we\'ve actually incorporated some of the
comments that you already have made, such as standardized concentrations
and prominent labeling to distinguish concentrated drops from the
suspension, and actually possibly a measuring device that would be
included to that product, for that product.

Because, you know, when you think about, well, we just put the dose on
it, and whether it\'s teaspoonsful or whatever, well, a teaspoon is not
a standard measurement in a lot of people\'s houses, and so when you
start thinking about these things and think, well, we\'ll just put the
correct information on and everything will be fine, we already know
today, well, everything isn\'t fine if you think you have the correct
information on products for people over two years of age.

And so it\'s a much more complex issue, and we actually are asking for
information to support, you know, what the wording should say so that,
you know, we get it right for the population of six months to two years
of age.

But I think it\'s important to understand that, you know, we\'ve
struggled with trying to get this rulemaking correct, and there\'s a lot
of issues in it, and it\'s just not as straightforward as folks think.
But it is a priority to get done.

CHAIRMAN CANTILENA: Okay. Thank you.

What I\'d like to move to now is the issue of drug interactions and, you
know, disease states having an influence on, you know, the risk of
acetaminophen usage, and I\'d like to use the same format. I think the
last two issues can be dealt with a lot faster, but I think I would like
to hear everyone\'s comments on this particular one.

So we\'ll start on the other side of the table, and really the question
here as I\'ve formulated it: is there sufficient information to make
label changes concerning drug-drug interactions or, you know, disease
states, you know, malnutrition, et cetera, et cetera that we talked
about earlier at this time?

And if the answer is yes, if you would sort of specify, you know, what
you\'re comfortable with in terms of adding at this point, you know, to
the label and what you feel we have to have, you know, further
information on, so further study.

So again, we\'re just specifically focusing on drug-drug interaction or,
you know, disease states and whether or not we should alter the label to
include, you know, warnings for those specifically, and if yes, what
should be included in terms of what you\'re comfortable for; and if no,
then if you can specify the kinds of studies that you think would help
you get to that point, if ever.

And so if we can start actually with Dr. Cohen, then we\'ll go around
this way.

DR. COHEN: I\'m going to pass on that for now.

CHAIRMAN CANTILENA: Okay. Took you by surprise.

Dr. Day.

DR. DAY: I would favor having something on for drug-drug interactions,
for what our current state of knowledge is about that. For the
subpopulations, I think they vary across the ones that we\'ve considered
from people with compromised livers to malnutrition and so on, and I
haven\'t heard much data today about malnutrition and so forth. So I
think that that\'s a varied category, and I think we should hear from
everybody across those different subpopulations.

CHAIRMAN CANTILENA: Okay. Dr. Wood.

DR. WOOD: Well, I guess the decision is already made with alcohol. So we
should \-- I certainly don\'t think we should remove that if that\'s the
question.

In regards to the others, I\'m not sure that we have data to support
labeling changes at this stage, and I think that would have to be
deferred until people had a better understanding of what induces 2E1,
and in terms of malnutrition, while intuitively it might appear
reasonable, I don\'t think there are data that give us a sense of
whether the person who\'s dieting to lose, you know, weight to get into
their bathing suit is at risk versus somebody who has got some cachectic
state.

So I don\'t think we can make labeling changes that will be helpful to
people at this stage.

CHAIRMAN CANTILENA: All right. How about on the issue of drug-drug
interactions, you know, enzyme induction?

DR. WOOD: Well, the original Matthew chart that was shown early on
actually said you should treat people with the antidote if they were on
enzyme inducers, anti-convulsants specifically, at a lower acetaminophen
concentration.

Bearing in mind that we\'re talking about consumer labeling here, that
seems to me to be going beyond what we could reasonably expect people to
deal with, and so I wouldn\'t advocate that at this stage, except that
as knowledge becomes available, that might change dramatically.

CHAIRMAN CANTILENA: Okay. Dr. Patten.

DR. PATTEN: The decision is made with regard to alcohol, and I\'m
wondering. When you talk about drug-drug, are you also including the
acetaminophen-acetaminophen?

CHAIRMAN CANTILENA: No.

DR. PATTEN: All right. Then I feel that I must defer to the physicians
in the group with regard to a position on drug-drug interaction.

With regard to malnutrition, I agree with Dr. Wood. We heard very
little. I\'m assuming that that is certainly one concern regarding
people who are addicted to alcohol, the malnutrition of alcohol.

A question that comes to mind, given that between five and ten percent
of teenage girls and young women are involved in anorexia or anorectic
type behavior, I just raise the question if there is any kind of a
research database regarding liver toxicity and acetaminophen use in that
particular subpopulation. I don\'t know the answer.

CHAIRMAN CANTILENA: Thank you.

Dr. Neill.

DR. NEILL: No, I don\'t think that we\'ve heard sufficient data to
suggest a need for label changes, and that, in turn, I think, creates an
impetus to make recommendations about so how do we get the data, and you
know, the two most compelling sources to me today came from Dr. Lee and
from Dr. Erush, and I think that to the extent that every time we have
one of these meetings one of the questions involves what studies do you
want; how could they be done; I think some additional thought needs to
be put into that.

Both Dr. Lee and Dr. Erush are, you know, giving us data that comes from
patients presenting to hospitals, and we\'ve already heard how the
poison control data is perhaps over representative of a different type
of population. Somebody smarter than me needs to think about how to
improve the surveillance that occurs to look for specific types of
either drug-drug or condition specific factors that would help guide
labeling if that\'s what we want to look at.

CHAIRMAN CANTILENA: Dr. Williams.

DR. WILLIAMS: I don\'t think we\'ve had the information that we really
need to put that label on, especially with the anti-seizure medications
and the other medications that have caused reaction.

I think we do need the studies to specifically demonstrate whether or
not there is a dose relationship and whether or not the indication
should be placed there. So I\'d defer until studies are brought back.

CHAIRMAN CANTILENA: Thank you.

Dr. Uden.

DR. UDEN: I agree. Don\'t have enough information.

CHAIRMAN CANTILENA: Dr. Johnson.

DR. JOHNSON: Agree that there\'s not enough information, and I think
particularly for drug-drug interactions there\'s no compelling evidence,
and I think even from a theoretical perspective you\'d be a little hard
pressed to come up with really convincing drugs that would be likely to
interact.

CHAIRMAN CANTILENA: Dr. Katz.

DR. KATZ: In terms of the malnutrition fasting, I agree that we\'re not
really heard enough consistent data to put any specific warning about
that, nor is it clear to me how one would actually define that in a
consumer label.

And with the liver disease, I think it\'s the same, that we have not
really heard consistent information yet that states that if somebody has
whatever kind of liver disease that they\'re at increased risk.

And we have data from Dr. Koff and his experience and his consortium
that may mitigate to the contrary, although I think that that data could
be formally analyzed and it would be more persuasive that way.

In terms of drug-drug interactions, I would also defer to people who
know more about that than I do. The one that I\'ve read about that I
would put forth to the committee for discussion, is that I\'ve read that
in some patients, acetaminophen can increase coumidin effect and
increase prothrombin times.

I would ask people more knowledgeable than myself on the committee, you
know, how significant a factor that is, but that\'s certainly in the
pain management literature for both acute and chronic pain management.

In terms of what studies could be done to help clarify these issues as
we go forward, to me it seems clear that the next step beyond the K
series, which is what we have now, would be a simple case control study
of trying to identify, you know, whether and to what extent
acetaminophen is associated with acute liver failure or hepatotoxicity
and what other factors either combined with that or separately are also
associated and then maybe causally related with hepatotoxicity.

CHAIRMAN CANTILENA: Thank you.

Dr. Clapp.

DR. CLAPP: No, for the general reasons previously stated.

CHAIRMAN CANTILENA: Dr. Alfano.

DR. ALFANO: I\'ve seen no compelling information here today that would
warrant the change at this time in this area.

CHAIRMAN CANTILENA: Dr. D\'Agostino?

