[Federal Register: April 29, 2009 (Volume 74, Number 81)]
[Rules and Regulations]
[Page 19385-19409]
[DOCID:fr29ap09-4]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. FDA-1977-N-0013] (formerly Docket No. 1977N-0094L)
RIN 0910-AF36

Organ-Specific Warnings; Internal Analgesic, Antipyretic, and
Antirheumatic Drug Products for Over-the-Counter Human Use; Final
Monograph

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Final rule.

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SUMMARY:  The Food and Drug Administration (FDA) is issuing this final
rule to require important new organ-specific warnings and related
labeling for over-the-counter (OTC) internal analgesic, antipyretic,
and antirheumatic (IAAA) drug products. The new labeling informs
consumers about the risk of liver injury when using acetaminophen and
the risk of stomach bleeding when using nonsteroidal anti-inflammatory
drugs (NSAIDS). The new labeling is required for all OTC IAAA drug
products whether marketed under an OTC drug monograph or an approved
new drug application (NDA).

DATES:  Effective Date: This final rule is effective April 29, 2010.
    Compliance Date: The compliance date for all products subject to
this final rule, including products with annual sales less than
$25,000, is April 29, 2010.

FOR FURTHER INFORMATION CONTACT:  Arlene Solbeck, Center for Drug
Evaluation and Research , Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, MS 5411, Silver Spring, MD 20993, 301-796-
2090.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Overview of This Document
II. Rulemaking History for OTC IAAA Drug Products
    A. Rulemakings Published Before the 2006 Proposed Rule
    B. 2006 Proposed Rule
III. Labeling Required for All OTC Internal Analgesics
    A. PDP
    B. Drug Facts
    C. Immediate Container
IV. Labeling Required for OTC Acetaminophen
    A. Liver Warning
    B. Concomitant Use Warning
    C. Liver Disease Warning
    D. Drug Interaction Warning
    E. Warnings for Certain Sub-Populations
V. Labeling Required for OTC NSAIDs
    A. Warnings
    B. Labeling Specific to Aspirin
VI. Analysis of Impacts
VII. Paperwork Reduction Act of 1995
VIII. Environmental Impact
IX. Federalism
X. References

Glossary

    (The definitions of terms used throughout this document are
included in this glossary because these terms are likely to be
unfamiliar to many readers.)
    AERS: FDA's Adverse Event Reporting System; a database of adverse
events reported to FDA for drugs and medical devices
    Acute Liver Failure: Severe liver injury without a history of
chronic liver disease that is associated with coagulopathy and
encephalopathy
    ALT: Alanine aminotransferase; a liver enzyme that is often tested
to evaluate individuals for liver disease
    AST: Aspartate aminotransferase; a liver enzyme that is often
tested to evaluate individuals for liver disease
    CFR: The Code of Federal Regulations; list of regulations created
by the executive departments and agencies of the Federal Government
    GRAS/E: Generally recognized as safe and effective
    GSH: Glutathione; tripeptide (protein fragment) necessary for
acetaminophen metabolism to avoid accumulation of the toxic metabolite
N-acetyl-p-benzo-quinone imine (NAPQI)
    HIV: Human immunodeficiency virus; a retrovirus that can lead to
acquired immunodeficiency syndrome (AIDS)
    IAAA: Internal analgesic, antipyretic, and antirheumatic drug
products
    INR: International normalized ratio; measurement that evaluates the
ability of blood to clot
    IU/L: International units per liter
    NAQPI: N-acetyl-p-benzo-quinone imine; a harmful by-product of
acetaminophen metabolism that can cause severe liver injury
    NDA: New Drug Application; application needed for approval of a new
drug by the FDA prior U.S. marketing
    NSAIDs: Nonsteroidal anti-inflammatory drugs (such as aspirin and
ibuprofen)
    PDP: Principal display panel; part of a label that is most likely
to be displayed, presented, shown, or examined under customary
conditions of display for retail sale.

I. Overview of This Document

    This document addresses comments and data in the 19 submissions
that we received in response to the December 26, 2006 (proposed rule)
(71 FR 77314), which is described in section II of this document. The
submissions comment on the labeling that we proposed for 21 CFR parts
201 and 343 as well as other issues where specific comments were sought
in the 2006 proposed rule. The proposed rule asked for comments on
issues related to the following:
     The safe and effective daily dose of acetaminophen
     Daily dose recommendation for alcohol abusers
     Combination products of acetaminophen combined with
methionine or acetylcysteine
     Package size and configuration limitations with
acetaminophen products
     Label warnings for individuals with Human Immunodeficiency
Virus (HIV)
     Drug interactions between acetaminophen and warfarin
    This document states our final conclusions on the labeling
requirements in 21 CFR part 201 and requires that manufacturers include
this labeling on their OTC IAAA drug products by the effective date
identified in this document (see DATES). We are currently evaluating
data and information regarding the remaining issues discussed in the
proposed rule, some of which include the following:
     Safe daily dose for acetaminophen (healthy users)
     Safe daily dose for acetaminophen users with chronic liver
disease
     Safe daily dose for acetaminophen with alcohol use
     Appropriate dosage for acetaminophen efficacy
     Package size restrictions for OTC IAAA drug products
     Pediatric dosing for OTC IAAA drug products
     Various warnings for OTC IAAA drug products that were
proposed in 21 CFR part 343 but not part 21 CFR part 201
     Acetaminophen-narcotic combinations
     Combinations of acetaminophen and N-acetylcysteine (NAC)
or methionine
     Prescription labeling for OTC IAAA drug products

     Education on safe use of OTC IAAA drug products
We believe these are very important issues and will address them in
separate Federal Register notices that address the OTC IAAA drug
monograph (21 CFR part 343). We are not addressing them in this
document because we believe there is a major public health benefit to
having the labeling in 21 CFR part 201 appear on products as soon as
possible. This new labeling in 21 CFR part 201 will advise consumers
about serious risks associated with using these products. By not
addressing other issues in this document that we are still evaluating,
we are able to more quickly implement the labeling in 21 CFR part 201.
    In this document, we are requiring the labeling changes proposed in
the 2006 proposed rule (see Table 1). In response to the submissions,
we are also requiring the following labeling that was not specifically
proposed in the 2006 proposed rule but was suggested by the submissions
received:
     Liver warning and stomach bleeding warnings required on
immediate container labels in addition to the carton or outer container
for all OTC IAAA drug products (21 CFR 201.326(a)(1)(iii)(A) and 21 CFR
201.326(a)(2)(iii))
     Revised acetaminophen concomitant use warning (21 CFR
201.326(a)(1)(iii)(B))
     New warning about taking warfarin and acetaminophen at the
same time (21 CFR 201.326(a)(1)(iii)(D))
     Revised directions statement for all OTC IAAA drug
products labeling for children under 12 years of age (21 CFR
201.326(a)(1)(iv)(B))
     Revised introductory sentence for stomach bleeding warning
(21 CFR 201.326(a)(2)).
In addition, we are allowing voluntary highlighting of information
under the ``Active Ingredient'' and ``Purpose'' headings in Drug Facts
for all OTC IAAA drug products.
    It should be noted that the 2006 proposed rule discussed added
labeling requirements in 21 CFR 201.325. However, in December 2007, we
added required labeling for OTC vaginal contraceptives in 21 CFR
201.325 (72 FR 71769). Therefore, in this document, required labeling
for OTC IAAA drug products is be added to 21 CFR 201.326.

II. Rulemaking History for OTC IAAA Drug Products

    The rulemaking history in this document focuses on rulemakings that
discuss labeling related to liver injury caused by acetaminophen and/or
related to stomach bleeding caused by NSAIDs.

A. Rulemakings Published Before the 2006 Proposed Rule

    In 1977, we published the report from the Advisory Review Panel on
OTC IAAA Drug Products (the Panel) (42 FR 35346). In its report, the
Panel recommended the following warnings related to stomach bleeding
and liver injury, respectively:
     For products containing 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 35493)
     For products containing acetaminophen:
Do not exceed the recommended dosage because severe liver damage may
occur (42 FR 35346 at 35494)
    Based on the Panel's report, we published a 1988 proposed rule,
referred to as a tentative final monograph (53 FR 46204). In the 1988
proposed rule, we tentatively adopted the Panel's recommended aspirin
warning with a slight modification. We decided not to adopt the liver
warning for acetaminophen as recommended by the Panel because we
concluded that warnings need not include information on the specific
injury to organs of the body caused by an acute overdose of a drug (53
FR 46204 at 46214). However, we proposed a modified warning because we
believed consumers should know that prompt medical attention is
essential if an acetaminophen overdose occurs (53 FR 46204 at 46215).
In the proposed rule, we included the following warnings related to
stomach bleeding and liver injury, respectively (53 FR 46204 at 46256):
     For products containing 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
(proposed 21 CFR 343 (c)(1)(v)(B)).
     For products containing acetaminophen:
Keep out of reach of children. In case of overdose, get medical help
or contact a Poison Control Center right away. Prompt medical
attention is critical for adults as well as for children even if you
do not notice any signs or symptoms (proposed 21 CFR
343.50(c)(1)(iii)).
This warning for products containing acetaminophen includes the general
overdose warnings in 330.1(g), as required in proposed 21 CFR
343.50(c)(1)(iii).
    In 1998, we published two final rules that (1) provide labeling
information to health professionals (i.e., labeling that is not
available on OTC IAAA drug products) that includes cardiovascular and
rheumatologic indications for aspirin (63 FR 56802), and (2) require an
alcohol warning for all IAAA drug products in 21 CFR 201.322 (63 FR
56789) as follows:
     For products containing acetaminophen:
Alcohol Warning: If you consume 3 or more alcoholic drinks every
day, ask a doctor whether you should take acetaminophen or other
pain relievers/fever reducers. Acetaminophen may cause liver damage.
     For products containing NSAIDs:
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.
    In 2002, we issued a proposed rule to include ibuprofen as a GRASE
active ingredient in the monograph for OTC IAAA drug products (67 FR
54139). The proposed rule includes additional warnings relating to
stomach problems, ulcers, bleeding problems, high blood pressure, heart
or kidney disease, and use of diuretics. The warnings also include
information specific to consumers over 65 years of age.

B. 2006 Proposed Rule

    On December 26, 2006, we published a proposed rule regarding IAAA
drug products (71 FR 77314). In the proposed rule, we proposed new
organ-specific warnings and related labeling for all OTC IAAA drug
products. The proposed labeling was designed to provide consumers with
information concerning liver injury caused by acetaminophen and stomach
bleeding caused by NSAIDs. We stated in the proposed rule that, when
labeled appropriately and used as directed, OTC IAAA drug products are
safe and effective drug products that benefit tens of millions of
consumers every year and that these products should continue to be
available to consumers in the OTC setting (71 FR 77314 at 77315).
However, we also stated that new labeling is necessary to ensure
consumers know these products can cause liver injury and stomach
bleeding (71 FR 77314 at 77331).
1. Scientific Basis for 2006 Proposed Rule
    As explained in the proposed rule, after reviewing a variety of
data demonstrating a risk for these two adverse drug effects, we are
concerned about liver injury and stomach bleeding associated with IAAA
drug products. For acetaminophen, we analyzed data from national
databases including emergency departments, hospital discharges,
mortality data, poison control centers, and spontaneous post-marketing
drug adverse event reports

reported to us through our AERS database from 1990-2001. In addition,
we considered results of acute liver failure studies in the United
States that were published by the U.S. Acute Liver Failure Study Group
as well as case series from the University of Pennsylvania Hospital. We
concluded from this data that unintentional overuse of acetaminophen is
associated with a large number of emergency department and hospital
admissions and is related to an estimated 100 deaths each year. For
NSAIDs, we primarily considered post-marketing case reports of stomach
bleeding and kidney injury collected by AERS between 1998 and 2001. We
concluded from this data that serious stomach bleeding events can occur
when NSAIDs are used according to the warnings and directions on the
OTC label.
2. 2006 Proposed Rule Labeling
    The proposed labeling was supported by our interpretation of the
data and was consistent with recommendations that we received from an
FDA Advisory Committee that met in 2002 to discuss OTC IAAA drug
products. The committee unanimously agreed that the evidence of risk
associated with unintentional overuse warrants a liver injury warning
for OTC drug products containing acetaminophen (71 FR 77314 at 77323 to
77324) and that for OTC NSAIDs data support a stomach bleeding warning
(71 FR 77314 at 77327). The committee recommended that the terms
``acetaminophen'' (71 FR 77314 at 77323) and ``NSAIDs'' (71 FR 77314 at
77328) appear prominently on the front panel or principal display panel
(PDP) of product labeling (so consumers are aware that acetaminophen or
NSAIDs are present in the products they are using to prevent
unintentional overdose). The committee also recommended an alcohol
warning separate from the liver injury and stomach bleeding warnings,
but we choose to combine the warnings (71 FR 77314 at 77331). We
discuss this decision further in section IV.A.5. of this document. The
2006 proposed rule also included additional warnings for these products
(see Table 1).

