[Federal Register Volume 71, Number 247 (Tuesday, December 26, 2006)]
[Proposed Rules]
[Pages 77314-77352]
From the Federal Register Online via the Government Publishing 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: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://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 http://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 http://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
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 77318]]

 
Transplant (%)                                                               6                        53                  51            36        <0.001
--------------------------------------------------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------
Age                                                      39                        33                     0.011
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Acetaminophen total (g)                                  20                        29                    NS
----------------------------------------------------------------------------------------------------------------
Antidepressant                                          36%                       34%                    NS
----------------------------------------------------------------------------------------------------------------
Alcohol (non-abuse use)                                 55%                       61%                    NS
----------------------------------------------------------------------------------------------------------------
Double use*                                             24%                        5%                     0.02
----------------------------------------------------------------------------------------------------------------
Narcotic/acetaminophen                                  54%                       14%                     0.001
----------------------------------------------------------------------------------------------------------------
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 
estimated to be 213 deaths per year (Ref. 5, Tab A).
     One manufacturer submitted an analysis of data from TESS 
(Ref. 5, Tab B). The manufacturer made the following conclusions from 
these data:
    1. The majority of hepatotoxicity cases (65 percent of cases in the 
year 2000) involved use of one acetaminophen-containing analgesic 
product.
    2. Acetaminophen-containing cough/cold medications were not a 
significant contributor to the total number of reports of acetaminophen 
associated hepatotoxicity (2 percent of cases in the year 2000).
    3. Only 1 percent of the reported cases of hepatotoxicity in 2000 
involved use of an OTC acetaminophen-containing cough/cold product 
concomitantly with other acetaminophen-containing product(s).
     One physician stated that 3 to 4 g of acetaminophen per 
day is the upper range of a safe dose (Ref. 5 Tab C). For an individual 
who is a regular user of alcohol, in a prolonged fasting or in a rapid 
weight loss program, the upper limit of a safe dose is unknown, but 
unlikely to not exceed 2 g of acetaminophen. No data were provided to 
support these observations.
     Several organizations urged that labeling be improved to 
provide clear directions about the appropriate doses for use and 
frequency of administration, especially for combination products (Ref. 
5 Tab D). Consumers need to know the type of medication and the dose of 
OTC analgesic in every combination product to ensure safe and effective 
use.
3. NDAC Deliberations and Recommendations Concerning Acetaminophen
    NDAC unanimously agreed that the evidence of risk associated with 
unintentional overdose of acetaminophen warrants FDA labeling changes, 
without awaiting the outcome of further studies. NDAC noted the 
following four major areas of concern:
    1. Unintentional use of multiple acetaminophen containing products
    2. Exceeding the recommended dose without recognizing the 
consequences
    3. Improper dosing of infants
    4. The unknown consequences of use in special populations, such as 
alcohol abusers.
    NDAC recommended that the minimum requirements for change should 
include, for all products containing acetaminophen (including those 
available by prescription), the addition of distinctive labeling 
(highlighted or bold type) on the front panel or PDP to state that the 
products contain acetaminophen. FDA noted that the nonproprietary name 
of prescription drugs must appear in labeling in letters at least half 
the size of the brand name (see 21 CFR 201.10(g)(2)). NDAC recommended 
that a similar provision also be applied to OTC drug products 
containing acetaminophen, such as a standard to ensure prominence of 
important information. NDAC stated that consumers need to be informed 
that combining products containing acetaminophen can result in 
exceeding the recommended dose.
    NDAC commented that there are insufficient data in the OTC setting 
on risk management, understanding consumer behavior, and the 
effectiveness of warnings on labels. This lack of data makes it 
difficult to determine which factors contribute to liver injury. 
Although these factors are not clearly understood, NDAC concluded that 
labeling revisions are needed to help minimize any risks.
     Separate liver toxicity and alcohol warnings. NDAC 
recommended a liver toxicity statement, separate from the alcohol 
warning, be added to the label so that the potential for liver toxicity 
would not appear to be applicable only to consumers who drink alcohol. 
NDAC noted that alcohol is not the only risk factor for hepatotoxicity. 
It was also felt to be important to warn consumers of the consequences 
of taking multiple products containing acetaminophen and that toxicity 
can be related to the total

[[Page 77324]]

dose of acetaminophen taken during a given period of time. NDAC felt it 
would be more prudent to describe these risks in a separate warning to 
more fully inform consumers who do not abuse alcohol.
    NDAC did not propose exact language. It was believed that it was 
important that the message not refer to ``overdose,'' but rather to a 
statement such as ``do not take more'' or ``do not exceed the 
recommended dose.'' NDAC believed that the term ``overdose'' would not 
be understood to be pertinent to consumers whose intent was to use the 
product safely. One NDAC member stated the term ``exceed'' is not part 
of consumers' common vocabulary and proposed that it would be more 
useful to inform consumers of a specific allowable total dose (e.g., 
not to take more than a specified number of tablets in a given period).
    NDAC re-examined the currently required alcohol warning for 
acetaminophen, which states: ``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.'' NDAC inquired why ``three 
drinks'' were used in the alcohol warning. FDA responded that the 
number is from recommendations of the American Heart Association as to 
what constitutes excessive alcohol use. FDA stated that it recognized 
this may seem arbitrary and asked NDAC to provide further 
recommendations. NDAC questioned whether doctors are well-informed with 
proper information about the relationship between alcohol and 
acetaminophen use and whether educational efforts should also include 
educational efforts directed at health care professionals and 
consumers. NDAC was concerned about the lack of available data on which 
to base such advice, noting that there is a lack of information about 
how to determine the amount of alcohol that may be harmful to any 
individual. NDAC noted that reducing the risk of drug adverse events is 
the goal, but believed that more data are essential for them to make 
specific recommendations.
    FDA asked NDAC to comment on whether the current maximum allowable 
daily dose of acetaminophen should be used by individuals consuming 
three or more drinks per day. One NDAC member agreed that was prudent 
to lower the dose, however, the majority of NDAC members believed that 
more information is needed before dose reductions could be implemented 
for this population. NDAC stated that, intuitively, a lower dose would 
decrease potential toxicity, but noted that there is a lack of 
information to support such labeling.
    One NDAC member mentioned that although some evidence appeared to 
show an association of increased acetaminophen toxicity for patients 
with pre-existing liver disease, this finding is contrary to 
hepatologists' experience with acetaminophen. Generally, acetaminophen 
is considered safe for use in patients with liver disease, including 
people awaiting liver transplantation. Most hepatologists recommend 
acetaminophen for such patients, but at reduced doses, such as 2 g 
maximum in a 24-hour period. NDAC urged more studies, not only of risk 
factors, but of a plan to reduce risk.
     Consumer and healthcare provider education. NDAC concluded 
that FDA and manufacturers have a joint responsibility to reduce the 
occurrence of unintentional overdoses from acetaminophen. NDAC 
considered it essential that consumer and professional educational 
programs heighten awareness of the risk, particularly to certain 
populations. NDAC believed consumers are unfamiliar with the term 
``acetaminophen'' and are more likely to know the brand names. NDAC 
stated that an effort should be made to create a broader educational 
campaign to inform consumers that acetaminophen is an analgesic, 
because most people are familiar with aspirin and not with 
acetaminophen. NDAC also suggested that the packaging, display, format, 
and wording recommendations in OTC drug product labeling should also be 
extended to all product advertisements, both in print and media, 
because advertising is an educational tool for many consumers.
    NDAC stated that many physicians and pharmacists may not be aware 
of the risks of unintentional overdose. NDAC added that, along with 
consumer education, professional programs are important, because 
prescription products containing acetaminophen are widely used. 
Education of pharmacists would be needed to support the use of 
additional labeling information (stick-on labels, etc.) attached to 
prescription containers. NDAC stated that auxiliary labeling is 
critical to conveying information that the prescription product 
contains acetaminophen.
     Pediatric dosage. NDAC also expressed concern about the 
lack of standardized pediatric dosage information, especially for 
infants under 2 years of age. FDA stated that a separate rulemaking on 
this issue was in progress and will be addressed in a future Federal 
Register publication.

C. Aspirin and Other NSAIDs

    On the second day of the meeting (September 20, 2002), NDAC 
considered safety issues related to the use of aspirin and other OTC 
NSAIDs. The primary areas for discussion included the potential for GI 
bleeding and renal toxicity from using these drugs. The prescription 
labeling for NSAIDs and the professional labeling for aspirin have 
warnings for GI bleeding and possible renal toxicity. Aside from the 
alcohol warning required on all OTC NSAID drug products, current OTC 
labeling does not have warnings about damage to specific organs.
1. Points for Discussion
    FDA asked NDAC to consider the relative risks for GI bleeding and 
renal toxicity associated with OTC doses of NSAIDs, including aspirin, 
and to consider the following issues:
     How should the relative risk of GI bleeding or renal 
toxicity be described to consumers who use the maximum recommended 
daily OTC dose?
     Are there subpopulations of consumers who are at a greater 
risk for developing GI bleeding or renal toxicity with OTC doses?
     If additional warnings are recommended, should such 
warnings inform consumers about the risk, provide information on the 
at-risk populations, or provide expanded information to all consumers 
about symptoms of toxicity?
     Should the warnings that are currently in professional 
labeling for aspirin be conveyed to consumers as part of the OTC 
labeling?
     If yes, which warnings should be conveyed and how should 
they appear in OTC drug product labeling?
     Are any additional studies needed to evaluate 
subpopulations at risk for serious adverse events, labeling revisions, 
and any other issues?
     Should the labeling and packaging of these products more 
prominently state that the product contains aspirin or the specific 
NSAID?
2. Presentations and Submissions to NDAC
GI bleeding
    FDA staff described cases of GI bleeding (spontaneous reports from 
AERS received by FDA between 1998 and 2001) in individuals who used OTC 
NSAIDS (including aspirin) as an analgesic and/or antipyretic (Ref. 8). 
The review was limited to cases that mentioned ``OTC'' in the narrative 
of the report. Any cases that appeared to involve prescription NSAID 
products were excluded. A total of 279 cases of

[[Page 77325]]

GI bleeding were included: 82 for aspirin and 197 for nonaspirin NSAIDs 
(i.e., ibuprofen, ketoprofen, and naproxen). The mean age was 59 years 
(ranging from 1 to 99 years). There were 138 (49.5 percent) males, 119 
(42.7 percent) females, and 22 cases (7.9 percent) in which gender was 
not reported.
    Cases that specified the location in the GI tract of the bleed 
included: Stomach (63 cases), duodenum (35 cases), unspecified upper GI 
site (15 cases), esophagus (13 cases), and rectum/colon/small intestine 
(9 cases). For nonaspirin NSAIDs, the median time to onset was 7 days. 
Time to onset was defined as the time between each person's first use 
of the drug and the time that bleeding occurred. For aspirin, time to 
onset was about 30 days. For both aspirin and nonaspirin NSAIDs, there 
was a wide range in time to onset. FDA reviewed the cases for common 
risk factors for GI bleeding that are recognized in the medical 
literature, including previous GI bleed or history of an ulcer, social 
history (alcohol or tobacco use), concomitant use of other drugs 
(NSAIDs, aspirin, anticoagulants, corticosteroids), use of doses higher 
than recommended, and advanced age (65 years and older). The results 
included 195 (70 percent) cases with at least one risk factor, 112 (40 
percent) cases with more than one risk factor, and 81 (29 percent) 
cases with no risk factors apparent in the report. The most commonly 
reported risk factors were:
     Concomitant use of another NSAID or aspirin (50 percent)
     Advanced age (40 percent)
     History of a previous GI bleed (18 percent)
     Using NSAID doses above the recommended OTC dose (14 
percent)
     Alcohol or tobacco use (5 percent).
    In the aspirin cases, only one person was reported to have exceeded 
the OTC recommended dose. Of the 279 aspirin and nonaspirin cases, 212 
people (76 percent) were hospitalized. Most recovered; however, 13 (4.7 
percent) people died.
    FDA indicated that these reports suggest that serious GI bleeding 
events can occur with NSAID and aspirin use at OTC dosage strengths, 
within the duration of use described in the OTC labeling.
    Dr. Byron Cryer, of the University of Texas Southwestern Medical 
School, provided an overview of the GI risks from NSAID use (Ref. 9). 
His review was not limited to OTC dosing of NSAIDs and extended to all 
NSAIDs. He made the following points:
     Despite the overall decrease in prevalence of 
uncomplicated ulceration, the incidence of complicated ulcerations 
(specifically, bleeding ulcers) has increased in the past few years. 
This is likely due to increased NSAID exposure, possibly from OTC use. 
Gastric ulceration (15 percent prevalence) associated with NSAIDs (at 
recommended doses) is much more common than duodenal ulceration (5 
percent prevalence). Clinically relevant ulceration (i.e., ulcers that 
present with bleeding), has a prevalence of approximately 2 percent.
     A history of prior bleeding, anticoagulant use, 
corticosteroid use, and increasing age are factors that increase the 
risk of bleeding associated with NSAIDs (Refs. 10 through 13).
     The prevalence of upper GI bleeding from aspirin use is 
different than for nonaspirin NSAID use. A study evaluated the 
prevalence of aspirin and nonaspirin NSAID use in 421 patients 
evaluated for upper GI bleeding (Ref. 14). Patients were asked at the 
time of hospital admission whether they were using prescription or OTC 
products and whether they were using nonaspirin NSAIDs or aspirin. The 
results show that 42 percent of GI bleeding was associated with aspirin 
use. Fourteen percent of patients admitted to the hospital were using 
prescription NSAIDs and 9 percent were using OTC NSAIDs.
     A recent study suggests that up to 80 percent of people 
with GI bleeding are taking an NSAID, primarily low dose aspirin (Ref. 
15). The relative risk (RR) (i.e., the probability of an event in the 
active group divided by the probability of the event in the control 
group) was 2.4 for a low/medium NSAID dose and 4.9 for a high dose.
     Another study compared the use of OTC aspirin, ibuprofen, 
naproxen, and acetaminophen between two case groups, one group who 
experienced GI bleeding events and a control group of cases who did not 
experience GI bleeding (Ref 16). The patients in the GI bleeding group 
were more likely to be taking aspirin or OTC NSAIDs prior to the GI 
bleeding event than were patients in the control group. The extent of 
use of acetaminophen was comparable between the two groups. This study 
included people with chronic disease and chronic analgesic exposure, 
providing information about a subgroup of patients that may be 
different from relatively healthy individuals exposed to OTC analgesics 
for acute, short-term, or intermittent use.
     The risk of combining low dose aspirin with nonaspirin 
NSAIDs was examined in a large national cohort study in Denmark (Ref. 
17) in which 27,000 people were given 100 to 150 mg aspirin every day. 
The study showed that there is an increased risk of upper GI bleeding 
in patients who combine low dose aspirin and other NSAIDs compared to 
the incidence of GI bleeding events in the general population (RR 5.6; 
95% confidence interval (CI) 4.4--7.0). The risk of GI bleeding among 
patients taking more than one NSAID was approximately double the risk 
among patients taking aspirin alone.
     In an American College of Gastroenterology Bleeding 
Registry (Ref. 18), cases of GI bleeding were assessed for use of 
aspirin or OTC NSAIDs and concomitant use of alcohol. These cases were 
compared to data from a control cohort of cases with no GI bleeding. 
The results suggest an increased risk of bleeding when alcohol is used 
while taking an OTC NSAID (odds ratio 4.47; 95 percent CI 2.73 -7.32) 
compared to the use of either alcohol or OTC NSAIDs alone (odds ratio 
for alcohol alone 2.07; 95 percent CI 1.48--2.88/ odds ratio for NSAID 
alone 2.76; 95 percent CI 2.03--3.74). Dr. Cryer noted that the results 
of the study were confounded because 12 percent of the subjects in the 
registry had gastric or esophageal varices (enlarged veins). He 
suggested that there may be an increased risk particularly to patients 
with an extensive history of alcohol use who are exposed to OTC NSAIDs.
     Another report (Ref. 19) evaluated subjects who regularly 
or occasionally used aspirin or ibuprofen and compared the RR of GI 
bleeding between those who never used alcohol and those who used 
alcohol. The results suggest a modest increase in RR of upper GI 
bleeding in alcohol users; however, the statistical analyses did not 
provide a strong distinction between alcohol users and non-users.
    Dr. Marie Griffin of Vanderbilt University discussed additional 
information obtained from large population studies regarding GI 
complications associated with the use of NSAIDs (Ref. 20). She made the 
following points:
     The risk of ulcer disease was shown to increase 10-fold in 
older people and this risk is increased further by use of NSAIDs (Ref. 
21). This ulcer hospitalization study found the absolute risks to 
increase from approximately 4 hospitalizations per 1,000 person-years 
in older non-users of NSAIDs to approximately 16 hospitalizations per 
1,000 person-years in older users of NSAIDs. In general, consumers 
taking NSAIDs for a year at moderate doses have about a 1 to 2 percent 
chance of being hospitalized with a complication.

[[Page 77326]]

     The risk of hospitalization for peptic ulcer disease 
(PUD), and risk of GI complications, increases with increasing NSAID 
doses (Refs. 20, 22, and 23).
     Data obtained from the Tennessee Medicaid database 
indicate that the greatest absolute risk for hospitalization for PUD 
occurs in the first 30 days of NSAID use among patients older than 65 
years of age (Ref. 23). For older patients, there were 26.3 
hospitalizations for PUD per 1,000 NSAID users per year within 30 days 
of starting NSAID therapy, 20.9 hospitalizations between 31 and 180 
days of use, and 16.2 hospitalizations for use longer than 180 days. In 
contrast, there were 4.2 hospitalizations per 1,000 NSAID non-users per 
year. Overall, people of all ages have a 1 to 2 percent chance of being 
hospitalized with a complication when using NSAIDs for over a year at 
moderate doses.
     Surveys in the 1980s showed that approximately 1 to 3 
percent of people 65 and older take a prescription corticosteroid drug. 
The concomitant use of an OTC NSAID with a corticosteroid increases the 
risk of ulcer complication 13- to 15-fold over NSAID non-users. The 
ulcer hospitalization rate in people using both drugs was about 5 to 6 
per 100 people per year.
     In the 1980s, 1 to 2 percent of the elderly population 
were co-prescribed warfarin (an anticoagulant drug) and NSAIDs. The 
risk of GI bleeding increased by 12 fold in patients who used both 
therapies compared to NSAID non-users. The risk of hospitalization for 
GI bleeding is approximately 3 per 100 per year in patients who use 
warfarin and NSAIDs.
    Several drug manufacturers and others provided additional comments 
(Ref. 4):
     One drug manufacturer of ibuprofen OTC drug products 
stated that the OTC ibuprofen daily regimen is 1,200 mg/day versus 
2,400 to 3,200 mg a day for prescription use. Unlike acetaminophen, the 
OTC directions clearly state to take one 200-mg tablet and, only if 
necessary, a second tablet may be taken. OTC use of NSAIDs is limited 
to a maximum of 10 days, whereas prescription use is chronic.
     One drug manufacturer stated that each analgesic 
ingredient requires appropriate labeling for its pattern of use and 
that it is inappropriate to label OTC products with risks associated 
with chronic, long-term prescription dosing. The prescription and OTC 
uses of NSAIDs are distinct and these two dose levels have different 
risk-benefit profiles. The OTC use is short-term for pain relief and 
fever reduction, with a low risk. Results of prevention studies of 
secondary and acute myocardial infarction have shown that for people 
whose 10-year risk of having a subsequent cardiovascular event is 
between 20 and 50 percent, the cardiovascular benefit of aspirin far 
outweighs the risks. The relative and absolute risks of aspirin are 
low.
     One consumer advocacy organization stated that GI bleeding 
caused by NSAIDs (reference to prescription or OTC products was not 
specified) is now recognized as the most common serious adverse drug 
reaction in the United States and accounts for as many as 16,000 deaths 
a year. The organization requested that: (1) Product labeling contain a 
clear organ-specific warning about GI bleeding, (2) packaging include 
consumer education on GI bleeding, such as a leaflet inside the 
packaging listing specific symptoms and factors associated with 
increased risk, and (3) a separate warning, about increased risk of GI 
bleeding associated with alcohol use, be added and directed at 
consumers who drink some alcohol.
    Several drug manufacturers submitted additional information (Ref. 
5):
     One manufacturer stated that the safety profile for OTC 
ibuprofen, generated over 18 years of OTC use by millions of consumers, 
indicates that the current labeling has been effective in informing 
consumers of the appropriate use of the drug (Ref. 5, Tab E). The 
manufacturer stated that FDA has received an average of 18 reports per 
year of GI perforations, ulcers, or hemorrhage associated with OTC use.
     One manufacturer stated that no antidote is available for 
aspirin or ibuprofen overdose (Ref. 5 Tab F). Acute overdose and 
chronic aspirin toxicity are associated with significant morbidity (as 
high as 25 percent). If acetaminophen was restricted, aspirin and other 
NSAID use would increase. Available data suggest that more people would 
die from aspirin and other NSAID-related GI bleeding. The net public 
health impact of changing labeling for OTC IAAA drug products should be 
taken into consideration in the formulation of any regulatory policy.
     One manufacturer stated that the risk patterns associated 
with use of acetaminophen and aspirin are distinct from one another and 
support different product labeling for the various ingredients in OTC 
IAAA drug products (Ref. 5, Tab G). There are no data to support the 
view that a balanced warning for acetaminophen will cause a significant 
number of patients to switch to another OTC analgesic. Available data 
indicate that both the absolute number, and the rate (per billion 
tablets sold), of fatalities associated with acetaminophen overdose in 
the United States significantly exceeds the corresponding figures for 
aspirin overdose.
     One manufacturer stated that the occurrence of GI adverse 
events with naproxen/naproxen sodium at single low dose (220 mg), at 
multiple doses (up to 880 mg), and as needed OTC doses, are comparable 
to the occurrence associated with use of placebo (Ref. 5, Tab H). 
Nausea, dyspepsia, and vomiting are the most common GI adverse events.
Renal effects
    FDA staff presented information about the potential for OTC NSAIDs 
to cause nephrotoxicity (Ref. 24) and made the following points:
     NSAID-induced nephrotoxicity at prescription doses is 
characterized by fluid and electrolyte disturbances leading to sodium 
retention, edema (accumulation of watery fluid in cells and tissues), 
and hyperkalemia (high concentration of potassium in the blood). These 
drugs can also cause blood pressure to increase. The majority of 
healthy people who are exposed to therapeutic doses of NSAIDs for a 
limited time tolerate these drugs without untoward renal effects. Some 
subsets of the population are more susceptible to potentially life-
threatening nephrotoxicity (e.g., acute renal failure and serious fluid 
and electrolyte disorders), including people who have volume depletion, 
underlying kidney disease, congestive heart failure, or liver 
dysfunction with ascites (accumulation of fluid in the peritoneal 
cavity of the abdomen), and the elderly. The use of NSAIDs in the last 
trimester of pregnancy has been associated with significant neonatal 
nephrotoxicity.
     Ideally, an assessment of the nephrotoxic risk associated 
with OTC NSAIDs should rely on data derived from prospective, 
randomized, placebo-controlled and adequately powered studies in 
healthy, as well as at-risk, populations. However, such data are not 
available. In 1995, the National Kidney Foundation (NKF) convened a 
group of investigators and clinicians to consider and develop 
recommendations on the issue of analgesic-related kidney disease. The 
database used to make their recommendations was comprised of 556 
articles published in the medical literature on aspirin, acetaminophen, 
aspirin-acetaminophen combinations, and NSAID-related nephrotoxicity. 
The NKF recommended ``[t]here should be an explicit label warning 
people taking over-the-counter NSAIDs of the potential renal risks of 
consuming the drugs.''