DR. D\'AGOSTINO: I don\'t see any compelling evidence also.

I think in terms of the studies, I mean, things like surveillance and
some of the cohort studies that exist, there are ways of getting a hold
of the population in terms of the use of these particular drugs as
opposed to doing it as a spontaneous reporting. Case controls and case
control studies and so forth I think are a real possibility and should
seriously be considered.

CHAIRMAN CANTILENA: Dr. Laine.

DR. LAINE: I would agree no because there is a lack of information to
support it.

I just would say that perhaps prospective observational studies from
cohorts of hospitals, such as Dr. Lee was doing with acute liver
failure, which could be sponsored by either governmental or industry
groups would be very reasonable to quickly \-- well, not quickly, but to
attempt to just try to get all patients presenting to the hospital with
acetaminophen overdoses would be very reasonable.

I\'d just point out that flying here there was a 757 patient in one of
our GI journals that looked at the effect of medications and outcome and
actually suggested that opioids, for instance, were associated with a
significantly worse outcome.

But if you had a large enough group of hospitals in the U.S. involved, I
don\'t know whether HICUP (phonetic) or some of the other national
databases do that now, but I would wonder if that\'s available now.

CHAIRMAN CANTILENA: Dr. Cryer.

DR. CRYER: Entirely agree with what\'s previously been said. Not
sufficient information to recommend additional risk categories, and
these are areas, however, for definite future research for specific
subpopulation evaluations.

CHAIRMAN CANTILENA: Dr. Lam.

DR. LAM: Based on the information that Dr. Slattery provided this
morning, I don\'t think we at this point in time need to worry as much
about SIP 1A2 and SIP 3A4, and I don\'t think we have enough information
about SIP 2UM modulation to actually require some sort of a labeling
change at this time.

CHAIRMAN CANTILENA: Dr. Davidoff.

DR. DAVIDOFF: Well, I would also agree that no is appropriate for now. I
would suggest though that there might very well be additional
information, important information to be found in areas that we haven\'t
really heard much about.

For example, genetic studies. I mean, if people are getting into
studying SNIPs now it seems to me it might be a very appropriate and
important thing to look at in the people who appear to be unduly
susceptible.

But that would be along with the notion of considering more seriously,
as I mentioned earlier, a multi-factorial model. It may be that the
mindset of looking for Subgroup A and then Subgroup B, which is
distinct, and then Subgroup C, each of them having a single risk factor,
isn\'t really going to give us the answers, and I would think that the
multi-risk factor model should be taken more seriously.

CHAIRMAN CANTILENA: Dr. Brass.

DR. BRASS: Since two colleagues mentioned the alcohol warning, I\'m
going to challenge that by asking where the number three drinks came
from.

(Laughter.)

DR. BRASS: And are we warning \-- does the three-drink warning mean
anything other than \-- so can anybody answer that question?

MS. LUMPKINS: Basically that three-drink number comes from the
recommendations of the American Heart Association as to what constitutes
sort of excessive alcohol use.

DR. BRASS: I was afraid of some answer like that because \--

(Laughter.)

MS. LUMPKINS: That was what we had.

DR. BRASS: You know, the relevance of that definition to any risk,
whether we believe there is one or not, you know, I\'m uncomfortable.
So, again, we don\'t have any data to change it, but I think we should
recognize that that is basically an arbitrary assessment and represents
one of the areas of need for clarifying this.

I\'m going to reluctantly agree that we don\'t have the data \-- well,
no, not reluctantly \-- sadly agree that we don\'t have the data to
change the labeling now, but based again on what we know about
acetaminophen\'s mechanism of toxicity, I feel viscerally that there is
a subgroup at risk, and we have not been able to identify it and,
therefore, can\'t warn them. But I think that makes it a little bit more
urgent in my mind that we work to define that population.

And I think there are three strategies that come to my mind. One has
already been mentioned. I think that a careful surveillance network
using standardized definitions, standardized collection techniques,
unbiased event adjudication might allow a lot of information to be
gathered very quickly about the populations we\'re talking about and
provide objective information.

Two, I think we can challenge some of the hypotheses that have been put
forth about risk factors and probe populations trying to identify those
outliers that may be a theoretical risk. My own concern again, as I\'ve
already alluded to, is that glutathione stores per body mass \-- I mean
per individual \-- are going to vary a lot, and just again intuitively
the petite female senior member of our society, not to be confused with
the little old lady, clearly has less glutathione than the typical NFL
football player.

And to say that therefore their risk threshold is identical just
doesn\'t make sense to me. So I think that there are technologies that
could be developed for noninvasively assessing glutathione stores,
probing 2E1 distributions, et cetera, that might challenge some of the
hypotheses and lead towards meaningful population subsets and obviously
can be combined with genetic work.

And the third, which is related to our previous discussion, is I think
we must understand fundamentally risk management strategies in the OTC
population. We do not have any guidance how to do this.

I mean, this is the same thing in our X population, I realize, but
we\'re talking about the OTC population, we\'re talking about problems
of risk management without any database to assess relative efficacy of
tools, effective interventions, et cetera, and I think research in that
area is desperately needed.

CHAIRMAN CANTILENA: Dr. Watkins.

DR. WATKINS: A couple of comments. First of all, I don\'t think it\'s
been mentioned, but the NIDDK, National Institutes of Diabetes and \--
Digestive Disease and Kidney \-- is that what it is? Okay \-- has put
out a request for awards for a hepatotoxicity network that will be three
to five clinical centers and a data coordinating center that I think
maybe along with the acute liver failure network will provide an
infrastructure to begin to analyze these questions.

And people have questioned whether it will be large enough and have
enough influence, enough patience to be any good, but clearly with
acetaminophen it will be good enough to get at, I think, a lot of the
epidemiologic questions just because the issue is so prevalent.

In terms of drug interactions and risk of hepatotoxicity, clearly there
is the ethanol issue. The difference over the last few years really is
\-- thanks to Dr. Slattery, there\'s a well worked out conceptual
mechanism, even a mathematical model that can be used to simulate the
extent of induction in P-450 2E1 and production of the toxic metabolite
as a function of blood level, of alcohol, and duration of exposure, and
that was more or less validated in the short study I showed you one
slide of that suggested drinking a typical bottle of wine over the
course of an evening would increase your susceptibility, in effect,
about 20 percent, 22 percent, statistically significant.

And although we\'d all agree that\'s a very minor amount of increase in
terms of susceptibility, the problem is the safety margin with the drug,
as we\'ve all heard today is quite, quite low. Even the data that we
were shown by Dr. Dart, I assume funded by the company, suggested that
somewhere in the range of ten grams per day, ten to 12 grams per day for
three days, which is about two and a half to threefold the recommended
doses, could cause irreversible liver injury in I think it was seven out
of the 42 people.

So a 22 percent increase, on the one hand, doesn\'t look very
substantial, but I think given the small exposure safety window, I think
that has to be taken seriously. So I\'m not sure where three drinks fits
in exactly, but I think three stiff drinks might correlate with a bottle
of wine.

And then the issue in terms of the adequacy of that warning. Obviously
if someone has a hangover at five in the morning and goes to their
medicine cabinet, they\'re not going to call their doctor, and even if
they did, it\'s not at all clear what that doctor or pharmacist would
tell them I don\'t think.

And the recommendation we heard, I think, in 1998 was to actually have
on the bottom reduced dosage, maximum 24-hour dosage, and that was
rejected because there was no data.

There\'s still no, of course, good data on that, but again, Dr.
Slattery\'s model does suggest the maximum induction you could get in
this model, which I think corresponded to drinking somewhere around 70
bottles of wine over a two-week period, was about a twofold increase.

So at least theoretically there would be a reason to consider adding to
that warning a reduction now. There\'s at least some theoretical basis
to reduce that, I think, possibly to two grams in that situation.

