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:
LOUIS CANTILENA, M.D., Ph.D., Chairman
SANDRA TITUS, Ph.D., Executive Secretary
LESLIE CLAPP, M.D., Member
PRESENT (Continued):
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:
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:
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:
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):
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
Dr. Debra Bowen 94
Dr. John Slattery 100
Dr. Richard Charles Dart 114
Dr. Raymond S. Koff 126
Dr. Anthony R. Temple 130
Wyeth
Dr. Stephen Cooper 139
Bayer
Dr. Allen H. Heller 144
GlaxoSmithKline
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.
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. 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 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 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, 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.
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 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