[Federal Register Volume 63, Number 205 (Friday, October 23, 1998)]
[Rules and Regulations]
[Pages 56789-56802]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-28520]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 77N-094W]


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

AGENCY: Food and Drug Administration, HHS.

ACTION:  Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations to require an alcohol warning for all over-the-counter 
(OTC) drug products, labeled for adult use, containing internal 
analgesic/antipyretic active ingredients. The required warning 
statements advise consumers with a history of heavy alcohol use to 
consult a physician for advice about the use of OTC internal analgesic/
antipyretic drug products. FDA is issuing this final rule after 
considering comments on the agency's proposed regulation for OTC 
internal analgesic, antipyretic, and antirheumatic drug products; a 
proposed regulation to establish an alcohol warning; recommendations of 
its Nonprescription Drugs Advisory Committee (NDAC) and Arthritis Drugs 
Advisory Committee (ADAC); and new data and information that have come 
to the agency's attention. This final rule is part of the ongoing

[[Page 56790]]

review of OTC drug products conducted by FDA.

EFFECTIVE DATE:  April 23, 1999.

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:

I. Background

    In the Federal Register of November 16, 1988 (53 FR 46204), FDA 
published a notice of proposed rulemaking, in the form of a tentative 
final monograph (TFM), that would establish conditions in part 343 (21 
CFR part 343) under which OTC internal analgesic, antipyretic, and 
antirheumatic drug products are generally recognized as safe and 
effective and not misbranded. In the preamble to the proposed rule of 
this current rulemaking, the agency addressed concerns raised in the 
1988 proceeding about 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 46217). The agency 
found that the available data did not provide a sufficient basis to 
require such a warning at that time. Interested persons were invited to 
submit new data or file written comments, objections, or requests for 
oral hearing before the Commissioner of Food and Drugs regarding the 
proposal.
    In response to the proposed rule, the agency received a number of 
comments containing new data addressing the need for an alcohol warning 
for acetaminophen. Copies of the comments received are on display in 
the Dockets Management Branch (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    On June 29, 1993, NDAC met to consider the need for an alcohol 
warning for acetaminophen. NDAC concluded that heavy drinkers are at 
increased risk for developing liver toxicity when using acetaminophen 
and recommended that the labeling of OTC analgesic/antipyretic drug 
products containing this ingredient bear an alcohol warning. However, 
NDAC recommended that the agency not implement an alcohol warning for 
OTC analgesic/antipyretic drug products containing acetaminophen until 
it had a chance to consider data on the risk of alcohol use with other 
internal analgesic/antipyretic ingredients.
    On September 8, 1993, NDAC and ADAC (the Committees) met jointly to 
evaluate the available data on the use of aspirin and other OTC 
analgesics by heavy alcohol users or abusers. The Committees concluded 
that the use of aspirin, ibuprofen, and naproxen sodium increases the 
risk of upper gastrointestinal (UGI) 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 a recommendation on the need for an alcohol warning for OTC drug 
products containing other monograph salicylates (carbaspirin calcium, 
choline salicylate, magnesium salicylate, or sodium salicylate) was 
outside their advisory scope.
    In the Federal Register of November 14, 1997 (62 FR 61041), the 
agency published a proposed amendment of part 201 (21 CFR part 201) 
that would establish alcohol warnings for all OTC drug products labeled 
for adult use containing internal analgesic/antipyretic active 
ingredients. This warning would be required for all OTC internal 
analgesic/antipyretic drug products whether marketed under an OTC drug 
monograph or an approved new drug application (NDA).
    In the proposal to amend part 201, the agency advised that any 
final rule based on the proposal will be effective 6 months after the 
date of publication in the Federal Register. Therefore, on or after 
April 23, 1999, any OTC drug product that is subject to this final 
rule, that contains nonmonograph labeling may not be initially 
introduced or initially delivered for introduction into interstate 
commerce unless it is the subject of an approved application or 
abbreviated application. Further, any OTC drug product subject to this 
final rule that is repackaged or relabeled after the effective date of 
the rule must be in compliance with the rule regardless of the date 
that the product was initially introduced or initially delivered for 
introduction into interstate commerce.

II. The Agency's Response to Comments

A. Comments on Specific Ingredients

    1. Two comments argued that the agency's proposed requirement for 
an alcohol warning for OTC analgesic/antipyretic drug products 
containing aspirin is not based on sound scientific evidence. One 
comment asserted that it is necessary for FDA to demonstrate that a 
significant risk of gastrointestinal (GI) bleeding would result if 
heavy alcohol users were not specifically warned against the use of 
aspirin. Both comments suggested that the proposed requirement is 
contrary to agency statements in the TFM for OTC internal analgesic/
antipyretic drug products that warning statements should be ``limited 
to those that are scientifically documented, clinically significant, 
and important for the safe and effective use of products by consumers'' 
(53 FR 46204 at 46213).
    In support of this position, one comment included data that purport 
to show that heavy alcohol use: (1) Does not increase the risk of 
stomach bleeding (Refs. 1 through 4), (2) alcohol protects against GI 
problems (Refs. 5 and 6), and (3) GI bleeding in patients who reported 
prior aspirin and alcohol use is not more severe (Ref. 7). The comment 
also asserted that its evaluation of the adverse drug reaction data 
contained in FDA's Spontaneous Reporting System (SRS) failed to 
demonstrate a correlation between GI bleeding and heavy alcohol use, 
although the results of this evaluation were not included.
    Another comment supporting the need for an alcohol warning for OTC 
analgesic/antipyretic drug products containing aspirin reviewed the 
data evaluated by the agency during the development of its proposal. To 
substantiate the need for an alcohol warning for aspirin, the comment 
also included data from a recently published study of the relationship 
between aspirin and nonsteroidal anti-inflammatory drug (NSAID) use and 
GI perforation (Ref. 8).
    The agency continues to believe that warning statements should be 
limited to those that are scientifically based, clinically relevant, 
and important for the safe and effective use of these products by 
consumers. The agency disagrees with the comments asserting that the 
alcohol warning is not based on solid scientific evidence. An alcohol 
warning is needed for OTC analgesic/antipyretic drug products 
containing nonsteroidal anti-inflammatory ingredients, including 
aspirin. This warning is based on the data and information on the 
adverse GI effects of aspirin and other NSAID ingredients, the adverse 
GI effects of alcohol use, and the documented risk of combining them.
    Although the previous comments pertain specifically to aspirin-
containing OTC analgesic/antipyretic products, the agency's response 
will provide the scientific reasoning for applying the alcohol warning

[[Page 56791]]