Now, in terms of other drug interactions, there\'s a lot of anecdotal
data that anti-seizure drugs can increase susceptibility to toxicity. We
heard from Dr. Slattery though that the studies he\'s done has not
supported that, and the qualification being these were small doses, 500
milligrams of acetaminophen, not much larger doses where some of the
other P-450s, like 3A4, might pick up the slack and begin to work.

But I would agree there\'s insufficient data to suggest a warning for,
say, anti-seizure drugs or other inducers right now. These studies that
have attempted to look at this carefully show that there is probably an
increase in clearance through the NAPQI, the reactive metabolite, but
it\'s offset by increased clearance through Phase 2 conjugation.

So the total amount that\'s produced is less, leading to the speculation
that maybe the effect of the drug wears off more quickly, making people
tend to take more than the recommended dose, in which case you could
then postulate a mechanism for increasing the total amount of NAPQI.

But at least right now I don\'t think there\'s any evidence or enough
evidence to suggest a warning for other inducers.

The only other drug that induces P-450 2E1 is isoniazid. There have been
a handful of cases of patients taking isoniazid who have gotten
acetaminophen liver injury apparently at doses less than 15 grams in a
24-hour period.

However, again, thanks to the work of Dr. Slattery, patients receiving
isoniazid actually have reduced 2E1 activity because of the substrate
inhibitor interaction. So you would have to postulate they would be risk
only when they stop taking isoniazid, and again, it gets confusing, and
I think right now there wouldn\'t be enough evidence to put a warning
for isoniazid treatment.

Now, the other two areas are starvation. That certainly looked
promising, and some of the initial association studies that came out,
but more recently that\'s not seeming to be a constant theme in terms of
susceptibility, and at least one study, Steve Shanker, the Spieg
(phonetic) study where they looked at moderate caloric restriction in
obese individuals sufficient to lose six pounds over a week, but not go
become ketotic. There was no evidence of altered metabolism or increase
in NAPQI.

So I also think that would be premature at this stage to consider a
warning for starvation or dieting.

And then finally, I don\'t think that although there was some apparently
convincing data shown of association with preexisting liver disease,
that really runs in the face of all the experience that hepatologists
have had with acetaminophen, where I think it\'s generally felt
acetaminophen is the safest of the analgesics that can be used in liver
disease, and that includes even very severe end stage liver disease
awaiting liver transplantation, where I think most hepatologists would
prefer acetaminophen in that situation, though they would reduce the
dose probably to two grams maximum in a 24-hour period.

And I think it would be doing a disservice if anything out of this
meeting went forward raising the possibility that people with
preexisting liver disease should avoid acetaminophen until we get more
data, perhaps through this network.

So I\'ll end there and pass the mic.

CHAIRMAN CANTILENA: Actually I just have a follow-up, if I may, Dr.
Watkins. If you were to or if a sponsor were to in an experiment with
humans show a comparable level of 2E1 induction to the high risk period
of alcohol, would you consider that a valid surrogate for, you know,
higher risk of a drug-drug interaction?

So if you did a drug-drug interaction with Compound X and you were able
to quantitate the induction of 2E1 and you were able to get it at the
same level as the vulnerable \-- you know, in a period with alcohol,
would that be in your mind sufficient to allow us to have that as a
drug-drug interaction on the label?

DR. WATKINS: I don\'t think that would be enough in and of itself, just
that observation, simply because the statement was made that whenever
anybody asked about anything else, that always comes back to 2E1, and
that\'s simply because we know the most about it. I think susceptibility
is also obviously related to glutathione stores and probably only
mitochondrial glutathione and other integrity issues in the liver.

And just that observation, I would be cautious without some sort of
other data, epidemiologic, to jump to the conclusion that there was a
risk.

CHAIRMAN CANTILENA: Okay. Thank you very much.

Dr. Wood, a comment on that?

DR. WOOD: Yeah. Paul, I\'m not sure I would agree. It would depend on
the data. I mean, I think if you had evidence of 2E1 induction and you
also had evidence that the same drug induced hepatotoxicity with
acetaminophen in animal model, which would be, you know, an afternoon\'s
work so that it wouldn\'t be unlikely that you\'d have that, I would
certainly if I was about to take both drugs \-- that would give me
pause, and I guess that\'s all you\'re trying to do in a label.

So it\'s hard to know how much further you could get than that. If you
had animal data to support it, which would be easy to get, and you had
evidence that you induced the pathway and produced increased amounts of
the mercaptopurine in the urine, that would be worrying to me at least.

DR. WATKINS: Well, I agree with that. I think part of the question was
though if the magnitude of induction was comparable to what had been
seen with ethanol, which is 22 percent. So we\'re talking about a minor
difference which I\'m willing to accept as important because of
additional clinical data that we have. It makes sense.

DR. WOOD: Right.

DR. WATKINS: As an isolated observation for such a small induction, I
think that would be a cause to really go after some clinical correlate
or some additional data. I\'m not sure that would be enough to jump to a
change in the label because, after all, ethanol probably is doing other
things, too, such as influencing glutathione stores.

But it\'s a debatable issue. No question.

CHAIRMAN CANTILENA: Okay. Very good.

Dr. Elashoff.

DR. ELASHOFF: I have two comments. Although most of the data we have on
risk factors or drug interactions is not very good, still I think
especially since we\'re interested in the possibility of multi-factors,
it might be worth doing some real in depth statistical analysis of
what\'s there, although that\'s not awfully likely to be really useful.
It\'s a lot cheaper than new studies and may give some hints as to what
ought to be done.

The second is if now or in the future some specific drug interaction or
state like the fasting state looks like it might be of concern, I think
we should not just say, \"Well, somebody should do some research.\" I
think we should put some teeth into that kind of recommendation, and
that such studies should be properly powered to really figure out what
might be going on and not just use a sample size that everybody else
uses in that kind of study.

CHAIRMAN CANTILENA: So your vote at this time is no for the label. Okay.

Dr. Cush.

DR. CUSH: I have nothing further to add. I also think that we need more
studies and more education, and I would underscore or second the
suggestion by Dr. Wood earlier about actually studying not only risk
factors, but an actual plan for risk reduction.

CHAIRMAN CANTILENA: Dr. Crawford.

DR. CRAWFORD: I vote in concurrence with what everyone else has said,
and there\'s no need to expand further because it\'s been so well
articulated primarily, but also because I think it would be difficult
for you to understand me through the chattering of my teeth.

(Laughter.)

CHAIRMAN CANTILENA: Dr. Furberg.

DR. FURBERG: At this time, no reason for change.

CHAIRMAN CANTILENA: Thank you.

I also vote no \-- oh, I\'m sorry. Yeah, go ahead, Dr. Cohen, and then I
will.

DR. COHEN: I wanted to vote no, and the reason for that was adding yet
more complexity to the label, and I wanted to, you know, have the
benefit of the discussion to make sure, but I didn\'t hear anything
either.

You know, we heard it before. Every time you take a step forward it
could be a step backward as well, and I think that was important to
consider.

CHAIRMAN CANTILENA: Thank you.

And I also vote no for the reasons that have been articulated.

DR. DAY: Could I clarify?

CHAIRMAN CANTILENA: I\'m sorry?

DR. DAY: Could I clarify my vote before when we were going around this
way?

CHAIRMAN CANTILENA: Oh, Dr. Day. I\'m sorry.

DR. DAY: I had said I voted yes for drug interactions. I was considering
alcohol and the possibility of strengthening that. I did not include
that other substances.

So given that it\'s been redefined in terms of the other substances,
then my vote is no.

CHAIRMAN CANTILENA: Okay. Yes, thank you.

In fact, right after you, Dr. Wood asked a clarifying question, and it
was not to include alcohol.

Okay. I think I have one more question that I think requires an
individual comment, and then the rest is fairly easy. And the question
for individual comment \-- and I guess we\'re starting over on this side
with Dr. Furberg this time \-- is regarding the total dose, total daily
dose, and the question is: based on what you\'ve heard and what you\'ve
understood and know, assuming equal efficacy is still maintained with a
reduction in total daily dose, do you see a reason at this point; have
you seen enough information that would allow you to recommend to FDA
that they consider lowering the total daily dose of acetaminophen
allowed to increase the margin of safety?

