[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;=""><0.0001), alcohol="" ingestion="" (or:="" 3.25;="" 95="" percent="" ci:="" 1.81-5.82;=""><0.0001), and="" peptic="" ulcer="" disease="" (or:="" 3.29;="" 95="" percent="" ci:="" 1.74-6.21;=""><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)=""><.001) and="" alcohol-related="" diagnoses="" were="" a="" significant="" independent="" predictor="" of="" increased="" risk=""><.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=""><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=""><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.="" 1.="" holvoet,="" j.="" et="" al.,="" ``relation="" of="" upper="" gastrointestinal="" bleeding="" to="" nonsteroidal="" anti-inflammatory="" drugs="" and="" aspirin:="" a="" case="" control="" study,''="" gut,="" 32:730-734,="" 1991.="" 2.="" coggon,="" d.,="" m.="" langman,="" and="" d.="" spiegelhalter,="" ``aspirin,="" paracetamol="" and="" haematemesis="" and="" melaena,''="" gut,="" 23:340-344,="" 1982.="" 3.="" bartle,="" w.,="" a.="" gupta,="" and="" j.="" lazor,="" ``nonsteroidal="" anti-="" inflammatory="" drugs="" and="" gastrointestinal="" bleeding:="" a="" case-control="" study,''="" archives="" of="" internal="" medicine,="" 146:2365-2367,="" 1986.="" 4.="" soll,="" a.,="" ``pathogenesis="" of="" peptic="" ulcer="" and="" implications="" for="" therapy,''="" new="" england="" journal="" of="" medicine,="" 322:909-916,="" 1990.="" 5.="" cohen,="" m.="" et="" al.,="" ``aspirin-induced="" human="" antral="" injury="" is="" reduced="" by="" vodka="" [[page="" 56800]]="" pretreatment,''="" digestive="" diseases="" and="" sciences,="" 33:513-517,="" 1988.="" 6.="" schubert,="" t.="" et="" al.,="" ``ulcer="" risk="" factors:="" interactions="" between="" helicobacter="" pylori="" infection,="" nonsteroidal="" use,="" and="" age,''="" american="" journal="" of="" medicine,="" 94:413-418,="" 1993.="" 7.="" jensen,="" d.="" et="" al.,="" ``effects="" of="" aspirin="" and="" alcohol="" exposure="" on="" outcomes="" of="" severe="" upper="" gastrointestinal="" hemorrhage,''="" draft="" of="" an="" unpublished="" paper="" included="" in="" comment="" no.="" c12,="" docket="" no.="" 77n-="" 094w,="" dockets="" management="" branch.="" 8.="" lanas,="" a.="" et="" al.,="" ``evidence="" of="" aspirin="" use="" in="" both="" upper="" and="" lower="" gastrointestinal="" perforation,''="" gastroenterology,="" 112:683-689,="" 1997.="" 9.="" gilman,="" a.="" g.="" et="" al.,="" editors,="" the="" pharmacological="" basis="" of="" therapeutics,="" 8th="" ed.,="" mcgraw-hill,="" new="" york,="" pp.="" 643="" and="" 664-668,="" 1990.="" 10.="" dukes,="" m.="" n.="" g.,="" editor,="" meyler's="" side="" effects="" of="" drugs,="" 12th="" ed.,="" elsevier,="" amsterdam,="" pp.="" 201-206,="" 1992.="" 11.="" gennaro,="" a.="" r.="" et="" al.,="" editors,="" remington's="" pharmaceutical="" sciences,="" 18th="" ed.,="" mack="" publishing="" co.,="" easton,="" pa,="" pp.="" 1112,="" 1117,="" and="" 1118,="" 1990.="" 12.="" van="" tyle,="" k.="" w.,="" ``internal="" analgesic="" products,''="" in="" handbook="" of="" nonprescription="" drugs,="" 10th="" ed.,="" american="" pharmaceutical="" association,="" washington,="" pp.="" 59="" and="" 62,="" 1993.="" 13.="" schafer,="" a.="" i.,="" ``effects="" of="" nonsteroidal="" antiinflammatory="" drugs="" on="" platelet="" function="" and="" systemic="" hemostasis,''="" journal="" of="" clinical="" pharmacology,="" 35:209-219,="" 1995.="" 14.