Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules 61041

Reduction Act of 1995 (44 U.S.C. 3501

et seq.).

List of Subjects in 9 CFR Part 94

Animal diseases, Imports, Livestock,

Meat and meat products, Milk, Poultry

and poultry products, Reporting and

recordkeeping requirements.

Accordingly, 9 CFR part 94 would be

amended as follows:

PART 94—RINDERPEST, FOOT-ANDMOUTH DISEASE, FOWL PEST (FOWL

PLAGUE), EXOTIC NEWCASTLE

DISEASE, AFRICAN SWINE FEVER,

HOG CHOLERA, AND BOVINE

SPONGIFORM ENCEPHALOPATHY:

PROHIBITED AND RESTRICTED

IMPORTATIONS

1. The authority citation for part 94

would continue to read as follows:

Authority: 7 U.S.C. 147a, 150ee, 161, 162,

and 450; 19 U.S.C. 1306; 21 U.S.C. 111, 114a,

134a, 134b, 134c, 134f, 136, and 136a; 31

U.S.C. 9701; 42 U.S.C. 4331 and 4332; 7 CFR

2.22, 2.80, and 371.2(d).

2. Section 94.1 would be amended as

follows:

a. In paragraph (a)(1), the words ‘‘or

(a)(3)’’ would be added immediately

after the words ‘‘paragraph (a)(2)’’.

b. In paragraph (a)(2), the word

‘‘Luxembourg,’’ would be added

immediately after the word ‘‘Japan,’’

and the word ‘‘Portugal,’’ would be

added immediately after the word

‘‘Poland,’’;

c. A new paragraph (a)(3) would be

added to read as set forth below.

d. In the introductory text of

paragraph (c), the words ‘‘paragraph (a)

of’’ would be removed and the words

‘‘paragraph (a)(2) of’’ would be added in

their place.

§ 94.1 Regions where rinderpest or footand-mouth disease exists; importations

prohibited.

(a) * * *

(3) The following regions are declared

to be free of rinderpest: Greece.

* * * * *

§ 94.3 [Amended]

3. Section 94.3 would be amended by

adding the words ‘‘where rinderpest or

foot-and-mouth disease exists, as’’

immediately before the word

‘‘designated’’.

§ 94.4 [Amended]

4. In § 94.4(a), the introductory text of

the paragraph would be amended by

adding the words ‘‘where rinderpest or

foot-and-mouth disease exists, as’’

immediately before the word

‘‘designated’’.

§ 94.6 [Amended]

5. In § 94.6, paragraph (a)(2) would be

amended by adding the words ‘‘France,

Greece,’’ immediately after the word

‘‘Finland,’’; by adding the word

‘‘Luxembourg,’’ immediately after the

word ‘‘Iceland,’’; and by adding the

word ‘‘Spain,’’ immediately after the

words ‘‘Republic of Ireland,’’.

§ 94.8 [Amended]

6. In § 94.8, the introductory text of

the section would be amended by

removing the words ‘‘Malta, and

Portugal’’ and adding in their place the

words ‘‘and Malta’’.

§ 94.11 [Amended]

7. In § 94.11, paragraph (a), the first

sentence would be amended by adding

the word ‘‘Luxembourg,’’ immediately

after the word ‘‘Japan,’’; by adding the

word ‘‘Portugal,’’ immediately after the

word ‘‘Poland,’’; and by removing the

reference ‘‘§ 94.1’’ and adding the

reference ‘‘§ 94.1(a)(2)’’ in its place.

§ 94.12 [Amended]

8. In § 94.12, paragraph (a) would be

amended by adding the word

‘‘Belgium,’’ immediately after the words

‘‘The Bahamas,’’; by adding the word

‘‘France,’’ immediately after the word

‘‘Finland,’’; and by adding the word

‘‘Portugal,’’ immediately after the word

‘‘Panama,’’.

§ 94.13 [Amended]

9. In § 94.13, the introductory text of

the section would be amended by

adding the word ‘‘Belgium,’’

immediately after the words ‘‘The

Bahamas,’’; by adding the word

‘‘France,’’ immediately after the word

‘‘Denmark,’’; and by adding the word

‘‘Portugal,’’ immediately after the words

‘‘Northern Ireland,’’.

Done in Washington, DC, this 12th day of

November 1997.

Terry L. Medley,

Administrator, Animal and Plant Health

Inspection Service.

[FR Doc. 97–30105 Filed 11–13–97; 8:45 am]

BILLING CODE 3410–34–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 77N–094W]

RIN 0910–AA01

Over the-Counter Drug Products

Containing Analgesic/Antipyretic

Active Ingredients for Internal Use;

Required Alcohol Warning

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice of proposed rulemaking.

SUMMARY: The Food and Drug

Administration (FDA) is issuing a notice

of proposed rulemaking that would

establish alcohol warnings for all overthe-counter (OTC) drug products

containing internal analgesic/antipyretic

active ingredients labeled for adult use.

The proposed warning statements

advise consumers who have a history of

heavy alcohol use or abuse to consult a

physician for advice about the use of

OTC internal analgesic/antipyretic drug

products. A warning would be required

for all OTC internal analgesic/

antipyretic drug products marketed

under an OTC drug monograph or an

approved new drug application (NDA).

FDA is issuing this notice of proposed

rulemaking after considering the reports

and recommendations of its

Nonprescription Drugs Advisory

Committee (NDAC) and Arthritis Drugs

Advisory Committee (ADAC), public

comments on the proposed rule for OTC

internal analgesic, antipyretic, and

antirheumatic drug products, and other

available information.

DATES: Written comments by January 28,

1998. Written comments on the agency’s

economic impact determination by

January 28, 1998. The agency is

proposing that any final rule based on

this proposal be effective 6 months after

the date of its publication in the Federal

Register.

ADDRESSES: Written comments to the

Dockets Management Branch (HFA–

305), Food and Drug Administration,

12420 Parklawn Dr., rm. 1–23,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:

Debbie L. Lumpkins, Center for Drug

Evaluation and Research (HFD–560),

Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857,

301–827–2241.

SUPPLEMENTARY INFORMATION:
61042 Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules

I. Background

In the Federal Register of July 8, 1977

(42 FR 35346), FDA published, under

§ 330.10(a)(6) (21 CFR 330.10(a)(6)), an

advance notice of proposed rulemaking

to establish a monograph for OTC

internal analgesic, antipyretic, and

antirheumatic drug products, together

with the recommendations of the

Advisory Review Panel on OTC Internal

Analgesic and Antirheumatic Drug

Products (the Panel), which was the

panel responsible for evaluating data on

the active ingredients in these drug

products. In that notice, the Panel

discussed the effects of alcohol

ingestion on the safe use of OTC

internal analgesic, antipyretic, and

antirheumatic drug products containing

aspirin and acetaminophen (42 FR

35346 at 35395).

Based on the data evaluated, the Panel

found evidence of a possible synergism

between alcohol and aspirin’s ability to

cause gastrointestinal (GI) bleeding (42

FR 35346 at 35395). The Panel stated

that the data supported the hypothesis

that aspirin may enhance or potentiate

bleeding from GI lesions, even though

aspirin alone may not initiate the lesion.

However, the Panel stopped short of

recommending a warning concerning

the use of aspirin with alcohol.

The Panel did not receive data on the

effect of alcohol use with other

salicylates. However, based on its

evaluation of the available data, the

Panel concluded that carbaspirin

calcium, choline salicylate, magnesium

salicylate, and sodium salicylate all

have safety profiles similar to aspirin

and should bear similar labeling (42 FR

35346 at 35417 through 35422).

In evaluating the safety of

acetaminophen (42 FR 35346 at 35413

to 35415), the Panel considered data on

the metabolism of acetaminophen in the

presence of various types of liver

disease, including alcoholic liver

cirrhosis. The Panel determined that the

decreased metabolism of acetaminophen

by the usual principal mechanisms

(glucuronidation and sulfation)

observed in some people with chronic

liver disease could potentially increase

the toxicity of acetaminophen by

increasing the relative fraction

metabolized through the other

pathway(s) leading to the toxic

metabolite. The Panel found that the

evidence suggested that the overall

elimination of acetaminophen by

conjugation is decreased in alcohol

abusers and is similar to that observed

in cases of decreased liver function. The

Panel suggested, however, that this

decreased conjugation and the increased

susceptibility of chronic alcohol abusers

to the hepatotoxicity of acetaminophen

was not necessarily due to liver

cirrhosis but resulted from the

induction of microsomal enzymes by

the chronic use of alcohol. However, the

Panel did not recommend a warning

concerning the use of normal doses of

acetaminophen by individuals with a

history of liver disease or chronic

alcohol abuse. The Panel’s

recommended label warning on liver

damage referred only to the welldocumented injury that can occur with

overdose. The Panel recommended the

following warning: ‘‘Do not exceed

recommended dosage because severe

liver damage may occur.’’

In the Federal Register of November

16, 1988 (53 FR 46204), the agency

published a proposed rule (tentative

final monograph) for OTC internal

analgesic, antipyretic, and

antirheumatic drug products. In the

preamble to the proposed rule, the

agency responded to a number of

comments concerning the Panel’s

recommended liver warning for

acetaminophen and the need for a

warning on the increased risk of liver

toxicity when acetaminophen is taken

with substances or drugs that induce

microsomal enzyme activity, i.e.,

alcohol, barbiturates, or prescription

drugs for epilepsy (53 FR 46204 at

46213 through 46218). The agency

found that the available data did not

provide a sufficient basis to require such

a warning.

The agency also received a number of

comments opposed to warnings that cite

organs of the body as possible cites for

damage from acute overdoses of internal

analgesic/antipyretic drug products. The

agency agreed with the comments and

determined that warnings for

acetaminophen need not specify the

toxic effects on particular organs of the

body that can be caused by acute

overdose of a drug, as in a suicide

attempt. However, the agency further

stated (53 FR 46204 at 46213):

* * * the warnings should include specific

information on the known side effects or

adverse reactions that may occur from use of

the drug according to labeled directions, as

well as potential dangers that may occur if

the labeled directions are exceeded.

The agency concludes that when medical

evidence shows that toxicity is associated

with the use of an OTC drug, either within

its recommended dosage or when used

beyond its recommended time limit or

dosage (except for acute overdose), it is

appropriate to warn consumers of the

potential toxicity. In some cases it may be

necessary to include organ-specific warnings

as well as general labeling statements.

The agency received no comments

concerning the Panel’s comments about

a possible synergism between alcohol

and aspirin’s ability to cause GI

bleeding or the lack of a reference to

such effect in labeling.

II. Summary of the Comments Received

In response to the proposed rule, the

agency received comments concerning

the need for an alcohol warning for

acetaminophen. One comment

recommended that the labeling of OTC

drug products containing

acetaminophen include the following

warning: ‘‘Do not drink alcoholic

beverages while taking acetaminophen.

To do so may increase the chance of

liver damage, especially if you drink

large amounts of alcoholic beverages

regularly.’’ Citing 75 incidences of liver

damage in alcohol abusers who

consumed acetaminophen for

therapeutic reasons (Refs. 1 through 27),

the comment asserted that the reports

strongly suggest that alcohol abuse

potentiates acetaminophen’s liver

toxicity.

The comment stated that the clinical

observation of increased liver toxicity of

acetaminophen in alcohol abusers has

been confirmed by experimental data in

animals and humans (Refs. 22 and 28

through 46). In the comment’s view,

these experimental data demonstrate

that: (1) Alcohol has a significant effect

on acetaminophen metabolism; (2)

chronic alcohol ingestion has been

shown to induce microsomal enzymes,

thereby increasing the formation of the

toxic intermediate metabolite of

acetaminophen, known as N-acetyl-pbenzoquinoneimine (NAPQI); and (3)

chronic alcohol ingestion interferes with

the detoxification of NAPQI by

depleting hepatic glutathione (GSH).

Citing information indicating that

alcohol is consumed by two-thirds of

the American population (12 percent of

this population considered to be heavy

drinkers (Ref. 47) and that

acetaminophen is widely available

(present in over 200 OTC drug

products), the comment asserted that

the concurrent use of alcohol and

acetaminophen can be predicted to be

extraordinarily common. The comment

suggested that the use of acetaminophen

with alcohol may be even greater

because heavy promotion stating that

acetaminophen causes less stomach

irritation than aspirin has made it the

preferred OTC internal analgesic/

antipyretic used in the presence of

alcohol-related gastric upset. The

comment asserted that these new data

suggest that alcohol abusers appear to be

at greater risk of hepatotoxicity from the

therapeutic use of acetaminophen.

Accordingly, the comment

recommended that the labeling of these

OTC drug products be strengthened to
Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules 61043

ensure that consumers who abuse

alcohol are not exposed to unnecessary

daily use of acetaminophen. The

comment added that warnings

concerning the use of acetaminophen by

alcohol abusers are included in the

United States Pharmacopeial Dispensing

Information (Refs. 48 and 49).

In addition to its proposed warning,

the comment suggested that the

maximum daily dose of acetaminophen

be reduced from 4 to 2 grams (g) per day

for this segment of the population.

However, the comment did not provide

data to support the reduced maximum

daily dose. The comment recommended

the following revision to the dosing

directions proposed for acetaminophen

in § 343.50(d)(2) (21 CFR 343.50(d)(2))

of the tentative final monograph: ‘‘If you

drink large amounts of alcoholic

beverages regularly, do not exceed 2

grams of acetaminophen (4 to 6 tablets)

a day.’’

