[Federal Register Volume 74, Number 81 (Wednesday, April 29, 2009)]
[Rules and Regulations]
[Pages 19385-19409]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-9684]


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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

[[Page 19386]]

     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

[[Page 19387]]

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
----------------------------------------------------------------------------------------------------------------
              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

[[Page 19388]]

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

[[Page 19389]]

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

[[Page 19390]]

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

[[Page 19391]]

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.

[[Page 19392]]

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

[[Page 19393]]

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

[[Page 19394]]

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

[[Page 19395]]

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

[[Page 19396]]

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

[[Page 19397]]

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

[[Page 19398]]

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.

[[Page 19399]]

    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

[[Page 19400]]

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.

[[Page 19401]]

    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.
---------------------------------------------------------------------------

    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

[[Page 19402]]

acetaminophen to be safe and effective when labeled and used correctly, 
using too much can lead to liver injury and death. Similarly, the use 
of NSAIDs can lead to stomach bleeding and kidney damage. The number of 
cases of injury reported is a very low percentage of the total use of 
OTC acetaminophen and NSAID drug products. For many people, the risks 
are quite low because they use these products only occasionally. The 
risks may be greater for people who use these products more frequently 
and/or do not follow the labeling information on the package. The risk 
of injury may be increased for certain populations and under certain 
conditions of use.
    There are multiple reasons for unintentional acetaminophen 
overdoses. First, acetaminophen is an active ingredient in a wide 
variety of both OTC and prescription drug products. For prescription 
products, the immediate prescription container may not state that the 
product contains acetaminophen or state the maximum daily dose limit. 
Consumers may often fail to recognize the presence and amount of 
acetaminophen ingredients in OTC and prescription drug products. This 
lack of knowledge can result in a person using two different products 
containing acetaminophen simultaneously. Moreover, many consumers are 
unaware that exceeding the recommended dosage for acetaminophen can 
lead to unintentional overdosing and cause potential harm. Based on the 
evidence discussed in this document, we find that there is sufficient 
incidence of liver injury associated with acetaminophen to warrant new 
labeling, and that without the new labeling, acetaminophen products 
would no longer be considered generally recognized as safe and 
effective and not misbranded for OTC use.
    Results of several large-scale clinical studies performed in the 
United States and in other countries have established that the use of 
NSAIDs is an important risk factor for serious stomach adverse events, 
especially bleeding. The risk is higher for certain populations. Based 
on the evidence discussed in this document, we further find that NSAIDs 
increase the risk for stomach adverse events and that, without a new 
stomach bleeding warning in the labeling for NSAIDs, the products would 
no longer be considered generally recognized as safe and effective and 
not misbranded for OTC use.
    The purpose of this final rule is to amend our OTC drug labeling 
regulations to include new warnings and other labeling requirements to 
advise consumers of potential risks and when to consult a doctor (see 
Table 1 in section I.B.2. of this document). We are also removing the 
alcohol warning in Sec.  201.322 and incorporating new alcohol-related 
warnings and other labeling for all OTC acetaminophen and NSAID drug 
products. We are requiring certain warning information targeted to age-
specific populations. In addition, we are requiring that the presence 
of acetaminophen or any NSAID would appear prominently on a product's 
principal display panel (PDP).

B. Impact of the Rule

    We contracted Eastern Research Group, Inc. (ERG) to assess the 
costs and benefits of the 2006 proposed rule on which this final rule 
is based. The results of ERG's analysis apply to this final rule 
because there are only minor differences between the proposed rule and 
this final rule. We do not believe any of these differences will 
significantly changes the costs and benefits determined by ERG. The 
following is a summary of ERG's analysis; the full report, including 
details on assumptions, cost calculations, and findings, is on file in 
the Division of Dockets Management (Ref. 56).
    Manufacturers and marketers of OTC acetaminophen and NSAID drug 
products would incur one-time costs to revise affected product labeling 
to comply with this rule. We assumed an implementation period of 12 
months for one-time costs for a major labeling revision. We estimated 
one-time costs for a major labeling revision using a pharmaceutical 
labeling revision cost model. This labeling model is described in 
detail in Appendix A of the ERG report.
    To develop the original model, we and ERG interviewed 
pharmaceutical representatives from regulatory, legal, manufacturing 
controls, and labeling departments to collect information on labeling 
change cost components, type of personnel affected, and costs. The 
model incorporates data on average industry costs by company size, 
including, where applicable, modifications to packaging configurations. 
Industry consultants also provided information on model inputs related 
to the OTC acetaminophen and NSAID drug product industry, the labeling 
revision process, the costs of modifying labeling, and the frequency of 
packaging reconfiguration changes.
    The baseline for this action is in full compliance with the format 
and content requirements for OTC drug product labeling in 21 CFR 
201.66. In the final rule that established these requirements on March 
17, 1999 (64 FR 13254), we accounted for the total incremental costs to 
comply with requirements, including 6 point font size and related costs 
for increased package size and longer labeling where applicable. We 
note that, although some forms of packaging (for small quantities) have 
been granted extensions on compliance dates, many packaging 
alternatives now exist to assure compliance.
    Manufacturers routinely change labels at varying intervals and have 
standardized procedures in place for complying with our requirements. 
The analysis assumes that one-half of the manufacturers of OTC 
acetaminophen and NSAID drug products typically redesign their label 
every 2 years, the remainder every 3 years, based on consultant input. 
For this analysis, ERG assumed that manufacturers whose label redesign 
cycle is less than the implementation period will not incur any 
regulatory costs. For example, if a company routinely revises its 
product labeling annually and is given at least that long to 
incorporate the required changes, ERG judged that the regulatory 
revision can be made at essentially no cost.
    The costs of labeling change depend on the type of labeling (e.g., 
carton and container label) and whether there is sufficient labeling 
space to accommodate the proposed changes. There are an estimated 
22,500 OTC acetaminophen and NSAID drug product stock keeping units 
(SKUs), split evenly among branded and private labels, according to an 
industry consultant.\10\ We assume branded SKUs are distributed as 
follows by firm size: 50 percent small, 17 percent medium, and 33 
percent large. Based on consultant input, we assumed the distribution 
of SKUs among OTC acetaminophen and NSAID drug products as follows: 
Acetaminophen, 45 percent; NSAIDs (except ibuprofen), 38 percent; 
ibuprofen, 15 percent; and combinations of acetaminophen and NSAIDs, 2 
percent. The ERG report presents model assumptions and methods for 
calculating costs.
---------------------------------------------------------------------------