[[Page 77327]]

     FDA staff identified all cases in the AERS database 
reporting acute renal failure, chronic renal failure, and renal failure 
in association with the use of OTC doses of NSAIDs. The time period 
reviewed was from the OTC approval date for ibuprofen (1984), naproxen 
sodium (1994), and ketoprofen (1995) through August 10, 1999. FDA's 
review included cases that specified that either OTC dosages and/or an 
OTC NSAID product had a role in the adverse reaction. People with pre-
existing conditions were not included. Table 9 shows the number of 
cases of renal failure reported, including 94 cases for ibuprofen, 26 
cases for naproxen sodium, and 1 case for ketoprofen. Fifty-six people 
who used ibuprofen required hospitalization; nine needed dialysis; and 
nine died. Renal failure occurred within less than 7 days of exposure 
to the drug. Fourteen ibuprofen cases were within the pediatric age 
group. For naproxen sodium, 25 people were hospitalized, 4 required 
dialysis, and 3 died. The single ketoprofen case was hospitalized.

                        Table 9.--FDA AERS Cases of Renal Failure at OTC Doses of NSAIDs
----------------------------------------------------------------------------------------------------------------
                                  Ibuprofen                  Naproxen Sodium                 Ketoprofen
----------------------------------------------------------------------------------------------------------------
Reporting Period                            15 years                       5 years                       4 years
----------------------------------------------------------------------------------------------------------------
Renal Failure Cases--                             94                            26                             1
 Total
----------------------------------------------------------------------------------------------------------------
Renal Failure Cases--                             80                            26                             1
 Adult
----------------------------------------------------------------------------------------------------------------
Renal Failure Cases--                             14                             0                             0
 Pediatric
----------------------------------------------------------------------------------------------------------------

    Next, Dr. Griffin discussed renal complications from the use of 
NSAIDs obtained from large population studies (Ref. 20). A study of 
patients 65 years of age and older in the Tennessee Medicaid database 
(Ref. 23) included the following information:
     Eighteen percent of the patients presenting with acute 
renal failure used NSAIDs at either prescription or OTC doses. A RR for 
acute renal failure in NSAID users was calculated to be 1.58 compared 
to NSAID non-users.
     The RR for acute renal failure with ibuprofen was dose 
related. The RR of acute renal failure associated with use of daily 
doses of less than 1,200 mg was approximately 1 compared to use of no 
ibuprofen. Daily doses of 1,200 to 2,400 mg (above the OTC range of 
1,200 mg per day or less) increased the RR of renal failure to 1.89.
     The greatest risk for renal failure was within the first 
30 days of therapy with an NSAID. The RR was 2.83.
    Several drug manufacturers and others provided additional comments 
(Ref. 4). One drug manufacturer stated that the incidence of renal 
failure and other serious renal events are rare with use of either 
prescription or OTC ibuprofen. One drug manufacturer claimed that there 
was an average of approximately five reports of renal failure per year 
from FDA's safety surveillance data. The manufacturers also suggested 
that serious renal events are almost always reversible, even in the 
elderly or chronically ill. It was stated that serious renal events 
following NSAID therapy almost always occur in patients with pre-
existing renal dysfunction, congestive heart failure, or compromised 
hepatic function.
    Several drug manufacturers submitted additional information 
suggesting that (Ref. 5):
     The number of renal side effects that have been reported 
with OTC ibuprofen are minimal (less than two cases of renal failure 
per year), confirming that the drug is well-tolerated.
     The renal safety profile of naproxen/naproxen sodium is 
consistent with other currently marketed NSAIDs with which it has been 
compared. Even at prescription doses, reports of adverse events 
involving the kidney have been rare.
3. NDAC Deliberations and Recommendations Concerning Aspirin and Other 
NSAIDs
     GI bleeding. NDAC members agreed that NSAIDs increase the 
risk for GI adverse events. The risk appears to be related to dose. 
Aspirin, even at lower doses, has some GI risks. However, the benefits 
from use far exceed any risks. NDAC stated that low dose aspirin should 
be available OTC for the elderly for cardiovascular prophylaxis as 
described in the professional labeling. NDAC believed that the absolute 
risk of GI bleeding from use of low dose aspirin is probably comparable 
to the risk from using aspirin at analgesic doses. Therefore, NDAC 
recommended that the information on risk provided in OTC aspirin 
labeling to consumers need not be categorized by dose.
    NDAC agreed that the data support a separate and distinct stomach 
bleeding warning and suggested that the heading ``stomach bleeding 
warning'' be used. NDAC recommended that this heading be in bold type 
and that the warning be included as one of the first warnings in 
labeling along with the Reye's syndrome warning. One NDAC member 
suggested the heading ``bleeding alert'' because aspirin and the other 
NSAIDs can cause more than stomach bleeding, and it is very important 
to stop using an OTC IAAA active ingredient when signs of bleeding are 
present (e.g., vomiting blood or bloody or black stools). Most NDAC 
members felt that stomach bleeding was the major safety problem and 
should be the focus of the warning statement.
    NDAC found that low dose aspirin, combined with another NSAID, will 
increase the risk for GI bleeding two to four times more than use of an 
NSAID alone. From the data reviewed, enteric-coated or buffered aspirin 
preparations do not change the risk associated with use of multiple 
NSAID products. NDAC recommended that the labeling for aspirin and 
other NSAIDs include a stomach bleeding warning advising consumers of 
the risks of taking more than directed or using more than one NSAID. In 
addition, NDAC concluded that the warning should advise consumers that 
the risk is greater for individuals who are over 65 years of age, have 
a history of ulcers, stomach, or bleeding problems, or are taking 
steroids or anticoagulants (blood thinners).
    A majority of NDAC members believed that there were insufficient 
data and a lack of a scientific rationale to support a warning about 
using alcohol while taking NSAIDs. Recognizing that the data are mixed 
and not conclusive, the members believed that a majority of the trials 
reviewed failed to show a direct and convincing association with 
alcohol. NDAC urged FDA to remove the existing alcohol warning from 
labeling and encouraged

[[Page 77328]]

FDA to examine future cases of GI bleeding in individuals who consume 
alcohol and are alcohol abusers to explore the impact of concomitant 
use of NSAIDs.
     Renal effects. NDAC considered particular groups at risk 
for short-term adverse renal consequences from NSAID use. While NDAC 
agreed that small increases in blood pressure of limited duration 
(e.g., several days) in normotensive or hypertensive individuals is not 
a significant risk, the labeling for NSAIDs should warn about the 
potential association of long-term use and renal failure in individuals 
who have high blood pressure, heart or kidney disease, use diuretics, 
or are over 65 years of age. NDAC agreed with the OTC labeling proposed 
for ibuprofen in the Federal Register of August 21, 2002, including the 
warning to ask a doctor before use in the presence of high blood 
pressure, heart or kidney disease, if also using a diuretic, or if over 
65 years of age.
    Labeling. NDAC members agreed that labeling continues to be a major 
factor in promoting the safe and effective use of OTC NSAID products. 
NDAC expressed concern that consumers do not read labels adequately and 
are often unaware of the names of the medicines that they are taking. 
This lack of awareness is especially problematic for people who are 
also taking prescription medicines concomitantly with OTC drug 
products. NDAC expressed concern about the ability to communicate 
meaningful information in the confines of a small package label, 
especially to the elderly. NDAC suggested that patient information be 
included in a package insert to provide expanded information beyond 
what could be presented clearly on a small label.
    NDAC strongly recommend that the term ``NSAID'' be used throughout 
OTC product labeling. The term NSAID is becoming more widely recognized 
and is often found in drug information leaflets. NDAC suggested that 
meaning of the NSAID acronym could be spelled out somewhere on the 
label. Additionally, NDAC recommended that this term should be included 
on the front panel or PDP, advising consumers that the product contains 
an NSAID, especially if the product is a combination containing an 
NSAID. Finally, NDAC members agreed that there is a need for additional 
label comprehension studies to identify ways to improve communication 
with consumers.

IV. FDA's Review of Additional Data and Information

A. Pre-existing Liver Disease as a Risk Factor for Acetaminophen 
Hepatotoxicity

    Following publication of the OTC IAAA TFM in 1988, FDA received 
comments urging adoption of a warning to advise consumers with pre-
existing liver disease against using acetaminophen, unless directed by 
a doctor. The comments cited reports in the medical literature 
concerning toxicity in persons with liver disease. Other comments 
asserted that there is no evidence to warrant a warning. At that time, 
FDA believed the evidence was insufficient to propose a warning. NDAC 
briefly discussed this issue in September 2002, but concluded that 
there were not sufficient data to make specific recommendations.
    FDA has reconsidered its previous position on this issue and now 
believes that the current evidence supports a warning. At the NDAC 
meeting, FDA reported information derived from mortality data of 
acetaminophen overdose (intentional and unintentional). Among patients 
with chronic alcoholic or other chronic liver disease, death associated 
with unintentional acetaminophen overdose was reported far more 
frequently than in association with intentional overdose (see table 4 
of this document). In the series of 282 AERS cases of hepatoxicity 
associated with acetaminophen use presented at the meeting, 70 cases 
were reported as having underlying liver disease.
    Metabolic activation and deactivation are involved in acetaminophen 
elimination (Ref. 25). At a therapeutic dose, the majority (greater 
than 90 percent) of acetaminophen combines with glucuronic acid (the 
major metabolic pathway for adults) and sulfuric acid (the major 
metabolic pathway for children). There is also a second, minor 
metabolic pathway in which a small portion of acetaminophen undergoes 
cytochrome P450 phase I metabolism to the toxic acetaminophen 
metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). This toxic metabolite 
is normally inactivated through combination with hepatic glutathione 
(GSH). Any factors that can change GSH availability (by decreasing 
synthesis and/or increasing utilization or interfering with the 
conjugation enzyme) could potentially influence the hepatotoxicity of 
acetaminophen. Any factors that disturb the balance between these two 
metabolic pathways may affect the amount of acetaminophen metabolized 
by each pathway. After the NDAC meeting, FDA conducted a literature 
review (1966 to January 2003) and determined that the following factors 
may place patients with pre-existing liver disease at a greater risk 
for acetaminophen toxicity (Ref. 26).
     Depletion of hepatic GSH has been found in both alcoholic 
and nonalcoholic liver diseases, suggesting that the diseased liver may 
have less capacity to inactivate the toxic metabolite of acetaminophen. 
(Refs. 27 through 34)
     The hepatic cytochrome P450 enzyme, P450-2E1, metabolizes 
acetaminophen to the toxic metabolite that causes hepatotoxicity. 
Expression of hepatic P450-2E1 tends to increase in stable chronic 
liver diseases.
     Studies have shown that the clearance of acetaminophen 
from the body is impaired in people with chronic liver disease (Refs. 
35, 36, and 37). The disease status of the liver alters drug metabolism 
and drug metabolites made by each metabolic pathway (Refs. 38 and 39).
     In chronic liver disease, hepatic glucuronide and sulfate 
conjugation are decreased (Refs. 40 through 43).
     Significant impairment of total hepatic P450 expression is 
found only in people with severe liver disease (hepatitis with liver 
failure and decompensated cirrhosis) (Ref. 38). Recent studies indicate 
that different types (viral, chemical, or immunological factors) and/or 
states (acute, chronic, or severe) of liver disease selectively 
influence expression of different P450 isozymes.
     Chronic alcohol use significantly induces hepatic P450-2E1 
and increases this enzyme's ability to metabolize acetaminophen to 
NAPQI (Ref. 44). In other types of human liver disease, changes in 
expression and activity of P450-2E1, as well as other P450 isozymes 
(1A2 and 3A4) involved in acetaminophen metabolism, are variable (Refs. 
38, 45, 46, and 47). Both human and animal studies show that hepatic 
P450-2E1 expression is significantly increased in a nonalcoholic fatty 
liver (Refs. 48 and 49).
    Few clinical trials directly assess the hepatotoxicity of 
acetaminophen in people with nonalcoholic liver disease. One double-
blind, placebo controlled, crossover study was conducted in 20 people 
with stable chronic liver disease (including Laennec's cirrhosis, 
alcoholic liver cirrhosis, primary biliary cirrhosis, or chronic 
hepatitis) (Ref. 50). The subjects received 1 g of acetaminophen or 
placebo every 4 hours (a total of 4 g/day) for 13 days. The author 
stated that there were no significant changes in laboratory tests or 
clinical status in the

[[Page 77329]]

acetaminophen and placebo treatments. The author concluded that 
underlying liver disease does not increase patient sensitivity to the 
hepatotoxic effects of acetaminophen at a therapeutic dose. Because of 
the small sample size and crossover study design, FDA believes this 
study is inadequate to make any conclusions regarding the risk for 
acetaminophen hepatotoxicity in patients with chronic liver disease.
    In summary, the single prospective clinical study found by FDA in 
the literature that evaluated the susceptibility of the diseased liver 
to acetaminophen toxicity was not definitive. Analyses of an 
acetaminophen overdose database and a review of the AERS case reports 
suggest, however, that people with a history of liver disease may have 
increased susceptibility to acetaminophen-induced hepatotoxicity. In 
addition, the depletion of hepatic GSH has been found in both alcoholic 
and nonalcoholic liver diseases, suggesting that the diseased liver may 
have less capacity to inactivate the toxic metabolite of acetaminophen. 
Expression of hepatic P450-2E1, a major enzyme for metabolic activation 
of acetaminophen, tends to be increased in stable chronic liver 
diseases, particularly in nonalcoholic fatty liver disease. FDA 
believes that these data collectively establish that it is necessary to 
alert patients with chronic liver disease that they may be at risk for 
developing acetaminophen hepatotoxicity, as an important factor in the 
safe and effective use of acetaminophen products.

B. Updated Literature About Acetaminophen Hepatoxicity

    The Acute Liver Study Group recently published an update of the 
prospective data in patients diagnosed with ALF at 22 tertiary care 
centers. Over a 6-year period from January 1, 1998, to December 31, 
2003, 662 patients fulfilled standard criteria for ALF. Of these cases, 
275 were attributed to acetaminophen hepatotoxicity. The criteria for 
attribution to acetaminophen included one or more of the following: (1) 
A history of potentially toxic acetaminophen ingestion (> 4 g/day) 
within 7 days of presentation; (2) detection of any level of 
acetaminophen in the serum; or (3) a serum alanine aminotransferase 
(ALT) > 1,000 IU/L with a history of acetaminophen ingestion, 
irrespective of acetaminophen level (Ref. 51).
    Of the 275 cases attributed to acetaminophen, the following 
observations were made:
     48% were designated as unintentional injury, 44% were 
designated as an intentional injury and 8% could not be classified to 
either group;
     147 (53%) used an OTC product, including 6 of 147 who used 
more than one OTC product at the same time and 41 of 147 who also used 
a prescription combination product;
     120 (44%) reported use of a narcotic/acetaminophen 
combination;
     55% had a history of alcohol use and 35% had a history of 
alcohol abuse;
     108 (39%) also used a antidepressant;
     65% survived without transplant; and
     22% used more than one acetaminophen product.
    The authors also compared characteristics between those classified 
as unintentional versus intentional liver injury. Females predominate 
in both groups. The clinical outcomes are similar for both groups. 
Narcotic/acetaminophen use was more prevalent in the unintentional 
injury group (63% vs. 18%). The unintentional injury group had a 
greater percentage with stage 3-4 hepatic coma score at admission and 
at peak during the hospitalization. FDA believes that these data 
support the previous NDAC conclusion that acetaminophen hepatotoxicity 
is an important public health consideration and that additional 
labeling is necessary for it to continue to be generally recognized as 
safe and effective.

C. Aspirin and Other NSAIDs

1. GI Bleeding
    Following the NDAC meeting, FDA reviewed additional data and 
information related to the use of OTC NSAIDs and GI bleeding.
     One individual asserted in a citizen petition that 
incomplete information about aspirin reaches consumers and increases 
the danger that aspirin will be misused with serious consequences (Ref. 
52). The citizen petition suggested that additional labeling for 
aspirin should be implemented without delay to state: ``CAUTION: This 
product can cause severe hemorrhaging and should not be taken for more 
than five days except under the supervision of a physician. When used 
for fever, if symptoms persist more than three days, consult a 
physician.''
     NSAIDs are being used by an estimated 17 million Americans 
on a daily basis (Ref. 53). The estimated rate of serious adverse 
events is about 1 percent for clinically significant GI bleeding in the 
first 3 months of use (Ref. 54). NSAID use is so widespread that NSAID-
induced gastropathy has been identified by some as one of the most 
prevalent, serious drug toxicities in the United States (Ref. 55). 
NSAID-associated serious GI complications are estimated to result in 
over 200,000 hospitalizations per year in the United States. Although 
these adverse event rates are for prescription and OTC NSAID 
formulations combined, there is a significant prevalence of OTC NSAID 
use among people presenting to hospitals with upper GI bleeding (Ref. 
56). The rate of consumption of OTC NSAIDs by consumers is estimated to 
be as much as seven times that of prescribed NSAIDs (Ref. 54).
     The American College of Gastroenterology guideline for 
treatment and prevention of NSAID-induced ulcers indicates an increased 
risk of NSAID-associated GI complications for people greater than 60 
years of age (Ref. 56). A United Kingdom (UK) population-based, 
retrospective case-control study evaluated the risk of various NSAIDs 
(Ref. 10). The study reported a RR of 3.7 for upper GI bleeding (UGIB) 
and GI perforation in people under 60 years old exposed to NSAIDs, 13.2 
in people 60 years and older exposed to NSAIDs, and 2.8 in people 60 
years and older not exposed to NSAIDs.
     FDA analyzed a series of studies that used the Medicaid 
population in Tennessee (Refs. 12, 13, 56, 57, and 58). These case-
controlled retrospective studies were based on hospitalizations for GI 
bleeds. The study population totaled 103,954 individuals, about 15 
percent of Tennessee's elderly population, with 209,066 person-years of 
followup. There were 1,371 hospitalizations for PUD. These studies 
found increased risk of GI bleeds in people who were:
     Over 65 years old (RR of 4.7),
     Taking an increased NSAID dose (RR of 2.8 for the lowest 
dose vs. RR of 8 for the highest dose category), or
     Taking concomitant corticosteroid (RR of 4.4) or anti-
coagulant (RR 12.7) drug products.
    In addition, the risk of GI bleeds among people taking NSAIDs was 
greatest within the first 30 days of use (RR of 7.2).
     A multicenter, case-control study of 550 people with UGIB 
admitted to a hospital with bloody stools or vomiting blood and 1,202 
controls identified from census lists, compared risks of major GI 
bleeding for plain, coated, and buffered formulations of low-dose 
aspirin (Ref. 59). Each of these types of low-dose aspirin formulations 
(less than 325 mg

