[Federal Register Volume 63, Number 205 (Friday, October 23, 1998)]
[Rules and Regulations]
[Pages 56802-56819]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-28519]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 343

[Docket No. 77N-094A]
RIN 0910-AA01


Internal Analgesic, Antipyretic, and Antirheumatic Drug Products 
for Over-The-Counter Human Use; Final Rule for Professional Labeling of 
Aspirin, Buffered Aspirin, and Aspirin in Combination With Antacid Drug 
Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing as a final 
rule professional labeling for over-the-counter (OTC) internal 
analgesic, antipyretic, and antirheumatic drug products containing 
aspirin, buffered aspirin, and aspirin in combination with an antacid. 
This portion of the final monograph is being issued prior to the entire 
monograph so that the professional labeling of these products will 
reflect the latest information on cardiovascular, cerebrovascular, and 
rheumatologic uses. 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 
amendment to the regulation, and data and information that have come to 
the agency's attention.

EFFECTIVE DATE: October 25, 1999.

FOR FURTHER INFORMATION CONTACT: Ida I. Yoder, Center for Drug 
Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of November 16, 1988 (53 FR 46204), FDA 
published, under 21 CFR 330.10(a)(7), 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 TFM (53 FR 
46204 at 46258 and 46259), the agency proposed professional labeling in 
Sec. 343.80 for the use of aspirin for rheumatologic diseases, for 
reducing the risk of recurrent transient ischemic attacks (TIA's) or 
stroke in men who have had transient ischemia of the brain due to 
fibrin platelet emboli, and for reducing the risk of death and/or 
nonfatal myocardial infarction (MI) in patients with a previous 
infarction or unstable angina pectoris. The agency also proposed 
professional labeling for the use of carbaspirin calcium, choline 
salicylate, magnesium salicylate, or sodium salicylate for 
rheumatologic diseases. 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 TFM, the agency received four comments and three 
citizen petitions related to the professional labeling of aspirin for 
cardiovascular and cerebrovascular uses (Ref. 1). No comments were 
received on the professional use of aspirin drug products for 
rheumatologic diseases. In response to two of the petitions, the agency 
proposed to amend the professional labeling section of the TFM for OTC 
internal analgesic, antipyretic, and antirheumatic drug products to 
include an indication for aspirin for suspected acute MI (61 FR 30002, 
June 13, 1996). In response to the proposed amendment, the agency 
received 10 comments (Ref. 2).
    In the TFM for OTC internal analgesic, antipyretic, and 
antirheumatic drug products (53 FR 46204 at 46205), and in the proposed 
amendment to the TFM (61 FR 30002), the agency proposed that any final 
rule that may issue based on the proposal will be effective 12 months 
after the date of publication in the Federal Register. Therefore, on or 
after October 25, 1998, the dissemination of professional labeling that 
does not comply with this final rule may result in regulatory action 
against the product, the marketer, or both. Manufacturers are 
encouraged to comply voluntarily with this final rule at the earliest 
possible date.
    The labeling in this final rule for professional use of aspirin 
drug products contains complete information on certain professional 
uses of aspirin, including information for professionals on the 
treatment of the signs and symptoms of rheumatologic disease. The 
labeling is organized and presented in a manner similar to that 
required of prescription drug products under Secs. 201.56 and 201.57 
(21 CFR 201.56 and 201.57). The labeling in this final rule also 
includes an optional highlights section that summarizes the 
professional indications and the recommended dosage and

[[Page 56803]]

administration for each professional indication.

II. The Agency's Conclusions on the Comments

A. Comments to the TFM

    1. One comment requested that aspirin be approved for use as a 
prophylaxis for primary (first) MI under a physician's supervision. The 
comment based its request on the preliminary report of a large, highly 
statistically significant, reduction (47 percent) in the risk of total 
(fatal and nonfatal) MI in subjects taking aspirin in the U.S. 
Physicians' Health Study (Ref. 3). A final report was published later 
(Ref. 4).
    The agency also considered the British Doctors Study, by Peto et 
al. (Ref. 5), that was similar in many respects to the U.S. Physicians' 
Health Study. It randomized 5,139 apparently healthy male doctors, to 
500 milligrams (mg) aspirin daily, or to no aspirin, to see whether 
aspirin would reduce the incidence of, and mortality from, stroke, MI, 
or other vascular conditions. The British Doctors Study, despite its 
similarity to the U.S. Physicians' Health Study, does not support the 
use of aspirin to prevent an initial MI. After 6 years of followup, 
there were 23.5 confirmed nonfatal MI reports per 1,000 participants in 
the aspirin group and 24 per 1,000 in the no-aspirin group. When 
possible MI reports were added, the total was 30 per 1,000 for the 
aspirin group and 26.4 per 1,000 for the no-aspirin group. From a 
safety viewpoint, disabling stroke was significantly more frequent in 
the aspirin group than the no-aspirin group (19.1 versus 7.4 per 10,000 
man years, p < 0.05). In addition, expected gastrointestinal (GI) 
events (e.g., nonfatal peptic ulcers, bleeding, dyspepsia) occurred in 
the aspirin group.
    On October 6, 1989, FDA's Cardiovascular and Renal Drugs Advisory 
Committee (the Committee) considered a claim for aspirin for the 
prevention of primary (first) heart attack based on the findings of the 
U.S. Physicians' Health Study (Refs. 3 and 4). The Committee was aware 
of the findings of the British Doctors Study, but only the findings 
from the U.S. Physicians' Health Study were presented in detail. The 
Committee recommended (by a 5 to 3 vote) that, although some claim 
should be considered for some high-risk group of patients, aspirin 
should not be used routinely in patients without risk factors or in 
women, until such patients had been studied. The Committee minority was 
concerned about the toxicity of aspirin and the number of normal 
individuals at low risk of having a heart attack who would be treated 
long term. The Committee unanimously agreed that patients should ask 
their doctor before beginning prophylactic therapy. The agency has 
considered the Committee's views in conjunction with the additional 
data that have been subsequently submitted to FDA.
    The agency does not consider the results of the aspirin component 
of the U.S. Physicians' Health Study adequate to support the 
effectiveness of aspirin in decreasing the risk of MI in healthy 
individuals without evidence of coronary artery disease because of 
concerns about the revised primary endpoint, the study population, and 
the results of the British Doctors Study.
    The primary endpoint described in the protocol for the aspirin 
component of the U.S. Physicians' Health Study was total cardiovascular 
mortality. On interim evaluations, however, it became clear to the Data 
Monitoring Board (DMB) for the study that the aspirin arm of the study 
had little chance of showing a survival effect before the year 2000, if 
then, because the mortality rate was far lower than expected and the 
study did not show even a positive trend for this endpoint. There were 
81 deaths in the aspirin group and 83 in the placebo group (p = 0.87). 
The DMB also took note of the reductions in total (fatal and nonfatal) 
MI, a finding they considered persuasive. Because the study had little 
hope of showing an effect on the primary endpoint and because of the 
reduction in MI, the DMB recommended early termination of the aspirin 
component of the trial (Ref. 3). The early stopping rule stated in the 
grant proposal (but not in the protocol) was that the trial would 
continue unless chi-square tests comparing treatments reached an 
extreme value, such as 9.0 (i.e., if p < 0.0027). The proposal did not 
state explicitly which endpoint was the basis for the early stopping 
rule. It is not clear which endpoint served as the basis for the early 
stopping rule. Thus, it is not clear how the reported p values should 
be adjusted retrospectively although some adjustment would be required.
    The finding of a reduction in risk of MI in the U.S. Physicians' 
Health Study is further weakened because some of the study patients had 
a prior MI, and aspirin is already known to reduce the risk of 
recurrent MI in such patients. According to the study protocol, 
subjects should not have had an MI before randomization. However, based 
on the agency's inspection of the subjects' records, at least 40 (about 
8 percent) of the 512 subjects who suffered a nonfatal MI during the 
study also had evidence of an old MI. The exact number of cases with 
prior MI in the entire study population at the time of randomization is 
not known. Therefore, it is not possible to determine with assurance 
how much of the effect of aspirin attributed to prevention of a primary 
MI was really prevention of a reinfarction.
    The U.S. Physicians' Health Study also found a statistically 
significant reduction in the risk of fatal acute MI in the aspirin 
group, but no overall effect on survival. The agency does not consider 
this finding persuasive. Assessing cause-specific mortality is usually 
difficult and the finding of benefit is of uncertain meaning in the 
face of equivalent total cardiovascular mortality (the original primary 
endpoint). Thus, the decrease in acute MI deaths in the aspirin group 
were almost matched by an increase in sudden deaths, not an obviously 
worthwhile effect. Redefinition of endpoints would, in any case, 
require adjustment for multiplicity, but it is difficult to describe 
the appropriate adjustment, as the number of possible secondary 
endpoints is unspecified. The nominally significant decrease of fatal 
MI (p = 0.004) thus needs considerable upward adjustment and would not 
be close to the significance level needed at an interim point (p < 
0.0027).
    In addition, some of the cause of death assignments are 
questionable. The agency evaluated the deaths in the study attributed 
to fatal acute MI (10 in the aspirin group and 28 in the placebo group) 
and to ``sudden death'' (22 in the aspirin group and 12 in the placebo 
group) and found that one death in the placebo group attributed to 
acute MI was due to stroke. Another placebo subject classified as MI 
had no evidence of MI, but could have been classified as a ``sudden 
death.'' Thus the number of confirmed MI's in the placebo group 
decreases from 28 to 26, and the number of ``sudden deaths'' increases 
from 12 to 13.
    On the other hand, the autopsy report of one aspirin subject 
categorized under ``sudden death'' listed acute MI as the cause of 
death. Another aspirin subject, in the sudden death category, 
experienced chest pain and vomiting before collapsing, and the autopsy 
showed ``moderate to severe 3-vessel atherosclerosis with apparent 
myocardial ischemia in a patient with right and left myocardial 
hypertension and extensive old septal scarring.'' It is likely that 
this patient's death was due to acute MI. Thus, if 2 of the 22 deaths 
in the aspirin group classified as ``sudden death'' had been classified 
as confirmed acute MI (increasing that

