Over the-Counter Drug Products Containing Analgesic/Antipyretic Active Ingredients for Internal Use; Required Alcohol Warning

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.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of

proposed rulemaking that would establish alcohol warnings for all over-

the-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:

[[Page 61042]]

I. Background

In the Federal Register of July 8, 1977 (42 FR 35346), FDA

published, under Sec. 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 well-

documented 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-p-benzoquinoneimine (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

[[Page 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 Sec. 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 acetaminophen-induced 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

[[Page 61044]]

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 aspirin-

prolonged 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

organ-specific (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 Sec. 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

[[Page 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

(mole/L) or 17.4 milligrams (mg)/deciliter (dL) (reference

bilirubin 3 to 25 mole/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 (g/mL). No liver

biopsy was done. N-acetylcysteine (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 mole/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-year-old 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 (kat/L) and ALT 14.0 kat/L).

Reference levels for AST and ALT were less than 0.7 kat/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 g/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 mole/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

[[Page 61046]]

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 mole/L or 5 mg/dL. At 6 hours post

ingestion, the serum acetaminophen level was 0.04 g/mL. On day

2 the level was 0.005 g/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

mole/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 mole/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 moles/L,

[[Page 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 mole/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

acetaminophen-induced 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 flu-like 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 g/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 mole/L. The serum

acetaminophen level was 5 g/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 acetaminophen-

containing 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 g/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 post-mortem 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 g/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

[[Page 61048]]

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 well-documented 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 half-life 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 max at approximately the same

time, Cmax for the nondrinkers was significantly higher than

for the alcohol abusers (20.2 g/mL versus 15.4 g/mL).

The CL was also significantly accelerated in the alcohol abusers (247.4

mL/minute (min) versus 154.4 mL/min, p 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 max, 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 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 1/2 was extended (p mole), p mole (p mole, respectively, baseline 4.66

mole). 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

[[Page 61050]]

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 anti-

inflammatory drugs (NSAID's), including ibuprofen, ketoprofen, and

naproxen sodium. The authors stated that NSAID's share the risks of

causing

[[Page 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, ingredient-specific 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 alcohol-

containing 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.

[[Page 61052]]

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 Sec. 201.322. A supplement must be

submitted under Sec. 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-

the-Counter 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

[[Page 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

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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

[[Page 61054]]

Journal of Gastroenterology, 22:701-704, 1987.

5. Emby, D. J., and B. N. Fraser, ``Hepatotoxicity of

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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

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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

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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

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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

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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

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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 Medicale, 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. Wojcicki, 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., ``Acetaminophen-Induced 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:

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United States Pharmacopeial Convention, Inc., Rockville, MD, pp. 3-

4.

49. United States Pharmacopeial Dispensing Information--1993:

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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 Experimental

Toxicology, 10:435-438, 1991.

55. Girre, C. et al., ``Increased Metabolism of Acetaminophen in

Chronically Alcoholic Patients,'' Alcoholism Clinical and

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[[Page 61055]]

58. Bidault, I. et al., ``Do Cases of Hepatitis Due to the

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90. Pirotte, J. H., ``Apparent Potentiation by Phenobarbital of

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91. Rosenberg, D. M. et al., ``Acetaminophen and Hepatic

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92. Ware, A. J. et al., ``Acetaminophen and the Liver,'' Annals

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of the American Medical Association, 272:1845-1850, 1994.

94. Letter from P. A. Malone, Stein, Mitchell, and Mezines, to

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96. Lee, W. M., ``Drug Induced Hepatotoxicity,'' New England

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Aspirin in British Male Doctors,'' British Medical Journal, 296:313-

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103. Juul-Moller, S. et al., ``Double-Blind Trial of Aspirin in

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Mortality After Myocardial Infarction,'' Lancet, II:1313-1315, 1979.

105. Fields W. S., et al., ``Controlled Trial of Aspirin in

Cerebral Ischemia,'' Stroke, 8:301-316, 1977.

106. UK-TIA Study Group, ``United Kingdom Transient Ischaemic

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[[Page 61056]]

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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 Sec. 201.322 is added to subpart G to read as follows:

Sec. 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 Sec. 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

[[Page 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 Sec. 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