requirement to the pharmacologic class of OTC analgesic/antipyretic 
drug products containing nonsteroidal anti-inflammatory ingredients, 
which include aspirin, nonaspirin salicylates, ibuprofen, ketoprofen, 
and naproxen sodium.
    These OTC analgesic/antipyretic drug products contain NSAID 
ingredients, which belong to the carboxylic acid class. Aspirin and 
other salicylates are salicyclic acids; ibuprofen, ketoprofen, and 
naproxen sodium are derivatives of propionic acid. All of these 
ingredients share certain pharmacologic properties, including 
inhibitory effects on prostaglandin synthesis and platelet function. As 
with aspirin, propionic acid derivatives produce adverse GI side 
effects, alter platelet function, and can affect bleeding time (Refs. 9 
through 14). Adverse GI effects are caused by aspirin and nonaspirin 
NSAID ingredients, which can irritate the mucosal epithelium (stomach 
lining) directly and/or can suppress prostaglandin synthesis. 
Prostaglandins normally help protect the stomach lining by promoting 
secretion of mucus and bicarbonate, repair of epithelial (lining) 
cells, immune cell function, and blood flow. Adverse bleeding effects 
can occur because NSAID's inhibit platelet aggregation.
    Although there are data and information available concerning all of 
these ingredients, the largest body of data relied upon by the agency 
pertains to aspirin. Because these NSAID ingredients all share similar 
pharmacologic properties and can all cause adverse GI effects, 
including bleeding, it is reasonable for the agency to rely on the data 
pertaining to individual ingredients and to reason and apply these data 
to all of these NSAID ingredients. More specific comments concerning 
other ingredients will be addressed elsewhere in section II of this 
document.
    Drug-related adverse effects can be evaluated through clinical data 
collected various ways, including randomized controlled trials, cohort 
studies, case-control studies, surveys, and spontaneous case reports. 
Prospective, randomized, blinded clinical trials require large patient 
enrollments to demonstrate a difference between groups when adverse 
events are infrequent, even if serious. Thus, most studies which 
examine the adverse GI effects of NSAID's are observational rather than 
experimental. Observational studies provide important information when 
investigating an association between a risk and a predisposing event. 
However, these studies may be subject to specific biases which should 
be considered. For example, case-control studies examine the prevalence 
of NSAID (and alcohol) exposure in patients who already have the 
outcome (GI events or bleeding) with a control population, which is 
matched for other factors. These studies may suffer from recall bias; 
that is, individuals in cases may be more likely than controls to 
remember that they took an NSAID (or alcohol). When reviewing these 
data from various studies, the agency has taken into account the 
limitations of each study method. Despite the limitations of individual 
studies, the data generated by each of these methods collectively 
provide a sound body of evidence from which it is scientifically 
reasonable to assess risk. Therefore, the agency believes that the 
collected body of scientific evidence supports the labeled warning.
    As previously discussed in the notice of proposed rulemaking (62 FR 
61041 at 61049), the adverse GI effects of aspirin are well known. 
Medical texts document adverse effects associated with the use of 
aspirin. These effects include, but are not limited to, gastritis, 
ulcerations, and colitis (Refs. 15 through 18). In addition, aspirin 
irreversibly interferes with normal platelet function for the life of 
the platelet, prolongs the bleeding time, and interferes with clotting 
whenever bleeding occurs (Ref. 13). Nonsalicylate NSAID ingredients 
reversibly inhibit platelet aggregation for as long as the drug is in 
the blood (Refs. 13 and 14). GI mucosal damage caused by aspirin has 
been widely acknowledged in the medical literature (Ref. 15 through 
18), confirmed by endoscopic observational studies (Ref. 19), and 
taught through medical texts to students of medicine (Ref. 20).
    In 1977, the Advisory Review Panel for OTC Analgesic and 
Antipyretic Drug Products (the Panel) first reviewed relevant data and 
concluded that aspirin causes adverse GI effects. The Panel concluded 
that the adverse effects of aspirin on the GI system range from 
relatively mild effects such as gastric distress (minor stomach pain, 
heartburn, or nausea), mucosal irritation and occult (not easily seen) 
bleeding, to less frequent but more serious effects such as mucosal 
erosion, ulceration, and life-threatening massive bleeding. The Panel 
further concluded that the acute use of aspirin may activate symptoms 
of both gastric and duodenal ulcer (42 FR 35346 at 35386 through 35397, 
July 8, 1977).
    In addition to the Panel's conclusions, FDA also evaluated 
published literature, including studies which demonstrate adverse GI 
effects even with low-dose aspirin use (Refs. 21 and 22). The agency 
also reviewed data from controlled, prospective clinical trials on 
aspirin for cardiovascular and cerebrovascular uses and established 
that bleeding can occur with long-term aspirin use, even at low doses 
(62 FR 61041 at 61050).
    Just as aspirin is well known to produce adverse GI effects, 
including bleeding, it is also well known that alcohol is a gastric 
toxin and that heavy alcohol use may cause a number of adverse GI 
effects, including bleeding. Routinely heavy alcohol use is associated 
with a number of medical conditions. These conditions include, but are 
not limited to, esophagitis, varices, acute gastritis, hemorrhagic 
lesions of the duodenal villi, and peptic ulcer disease (Refs. 23 
through 28). Also, chronic heavy alcohol use can cause bleeding because 
of increased prothrombin time, decreased circulating platelets, and 
altered function of platelets (Ref. 13). Early (Ref. 23) and continuing 
(Refs. 24 through 26) study of the effects of alcohol on the stomach 
have been widely published in the scientific literature and alcoholic 
gastritis is a well-recognized cause of acute hemorrhagic gastritis 
(Ref. 29). These effects of heavy, chronic alcohol use on the GI system 
and bleeding parameters are explained in many standard medical 
textbooks (Refs. 25, 27 and 28).
    The Panel recognized alcohol as a major factor that may produce 
acute gastric mucosal lesions, and thus increase the risk of bleeding 
from the use of aspirin (42 FR 35346 at 35479). Given these 
observations and the well established and recognized medical acceptance 
of GI and bleeding problems associated with the use of either aspirin 
or alcohol, the agency was concerned about the risks present for 
consumers who routinely and heavily drink alcohol and also use aspirin. 
This concern led to a review of relevant medical literature and studies 
(Refs. 8, 30, and 31), which confirmed the increased risk of adverse GI 
events, including bleeding, when alcohol use and aspirin use are 
combined.
    Published studies which include randomized controlled clinical 
trials (Refs. 32 through 35), case-control studies (Refs. 8, 36 through 
39a), cohort studies (Ref. 40), meta-analyses (Refs. 41 and 42), 
physician surveys (Ref. 31), and case reports (Ref. 43) have 
established an association between NSAID's, including aspirin, and 
adverse GI events, including bleeding. Because chronic alcohol use 
causes GI disease and bleeding, some studies simply exclude these 
patients from entry or analysis when assessing the risk of NSAID use on 
adverse GI outcomes (Ref.

[[Page 56792]]

44). However, some studies have examined both NSAID and alcohol use 
(Refs. 8, 30, 31, and 45) and assessed the risk of developing adverse 
GI events, including bleeding.
    P. J. DeSchepper et al. (Ref. 45) measured fecal blood loss in 10 
healthy males in a double-blind, parallel study and in 12 healthy 
subjects in a double-blind crossover study. Fecal blood loss was 
demonstrated with aspirin ingestion and concomitant ingestion of 
alcohol significantly increased (by three times) this blood loss.
    D. Aarons et al. (Ref. 30) conducted a double blind prospective 
study of 27 healthy volunteers with initial normal baseline endoscopies 
who were given alcohol and either placebo, aspirin, or acetaminophen. 
Repeat endoscopy showed that alcohol and aspirin together caused 
significantly greater erythema (redness) due to irritation and 
hemorrhage in the stomach than alcohol alone.
    The agency has reviewed adverse events reported to its SRS data 
base (Ref. 43). From 1993 to 1995, 37 case reports were submitted for 
serious UGI bleeding, 36 involving hospitalizations and 1 death. Most 
bleeds were documented by endoscopy. In these reports, ibuprofen was 
listed as the suspect drug in patients who reported chronic alcohol use 
(nearly 80 percent reported alcoholism or more than two drinks/day). Of 
important note, concomitant use of salicylates, primarily aspirin, was 
reported in almost 50 percent of these cases, thus associating both 
ibuprofen and/or salicylates with these reports of bleeding. From 1994 
to 1996, five case reports were submitted for serious UGI bleeding with 
naproxen sodium listed as the suspect drug in patients who reported 
daily (or binge) alcohol ingestion. Two of these reports also listed 
salicylate use and two reports listed concomitant ibuprofen use. From 
1993 to 1996, 10 case reports were submitted for serious UGI bleeding 
with aspirin listed as the suspect drug in patients who also reported 
alcohol ingestion (more than 2 drinks/day or unspecified). All 10 cases 
were hospitalized. Cases of concomitant NSAID ingredient use were 
excluded. Thus, the agency's SRS data base provides additional serious 
adverse events documenting the association between NSAID ingredient use 
and UGI bleeding in persons with a history of chronic alcohol use.
    In a prospective community clinical case study, Lee et al. (Ref. 
46) endoscoped 400 consecutive patients hospitalized for UGI hemorrhage 
to identify factors which predispose patients who bleed from 
hemorrhagic erosive gastritis. Of the 74 patients with stomach 
bleeding, salicylate use (31 percent), alcohol use, usually chronic (27 
percent), or both (16 percent) were reported. There was no case-matched 
control and relative risk was not assessed. However, this study 
demonstrates that patients who have experienced hemorrhagic erosive 
gastritis (stomach bleeding) commonly report having used alcohol and/or 
salicylates.
    Peura et al. (Ref. 31) surveyed American College of 
Gastroenterology physicians to assess demographics, management 
strategies, and outcomes for 1,235 patients who were diagnosed with GI 
bleeding. OTC doses of NSAID's were associated with a three-fold 
increased risk for developing GI bleeding and alcohol use increased 
this risk to four-fold.
    Lanas et al. (Ref. 8) conducted a single-center, prospective, case-
controlled study, which examined the relationship between NSAID use, 
including aspirin, and GI perforation. Detailed clinical histories and 
laboratory tests were obtained in 76 hospital admitted patients with 
surgically documented GI perforations and in 152 matched case controls. 
Histories of NSAID use were confirmed by measuring platelet cyclo-
oxygenase activity. In the study cohort, 67 percent of the patients 
used aspirin (90 percent of these were over-the-counter formulations). 
The calculated odds ratio (OR) for GI perforation in patients who had 
used an NSAID within a week prior to hospitalization was 6.64 (95 
percent confidence interval: 3.6-12.2; p < 0.0001) as compared to those 
who had not. Other independent risk factors for perforation included 
smoking (OR: 3.88; 95 percent CI: 2.15-7.0; p<0.0001), alcohol 
ingestion (OR: 3.25; 95 percent CI: 1.81-5.82; p<0.0001), and peptic 
ulcer disease (OR: 3.29; 95 percent CI: 1.74-6.21; p<0.0005). The 
combination of NSAID's, smoking, and alcohol increased the risk of GI 
perforation (OR: 10.69; 95 percent CI: 3.60-29.87). Because the study 
was conducted in Spain, a small number of patients in both cohorts 
reported use of NSAID's which are not available in the United States. 
However, the study conclusions remain valid for the NSAID class and, 
importantly, for nonprescription aspirin.
    Although acute ingestion of aspirin and alcohol causes gastric 
hemorrhage (Ref. 30) in previously normal gastric mucosa, the increased 
bleeding risk from NSAID's in chronic heavy alcohol users can be 
further compounded by coexisting problems such as prolonged prothrombin 
time due to liver disease, decreased number of circulating platelets, 
and pre-existing GI disease (e.g., esophageal varices, ulcers, or 
alcoholic gastritis) (Ref. 13). Alcohol also potentiates the 
prolongation of bleeding time produced by aspirin and nonaspirin 
NSAID's, including ibuprofen (Ref. 14). A retrospective cohort study, 
using a Medicaid data base, was designed to determine the risk and cost 
of adverse GI effects associated with NSAID use (Ref. 47). Logistic 
regression analysis showed NSAID use was significantly associated with 
each defined GI side effect (i.e., ulcers, gastritis, bleeding) 
(p<.001) and alcohol-related diagnoses were a significant independent 
predictor of increased risk (p<.05) for GI bleeding and hemorrhagic 
gastritis. Therefore, co-existing GI and bleeding problems in chronic 
heavy alcohol users may pre-dispose to the increased bleeding risk from 
NSAID ingredients.
    The data and studies presented provide sound and convincing 
evidence to support the conclusion that consumers are at increased risk 
of adverse GI effects when using OTC analgesic/antipyretic products, 
including aspirin, in combination with routine heavy alcohol use (Refs. 
8 and 31). While the data and studies show that there is an increased 
risk to consumers who combine these drug products with routine heavy 
alcohol use, the agency acknowledges that the data differ as to the 
exact magnitude of this increased risk.
    The agency again convened expert advisors in 1993 (Refs. 48 to 50) 
in three separate advisory committee meetings with NDAC and ADAC, to 
discuss the question of whether OTC analgesic/ antipyretic products 
containing aspirin should bear an alcohol warning. The advisory 
committee experts concluded that aspirin increases the risk of UGI 
bleeding in heavy alcohol users or abusers and overwhelmingly concluded 
that the data support an alcohol warning for aspirin. A complete 
discussion of this conclusion can be found in the proposed rulemaking 
(62 FR 61043 through 61044).
    The agency has reviewed the data and information submitted with the 
comments, which both oppose and support a requirement for an alcohol 
warning on OTC analgesic/antipyretic drug products containing NSAID 
ingredients, including aspirin. The agency's analysis of these data 
follows.
    Holvoet et al. (Ref. 1) was reviewed by the Committees which 
heavily criticized the study design and did not use it as a basis for 
their recommendation (Ref. 48). Coggon, Langman, and Spiegelhelter 
(Ref. 2) was a case-control