DR. KATZ: Just to be clear, that assumption is not correct.

CHAIRMAN CANTILENA: Well, the part that\'s complicated is if you
recommend \-- you really can\'t isolate safety, I mean, in the absence
of lost efficacy because when you lose efficacy, you\'re probably going
to use more, as has been suggested.

So I guess the question is trying to get at the issue of margin of
safety, and I thought we would isolate it by the assumption.

If others have another way to ask the question which gets at should we
increase the margin of safety \--

DR. LAINE: Can I ask a question?

CHAIRMAN CANTILENA: \-- I\'m happy to hear that.

DR. LAINE: Can I ask a question? What you\'re saying is if it\'s just as
effective at a lower dose? I mean, I don\'t understand. Why would
anybody suggest using the higher dose if the lower dosage was just as
effective in a drug in which we have some safety concerns?

I guess I\'m not understanding the question.

CHAIRMAN CANTILENA: Yeah, actually that exists with other drugs, for
example, because then, you know, your onset is shorter and you have an
advantage for, you know, marketing.

DR. LAINE: Well, there\'s a difference in efficacy somehow then.

CHAIRMAN CANTILENA: You know, time to onset, we\'re sort of, you know,
separating. I guess since we\'re here to advise FDA, I guess, should \--
Dr. Ganley, would it be helpful for us to address the issue of total
dose or would you rather not get advice in that area?

DR. GANLEY: Well, I think it was the way we had set it up originally was
in the context of the subpopulations, and Dr. Watkins had pointed out,
you know, that he thought a lower dose for the people with chronic
alcohol abuse would be appropriate.

Now, because when you think about it, you know, you have to \-- and I\'m
presuming you\'re saying that because it will give you a wider margin of
safety because we don\'t know if they\'re more sensitive to it, and it
seems that there\'s a fair number of individuals in many of the \-- you
know, Dr. Lee\'s, and the AERs, and the University of Pennsylvania\'s,
alcohol seemed to be a factor.

So if you\'re going to try to make it safer, and we don\'t know all of
these other factors, you could lower and say that the total daily dose.
The current recommendation to physicians now is just continue the four
grams a day dose.

And if we think it\'s not an issue of, you know, the total four grams
dose, and it\'s just that they\'re using too much, then we don\'t even
need to point out chronic alcoholism. We just need to point out you just
don\'t take too much. Okay?

But the issue is if they\'re a subpopulation that is at risk, okay, do
you lower the total daily dose? And that\'s what I thought you were
suggesting in your comments, is that they seem to be at risk, and it
seems that a total daily dose of two grams would be more appropriate
because otherwise if it\'s just an issue that people are misusing this
and using too much, well, it doesn\'t matter if you\'re a chronic
alcoholic or you have any of these other factors. It\'s just using too
much.

So that\'s sort of the rationale of, you know, getting into that
discussion, and that\'s what I thought you were talking about, is that
we don\'t really know what the answer is. These folks are more
sensitive. There are going to be some outliers that actually four grams
a day is going to be a problem, and we should just lower the total daily
dose, and I think that\'s what we\'re sort of trying to get some sense
of.

DR. BRASS: It seems having this discussion after our last round is very
difficult. I mean, I really do understand the question, and it\'s not
assuming equal efficacy. It\'s assuming that the safety no longer
justifies that.

But we\'ve just gone around the room and saying we don\'t know who that
subgroup is, and so without knowing who the subgroup is, I don\'t know
how to recommend who would get a lower dose. If I knew who the subgroup
was, that\'s who I\'d be concerned about, and, yes, I would try to keep
the dose lower than the proportionate reduction in their risk threshold,
but without identifying the subgroup.

And now, the alcohol is there, but since we\'ve agreed that \-- well,
I\'ve agreed \-- that the three-drink thing is completely arbitrary and
has no quantitative risk, you know, association with it, but I kind of
do think it\'s better than nothing, again, how to titrate beyond that
\--

DR. GANLEY: But what you\'re doing is, you know, we\'re deferring to
physicians, but not giving them any information of guidance, and the
only guidance that they\'re getting is from the manufacturers that are
saying take four grams a day.

Well, that\'s what a regular person without any risk factors would take.
Okay? So to me why do I even need an alcohol warning? I should just say,
\"Don\'t take more of this because it will cause some harm.\"

But if you believe that alcohol is a risk factor and that you want to
\-- you know, this issue of outliers, that some people may be more
sensitive at four grams if they have alcohol disease \--

DR. BRASS: Okay. So my answer to that would be so now we\'re talking
about really professional education, not the label indication. But I
would say (a) I want the person who\'s drinking more than three drinks a
day to talk to the physician whether or not they\'re taking
acetaminophen or not.

So that if this is the mode for them to get to the physician, I\'m very
happy.

CHAIRMAN CANTILENA: You\'re never going to get an appointment.

(Laughter.)

DR. BRASS: You just \-- well, no, I won\'t say that.

Two, there is a wide range of three drinks or more, and that a physician
might use that to make a very comprehensive assessment of the risks to
benefit in that kind of setting, again, using largely judgment because
that physician won\'t have any more information than we have, but we\'ll
integrate all of the information on an individual basis to make a
recommendation.

And how they interpret the existing data in the context of an individual
patient, I think, is a challenge, but is you know why they get the big
bucks.

And so I think that in terms of removing that from an OTC sphere is not
inconsistent with what was said about our lack of understanding of the
magnitude of the risk or how to manage it in the OTC setting.

CHAIRMAN CANTILENA: Okay. So I mean, how I was thinking about this is if
we can just focus on the alcoholics or the person over three drinks a
day. Would the committee favor or not reducing the total daily dose in
that specific population?

That\'s probably a little bit more focused. Is that what you were
thinking of, Dr. Ganley?

DR. GANLEY: Well, I think that gets back to, you know, what populations
you think are at risk and if you think alcoholics are at risk, and you
know, I don\'t disagree with what you said, Eric, but I don\'t think a
lot of physicians out there know the data on alcohol and, you know, the
interaction with acetaminophen.

And so we let them out there be floundering, and you know, we\'re not
conveying information to them, and you know, the manufacturers are, and
they\'re saying it\'s four grams a day. Well, that\'s what it says to
give anyone.

And so I think that\'s what we\'re trying to get out here. Should we be,
you know, saying that it should be lower than four grams a day in
certain subpopulations?

CHAIRMAN CANTILENA: Okay. Well, how about if we do this? The last
question specifically, you know, excluded the alcohol as a drug-drug
interaction. So let\'s just come back and ask the question whether or
not the population consuming three or more alcoholic drinks every day
should \-- it should be included in the label that their total dose be
less than four grams. And we\'re not going to come down to a number
obviously, but just that, you know, the information here to ask a doctor
is not sufficient to get to a safety zone, if you will, for over the
counter.

That\'s sort of what\'s implied in answering in the affirmative that
they should be labeled to have less than four grams. So I think that\'s
a little bit more clear and can be done, I think, relatively quickly.

So, again, I\'d like to start at this end, Dr. Furberg, and the question
specifically is: should individuals, the subpopulation consuming three
or more drinks per day, should their maximum allowable, you know, dose
of acetaminophen be less than what\'s currently allowed for the rest of
the population?

And yes or no, I think, is the way to go, and if you\'d like to comment
on it.

DR. KATZ: But just to be clear, are we still talking about the consumer
label that\'s on the bottle or are we talking about the actual \-- you
know, the PDR or are we talking about professional education? What are
we now asking?

CHAIRMAN CANTILENA: I was actually talking about the Drug Facts. So the
over-the-counter drugs.

Dr. Furberg.

DR. FURBERG: It would seem prudent to say yes.

CHAIRMAN CANTILENA: Okay. Dr. Crawford.

DR. CRAWFORD: Sorry. I have to vote no again for right now. I\'m
comfortable with the data that we\'ve been presented, and I just think
more information is needed.