="" deykin,="" d.,="" et="" al.,="" ``ethanol="" potentiation="" of="" aspirin-="" induced="" prolongation="" of="" the="" bleeding="" time,''="" new="" england="" journal="" of="" medicine,="" 306:852-54,="" 1982.="" 15.="" schukit,="" a.,="" ``alcoholism="" and="" drug="" dependency,''="" in="" harrison's="" principles="" of="" internal="" medicine,="" 13th="" ed.,="" edited="" by="" k.="" j.="" isselbacher="" et="" al.,="" mcgraw-hill="" health="" professions="" division,="" new="" york,="" pp.="" 2421-2422,="" 1994.="" 16.="" krome,="" r.,="" ``peptic="" ulcer="" disease,''="" in="" emergency="" medicine="" a="" comprehensive="" guide,="" 2nd="" ed.,="" edited="" by="" j.="" isselbacher,="" r.="" krome,="" and="" e.="" ruiz,="" mcgraw-hill="" book="" co.,="" new="" york,="" p.="" 310,="" 1988.="" 17.="" venho,="" v.,="" ``toxicants="" in="" the="" gastrointestinal="" tract,''="" in="" gastrointestinal="" toxicology,="" edited="" by="" k.="" rozman="" and="" o.="" hannien,="" elsevier,="" amsterdam,="" p.="" 386,="" 1986.="" 18.="" lichtenstein,="" d.,="" ``approach="" to="" patient="" with="" acute="" gastrointestinal="" hemorrhage,''="" in="" gastrointestinal="" emergencies,="" edited="" by="" m.="" taylor,="" williams="" and="" wilkins,="" baltimore,="" p.="" 105,="" 1992.="" 19.="" lanza,="" f.,="" g.="" royer,="" and="" r.="" nelson,="" ``endoscopic="" evaluation="" of="" the="" effects="" of="" aspirin,="" buffered="" aspirin,="" and="" enteric-coated="" aspirin="" on="" gastric="" and="" duodenal="" mucosa,''="" the="" new="" england="" journal="" of="" medicine,="" 303:136-138,="" 1980.="" 20.="" cello,="" j.="" p.,="" ``figure="" 28="" and="" 29,="" color="" plate="" iv,''="" in="" gastrointestinal="" disease="" pathophysiology/diagnosis/management,="" edited="" by="" m.="" h.="" sleisenger="" and="" j.="" s.="" fortran,="" w.="" b.="" saunders,="" philadelphia,="" 1993.="" 21.="" naschitz,="" j.="" e.="" et="" al.,="" ``overt="" gastrointestinal="" bleeding="" in="" the="" course="" of="" chronic="" low-dose="" aspirin="" administration="" for="" secondary="" prevention="" of="" arterial="" occlusive="" disease,''="" american="" journal="" of="" gastroenterology,="" 85:408-411,="" 1990.="" 22.="" weil,="" j.="" et="" al.,="" ``prophylactic="" aspirin="" and="" risk="" of="" peptic="" ulcer="" bleeding,''="" british="" medical="" journal,="" 310:827-830,="" 1995.="" 23.="" beaumont,="" w.,="" experiments="" and="" observations="" on="" the="" gastric="" juice="" and="" the="" physiology="" of="" digestion,="" reprinted="" for="" xiiith="" international="" physiology="" congress,="" boston,="" 1929.="" 24.="" wolf,="" s.="" and="" h.="" g.="" wolff,="" human="" gastric="" function="" an="" experimental="" study="" of="" a="" man="" and="" his="" stomach,="" oxford="" university="" press,="" london.="" 25.="" palmer="" e.="" d.,="" ``gastritis:="" a="" reevaluation,''="" medicine,="" 33:199,="" 1954.="" 26.="" tarnawski,="" a.="" et="" al.,="" ``alcohol="" injury="" to="" the="" normal="" gastric="" mucosa:="" endoscopic,="" histologic,="" and="" functional="" assessment,''="" clinical="" investigations="" in="" medicine,="" 10:259-263,="" 1987.="" 27.="" bockus="" gastroenterology,="" edited="" by="" w.="" s.="" haubrich="" and="" f.="" schaffner,="" w.="" b.="" saunders="" co.,="" philadelphia,="" pp.="" 664-665,="" 1994.="" 28.="" weinstein,="" w.="" m.="" ``gastritis="" and="" gastropathies,''="" in="" gastrointestinal="" disease="" pathophysiology/diagnosis/management,="" edited="" by="" m.