[[Page 77330]]

per day) had about a 2.5 to 3 times increased risk of major UGIB.
     A double-blind, randomized, placebo-controlled, ulcer 
prevention study in 8,843 people with rheumatoid arthritis identified 
several risk factors for upper GI complications from NSAID use: (1) Age 
75 years or older (odds ratio 2.48), (2) prior peptic ulcer (odds ratio 
2.29), (3) prior GI bleeding (odds ratio 2.56), and (4) history of 
cardiovascular disease (odds ratio 1.84) (Ref. 60).
     A case control study of 1,122 subjects admitted 
consecutively for UGIB to four hospitals in Spain and 2,231 controls 
from the same geographic area, showed that a prior history of UGIB is a 
risk factor (odds ratio 3.7) for UGIB in people who used NSAIDs (Ref. 
61).
    In summary, results of several large-scale clinical studies, 
conducted in the United States and worldwide, have established that use 
of OTC NSAIDs is an important risk factor for serious GI adverse 
events, especially bleeding. The risk is higher for people age 60 or 
older, who have a history of stomach ulcers or bleeding problems, or 
who use corticosteroids or anticoagulants.
2. Renal Effects
    NSAIDs decrease renal prostaglandin production, which may result in 
acute reduction in renal blood flow and glomerular filtration, leading 
to fluid retention, edema, and elevation of serum creatinine (Ref. 62). 
Marked reduction in renal blood flow may result in renal failure.
    NSAID use may also result in higher than normal levels of potassium 
in the bloodstream. This occurs most commonly in people with diabetes 
mellitus or mild to moderate renal insufficiency as well as in people 
taking beta-blocker, angiotensin-converting enzyme inhibitor, or 
potassium-sparing diuretic drugs.
    By inhibiting the production of vasodilatory prostaglandins, NSAIDs 
may decrease renal blood flow and the rate of glomerular filtration in 
subjects with congestive heart failure, liver failure with ascites, 
chronic renal disease, or those who are hypovolemic (abnormal volume 
decrease of circulating fluid (plasma) in the body) (Refs. 63, 64, and 
65).
    a. Pediatric population. The medical literature includes sporadic 
reports of acute renal failure in pediatric subjects taking ibuprofen 
within the OTC dose range, including the following cases:
     One article describes three cases in children 5-, 6.5-, 
and 7.5-years-old in which ibuprofen treatment led to varying degrees 
of renal failure (Ref. 66). Two subjects with dehydration and pre-
existing renal problems were prescribed ibuprofen for the treatment of 
fever due to acute illness. Both had a recovery of renal function on 
withdrawal of the drug. The third child (a 7.5-year-old girl) developed 
progressive chronic renal failure. She had underlying hyper Ig-E 
syndrome and was treated with a single dose of ibuprofen 5 mg /kg for 
fever due to severe pulmonary infection. Her illness was also 
complicated by moderate dehydration. Her renal biopsy showed evidence 
of kidney damage consistent with loss of blood circulation.
     Ibuprofen-induced acute renal failure was reported in a 9-
month-old girl (Ref. 67). A family practitioner treated the infant for 
diarrhea, vomiting, and fever. She was given oral rehydration therapy 
and acetaminophen and was sent home. Symptoms persisted for 48 hours 
and the acetaminophen was changed to ibuprofen 50 mg (5 mg/kg/dose) 
three times a day. Seven doses of ibuprofen were given over a 40-hour 
period, but the child's clinical state deteriorated. She was admitted 
to an emergency facility 18 hours after the last dose with a creatinine 
concentration of 2.1 mg/deciliter (dL). For the first 12 hours after 
admission, the infant's kidneys failed to secrete urine in spite of 
receiving adequate hydration and an intravenous diuretic (furosemide). 
The creatinine concentration increased to 2.4 mg/dL. Renal function 
slowly recovered; 4 days after admission her creatinine was 0.9 mg/dL 
and 3 weeks later was 0.5 mg/dL. Clinical diagnosis was kidney damage 
secondary to ibuprofen use in a dehydrated child.
     Primack, et al. reported acute renal failure with use of 
ibuprofen in an 11-year-old boy (Ref. 68). The child was diagnosed with 
possible sinusitis and given an antibiotic; on the third day symptoms 
worsened with associated headaches, fatigue and anorexia, and his serum 
creatinine was 0.7 mg/dL. The antibiotic was continued and ibuprofen 
200 mg was added, alternating with acetaminophen every 4 hours for 
fever. He received a total of 24 200-mg ibuprofen tablets during the 12 
days prior to hospitalization. The fever persisted with improvement in 
the other symptoms. The child became progressively weaker and began 
vomiting. Approximately 2 weeks after his illness began, the child was 
admitted with a serum creatinine of 7.6 milliequivalent/L. After 3 days 
of symptomatic treatment, his serum creatinine was 4.1 mg/dL and 1 week 
later his serum creatinine was 2.2 mg/dL. Findings of renal biopsy on 
the third hospital day were consistent with acute interstitial 
nephritis, which the authors attributed to beta-lactam antibiotic use.
    These case reports demonstrate the variety of situations in which 
ibuprofen-associated renal toxicity can occur. In many of the cases, 
the children were already at risk for renal adverse effects because of 
underlying disease states, concomitant medications, or dehydration. 
Children with underlying illnesses or those dehydrated are at greatest 
risk for this injury. FDA currently requires all OTC pediatric products 
containing ibuprofen marketed under new drug applications to include 
warnings for children ages 2 to 11 years to ask a doctor before use if 
the child has ``not been drinking fluids'' or has ``lost a lot of fluid 
due to continued vomiting or diarrhea.''
    b. Alcohol use. Binge drinking of alcohol reduces the production of 
antidiuretic hormone causing increased urine production. Two cases of 
reversible acute deterioration in renal function following binge 
drinking of beer with use of NSAIDs have been reported in adults (Ref. 
69):
     The authors reported a case of a 22-year old male admitted 
to the hospital with low back pain and worsening renal function. Four 
days prior to admission, he had consumed an unknown amount of beer; 2 
days later as the pain intensified he had taken six doses of 400-mg 
ibuprofen with no relief. Upon admission, his serum creatinine was 3.1 
mg/dL. Biopsy of the kidney was consistent with the diagnosis of acute 
kidney failure. The subject's serum creatinine increased to a peak of 
6.5 mg/dL on the fourth day and decreased to 1.4 mg/dL 6 days later.
     In a second case, a 20-year old male was admitted because 
of flank and back pain of 24 hours' duration. Four days before 
admission, the subject drank 8 to 10 bottles of beer (355 mL per 
bottle). On the evening of admission, he had taken 6 to 8 tablets of 
325-mg aspirin for pain relief. The laboratory data showed a 2.0 mg/dL 
serum creatinine level. Following intravenous fluid administration, the 
subject urinated frequently for over 16 hours. Followup serum 
creatinine 1 week later was 1.2 mg/dL. The authors concluded that 
dehydration is a frequent consequence of heavy alcohol ingestion due to 
water diuresis. The volume contraction may be further aggravated by 
nausea and vomiting.
    In the proposed rule to amend the TFM for OTC IAAA drug products to 
include ibuprofen, FDA included the results of the agency's evaluation 
of the adverse renal effects of OTC doses of ibuprofen (67 FR 54139 at 
54144). Based on its evaluation of the data, FDA

[[Page 77331]]

concluded that OTC doses of ibuprofen can exert a variety of adverse 
renal effects, particularly in those who are dependent on adequate 
prostaglandin levels to maintain renal hemodynamic perfusion (i.e., 
congestive heart failure, liver failure with ascites, etc.). It was 
further noted that although the sporadic nature of idiosyncratic drug-
induced ibuprofen nephrotoxicity makes it impossible to predict which 
group of individuals is at risk for developing this event, this is not 
the case with individuals who experience prostaglandin-dependent 
hemodynamic changes. The latter, if recognized, is reversible upon 
discontinuation of the drug (67 FR 54139 at 54145).

V. FDA's Tentative Conclusions

    FDA has carefully considered NDAC's recommendations and other 
available data and information and determined that labeling revisions 
are necessary for OTC IAAA drug products to advise consumers of 
potential health risks and to recommend, under certain circumstances, 
that they consult a doctor for advice about taking products containing 
OTC IAAA active ingredients.
    FDA continues to believe that acetaminophen and NSAIDs, when 
labeled appropriately and used as directed, are generally recognized as 
safe and effective OTC IAAA drugs for consumer self-use. However, the 
available evidence clearly indicates that both drugs can cause serious 
side effects. When taken in excess amounts, acetaminophen can cause 
liver injury. NSAIDs have the potential to cause GI bleeding and renal 
(kidney) injury even at OTC dosing levels.
    When compared to the extensive use of OTC acetaminophen and NSAID 
drug products, the incidence of injury appears relatively low. However, 
based on the available evidence and the seriousness of the risks, FDA 
believes it is necessary for consumers to be made aware of the possible 
serious side effects associated with using these products. For many 
people, the risks are quite low because they use these products only 
occasionally. The risks may be greater for people who use these 
products more frequently, have certain risk factors, and/or do not 
follow the labeling information on the package. FDA believes that 
providing additional labeling information about how to correctly use 
OTC drug products containing acetaminophen and NSAIDs could reduce 
injuries and is necessary for the products to be considered generally 
recognized as safe and effective and not misbranded.
    FDA plans to act on several fronts:
     Propose revised OTC labeling for these products
     Continue a consumer and health provider educational 
campaign
     Continue to monitor AERS in various databases
     Examine available data to determine whether other measures 
may be needed in the future to try to decrease morbidity associated 
with OTC acetaminophen and NSAIDs.
    In addition to the changes to the IAAA TFM proposed in this 
document, FDA encourages manufacturers of these products to undertake 
education initiatives regarding safe use of OTC products containing 
acetaminophen and NSAIDs. FDA plans to increase its monitoring of AERS 
in various databases to see how this new proposed labeling, if 
implemented, is working to reduce injuries resulting from OTC 
acetaminophen and NSAID drug products and to determine whether further 
measures need to be proposed.

A. Acetaminophen

1. Hepatotoxicity
    FDA tentatively concludes that additional new labeling is needed 
for OTC drug products that contain acetaminophen. Data from Lee (Ref. 
6), a case series from the University of Pennsylvania Hospital (Ref. 
4), and the FDA AERS database show that unintentional overuse of 
acetaminophen is associated with severe hepatic injury. One 
manufacturer provided calculations of a ``worst case'' scenario for 
acetaminophen hepatic failure deaths using estimates by Lee (Ref. 70) 
and calculated 213 deaths per year. FDA does not know the exact number 
of cases of liver failure or deaths related to unintentional 
acetaminophen overdose. FDA thinks that improved labeling may help 
prevent events that are catastrophic to the unintentional victims and 
their family members. FDA has determined that adding a liver warning is 
necessary for safe and effective use of the drug and to reduce the 
number of unintentional overdoses. Thus, FDA is proposing a ``liver 
warning'' stating use factors that could lead to liver injury.
    FDA notes that NDAC recommended both an alcohol warning and a liver 
toxicity statement separate from the alcohol warning for OTC drug 
products containing acetaminophen. FDA has combined this information 
because it is interrelated and a shorter warning saves label space on 
products that already contain extensive labeling information. FDA 
believes that two, separate warnings may be less likely to be read and 
understood by consumers.
    FDA also tentatively concludes that a new warning is needed to 
advise consumers who have liver disease to consult a doctor before 
using OTC drug products that contain acetaminophen. FDA notes that many 
of the case reports in the databases involved people who had pre-
existing liver disease (the rate of the number of cases in the 
databases exceeds the rate of underlying liver disease in the general 
population). This observation may also be due to a difference in the 
use of acetaminophen by people with chronic liver disease or that they 
are at greater risk to develop liver failure in general. As described 
in section IV.A of this document, people with chronic liver disease can 
have changes in the liver enzymes responsible for the metabolism of 
acetaminophen. It is not clear whether these changes increase the risk 
in these individuals. It was noted at NDAC that some physicians who 
treat patients with chronic liver disease recommend lower total daily 
doses. FDA believes this additional warning will alert patients with 
chronic liver disease to ask their doctor before using acetaminophen. 
FDA recognizes there is limited information supporting the need for 
different dose recommendations in people with liver disease. FDA seeks 
comment on the information this warning should provide and encourages 
healthcare providers and researchers who treat patients with chronic 
liver disease to provide information on how much they recommend as an 
appropriate dose and the basis for their recommendation.
2. Other Labeling
    FDA also tentatively concludes that the name ``acetaminophen'' on 
the PDP should be enhanced to allow consumers to better identify 
acetaminophen containing products among the many products currently 
available on the OTC market. First, FDA is proposing that the name be 
highlighted (e.g., in fluorescent or color contrast to other 
information on the PDP) or in bold type so that the name is prominent 
and stands out from other text. Second, FDA is proposing that the name 
have a size that is prominent compared to other printed matter on the 
PDP. FDA's regulation for the statement of identity for OTC drug 
products in Sec.  201.61(c) (21 CFR 201.61(c)) states that ``the 
statement of identity shall be presented in bold face type on the PDP, 
shall be in a size reasonably related to the most prominent printed 
matter on such panel ***.'' FDA is proposing that manufacturers 
determine the prominence of the name ``acetaminophen'' on the PDP by

[[Page 77332]]

selecting, from the two options that follow, the print size option that 
is greater:
     The name ``acetaminophen'' is at least one-quarter as 
large as the size of the most prominent printed matter on the PDP; or
     The name ``acetaminophen'' is at least as large as the 
size of the ``Drug Facts'' title, as required in Sec.  201.66(d)(2) (21 
CFR 201.66(d)(2)).
    Finally, FDA notes that NDAC expressed concern about the lack of 
standardized pediatric dosage information, especially for infants under 
2 years of age. FDA intends to address this issue in another Federal 
Register publication.

B. Aspirin and Other NSAIDs

1. GI Bleeding
    FDA tentatively concludes that epidemiological data indicate a 
dose-related risk for GI bleeding with NSAIDs. The data demonstrate a 
slight increase in risk for GI bleeding at OTC daily doses. Because 
many people use OTC NSAIDs intermittently, the risk for bleeding for 
the average person is quite low. People who use NSAIDs for several days 
may be at greater risk but it is still low compared to chronic NSAID 
users. People who have certain identifiable risk factors (e.g., stomach 
ulcers or bleeding problems, taking certain other drugs or alcohol 
concurrently) are at greater risk of GI bleeding when they take a 
product containing an NSAID. FDA believes that additional warnings 
alerting these people about these potential risks and some of the 
symptoms associated with GI bleeding could reduce morbidity from using 
these OTC NSAID drug products.
    Based on the NDAC's recommendations and the agency's review of the 
literature, FDA has determined that additional new warning labeling is 
needed to continue to consider OTC NSAID products generally recognized 
as safe and effective. Such warnings should advise people not to take 
more than one product containing NSAIDs (aspirin, ibuprofen, naproxen, 
or others) and not to take more drug or take the drug for a longer time 
than recommended in product labeling. NDAC also acknowledged that 
people age 65 and older are at increased risk for GI bleed.
    FDA subsequently reviewed the results of several large-scale 
clinical studies, conducted in the United States and worldwide, and has 
established that use of NSAIDs is an important risk factor for serious 
GI adverse events, especially bleeding. These studies show that the 
risk is higher for people age 60 or older, who have had stomach ulcers 
or bleeding problems, or who use corticosteroids or anticoagulants 
(Refs. 10 and 55). Based on these studies, FDA believes that people 60 
years of age and older are at increased risk and is proposing to 
include this age group in the warning.
    In September 1993, NDAC concluded that the use of aspirin, 
ibuprofen, and naproxen sodium increases the risk of UGIB in people who 
are heavy alcohol users or abusers. At the September 2002 meeting, 
during discussion of the relative risks for GI bleeding associated with 
the use of OTC NSAIDs, some NDAC members questioned whether the 
incidence of GI bleeding is increased by the concurrent use of NSAIDs 
and alcohol. NDAC members were divided almost equally. Some members 
thought that there was no clear evidence that alcohol potentiates the 
risk of bleeding in NSAID or aspirin users. They proposed removal of 
the existing alcohol warning. Other NDAC members suggested that the 
alcohol warning should remain in effect, but be separated from the GI 
bleeding warning.
    Subsequently, FDA considered NDAC's recommendations and evaluated 
the alcohol warning for OTC drug products containing an NSAID. FDA did 
a new literature search, selecting new articles describing the 
relationship between alcohol use and the risk of GI bleeding in OTC 
IAAA users. After reviewing these articles (Ref. 71), FDA finds that 
these studies, despite some flaws in their design and methodology, 
suggest that combining NSAIDs with alcohol increases the risks of a GI 
bleed. FDA has determined that it is necessary to retain a warning 
regarding use of OTC NSAID drug products with alcohol. FDA tentatively 
concludes that a warning about this risk should be incorporated in a 
``Stomach bleeding warning'', in place of the current alcohol warning. 
Although NDAC recommended that a GI bleeding warning be distinct from a 
warning against alcohol ingestion with NSAIDs, FDA is proposing to 
combine these two warnings to conserve labeling space and avoid 
redundancy.
2. Renal Effects
    FDA tentatively concludes that people who get acute renal 
insufficiency from using NSAIDs generally have a pre-existing condition 
that will predispose them to this insufficiency. There is a 
pharmacological basis for this to occur. Normal renal blood flow 
depends on prostaglandin metabolism. NSAIDs inhibit renal prostaglandin 
production. In predisposed people, suppression of prostaglandin 
production may result in acute reduction in renal blood flow and 
glomerular filtration, leading to renal insufficiency. These cases are 
often reversible. Although the epidemiological data are limited and the 
number of reported cases are rare relative to their use, FDA believes 
it is important to alert consumers about underlying conditions that may 
increase their risk if they take an NSAID without first asking a doctor 
because of potential serious side effects.
    NDAC agreed with the OTC labeling proposed for ibuprofen in the 
Federal Register of August 21, 2002, including the warning to ask a 
doctor before use in the presence of high blood pressure, heart or 
kidney disease, concomitant use of a diuretic, or if they are over 65 
years of age. Based upon a further review of the literature that 
indicates that the risk is higher for people age 60 or older, FDA is 
proposing to lower the age from 65 years of age to 60 years of age.
    Children's NSAID products marketed under an NDA already have 
warnings regarding dehydration and fluid loss. FDA tentatively 
concludes that similar language is needed for children's NSAIDs 
products marketed under the OTC drug monograph. There are, however, few 
case reports suggesting a problem in adults. FDA is seeking comment on 
the need for similar language for adults. Although there are few 
reported cases in adults, it is anticipated that prostaglandin has 
similar effects on renal physiology.
3. Other Labeling
    FDA agrees with NDAC that the term ``NSAID'' should be prominently 
displayed in OTC drug product labeling so consumers are aware of the 
presence of the ingredient in the product. The term should also be 
defined in the labeling as ``nonsteroidal anti-inflammatory drug.'' FDA 
tentatively concludes that the presence of an ``NSAID'' ingredient in 
an OTC drug product should be prominently stated on the PDP and in the 
Drug Facts labeling.
    In section V.A.2 of this document, FDA discusses its proposed 
requirements for the name ``acetaminophen'' to be prominently presented 
on the PDP. FDA considers the same degree of prominence necessary to 
identify the presence of an ``NSAID'' ingredient in an OTC IAAA drug 
product. Accordingly, FDA is proposing that the name of the NSAID 
ingredient and the word ``(NSAID)'' be highlighted (e.g., fluorescent 
or color contrast) or in bold type, be in lines generally parallel to 
the base on which the package rests as it is designed to be

[[Page 77333]]

displayed, and be in one of the following sizes, whichever is greater: 
(1) At least one-quarter as large as the size of the most prominent 
printed matter on the PDP, or (2) at least as large as the size of the 
``Drug Facts'' title, as required in Sec.  201.66(d)(2). In the Drug 
Facts labeling, FDA is proposing that the active ingredient(s) section, 
as defined in Sec.  201.66(c)(2), be required to contain the term 
``(NSAID)'' after the NSAID active ingredient with an asterisk 
statement at the end of the active ingredient(s) section that defines 
the term ``NSAID'' as a `` * nonsteroidal anti-inflammatory drug.''
    In addition, FDA has conducted a detailed review of available data 
regarding the potential risks of serious cardiovascular events in 
patients receiving COX-2 selective and non-selective NSAIDs. FDA also 
held a joint meeting of its Arthritis and Drug Safety and Risk 
Management on February 16-18, 2005, to consider these issues. FDA is 
currently considering whether additional labeling changes related to 
these risks are warranted, and will address this in a future issue of 
the Federal Register.

VI. FDA's Proposal

    Based on the available evidence, FDA is proposing to amend its 
regulations and the OTC IAAA TFM to make a number of changes. FDA is 
proposing new labeling for OTC IAAA drug products (proposed Sec.  
201.325). This labeling includes a number of important new warnings. To 
alert consumers to these new warnings, FDA is proposing to require that 
the statement ``See new warnings information'' appear on the PDP of all 
OTC IAAA drug products for a limited time after the effective date of a 
final rule based on this proposal (proposed Sec.  201.325(b)).
    The labeling statements in this proposed rule are in the OTC Drug 
Facts labeling format (see Sec.  201.66), which is being implemented 
for all OTC drug products. For ease of reading, the following 
descriptions of the proposed labeling statements do not include the 
bracketed formatting instructions included in the codified portion of 
this document.

A. Alcohol Warning

    FDA is proposing to remove Sec.  201.322 of the regulations 
entitled ``Over-the-counter drug products containing internal 
analgesic/antipyretic active ingredients required alcohol warning.''