[[Page 56804]]

total from 10 to 12), the ``sudden death'' total would be decreased 
from 22 to 20. The cause of death could not be established with 
certainty in most subjects. All subjects in the ``sudden death'' 
category for whom relevant information was available had a history of 
atherosclerotic cardiovascular disease, peripheral vascular disease, or 
hypertension. Therefore, all of the cases of sudden death could have 
resulted from an acute MI. Thus, there could have been 32 cases (12 
identified, 20 possible) of fatal MI in the aspirin group versus 39 (26 
identified, 13 possible) in the placebo group. This difference is not 
statistically significant (p > 0.50). This analysis could be considered 
a ``worst case'' analysis of the fatal MI finding, but it illustrates 
the difficulty of cause-specific mortality findings.
     The agency also does not believe the reported 18 percent reduction 
in the endpoint of nonfatal MI, nonfatal stroke, and total 
cardiovascular mortality can be taken as significant. For the combined 
endpoint, there were 307 subjects in the aspirin group and 370 in the 
placebo group (relative risk 0.82; p = 0.01). The reported p value of 
0.01 is well above the stopping rule p value of 0.0027. Therefore, the 
study did not provide persuasive evidence that aspirin has a beneficial 
effect on the combined endpoint. In addition, the isolated finding of a 
statistically significant effect on nonfatal MI is not persuasive. Of 
note is the fact that the British Doctors Study completely failed to 
replicate this finding.
    The reduction in incidence of fatal and nonfatal MI was also 
accompanied by an increase in strokes, especially severe, fatal, 
hemorrhagic stroke, and by a greater incidence of sudden death and 
``other'' cardiovascular deaths. Thus, there was no overall benefit or 
favorable trend on mortality. Cerebral hemorrhage as a cause of stroke 
was reported more often in the aspirin group than in the placebo group 
(23 versus 12). The incidence of ulcers, ``other noninfectious diseases 
of the digestive tract,'' bleeding problems, and the need for 
transfusion, also was significantly increased, and one aspirin subject 
died from GI bleeding. Although these side effects would not prevent 
the use of aspirin if its net benefit on coronary artery and 
cerebrovascular events were favorable, the effects are not trivial.
    It seems probable that the net benefit of aspirin is critically 
dependent on the underlying risk for coronary and cerebral events, and 
that use of aspirin requires knowing more about its effects in various 
populations. In people at low risk for acute MI, the increased risk of 
stroke may result in a net disadvantage. In at least some people at 
higher risk (people who have had an acute MI or have TIA's), aspirin is 
known to provide a net benefit. There may be other populations in whom 
the net effect of aspirin is favorable, but the U.S. Physicians' Health 
Study does not define such groups. The investigators did not identify 
any group in which aspirin could reduce the incidence of fatal and 
nonfatal heart attack without increasing the incidence of other causes 
of death or disability.
    The Steering Committee of the U.S. Physicians' Health Study 
Research Group (Ref. 4) suggested that aspirin is beneficial in 
prevention of the first heart attack (at least in men over 50), but 
stated: ``Although the short-term benefit of aspirin in these 
populations appears to outweigh its risks, the long-term advantage and 
toxicity of the drug remain uncertain.'' In a more recent review 
article (Ref. 6) by several members of the U.S. Physicians' Health 
Study Research Group, members of the Steering Committee, and others, 
concerning primary prevention of MI, the authors concluded the 
following: ``Any decision to use aspirin prophylaxis should be made on 
an individual basis and, in general, should be considered only for 
those whose absolute risk of a first MI is sufficiently high to warrant 
accepting the potential adverse effects of long-term aspirin use.''
    In summary, the U.S. Physicians' Health Study failed to show a 
significant effect, or even a beneficial trend, on the specified 
primary study endpoint of total cardiovascular mortality. The study was 
stopped early and multiple secondary endpoints were evaluated. The 
effects of aspirin on fatal acute MI and on the combined endpoint of 
nonfatal MI, nonfatal stroke, and total cardiovascular mortality were 
not statistically significant when adjustments were made for early 
stopping. There was an isolated finding of a statistically significant 
effect on nonfatal MI (a secondary endpoint), but the value of this 
finding is questionable in the face of adverse trends on stroke and 
causes of death other than acute MI. Of note is the fact that the 
British Doctors Study completely failed to replicate this finding on 
nonfatal MI. Thus, the agency concludes that the available data do not 
support the professional labeling of aspirin for the prevention of 
first MI. The U.S. Physicians' Health Study (Refs. 3 and 4), in 
particular, did not show a statistically significant effect when all 
deaths as well as nonfatal MI and stroke were combined.
    2. One comment asked that the professional labeling in proposed 
Sec. 343.80(b) for aspirin for TIA include both men and women, not just 
men. The comment cited results from the Second International Study of 
Infarct Survival (ISIS-2) (Ref. 7), based on an analysis of a subset of 
data for men and women separately, to support its request. The absolute 
decrease in mortality for the aspirin group compared to placebo was 2.4 
percent for men and 2.6 percent for women. The comment concluded that 
this study showed that, up to 5 weeks, mortality was significantly 
reduced (p < 0.01) in both men and women who had suffered acute MI and 
were treated for 1 month with aspirin. The comment added that this 
study also showed that aspirin reduced the incidence of nonfatal stroke 
and nonfatal MI in both men and women.
    The comment complained that the study (Ref. 8) supporting the use 
of aspirin only in men to reduce the risk of recurrent TIA or stroke 
was only one small trial with a marginally significant overall result. 
The comment mentioned that the results of this study were subdivided by 
gender, and a data-dependent subgroup analysis suggested an effect only 
in men. Such subgroup analysis, the comment contended, is frequently 
unreliable. The comment suggested that the ISIS-2 study results, which 
showed reduced mortality in both men and women given aspirin following 
acute MI, should ``illuminate'' data from trials in a different 
occlusive vascular disease (TIA).
    The agency is in substantial agreement with the comment that there 
is no reason to distinguish between genders with respect to using 
aspirin to reduce the risk of recurrent TIA or stroke. Although subset 
differences are known to occur, in general, results are considered 
applicable to the whole group unless there is reason not to do so (Ref. 
9). In the present case there was, initially, reason to limit the TIA 
claim to males. The indication in proposed Sec. 343.80(b) was based on 
results of the Canadian Cooperative Study Group trial (Ref. 8) and the 
Fields study (Ref. 10). In these studies, there seemed to be a 
difference in response with gender when subset analyses were done. 
However, there were very few women in the trials and the number of 
events reported was small.
    Data from subsequent trials do not substantiate a gender difference 
in the effect of aspirin on cerebrovascular events, and trends in women 
have been similar to results seen in men. The UK-TIA aspirin trial 
(Ref. 11), in which 25 percent of the subjects were women, showed 
favorable trends for the

[[Page 56805]]