    \10\ Estimates of affected SKUs are 18,000 by FDA and 20,000 to 
25,000 by industry consultant. This number of SKUs includes products 
marketed by manufacturers, repackers, relabelers, and distributors.
---------------------------------------------------------------------------

    ERG visited five stores--two major chain drug stores and three 
convenience stores--to collect information on the distribution of types 
of OTC acetaminophen and NSAID drug product packaging. Roughly 80 
percent of OTC acetaminophen and NSAID drug products were packaged in 
cartons and 20 percent in containers. To assess the

[[Page 19403]]

increase in label space requirements, ERG purchased 45 affected 
products, with an emphasis on smaller packages.
1. Label Area Changes
    ERG collected and recorded descriptive packaging information on the 
sampled products and measured existing font size, labeling area and 
labeling text on packages, and the area needed for replacement text. 
ERG then calculated the percentage increase in square millimeters 
needed to accommodate the proposed labeling changes. In all cases, ERG 
determined that the requirement to add active ingredient names on the 
PDP, while requiring major redesign in some cases, did not impose a 
change in the size of the PDP or the addition of non-standard labeling 
(such as adding a fifth carton panel or peel back label). ERG estimates 
that the increase in existing label area needed to accommodate the 
additional proposed label warnings and text ranges from 8 percent 
(acetaminophen) to 32 percent (ibuprofen).
2. Package Size or Type Changes
    ERG measured the available panels and white space on the 45 
packages sampled. If the available white space was greater than the 
estimated increase in space necessary to accommodate the new label 
warnings, ERG determined the product would not require an increase in 
carton or container size. Based on this review, ERG assumed that all 
current packaging can accommodate the required changes in this proposal 
without altering label sizes, package sizes, or adding non-standard 
labels. Therefore, ERG did not assign costs for adjustments to 
packaging. Although finding only a few small foil packs that did not 
comply with the OTC Drug Facts labeling requirements, ERG noted that 
alternative types of packaging are now available to replace the older 
packages.
    Table 2 presents the estimated total and annualized costs of 
compliance with the OTC acetaminophen and NSAID drug product final 
rule. The total estimated one-time costs to revise labeling are $32.6 
million. The estimated annualized cost over the relevant relabeling 
period is $15.2 million at a 7 percent discount rate. The estimated 
average annualized cost per SKU is $677 (i.e., $15.2 million for 22,500 
SKUs).

     Table 2--Estimated Total and Annualized Costs (at 7 Percent Discount Rate) of Compliance With This Rule
----------------------------------------------------------------------------------------------------------------
                                                        Dollars (in millions)
                    --------------------------------------------------------------------------------------------
                                                                                               Combinations of
                       Company Type      Acetaminophen     NSAIDs except       Ibuprofen      Acetaminophen and
                                                             Ibuprofen                              NSAIDs
----------------------------------------------------------------------------------------------------------------
Total Costs
----------------------------------------------------------------------------------------------------------------
  Small Brand                     2.2               1.8               0.7              0.1                   4.9
----------------------------------------------------------------------------------------------------------------
  Medium Brand                    2.1               1.8               0.7              0.09                  4.7
----------------------------------------------------------------------------------------------------------------
  Large Brand                     6.0               5.1               2.0              0.3                  13.3
----------------------------------------------------------------------------------------------------------------
  Private Label                   4.4               3.7               1.5              0.2                   9.7
----------------------------------------------------------------------------------------------------------------
  Total                          14.7              12.4               4.9              0.7                  32.6
----------------------------------------------------------------------------------------------------------------
Total Annualized Costs
----------------------------------------------------------------------------------------------------------------
  Small Brand                     1                 0.9               0.3              0.05                  2.7
----------------------------------------------------------------------------------------------------------------
  Medium Brand                    1.0               0.8               0.3              0.04                  2.2
----------------------------------------------------------------------------------------------------------------
  Large Brand                     2.8               2.4               0.9              0.1                   6.2
----------------------------------------------------------------------------------------------------------------
  Private Label                   2.0               1.7               0.7              0.09                  4.5
----------------------------------------------------------------------------------------------------------------
  Total                           6.9               5.8               2.3              0.3                  15.2
----------------------------------------------------------------------------------------------------------------

C. Impact on Affected Sectors

    Manufacturers of OTC drug products are classified in North American 
Industry Classification System (NAICS) 325412, pharmaceutical 
preparation manufacturing. This classification code includes all 
manufacturers of prescription and OTC pharmaceutical preparations, but 
does not include relabelers, repackers, and distributors. The Small 
Business Administration (SBA) defines a small business in this industry 
classification code as one with fewer than 750 employees. In NAICS 
325412, over 90 percent are considered small entities. The affected 
industry is a subset of the OTC pharmaceutical industry. This final 
rule affects an estimated 258 manufacturers of OTC acetaminophen and 
NSAID drug products (200 of which are small businesses).
    Manufacturers often package private label products, although some 
chains package their own brands. SBA considers the following to be 
small: (1) Any pharmacy or drug store with annual sales under $6 
million, and (2) supermarkets and other grocery stores and warehouses 
and superstores with sales under $23 million. Generally, only the 
largest supermarket and drug store chains (263 firms) or superstores (9 
firms) would have their own private label. ERG included only those 
largest retail chains with annual sales of $100 million or more as 
having their own private labels. Thus, we believe that there are no 
small entities in these retail sectors that are affected. Marketers of 
private label OTC drug products are classified as follows:
     NAICS 446110: Pharmacies and drug stores
     NAICS 445110: Supermarkets and other grocery stores
     NAICS 452910: Warehouse clubs and superstores.
Packaging and labeling services that contract with pharmaceutical 
manufacturing firms may also be

