Organ-Specific Warnings; Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Final Monograph, 19385-19409 [E9-9684]

Agencies

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

[Federal Register Volume 74, Number 81 (Wednesday, April 29, 2009)]
[Rules and Regulations]
[Pages 19385-19409]
From the Federal Register Online via the Government Printing 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 su