="" h.="" sleisenger="" and="" j.="" s.="" fortran,="" w.="" b.="" saunders,="" philadelphia,="" p.="" 547,="" 1993.="" 29.="" u.s.="" department="" of="" health="" and="" human="" services,="" phs,="" national="" institutes="" of="" health,="" nih="" publication="" no.="" 94:1447,="" p.="" 783,="" 1994.="" 30.="" aarons,="" d.="" et="" al.,="" ``comparative="" effects="" of="" alcohol="" alone="" or="" in="" combination="" with="" aspirin="" or="" acetaminophen="" on="" human="" gastric="" mucosa,''="" (abs.),="" gastrointestinal="" endoscopy,="" 28:124,="" 1982.="" 31.="" peura,="" d.="" a.,="" et="" al.,="" ``the="" american="" college="" of="" gastroenterology="" bleeding="" registry:="" preliminary="" findings,''="" american="" journal="" of="" gastroenterology,="" 92:924-928,="" 1997.="" 32.="" uk-tia="" study="" group,="" ``united="" kingdom="" transient="" ischaemic="" attack="" (uk-tia)="" aspirin="" trial:="" interim="" results,''="" british="" medical="" journal,="" 296:316-320,="" 1988.="" 33.="" the="" salt="" collaborative="" group,="" ``swedish="" aspirin="" low-dose="" trial="" (salt)="" of="" 75="" mg="" aspirin="" as="" secondary="" prophylaxis="" after="" cerebrovascular="" ischaemic="" events,''="" lancet,="" 338:1345-1349,="" 1991.="" 34.="" steering="" committee="" of="" the="" physicians'="" health="" study="" research="" group,="" ``final="" report="" on="" the="" aspirin="" component="" of="" the="" ongoing="" physicians'="" health="" study,''="" new="" england="" journal="" of="" medicine,="" 321:129-135,="" 1989.="" 35.="" sievert,="" w.="" et="" al.,="" ``low-dose="" antacids="" and="" nonsteroidal="" anti-inflammatory="" drug-induced="" gastropathy="" in="" humans,''="" journal="" of="" clinical="" gastroenterology,="" 13:s145-48,="" 1991.="" 36.="" laporte,="" j.="" et="" al.,="" ``upper="" gastrointestinal="" bleeding="" in="" 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.="" 39a.="" nobili,="" a.,="" et="" al.,="" ``non-steroidal="" anti-inflammatory="" drugs="" 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.="" 41.="" bollini,="" p.="" et="" al.,="" ``the="" impact="" of="" research="" quality="" and="" study="" design="" on="" epidemiologic="" estimates="" of="" the="" effect="" of="" nonsteroidal="" anti-inflammatory="" drugs="" on="" upper="" gastrointestinal="" tract="" disease,''="" archives="" of="" internal="" medicine,="" 152:1289-95,="" 1992.="" 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.="" 45.="" deschepper,="" p.="" j.="" et="" al.,="" ``diflunisal="" versus="" aspirin:="" a="" comparative="" study="" of="" their="" effect="" on="" faecal="" blood="" loss="" in="" the="" presence="" and="" absence="" of="" alcohol,''="" current="" medical="" research="" and="" opinion,="" 5:520-524,="" 1978.="" 46.="" lee="" et="" al.,="" ``hemorrhagic="" erosive="" gastritis,''="" american="" journal="" of="" gastroenterology,="" 3:201-208,="" 1975.="" 47.="" bloom,="" b.="" s.,="" ``risk="" and="" cost="" of="" gastrointestinal="" side="" effects="" associated="" with="" nonsteroidal="" anti-inflammatory="" drugs,''="" archives="" of="" internal="" medicine,="" 149:1019-1022,="" 1989.="" 48.="" summary="" of="" the="" minutes="" of="" the="" september="" 8,="" 1993,="" joint="" meeting="" of="" the="" fda="" nonprescription="" drugs="" and="" arthritis="" drugs="" advisory="" committees,="" in="" otc="" vol.="" 03awnpr,="" docket="" no="" 77n-094w,="" dockets="" management="" branch,="" food="" and="" drug="" administration.