`[Federal Register Volume 62, Number 220 (Friday, November 14, 1997)]
[Proposed Rules]
[Pages 61041-61057]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-30035]


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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 < 0.01). 
While both groups achieved Cmax at approximately the same 
time, Cmax for the nondrinkers was significantly higher than 
for the alcohol abusers (20.2 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 < 0.001).
    Girre et al. (Ref. 55) obtained similar results in a comparison of 
the pharmacokinetics of acetaminophen in 12 chronic alcohol abusers and 
12 healthy controls. The mean daily alcohol consumption for the alcohol 
abusers was 210  95 g of absolute alcohol for a mean 
duration of 14.5  9.5 years. Control subjects drank only 
moderately (defined in the study as a weekly alcohol consumption < 80 
g) and were asked to abstain from alcohol consumption for 36 hours 
before the trial. A single, 1-g acetaminophen dose was administered 
following a 12-hour fast. Blood samples were taken before acetaminophen 
intake and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24 hours 
thereafter.
    The following pharmacokinetic parameters were determined: 
Cmax, tmax, AUC, CL, and t1/2. A 
comparison of Cmax and tmax showed no significant 
differences between the two groups. However, in the alcohol abusers, 
t1/2 was significantly shorter than for the controls (1.71 
versus 2.84 hours, p < 0.05). CL was increased in the alcohol abusers 
(30.34 versus 26.52 L/hour, p < 0.05).
    Observed increases in the excretion of metabolites (mercapturate 
and cysteine) of the microsomal pathway also suggest increased activity 
of this pathway in this population. Villeneuve et al. (Ref. 27) 
observed an increased urinary excretion of cysteine and mercapturate 
metabolites of acetaminophen in alcohol abusers. The authors compared 
the pharmacokinetics of acetaminophen metabolism in nine alcohol 
abusers (457  50 g ethanol per day for at least 3 months), 
eleven subjects with alcoholic cirrhosis, and six healthy normal 
subjects. Subjects in the control group consumed no alcohol or other 
medications.
    Subjects with a history of alcohol abuse were selected based on the 
absence of alcoholic hepatitis or cirrhosis (determined by physical 
examination and standard biological tests for liver function) and the 
lack of drug use (other than alcohol). The diagnosis of cirrhosis was 
confirmed by liver biopsy. Cirrhotic subjects were hospitalized at the 
time of the study and did not consume alcohol for at least 30 days 
prior to the start of the study. Five of the cirrhotic subjects 
received spironolactone (100 mg/day) for treatment of their ascites.
    After 12 hours of fasting, a liquid preparation of acetaminophen 
was administered orally at a dose of 12 mg/kilogram with 200 mL of 
water (mean dose: Controls 920 mg, alcohol abusers 805 mg, and 
cirrhotics 872 mg). Blood samples were taken at 0, 5, 15, 30, 45, 60, 
90, 120, 180, 240, 300, 360, and 420 minutes after ingesting 
acetaminophen. Urine was collected for 24 hours after ingestion. The 
apparent oral clearance (CLo), AUC, and t1/2 were 
determined.
    The percentage of the acetaminophen dose eliminated in the urine of 
alcohol abusers was significantly decreased from the controls (88.6 to 
63.4 percent). In the cirrhotics, clearance was decreased by 50 percent 
(p < 0.05), t1/2 was extended (p < 0.05), and urinary 
elimination was not significantly decreased in relation to the 
controls. The level of glucuronide and sulfate conjugates in the 
alcohol abusers was not significantly different in comparison to the 
controls. The excretion of cysteine and mercapturate metabolites of 
acetaminophen was increased in a significant manner for the alcohol 
abusers (p < 0.05). When this increase

