Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Required Warnings and Other Labeling, 77314-77352 [E6-21855]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 71, Number 247 (Tuesday, December 26, 2006)]
[Proposed Rules]
[Pages 77314-77352]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E6-21855]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 343

[Docket No. 1977N-0094L]
RIN 0910-AF36


Internal Analgesic, Antipyretic, and Antirheumatic Drug Products 
for Over-the-Counter Human Use; Proposed Amendment of the Tentative 
Final Monograph; Required Warnings and Other Labeling

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its over-the-counter (OTC) labeling regulations and the tentative final 
monograph (TFM) for OTC internal analgesic, antipyretic, and 
antirheumatic (IAAA) drug products to include new warnings and other 
labeling requirements advising consumers about potential risks and when 
to consult a doctor. FDA is also proposing to remove the alcohol 
warning in its regulations and add new warnings and other labeling for 
all OTC IAAA drug products. The new labeling would be required for all 
OTC drug products containing an IAAA active ingredient whether marketed 
under an OTC drug monograph or an approved new drug application (NDA). 
FDA is issuing this proposal as part of its ongoing review of OTC drug 
products after considering the advice of its Nonprescription Drugs 
Advisory Committee (NDAC) and other available information. FDA is 
proposing these labeling changes because it has tentatively concluded 
they are necessary for these ingredients to be considered generally 
recognized as safe and effective and not misbranded for OTC use. FDA 
will address information about the cardiovascular risks of nonsteroidal 
anti-inflammatory drugs (NSAIDs) that was discussed at a February 16-
18, 2005, FDA advisory committee meeting, and the ``Allergy alert'' 
warning for NSAID products, in a future issue of the Federal Register.

DATES: Submit written or electronic comments, including comments on 
FDA's economic impact determination, by May 25, 2007. The specified 
comment period is longer than is normally provided for proposed rules. 
Because of the complexity of the proposed rule, FDA is providing an 
additional 60 days (beyond the normal comment period) for comments to 
be submitted and does not plan to extend the comment period beyond this 
date. Please see section XV of this document for the proposed effective 
and compliance dates of any final rule that may publish based on this 
proposal.

ADDRESSES: You may submit comments, identified by Docket No. 1977N-
0094L and Regulatory Information Number (RIN) 0910-AF36 by any of the 
following methods:
Electronic Submissions
    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://www.fda.gov/dockets/ecomments. 
Follow instructions for submitting comments on the agency Web site.
Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No. and RIN for this rulemaking. All comments received may 
be posted without change to https://www.fda.gov/ohrms/dockets/
default.htm, including any personal information provided. For 
additional information on submitting comments, see the ``Comments'' 
heading of the SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to https://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Marina Chang, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD, 20993-0002, 301-796-2090.

[[Page 77315]]


SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
II. Background
    A. Development of OTC IAAA Drug Product Warnings
    B. Completion of the OTC IAAA Drug Products Final Monograph (FM)
III. NDAC Meeting
    A. Data and Information Reviewed
    B. Acetaminophen
    C. Aspirin and Other NSAIDs
IV. Additional Data and Information FDA Reviewed
    A. Pre-existing Liver Disease as a Risk Factor for Acetaminophen 
Hepatotoxicity
    B. Updated Literature about Acetaminophen Toxicity
    C. Aspirin and Other NSAIDs
V. FDA's Tentative Conclusions
    A. Acetaminophen
    B. Aspirin and Other NSAIDs
VI. FDA's Proposal
    A. Alcohol Warning
    B. Acetaminophen
    C. Aspirin and other NSAIDs
    D. Requirements to Supplement Approved Applications
    E. Regulatory Action
    F. Conforming Changes to the OTC IAAA TFM
VII. Additional Issues for Consideration
    A. Safe and Effective Daily Acetaminophen Dose
    B. Daily Dose Recommendations for Alcohol Abusers
    C. Combinations With Methionine or Acetylcysteine
    D. Package Size and Configuration Limitations
    E. Label Warning for Individuals With Human Immunodeficiency Virus 
(HIV)
    F. Drug Interactions Between Acetaminophen and Warfarin
VIII. Legal Authority
    A. Statement About Warnings
    B. Marketing Conditions
IX. Voluntary Implementation
X. Analysis of Impacts
    A. Need for the Rule
    B. Impact of the Rule
    C. Impact on Affected Sectors
    D. Alternatives
    E. Benefits
XI. Paperwork Reduction Act of 1995
XII. Environmental Impact
XIII. Federalism
XIV. Request for Comments
XV. Proposed Effective and Compliance Dates
XVI. References

I. Introduction

    FDA is proposing to: (1) Amend the TFM for OTC IAAA drug products, 
(2) remove the alcohol warning, and (3) add new warnings and other 
labeling for all OTC IAAA drug products. The proposed warnings and 
other labeling requirements will advise consumers of potential risks 
and when to consult a doctor. More specifically, FDA is proposing the 
following changes to the labeling:
     Requiring a new liver warning for products that contain 
acetaminophen.
     Requiring a new stomach bleeding warning for products that 
contain an NSAID (e.g., aspirin or ibuprofen).
     Removing the alcohol warning currently required for all 
OTC IAAA drug products in Sec.  201.322 (21 CFR 201.322) and 
incorporating an alcohol warning in the new liver warning for 
acetaminophen and the new stomach bleeding warning for NSAIDs.
     Requiring that the ingredient acetaminophen be prominently 
identified on the product's principal display panel (PDP) of the 
immediate container and the outer carton, if applicable.
     Requiring that the name of the NSAID ingredient followed 
by the term ``NSAID'' be prominently identified on the product's PDP of 
the immediate container and the outer carton, if applicable.
    This new labeling would be required for all OTC drug products 
containing an IAAA active ingredient, whether marketed under an OTC 
drug monograph or an approved NDA. FDA bases this proposal on its 
reviews of the medical literature, data provided to FDA, and 
recommendations made by NDAC. FDA has tentatively concluded that new 
labeling for OTC IAAA drug products is necessary for the safe and 
effective use of these products by consumers.