         Table 1--Overview of Proposed Labeling Changes for OTC IAAA Drug Products in 2006 Proposed Rule
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              Type of Product                                   Proposed Labeling Requirements
----------------------------------------------------------------------------------------------------------------
Acetaminophen products                        Warning to include information on severe liver injury
                                              Ingredient name (i.e., ``Acetaminophen'') highlighted or
                                              in bold type and in a prominent print size on the PDP
                                              Statement ``See new warnings information'' highlighted or
                                              in bold type and in a prominent print size on the PDP for 12
                                              months following publication of this rule
                                              Alcohol warning as part of liver warning (instead of
                                              separate alcohol warning previously required in 21 CFR 201.322)
----------------------------------------------------------------------------------------------------------------
NSAID products                                Warning to include information on severe stomach bleeding
                                              Ingredient name (e.g., ``Aspirin'') highlighted or in bold
                                              type on the PDP
                                              Term ``(NSAID)'' highlighted or in bold type and in a
                                              prominent print size on the PDP as part of the established name of
                                              the drug or after the general pharmacological (principal intended)
                                              action of the NSAID ingredient
                                              Statement ``See new warnings information'' highlighted or
                                              in bold type and in a prominent print size on the PDP for 12
                                              months following publication of this rule
                                              Alcohol warning as part of stomach bleeding warning
                                              (instead of separate alcohol warning previously required in 21 CFR
                                              201.322)
----------------------------------------------------------------------------------------------------------------
Combination products containing               All ingredient names (e.g., ``Acetaminophen'' or
 acetaminophen or an NSAID plus a non-        ``Aspirin'') highlighted or in bold type and in a prominent print
 analgesic ingredient                         size and the names of the other active ingredients on the PDP
                                              Term ``(NSAID)'' highlighted or in bold type and in a
                                              prominent print size on the PDP as part of the established name of
                                              the drug or after the general pharmacological (principal intended)
                                              action of the NSAID ingredient if the product contains an NSAID
                                              ingredient
----------------------------------------------------------------------------------------------------------------

III. Discussion of Submissions Regarding Proposed Labeling for All OTC
Internal Analgesics

A. PDP

1. General Issues
    Some of the submissions concern labeling that appears on the PDP of
all OTC IAAA drug products (i.e., acetaminophen and NSAIDs). A
manufacturer of OTC acetaminophen products (Ref. 1) agrees that the
proposed PDP labeling is beneficial to consumers. The manufacturer
states that, prior to the 2006 proposed rule, it had voluntarily
implemented labeling similar to the proposed labeling. Another
submission (Ref. 2) argues that the proposed labeling may cause
crowding on the PDP, making it difficult for consumers to read the
label. The submission contends that to accommodate the proposed
labeling, manufacturers may be forced to increase the size of their
packages, which could have significant economic consequences for
industry. A third submission (Ref. 3) questions the readability of the
warnings on OTC NSAID products, arguing that the print size is too
small. The submission suggests placing the warnings on the PDP in bold
print to increase the readability of important warnings.
    We are not revising the proposed PDP labeling in this document. We
believe the proposed labeling, including highlighting the terms
acetaminophen or NSAIDs on the PDP, is important to help ensure the
safe and effective use of OTC IAAA drug products. We disagree that the
required labeling will cause crowding on the PDP. If a PDP is crowded,
manufacturers can reduce the font size of the trade name and
promotional material to allow room for the labeling required in this
document. Reducing the prominence of the trade name and promotional
material will not decrease the safety or efficacy of OTC IAAA drug
products. It is important that consumers be able to identify products
that contain acetaminophen and NSAIDS. We believe that manufacturers
should be able to include the name of the ingredient on the PDP as
specified in the proposed rule without having to increase the package
sizes. Because all manufacturers will be equally affected by these
requirements, there is no marketing disadvantage to certain
manufacturers, as argued by some submissions.
    We disagree that the print size of the warnings on OTC IAAA drug
products

is too small and that the warnings should appear on the PDP in bold
print. OTC drug regulations (21 CFR 201.66(d)(2)) require that warnings
on all OTC drug products appear in a standard Drug Facts format and
specify minimum type sizes. We developed these regulations based, in
part, on data concerning readability of different font sizes.
    We believe the statement ``see new warnings'' that is required on
the PDP (21 CFR 201.326(b)) and that refers consumers to the warnings
in Drug Facts is adequate without including the actual warnings on the
PDP. Including the warnings themselves would require a large amount of
the available PDP space and would make the information on the PDP
difficult to read because of crowding or could require larger package
sizes.
2. Statement of Identity
    Three submissions address the statement of identity required on the
PDP. The first submission (Ref. 4) supports the proposed prominence of
the statement of identity. The second submission (Ref. 2) proposes
revising the statement of identity on OTC acetaminophen products from
``acetaminophen'' to ``contains acetaminophen.'' Likewise, the second
submission proposes revising the statement of identity on OTC NSAID
products from ``(name of the NSAID), NSAID'' to ``contains (name of
NSAID), a pain medication.'' The second submission argues that
consumers may be confused without this revision because the term
``acetaminophen'' identifies an active ingredient while the term
``NSAID'' describes a class of drugs.
    The third submission (Ref. 5) argues that requiring the statement
of identity in a type size at least one-quarter as large as the most
prominent print is unnecessary and arbitrary. The submission contends
that we do not have data to support this requirement. The submission
suggests that the statement of identity should be as large as the
``Drug Facts'' title on the outside container, giving it adequate
prominence without crowding the PDP or inhibiting brand competition.
The submission argues that consumers should primarily refer to the Drug
Facts box, rather than the PDP, for information concerning the safe and
effective use of OTC drug products. The submission also requests that
we require only the term ``NSAID'' to be highlighted on the PDP, rather
than highlighting both ``NSAID'' and the active ingredient as proposed.
The submission argues that this change would be consistent with a June
2005 letter that we sent to NDA holders for OTC NSAID products (Ref.
6).
    We disagree with the two submissions arguing that the statement of
identity requirements in the 2006 proposed rule should be revised. We
do not believe it is necessary to require the statement of identity on
the PDP to include ``contains'' before the active ingredient, as argued
by one of the two submissions. The statement of identity without
``contains'' is consistent with the statement of identity required on
all OTC drug products (21 CFR 201.61). We believe the name of the
active ingredient followed by the pharmacological category is clear
without adding the word ``contains.'' For example, the statement of
identity for an OTC ibuprofen product--``ibuprofen (NSAID), pain
reliever/fever reducer''--allows consumers to recognize the active
ingredient and pharmacological action of the active ingredient. For
this same reason, we do not believe addition of ``pain medication'' is
necessary in the NSAID statement of identity.
    The other submission discusses statement of identity requirements
that are general requirements for all OTC drug products and are not
specific to OTC IAAA products. We do not believe it is appropriate to
address these requirements for all OTC drug products in this document,
which is specific to OTC internal analgesics. If any parties would like
us to revise the statement of identity requirements because of crowding
or other concerns, we suggest they submit a citizen petition in
accordance with 21 CFR 10.30. Such a petition could address the
requirements for all OTC drug products.
    We agree with the submission requesting that we require only the
term ``NSAID'' to be highlighted on the PDP, rather than both the
ingredient name and ``NSAID.'' This would be consistent with the June
2005 letter that we sent to NDA holders and would avoid the need for
manufacturers to re-label products that otherwise comply with this
rule. The purpose of highlighting ``NSAID'' is to prevent consumers
from using multiple NSAID products at the same time. Highlighting only
``NSAID'' should achieve this intent. Therefore, we are revising the
NSAID statement of identity in this document (21 CFR 201.326(a)(2)(i))
to require only highlighting of ``NSAID.''
3. Warning Flag
    We received a submission (Ref. 5) concerning the proposed warning
flag: ``See new warnings information'' (proposed 21 CFR
201.325(vi)(b)). The submission argues that the proposed type size
(i.e., one-quarter as large as the most prominent print) is unnecessary
and arbitrary. The submission contends that we have no data to support
this requirement. The submission also suggests that we should not
require the warning flag in type parallel to the package base because
it is unnecessarily restrictive, arguing that 45 degrees is just as
effective. The submission requests that we only require the warning
flag for 6 or 9 months after the final rule publishes rather than for
one year, as proposed. Alternatively, the submission requests that we
allow exemptions after publication of the final rule if a product has
already contained a ``new'' flag (i.e., a flag that states ``new'' and
refers to a new formulation, new flavor, etc.). Finally, the submission
suggests that we allow flexibility so that a product does not have to
concurrently include a ``new'' flag and the proposed warning flag.
    We disagree with the submission. We continue to believe that
requiring the flag to be displayed in a standard format, parallel to
the drug product package base and in a minimum size (at least one-
quarter as large as the most prominent type size) on the PDP will make
this information more easily seen by consumers. We do not believe the
size is unnecessary and arbitrary. We believe the flag must be
prominent and proposed the minimum size to be one of the following,
whichever is larger:
     At least one-quarter as large as the most prominent type
size or
     At least as large as the size of the ``Drug Facts'' title
(21 CFR 201.326(b)).
We believe this proposal ensures that consumers will see the flag while
allowing manufacturers labeling flexibility. Furthermore, we believe
that it is more important to make consumers aware of new warning
information than it is of other promotional material such as ``new''
taste.
    We are not revising the labeling requirements in the 2006 proposed
rule to accommodate other ``new'' flags that manufacturers choose to
place on the PDP (i.e., a flag that states ``new'' and refers to a new
formulation, new flavor, etc.). These ``new'' flags are generally
promotional in nature and are not related to the safe and effective use
of OTC IAAA drug products. Therefore, manufacturers need to determine
whether and how to display any promotional material on their products
without interfering with the ``See New Warnings'' flag. We will require
that the ``See New Warnings'' flag appear on the PDP for one year after
the final rule is published, rather than for the 6 or 9 months
suggested by the submission. Because of the nature of the new

warnings, we continue to believe that educating consumers about the
risks associated with OTC IAAA drug products is very important and more
likely to be successful if the flag remains on products for 1 year.

B. Drug Facts

    We received four submissions concerning the proposed Drug Facts
labeling. The first submission (Ref. 5) seeks clarification about
whether we will allow voluntary highlighting of the active ingredient
and purpose (i.e., ``pain reliever/fever reducer'') section in Drug
Facts to draw attention to the presence of acetaminophen. The
submission points out that many marketed OTC internal analgesic
products are already labeled as such. The second and third submissions
concern the ``Warnings'' section of Drug Facts. The second submission
(Ref. 7) opposes additional warnings on OTC internal analgesics for the
following reasons:
     Because these medicines have been used for a long time,
consumers will not change their usage patterns even if additional
warnings appear in the labeling.
     The proposed warnings would reduce the impact of similar
warnings on other dangerous drugs.
The submission proposes to inform the public about new safety concerns
through press releases rather than by requiring more warnings on the
label. The third submission (Ref. 2) is concerned that the proposed
warnings may cause consumers to avoid OTC internal analgesic products
because of the emphasis on risks.
    The first and fourth submissions concern the ``Directions'' section
of Drug Facts. Both submissions agree with the proposed required
statement in ``Directions'' on products labeled only for use by
children: ``This product does not contain directions or warnings for
adult use.'' The fourth submission (Ref. 1) requests that we allow
flexibility to place this statement under the ``Do not use'' subheading
of the ``Warnings'' section instead of in the ``Directions'' section.
The argument is that the ``Directions'' section of pediatric OTC drug
products is often lengthy and crowded with information. The first
submission (Ref. 5) points out that we asked companies to submit
supplements with the phrase ``directions or complete warnings'' in the
July 2005 letter to NDA holders of OTC NSAID products (Ref. 6). The
submission requests that we allow the use of the word ``complete'' so
that OTC NSAID products that otherwise comply with this rule do not
have to be relabeled.
    We agree with the first submission and are revising the statement
in the ``Directions'' section of pediatric internal analgesic products
to read, ``This product does not contain directions or complete
warnings for adult use.'' We believe consumers will better understand
the meaning of this revised statement compared to the proposed
statement. This revision also makes the statement consistent with the
June 2005 letter to holders of NDAs for NSAID products. This revision
prevents products that already include this statement and otherwise
comply with this rule from having to be relabeled. Similarly, we will
allow voluntary highlighting of the ``active ingredient and its
purpose'' section in Drug Facts to increase the prominence of the
active ingredient and to be consistent with the labeling of many
currently marketed OTC IAAA drug products, avoiding the need for re-
labeling of products that otherwise comply with this rule. We are
allowing this voluntary highlighting because of the seriousness of
liver injury that may result from use of multiple acetaminophen-
containing products at the same time.
    We disagree with most of the comments in the second submission
(Ref. 8). The submission does not include any information or data
supporting its belief that the warnings in the 2006 proposed rule will
not change consumer behavior when using OTC IAAA drug products. We do
agree with this submission that press releases can help educate
consumers about the potential risks associated with OTC IAAA drug
products. However, product labeling is the most important means to
ensure that consumers have access to important warning information each
time the drug product is purchased and used. We disagree with the third
submission that additional warnings may cause consumers to avoid using
OTC IAAA drug products because of the emphasis on risks. We are not
aware of data supporting the submission's argument. The warnings
identify risks that we believe consumers need to know in order to use
these products safely.
    We disagree with the fourth submission (Ref. 1) requesting that we
allow flexibility to place the Directions statement under the ``Do not
use'' subheading of the ``Warnings'' section. Although we agree that
the ``Directions'' section of pediatric OTC drug products is often
crowded with other information, we believe that because pediatric drug
products are dispensed by adults, it is important that the placement of
this statement be consistent with OTC IAAA drug products intended for
adults.