The comment subsequently submitted

additional data to support its

recommendations that included the

following: (1) Reports of acetaminophen

hepatotoxicity in alcohol abusers or

associated with Psittacosis (Refs. 50

through 53), (2) a retrospective study of

the effects of chronic alcohol intake on

the prognosis and outcome of

acetaminophen overdose (Ref. 54), and

(3) a study of acetaminophen

metabolism in alcohol abusers (Ref. 55).

Two comments disagreed with the

need for the proposed warning, arguing

that the existing data provide no

rational basis for a warning. Citing its

review of the scientific literature (Ref.

56), one comment questioned the

number of cases of acetaminopheninduced liver toxicity due to the

ingredient’s therapeutic use by alcohol

abusers. The comment stated that the

majority of the reports involved subjects

with a history of alcohol abuse and use

of amounts of acetaminophen far in

excess of the maximum daily

therapeutic dose. The comment

contended that the reliability of the

history of acetaminophen use and the

regularity of dosing included in these

reports was questionable. The comment

cited six additional published articles

(Refs. 57 through 62) containing reports

of acetaminophen-induced liver toxicity

in alcohol abusers and contended that

none of these reports supports an

alcohol warning.

One of the comments disagreed with

the assertion that experimental data in

animals and humans have demonstrated

chronic microsomal induction or

increased NAPQI production in

association with acetaminophen-alcohol

use. The comment cited studies by

Critchley et al. (Refs. 63 and 64) and

Lauterberg and Velez (Ref. 65) in which

no evidence of microsomal induction

was found in heavy drinkers. Moreover,

the comment cited additional studies

(Refs. 66, 67, and 68) that it asserted

demonstrated a reduction of microsomal

enzyme activity in subjects with liver

disease (including alcoholic hepatitis).

The comment noted the results of a

study in mice by Mitchell et al. (Ref. 35)

that demonstrated for covalent binding

or hepatic necrosis to occur GSH levels

need to be reduced to approximately 20

to 30 percent of normal. The comment

asserted that a reduction of such

magnitude is unlikely except in severe

malnutrition. Concerning the cited

animal data, the comment noted that in

the vast majority of studies the amounts

of acetaminophen ingested would

correspond to overdose amounts in

humans.

The comment concluded by stating

that the safety profile of acetaminophen

in alcohol abusers should be evaluated

in the context of their inclination to

develop gastritis, gastroduodenal

ulceration, hepatic cirrhosis,

impairment of coagulation mechanisms,

portal hypertension, and GI hemorrhage.

Citing the fact that doctors frequently

recommend acetaminophen to their

alcohol abusing patients because it does

not cause GI irritation or have platelet

inhibiting effects, the comment asserted

that an alcohol warning for OTC drug

products containing acetaminophen

would be contrary to the public interest.

The comment suggested that such a

warning might encourage individuals

who abuse alcohol to use other OTC

internal analgesic/antipyretic drug

products containing ingredients that

carry a greater risk of injury.

III. The Advisory Committees Meetings

The agency subsequently asked NDAC

for advice on the need for an alcohol

warning for OTC drug products

containing acetaminophen. On June 29,

1993, NDAC met to consider the issue.

The agency provided NDAC the

following data and information: (1) The

history of the agency’s evaluation of the

issue, (2) a summary of issues raised by

comments in response to the tentative

final monograph, (3) published reports

of acetaminophen-induced liver toxicity

in alcohol users at various

acetaminophen doses, (4) data on the

pharmacokinetics of acetaminophen

metabolism in alcohol abusers, (5) data

on microsomal enzyme induction in

subjects with liver disease, (6)

epidemiological data on the effect of

alcohol abuse on acetaminophen

overdose, (7) animal data on the effects

of ethanol on acetaminophen

metabolism, and (8) animal studies of

the effect of diet on glutathione levels.

A copy of this information is on file in

the Dockets Management Branch (Ref.

69). Interested parties were also given

the opportunity to present their

positions.

The agency asked NDAC to consider:

(1) Whether the data supported the need

for an alcohol warning for OTC drug

products containing acetaminophen; (2)

the population at risk in terms of

alcohol consumption, e.g., people who

rarely drink, social drinkers, or alcohol

abusers, and the acetaminophen dose

ingested; (3) any special benefit/risk

considerations concerning the use of an

alcohol warning in the population at

risk, e.g., will alcohol abusers switch to

other OTC internal analgesic/antipyretic

ingredients that have equivalent or

greater risks; (4) the type of information

that should be included in an alcohol

warning, e.g., organ-specific

information, description of alcohol

amount, or other information; (5)

whether the data are sufficient to

support a reduced maximum daily

acetaminophen dose for alcohol abusers;

and (6) if so, what the reduced

maximum daily dose should be.

NDAC concluded that alcohol abusers

or heavy drinkers are at increased risk

for developing liver toxicity when using

acetaminophen. Based on this

conclusion, NDAC recommended that

an alcohol warning informing heavy

alcohol users or abusers of their

increased risk from the use of

acetaminophen be included in the

labeling of such products.

Recommending that the exact wording

of such a warning be developed by the

agency, NDAC advised that the warning

should specifically refer to possible

liver damage. However, NDAC did not

recommend a reduced maximum daily

dose of acetaminophen for alcohol

abusers. NDAC was concerned that an

alcohol warning on OTC drug products

containing acetaminophen in the

absence of a similar warning on

products containing other internal

analgesic/antipyretic ingredients would

cause alcohol abusers to switch to

products containing those other

ingredients, which may have equivalent

or greater risks. Therefore, NDAC

recommended that the agency not

implement an alcohol warning for OTC

drug products containing

acetaminophen until NDAC had a

chance to consider data on the risk of

alcohol use with other internal

analgesic/antipyretic ingredients (Ref.

70).

On September 8, 1993, NDAC and

ADAC (the Committees) met jointly to

consider data on the risk of the use of

aspirin and other OTC analgesics by
61044 Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules

heavy alcohol users or abusers. The

agency provided the Committees the

following data and information: (1)

Published and unpublished

epidemiological data on the risk of

upper GI bleeding associated with the

use of alcohol and aspirin, ibuprofen,

and naproxen sodium; (2) data on the

additive effects of these ingredients and

alcohol on the GI tract; (3) data on the

ability of alcohol to potentiate aspirinprolonged bleeding times; (4) data on

the effect of aspirin on ethanol

pharmacokinetics; and (5) the Panel’s

conclusions on the safety of the OTC

use of acetaminophen, aspirin,

carbaspirin calcium, choline salicylate,

magnesium salicylate, and sodium

salicylate. A copy of this information is

on file in the Dockets Management

Branch (Ref. 71). Interested parties were

also given the opportunity to present

their positions.

The agency asked the Committees to

consider the following in evaluating the

data: (1) Whether the data are sufficient

to support an alcohol warning for OTC

drug products containing aspirin,

ibuprofen, and naproxen sodium; (2)

whether the data are sufficient to

support an alcohol warning for other

salicylates (carbaspirin calcium, choline

salicylate, magnesium salicylate, or

sodium salicylate); (3) the type of

information an alcohol warning should

include, i.e., organ specific information

or statement of risk; and (4) the type of

information that should appear in the

labeling of combination drug products

containing aspirin and acetaminophen.

The Committees concluded that the

use of aspirin, ibuprofen, and naproxen

sodium increases the risk of upper GI

bleeding in heavy alcohol users or

abusers. Concerning whether the data

support an alcohol warning for OTC

drug products containing these

ingredients, the Committees voted 12

yes, 2 no for aspirin; 12 yes, 2 no for

ibuprofen, and 12 yes, 1 no, and 1

abstention for naproxen sodium. The

Committees further concluded that there

are no data to support a warning for

nonaspirin salicylates and, therefore, a

recommendation on the need for an

alcohol warning for these OTC drug

products was outside their advisory

scope. Regarding the type of information

that should be included in an alcohol

warning, the Committees recommended

that the warning not mention a specified

level of alcohol consumption, but were

unable to reach a consensus whether the

warning should be general or organspecific (Ref. 72).

IV. Summary of Comments on the

Committees’ Recommendations

In response to the Committees’

recommendations, the agency received

11 comments. Several comments from a

manufacturers’ association urged the

agency to reject the Committees’

recommendation for an alcohol warning

for OTC aspirin drug products. One

comment suggested that such a warning

may jeopardize the compliance of

individuals on low-dose aspirin

regimens for cardiovascular indications.

Other comments contended that the

recommendation was not supported by

reliable scientific data, but reflected

concerns about unsubstantiated risks

from the use of aspirin by individuals

with a history of alcohol use. These

concerns, the comments asserted, were

based on submissions that included

inaccurate summaries of studies without

raw data and erroneous projections of

morbidity and mortality based on

incorrect assumptions. The comment

suggested that these distortions had a

significant impact on the Committees’

recommendations.

In support of its contentions, the

comment noted: (1) Criticisms of the

available published data made by some

Committee members during

deliberations, and (2) specific comments

made by an agency reviewer concerning

unpublished epidemiological data

presented to the Committees (Ref. 73).

The comment pointed out that most of

the studies were uniformly rejected by

the Committees’ members or the

agency’s reviewer, and thus the meeting

produced no reliable evidence on which

to justify a label warning regulation.

The comments also included critical

assessments of the unpublished

epidemiological data presented to the

Committees: (1) A prospective

observational study (Ref. 74), (2) a

retrospective study of adverse drug

reaction reports (Ref. 75), (3) a study

conducted at the SUNY-Health Science

Center (Ref. 76), (4) a study conducted

at the Sloane Epidemiology Unit (Ref.

77), (5) a study conducted by Strom

(Ref. 78), and (6) a study conducted at

the University of Newcastle (Ref. 79).

The comments contended that, based on

these criticisms, the data from these

studies could not be relied upon to

support the need for an alcohol warning

for OTC aspirin drug products. The

comments asserted that an independent

analysis of the data from two of the

epidemiological studies (Refs. 77 and

79) is necessary to verify the studies’

conclusions and requested that the

agency obtain the raw data from the

studies.

The comments asserted that the

Committees misunderstood the agency’s

proposed warning in § 343.50(c)(1)(v)(B)

that advises against the use of aspirin by

persons that have stomach problems

that persist or recur, or have ulcers, or

bleeding problems, without consulting a

doctor. The comments noted that most

of the data submitted related to upper GI

bleeding by persons with existing GI

disease. The comments advised FDA to

base its decision on the available

scientific data and concluded that those

data do not demonstrate that heavy

alcohol users or abusers, with no

preexisting ulcers or recurrent stomach

or bleeding problems, are at an

increased risk of upper GI bleeding from

the use of OTC aspirin drug products.

In response to the comments’

assertions, the agency received reply

comments from members of the

Committees (Ref. 80). One member

stated that the Committees’ final

decision was based on the information

available and was justified. Another

member contended that if

acetaminophen is to have a warning,

then all OTC internal analgesic/

antipyretic drug products should have a

warning, preferably the same for all

products. A third member expressed

disagreement with the Committees’

recommendation, explaining that a test

of enhanced risk should be an odds ratio

substantially greater than one. The

member further recommended that an

odds ratio of two or greater should be

required, and the difference from one

should be statistically significant.

A number of comments from the

investigators for three of the

unpublished epidemiological studies

presented to the Committees addressed

point by point the criticisms raised

about the studies. These comments

concluded that the data from these

studies support the need for an alcohol

warning. Another comment concluded

that the data from these studies show

that: (1) There is an increased risk of

major upper GI bleeding in aspirin users

that is independent of alcohol use, (2)

there is an increased risk of major upper

GI bleeding in alcohol users that is

independent of aspirin use, and 3)

aspirin further increases this risk in

alcohol users.

V. The Agency’s Tentative Conclusions

on the Committees’ Recommendations

A. Acetaminophen

After considering NDAC’s

recommendations and all available data

and information, the agency has

determined that the data are sufficient

to warrant an alcohol warning for OTC

drug products containing
Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules 61045

acetaminophen. Based on an evaluation

of the scientific literature, the agency

has determined that individuals with a

history of heavy alcohol use or abuse

have an increased risk from the

hepatotoxic effects of acetaminophen. In

order to advise consumers with such a

history to consult a physician for advice

on the use of OTC acetaminophen drug

products, the agency is proposing that

OTC analgesic/antipyretic drug

products containing acetaminophen

bear an alcohol warning.

Acetaminophen is considered a dose

dependent hepatotoxin (Ref. 81). Acute

doses of acetaminophen of 15 g or more

in adults have been associated with

hepatotoxicity (Refs. 81 and 82).

However, the scientific literature from

1966 to the present contains at least 97

reports of hepatotoxicity attributed to

the ingestion of less than 15 g of

acetaminophen (Refs. 1 through 27, 51,

52, 53, 57 through 62, and 83 through

93). With few exceptions, these case

reports describe a clinical and

laboratory picture consistent with

acetaminophen overdose: Nausea,

vomiting, hematemesis (bloody

vomitus), jaundice, markedly elevated

liver enzymes (aspartate

aminotransferase (AST) and alanine

aminotransferase (ALT)), elevated

bilirubin, prolonged prothrombin time,

and liver biopsy results (when obtained)

demonstrating centrilobular necrosis.

Seventy-one of the 97 cases (73

percent) involve a history of heavy

alcohol use or abuse (Refs. 1, 2, 3, 5

through 20, 22 through 26, 52, 53, 57

through 62, 86, 87, and 93). While a

number of these reports lack sufficient

information to permit a detailed

assessment, the long history of the

reports, their diverse countries of origin,

consistent presentation and pattern of

usage suggest that individuals with a

history of heavy alcohol use or abuse are

more susceptible to acetaminophen’s

hepatotoxic effects. Further, a majority

of the 71 cases (41 cases or 58 percent)

are associated with acetaminophen

doses at or below the currently

proposed maximum daily OTC dose (4

g per day) or moderate overdoses of

approximately 6 g (Refs. 7, 12 through

18, 20, 22, 23, 24, 26, 52, 53, 57, 58, 60,

61, 62, 86, 87, and 93).