[[Page 19404]]

affected, but we assume manufacturers bear the costs of any labeling 
changes. Both the manufacturing and marketing sectors will most likely 
share costs, but the extent is not known. Therefore, this impact 
analysis first assumes that manufacturers absorb all of the labeling 
costs. We then assume that all private labeling costs are absorbed by 
chain stores and calculate impacts.
    To assess the impact on entities in the pharmaceutical-
manufacturing sector (NAICS 325412), ERG adjusted SBA data on firm size 
and revenues to estimate average receipts per firm for the affected 
sector. ERG applied modeling assumptions to estimate the number of 
large and small affected firms. ERG further assumed the distribution of 
all 22,500 affected SKUs is one-third for large firms (producing either 
branded or private label products) and two-thirds for small firms. To 
estimate the share of total compliance costs for each size category, 
ERG distributed the SKUs attributed to small businesses in the same 
proportion as employment. The distribution of SKUs determines the 
distribution of compliance costs by employment size category. Table 3 
summarizes the estimated impacts for pharmaceutical manufacturers, the 
total cost per firm based on $677 per SKU, and the compliance costs as 
a percent of revenues.

       Table 3--Estimated Impacts on Pharmaceutical Preparation Manufacturing Firms by Size (NAICS 325412)
----------------------------------------------------------------------------------------------------------------
                          Average
 Firm Size (Number     Receipts per     Assumed  Number                     Total Firm Cost   Compliance Cost (%
   of Employees)     Firm (Dollars in       of SKUs        SKUs per Firm      (Dollars in        of Receipts)
                         Millions)                                           Thousands)\1\
----------------------------------------------------------------------------------------------------------------
<20                               1.7               841                 9               6.0              0.34%
----------------------------------------------------------------------------------------------------------------
20-99                            12.2             2,591                65              43.8              0.361%
----------------------------------------------------------------------------------------------------------------
100-499                          61.9             5,506               148             100.2              0.162%
----------------------------------------------------------------------------------------------------------------
500-749                         366.8             6,062               225             151.9              0.041%
----------------------------------------------------------------------------------------------------------------
Total small                      29.1            15,000                75              50.8              0.175%
----------------------------------------------------------------------------------------------------------------
>750                            947.8             7,500               130              88.1              0.009%
----------------------------------------------------------------------------------------------------------------
Total                           109.6            22,500                87              59.1              0.054%
----------------------------------------------------------------------------------------------------------------
\1\ Number of SKUs x $677 per SKU.
Source: SBA, 1999 and ERG estimates.

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

D. Alternatives

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

E. Benefits

    Our final rule requirements are intended to enhance consumer 
awareness and knowledge of the active ingredient in OTC acetaminophen 
and NSAID drug products. These new warnings include:
     New label warnings
     Age-specific information
     Advising consumers of potential risks and when to consult 
a doctor
     Prominent display of active ingredients on the PDP
The revised alcohol statements are intended to provide clearer warnings 
to high-risk individuals about product use. The overall intent of these 
requirements is to reduce the liver injury and stomach bleeding 
episodes that occur due to unintentional overdosing with these drugs. 
The requirements are also intended to reduce the incidence of adverse 
health outcomes among high-risk subpopulations consuming proper doses 
of OTC acetaminophen and NSAID drug products (e.g., people with liver 
disease or prone to stomach bleeding).
    To estimate the benefits of this final rule, we developed baseline 
information on the frequency of hospitalizations, emergency room 
visits, and deaths related to unintentional overdosing with OTC 
acetaminophen and NSAID drug products. We used a value of $5 million to 
represent the premature loss of a statistical life in previous analyses 
(66 FR 6137). We quantified the related hospital and emergency room 
costs, estimated related morbidity costs, applied a value of $5 million 
to the premature loss of a statistical life, and

[[Page 19405]]

estimated annual savings if 1 to 3 percent of these adverse events and 
deaths are avoided (71 FR 77314 at 77341).
    We lack evidence to predict with certainty a specific level of 
reduction in adverse events. Nonetheless, we believe that presenting 
consumers with improved label warnings and more prominently displaying 
the active ingredients on the PDP will promote safer use of OTC 
acetaminophen and NSAID drug products. Specifically, prominent display 
of the active ingredients on the PDP would alert consumers to the 
presence of the active ingredients in OTC acetaminophen and NSAID drug 
products and help minimize the risks of unintentional overdosing. The 
revised warnings are intended to assist consumers, including higher 
risk individuals, to use OTC acetaminophen and NSAID drug products more 
safely and lead to at least a modest reduction in unintentional 
overdosing.
    Table 4 summarizes the baseline and estimates of the number of 
avoidable hospitalizations and emergency room visits, the average cost 
per case, and potential savings from events avoided. These data do not 
include reported cases of intentional overdosing. Based on the total 
monetized costs per adverse health outcome and the number of cases 
estimated to be avoided each year (from 1 to 3 percent), the total 
monetized benefits of illness avoided range from $0.6 million to $1.8 
million per year ($592,600 to $1,777,900).

