Federal Register / Vol. 74, No. 81 / Wednesday, April 29, 2009 / Rules and Regulations 19385 

Dated: April 24, 2009. 

Matthew S. Borman, 

Acting Assistant Secretary for Export 

Administration. 

[FR Doc. E9–9817 Filed 4–28–09; 8:45 am] 

BILLING CODE 3510–33–P 

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 Overthe-Counter Human Use; Final 

Monograph 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final rule. 

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 antiinflammatory 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 SubPopulations 

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-benzoquinone 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 antiinflammatory 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 


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• 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 postmarketing drug adverse event reports 


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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 acetaminophen or an NSAID plus a non-analgesic ingredient • All ingredient names (e.g., ‘‘Acetaminophen’’ or ‘‘Aspirin’’) highlighted or in bold type and in 

a prominent print 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 


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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 


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1The 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 

Continued 

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 only1, and (3) one for 


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than 5 doses in 24 hours [bullet] with other drugs 

containing acetaminophen.’’ 

2The 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.’’ 

products labeled for adults and children 

under 12 years of age2. The proposed 

warning for adults reads as follows: 

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 populationbased 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 acetaminophenrelated 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 


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3For 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.’’ 

4For 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.’’ 

5For 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.’’ 

6Products 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.’’ 

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 

age3, and one for adults and children 

under 12 years of age4. The modified 

liver warning language proposed in the 

submission for adults reads as follows: 

‘‘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 adults5,6 to read: • 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. 


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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 acetaminophenrelated 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, doubleblinded, randomized, placebocontrolled 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 


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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 acetaminopheninduced 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 acetaminophencontaining 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 


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7The warning for products labeled for children 

under 12 years of age reads: ‘‘Ask a doctor before 

use if the child has liver disease’’. 8The warning for products labeled for adults and 

children reads: ‘‘Ask a doctor before use if the user 

has liver disease.’’ 

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 age7 and for products labeled 

for adults and children8. 

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 crossover 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 


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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 drugdrug 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 warfarincontaining 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 


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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, placebocontrolled, 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, placebocontrolled 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 HIVinfected 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 


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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 Nacetylcysteine, 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 HIVinfected individuals after Nacetylcysteine treatment lead to 

improved survival. 

Although many of the studies did not 

demonstrate clinically meaningful 

effects of low GSH levels in HIVinfected 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 HIVinfected 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 acetaminopheninduced liver injury than uninfected 

individuals based on these reports. In 

the first report, a 45 year old HIVinfected 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 HIVinfected 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 


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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 HIVinfected 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 acetaminopheninduced 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. 


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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 


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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. 


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9Per the Office of Management and Budget 

(OMB) Circular A4, revised in 2003. 

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 onetime 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. 

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 


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10Estimates 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. 

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 

§ 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. 

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 


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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) 

Company Type Acetaminophen NSAIDs except 

Ibuprofen Ibuprofen 

Combinations of 

Acetaminophen and 

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 


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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) 

Firm Size (Number of Employees) 

Average 

Receipts per 

Firm (Dollars in 

Millions) 

Assumed 

Number of SKUs SKUs per Firm 

Total Firm Cost 

(Dollars in 

Thousands)1

Compliance Cost (% 

of Receipts) 

<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 

§ 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 highrisk 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 


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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) 

Adverse Health Event Hospital Costs 

Willing to 

Pay to Avoid 

Illness 

Total 

Monetized 

Value of Illness 

Avoided 

Potentially 

Preventable 

Baseline 

Cases per 

Year1

Annual Number of Cases 

Avoided Due 

to This Rule2

Total Annual 

Monetized 

Benefits of Illness Avoided 

(Dollars in 

Thousands) 

Minor drug toxicity or emergency room 

visits $209 $301 $510 3,380 34–101 $17.2–$51.7 

Acetaminophen poisoning episode with 

hospitalization $8,579 $2,000 $,10,579 3,424 34–103 $362.2– 

$1,086.8 

NSAID poisoning episode with hospitalization $8,579 $357 $8,936 2,269 23–68 $202.8–$608.3 

Acute kidney failure with hospitalization $22,251 Not Estimated $22,251 5 0.05–0.15 $1.1–$3.3 

Acute kidney failure with dialysis $22,251 Not Estimated $22,251 0.7 0.007–0.021 $0.2–$0.5 

Stomach bleeding $14,653 $357 $15,010 61 0.6–1.8 

Total monetized benefit of illness avoided NA NA NA NA NA $592.6– 

$1,777.9 

1The 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. 2Assumes this final rule would reduce annual adverse event cases by 1 to 3 percent (71 FR 77314 at 77344). 