endpoint of major stroke, MI, or death. The AICLA study (Ref. 12), 
which reportedly showed an effect of aspirin for secondary cerebral 
events in a group that included 30 percent women, showed no significant 
difference between men and women. Although the study was small, subset 
analysis showed a trend favoring women, with a numerically larger 
effect on stroke in women than in men. The study by Sivenius et al. 
(Ref. 13) included a larger proportion of women (42 percent in the 
intent-to-treat analysis and 44 percent in the explanatory analysis), 
and the investigators reported a statistically significant effect in 
women. That study did not include an aspirin-only arm, but there is 
little evidence that dipyridamole contributes to the effect of the 
aspirin plus dipyridamole combination (Refs. 12 and 14); thus, this 
study provides some support for an effect of aspirin in women. The 
Swedish Cooperative study (Ref. 15) failed to show an effect for 
aspirin overall, in men or in women.
    The agency believes the available data support the conclusion that 
women with a history of TIA should benefit from aspirin therapy. Early 
evidence supporting this use of aspirin came from studies that included 
mostly men, but studies since the Canadian and Fields studies show 
numerically similar results for men and women. Favorable trends have 
generally been seen in women as well as men. Therefore, the agency is 
revising the professional labeling in Sec. 343.80 for cerebrovascular 
uses so that the indication is for ``patients'' rather than for 
``men.''
     3. One comment asked that the dosage for aspirin for TIA in 
proposed Sec. 343.80(b) be reduced from 1,300 mg to 300 mg a day. The 
comment contended that data from many different trials of antiplatelet 
treatments in many different occlusive vascular conditions could be 
viewed together. The comment stated that this approach could be used 
because, no matter what the prior medical condition may have been, the 
chief diseases to be prevented (occlusive stroke and coronary artery 
occlusion) may be much the same. The comment explained that aspirin 
doses of only 100 to 200 mg daily inhibit cyclo-oxygenase-dependent 
platelet aggregation so completely that little extra effect would 
result from higher daily doses. The comment cited the ISIS-2 study 
(Ref. 7) as showing that 160 mg aspirin daily was highly protective in 
preventing death (p < 0.01) and in reducing nonfatal stroke and 
nonfatal MI in subjects who suffered an acute MI.
    The comment also cited the Trialists' report (Ref. 16), a meta-
analysis of the results of 25 randomized clinical trials of the 
prolonged treatment with drugs that inhibit platelet aggregation. The 
comment stated that when the trials are viewed together: (1) The 
benefits of antiplatelet treatment are about the same in cardiac 
patients (unstable angina and MI) as in cerebral patients (TIA and 
stroke thought to be occlusive), and (2) the various treatments used, 
including 300 mg of aspirin daily, were comparable. The comment 
mentioned that aspirin gastrotoxicity is dose-related, and cited the 
UK-TIA trial (Ref. 11) in which more GI symptoms (indigestion, nausea, 
heartburn, or vomiting) occurred with 1,200 mg than 300 mg daily 
aspirin (a difference of 9.4 percent (2p < 0.001)).
    Another comment asked the agency to consider lower doses of aspirin 
for maintenance therapy. The comment described several serious nasal 
hemorrhages that occurred when taking maintenance therapy of ``one half 
aspirin tablet (strength not stated) daily.'' The comment also 
mentioned a number of instances of sustained bleeding from shaving 
nicks, bleeding after accidents, bleeding ulcers, and complications 
during surgery based on personal experience or the experiences of 
friends or neighbors who were taking aspirin for maintenance therapy. 
The comment concluded that the proposed FDA dosage is several times the 
dosage needed for most maintenance therapy and that FDA should lower 
the dosage.
    The agency has considered the dosage of aspirin for cardiovascular 
and cerebrovascular conditions and concludes that specific doses for 
specific uses of aspirin, supported by appropriate data, are necessary 
for an optimum benefit to the user, and, in general, that a minimum 
effective dose established for a given indication should be used to 
minimize dose-related adverse effects. The agency has determined that 
the ISIS-2 study (Ref. 7) supports the professional labeling of aspirin 
in the treatment of suspected acute MI at a dosage of 160 to 162.5 mg 
daily. However, the ISIS-2 study did not show, nor was it intended to 
show, the effect of aspirin on subjects with TIA or other 
cerebrovascular events.
    The Trialists' report (Ref. 16) evaluated antiplatelet treatment of 
subjects with a range of symptoms (e.g., TIA, occlusive stroke, 
unstable angina, and MI) using a number of antiplatelet agents, not 
only aspirin. Some of the studies (Refs. 8, 10 through 12, 15, and 17 
through 19) used aspirin alone and included cerebrovascular subjects 
given dosages ranging from 990 to 1,500 mg daily, except one arm of the 
UK-TIA study that used a dosage of 300 mg daily in parallel with a 
1,200 mg dose. The primary endpoints of most of these studies were 
combined events, including strokes (fatal and nonfatal) and death. In 
some of the studies, TIA or MI was also included in the primary 
endpoint. The Trialists' group (Ref. 16) did a meta-analysis suggesting 
the effectiveness of lower doses of aspirin (less than 160 to 324 mg 
per day) in reducing combined events (nonfatal stroke, MI, or vascular 
death), but all studies except the UK-TIA study involved subjects with 
a history of MI or angina rather than a history of cerebrovascular 
events.
    In a subsequent publication (Ref. 20), the Trialists' group 
provided some support for the role of antiplatelet therapy in 
prevention of nonfatal strokes in subjects with prior stroke or TIA. 
Among the 10 trials that used aspirin alone, dosages ranged from 50 to 
1,300 mg per day. Three of these trials (UK-TIA, Danish Very-Low-Dose, 
and Swedish Aspirin Low-Dose Trial (SALT)) used comparatively low doses 
of aspirin (Refs. 11, 21, and 22).
    The UK-TIA study (Ref. 11) alone showed no difference in 
effectiveness between the 300 mg and the 1,200 mg aspirin daily dose in 
a TIA population, but the incidence of side effects, especially GI, was 
greater for the 1,200 mg dose. The beneficial effect of aspirin on 
major stroke alone and on the composite events, disabling stroke or 
vascular death, was not sufficient to show a significant difference 
between aspirin and placebo, but it did show a trend in favor of 
aspirin. For the combined endpoint of all death, nonfatal major stroke, 
and nonfatal MI, the study showed an 18-percent (95 percent confidence 
interval, 2 to 31 percent) reduction by aspirin (combined 300 and 1,200 
mg groups). The Danish Very-Low-Dose Study (Ref. 21) used aspirin doses 
ranging from 50 to 100 mg per day in subjects with TIA, stroke, or 
acute MI who had recently undergone carotid endarterectomies. The study 
showed no significant effect of aspirin and side effects were minimal. 
In the SALT study (Ref. 22), 75 mg aspirin daily reduced the risk of 
stroke and death by 18 percent in subjects who previously had TIA, 
minor ischemic stroke, or retinal artery occlusion. The agency also 
considered the findings of the second European Stroke Prevention Study 
(ESPS-2) (Ref. 23) in which 50 mg daily aspirin had a significant 
beneficial effect on the combined risk of stroke or death in subjects 
with a prior TIA or ischemic stroke. (See section II.A, comment 4 of 
this document.)
    The proposed indication for aspirin to reduce the risk of recurrent 
TIA or

[[Page 56806]]

stroke in subjects with TIA, at a dosage of 1,300 mg daily, was based 
primarily on two small studies (Refs. 8 and 10). Other, more recently 
published studies (Refs. 11, 12, 22, and 23) have shown a significant 
effect or trend in favor of aspirin in a population with 
cerebrovascular events. The agency has reevaluated the available 
studies and the overall outcome of the available studies, looking at 
the role of aspirin on the endpoint of stroke alone and the broader 
composite endpoint of stroke and death, both individually and 
collectively. (See section II.A, comment 4 of this document.)
    Although there is more evidence for effectiveness of aspirin for 
subjects with TIA or cerebral ischemia at higher doses (900 to 1,500 mg 
daily) than at lower doses (Ref. 24), the ESPS-2 (50 mg daily aspirin) 
(Ref. 23), the SALT study (75 mg aspirin daily) (Ref. 22), and UK-TIA 
study (300 mg versus 1,200 mg aspirin daily) (Ref. 11), lend support 
for a lower dose. Certain adverse reactions, such as excessive bleeding 
described by one of the comments, occur in some individuals taking 
aspirin, but there are generally fewer such reactions at lower doses 
than higher doses. This is supported by the UK-TIA study (Ref. 12). The 
benefit/risk must be taken into account for each indication. In this 
regard, the agency proposed a warning in Sec. 343.50(c)(1)(v)(B) of the 
TFM to alert people who have bleeding problems not to take aspirin 
unless directed by a doctor (53 FR 46204 at 46256). Also, the 
professional labeling in this final rule lists GI bleeding in the 
adverse reactions section and notes that many adverse reactions due to 
aspirin ingestion are dose related.
    In summary, there is clinical trial support for a lower dose of 
aspirin for subjects with a history of TIA or cerebral ischemia and 
considerable evidence supporting lower doses in patients with MI. It is 
also clear that the effect of aspirin on platelet function is complete 
at lower doses. The positive findings at lower dosages (e.g., 50, 75, 
and 300 mg daily), along with the higher incidence of side effects 
expected at the higher dosage (e.g., 1,300 mg daily), are sufficient 
reason to lower the dosage of aspirin for subjects with TIA and 
ischemic stroke. The agency believes a dose of 50 to 325 mg is an 
effective daily dose for subjects with TIA or cerebral ischemia. 
Therefore, in this final rule, the agency is providing for a dosage of 
50 to 325 mg aspirin daily.
    4. One comment suggested the following indication for low-dose 
aspirin: ``For reduction of the risk of MI, stroke, and vascular death 
among men or women with a history of occlusive cerebral vascular or 
cardiovascular disease. The optimal dose is not known, but there is no 
good evidence that doses above 300 mg/day are necessary.''
    The agency reviewed a number of published reports (individually and 
collectively) to further evaluate the effects of aspirin in subjects 
with premonitory cerebrovascular events. The agency evaluated studies 
that: (1) Compared aspirin alone to placebo in subjects with a history 
of cerebrovascular events, and (2) evaluated and adequately presented 
the endpoint of stroke and the composite endpoint of stroke and death. 
The agency considered reviews by the Antiplatelet Trialists' group 
(Refs. 16 and 20) and Matchar et al. (Ref. 24), but did not include 
combination arms (e.g., aspirin and dipyridamole) and studies of post-
endarterectomy subjects (e.g., Danish Very-Low-Dose Study) (Ref. 21). 
The following studies met the criteria: SALT (Ref. 22), AICLA (Ref. 
12), Canadian Cooperative (Ref. 8), AITIA (Ref. 10), Danish Cooperative 
(Ref. 18), Swedish Cooperative (Ref. 15), and UK-TIA (Ref. 11). The 
agency evaluated the available data in the published reports, which in 
some cases differed from the data listing in the Trialists' reports 
(Refs. 16 and 20), because of their independent review of outcomes.
    The SALT study (Ref. 22) compared aspirin (75 mg daily) and placebo 
in 1,360 subjects with a TIA, minor ischemic stroke, or retinal artery 
occlusion. Subjects were excluded if they had any of the following: (1) 
A potential cardiac source of emboli, including an MI, within 3 months 
prior to entry; (2) planned carotid surgery; (3) contraindications to 
aspirin; or (4) the need for long-term anticoagulation. The median 
duration of followup was 32 months. The primary outcome measure was 
all-cause mortality and stroke of any severity. The following were 
planned secondary analyses: (1) All strokes (fatal and nonfatal), (2) 
stroke or two or more TIA's within 1 week necessitating a change in 
therapy, and (3) all MI's (fatal and nonfatal). The primary and 
secondary outcome events are listed in Table 1 of this document.

                        Table 1.--Primary and Secondary Outcome Events in the SALT Study
----------------------------------------------------------------------------------------------------------------
                                                                                  Number of Subjects
                                                                     -------------------------------------------
                           Primary events                                    Aspirin               Placebo
                                                                     -------------------------------------------
                                                                             (n=676)               (n=684)
----------------------------------------------------------------------------------------------------------------
    Primary events
Nonfatal stroke
  Cerebral infarction, minor                                                   55                    68
  Cerebral infarction, major                                                   17                    30
  Intracerebral hemorrhage                                                      4                     3
  Subarachnoid hemorrhage                                                       1                     1
Fatal stroke
  Cerebral infarction, major                                                   10                     7
  Intracerebral hemorrhage                                                      4                     0
  Subarachnoid hemorrhage                                                       2                     0
  Unknown                                                                       0                     3
Nonstroke deaths
  MI                                                                           18                    28
  Other vascular deaths                                                        14                    12
  Malignant disorders                                                          10                    15
  Other (infection, diabetes, trauma)                                           1                     3
  Unknown                                                                       2                     1
Total primary outcome events                                                  138                   171
    Secondary events
Stroke (fatal and nonfatal)                                                    93                   112
Stroke or > 2 TIA's within 1 week, necessitating change in therapy            101                   128

[[Page 56807]]

MI (fatal and nonfatal)                                                        54                    68
----------------------------------------------------------------------------------------------------------------

    Log-rank analysis of stroke-free survival showed that aspirin was 
significantly superior to placebo (p = 0.02). Analysis of the same 
outcomes by ``accumulated number of events''during the followup period 
showed a significant (p = 0.05) risk reduction of 18 percent (relative 
risk 0.82, 95 percent confidence interval 0.67 to 0.99) for nonfatal 
stroke or death. The risk reduction was similar in men and women (19 
percent and 17 percent, respectively). More deaths were attributed to 
nonstroke events than to stroke in both the aspirin and placebo arms. 
Most of the nonstroke deaths in this study were attributed to MI, other 
vascular deaths, and malignant disorders. Fatal hemorrhagic stroke 
occurred in six subjects in the aspirin group and none in the placebo 
group (p = 0.03). Overall, more adverse effects were reported in the 
aspirin group than in the placebo group, particularly bleeding events 
(see Table 2 of this document).