 Table 4--Summary of Annual Monetized Benefits of Illnesses Avoided Associated With This Rule (in 2001 Dollars)
----------------------------------------------------------------------------------------------------------------
                                                                                                   Total Annual
                                                       Total                                         Monetized
                                    Willing to       Monetized      Potentially    Annual Number    Benefits of
 Adverse Health   Hospital Costs   Pay to Avoid      Value of       Preventable      of Cases         Illness
      Event                           Illness         Illness     Baseline Cases  Avoided Due to      Avoided
                                                      Avoided       per Year\1\    This Rule\2\     (Dollars in
                                                                                                    Thousands)
----------------------------------------------------------------------------------------------------------------
Minor drug                  $209            $301            $510           3,380          34-101     $17.2-$51.7
 toxicity or
 emergency room
 visits
----------------------------------------------------------------------------------------------------------------
Acetaminophen             $8,579          $2,000        $,10,579           3,424          34-103  $362.2-$1,086.
 poisoning                                                                                                     8
 episode with
 hospitalization
----------------------------------------------------------------------------------------------------------------
NSAID poisoning           $8,579            $357          $8,936           2,269           23-68   $202.8-$608.3
 episode with
 hospitalization
----------------------------------------------------------------------------------------------------------------
Acute kidney             $22,251   Not Estimated         $22,251               5       0.05-0.15       $1.1-$3.3
 failure with
 hospitalization
----------------------------------------------------------------------------------------------------------------
Acute kidney             $22,251   Not Estimated         $22,251             0.7     0.007-0.021       $0.2-$0.5
 failure with
 dialysis
----------------------------------------------------------------------------------------------------------------
Stomach bleeding         $14,653            $357         $15,010              61         0.6-1.8  ..............
----------------------------------------------------------------------------------------------------------------
Total monetized               NA              NA              NA              NA              NA  $592.6-$1,777.
 benefit of                                                                                                    9
 illness avoided
----------------------------------------------------------------------------------------------------------------
\1\ The number of potentially preventable baseline cases per year is derived from data on emergency department
  and hospital cases of overdosing, poisoning, or other serious adverse outcomes associated with acetaminophen
  and NSAID use, adjusted to estimate only unintentional cases.
\2\ Assumes this final rule would reduce annual adverse event cases by 1 to 3 percent (71 FR 77314 at 77344).

    In addition to estimating the value of preventing adverse drug 
events that result in emergency department or hospitalization, we 
considered the annual number of deaths related to unintentional 
acetaminophen overdoses. We estimate that from 1996 to 1998, an annual 
average of 100 adult deaths were related to unintentional acetaminophen 
overdoses (71 FR 77314 at 77344). We assume this rule would reduce 
deaths by 1 to 3 percent annually. Applying a value of $5 million for 
each death prevented, we estimate the total benefits associated with 
preventing 1 to 3 deaths to be $5 to $15 million annually (in 2001 
dollars).
    If the required improved labeling and warnings reduced serious 
adverse events by 1 to 3 percent each year, the total monetized value 
of preventing illness and death would be $5.6 million to $16.8 million 
per year, respectively. These benefits are presented in 2001 dollars.

Benefit Cost Comparison.

    Industry would incur the one-time costs of the final rule of $32.6 
million in the first year. In 2001, the costs were $32.0 million. 
However, the estimated savings from reduced hospital costs and deaths 
avoided, from $5.6 to $16.8 million, would accrue each year. Over a 10-
year period, the $5.6 to $16.8 million per year in benefits has a 
present value of $41.2 to $126.1 million at a discount rate of 7 
percent, and a present value of $49.1 to $147.4 million at a discount 
rate of 3 percent. Thus, the benefits of this final rule, assuming a 1 
percent reduction in current levels of adverse health outcomes 
associated with the use of OTC acetaminophen and NSAID drug products, 
will more than offset the costs of this rule. Table 5 summarizes the 
estimated benefits and costs of this final rule.

                       Table 5--Summary of Impacts
------------------------------------------------------------------------
                 Benefits/Costs                   Dollars (in Millions)
------------------------------------------------------------------------
Benefits:
 Monetized 1 and 3 percent reduction in  $6-$17
 illnesses and deaths per year
 Present value over 10 years at 7        $41-$126
 percent
 Present value over 10 years at 3        $49-$147
 percent
------------------------------------------------------------------------
Costs:

[[Page 19406]]

 
 One-time label revision, first year     $33
------------------------------------------------------------------------

Break-Even Analysis.

    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 break-even point (i.e., the cost of 
compliance/present value of avoiding one death each year for 10 years). 
This final rule would need to prevent about 1 death each year over 10 
years [0.9 deaths ($32/$37.6 million at a 7 percent discount rate) and 
0.7 deaths ($32/$43.9 million at a 3 percent discount rate)]. 
Alternatively, if no deaths are avoided, the final rule would need to 
prevent about 476 hospitalizations ($32 million/$67,000) each year over 
the 10-year period. This estimate uses the present value of the lowest 
benefit category of poisoning episode with hospitalizations, $8,936 per 
episode over 10 years at a 7 percent discount rate. At a 3 percent 
discount rate, an average of 407 hospitalizations ($32 million/$79,000) 
would need to be avoided annually over the period.
    Although we lack evidence to predict with certainty a specific 
level of reduction in adverse events, if we assume only a 1-percent 
reduction in the illnesses and deaths analyzed, the benefits of this 
final rule outweigh the costs. We find that this final rule will 
enhance public health and promote the safer use of OTC acetaminophen 
and NSAID drug products.
    This economic analysis, together with other relevant sections of 
this document, serves as our final regulatory flexibility analysis, as 
required under the Regulatory Flexibility Act. We did not receive any 
submissions regarding the economic analysis in the 2006 PR.

VII. Paperwork Reduction Act of 1995

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

VIII. Environmental Impact

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

IX. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. We provided the States with an 
opportunity for appropriate participation in this rulemaking when we 
sought input from all stakeholders through publication of the proposed 
rule in the Federal Register of December 26, 2006 (71 FR 77314).
    On December 27, 2006, FDA's Division of Federal and State Relations 
provided notice via email transmission of a letter to elected officials 
of State governments and their representatives. The letter advised the 
States of the publication of the proposed rule and stated that when 
published as a final rule, this regulation would preempt State law in 
accordance with section 751 of the Federal Food, Drug, and Cosmetic Act 
(the act) (21 U.S.C. 379r(a)). The letter encouraged State and local 
governments to review the proposed rule and to provide any comments to 
the docket (Docket No. 1977N-0094L) by May 25, 2007, or to contact 
certain named individuals. FDA did not receive any comments in response 
to this notice, or any comments from the States in response to the 
publication of the proposed rule.
    In conclusion, we believe that we have complied with all of the 
applicable requirements under the Executive order and have determined 
that the preemptive effects of this rule are consistent with Executive 
Order 13132.

X. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) under Docket No. 1977N-0094L and may be seen 
by interested persons between 9 a.m. and 4 p.m., Monday through Friday.