[[Page 56793]]

study in patients with GI bleeding which reported an increased risk (OR 
of 3.7, 95 percent CI: 2.2-6.4) for patients who had recently used 
aspirin; but this study did not detect an added risk associated with 
alcohol use. However, the study groups were not balanced for alcohol-
use history (p<0.02), compromising the ability of the study to 
determine the additional risk, if any, in heavy alcohol users. Bartle, 
Gupta, and Lazor (Ref. 3) failed to detect an increased risk of acute 
UGI bleeding with weekly alcohol ingestion of 280 milliliters. The 
investigators noted, and the agency concurs, that more patients would 
be required to assess whether or not an association exists. Although 
Schubert et al. (Ref. 6) reported a decreased risk of duodenal ulcer 
disease with alcohol use, the study lacked a matched case-control 
comparator arm and failed to quantify alcohol ingestion and other co-
factors which may be associated with risks for developing ulcer 
disease.
    Likewise, the Cohen et al. (Ref. 5) study submitted to demonstrate 
that alcohol is protective against GI bleeding caused by aspirin is not 
relevant because this study excluded patients without existing GI 
disease and those who drank more than two alcoholic drinks per day. 
Thus, the study excluded the very target population required to answer 
the question addressed by the agency, namely, individuals who consume 
three or more alcoholic drinks every day and/or have concomitant 
alcohol associated GI disease. The investigators concluded, and the 
agency concurs, that it is impossible to determine from this study that 
alcohol protects patients who take aspirin.
     Jensen et al. (Ref. 7) reported that alcohol and aspirin use prior 
to hospital admission for the treatment of UGI bleeding was not 
associated with certain surrogate variables which were used to estimate 
the severity of GI bleeding. All patients were selected because they 
required medical treatment for severe UGI hemorrhage, and information 
was collected regarding alcohol and aspirin use. However, the study was 
not analyzed to evaluate whether reported concomitant aspirin and 
alcohol use is associated with a higher risk for developing UGI 
bleeding. Therefore, this study did not address the basic question 
before the agency, namely, whether there is an increased risk of 
stomach bleeding in patients who consumed both alcohol and aspirin.
    Soll (Ref. 4) is a review article on peptic ulcer disease presented 
by an expert gastroenterologist. The article reviews the scientific 
literature and concludes that NSAID's, including aspirin, produce 
topical irritative effects on the mucosa as well as ulcerations as a 
consequence of a systemic effect. Therefore, NSAID's, which are 
rectally delivered or enteric coated may still cause adverse GI 
effects. Similar reviews have been published elsewhere (Refs. 51 and 
52). Thus, while the article was submitted in opposition to a warning, 
the information in the article supports the scientific rationale for a 
warning.
    A case-controlled study was also submitted which supports the need 
for an alcohol warning on OTC analgesic/antipyretic drugs containing 
NSAID ingredients (Ref. 8). This study has been previously summarized 
earlier in this response to comment 1 of section II.A of this document.
    Given the data available at this time, the agency cannot precisely 
quantify the increased risk of combining routine heavy alcohol use and 
these OTC drug products. In order to require an alcohol warning, 
however, it is not necessary that the agency be able to demonstrate 
precisely how much the risk is increased. The available data 
demonstrate clearly that the risk to consumers of combining heavy 
routine alcohol use with these drug products is greater than the risk 
of using either alcohol or these drug products alone. These data are 
sufficient to establish the need for an alcohol warning on these OTC 
products. In light of the clearly demonstrated increased risk to 
consumers, the agency is requiring an alcohol warning about the risk of 
stomach bleeding on aspirin and other NSAID-containing OTC drug 
products.
    In summary, OTC analgesic/antipyretic drug products, including 
aspirin, are known to cause adverse GI effects, including bleeding. 
Chronic, heavy alcohol use is also associated with adverse GI effects, 
including bleeding. Based on the agency's review of a large body of 
scientific information and in concurrence with expert advisors, FDA has 
determined that routine, heavy (three or more alcoholic drinks every 
day) alcohol use in combination with use of OTC analgesic/antipyretic 
drug products containing NSAID ingredients increases the risk of 
adverse GI events, including stomach bleeding. The agency believes that 
the most appropriate public health response to this information 
concerning risk is to warn consumers who drink three or more alcoholic 
drinks every day to consult their doctor about their use of these OTC 
drug products. This conclusion is scientifically based, clinically 
relevant, and important for the safe and effective use by consumers of 
OTC analgesic/antipyretic drug products containing NSAID ingredients.
    2. One comment argued that FDA's conduct of this rulemaking 
violates the Administrative Procedure Act (APA). The comment stated 
that the APA requires that a notice of proposed rulemaking include 
``either the terms or substance of the proposed rule or a description 
of the subjects and issues involved'' (5 U.S.C. 553(b)). The comment 
maintained that the agency's proposal fails to adequately describe the 
basis for the requirement for an alcohol warning for OTC drug products 
containing aspirin. The comment asserted that FDA denied interested 
parties adequate notice of the action by failing to expressly state its 
reliance on a ``switch rationale,'' i.e, the concern that an alcohol 
warning on one analgesic would cause inappropriate ``switching'' to 
other OTC analgesic/antipyretic drug products. The comment further 
argued that the agency's failure to obtain the raw data from 
unpublished epidemiological studies presented to the Committees that 
made recommendations also effectively denied interested parties the 
opportunity to comment fully.
    Another comment suggested that the ``switch rationale'' is flawed. 
The comment asserted that there is no evidence that heavy alcohol users 
would be persuaded to change their analgesic use based on an alcohol 
warning. One comment noted that after several years of voluntary 
alcohol warnings on products other than aspirin, market tracking data 
for aspirin sales for the years of 1994 to 1997 have demonstrated that 
``switching'' does not occur.
    The intent of the warning is to advise consumers with a history of 
heavy alcohol use (three or more alcoholic drinks every day) to consult 
a physician for advice about the use of all OTC analgesic/antipyretic 
products and to advise that there is a specific risk associated with 
use of these products. The agency agrees that it is important not to 
encourage consumers who consume three or more alcoholic drinks every 
day to begin to use another OTC analgesic/antipyretic drug product 
before consulting their physician. In comment 1 of section II.A. of 
this document, the agency describes the scientific basis for requiring 
an alcohol warning for OTC analgesic/antipyretic drug products 
containing NSAID's, including aspirin. This rationale is also present 
in the agency's proposal (62 FR 61041 at 61049).
    As discussed in the proposed rule (62 FR 61041 at 61049), the 
agency agreed with the assessment of the Advisory