II. Background

    FDA believes that acetaminophen and NSAIDs, when labeled 
appropriately and used as directed, are safe and effective OTC drug 
products that benefit tens of millions of consumers every year. FDA 
believes that these products should continue to be accessible to 
consumers in the OTC setting.
     Internal analgesics have long been very effective OTC drug 
products for the intermittent treatment of minor aches and pains and 
fever.
     At their recommended OTC doses, these products are only 
rarely associated with serious adverse events relative to the number of 
consumers who use these products.

A. Development of OTC IAAA Drug Product Warnings

    The development of a monograph for OTC IAAA drug products began in 
1977 with publication of an expert panel report and continued in 1988 
with publication of the TFM. The development of labeling for OTC IAAA 
drug products is recorded in the following documents.
1. Warnings for Aspirin and Acetaminophen
    In the Federal Register of July 8, 1977 (42 FR 35346), FDA 
published the report of the Advisory Review Panel on OTC Internal 
Analgesic, Antipyretic, and Antirheumatic Drug Products (the IAAA 
Panel) for OTC IAAA active ingredients: Acetaminophen, aspirin, 
carbaspirin calcium, choline salicylate, magnesium salicylate, and 
sodium salicylate. The recommendations included labeling and warnings 
for:
     Aspirin: ``Caution: Do not take this product if you have 
stomach distress, ulcers or bleeding problems except under the advice 
and supervision of a physician'' (42 FR 35346 at 35387), and
     Acetaminophen: ``Do not exceed recommended dosage because 
severe liver damage may occur'' (42 FR 35346 at 35415).
    In the Federal Register of November 16, 1988 (53 FR 46204), FDA 
published a tentative monograph with the following warnings for:
     Aspirin: ``Do not take this product if you have stomach 
problems (such as heartburn, upset stomach, or stomach pain) that 
persist or recur, or if you have ulcers or bleeding problems, unless 
directed by a doctor'' (53 FR 46204 at 46256), and
     Acetaminophen: ``Prompt medical attention is critical for 
adults as well as for children even if you do not notice any signs or 
symptoms.'' This warning follows the general overdose warnings in 21 
CFR 330.1(g) (53 FR 46204 at 46213).
2. Warnings in the Professional Labeling for Aspirin
    In the Federal Register of October 23, 1998 (63 FR 56802), FDA 
published labeling for health professionals (not available in OTC drug 
product labeling) that provided for cardiovascular and rheumatologic 
indications. The labeling listed adverse reactions reported in the 
literature, e.g., hypotension (low blood pressure); tachycardia (rapid 
heart rate); dizziness; headache; dyspepsia (indigestion); bleeding, 
ulceration, and perforation of the gastrointestinal (GI) tract; nausea; 
and vomiting. FDA determined that consumers were not able to determine 
when they needed to take aspirin to prevent cardiovascular events, such 
as stroke, myocardial infarction (damage to the heart muscle), or other 
conditions. FDA did not

[[Page 77316]]

consider it possible to provide adequate directions and warnings to 
enable the layperson to make a reasonable self-diagnosis of these 
cardiovascular and rheumatologic conditions.
3. Alcohol Warnings for Acetaminophen and NSAIDs
    In the Federal Register of October 23, 1998 (63 FR 56789), FDA 
published a final regulation stating that any OTC drug product, labeled 
for adult use, containing acetaminophen, aspirin, carbaspirin calcium, 
choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, 
naproxen sodium, and sodium salicylate must bear an alcohol warning 
statement in its labeling. Section 201.322 requires the following 
statements:
     For products containing acetaminophen:
    Alcohol Warning: If you consume 3 or more alcoholic drinks every 
day, ask your doctor whether you should take acetaminophen or other 
pain relievers/fever reducers. Acetaminophen may cause liver damage.
     For products containing aspirin, carbaspirin calcium, 
choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, 
naproxen sodium, and sodium salicylate:
    Alcohol Warning: If you consume 3 or more alcoholic drinks every 
day, ask your doctor whether you should take (name of active 
ingredient) or other pain relievers/fever reducers. (Name of active 
ingredient) may cause stomach bleeding.
     For products containing acetaminophen with other IAAA 
active ingredients:
    Alcohol Warning: If you consume 3 or more alcoholic drinks every 
day, ask your doctor whether you should take (insert acetaminophen and 
one other IAAA active ingredient--including, but not limited to 
aspirin, carbaspirin calcium, choline salicylate, magnesium salicylate, 
or sodium salicylate) or other pain relievers/fever reducers. 
Acetaminophen and (insert name of one other IAAA active ingredient--
including, but not limited to aspirin, carbaspirin calcium, choline 
salicylate, magnesium salicylate, or sodium salicylate) may cause liver 
damage and stomach bleeding.
4. Proposed Amendment to Include Ibuprofen as a Generally Recognized 
Safe and Effective OTC IAAA Active Ingredient
    In the Federal Register of August 21, 2002 (67 FR 54139), FDA 
proposed to include ibuprofen in the monograph for OTC IAAA drug 
products with additional warnings:
    Ask a doctor before use if you have:
     Problems or serious side effects from taking pain 
relievers or fever reducers
     Stomach problems that last or come back, such as 
heartburn, upset stomach, or pain
     Ulcers
     Bleeding problems
     High blood pressure, heart or kidney disease, are taking a 
diuretic, or are over 65 years of age.
    FDA received several comments (Refs. 1 and 2) about the proposed 
warning for kidney disease and reopened the administrative record on 
June 4, 2003 (68 FR 33429), to allow for additional public comment. FDA 
continues to propose a warning about kidney disease for ibuprofen and 
other NSAIDs in this document. In a future issue of the Federal 
Register, we will publish our final decision about this warning and the 
proposed inclusion of ibuprofen in the monograph.