A number of these cases provide

sufficient detail to suggest

acetaminophen induced hepatotoxicity

in heavy alcohol users or abusers at

acetaminophen doses of 6 g or below.

Bell, Schonsby, and Raknerud (Ref. 57)

reported a 32-year-old male ‘‘periodic

alcoholic’’ (patient 3) who began

drinking after a period of abstinence,

used acetaminophen to treat withdrawal

symptoms, and took 3.4 g

acetaminophen per day for 5 days prior

to hospital admission. On the day of

admission, the patient developed

nausea and hematemesis. Jaundice and

bruising were also observed.

Laboratory tests revealed elevated

liver enzymes (AST 13,420 International

Units/Liter (IU/L) and ALT 7,510 IU/L

(reference AST and ALT 10 to 40 IU/L))

and hyperbilirubinemia (297

micromole/liter (μmole/L) or 17.4

milligrams (mg)/deciliter (dL) (reference

bilirubin 3 to 25 μmole/L or 0.2 to 1.5

mg/dL)). Tests for hepatitis C surface

antigen, hepatitis A and

cytomegalovirus antibody, and

Monospot were negative. The serum

acetaminophen level 2 days after the

last dose was 2.5 micrograms/milliliter

(μg/mL). No liver biopsy was done. Nacetylcysteine (NAC) was not

administered. The patient improved

with supportive treatment and was

discharged. At outpatient followup, 5

weeks after admission, all laboratory

tests were normal.

Bell, Schonsby, and Raknerud (Ref.

57) also reported a 57-year-old woman

(patient 4) with a history of gout who

ingested 40 to 50 g of alcohol a day. For

several years, she had taken 400 mg

acetaminophen and 5 mg prednisone

per day. In response to an increase in

leg pain, she increased her intake to 2.4

to 3.2 g acetaminophen per day for

several days. On the day of hospital

admission, she vomited blood and

developed symptoms compatible with

hepatic encephalopathy (jaundice,

somnolence, and bruising).

Laboratory tests revealed elevated

aminotransferases (AST 16,180 IU/L and

ALT 8,950 IU/L). Bilirubin was 123

μmole/L or 7.2 mg/dL. NAC was not

administered. The patient died the day

following admission with massive

hematemesis and hypotension. Autopsy

revealed abundant blood in the stomach

and intestines but no sign of an ulcer.

Microscopically, a marked centrilobular

liver cell necrosis was seen.

Floren, Thesleff, and Nilsson (Ref. 7)

described hepatotoxicity in a 58-yearold woman (patient 1) who regularly

consumed a bottle of red wine a day.

The patient was hospitalized due to a

slight intoxication. Before admission,

she admitted to ingesting 1 to 1.5 g

acetaminophen, sedatives (oxazepam),

and antidepressants (lorazepam) for an

unspecified period of time. The patient

was transferred from the psychiatric

ward to the medical clinic due to

elevated liver enzymes (AST 14.3

microkatal/L (μkat/L) and ALT 14.0

μkat/L). Reference levels for AST and

ALT were less than 0.7 μkat/L.

At the time of transfer, the

concentration of acetaminophen in

serum was not measurable and NAC

was not administered. Tests for hepatitis

B surface antigen and hepatitis A were

negative. A liver biopsy demonstrated

centrilobular necrosis with normal

portal zones. The biopsy revealed no

evidence of steatosis, fibrosis, or

cirrhosis. The patient recovered

uneventfully.

Licht, Seeff, and Zimmerman (Ref. 20)

reported a 53-year-old man who

ingested 2.6 to 3.9 g acetaminophen

daily for an undisclosed period of time.

He admitted to a 15-year history of

excessive alcohol intake with a recent

intake of 2 quarts of whiskey daily. He

entered the hospital after 3 days of

weakness, abdominal discomfort, and

jaundice.

Laboratory values at the time of

admission indicated markedly elevated

liver enzymes (AST 19,710 milliunits

(mU)/mL) and ALT 4,560 mU/mL), a

bilirubin of 13 mg/dL, and a prolonged

prothrombin time of 22 seconds (control

10 seconds). A serum acetaminophen

level obtained 12 hours after ingestion

was in the nontoxic range (2 μg/mL). A

test for hepatitis B surface antigen was

negative. No liver biopsy was obtained.

NAC was not administered. The patient

recovered.

Luquel et al. (Ref. 60) described a 49-

year-old man who was admitted to the

hospital with confusion, hematemesis,

and decreased urine output. In addition

to increasing his beer intake, he also

took 1.2 g acetaminophen and 25 mg

ethyl loflazepate for 2 days prior to

hospitalization. Laboratory values were

AST 1,870 IU/L, ALT 640 IU/L, total

bilirubin 39 μmole/L or 2.3 mg/dL, and

a prothrombin rate of 75 percent. No

serum acetaminophen was detected, and

NAC was not administered. The results

of a liver biopsy performed on the third

day of hospitalization revealed

centrilobular necrosis. The patient

recovered uneventfully.

Seeff et al. (Ref. 26) reported six cases

of acetaminophen hepatotoxicity in

alcohol abusers. Three cases (patients 2,

3, and 6) involved doses of

approximately 4 g acetaminophen.

Patient 2 was a 30-year-old male chronic

alcohol abuser who ingested 12.5 g

acetaminophen over a 3-day period for

pain related to a dental abscess.

(Assuming that the doses were evenly

distributed over the 3 days, he ingested

approximately 4.2 g acetaminophen per

day.) His laboratory values showed

elevated liver enzymes (AST greater

than 10,000 IU/L and ALT 7,610 IU/L),

a bilirubin of 2.4 mg/dL, and a

prothrombin time 9.3 seconds longer

than control. A test for hepatitis B

surface antigen was negative. Serum

acetaminophen level and liver biopsy
61046 Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules

were not done. The patient was treated

with NAC, improved, and was released

from the hospital.

Patient 3 was a 39-year-old man who

was hospitalized for a submandibular

infection following a fracture. Over a 1-

week period, he had taken

approximately 3.8 g acetaminophen per

day. On admission, his laboratory

values revealed elevated liver enzymes

(AST 5,640 IU/L and ALT 354 IU/L),

bilirubin 16.5 mg/dL, and a

prothrombin time twice the control.

Serum acetaminophen levels were not

determined, nor was a liver biopsy

performed. NAC was not administered.

The patient improved over the next few

weeks and was discharged.

Patient 6 was admitted to the hospital

for acute alcohol withdrawal syndrome.

During the 3 days prior to admission,

she took approximately 3.7 g

acetaminophen a day for headache.

Laboratory values included AST 6,888

IU/L, ALT 2,480 IU/L, total bilirubin 6.6

mg/dL, and a prothrombin time 10

seconds longer than control. Serum

acetaminophen level, liver biopsy, and

viral screening were not performed.

NAC was not administered and with

supportive treatment, the patient

recovered.

Edwards and Oliphant (Ref. 86)

described a 46-year-old man who

presented to the hospital with a 2-hour

history of epigastric pain with

hematemesis. The patient gave a history

of regular alcohol consumption. In the

week prior to admission, he had

consumed two 1,250 mL spirits over the

week and 12 cans of beer daily and

concurrently taken not more than 3 g of

acetaminophen daily for hangover, up to

a total dosage of 18 g. He took an

additional 3 g of acetaminophen 6 hours

prior to his admission to the hospital.

Liver function tests conducted on day

2 of hospitalization showed markedly

abnormal aminotransferases (AST

30,000 IU/L and ALT 9,750 IU/L) and a

bilirubin of 86 μmole/L or 5 mg/dL. At

6 hours post ingestion, the serum

acetaminophen level was 0.04 μg/mL.

On day 2 the level was 0.005 μg/mL.

Hepatitis serology was negative for

hepatitis A, B, and C. No liver biopsy

was performed. NAC was not

administered. The patient’s

convalescence was slow but uneventful.

Johnson, Friedman, and Mitch (Ref.

12) described a 23-year-old female

alcohol abuser who developed acute

hepatitis and renal failure 3 days after

ingesting a bottle of cold medication

containing 6 g acetaminophen in 25

percent alcohol. The patient’s medical

history included a previous hepatitis

infection. Laboratory values at

admission were AST 4,320 IU/L, ALT

1,130 IU/L, total serum bilirubin 10 mg/

dL, and a prothrombin time of 13.1

seconds (control 12 seconds). Serum

acetaminophen was undetectable 6 days

after acetaminophen ingestion. A test for

hepatitis B surface antigen was negative.

Antibodies to hepatitis B surface antigen

were detected. No liver biopsy was

conducted. NAC was not administered.

Hepatic function gradually improved

and the patient was discharged.

Kartsonis, Reddy, and Schiff (Ref. 13)

reported a 39-year-old male alcohol

abuser who developed vague inguinal

discomfort and began self-medicating

with 5 g acetaminophen per day over a

6-day period. He presented to the

hospital with nausea, vomiting, and

abdominal pain. Laboratory tests

revealed elevated aminotransferases

(AST more than 8,270 IU/L and ALT

6,494 IU/L), total bilirubin 4.2 mg/dL,

and an extended prothrombin time of 21

seconds (control 12 seconds).

Acetaminophen was not detectable in

the blood. Neither a liver biopsy nor

viral screening were done. NAC was not

administered. The man had an

uneventful recovery with supportive

care and was discharged from the

hospital after 7 days.

O’Dell, Zetterman, and Burnett (Ref.

24) reported a 38-year-old woman who

took 6 g acetaminophen for 5 days for

stomach pain. She had a history of

chronic pancreatitis and chronic

alcoholism (approximately 200 g

ethanol a day for 10 years). She

presented to the hospital with nausea,

vomiting, and abdominal pain. Liver

enzymes on admission were AST 1,512

IU/L and ALT 554 IU/L. Bilirubin levels

and prothrombin times were normal.

Acetaminophen blood levels were not

determined. A liver biopsy revealed

centrilobular necrosis without signs of

alcoholic hepatitis or centrilobular

fibrosis.

Acetaminophen administration was

discontinued and liver enzymes

returned to normal. The patient was

counseled about acetaminophen and

alcohol toxicity, and discharged.

Subsequently, she was readmitted to the

hospital with abdominal pain of 2

weeks duration for which she had taken

6 g acetaminophen a day.

On admission, her liver enzymes were

AST 5,210 IU/L and ALT 1,580 IU/L,

and total bilirubin was 1.1 mg/dL. A

serum acetaminophen level was not

determined. A second biopsy showed

extensive centrilobular fibrosis.

Alcoholic hyalin and

polymorphonuclear leukocyte

inflammation were not observed. The

periportal regions were normal and

there was no portal fibrosis. The patient

recovered and was discharged from the

hospital.

Seeff et al. (Ref. 26) reported a 58-

year-old male chronic alcohol abuser

hospitalized for alcoholic hepatitis and

cervical neck pain. The patient’s history

included a recent increase in alcohol

consumption and chronic ingestion of 4

to 6 g acetaminophen daily for an

unspecified period of time. On

admission, AST was 2,870 IU/L,

bilirubin was 3.6 mg/dL, and

prothrombin time was 14 seconds

(control 11.3 seconds). ALT was not

reported, and serum acetaminophen

levels were not determined. NAC was

not administered. Laboratory values on

the next day included an AST level of

790 IU/L and an ALT level of 2,300 IU/

L. Serologic tests for hepatitis B were

negative. No liver biopsy was done.

Serum aminotransferases and

prothrombin time returned to normal,

and the patient was discharged 12 days

after admission.

Kumar and Rex (Ref. 52) reported six

cases of hepatotoxicity, four of which

involved acetaminophen doses of 5 to 6

g. Case 2 was a 65-year-old female

alcohol abuser admitted to the hospital

after 1 day of vomiting. Her admitting

AST and ALT levels were 3,199 IU/L

and 1,270 IU/L, respectively. Her total

bilirubin level peaked at 41 μmole/L or

2.4 mg/dL. After 2 days of observation

and improvement, it was discovered

that she had been taking about 6 g/day

acetaminophen for back pain. Serum

acetaminophen level, liver biopsy, and

viral screening were not done. She was

discharged in stable condition with near

normal liver test results.

Case 3 was a 43-year-old woman

admitted to the hospital with a 6-day

history of fatigue, malaise, nausea, and

vomiting. Peak laboratory values

included elevated liver enzymes (AST

14,920 IU/L and ALT 3,304 IU/L), total

bilirubin 126 μmole/L or 7.4 mg/dL, and

a prothrombin time of 46 seconds (no

control reported). No serum

acetaminophen levels, liver biopsy, or

viral screening was performed. Initially,

the woman denied alcohol or

acetaminophen use. However, a friend

subsequently reported that she was a

heavy drinker and had been taking 5 g

acetaminophen daily for an unspecified

period of time. NAC was not

administered, and she was discharged

in stable condition.

Kumar and Rex (Ref. 52) also

described a 55-year-old man (case 4)

with a history of heavy alcohol use who

was hospitalized after 3 to 4 weeks of

nausea and vomiting. On admission,

laboratory values included elevated

liver enzymes (AST 1,240 IU/L and ALT

252 IU/L), total bilirubin 35 μmoles/L,
Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules 61047

and a prothrombin time of 15 seconds

(no control reported). His liver enzyme

levels peaked on day 2 (AST 7,225 IU/

L and ALT 1,280 IU/L). It was later

determined that he had ingested 6 g

acetaminophen daily for an unspecified

period of time for headaches and

arthritic pain. Serum acetaminophen

level, viral screening, and liver biopsy

were not done. The patient was

discharged after 20 days with normal

liver function tests.