B. Acetaminophen

1. For All Acetaminophen Products
    Proposed Sec.  201.325(a)(1)(i) includes the following provisions:
     The presence of acetaminophen in the product must be 
prominently stated on the PDP. The word ``acetaminophen'' must appear 
highlighted (e.g., fluorescent or color contrast) or in bold type, be 
in lines generally parallel to the base on which the package rests as 
it is designed to be displayed, and be in one of the following sizes, 
whichever is greater: (1) At least one-quarter as large as the size of 
the most prominent printed matter on the PDP, or (2) at least as large 
as the size of the ``Drug Facts'' title, as required in Sec.  
201.66(d)(2).
     The presence of acetaminophen must appear as part of the 
established name of the drug, as defined in Sec.  299.4 (21 CFR 299.4).
     Combination products containing acetaminophen and a non-
analgesic ingredient(s) (e.g., cough-cold) must include the name 
``acetaminophen'' and the names of the other active ingredients in the 
product on the PDP. Only the name ``acetaminophen'' must appear 
highlighted (e.g., fluorescent or color contrast) or in bold type, and 
be in one of the following sizes, whichever is greater: (1) At least 
one-quarter as large as the size of the most prominent printed matter 
on the PDP, or (2) at least as large as the size of the ``Drug Facts'' 
title, as required in Sec.  201.66(d)(2).
2. For Acetaminophen Products Labeled for Adults Only
    Under proposed Sec.  201.325(a)(1)(iii), the labeling would be 
required to include the following statement:
    Liver warning: This product contains acetaminophen. Severe liver 
damage may occur if you take
     more than (insert maximum number of daily dosage units) in 
24 hours
     with other drugs containing acetaminophen
     3 or more alcoholic drinks every day while using this 
product.
    This ``Liver warning'' would be the first warning under the 
``Warnings'' heading. For products that contain both acetaminophen and 
aspirin, the ``Liver warning'' would appear after the ``Reye's 
syndrome'' and ``Allergy alert'' warnings in Sec.  201.66(c)(5)(ii)(A) 
and (c)(5)(ii)(B) and before the NSAID ``Stomach bleeding warning'' in 
proposed Sec.  201.325(a)(2)(iii)(A).
    The labeling would also be required to include the statements ``Do 
not use with any other drug containing acetaminophen (prescription or 
nonprescription). Ask a doctor or pharmacist before using with other 
drugs if you are not sure'' and ``Ask a doctor before use if you have 
liver disease.''
3. For Acetaminophen Products Labeled Only for Children Under 12 Years 
of Age
    Under proposed Sec.  201.325(a)(1)(iv), the labeling would be 
required to include the following statement:
    Liver warning: This product contains acetaminophen. Severe liver 
damage may occur if the child takes
     more than 5 doses in 24 hours
     with other drugs containing acetaminophen.
    This ``Liver warning'' must be the first warning under the 
``Warnings'' heading.
    The labeling would also be required to include the statements ``Do 
not use with any other drug containing acetaminophen (prescription or 
nonprescription). Ask a doctor or pharmacist before using with other 
drugs if you are not sure'' and ``Ask a doctor before use if the child 
has liver disease.''
    FDA is aware that products labeled for children only are sometimes 
used by adults who cannot take solid oral dosage forms or who are 
taking a product marketed in children's strengths. Accordingly, FDA is 
proposing to include the statement ``this product does not contain 
directions or warnings for adult use'' in bold type in the labeling of 
these products under the heading ``Directions''.
4. For Acetaminophen Products Labeled for Adults and Children Under 12 
Years of Age
    Under proposed Sec.  201.325(a)(1)(v), the labeling would be 
required to include all of the warnings for adults with the following 
modifications:
    Liver warning: This product contains acetaminophen. Severe liver 
damage may occur if
     adult takes more than [insert maximum number of daily 
dosage units] in 24 hours
     child takes more than 5 doses in 24 hours
     taken with other drugs containing acetaminophen.
     adult has 3 or more alcoholic drinks every day while using 
this product.
    This ``Liver warning'' must be the first warning under the 
``Warnings'' heading. FDA is proposing to use the term ``the user'' 
instead of ``you or the child'' for warnings applying to both children 
and adults. The ``ask a doctor'' statement is modified to read: ``Ask a 
doctor before use if the user has liver disease.''

C. Aspirin and Other NSAIDs

    The NSAID category includes, but is not limited to, aspirin, 
carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, 
magnesium salicylate,

[[Page 77334]]

naproxen sodium, and sodium salicylate. In the Federal Register of 
August 21, 2002 (67 FR 54139 at 54159), FDA proposed a number of 
warnings for products containing ibuprofen if added to the OTC IAAA 
drug products monograph. FDA is adding information and further revising 
portions of some of those warnings in this document and proposing these 
warnings be applicable to all OTC NSAIDs.
1. For All Products Containing NSAIDs
    Proposed Sec.  201.325(a)(2)(i) includes the following provisions:
     The presence of an NSAID ingredient in the product must be 
prominently stated on the PDP. The name of the NSAID ingredient and the 
word ``(NSAID)'' must appear highlighted (e.g., fluorescent or color 
contrast) or in bold type, be in lines generally parallel to the base 
on which the package rests as it is designed to be displayed, and be in 
one of the following sizes, whichever is greater: (1) At least one-
quarter as large as the size of the most prominent printed matter on 
the PDP, or (2) at least as large as the size of the ``Drug Facts'' 
title, as required in Sec.  201.66(d)(2).
     For single ingredient products, the word ``(NSAID)'' must 
appear as part of the established name of the drug, as defined in Sec.  
299.4 of this chapter, or as part of the statement of identity of the 
drug, as defined in Sec.  201.61 of this chapter. For example, either 
of the following would be acceptable:
     Ibuprofen Tablets (NSAID)
    Pain reliever/ fever reducer
    or
     Ibuprofen Tablets
    Pain reliever/ fever reducer (NSAID)
     Combination products containing an NSAID and a non-
analgesic ingredient(s) (e.g., cough-cold) must include the name of the 
NSAID ingredient and the names of the other active ingredients in the 
product on the PDP. The word ``(NSAID)'' must appear after either the 
name of the NSAID ingredient or the general pharmacological (principal 
intended) action of the NSAID ingredient (see previous examples). Only 
the name of the NSAID ingredient and the word ``(NSAID)'' must appear 
highlighted (e.g., fluorescent or color contrast) or in bold type, and 
be in one of the following sizes, whichever is greater: (1) At least 
one-quarter as large as the size of the most prominent printed matter 
on the PDP, or (2) at least as large as the size of the ``Drug Facts'' 
title, as required in Sec.  201.66(d)(2).
2. For NSAID Products Labeled for Adults Only
    Warnings for NSAIDS are proposed in Sec.  201.325(a)(2)(iii). Some 
of the proposed warning statements are discussed here.
    Stomach bleeding warning: This product contains a nonsteroidal 
anti-inflammatory drug (NSAID), which may cause stomach bleeding. The 
chance is higher if you:
     are age 60 or older
     have had stomach ulcers or bleeding problems
     take a blood thinning (anticoagulant) or steroid drug
     take other drugs containing an NSAID (aspirin, ibuprofen, 
naproxen, or others)
     have 3 or more alcoholic drinks every day while using this 
product
     take more or for a longer time than directed.
    This ``Stomach bleeding warning'' would appear after the ``Reye's 
syndrome'' and ``Allergy alert'' warnings in Sec.  201.66(c)(5)(ii)(A) 
and (c)(5)(ii)(B). For products that contain both acetaminophen and 
aspirin, the acetaminophen ``Liver warning'' would appear before the 
NSAID ``Stomach bleeding warning.''
    The labeling would be required to include the following statement:
    Ask a doctor before use if you have
     stomach problems that last or come back, such as 
heartburn,
    upset stomach, or stomach pain
     ulcers
     bleeding problems
     high blood pressure
     heart or kidney disease
     taken a diuretic
     reached age 60 or older.
    The labeling would be required to include the statement:
    Ask a doctor or pharmacist before use if you are
     taking any other drug containing an NSAID (prescription or 
nonprescription)
     taking a blood thinning (anticoagulant) or steroid drug
    The labeling would be required to include the statement:
    Stop use and ask a doctor if
     you feel faint, vomit blood, or have bloody or black 
stools. These are signs of stomach bleeding.
     stomach pain or upset gets worse or lasts
3. For NSAID Products Labeled Only for Children Under 12 Years of Age
    Under proposed Sec.  201.325(a)(2)(iv), the labeling would be 
required to include the following statement:
    Stomach bleeding warning: This product contains a nonsteroidal 
anti-inflammatory drug (NSAID), which may cause stomach bleeding. The 
chance is higher if the child:
     has had stomach ulcers or bleeding problems
     takes a blood thinning (anticoagulant) or steroid drug
     takes other drugs containing an NSAID (aspirin, ibuprofen, 
naproxen, or others)
     takes more or for a longer time than directed.
    The ``Stomach bleeding warning'' would appear after the ``Reye's 
syndrome'' and ``Allergy alert'' warnings in Sec.  201.66(c)(5)(ii)(A) 
and (c)(5)(ii)(B).
    The labeling would be required to include the following statement:
    Ask a doctor before use if the child has
     stomach problems that last or come back, such as 
heartburn, upset stomach, or stomach pain
     ulcers
     bleeding problems
     not been drinking fluids
     lost a lot of fluid due to vomiting or diarrhea
     high blood pressure
     heart or kidney disease
     taken a diuretic.
    The labeling would be required to include the statement:
    Ask a doctor or pharmacist before use if the child is
     taking any other drug containing an NSAID (prescription or
    nonprescription)
     taking a blood thinning (anticoagulant) or steroid drug
    The labeling would also be required to include the statement:
    Stop use and ask a doctor if
     the child feels faint, vomits blood, or has bloody or 
black stools. These
    are signs of stomach bleeding.
     stomach pain or upset gets worse or lasts
    FDA is aware that products labeled only for children are sometimes 
used by adults who cannot take solid oral dosage forms or who are 
taking a product marketed in children's strengths. Accordingly, FDA is 
proposing to include the statement ``this product does not contain 
directions or warnings for adult use'' in bold type in the labeling of 
these products under the heading ``Directions''.
4. For NSAID Products Labeled for Adults and Children Under 12 Years of 
Age
    Under proposed Sec.  201.325(a)(2)(v), the labeling would be 
required to include all of the warnings for adults with the following 
modifications:
    Stomach bleeding warning: This product contains a nonsteroidal 
anti-

[[Page 77335]]

inflammatory drug (NSAID), which may cause stomach bleeding. The chance 
is higher if the user:
     has had stomach ulcers or bleeding problems
     takes a blood thinning (anticoagulant) or steroid drug
     takes other drugs containing an NSAID (aspirin, ibuprofen, 
naproxen, or others)
     takes more or for a longer time than directed
     is age 60 or older
     has 3 or more alcoholic drinks everyday while using this 
product.
    The ``Stomach bleeding warning'' would appear after the ``Reye's 
syndrome'' and ``Allergy alert'' warnings in Sec.  201.66(c)(5)(ii)(A) 
and (c)(5)(ii)(B).
    FDA is proposing to use the term ``the user'' instead of ``you or 
the child'' for warnings applying to both children and adults in the 
above and following modified statements.
    The labeling would be required to include the following statement:
    Ask a doctor before use if the user has
     stomach problems that last or come back, such as 
heartburn, upset stomach, or stomach pain
     ulcers
     bleeding problems
     high blood pressure
     heart or kidney disease
     taken a diuretic
     not been drinking fluids
     lost a lot of fluid due to vomiting or diarrhea
     reached age 60 or older
    The labeling would be required to include the statement:
    Ask a doctor or pharmacist before use if the user is
     taking any other drug containing an NSAID (prescription or 
nonprescription)
     taking a blood thinning (anticoagulant) or steroid drug
    The labeling would also be required to include the statement:
    Stop use and ask a doctor if
     the user feels faint, vomits blood, or has bloody or black 
stools. These are signs of stomach bleeding.
     stomach pain or upset gets worse or lasts.
5. Active Ingredients
    Under proposed Sec.  201.325(a)(2)(v), the active ingredient(s) 
section of the product's labeling, as defined in Sec.  201.66(c)(2), 
would be required to contain the term ``(NSAID)*'' after the NSAID 
active ingredient with an asterisk statement at the end of the active 
ingredient(s) section that defines the term ``NSAID'' as a ``* 
nonsteroidal anti-inflammatory drug.''

D. Requirements to Supplement Approved Applications

    Holders of approved applications for OTC IAAA drug products who 
voluntarily implement the proposed labeling changes in proposed Sec.  
201.325(a) would be required to submit supplements under Sec.  
314.70(c) (21 CFR 314.70(c)), but could implement the proposed labeling 
without advance approval from FDA, provided the labeling includes the 
information in proposed Sec.  201.325(a). See section IX of this 
document on voluntary implementation.

E. Regulatory Action

    Proposed Sec.  201.325(c) sets out the implementation dates for the 
proposed labeling changes after publication of any final rule based on 
this proposal. See section VIII.B of this document on marketing 
conditions.

F. Conforming Changes to the OTC IAAA TFM

    This proposed rule includes changes to the OTC IAAA TFM in proposed 
Sec.  343.50. Proposed Sec.  343.50(c)(1)(i), (c)(1)(iii), 
(c)(1)(iv)(A), (c)(1)(v)(A), (c)(1)(v)(B), (c)(1)(v)(C), (c)(1)(ix)(A), 
(c)(1)(ix)(B), (c)(1)(ix)(C), (c)(1)(ix)(E), (c)(2)(i), (c)(2)(iii), 
(c)(2)(iv)(A), (c)(2)(v)(A), (c)(2)(v)(B) and (c)(2)(v)(C) (as proposed 
in 53 FR 46204 and 67 FR 54139) would be amended and new paragraphs 
(b)(4)(i)(c) and (c)(3)(i) through (c)(3)(v)(C) would be added to 
either include references to proposed Sec.  201.325 and/or additional 
language to conform to that section.

VII. Additional Issues for Consideration

A. Safe and Effective Daily Acetaminophen Dose

    In 1960, FDA first approved (under the NDA process) a 325-mg 
immediate-release acetaminophen tablet formulation for OTC marketing in 
the United States. The recommended dose was one to two tablets every 4 
to 6 hours, with a maximum daily dose of 3,900 mg in a 24-hour period 
(Ref. 3).
    In 1973, FDA approved (under the NDA process) a 500-mg immediate-
release acetaminophen capsule formulation for OTC marketing in the 
United States. The sponsor's rationale for this product was that the 
higher strength would have greater analgesic efficacy. Four double-
blind, placebo-controlled, post partum pain studies evaluated the 
effectiveness of a single dose of two 500-mg capsules (1,000 mg) to a 
single dose of two 325-mg tablets (650 mg) in 338 subjects. Two of the 
studies demonstrated that a single 1,000-mg dose was significantly more 
effective than a single 650-mg dose. One of the other studies failed to 
demonstrate a dose response between the two doses, and the last study 
failed to show separation of the active treatments from placebo. The 
overall safety profile for the 1,000-mg dose was similar to the 650-mg 
dose, with the exception of a higher incidence of dizziness. In 1975, 
FDA approved a 500-mg immediate-release tablet. Data from two crossover 
bioequivalence studies comparing two 500-mg capsules to two 500-mg 
tablets demonstrated the bioequivalence of the two formulations (Ref. 
3).
    The IAAA Panel further evaluated acetaminophen and recommended in 
its 1977 report (42 FR 35346) that acetaminophen be generally 
recognized as safe and effective. The IAAA Panel's evaluation of 
effectiveness was based on data from a number of controlled and 
uncontrolled studies of the effectiveness of a variety of acetaminophen 
doses, i.e., 300, 325, 330, 500, 600, 1,000, and 1,200 mg (42 FR 35346 
at 35412). However, the IAAA Panel's evaluation did not include an 
assessment of the relative effectiveness of each of the dosage 
strengths. The Panel determined the maximum daily safe dosage to be not 
greater than 4 g in a 24-hour period. Upon publication of that 
document, FDA permitted OTC marketing without an NDA provided the 
product was consistent with the IAAA Panel's recommended labeling. 
FDA's 1988 TFM for OTC IAAA drug products proposed to include 
acetaminophen as a monograph ingredient (53 FR 46204 at 46255). FDA 
revised the IAAA Panel's recommended dosing regimens but maintained the 
maximum limit of 4 g in a 24-hour period.
    To determine the maximum daily safe dosage (4 g of acetaminophen in 
a 24-hour period), the Panel reviewed numerous references that describe 
cases of serious liver damage associated with excessive use of 
acetaminophen (42 FR 35346 at 35413). Most of these cases were 
associated with single dose oral ingestions of greater than 15 g of 
acetaminophen. Based on this information, the Panel concluded that a 
single dose less than 15 g is not usually associated with serious liver 
injury. The Panel also noted that 15 g is 23 times the usual 
recommended dose of 650 mg and approximately 4 times the maximum 
recommended daily dose of 4 g. In estimating the safety margin, the 
Panel decided the comparison with the single dose (650 mg) was probably 
more appropriate than the comparison with the daily therapeutic dose (4 
g). The current information on unintentional overdose suggests that the 
margin of

[[Page 77336]]

safety may be less than originally determined. The data on liver 
failure presented by Dr. Lee at the September 2002 NDAC meeting and the 
adverse event reports in the FDA AERS data suggest daily doses less 
than 10 g, ingested on consecutive days, presents a risk for liver 
injury in some individuals.
    FDA invites comment on whether there are subpopulations of 
individuals who are more susceptible to developing liver injury when 
taking acetaminophen. The dosing information included in the AERS cases 
of hepatotoxicity reported for acetaminophen suggest that the median 
daily dose is in the 5- to 6-g range. FDA recognizes, however, that 
dosing information in the AERS reports is sometimes inaccurate and is 
difficult to validate. The information in the AERS cases of 
hepatotoxicity is adequate to raise concerns that there may be 
subpopulations at risk for developing hepatotoxicity with doses lower 
than the currently labeled maximum daily dose of 4 g. If such 
subpopulations can be identified, the maximum daily dose of 4 g may no 
longer be considered safe for those individuals and should be lowered. 
If the at risk subpopulations cannot be identified, or addressed 
through appropriate labeling, and cases of liver injury continue to be 
reported, FDA may reconsider whether the labeled maximum daily dose is 
still generally recognized as safe and effective for use in the general 
population.

B. Daily Dose Recommendation for Alcohol Abusers

    Following publication of the IAAA TFM in 1988, FDA received a 
comment recommending that the maximum daily dose of acetaminophen be 
reduced from 4 to 2 g per day for alcohol abusers. The comment did not 
provide any data to support a reduced maximum daily dose. In June 1993, 
NDAC considered: (1) Identifying a population at risk in terms of 
alcohol consumption, e.g., people who rarely drink, social drinkers, or 
alcohol abusers, (2) whether the data are sufficient to support a 
reduced maximum daily dose for alcohol abusers, and (3) if yes, what 
the reduced maximum daily dose should be. NDAC found the data 
insufficient and was unable to recommend a reduced maximum daily 
acetaminophen dose for alcohol abusers.
    At the September 19, 2002, NDAC meeting, FDA described cases of 
hepatotoxicity involving the use of prescription combination (narcotic/
acetaminophen) products (Refs. 6 and 7). Many of these cases involved 
people with a history of alcohol abuse. NDAC was unable to recommend a 
reduced maximum daily acetaminophen dose for alcohol abusers, because 
of a lack of specific data.
    One drug manufacturer issued a ``Dear Doctor'' letter to inform 
health professionals about the September 2002 NDAC meeting (Ref. 72). 
The letter stated: ``The NDAC proceedings may generate media interest 
and, as a result, people may contact you with questions about OTC pain 
relievers such as acetaminophen.'' The letter summarized the existing 
data that support the safety of acetaminophen, including the statement: 
``Prospective data indicate that chronic alcoholics can take 
recommended doses of acetaminophen up to 4,000 mg/day without risk of 
liver injury.'' The letter cited two references from the medical 
literature to support the statement (Refs. 73 and 74). The letter 
continued: ``Acetaminophen can be used safely, at recommended doses, by 
the occasional moderate consumer of alcohol.''
    FDA has reviewed the two references (studies of hepatotoxicity of 
the therapeutic dose of acetaminophen in people with alcohol abuse, 
conducted by the same investigators). One (Ref. 73) is a full study 
report of 201 people (102 on acetaminophen and 99 on placebo). The 
other (Ref. 75) was an abstract describing a pilot trial with 60 people 
(30 each on acetaminophen and placebo). A full report of this study is 
not available (Ref. 75).
    Both studies were randomized, double-blind, placebo-controlled 
clinical trials conducted in an alcohol detoxification center to 
evaluate the hepatotoxicity of maximum therapeutic dosing of 
acetaminophen in long-term alcoholic subjects. In both studies, the 
subjects were treated with the maximum therapeutic dose of 
acetaminophen (1g four times a day) for 2 days, followed by a 2-day 
observation. The results showed that acetaminophen treatment did not 
significantly increase serum ALT, Aspartate Aminotransferase (AST), and 
International Normalized Ratio (INR), as compared to the placebo 
control. The authors concluded that there was no evidence that the 
daily maximum therapeutic dose of acetaminophen caused liver injury in 
alcoholics. However, FDA finds the data insufficient to support this 
conclusion.
    Neither study included an assessment of the quantity, frequency, 
and duration of alcohol use by the subjects. Alcoholic detoxification 
history and information on alcohol-related disorders, including more 
specific hepatic evaluations (such as hepatic CYP2E1 p450 enzyme 
levels, glutathione levels, or biopsy), were not reported. That 
information would have enabled a better evaluation of chronic alcohol 
use and underlying alcohol-induced liver abnormalities. Subjects with 
AST and ALT higher than 120 IU/L were excluded from the study, so no 
evaluation of subjects with underlying liver damage evidenced by slight 
elevations of liver function tests could be assessed. Such subjects may 
respond differently than those with more substantial hepatic 
impairment. Other investigators have similarly criticized the studies 
(Refs. 76 and 77). Assessing the change in liver function tests after 
drug administration may not adequately support a conclusion that the 
drug is without risk of liver injury in this population. If 
subpopulations of chronic alcoholics are sensitive to lower doses of 
acetaminophen, this type of study would be inadequate to make any 
assessment of risk.
    FDA also finds that a 2-day treatment period may be too short to 
deplete the lowered hepatic gluthianone capacity in alcoholic people. 
The 2-day regimen cannot be extrapolated into the recommended 10-day 
dosing regimen in OTC drug product labeling. One individual agreed, 
stating that the investigators gave no rationale for dosing 
acetaminophen for only 2 consecutive days while the drug is approved 
for 4 g/day for 10 consecutive days and commonly used for prolonged 
periods of time (Ref. 78). Further, the individual stated that the lack 
of elevation in liver enzyme values after only 2 days of acetaminophen 
lends little support to the authors' conclusion regarding its safety in 
alcoholic people. FDA's detailed assessment of these studies is on file 
in the Division of Dockets Management (Ref. 79).
    FDA concludes that these studies do not provide reliable evidence 
that people with chronic alcohol use can safely take 4 g/day of 
acetaminophen, particularly for up to 10 days in accordance with OTC 
drug product labeling. Based on the data presented by Dr. Lee on liver 
failure, the experience in the University of Pennsylvania Hospital 
series, and data from the AERS database, FDA believes that alcohol 
users are a significant percentage of persons who develop severe liver 
injury. Acetaminophen products already have an alcohol warning to alert 
consumers of the risk for developing hepatotoxicity. It is important to 
determine whether the labeling should include a lower daily dose for 
chronic alcohol users. At this time, FDA is seeking both comments and 
data to support a specific dosage for acetaminophen as safe and 
effective in people who consume alcohol.