CHAIRMAN CANTILENA: That\'s fine.

Dr. Cush.

DR. CUSH: I agree. I think more information is needed, and that\'s an
issue that needs to be studied better before it goes into the label.

CHAIRMAN CANTILENA: Dr. Elashoff.

DR. ELASHOFF: I haven\'t personally seen enough information to convince
me that the four grams a day as a recommended dose, especially given as
1,000 every six hours and then leaving you hanging for the rest of the
day, is based on any sensible, real efficacy studies.

For example, would you be better to take 500 milligrams every four hours
to even out the duration rather than worrying only about onset? And I
don\'t see any information on individual variability in what kind of
doses people really ought to be taking.

So personally for the whole safety issue, totally ignoring
subpopulations, I haven\'t seen enough real information to support the,
quote, recommended dose, unquote.

CHAIRMAN CANTILENA: Dr. Watkins.

DR. WATKINS: One thing that was very helpful in getting all of the
briefing documents was to understand the complexity of all the issues
involved and the idea that things that seem logical aren\'t always the
best in terms of long-term outcome and switching people from
acetaminophen to other potentially more dangerous drugs.

So ignoring that for the time being, I think, and assuming that four
grams can\'t be lowered and still be effective and useful in the general
population because that would obviously be desirable to go to two grams
in everybody and widen the margin from threefold to sixfold, it does
make sense to me in the one population that now I think everyone would
agree is at increased risk to recommend on the label a lower dose.

Now, whether that\'s, you know, three grams or two grams is, I think,
debatable, and what I would think would be to say do not take more than
two grams in a 24 hour period without consulting your physician or
perhaps pharmacist.

So that at least at five in the morning when someone is in their
medicine cabinet, there\'s some direction that gets them going at least
in relieving their pain.

But, again, I understand after reading all of this this is a complex
issue, and sometimes the big picture is not the same as, you know, my
view of it.

CHAIRMAN CANTILENA: Dr. Brass.

DR. BRASS: I remain a little bit confused because I think the current
label says, \"Do not use. Consult your physician,\" and I don\'t want to
then say, \"Do not use. Consult the physician, but if you insist, please
use a lower dose.\" That doesn\'t make sense.

On the other hand, I\'m sensitive to making sure of the public education
because certainly, again, I would hope that if a person like this
entered the health care system, the care would be individualized and
certainly on an individual basis using the least effective dose for that
person.

So you would not start therapy with that person at four grams a day, and
you wouldn\'t get the four grams a day without monitoring and
considering the alternative therapies.

So I think my answer is \-- I don\'t know what my answer is.

(Laughter.)

DR. BRASS: So is that a no or a yes? But that\'s my answer.

CHAIRMAN CANTILENA: Thank you, Dr. Brass. We\'ll come back when we
figure out what you\'ve said.

DR. JENKINS: Dr. Cantilena.

CHAIRMAN CANTILENA: Dr. Jenkins.

DR. JENKINS: I think it\'s important that we read what the alcohol
warning actually says because I think Dr. Brass maybe didn\'t get it
exactly right. What it says is, \"Alcohol warning. If you consume three
or more alcoholic drinks every day, ask your doctor whether you should
take acetaminophen or other pain relievers/fever reducers. Acetaminophen
may cause liver damage.\"

So it\'s not exactly that says, \"Don\'t use it.\"

DR. BRASS: Well, that may be one of those label comprehension things
because I \--

(Laughter.)

DR. BRASS: \-- because I thought the intent of that was not to use it.

CHAIRMAN CANTILENA: Right.

DR. BRASS: Whether it conveyed that or not, I don\'t know, but I
interpret the intent of that was not to use it.

DR. JENKINS: I think it can be interpreted by others that it\'s
permissive, that you should talk to your doctor, but it does not say
that you absolutely cannot use it.

DR. CUSH: But i also sounds permissive to using the drug as well.

DR. JENKINS: Yes.

DR. CUSH: Meaning using acetaminophen, which I think is sort of against
the intent. I would think it would be.

DR. NEILL: As if our putting on the label \"don\'t use\" for an
alcoholic who is told, \"Don\'t drink.\" Why don\'t we just put,
\"Don\'t drink\"?

(Laughter.)

CHAIRMAN CANTILENA: Well, that\'s the subject of another meeting.

DR. NEILL: Yeah, but it makes it easier to answer.

CHAIRMAN CANTILENA: Right. I think that we\'ve just enrolled the first
two subjects in our comprehension study of the label.

Dr. Wood.

DR. WOOD: You know, I have great concern about us punting this to the
physician. You know, I was just sitting here thinking of being in bed at
five in the morning and the phone ringing from some drunken guy, you
know, calling me up to ask me if he should take four Tylenol or two
Tylenol, and I can imagine what I\'d say, and it wouldn\'t wouldn\'t be
thinking about 2E1 activity or whatever.

You know, I think the whole concept actually is flawed. I mean, it goes
beyond this issue, and it goes back to this issue of risk reduction.

I think we are kidding ourselves if we think we\'re reducing the risk of
a drug by telling a patient who\'s standing in a pharmacy or standing at
their bathroom cabinet to call their physician, who has no concept of
this.

You know, here we have spent days reading, you know \-- my Federal
Express man practically died delivering this stuff.

(Laughter.)

DR. WOOD: And, you know, we\'ve been through all of that, and you know,
these great minds can\'t decide what to do, and yet we have utter
confidence that we can say to patients, \"Call your physician at five in
the morning and he\'ll tell you exactly what to do.\"

That\'s nuts. So, I mean, I think we should back away from these
warnings that make us all feel good, but in fact just defer the decision
to someone else who is certainly not as well read on this as the people
in this room.

So I think, you know, that makes me \-- you know, I laughed about the
rocks, you know, \"beware of falling rocks,\" but we\'re in the same
business here. So I think, first of all, I don\'t think we have data to
say what we should do with the dose. That\'s the first thing, and to
grab some number out of thin air certainly makes me very uncomfortable.

Somebody said already, you know, you ought not to drink, you ought not
to smoke, and you ought not to drive your car too fast, and so on. But
clearly coming up with some arbitrarily chosen number plucked literally
out of thin air has no possible basis, scientific basis, and nor does
asking your doctor to do that at five in the morning, you know, in God
knows where, Tennessee.

CHAIRMAN CANTILENA: Right, but the question is really for a lower dose
and not a specific number, you know, just to clarify that part.

Dr. Davidoff.

DR. DAVIDOFF: Well, I have at least as much discomfort \-- I would have
\-- saying either yes or no as those who have already spoken, but I
guess if I had to tilt in one direction or the other, and statisticians
are familiar with the notion of a trend as compared with a fairly
clear-cut statistical significance, I think I would trend to actually
including some indication of limiting the dose at least in people who
drink a great deal.

That\'s I think probably just a sense of being conservative. After all,
it seems the related question that kind of we started out with was how
much analgesic efficacy would be lost by doing that, and I think it
would probably be a moderate or modest amount would be lost.

So I think that the tradeoff seems reasonable to me from that point of
view.

We\'ve also heard that gastroenterologists at least anecdotally tend to
limit the maximum dose of acetaminophen they use in their Hepatitis C
patients when they\'re getting interferons, which kind of bolsters the
sense that this trend might be not inappropriate.

On the other hand, we\'ve heard that the French are raising the dose,
the maximum dose. But that\'s France.

PARTICIPANT: That\'s up to the U.S. level.

DR. DAVIDOFF: Up to the U.S. level, but they\'re going in the opposite
direction, in any event.

So I think if I had to say one thing or the other, I would probably say
yes, but with a lot of caution.

CHAIRMAN CANTILENA: Dr. Lam.

DR. LAM: Based on what we know about the mechanism of toxicity, I would
say theoretically yes, but practically I don\'t think we have enough
information for me to say do it now.

CHAIRMAN CANTILENA: Dr. Cryer.