[[Page 61049]]

was expressed as a percent of the administered dose, the mean 
augmentation for the alcohol abusers was 92 percent. In cirrhotics, the 
profile of these metabolites was comparable to the controls.
    An additional mechanism of the increased sensitivity of alcohol 
abusers to acetaminophen toxicity has been postulated to be a 
diminished capacity to detoxify NAPQI by conjugation with GSH. 
Lauterberg and Velez (Ref. 65) studied glutathione levels and the 
formation of the toxic metabolite of paracetamol (acetaminophen) in 
chronic alcohol abusers. Study subjects were recruited from an alcohol 
treatment program and had a history of heavy drinking (average 
consumption of 180 g ethanol per day) up to 2 days prior to study 
initiation. Some of these subjects received chlorodiazepoxide (last 
dose 10 mg more than 10 hours prior to the study) as part of their 
treatment. Control subjects denied consumption of alcohol in excess of 
10 g/day and were not taking any medications.
    The study determined the plasma GSH levels of alcohol abusers 
without clinical evidence of alcoholic liver disease and in controls 
following an overnight fast. The GSH plasma concentration was about 50 
percent lower in alcohol abusers than in the controls (8.48 versus 4.35 
micromoles (mole), p < 0.05). In contrast, the plasma 
concentration of free cysteine was similar for alcohol abusers and for 
controls.
    The study also examined the effect of acetaminophen administration 
on plasma GSH. Subjects were given a 2 g acetaminophen dose in lemonade 
after a 10-hour fast. Blood samples were taken hourly for 4 hours. 
Urine was collected for 6 hours. After the administration of 
acetaminophen, the plasma GSH concentration in controls was 
significantly decreased at 3 hours from a mean concentration of 8.37 to 
6.26 mole (p < 0.02 by paired t-test). The plasma GSH levels 
in alcohol abusers were significantly lower than baseline at 2 and 3 
hours (3.10 and 2.40 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.
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Medication and Alcohol Abuse: A Dangerous Combination for the Liver 
and the Kidney,'' Scandinavian

[[Page 61054]]

Journal of Gastroenterology, 22:701-704, 1987.
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    34. McLean, A. E. M., and P. A. Day, ``The Effect of Diet on the 
Toxicity of Paracetamol and the Safety of Paracetamol-Methionine 
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    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.
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[[Page 61055]]

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Poisoning,'' British Medical Journal, 3:557-558, 1970.
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Fibrosis Due to Low Doses of Paracetamol,'' Lancet, 1:1016-1018, 
1978.
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Prolonged Use of Acetaminophen: Case Report,'' Boletin-Asociacion 
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Chronic Alcohol Abusers--A Plea for Greater Consumer Awareness,'' 
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Intake of Low Doses of Paracetamol,'' Journal of Internal Medicine, 
231:567-570, 1992.
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with Acetaminophen,'' Hepato-Gastroenterology, 30:58, 1983.
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Paracetamol,'' Lancet, 2:152-153, 1978.
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Hepatotoxicity from Small Doses of Acetaminophen,'' Annals of 
Internal Medicine, 101:403, 1984.
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Dysfunction in Infectious Mononucleosis,'' Southern Medical Journal, 
70:660-661, 1977.
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of Internal Medicine, 88:267-268, 1978.
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Acetaminophen Hepatotoxicity with Fasting and Ethanol Use,'' Journal 
of the American Medical Association, 272:1845-1850, 1994.
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D. A. Kessler, FDA, dated March 11, 1996, in OTC Vol. 03AWNPR, 
Docket No. 77N-094W, Dockets Management Branch.
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(Paracetamol) Hepatotoxicity with Regular Intake of Alcohol: 
Analysis of Instances of Therapeutic Misadventure,'' Hepatology, 
22:767-773, 1995.
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Journal of Medicine, 333:1118-1127, 1995.
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Mucosa: Endoscopic, Histologic, and Functional Assessment,'' 
Clinical Investigations in Medicine, 10:259-263, 1987.
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19th ed., edited by J. B. Wyngaarden, L. H. Smith, and J. C. 
Bennett, W. B. Saunders Co., Philadelphia, pp. 649-650, 1992.
    99. Domschke, S., and W. Domschke, ``Gastrointestinal Damage Due 
to Drugs, Alcohol and Smoking,'' in Clinics in Gastroenterology, W. 
B. Saunders Co., London, pp. 419-424, 1984.
    100. MacMath, T. L., ``Alcohol and Gastrointestinal Bleeding,'' 
Emergency Medicine Clinics of North America, 8:859-872, 1990.
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Group, ``Final Report on the Aspirin Component of the Ongoing 
Physicians' Health Study,'' New England Journal of Medicine, 
321:129-135, 1989.
    102. Peto, R. et al., ``Randomized Trial of Prophylactic Daily 
Aspirin in British Male Doctors,'' British Medical Journal, 296:313-
316, 1988.
    103. Juul-Moller, S. et al., ``Double-Blind Trial of Aspirin in 
Primary Prevention of Myocardial Infarction in Patients with Stable 
Chronic Angina Pectoris,'' Lancet, 340:1421-1425, 1992.
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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.
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Attack (UK-TIA) Aspirin Trial: Interim Results,'' British Medical 
Journal, 296:316-320, 1988.
    107. Bousser, M. G. et al., ```AICLA' Controlled Trial of 
Aspirin and Dipyridamole