C. Immediate Container

    We received a submission (Ref. 9) that believes there is a ``dire
need'' for the proposed labeling and suggests that, in addition to the
outer container, we should also require the proposed labeling on the
immediate container. We agree with the submission. Consumers may
discard the carton or outer container, which contains the Drug Facts
box, after purchasing an OTC drug product. Therefore, important
warnings, directions, and other Drug Facts information may not be
available to consumers every time they use a product. While we believe
that OTC IAAA drug products can be safe and effective when used as
directed, it is important to alert consumers that acetaminophen can
potentially cause liver injury and NSAIDs can potentially cause stomach
bleeding. Because of the serious consequences associated with these
adverse events, we believe that the associated warnings should be
available every time an OTC IAAA drug product is used. Therefore, we
are requiring that the liver warning appear on the immediate container
of all OTC internal analgesic drug products containing acetaminophen
(21 CFR 201.326(a)(1)(iii)(A)). Likewise, we are requiring that the
stomach bleeding warning appear on the immediate container of all OTC
internal analgesic drug products containing an NSAID (21 CFR
201.326(a)(2)(iii)(A)).
    If the immediate container of an OTC IAAA drug product is a blister
pack, the labeling space may need to be expanded to accommodate these
warnings along with other required labeling. We believe the need for
these warnings justifies any expansion of labeling space that may be
necessary. Ideally, the blister pack should be designed so that the
warnings can be read after removal of individual doses from the blister
pack.

IV. Labeling Required for OTC Acetaminophen

A. Liver Warning

    In this document, we are requiring a liver warning that is
identical to the warning in the 2006 proposed rule except the first
bulleted statement is modified slightly. We proposed three similar
versions of this warning in the 2006 proposed rule (71 FR 77314 at
77349 to 77350): (1) one for products labeled for adults only, (2) one
for products labeled for children under 12 years of age only\1\, and
(3) one for

products labeled for adults and children under 12 years of age\2\. The
proposed warning for adults reads as follows:
---------------------------------------------------------------------------

    \1\ The wording of the warning for children under 12 years of
age only reads: ``Liver warning: 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.''
    \2\ The wording of the warning for adults and children under 12
years of age reads: ``Liver warning: 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] taken with other drugs containing acetaminophen [bullet]
adult has 3 or more alcoholic drinks every day while using this
product.''

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.

    In the 2006 proposed rule, we explain that the liver warning is
necessary to advise consumers about the occurrence of unintentional
liver injury associated with ingesting too much acetaminophen (i.e.,
more than the maximum daily dose of 4 grams). In that document, we
present data and evidence supporting the need for the liver warning.
The proposed liver warning also includes a version of the alcohol
warning already required for all OTC drug products labeled for adult
use that contain acetaminophen or NSAIDs (21 CFR 201.322). We proposed
incorporating the alcohol warning into the liver warning because the
alcohol warning for acetaminophen relates to liver injury. In addition,
we believe that one warning may be more likely to be read and
understood by consumers.
    We received many submissions expressing support for the proposed
liver warning. Two of these submissions state that, although
acetaminophen is generally a safe drug, it can cause severe and even
fatal liver injury in certain cases, such as simultaneously using
multiple drugs containing acetaminophen (Refs. 10 and 11). One of these
submissions states that it is important for consumers to be aware that
acetaminophen must be used in appropriate doses and in the right
circumstances to avoid liver injury (Ref. 10). Another submission
states that our liver warning is appropriate because the risk of liver
injury with acetaminophen use is well documented (Ref. 12). The
submission also argues that the proposed liver warning will provide
information to consumers regarding the risk of liver injury and
predisposing conditions as well as actions they may take to minimize
the risk of liver injury. Only one submission argues that a liver
warning is not needed (Ref. 1). The submission also argues that, if we
do require the warning, we should modify the liver warning language.
Another submission also recommends that we modify the wording of the
proposed liver warning (Ref. 11).
    All of the submissions related to the liver warning are discussed
in the next five sections of this document. The first section (IV.A.1.)
discusses scientific support for the liver warning. The second section
(IV.A.2.) discusses the introductory sentences of the warning. The
third, fourth, and fifth sections (IV.A.3. through IV.A.5.) discuss the
three bulleted statements of the liver warning, respectively.
1. Scientific Support for the Liver Warning
    One submission states that it is inappropriate for us to rely on
the case series and databases cited in the 2006 proposed rule to
support the need for a liver warning (Ref. 1). The submission argues
that these data sources have serious limitations, and those limitations
prevent the data from demonstrating that therapeutic doses of
acetaminophen (i.e., no more than 4 grams daily for not longer than 10
days) cause liver injury, according to the submission. The submission
provides a reanalysis of the same databases and case series described
in the 2006 proposed rule plus data from more recent years. The
submission also includes the annual number of patients receiving liver
transplants associated with drug-related acute liver failure from the
United Network for Organ Sharing (UNOS) database. Based on these data,
the submission argues that acetaminophen overdoses, acetaminophen-
associated liver injury, and acetaminophen-associated deaths, whether
intentional or unintentional, are not increasing. The submission also
states that hospital rates for acute liver failure in the United States
from 1999 through 2006 have been fairly stable.
    Despite the information in this submission, we still believe that
overuse of acetaminophen, whether intentional or unintentional, is
associated with severe liver injury and death and it is important to
have appropriate labeling to inform users of the risk of injury. While
the submitted data may not demonstrate increasing numbers of liver
injury or deaths associated with acetaminophen use annually, the number
of cases of liver injury or deaths reported each year with
acetaminophen use is not acceptable. The analyses included in the
submission have the same limitations as the databases discussed in the
proposed rule. Furthermore, our AERS database continues to include many
reports of liver injury associated with acetaminophen use each year.
    Other information supports our determination. Since the publication
of the 2006 proposed rule, a study (Ref. 13) was published with data
that raises concern about the number of cases of acetaminophen-related
liver injury. This study was a prospective population-based
surveillance program in eight counties in metropolitan Atlanta over a
period of five years (2000-2004) and is the first population based
study of acute liver failure conducted in the United States. In this
study, 94 patients were hospitalized with acute liver failure, but only
65 of the patients were included in the study. The remaining subjects
refused to participate or could not be contacted following hospital
discharge. Of the 65 patients, 49 were adults and 16 were children. Of
the 49 adults in this study, 29 (41 percent) were identified as having
acetaminophen-related acute liver failure, suggesting that
acetaminophen is the most common cause of acute liver failure in
adults. Of these 29 adults, 45 percent were intentional overdoses, and
55 percent were unintentional. The data were used to calculate an
annual acute liver failure rate of 5.5 cases per million individuals in
metropolitan Atlanta. By extrapolating this incidence rate to the
entire U.S. population, the study authors estimate that approximately
1,600 cases (1200 adult cases, 400 child cases) of acute liver failure
occur each year. This could result in approximately 640 cases of acute
liver failure (350 unintentional) associated with acetaminophen use in
the United States each year. We believe this study further justifies
the need for the proposed liver warning.
    Another recent study raises concerns about the ability of
acetaminophen to cause liver function test abnormalities. The study was
a prospective, blinded, randomized, parallel group study involving 145
subjects (Ref. 14). The subjects were divided into the following five
groups, which were roughly equal in size:
    (1) Placebo
    (2) Acetaminophen
    (3) Acetaminophen + oxycodone
    (4) Acetaminophen + hydromorphone
    (5) Acetaminophen + morphine
    Each acetaminophen group took 4 grams acetaminophen daily for 14
days. Thirty-one to forty-four percent of the subjects in each of the
acetaminophen groups had a maximum increase in ALT values of three
times the upper limit of normal. Enzyme levels returned to normal when
acetaminophen was stopped. The subjects in the placebo

group did not have elevated ALT values. This study demonstrates that
healthy individuals using the maximum dosage amount of OTC
acetaminophen can experience abnormalities of liver function tests. The
clinical significance of the abnormalities is not known at this time.
    All of the data available concerning acetaminophen use and liver
injury suggest that there are some consumers at risk for liver injury.
Based on this data, we believe it is important to warn consumers about
the potential for liver injury. We will consider revising the warning
if we become aware of data better defining the risk factors for
acetaminophen-induced liver injury.
2. Introductory Sentence of Liver Warning
    One submission (Ref. 1) disagrees with our proposal to use the term
``severe'' to qualify liver damage in the introductory sentences of the
liver warning: ``This product contains acetaminophen. Severe liver
damage may occur if you take. . .'' The submission argues that use of
modifiers such as ``severe'' must be consistently applied to all OTC
drug products. The submission points out that such a modifier is not
used in the language of the proposed stomach bleeding warning on OTC
NSAID products, where the submission argues it would be more
appropriate. This submission also requests that we modify the
introductory sentences of the liver warning to be clearer that liver
injury results from using more than the recommended dose of
acetaminophen (overdose), and to state situations to avoid that may
result in using too much acetaminophen.
    The submission recommends three versions of the liver warning that
are similar to the warning in the 2006 proposed rule: one for adults,
one modified for children under 12 years of age\3\, and one for adults
and children under 12 years of age\4\. The modified liver warning
language proposed in the submission for adults reads as follows:
---------------------------------------------------------------------------

    \3\ For products labeled for children under 12 years of age
only, the first bullet of the modified warning reads, ``give the
child more than 5 doses in 24 hours.''
    \4\ For products labeled for adults and children under 12 years
of age, the first bullet of the modified warning reads, ``give the
child more than 5 doses in 24 hours'', the second bullet reads
``take more than 8 caplets in 24 hours.'' The third bullet reads
``with other drugs containing acetaminophen.''
---------------------------------------------------------------------------