Another case reported by Kumar and

Rex (Ref. 52) was a 59-year-old male

alcohol abuser (case 5) who was

admitted to the hospital with dizziness

and orthostatic hypotension. He

reported ingesting 5 g acetaminophen

daily for 1 month for hip pain. Peak

liver test abnormalities were present on

the day of admission (AST 3,000 IU/L,

ALT 290 IU/L, total bilirubin 133

μmole/L, and prothrombin time 19

seconds, no control reported). Serum

acetaminophen levels, liver biopsy, and

viral screening were not done. NAC was

not administered. The patient

subsequently developed sepsis and GI

bleeding and died 2 weeks after

hospitalization.

The agency subsequently received an

additional 19 reports of acetaminophen

liver toxicity (Ref. 94). Fifteen of these

reports involved acetaminophen doses

of less than 6 g daily in individuals with

a history of moderate to heavy alcohol

use. Five of the reports (case numbers 9,

11, 12, 13, and 19) provided sufficient

detail to suggest acetaminopheninduced hepatotoxicity.

Case number 9 was a 45-year-old

woman with a history of alcohol abuse

who, at the time of admission, had a

history of ingesting one to two glasses

of wine daily (only at night). The patient

had a history of acetaminophen use

along with alcohol. For approximately 5

days prior to admission, the patient

reportedly took acetaminophen at the

recommended dose (4 g per day) for flulike symptoms. The patient vomited

(some ‘‘coffee ground’’ emesis) for 5

days prior to admission, and for 2 days

had a progressive deterioration of

mental status. On the night prior to

admission, she became delirious and

was brought to the emergency room.

Laboratory values showed grossly

elevated liver enzymes (AST 15,205 IU/

L and ALT 4,051 IU/L ), a prothrombin

time of 63.7 seconds (no control

reported), and a total bilirubin of 3.8

mg/dL. The serum acetaminophen level

was 12 μg/mL (time after last dose

unknown). No record of hepatitis

screening was provided. During the

hospital stay, an upper endoscopy

showed bleeding secondary to diffuse

gastritis and portal gastropathy. The

patient continued to deteriorate and

died 1 month after hospital admission.

Autopsy findings included diffuse

hepatic necrosis with micro vesicular fat

and bile stasis.

Case number 11 was a 43-year-old

man with a long-standing history of

alcohol abuse (at least 12 cans of beer

daily for 16 years). He developed lower

abdominal pain and fever, followed 2

days later by nausea and vomiting, for

which he took two medications

containing acetaminophen (estimated

dose less than 4 g per day) for at least

1 day. He was admitted to the hospital

2 days later with hypotension and

abnormal liver and renal function.

Laboratory values showed elevated

liver enzymes (AST 5,450 IU/L and ALT

2,251 IU/L) a prothrombin time of 55.9

seconds (no control reported), and a

total bilirubin of 89 μmole/L. The serum

acetaminophen level was 5 μg/mL (time

after last dose unknown). The patient

died 10 days after admission to the

hospital. No record of hepatitis

screening was provided. Post-mortem

findings included centrilobular necrosis

and widespread mucosal hemorrhages

consistent with coagulopathy. The

autopsy report noted that while there

was no evidence of cirrhosis, the

presence of ascites, muscle wasting, and

testicular wasting was consistent with

the effect of chronic liver disease.

Case number 12 was a 41-year-old

man who had taken acetaminophencontaining drugs for 2 days (4 to 5 g/

day) to alleviate the pain of fractured

ribs. He had a history of alcohol abuse

and had recently been drinking 12 beers

a day. He was admitted to the hospital

with complaints of shortness of breath

and left-side chest pain. On

examination, he was found to have

greater than an 80-percent

pneumothorax of the left lung and was

also deeply jaundiced. A blood alcohol

level done at time of admission was

reported as ‘‘0.’’

Laboratory findings included AST

21,900 IU/L, ALT 11,200 IU/L, total

bilirubin 17.8 mg/dL, and a

prothrombin time of 40 seconds (no

control reported). The serum

acetaminophen level was 2.1 μg/mL 4

days after the last acetaminophen

ingestion. The results of screening for

hepatitis A antibody, hepatitis B surface

antigen and antibody, and hepatitis B

core antibody were negative. Screening

for Epstein-Barr surface antigen was also

negative. A liver biopsy showed

fulminant hepatic necrosis with mild to

moderate evidence of alcohol-related

liver disease. A diagnosis of acute toxic

liver failure was made, and the patient

was transferred to a second hospital for

a liver transplant, which was done

within 72 hours of transfer. Following

the transplant, the patient was

discharged in stable condition. Sections

of the removed liver showed extensive

centrilobular necrosis, with up to 50 or

60 percent necrosis in some areas.

Case number 13 was a 62-year-old

man with a history of heavy alcohol use

and severe steroid-dependent chronic

obstructive pulmonary disease. He

subsequently reduced his alcohol intake

to two to four beers a day for several

years. A few days prior to admission, he

developed flu-like symptoms (sore

throat, myalgia, and sleeping difficulty)

for which he took an estimated 4 to 5

g acetaminophen over an 8-hour period.

He became progressively weaker and

fell on the day prior to admission.

On admission, he was found to have

hypotension, weakness, grossly elevated

liver function tests (AST 16,279 IU/L,

ALT 10,942 IU/L, a total bilirubin of 7.8

mg/dL, and a prothrombin time of 55.7

seconds, no control reported). Serum

acetaminophen levels were not

determined. The patient was diagnosed

with acute hepatic failure and died

within 24 hours of admission. A postmortem liver biopsy revealed massive

hepatocellular necrosis.

Case number 19 was a 30-year-old

man with a history of occasional alcohol

use. Four days prior to admission, he

developed malaise and a sore throat and

drank six glasses of wine prior to

retiring for the evening. His symptoms

became progressively worse, and he

took acetaminophen (4 g per day) for 3

to 4 days. On the morning of admission,

he became disoriented, unable to speak,

and agitated.

Admission laboratory data revealed

markedly elevated liver enzymes (AST

13,580 and ALT 11,250 IU/L), a

prothrombin time of 32.4 seconds (no

control reported), and a bilirubin of 7.0

mg/dL. No blood alcohol was detected.

A serum acetaminophen level of 7 μg/

mL was obtained approximately 48

hours after the last acetaminophen dose.

Screening for hepatitis B surface antigen

and core antibody was negative. Tests

for herpes simplex virus were initially

negative but were positive after

transfusions. The patient deteriorated

rapidly and lapsed into a coma. A liver

transplant was done, after which the

patient was initially stable, but

subsequently developed deteriorating

kidney function. The liver pathology

report described extensive centrilobular

hemorrhagic necrosis.

Zimmerman and Maddrey (Ref. 95)

reported 67 additional cases of hepatic

injury in regular alcohol users

associated with the use of

acetaminophen for therapeutic

purposes. The majority of cases
61048 Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules

involved subjects considered to be

alcohol abusers or who reported alcohol

intakes of at least 60 g/day. In 27 of the

cases (40 percent), hepatic injury was

attributed to acetaminophen doses

under 4 g/day. In another 13 cases (19.4

percent), hepatic injury was associated

with acetaminophen doses of 4.1 to 6 g/

day. Unfortunately, specific details of

the individual cases were not provided.

Thus, a definitive assessment of the role

of acetaminophen in the reported liver

injuries is difficult.

Acetaminophen is metabolized

principally by glucuronide and sulphate

conjugation in the liver. When

acetaminophen is taken at therapeutic

doses, glucuronide and sulphate

metabolites account for 80 to 90 percent

of the acetaminophen metabolites in

urine (Ref. 80). Ordinarily, a small

fraction of acetaminophen is

metabolized by microsomal enzyme

cytochrome P450 2E1 to NAPQI (Ref.

96), but if the capacity of the

glucuronidation and sulfation metabolic

pathways is exceeded, as in overdose, or

if the synthesis of P450 2E1 is induced,

increased amounts of NAPQI are

produced.

NAPQI is avidly electrophilic and can

bind to liver cell macromolecules,

disrupt cell function, and ultimately

cause liver cell death. The binding of

NAPQI to liver cell components is

prevented if the compound is detoxified

by conjugation with GSH or other

sulfhydryl compound. The

detoxification of NAPQI generates,

through a series of reactions,

mercapturic acid and cysteine

metabolites. GSH is depleted in the

detoxification process and must be

replenished by sulfhydryl compounds

from the diet or by drugs given as

therapy, e.g., the cysteine containing

compound NAC. NAC has welldocumented effectiveness as an antidote

for acetaminophen overdose. More

recently, it has been recommended for

the treatment of acetaminophen liver

toxicity after ingestion of therapeutic

doses of acetaminophen by individuals

with a history of heavy alcohol use or

abuse (Ref. 95).

Pharmacokinetic studies in humans

suggest an increased sensitivity of heavy

alcohol users or abusers to the

hepatotoxic effects of acetaminophen.

The data suggest that the ingestion of

even relatively small doses of

acetaminophen (1 g) by heavy alcohol

users or abusers results in a higher than

normal percentage of acetaminophen

metabolized by the microsomal enzyme

pathway that yields NAPQI. The

available pharmacokinetic data suggest

that the rate of metabolism of

acetaminophen is increased in alcohol

abusers (as evidenced by an increase in

the plasma clearance rate (CL) and a

decrease in the plasma elimination halflife of acetaminophen (t1/2)). This

increased metabolism suggests

increased activity of the microsomal

pathway in this population.

Dietz et al. (Ref. 28) compared the

metabolism of acetaminophen in six

healthy alcohol abusers (240 to 480 mL

alcohol daily for 2 to 40 years) to eight

healthy nondrinking adults. The alcohol

abusers had stopped drinking within the

previous 48 hours. Baseline laboratory

data were obtained from both groups.

Following a 12-hour fast, a single 1 g

dose of acetaminophen was

administered. Blood samples were

collected immediately before

acetaminophen administration and at

30, 60, 90, 120, and 240 minutes

thereafter. Acetaminophen plasma data

were fit to a one-compartment open

model for oral dosing using nonlinear

regression analysis. The time to peak

concentration (tmax), peak plasma

concentration (Cmax), the area under the

concentration-time curve (AUC), and CL

were determined. Laboratory screening

data revealed significant differences

between the controls and alcohol

abusers only in gamma-glutamyl

transpepsidase activity (12.6 units in

controls and 204.7 units in alcohol

abusers, p = 0.01). There was no

significant difference in renal function

between the two groups. The

acetaminophen plasma AUC’s for the

groups were significantly different (p <

0.01). While both groups achieved Cmax

at approximately the same time, Cmax for

the nondrinkers was significantly higher

than for the alcohol abusers (20.2 μg/mL

versus 15.4 μg/mL). The CL was also

significantly accelerated in the alcohol

abusers (247.4 mL/minute (min) versus

154.4 mL/min, p < 0.001).

Girre et al. (Ref. 55) obtained similar

results in a comparison of the

pharmacokinetics of acetaminophen in

12 chronic alcohol abusers and 12

healthy controls. The mean daily

alcohol consumption for the alcohol

abusers was 210 ± 95 g of absolute

alcohol for a mean duration of 14.5 ± 9.5

years. Control subjects drank only

moderately (defined in the study as a

weekly alcohol consumption < 80 g) and

were asked to abstain from alcohol

consumption for 36 hours before the

trial. A single, 1-g acetaminophen dose

was administered following a 12-hour

fast. Blood samples were taken before

acetaminophen intake and at 0.25, 0.5,

0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24

hours thereafter.

The following pharmacokinetic

parameters were determined: Cmax, tmax,

AUC, CL, and t1/2. A comparison of Cmax

and tmax showed no significant

differences between the two groups.

However, in the alcohol abusers, t1/2 was

significantly shorter than for the

controls (1.71 versus 2.84 hours, p <

0.05). CL was increased in the alcohol

abusers (30.34 versus 26.52 L/hour, p <

0.05).

Observed increases in the excretion of

metabolites (mercapturate and cysteine)

of the microsomal pathway also suggest

increased activity of this pathway in

this population. Villeneuve et al. (Ref.

27) observed an increased urinary

excretion of cysteine and mercapturate

metabolites of acetaminophen in alcohol

abusers. The authors compared the

pharmacokinetics of acetaminophen

metabolism in nine alcohol abusers (457

± 50 g ethanol per day for at least 3

months), eleven subjects with alcoholic

cirrhosis, and six healthy normal

subjects. Subjects in the control group

consumed no alcohol or other

medications.

Subjects with a history of alcohol

abuse were selected based on the

absence of alcoholic hepatitis or

cirrhosis (determined by physical

examination and standard biological

tests for liver function) and the lack of

drug use (other than alcohol). The

diagnosis of cirrhosis was confirmed by

liver biopsy. Cirrhotic subjects were

hospitalized at the time of the study and

did not consume alcohol for at least 30

days prior to the start of the study. Five

of the cirrhotic subjects received

spironolactone (100 mg/day) for

treatment of their ascites.

After 12 hours of fasting, a liquid

preparation of acetaminophen was

administered orally at a dose of 12 mg/

kilogram with 200 mL of water (mean

dose: Controls 920 mg, alcohol abusers

805 mg, and cirrhotics 872 mg). Blood

samples were taken at 0, 5, 15, 30, 45,

60, 90, 120, 180, 240, 300, 360, and 420

minutes after ingesting acetaminophen.