DR. CRYER: Yeah, I entirely concur. It\'s a very, very concerning issue.
You know, when you look at Dr. Lee\'s database, there are 70 percent of
the people who had failure were taking \-- on acetaminophen were taking
four grams a day or less. And so, yes, we\'re concerned, and yes,
intuitively we say there should be some lower dose to decrease the
potential for toxicity, but we just don\'t have \-- this is not a data
driven decision, and we don\'t have sufficient information.

Additionally, in terms of how we uniformly apply this across
acetaminophen containing products becomes more concerned, more
problematic. What do you do with all of the prescribed products where
there are acetaminophen combinations?

And you would have to also implement the standard across the prescribed
products as well as the combination products. And so if the answer is
yes and if the answer is yes at a certain quantity, then you\'re also
going to have to have these discussions about how you do this across all
of these products.

So for now, although concerning, I would say no.

CHAIRMAN CANTILENA: Dr. Laine?

DR. LAINE: I equally have angst about this. One of the things I was
considering at least is under the alcohol warning saying something like
acetaminophen may cause liver damage when taken as directed or when
taken at full dose as directed, at the full doses, because somehow get
across the point it can happen, although I\'m not sure it will really
help that much compared to the typical alcohol warning.

So for that reason, although I considered that, I\'m going to go down
no.

CHAIRMAN CANTILENA: Dr. D\'Agostino.

DR. D\'AGOSTINO: I\'m going to say no. If I recall the efficacy studies,
and I remember reviewing them, there are a number of these. There is a
difference between the dose level, and you drop the dose now and they
get no effect. They start taking another pill to sort of catch up, and
so forth. You do get yourself in a spin.

We just don\'t have the data at this point. No.

CHAIRMAN CANTILENA: Dr. Alfano.

DR. ALFANO: So I don\'t vote, but the alcoholic warning as it says
\"alcoholic warning,\" and I don\'t know about most of you, but I\'ve
been in social settings where over a dinner people have said, \"I guess
I\'m having wine tonight. I have a headache, but I\'m not going to take
my Tylenol.\"

So it does have some impact. Admittedly that\'s not focused at the
alcoholic, and I give physicians a little more credit for being able to
guide their patients not necessarily to a specific lower dose of two
grams or three grams, but to use it wisely, to use it sparingly, which
is typically what would play out.

So I don\'t think it\'s bad at all the way it currently exists.

CHAIRMAN CANTILENA: Dr. Clapp.

DR. CLAPP: Dr. Lam expressed my sentiments, and as well, I have concerns
about the confusion with the dosing. If you\'re reducing it to two
grams, are then we advising our patients who drink to take one 500
milligram every six hours, or are they going to take two every 12 or,
you know, are we going to get more specific with a dosage that we expect
will be efficacious in a patient who has alcoholic liver disease?

It\'s getting a little confusing.

CHAIRMAN CANTILENA: Dr. Katz.

DR. KATZ: I vote no for lowering the dose recommendations for that or
any other particular subgroup for the reasons that everybody mentioned.
The only one that I\'ll add is that what I think many of us are
forgetting is there\'s a fair amount of interindividual variability in
the dose response curve to acetaminophen and all other analgesics, and
there are a fair number of people out there who need higher doses than
four grams a day of acetaminophen, and that\'s the right thing to do in
those patients, and they do fine.

And the whole concept that I\'ve heard mentioned a number of times today
of acetaminophen having a narrow therapeutic window makes no sense to me
whatsoever. I mean, given all of the exposures that are out there, if
acetaminophen has a therapeutic window, what about all the other
medications that we use? It clearly has the widest therapeutic window of
any of our alternatives for analgesia. The only thing that has a bless
of a \-- has a wider therapeutic window is leave the patient suffering
in pain.

So I personally think that we should not make dosage reductions, and I
think that even in professional education we should also take pains to
tell physicians that many patients have mainly to increase the dose
beyond four grams a day.

CHAIRMAN CANTILENA: Dr. Johnson.

DR. JOHNSON: I would vote no for changes on several grounds. One, I
agree with Dr. Brass that there\'s a certain amount of illogic in
advising them something that suggests not to take it until they call
their physician, but then giving them a dose maximum if they\'re going
to take it.

If we did want to do that though, I don\'t believe we have any data on
which we would make a decision about what that dose maximum should be,
and I think telling them to take less than four grams without a specific
dose also provides no information because less than four grams is 3.99
grams. That is okay.

So I don\'t think that just saying less than four grams would provide
information that would be valuable to anyone.

CHAIRMAN CANTILENA: Dr. Uden.

DR. UDEN: Sine apparently it\'s okay to have arbitrary information on a
label, I think I\'ve solved this. If you drink 12 drinks a day, it\'s
one gram maximum; six drinks, it\'s three grams; three drinks, it\'s \--
yeah, six drinks, it\'s two grams; three drinks, it\'s three grams; and
if you drink one drink a day it\'s four grams.

I have to abstain from voting. I don\'t have enough information going
from one to the other.

CHAIRMAN CANTILENA: Dr. Williams.

DR. HENRY WILLIAMS: Without the specific calculations I vote no also.

CHAIRMAN CANTILENA: Dr. Neill.

DR. NEILL: No.

CHAIRMAN CANTILENA: Dr. Patten.

DR. PATTEN: I would vote no, except I would also say that I think that
the alcohol warning as stated here is a bit confusing. When it says,
\"As your doctor whether you should take acetaminophen or other pain
relievers/fever reducers,\" that could be interpreted two different
ways.

I have to ask my doctor whether I should take acetaminophen or whether I
should take other pain relievers, or I should ask my doctor whether I
should take acetaminophen or any other pain reliever.

In other words, are they all presenting the same potential risk as
acetaminophen? So I suggest that the warning as stated be thought
through a little more carefully even if we\'re not going to enter
information on suggested lowered dose.

CHAIRMAN CANTILENA: Okay. Dr. Wood, do you have any further comments?

DR. WOOD: No.

CHAIRMAN CANTILENA: Dr. Day?

DR. DAY: I vote no, but I\'d like to add some other reasons why, and
that is if you put different dosing information up under warnings, then
you have dosing in two areas in the Drug Facts label, both in the
warning section and the directions section, and you could get into the
problem of the person at 5:00 a.m. in the medicine cabinet who\'s not an
alcoholic pulls it out and sees that and takes that dosage.

I did want to inquire on other OTC labels are there different dosage
levels for subpopulations, such as alcoholics, and if so, what\'s been
the experience with that? Do we have any evidence?

CHAIRMAN CANTILENA: The only one that I\'m aware of is napersin
over-the-counter in elderly has a different interval.

DR. DAY: Right. So we have it for age. So we\'ll have it for age across
a number of situations, but not for populations, such as we\'ve been
talking about today.

CHAIRMAN CANTILENA: Not that I\'m aware of.

Dr. Ganley, any?

Dr. Cohen?

DR. COHEN: No, not without more information, and I think the warning
that\'s there currently, it\'s a pretty good signal of you need to do
something with the dosing if you\'re drinking. So without more
information, I don\'t think so.

CHAIRMAN CANTILENA: Okay. A comment from Dr. Neill?

DR. NEILL: Just a comment about categorization as an alcoholic. My
understanding is that patients ought to \-- in order to choose a
medicine for OTC use \-- ought to be able to self \-- recognize the
condition that they\'re treating and self-select, and I\'m unaware that
patients that I may diagnose with alcoholism can self-select.

So regardless of how we vote, within the real world of FDA deciding
about the applicability of the label, simply putting it on the label
won\'t allow patients to self-select in that way.

CHAIRMAN CANTILENA: Okay, and I also vote no for the reasons stated, but
I share Dr. Wood\'s, you know, concern with the alcohol warning label
and its ultimate effect and outcome.

Okay. To expedite things, let me just say when we turn our attention to
what was discussion point number three with the combinations, does
anyone not agree with the recommendation that any information in terms
of ingredient identification should be also in the Rx combos clearly for
the consumer? Is there anyone who feels otherwise?