                             Table 2.--Adverse Effects of Aspirin in the SALT Study
----------------------------------------------------------------------------------------------------------------
                                                                           Number (%) of Subjects
                                                           -----------------------------------------------------
                                                                     Aspirin                    Placebo
----------------------------------------------------------------------------------------------------------------
Gastrointestinal (excluding bleeding)
  Total                                                             85 (12.5)                  73 (10.7)
  Severe or causing discontinuation of study drug                    21 (3.1)                   18 (2.6)
Bleeding
  Total                                                              49 (7.2)                   22 (3.2)
  Gastrointestinal                                                   11 (1.6)                    4 (0.6)
  Intracranial                                                       10 (1.5)                    3 (0.4)
  Other                                                              28 (4.1)                   15 (2.2)
Severe bleeding, or causing discontinuation of study drug            20 (3.0)                    9 (1.3)
  Gastrointestinal                                                    9 (1.3)                    4 (0.6)
  Intracranial                                                       10 (1.5)                    3 (0.4)
  Other                                                               1 (0.1)                    2 (0.3)
Other adverse effects
  Total                                                              31 (4.6)                   42 (6.1)
  Severe, or causing discontinuation of study drug                    9 (1.3)                   11 (1.6)
Total number of subjects with adverse effects1                     147 (21.7)                 123 (18.0)
----------------------------------------------------------------------------------------------------------------
\1\ Some subjects had more than one adverse effect.

    The SALT study (Ref. 22) is generally a well-controlled and 
carefully done study that supports the use of low-dose aspirin to 
reduce the risk of death or stroke in subjects with TIA or minor 
ischemic stroke (see section II.A, comment 3 of this document).
    The six additional studies identified were relatively small, except 
for the UK-TIA study. The Danish Cooperative study (Ref. 18) studied 
the effect of aspirin in subjects with reversible cerebral ischemic 
attack. The primary endpoint was stroke or death. TIA, reversible 
ischemic neurologic disability, and nonfatal MI were also monitored. 
The AICLA, Canadian Cooperative, AITIA, Swedish Cooperative, and UK-TIA 
studies are discussed in section II.A, comments 2 and 3 of this 
document. The Canadian Cooperative study and the AITIA study were also 
discussed in comment 49 of the TFM (53 FR 46204 at 46228 to 46230).
    FDA performed a statistical analysis and tabulated the endpoints of 
all strokes and strokes plus death for these seven studies. The agency 
considered the overall combined results and estimated a common odds 
ratio for the selected set of available data. The SALT study was 
considered an independently positive study for the composite endpoint 
of stroke and death. To see whether that finding was substantiated by 
other data, the agency did a combined analysis for that endpoint that 
included all the studies except SALT. A summary of the entry criteria 
for the seven studies appears in Table 3 of this document.

                                                   Table 3.--Study Criteria of Cerebrovascular Trials
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                         Aspirin             Months
             Study                                       Entry Criteria                                  n         -------------------------------------
                                                                                                                          mg/day            followup
--------------------------------------------------------------------------------------------------------------------------------------------------------
SALT                            TIA, retinal artery occlusion, or minor stroke                               1,360                 75                 32
AICLA                           Cerebral or retinal ischemic event                                             402                990                 36
Canadian                        TIA or partial nonprogressing stroke                                           283              1,300                 26
Fields                          TIA                                                                            178              1,300            6 to 24
UK-TIA                          TIA or minor ischemic stroke                                                 2,435       1,200 or 300          48 (mean)

[[Page 56808]]

Danish                          Reversible cerebral ischemic attack                                            203              1,000       43 (mean 24)
Swedish                         Minor or major stroke due to cerebral infarction                               505              1,500                 24
--------------------------------------------------------------------------------------------------------------------------------------------------------

    The estimated odds ratios and 95 percent confidence intervals for 
aspirin versus placebo for the composite endpoint stroke and death 
(includes vascular and nonvascular) and for all strokes (includes fatal 
and nonfatal) are summarized in Table 4 of this document.

                                                   Table 4.--Outcome Events of Cerebrovascular Trials
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                      Number of Events
                        Study                        --------------------------------------------------        Odds Ratio        95% Confidence Interval
                                                              Aspirin                  Placebo
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Strokes and Deaths
AICLA                                                                  27/198                   36/204                     0.74               0.43, 1.26
Canadian                                                               26/144                   30/139                     0.80               0.45, 1.44
Fields                                                                  13/88                    19/90                     0.65               0.30, 1.40
UK-TIA                                                              382/1,621                  220/814                     0.83               0.68, 1.01
Danish                                                                 21/101                   17/102                     1.04               0.65, 2.65
Swedish                                                                57/253                   55/252                     1.04               0.68, 1.58
All Studies                                                         526/2,405                377/1,601                     0.86              0.73, 0.999
    All Strokes
SALT                                                                   93/676                  112/684                     0.82               0.61, 1.10
AICLA                                                                  17/198                   31/204                     0.53               0.29, 0.98
Canadian                                                               22/144                   20/139                     1.07               0.56, 2.06
Fields                                                                  11/88                    14/90                     0.78               0.33, 1.81
UK-TIA                                                              163/1,621                   98/814                     0.81               0.62, 1.07
Danish                                                                 17/101                   11/102                     1.66               0.75, 3.68
Swedish                                                                32/253                   32/252                     1.00               0.59, 1.68
All Studies                                                         355/3,081                318/2,285                     0.84               0.71, 0.99
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Four of the seven studies showed trends in favor of aspirin for the 
endpoint of stroke, and five of seven for the composite endpoint of 
stroke and death, although most of them did not independently show a 
statistically significant difference between aspirin and placebo. Of 
the studies evaluated, only the AICLA study (Ref. 12) independently 
provides statistically significant results in favor of aspirin for the 
endpoint of stroke alone. The agency notes that the AICLA study was a 
small study that, when compared to the other studies, showed an 
unusually large magnitude of effect on stroke as an endpoint. A 
detailed report of the study was not submitted to the agency for 
review. Without a detailed report, the agency cannot draw definitive 
conclusions on the effect of aspirin on the endpoint of stroke alone 
based on this small study. However, the collective evaluation of all 
the studies, including SALT, showed a statistically significant effect 
in favor of aspirin for the endpoint of stroke alone.
     For the composite endpoint of stroke and death, the SALT study 
independently showed a statistically significant effect of aspirin 
compared to placebo in subjects with cerebrovascular problems. The 
collective results of the six other studies (without SALT) confirmed 
the finding (see Table 4 of this document). The composite endpoint of 
stroke and death in the studies evaluated includes those deaths 
attributed to cerebral, MI, and other fatal events.
    On January 23, 1997, the Cardiovascular and Renal Drugs Advisory 
Committee and the Nonprescription Drugs Advisory Committee (the Joint 
Advisory Committee) met to consider professional labeling for 
cardiovascular uses of aspirin. The Joint Advisory Committee 
unanimously recommended an indication for aspirin for subjects with 
prior occlusive stroke (both major and minor), pending the outcome of 
the agency's evaluation of the ESPS-2 (Ref. 23). The agency 
subsequently evaluated data from the aspirin (50 mg daily) and placebo 
arms of that study (Ref. 25). The study was a randomized, double blind, 
multicenter trial of about 6,600 subjects to show the effect of 
antiplatelet agents on subjects that had experienced TIA or completed 
ischemic stroke. After 2 years of treatment, the risk of stroke and the 
combined risk of stroke or death were reduced in the aspirin only arm 
compared to placebo.
    Thus, the SALT study and the ESPS-2 study provide primary support 
for an indication for aspirin to reduce the combined risk of death or 
nonfatal stroke in subjects with TIA or ischemic stroke. The collective 
results of the six additional studies lend further support for this 
indication. Therefore, the agency is revising the indication as 
follows: ``To reduce the combined risk of death and nonfatal stroke in 
patients who have had ischemic stroke or transient ischemia of the 
brain due to fibrin platelet emboli.''
    5. One comment recommended that the agency allow consumer-directed 
OTC labeling for the TIA, MI, unstable angina, and other thromboembolic 
indications, with complete information on warnings, recommended 
dosages, and side effects, provided the product is not advertised to 
the general public. The comment also recommended that such labeling for 
these uses should be separate from any labeling for the analgesic, 
antipyretic, and antirheumatic uses of aspirin. The comment stated that 
aspirin is already widely used in the treatment of these non-analgesic 
conditions, and that it

[[Page 56809]]