Urine was collected for 24 hours after

ingestion. The apparent oral clearance

(CLo), AUC, and t1/2 were determined.

The percentage of the acetaminophen

dose eliminated in the urine of alcohol

abusers was significantly decreased

from the controls (88.6 to 63.4 percent).

In the cirrhotics, clearance was

decreased by 50 percent (p < 0.05), t1/2

was extended (p < 0.05), and urinary

elimination was not significantly

decreased in relation to the controls.

The level of glucuronide and sulfate

conjugates in the alcohol abusers was

not significantly different in comparison

to the controls. The excretion of

cysteine and mercapturate metabolites

of acetaminophen was increased in a

significant manner for the alcohol

abusers (p < 0.05). When this increase
Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules 61049

was expressed as a percent of the

administered dose, the mean

augmentation for the alcohol abusers

was 92 percent. In cirrhotics, the profile

of these metabolites was comparable to

the controls.

An additional mechanism of the

increased sensitivity of alcohol abusers

to acetaminophen toxicity has been

postulated to be a diminished capacity

to detoxify NAPQI by conjugation with

GSH. Lauterberg and Velez (Ref. 65)

studied glutathione levels and the

formation of the toxic metabolite of

paracetamol (acetaminophen) in chronic

alcohol abusers. Study subjects were

recruited from an alcohol treatment

program and had a history of heavy

drinking (average consumption of 180 g

ethanol per day) up to 2 days prior to

study initiation. Some of these subjects

received chlorodiazepoxide (last dose

10 mg more than 10 hours prior to the

study) as part of their treatment. Control

subjects denied consumption of alcohol

in excess of 10 g/day and were not

taking any medications.

The study determined the plasma

GSH levels of alcohol abusers without

clinical evidence of alcoholic liver

disease and in controls following an

overnight fast. The GSH plasma

concentration was about 50 percent

lower in alcohol abusers than in the

controls (8.48 versus 4.35 micromoles

(μmole), p < 0.05). In contrast, the

plasma concentration of free cysteine

was similar for alcohol abusers and for

controls.

The study also examined the effect of

acetaminophen administration on

plasma GSH. Subjects were given a 2 g

acetaminophen dose in lemonade after a

10-hour fast. Blood samples were taken

hourly for 4 hours. Urine was collected

for 6 hours. After the administration of

acetaminophen, the plasma GSH

concentration in controls was

significantly decreased at 3 hours from

a mean concentration of 8.37 to 6.26

μmole (p < 0.02 by paired t-test). The

plasma GSH levels in alcohol abusers

were significantly lower than baseline at

2 and 3 hours (3.10 and 2.40 μmole,

respectively, baseline 4.66 μmole). All

GSH levels in the alcohol abusers were

significantly lower (p < 0.05) than the

corresponding values in the control

group. The decrease in plasma cysteine

was not significantly different from

control values. Urinary excretion of

mercapturic acid and cysteine

conjugates was slightly increased in

alcohol abusers. However, the difference

was not statistically significant. There

was no significant difference in the

relative amounts or proportions of

glucuronide and sulfate metabolites

between alcohol abusers and controls,

suggesting no impact of alcohol abuse

on these metabolic pathways.

To confirm that low plasma GSH

levels reflect low intrahepatic GSH, the

authors measured hepatic GSH in liver

samples obtained from alcohol abusers

in whom a percutaneous liver biopsy

was indicated. The biopsied subjects all

had histological evidence of alcoholic

hepatitis with and without cirrhosis and

had more severe liver disease than the

alcohol abusers in whom plasma GSH

was measured. The hepatic

concentration of GSH in the biopsied

subjects was about 50 percent lower

than in subjects without liver disease

and subjects with a mild inflammatory

process or nonalcoholic cirrhosis.

Based on the data discussed above,

the agency concludes that chronic heavy

alcohol use or abuse has a significant

effect on the metabolism of

acetaminophen and the detoxification of

acetaminophen’s toxic metabolite,

NAPQI. These changes put individuals

with a history of heavy alcohol use or

abuse at an increased risk from

acetaminophen liver toxicity. Therefore,

the agency believes that an alcohol

warning for adult OTC internal

analgesic/antipyretic drug products

containing acetaminophen is warranted.

However, the agency does not find the

submitted data sufficient to demonstrate

the safety of a lower maximum daily

dose (2 g acetaminophen) in heavy

alcohol users or abusers or to support a

specific labeling recommendation to

that effect. Therefore, the agency is not

proposing a reduction in the

recommended maximum OTC daily 4 g

dose of acetaminophen at this time.

Rather, the agency believes that OTC

labeling should recommend contact

with a physician to these individuals. A

physician familiar with a consumer’s

history can advise them on whether a

particular OTC analgesic/antipyretic

drug product is appropriate for their

use, suggest other appropriate therapies,

and counsel them about their alcohol

use.

B. Other Monograph Ingredients

The agency has carefully considered

the Committees’ recommendations, all

comments received in response to those

recommendations, and all available data

and information and has determined

that an alcohol warning for OTC

internal analgesic/antipyretic drug

products containing aspirin is

warranted. The agency agrees with the

comments that the unpublished

epidemiological data presented to the

Committees at the September 8, 1993,

meeting alone were insufficient to

document an increased risk of GI

bleeding associated with aspirin use by

individuals with a history of heavy

alcohol use or abuse. At that meeting

(Ref. 72), agency representatives stated

that the unpublished studies had design

problems and did not convince them

that the use of alcohol with OTC

internal analgesic/antipyretic

ingredients (such as aspirin) can cause

excess GI bleeding. Agency

representatives also stated that, based

on these studies, the magnitude of the

risk and the confidence level of the

estimated risk were uncertain.

However, the irritant effects of aspirin

on the gastric mucosa are well

documented. In discussing the effect of

aspirin on the gastric mucosa (42 FR

35346 at 35386 to 35397), the Panel

concluded that aspirin and salicylic

acid have a direct local irritant effect on

the surface of mucosal cells lining the

GI tract. The Panel asserted that the

acute use of aspirin may activate

symptoms of both gastric and duodenal

ulcer, such as epigastric pain and GI

hemorrhage. The Panel stated that the

initiation or exacerbation of stomach

ulcers, stomach irritation, and intestinal

inflammation occurs in a significant

number of aspirin users. Individuals

particularly at risk are those with a

history of symptoms of GI problems.

Alcohol is also a gastric irritant.

Tarnawski et al. (Ref. 97) studied the

effect of the intragastric administration

of 100 mL of 40 percent ethanol (the

alcohol content of 80 proof whiskey) or

saline in 15 healthy volunteers (ten test

and five control subjects). Changes in

the appearance of the gastric mucosa,

mucosal histology, luminal pH, and

gastric mucosal potential were

evaluated. The authors found that a

single dose of 40 percent alcohol

produced rapid endoscopic changes

(congestion and focal hemorrhages) and

prominent histologic changes

(exfoliation of the surface epithelium,

edema of the lamina propria, and

hemorrhagic lesions associated with

mucosal microvascular damage).

Histologic changes were seen as early as

5 minutes after alcohol administration.

Individuals with a history of heavy

alcohol consumption commonly

develop characteristic subepithelial

hemorrhages with the endoscopic

appearance of ‘‘blood under plastic

wrap.’’ Although termed ‘‘hemorrhagic

gastritis,’’ these lesions are composed of

hemorrhage and edema in the

interstitial space under the surface

epithelium, without inflammation (Ref.

98). While there are no controlled

studies demonstrating that ethanol in

lower doses will precipitate relevant

gastric hemorrhage, acute hemorrhagic

gastritis accounts for 25 percent of the

cases of major bleeding in alcohol
61050 Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules

abusers compared to 5 percent in the

population without a history of prior

alcohol abuse (Ref. 99). As with gastritis

from other causes, individuals with

alcoholic gastritis may have no

symptoms whatsoever (Ref. 100).

Currently available data do not provide

sufficient information to assess the

magnitude of the risk of aspirin use by

individuals with a history of heavy

alcohol use or abuse.

Further, in the last 15 to 20 years, the

use of aspirin for the prevention of

recurrent myocardial infarction (MI),

transient ischemic attacks (TIA), and

stroke has become prevalent. The

agency has evaluated the available

literature on aspirin for cerebral

vascular and cardiovascular indications

and the incidence of GI bleeding and

ulcers in these studies. Eighteen of the

19 studies that included aspirin and

placebo groups and evaluated GI

bleeding reported an increase in GI

bleeds in the aspirin group when

compared to the placebo group (Refs.

101 through 118). One study reported

no GI bleeds in either group (Ref. 119).

Aspirin dosages in the studies ranged

from 75 to 1,500 mg daily. Increases in

bleeding were reported at all aspirin

dosage levels when compared to the

control groups. The number of subjects

in the studies ranged from 125 to

22,071. The overall results of these

studies show that GI bleeding increases

with long-term aspirin use, even at low

aspirin doses.

The UK–TIA study (Ref. 106)

suggested a risk of GI bleeding that

increased in a dose-dependent manner.

The odds ratio (95 percent confidence

interval) was 3.3 (1.2 to 9.0) for 300 mg

daily aspirin and 6.4 (2.5 to 16.5) for

1,200 mg daily aspirin (Ref. 120).

Several studies reported the number of

ulcers in the aspirin and placebo

groups. The Aspirin Myocardial

Infarction Study Research Group (Ref.

112) reported ‘‘symptoms suggestive of

peptic ulcer, gastritis, or erosion of

gastric mucosa’’ in 14.9 percent of the

placebo group and in 23.7 percent of the

aspirin group. The British Doctors’

Study (Ref. 102) reported a significant

increase in peptic ulcers in the aspirin

group compared to the placebo group.

The Physicians’ Health Study (a 325

mg aspirin dose on alternate days (Ref.

101) reported a nonsignificant increase

in upper GI ulcers in the aspirin arm

compared to placebo (169/11,037 versus

138/11,034, p = 0.08). However, a

statistically significant increase in the

number of duodenal ulcers was reported

in the aspirin group (46/11,037 versus

27/11,034, p = 0.03), where most of the

subjects reported some alcohol use

(more than 70 percent of the subjects

reporting daily or weekly use).

The agency is currently evaluating

several new professional vascular uses

of aspirin and is aware that more people

are taking aspirin chronically for

cardiovascular and/or cerebrovascular

indications and thus may have an

increased risk of GI bleeding or

susceptibility to ulcers. Further, the

magnitude of the risk of heavy alcohol

use in this population is not clearly

defined.

The agency is aware that numerous

studies have examined the effects of

alcohol consumption on the rate of

cardiovascular disease. In a review of

these studies, Marmot and Brunner (Ref.

121) concluded that the evidence

suggests that two drinks a day do not

cause cardiovascular harm and may be

protective against coronary heart

disease. Above two drinks per day, the

authors found evidence of harmful

effects. Heavier alcohol intakes have

been associated with an increase in

cardiovascular diseases, such as heart

muscle disease, hypertension,

disturbances in heart rhythm, and stroke

(Ref. 122). Pohorecky (Ref. 123) found

that the risk for hypertension among

individuals drinking three to four drinks

per day was 50 percent higher than

among nondrinkers.

The American Heart Association

(AHA) (Ref. 124) does not currently

recommend the ingestion of moderate

amounts of alcohol for its protective

effect against cardiovascular disease.

However, based on the adverse effects of

alcohol on blood pressure, the AHA

recommends that alcohol intake should

not exceed two drinks per day (Ref.

124). The Dietary Guidelines of the U.S.

Departments of Agriculture and Health

and Human Services (Ref. 125) also

recommend moderate alcohol

consumption. These guidelines define

moderate alcohol consumption as one

drink (12 ounces (oz) of regular beer, 5

oz of wine, or 1.5 oz of 80-proof

distilled spirits) per day for women and

two drinks per day for men. Based on

these recommendations, the agency

believes that the proposed warning

provides appropriate advice to

consumers on low-dose prophylactic

aspirin regimens.

The agency acknowledges the

Committees’ conclusion that there are

no clinical trial data supporting the

need for an alcohol warning on OTC

internal analgesic/antipyretic drug

products containing carbaspirin

calcium, choline salicylate, magnesium

salicylate, and sodium salicylate.

However, the agency is concerned that

the absence of an alcohol warning on

OTC drug products containing these

ingredients may lead consumers to

conclude that they are safer to use with

alcohol, when there are no data upon

which to base such a conclusion.

Therefore, based, among other things,

on the Panel’s conclusions that these

OTC internal analgesic/antipyretic

active ingredients all have safety

profiles similar to aspirin and should

bear similar labeling, the agency is also

proposing that OTC drug products

containing carbaspirin calcium, choline

salicylate, magnesium salicylate, and

sodium salicylate bear an alcohol

warning.

C. OTC Internal Analgesic/Antipyretic

Ingredients Switched From Prescription

Status

After reviewing current data and

information, and based on the

Committees’ recommendations, the

agency is proposing to require an

alcohol warning on all OTC drug

products containing ibuprofen,

ketoprofen, and naproxen sodium.

Ibuprofen, ketoprofen, and naproxen

sodium have been extensively marketed

as prescription drugs at higher doses.

Lower doses have been approved for

OTC marketing through the new drug

approval process. All OTC ketoprofen

and naproxen sodium drug products are

currently marketed with the following

alcohol warning: ‘‘ALCOHOL

WARNING [heading in bold face type]:

If you generally consume 3 or more

alcohol-containing drinks per day, you

should consult your physician for

advice on when and how you should

take [product name inserted] and other

pain relievers.’’