Okay. Very good. So everything that we said about that will apply to the
Rx combos in terms of total dose and recognition of ingredients.

The other area that I wanted to touch on briefly, and we could just do
this very quickly, to advise the FTC and get comments from the members
concerning things that they think should be included in direct to
consumer advertising sort of in the spirit of, you know, the fair
balance statements that occur at the end of the Rx DTC.

Is there anything specific that you would like to be included in that to
warn, you know, patients?

We\'ll just open it up so that we don\'t go around the table again. Dr.
Cush.

DR. CUSH: Not that I would want anything additionally included. I think
the content of what\'s been said should just basically fall under the
same directives regarding DTCA for prescribed products, and this should
be overseen by the FDA and DDMAC and whoever ultimately might be
appropriate.

CHAIRMAN CANTILENA: Any other comments on advertising, marketing for our
FTC?

Dr. Cohen.

DR. COHEN: I know I mentioned it a couple of times, but I really am
concerned about the use of a brand name throughout a product line when
there are different ingredients from one item to another to another, to
another.

I think that\'s caused a great deal of confusion not just with
consumers, but also with health care practitioners, and I think it would
be worthwhile.

I know I\'ve seen those ads, public service ads, that NCPIE was running
as well, and I thought they were outstanding. That could be the subject
of one of them.

CHAIRMAN CANTILENA: Dr. Wood.

DR. WOOD: I think there should be some warning of not to take whatever
the product is being advertised with other acetaminophen containing
products, and that should be explicit because that seems to be an
obvious source of risk.

CHAIRMAN CANTILENA: Dr. Ganley?

DR. GANLEY: Can we just do making the assumption that FTC may not have
the authority to make them do that? Okay? And so the issue here is one
either of a legal issue or what you think the responsibility of the
manufacturer is.

I mean, I think it\'s unfortunate that we have to do everything by
regulation here, and it\'s not based on what is the right thing to do or
what\'s the wrong thing to do or somewhere in between. But I just don\'t
think that we should just operate like that.

You know, if the FTC may not have any ability to make them do it, and so
going around like this is not going to necessarily be very helpful. But
I think the issue is, you know, what should companies do.

As I said, if they don\'t have the authority, it may require not just a
regulation, but a law. Okay? So I think the issue is what would you like
companies to do, and then we can translate that into something of
whether it should require some regulation.

But to say that FTC should do this is not, I think, the approach to
take. It\'s what do you think companies should do.

CHAIRMAN CANTILENA: Okay. So should we translate the comment then to a
vote? You know, would that help in terms of, you know, as an action item
from the Advisory Committee or \--

DR. GANLEY: I think, you know, the issue is if you think \-- you know,
it gets between this issue of how do you educate consumers. Is it
through advertising or do you have different educational campaigns?

And so if you think it\'s through advertising, then you should be
telling the companies, well, this is how we think you should be
educating consumers also.

I think advertising is education for many consumers, and so I think
that\'s really, you know, we\'re talking about consumer education and
physician education, but one mechanism in education is the advertising.

So I think that\'s how it has \-- if we\'re going to, you know, make
comments on that, it\'s, you know, in the broad sense of education. Do
they go out and just support the efforts of NCPIE or is it \-- you know,
all of the efforts of NCPIE may not make a difference if the advertising
doesn\'t change then, too.

CHAIRMAN CANTILENA: Dr. Wood.

DR. WOOD: Charles, I think the way maybe to handle it would be to say
the following, that we talked earlier about the FDA and the company
having a joint responsibility to reduce the instance of overdoses from
acetaminophen within some defined period, and you ought to come back
here, you know, meaning to the world at large and tell us how you\'ve
done.

Now, I think if the company and the FDA come up with an action plan to
get that done that includes these things, then the companies involved
are likely to be cooperative to do that.

If you come up with some better plan that works just as well, then
that\'s fine, but I think the bottom line here ought not to be this
focus on, you know, which things we\'re going to dicker with rather than
recognizing that really the bottom line is reducing the instance of bad
outcomes, and that we ought to expect some deliverable to be actually
delivered, and that that\'s the way to get pressure on it.

CHAIRMAN CANTILENA: So, Charlie, if I can just try to pin you down, in
terms of this issue of education and the sponsors of the industry
responsibility, would it be more helpful for FDA if we voted on the
sorts of emphasis that we think should be included in these programs? Is
that probably more helpful?

Okay. Then lets craft a question, and I have to admit I\'m starting to
run on empty. Let\'s see. I guess the question should be \-- please.
I\'m on empty.

DR. CUSH: That we recommend that the revisions that have been accepted
thus far as they pertain to packaging and display, format and wording
should also be equally extended to all advertisements both in print and
media. So that would include recognition of the actual name of the
product that\'s included. This product contains acetaminophen. That the
cautionary wording that\'s included, that, you know, if you\'re an
alcoholic or there should be caution about using this with combined
products, et cetera, et cetera.

But basically the recommendation we made be extended and included in all
print and media advertisements.

CHAIRMAN CANTILENA: Okay. So any discussion on that? Dr. Johnson.

DR. JOHNSON: I would agree with that. I guess the one concern I would
have or the one approach I would take with this is that we not focus
just on acetaminophen, but that for all of the over-the-counter
products, that the risks of those products should be sort of on display
just like they are for the Rx products so that it\'s not just an
acetaminophen issue.

Because all of the OTC drugs have certain risk, and so I think it\'s
something that if it can happen, if that can be sort of enforced, it
should happen for all OTC drugs.

DR. CUSH: But the problem with that is that those rules, you know,
regarding a brief summary as indications and then all of those, you
know, common side effects and bizarre side effects, those right now only
apply to, by rule, to prescribed products. I don\'t know if we can
extend that without changing legislation and internal rules to \--
without major effort \-- to these over-the-counter products.

DR. JOHNSON: Right, but I mean, I agree with that, but I also would
argue that if that\'s true, then it can\'t be changed for just
acetaminophen. Those rules won\'t be changed just for acetaminophen.

So it would sort of either need to be across the OTC class if there was
a rule change. It would seem the only logical way to do it.

CHAIRMAN CANTILENA: Okay. Well, in approximately 14 hours, we\'ll be
talking about another class of drugs. Any other comments?

DR. JENKINS: Dr. Cantilena?

CHAIRMAN CANTILENA: I\'m sorry.

DR. JENKINS: If I can make a suggestion, we\'re kind of bridging into a
very unusual area here because this is an Advisory Committee to the FDA,
and we\'ve already acknowledged that FDA does not regulate the
advertising of these over-the-counter products.

We don\'t have anyone from the FTC here to articulate their boundaries,
their regulations, their rules, and I think it might be better if the
committee has ideas about educational efforts or things you might like
to see sponsors do in their advertisements, maybe you could articulate
those, but I don\'t really think we need to have a vote on specific
recommendations because it\'s kind of out of context. We don\'t have the
right people here to help us understand the context that we can work in
from the FTC.

CHAIRMAN CANTILENA: Right. Yes, thank you for that perspective.

I had asked early on this afternoon if there was a mechanism in place
where the information or the recommendations from our group can find
their way back to the FTC, and that\'s why we\'re going to have this
conversation.

But I guess if you would prefer that we just open it up to general
suggestions, then I\'m fine with that.

DR. JENKINS: But I think at issue here is that even though that\'s sort
of not part of the rules, we\'re questioning the rules. We\'re saying
that it should fall under the purview of the FDA to oversee how these
drugs are marketed and advertised.

MR. GALSON: Let me just say something. Not to disagree with you that
that\'s not the point, but that\'s the sort of determination that
Congress makes, that kind of question, and you\'re not advisory to
Congress.

It\'s fine to talk about it, but it\'s not going to do any good really.

(Laughter.)

MR. GALSON: So it \--

DR. CUSH: Well, I could start here and then work our way up.

(Laughter.)

MR. GALSON: No. I\'m trying to have you all be as focused and effective
as possible. The most effective thing you can do is make recommendations
to the agency about things that are within our purview.