[[Page 56794]]

Committees who made recommendations on the unpublished data presented 
before the committees. Raw data were not evaluated by the agency, do 
not serve as the agency's basis for this final rule, and are not 
required to be placed in the administrative record. The agency 
disagrees that interested parties were given insufficient opportunity 
to comment fully on the data. Comments on the presentations to the 
Committees as well as the Committees' recommendations (Ref. 53) were 
included in the administrative record. Further, the comments' 
criticisms of the unpublished data presented in September 1993 were 
sent to the members of the Committees for their specific comment. Of 
the responses received (Ref. 54), none stated that the comments' 
criticisms changed their recommendation. The agency has included in the 
administrative record the relevant data and information that were 
considered and relied upon regarding the warning statement requirements 
of the final rule. Therefore, the agency considers the requirements of 
the APA to be fully satisfied.
    3. Three comments asserted that the imposition of an alcohol 
warning on aspirin could result in a significant adverse impact on 
public health. The comments said that placing an unnecessary ``stomach 
bleeding'' warning on aspirin may cause consumers taking it for its 
cardiovascular and cerebrovascular benefits to avoid using aspirin. The 
comments suggested that poor compliance with cardiovascular and 
cerebrovascular aspirin regimens could be detrimental to consumers at 
risk for these events. One comment noted that consumers on a long-term 
professional use regimen would be under a doctor's supervision and 
would presumably be warned about the risks of aspirin use and would be 
monitored for GI injury. Another comment maintained that the low doses 
used in long-term professional use aspirin regimens have not been 
associated with significant GI problems.
    In its proposal, the agency evaluated the published literature on 
aspirin for cardiovascular and cerebrovascular uses and determined that 
bleeding can occur with long-term aspirin use, even at low aspirin 
doses. The proposal also discussed the use of alcohol in patients with 
cardiovascular problems and noted the recommendations of the American 
Heart Association (AHA) that consumers with these conditions should not 
consume alcohol heavily (62 FR 61041 at 61050). The proposal further 
reviewed the increased risk of cardiovascular diseases, such as heart 
muscle disease, hypertension, disturbances in heart rhythm, and stroke 
from heavy alcohol use. The intended purpose of this warning is to 
promote a dialogue between physicians and individuals who consume three 
or more drinks every day. The agency believes that this dialogue should 
extend to consumers on long-term aspirin regimens who may be adding to 
their risk of adverse vascular events by their alcohol consumption. 
Therefore, the agency concludes that an alcohol warning on OTC 
analgesic/antipyretic drug products containing aspirin will provide 
important advice to consumers on long-term, low-dose vascular regimens.
    4. Two comments argued that to the limited extent that consumers 
are at risk from aspirin use, they are already alerted to this risk by 
warnings included in the TFM for OTC internal analgesic/antipyretic 
drug products (53 FR 46204). Specifically, the comments asserted that 
the proposed warning in Sec. 343.50(c)(1)(v)(B) that states: ``Do not 
take this product if you have stomach problems (such as heartburn, 
upset stomach, or stomach pain) that persist or recur, or if you have 
ulcers or bleeding problems, unless directed by a doctor,'' is 
sufficient to warn consumers with stomach problems, whether due to 
heavy alcohol use or another condition, about the risk of aspirin.
    The warning in Sec. 343.50(c)(1)(v)(B) is intended to warn 
consumers with diagnosed stomach ulcer or symptoms of stomach distress 
to avoid the use of aspirin, unless directed to do so by a doctor. 
However, as noted in the agency's proposal, acute hemorrhagic gastritis 
accounts for 25 percent of major bleeding in heavy, chronic alcohol 
users and this condition may be asymptomatic (62 FR 61041 at 61049). 
For this reason, the agency finds that the currently proposed stomach 
distress warning does not adequately inform individuals who consume 
three or more alcoholic drinks every day of their risk.
    5. Two comments stated the belief that the agency's proposed 
rulemaking did not evaluate the totality of the data for 
nonprescription ibuprofen. One comment argued that ibuprofen, even at 
prescription doses, has excellent GI tolerability. In support of its 
position, the comment cited data from a variety of different studies 
(Ref. 55) assessing the relative GI tolerability of prescription and 
OTC ibuprofen. The comments continued that the proposed rule does not 
acknowledge data demonstrating the excellent GI tolerabililty of 
ibuprofen, even when taken by individuals who regularly consume 
alcohol. Cited by the comment were: (1) The results of an endoscopic 
study of the effects of alcohol administration on the GI tolerability 
of 2,400 milligrams (mg) ibuprofen (twice the maximum daily OTC dose)/
day (d) in healthy subjects (Ref. 56), (2) epidemiological studies 
previously evaluated by the agency (Refs. 57, 58, and 59) , and (3) an 
assessment of adverse reaction reports for OTC analgesic/antipyretic 
drug products containing ibuprofen (both prescription and OTC) 
contained in the agency's SRS data base for 1974 to 1993.
    Another comment noted that while OTC drug products containing 
ketoprofen and naproxen sodium have been required to include an alcohol 
warning in their label, there are no clinical or meaningful 
epidemiological data to support the need for a warning on these 
products. Based on this lack of data, the comment maintained that an 
alcohol warning should not be required for any of the currently 
approved OTC NSAID's. To support its position, the comment cited the 
lack of reports of injury from the use of these products with alcohol 
and few reports of GI bleeding when these products are used as 
directed.
    The agency concludes that an alcohol warning is needed for OTC 
analgesic/antipyretic drug products containing ibuprofen. Endoscopic 
data (Ref. 56) evaluating the GI tolerability in healthy subjects of 
prescription doses of ibuprofen (2,400 mg/d for 1 day) with 100-proof 
vodka are not adequate because the study did not assess the safety of 
ibuprofen use in individuals who consume three or more alcoholic drinks 
every day. Carson et al. (Ref. 59) reported that subjects with an 
alcohol-related diagnosis who took prescription ibuprofen had no 
material increase in bleeding. However, the Committees' evaluated the 
study by Carson and concluded that the population studied may not be 
generalizable (Ref. 48). The agency evaluated and discussed other 
studies (Refs. 57 and 58), which were not convincing as discussed in 
the proposed rule (62 FR 61041 at 61050).
    Data concerning the relative GI tolerability of OTC ibuprofen are 
not sufficient to support the safety of ibuprofen in heavy alcohol 
users. Data from case-control studies which looked at the association 
between NSAID use and GI bleeding by Griffin et al. (Ref. 60), Savage 
et al. (Ref. 39), and Garcia Rodriguez and Jick (Ref. 61) were 
presented and publicly discussed at the October 11 and 12, 1995, 
Arthritis Advisory Committee Meeting (Ref. 62). All three of these 
studies found the use

[[Page 56795]]

of ibuprofen to be associated with a dose-dependent increase in risk 
for GI bleeding. The study by Somerville et al. (Ref. 38), which also 
looked at this issue, adds nothing to the discussion. Bradley et al. 
(Ref. 63) compared the effectiveness of low-dose ibuprofen (1,200 mg/d) 
to high-dose ibuprofen (2,400 mg/d) and high-dose acetaminophen (4,000 
mg/d) in patients with osteoarthritis. This study confirmed the dose-
dependent increase in GI symptoms associated with ibuprofen use (1,200 
mg/d: 7/62, 11.3 percent; versus 2,400 mg/d: 14/61, 23.0 percent). None 
of these studies looked at the associated risks for gastrotoxicity and 
ibuprofen in individuals who consume three or more alcoholic drinks 
every day. DeArmond et al. (Ref. 64) is an abstract of safety data 
generated from 48 clinical trials evaluating OTC naproxen sodium versus 
ibuprofen and acetaminophen.
    As previously discussed, study results displaying comparative risks 
among these analgesic products are difficult to interpret. However, 
because adverse GI effects, including bleeding, occur with all NSAID 
ingredients covered by this final rule, the warning is needed for all 
of these ingredients.
    In conclusion, as previously discussed in comment 1 of section 
II.A. of this document, based on the similar pharmacologic properties 
of the nonaspirin NSAID ingredients available OTC as antipyretic/ 
analgesic drug products, the available scientific data for NSAID 
ingredients, alcohol, and the combination of nonaspirin NSAID's and 
alcohol, the agency concludes that an alcohol warning is needed for the 
safe and effective use of OTC drug products containing ibuprofen, 
ketoprofen, or naproxen sodium.
    6. Several comments objected to the agency's requirement for an 
alcohol warning on OTC drug products containing carbaspirin calcium, 
choline salicylate, magnesium salicylate, and sodium salicylate. These 
objections were based on the lack of data supporting the risk of the 
use of these products by individuals with a history of heavy alcohol 
use. The comments did not include data.
    The agency notes that carbaspirin calcium, choline salicylate, 
magnesium salicylate, and sodium salicylate were recognized by the 
Panel as having similar adverse effects on the GI tract as aspirin (42 
FR 35346 at 35417 through 35422). Similar to aspirin, these adverse 
effects include gastric ulcer, exacerbation of peptic ulcer symptoms 
(heartburn and dyspepsia), GI hemorrhage and erosive gastritis (Ref. 
65). These adverse effects can occur even at low doses. Based on the 
recognized individual GI toxicities of carbaspirin calcium, choline 
salicylate, magnesium salicylate, sodium salicylate, and alcohol as 
well as the Panel's recommendation that these OTC analgesic/antipyretic 
drug products bear similar labeling, including a warning against use of 
these OTC products in the presence of stomach distress, the agency 
concludes that an alcohol warning is necessary for the safe and 
effective use of OTC drug products containing these ingredients.