[[Page 61056]]

in the Secondary Prevention of Athero-Thrombotic Cerebral 
Ischemia,'' Stroke, 14:5-14, 1983.
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Acid After Cerebral Infarction,'' Stroke, 18:325-334, 1987.
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Cerebral Ischemia. Part II: Surgical Group,'' Stroke, 9:309-318, 
1978.
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Trial (SALT) of 75 mg Aspirin as Secondary Prophylaxis After 
Cerebrovascular Ischaemic Events,'' Lancet, 338:1345-1349, 1991.
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Coronary Heart Disease,'' Journal of Chronic Disease, 29:625-642, 
1976.
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Randomized, Controlled Trial of Aspirin in Persons Recovered from 
Myocardial Infarction,'' Journal of the American Medical 
Association,'' 243:661-669, 1980.
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``Persantine and Aspirin in Coronary Heart Disease,'' Circulation, 
62:449-461, 1980.
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Comparison of Acetylsalicylic Acid, Placebo and Phenprocoumon in 
Secondary Prevention of Myocardial Infarction,'' Circulation, 62 
(Suppl V):63-72, 1980.
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Against Acute Myocardial Infarction and Death in Men with Unstable 
Angina,'' New England Journal of Medicine, 309:396-403, 1983.
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of Warfarin and Aspirin for Prevention of Thromboembolic 
Complications in Chronic Atrial Fibrillation,'' Lancet, 1:175-179, 
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Occlusion by Low-Dose Aspirin and Dipyridamole,'' Circulation, 
82:765-773, 1990.
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Improves Vein Graft Patency Early and Late After Coronary Artery 
Bypass Graft Surgery,'' Circulation, 83:1526-1533, 1991.
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Acetyl-Salicylic Acid in the Secondary Prevention of Mortality from 
Myocardial Infarction,'' British Medical Journal, 1:436-440, 1974.
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Disease: The Status of the U-Shaped Curve,'' British Medical 
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the Cardiovascular Level,'' Alcohol, 7:537-546, 1990.
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Health and Human Services, Home and Garden Bulletin No. 232, U.S. 
Department of Agriculture.
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Sciences, 18th ed., Mack Publishing Co., Easton, PA, pp. 1112, 1117, 
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03AWNPR, Docket No. 77N-094W, Dockets Management Branch.
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03AWNPR, Docket No. 77N-094W, Dockets Management Branch.
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03AWNPR, Docket No. 77N-094W, Dockets Management Branch.
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19-872, in OTC Vol. 03AWNPR, Docket No. 77N-094W, Dockets Management 
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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`