    1. Comment No. C7.
    2. Comment No. C3.
    3. Comment No. EMC1.
    4. Comment No. EREG4.
    5. Comment No. C6.
    6. Letter from Charles Ganley, FDA, to NSAID NDA Holders, July 
2005.
    7. Comment No. EC1.
    8. Comment No. EC2.
    9. Comment No. EREG1.
    10. Comment No. C5.
    11. Comment No. EC4.
    12. Comment No. C8.
    13. Bower, W. A. et al., ``Population-Based Surveillance for 
Acute Liver Failure,'' 8th Ed., 102:2459-63, 2007.
    14. Watkins, P. B. et al., ``Aminotransferase Elevations in 
Healthy Adults Receiving 4 Grams of Acetaminophen Daily: a 
Randomized Controlled Trial,'' Journal of the American Medical 
Association, 296:87-93, 2006.
    15. Larson, A. M. et al., ``Acetaminophen-Induced Acute Liver 
Failure: Results of a United States Multicenter, Prospective 
Study,'' Hepatology, 42:1364-1372, 2005.
    16. Johnston, S. C. and L. L. Pelletier, ``Enhanced 
Hepatotoxicity of Acetaminophen in the Alcohol Patient,'' Medicine, 
76:185-191, 1977.
    17. Schiodt, F. V. et al., ``Acetaminophen Toxicity in an Urban 
County Hospital,'' New England Journal of Medicine, 337:1112-7, 
1997.
    18. Zimmerman, H. J. and W. C. Maddrey, ``Acetaminophen 
(Paracetamol) Hepatotoxicity with Regular Intake of Alcohol,'' 
Hepatology, 22:767-7773, 1995.
    19. Heard, K. et al., ``A Randomized Trial to Determine the 
Change in Alanine Aminotransferase During 10 Days of Paracetamol 
(Acetaminophen) Administration in Subjects Who Consume Moderate 
Amounts of Alcohol,'' Alimentary Pharmacology & Therapeutics, 
26:283-90, 2007.
    20. Benson, G. D., ``Acetaminophen in Chronic Liver Disease,'' 
Clinical Pharmacology and Therapeutics, 33:95-101, 1983.
    21. Andreasen, P. B. and L. Hutters, ``Paracetamol 
(Acetaminophen) Clearance in Patients with Cirrhosis of the Liver,'' 
Acta Medica Scandinavica Supplement, 124:99-105, 1979.
    22. Green, J. L. et al., ``Hepatic Function in Alcoholics 
Throughout 5 Days of Maximal Therapeutic Dosing of Acetaminophen 
(APAP),'' Clinical Toxicology, 43:683, 2005.
    23. Dargere, S. et al., ``Lack of Toxicity of Acetaminophen in 
Patients with Chronic Hepatitis C: A Randomized Controlled Trial,'' 
Gastroenterology, 118:A947, 2000.
    24. ``Action Plan for Liver Disease Research. A Report of the 
Liver Disease Subcommittee of the Digestive Diseases Interagency 
Coordinating Committee,'' NIH Publication No. 04-5491, 2004.
    25. Hansten, P. and J. Horn, ``Isoniazid (INH) Interactions: 
Acetaminophen (Tylenol)'' in Drug Interactions and Updates, ed., 
Vancouver,WA: Applies Therapeutics, Inc., 231, 1993.
    26. Mah[eacute], I. et al., ``Interaction Between Paracetamol 
and Warfarin in Patients: a Double-blind, Placebo-Controlled, 
Randomized Study,'' Haematologica, 91:1621-7, 2006.
    27. Parra, D., N. P. Beckey, and G. R. Stevens, ``The Effect of 
Acetaminophen on the International Normalized Ratio in Patients 
Stabilized on Warfarin Therapy,'' Pharmacotherapy, 27:675-83, 2007.

[[Page 19407]]