B. Comments on Labeling

    7. Several comments objected to the inclusion of trade names and 
brand names in the proposed warning, because it would be confusing to 
consumers and would use up valuable label space. Two comments suggested 
using the name of the analgesic/antipyretic ingredient. Two comments 
suggested using the term ``this product,'' ``the product,'' or 
``product'' in place of the trade name or brand name so that the 
warning would be generic for all OTC analgesic drug products. One 
comment suggested that even these terms (``this product,'' etc.) are 
superfluous and unnecessary. A comment contended that for cough/cold 
and analgesic combination drug products, the trade name could confuse 
consumers because only the analgesic ingredients pertains to the 
alcohol warning. Thus, consumers may infer that the warning was 
directed at each of the ingredients in a combination drug product.
    The agency agrees that clear labeling is necessary. Inclusion of 
the name of the ingredient helps educate and alert the consumer by 
making the warning more precise. The agency also believes that the name 
of the specific analgesic/antipyretic active ingredient would generally 
be more informative than the term ``this product'' or other similar 
terms. Therefore, the agency is revising the warning to include the 
analgesic/antipyretic ingredient name instead of the brand name.
    8. A number of comments were in disagreement as to the relative 
importance of the warnings for acetaminophen, aspirin, and other 
NSAID's. A number of comments said the established risks of 
acetaminophen use by heavy alcohol users far outweigh the risks of 
aspirin use by the same consumers. One comment submitted data from a 
comparative risk analysis of aspirin and acetaminophen (Ref. 66). Based 
on this analysis, the comment maintained that the number of expected 
deaths from acetaminophen toxicity when used for the short-term 
treatment of fever and pain is 12 times higher than that expected with 
aspirin.
    Several comments complained that despite the much greater risk for 
acetaminophen, the proposed alcohol warning conveys the impression that 
for heavy alcohol users, the hazards of acetaminophen use and aspirin 
(or NSAID) use is essentially the same. Thus, consumers may be led to 
believe that they face a comparable risk with either analgesic. The 
comments said the proposed warning minimizes the essential messages. In 
support of this position, the comment included the results of a 
labeling comprehension study (Ref. 67) that it maintained demonstrated 
that consumers interpreted the warnings as conveying equivalent risks.
    The agency has reviewed the analysis submitted by one comment (Ref. 
66). There were numerous flaws in the baseline assumptions, some of 
which were noted by the analysis. The authors assumed that the maximum 
recommended daily dose of aspirin is 2,600 mg, but the maximum daily 
dose in OTC aspirin labeling is 4,000 mg. For comparative purposes, 
alcohol consumption should have been defined in terms of absolute 
alcohol. Deaths for GI bleeding and hepatotoxicity were based on 
articles from the literature rather than actual death rates in the 
United States attributed to either of these conditions. The authors 
summarized the data from case reports of hepatotoxicity due to 
``therapeutic misadventure'' with acetaminophen to estimate the rate of 
hepatotoxicity associated with the drug. Cases of hepatotoxicity 
requiring transplantation were discounted in the analysis. It was 
assumed that the risk of GI bleeding with aspirin use starts at doses 
of 1,500 mg/d and the risk of hepatotoxicity with acetaminophen starts 
at about 4,000 mg/d. These data do not support an alcohol warning with 
comparative rates of risk.
    The agency has also reviewed the labeling comprehension study (Ref. 
67) and has determined that this study did not assess the risk 
communication of either warning. In the study, the warnings were not 
presented in context, as a consumer would be seeing them. Subjects were 
not allowed to perform comparative assessments of the two labels. In 
addition, the phrasing of three of the four agree/disagree statements 
made ``agree'' responses more likely. Finally, the results were not 
framed in terms of alcohol use, a key element in the relevant 
population of consumers. However, the study did reveal how few 
consumers were aware of these potential toxicities associated with 
aspirin or acetaminophen.

[[Page 56796]]

    Although the risk of GI bleeding with aspirin is dose dependent, it 
can occur at any dose, depending on other comorbidity factors (Ref. 
68). In addition to dosage, hepatotoxicity due to acetaminophen use is 
also dependent on factors such as liver glutathione stores, nutritional 
state, age, and in some cases, chronicity of usage. Thus, the agency 
concludes that the relative degree of risk between aspirin use and 
acetaminophen use can not be drawn from this analysis.
    Finally, the agency believes there is some degree of risk for all 
OTC analgesic/antipyretic drug products in subjects that are chronic, 
heavy alcohol users. This risk is greater than for consumers of these 
products who are not chronic, heavy alcohol users. However, the degree 
of risk cannot be precisely calculated for the ``at risk'' population 
because different risk assessments vary from study to study and may 
increase with comorbid factors (Refs. 8 and 31) (62 FR 61041 at 61047). 
Nevertheless, it is likely that the degree of risk is not exactly the 
same for any two of these drug products or for any two individuals who 
consume three or more alcoholic drinks every day. The purpose of the 
alcohol warning in this final rule is to alert heavy alcohol users that 
serious, specific adverse events can occur with concomitant use of OTC 
drug products containing analgesic/ antipyretic ingredients and to seek 
advice from their doctor in order to prevent serious adverse events 
whenever possible.
    9. Several comments stated that the proposed alcohol warning for 
acetaminophen does not describe the severity of potential liver damage. 
One comment said the problem is not liver damage, but a significant 
risk of dying. A second comment said the term ``liver damage'' is vague 
and recommended that the warning include the phrase ``acute liver 
failure'' or ``sudden liver failure,'' or the term ``severe liver 
damage.''
    In the majority of case reports the agency evaluated, 
acetaminophen-induced liver damage in heavy alcohol users did not 
result in liver failure or death. Therefore, the agency concludes that 
the statement ``Acetaminophen may increase your risk of liver damage'' 
provides an accurate description to the consumer.
    10. One comment argued that the proposed three-drink threshold is 
not appropriate for the acetaminophen warning because it is far below 
what is reported in the cases cited by the agency. Therefore, the 
comment recommended that language be added to the warning to accurately 
describe the chronic heavy alcohol user. However, suggested language 
was not provided. One comment said that stating a specific number of 
drinks (``3 or more alcoholic beverages daily'') would be better than 
the general term ``excessive,'' because the later is very subjective 
and each person could define it differently. Another comment suggested 
that the warning does not adequately protect women. The comment based 
its contention on the U.S. Departments of Agriculture (USDA) and the 
Department of Health and Human Services (DHHS) guidelines that 
recommend only one drink per day for women (two for men) and evidence 
(Refs. 69 and 70) it believes demonstrates that women are more 
susceptible to the hepatic effects of alcohol. The comment suggested 
that the warning should be gender specific or should be changed to ``2 
or more drinks a day'' in order to provide adequate protection for 
women.
    The agency acknowledges that the level of alcohol consumption 
included in the proposed warning was intended as a general guideline to 
help consumers quantify their level of alcohol consumption (62 FR 61041 
at 61052). This threshold is based on the recommendations from the 
dietary guidelines set by the USDA and DHHS and the standard set by the 
AHA. The agency notes that while the dietary guidelines for alcohol 
consumption set by USDA and DHHS differentiate between men and women, 
the standard set by AHA does not (62 FR 61041 at 61052).
    The agency agrees with the comment that suggested a specific number 
of drinks is better than using the term ``excessive'' as a reference 
point for consulting a physician because it is more meaningful to many 
individuals as a specific number. The warning is intended to aid 
consumers in characterizing heavy alcohol consumption, in view of the 
inherent variability of individuals in their susceptibility to the 
toxic effects of both alcohol and OTC analgesic/antipyretic drug 
products.
    11. One comment suggested using the word ``drinks'' instead of 
``beverages'' in the proposed warning which states: ``If you drink 3 or 
more alcoholic beverages daily * * *.'' The comment said ``drinks'' is 
better understood by consumers, and noted that the agency based its 
analysis of alcohol consumption on the Dietary Guidelines for 
Americans, which defines ``drink.'' The comment said number of 
``beverages'' could be perceived as the number of different kinds of 
drinks. For instance, a person could perceive four glasses of wine and 
four beers as two beverages. Another comment suggested using the term 
``every day'' rather than ``daily'' in the warning because ``daily'' is 
often misunderstood to mean a single day, whereas ``every day'' is 
clearer in communicating a repetitive pattern of drinking behavior.
    The agency agrees with the comments that the terms ``drinks'' and 
``every day'' would better convey the intended message to consumers and 
has revised the warning to state: ``If you consume 3 or more alcoholic 
drinks every day * * *.''
    12. One comment suggested that organ-specific warnings may be more 
appropriate for professionals than for consumers. The comment 
questioned whether the proposed warning would leave consumers puzzled 
as to which product to choose, one that causes liver damage or one that 
causes stomach bleeding. Thus an organ-specific warning may discourage 
consumers from consulting their physician, believing they can rely on 
their ability to self-diagnose liver damage or stomach bleeding. The 
comment also refuted the agency's evaluation of data relating to 
consumers' perception of label warnings, cited in the proposed rule (62 
FR 61041 at 61051), suggesting that a general alcohol warning is less 
likely to prompt consumers into appropriate action than an explicit 
warning. The comment said the study was not designed to determine 
consumer understanding of the warnings tested and that flaws in that 
study prevent meaningful conclusions. The comment submitted no data to 
support its contention.
    The agency considers organ specific warnings to be more effective 
than general warnings. Consumers are better equipped to make a decision 
on whether to take a medicine or contact their doctor when they know 
the specific risk involved. The agency believes that consumers with a 
history of heavy alcohol use need to know the potential risk of OTC 
analgesic/antipyretic use. If consumers are not advised of what may 
happen (liver damage or stomach bleeding) or what to do (ask their 
doctor), the agency believes they would be less likely to take the 
warning seriously or to consult their doctor.
    13. Two comments recommended that the proposed warning be formatted 
in a style that more closely follows the February 27, 1997 (62 FR 
9024), proposed rule on OTC label format. One comment contended that 
the use of specific headers for specific warnings are unnecessary and 
redundant. Also, specific warnings take up additional space, disrupt 
the logical flow of information, and distract from consumer