B. Completion of the OTC IAAA Drug Products FM

    In the process of completing the FM for OTC IAAA drug products, FDA 
reviewed a variety of data regarding the safety of acetaminophen, 
aspirin, and other NSAIDs. FDA continued to receive serious adverse 
event reports associated with the use of these products during this 
review. These serious adverse events included unintentional 
acetaminophen hepatotoxicity and NSAID-related GI bleeding and renal 
toxicity. Although the occurrence of these events is rare, relative to 
the extensive use of the products, as described in the text that 
follows, FDA believes that labeling changes are necessary for the safe 
and effective use of these products and to reduce the associated 
morbidity.
1. Unintentional Acetaminophen Hepatotoxicity
    Acetaminophen is widely available in numerous single ingredient and 
combination OTC drug products, and in many prescription drug products, 
as a pain reliever and/or fever reducer. OTC acetaminophen drug 
products, as currently labeled and used, have been reported to be 
associated with unintentional overdose that may lead to serious 
hepatotoxicity (Ref. 3). The IAAA Panel discussed overdose-related 
hepatotoxicity (42 FR 35346 at 35413 to 35414), and FDA addressed it in 
the IAAA TFM (53 FR 46204 at 46213 to 46218). (See section II.A.1 of 
this document.)
2. Aspirin and Other NSAIDs--GI Bleeding and Renal Toxicity
    Aspirin and other NSAIDs are available OTC for the treatment of 
minor aches and pain, for the treatment of headaches, and for fever 
reduction. Per aspirin's professional labeling (not part of the OTC 
drug product labeling), aspirin may be used to reduce the risk of 
serious cardiovascular events when taken on a daily basis under the 
direction of a physician. Aspirin is also effective in treating a 
variety of rheumatologic diseases under the direction of a physician. 
The professional labeling also includes information about the potential 
risk of GI bleeding and renal toxicity associated with aspirin.
    OTC nonaspirin salicylates include the NSAIDs ibuprofen, naproxen 
sodium, and ketoprofen. The product labels for these products are not 
required to contain warnings about GI bleeding and renal toxicity. 
These ingredients are, however, also available by prescription at 
strengths higher than in OTC products and the prescription product 
labeling contains warnings about these risks.

III. NDAC Meeting

    At a September 19 and 20, 2002, meeting, NDAC considered products 
currently marketed with OTC IAAA ingredients, including acetaminophen, 
aspirin, carbaspirin calcium, choline salicylate, ibuprofen, 
ketoprofen, magnesium salicylate, naproxen sodium, and sodium 
salicylate. FDA expressed its belief that these products should remain 
available OTC given their overall effectiveness and safety, the benefit 
to consumers of having a pain reliever and fever reducer available OTC, 
and the use of these products by tens of millions of people weekly. FDA 
suggested that certain interventions could decrease the frequency and 
morbidity of these serious adverse events. NDAC members were asked to 
consider which additional interventions were necessary to reduce the 
occurrence of serious adverse events. The presentations made at the 
meeting, and NDAC's findings, are summarized in this document. More 
information about the September 2002 NDAC meeting is available on the 
Internet and in the Division of Dockets Management (see ADDRESSES).

A. Data and Information Reviewed

    FDA provided NDAC with the following data and information (Ref. 3):
     Applicable sections of rulemakings for OTC IAAA active 
ingredients.

[[Page 77317]]

     Proposed and final rules for the alcohol warning for OTC 
IAAA drug products.
     Final rule for professional labeling of OTC drug products 
containing aspirin.
     Amendment to propose inclusion of ibuprofen in the 
monograph for OTC IAAA drug products.
     For acetaminophen, FDA reviews of data, poisoning data in 
Toxic Exposure Surveillance System (TESS), exposure data from poison 
control centers, overdose reference articles, and an abstract 
describing trends in acute liver failure in the United States.
     For aspirin/NSAIDs, FDA reviews of data and articles from 
the medical literature.
    NDAC also considered submissions and presentations from industry 
and individuals during the open public sessions (Refs. 4 and 5).

B. Acetaminophen

    On the first day of the meeting (September 19, 2002), NDAC 
considered safety issues related to the use of acetaminophen, 
unintentional overdose, and the potential for hepatotoxicity from both 
OTC and prescription acetaminophen products.
1. Points for Discussion
    FDA asked NDAC to discuss possible factors that might contribute to 
unintentional overdose (Ref. 3) and provided the following points for 
consideration:
     Acetaminophen is available to consumers in many OTC and 
prescription drug products (i.e., single ingredient and combinations 
with various other active ingredients).
     Consumers fail to identify acetaminophen as an ingredient 
in their OTC and prescription drug products.
     Consumers are unaware of the risks of exceeding the 
recommended dose of acetaminophen with a single product, or of 
simultaneously using multiple products containing acetaminophen.
    FDA asked NDAC what additional measures could be taken to better 
ensure that prescribers and other people are aware of the potential 
risks associated with exceeding the recommended dose of prescription or 
OTC drug products containing acetaminophen and with using multiple 
products containing acetaminophen. FDA suggested the following possible 
measures for OTC drug products:
     Consumer education
     Changes in labeling that identify and highlight the risks
     Packaging that may enhance appropriate use
     Consumer inserts.
    For prescription products, FDA suggested:
     Unit of use packaging with labeling on each blister pack
     Physician and pharmacist education
     Publication of information in professional journals
     Consumer education
     FDA publications to identify and highlight the danger and 
risk
     Providing patient information leaflets and stickers when 
dispensing the prescription.
    FDA also asked NDAC if there are identifiable factors that might 
make some individuals more susceptible to hepatic toxicity (e.g., 
underlying liver disease, malnutrition, drug interactions, and alcohol 
users). If subpopulations at increased risk of acetaminophen-induced 
hepatotoxicity could be identified, FDA asked NDAC what reasonable 
measures could be taken to decrease their risk. FDA suggested some 
possible measures:
     Adjustment of the maximum total daily dose or dosing 
interval
     Changes in labeling that identify the population and 
highlight the risks
     Additional research on specific subpopulations
     Consumer and physician education.
    FDA asked NDAC whether additional studies are needed to evaluate 
these issues. FDA suggested a number of subjects for potential 
research:
     Evaluation of the effectiveness of educational programs
     Evaluation of revised labeling
     Surveillance of serious acetaminophen hepatotoxicity cases
     Enhanced collection of information when medication errors 
occur
     Better understanding of consumer use of these products.
2. Presentations and Submissions to NDAC
    As a lead-in to the liver toxicity discussion, Dr. William Lee, of 
the University of Texas Southwestern Medical Center at Dallas, 
presented the results of acute liver failure (ALF) studies in the 
United States (Ref. 6). He estimated that between 1,000 and 2,000 ALF 
cases occur in the United States each year and are associated with high 
mortality. Dr. Lee conducted a retrospective analysis of 177 cases of 
ALF reported in the literature between 1986 and 1998. Of these, 20 
percent were attributed to acetaminophen toxicity. To study ALF 
prospectively, Dr. Lee also formed a study group of 25 treatment 
centers in 1998. Details of the group's initial 308 cases are presented 
in table 1. Approximately 40 percent of the cases were due to 
acetaminophen toxicity, which was increased when compared to the rate 
of acetaminophen toxicity in the cohort from Dr. Lee's retrospective 
analysis.