[[Page 77337]]

C. Combinations With Methionine or Acetylcysteine

    FDA is currently evaluating different safety measures to reduce the 
relative risks for hepatotoxicity associated with the use of 
acetaminophen. Theoretically, one method might be to administer 
acetaminophen and N-acetylcysteine (NAC) together. NAC is a chemical 
produced by the body that enhances the production of the enzyme 
glutathione. A small portion of acetaminophen undergoes cytochrome 
P450-mediated N-hydroxylation to form N-acetyl-p-benzoquinoneimine 
(NAPQI, a toxic metabolite of acetaminophen). Liver toxicity from 
acetaminophen overdose depends in part on production of NAPQ to levels 
that exceed the ability of the normal hepatic detoxification pathway to 
eliminate NAPQ. Glutathione is produced predominantly in the liver and 
is an important detoxifier of NAPQ. In the event of acetaminophen 
overdose in people with enhanced activity of CYP 2E1 (alcoholics, or 
people using anticonvulsants), glutathione liver stores are depleted. 
One substrate for glutathione synthesis is cysteine. NAC protects 
against liver damage in early acetaminophen poisoning by production of 
cysteine, a glutathione precursor. The administration of precursors of 
cysteine, such as NAC or methionine, may prevent depletion of 
glutathione and, thus, liver injury (Refs. 80 and 81).
    Scientific data supports the efficacy of treating acute 
acetaminophen overdose with early administration of NAC (Refs. 82 
through 85). To determine whether there is any usage data of 
acetaminophen with NAC or methionine for the purposes of prevention of 
liver toxicity, FDA examined the literature from 1975 to December 2002. 
FDA did not find any articles that specifically addressed whether 
either combination (when used at the therapeutic dose level) would 
prevent liver toxicity.
    The UK is the only country where a combination product containing 
acetaminophen and methionine is available. The marketed product 
contains 500 mg acetaminophen and 100 mg methionine. One published 
study summarized the issues related to combining acetaminophen and 
methionine (Ref. 85). The authors acknowledge that there are no data 
available on the relative efficacy or the prophylactic antidotal dose 
of methionine for protecting the liver after acetaminophen overdose in 
humans.
    At this time, FDA finds insufficient evidence that combinations of 
acetaminophen with NAC or methionine would prevent or reduce 
acetaminophen-induced liver toxicity. FDA seeks comments and data on 
this issue.

D. Package Size and Configuration Limitations

    At the September 19, 2002, NDAC meeting, a representative from a 
national consumer organization reported that the UK implemented package 
size restrictions on acetaminophen. He noted that an early assessment 
of the effect of the package size restrictions in the UK shows 
decreases in total and severe acetaminophen overdoses, as well as 
decreases in acetaminophen related toxicity leading to liver transplant 
or death. The representative did not provide any data to support his 
comments. FDA seeks comments on package size and package configuration 
limitations as a mechanism to increase safe use of acetaminophen 
products by reducing overdose. Comments should address the possible 
impact of such measures on unintentional and intentional overdose.

E. Label Warning for Individuals With Human Immunodeficiency Virus 
(HIV)

    A citizen petition (Refs. 86 and 87) requested that FDA consider 
the need for a warning about the increased risk of liver injury from 
the use of acetaminophen by individuals infected with HIV. The request 
is based on the following reasoning:
     Glutathione (GSH) deficiency is frequent in HIV-infected 
individuals.
     Acetaminophen depletes GSH (essential for the 
detoxification of acetaminophen's toxic metabolite) and is potentially 
more toxic to GSH-deficient individuals.
     GSH deficiency is associated with impaired survival in 
persons with HIV disease, and acetaminophen may further reduce survival 
by depleting GSH.
    In support of this request, the petitioner (Ref. 86) provided 
published studies of: (1) GSH and cysteine levels in plasma, peripheral 
blood monocytes and lymphocytes, and in the pleural fluid of HIV-
positive individuals, and (2) the effects of GSH replacement in model 
systems and HIV-infected individuals. A subsequent submission (Ref. 87) 
provided a search of the worldwide literature that included studies of: 
(1) Nonhepatic GSH levels in numerous disease states, (2) the effects 
of treatment with NAC or other GSH-replenishing drugs in diseases and 
conditions in which GSH is decreased, (3) the causes of GSH deficiency 
in persons with HIV disease, (4) an association between GSH deficiency 
and impaired survival in persons with HIV disease, and (5) the effect 
of NAC replacement therapy on clinical outcomes in persons with HIV 
disease.
    A comment (Ref. 88) disagreed with the petitioner's assertions for 
the following reasons:
     The available data do not demonstrate that acetaminophen 
reduces total body or circulating GSH when taken as recommended.
     There currently are no studies that demonstrate that 
acetaminophen has any impact on the survival of HIV patients.
     The depletion of hepatic GSH that occurs after 
acetaminophen overdose is not related to plasma GSH levels.
     The source of plasma GSH in humans is not clearly defined.
    FDA finds that although data from in vitro and in vivo studies 
(Refs. 89 through 96) have documented low levels of GSH and its 
precursors in HIV infection, the effect of this deficiency on survival 
has not been clearly established. Data from in vitro studies (Refs. 97 
through 100) have demonstrated improvement in healthy and HIV-infected 
T-cell functioning post exposure to NAC. However, these findings have 
not been correlated with survival from in vivo studies. While some 
studies of the effects of NAC administration in HIV-infected 
individuals (Refs. 89, 90, and 101 through 104) have demonstrated an 
increase in GSH, the majority of studies were not designed to assess 
survival.
    Herzenberg, et al. (Ref. 102) discussed results from several 
studies in HIV-infected patients that evaluated the relationship 
between GSH levels and survival, the administration of NAC in patients 
with low GSH levels in whole blood and in CD4 T cells, and the effect 
of NAC on survival in patients with low GSH levels in CD4 T cells. The 
presentation of data in the report made it difficult to understand the 
study design details. Other problems based on the information presented 
included: Survival data was not collected in a significant proportion 
of the population (17 percent), baseline characteristics of the 
individuals in all of the trials were not presented, the use of 
antiviral treatments and other medications before and during the 
studies was not provided, and NAC administration after 8 weeks was not 
randomized. In their conclusions, the authors recommend that excessive 
exposure to acetaminophen be avoided in HIV-infected individuals. The 
report references acetaminophen overdose leading to GSH deficiency as a 
basis to support their recommendation. However, it does not provide 
sufficient

[[Page 77338]]

information suggesting that intermittent or short-term use presents a 
problem in HIV patients. FDA concludes that this report does not 
provide a sufficient basis to restrict that use of acetaminophen in 
patients infected with HIV.
    Further, a search of FDA's AERS database for hepatic adverse events 
in HIV-infected individuals who took acetaminophen failed to identify 
any case reports which fit the search parameters, i.e., acetaminophen, 
HIV infection, and hepatotoxicity. Thus, there is no clinical evidence 
of toxicity or decrease survival that can be attributed to the 
recommended use of acetaminophen in HIV-infected individuals since GSH 
levels were never validated to predict survival.
    Given these facts, FDA does not consider the current data a 
sufficient basis for a warning. However, the issues raised by the 
petition highlight the need for additional information or research to 
clarify whether acetaminophen poses additional risk for certain 
population subgroups (e.g., conditions in which GSH is reduced). 
Therefore, FDA invites the submission of data and comments on this 
issue.

F. Drug Interactions Between Acetaminophen and Warfarin

    The labeling for a currently marketed warfarin-containing 
prescription drug product lists acetaminophen as a drug that can 
increase warfarin's anticoagulant effect (Ref. 105). A reciprocal 
warning is not currently included on the consumer labeling for any OTC 
drug products that contain acetaminophen. To evaluate the need for a 
consumer warning regarding co-administration of warfarin-containing 
drugs with acetaminophen, FDA considered postmarketing adverse event 
case reports in our AERS database, studies published in the worldwide 
literature (Refs. 106 through 125), and three consultative reviews 
(Ref. 126, 127, and 128).
    In the consultative reviews, FDA epidemiologists identified a 
cumulative total of 20 (3 probable and 17 possible) postmarketing 
adverse event case reports of prolongation of laboratory tests that 
monitor the ability of the blood to clot. These tests are the INR or 
Prothrombin Time (PT). These reports occur in individuals treated 
chronically with warfarin who concomitantly took acetaminophen and had 
minor or severe bleeding events. Of note, the only background 
characteristics that were identifiable in these case reports were that 
the individuals involved were generally elderly, had been on stable 
anticoagulant therapy for a prolonged period of time (several months to 
years), and used acetaminophen ``regularly'' instead of 
``intermittently'' for approximately 3 to 14 days prior to the 
discovery of their abnormally prolonged INR or PT. The dosages of 
acetaminophen reportedly ingested by these individuals ranged from 1.2 
to 4.5g/day. FDA's epidemiologists attribute the small number of 
postmarketing case reports collected to underreporting. We believe that 
the actual number of cases is much higher, based on the numbers of 
people who are treated with anticoagulant therapy.
    FDA's epidemiologists also conducted two literature searches on 
this topic. In the first (Ref. 126), FDA reviewed 11 published articles 
describing three double-blind, placebo-controlled, randomized studies 
that demonstrated a prolongation of warfarin's anticoagulant effect 
when acetaminophen was used concomitantly in a chronic manner (Refs. 
110, 112, and 113). Two additional published double-blind, crossover 
studies showed that people on a stable warfarin dose who were acutely 
dosed with acetaminophen did not experience any changes in their 
anticoagulant status (Refs. 111 and 117). A prospective, case-control 
study looked at a cohort of people from an anticoagulant clinic, each 
of whom were noted to have an INR greater than 6 on a routine followup 
clinic visit. The study found that after controlling for other risk 
factors associated with prolongation of anticoagulant status (i.e., 
medication use, recent diet, illness, alcohol consumption, and actual 
warfarin use), the use of acetaminophen was an independent dose-
dependent risk factor for having an INR over 6 (P-value for trend 
<0.001). Other independent variables associated with the development of 
a prolonged INR were identified and included: Advanced malignancy (odds 
ratio [OR], 16.4; 95 percent confidence interval [CI], 2.4 to 111.0), 
recent diarrheal illness (OR, 3.5; 95 percent CI, 1.4 to 8.6), 
decreased oral intake (OR, 3.6; 95 percent CI, 1.3 to 9.7), ingesting a 
higher dose of warfarin than prescribed (OR, 8.1; 95 percent CI, 2.2 to 
30.0), and taking new medications known to interact with warfarin (OR, 
8.5; 95 percent CI, 2.9 to 24.7) (Ref. 113). The validity of this 
study's findings was subsequently questioned when it was publicly 
criticized in the literature for its flawed methodological design, such 
as the overlapping of risk factors in the population studied (i.e., 
fever and the use of acetaminophen), and the lack of reported adverse 
events (Refs. 115, 116, and 118). Additionally, the mechanism by which 
a possible acetaminophen-warfarin interaction occurs has yet to be 
clearly identified (Refs. 119 and 120).
    The second updated literature review (Ref. 127) noted two 
additional case controlled studies generated from patient cohorts 
followed in anticoagulation clinics that were published in the European 
literature (Refs. 123 and 124). Both of these studies failed to 
document the existence of a possible drug-drug interaction in stable 
anticoagulated people treated with the warfarin analogues phenprocoumon 
or acenocoumarol and using acetaminophen concomitantly.
    The data generated from the literature searches are conflicting. 
Although many of the studies controlled for other variables known to 
potentate warfarin's anticoagulant effect, it is not known if they all 
also controlled for life style factors such as diet, the use of 
vitamins and herbal medications, physical activity, concurrent illness, 
or liver status. Extrapolating the clinical findings generated from the 
study by Fattinger, et al. may not be applicable to real life 
situations, since this trial was conducted in people where background 
life style factors such as diet and physical activity did not come into 
play due to the controlled study environment (Ref. 124). The study by 
van den Bemt, et al. may have also failed to demonstrate the existence 
of an adverse drug-drug interaction associated with the concomitant use 
of acetaminophen with either of the warfarin analogues phenprocoumon or 
acenocoumarol, because these drugs may be metabolized differently than 
warfarin (Ref. 123). FDA believes that the current available data do 
not demonstrate sufficient evidence to warrant a consumer warning for 
warfarin-acetaminophen interaction. However, we are seeking comments or 
data on whether additional labeling about this drug-drug interaction is 
warranted at this time.

VIII. Legal Authority

A. Statement About Warnings

    Mandating warnings in an OTC drug monograph does not require a 
finding that any or all of the OTC drug products covered by the 
monograph actually caused an adverse event, and FDA does not so find. 
Nor does FDA's requirement of warnings repudiate the prior OTC drug 
monographs and monograph rulemakings under which the affected drug 
products have been lawfully marketed. Rather, as a consumer protection 
agency, FDA has determined that warnings are necessary to ensure that 
these OTC drug products continue to be safe and effective for their 
labeled indications under ordinary conditions

[[Page 77339]]

of use as those terms are defined in the Federal Food, Drug, and 
Cosmetic Act (the act). This judgment balances the benefits of these 
drug products against their potential risks (see 21 CFR 330.10(a)).
    FDA's decision to act in this instance need not meet the standard 
of proof required to prevail in a private tort action (Glastetter v. 
Novartis Pharmaceuticals Corp., 252 F. 3d 986, 991 (8th Cir. 2001)). To 
mandate warnings, or take similar regulatory action, FDA need not show, 
nor do we allege, actual causation. For an expanded discussion of case 
law supporting FDA's authority to require such warnings, see the final 
rule on ``Labeling of Diphenhydramine-Containing Drug Products for 
Over-the Counter Human Use'' (67 FR 72555, December 6, 2002).

B. Marketing Conditions

    This proposal applies to all OTC internal analgesic/antipyretic 
drug products that contain an ingredient included in proposed Sec.  
201.325(a). Upon issuance of a final rule, any new labeling will apply 
to any product that is initially introduced or initially delivered for 
introduction into interstate commerce. Such products would be 
misbranded under section 502 of the act (21 U.S.C. 352) and would be 
subject to regulatory action unless:
     Products marketed without an NDA include the required 
labeling within 12 months after any final rule that is issued based on 
this proposal.
     Products marketed with an NDA include the required 
labeling within 12 months after any final rule that is issued based on 
this proposal. The labeling may be put into use without advance FDA 
approval provided it includes the information described in the final 
rule. Manufacturers should submit a supplement under Sec.  314.70(c).
    If companies voluntarily implement the labeling in this proposal 
before a final rule issues, FDA intends to provide those companies 18 
months to implement the labeling in the final rule.

IX. Voluntary Implementation

    The labeling proposed in this document represents a change from the 
current labeling required for OTC IAAA drug products. Although FDA 
considers these proposed labeling changes to be very important, holders 
of approved NDAs for OTC IAAA drug products will not be required to 
implement the proposed labeling at this time. However, holders of 
approved NDAs for these drug products may implement the proposed 
labeling without advance FDA approval provided the labeling includes 
the information in proposed Sec.  201.325. A supplement must be 
submitted under Sec.  314.70(c) to provide for the implementation of 
such labeling. The supplement and its mailing cover should be clearly 
marked: ``Special Supplement--Changes Being Effected.''
    FDA considers the proposed labeling in this document to be 
important to the safe use of OTC IAAA drug products and strongly 
encourages manufacturers of these products to voluntarily implement the 
proposed labeling changes before FDA issues a final rule. However, 
voluntary compliance with the proposed labeling in this document is 
subject to the possibility that FDA may revise the wording of some of 
the proposed statements or changes, or not require the statement or 
change, as a result of comments filed in response to this proposal. 
Because FDA wishes to encourage the voluntary use of the proposed 
labeling statements and changes, FDA advises that manufacturers will be 
given 18 months after publication of a final rule to use up any 
labeling implemented in conformance with this proposal (see section XV 
of this document).

X. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, if a rule may have a significant economic impact on a 
substantial number of small entities, an agency must analyze regulatory 
options that would minimize any significant impact of the rule on small 
entities. Section 202(a) of the Unfunded Mandates Reform Act of 1995 
requires that agencies prepare a written statement, which includes an 
assessment of anticipated costs and benefits, before proposing ``any 
rule that includes any Federal mandate that may result in the 
expenditure by State, local, and tribal governments, in the aggregate, 
or by the private sector of $100 million or more (adjusted annually for 
inflation) in any one year.''
    FDA tentatively concludes that this proposed rule is consistent 
with the principles set out in Executive Order 12866 and in these two 
statutes. This proposed rule is not a significant regulatory action as 
defined by the Executive Order and so is not subject to review under 
the Executive Order. As discussed in this section, FDA has tentatively 
determined that this proposed rule will not have a significant economic 
impact on a substantial number of small entities. Because the rule does 
not impose any mandates on state, local or tribal governments, or the 
private sector that will result in an expenditure in any one year of 
$100 million or more, FDA is not required to perform a cost-benefit 
analysis according to the Unfunded Mandates Reform Act. The current 
threshold after adjustment for inflation is about $110 million.
    FDA estimates that manufacturers and marketers of OTC IAAA drug 
products would incur one-time compliance costs of $32 million in the 
first year to revise labeling to conform to the proposed rule. The 
benefits of this proposed rule are based on estimated annual reductions 
from 1 to 3 percent in serious illnesses and related hospital and 
emergency room costs and in deaths related to unintentional overdosing. 
If 1 to 3 percent of these adverse events are avoided, the monetized 
benefits would be $6 million to $17 million per year, respectively. The 
present value of the monetized benefits over a 10-year period is $41 
million to $126 million assuming a 7-percent discount rate,\1\ and $49 
million to $147 million at a 3-percent discount rate. If we assume only 
a 1 percent reduction in the illnesses and fatalities analyzed, the 
benefits of this proposed rule outweigh the costs. We summarize the 
impacts in Table 10 of this document.
---------------------------------------------------------------------------

    \1\Per the Office of Management and Budget (OMB) Circular A4, 
revised in 2003.
---------------------------------------------------------------------------

    FDA notes that we lack the data needed to confidently predict a 
percent reduction in serious cases related to unintentional overdosing. 
Because of the uncertainty in these estimates, we estimated an annual 
average number of adverse events that would need to be avoided over a 
10-year period to reach a breakeven point. Social benefits would equal 
the costs of compliance if the proposed rule prevented about 1 fatality 
each year (0.9 and 0.7 fatalities over 10 years at a 7-percent and a 3-
percent discount rate, respectively). Alternatively, if no fatalities 
are avoided, the proposed rule would need

[[Page 77340]]

to prevent about 475 hospitalizations per year over the 10-year period 
at a 7-percent discount rate. At a 3-percent discount rate, an average 
reduction of 410 hospitalizations per year is needed.