would be harmful to the public for the information not to be included 
in the consumer labeling.
    Section 502(f) of the Federal Food, Drug, and Cosmetic Act (the 
act) (21 U.S.C. 352(f)) states that a drug shall be deemed misbranded: 
``Unless its labeling bears (1) adequate directions for use; and (2) 
such adequate warnings against use in those pathological conditions * * 
* where its use may be dangerous to health, or against unsafe dosage or 
methods or duration of administration or application, in such manner 
and form, as are necessary for the protection of users * * *.'' The 
directions for use or the warnings may be inadequate if the labeling 
refers to uses or conditions for which the drug can be safely used only 
under the supervision of a practitioner licensed by law (see 21 CFR 
201.5). The agency considers the conditions and uses of aspirin that 
are the subject of this final rule to require the supervision of a 
physician (or other practitioner licensed to prescribe drugs) to ensure 
safe use. The agency therefore disagrees with the comment's 
recommendation.
    Consumers are not in a position to determine when they need to take 
aspirin to prevent vascular events, such as stroke, MI, or 
cardiovascular death, and other thromboembolic conditions. The need for 
drug therapy and the safety of indicating it, for this purpose, is 
dependent on a variety of factors, including a person's medical 
history, age, gender, lifestyle, and concomitant medications. Medical 
intervention aimed at reducing the risk of any of these vascular events 
is both multifaceted and long term. In addition, intervention by a 
practitioner licensed to prescribe drugs is required for the ongoing 
management of the medical conditions being treated. Any prolonged use 
of aspirin has certain possible risks, e.g., increased or prolonged 
bleeding, GI hemorrhage, and ulceration. An increase in hemorrhagic 
stroke has also been reported (Refs. 4 and 5). It is not possible, in 
OTC drug product labeling, to provide adequate directions and warnings 
to enable the layperson to make a reasonable self assessment of these 
factors. Therefore, safe and effective use of aspirin to influence the 
risk of vascular events requires medical supervision by a practitioner 
licensed to prescribe drugs.
    An OTC drug, such as aspirin, may have some uses that can be 
properly labeled for direct consumer use and other uses that cannot be 
adequately labeled for direct consumer use. Professional labeling 
should be provided only to practitioners licensed to prescribe drugs, 
but not to the general public.
    6. The agency also received a citizen petition (CP12) (Ref. 1) that 
requested an amendment to the professional labeling for aspirin in 
secondary prevention of cardiovascular morbidity and mortality in men 
and women at elevated risk for cardiovascular events. The petition's 
requests for professional labeling for aspirin included indications 
for: (1) Patients undergoing coronary, cerebral, or peripheral arterial 
revascularization procedures; (2) patients with chronic nonvalvular 
atrial fibrillation; (3) patients requiring hemodialysis access with a 
fistula or shunt; and (4) other patients deemed to be at elevated risk 
due to some form of vascular disease or other condition implying an 
increased risk of occlusive vascular disease. The authors of the 
petition subsequently clarified that they were requesting an aspirin 
indication, at a maintenance dose of at least 75 to 81 mg per day, only 
for those patients who have already been diagnosed as having had some 
occlusive arterial disease and who currently have no special 
contraindications to low-dose aspirin. The petition also included 
information on the use of aspirin for subjects with chronic stable 
angina pectoris. The agency evaluated the petition and presented its 
review of the petition at a meeting on April 25, 1996. Minutes of that 
meeting, including the agency's review of the petition, are on file in 
the Dockets Management Branch (Ref. 26). The petition cited published 
reports of two studies as support for an indication for chronic stable 
angina pectoris. The first study was the Swedish Angina Pectoris 
Aspirin Trial (SAPAT) (Ref. 27), and the second study was an assessment 
of those male physicians who entered the U.S. Physicians' Health Study 
with chronic stable angina (Ref. 28).
     The SAPAT study was a randomized, multicenter, double-blind, 
prospective study designed to assess the role of aspirin for prevention 
of MI in 2,035 subjects with chronic stable angina pectoris. Subjects 
were randomized to receive daily doses of either 75 mg of aspirin plus 
sotalol (aspirin group) or placebo plus sotalol (placebo group) daily. 
The primary endpoint of the study was the combined rates of first fatal 
or nonfatal MI or sudden death. Secondary endpoints were vascular 
events (first occurrence of nonfatal MI, nonfatal stroke, or vascular 
death), vascular death, all-cause mortality, and stroke. Primary and 
secondary endpoint data appear in Table 5 of this document.

                                              Table 5.--Primary and Secondary Endpoints in the SAPAT Study
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                      Aspirin +         Placebo +
                                    Endpoint                                       Sotalol n=1,009   Sotalol n=1,026   Percent Change           p
--------------------------------------------------------------------------------------------------------------------------------------------------------
Primary:                                                                               81               124               -34                  .003
  nonfatal MI                                                                          47                78                -3.9                .006
  fatal MI                                                                             15                15                 0
   sudden death                                                                        19                31               -38                  .097
Secondary:
  vascular events                                                                     108               161               -32                 <.001
  vascular deaths                                                                      51                70               -26                  .114
  all cause mortality                                                                  82               106               -22                  .103
  stroke                                                                               28                38               -25                  .246
    hemorrhagic                                                                         5                 2
    nonhemorrhagic                                                                     23                36
--------------------------------------------------------------------------------------------------------------------------------------------------------

    The SAPAT study supports the use of 75 mg aspirin daily in subjects 
with chronic stable angina pectoris. The study showed a significant 
reduction in the primary endpoint of fatal or nonfatal MI and sudden 
death, and the secondary endpoint of vascular events (first occurrence 
of MI, stroke, or vascular death). The study also showed a significant 
overall reduction in a major component of the primary endpoint, 
nonfatal MI. Although the decreases in vascular deaths and all cause 
mortality were not statistically significant, there was a favorable 
trend in the aspirin

[[Page 56810]]

group for both of these endpoints and a weakly favorable trend for 
stroke. There were more reports of serious bleeds in the aspirin group 
than in the placebo group, but the difference was not significant. As 
in many other studies, however, there were more hemorrhagic strokes in 
the aspirin group than the placebo group. All the subjects in the SAPAT 
study were treated with sotalol. Therefore, the question arises as to 
whether it can be concluded that aspirin is effective in angina 
patients not receiving sotalol (or some other beta blocker). Although 
there are not specific data on this point, the ability of aspirin to 
decrease the rate of thrombotic vascular events in various settings has 
not required or, to date, been related to, the presence or absence of 
beta blockers. Therefore, the agency concludes that the SAPAT study 
supports the use of aspirin in patients with chronic stable angina, 
with or without sotalol.
    The agency presented a summary of its findings for the SAPAT study 
at the meeting of the Joint Advisory Committee on January 23, 1997. The 
Joint Advisory Committee unanimously agreed that the SAPAT study 
supports the use of aspirin in subjects with chronic stable angina 
pectoris, and that an indication for low-dose aspirin should be 
extended to that population.
    Ridker et al. (Ref. 28) assessed those subjects with chronic stable 
angina who entered the U.S. Physicians' Health Study (Ref. 4). The 
authors concluded that aspirin therapy reduced the risk of first MI 
among patients with chronic stable angina. However, the agency found 
that some of the subjects entered into the U.S. Physicians' Health 
Study had evidence of a previous MI. Thus, it is possible that in the 
subgroup of subjects with chronic stable angina pectoris, some subjects 
may also have had a previous MI. Aspirin has already been shown to be 
effective in subjects with a previous MI and, therefore, some of the 
positive results found in the Ridker study may in part be due to 
aspirin's demonstrated effectiveness in patients with previous MI. 
Nevertheless, the results of the Ridker study are consistent with the 
findings in the SAPAT study, and lend some additional support for an 
indication for aspirin for subjects with chronic stable angina 
pectoris.
    The agency is, therefore, extending the indication for aspirin for 
cardiovascular uses in proposed Sec. 343.80(c) to include reducing the 
combined risk of MI and sudden death in patients with chronic stable 
angina pectoris. This conclusion is also supported by substantial 
additional controlled trials in other populations with coronary artery 
disease that show reduced risk for similar endpoints, specifically 
patients with a prior MI. The dosage range is also revised from ``300 
to 325 mg daily'' to ``75 to 325 mg daily,'' to include the lower dose 
used in the SAPAT study, and the ``Clinical Studies'' section of the 
professional labeling includes information on this study.
    The agency has considered the petition's request for an indication 
for aspirin for subjects who have undergone revascularization 
procedures including coronary artery bypass graft (CABG), percutaneous 
transluminal coronary angioplasty (PTCA), carotid endarterectomy, 
peripheral artery grafts, peripheral arterial fistula or shunt, or 
peripheral angioplasty. The agency considered the published reports 
submitted by the petitioner that evaluated aspirin alone in one arm 
versus a placebo or other active ingredient, and additional information 
from the report of the Fourth American College of Chest Physicians 
(ACCP) Consensus Conference on Antithrombotic Therapy (Ref. 29). The 
agency concluded (Ref. 26) that there was insufficient evidence, based 
on the published studies, to support the professional labeling of 
aspirin alone in patients who have undergone revascularization 
procedures, although some studies have suggested benefit in these 
patients (Refs. 30 through 34).
    The issue of aspirin use in patients who have undergone 
revascularization procedures was considered by the Joint Advisory 
Committee on January 23, 1997. The panel members concluded that 
specific studies have not been presented to show effectiveness of 
aspirin for this population. However, they noted that almost all 
patients who undergo coronary revascularization procedures have already 
had symptomatic coronary disease, such as stable or unstable angina or 
MI. The Joint Advisory Committee recommended unanimously that aspirin 
be recommended for subjects who have undergone revascularization 
procedures such as CABG or PTCA if there is a preexisting condition for 
which aspirin is already indicated. However, the Joint Advisory 
Committee made no specific recommendation regarding the use of aspirin 
in subjects who have undergone carotid endarterectomy.
    The agency agrees with the Joint Advisory Committee's 
recommendation that the professional labeling of aspirin should include 
subjects who have undergone revascularization procedures for 
symptomatic coronary artery disease. It is a reasonable assumption 
that, in general, subjects who have had CABG or PTCA procedures have an 
underlying condition for which aspirin is indicated. Similarly, the 
agency believes subjects with lesions of the carotid bifurcation 
sufficient to require carotid endarterectomy are likely to have had a 
TIA or stroke, and may also have coexisting coronary artery disease 
(Ref. 34). Therefore, the agency is adding an indication to the 
professional labeling for subjects who have had specific arterial 
revascularization procedures (i.e., CABG, PTCA, or carotid 
endarterectomy). Likewise, the agency believes it is reasonable to 
recommend the standard dosages being used in clinical practice (Refs. 
35 through 37) during the preoperative period. The following dosages 
are included in this final rule: CABG, 325 mg daily, starting 6 hours 
post-procedure and continued 1 year; PTCA, 325 mg 2 hours presurgery, 
followed by maintenance therapy of 160 to 325 mg daily; and carotid 
endarterectomy, 80 mg daily to 650 mg twice daily preoperatively and 
continued indefinitely.
    The issue of an indication for aspirin for subjects with peripheral 
arterial disease was also considered by the Joint Advisory Committee. 
The Joint Advisory Committee concluded that the trials that used 
aspirin alone showed no effect on subjects with peripheral arterial 
disease, despite a sizable data base in which to examine this effect. 
By a vote of 11 to 4, the members recommended not to label aspirin for 
the indication. The agency agrees with the Committee and concludes that 
there is insufficient data to support professional labeling for aspirin 
alone in subjects with peripheral arterial disease, including subjects 
with and without peripheral artery grafts or peripheral angioplasty.
    The petitioner has withdrawn the request for an indication for 
aspirin for subjects requiring hemodialysis access with a fistula or 
shunt, and for subjects with atrial fibrillation (Ref. 38).