                                                  Table 1.-- Study Group Series of ALF Cases (N = 308)
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                                                                                                  ALF Etiology
                                                       -------------------------------------------------------------------------------------------------
                   Case Report Data                                                                                               All Other
                                                          Acetaminophen Induced    Drug (Not Acetaminphen)     Indeterminate       Causes       P value
                                                                 (n=120)               Induced (n=40)          Cause (n=53)        (n=95)
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Sex (% Female)                                                              79                        73                  60            72       NS*
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Age (years)                                                                 36                        41                  38            43         0.02
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Jaundice (days)                                                              1                        12                  12             4        <0.001
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Coma (%)                                                                    50                        43                  47            47        NS
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Alanine aminotransferase (ALT) (International Units/                      4310                       574                 947          1060        <0.001
 Liter (IU/L))**
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Bilirubin                                                                    4.3                      20.2                24.5          12.6      <0.001
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[[Page 77318]]

 
Transplant (%)                                                               6                        53                  51            36        <0.001
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Spontaneous survival (%)                                                    68                        25                  17            33        <0.001
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Overall survival (%)                                                        73                        70                  64            61        NS
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* Not significant ** ALT (normal range 0-35 IU/L)

    Of the 120 acetaminophen toxicity cases identified in Dr. Lee's 
series, 12 were omitted due to concomitant patient issues that would 
have confounded the analysis. The remaining 108 cases were analyzed and 
showed that alcohol use was reported in 57 percent of the cases and 
alcohol abuse was reported in 19 percent of the cases. Individuals in 
38 percent of the cases were taking both narcotic-acetaminophen 
prescription products and OTC acetaminophen products at the same time, 
some for as long as 2 to 3 months. In 70 percent of the cases, patients 
ingested more than 4 grams (g) of acetaminophen per day (recommended 
maximum daily dose), and 32 percent of the cases reported ingestion of 
more than 10 g per day.
    A comparison was conducted among the 108 cases of toxicity due to 
accidental (ingestion of drugs for pain relief, without suicidal 
intent) and suicidal (ingestion with admitted suicidal attempt) 
ingestion. The type of ingestion could not be determined in 5 cases, 
resulting in a comparison of 103 cases (table 2). More than half of the 
acetaminophen toxicity cases (57 percent) were accidental.

                            Table 2.--Suicidal vs. Accidental Acetaminophen ALF Cases
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                                         Accidental (n=59)          Suicidal (n=44)              p-value
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Age                                                      39                        33                     0.011
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Acetaminophen total (g)                                  20                        29                    NS
----------------------------------------------------------------------------------------------------------------
Antidepressant                                          36%                       34%                    NS
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Alcohol (non-abuse use)                                 55%                       61%                    NS
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Double use*                                             24%                        5%                     0.02
----------------------------------------------------------------------------------------------------------------
Narcotic/acetaminophen                                  54%                       14%                     0.001
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ALT (IU/L)                                            3,616                     5,929                    <0.001
----------------------------------------------------------------------------------------------------------------
Creatine                                                  2.5                       1.3                   0.008
----------------------------------------------------------------------------------------------------------------
Survival                                                71%                       75%                    NS
----------------------------------------------------------------------------------------------------------------
* Use of more than one acetaminophen containing product.

    The incidence of use of antidepressants and alcohol was nearly 
identical in the accidental and suicidal groups. The accidental cases 
included a larger percentage of subjects who double-dosed or used a 
narcotic/acetaminophen combination product. Survival rates were also 
similar. Lee concluded that acetaminophen toxicity accounted for about 
a third of all deaths from ALF in this case series and appears to be a 
growing problem in the United States.
    FDA staff presented a safety analysis of hepatotoxicity associated 
with acetaminophen (Ref. 7). The cases were reported as ``intentional 
overdose'' and ``unintentional overdose.'' The reported doses were 
rarely within the recommended range. Four national databases were used 
to estimate the occurrence of these events:
    1. National Hospital Ambulatory Care Survey: Emergency Department 
(ED) Component--a probability survey sampling of visits made to 
emergency departments and short stay hospitals in the United States.
    2. National Electronic Injury Surveillance System--collects 
information on consumer product-related injuries treated in emergency 
departments of 66 selected hospitals.
    3. National Hospital Discharge Survey--a probability survey 
sampling of patient discharge records from non-Federal, short stay 
hospitals in the United States.
    4. Multiple Cause of Death Files--a data file that contains 
information from death certificates.
    Acetaminophen overdose (unintentional and intentional) was 
associated with an annual average of over 56,000 emergency department 
visits (1993 to 1999) and more than 26,000 hospitalizations (1990 to 
1999). Between 1996 and 1998, an annual average of 458 deaths was 
attributed, at least in part, to acetaminophen overdose. Unintentional 
acetaminophen overdose was associated with an annual average of over 
13,000 emergency department visits (1993 to 1999), 2,189 
hospitalizations (1990 to 1999), and 100 deaths (1996 to 1998). Each 
event in these tallies is independent from the others. No information 
about associated

[[Page 77319]]

hepatotoxicity was available for these cases. FDA reviewed the age 
distribution for acetaminophen overdoses. Medication use varies by age 
and different OTC drug products containing acetaminophen are available 
for different age groups. The age distribution of unintentional 
overdose cases varies among reporting databases and is shown in table 
3. While emergency department visits are most prevalent among young 
people, this age group accounts for the lowest percentage of cases of 
mortality.