                                          Table 10.--Summary of Impacts
----------------------------------------------------------------------------------------------------------------
                       Benefits:                                               ($ Million)
----------------------------------------------------------------------------------------------------------------
Monetized 1 and 3-percent reduction in illnesses and                                                     $5--$17
 mortality, per year
Present value over 10 years at 7 percent                                                               $41--$126
Present value over 10 years at 3 percent                                                               $49--$147
----------------------------------------------------------------------------------------------------------------
Costs:                                                                                               ($ Million)
One-time label revision, first year                                                                          $32
----------------------------------------------------------------------------------------------------------------

A. Need for the Rule

    In September 2002, FDA's NDAC recommended changes to the labeling 
of OTC IAAA drug products to better inform consumers about the active 
ingredients and possible side effects caused by improper use. Although 
FDA considers acetaminophen to be safe and effective when labeled and 
used correctly, taking too much can lead to liver damage and death. 
Similarly, the use of NSAIDs can lead to GI bleeding and renal 
toxicity. The number of cases of injury reported is a very low 
percentage of the total use of OTC acetaminophen and NSAID drug 
products. For many people, the risks are quite low because they use 
these products only occasionally. The risks may be greater for people 
who use these products more frequently and/or do not follow the 
labeling information on the package. The risk of injury may be 
increased for certain populations and under certain conditions of use.
    There are multiple reasons for unintentional acetaminophen 
overdoses. First, acetaminophen is an active ingredient in a wide 
variety of both OTC and prescription drug products. For prescription 
products, the immediate prescription container may not state that the 
product contains acetaminophen or state the maximum daily dose limit. 
Consumers may often fail to recognize the presence and amount of 
acetaminophen ingredients in OTC and prescription drug products. This 
lack of knowledge can result in a person taking two different products 
containing acetaminophen simultaneously. Moreover, many consumers are 
unaware that exceeding the recommended dosage for acetaminophen can 
lead to unintentional overdosing and cause potential harm. Based on the 
evidence discussed in this document, FDA finds that there is sufficient 
incidence of liver damage associated with acetaminophen to warrant new 
labeling, and that without the new labeling, acetaminophen products 
would no longer be considered generally recognized as safe and 
effective and not misbranded for OTC use.
    Results of several large-scale clinical studies performed in the 
United States and in other countries have established that the use of 
NSAIDs is an important risk factor for serious GI adverse events, 
especially bleeding. The risk is higher for certain populations. Based 
on the evidence discussed in this document, FDA further finds that 
NSAIDs increase the risk for GI adverse events and that without a new 
stomach bleeding warning in the labeling for aspirin and other NSAIDs 
the products would no longer be considered generally recognized as safe 
and effective and not misbranded for OTC use.
    The purpose of this proposed rule is to amend FDA's OTC drug 
labeling regulations and the TFM for OTC IAAA drug products to include 
new warnings and other labeling requirements to advise consumers of 
potential risks and when to consult a doctor. FDA is also proposing to 
remove the alcohol warning in Sec.  201.322 and incorporate new 
alcohol-related warnings and other labeling for all OTC IAAA drug 
products. FDA is proposing certain warning information targeted to age 
specific populations. In addition, FDA is proposing that the presence 
of acetaminophen or any NSAID would appear prominently on the products' 
PDP. Table 11 presents an overview of the proposed changes by type of 
product.

                        Table 11.--Overview of the Proposed Label Changes by Product Type
----------------------------------------------------------------------------------------------------------------
                Type of Product                                          Proposed Change
----------------------------------------------------------------------------------------------------------------
Acetaminophen                                    Add a new warning to include information on serious liver
                                                  injury. Include the name acetaminophen [highlighted or in bold
                                                  type, and in a prominent print size] on the PDP.
----------------------------------------------------------------------------------------------------------------
NSAIDs (e.g., aspirin or ibuprofen)              Add a new warning to include information on stomach bleeding.
                                                  Include the name of the NSAID ingredient [highlighted or in
                                                  bold type] on the PDP. Include the word ``(NSAID)''
                                                  [highlighted or in bold type, and in a prominent print size]
                                                  on the PDP either as part of the established name of the drug
                                                  or after the general pharmacological (principal intended)
                                                  action of the NSAID ingredient.
----------------------------------------------------------------------------------------------------------------
Combination products containing acetaminophen    Include the name acetaminophen or the name of the NSAID
 or an NSAID and a nonanalgesic ingredient        ingredient [highlighted or in bold type, and in a prominent
                                                  print size] and the names of the other active ingredients on
                                                  the PDP. Products containing an NSAID ingredient must include
                                                  the word ``(NSAID)'' as stated under NSAIDS.
----------------------------------------------------------------------------------------------------------------

[[Page 77341]]

 
All IAAA drug products                           Remove the current alcohol warning in Sec.   201.322, and
                                                  incorporate new alcohol-related warnings format. For a
                                                  specific period of time, add to the PDP the statement ``See
                                                  new warnings information''. We are proposing that this
                                                  statement appear highlighted in the same way that the name
                                                  ``acetaminophen'' or the presence of an NSAID appear on the
                                                  PDP. The statement would appear highlighted (e.g., fluorescent
                                                  or color contrast) or in bold type; and be in one of the
                                                  following sizes, whichever is greater: (1) At least one-
                                                  quarter as large as the size of the most prominent printed
                                                  matter on the PDP, or (2) at least as large as the size of the
                                                  ``Drug Facts'' title, as required in Sec.   201.66(d)(2).
----------------------------------------------------------------------------------------------------------------

B. Impact of the Rule

    FDA contracted with Eastern Research Group, Inc. (ERG) to assess 
the costs and benefits of this proposed rule. The following is a 
summary of ERG's analysis; the full report, including details on 
assumptions, cost calculations, and findings, is on file in the 
Division of Dockets Management (Ref. 129).
    Manufacturers and marketers of OTC IAAA drug products would incur 
one-time costs to revise affected product labeling to comply with the 
proposed labeling changes. We assumed an implementation period of 12 
months for one-time costs for a major labeling revision. We estimated 
one-time costs for a major labeling revision using a pharmaceutical 
labeling revision cost model. This labeling model is described in 
detail in Appendix A of the ERG report (Ref. 129).
    To develop the original model, FDA and ERG interviewed 
pharmaceutical representatives from regulatory, legal, manufacturing 
controls, and labeling departments to collect information on labeling 
change cost components, type of personnel affected, and costs. The 
model incorporates data on average industry costs by company size, 
including, where applicable, modifications to packaging configurations. 
Industry consultants also provided information on model inputs related 
to the OTC IAAA industry, the labeling revision process, the costs of 
modifying labeling, and the frequency of packaging reconfiguration 
changes.
    The baseline for this proposed action is full compliance with the 
format and content requirements for OTC drug product labeling in 21 CFR 
201.66. In the final rule that established these requirements on March 
17, 1999 (64 FR 13254), FDA accounted for the total incremental costs 
to comply with requirements, including 6.0 font size and related costs 
for increased package size and longer labeling where applicable. FDA 
notes that although some forms of packaging (for small quantities) have 
been granted extensions on compliance dates, many packaging 
alternatives now exist to assure compliance.
    Manufacturers routinely change labels at varying intervals and have 
standardized procedures in place for complying with FDA requirements. 
The analysis assumes that one-half of the manufacturers of OTC IAAA 
drug products typically redesign their label every 2 years, the 
remainder every 3 years, based on consultant input. For this analysis, 
ERG assumed that manufacturers whose label redesign cycle is less than 
the implementation period will not incur any regulatory costs. For 
example, if a company routinely revises its product labeling annually 
and is given at least that long to incorporate the required changes, 
ERG judged that the regulatory revision can be made at essentially no 
cost.
    The costs of labeling change depend on the type of labeling (e.g., 
carton and container label) and whether there is sufficient labeling 
space to accommodate the proposed changes. There are an estimated 
22,500 OTC IAAA drug product stockkeeping units (SKUs), split evenly 
among branded and private labels, according to an industry 
consultant.\2\ FDA assumes branded SKUs are distributed by firm size: 
50 percent small, 17 percent medium, and 33 percent large. Based on 
consultant input, we assumed the distribution of SKUs among OTC IAAA 
drug products as follows: Acetaminophen, 45 percent; NSAIDS (except 
ibuprofen), 38 percent; ibuprofen, 15 percent; and combinations of 
IAAAs (i.e., contain acetaminophen and aspirin), 2 percent. Cost 
estimates are for small, medium, and large branded companies, private 
label companies, and by affected product group. The ERG report presents 
model assumptions and methods for calculating costs.
---------------------------------------------------------------------------

    \2\Estimates of affected SKUs are 18,000 (CDER) and from 20,000 
to 25,000 (per industry consultant). This number of SKUs includes 
products marketed by manufacturers, repackers, relabelers, and 
distributors.
---------------------------------------------------------------------------

    ERG visited five stores--two major chain drug stores and three 
convenience stores--to collect information on the distribution of types 
of OTC IAAA drug product packaging. Roughly 80 percent of OTC IAAA drug 
products were packaged in cartons and 20 percent in containers. To 
assess the increase in label space requirements, ERG purchased 45 
affected products, with an emphasis on smaller packages.
1. Label Area Changes
    ERG collected and recorded descriptive packaging information on the 
sampled products and measured existing font size, labeling area and 
labeling text on packages, and the area needed for replacement text. 
ERG then calculated the percentage increase in square millimeters 
(mm\2\) needed to accommodate the proposed labeling changes. In all 
cases, ERG determined that the requirement to add active ingredient 
names on the PDP, while requiring major redesign in some cases, did not 
impose a change in the size of the PDP or the addition of non-standard 
labeling (such as adding a fifth carton panel or peelback label). ERG 
estimates that the increase in existing label area needed to 
accommodate the additional proposed label warnings and text ranges from 
8 percent (acetaminophen) to 32 percent (ibuprofen).
2. Package size or type changes
    ERG measured the available panels and white space on the 45 
packages sampled. If the available white space was greater than the 
estimated increase in space necessary to accommodate the new label 
warnings, ERG determined the product would not require an increase in 
carton or container size. Based on this review, ERG assumed that all 
current packaging can accommodate the required changes in this proposal 
without altering label sizes, package sizes, or adding non-standard 
labels. Therefore, ERG did not assign costs for adjustments to 
packaging. Although

[[Page 77342]]

finding only a few small foil packs that did not comply with the OTC 
Drug Facts labeling requirements, ERG noted that alternative types of 
packaging are now available to replace the older packages.
    Table 12 presents the estimated total and annualized costs of 
compliance with the OTC IAAA drug product proposed rule. The total 
estimated one-time costs to revise labeling are $32.6 million. The 
estimated annualized cost over the relevant relabeling period is $15.2 
million at a 7-percent discount rate. The estimated average annualized 
cost per SKU is $677 ($15.2 million/22,500 SKUs).

                                        Table 12.--Estimated Total and Annualized Costs of Compliance ($ Million)
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                Product Type
                                                 ----------------------------------------------------------------------------------------------------------
                                                                                                                                                     Total
                                                                                                                                                    -------
                                                                                             NSAID (except                         Combinations of   Total
                                                     Company Type        Acetaminophen        Ibuprofen)          Ibuprofen             IAAAs         One-
                                                                                                                                                      time
                                                                                                                                                     Costs
--------------------------------------------------------------------------------------------------------------------------------------------------- -------
Small Brand                                                      2.2                 1.8                 0.7              0.1                   4.9
-----------------------------------------------------------------------------------------------------------------------------------------------------
Medium Brand                                                     2.1                 1.8                 0.7              0.09                  4.7
-----------------------------------------------------------------------------------------------------------------------------------------------------
Large Brand                                                      6.0                 5.1                 2.0              0.3                  13.3
-----------------------------------------------------------------------------------------------------------------------------------------------------
Private Label                                                    4.4                 3.7                 1.5              0.2                   9.7
-----------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                           14.7                12.4                 4.9              0.7                  32.6
-----------------------------------------------------------------------------------------------------------------------------------------------------
 
----------------------------------------------------------------------------------------------------------------------------------------------------
Total Annualized Costs (at 7-percent discount rate)
----------------------------------------------------------------------------------------------------------------------------------------------------
Small Brand                                                                                                                                          1.0
-----------------------------------------------------------------------------------------------------------------------------------------------------
Medium Brand                                                                                                                                         1.0
-----------------------------------------------------------------------------------------------------------------------------------------------------
Large Brand                                                                                                                                          2.8
-----------------------------------------------------------------------------------------------------------------------------------------------------
Private Label                                                                                                                                        2.0
-----------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                                6.9
--------------------------------------------------------------------------------------------------------------------------------------------------------

C. Impact on Affected Sectors

    Manufacturers of OTC drug products are classified in North American 
Industry Classification System (NAICS) 325412, pharmaceutical 
preparation manufacturing. This classification code includes all 
manufacturers of prescription and OTC pharmaceutical preparations, but 
does not include relabelers, repackers, and distributors. The Small 
Business Administration (SBA) defines a small business in this industry 
classification code as one with fewer than 750 employees. In NAICS 
325412, over 90 percent are considered small entities. The affected 
industry is a subset of the OTC pharmaceutical industry. This proposed 
rule affects an estimated 258 manufacturers (of which 200 are small) of 
OTC IAAA drug products.
    Manufacturers often package private label products, although some 
chains package their own brands. SBA considers the following to be 
small: (1) Any pharmacy or drug store with annual sales under $6 
million, and (2) supermarkets and other grocery stores and warehouses 
and superstores with sales under $23 million. Generally, only the 
largest supermarket and drug store chains (263 firms) or superstores (9 
firms) would have their own private label. ERG included only those 
largest retail chains with annual sales of $100 million or more as 
having their own private labels. Thus, FDA believes that there are no 
small entities in these retail sectors that are affected. Marketers of 
private label OTC drug products are classified as follows:
    NAICS 446110, Pharmacies and drug stores
    NAICS 445110, Supermarkets and other grocery stores
    NAICS 452910, Warehouse clubs and superstores.
    Packaging and labeling services that contract with pharmaceutical 
manufacturing firms may also be affected, but we assume manufacturers 
bear the costs of any labeling changes. Both the manufacturing and 
marketing sectors will most likely share costs, but the extent is not 
known. Therefore, this impact analysis first assumes that manufacturers 
absorb all of the labeling costs. We then assume that all private 
labeling costs are absorbed by chain stores and calculate impacts.
    To assess the impact on entities in the pharmaceutical-
manufacturing sector (NAICS 325412), ERG adjusted SBA data on firm size 
and revenues to estimate average receipts per firm for the affected 
sector. ERG applied modeling assumptions to estimate the number of 
large and small affected firms. ERG further assumed the distribution of 
all 22,500 affected SKUs is one-third for large firms (producing either 
branded or private label products) and two-thirds for small firms. To 
estimate the share of total compliance costs for each size category, 
ERG distributed the SKUs attributed to small businesses in the same 
proportion as employment. The distribution of SKUs determines the 
distribution of compliance costs by employment size category. Table 13 
summarizes the estimated impacts for pharmaceutical manufacturers, the 
total cost per firm based on $677 per SKU, and the compliance costs as 
a percent of revenues.

[[Page 77343]]



                          Table 13.--Estimated Impacts on Pharmaceutical Preparation Manufacturing Firms by Size (NAICS 325412)
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                          Average Receipts     Assumed No. of                        Total Firm Cost    Compliance Cost
                    Employment Size                        per Firm ($mil)          SKUs          SKUs per Firm         ($000)\1\       as % of Receipts
--------------------------------------------------------------------------------------------------------------------------------------------------------
<20                                                                     1.7                841                  9                 6.0           0.340%
--------------------------------------------------------------------------------------------------------------------------------------------------------
20-99                                                                  12.2              2,591                 65                43.8           0.361%
--------------------------------------------------------------------------------------------------------------------------------------------------------
100-499                                                                61.9              5,506                148               100.2           0.162%
--------------------------------------------------------------------------------------------------------------------------------------------------------
500-749                                                               366.8              6,062                225               151.9           0.041%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total Small                                                            29.1             15,000                 75                50.8           0.175%
--------------------------------------------------------------------------------------------------------------------------------------------------------
>750                                                                  947.8              7,500                130                88.1           0.009%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                 109.6             22,500                 87                59.1           0.054%
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\Number of SKUs x $677 per SKU.
Source: SBA, 1999 and ERG estimates.

    Total estimated compliance costs per firm ranged from $6,000 for 
firms with fewer than 20 employees to $152,000 for firms with 500 to 
749 employees. The compliance cost as a percent of receipts is less 
than 1 percent for all firms; 0.18 percent for all small firms and 0.01 
for large firms. This estimate of impacts is somewhat understated 
because the census data used to derive estimates includes both OTC and 
prescription drug manufacturers. However, no alternative revenue and 
employment size information for affected product lines is available. We 
tentatively conclude that this estimate of the impacts of the proposed 
rule does not constitute a significant economic impact on a substantial 
number of small entities.
    In a similar analysis, we assume chain stores absorb costs for all 
11,250 private label SKUs. Compliance costs as a percent of receipts 
are less than 0.001 percent for all of the affected sectors: 
Pharmacies, drug stores, superstores, supermarkets, and other grocery 
stores. No small entities are affected.
    Manufacturers routinely change labels at varying intervals and have 
standardized procedures in place for complying with FDA requirements. 
The proposed rule would not require any new reporting and record 
keeping activities and no additional professional skills are needed. 
There are no other Federal rules that duplicate, overlap, or conflict 
with the proposed rule; FDA is proposing to remove the existing alcohol 
warning in Sec.  201.322.

D. Alternatives

    FDA does not believe that there are any alternatives to the 
proposed rule that would adequately provide for the safe and effective 
use of OTC drug products containing IAAA active ingredients. 
Nonetheless, FDA considered but rejected the following alternatives: 
(1) Not adding the new information to OTC IAAA drug product labeling, 
and (2) a longer implementation period. FDA does not consider either of 
these approaches acceptable because they do not assure that consumers 
will have the most current labeling information needed for the safe and 
effective use of these products. FDA considers this proposed rule the 
least burdensome alternative that meets the public health objectives of 
this rule.

E. Benefits

    FDA's proposed requirements are intended to enhance consumer 
awareness and knowledge of the active ingredient in OTC IAAA drug 
products. These new proposals include:
     New label warnings
     Age specific information
     Advising consumers of potential risks and when to consult 
a doctor
     Prominent display of active ingredients on the PDP
    The revised alcohol statements are intended to provide clearer 
warnings to high-risk individuals about product use. The overall intent 
of these proposed requirements is to reduce the liver damage and GI 
bleeding episodes that occur due to unintentional overdosing with these 
drugs. The proposed requirements are also intended to reduce the 
incidence of adverse health outcomes among high-risk subpopulations 
consuming proper doses of OTC IAAA drug products (e.g., people with 
liver disease or prone to GI bleeding).
    To estimate the benefits of this proposed rule, we developed 
baseline information on the frequency of hospitalizations, emergency 
room visits, and deaths related to unintentional overdosing with OTC 
IAAA drug products. We used a value of $5 million to represent the 
premature loss of a statistical life in previous analyses (see 66 FR 
6137, January 19, 2001). We quantified the related hospital and 
emergency room costs, estimated related morbidity costs, applied a 
value of $5 million to the premature loss of a statistical life, and 
estimated annual savings if 1 to 3 percent of these adverse events and 
deaths are avoided (Ref. 129).
    We lack evidence to predict with certainty a specific level of 
reduction in adverse events. Nonetheless, we believe that presenting 
consumers with improved label warnings and more prominently displaying 
the active ingredients on the PDP will promote safer use of OTC IAAA 
drug products. Specifically, prominent display of the active 
ingredients on the PDP would alert consumers to the presence of the 
active ingredients in OTC IAAA drug products and help minimize the 
risks of unintentional overdosing. The revised warnings are intended to 
assist consumers, including higher risk individuals, to use OTC IAAA 
drug products more safely and lead to at least a modest reduction in 
unintentional overdosing.
    Table 14 summarizes the baseline and estimates of the number of 
avoidable hospitalizations and emergency room visits, the average cost 
per case, and potential savings from events avoided. These data do not 
include reported cases of intentional overdosing. Based on the total 
monetized costs per adverse health outcome and the number of cases 
estimated to be avoided each year (from 1 to 3 percent), the total 
monetized benefits of illness avoided range from $0.6 million to $1.8 
million per year ($592,600 to $1,777,900).

[[Page 77344]]



                    Table 14. --Summary of Annual Monetized Benefits of Illnesses Avoided Associated with the Proposed Rule (2001 $)
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                           Potentially                                  Total Annual
                                                       Willing to Pay  Total Monetized     Preventable      Annual Number of Cases   Monetized Benefits
        Adverse Health Event          Hospital Costs      to Avoid         Value of       Baseline Cases   Avoided Due to Proposed   of Illness Avoided
                                                          Illness      Illness Avoided     per Year(1)             Rule(2)                 ($000)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Minor drug toxicity or emergency                $209             $301             $510              3,380                   34-101           $17.2-$51.7
 room visits
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acetaminophen poisoning episode               $8,579           $2,000          $10,579              3,424                   34-103       $362.2-$1,086.8
 with hospitalization
--------------------------------------------------------------------------------------------------------------------------------------------------------
NSAID poisoning episode with                  $8,579             $357           $8,936              2,269                    23-68         $202.8-$608.3
 hospitalization
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acute renal failure with                     $22,251    Not Estimated          $22,251                  5                0.05-0.15             $1.1-$3.3
 hospitalization
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acute renal failure with dialysis            $22,251    Not Estimated          $22,251                0.7              0.007-0.021             $0.2-$0.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
GI bleeding                                  $14,653             $357          $15,010                 61                  0.6-1.8            $9.2-$27.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total monetized benefit of illness                NA               NA               NA                 NA                       NA       $592.6-$1,777.9
 avoided
--------------------------------------------------------------------------------------------------------------------------------------------------------
(1) The number of potentially preventable baseline cases per year is derived from data on emergency department and hospital cases of overdosing,
  poisoning, or other serious adverse outcomes associated with acetaminophen and NSAID use, adjusted to estimate only unintentional cases.
(2) Assumes this proposed rule would reduce annual adverse event cases by 1 to 3 percent.
Source: FDA Section III.B.2 of this document and ERG report (Ref. 129).