="" 49.="" summary="" minutes="" of="" the="" june="" 28="" and="" 29,="" 1993="" meeting="" of="" the="" fda="" nonprescription="" drugs="" advisory="" committee,="" in="" otc="" vol.="" 03awnpr,="" docket="" no.="" 77n-094w,="" dockets="" management="" branch.="" 50.="" summary="" minutes="" of="" the="" june="" 1,="" 1993,="" meeting="" of="" the="" fda="" arthritis="" and="" nonprescription="" drugs="" advisory="" committees.="" 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="" gastroenteropathy:="" the="" second="" hundred="" years,''="" gastroenterology,="" 112:1,000-1,006,="" 1997.="" 53.="" comments="" no.="" c193,="" c206,="" and="" mm19,="" docket="" no.="" 77n-0094,="" dockets="" management="" branch.="" 54.="" comments="" no.="" c198,="" c199,="" c200,="" docket="" no.="" 77n-0094,="" dockets="" management="" branch.="" 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,="" dockets="" management="" branch.="" 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.="" 59.="" carson,="" j.="" et="" al.,="" ``the="" relative="" gastrointestinal="" toxicity="" of="" the="" nonsteroidal="" anti-inflammatory="" drugs,''="" archives="" of="" internal="" medicine,="" 147:1054-1059,="" 1987.="" 60.="" griffin,="" m.="" et="" al.,="" ``nonsteroidal="" anti-inflammatory="" drug="" use="" and="" increased="" risk="" for="" peptic="" ulcer="" disease="" in="" elderly="" persons,''="" annals="" of="" internal="" medicine,="" 114:257-263,1991.="" 61.="" garcia="" rodriguez,="" l.,="" and="" h.="" jick,="" ``risk="" of="" upper="" gastrointestinal="" bleeding="" and="" perforation="" associated="" with="" individual="" nonsteroidal="" anti-inflammatory="" drugs,''="" lancet,="" 343:769-772,="" 1994.="" 62.="" transcripts="" of="" the="" october="" 11="" and="" 12,="" 1995,="" meeting="" of="" the="" fda="" arthritis="" drugs="" advisory="" committee,="" in="" otc="" vol.="" 03awnfr,="" docket="" no.="" 77n-094a,="" dockets="" management="" branch.="" 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="" england="" journal="" of="" medicine,="" 325:87-91,="" 1991.="" 64.="" dearmond,="" b.="" et="" al,="" ``safety="" profile="" of="" nonprescription="" naproxen="" sodium,''="" clinical="" pharmacology="" and="" therapy,="" 57:136,="" 1995.="" 65.="" insel,="" p.="" a.,="" ``analgesic-antipyretic="" and="" anti-inflammatory="" agents="" and="" drugs="" employed="" in="" the="" treatment="" of="" gout:="" the="" salicylates;="" gastrointestinal="" effects,''="" in="" ``goodman="" and="" gilman's="" the="" pharmacological="" basis="" of="" therapeutics,''="" 9th="" ed.,="" edited="" by="" j.="" g.="" hardman,="" a.="" g.="" gilman,="" and="" l.="" e.="" limbird,="" mcgraw-hill,="" new="" york,="" p.="" 626,="" 1996.="" 66.="" cher,="" d.,="" r.="" morgan,="" and="" s.="" hyg,="" ``comparison="" of="" the="" risks="" of="" aspirin="" and="" acetaminophen="" in="" alcohol="" users:="" application="" of="" decision="" analysis''="" draft="" of="" an="" unpublished="" paper="" in="" comment="" no.="" c12,="" docket="" no.="" 77n-094a,="" dockets="" management="" branch.="" 67.="" ``a="" study="" of="" two="" pain="" reliever="" warning="" statements''="" by="" guideline="" research="" corp.,="" draft="" of="" an="" unpublished="" paper="" in="" comment="" no.="" c12,="" docket="" no.="" 77n-094a,="" dockets="" management="" branch.="" 68.="" willett,="" l.,="" j.="" carson,="" and="" b.="" strom,="" ``epidemiology="" of="" gastrointestinal="" damage="" associated="" with="" nonsteroidal="" anti-="" inflammatory="" drugs,''="" drug="" safety,="" 10:170-181,="" 1994.