                                Table 3.--Age Distribution of Unintentional Cases
----------------------------------------------------------------------------------------------------------------
                                                                   Age (years)
                                --------------------------------------------------------------------------------
                                            <17                       17--64                      >65
----------------------------------------------------------------------------------------------------------------
Emergency department visit                             74%                        25%                        <1%
----------------------------------------------------------------------------------------------------------------
Hospitalization                                        23%                        70%                         7%
----------------------------------------------------------------------------------------------------------------
Mortality                                               1%                        75%                        23%
----------------------------------------------------------------------------------------------------------------

    Chronic liver disease has been postulated to be one of the factors 
that increases the risk of hepatotoxicity from acetaminophen. Using the 
multiple cause of death database, the presence of chronic liver disease 
among cases of unintentional and intentional overdose with mortality 
outcomes was examined (table 4).

 Table 4.--Percent of Liver Disease Reported Among Fatal Acetaminophen Overdose Cases, Mortality Data, 1996-1998
----------------------------------------------------------------------------------------------------------------
               Liver Disease Reported                     Unintentional (N=235)         Intentional (N=1,010)
----------------------------------------------------------------------------------------------------------------
Chronic alcoholic                                                              13%                            1%
----------------------------------------------------------------------------------------------------------------
Other chronic liver disease                                                    48%                            8%
----------------------------------------------------------------------------------------------------------------

    These findings suggest that chronic liver disease, in the presence 
or absence of alcohol, may be a risk factor for developing or 
increasing severity of hepatotoxicity among people with unintentional 
overdose. However, this analysis has limitations. If the presence of 
alcohol or alcohol use was not mentioned on the death certificate, 
alcohol related liver disease may be misclassified as other chronic 
liver disease. In addition, suicide cases may be misclassified as 
unintentional overdose to protect privacy.
    FDA also presented an analysis of cases of hepatotoxicity 
associated with acetaminophen from the published literature. A MEDLINE 
search identified all U.S. case series containing at least 10 cases 
that had been published in the previous 10 years (Ref. 7). Eight case 
series were identified, four of which were derived exclusively from 
review of hospital medical charts. In two series, cases were obtained 
from hospitals, published cases, the FDA adverse event reporting 
system, and poison control center databases. One case series was from a 
registry of cases reported by hepatologists and other practitioners. 
One case series was obtained exclusively from a consortium of liver 
transplant centers. The number of cases per series ranged from 47 to 
73. Two case series were largely pediatric, and the remaining six case 
series consisted of largely adult populations. Six of the case series 
reported gender, and in all six there was a preponderance of females. 
Intentionality was reported in five of the series. Table 5 shows the 
acetaminophen dose reported among in the unintentional overdose groups.

                          Table 5.--Hepatotoxicity Series: Unintentional Toxicity Cases
----------------------------------------------------------------------------------------------------------------
                                                                                      No. of Cases With Typical
      Case Series       Reported Daily Doses (g/day)     No. of Cases in Series        Daily Dose of <=4g/day
----------------------------------------------------------------------------------------------------------------
Johnston                                      1.3-20                            53                             9
----------------------------------------------------------------------------------------------------------------
Schiodt                                         2-30                            21                             3
----------------------------------------------------------------------------------------------------------------
Zimmerman                            ``<4''-``>15''*                            67                            27
----------------------------------------------------------------------------------------------------------------
Whitcomb                                      3.5-25                            21                          None
----------------------------------------------------------------------------------------------------------------
Broughan                                 15.9 (mean)                             8                          None
----------------------------------------------------------------------------------------------------------------
* Dose was reported categorically.

    Nine people in the Johnston case series and three people in the 
Schiodt case series ingested 4 g/day or less of acetaminophen. In the 
Zimmerman case series, 27 people used acetaminophen at the recommended 
dose, while 13 people used between 4.1 and 6 g/day. In the Whitcomb 
case series, 3 people used acetaminophen at, or slightly above, the 
recommended dose (i.e., 3.5 to 5 g/day in one case and 4 to 6 g/day in 
two cases). In the Broughan case study, none of the people took 
acetaminophen at the recommended dose.

[[Page 77320]]

    Table 6 compares the number of deaths and serious outcomes for the 
unintentional and intentional groups. Intentionality could only be 
compared in the adult case series. Serious outcomes were defined as 
hepatic coma, acute liver failure, and liver transplant.

    Table 6.--Comparison of Unintentional and Intentional Toxicity Groups: Cases of Death or Serious Outcome
----------------------------------------------------------------------------------------------------------------
                     Case Series                              Unintentional                  Intentional
----------------------------------------------------------------------------------------------------------------
Johnston                                                                     17/53                           NA*
----------------------------------------------------------------------------------------------------------------
Schiodt                                                                      11/21                          4/50
----------------------------------------------------------------------------------------------------------------
Zimmerman                                                                    13/67                           NA*
----------------------------------------------------------------------------------------------------------------
Whitcomb                                                                      5/21                          NR**
----------------------------------------------------------------------------------------------------------------
Broughan                                                                       2/8                          0/40
----------------------------------------------------------------------------------------------------------------
*NA: Not applicable; **NR: Not reported