    In addition to estimating the value of preventing adverse drug 
events that result in emergency department or hospitalization, we 
consider the annual number of deaths related to unintentional 
acetaminophen overdoses. FDA estimates that from 1996 to 1998, an 
annual average of 99 adult deaths were related to unintentional 
acetaminophen overdoses (see section III.B.2 of this document and the 
ERG report (Ref. 129)). We assume the proposed rule would reduce 
fatalities by 1 to 3 percent annually. Applying a value of $5 million 
for each fatality prevented, we estimate the total benefits associated 
with preventing 1 to 3 fatalities to be $5 to $15 million annually 
($2001).
    If the proposed improved labeling and warnings reduced serious 
adverse events by 1 to 3 percent each year, the total monetized value 
of preventing illness and fatalities because of improved labeling and 
warnings would be $5.6 million to $16.8 million per year, respectively. 
These benefits are presented in 2001 dollars.
    Benefit Cost Comparison. Industry would incur the one-time costs of 
the proposed rule of $32.6 million in the first year. In 2001, the 
costs were $32.0 million. However, the estimated savings from reduced 
hospital costs and deaths avoided, from $5.6 to $16.8 million, would 
accrue each year. Over a 10-year period, the $5.6 to $16.8 million per 
year in benefits has a present value of $41.2 to $126.1 million at a 
discount rate of 7 percent, and a present value of $49.1 to $147.4 
million at a discount rate of 3 percent. Thus, the benefits of this 
proposed rule, assuming a 1-percent reduction in current levels of 
adverse health outcomes associated with the use of OTC IAAA drug 
products, will more than offset the costs of the proposed rule. Table 
15 summarizes the estimated benefits and costs of this proposed rule.

                      Table 15.--Summary of Impacts
------------------------------------------------------------------------
     Benefits/Costs                         ($Million)
------------------------------------------------------------------------
Benefits:
------------------------------------------------------------------------
Monetized 1 and 3                                            $5.6-$16.8
 percent reduction in
 illnesses and
 mortality, per year
Present value over 10                                          $41-$126
 years at 7 percent

[[Page 77345]]

 
Present value over 10                                          $49-$147
 years at 3 percent
------------------------------------------------------------------------
Costs:
------------------------------------------------------------------------
One-time label revision,                                          $32.6
 first year
------------------------------------------------------------------------

    Break-even Analysis. FDA notes that we lack the data needed to 
confidently predict a percent reduction in serious cases related to 
unintentional overdosing. Because of the uncertainty in these 
estimates, we estimated an annual average number of adverse events that 
would need to be avoided over a 10-year period to reach a breakeven 
point (i.e., the cost of compliance/present value of avoiding one death 
each year for 10 years). The proposed rule would need to prevent about 
1 fatality each year over 10 years [0.9 fatality ($32/$37.6 million at 
a 7-percent discount rate) and 0.7 fatality ($32/$43.9 million at a 3 
percent discount rate)]. Alternatively, if no fatalities are avoided, 
the proposed rule would need to prevent about 476 hospitalizations ($32 
million/$67,000) each year over the 10-year period. This estimate uses 
the present value of the lowest benefit category of poisoning episode 
with hospitalizations, $8,936 per episode over 10 years at a 7-percent 
discount rate. At a 3 percent discount rate, an average of 407 
hospitalizations ($32 million/$79,000) would need to be avoided 
annually over the period.
    Although we lack evidence to predict with certainty a specific 
level of reduction in adverse events, if we assume only a 1-percent 
reduction in the illnesses and fatalities analyzed, the benefits of 
this proposed rule outweigh the costs. FDA finds that this proposed 
rule will enhance public health and promote the safer use of OTC IAAA 
drug products.
    This economic analysis, together with other relevant sections of 
this document, serves as FDA's initial regulatory flexibility analysis, 
as required under the Regulatory Flexibility Act.
    FDA invites public comment regarding any significant economic 
impact that this rulemaking would have on affected manufacturers of 
these OTC IAAA drug products. Comments regarding the impact of this 
rulemaking should be accompanied by appropriate documentation. FDA is 
providing 150 days from the date of publication of this proposed rule 
in the Federal Register for comments on this subject to be developed 
and submitted. FDA will evaluate any comments and supporting data that 
are received and will reassess the economic impact of this rulemaking 
in the preamble to any final rule.

XI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling requirements proposed 
in this document are not subject to review by the Office of Management 
and Budget because they do not constitute a ``collection of 
information'' under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 
et seq.). Rather, the proposed labeling statements are public 
disclosures of information originally supplied by the Federal 
Government to the recipient for the purpose of disclosure to the public 
(5 CFR 1320.3(c)(2)).

XII. Environmental Impact

    FDA has determined under 21 CFR 25.31(a) that this proposed action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

XIII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule, if finalized as proposed, would have a preemptive 
effect on State law. Section 4(a) of the Executive Order requires 
agencies to ``construe* * *a Federal statute to preempt State law only 
where the statute contains an express preemption provision or there is 
some other clear evidence that the Congress intended preemption of 
State law, or where the exercise of State authority conflicts with the 
exercise of Federal authority under the Federal statute.'' Section 751 
of the Federal Food, Drug, and Cosmetic Act (act) (21 U.S.C. 379r) is 
an express preemption provision that applies to nonprescription drugs. 
Section 751(a) of the act (21 U.S.C. 379r(a)) provides that:
    * * no State or political subdivision of a State may establish 
or continue in effect any requirement-- * * * (1) that relates to 
the regulation of a drug that is not subject to the requirements of 
section 503(b)(1) or 503(f)(1)(A); and (2) that is different from or 
in addition to, or that is otherwise not identical with, a 
requirement under this Act, the Poison Prevention Packaging Act of 
1970 (15 U.S.C. 1471 et seq.), or the Fair Packaging and Labeling 
Act (15 U.S.C. 1451 et seq.). * * *
    Currently, this provision operates to preempt States from imposing 
requirements related to the regulation of nonprescription drug 
products. (See section 751(b), (c), (d), and (e) of the act for the 
scope of the express preemption provision, the exemption procedures, 
and the exceptions to the provision.) This proposed rule, if finalized 
as proposed, would amend the labeling for over-the-counter IAAA drug 
products to include new warnings and other labeling requirements 
advising consumers about potential risks and when to consult a doctor. 
Although any final rule would have preemptive effect, in that it would 
preclude States from issuing requirements related to the labeling of 
IAAA drug products that are different from or in addition to, or not 
otherwise identical with a requirement in the final rule, this 
preemptive effect is consistent with what Congress set forth in section 
751 of the act. Section 751(a) of the act displaces both state 
legislative requirements and state common law duties. We also note that 
even where the express preemption provision is not applicable, implied 
preemption may arise. See Geier v. American Honda Co., 529 U.S. 861 
(2000).
    FDA believes that the preemptive effect of the proposed rule, if 
finalized as proposed, would be consistent with Executive Order 13132. 
Section 4(e) of the Executive Order provides that ``when an agency 
proposes to act through adjudication or rulemaking to preempt State 
law, the agency shall provide all affected State and local officials 
notice and an opportunity for appropriate participation in the 
proceedings.'' FDA is providing an opportunity for State and local 
officials to comment on this rulemaking, and will conduct outreach to 
State and local governments or organizations representing them.

[[Page 77346]]

XIV. Request for Comments

    In addition to requesting general comments on the proposal and the 
economic analysis, we are seeking comment on the following specific 
issues identified in the description of the proposed rule (presented 
here for the convenience of the reader):
    1. Both comment and data on whether adult NSAID products should 
contain a warning regarding fluid loss or dehydration similar to 
children NSAID products (see section V.B.2 of this document).
    2. Appropriate approaches to reduce unintentional acetaminophen 
overdose (see section VII.A of this document).
    3. Whether more specific directions, such as those currently 
required for OTC drug products containing ibuprofen, should be 
considered for acetaminophen (see section VII.A of this document).
    4. Both comment and data on whether there are specific populations 
of people for whom the maximum daily dose for acetaminophen is not safe 
and effective and should be lowered (see section VII.A of this 
document).
    5. Both comment and data on specific dosage for safe and effective 
use of acetaminophen in people who consume alcohol (see section VII.B 
of this document).
    6. Both comment and data on whether combinations of acetaminophen 
with NAC or methionine would prevent or reduce acetaminophen-induced 
liver toxicity (see section VII.C of this document).
    7. Both comment and data on package size or package configuration 
limitations on the sale of acetaminophen (see section VII.D of this 
document).
    8. Both comment and data on whether acetaminophen poses additional 
risk for certain population subgroups (e.g., conditions in which GSH is 
reduced) (see section VII.E of this document).
    9. Both comment and data on whether additional labeling is 
necessary regarding acetaminophen-warfarin drug-drug interaction (see 
section VII.F of this document).
    10. Comment on the proposal to include a warning on acetaminophen 
products for patients with liver disease to ask their doctor for 
advice. Also, request information and data on the current dosing 
practices of health providers who treat patients with underlying liver 
disease.
    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or three hard copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document and may be accompanied by a supporting 
memorandum or brief. Received comments may be seen in the Division of 
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

XV. Proposed Effective and Compliance Dates

    Because of the importance of the proposed labeling to the safe use 
of OTC IAAA drug products, FDA is proposing that any final rule that 
may publish based on this proposal become effective 12 months after its 
date of publication in the Federal Register. Manufacturers who 
voluntarily implement the labeling included in this proposal before the 
final rule is published will have 18 months after the date of 
publication of the final rule in the Federal Register to be in 
compliance with that final rule.

XVI. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES), under Docket No. 1977N-0094L, unless 
otherwise indicated, and may be seen by interested persons between 9 
a.m. and 4 p.m., Monday through Friday. (FDA has verified the Web site 
addresses, but we are not responsible for subsequent changes to the Web 
sites after this document publishes in the Federal Register.)
    1. Comment No. C1, Docket No. 1977N-0094I (formerly Docket No. 
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    90. Breitfkreutz, R. N. et al., ``Improvement of Immune 
Functions in HIV Infection by Sulfur Supplementation: Two Randomized 
Trials,'' Journal of Molecular Medicine, 78(1):55-62, 2000.
    91. Marmor, P. et al., ``Low Serum Thiol Levels Predict Shorter 
Times-to-Death Among HIV-Infected Injecting Drug Users,'' AIDS, 
11(11):1389-1393, 1997.
    92. Westendorp, M. O. et al., ``HIV-1 TAT Potentiates TNF-
Induced NF-KappaB Activation and Cytotoxicity by Altering the 
Cellular Redox State,'' EMBO Journal, 14(3):546-554, 1995.
    93. Opalenik, S. R. et al., ``Glutathione Depletion Associated 
With the HIV-1 TAT Protein Mediates the Extracellular Appearance of 
Acidic Fibroblast Growth Factor,'' Archives of Biochemistry and 
Biophysics, 351(1):17-26, 1998.
    94. Choi, J. et al., ``Molecular Mechanism of Decreased 
Glutathione Content in Human Immunodeficiency Virus Type 1 TAT-
Transgenic Mice,'' Journal of Biological Chemistry, 275(5): 3693-
3698, 2000.
    95. Ehret, A. et al., ``Resistance of Chimpanzee T Cells to 
Human Immunodeficiency Virus Type 1 TAT-Enhanced Oxidative Stress 
and Apoptosis,'' Journal of Virology, 70 (9):6502-6507, 1996.
    96. Aukrust, P. et al., ``Tumor Necrosis Factor (TNF) System 
Levels in Human Immunodeficiency Virus-Infected Patients During 
Highly Active Antiretroviral Therapy: Persistent TNF Activation is 
Associated With Virologic and Immunologic Treatment Failure,'' 
Journal of Infectious Diseases, 179(1):74-82, 1999.
    97. Malorni, W. et al., ``The Role of Oxidative Imbalance in 
Progression to AIDS: Effect of the Thiol Supplier N-
Acetylcystiene,'' AIDS Research and Human Retroviruses, 14(17):1589-
1596, 1998.
    98. Roberts, R. L. et al., ``N-Acetylcysteine Enhances Antibody-
Dependent Cellular Cytotoxicity in Neutrophils and Mononuclear Cells 
From Healthy Adults and Human Immunodeficiency Virus-Infects 
Patients,'' Journal of Infectious Diseases, 172(6): 1492-1502, 1995.
    99. Eylar, E. et al, ``N-Acetylcysteine Enhances T Cell 
Functions and T Cell Growth in Culture,'' International Immunology, 
5(1):97-101, 1993.
    100. Droge, W. et al., ``Modulation of Lymphocyte Functions and 
Immune Responses by Cysteine and Cysteine Derivatives,'' American 
Journal of Medicine, 91(Supplement C):140S-144S, 1991.
    101. DeRosa, S. C. et al., ``N-Acetylcysteine (NAC) Replenishes 
Glutathione in HIV Infection,'' European Journal of Clinical 
Investigation, 30:841-856, 2000.
    102. Herzenberg, L. A. et al., ``Glutathione Deficiency is 
Associated With Impaired Survival in HIV Disease,'' Proceedings of 
the National Academy of Sciences, 94:1967-72, 1997.
    103. Holroyd, K. J. et al., ``Correction of Glutathione 
Deficiency in the Lower Respiratory Tract of HIV Seropositive 
Individuals by Glutathione Aerosol Treatment,'' Thorax, 48(10):985-
89, 1993.
    104. Jahoor, F., ``Erythrocyte Glutathione Deficiency in 
Symptom-Free HIV Infection is Associated With Decreased Synthesis 
Rate,'' American Journal of Physiological-Endocrinological 
Metabolism, 39(1):E205-E211, 1999.
    105. ``A Patient's Guide to Using Coumadin,'' DuPont 
Pharmaceuticals, Wilmington, DE, 2000.
    106. Orme, M., A. Breckenridge, and P. Cook, ``Warfarin and 
Distalgesic Interaction,'' British Medical Journal, 1(6003):200, 
1976.
    107. Jones, R. V., ``Warfarin and Distalgesic Interaction 
[letter],'' British Medical Journal, 1(6007):460, 1976.
    108. Justice, J. L., and S. S. Kline, ``Analgesics and Warfarin: 
A Case That Brings Up Questions and Cautions,'' Postgraduate 
Medicine, 83 (5):217-8, 220, 1988.
    109. Bartle, W. R., and J. A. Blakely, ``Potentiation of 
Warfarin Anticoagulation by Acetaminophen [letter],'' The Journal of 
the American Medical Association, 265(10):1260, 1991.
    110. Antlitz, A. M., J. A. Mead, and M. A. Tolentino, 
``Potentiation of Oral Anticoagulant Therapy By Acetaminophen,'' 
Current Therapeutic Research, 10(10):501-507, 1968.
    111. Antlitz, A. M., and L. F. Awalt, ``A Double-Blind Study of 
Acetaminophen Used in Conjunction With Oral Anticoagulant Therapy, 
`` Current Therapeutic Research, 11(6):360-361, 1969.
    112. Boeijinga, J. J. et al., ``Interaction Between Paracetamol 
and Coumarin Anticoagulants [letter],'' Lancet, 1(8270):506, 1982.
    113. Rubin, R. N., R. L. Mentzer, and A. Z. Budzynski, 
``Potentiation of Anticoagulant Effect of Warfarin by Acetaminophen 
(Tylenol) [abstract],'' Clinical Research, 32(3):698A, 1984.
    114. Hylek, E. M. et al., ``Acetaminophen and Other Risk Factors 
for Excessive Warfarin Anticoagulation,'' The Journal of the 
American Medical Association, 279(9): 657-662, 1998.
    115. Amato, M. G. et al., ``Acetaminophen and Risk Factors for 
Excess Anticoagulation With Warfarin [letter],'' The Journal of the 
American Medical Association, 280(8): 695-696, 1998.
    116. Riser, J. et al., ``Acetaminophen and Risk Factors for 
Excess Anticoagulation With Warfarin [letter],'' The Journal of the 
American Medical Association, 26; 280(8): 696, 1998.
    117. Kwan, D., W. R. Bartle, and S. E. Walker, ``The Effects of 
Acetaminophen on Pharmacokinetics and Pharmacodynamics of 
Warfarin,'' Journal of Clinical Pharmacology, 39:68-75, 1999.
    118. Shek, K. L. A., L. N. Chan, and E. Nutescu, ``Warfarin-
Acetaminophen Drug Interaction Revisited,'' Pharmacotherapy, 
19(10):1153-1158, 1999.
    119. Lehmann, D. F., ``Enzymatic Shunting: Resolving the 
Acetaminophen-Warfarin Controversy,'' Pharmacotherapy, 20(12):1464-
1468, 2000.
    120. Whyte, I. M. et al., ``Acetaminophen Causes an Increased 
International Normalized Ratio by Reducing Functional Factor VII,'' 
Therapeutic Drug Monitoring, 22(6):742-748, 2000.
    121. Bell, W. R., ``Acetaminophen and Warfarin: Undesirable 
Synergy [editorial],''

[[Page 77349]]

The Journal of the American Medical Association, 279(9): 702-703, 
1998.
    122. Caraco, Y., J. Sheller, and A. J. Wood, ``Pharmacogenetic 
determination of the effects of codeine and prediction of drug 
interactions,'' Journal of Pharmacology and Experimental 
Therapeutics, 278(3):1165-1174, 1996.
    123. van den Bemt, P. M. et al., ``The potential interaction 
between oral anticoagulants and acetaminophen in everyday 
practice,'' Pharmaceutical World Science, 24(5):201-204, 2002.
    124. Fattinger, K. et al., ``No clinically relevant drug 
interaction between paracetamol and phenoprocoumon based on a 
pharmacoepidemiological cohort study in medical in people,'' 
European Journal of Clinical Pharmacology, 57(12): 863-867, 2002.
    125. La Grenad, L., D. J. Graham, and P. Nourjah, 
``Underreporting of hemorrhagic stroke associated with 
phenylpropanolamine,'' The Journal of the American Medical 
Association; 286: 3081, 2001.
    126. Phelan, K., ``OPDRA Postmarketing Safety Review: 
Acetaminophen and Coumadin (drug interaction affecting 
anticoagulation),'' FDA review dated April 20, 2001.
    127. Karwoski, C. B., ``Office of Drug Safety Postmarketing 
Safety Review (DO30283) Drugs--Acetaminophen and Warfarin, Reaction: 
Drug Interaction affecting Anticoagulation (update),'' FDA review 
dated June 27, 2003.
    128. Neuner, R., ``Potentiation of Anticoagulaton Status Due to 
a Possible Adverse Drug Interaction Between Warfarin and 
Acetaminophen,'' FDA review dated July 9, 2003.
    129. Eastern Research Group, Inc. ``Cost Benefit Analysis of 
Proposed FDA Rule on Over-the-Counter Internal Analgesic, 
Antipyretic, and Antirheumatic Drug Products; Required Warnings'', 
Final Report, October 6, 2004.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 343

    Labeling, Over-the-counter drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 201 and 343 (as proposed in the Federal 
Register of November 16, 1988 and August 21, 2002) be amended as 
follows:

PART 201--LABELING

    1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360g-360s, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

0
2. Section 201.66 is amended by revising paragraph (c)(5)(ii)(E) to 
read as follows:


Sec.  201.66  Format and content requirements for over-the-counter 
(OTC) drug product labeling.

* * * * *
    (c) * * *
    (5) * * *
    (ii) * * *
    (E) Liver warning set forth in Sec.  201.325(a)(1)(iii) and/or 
stomach bleeding warning set forth in Sec.  201.325(a)(2)(iii). The 
liver warning shall follow the subheading ``Liver warning:'' and the 
stomach bleeding warning shall follow the subheading ``Stomach bleeding 
warning:''
* * * * *


Sec.  201.322  [Removed]

    3. Section 201.322 is removed.
    4. Section 201.325 is added to subpart G to read as follows:


Sec.  201.325  Over-the-counter drug products containing internal 
analgesic/antipyretic active ingredients; required warnings and other 
labeling.