``Liver warning: This product contains acetaminophen. Liver damage
may occur if you take more than the recommended dose (overdose).
Do not:
take more than 8 caplets in 24 hours
use with other drugs containing acetaminophen''
    We disagree with the comment in the submission regarding the word
``severe'' and believe it is appropriate in the liver warning. The data
and information described in the 2006 proposed rule to support the need
for this warning indicate that acetaminophen-induced liver injury can
often be serious, even fatal. As we state in the 2006 proposed rule (71
FR 77314 at 77316), acetaminophen-related liver injury led to
approximately
     56,000 emergency department visits (1993-1999),
     26,000 hospitalizations (1990-1999), and
     458 deaths (1996-1998).
    Of these cases, unintentional acetaminophen overdose was associated
with
     13,000 emergency department visits (1993-1999),
     2189 hospitalizations (1990-1999), and
     100 deaths (1996-1998) (71 FR 77314 at 77318).
In addition, as discussed in section IV.A.1. of this document, we have
recent data suggesting that acetaminophen may be the most common cause
of acute liver failure in the United States (Ref. 13). Therefore, we
believe that the word ``severe'' is appropriate in the liver warning.
In addition, we agree with the submission that the word ``severe'' is
also appropriate in the stomach bleeding warning on OTC NSAID products.
Therefore, we are requiring that the introductory sentences of the
stomach bleeding warning be revised to include the word ``severe'' (see
section V.A. of this document).
    We are not going to include the word ``overdose'' in the
introductory sentences of the liver warning as the submission suggests
because we are not sure whether consumers will understand the term
``overdose'' in this case. We believe that consumers typically relate
``overdose'' to deliberate overdose (i.e., suicide) or unintentional
overdose of illegal drugs used for recreational purposes. We do not
think that consumers will understand ``overdose'' in the liver warning
to mean ``exceeded the recommended dose.'' However, we are going to
modify the liver warning as the submission requests to be clear that
consumers should not use more than the recommended dose of
acetaminophen. We are making this modification in the first bulleted
statement instead of the introductory text (see section IV.A.3. of this
document).
3. First Bulleted Statement: Maximum Safe Daily Dose of Acetaminophen
    One submission requests that we consider stating in the liver
warning that using the maximum daily dose of 4 grams for five or more
consecutive days could cause severe liver injury (Ref. 11). Another
submission requests that we modify the liver warning language to more
clearly state that liver injury from acetaminophen results from using
more than the recommended dose (Ref. 1).
    We are not modifying the wording of the first bulleted statement in
the liver warning to advise that liver injury can occur from using 4
grams acetaminophen daily for five or more consecutive days. The
submission does not include any data to support this recommendation. A
study discussed previously (Ref. 15) demonstrated asymptomatic
elevations of liver function tests in healthy subjects after receiving
4 grams of acetaminophen for several days. As we noted, the clinical
significance of these test abnormalities are unclear at this time and
additional study is needed. We are interested in any data that may
allow us to better assess how the risk of liver injury increases with
increasing number of days of acetaminophen use. If we become aware of
such data, we will consider revising the liver warning at that time.
    We are modifying the first bullet of the liver warning to more
clearly advise consumers that liver injury may occur from using more
than the recommended dose of acetaminophen. In this document, we are
revising the first bulleted statement of the liver warning for
adults\5,6\ to read:
---------------------------------------------------------------------------

    \5\ For products labeled for children under 12 years of age
only, the first bulleted statement of the liver warning reads,
``[bullet] child takes more than [insert maximum number of daily
dosage units] in 24 hours, which is the maximum daily amount.''
    \6\ Products labeled for adults and children under 12 years of
age contain two bulleted statements regarding the recommended daily
dose. The first bulleted statement of the liver warning reads,
``[bullet] adult takes more than [insert maximum number of daily
dosage units] in 24 hours, which is the maximum daily amount
[bullet] child takes more than [insert maximum number of daily
dosage units] in 24 hours, which is the maximum daily amount.''
---------------------------------------------------------------------------

 more than [insert maximum number of daily dosage units] in
24 hours, which is the maximum daily amount
Although this revised bulleted statement is longer than the statement
in the 2006 proposed rule, we believe consumers will be more likely to
understand that the risk of liver injury increases if they exceed the
maximum daily dose.

4. Second Bulleted Statement: Concomitant Use
    In this document, we are requiring two concomitant use warnings:
(1) the second bullet of the liver warning and (2) the ``Do not use''
warning (see section IV.B. of this document). Both were included in the
2006 proposed rule. As discussed in the 2006 proposed rule, we believe
that simultaneous use of multiple acetaminophen-containing drug
products is a strong risk factor for liver injury caused by exceeding
the recommended daily dose of acetaminophen. The second bulleted
statement of the proposed liver warning cautions consumers about using
more than one product containing acetaminophen at a time (see section
IV.A. of this document). We are including the same language for this
warning as included in the 2006 proposed rule. This language is
supported by four submissions stating the importance of this warning
without suggesting any modification (Refs. 1, 2, 10, and 11). We did
not receive any submission suggesting any modifications.
5. Third Bulleted Statement: Alcohol Warning
    In this document, we are requiring the alcohol warning included in
the 2006 proposed rule. We are including it as the third bulleted
statement of the liver warning as proposed. It advises consumers that
severe liver injury may occur if they take 3 or more alcoholic drinks
while using acetaminophen drug products. We have considered the data
discussed in the proposed rule and new data submitted to us, including
recent clinical studies. We do not believe the new data demonstrate
that alcohol users have the same risk for liver injury as non-users of
alcohol. Therefore, we are requiring the alcohol warning as part of the
liver warning because they are interrelated and are more likely to be
understood as a single warning than as separate warnings.
    In the 2006 proposed rule (71 FR 77314 at 77329), we discuss a
prospective clinical study in which 275 individuals were identified as
developing acute liver failure due to acetaminophen use during a 6-year
span at 22 centers (Ref. 15). Of these individuals, those who abused
alcohol had median acetaminophen blood levels that were half as much as
those who did not abuse alcohol (p = 0.003). The investigators found
that the subjects with acute liver failure who reported taking 4 grams
or less of acetaminophen daily were often alcohol abusers (65 percent).
The investigators also found that patients with acute liver failure who
were taking more than 4 grams acetaminophen daily consumed less alcohol
than those who took less than 4 grams acetaminophen daily. The patients
who used alcohol reported using less acetaminophen daily than the
patients who did not use alcohol. The investigators commented that
alcohol may be an important risk factor for acute liver failure in the
subjects taking 4 grams or less of acetaminophen daily.
    In the proposed rule, we also discussed retrospective data from our
AERS database that suggest the same conclusion (71 FR 77314 at 77320 to
77321). Of the 132 individuals identified in this database as
developing liver disease after using acetaminophen, alcohol users had
used less acetaminophen than those who did not use alcohol (5.6 grams
for users vs. 6.9 grams for non-users). Of the 65 individuals
identified as developing severe liver disease after using
acetaminophen, where dosing information was available, alcohol users
had used less acetaminophen than those who did not use alcohol (6.0
grams for users vs. 8.6 grams for non-users). These data suggest that
lesser amounts of acetaminophen may cause liver damage in people who
use alcohol compared to those who do not.
    After publication of the 2006 proposed rule, we received five
submissions concerning the alcohol warning (Refs. 1, 4, 10, 11, and
12). Four of the five submissions support the proposed alcohol warning,
and one does not. Two of these four submissions (Refs. 11 and 12) argue
that the prospective clinical study discussed in the 2006 proposed rule
(Ref. 15) supports the occurrence of liver injury in consumers who use
OTC acetaminophen and consume alcohol. One of these submissions (Ref.
12) cites three clinical case series suggesting an association between
alcohol use and unintentional acetaminophen-related liver injury (Refs.
16, 17, and 18). In these case series, between 14 and 40 percent of the
cases involved individuals consuming OTC acetaminophen doses (i.e., no
more than 4 grams daily). The submission also cites mechanistic studies
suggesting that regular alcohol use may significantly alter the
metabolism of acetaminophen, leading to liver injury.
    The submission that objects to the warning states that an alcohol
warning for OTC acetaminophen drug products is not necessary because
individuals with a history of alcohol use can safely use the maximum
daily dose of acetaminophen (Ref. 1). The submission argues that
current scientific data suggest that the risk of acetaminophen-related
liver injury is associated with using more than the maximum OTC daily
dose of acetaminophen, irrespective of alcohol use. While we had
previously reviewed much of the submitted data in preparing the 2006
proposed rule, there are some studies that were submitted that we had
not previously reviewed. As described in section IV.C. of this
document, we believe the most clinically meaningful of these studies
are the prospective clinical studies. Therefore, our review in this
section focuses on these studies.
    There are six prospective, double-blinded, randomized, placebo-
controlled studies designed to evaluate whether maximum therapeutic
doses of acetaminophen (4 grams daily) cause liver injury in alcoholic
patients (Ref. 1). Four studies were coordinated by the Rocky Mountain
Poison and Drug Center (RMPDC) and are similar in design to each other.
These studies involved acetaminophen use (4 grams daily) for 2, 2, 3,
and 5 days, respectively. The fifth study, a 4-day study, was of
similar design but is available only as an abstract. Therefore, we did
not consider this study in our evaluation. The sixth study enrolled
subjects who used 4 grams of acetaminophen daily for 10 days.
    We discussed both 2-day studies in the 2006 proposed rule. Although
neither revealed liver injury, we stated that they did not ``provide
reliable evidence that people with chronic alcohol use can safely take
4[grams]/day of acetaminophen, particularly for up to 10 days in
accordance with OTC drug product labeling'' because of study design
limitations (71 FR at 77314 at 77336). The major limitations were that
the duration of acetaminophen use was not long enough (i.e., not 10
days) and the liver function exclusion criteria did not allow subjects
with AST and ALT values above certain levels. Therefore, we could not
draw conclusions about alcohol and acetaminophen use from these
studies.
    The 3- and 5-day studies were designed to address the limitations
of the two-day studies. They enrolled chronic heavy alcohol users
entering alcohol detoxification facilities. A total of 372 subjects
completed the 3-day study, and 130 subjects completed the 5-day study.
The submission argues that these patients represent the alcohol users
at greatest risk for liver injury when using acetaminophen. The study
subjects had AST and ALT <=200 IU/L and INR <=1.5 which expanded the
population and included more alcoholic subjects than the two-day
studies. The primary endpoint was liver function

tests. There were not any statistically significant differences in
liver function tests after acetaminophen use. Therefore, the studies
did not reveal signs of liver injury when using OTC acetaminophen for 3
or 5 days.
    The other prospective study enrolled 150 subjects who consumed one
to three alcohol drinks daily and took 4 grams acetaminophen or placebo
daily for 10 days (Ref. 19). The primary endpoint was liver function
testing (ALT, AST, total bilirubin, alkaline phosphatase, and total
protein) at days 0, 4, and 11. There were no changes in liver function
in the placebo group on days 4 or 11 compared to day 0. There were no
changes in liver function in the acetaminophen group on day 4 compared
to day 0. However, there was a statistically significant increase in
ALT in the acetaminophen group on day 11 compared to day 0. Of the 100
subjects in the acetaminophen group that had elevated ALT values, the
ALT was 1 to 3 times the upper limit of normal for 19 subjects, 3 to 5
times the upper limit of normal for 1 subject. There was also a
rechallenge in 10 subjects (one placebo and nine acetaminophen) showing
similar results, except ALT increases on day 11 were slightly smaller.
These changes in ALT blood levels are similar to those observed in
healthy subjects (Ref. 15) when given 4 grams of acetaminophen daily.
The clinical significance of these findings is not apparent at this
time.
    We do not believe the new studies justify removal of the alcohol
warning. We cannot draw conclusions from these new studies for numerous
reasons. First, only one of the studies involves the maximal OTC
acetaminophen use (i.e., 4 grams daily for 10 days). Second, the number
of subjects enrolled in the studies is small. The largest number of
subjects using 4 grams acetaminophen daily was 258 subjects in the 3-
day study. The one study involving the maximal OTC acetaminophen use
(i.e., 4 grams daily for 10 days) only enrolled 150 subjects. With
these sample sizes, it is possible that significant changes in liver
function would not be detected. It is difficult to use these studies as
evidence to demonstrate that a specific population is not at increased
risk for liver injury. Third, there are a significant percentage of
alcohol users in the various liver injury databases. This may only
represent a small percentage of the overall population of users and, as
such, will make it difficult to understand all of the factors that may
have contributed to their developing liver injury. Many of them are
reported to have developed liver injury with doses close to the current
daily recommended dose. Until we have a better understanding of the
mechanism in these individuals, studies such as those submitted to us
and discussed in this document will not be adequate to establish the
safe dose of acetaminophen in all alcoholics. Fourth, the studies were
not open for enrollment to a representative population of all people
who use alcohol. The population of alcohol users is not homogenous and
all are not represented in these studies. Alcohol users will have
variable degrees of underlying alcohol related liver injury and
variable ability to metabolize acetaminophen. As a consequence, it is
difficult to generalize the results of these studies to all people who
use alcohol. Additional research needs to be conducted to better
understand why people who use alcohol make up a disproportionate
percentage of subjects in the liver injury databases and determine what
dose adjustment may be considered for this population.
    Because these new studies do not adequately demonstrate that
alcohol use is not a risk factor for acetaminophen-induced liver
injury, we believe an alcohol warning continues to be necessary. An
alcohol warning has been required on acetaminophen products since 1999.
There has been a concern for a long time of the increased risk to
regular users of alcohol. We describe numerous data in the 2006
proposed rule (summarized earlier in this section of the document) that
suggest alcohol use may increase the risk of acetaminophen-induced
liver injury. The studies provided in the submission are not adequately
designed to dismiss the previously available data. Very large safety
studies are needed to better establish the risk for liver injury, the
safe dose of acetaminophen in this population and identify
subpopulations within alcohol users who may be at the greatest risk for
liver injury.
    The submission that argues against requiring the alcohol warning
also suggests a modified warning (Ref. 1). The submission states that,
if we continue to believe that an alcohol warning is necessary, then
the warning should be separated from the liver warning and read as
follows:
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. Taking more than the recommended dose
(overdose) of acetaminophen may cause liver damage.
The submission argues that we do not provide evidence to support our
rationale for incorporating the alcohol warning as part of the liver
warning. The submission argues that combining the two warnings will
mislead and confuse consumers. The submission also argues that its
suggested alcohol warning language better reflects the available
scientific evidence, which demonstrates that the risk of acetaminophen-
induced liver injury is not affected by alcohol use.
    We disagree with the submission. We are requiring the proposed
alcohol warning as the third bullet of the liver warning. We continue
to believe that the two warnings are interrelated and combining the two
warnings will be less confusing to consumers than separating the two
warnings. The warning proposed by the submission suggests that liver
injury in alcohol users occurs only with doses greater than 4 grams per
day. We have clinical reports of liver injury in people who use alcohol
at doses very close to 4 grams per day. As a consequence, we are not in
a position now to state that liver injury only occurs with doses
greater than 4 grams per day.