    FDA also presented case data from the TESS of the American 
Association of Poison Control Centers (AAPCC). At that time, AAPCC had 
a repository of over 27 million human poison exposures reported by over 
60 participating centers. These centers covered over 90 percent of the 
U.S. population. Examination of AAPCC's annual reports from 1995 to 
1999 of cases listing acetaminophen as the primary (first) agent showed 
acetaminophen to be the leading cause of poisonings. In 1999, 
acetaminophen-related calls represented 10 percent of all calls to 
AAPCC. There was a decrease in calls between 1995 (111,175) and 1999 
(108,102). In 1999, nearly 50 percent of the poison victims associated 
with the calls received treatment in health care facilities. Two 
percent of these victims were reported to have developed major effects 
resulting from the poisoning, i.e., the signs or symptoms occurring as 
a result of acetaminophen exposure were life-threatening or resulted in 
significant residual disability. Fifty percent of the calls involved 
children and adolescents (19 years of age or under). Of the 
acetaminophen related calls regarding children under 6 years of age 
(approximately 40,000 calls), 22 percent occurred in children who 
ingested adult formulations of acetaminophen.
    In 1995, there were at least 76 acetaminophen-related fatalities. 
By 1999, the number of acetaminophen-related fatalities increased to 
141. Of these, 92 (65 percent) were a result of suicidal intent, 43 (30 
percent) were unintentional, and the dosing intent for 6 (4 percent) 
was undetermined. Among the 43 unintentional fatalities, 28 (65 
percent) took one OTC drug product containing only acetaminophen; 4 (9 
percent) took one prescription product containing acetaminophen, and 11 
(26 percent) took more than one acetaminophen product simultaneously. 
These AAPCC data may underreport the actual number of acetaminophen 
toxicity cases, because serious cases that go directly to emergency 
departments, and chronic users of acetaminophen, are unlikely to 
generate poison control center contacts.
    FDA staff reviewed spontaneous reports of hepatoxicity in FDA's 
adverse event reporting system (AERS). U.S. cases were identified that 
had been received by FDA between January 1998 and July 2001 and in 
which one or more acetaminophen containing products had been ingested. 
Of 633 reports, 43 were duplicates. Another 283 were excluded for 
various reasons, primarily to exclude cases in which there was apparent 
suicidal intent. A total of 307 cases were included in FDA's analysis 
(25 pediatric and 282 adult cases).
    Pediatric cases (of children age 1 day to 8 years) consisted 
primarily of males (approximately 70 percent), although gender was not 
reported in each case. Fifteen of the 25 pediatric cases involved 
severe, life-threatening liver injury. Of the 25 children, 10 died, 21 
were hospitalized, and 2 required only treatment in an emergency 
department. The dose was estimated, based upon reported daily doses and 
weight, in 10 cases to be 106 to 375 milligrams/kilogram (mg/kg) per 
day. The recommended pediatric dose is 75 mg/kg/day (Ref. 7). Twenty-
two of the children (88 percent) took only 1 product containing 
acetaminophen and 3 children (12 percent) took 2 or more products 
containing acetaminophen. Sixteen of the cases (53 percent) reported 
ingestion of a single ingredient acetaminophen product (APAP), 12 cases 
(40 percent) reported ingestion of an ``unspecified APAP product'' and 
the remainder of the cases reported ingestion of combination products. 
Of the single ingredient products, concentrated drops containing 
acetaminophen 100 mg/milliliter (mL) were reportedly ingested in seven 
cases.
    In 20 of the pediatric cases, 1 or more medication errors were 
reported. In three cases, the wrong product was used, i.e., the 
concentrated drops instead of the children's acetaminophen liquid 
formulation. In four cases, incorrect measuring devices were used, 
i.e., teaspoonfuls instead of dropperfuls. Five cases reported 
instances of misinterpretation of labeled dosing guidelines or 
misinterpretation of instructions provided by a health care provider.
    Sixty percent of the 282 adult cases (15 to 85 years old) were 
female and 229 required hospitalization. A total of 169 adults 
experienced severe, life-threatening liver injury; 124 of these 
patients died and 7 required a liver transplant. One hundred ninety-
nine (71 percent) adults reported using an acetaminophen product for a 
therapeutic indication, primarily analgesia. In 74 (26 percent) cases, 
the indication for use was unknown, and in 9 (3 percent) cases, abuse 
of a narcotic-acetaminophen prescription product was reported. One 
hundred thirty-eight (38 percent) cases listed an unspecified 
acetaminophen product (unknown whether single ingredient or combination 
product and whether OTC or prescription), 122 (33 percent) cases 
involved the use of a narcotic-acetaminophen prescription product, and 
76 (21 percent) cases reported use of an OTC single ingredient 
acetaminophen product. Approximately 25 percent of all adult cases 
reported use of more than one acetaminophen product. When more than one 
acetaminophen product was reported, a narcotic-acetaminophen 
prescription product in combination with an OTC product containing 
acetaminophen was used more often than any other

[[Page 77321]]

combination of acetaminophen products. These cases also used higher 
doses than people who took only one acetaminophen-containing product.
    Dosing amounts were reported in 132 of the 282 adult cases. The 
mean and median daily dose were 6.5 and 5 g, respectively, but ranged 
from 650 mg to 30 g/day. Where the dosage strength was known, 500 mg 
acetaminophen was reported most often. If a dose range was reported in 
the case, the mid-point was used in the analysis. If the strength was 
unknown, a 500-mg strength was assumed. Dosing in the 65 adults with 
severe liver injury from this group showed a mean and median daily dose 
of 7.1 and 6.23 g, respectively. Twenty-three of the 65 cases with 
severe liver injury reported doses of less than 4 g/day. People who 
used more than one acetaminophen product reported taking higher doses 
than people who took a single product. Qualitative dosing information 
was provided for an additional 43 (15 percent) cases with terms such as 
``excessive doses'' or ``recommended doses.'' Two out of three of these 
cases suggest that greater than recommended doses were used.
    Alcohol use was reported in 116 of the adult cases and the content 
of the reports was highly variable. Alcohol use in these cases was 
defined by FDA as alcoholism or alcohol abuse in 64 cases; regular, 
daily, or moderate use in 23 cases; occasional use in 10 cases; 
previous use in 6 cases; and 13 cases did not provide a description. 
Eighty-six (74 percent) of the 116 alcohol users developed severe liver 
injury. For those cases with acetaminophen dose information, the mean 
dose associated with toxicity was lower for alcohol users compared to 
nonalcohol users (table 7).

                                  Table 7.--Acetaminophen Dose and Alcohol Use
----------------------------------------------------------------------------------------------------------------
     Category of Liver Disease (Developed Post-
                   Acetaminophen)                       Alcohol Users (Mean Dose)       Non-Users (Mean Dose)
----------------------------------------------------------------------------------------------------------------
All (N=132)                                                           5.6 g (N=53)                  6.9 g (N=79)
----------------------------------------------------------------------------------------------------------------
Severe only (N=65)                                                    6.0 g (N=38)                  8.6 g (N=27)
----------------------------------------------------------------------------------------------------------------

    A history of prior liver disease, or possible underlying liver 
disease, was reported in 70 cases. In at least 20 of these cases, the 
pre-existing liver disease was reportedly due to alcohol. Twenty-three 
people reported a history of, or possible, viral hepatitis. Among the 
70 cases with pre-existing liver disease, 49 percent (70 percent) 
developed severe liver injury. Table 8 shows the dose that was 
associated with liver injury for cases with and without pre-existing 
liver disease. The first row includes all cases (all degrees of acute 
liver injury) that reported dosing information. The second row shows a 
dose comparison in people who experienced severe liver injury after 
acetaminophen exposure.