2Assumes 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 illnesses and deaths 

per year 

$6–$17 

• Present value over 10 years at 

7 percent 

$41–$126 

• Present value over 10 years at 

3 percent 

$49–$147 

Costs: 


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TABLE 5—SUMMARY OF IMPACTS— 

Continued 

Benefits/Costs Dollars (in 

Millions) 

• 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., ‘‘AcetaminophenInduced 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. Mahe ́, 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. 


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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 UnderRecognized 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 UDPGlucuronosyltransferase 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. Pe ́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. Cla`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. 

■ 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 

■ 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. 

■ 2. Section 201.66 is amended by 

revising paragraph (c)(5)(ii)(E) to read as 

follows: 

§ 201.66 Format and content requirements 

for over-the-counter (OTC) drug product 

labeling. 

* * * * * 

(c) * * * 

(5) * * * 

(ii) * * * 

(E) Liver warning set forth in 

§ 201.326(a)(1)(iii) and/or stomach 

bleeding warning set forth in 

§ 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:’’ 

* * * * * 

§ 201.322 [Removed] 

■ 3. Remove § 201.322. 

■ 4. Section 201.326 is added to subpart 

G to read as follows: 

§ 201.326 Over-the-counter drug products 

containing internal analgesic/antipyretic 

active ingredients; required warnings and 

other labeling. 

(a) Labeling. The labeling for all overthe-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 §§ 201.60, 201.61, and 

201.66. 

(1) Acetaminophen. 

(i) Statement of identity. The 

statement of identity appears in accord 

with §§ 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 

§ 201.66(d)(2). The presence of 

acetaminophen must appear as part of 

the established name of the drug, as 

defined in § 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 § 201.66(c)(2) and (c)(3) of this 

chapter must be included under these 


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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 § 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 §§ 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 

§ 201.66(d)(2). The word ‘‘(NSAID)’’ 

must appear as part of the established 

name of the drug, as defined in § 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 § 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 § 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 antiinflammatory 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 antiinflammatory 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 § 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 


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Federal Register / Vol. 74, No. 81 / Wednesday, April 29, 2009 / Rules and Regulations 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 antiinflammatory 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 § 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 antiinflammatory 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 

§ 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 § 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 

§ 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 § 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 

DEPARTMENT OF THE TREASURY 

Alcohol and Tobacco Tax and Trade 

Bureau 

27 CFR Part 9 

[TTB Docket No. 2008–0006; T.D. TTB–76; 

Re: Notice No. 87] 

RIN 1513–AB42 

Establishment of the Lake Chelan 

Viticultural Area (2007R–103P) 

AGENCY: Alcohol and Tobacco Tax and 

Trade Bureau, Treasury. 

ACTION: Final rule; Treasury decision. 

SUMMARY: This Treasury decision 

establishes the 24,040-acre ‘‘Lake 

Chelan’’ American viticultural area in 

Chelan County, Washington. It lies 

within the larger Columbia Valley 

viticultural area in north-central 

Washington. We designate viticultural 

areas to allow vintners to better describe 

the origin of their wines and to allow 

consumers to better identify wines they 

may purchase. 

DATES: Effective Date: May 29, 2009. 

FOR FURTHER INFORMATION CONTACT: 

Christopher Thiemann, Regulations and 

Rulings Division, Alcohol and Tobacco 

Tax and Trade Bureau, 1310 G Street, 

NW., Room 200E, Washington, DC 

20220; phone 202–927–8210. 

SUPPLEMENTARY INFORMATION: 


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