[[Page 56797]]

comprehension. No data were submitted by the comments.
    The issue of labeling format for specific warnings is broader than 
this rulemaking which concerns a single alcohol warning. This issue 
will be addressed in a future issue of the Federal Register when the 
agency issues a final rule regarding labeling requirements for OTC drug 
products.
    14. Several comments recommended reducing the maximum daily dose of 
acetaminophen to 2 grams (g) for heavy alcohol users but submitted no 
new data. Another comment supported the currently recommended maximum 
daily dose of 4 g acetaminophen.
    The agency addressed this issue in the proposed rule (62 FR 61041 
at 61044 to 61049) and evaluated a placebo-controlled, double-blind, 
randomized study of various dosages of acetaminophen in alcoholics 
(Ref. 71). The agency concludes that there is not sufficient evidence 
to recommend a specific dosage of acetaminophen which is safe and 
effective in subjects who use alcohol heavily.
    15. One comment suggested that the acetaminophen labeling should 
warn against the use of more than one acetaminophen-containing product 
at a time. The comment also recommended that, because of overdose risk 
and risk of liver injury, acetaminophen preparations intended only for 
adults should contain warnings against use in children, and pediatric 
formulations should convey the need to follow instructions very 
carefully. The comment also noted that the warning does not address the 
effects of fasting on acetaminophen toxicity.
    The issues raised by the comment are outside of this rulemaking 
which specifically addresses the need for an alcohol warning. However, 
the issues raised by the comment will be addressed in the final rule 
for OTC internal analgesic, antipyretic, and antirheumatic drug 
products in a future issue of the Federal Register.
    16. One comment supported the agency's proposal and suggested that 
the warning should be put on the leaflet inside the package.
    Information required to appear on the labeling by or under 
authority of section 502(c) of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 352(c)) must be placed conspicuously so as to be read and 
understood by the consumer under customary conditions of purchase and 
use. Manufacturers may also include package inserts containing the 
required information, but such inserts are not required.

C. Comments on Product Exemptions

    17. One comment maintained that enteric-coated products provide 
additional safety for aspirin users and urged FDA to recognize the 
documented health and safety benefits of enteric coatings on aspirin. 
The comment said that the enteric-coating minimizes gastric irritation 
because the enteric-coating delays dissolution of aspirin in the acidic 
environment of the gastric lumen. The comment further argued that this 
delayed absorption reduces the intracellular accumulation of aspirin in 
the gastric mucosa that can lead to cellular injury. In support of this 
position, the comment included data from published clinical research 
(Refs. 72, 73, and 74) and cited references (Refs. 75 and 76) to 
demonstrate the safety of enteric-coated aspirin. Based on these 
arguments, the comment suggested the agency take one of the following 
actions: (1) Exempt enteric-coated aspirin from the proposed warning, 
(2) defer action on a warning for this dosage form until the agency can 
gather data that would challenge the documented benefits of enteric-
coated aspirin, or (3) require a separate warning for enteric-coated 
products.
     The agency disagrees with the comment. The data provided by the 
comments do not demonstrate the safety of enteric-coated dosage forms 
of aspirin in consumers with a history of heavy alcohol use. 
Furthermore, as previously discussed, aspirin's adverse GI effects are 
due both to direct local irritation (the Davenport mechanism) and to 
systemic effects which result in prostaglandin inhibition and platelet 
dysfunction (Refs. 10 and 13).
    As discussed in comment 1 of section II.A of this document, 
enteric-coated dosage forms may exert less direct local effect on the 
gastric mucosa, but they are associated with the same risks (and 
benefits) of other systemically absorbed aspirin products (Refs. 4 and 
51). J. P. Kelly et al. (Ref. 77) examined 550 cases of UGI bleeding 
confirmed by endoscopy and 1,202 controls in a multicenter case-control 
study. Multiple logistic regression analysis demonstrated a similar 
relative risk for plain, enteric-coated, and buffered aspirin at high 
(RR: 5.8-7.0) and low (RR: 2.6-3.1) doses. C. A. Silagy et al. (Ref. 
78) examined the adverse effects of low-dose enteric-coated aspirin 
(100 mg/d) in 400 subjects 70 years or older for 12 months in a double-
blind, randomized, placebo-controlled trial. Clinically evident GI 
bleeding occurred in the enteric-coated aspirin treated group but not 
in the controls. Clinically evident bleeding from any site and 
decreased hemoglobin levels were significantly greater (p<0.05) in the 
aspirin-treated group than in the control group. In summary, clinical 
trials demonstrate UGI bleeding in patients who also take enteric-
coated aspirin products. Therefore, the agency will require an alcohol 
warning for these products.
    18. One comment requested that antacid and aspirin combination 
products (highly buffered aspirin in solution) that produce sodium 
acetylsalicylate, sodium citrate, and carbon dioxide when added to 
water prior to ingestion, not bear an alcohol warning. In support of 
this request, the comment submitted data documenting the chemical 
characteristics and safety profile distinguishing these products from 
plain aspirin. These data were previously reviewed by the Panel (42 FR 
35346 at 35417) and are not resummerized in this document.
    The agency disagrees with the comment. The Panel believed there is 
no valid clinical evidence to support the claim that highly buffered 
aspirin for solution has significantly less potential to induce major 
GI hemorrhage than other dosage forms of aspirin (42 FR 35346 at 
35471). The agency concurred in comment 31 of the proposed rule for OTC 
internal analgesics drug products that the direct toxic effects from 
the Davenport mechanism may be reduced, but not eliminated, in highly 
buffered aspirin-for-solution products (53 FR 46204 at 46220). In 
addition, the indirect effects on systemic prostaglandin inhibition 
still play an important role in the toxicity of such products. 
Therefore, the agency will require an alcohol warning for these 
products.
    19. One comment contended that OTC analgesic/antipyretic drug 
products differ in their benefits and potential for injury, and that 
any proposal to change the current labeling on such products should be 
on a product-by-product basis. The comment argued that alcohol warnings 
are not appropriate for products intended for relief of mild to 
moderate symptoms associated with menstrual periods in teenagers, or 
for OTC highly buffered aspirin solution products indicated for 
overindulgence of food and drink.
    The agency disagrees that these products should be exempt from the 
alcohol warnings. In comment 18 in section II.C of this document, the 
agency discusses the need for an alcohol warning for OTC highly 
buffered aspirin solution products. Concerning the need for warnings on 
products intended for relief of mild to moderate symptoms associated 
with menstrual periods in

[[Page 56798]]

teenagers, this population is not immune to heavy alcohol use as up to 
32 percent of high school students have reported heavy drinking (Ref. 
79).