    28. Gebauer, M. G. et al., ``Warfarin and Acetaminophen 
Interaction,'' Pharmacotherapy, 23:109-12, 2003.
    29. Dharmarajan, L. and W. Sajjad, ``Potentially Lethal 
Acetaminophen-Warfarin Interaction in an Older Adult: an Under-
Recognized Phenomenon?,'' Journal of American Medical Directors 
Association, 8:545-7, 2007.
    30. Kotirum, S. et al., ``Utilization Review of Concomitant Use 
of Potentially Interacting Drugs in Thai Patients Using Warfarin 
Therapy,'' Pharmacoepidemiology and Drug Safety, 16:216-22, 2007.
    31. Lehmann, D. E., ``Enzymatic Shunting: Resolving the 
Acetaminophen-Warfarin Controversy,'' Pharmacotherapy, 20:1464, 
2000.
    32. Thijssen, H. H. et al., ``Paracetamol (Acetaminophen) 
Warfarin Interaction: NAPQI, the Toxic Metabolite of Paracetamol, Is 
an Inhibitor of Enzymes in the Vitamin K Cycle,'' Thrombosis and 
Haemostasis, 92:797-802, 2004.
    33. Toes, M. J., A. L. Jones, and L. Prescott, ``Drug 
Interactions with Paracetamol,'' American Journal of Therapeutics, 
12:56-66, 2005.
    34. Ansell, J. et al., ``Managing Oral Anticoagulant Therapy,'' 
Chest, 119:22S-38S, 2001.
    35. Moling, O. et al., ``Severe Hepatotoxicity After Therapeutic 
Doses of Acetaminophen,'' Clinical Therapeutics, 28:755-60, 2006.
    36. Shriner, K. and M. B. Goetz, ``Severe Hepatotoxicity in a 
Patient Receiving Both Acetaminophen and Zidovudine,'' American 
Journal of Medicine, 93:94-6, 1992.
    37. Becker, K. et al., ``Glutathione and Association Antioxidant 
Systems in Protein Energy Malnutrition: Results of a Study in 
Nigeria,'' Free Radical Biology and Medicine, 18:257-263, 1995.
    38. Lauterburg, B. H., ``Analgesics and Glutathione,'' American 
Journal of Therapeutics, 9:225-33, 2002.
    39. Zenger, F. et al., ``Decreased Glutathione in Patients with 
Anorexia Nervosa. Risk Factor for Toxic Liver Injury?,'' European 
Journal of Clinical Nutrition, 58:238-43, 2004.
    40. Schenker, S. et al., ``The Effects of Food Restriction in 
Man on Hepatic Metabolism of Acetaminophen,'' Clinical Nutrition, 
20:145-50, 2001.
    41. Whitcomb, D. C., D. Geoffery, and G. D. Block, ``Association 
of Acetaminophen Hepatotoxicity with Fasting and Ethanol Use,'' 
Journal of the American Medical Association, 272:1845-1850, 1994.
    42. Kurtovic, J. and S. M. Riordan, ``Paracetamol-Induced 
Hepatotoxicity at Recommended Dosage,'' Journal of Internal 
Medicine, 253:240-243, 2003.
    43. Schmid, R., ``Gilbert's Syndrome--A Legitimate Genetic 
Anomaly?,'' New England Journal of Medicine, 333:1117-8, 1995.
    44. Bosma, P. J. et al., ``The Genetic Basis of the Reduced 
Expression of Bilirubin UDP-Glucuronosyltransferase 1 in Gilbert's 
Syndrome,'' New England Journal of Medicine, 333:1171-5, 1995.
    45. Gelotte, C. K. et al., ``Disposition of Acetaminophen at 4, 
6, and 8 g/day For 3 Days in Healthy Young Adults,'' Clinical 
Pharmacology and Therapeutics, 81:840-8, 2007.
    46. de Morais, S. M., J. P. Uetrecht, and P. G. Wells, 
``Decreased Glucuronidation and Increased Bioactivation of 
Acetaminophen in Gilbert's Syndrome,'' Gastroenterology, 102:577-
586, 1992.
    47. Esteban, A. and M. P[eacute]rez-Mateo, ``Heterogeneity of 
Paracetamol Metabolism in Gilbert's Syndrome,'' European Journal of 
Drug Metabolism and Pharmacokinetics, 24:9-13, 1999.
    48. Ullrich, D. et al., ``Normal Pathways for Glucuronidation, 
Sulphation and Oxidation of Paracetamol in Gilbert's Syndrome,'' 
European Journal of Clinical Investigation, 17:237-240, 1987.
    49. Comment No. C1.
    50. Cl[agrave]ria, J. et al., ``Effects of Celecoxib and 
Naproxen on Renal Function in Nonazotemic Patients with Cirrhosis 
and Ascites,'' Hepatology, 41:579-87, 2005.
    51. Arroyo, V. et al., ``Sympathetic Nervous Activity, Renin-
Angiotensin System and Renal Excretion of Prostaglandin E2 in 
Cirrhosis. Relationship to Functional Renal Failure and Sodium and 
Water Excretion,'' European Journal of Clinical Investigation, 
13:271-8, 1983.
    52. ACP Medicine A Publican of the American College of 
Physicians, WebMD, 2005.
    53. Goldfrank's Toxicologic Emergencies, 8th Ed., McGraw-Hill, 
2006.
    54. Pharmacotherapeutics: A Primary Care Clinical Guide, 2nd 
Ed., Pearson Prentice Hall, Upper Saddle River, NJ, 2005.
    55. Comment No. C4.
    56. Eastern Research Group, Inc. ``Cost Benefit Analysis of 
Proposed FDA Rule on Over-the-Counter Internal Analgesic, 
Antipyretic, and Antirheumatic Drug Products; Required Warnings,'' 
Final Report, October 6, 2004, with Addendum, July 30, 2007.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
201 is amended as follows:

PART 201--LABELING

0
1. The authority citation for 21 CFR part 201 continues to read as 
follows:

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

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


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

* * * * *
    (c) * * *
    (5) * * *
    (ii) * * *
    (E) Liver warning set forth in Sec.  201.326(a)(1)(iii) and/or 
stomach bleeding warning set forth in Sec.  201.326(a)(2)(iii). The 
liver warning shall follow the subheading ``Liver warning:'' and the 
stomach bleeding warning shall follow the subheading ``Stomach bleeding 
warning:''
* * * * *


Sec.  201.322   [Removed]

0
3. Remove Sec.  201.322.

0
4. Section 201.326 is added to subpart G to read as follows:


Sec.  201.326   Over-the-counter drug products containing internal 
analgesic/antipyretic active ingredients; required warnings and other 
labeling.

    (a) Labeling. The labeling for all over-the-counter (OTC) drug 
products containing any internal analgesic/antipyretic active 
ingredients (including, but not limited to, acetaminophen, aspirin, 
carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, 
magnesium salicylate, naproxen sodium, and sodium salicylate) alone or 
in combination must bear the following labeling in accordance with 
Sec. Sec.  201.60, 201.61, and 201.66.
    (1) Acetaminophen.
    (i) Statement of identity. The statement of identity appears in 
accord with Sec. Sec.  201.61 and 299.4 of this chapter. The ingredient 
name ``acetaminophen'' must appear highlighted (e.g., fluorescent or 
color contrast) or in bold type, be in lines generally parallel to the 
base on which the package rests as it is designed to be displayed, and 
be in one of the following sizes, whichever is greater:
    (A) At least one-quarter as large as the size of the most prominent 
printed matter on the principal display panel (PDP), or
    (B) At least as large as the size of the ``Drug Facts'' title, as 
required in Sec.  201.66(d)(2). The presence of acetaminophen must 
appear as part of the established name of the drug, as defined in Sec.  
299.4 of this chapter. Combination products containing acetaminophen 
and a nonanalgesic ingredient(s) (e.g., cough-cold) must include the 
name ``acetaminophen'' and the name(s) of the other active 
ingredient(s) in the product on the PDP in accord with this paragraph. 
Only the name ``acetaminophen'' must appear highlighted or in bold 
type, and in a prominent print size, as described in this paragraph.
    (ii) Active Ingredient and Purpose Headings. The information 
required under Sec.  201.66(c)(2) and (c)(3) of this chapter must be 
included under these