B. Concomitant Use Warning

    We are requiring a separate concomitant use warning under the ``Do
not use'' subheading in addition to the concomitant use warning
included as part of the liver warning (see section IV.A.4. of this
document). Both warnings advise consumers to avoid using multiple
acetaminophen-containing drug products at the same time. The ``Do not
use'' warning also advises consumers to consult a doctor or pharmacist
if consumers do not know whether a drug product contains acetaminophen.
    We are revising the proposed warning included in the 2006 proposed
rule, which reads, ``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''
(proposed 21 CFR 201.325(a)(1)(iii)(B)). In this document, the first
sentence is the same, but the second sentence reads, ``If you are not
sure whether a drug contains acetaminophen, ask a doctor or
pharmacist.'' We received one submission proposing this modified
wording (Ref. 1). The submission states that the meaning of our
proposed second sentence is unclear. We agree with the submission. We
believe the revised sentence is clearer than the proposed sentence
without making the sentence significantly longer. Therefore, the
revised warning appears in 21 CFR 201.326(a)(1)(iii)(B) of this
document.

C. Liver Disease Warning

    In this document, we are requiring the liver disease warning
included in the 2006 proposed rule. This warning

advises consumers with liver disease against using acetaminophen unless
directed by a doctor. As discussed in the 2006 proposed rule, we
proposed the liver disease warning primarily because we identified
cases from our AERS database and the Multiple Cause of Death Files
suggesting that chronic liver disease may be a risk factor for
developing or increasing the severity of liver injury when using
acetaminophen (71 FR 77314 at 77328 to 77329). We also cite
acetaminophen metabolism studies suggesting that consumers with liver
disease may be at higher risk of producing the toxic metabolite NAPQI
than consumers without liver disease.
    Since publication of the 2006 proposed rule, we received and
reviewed additional data and information concerning OTC acetaminophen
use by consumers with liver disease (Refs. 1, 11, and 12). After
reviewing these data, we still have concerns that some people with
underlying liver disease are at higher risk for liver injury with
acetaminophen. Therefore, we are requiring the proposed liver disease
warning because we believe it is necessary to alert consumers with
liver disease that they should ask a doctor before using acetaminophen.
The required warning for products labeled only for adults reads: ``Ask
a doctor before use if you have liver disease.'' We are requiring
similar warnings for products labeled for children under 12 years of
age\7\ and for products labeled for adults and children\8\.
---------------------------------------------------------------------------

    \7\ The warning for products labeled for children under 12 years
of age reads: ``Ask a doctor before use if the child has liver
disease''.
    \8\ The warning for products labeled for adults and children
reads: ``Ask a doctor before use if the user has liver disease.''
---------------------------------------------------------------------------

    In response to the 2006 proposed rule, we received three
submissions containing data and information concerning the liver
disease warning, including over 200 studies (Refs. 1, 11, and 12). Two
of the three submissions support the need for the liver disease warning
(Refs. 11 and 12). Both argue that the proposed liver disease warning
is based on sound scientific data. The submissions reference data
presented in the 2006 proposed rule as well as acetaminophen metabolism
studies suggesting that consumers with liver disease metabolize
acetaminophen differently. One of the submissions, from the American
Association for the Study of Liver Disease (AASLD), cites its
``Practice Guideline on Treatment of Chronic Hepatitis C'' as
supporting the proposed warning. According to the guideline, patients
with chronic hepatitis C (a form of liver disease) should be treated
with a maximum daily dose of 2 grams rather than the OTC labeled
maximum daily dose of 4 grams.
    The third submission (Ref. 1), from a manufacturer of
acetaminophen, argues that data demonstrate the proposed liver disease
warning is not needed. The submission contends that liver disease is
not a risk factor for developing liver injury with OTC doses of
acetaminophen and that the data cited in the 2006 proposed rule do not
support the need for the liver disease warning. The submission proposes
the following hierarchy of data, going from the highest to lowest level
of evidence:
    1. Data revealing clinical outcomes following acetaminophen use
    2. Human acetaminophen metabolism studies
    3. Human acetaminophen metabolism studies using probe molecules
(e.g., chlorzoxazone)
    4. In vivo animal studies
    5. In vitro cellular studies
    6. Studies using surrogate markers for acetaminophen metabolism
(e.g., plasma glutathione levels)
It should be noted that clinical outcome refers to liver function
testing, acute liver failure, liver transplant, death, etc. Although
the submission includes studies from all levels of this hierarchy, it
emphasizes the importance of the studies with clinical outcomes over
all other studies. According to the submission, these studies do not
reveal any evidence of an adverse outcome when consumers with liver
disease use acetaminophen, meaning none of the study subjects developed
liver failure, and liver function tests did not suggest liver injury.
    We focused our review on the data with clinical outcomes. We
received five clinical studies:
     Benson 1983 (Ref. 20)
     Andreasen 1979 (Ref. 21)
     McNeil 2007 (Ref. 1)
     Green 2005 (Ref. 22)
     Dargere 2000 (Ref. 23)
Throughout the remainder of this section, we discuss the three of the
five clinical studies. We do not discuss the Green 2005 and Dargere
2000 studies because, although these two studies do not reveal
different clinical outcomes for consumers with or without liver disease
who use OTC acetaminophen, we do not have complete study reports for
these studies. Therefore, we cannot draw any conclusions based on
abstracts for these two studies.
    Before describing the studies with clinical outcomes, we should
note that we also considered the second level of evidence (human
acetaminophen metabolism studies) in the proposed hierarchy. We believe
these studies may be meaningful in determining whether liver disease is
a risk factor for liver injury when using OTC acetaminophen. We
received 26 acetaminophen metabolism studies (Ref. 1), but could not
draw conclusions from them because of a number of limitations. Only 13
of the 26 studies examined the levels of acetaminophen and its
metabolites (e.g., glutathione, sulfate, and thiol metabolites) in the
blood after subjects take acetaminophen. We agree that knowing the
level of acetaminophen in a person's blood alone does not necessarily
improve our understanding of acetaminophen metabolism in consumers with
liver disease as it relates to an increased risk for acetaminophen-
induced liver injury. Of those 13 studies that include acetaminophen
metabolites, only one study involved multiple doses of acetaminophen.
The multiple-dose study included consumers with liver disease who used
4 grams acetaminophen daily for 4 days. None of the metabolism studies
included study subjects who used acetaminophen for the maximum OTC
labeled dose (i.e., 4 grams daily for 10 days). We cannot draw
conclusions about the risk for liver injury due to acetaminophen from
the human acetaminophen metabolism studies.
    The submission from the acetaminophen manufacturer provides
additional data for the Benson 1983 study that we cite in the 2006
proposed rule (71 FR 77314 at 77328 to 77329). We stated that the study
shows no difference in liver function test results for consumers with
liver disease who used 4 grams acetaminophen daily for 13 days as
compared to consumers with liver disease who used a placebo for 13
days. We stated that the small sample size of 20 subjects with liver
disease and cross-over study design prevent us from drawing conclusions
from the study. The submission argues that the cross-over study design
is adequate and not a limitation. We now agree that the crossover
design may not be a major study limitation. The number of subjects,
however, is small and do not allow for broad conclusions in the entire
population of people with underlying liver disease. Therefore, this
study does not provide sufficient data from which to conclude that four
grams per day is a safe dose for all patients with underlying liver
disease.
    The submission also included the Andreasen 1979 study that we cite
in the 2006 proposed rule (71 FR 77314 at 77328 to 77329). We cited
this study as evidence of altered acetaminophen metabolism in consumers
with liver disease. The study enrolled 4 subjects

with liver disease (cirrhosis) and 9 control subjects receiving
multiple doses of acetaminophen or placebo. Study subjects were given 3
grams acetaminophen or placebo daily for 5 days. Liver function tests
were conducted on the study subjects. These tests did not suggest any
difference in liver function between the control subjects and those
with liver disease, although the study did show prolonged clearance of
acetaminophen in patients with liver disease. It is difficult to draw
any conclusions from this small study.
    An unpublished 2007 study included in the submission that was
conducted by a manufacturer of acetaminophen enrolled 12 subjects with
liver disease (cirrhosis) who used 4 grams acetaminophen daily for 4
days (one dose on day 5). The liver function test results after using
acetaminophen did not differ from those before using acetaminophen.
This study does not provide sufficient information to make any
conclusions regarding the safe dose of acetaminophen or the risk of
liver injury in users with chronic liver disease.
    Limitations of the studies prevent us from drawing any conclusions
about the safety of acetaminophen use in patients with liver disease
using 4 grams acetaminophen over 10 days. The two most significant
limitations are the small number of study subjects and the duration of
acetaminophen use. The three clinical studies only enrolled a total of
36 subjects with liver disease. Two of the studies only involved
acetaminophen use for 4 or 5 days. The lack of liver injury or signs of
liver injury in these studies does not mean that the same results would
be seen in studies enrolling larger numbers of subject using
acetaminophen for longer periods of time.
    Although these prospective clinical studies are inconclusive, the
retrospective data cited in the 2006 proposed rule suggest that
consumers with liver disease may be at increased risk for liver injury
when using OTC acetaminophen. As discussed in the 2006 proposed rule,
we identified a total of 282 adult cases of liver injury associated
with acetaminophen in our AERS database between January 1998 and July
2001. A history of prior liver disease, or possible underlying liver
disease, was reported in 70 cases (25 percent). Among the 70 cases with
liver disease, 49 percent developed severe liver injury.
    We also reviewed the Multiple Cause of Death Files between 1996 and
1998. These death certificates showed that unintentional acetaminophen
overdose was associated with an annual average of 100 deaths. In these
deaths, the presence of chronic liver disease was reported in 61
percent of the unintentional acetaminophen overdose cases. The high
prevalence rate of liver disease from these two databases (25 and 61
percent) suggests that liver disease increases the risk of liver injury
when using acetaminophen because only 2 to 3 percent of U.S. adults
have chronic liver disease (Ref. 24). The fact that people with
underlying liver disease make up a disproportionate percent of the
cases of severe liver injury relative to its prevalence in the general
population suggests that there is a higher risk for persons with liver
diseases. It is difficult to refute this type of data without
conducting larger studies with repeated exposures over an extended
period time.
    Based on this data, we believe that it is appropriate to advise
consumers with liver disease to ask a doctor before using acetaminophen
because they may be at risk for developing more serious liver injury.
We also agree with the second submission (Ref. 11) that the warning is
appropriate because it will advise liver disease patients about a
potential risk of further liver injury without advising them to avoid
using acetaminophen or limiting use to a pre-determined dose. The
submission states that such an open-ended warning will permit
healthcare providers to advise their liver disease patients on a case-
by-case basis. We plan to continue to require the warning unless and
until we become aware of adequate studies demonstrating that consumers
with liver disease are not at risk for liver injury when using OTC
acetaminophen or we obtain additional information that may be more
informative in providing dosing recommendations.