Ibuprofen, ketoprofen, and naproxen

sodium are derivatives of propionic acid

and, as such, share common

pharmacologic effects. As with aspirin,

propionic acid derivatives produce

adverse GI side effects, alter platelet

function, and prolong bleeding time

(Refs. 126 through 129). GI

complications are the most common

side effects of these drugs and can

include problems such as irritation,

nausea, vomiting, bleeding,

hematemesis, and activation of peptic

ulcer (Refs. 127 and 128).

Articles in the scientific literature

suggest a definitive relationship

between the ingestion of propionic acid

derivatives at prescription doses and GI

complications. In a review article,

Greene and Winickoff (Ref. 130)

discussed the effectiveness, side effects,

and costs of aspirin and various

prescription nonsteroidal antiinflammatory drugs (NSAID’s),

including ibuprofen, ketoprofen, and

naproxen sodium. The authors stated

that NSAID’s share the risks of causing
Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules 61051

gastric ulcer, upper GI bleeding, and GI

perforation, and that GI side effects

occur in roughly 25 percent of NSAID

users. The authors also cited studies

(Ref. 130) that attribute a relative risk of

4.03 for gastric ulcer and 3.09 for upper

GI bleeding in users of these drug

products.

Langman et al. (Ref. 131) compared

previous use of propionic acid

derivatives and other prescription

NSAID’s in patients age 60 and older

admitted to hospitals with bleeding

from peptic ulcers to controls (in

hospital and community) matched for

sex and age. The investigators found

that peptic ulcer bleeding was strongly

associated with the use of propionic

acid derivatives, aspirin, and other

prescription NSAID’s during the 3

months before admission and that the

risk of bleeding increased as dosage

increased. An analysis of the risk

according to drug dose (low, medium,

high) revealed an odds ratio of 2.5 (1.7

to 3.8, 95 percent confidence interval)

when exposure was to lower doses of

these drugs and increased to 4.5 (3.3 to

6.0, 95 percent confidence interval)

when exposure was to moderate doses.

The study defined low dose as: (1) Less

than 1,200 mg/day (OTC maximum

daily dose) for ibuprofen, (2) less than

500 mg/day for naproxen (OTC

maximum daily dose 660 mg/day), and

(3) less than 100 mg/day for ketoprofen

(OTC maximum daily dose 75 mg).

The use of ibuprofen, ketoprofen, or

naproxen sodium may also predispose

an individual to bleeding from a

preexisting ulcer or other upper GI

lesion. Increased severity of GI irritation

is related to increased dosage of drug.

While less severe irritation could be

expected at the lower OTC doses, there

are no data to clarify the magnitude of

the risk for individuals with preexisting

GI lesions due to a history of heavy

alcohol use or abuse. In fact, more

recent information (Ref. 132) suggests

that OTC doses of ibuprofen or

naproxen sodium increase by three

times the risk of GI bleeding and that

this risk is increased when OTC drug

products containing these ingredients

are used by individuals who consume

alcohol.

The Committees discussed the

relationship between alcohol and

toxicities associated with OTC internal

analgesic/antipyretic drug products

(Ref. 72) and concluded that the effect

of alcohol and ibuprofen or naproxen

sodium was at least additive and that

heavy and/or chronic drinkers of

alcohol are at an increased risk of severe

gastritis and GI bleeding. The

Committees recommended that an

alcohol warning should be required on

OTC drug products containing

ibuprofen or naproxen sodium.

On July 14, 1995, the Committees

discussed two NDA’s for OTC

ketoprofen products (Ref. 133). The

Committees agreed that ketoprofen can

be used safely and effectively OTC.

However, the Committees voted

unanimously that, based on past

Committee discussions, products

containing this new OTC ingredient

should be required to have the same

alcohol warning in their labeling as that

required for naproxen sodium.

Based on the Committees’

recommendations and information in

the literature, the agency has concerns

that the use of OTC internal analgesic/

antipyretic drug products containing

aspirin, carbaspirin calcium, choline

salicylate, ibuprofen, ketoprofen,

magnesium salicylate, naproxen

sodium, and sodium salicylate by

individuals with a history of heavy

alcohol use or abuse may increase their

risk of adverse GI effects, including

serious GI bleeding. Therefore, the

agency has determined that an alcohol

warning is needed for OTC internal

analgesic/antipyretic drug products

containing these ingredients. The

agency invites the submission of

comments and additional data

supporting the safe use of these

ingredients by individuals with a

history of heavy alcohol use or abuse.

VI. The Agency’s Proposal

Current data and information indicate

that individuals with a history of heavy

alcohol use or abuse have an increased

sensitivity to the hepatotoxic effects of

acetaminophen. Currently available data

on the use of OTC internal analgesic/

antipyretic drug products containing

aspirin, carbaspirin calcium, choline

salicylate, ibuprofen, ketoprofen,

naproxen sodium, magnesium

salicylate, and sodium salicylate raise

the logical concern that these OTC

products pose an increased risk of GI

bleeding to these individuals (i.e.,

individuals with a history of heavy

alcohol use or abuse). However, the

available data are not sufficient to assess

the magnitude of this risk. Therefore,

the agency is proposing that all OTC

internal analgesic/antipyretic drug

products and any combination product

containing one of these ingredients

labeled for adult use, whether marketed

pursuant to an OTC drug monograph or

an NDA, bear an alcohol warning. This

proposal follows the agency’s

Committees’ (NDAC and ADAC)

recommendations for such a warning on

OTC internal analgesic/antipyretic drug

products containing acetaminophen,

aspirin, ibuprofen, ketoprofen, and

naproxen sodium.

A comment submitted in response to

NDAC’s recommendation for an alcohol

warning for OTC acetaminophen drug

products advised that all OTC internal

analgesic/antipyretic drug products

should bear a common alcohol warning.

The comment proposed the following

warning: ‘‘Use of certain medicines with

alcohol can cause adverse effects.

Consult a physician for appropriate use

of this or other pain relievers if every

day you consume excessive amounts of

alcohol.’’ The comment suggested that

this warning would avoid the potential

consumer confusion that could result

from a more-detailed, ingredientspecific warning. The comment

mentioned the following advantages of

this warning: (1) Its educational nature,

i.e., the warning heightens consumer

awareness of a possible interaction

between alcohol and OTC internal

analgesic/antipyretic drug products, and

(2) it helps consumers to understand

that they simply cannot switch to

another OTC internal analgesic/

antipyretic drug product to avoid this

risk.

Under the new drug approval process,

the agency has approved the marketing

of OTC internal analgesic/antipyretic

drug products containing ketoprofen

and naproxen sodium. The following

warning was included in the products’

approved labeling (Refs. 134, 135, and

136): ‘‘ALCOHOL WARNING: If you

generally consume 3 or more alcoholcontaining drinks per day, you should

consult your physician for advice on

when and how you should take [product

name] and other pain relievers.’’

Subsequently, this warning was

included in the approved labeling of an

OTC extended release drug product

containing acetaminophen (Ref. 136). In

April of 1996, the agency requested the

voluntary implementation of this

alcohol warning on all OTC analgesic/

antipyretic drug products (Ref. 138).

This request was based on a lack of

uniformity in the use of an alcohol

warning and the resultant consumer

confusion.

In the Federal Register of February

27, 1997 (62 FR 9024), the agency

published a proposed rule to establish a

standardized format for the labeling of

OTC drugs. During the agency’s

evaluation of data relating to consumers’

perception of label warnings it became

clear that more specific information

heightens the effectiveness of risk

communication (Ref. 139). Therefore,

the agency is concerned about the

effectiveness of the general alcohol

warning currently used and is proposing

more specific alcohol warnings.
61052 Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules

The warnings being proposed are

similar to that suggested by the

comment but contain more specific

information. The warnings specify ‘‘3 or

more’’ instead of the general term

‘‘excessive.’’ The agency has included a

specific number of drinks in the

warnings to help consumers identify a

level of alcohol consumption that may

increase their risk from the use of OTC

internal analgesic/antipyretic drug

products. However, the agency

acknowledges that the data are not

sufficient to clearly identify a level of

alcohol consumption that increases the

risk of OTC internal analgesic/

antipyretic drug use.

In the proposed warnings, the agency

has included a level of alcohol

consumption that is consistent with

limitations on daily intake

recommended by the AHA (Ref. 124)

and by the Dietary Guidelines for

Americans developed by the U.S.

Departments of Agriculture and Health

and Human Services (Ref. 125). The

AHA recommends that men and women

limit alcohol intake to 1 oz of alcohol

per day and defines this amount as

follows: (1) 2 oz of 100-proof whiskey,

(2) 3 oz of 80-proof whiskey, (3) 8 oz of

wine, or (4) 24 oz of beer. The Dietary

Guidelines recommend no more than

two drinks per day for men and one

drink per day for women. The

guidelines define one drink as follows:

(1) 12 oz of regular beer, (2) 5 oz of

wine, or (3) 1.5 oz of 80-proof distilled

spirits. The agency believes that the

number of drinks included in the

proposed warnings are consistent with

these recommendations. However, the

agency invites comment on the

proposed warnings specifying ‘‘3 or

more alcoholic beverages daily.’’

In addition, the warnings being

proposed include organ-specific

information. When NDAC discussed a

warning for acetaminophen, it

recommended that product labeling

refer specifically to possible damage to

the liver. However, when the

Committees considered the need for an

alcohol warning for other OTC internal

analgesic/antipyretic drug products

(e.g., aspirin), they were unable to reach

a consensus on whether the warning

should be general or should specify

bleeding or GI effects. Based on its

recent experience with OTC consumer

labeling, the agency has concluded that

warnings containing more specific

information are more effective.

Therefore, the agency is proposing that

OTC analgesic/antipyretic drug

products containing acetaminophen,

labeled for adult use, should bear the

following warning: ‘‘Alcohol Warning’’

[heading in boldface type]: ‘‘If you drink

3 or more alcoholic beverages daily, ask

your doctor whether you should take

[insert product name] or other pain

relievers. [Product name] may increase

your risk of liver damage.’’ For OTC

analgesic/antipyretic drug products

containing other OTC active ingredients,

i.e., aspirin, carbaspirin calcium,

choline salicylate, ibuprofen,

ketoprofen, naproxen sodium,

magnesium salicylate, and sodium

salicylate, labeled for adult use, the

agency is proposing the following

warning: ‘‘Alcohol Warning’’ [heading

in boldface type]: ‘‘If you drink 3 or

more alcoholic beverages daily, ask your

doctor whether you should take [insert

product name] or other pain relievers.

[Product name] may increase your risk

of stomach bleeding.’’ The agency is

proposing that OTC analgesic/

antipyretic drug products containing

acetaminophen in combination with any

other OTC analgesic/antipyretic

ingredient, labeled for adult use, should

bear the following warning: ‘‘Alcohol

Warning’’ [heading in boldface type]: ‘‘If

you drink 3 or more alcoholic beverages

daily, ask your doctor whether you

should take [insert product name] or

other pain relievers. [Product name]

may increase your risk of liver damage

and stomach bleeding.’’ However, the

agency invites comment on the above

organ-specific alcohol warnings.

VII. Voluntary Implementation

The agency acknowledges that these

proposed alcohol warnings represent a

significant change from the labeling

required for OTC analgesic/antipyretic

new drug products approved since

naproxen sodium. Therefore, holders of

approved applications for OTC internal

analgesic/antipyretic drug products will

not be required to implement the

proposed warnings at this time.

However, holders of approved

applications for these drug products

may implement the proposed warning

without advance approval from FDA

provided the warning includes at least

the information in proposed § 201.322.

A supplement must be submitted under

§ 314.70(c) (21 CFR 314.70(c)) in order

to provide for the implementation of

such labeling. The supplement and its

mailing cover should be clearly marked:

‘‘Special Supplement—Changes Being

Effected.’’

Voluntary compliance with these

proposed warnings is subject to the

possibility that FDA may change the

wording of the statement, or not require

the statement, as a result of comments

filed in response to this proposal.

Because FDA wishes to encourage the

voluntary use of the proposed labeling

statements, the agency advises that

manufacturers will be given ample time

after publication of a final rule to use up

any labeling implemented in

conformance with this proposal.

VIII. Analysis of Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866 and the Regulatory Flexibility Act

(5 U.S.C. 601–612). 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 has

a significant 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.

Title II of the Unfunded Mandates

Reform Act (2 U.S.C. 1501 et seq.)

requires that agencies prepare a written

statement and economic analysis before

proposing any rule that may result in an

expenditure by State, local, and tribal

governments, in the aggregate, or by the

private sector of $100 million (adjusted

annually for inflation) in any 1 year.

The agency believes that this

proposed rule is consistent with the

principles set out in the Executive Order

and in these two statutes. The purpose

of this proposed rule is to add a warning

statement to the labeling of OTC drug

products labeled for adult use

containing internal analgesic/antipyretic

active ingredients. The warning

statement concerns the increased risk of

adverse effects from the use of OTC

analgesic/antipyretic drug products by

individuals with a history of heavy

alcohol use or abuse. Potential benefits

include a reduced risk of adverse effects

when these consumers use these

products.

This proposed rule amends Subpart

C—Labeling Requirements of Over-theCounter Drugs of 21 CFR part 201 and

will require relabeling for many OTC

drug products containing internal

analgesic/antipyretic active ingredients.