D. Comments on Implementation

    20. A number of comments objected to the agency's proposed 6-month 
implementation date for the final rule because of the potential 
economic impact of the rule based on that timeframe. One comment 
requested flexibility in considering the appropriate implementation 
period for all OTC analgesic/antipyretic drug products or, at minimum, 
for cough-cold products containing these ingredients. The comment 
contended that the seasonal nature of cough-cold products requires 
large inventory stockpiles and shipments prior to the cough-cold 
season. Therefore, depending on the time of year that the rule becomes 
final, significant inventory may need to be destroyed if products are 
not shipped with required labeling by the effective date. The comment 
stated that industry estimates indicate that the average time to 
redesign and produce new labeling is 9.25 months. Therefore, it would 
be impossible to comply with the proposed 6-month implementation 
period. Trying to force these changes more quickly could lead to 
labeling errors, resulting in consumer confusion, potential recalls, 
and unavailability of some products in the marketplace.
    Although the agency has suggested stick-on labeling as a means to 
comply with the 6-month implementation date, one comment believed that 
this would not be practical or cost-effective for most combination 
cough-cold products. This comment further argued that current warnings 
dictated by monographs expend most of the available space on containers 
and cartons, leaving insufficient room for placement of a sticker 
containing the additional warnings.
    Several comments urged the agency to coordinate the implementation 
of the alcohol warning with other labeling proposals impacting these 
products. One comment requested that the agency make the rule effective 
no sooner than the effective date of the final rule for a standardized 
OTC labeling format (62 FR 9024). The comment noted that the agency 
expects that the standardized labeling final rule will result in major 
format and content changes to current OTC product labeling. If the 
final rule for the alcohol warning is effective prior to the 
standardized format final rule, manufacturers will incur significant 
labeling costs for each of these rules separately. Another comment 
requested that FDA extend the implementation date to 12 months.
    One comment stated that 8 months had already been expended to 
complete the addition of the voluntary warning on its acetaminophen 
products. The comment contended that 14 additional months would be 
required to implement the alcohol warning for all products covered by 
the final rule. The comment recommended that an effective date of 24 
months be established for implementation of the final rule for affected 
products that have not been updated to include the voluntary warning 
suggested in the proposed rule, and 36 months for products that already 
comply with the voluntary warning.
    Although the final rule will have an economic impact on some 
manufacturers, the agency believes that the potential benefits of the 
rule, including reduced risk of adverse effects, override any economic 
concerns (see section III.C of this document). In an attempt to 
minimize the economic impact, the agency has allowed for a 6-month 
implementation period and the use of supplementary labeling (e.g., 
stick-on labels) to comply with the final rule. Further, manufacturers 
that voluntarily included in their labeling the exact warning in the 
agency's proposed rule will be permitted to exhaust their inventory of 
labels. The agency believes that these measures will help reduce 
labeling costs that manufacturers will incur to make the required 
labeling changes. The agency concludes that a 6-month implementation 
period for the required warning will ensure that consumers have the 
most recent information for the safe and effective use of OTC 
analgesic/antipyretic drug products.

III. Analysis of Impacts

    FDA has examined the impacts of this final 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 economic impact on a 
substantial number of small entities, an agency must analyze regulatory 
options that would minimize any significant impact of the rule on small 
entities.
    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 rule is consistent with the 
principles set out in the Executive Order and in these two statutes. 
The purpose of this rule is to add warning statements to the labeling 
of OTC drug products labeled for adult use that contain internal 
analgesic/antipyretic active ingredients. The added statements warn of 
the increased risk of adverse effects from the use of OTC analgesic/
antipyretic drug products by individuals who consume three or more 
alcoholic drinks every day. This rule is intended to reduce the number 
of specific adverse events associated with the use of these products by 
such individuals.

A. Benefits

    As described earlier in this document, FDA finds that individuals 
who routinely drink alcohol heavily (three or more drinks every day) 
should be specifically warned of risk associated with their use of OTC 
analgesic/antipyretic drug products. For example, both aspirin and 
other NSAID's carry a dose-related risk of GI bleeding. Alcoholics are 
also known to be at increased risk of liver damage and UGI bleeding. 
However, because UGI bleeding and liver damage are not unexpected in 
alcohol users, medical personnel may not routinely investigate the use 
of OTC drug products by patients presenting with these problems. 
Recently, in a number of cases, use of acetaminophen was found to be 
associated with pathognomonic hepatotoxic changes among heavy alcohol 
users and to be a contributing factor in their hospitalization. Many of 
these patients required an extended hospital stay.
    FDA cannot quantify the expected benefits of this rule, because it 
lacks the data to conduct a quantitative risk assessment. The agency 
notes, however, that an estimated 11 million Americans, or about 5.5 
percent of the U.S. population age 12 and older, are heavy drinkers 
and, therefore, at risk (Ref. 80). Because alcohol warnings on OTC 
analgesic/antipyretic drug products could reduce the number of 
hospitalizations of heavy alcohol users for hepatic damage and UGI 
bleeding, the potential benefits of the rule are substantial. For 
example, the cost of a 7-day hospital stay (the average length of stay 
in 1994 for an alcohol related discharge) is about $10,000 (Ref. 81). 
(Length of stay was calculated as

[[Page 56799]]

weighted average of alcohol first-listed hospital discharges. Cost of 
stay was estimated from the 1987 National Medical Expenditure Survey; 
cost was converted to 1995 dollars using the CPI-U (consumer price 
index--urban areas) for medical services.) If, among the 11 million 
consumers potentially at risk, this rule prevented even 500 hospital 
visits annually, the present value of the avoided costs would be about 
$75 million. (This assumes a 7 percent discount rate and an infinite 
time horizon.)

B. Costs

     OTC drug products containing internal analgesic/antipyretic active 
ingredients, labeled for adult use, will require new labeling to 
incorporate the warning statements. The agency's Drug Listing System 
identifies 5,000 to 6,000 OTC analgesic/antipyretic drug products. 
Assuming an average of 3 stock keeping units (SKU's)/product, up to 
18,000 SKU's will require the alcohol warnings. In its analysis of the 
proposed rule, FDA estimated the cost of redesigning a label at from 
$2,000 to $3,000/SKU. No industry comment questioned this estimate. 
Nevertheless, FDA now believes that the lower end of that range is more 
likely, because the added warning requires only a straight-forward text 
change without significant graphics redesign. Alternatively, a private-
label manufacturer estimated that the shorter implementation period 
would add about $700/SKU. On the assumption that lost inventory cost 
for branded SKU's will be twice as high, or $1,400, and that the market 
share of branded and private label SKU's is 70 and 30 percent, 
respectively, the added cost will amount to about $900. Thus, FDA 
projects the total cost of the new warnings at about $3,000/SKU. 
Consequently, the estimated one-time cost of this rule is about $54 
million. The actual cost may be lower, because the agency is allowing 
supplementary labeling (e.g., stick-on labeling), which could reduce 
inventory losses.

C. Small Business Impacts

    The agency estimates that fewer than 75 OTC drug manufacturers will 
incur costs. FDA does not have data on the size distribution of these 
affected firms, but an analysis of an IMS America, Ltd. listing of OTC 
drug manufacturers indicates that approximately 70 percent of all 
identified OTC drug manufacturers employ fewer than 750 employees, 
which is the Small Business Administration's definition of a small 
pharmaceutical firm. Consequently, the agency finds that this rule may 
have a significant impact on some OTC drug manufacturers, including 
smaller firms and manufacturers of private label products. The effect 
on individual firms will vary with the number of the firm's SKU's that 
require relabeling and the size and cost of the firm's labeling 
inventory. Most small firms will not incur significant regulatory costs 
because they manufacture few affected SKU's and use less expensive 
labeling stock. On the other hand, smaller firms tend to keep 
relatively larger labeling inventories because of the volume price 
discounts offered by printers. These firms could experience relatively 
higher costs for lost inventories.
    This rule will not require any new reporting or recordkeeping 
activities. Therefore, no additional professional skills are needed. No 
small entities commented on the impact of the proposed rule or 
suggested alternatives that would reduce the economic impact on their 
establishments.

D. Alternatives

    The agency considered but rejected several less costly regulatory 
alternatives, because they would not provide adequate health and safety 
benefits. First, the agency considered extending the implementation 
period from 6 months to 1 year. This alternative would have saved an 
estimated $18 million due to smaller labeling inventory losses. 
Nevertheless, as stated in section II.D of this document, in comment 
20, the required warnings are necessary to alert consumers to the 
potential for serious health outcomes. As the warnings provide 
consumers with the critical information needed for making informed 
decisions, the longer implementation phase-in would increase the period 
over which consumers may make inappropriate choices. The agency 
concluded that the reduced labeling cost associated with the longer 
phase-in would not justify the increased risk to the public health that 
would occur over the additional 6-month period.
    The agency then considered permitting a 1-year implementation 
period for those products already labeled with less specific alcohol 
warnings. This alternative also was rejected, based on the agency's 
determination that most current warnings are inadequate, because they 
fail to address the specific nature of the adverse consequence.

E. Conclusion

    The above cost estimates demonstrate that this rule is not 
economically significant under Executive Order 12866. As discussed 
previously, the agency concludes that this rule is the least burdensome 
alternative that meets the agency objective of providing the public 
with important health and safety information in a timely manner. As 
this rule may have a significant impact on a substantial number of 
small entities, this analysis, together with other relevant sections of 
this document, serve as the agency's regulatory flexibility analysis, 
as required under the Regulatory Flexibility Act. Finally, the Unfunded 
Mandates Reform Act does not require a cost-benefit analysis of this 
rule, because the rule will 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.