D. Drug Interaction Warning

    In this document, we are requiring a warning on OTC acetaminophen
drug products about a potential drug-drug interaction between
acetaminophen and warfarin. We did not specifically propose this type
of warning in the December 2006 proposed rule because we thought that
the data available at the time did not demonstrate the need for such a
consumer warning. The proposed rule did, however, request comments and
data concerning the need for a drug-drug interaction warning on OTC
acetaminophen drug products. Since the publication of the December 2006
proposed rule, we have determined that a consumer drug-drug interaction
warning is needed based on the current data and information available
to us.
    As stated in the proposed rule (71 FR 77314 at 77338), labeling for
warfarin-containing prescription drug products lists acetaminophen as a
drug that can increase warfarin's anticoagulant effect. The proposed
rule also discussed data concerning the potential drug-drug interaction
between acetaminophen and warfarin:
     20 bleeding adverse events (3 probable and 17 possible)
reported by consumers using warfarin and acetaminophen concurrently in
our AERS databases
     Numerous clinical studies examining the ability of
acetaminophen to interact with warfarin by measuring tests of blood
clotting
     Two studies examining the mechanism of a drug interaction
between acetaminophen and warfarin.
We stated that we believe that the actual numbers of bleeding events
may be much higher than reported in our AERS database because adverse
events are significantly underreported. We stated that the results of
studies measuring coagulation tests were conflicting with regard to the
effect of acetaminophen on warfarin anticoagulation. At that time, we
thought we could not draw firm conclusions from these studies on which
to base a consumer warning because they did not control for other
factors that may affect warfarin anticoagulation in consumers using
warfarin (e.g., vitamin K use). We also stated that the mechanism of
the potential drug-drug interaction is unknown. Because we thought that
the currently available data did not demonstrate sufficient evidence to
warrant a consumer warning, we requested comment and data from the
public on this issue to gather more information.
    In response to our request, we received two submissions (Refs. 11
and 12). Both submissions state that we should require a warning to ask
a doctor before using OTC acetaminophen if using warfarin. They provide
the following data to support their request:
     A prospective study examining the effect of acetaminophen
in consumers on warfarin therapy
     Retrospective data on the use of acetaminophen by
consumers on warfarin therapy
     Articles examining the mechanism of an interaction between
acetaminophen and warfarin.
In addition, one of the submissions (Ref. 11) argues that drug-drug
interaction warnings are also needed on OTC acetaminophen for
phenobarbital and isoniazid, but does not include any data to support
this request. We found one reference source that noted the risk for
liver injury may be increased in people taking isoniazid or
phenobarbitol if they

take more than the recommended dose of acetaminophen (Ref. 25).
However, since we are already warning people not to use more than the
recommended amount of acetaminophen, we are not requiring a warning
about the potential drug-drug interaction between phenobarbital or
isoniazid.
    After reviewing the data, we believe it demonstrates that consumers
using acetaminophen with warfarin may increase their International
Normalized Ratio (INR), which may serve as a sign of increased risk for
bleeding. This conclusion is based primarily on the submitted
prospective study (Ref. 26) and another prospective study (Ref. 27)
that we identified from the published literature.
    The retrospective data include a case report of a 74-year old man
on warfarin therapy who experienced an abrupt increase in INR after
using acetaminophen (Ref. 28). INR returned to normal after stopping
the acetaminophen. There is another case report of 81-year old woman
whose INR reached 16, leading to bleeding, after using acetaminophen
(Ref. 29). The other retrospective data consists of medical records
from 1,093 patients on warfarin therapy over a 5 year period (Ref. 30).
The records show that 316 (29 percent) of these patients experienced
increased INR when using acetaminophen and warfarin at the same time.
These data suggest that OTC acetaminophen may increase the
anticoagulation effect of warfarin, although other factors that may
affect coagulation (e.g., vitamin K use) were not controlled for and
the acetaminophen dosing was unknown. Similarly, the studies examining
the mechanism of this potential drug-drug interaction speculate on
possible mechanisms of interaction between acetaminophen and warfarin,
although they do not clearly demonstrate the mechanism (Refs. 31, 32,
and 33).
    The submitted prospective study was a randomized, double-blinded,
placebo-controlled, cross-over study (Ref. 26). In the study, 18
consumers on chronic warfarin therapy were given 4 grams of
acetaminophen or placebo for 14 days. The two 14-day treatment periods
were separated by a 2-week wash-out period. The mean INR at the
beginning of the treatment periods for placebo and acetaminophen were
similar (2.31  0.31 and 2.25  0.33,
respectively). Only a modest increase in the maximum INR compared to
baseline was observed when the subjects took placebo (mean maximum INR
= 2.66  0.73). A significant increase in the maximum INR
over baseline was observed when the subjects took acetaminophen (mean
maximum INR = 3.45  0.78). Therefore, this study suggests
that acetaminophen (4 grams daily for 2 weeks) increases the
anticoagulation action of warfarin.
    The second prospective study was a randomized, double-blinded,
placebo-controlled study (Ref. 27). In this study, 36 subjects on
chronic warfarin therapy were randomly assigned to three groups: (1) 2
grams acetaminophen daily, (2) 4 grams acetaminophen daily, or (3)
placebo. The subjects took acetaminophen or placebo for four weeks. The
primary end point of this study was difference in the mean INR at
weekly intervals, and the secondary end point was mean serum liver
enzymes at weekly intervals. The baseline mean INR in all groups was
similar (2.4  0.3, 2.5  0.2, and 2.5  0.3). The mean INR of the placebo group did not change during
the 4 weeks of the study. The 2 gram acetaminophen group reached the
highest mean INR at week 2 (3.1  0.5). The 4 gram
acetaminophen group reached the highest mean INR at week 3 (3.4  0.7). Both of these increases in INR were statistically
significant compared to placebo (p < 0.05). There were no statistically
significant differences in liver enzyme levels in the acetaminophen
groups at any time during the 4 weeks. Therefore, this study suggests
that acetaminophen (2 or 4 grams daily for 4 weeks) modestly increases
the anticoagulation action of warfarin.
    Both studies demonstrate increases in INR when using acetaminophen
and warfarin at the same time. In addition, the case report of bleeding
in the 81-year old woman with an INR of 16 supports the need for the
warning on the prescription labeling. We believe these data also
support the need for a consumer labeling statement for OTC
acetaminophen about the potential for interaction between warfarin and
acetaminophen, and we are including a warning statement in this final
rule. We are primarily concerned with the chronic use of acetaminophen
in patients using warfarin. These are patients who use acetaminophen
regularly for chronic pain from conditions, such as osteoarthritis or
fibromyalgia.
    Typically, patients receiving warfarin undergo monthly testing of
their INR. As noted in one of the interaction studies, the peak effect
is noted after 2 or 3 weeks depending on the dose of acetaminophen.
Thus, an increase in INR is likely to be detected during the monthly
check of the INR. Therefore, a drug-drug interaction warning for
coadministration of acetaminophen with warfarin is important to educate
healthcare providers and consumers about the possible interaction
between these two drugs and to consider this as a possible cause of an
increase in INR for patients on warfarin. The warning reads as follows:
``Ask a doctor or pharmacist before use if you are taking the blood
thinning drug warfarin'' (21 CFR 201.326(a)(1)(iii)(D)). This warning
is required on all OTC acetaminophen products except those also
containing NSAID(s). Combination products containing acetaminophen and
NSAID(s) are required to include a warning about blood thinning drugs
under the stomach bleeding warning for NSAIDs. It would be
unnecessarily redundant to include the same warning under the ``Ask a
doctor or pharmacist before use'' heading. We believe the warning will
encourage patients on chronic warfarin therapy to ask their doctor
about the use of acetaminophen with the warfarin and remind healthcare
providers to consider this interaction when evaluating elevated INRs in
their patients.

E. Warnings for Certain Sub-Populations

1. Warning for Consumers Infected With Human Immunodeficiency Virus
(HIV)
    In this document, we are not adding any warning that HIV-infected
consumers are at increased risk of liver injury when using
acetaminophen. We reached this conclusion after reviewing the available
data on the use of acetaminophen by HIV-infected individuals. We find
the currently available data do not adequately demonstrate that
acetaminophen, when used according to the OTC label (i.e., maximum
daily dose of 4 grams for no longer than 10 days), poses risk for HIV-
infected individuals.
    In the 2006 proposed rule, we requested comments and data on
whether the maximum daily dose (4 grams) of acetaminophen is unsafe for
HIV-infected consumers (71 FR 77314 at 77337 to 77338). As discussed in
the proposed rule, this safety concern stems from a citizen petition
that makes the following arguments to support the need for an HIV
warning:
     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
people with HIV disease, and acetaminophen may further reduce survival
by depleting GSH.
After submission of the petition, we received a submission from a
manufacturer of OTC acetaminophen

products arguing that an HIV warning is unnecessary (Ref. 1). The
submission included numerous in vitro and in vivo studies both
supporting and refuting that HIV-infected patients are at increased
risk of liver injury when using acetaminophen.
    In the proposed rule, we did not propose an HIV warning because
there was not adequate data demonstrating that use of acetaminophen
decreased the survival rate of HIV-infected consumers. In vitro and in
vivo studies did demonstrate low levels of GSH and its precursors in
HIV-infected consumers, suggesting the toxic acetaminophen metabolites
may accumulate in these individuals. However, we were not aware of any
data demonstrating that these low levels of GSH are clinically
meaningful (i.e., impact survival or increase acetaminophen liver
injury). In vitro studies also demonstrated that N-acetylcysteine,
which is used to treat acetaminophen overdoses, improved the
performance of T cells from healthy and HIV-infected individuals.
However, these studies did not demonstrate that the increased GSH
levels in HIV-infected individuals after N-acetylcysteine treatment
lead to improved survival.
    Although many of the studies did not demonstrate clinically
meaningful effects of low GSH levels in HIV-infected individuals, as
stated in the proposed rule, we did review clinical studies
demonstrating the relationship between GSH levels and survival. We
could not conclude that decreased GSH levels in HIV-infected
individuals lead to decreased survival rates because of the following
deficiencies:
     No clear description of the study design
     Survival data were not collected for 17 percent of the
study population
     No baseline characteristics provided for individuals
participating in the clinical trial
     No documentation of antiviral treatment or concomitant use
of other medications
     N-acetylcysteine administration was not randomized
We also could not find any hepatic adverse events in the AERS database
associated with HIV infection and acetaminophen use.
    In response to the request for data and comment in the proposed
rule, we received three submissions regarding an HIV warning. Two
submissions argue that currently available data do not support the need
for an HIV warning (Refs. 1 and 11). The third submission argues that
we should require an HIV warning (Ref. 12). All three submissions cite
in vitro and in vivo data to support their arguments. However, the only
data that demonstrate a clinically meaningful adverse effect of
acetaminophen use by HIV-infected individuals are two case reports. The
remaining studies examine the relationship of GSH and acetaminophen
metabolites levels in HIV infection. Some of the studies demonstrate a
correlation between GSH and acetaminophen metabolites levels and HIV
infection, while others do not. Regardless of the study results, these
studies do not provide us with evidence that the HIV-infected patients
experience liver injury when using acetaminophen.
    There are case reports of two HIV-infected individuals experiencing
liver injury after consumption of therapeutic doses of acetaminophen
(i.e., less than or equal to 4 grams daily). We cannot conclude that
HIV-infected individuals are at higher risk of acetaminophen-induced
liver injury than uninfected individuals based on these reports. In the
first report, a 45 year old HIV-infected male developed signs of severe
liver injury after using 4 grams acetaminophen daily for 5 days (Ref.
35). The signs of liver injury went away after treatment with N-
acetylcysteine. It is difficult to determine whether the HIV infection
placed this patient at greater risk for acetaminophen liver injury
because there were many other potential risk factors: chronic alcohol
use, tobacco use, opiate use, malnutrition, and hepatitis B and C
infection. In the second report, a 31 year old HIV-infected male was
hospitalized with liver injury after using 2 grams acetaminophen on the
previous day (Ref. 36). Again, there were many other potential risk
factors for liver injury: alcohol abuse, malnutrition, and concomitant
chronic use of zidovudine (in combination with ribavirin).
    We are not requiring an HIV warning in this document because we are
not aware of data demonstrating that HIV-infected patients (in the
absence of other risk factors) are at greater risk of acetaminophen-
induced liver injury. We will reconsider our position if new data
become available.
2. Warning for Malnourished Consumers
    In this document, we are not requiring any warning that
malnourished consumers are at increased risk of liver injury when using
acetaminophen as directed (i.e., no more than 4 grams daily for up to
10 days). By malnourished, we mean consumers who fast, have eating
disorders, or whose diets do not provide a healthy minimum caloric
intake for other reasons. We arrived at this conclusion after reviewing
the currently available data on the use of acetaminophen by these
consumers. These data do not sufficiently demonstrate that
acetaminophen when used according to labeling poses an increased risk
of liver injury in these individuals relative to other individuals.
    We are considering this issue because, in the 2006 proposed rule,
we requested comments and data on whether the maximum daily dose of
acetaminophen is unsafe for individuals who have reduced glutathione
levels. A small amount of acetaminophen is metabolized through a
pathway that generates a potentially toxic intermediate, NAQPI.
Glutathione conjugates with NAQPI and the conjugate is then excreted in
the urine. Malnourished individuals have been shown to have reduced
glutathione levels (Refs. 37, 38, and 39). Therefore, it is possible
that low glutathione levels may increase the risk for liver injury
because there would be less available to bind to NAQPI. Low glutathione
levels may a surrogate for identifying a population at increased risk
of liver injury with acetaminophen, but it was unclear how much of the
deficiency is necessary.
    In response to our request, we received three submissions regarding
malnourished consumers (Refs. 1, 11, and 12). One submission (Ref. 12)
argues that we should require such a warning because malnourished
consumers may be at greater risk for acetaminophen-induced liver injury
than other consumers. In addition, the submission recommends additional
studies to further evaluate the liver injury risk for malnourished
consumers. The second submission (Ref. 11) also states the need for
such studies but does not discuss the need for a warning. The third
submission (Ref. 1) argues that data do not demonstrate the need for a
warning. The three submissions cite the following types of data to
support their arguments:
     A prospective study examining the effect of fasting on
acetaminophen metabolism
     Retrospective data (case reports and case report series)
concerning the use of acetaminophen and liver injury in malnourished
individuals
     Human studies examining the effect of fasting on
glutathione levels
     Review articles on glutathione and analgesics.
    After reviewing this information, we cannot make a conclusion about
the risk of liver injury due to acetaminophen in malnourished
individuals. In the prospective study (Ref. 40), six obese individuals
were given 500 calorie diets