B. Comments to the Proposal to Include Acute MI in Professional 
Labeling of Aspirin

    7. The agency received four comments (Ref. 2) that addressed the 
need for additional warnings relating to the use of aspirin for 
cardiovascular and cerebrovascular indications. Two comments 
recommended that additional information about adverse events be 
included in the professional and consumer labeling. Two comments argued 
against the need for additional warnings.
    One comment recommended that professional aspirin labeling be 
revised to provide the following: (1) Information

[[Page 56811]]

for physicians on the risk of adverse GI effects associated with the 
long-term use of low-dose aspirin, and (2) advice to physicians 
concerning appropriate analgesic and antipyretic use in their patients 
who are taking long-term low-dose aspirin for cardiovascular 
indications. The comment further recommended that consumer aspirin 
labeling should be revised to: (1) Alert consumers to the signs and 
symptoms of adverse events that might occur with therapeutic (labeled) 
doses of aspirin, and (2) advise patients that they should consult 
their physician prior to any analgesic use for pain or fever relief if 
they are taking low-dose aspirin under a physician's care for 
cardiovascular indications. The comment asserted that adverse GI 
effects are present with aspirin in doses as low as 30 mg per day and 
that the risk of adverse GI events increases as the aspirin dose 
increases. In support of this position, the comment included literature 
articles (Refs. 4, 11, 22, and 39 through 46).
    Another comment acknowledged that adverse events from aspirin use 
have been carefully studied and characterized, and stated that even at 
the highest doses studied, 1,500 mg per day, the incidence of serious 
adverse events is small. The comment noted that the internal analgesic 
TFM proposes a total daily aspirin dose of 4,000 mg for acute pain 
management. The comment concluded that none of the studies cited by the 
first comment demonstrate that a person taking 75 to 325 mg per day of 
aspirin is at risk of adverse events other than those already labeled 
if additional aspirin is taken for short-term analgesic or antipyretic 
use. The comment concluded that labeling should not be proposed which 
could interfere with a physician's guidance to a patient, and that 
aspirin should not be singled out for special consideration. One 
comment noted that professional labeling already includes information 
concerning adverse reactions and no further changes are necessary.
    The agency agrees that physicians should be provided information on 
potential adverse events from long-term low-dose aspirin use. The 
agency believes this information should not be limited to potential 
adverse GI events, but that professional labeling should include 
complete prescribing information for practitioners licensed to 
prescribe drugs. Therefore, the agency has developed aspirin 
professional labeling containing the type of prescribing information 
included in prescription drug labeling in a format similar to that 
required for prescription drugs under Secs. 201.56 and 201.57. In 
addition, the agency has consolidated all of the professional uses of 
aspirin into a single labeling format. The final aspirin professional 
labeling also includes an optional highlights section that summarizes 
the professional indications for aspirin and the recommended dosage and 
administration for each indication. The highlights section, if 
disseminated, must accompany the required professional labeling as 
provided in Sec. 343.80(a). Dissemination of the highlights section, 
however, is not required.
    This professional labeling also includes complete information on 
adverse reactions. The labeling states, ``Many adverse reactions due to 
aspirin ingestion are dose-related.'' Among the adverse reactions 
listed are GI bleeding, ulceration, and perforation, as requested by 
the comment. Also, this labeling warns against concurrent use of 
aspirin with other analgesics with similar adverse drug event profiles 
because this may result in an increase in adverse drug reactions, and 
it includes a warning regarding bleeding risks associated with chronic, 
heavy use of alcohol. (See the final rule published elsewhere in this 
issue of the Federal Register entitled ``Over-the-Counter Drug Products 
Containing Analgesic/Antipyretic Active Ingredients for Internal Use; 
Required Alcohol Warning''.)
    The agency does not believe that this labeling will interfere with 
a physician's guidance to a patient. Rather, both the content and the 
format of the labeling is expected to enhance appropriate choices.
    The agency will address consumer aspirin labeling in the final rule 
for internal analgesic, antipyretic, and antirheumatic drug products, 
which will be published in a future issue of the Federal Register.
    8. One comment asked the agency to include an indication for acute 
MI in OTC consumer drug labeling. The comment stated that a significant 
number of people who die of heart attacks do so beyond the reach of 
health-care providers. The comment argued that by limiting the proposed 
indication to professional labeling, the agency neglects consumers at 
risk for heart attack. The comment said that this population needs to 
know that a half an aspirin can reduce their risk of cardiovascular 
morbidity and mortality. The comment also recommended a warning stating 
that patients should seek immediate diagnosis and treatment by a 
doctor.
    The issue of whether consumer labeling is appropriate for an 
indication such as acute MI is addressed generally in section II.A, 
comment 5 of this document. The agency will address consumer aspirin 
labeling in the final rule for internal analgesic, antipyretic, and 
antirheumatic drug products, which will be published in a future issue 
of the Federal Register.
    9. One comment asked the agency to consider several proposed 
wording changes. The comment suggested changing the proposed sentence 
``a dose of 162.5 mg/day, started as soon as possible after a suspected 
infarction'' to ``a dose of 162.5 mg/day, started as soon as possible 
during' a suspected infarction.'' The comment suggested that the 
current wording is misleading and implies that treatment not be 
initiated until a diagnosis of infarction is established.
    The agency agrees that the dosing information for suspected acute 
MI should be revised to emphasize the immediate use of aspirin for 
suspected acute MI. However, the agency believes that instructions for 
the initial dose of aspirin to be administered ``as soon as an MI is 
suspected'' better conveys the need for immediate action and has 
included this information in the professional labeling for suspected 
acute MI.
    10. One comment recommended a dosage range of 162.5 to 325 mg 
aspirin per day for suspected acute MI. In support of its request, the 
comment cited the results of the ISIS-2 and ISIS pilot studies. The 
comment suggested that this dosage range for suspected acute MI is more 
consistent with agency dosing recommendations for other professional 
labeling indications for aspirin, e.g., 300 to 325 mg aspirin for the 
prevention of a second heart attack.
    In the preamble to the proposed rule for the use of aspirin, 
buffered aspirin, and aspirin/antacid combinations to reduce the risk 
of vascular mortality in people with suspected acute MI (61 FR 30002), 
the agency discussed the basis for its conclusions on the effective 
dose of aspirin for this use. The results of the ISIS-2 study (162.5 mg 
aspirin per day) (Ref. 7) were accepted by the agency as the primary 
support for the indication. Concerning the ISIS pilot study (Ref. 47), 
the agency noted that a 325 mg aspirin dose every other day produced: 
(1) A nonsignificant reduction in nonfatal reinfarction, (2) a 
significantly lower rate of in-hospital deaths (all causes), and (3) 
similar rates of post-hospital deaths (61 FR 30005). Therefore, the 
ISIS pilot study does not provide a basis to support a 325 mg aspirin 
dose for suspected acute MI and this dose is not included in this final 
rule.

[[Page 56812]]

III. Summary of Changes

    1. The TFM for OTC analgesic, antipyretic, and antirheumatic drug 
products included an indication for the professional use of aspirin, 
carbaspirin calcium, magnesium salicylate, or sodium salicylate for 
rheumatologic diseases (53 FR 46204 at 46244). The indication was based 
on the recommendations of the Panel made in 1977. No comments were 
received in response to the TFM concerning this indication. The 
indication for the use of aspirin in rheumatologic diseases has been 
updated. For completeness, the agency has included full prescribing 
information for the professional uses of aspirin, including full 
information for the treatment of the signs and symptoms of 
rheumatologic disease. However, professional labeling on the use of 
other Category I salicylates for rheumatologic diseases has not been 
included and will be addressed in the final rule for OTC internal 
analgesic, antipyretic, and antirheumatic drug products to be published 
in a future issue of the Federal Register.
    2. To allow for the codification of the professional labeling, the 
agency is: (1) Finalizing certain sections of the proposed rule 
pertaining to scope, definitions, and testing procedures that apply to 
both OTC and professional labeling; (2) adding definitions in 
Sec. 343.3; and (3) adding Secs. 343.12, 343.13 and 343.22 which 
include cardiovascular and rheumatologic active ingredients and 
permitted combinations of active ingredients.
    3. The heading for Sec. 343.90 under ``Testing Procedures'' has 
been changed from ``Dissolution testing'' to ``Dissolution and drug 
release testing'' to include the current United States Pharmacopeia 
(USP) terminology for testing delayed-release products. The agency has 
updated the dissolution tests in Sec. 343.90 from those contained in 
USP XXI, which were in effect when the TFM was published, to those 
currently in effect in USP 23. The dissolution testing procedures have 
been added for aspirin, alumina, and magnesium oxide tablets and 
aspirin effervescent tablets for oral solution in Sec. 343.90(f) and 
(g), respectively. (A monograph for these products were included in the 
USP after publication of the TFM.) Proposed Sec. 343.90(f) for buffered 
aspirin tablets is now Sec. 343.90(h).
    4. The minimum dosages for the vascular indications in this final 
rule are lower than those proposed in the TFM. The agency is concerned 
about the impact of formulation on the effectiveness of the lower-dose 
aspirin. Therefore, this final rule allows professional labeling only 
for those products that meet USP dissolution and drug release standards 
in Sec. 343.90.
    5. In the TFM, the agency proposed professional labeling 
indications for TIA and rheumatologic diseases for aspirin and buffered 
aspirin drug products identified in Sec. 343.10(b), except those 
buffered with sodium. The TFM did not include these indications for 
aspirin in combination with antacids identified in Sec. 343.20(b)(3). 
The agency is expanding the professional labeling indications for TIA 
and rheumatologic diseases in this final rule to include aspirin drug 
products buffered with sodium and aspirin in combination with antacid. 
The agency has taken this action based on: (1) The additional 
prescribing information included in this final rule on the use of 
sodium-containing products in patients who need to restrict their 
sodium intake; (2) data that show there is no significant difference 
between the plasma aspirin levels obtained with aspirin, buffered 
aspirin, and aspirin in combination with antacids (Refs. 48 and 49); 
(3) the lower dosage of aspirin for TIA; and (4) the physician's 
routine practice of titrating the dosage of aspirin to an effective 
blood level for rheumatologic diseases.
    6. Portions of the proposed rule would have amended 21 CFR 310.201, 
369.20, and 369.21. This final rule is one segment of the proposed rule 
and does not affect these sections. The other portions of the proposed 
rule will be discussed in a future issue of the Federal Register.