                                 Table 8.--Acetaminophen Dose and Liver Disease
----------------------------------------------------------------------------------------------------------------
  Category of Liver Injury Associated With      Cases With Pre-existing Liver   Cases With No Pre-existing Liver
            Acetaminophen Dosing                     Disease (Mean Dose)               Disease (Mean Dose)
----------------------------------------------------------------------------------------------------------------
All (N=132)                                                       5.4 g (N=36)                      6.8 g (N=96)
----------------------------------------------------------------------------------------------------------------
Severe only (N=65)                                                5.7 g (N=23)                      7.8 g (N=42)
----------------------------------------------------------------------------------------------------------------

    Some additional factors may have contributed to the development of 
hepatotoxicity in these adults. Use of other medications that may have 
contributed to hepatotoxicity was reported in 93 cases, including 63 
cases that involved products that are labeled with warnings about 
potential hepatotoxicity. A small number of reports also mentioned the 
existence of concomitant malnutrition or decreased oral intake.
    FDA noted that there are limitations to interpreting the AERS data. 
Dosing information may be unreliable. Acetaminophen products are 
generally taken on an as-needed basis, so the actual dose ingested can 
be difficult to ascertain. There is no certainty that all of the adult 
cases included in this analysis were unintentional. Stigma may be 
associated with reporting suicide, so cases may be reported as 
unintentional when they were intentional overdoses. In addition, 
spontaneous reporting systems cannot provide certainty that 
acetaminophen was the cause of any of the reported adverse event. 
Furthermore, incidence rates cannot be determined, because the 
numerator or denominator descriptors for the entire population are not 
available. Overall, spontaneous reports may be subject to significant 
underreporting.
    The AERS cases strongly suggest that particular circumstances were 
likely to have led to hepatotoxicity. Some examples of those 
circumstances follow:
     Errors related to product confusion were mostly observed 
in pediatric cases. These errors primarily involved confusion over 
varying product formulations and strengths and use of inappropriate 
measuring devices.
     Many adults were taking more than the recommended dose of 
acetaminophen and, in some cases, use of multiple products likely 
contributed to hepatotoxicity.
     Risk factors, such as alcohol use or pre-existing liver 
disease, were identified and may have increased the risk for 
hepatotoxicity.
    FDA presented NDAC with several questions that remained unaddressed 
by FDA's review:
     Do users lack knowledge of the potential for and symptoms 
of hepatotoxicity when using a product containing acetaminophen?
     Does malnutrition or fasting affect severity of 
hepatoxicity?
     What is the contribution of concomitant hepatotoxic 
medication?
     What additional factors place a small number of 
individuals at risk for severe hepatotoxicity at various dose levels 
(i.e., under, at, or above the recommended dose)?
    It is clear that unintentional acetaminophen doses are associated 
with a large number of emergency department and hospital admissions and 
are related to an estimated 100 deaths each year. Using a number of 
data sources, analyses have shown that circumstances leading to

[[Page 77322]]

acetaminophen hepatotoxicity are multifactorial. FDA asked the 
committee to consider the contribution of each of the following in 
producing unintentional overdose toxicity:
     Product--the ingredient is present in multiple 
prescription and OTC drug products and in multiple oral formulation 
strengths
     Knowledge--since a number of cases have occurred from 
multiple product use and overuse, there is likely a lack of knowledge 
about safe use of acetaminophen
     Risk factors--multiple data sources identify alcohol and 
underlying liver disease as risk factors that may increase the 
potential for hepatotoxicity.
    Several drug manufacturers and other interested parties provided 
additional comment (Ref. 4):
     One major manufacturer of acetaminophen OTC drug products 
provided the following comments:
    1. The precise incidence of harmful, unintentional overuse cannot 
be accurately determined from the current databases. Forty-eight 
million American adults use products containing acetaminophen in any 
single week; thus, harm is rare and is caused by inadvertent overdose.
    2. There are limitations to the AERS data set for assessing hepatic 
events. Patients consistently underestimate the dose taken, and suicide 
attempts are often not recorded in patients who are found unconscious 
or intoxicated. The AERS reports found to be definitely associated with 
acetaminophen involved substantial overdose in individuals with self-
abusive behaviors (e.g., alcohol abuse, bulimia). Causality cannot be 
ascertained using retrospective data, especially case reports, because 
the dose history is often inaccurate.
    3. Formulations most commonly reported were OTC single-ingredient 
and prescription combination acetaminophen products. OTC acetaminophen 
combination products were rarely reported.
    4. Serious hepatotoxicity occurs following substantial overdose (a 
single dose of approximately 15 g or use of approximately 12 g for 
multiple days).
    5. FDA focused on unintentional misuse. The manufacturer noted they 
had implemented labeling changes to minimize the inadvertent overuse of 
analgesics. The manufacturer recommended an organ specific overdose 
warning.
     One manufacturer of ibuprofen OTC drug products provided 
the following comments:
    1. In overdose situations, in any given year, the number of deaths 
for acetaminophen reported by the AAPCC is approximately 20 times that 
for ibuprofen.
    2 . Unintentional overdose of acetaminophen can put consumers in a 
life-threatening situation due to the delayed onset of clinical 
symptoms of toxicity.
    3. Advertising portrays acetaminophen as a totally safe ingredient. 
This portrayal may exacerbate use and contribute to the silent danger 
resulting from overdose.
     One individual presented a review of acetaminophen 
overdose admissions at the University of Pennsylvania hospital over a 
4-year period. Fifty-four reports of acetaminophen overdose were found 
in the hospital's database. Of the 47 cases reviewed to date, 23 (50 
percent) were reported to be unintentional overdoses. In 13 of these 23 
cases, the reviewer was able to document that an attending physician or 
a psychiatry consultant concluded that there had been no suicidal 
intent.
    1. The median and average doses were between 6 and 8 g/day. These 
values are above the recommended maximum daily dose (4 g/day), but 
below the 10 to 15 g dosage usually considered to be toxic. There were 
three cases of intentional overdose and three cases of unintentional 
overdose involving prescription acetaminophen products. OTC products 
were associated with 20 intentional and 21 unintentional overdoses. 
More patients in the unintentional overdose group used single 
ingredient acetaminophen (i.e., not a combination product). The primary 
reason reported for exceeding the maximum dose was to treat unrelieved 
pain. Many patients stated that they knew they were exceeding the 
recommended dose and did so because they thought it was a safe drug. 
Thirty percent of the patients used the drug over a period of greater 
than 7 days.
    2. The unintentional overdose group experienced greater morbidity 
and mortality than the intentional overdose group. The peak 
acetaminophen levels in the intentional overdose group were much lower 
compared to the unintentional overdose group (27.8 versus 115.1 mg/L). 
The unintentional overdose group had much higher peak levels of Alanine 
aminotransferase (ALT) (5,193 versus 3,065 units/L), Aspartate 
aminotransferase (AST) (6,819 versus 2,742 units/L), International 
Normalized Ratio (INR) (4 versus 2.5), and total bilirubin (5.87 versus 
1.87 mg/dL). Patient outcomes were generally worse in the unintentional 
overdose group, in which more patients failed to have resolution of the 
liver problems from the overdose (31 versus 4 percent). More patients 
were evaluated for transplants (11 versus 9), received transplants (2 
versus 0), and died (3 versus 0) as a result of unintentional 
overdoses.
    3. Compared to the intentional overdose group, the unintentional 
overdose group was more likely to have one or more of the following 
risk factors for acetaminophen toxicity: (1) Hepatic disease, (2) acute 
or chronic alcohol use, (3) drug abuse, or (4) concomitant disease. 
Ninety-six percent of cases in the unintentional overdose group had one 
or more of these risk factors, as compared to 70 percent in the 
intentional group. Acute and chronic alcohol use was present in 87 
percent of unintentional overdose cases, as compared to 61 percent of 
the intentional overdose cases. Thus, the existence of risk factors may 
have an impact on toxicity in unintentional ingestions.
     One individual described the untimely death of her son who 
initially used a prescription product. When the prescription was 
finished, he purchased an OTC acetaminophen product and developed flu 
like symptoms. Another OTC acetaminophen product was subsequently used 
to treat the flu symptoms, resulting in hepatotoxicity. He was 
hospitalized and ultimately died.
     A professional pharmaceutical association encouraged 
consumers to carefully read product labeling. The association also 
recommended: (1) Clear labeling on all prescription and OTC drug 
products containing acetaminophen with special statements (e.g., 
``contains acetaminophen'' on the product's PDP), and (2) pharmacists 
placing auxiliary labels on the vial of prescription drug products 
containing acetaminophen to identify this ingredient.
     A consumer public health organization described a consumer 
survey showing that many consumers do not recognize the potential for 
harm from: (1) Taking more than the recommended dose, (2) taking more 
than one product containing acetaminophen, or (3) inappropriately 
combining OTC and prescription drug products containing acetaminophen.
     A member of a national health foundation expressed concern 
that present marketing practices make it very difficult to find the 
standard 325-mg acetaminophen dosage unit. As a result, many consumers 
believe that the 500-mg product is the only one available. This failure 
to more broadly market the lower dose may contribute to increased 
adverse events. The individual