for 5 days (group 1), and three obese individuals were given 1000
calorie diets for 13 days (group 2). The study subjects did not have a
history of alcohol abuse and had normal liver and kidney function prior
to study enrollment. The subjects in group one took 2 grams
acetaminophen on days 1 and 5. The urine of study subjects was
collected every 2 hours for 12 hours after the acetaminophen dose. The
subjects in group two took 2 grams acetaminophen on days 1, 7, and 13.
The urine of study subjects was collected every 2 hours for 10 hours
after the acetaminophen dose. Liver tests were performed at 12, 24, 36,
and 120 hours after the acetaminophen dose. The clearance of
acetaminophen on day 1 in both groups was nearly identical to the
clearance on subsequent days. The same is true for acetaminophen
metabolites (i.e., glucouronide, sulfate, and thiols). Liver function
tests remained unchanged throughout the study. This study suggests that
acetaminophen metabolism is not altered in malnourished consumers. It
is difficult to make any conclusions about the risk of liver injury
with acetaminophen based on this data. The small sample size of this
study and the intermittent dosing at less than the maximum daily dose
prevents us from drawing any conclusions. Additionally, if differences
in metabolism were detected, it would be difficult to assess what
amount of difference was clinically meaningful.
    Two submissions (Refs. 1 and 12) provide retrospective data
concerning acetaminophen-induced liver injury in malnourished
consumers. The first retrospective data is a case series report
describing liver injury caused by acetaminophen overdose in association
with alcohol and fasting (Ref. 41). This report identifies 21 patients
who developed severe liver injury when using acetaminophen. All of the
patients took more than 4 grams acetaminophen daily and nearly all were
recently fasting. The study authors concluded that fasting is a risk
factor for acetaminophen-induced liver injury. However, we do not
believe the study supports this conclusion for OTC use of
acetaminophen. All of the patients exceeded the maximum OTC
acetaminophen dose of 4 grams daily, with 11 patients using more than
10 grams daily. Because the patients ingested more than the recommended
amount of acetaminophen and also ingested alcohol, it is difficult to
identify the contribution of fasting to the development of liver
injury.
    The other retrospective data consist of case reports. One
submission describes relevant reports from our AERS database (Ref. 1).
The database includes 20 reports of liver injury in individuals using
acetaminophen who appear to be malnourished. In 17 out of 20 reports,
the acetaminophen dose was not known or exceeded the maximum OTC daily
dose. Only three reports concerned malnourished consumers using
acetaminophen at therapeutic doses (i.e., no more than 4 grams daily).
This submission also refers to a literature search that revealed 60
reports of liver injury when malnourished individuals took
acetaminophen. In 44 cases, the acetaminophen dose exceeds the maximum
OTC dose, and, in 11 cases, the acetaminophen dose was not reported.
There were five cases of liver injury when using recommended OTC doses
of acetaminophen.
    There were also two published case reports submitted. The first
case report (Ref. 36) describes a malnourished HIV-infected individual,
who was hospitalized after using 2 grams of acetaminophen. In this
case, the patient was a chronic alcohol user taking zidovudine (AZT)
for HIV. The second report (Ref. 42) describes a 53 year old women who
developed liver injury after using acetaminophen (4 grams) daily
following a period of fasting.
    Of all these cases, there are nine cases of liver injury resulting
from acetaminophen use at or below 4 grams daily. Nine case reports
represent a small fraction of the overall number of case reports.
Therefore, the case reports by themselves do not demonstrate that
malnourished individuals are at higher risk of liver injury when using
OTC acetaminophen than non-malnourished individuals.
    The submitted data are not sufficient to conclude that
acetaminophen used at maximum daily OTC dose (4 grams daily for 10
days) by malnourished individuals poses additional risk of liver injury
in these individuals. Therefore, we are not requiring any warning for
these individuals at this time. If new data become available, we will
reconsider our position on this issue.
3. Warning for Consumers with Gilbert's Syndrome
    In this document, we are not requiring any warning for consumers
with Gilbert's syndrome. Available data do not demonstrate that
acetaminophen used according to the OTC label (i.e., a maximum of 4
grams daily for 10 days) presents any additional risk for these
consumers compared to consumers without this condition. We considered
the need for such a warning because we received a submission (Ref. 1)
recognizing the potential risk of liver injury for consumers with
Gilbert's syndrome who use acetaminophen. The submission argues that a
warning regarding Gilbert's syndrome should not be required based on
the available studies. We received this submission in response to our
request in the 2006 proposed rule for comments and data on specific
subsets of the population that may be at increased risk of liver injury
when using the maximum daily dose of acetaminophen (71 FR 77314 at
77346).
    Gilbert's syndrome is clinically characterized by serum bilirubin
levels higher than normal and, in the cases where signs are apparent,
causes yellow eyes and skin (jaundice). Gilbert's syndrome is harmless
and requires no treatment (Ref. 43). Doctors diagnose patients as
having the condition when examinations and tests do not reveal the
existence of any other condition causing the high bilirubin levels. The
main cause of high levels of unconjugated bilirubin in these
individuals is believed to be due to the reduced activity of the enzyme
bilirubin-uridine diphosphate glucuronosyltransferase (UDP-GT), which
is essential for the bilary excretion of bilirubin (Ref. 44).
Acetaminophen is primarily eliminated by UDP-GT enzymes through a
process called glucuronidation (Ref. 45). If the UDP-GT enzymes that
metabolize acetaminophen do not function properly, then acetaminophen
is metabolized through a metabolic pathway that produces the toxic
metabolite NAPQI. Therefore, it has been suggested that individuals
with Gilbert's syndrome may be at increased risk for acetaminophen-
induced injury.
     We are not requiring a warning for consumers with
Gilbert's syndrome because the available data do not demonstrate that
consumers with Gilbert's syndrome are more likely to produce excess
formation of NAPQI when using acetaminophen.
    The submission that we received provided numerous articles and
studies concerning Gilbert's syndrome (Ref. 1). Of these studies, the
most meaningful in determining the risk of acetaminophen-induced liver
injury are the three acetaminophen metabolism studies in individuals
with Gilbert's syndrome (Refs. 46, 47, and 48). The studies compare the
amount of the most abundant acetaminophen metabolites (conjugation
products- glucorounides and sulphates) and/or the least abundant
acetaminophen metabolites (oxidation products- cysteines and
mercaptures) between the groups. The oxidation metabolites are formed
through a process that generates NAPQI. Therefore, the metabolites are
used as surrogates for NAPQI production.

    The first study (Ref. 47) enrolled 32 control subjects and 18
Gilbert's syndrome subjects. The Gilbert's syndrome subjects were
divided into two groups: (1) those who produced more conjugation
acetaminophen metabolites than oxidation metabolites and (2) those who
produced more oxidation acetaminophen metabolites than conjugation
metabolites. The second Gilbert's syndrome group represents subjects
with abnormal acetaminophen metabolism because more conjugation
acetaminophen metabolites than oxidation metabolites should be
produced. One dose of acetaminophen (1.5 grams) was used, and urine was
collected for 24 hours. Neither the control group nor the first
Gilbert's syndrome group showed any statistically significant
differences in the level of acetaminophen or any of its metabolites.
The second Gilbert's syndrome group showed a statistically significant
increase in oxidation metabolites and decrease in conjugation
metabolites.
    The second study was performed on six individuals with Gilbert's
syndrome, and six control individuals (Ref. 46). Acetaminophen, 1.2
grams to 1.8 grams, was given. The conjugation metabolites were
measured in plasma 2 hours after acetaminophen dosing, whereas the
oxidation metabolites were measured in urine 24 hours after dosing. The
conjugation metabolite levels were 31 percent lower in Gilbert's
syndrome individuals compared to control individuals. The oxidation
metabolites were 70 percent higher in Gilbert's syndrome individuals
than controls. This study demonstrates statistically significant
differences in both groups, and suggests lower glucuronidation and
enhanced excretion of the oxidation metabolites in 24 hour urine
samples of Gilbert's syndrome individuals. It is important to note that
none of the Gilbert's syndrome individuals showed any elevation in
liver function tests or any other sign of liver injury.
    In the third study, 11 individuals with Gilbert's syndrome and 10
control subjects received 1 gram of acetaminophen orally (Ref. 48).
Eight hours later urinary acetaminophen and its metabolites were
measured by high performance liquid chromatography. The conjugation
metabolites were 37.5  4.7 percent versus 32.4
2.4 percent in individuals with Gilbert's syndrome and control group,
respectively. The oxidation metabolites levels were 5.2
1.8 percent versus 4.6  1.2 percent in individuals with
Gilbert's syndrome and control group, respectively. These results
demonstrate that the relative amount of each metabolite was not
significantly different between groups. Therefore, this study suggests
that metabolism of acetaminophen is not altered in individuals with
Gilbert's syndrome.
    Results of the three metabolism studies are conflicting. The first
two studies suggest decreased conjugation and increased oxidation of
acetaminophen in individuals with Gilbert's syndrome. This finding
suggests that greater amounts of the toxic metabolite may be produced
by individuals with Gilbert's Syndrome. It is not clear, however, that
this translates into an increased risk for developing acetaminophen-
induced liver injury. However, the third study shows no difference in
the conjugation and oxidation metabolite levels between individuals
with or without Gilbert's syndrome. This finding suggests that these
individuals may not produce different amounts of metabolites. We do not
believe these three studies adequately demonstrate that individuals
with Gilbert's syndrome are at higher risk of liver injury than
individuals without Gilbert's syndrome when using up to 4 grams
acetaminophen daily.