="" 69.="" norton,="" r.,="" ``alcohol="" consumption="" and="" the="" risk="" of="" alcohol="" related="" cirrhosis="" in="" women,''="" british="" medical="" journal,="" 295:80-82,="" 1987.="" 70.="" mezey,="" e.="" et="" al.,="" ``alcohol="" and="" dietary="" intake="" in="" the="" development="" of="" chronic="" pancreatitis="" and="" liver="" disease="" in="" alcoholism,''="" american="" journal="" of="" clinical="" nutrition,="" 48:148-151,="" 1988.="" 71.="" kuffner,="" e.,="" g.="" bogdan,="" and="" r.="" dart,="" ``evaluation="" of="" hepatotoxicity="" in="" alcoholics="" from="" therapeutic="" dosing="" of="" acetaminophen,''="" journal="" of="" toxicology,="" 35:561,="" 1997.="" 72.="" petroski,="" d.,="" ``a="" comparison="" of="" enteric-coated="" aspirin="" granules="" with="" plain="" and="" buffered="" aspirin:="" a="" report="" of="" two="" studies,''="" the="" american="" journal="" of="" gastroenterology,="" 81:26-28,="" 1986.="" 73.="" lanza,="" f.,="" g.="" royer,="" and="" r.="" nelson,="" ``endoscopic="" evaluation="" of="" the="" effects="" of="" aspirin,="" buffered="" aspirin,="" and="" enteric-coated="" aspirin="" on="" gastric="" and="" duodenal="" mucosa,''="" the="" new="" england="" journal="" of="" medicine,="" 303:136-138,="" 1980.="" 74.="" savon,="" j.="" et="" al.,="" ``gastrointestinal="" blood="" loss="" with="" low="" dose="" (325="" mg)="" plain="" and="" enteric-coated="" aspirin="" administration,''="" the="" american="" journal="" of="" gastroenterology,="" 90:581-585,="" 1995.="" 75.="" petroski,="" d.,="" ``endoscopic="" comparison="" of="" three="" aspirin="" preparations="" and="" placebo,''="" excerpta="" medica,="" pp.="" 314-320,="" 1993.="" 76.="" petroski,="" d.,="" ``endoscopic="" comparison="" of="" various="" aspirin="" preparations-gastric="" mucosal="" adaptability="" to="" aspirin="" restudied,''="" current="" therapeutic="" research,="" 45:945-954,="" 1989.="" 77.="" kelly,="" j.="" p.="" et="" al.,="" ``risk="" of="" aspirin-associated="" major="" upper-gastrointestinal="" bleeding="" with="" enteric-coated="" or="" buffered="" product,''="" lancet,="" 348:1413-1416,="" 1996.="" 78.="" silagy,="" c.="" a.="" et="" al.,="" ``adverse="" effects="" of="" low-dose="" aspirin="" in="" a="" healthy="" elderly="" population,''="" clinical="" pharmacology="" and="" therapeutics,="" 54:84-89,="" 1993.="" 79.="" national="" institutes="" of="" health,="" eighth="" special="" report="" to="" the="" u.s.="" congress="" on="" alcohol="" and="" health="" from="" the="" secretary="" of="" health="" and="" human="" services,="" u.s.="" department="" of="" health="" and="" human="" services,="" national="" institutes="" of="" health,="" and="" national="" institute="" on="" alcohol="" abuse="" and="" alcoholism,="" nih="" publication="" no.="" 94-3699,="" pp.="" 21-23,="" 1994.="" 80.="" substance="" abuse="" and="" mental="" health="" service="" administration,="" ``preliminary="" results="" from="" the="" 1996="" national="" household="" survey="" on="" drug="" abuse;''="" published="" august="" 1997;="">http://www.health.org/pubs/
nhsda/96hhs/httoc.htm>
81. National Institute on Alcohol Abuse and Alcoholism,
``Surveillance Report #40: Trends in Alcohol-Related Morbidity Among
Short-Stay Community Hospital Discharges, United States, 1979-94'',
published December 1996, ``http://silk/niaaa1/publication/
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