The agency’s Drug Listing System

identifies approximately 600

manufacturers and distributors of 5,000

to 6,000 OTC analgesic/antipyretic drug

products with an average of 3 stock

keeping units (SKU) (individual

products, packages, and sizes) per

product. It is also likely that there are

some additional marketers and products

that are not currently included in the

agency’s system. Nonetheless, the

agency estimates that there are a total of
Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules 61053

600 manufacturers and distributors and

an estimated 18,000 SKU’s.

The agency has been informed that

relabeling costs of this type generally

average about $2,000 to $3,000 per SKU.

Assuming that there are approximately

18,000 affected SKU’s in the

marketplace, total one-time costs of

relabeling would be $36 to $48 million.

However, the agency believes that the

actual costs may be lower because the

agency is allowing supplementary

labeling (e.g., stick on labeling) to be

used for products not undergoing a new

labeling printing within the 6-month

implementation period. The agency

solicits comments on whether these

estimates are accurate and whether

there are other effects that the agency

should consider (e.g., the cost to

manufacturers due to the effect on sales

because of the decreased use of these

products; or the implications to patients

who take these products

prophylactically for conditions such as

heart ailments).

The proposed rule would not require

any new reporting and recordkeeping

activities. Therefore, no additional

professional skills are needed. There are

no other Federal rules that duplicate,

overlap, or conflict with the proposed

rule. The agency does not believe that

there are any significant alternatives to

the proposed rule that would adequately

provide for the safe and effective use of

OTC drug products containing

analgesic/antipyretic active ingredients.

This proposed rule may have a

significant economic impact on some

small entities. The labeling of some of

the affected products is prepared by

private label manufacturers for small

marketers. Census data provide

aggregate industry statistics on the total

number of manufacturers for

Standardized Industrial Classification

Code 2384 Pharmaceutical Preparations

by establishment size, but do not

distinguish between manfacturers of

prescription and OTC drug products.

According to the U.S. Small Business

Administration (SBA) designations for

this industry, however, over 92 percent

of the roughly 700 establishments and

over 87 percent of the 650 firms are

small. (Because census size categories

do not correspond to the SBA

designation of 750 employees, these

figures are based on 500 employees.)

An analysis of IMS America listings

for manufacturers of OTC drug products

found that from 46 to 69 percent of the

400 listed firms are small using the SBA

definition of 750 employees. The

agency’s Drug Listing System indicates

that about 600 marketers will need to

relabel. Thus, the agency believes that

many of the manufacturers affected by

this proposal would be small. Further,

some entities, such as those private

label manufacturers that provide

labeling for a number of the affected

products may also incur a significant

impact. However, the agency has

allowed for a 6-month implementation

period and the use of supplementary

labeling (e.g., stick-on labeling) in an

attempt to minimize the economic

impact of the proposed regulation. The

agency believes that these measures

should help reduce relabeling costs for

small entities.

The agency considered but rejected

the following alternatives: (1) Voluntary

relabeling, and (2) a longer

implementation period. However, the

agency does not consider either of these

approaches acceptable because they do

not ensure that consumers will have the

most recent needed information for the

safe and effective use of OTC drug

products containing internal analgesic/

antipyretic drug active ingredients.

This analysis shows that this

proposed rule is not economically

significant under Executive Order 12866

and that the agency has undertaken

important steps to reduce the burden of

small entities. Nevertheless, some

entities, especially those private label

manufacturers that provide labeling for

a number of the affected products, may

incur significant impacts. Thus, this

economic analysis, together with other

relevant sections of this document,

serves as the agency’s initial regulatory

flexibility analysis, as required under

the Regulatory Flexibility Act. Finally,

this analysis shows that the Unfunded

Mandates Act does not apply to the

proposed rule because it would not

result in an expenditure by State, local,

or tribal governments, in the aggregate,

or by the private sector, of $100 million

in any 1 year.

The agency invites public comment

regarding any substantial or significant

economic impact that this rulemaking

would have on manufacturers of drug

products that contain OTC internal

analgesic/antipyretic active ingredients.

Comments regarding the impact of this

rulemaking on these drug products

should be accompanied by appropriate

documentation. A period of 75 days

from the date of publication of this

proposed rulemaking in the Federal

Register will be provided for comments

on this subject to be developed and

submitted. The agency will evaluate any

comments and supporting data that are

received and will reassess the economic

impact of this rulemaking in the

preamble to the final rule.

IX. Paperwork Reduction Act of 1995

FDA tentatively concludes that the

labeling requirement proposed in this

document is not subject to review by the

Office of Management and Budget

because it does not constitute a

‘‘collection of information’’ under the

Paperwork Reduction Act of 1995 (44

U.S.C. 3501 et seq.). Rather, the

proposed warning statement is 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)).

X. Environmental Impact

The agency has determined under 21

CFR 25.24(c)(6) 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.

XI. Public Comment

Interested persons may, on or before

January 28, 1998, submit to the Dockets

Management Branch (address above)

written comments regarding this

proposal. Written comments on the

agency’s economic impact

determination may be submitted on or

before January 28, 1998. Three copies of

all comments are to be submitted,

except that individuals may submit one

copy. Comments are to be identified

with the docket number found in

brackets in the heading of this

document and may be accompanied by

a supporting memorandum or brief.

Received comments may be seen in the

office above between 9 a.m. and 4 p.m.,

Monday through Friday.

XII. References

The following references have been

placed on display in the Dockets

Management Branch (address above)

and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday

through Friday.

1. Baeg, N., H. C. Bodenheimer, and K.

Burchard, ‘‘Long-Term Sequelae of

Acetaminophen-Associated Fulminant

Hepatic Failure: Relevance of Early

Histology,’’ American Journal of

Gastroenterology, 83:569–571, 1988.

2. Barker, J. D., D. J. deCarle, and S.

Anuras, ‘‘Chronic Excessive Acetaminophen

Use and Liver Damage,’’ Annals of Internal

Medicine, 87:299–301, 1977.

3. Black, M. et al., ‘‘Late Presentation of

Acetaminophen Hepatotoxicity,’’ Digestive

Diseases and Sciences, 27:370–374, 1982.

4. Dennison, H., J. Kaczynski, and S.

Wallerstedt, ‘‘Paracetamol Medication and

Alcohol Abuse: A Dangerous Combination

for the Liver and the Kidney,’’ Scandinavian
61054 Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules

Journal of Gastroenterology, 22:701–704,

1987.

5. Emby, D. J., and B. N. Fraser,

‘‘Hepatotoxicity of Paracetamol Enhanced by

Ingestion of Alcohol,’’ South African Medical

Journal, 51:208–209, 1977.

6. Fleckenstein, J. L., ‘‘Nyquil and Acute

Hepatic Necrosis,’’ New England Journal of

Medicine, 1:48, 1985.

7. Floren, C., P. Thesleff, and A ̊ . Nilsson,

‘‘Severe Liver Damage Caused by Therapeutic

Doses of Acetaminophen,’’ Acta Medica

Scandinavia, 222:285–288, 1987.

8. Foust, R. T. et al., ‘‘Nyquil-Associated

Liver Injury,’’ American Journal of

Gastroenterology, 84:422–425, 1989.

9. Gerber, M. A. et al., ‘‘Acetaminophen

Associated Hepatic Injury—Report of Two

Cases Showing Unusual Portal Tract

Reactions,’’ Human Pathology, 11:37–42,

1980.

10. Goldfinger, R. et al., ‘‘Concomitant

Alcohol and Drug Abuse Enhancing

Acetaminophen Toxicity,’’ American Journal

of Gastroenterology, 70:385–388, 1978.

11. Himmelstein, D. U., S. J. Woolhander,

and R. D. Adler, ‘‘Elevated SGOT/SGPT Ratio

in Alcoholic Patients with Acetaminophen

Hepatotoxicity,’’ American Journal of

Gastroenterology, 79:718–720, 1984.

12. Johnson, M. W., P. A. Friedman, and

W. E. Mitch, ‘‘Alcoholism, Nonprescription

Drugs and Hepatotoxicity–The Risk From

Unknown Acetaminophen Ingestion,’’

American Journal of Gastroenterology,

76:530–532, 1981.

13. Kartsonis, A., K. R. Reddy, and E. R.

Schiff, ‘‘Alcohol, Acetaminophen, and

Hepatic Necrosis,’’ Annals of Internal

Medicine, 105:138–139, 1986.

14. Kaysen, G. A. et al., ‘‘Combined

Hepatic and Renal Injury in Alcoholics

During Therapeutic Use of Acetaminophen,’’

Archives of Internal Medicine, 145:2019–

2023, 1985.

15. Kromhout, J. P., J. D. Holtzman, and C.

J. McClain, ‘‘Potentiation of Acetaminophen

Hepatotoxicity by Alcohol,’’

Gastroenterology, 76:1288, 1980.

16. LaBreque, D. R., and F. A. Mitros,

‘‘Increased Hepatotoxicity of Acetaminophen

in the Alcoholic,’’ Gastroenterology, 78:1310,

1980.

17. Leist, M. H., L. E. Gluskin, and J. A.

Payne, ‘‘Enhanced Toxicity of

Acetaminophen in Alcoholics: Report of

Three Cases,’’ Journal of Clinical

Gastroenterology, 7:55–59, 1985.

18. Lesser, P. B., M. M. Vietti, and W. D.

Clark, ‘‘Lethal Enhancement of Therapeutic

Doses of Acetaminophen by Alcohol,’’

Digestive Diseases and Sciences, 31:103–105,

1986.

19. Levinson, M., ‘‘Ulcer, Back Pain, and

Jaundice in an Alcoholic,’’ Hospital Practice,

Oct:48N and 48S, 1983.

20. Licht, H., L. B. Seeff, and H. J.

Zimmerman, ‘‘Apparent Potentiation of

Acetaminophen Hepatotoxicity by Alcohol,’’

Annals of Internal Medicine, 12:511, 1985.

21. Litovitz, T. L. et al., ‘‘1987 Annual

Report of the American Association of Poison

Control Centers National Data Collection

System,’’ American Journal of Emergency

Medicine, 6:479–515, 1988.

22. McClain, C. J. et al., ‘‘Potentiation of

Acetaminophen Hepatotoxicity by Alcohol,’’

Journal of the American Medical Association,

244:251–253, 1980.

23. McClain, C. J. et al., ‘‘Clinical Features

of Acetaminophen Toxicity,’’ Journal of

Clinical Gastroenterology, 10:76–80, 1988.

24. O’Dell, J. R., R. K. Zetterman, and D.

A. Burnett, ‘‘Centrilobular Hepatic Fibrosis

Following Acetaminophen-Induced Hepatic

Necrosis in an Alcoholic,’’ Journal of the

American Medical Association, 255:2632–

2633, 1986.

25. Pezzano, M. et al., ‘‘Hepatic and Renal

Toxicity of Paracetamol in Chronic Alcoholic

Subjects,’’ Press Me ́dicale, 17:21–24, 1988.

26. Seeff, L. B. et al., ‘‘Acetaminophen

Hepatotoxicity in Alcoholics,’’ Annals of

Internal Medicine, 104:399–404, 1986.

27. Villeneuve, J. P. et al.,

‘‘Pharmacokinetics and Metabolism of

Acetaminophen in Normal, Alcoholic, and

Cirrhotic Subjects,’’ Gastroenterology and

Clinical Biology, 7:898–902, 1983.

28. Dietz, A. J. et al., ‘‘Effects of Alcoholism

on Acetaminophen Pharmacokinetics in

Man,’’ Journal of Clinical Pharmacology,

24:205–208, 1984.

29. Wo ́jcicki, J. et al., ‘‘The Effect of a

Single Dose of Ethanol on the

Pharmacokinetics of Paracetamol,’’ Polish

Journal of Pharmacology and Pharmacy,’’

30:749–753, 1978.

30. Peterson, F. J. et al., ‘‘Ethanol Induction

of Acetaminophen Toxicity and

Metabolism,’’ Life Sciences, 27:1705–1711,

1980.

31. Teschke, R., G. Stutz, and G.

Strohmeyer, ‘‘Increased Paracetamol-Induced

Hepatotoxicity After Chronic Alcohol

Consumption,’’ Biochemical and Biophysical

Research Communications, 91:368–374,

1979.

32. Guerri, C., and S. Grisolia, ‘‘Decreased

Glutathione in Rats Due to Chronic Intake of

Ethanol,’’ Federation Proceedings, 36:1541,

1978.

33. Pessayre, D. et al., ‘‘Effect of Fasting on

Metabolite-Mediated Hepatotoxicity in the

Rat,’’ Gastroenterology, 77:264–271, 1979.

34. McLean, A. E. M., and P. A. Day, ‘‘The

Effect of Diet on the Toxicity of Paracetamol

and the Safety of Paracetamol-Methionine

Mixtures,’’ Biochemical Pharmacology,

24:37–42, 1975.

35. Mitchell, J. R. et al., ‘‘AcetaminophenInduced Hepatic Necrosis IV Protective Role

of Glutathione,’’ Journal of Pharmacology

and Experimental Therapeutics, 187:211–

217, 1973.

36. Wright, N., and L. F. Prescott,

‘‘Potentiation by Previous Drug Therapy of

Hepatotoxicity Following Paracetamol

Overdosage,’’ Scottish Medical Journal,

18:56–58, 1973.

37. Strubelt, O., F. Obermeier, and C. P.

Siegers, ‘‘The Influence of Ethanol

Pretreatment on the Effects of Nine

Hepatotoxic Agents,’’ Acta Pharmacologica

and Toxicologica, 43:211–218, 1978.

38. Sato, C., Y. Matsuda, and C. S. Lieber,

‘‘Increased Hepatotoxicity of Acetaminophen

after Chronic Ethanol Consumption in the

Rat,’’ Gastroenterology, 80:140–148, 1981.