V. Labeling Required for OTC NSAIDs

A. Warnings

    In response to the 2006 proposed rule, we received five submissions
regarding warnings for OTC NSAIDs (Refs. 1, 2, 4, 5, and 49). While
three submissions (Refs. 2, 4, and 49) agree with the proposed
warnings, two submissions (Refs. 1 and 5) request the following
revisions to the proposed warnings:
    1. Revise the ``Ask a doctor or pharmacist before use if you are''
subheading in proposed 21 CFR 201.325(a)(2)(iii)(B) to read ``Ask a
doctor or pharmacist before use if you are taking.''
    2. Include ``liver disease'' in the kidney damage warning (proposed
201.325(a)(2)(iii)(b)).
    The first request was made because the proposed bulleted statements
under the subheading all begin with ``taking;'' therefore, ``taking''
should be moved from the bulleted statements to the subheading. This
revision would decrease the overall number of words for the warning.
The second request concerns the warning that deals primarily with risk
factors for kidney damage when using OTC NSAIDs. The submission (Ref.
1) includes data regarding the occurrence of kidney damage in patients
with severe liver disease with ascites when using OTC NSAIDs.
    We are not revising the proposed NSAID warnings in this document as
suggested by the two submissions. Regarding the first request (Ref. 5),
we cannot revise the warning subheading statement in proposed 21 CFR
201.325(a)(2)(iii)(B) because there are other proposed bulleted
statements under this heading from the 2002 IAAA proposed rule (67 FR
54139 at 54150; 21 CFR 343.50(c)). One of the other proposed bulleted
statements reads, ``under a doctor's care for any serious condition.''
This bulleted statement would not make sense if ``taking'' is included
in the warning subheading.
    Regarding the second request, we are adding ``liver cirrhosis'' to
the ``Ask a doctor before use if you have'' warning. The submission
making this request submitted many different types of studies (Ref. 1).
We believe the most clinically meaningful of the submitted studies are
the seven prospective studies examining kidney function in patients
with liver disease using NSAIDs. These studies enrolled a total of 112
patients with liver disease who took an NSAID. All of the patients had
cirrhosis with ascites, a severe form of liver disease in which fluid
collects in the abdomen. Fourteen of these patients also had functional
kidney failure. The study end points examined kidney function by
typical laboratory parameters, such as glomerular filtration rate,
renal plasma flow, and serum creatinine levels.
    Taken together, the study results suggest that kidney function
decreases in these patients when they use an NSAID. For example, one
study (Ref. 50) found that the decreases in three of the parameters
were statistically significant (p < 0.05): glomerular filtration rate,
renal plasma flow, and serum creatinine levels.
    Patients with cirrhosis and ascites constitute a subset of the
patients who have liver disease and represents a severe stage of liver
disease. We are not aware of data demonstrating the patients with less
severe forms of liver disease are at higher risk than consumers without
liver disease. One of the submitted studies found only one of the seven
kidney function parameters decreased significantly when comparing
patients who had liver disease without ascites to patients who did not
have liver disease (Ref. 51). In contrast, five of the seven kidney
function parameters decreased significantly when comparing patients who
had liver disease with ascites to patients who did not have liver
disease. This result is consistent with what one would expect to see in
patients with ascites, which causes loss of intravascular fluid due to
accumulation of fluid in the abdominal cavity. The renin angiotensin
system is

activated, which results in renal vasoconstriction. The kidney produces
vasodilating prostaglandins which help maintain renal function. In
patients with cirrhosis and ascites, NSAIDs reduce the production of
vasodilating prostaglandins, which could lead to a decline in renal
function and development of renal failure (Refs. 52, 53, and 54).
    In conclusion, we are including ``liver cirrhosis'' in the ``ask a
doctor'' warnings instead of ``liver disease'' as requested by the
submission because the results of the studies are consistent with an
intravascular volume depleted condition caused by liver cirrhosis and
ascites. It is important to note that these patients are typically
under a high level of care by doctors because of the severity of the
disease state. This is demonstrated by the submitted studies, in which
85 of the 112 patients were hospitalized when they were enrolled in the
studies. The medications that these patients receive are scrutinized by
their health providers. Furthermore, we are not aware of data
demonstrating that the majority of patients with less severe liver
disease are at higher risk to develop a decrease in kidney function.
Therefore, ``liver disease'' would be too vague, because it would also
apply to patients with less severe forms of liver disease.
    In addition to adding ``liver cirrhosis'' to the warnings, we are
making other revisions to the warnings that we believe will improve the
safe use of these products. We are revising the introductory sentences
of the stomach bleeding warning to include ``severe'' before ``stomach
bleeding.'' We are making this modification because a submission (Ref,
1) argues that the term ``severe'' to qualify liver damage should be
consistently applied to all OTC analgesics but was only proposed as
part of the liver warning and was not proposed in the stomach bleeding
warning (see Section IV.A.2. of this document). The same submission
also argues that the term ``severe'' should not be used in either the
liver warning or the stomach bleeding warning. However, we believe that
the term is accurate and appropriate in both warnings because the drug-
induced liver damage and bleeding can both potentially lead to death.
    We are revising the introductory sentences of the stomach bleeding
warning to remove the words ``nonsteroidal anti-inflammatory drug''
immediately before ``(NSAID).'' The term ``NSAID'' is defined under the
``Active ingredient/Purpose'' heading (21 CFR 201.326(a)(2)(ii)). It
does not need to be defined a second time in the stomach bleeding
warning. The introductory sentences of the stomach bleeding warning
required in this document reads: ``Stomach bleeding warning: This
product contains an NSAID, which may cause severe stomach bleeding. The
chance is higher if you.'' These sentences are followed by the bulleted
statements identifying risk factors.
    We are also removing warnings that are not part of the stomach
bleeding warning but are related. There are five bulleted statements
under the ``Ask a doctor before use if you have'' and ``Ask a doctor or
pharmacist before use if you have'' headings that are redundant with
bulleted statements under the stomach bleeding warning (proposed 21 CFR
201.325(a)(2)(iii)(B) and (C)):
     ulcers
     bleeding problems
     reached age 60 or older
     taking any other drug containing an NSAID (prescription or
nonprescription)
     taking a blood thinning (anticoagulant) or steroid drug.
The stomach bleeding warning informs consumers of risk factors for
stomach bleeding. These five bulleted statements instruct consumers to
ask a doctor or pharmacist before using an NSAID if they have any of
the stomach bleeding risk factors. Therefore, all of these proposed
warnings are necessary. However, we believe the five bulleted
statements can be simplified into one warning: ``Ask a doctor before
use if the stomach bleeding warning applies to you.'' This revised
warning will provide consumers with the same information while taking
much less labeling space. We should also note that this revision
changes the heading so that we are also making minor revisions to the
other bulleted statements under the ``Ask a doctor before use if''
heading.
    All five bulleted statements are identical to the bulleted
statements in the stomach bleeding warning except the statement about
NSAID use. This statement specifies ``prescription or
nonprescription,'' which is not specified in the stomach bleeding
warning. We believe this is important information that consumers should
continue to be aware of. Therefore, we are revising the fourth bulleted
statement in the stomach bleeding warning to include this information:
``take other drugs containing prescription or nonprescription NSAIDs
(aspirin, ibuprofen, naproxen, or others).''
    There are also two warnings related to stomach bleeding under the
``Stop use and ask a doctor if'' heading (proposed 21 CFR
201.325(a)(2)(iii)(D)):
     you feel faint, vomit blood, or have bloody or black
stools. These are signs of stomach bleeding
     stomach pain or upset gets worse
We continue to believe these warnings are important to the safe use of
OTC NSAIDs. The stomach bleeding warning and the new warning ``Ask a
doctor before use if the stomach bleeding warning applies to you''
provide information that consumers need to know before using an OTC
NSAID. The warnings under the ``Stop use and ask a doctor if'' heading
provide information that consumers need to know after they begin using
an OTC NSAID. In this document, we are revising the warnings to make it
clearer that both warnings relate to signs of stomach bleeding:
Stop use and ask a doctor if
 you experience any of the following signs of stomach
bleeding:
     feel faint
     vomit blood
     have bloody or black stools
     have stomach pain that does not get better.
We believe this revision will allow consumers to more easily identify
symptoms of stomach bleeding.
    In addition to the revisions related to stomach bleeding, we are
revising the warning related to stomach pain and discomfort that can be
caused by NSAID use (proposed 21 CFR 201.325(a)(2)(iii)(B)): ``Ask a
doctor before use if you have stomach problems that last or come back,
such as heartburn, upset stomach, or stomach pain.'' We continue to
believe that OTC NSAIDs are more likely to lead to stomach pain and
discomfort in consumers who have a history of stomach problem than
those who do not (53 FR 46204 at 46220). Therefore, we are continuing
to require this warning. But, we are revising it to make it more
concise and easier to understand: ``Ask a doctor before use if you have
a history of stomach problems, such as heartburn.'' We believe all of
the revisions that we are making to the OTC NSAID warnings in this
document will better ensure safe use of these products.

B. Labeling Specific to Aspirin

    In response to the 2006 proposed rule, we received one submission
from a manufacturer of OTC aspirin products (Ref. 55). The submission
requests the following for OTC aspirin products:
    (1) Do not require the word ``NSAID'' on the PDP;
    (2) Allow the indication statement ``as directed by a doctor for
prevention of heart attack and stroke''; and
    (3) Do not require the cardiovascular risk warning proposed for all
OTC NSAIDs.

    In support of these requests, the submission cites the safe
marketing history of aspirin and the unique pharmacological properties
of aspirin that distinguish it from the other NSAIDs. The submission
does not include any data to support these requests.
    In this document, we are requiring the labeling proposed for
aspirin in the 2006 proposed rule. The carton labeling covered by this
final rule will include aspirin products. Regarding the submission's
first request, we believe it is important to identify OTC aspirin
products as being an ``NSAID.'' In the 2006 proposed rule, we proposed
that the name of the NSAID ingredient (e.g., ``aspirin'') should be
followed by the term ``(NSAID)'' as highlighted text on the PDP on all
OTC NSAID products (71 FR 77314 at 77350). We proposed this labeling be
required to help consumers identify NSAID-containing products and avoid
adverse drug effects (e.g., stomach bleeding) caused by accidentally
using multiple NSAID products at the same time. We believe that these
adverse drug effects may occur regardless of whether an NSAID product
contains aspirin or another NSAID. We are not aware of any data
demonstrating that aspirin is significantly less likely to cause these
adverse drug effects. For example, our AERS database reveals 279 cases
of stomach bleeding associated with aspirin and other NSAIDs between
1998 and 2001, and the majority of reports involve aspirin (71 FR 77314
at 77325). Therefore, we continue to believe that the term ``NSAID''
prominently displayed on all OTC NSAID products, including aspirin, is
important for the safe use of these products.
    Regarding the submission's second request, we are not allowing OTC
aspirin products to include the indication statement ``as directed by a
doctor for prevention of heart attack and stroke'' in the ``Uses''
section of the ``Drug Facts'' label. OTC use of aspirin for
cardiovascular uses is allowed under professional labeling for OTC
aspirin products, although the indication statement is different than
that included in the submission (21 CFR 343.80). In a 1993 proposed
rule, we proposed the following warning be included on OTC aspirin
labeling (58 FR 54224 at 54225): ``IMPORTANT: See your doctor before
taking this product for your heart or for other new uses of aspirin,
because serious side effects could occur with self treatment.'' The
intent of the recommended indication statement and proposed warning is
to encourage consumers to seek a doctor's advice when using aspirin to
prevent heart attack or stroke. We will consider these and other
labeling options in a future Federal Register publication. In this
document, we are not addressing the submission's third request to
exclude OTC aspirin products from including the cardiovascular risk
warning (i.e., ``long term continuous use may increase the risk of
heart attack or stroke''). This warning was included on all OTC NSAID
products except aspirin marketed under an NDA, as specified in the July
2005 letter sent to all OTC NSAID NDA holders (Ref. 6). We have not
required that this warning be included on any aspirin containing
products. We have not proposed this warning for OTC NSAIDs marketed
under the monograph. We will address this warning for OTC NSAIDs
marketed under the monograph in a separate Federal Register notice
because it was not included in the 2006 proposed rule (i.e., is not in
proposed 21 CFR part 201).

VI. Analysis of Impacts

    We have examined the impacts of this final 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 $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is about $130 million, using the most current (2007)
Implicit Price Deflator for the Gross Domestic Product.
    We conclude that this final rule is consistent with the principles
set out in Executive Order 12866 and in these two statutes. This final
rule is not a significant regulatory action as defined by the Executive
Order and, therefore, is not subject to review under the Executive
order. As discussed in this section, we have determined that this final
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 expenditure in any one year of $100 million or more, we are
not required to perform a cost-benefit analysis according to the
Unfunded Mandates Reform Act.
    We estimate that manufacturers and marketers of OTC acetaminophen
and NSAID drug products would incur one-time compliance costs of $32
million in the first year to revise labeling to conform to this rule.
The benefits of this final 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,\9\ and $49 million to $147 million at a 3 percent
discount rate. If we assume only a 1 percent reduction in the illnesses
and deaths analyzed, the benefits of this rule outweigh the costs.
---------------------------------------------------------------------------

    \9\ Per the Office of Management and Budget (OMB) Circular A4,
revised in 2003.
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    We note 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 rule prevents about 1 death each year
(0.9 and 0.7 deaths over 10 years at a 7 percent and a 3 percent
discount rate, respectively). Alternatively, if no deaths are avoided,
the rule would need 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.

A. Need for the Rule

    In 2002, an FDA Advisory Committee recommended changes to the
labeling of OTC acetaminophen and NSAID drug products to better inform
consumers about the active ingredients and possible side effects caused
by improper use. Although we consider

acetaminophen to be safe and effective when labeled and used correctly,