[[Page 19408]]

headings. The information under these headings, but not the headings, 
may appear highlighted.
    (iii) For products labeled for adults only. The labeling of the 
product states the following warnings under the heading ``Warnings'':
    (A) ``Liver warning [heading in bold type]: This product contains 
acetaminophen. Severe liver damage may occur if you take [bullet] more 
than [insert maximum number of daily dosage units] in 24 hours, which 
is the maximum daily amount [bullet] with other drugs containing 
acetaminophen [bullet] 3 or more alcoholic drinks every day while using 
this product''. This ``Liver warning'' must be the first warning under 
the ``Warnings'' heading. For products that contain both acetaminophen 
and aspirin, this ``Liver warning'' must appear after the ``Reye's 
syndrome'' and ``Allergy alert'' warnings in Sec.  201.66(c)(5)(ii)(A) 
and (c)(5)(ii)(B) and before the ``Stomach bleeding warning'' in 
paragraph (a)(2)(iii)(A) of this section. If there is an outer and 
immediate container of a retail package, this warning must appear on 
both the outer and immediate containers.
    (B) ``Do not use with any other drug containing acetaminophen 
(prescription or nonprescription). If you are not sure whether a drug 
contains acetaminophen, ask a doctor or pharmacist.''
    (C) ``Ask a doctor before use if you have liver disease''.
    (D) ``Ask a doctor or pharmacist before use if you are taking the 
blood thinning drug warfarin'' except on the labeling of combination 
products that contain acetaminophen and NSAID(s).
    (iv) For products labeled only for children under 12 years of age.
    (A) Warnings. The labeling of the product states the following 
warnings under the heading ``Warnings'':
    (1) ``Liver warning [heading in bold type]: This product contains 
acetaminophen. Severe liver damage may occur if your child takes 
[bullet] more than 5 doses in 24 hours, which is the maximum daily 
amount [bullet] with other drugs containing acetaminophen''. This 
``Liver warning'' must be the first warning under the ``Warnings'' 
heading. If there is an outer and immediate container of a retail 
package, this warning must appear on both the outer and immediate 
containers.
    (2) ``Do not use with any other drug containing acetaminophen 
(prescription or nonprescription). If you are not sure whether a drug 
contains acetaminophen, ask a doctor or pharmacist.''
    (3) ``Ask a doctor before use if your child has liver disease''.
    (4) ``Ask a doctor or pharmacist before use if your child is taking 
the blood thinning drug warfarin'' except on the labeling of 
combination products that contain acetaminophen and NSAID(s).
    (B) Directions. The labeling of the product contains the following 
information under the heading ``Directions'': ``this product does not 
contain directions or complete warnings for adult use'' [in bold type].
    (v) For products labeled for adults and children under 12 years of 
age. The labeling of the product states all of the warnings in 
paragraphs (a)(1)(iii)(A), (a)(1)(iii)(B), and (a)(1)(iii)(C) of this 
section with the following modifications:
    (A) The liver warning states ``Liver warning [heading in bold 
type]: This product contains acetaminophen. Severe liver damage may 
occur if [bullet] adult takes more than [insert maximum number of daily 
dosage units] in 24 hours, which is the maximum daily amount [bullet] 
child takes more than 5 doses in 24 hours [bullet] taken with other 
drugs containing acetaminophen [bullet] adult has 3 or more alcoholic 
drinks everyday while using this product.'' If there is an outer and 
immediate container of a retail package, this warning must appear on 
both the outer and immediate containers.
    (B) ``Ask a doctor before use if the user has liver disease.''
    (C) ``Do not use with any other drug containing acetaminophen 
(prescription or nonprescription). If you are not sure whether a drug 
contains acetaminophen, ask a doctor or pharmacist.''
    (D) ``Ask a doctor or pharmacist before use if the user is taking 
the blood thinning drug warfarin'' except on the labeling of 
combination products that contain acetaminophen and NSAID(s).
    (2) Nonsteroidal anti-inflammatory analgesic/antipyretic active 
ingredients--including, but not limited to, aspirin, carbaspirin 
calcium, choline salicylate, ibuprofen, ketoprofen, magnesium 
salicylate, naproxen sodium, and sodium salicylate.
    (i) Statement of identity. The statement of identity appears in 
accord with Sec. Sec.  201.61 and 299.4 of this chapter. The word 
``(NSAID)'' must appear highlighted (e.g., fluorescent or color 
contrast) or in bold type, be in lines generally parallel to the base 
on which the package rests as it is designed to be displayed, and be in 
one of the following sizes, whichever is greater:
    (A) At least one-quarter as large as the size of the most prominent 
printed matter on the PDP, or
    (B) At least as large as the size of the ``Drug Facts'' title, as 
required in Sec.  201.66(d)(2). The word ``(NSAID)'' must appear as 
part of the established name of the drug, as defined in Sec.  299.4 of 
this chapter, or after the general pharmacological (principal intended) 
action of the NSAID ingredient. Combination products containing an 
NSAID and a nonanalgesic ingredient(s) (e.g., cough-cold) must include 
the name of the NSAID ingredient and the word ``(NSAID)'' in accordance 
with this paragraph, and the name(s) of the other active ingredient(s) 
in the product on the PDP. Only the word ``(NSAID)'' needs to appear 
highlighted or in bold type, and in a prominent print size, as 
described in this paragraph.
    (ii) Active Ingredient and Purpose Headings. The information 
required under Sec.  201.66(c)(2) and (c)(3) of this chapter must be 
included under these headings. The active ingredient(s) section of the 
product's labeling, as defined in Sec.  201.66(c)(2), contains the term 
``(NSAID*)'' after the NSAID active ingredient with an asterisk 
statement at the end of the active ingredient(s) section that defines 
the term ``NSAID'' and states ``* nonsteroidal anti-inflammatory 
drug.'' The information under these headings may appear highlighted. 
However, the headings ``Active Ingredient'' and ``Purpose'' may not 
appear highlighted.
    (iii) For products labeled for adults only. The labeling of the 
product states the following warnings under the heading ``Warnings'':
    (A) ``Stomach bleeding warning [heading in bold type]: This product 
contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause 
severe stomach bleeding. The chance is higher if you [bullet] are age 
60 or older [bullet] have had stomach ulcers or bleeding problems 
[bullet] take a blood thinning (anticoagulant) or steroid drug [bullet] 
take other drugs containing prescription or nonprescription NSAIDs 
(aspirin, ibuprofen, naproxen, or others) [bullet] have 3 or more 
alcoholic drinks every day while using this product [bullet] take more 
or for a longer time than directed''. This ``Stomach bleeding warning'' 
must appear after the ``Reye's syndrome'' and ``Allergy alert'' 
warnings in Sec.  201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). For products 
that contain both acetaminophen and aspirin, the acetaminophen ``Liver 
warning'' in paragraph (a)(1)(iii) of this section must appear before 
the ``Stomach bleeding warning'' in this paragraph. If there is