    (a) Labeling. The labeling for all over-the-counter (OTC) drug 
products containing any internal analgesic/antipyretic active 
ingredients (including, but not limited to, acetaminophen, aspirin, 
carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, 
magnesium salicylate, naproxen sodium, and sodium salicylate) alone or 
in combination must bear the following labeling in accordance with 
Sec. Sec.  201.60, 201.61, and 201.66.
    (1) Acetaminophen.
    (i) Principal display panel. The presence of ``acetaminophen'' in 
the product must be prominently stated on the principal display panel 
(PDP), as defined in Sec.  201.60.
    (ii) Statement of identity. The statement of identity appears in 
accord with Sec. Sec.  201.61, 299.4, and 343.50(a) of this chapter. 
The ingredient name acetaminophen must appear highlighted (e.g., 
fluorescent or color contrast) or in bold type, be in lines generally 
parallel to the base on which the package rests as it is designed to be 
displayed, and be in one of the following sizes, whichever is greater: 
(1) At least one-quarter as large as the size of the most prominent 
printed matter on the PDP, or (2) at least as large as the size of the 
``Drug Facts'' title, as required in Sec.  201.66(d)(2). The presence 
of acetaminophen must appear as part of the established name of the 
drug, as defined in Sec.  299.4 of this chapter. Combination products 
containing acetaminophen and a nonanalgesic ingredient(s) (e.g., cough-
cold) must include the name ``acetaminophen'' and the name(s) of the 
other active ingredient(s) in the product on the PDP in accord with 
this paragraph. Only the name ``acetaminophen'' must appear highlighted 
or in bold type, and in a prominent print size, as described in this 
paragraph.
    (iii) For products labeled for adults only. Warnings. The labeling 
of the product states the following warnings under the heading 
``Warnings'':
    (A) ``Liver warning [heading in bold type]: This product contains 
acetaminophen. Severe liver damage may occur if you take [bullet] more 
than [insert maximum number of daily dosage units] in 24 hours [bullet] 
with other drugs containing acetaminophen [bullet] 3 or more alcoholic 
drinks every day while using this product''. This ``Liver warning'' 
must be the first warning under the ``Warnings'' heading. For products 
that contain both acetaminophen and aspirin, this ``Liver warning'' 
must appear after the ``Reye's syndrome'' and ``Allergy alert'' 
warnings in Sec.  201.66(c)(5)(ii)(A) and (c)(5)(ii)(B) and before the 
``Stomach bleeding warning'' in paragraph (a)(2)(iii)(A) of this 
section.
    (B) ``Do not use [heading in bold type] with any other drug 
containing acetaminophen (prescription or nonprescription). Ask a 
doctor or pharmacist before using with other drugs if you are not 
sure.''
    (C) ``Ask a doctor before use if you have [heading in bold type] 
liver disease''.
    (iv) For products labeled only for children under 12 years of age. 
(A) Warnings. The labeling of the product states the following warnings 
under the heading ``Warnings'':
    (1) ``Liver warning [heading in bold type]: This product contains 
acetaminophen. Severe liver damage may occur if the child takes 
[bullet] more than 5 doses in 24 hours [bullet] with other drugs 
containing acetaminophen''. This ``Liver warning'' must be the first 
warning under the ``Warnings'' heading.
    (2) ``Do not use [heading in bold type] with any other drug 
containing acetaminophen (prescription or nonprescription). Ask a 
doctor or pharmacist before using with other drugs if you are not 
sure.''
    (3) ``Ask a doctor before use if the child has [heading in bold 
type] liver disease''.
    (B) Directions. The labeling of the product contains the following 
information under the heading ``Directions'': ``this product does not

[[Page 77350]]

contain directions or warnings for adult use'' [in bold type].
    (v) For products labeled for adults and children under 12 years of 
age. Warnings. The labeling of the product states all of the warnings 
in paragraphs (a)(1)(iii)(A), (a)(1)(iii)(B), and (a)(1)(iii)(C) of 
this section with the following modifications:
    (A) The Liver warning states ``Liver warning [heading in bold 
type]: This product contains acetaminophen. Severe liver damage may 
occur if [bullet] adult takes more than [insert maximum number of daily 
dosage units] in 24 hours [ bullet] child takes more than 5 doses in 24 
hours [bullet] taken with other drugs containing acetaminophen [bullet] 
adult has 3 or more alcoholic drinks everyday while using this 
product.''
    (B) ``Ask a doctor before use if the user [heading in bold type] 
has liver disease.''
    (2) Nonsteroidal anti-inflammatory analgesic/antipyretic active 
ingredients--including, but not limited to, aspirin, carbaspirin 
calcium, choline salicylate, ibuprofen, ketoprofen, magnesium 
salicylate, naproxen sodium, and sodium salicylate.
    (i) Principal display panel. The presence of an ``NSAID'' 
ingredient in the product must be prominently stated on the principal 
display panel (PDP), as defined in Sec.  201.60.
    (ii) Statement of identity. The statement of identity appears in 
accord with Sec. Sec.  201.61, 299.4, and 343.50(a) of this chapter. 
The name of the NSAID ingredient and the word ``(NSAID)'' must appear 
highlighted (e.g., fluorescent or color contrast) or in bold type, be 
in lines generally parallel to the base on which the package rests as 
it is designed to be displayed, and be in one of the following sizes, 
whichever is greater: At least one-quarter as large as the size of the 
most prominent printed matter on the PDP, or at least as large as the 
size of the ``Drug Facts'' title, as required in Sec.  201.66(d)(2). 
The word ``(NSAID)'' must appear as part of the established name of the 
drug, as defined in Sec.  299.4 of this chapter, or after the general 
pharmacological (principal intended) action of the NSAID ingredient. 
For example, either of the following would be acceptable: Ibuprofen 
Tablets (NSAID) or Pain reliever/ fever reducer (NSAID). Combination 
products containing an NSAID and a nonanalgesic ingredient(s) (e.g., 
cough-cold) must include the name of the NSAID ingredient and the word 
``(NSAID)'' in accord with this paragraph, and the name(s) of the other 
active ingredient(s) in the product on the PDP. Only the name of the 
NSAID ingredient and the word ``(NSAID)'' need to appear highlighted or 
in bold type, and in a prominent print size, as described in this 
paragraph.
    (iii) For products labeled for adults only. Warnings. The labeling 
of the product states the following warnings under the heading 
``Warnings'':
    (A) ``Stomach bleeding warning [heading in bold type]: This product 
contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause 
stomach bleeding. The chance is higher if you [bullet] are age 60 or 
older [bullet] have had stomach ulcers or bleeding problems [bullet] 
take a blood thinning (anticoagulant) or steroid drug [bullet] take 
other drugs containing an NSAID [aspirin, ibuprofen, naproxen, or 
others] [bullet] have 3 or more alcoholic drinks every day while using 
this product [bullet] take more or for a longer time than directed''. 
This ``Stomach bleeding warning'' must appear after the ``Reye's 
syndrome'' and ``Allergy alert'' warnings in Sec.  201.66(c)(5)(ii)(A) 
and (c)(5)(ii)(B). For products that contain both acetaminophen and 
aspirin, the acetaminophen ``Liver warning'' in Sec.  
201.325(a)(1)(iii) must appear before the ``Stomach bleeding warning'' 
in this paragraph.
    (B) ``Ask a doctor before use if you have [heading in bold type] 
[bullet] stomach problems that last or come back, such as heartburn, 
upset stomach, or stomach pain [bullet] ulcers [bullet] bleeding 
problems [bullet] high blood pressure [bullet] heart or kidney disease 
[bullet] taken a diuretic [bullet] reached age 60 or older''.
    (C) ``Ask a doctor or pharmacist before use if you are [heading in 
bold type] [bullet] taking any other drug containing an NSAID 
(prescription or nonprescription) [bullet] taking a blood thinning 
(anticoagulant) or steroid drug''.
    (D) ``Stop use and ask a doctor if [heading in bold type] [bullet] 
you feel faint, vomit blood, or have bloody or black stools. These are 
signs of stomach bleeding. [bullet] stomach pain or upset gets worse or 
lasts''.
    (iv) For products labeled only for children under 12 years of age. 
Warnings. (A) The labeling of the product states the following warnings 
under the heading ``Warnings'':
    (1) ``Stomach bleeding warning [heading in bold type]: This product 
contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause 
stomach bleeding. The chance is higher if the child [bullet] has had 
stomach ulcers or bleeding problems [bullet] takes a blood thinning 
(anticoagulant) or steroid drug [bullet] takes other drugs containing 
an NSAID (aspirin, ibuprofen, naproxen, or others) [bullet] takes more 
or for a longer time than directed''. The ``Stomach bleeding warning'' 
must appear after the ``Reye's syndrome'' and ``Allergy alert'' 
warnings in Sec. Sec.  201.66(c)(5)(ii)(A) and (c)(5)(ii)(B).
    (2) ``Ask a doctor before use if the child has [heading in bold 
type] [bullet] stomach problems that last or come back, such as 
heartburn, upset stomach, or stomach pain [bullet] ulcers [bullet] 
bleeding problems [bullet] not been drinking fluids [bullet] lost a lot 
of fluid due to vomiting or diarrhea [bullet] high blood pressure 
[bullet] heart or kidney disease [bullet] taken a diuretic''.
    (3) ``Ask a doctor or pharmacist before use if the child is 
[heading in bold type] [bullet] taking any other drug containing an 
NSAID (prescription or nonprescription) [bullet] taking a blood 
thinning (anticoagulant) or steroid drug''.
    (4) ``Stop use and ask a doctor if [heading in bold type] [bullet] 
the child feels faint, vomits blood, or has bloody or black stools. 
These are signs of stomach bleeding. [bullet] stomach pain or upset 
gets worse or lasts''.
    (B) Directions. The labeling of the product contains the following 
information under the heading ``Directions'': ``this product does not 
contain directions or warnings for adult use'' [in bold type].
    (v) For products labeled for adults and children under 12 years of 
age. Warnings. The labeling of the product states all of the warnings 
in paragraphs (2)(iii)(A) through (2)(iii)(D) of this section with the 
following modifications:
    (A) The Stomach bleeding warning states ``Stomach bleeding warning 
[heading in bold type]: This product contains a nonsteroidal anti-
inflammatory drug (NSAID), which may cause stomach bleeding. The chance 
is higher if the user [bullet] has had stomach ulcers or bleeding 
problems [bullet] takes a blood thinning (anticoagulant) or steroid 
drug [bullet] takes other drugs containing an NSAID [aspirin, 
ibuprofen, naproxen, or others] [bullet] takes more or for a longer 
time than directed [bullet] is age 60 or older [bullet] has 3 or more 
alcoholic drinks everyday while using this product''. The ``Stomach 
bleeding warning'' must appear after the ``Reye's syndrome'' and 
``Allergy alert'' warnings in Sec. Sec.  201.66(c)(5)(ii)(A) and 
(c)(5)(ii)(B).
    (B) The labeling states ``Ask a doctor before use if the user has 
[heading in bold type] [bullet] stomach problems that last or come 
back, such as heartburn, upset stomach, or stomach

[[Page 77351]]

pain [bullet] ulcers [bullet] bleeding problems [bullet] high blood 
pressure [bullet] heart or kidney disease [bullet] taken a diuretic 
[bullet] not been drinking fluids [bullet] lost a lot of fluid due to 
vomiting or diarrhea [bullet] reached age 60 or older.''
    (C) The labeling states ``Ask a doctor or pharmacist before use if 
the user is [heading in bold type] [bullet] taking any other drug 
containing an NSAID (prescription or nonprescription) [bullet] taking a 
blood thinning (anticoagulant) or steroid drug''.
    (D) The labeling states ``Stop use and ask a doctor if [heading in 
bold type] [bullet] the user feels faint, vomits blood, or has bloody 
or black stools. These are signs of stomach bleeding. [bullet] stomach 
pain or upset gets worse or lasts''.
    (vi) Active ingredient(s). The active ingredient(s) section of the 
product's labeling, as defined in Sec.  201.66(c)(2), contains the term 
``(NSAID)*'' after the NSAID active ingredient with an asterisk 
statement at the end of the active ingredient(s) section that defines 
the term ``NSAID'' and states ``* nonsteroidal anti-inflammatory 
drug.''
    (b) New warnings information statement. The labeling of any drug 
product subject to this section that is initially introduced or 
initially delivered for introduction into interstate commerce before 
the effective date and within 12 months after the effective date of the 
final rule or if relabeled at any time before the effective date of the 
final rule must bear on its principal display panel (PDP), as defined 
in Sec.  201.60, the statement ``See new warnings information.'' This 
statement must appear highlighted (e.g., fluorescent or color contrast) 
or in bold type, be in lines generally parallel to the base on which 
the package rests as it is designed to be displayed, and be in one of 
the following sizes, whichever is greater:
    (1) At least one-quarter as large as the size of the most prominent 
printed matter on the PDP, or
    (2) At least as large as the size of the ``Drug Facts'' title, as 
required in Sec.  201.66(d)(2).
    (c) Requirements to supplement approved application. Holders of 
approved applications for OTC drug products that contain internal 
analgesic/antipyretic active ingredients that are subject to the 
requirements of paragraph (a) of this section must submit supplements 
under Sec.  314.70(c) of this chapter to include the required 
information in the product's labeling. Such labeling may be put into 
use without advance approval of FDA provided it includes at least the 
exact information included in paragraph (a) of this section.
    (d) Regulatory action. Any drug product subject to this section 
that is not labeled as required and that is initially introduced or 
initially delivered for introduction into interstate commerce after 
[date 12 months after date of publication of the final rule in the 
Federal Register] is misbranded under section 502 of the Federal Food, 
Drug, and Cosmetic Act (the act) (21 U.S.C. 352) and is subject to 
regulatory action. Any drug product for which the labeling required in 
this section was voluntarily implemented before the date of publication 
of the final rule that is initially introduced or initially delivered 
for introduction into interstate commerce after [date 18 months after 
date of publication of the final rule in the Federal Register] and that 
is not labeled as required is misbranded under section 502 of the act 
and is subject to regulatory action.

PART 343--INTERNAL ANALGESIC, ANTIPYRETIC, AND ANTIRHEUMATIC DRUG 
PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

    4. The authority citation for 21 CFR part 343 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
    5. Section 343.50, as proposed at 53 FR 46255, November 16, 1988, 
and 67 FR 54158, August 21, 2002, is further amended by revising 
paragraphs (c)(1)(i), (c)(1)(iii), (c)(1)(iv)(A), (c)(1)(v)(A) through 
(c)(1)(v)(C), (c)(1)(ix)(A), (c)(1)(ix)(B), (c)(1)(ix)(C), 
(c)(1)(ix)(E), (c)(2)(i), (c)(2)(iii), (c)(2)(iv)(A), (c)(2)(v)(A) 
through (c)(2)(v)(C)\3\ and adding new paragraphs (b)(4)(i)(C) and 
(c)(3)(i) through (c)(3)(v)(C) to read as follows:
---------------------------------------------------------------------------

    \3\The warnings in these sections are revised to conform with 
Sec.  201.66 (Drug Facts format). Other warnings remain as proposed 
in the TFM and will be revised into the Drug Facts format in a 
future issue of the Federal Register.
---------------------------------------------------------------------------


Sec.  343.50  Labeling of analgesic-antipyretic drug products.

* * * * *
    (b) * * *
    (4) * * *
    (i) * * *
    (C) The product states the following statement under the heading 
``Directions,'' ``this product does not contain directions or warnings 
for adult use''. This statement is not required for products containing 
ibuprofen as identified in Sec.  343.10 (g).
* * * * *
    (c) * * *
    (1) * * *
    (i) For products containing any ingredient in Sec.  343.10 (a) 
through (f) The labeling states ``Stop use and ask a doctor if [heading 
in bold type] [bullet]\1\ pain gets worse or lasts more than 10 days 
[bullet] fever gets worse or lasts more than 3 days [bullet] redness or 
swelling is present [bullet] any new symptoms appear''.
---------------------------------------------------------------------------

    \1\See Sec.  201.66(b)(4) of this chapter for definition of 
bullet symbol.
---------------------------------------------------------------------------

* * * * *
    (iii) For products containing acetaminophen identified in Sec.  
343.10(a). The labeling states the warnings in Sec.  
201.325(a)(1)(iii)(A), (a)(1)(iii)(B), and (a)(1)(iii)(C) and the 
following statement must follow the general warning identified in Sec.  
330.1(g) of this chapter: ``Prompt medical attention is critical for 
adults as well as for children even if you do not notice any signs or 
symptoms.''
    (iv) * * *
    (A) The labeling states the warning in paragraph (c)(1)(v)(B) plus 
the bulleted statement ``asthma''.
* * * * *
    (v) * * *
    (A) The labeling states the warning in paragraph (c)(1)(i) of this 
section plus ``[bullet] you feel faint, vomit blood, or have bloody or 
black stools. These are signs of stomach bleeding. [bullet] stomach 
pain or upset gets worse or lasts [bullet] ringing in the ears or loss 
of hearing occurs''.
    (B) The labeling states ``Ask a doctor before use if you have 
[heading in bold type] [bullet] stomach problems that last or come 
back, such as heartburn, upset stomach, or stomach pain [bullet] ulcers 
[bullet] bleeding problems [bullet] high blood pressure [bullet] heart 
or kidney disease [bullet] taken a diuretic [bullet] reached age 60 or 
older''.
    (C) The labeling states ``Ask a doctor or pharmacist before use if 
you are [heading in bold type] [bullet] taking any other drug 
containing an NSAID (prescription or nonprescription) [bullet] taking a 
blood thinning (anticoagulant) or steroid drug [bullet] taking a 
prescription drug for diabetes, gout, or arthritis''.
* * * * *
    (ix) * * *
    (A) The stomach bleeding warning set forth in Sec.  
201.325(a)(2)(iii)(A), (a)(2)(iv)(A), or (a)(2)(v)(A) of this chapter 
appears after the subheading ``Stomach bleeding warning:''.
    (B) The labeling states ``Ask a doctor before use if you have 
[heading in bold type] [bullet] problems or serious side effects from 
taking pain relievers or fever reducers [bullet] stomach problems that 
last or come back, such as

[[Page 77352]]

heartburn, upset stomach, or stomach pain [bullet] ulcers [bullet] 
bleeding problems [bullet] high blood pressure [bullet] heart or kidney 
disease [bullet] taken a diuretic [bullet] reached age 60 or older''.
    (C) The labeling states ``Ask a doctor or pharmacist before use if 
you are [heading in bold type] [bullet] taking any other drug 
containing an NSAID (prescription or nonprescription [bullet] taking a 
blood thinning (anticoagulant) or steroid drug [bullet] under a 
doctor's care for any serious condition [bullet] taking any other 
drug''.
* * * * *
    (E) In addition to the warning required in Sec.  201.324(c) of this 
chapter after the subheading ``Stop use and ask a doctor if'' [heading 
in bold type], the following statements also appear: ``[bullet] you 
feel faint, vomit blood, or have bloody or black stools. These are 
signs of stomach bleeding. [bullet] pain gets worse or lasts more than 
10 days [bullet] fever gets worse or lasts more than 3 days [bullet] 
stomach pain or upset gets worse or lasts [bullet] redness or swelling 
is present in the painful area [bullet] any new symptoms appear``.
* * * * *
    (2) * * *
    (i) For products containing any ingredient in Sec.  343.10 (a) 
through (f) The labeling states ``Stop use and ask a doctor if [heading 
in bold type] [bullet] pain gets worse or lasts more than 5 days 
[bullet] fever gets worse or lasts more than 3 days [bullet] redness or 
swelling is present [bullet] any new symptoms appear ''.
* * * * *
    (iii) For products containing acetaminophen identified in Sec.  
343.10(a). The labeling states the warnings in Sec.  
201.325(a)(1)(iv)(A)(1), (a)(1)(iv)(A)(2), and (a)(1)(iv)(A)(3) and the 
following statement must follow the general warning identified in Sec.  
330.1(g) of this chapter: ``Prompt medical attention is critical even 
if you do not notice any signs or symptoms.''
    (iv) * * *
    (A) The labeling states the warning in paragraph (c)(2)(v)(B) plus 
the bulleted statement ``asthma''.
* * * * *
    (v) * * *
    (A) The labeling states the warning in paragraph (c)(2)(i) of this 
section plus ``[bullet] the child feels faint, vomits blood, or has 
bloody or black stools. These are signs of stomach bleeding. [bullet] 
stomach pain or upset gets worse or lasts [bullet] ringing in the ears 
or loss of hearing occurs''.
    (B) The labeling states ``Ask a doctor before use if the child has 
[heading in bold type] [bullet] stomach problems that last or come 
back, such as heartburn, upset stomach, or stomach pain [bullet] ulcers 
[bullet] bleeding problems [bullet] not been drinking fluids [bullet] 
lost a lot of fluid due to vomiting or diarrhea [bullet] high blood 
pressure [bullet] heart or kidney disease [bullet] taken a diuretic''.
    (C) The labeling states ``Ask a doctor or pharmacist before use if 
the child is [heading in bold type] [bullet] taking any other drug 
containing an NSAID (prescription or nonprescription) [bullet] taking a 
blood thinning (anticoagulant) or steroid drug [bullet] taking a 
prescription drug for diabetes, gout, or arthritis''.
* * * * *
    (3) * * *
    (i) For products containing any ingredient in Sec.  343.10 (a) 
through (f). The labeling states ``Stop use and ask a doctor if 
[heading in bold type] [bullet] adult's pain gets worse or lasts more 
than 10 days [bullet] child's pain gets worse or lasts more than 5 days 
[bullet] fever gets worse or lasts more than 3 days [bullet] redness or 
swelling is present [bullet] any new symptoms appear''.
    (ii) The warning in Sec.  343.50(c)(1)(ii), if applicable.
    (iii) For products containing acetaminophen identified in Sec.  
343.10(a). The labeling states the warnings in Sec.  201.325(a)(1)(v) 
of this chapter. The warning in Sec.  201.325 (a)(1)(v)(B) is modified 
to read: `` Ask a doctor before use if the user [heading in bold type] 
[bullet] has liver disease [bullet] is a child with pain of 
arthritis''. The following statement must follow the general warning 
identified in Sec.  330.1(g) of this chapter: ``Prompt medical 
attention is critical for adults as well as for children even if you do 
not notice any signs or symptoms.''
    (iv) The warnings in Sec.  343.50(c)(1)(iv), if applicable.
    (v) For products containing aspirin, carbaspirin calcium, choline 
salicylate, magnesium salicylate, or sodium salicylate identified in 
Sec. Sec.  343.10(b), (c), (d), (e) and ( f).
    (A) The labeling states the warning in paragraph (c)(3)(i) of this 
section plus ``[bullet] the user feels faint, vomits blood, or has 
bloody or black stools. These are signs of stomach bleeding. [bullet] 
stomach pain or upset gets worse or lasts [bullet] ringing in the ears 
or loss of hearing occurs''.
    (B) The labeling states the warning in Sec.  201.325(a)(2)(v)(B) 
plus ``[bullet] is a child with pain of arthritis''.
    (C) The labeling states the warning in Sec.  201.325(a)(2)(v)(C) 
plus ``[bullet] taking a prescription drug for diabetes, gout, or 
arthritis''.

    Dated: November 22, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-21855 Filed 12-19-06; 8:45 am]
BILLING CODE 4160-01-S