IV. Paperwork Reduction Act of 1995

    FDA concludes that the warning statement set forth 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 
required 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)).

V. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) 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.

VI. 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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Reduced by Vodka

[[Page 56800]]

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Institutes of Health, NIH Publication No. 94:1447, p. 783, 1994.
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Group, ``Final Report on the Aspirin Component of the Ongoing 
Physicians' Health Study,'' New England Journal of Medicine, 
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Anti-inflammatory Drug-Induced Gastropathy in Humans,'' Journal of 
Clinical Gastroenterology, 13:S145-48, 1991.
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Relation to Previous Use of Analgesics and Non-steroidal Anti-
inflammatory drugs,'' Lancet, 337:85-89, 1991.
    37. Griffin, M.R., et al., ``Nonsteroidal Anti-Inflammatory Drug 
Use and Death from Peptic Ulcer in Elderly Persons,'' Annals of 
Internal Medicine, 109:359-363, 1988.
    38. Somerville, K., G. Faulkner, and M. Langman, ``Nonsteroidal 
Anti-inflammatory Drugs and Bleeding Peptic Ulcer,'' Lancet, 1:462-
464, 1986.
    39. Savage, R. et al., ``Variation in the Risk of Peptic Ulcer 
Complications with Nonsteroidal Anti-inflammatory Drug Therapy,'' 
Arthritis Rheumatology, 36:84-90, 1993.
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and Upper Gastrointestinal Bleeding, a Post-marketing Surveillance 
Case-control Study,'' Pharmacoepidemiology and Drug Safety, 1:65-72, 
1992.
    40. Guess, H. A. et al., ``Fatal Upper Gastrointestinal 
Hemorrhage or Perforation Among Users and Nonusers of Nonsteroidal 
Anti-inflammatory Drugs in Saskatchewan, Canada 1983,'' Journal of 
Clinical Epidemiology, 47:35-45, 1988.
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Study Design on Epidemiologic Estimates of the Effect of 
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    42. Gabriel, S. E. et al., ``Risk for Serious Gastrointestinal 
Complications Related to Use of Nonsteroidal Anti-inflammatory 
Drugs: A Meta-analysis,'' Annals of Internal Medicine, 115:787-96, 
1991.
    43. Report from FDA Spontaneous Reporting System Database.
    44. Levy, M. et al., ``Major Upper Gastrointestinal Tract 
Bleeding: Relation to the Use of Aspirin and Other Nonnarcotic 
Analgesics,'' Archives of Internal Medicine, 148:281-285, 1988.
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Comparative Study of Their Effect on Faecal Blood Loss in the 
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Opinion, 5:520-524, 1978.
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Journal of Gastroenterology, 3:201-208, 1975.
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Effects Associated With Nonsteroidal Anti-inflammatory Drugs,'' 
Archives of Internal Medicine, 149:1019-1022, 1989.
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meeting of the FDA Nonprescription Drugs and Arthritis Drugs 
Advisory Committees, in OTC Vol. 03AWNPR, Docket No 77N-094W, 
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    49. Summary minutes of the June 28 and 29, 1993 meeting of the 
FDA Nonprescription Drugs Advisory Committee, in OTC Vol. 03AWNPR, 
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    50. Summary minutes of the June 1, 1993, meeting of the FDA 
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    51. Soll, A. H., ``Nonsteroidal Anti-inflammatory Drugs and 
Peptic Ulcer Disease,'' Annals of Internal Medicine, 114:307-319, 
1991.
    52. Wallace, J. L., ``Nonsteroidal Anti-inflammatory Drugs and 
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112:1,000-1,006, 1997.
    53. Comments No. C193, C206, and MM19, Docket No. 77N-0094, 
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    55. Comment No. C11, Docket No. 77N-094A, Dockets Management 
Branch.

[[Page 56801]]

    56. Lanza, F. et al., ``Ethanol, Aspirin, Ibuprofen, and the 
Gastroduodenal Mucosa: An Endoscopic Assessment,'' American Journal 
of Gastroenterology, 80:767-769, 1985.
    57. Kelly, J., D. Kaufman, and S. Shapiro, ``The Risk of Major 
Upper Gastrointestinal Bleeding among Users of Aspirin, Ibuprofen, 
Naproxen, at Various Levels of Alcohol Consumption,'' draft of an 
unpublished paper included in Comment No. C188, Docket No. 77N-0094, 
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    58. Henry, D., A. Dobson, and C. Turner, ``Variability in the 
Risk of Major Gastrointestinal Complications from Nonaspirin 
Nonsteroidal Anti-inflammatory Drugs,'' Gastroenterology, 105:1078-
1088, 1993.
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of the Nonsteroidal Anti-inflammatory Drugs,'' Archives of Internal 
Medicine, 147:1054-1059, 1987.
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Use and Increased Risk for Peptic Ulcer Disease in Elderly 
Persons,'' Annals of Internal Medicine, 114:257-263,1991.
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Gastrointestinal Bleeding and Perforation Associated with Individual 
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FDA Arthritis Drugs Advisory Committee, in OTC Vol. 03AWNFR, Docket 
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    63. Bradley, J. et al, ``Comparison of an Anti-inflammatory Dose 
of Ibuprofen, an Analgesic Dose of Ibuprofen, and Acetaminophen in 
the Treatment of Patients with Osteoarthritis of the Knee,'' New 
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Naproxen Sodium,'' Clinical Pharmacology and Therapy, 57:136, 1995.
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Agents and Drugs Employed in the Treatment of Gout: The Salicylates; 
Gastrointestinal Effects,'' in ``Goodman and Gilman's The 
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Hardman, A. G. Gilman, and L. E. Limbird, McGraw-Hill, New York, p. 
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of Aspirin and Acetaminophen in Alcohol Users: Application of 
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Guideline Research Corp., draft of an unpublished paper in Comment 
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of the Effects of Aspirin, Buffered Aspirin, and Enteric-Coated 
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Dose (325 mg) Plain and Enteric-Coated Aspirin Administration,'' The 
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Upper-Gastrointestinal Bleeding with Enteric-Coated or Buffered 
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SR40.pdf''.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
201 is amended as follows:

PART 201--LABELING

    1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

    2. Section 201.322 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 (three 
or more drinks every day) have an increased risk of adverse effects 
(possible liver damage or gastrointestinal bleeding). OTC drug products 
containing internal analgesic/antipyretic active ingredients may cause 
similar adverse effects. 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 to consult 
a physician. Accordingly, any OTC drug product, labeled for adult use, 
containing any internal analgesic/antipyretic active ingredients 
(including, but not limited to, acetaminophen, aspirin, carbaspirin 
calcium, choline salicylate, ibuprofen, ketoprofen, magnesium 
salicylate, naproxen sodium, and sodium salicylate) alone or in 
combination shall bear an alcohol warning statement in its labeling as 
follows:
    (1) Acetaminophen. ``Alcohol Warning'' [heading in boldface type]: 
``If you consume 3 or more alcoholic drinks every day, ask your doctor 
whether you should take acetaminophen or other pain relievers/fever 
reducers. Acetaminophen may cause liver damage.''
    (2) Nonsteroidal anti-inflammatory analgesic/antipyretic active 
ingredients--including but not limited to aspirin, carbaspirin calcium, 
choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, 
naproxen sodium, and sodium salicylate. ``Alcohol Warning'' [heading in 
boldface type]: ``If you consume 3 or more alcoholic drinks every day, 
ask your doctor whether you should take [insert one nonsteroidal anti-
inflammatory analgesic/antipyretic active ingredient] or other pain 
relievers/fever reducers. [Insert one nonsteroidal anti-inflammatory 
analgesic/antipyretic active ingredient] may cause stomach bleeding.''
    (3) Combinations of acetaminophen with nonsteroidal anti-
inflammatory analgesic/antipyretic active ingredients--including but 
not limited to aspirin, carbaspirin calcium, choline

[[Page 56802]]

salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen 
sodium, and sodium salicylate. ``Alcohol Warning'' [heading in boldface 
type]: ``If you consume 3 or more alcoholic drinks every day, ask your 
doctor whether you should take [insert acetaminophen and one 
nonsteroidal anti-inflammatory analgesic/antipyretic active 
ingredient--including, but not limited to aspirin, carbaspirin calcium, 
choline salicylate, magnesium salicylate, or sodium salicylate] or 
other pain relievers/fever reducers. [Acetaminophen and (insert one 
nonsteroidal anti-inflammatory analgesic/antipyretic ingredient--
including, but not limited to aspirin, carbaspirin calcium, choline 
salicylate, magnesium salicylate, or sodium salicylate] may cause 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 the exact 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 April 23, 1999, is 
misbranded under section 502 of the Federal Food, Drug, and Cosmetic 
Act (21 U.S.C. 352) and is subject to regulatory action.

    Dated: July 22, 1998.
Michael A. Friedman,
Acting Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 98-28520 Filed 10-21-98; 10:58 am]
BILLING CODE 4160-01-F