[[Page 77323]]

advocated educational efforts to help minimize this problem.
     A spokesperson for a national consumer organization 
described marketing limitations that are employed in the United Kingdom 
and intended to limit the potential for overdose. In September 1998, a 
restriction was placed on the number of tablets in acetaminophen 
packages for sale without a prescription. If sold in a supermarket, the 
maximum is 16 tablets per package. If sold in a pharmacy, the maximum 
is 32 tablets per package. There is also an overall restriction that a 
maximum of 100 tablets can be purchased at one time. The representative 
stated that early evaluations of this program have shown decreases in 
(1) total and severe acetaminophen overdoses and (2) overdoses related 
to liver transplant and death.
    Several drug manufacturers and others submitted additional 
information for the committee to review (Ref. 5):
     One major manufacturer of acetaminophen OTC drug products 
provided the following comments (Ref. 5, Tab A):
    1. AERS serves as a signal generating system for rare, unexpected 
adverse events in marketed products. It cannot be used to determine 
event rates, dose ingested, or patient dosing intent.
    2. FDA's review of the AERS data set was intended to exclude 
obvious suicide, usually associated with very large drug ingestion. 
Thus, the reported dosage (which could only be estimated in 48 percent 
of the reports in the data set) is skewed significantly toward labeled 
directions for use, so cases may falsely appear to be consistent with 
inadvertent misuse.
    3. The selective data in FDA's AERS review cannot be used to 
determine an acetaminophen toxicity threshold associated with any 
patient condition (i.e., concomitant drug, alcohol history, or pre-
existing concomitant disease).
    4. The quality of the 281 adult reports in AERS was evaluated by 
the manufacturer. The manufacturer concluded that 168 reports (24 
percent) contained insufficient information to estimate the dose taken 
and 212 reports (88 percent) contained no liver pathology information. 
AST and ALT levels were not reported in 108 cases (38 percent). Only 61 
reports (25 percent) had information about viral hepatitis testing and, 
of these, 29 reports were positive for hepatitis A, B, or C.
    5. There are flaws in the derivation of FDA's theory that alcohol 
use, underlying/history of liver disease, and potentially the use of 
hepatotoxic concomitant medications, may increase susceptibility to 
acetaminophen-associated hepatotoxicity at unexpectedly low doses of 
acetaminophen. The manufacturer provided arguments that the existence 
of any of these factors in a case report may each inherently interfere, 
for various reasons, with establishing the correct assessment of a 
hepatotoxic dose of acetaminophen.
     An expert panel sponsored by a manufacturer of 
acetaminophen products reviewed all 281 adult reports in AERS and 
assigned a probability category relating the reported hepatic adverse 
events to acetaminophen exposure. In 3 reports the adverse event and 
exposure were considered ``definitely'' related, in 74 reports they 
were ``probably'' related, 47 reports they were ``possibly'' related, 
in 53 reports they were unlikely to be related, and in 27 reports they 
were definitely not related. Data were considered insufficient in 73 
reports, 3 reports were not able to be evaluated and there was no 
consensus regarding the evaluation of 1 report.
    Based on an assessment of several databases, a sponsor calculated 
that the worst case scenario of deaths from acetaminophen overdose is 
e