IV. References

    The following references are 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) Comment Nos. C146, C153, C154, C155, CP9, CP10, and CP12, 
Docket No. 77N-0094, Dockets Management Branch.
    (2) Comment Nos. C1-C10, Docket No. 77N-0094A, Dockets 
Management Branch.
    (3) Steering Committee of the Physicians' Health Study Research 
Group, ``Preliminary Report: Findings from the Aspirin Component of 
the Ongoing Physicians' Health Study,'' New England Journal of 
Medicine, 318:262-264, 1988.
    (4) 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.
    (5) Peto, R. et al., ``Randomized Trial of Prophylactic Daily 
Aspirin in British Male Doctors,'' British Medical Journal, 296:313-
316, 1988.
    (6) Manson, J. E. et al., ``Medical Progress: The Primary 
Prevention of Myocardial Infarction,'' New England Journal of 
Medicine, 326:1406-1416, 1992.
    (7) ISIS-2 (Second International Study Of Infarct Survival) 
Collaborative Group, ``Randomized Trial of Intravenous 
Streptokinase, Oral Aspirin, Both, or Neither Among 17,187 Cases of 
Suspected Acute Myocardial Infarction: ISIS-2,'' Lancet, 2:349-360, 
1988.
    (8) The Canadian Cooperative Study Group, ``A Randomized Trial 
of Aspirin and Sulfinpyrazone in Threatened Stroke,'' New England 
Journal of Medicine, 299:53-59, 1978.
    (9) Yusef, S., ``Analysis and Interpretation of Treatment 
Effects in Subgroups of Patients in Randomized Clinical Trials,'' 
Journal of the American Medical Association, 266:93-98, 1991.
    (10) Fields, W. S. et al., ``Controlled Trial of Aspirin in 
Cerebral Ischemia,'' Stroke, 8:301-316, 1977.
    (11) UK-TIA Study Group, ``United Kingdom Transient Ischaemic 
Attack (UK-TIA) Aspirin Trial: Interim Results,'' British Medical 
Journal, 296:316-320, 1988.
    (12) Bousser, M. G. et al., ```AICLA' Controlled Trial of 
Aspirin and Dipyridamole in the Secondary Prevention of Athero-
Thrombotic Cerebral Ischemia,'' Stroke, 14:5-14, 1983.
    (13) Sivenius, J. et al., ``The European Stroke Prevention 
Study: Results According to Sex,'' Neurology, 41:1189-1192, 1991.
    (14) The American-Canadian Co-Operative Study Group, 
``Persantine Aspirin Trial in Cerebral Ischemia Part II: Endpoint 
Results,'' Stroke, 16:406-415, 1985.
    (15) A Swedish Cooperative Study, ``High-Dose Acetylsalicylic 
Acid after Cerebral Infarction,'' Stroke, 18:325-334, 1987.
    (16) Antiplatelet Trialists' Collaboration, ``Secondary 
Prevention of Vascular Disease by Prolonged Antiplatelet 
Treatment,'' British Medical Journal, 296:320-331, 1988.
    (17) Fields, W. S. et al., ``Controlled Trial of Aspirin in 
Cerebral Ischemia. Part II: Surgical Group,'' Stroke, 9:309-318, 
1978.
    (18) Sorensen, P. S. et al., ``Acetylsalicylic Acid in the 
Prevention of Stroke in Patients with Reversible Cerebral Ischemic 
Attacks. A Danish Cooperative Study,'' Stroke, 14:15-22, 1983.
    (19) Reuther, R., and W. Dorndorf, ``Aspirin in Patients with 
Cerebral Ischemia and Normal Angiograms. The Results of a Double 
Blind Trial,'' in Acetylsalicylic Acid in Cerebral Ischaemic and 
Coronary Artery Disease, edited by Breddin, K. et al., Schatauer 
Verlag, Stuttgart Germany, pp. 97-106, 1978.
    (20) Antiplatelet Trialists' Collaboration, ``Collaborative 
Overview of Randomized Trials of Antiplatelet Therapy--I: Prevention 
of Death, Myocardial Infarction, and Stroke by Prolonged 
Antiplatelet Therapy in Various Categories of Patients,'' British 
Medical Journal, 308:81-106, 1994.
    (21) Boysen, G. et al., ``Danish Very-Low-Dose Aspirin after 
Carotid Endarterectomy Trial,'' Stroke, 19:1211-1215, 1988.
    (22) 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.
    (23) Diener, H. C. et al., ``European Stroke Prevention Study 2. 
Dipyridamole and

[[Page 56813]]

Acetylsalicylic Acid in the Secondary Prevention of Stroke,'' 
Journal of Neurological Sciences, 143:1-13, 1996.
    (24) Matchar, D. B. et al., ``Medical Treatment for Stroke 
Prevention,'' Annals of Internal Medicine, 121:41-53, 1994.
    (25) FDA evaluation of ESPS-2 data, OTC Volume 03BFMP, Docket 
No. 77N-0094, Dockets Management Branch.
    (26) Minutes of Meeting between representatives of FDA and The 
Aspirin Strategy Group, on April 25, 1996, Coded MM21, Docket No. 
77N-0094, Dockets Management Branch.
    (27) Juul-Moller, S. et al., ``Double-Blind Trial of Aspirin in 
Primary Prevention of Myocardial Infarction in Patients with Stable 
Chronic Angina Pectoris,'' Lancet, 340:1421-1425, 1992.
    (28) Ridker, P. M. et al., ``Low-Dose Aspirin Therapy for 
Chronic Stable Angina,'' Annals of Internal Medicine, 114:835-839, 
1991.
    (29) Dalen, J. E., and J. Hirsh, (Guest Editors), Fourth ACCP 
Consensus Conference on Antithrombotic Therapy, Chest, 108:225S-
522S, October 1995 (Supplement).
    (30) Goldman, S. et al., ``Improvement in Early Saphenous Vein 
Graft Patency after Coronary Artery Bypass Surgery with Antiplatelet 
Therapy: Results of a Veterans Administrative Cooperative Study,'' 
Circulation, 77:1324-1332, 1988.
    (31) Goldman, S. et al., ``Saphenous Vein Graft Patency 1 Year 
after Coronary Artery Bypass Surgery and Effects of Antiplatelet 
Therapy: Results of a Veterans Administration Cooperation Study,'' 
Circulation, 80:1190-1197, 1989.
    (32) Lorenz, R. L. et al., ``Improved Aortocoronary Bypass 
Patency by Low-Dose Aspirin (100 mg Daily),'' Lancet, pp. 1261-1263, 
1984.
    (33) Brown, G. B. et al., ``Improved Graft Patency in Patients 
Treated with Platelet-inhibiting Therapy after Coronary Bypass 
Surgery,'' Circulation, 72:138-146, 1985.
    (34) Kretschmer, G. et al., ``Antiplatelet Treatment Prolongs 
Survival after Carotid Bifurcation Endarterectomy,'' Annals of 
Surgery, 211:317-322, 1990.
    (35) Stein, P. D. et al., ``Antithrombotic Therapy in Patients 
with Saphenous Vein and Internal Mammary Artery Bypass Grafts,'' 
Chest, 108:424S-430S, 1995.
    (36) Popma, J. J. et al., ``Antithrombotic Therapy in Patients 
Undergoing Coronary Angioplasty,'' Chest, 108:486S-501S, 1995.
    (37) Clagett, P. G. et al., ``Antithrombotic Therapy in 
Peripheral Arterial Occlusive Disease,'' Chest, 108:431S-443S, 1995.
    (38) Letter from C. H. Hennekens, Chairman Aspirin Strategy 
Group, to W. E. Gilbertson, FDA, coded LET134, Docket No. 77N-0094, 
Dockets Management Branch.
    (39) Kurata, J. H., and D. E. Abbey, ``The Effect of Chronic 
Aspirin Use on Duodenal and Gastric Ulcer Hospitalization,'' Journal 
of Clinical Gastroenterology, 12:260-266, 1990.
    (40) Laporte, J. R. et al., ``Upper Gastrointestinal Bleeding in 
Relation to Previous Use of Analgesics and Nonsteroidal 
Antiinflammatory Drugs,'' Lancet, 337:85-89, 1991.
    (41) Levy, M. et al., ``Major Upper Gastrointestinal Tract 
Bleeding: Relation to Use of Aspirin and Other Nonnarcotic 
Analgesics,'' Archives of Internal Medicine, 148:281-285, 1988.
    (42) The Dutch TIA Trial Study Group, ``A Comparison of Two 
Doses of Aspirin (30 mg vs. 283 mg a Day) in Patients after a 
Transient Ischemic Attack or Minor Ischemic Stroke,'' New England 
Journal of Medicine, 325:1261-1266, 1991.
    (43) Weil, J. et al., ``Prophylactic Aspirin and Risk of Peptic 
Ulcer Bleeding,'' British Medical Journal, 310:827-830, 1995.
    (44) Kelly, J. P. et al., ``Risk of Aspirin-Associated Major 
Upper-Gastrointestinal Bleeding with Enteric-Coated or Buffered 
Product,'' Lancet, 348-1413-1416, 1996.
    (45) Soll, A. H. et al., ``Nonsteroidal Antiinflammatory Drugs 
and Peptic Ulcer Disease,'' Annals of Internal Medicine, 114:307-
319, 1991.
    (46) Fuster, V. et al., ``Aspirin as a Therapeutic Agent in 
Cardiovascular Disease,'' Circulation, 87(2):659-675, 1993.
    (47 ) ISIS Pilot Study Investigators, ``Randomized Factorial 
Trial of High-Dose Intravenous Streptokinase, of Oral Aspirin, and 
of Intravenous Heparin in Acute Myocardial Infarction,'' European 
Heart Journal, 8:634-642, 1987.
    (48) Itthipanichpong, C. et al., ``The Effect of Antacid on 
Aspirin Pharmacokinetics in Healthy Thai Volunteers,'' Drug 
Metabolism and Drug Interaction, 10:213-228, 1992.
    (49) Vigano, G. et al., ``Pharmacokinetic Study of a New Oral 
Buffered Acetylsalicylic Acid (ASA) Formulation in Comparison with 
Plain ASA in Healthy Volunteers,'' International Journal for 
Clinical Pharmacological Research, 11:129-135, 1991.