39. Sato, C., M. Nakano, and C. S. Lieber,

‘‘Prevention of Acetaminophen-Induced

Hepatotoxicity by Acute Ethanol

Administration in the Rat: Comparison with

Carbon Tetrachloride-Induced

Hepatotoxicity,’’ Journal of Pharmacology

and Experimental Therapeutics, 218:805–

810, 1981.

40. Sato, C., and C. S. Lieber, ‘‘Mechanism

of the Preventive Effect of Ethanol on

Acetaminophen-Induced Hepatotoxicity,’’

Journal of Pharmacology and Experimental

Therapeutics, 218:811–815, 1981.

41. Rumack, B. H. et al., ‘‘Acetaminophen

Overdose,’’ Archives of Internal Medicine,

141:380–385, 1981.

42. Lieber, C. S, ‘‘Interaction of Alcohol

and Drugs,’’ Practical Gastroenterology, 7:23–

24, 29–30, and 48, 1983.

43. Altomare, E. et al., ‘‘Interaction of

Ethanol with Acetaminophen Metabolism in

the Baboon,’’ Biochemical Pharmacology,

31:2207–2212, 1984.

44. Banda, P. W., and B. D. Quart, ‘‘The

Effect of Mild Alcohol Consumption on the

Metabolism of Acetaminophen in Man,’’

Research Communications in Chemical

Pathology and Pharmacology, 38:57–70,

1982.

45. Strubelt, O., ‘‘Alcohol Potentiation of

Liver Injury,’’ Fundamental and Applied

Toxicology, 4:144–151, 1984.

46. Rosen, G. M. et al., ‘‘Acetaminophen

Hepatotoxicity an Alternative Mechanism,’’

Biochemical Pharmacology, 32:2053–2059,

1983.

47. The Encyclopedia of Alcoholism, Facts

on File Publication, New York, 1982, s.v.

‘‘alcoholism’’ and ‘‘consumption’’.

48. United States Pharmacopeial

Dispensing Information—1993: Vol. I Drug

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13th ed., United States Pharmacopeial

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49. United States Pharmacopeial

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for the Patient Drug Information in Lay

Language, 13th ed., United States

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MD, p. 3.

50. Black, M., ‘‘Acetaminophen, Alcohol,

and the Liver,’’ Philadelphia Medicine,

82:230–237, 1986.

51. Davis, A. M. et al., ‘‘Severe Hepatic

Damage After Acetaminophen Use in

Psittacosis,’’ American Journal of Medicine,

74:349–352, 1983.

52. Kumar, S., and D. Rex, ‘‘Failure of

Physicians to Recognize Acetaminophen

Hepatotoxicity in Chronic Alcoholics,’’

Archives of Internal Medicine, 151:1189–

1191, 1991.

53. Wooton, F., and W. Lee,

‘‘Acetaminophen Hepatotoxicity in the

Alcoholic,’’ Southern Medical Journal,

83:1047–1049, 1990.

54. Bray, G. et al., ‘‘The Effect of Chronic

Alcohol Intake on Prognosis and Outcome in

Paracetamol Overdose,’’ Human

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55. Girre, C. et al., ‘‘Increased Metabolism

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Patients,’’ Alcoholism Clinical and

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56. Comment No. C150, Docket No. 77N–

0094, Dockets Management Branch.

57. Bell, H., H. Schonsby, and N.

Raknerud, ‘‘Severe Liver Damage After

Therapeutic Doses of Paracetamol,’’ Journal

of the Norwegian Medical Association,

107:1037–1040, 1987.
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58. Bidault, I. et al., ‘‘Do Cases of Hepatitis

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Acetaminophen Exist?,’’ Therapy, 42:387–

388, 1987.

59. Erickson, R. A., and B. A. Runyon,

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with Alcoholic Pancreatitis,’’ Archives of

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60. Luquel, L. et al., ‘‘Acute HepatoNephritis in an Alcoholic Following a

Therapeutic Dose of Acetaminophen,’’ La

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61. Stolt, C., and S. Johnsen, ‘‘A

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62. Vilstrup, V., N. C. Henningsen, and L.

F. Hansen, ‘‘Liver Damage After

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834, 1977.

63. Critchley, J. et al., ‘‘Is There a Place for

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1376, 1983.

64. Critchley, J. et al., ‘‘Paracetamol

Metabolism in Heavy Drinkers,’’ British

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277P, 1982.

65. Lauterburg, B. H., and M. E. Velez,

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29:1153–1157, 1988.

66. Farrell, G. C., W. G. E. Cooksley, and

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492, 1979.

67. Gabrielle, L. et al., ‘‘Determination of

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782, 1977.

68. Schoene, B. et al., ‘‘Determination of

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69. Data and information provided for June

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094W, Dockets Management Branch.

70. Summary minutes of the June 28 and

29, 1993, meeting of the FDA

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71. Data and information provided for the

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1993, joint meeting of the FDA

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75. ‘‘A Retrospective Review of Serious

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76. ‘‘Summary of Prospective Case Control

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89. Olsson, R., ‘‘Increased Hepatic

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90. Pirotte, J. H., ‘‘Apparent Potentiation by

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91. Rosenberg, D. M. et al.,

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103. Juul-Mo ̈ller, S. et al., ‘‘Double-Blind

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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, it is proposed that

21 CFR part 201 be amended as follows:

PART 201—LABELING

1. The authority citation for 21 CFR

part 201 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352,

353, 355, 356, 357, 358, 360, 360b, 360gg–

360ss, 371, 374, 379e; 42 U.S.C. 216, 241,

262, 264.

2. New § 201.322 is added to subpart

G to read as follows:

§ 201.322 Over-the-counter drug products

containing internal analgesic/antipyretic

active ingredients; required alcohol

warning.

(a) People who regularly consume

large quantities of alcohol have an

increased risk of adverse effects

(possible liver damage or

gastrointestinal bleeding) when they use

over-the-counter (OTC) drug products

containing internal analgesic/antipyretic

active ingredients. FDA concludes that

the labeling of OTC drug products

containing internal analgesic/antipyretic

active ingredients should advise

consumers with a history of heavy

alcohol use or abuse to consult a

physician about the use of these

products. Accordingly, any OTC drug

product, labeled for adult use,

containing 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) shall bear an alcohol

warning statement in its labeling as

follows:

(1) Acetaminophen. ‘‘Alcohol

Warning’’ [heading in boldface type]: ‘‘If

you drink 3 or more alcoholic beverages

daily, ask your doctor whether you

should take [insert product name] or

other pain relievers. [Product name]

may increase your risk of liver damage.’’

(2) Aspirin, carbaspirin calcium,

choline salicylate, ibuprofen,

ketoprofen, magnesium salicylate,

naproxen sodium, and sodium

salicylate. ‘‘Alcohol Warning’’ [heading

in boldface type]: ‘‘If you drink 3 or

more alcoholic beverages daily, ask your

doctor whether you should take [insert

product name] or other pain relievers.

[Product name] may increase your risk

of stomach bleeding.’’

(3) Combinations of acetaminophen

with other analgesic/antipyretic active

ingredients listed in § 201.322(a)(2).

‘‘Alcohol Warning’’ [heading in boldface

type]: ‘‘If you drink 3 or more alcoholic

beverages daily, ask your doctor

whether you should take [insert product
Federal Register / Vol. 62, No. 220 / Friday, November 14, 1997 / Proposed Rules 61057

name] or other pain relievers. [Product

name] may increase your risk of liver

damage and stomach bleeding.’’

(b) 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 warning

in the product’s labeling. Such labeling

may be put into use without advance

approval of FDA provided it includes at

least the information included in

paragraph (a) of this section.

(c) Any drug product subject to this

section that is not labeled as required

and that is initially introduced or

initially delivered for introduction into

interstate commerce after (date 6

months after

date of publication of the final rule in

the Federal Register), is misbranded

under section 502 of the Federal Food,

Drug, and Cosmetic Act and is subject

to regulatory action.

Dated: August 20, 1997.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 97–30035 Filed 11–13–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF THE INTERIOR

Bureau of Indian Affairs

25 CFR Part 11

RIN 1076–AD76

Law and Order on Indian Reservations;

Correction

AGENCY: Bureau of Indian Affairs,

Interior.

ACTION: Correction to proposed

regulations.

SUMMARY: This document contains

corrections to the proposed regulations

which were published Friday, July 5,

1996 (61 FR 35158) and corrections to

the proposed regulations which were

published Wednesday, February 26,

1997 (62 FR 8665). The proposed rule

amends regulations governing Courts of

Indian Offenses.

DATES: Comments must be received on

or before December 15, 1997.

ADDRESSES: Comments are to be mailed

to Bettie Rushing, Office of Tribal

Services, Bureau of Indian Affairs, 1849

C Street, NW, MS 4641–MIB,

Washington, DC 20240; or, hand

delivered to Room 4641 at the same

address.

FOR FURTHER INFORMATION CONTACT:

Bettie Rushing, Bureau of Indian Affairs

(202) 208–4400.

SUPPLEMENTARY INFORMATION:

Background

The proposed rule that is the subject

of these corrections supersedes 25 CFR

11.100(a) and affects those tribes that

have exercised their inherent

sovereignty by removing the names of

those tribes from the list of Courts of

Indian Offenses.

The Assistant Secretary-Indian

Affairs, or her designee, has received

law and order code adopted by the

Confederated Tribes of the Goshute

Reservation of Nevada in accordance

with their constitutions and by-laws and

approved by the appropriate bureau

official. The Assistant Secretary-Indian

Affairs recognizes that this court was

established in accordance with the

tribe’s constitutions and by-laws. Also,

the list of Courts of Indian Offenses has

been corrected to include tribes

inadvertently omitted from the

correction and to reflect the decision of

the Court in Fletcher v. United States,

No. 95–5208 (10th Cir. Dec. June 10,

1997, reh. den. Aug. 18, 1997).

Inclusion in § 11.100, Where are

Courts of Indian Offenses established?,

does not defeat the inherent sovereignty

of a tribe to establish tribal courts and

exercise jurisdiction under tribal law.

Tillett v. Lujan, 931 F.2d 636, 640 (10th

Cir. 1991) (CFR courts ‘‘retain some

characteristics of an agency of the

federal government’’ but they ‘‘also

function as tribal courts’’); Combrink v.

Allen, 20 Indian L. Rep. 6029, 6030 (Ct.

Ind. App., Tonkawa, Mar. 5, 1993) (CFR

court is a ‘‘federally administered tribal

court’’); Ponca Tribal Election Board v.

Snake, 17 Indian L. Rep. 6085, 6088 (Ct.

Ind. App., Ponca, Nov. 10, 1988) (‘‘The

Courts of Indian Offenses act as tribal

courts since they are exercising the

sovereign authority of the tribe for

which the court sits.’’). Such exercise of

inherent sovereignty and the

establishment of tribal courts shall

comply with the requirements in 25

CFR 11.100(c).

Need for Correction

As published, the proposed rule and

the correction to the proposed rule

contain errors which may prove to be

misleading and are in need of

clarification.

Correction of Publication

Accordingly, the publication on July

5, 1996 (61 FR 35158), of the proposed

regulations, which were the subject of

FR Doc. 96–16039, and the publication

of February 26, 1997 (62 FR 8664),

corrections to the proposed regulations,

which were the subject of FR Doc. 97–

4686, are corrected as follows:

§ 11.100 [Corrected]

In the Federal Register published July

5, 1996 on page 35159, and corrected on

February 26, 1997 on 1997 on page

8665, in § 11.100, paragraph (a) is,

corrected to read as follows:

§ 11.100 Where are Courts of Indian

Offenses established?

(a) Unless indicated otherwise in this

part, the regulations in this part apply

to the Indian country (as defined in 18

U.S.C. 1151) occupied by the tribes

listed below:

(1) Red Lake Band of Chippewa

Indians (Minnesota).

(2) Te-Moak Band of Western

Shoshone Indians (Nevada).

(3) Yomba Shoshone Tribe (Nevada).

(4) Kootenai Tribe (Idaho).

(5) Shoalwater Bay Tribe

(Washington).

(6) Eastern Band of Cherokee Indians

(North Carolina).

(7) Ute Mountain Ute Tribe

(Colorado).

(8) Quechan Indian Tribe (Arizona)

(except resident members).

(9) Hoopa Valley Tribe, Yurok Tribe

and Coast Indian Community of

California (California jurisdiction

limited to special fishing regulations).

(10) Louisiana Area (includes

Coushatta and other tribes located in the

State of Louisiana which occupy Indian

country and which accept the

application of this part); Provided, that

this part shall not apply to any

Louisiana tribe other than the Coushatta

Tribe until notice of such application

has been published in the Federal

Register.

(11) For the following tribes located in

the former Oklahoma Territory

(Oklahoma):

(i) Absentee Shawnee Tribe of Indians

of Oklahoma.

(ii) Apache Tribe of Oklahoma.

(iii) Caddo Tribe of Oklahoma.

(iv) Cheyenne-Arapaho Tribe of

Oklahoma.

(v) Citizen Band of Potawatomi

Indians of Oklahoma.

(vi) Comanche Tribe of Oklahoma

(Except Comanche Children’s Court).

(vii) Delaware Tribe of Western

Oklahoma.

(viii) Fort Sill Apache Tribe of

Oklahoma.

(ix) Iowa Tribe of Oklahoma.

(x) Kaw Tribe of Oklahoma.

(xi) Kickapoo Tribe of Oklahoma.

(xii) Kiowa Tribe of Oklahoma.

(xiii) Otoe-Missouria Tribe of

Oklahoma.