CHAIRMAN CANTILENA: Okay. Well, we have two choices. We can vote on
whether or not to vote or we can just make recommendations or we can go
on to the next topic, but I understand your point of view.

Dr. Brass.

DR. BRASS: Yeah. I think this is really straightforward. I think it has
been a consistent theme throughout the discussion that there are
critical areas that are sources of problems, and that clearly a major
component of any risk reduction effort hopefully assessed over time is
going to be education, education of consumers, education of health care
professionals, broadly based, and I think simply acknowledging that
theme without recapitulating all of the specifics I think might be
sufficient.

CHAIRMAN CANTILENA: All right. Well, how about at the risk of, you know,
wasting our time, if the question were posed such as would all of the
recommendations we\'ve made for the reduction in risk in terms of
labeling and programs \-- are you in favor of having those apply to
advertising and consumer education if possible? Is that something that
you would vote in favor of?

Is that \-- Dr. Wood?

DR. WOOD: Would it be reasonable to suggest that we invite the FDA to
explore with the colleagues at the FTC how something like that could be
implemented as a recommendation, rather than a recommendation to the
FDA?

CHAIRMAN CANTILENA: Yeah.

DR. WOOD: Would that get everybody off the hook?

DR. JENKINS: Yeah, we would be very happy to share with our colleagues
at the FTC, who I think Dr. Bull mentioned earlier we do have mechanisms
to interact with them, some of the thought that you have.

Again, the reason I think I would like to avoid or make the
recommendation that you don\'t take a vote is we don\'t have the
knowledge they have about the boundaries in which they work. We
understand the boundaries under which FDA works. We don\'t understand
the boundaries under which FTC works.

I think it would be best that you help us understand what your concerns
are, and we can relay those concerns. I would give as an example even
the prescription drugs, when they advertise, they don\'t disclose every
risk associated with the drug. They disclose or are required to disclose
the most important risks.

So there\'s judgment involved. There\'s a lot of fine detail that goes
beyond just making a recommendation that everything you\'ve recommended
for the label be included in every advertisement. That may be a very
expansive recommendation.

CHAIRMAN CANTILENA: Just a couple more comments, and then we\'ll
actually come to closure on this what I thought was an easy topic.

Dr. Cush.

DR. CUSH: What better way to offer an opinion than to have a vote from
the whole committee? And what better way to educate than to sort of
direct a marketing effort?

CHAIRMAN CANTILENA: Dr. Alfano.

DR. ALFANO: Let me try to offer a little bit of perspective and actually
read something that is a briefing document from CHPA, and it\'s some
comments on the Federal Trade Commission oversight, and I\'m actually
going to read it because presumably lawyers put this together.

The Federal Trade Commission uses three basic regulatory standards or
policies to address consumer advertising:

One, reasonable prior basis, prior substantiation policy under which FTC
requires objective claims, express or implied, to be supported by
adequate documentation. FTC typically looks to FDA determinations or
works with FDA to address OTC advertising issues.

The second two are probably more relevant to the issue at hand. The
first part of this is deception policy, which is based on material
representations, omissions, or practices likely to mislead a consumer
acting reasonably under the circumstances.

And the third policy is the unfairness policy, which defines unfairness
as acts or practices likely to cause substantial injury to consumers and
that are not reasonably avoidable by consumers themselves or outweighed
by benefits to consumers or businesses.

There\'s another CHPA piece which really does endeavor to explain why
the advertising piece is regulated by the FTC as opposed to the FDA, and
the premise is \-- you might disagree with it \-- but the premise is
that they regulate all consumer advertising, and that there\'s a benefit
to the consumer overall that advertising has a consistency to it in
terms of the way material is presented, whether you\'re talking about
food or cars or drugs.

And so that\'s why I believe Congress at some point in its wisdom or not
elected to separate those things.

Another perspective is that, you know, the warnings, the true
information that the patient is to use has always been delivered via the
label. That\'s the primary purpose of the label.

Advertising has a different purpose. Advertising is designed to
introduce people to new products and to allow for brands to be
differentiated in one way or another.

And so probably not too many of you saw this, but if you try to do too
much in an ad, you run into the situation that exists now in some of the
Rx ads that are on television, which led to one of the funniest
\"Saturday Night Live\" skits I ever saw in which they talked about some
fictitious drug, and there was bucolic scenes of the drug making you
wonderful and people romping through the woods or whatever, and then
they read the side effect profile.

And I remember two of them. The first side effect was seeing the dead
and the second side effect was a condition known as hot dog fingers.

And the point is this is society reacting sometimes to overkill on the
label, and we could end up \-- or the advertising, as the case may be
\-- with de minimis benefits to the consumers because we\'ve so
overloaded them in the desire to try not to leave anything out.

Finally, earlier I pointed to the success with Reye\'s. We reduced \--
and this was a team effort on the part of the industry, FDA, and the
reporters, the reporters in the room. Reye\'s went down not simply, in
my opinion, because of the labeling. There was wonderful consumer
advocacy involved at the time.

My recollection is there was nothing in the ads. Okay? It was the Jane
Brodys writing in [The New York Times]{.underline}. It was the [Good
Housekeeping]{.underline} articles that, you know, thoughtful parents
read so as not to make that mistake in the future.

And that\'s a model that could be very helpful here. I don\'t think
advertising is the way to effect these changes.

CHAIRMAN CANTILENA: Okay. Thank you.

Just to get really to closure then, I guess what I suggest we do is just
say does anyone disagree with the recommendation that FDA consider
and/or the sponsors, the industry, work toward applying some of the
recommendations and thoughts we\'ve had toward labeling into consumer
education and health care, you know, education.

Does anyone object to making that statement? We\'re avoiding the vote
and we\'re not specifying a pathway. We\'re just expressing a desire
globally.

DR. CUSH: And we\'re not specifying advertising either.

CHAIRMAN CANTILENA: Right. Well, you know, consumer education.

DR. CUSH: But I think we spent most of today talking about education,
and everybody agreed that was what we need to do. So we don\'t even need
a vote on that.

CHAIRMAN CANTILENA: Okay. Well, actually we\'re not voting. I\'m just
asking if anyone objects.

Dr. D\'Agostino.

DR. D\'AGOSTINO: We don\'t want to lose the educational aspects and so
forth and get that carried away or get that mixed in with the
advertising because we\'ve been very forceful in the past as a committee
in terms of making recommendations for education, and we\'ve been saying
that all along.

So really I think this is really sort of the sort of advertising that is
at issue, not the education.

CHAIRMAN CANTILENA: So you would prefer that we specify that these
recommendations, et cetera, be translated to advertising and consumer
education.

Does anyone not agree with that? Should we include advertising and
consumer education in our recommendation?

Okay. Hearing no nays, then I think we shall ask FDA if they\'ve had
enough advice for the day.

(Laughter.)

CHAIRMAN CANTILENA: I won\'t ask the committee if they\'re ready to
adjourn, but I will ask Dr. Jenkins, Dr. Ganley, Dr. Bull. Any other
areas that you seek?

DR. JENKINS: I think we\'ve gotten very good advice and information from
the committee today. The only area that we didn\'t specifically go
around the room for was the issue of additional studies needed, but I
think you\'ve covered much of that in some of your answers to other
questions.

So unless people had specific additional suggestions for additional
studies they think needed to be done that haven\'t been addressed
already, I think we\'ve gotten the information needed from the committee
today.

CHAIRMAN CANTILENA: Okay. Are there any specific areas or types of
studies that have not been mentioned that you\'d like to suggest?

(No response.)

CHAIRMAN CANTILENA: Okay. Hearing none, everyone, thank you very much.
Thank the sponsors. Thank the FDA staff.

We will reconvene tomorrow at 8:00 a.m.

(Whereupon, at 5:53 p.m., the meeting in the above-entitled matter was
adjourned, to reconvene at 8:00 a.m., Friday, September 20, 2002.)