[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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[[Page 61054]]
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19. Levinson, M., ``Ulcer, Back Pain, and Jaundice in an
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27. Villeneuve, J. P. et al., ``Pharmacokinetics and Metabolism
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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
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Pharmacology and Experimental Therapeutics, 187:211-217, 1973.
36. Wright, N., and L. F. Prescott, ``Potentiation by Previous
Drug Therapy of Hepatotoxicity Following Paracetamol Overdosage,''
Scottish Medical Journal, 18:56-58, 1973.
37. Strubelt, O., F. Obermeier, and C. P. Siegers, ``The
Influence of Ethanol Pretreatment on the Effects of Nine Hepatotoxic
Agents,'' Acta Pharmacologica and Toxicologica, 43:211-218, 1978.
38. Sato, C., Y. Matsuda, and C. S. Lieber, ``Increased
Hepatotoxicity of Acetaminophen after Chronic Ethanol Consumption in
the Rat,'' Gastroenterology, 80:140-148, 1981.
39. Sato, C., M. Nakano, and C. S. Lieber, ``Prevention of
Acetaminophen-Induced Hepatotoxicity by Acute Ethanol Administration
in the Rat: Comparison with Carbon Tetrachloride-Induced
Hepatotoxicity,'' Journal of Pharmacology and Experimental
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40. Sato, C., and C. S. Lieber, ``Mechanism of the Preventive
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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