[[Page 19409]]

an outer and immediate container of a retail package, this warning must 
appear on both the outer and immediate containers.
    (B) ``Ask a doctor before use if [bullet] stomach bleeding warning 
applies to you [bullet] you have a history of stomach problems, such as 
heartburn [bullet] you have high blood pressure, heart disease, liver 
cirrhosis, or kidney disease [bullet] you are taking a diuretic''.
    (C) ``Stop use and ask a doctor if [bullet] you experience any of 
the following signs of stomach bleeding:'' [add the following as second 
level of statements: ``[bullet] feel faint [bullet] vomit blood 
[bullet] have bloody or black stools [bullet] have stomach pain that 
does not get better''].
    (iv) For products labeled only for children under 12 years of age.
    (A) Warnings. The labeling of the product states the following 
warnings under the heading ``Warnings'':
    (1) ``Stomach bleeding warning [heading in bold type]: This product 
contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause 
severe stomach bleeding. The chance is higher if your child [bullet] 
has had stomach ulcers or bleeding problems [bullet] takes a blood 
thinning (anticoagulant) or steroid drug [bullet] takes other drugs 
containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, 
naproxen, or others) [bullet] takes more or for a longer time than 
directed''. The ``Stomach bleeding warning'' must appear after the 
``Reye's syndrome'' and ``Allergy alert'' warnings in Sec.  
201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). If there is an outer and 
immediate container of a retail package, this warning must appear on 
both the outer and immediate containers.
    (2) ``Ask a doctor before use if [bullet] stomach bleeding warning 
applies to your child [bullet] child has a history of stomach problems, 
such as heartburn [bullet] child has not been drinking fluids [bullet] 
child has lost a lot of fluid due to vomiting or diarrhea [bullet] 
child has high blood pressure, heart disease, liver cirrhosis, or 
kidney disease [bullet] child is taking a diuretic''.
    (3) ``Stop use and ask a doctor if [bullet] child experiences any 
of the following signs of stomach bleeding:'' [add the following as 
second level of statements: [bullet] feels faint [bullet] vomits blood 
[bullet] has bloody or black stools [bullet] has stomach pain that does 
not get better''].
    (B) Directions. The labeling of the product contains the following 
information under the heading ``Directions'': ``this product does not 
contain directions or complete warnings for adult use'' [in bold type].
    (v) For products labeled for adults and children under 12 years of 
age. The labeling of the product states all of the warnings in 
paragraphs (a)(2)(iii)(A) through (a)(2)(iii)(C) of this section with 
the following modifications:
    (A) The Stomach bleeding warning states ``Stomach bleeding warning 
[heading in bold type]: This product contains a nonsteroidal anti-
inflammatory drug (NSAID), which may cause severe stomach bleeding. The 
chance is higher if the user [bullet] has had stomach ulcers or 
bleeding problems [bullet] takes a blood thinning (anticoagulant) or 
steroid drug [bullet] takes other drugs containing prescription or 
nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) 
[bullet] takes more or for a longer time than directed [bullet] is age 
60 or older [bullet] has 3 or more alcoholic drinks everyday while 
using this product''. The ``Stomach bleeding warning'' must appear 
after the ``Reye's syndrome'' and ``Allergy alert'' warnings in Sec.  
201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). If there is an outer and 
immediate container of a retail package, this warning must appear on 
both the outer and immediate containers.
    (B) The labeling states ``Ask a doctor before use if [bullet] 
stomach bleeding warning applies to user [bullet] user has history of 
stomach problems, such as heartburn [bullet] user has high blood 
pressure, heart disease, liver cirrhosis, or kidney disease [bullet] 
user takes a diuretic [bullet] user has not been drinking fluids 
[bullet] user has lost a lot of fluid due to vomiting or diarrhea''.
    (C) The labeling states ``Stop use and ask a doctor if [bullet] 
user experiences any of the following signs of stomach bleeding:'' [add 
the following as second level of statements: [bullet] feels faint 
[bullet] vomits blood [bullet] has bloody or black stools [bullet] has 
stomach pain that does not get better''].
    (b) New warnings information statement. The labeling of any drug 
product subject to this section that is initially introduced or 
initially delivered for introduction into interstate commerce before 
the effective date and within 12 months after the effective date of the 
final rule must bear on its PDP, as defined in Sec.  201.60, the 
statement ``See new warnings information.'' This statement must appear 
highlighted (e.g., fluorescent or color contrast) or in bold type, be 
in lines generally parallel to the base on which the package rests as 
it is designed to be displayed, and be in one of the following sizes, 
whichever is greater: (1) At least one-quarter as large as the size of 
the most prominent printed matter on the PDP, or (2) At least as large 
as the size of the ``Drug Facts'' title, as required in Sec.  
201.66(d)(2).
    (c) Requirements to supplement approved application. Holders of 
approved applications for OTC drug products that contain internal 
analgesic/antipyretic active ingredients that are subject to the 
requirements of paragraph (a) of this section must submit supplements 
under Sec.  314.70(c) of this chapter to include the required 
information in the product's labeling. Such labeling may be put into 
use without advance approval of FDA provided it includes at least the 
exact information included in paragraph (a) of this section.

    Dated: April 8, 2009.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E9-9684 Filed 4-28-09; 8:45 am]
BILLING CODE 4160-01-S