V. Analysis of Impacts

    An analysis of the costs and benefits of this regulation conducted 
under Executive Order 12291 was discussed in the TFM for OTC internal 
analgesic, antipyretic, and antirheumatic drug products (53 FR 46204 at 
46254). No comments on the economic impact related to professional 
labeling for aspirin were received in response to the agency's request 
for specific comment on the economic impact of this rulemaking. 
Executive Order 12291 has been superseded by Executive Order 12866.
    FDA has examined the impacts of the final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). 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). The agency believes that 
this final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the final 
rule is not a significant regulatory action as defined by the Executive 
Order and, thus, is not subject to review under the Executive Order. 
This rule also does not trigger the requirement for a written statement 
under section 202(a) of the Unfunded Mandates Reform Act because it 
does not impose a mandate that results in an expenditure of $100 
million or more by State, local, and tribal governments in the 
aggregate, or by the private sector, in any 1 year.
    If a rule would have a significant impact on a substantial number 
of small entities, the Regulatory Flexibility Act requires agencies to 
analyze regulatory options that would minimize the impact of the rule 
on small entities. This final rule will impose direct one-time costs 
associated with changing professional labeling to reflect current 
information. In the June 13, 1996 (61 FR 30002 at 30007), amendment to 
the TFM, the agency certified that the rule would not have a 
significant economic impact on a substantial number of small entities, 
based on the fact that few manufacturers of aspirin products appear to 
distribute professional labeling for their products and that 
manufacturers who do distribute such professional labeling will have 1 
year after publication of this final rule to implement this relabeling. 
The economic impact of this final rule on manufacturers appears to be 
minimal. The agency did not receive any comments challenging the basis 
for its initial proposed certification. Accordingly, the agency 
certifies that the final rule will not have a significant economic 
impact on a substantial number of small entities. Therefore, under the 
Regulatory Flexibility Act, no further analysis is required.

VI. Paperwork Reduction Act of 1995

    FDA concludes that the labeling requirements in this final rule are 
not subject to review by the Office of Management and Budget because 
they do not constitute a ``collection of information'' under the 
Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the 
labeling statements are 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)).

VII. Environmental Impact

    The agency has determined under 21 CFR 25.24(c)(6) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

[[Page 56814]]

List of Subjects in 21 CFR Part 343

    Labeling, Over-the-counter drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR 
Chapter I is amended as follows:
    1. Part 343 is added to read as follows:

PART 343--INTERNAL ANALGESIC, ANTIPYRETIC, AND ANTIRHEUMATIC DRUG 
PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

Subpart A--General Provisions

Sec.
343.1     Scope.
343.3     Definitions.

Subpart B--Active Ingredients

343.10     [Reserved]
343.12     Cardiovascular active ingredients.
343.13     Rheumatologic active ingredients.
343.20     [Reserved]
343.22     Permitted combinations of active ingredients for 
cardiovascular-rheumatologic use.

Subpart C--Labeling

343.50     [Reserved]
343.60     [Reserved]
343.80     Professional labeling.

Subpart D--Testing Procedures

343.90     Dissolution and drug release testing.
    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

Subpart A--General Provisions


Sec. 343.1  Scope.

    (a) An over-the-counter analgesic-antipyretic drug product in a 
form suitable for oral administration is generally recognized as safe 
and effective and is not misbranded if it meets each of the conditions 
in this part in addition to each of the general conditions established 
in Sec. 330.1 of this chapter.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise 
noted.


Sec. 343.3  Definitions.

    As used in this part:
    Analgesic-antipyretic drug. An agent used to alleviate pain and to 
reduce fever.
    Cardiovascular drug. An agent used to prevent ischemic events.
    Rheumatologic drug. An agent used for the treatment of 
rheumatologic disorders.

Subpart B--Active Ingredients


Sec. 343.10  [Reserved]


Sec. 343.12  Cardiovascular active ingredients.

    (a) Aspirin.
    (b) Buffered aspirin. Aspirin identified in paragraph (a) of this 
section may be buffered with any antacid ingredient(s) identified in 
Sec. 331.11 of this chapter provided that the finished product contains 
at least 1.9 milliequivalents of acid-neutralizing capacity per 325 
milligrams of aspirin as measured by the procedure provided in the 
United States Pharmacopeia 23/National Formulary 18.


Sec. 343.13  Rheumatologic active ingredients.

    (a) Aspirin.
    (b) Buffered aspirin. Aspirin identified in paragraph (a) of this 
section may be buffered with any antacid ingredient(s) identified in 
Sec. 331.11 of this chapter provided that the finished product contains 
at least 1.9 milliequivalents of acid-neutralizing capacity per 325 
milligrams of aspirin as measured by the procedure provided in the 
United States Pharmacopeia 23/National Formulary 18.


Sec. 343.20  [Reserved]


Sec. 343.22  Permitted combinations of active ingredients for 
cardiovascular-rheumatologic use.

    Combinations containing aspirin must meet the standards of an 
acceptable dissolution test, as set forth in Sec. 343.90. The following 
combinations are permitted: Aspirin identified in Secs. 343.12 and 
343.13 may be combined with any antacid ingredient identified in 
Sec. 331.11 of this chapter or any combination of antacids permitted in 
accordance with Sec. 331.10(a) of this chapter provided that the 
finished product meets the requirements of Sec. 331.10 of this chapter 
and is marketed in a form intended for ingestion as a solution.

Subpart C--Labeling


Sec. 343.50  [Reserved]


Sec. 343.60  [Reserved]


Sec. 343.80  Professional labeling.

    The labeling of an over-the-counter drug product written for health 
professionals (but not for the general public) shall consist of the 
following:
    (a) For products containing aspirin identified in Secs. 343.12 and 
343.13 or permitted combinations identified in Sec. 343.22. (These 
products must meet United States Pharmacopeia (USP) standards for 
dissolution or drug release in Sec. 343.90.)
    (1) The labeling contains the following prescribing information 
under the heading ``Comprehensive Prescribing Information'' and the 
subheadings ``Description,'' ``Clinical Pharmacology,'' ``Clinical 
Studies,'' ``Animal Toxicology,'' ``Indications and Usage,'' 
``Contraindications,'' ``Warnings,'' ``Precautions,'' ``Adverse 
Reactions,'' ``Drug Abuse and Dependence,'' ``Overdosage,'' ``Dosage 
and Administration,'' and ``How Supplied'' in the exact language and 
the exact order provided as follows:

COMPREHENSIVE PRESCRIBING INFORMATION

DESCRIPTION

    (Insert the proprietary name and the established name (if any) 
of the drug, type of dosage form (followed by the phrase ``for oral 
administration''), the established name(s) and quantity of the 
active ingredient(s) per dosage unit, the total sodium content in 
milligrams per dosage unit if the sodium content of a single 
recommended dose is 5 milligrams or more, the established name(s) 
(in alphabetical order) of any inactive ingredient(s) which may 
cause an allergic hypersensitivity reaction, the pharmacological or 
therapeutic class of the drug, and the chemical name(s) and 
structural formula(s) of the drug.) Aspirin is an odorless white, 
needle-like crystalline or powdery substance. When exposed to 
moisture, aspirin hydrolyzes into salicylic and acetic acids, and 
gives off a vinegary-odor. It is highly lipid soluble and slightly 
soluble in water.

CLINICAL PHARMACOLOGY

    Mechanism of Action: Aspirin is a more potent inhibitor of both 
prostaglandin synthesis and platelet aggregation than other 
salicylic acid derivatives. The differences in activity between 
aspirin and salicylic acid are thought to be due to the acetyl group 
on the aspirin molecule. This acetyl group is responsible for the 
inactivation of cyclo-oxygenase via acetylation.

PHARMACOKINETICS

    Absorption: In general, immediate release aspirin is well and 
completely absorbed from the gastrointestinal (GI) tract. Following 
absorption, aspirin is hydrolyzed to salicylic acid with peak plasma 
levels of salicylic acid occurring within 1-2 hours of dosing (see 
Pharmacokinetics--Metabolism). The rate of absorption from the GI 
tract is dependent upon the dosage form, the presence or absence of 
food, gastric pH (the presence or absence of GI antacids or 
buffering agents), and other physiologic factors. Enteric coated 
aspirin products are erratically absorbed from the GI tract.
    Distribution: Salicylic acid is widely distributed to all 
tissues and fluids in the body including the central nervous system 
(CNS), breast milk, and fetal tissues. The highest concentrations 
are found in the plasma, liver, renal cortex, heart, and lungs.

[[Page 56815]]

 The protein binding of salicylate is concentration-dependent, i.e., 
non-linear. At low concentrations (< 100 micrograms/milliliter 
(g/mL)), approximately 90 percent of plasma salicylate is 
bound to albumin while at higher concentrations (> 400 g/
mL), only about 75 percent is bound. The early signs of salicylic 
overdose (salicylism), including tinnitus (ringing in the ears), 
occur at plasma concentrations approximating 200 g/mL. 
Severe toxic effects are associated with levels > 400 g/mL. 
(See Adverse Reactions and Overdosage.)
    Metabolism: Aspirin is rapidly hydrolyzed in the plasma to 
salicylic acid such that plasma levels of aspirin are essentially 
undetectable 1-2 hours after dosing. Salicylic acid is primarily 
conjugated in the liver to form salicyluric acid, a phenolic 
glucuronide, an acyl glucuronide, and a number of minor metabolites. 
Salicylic acid has a plasma half-life of approximately 6 hours. 
Salicylate metabolism is saturable and total body clearance 
decreases at higher serum concentrations due to the limited ability 
of the liver to form both salicyluric acid and phenolic glucuronide. 
Following toxic doses (10-20 grams (g)), the plasma half-life may be 
increased to over 20 hours.
    Elimination: The elimination of salicylic acid follows zero 
order pharmacokinetics; (i.e., the rate of drug elimination is 
constant in relation to plasma concentration). Renal excretion of 
unchanged drug depends upon urine pH. As urinary pH rises above 6.5, 
the renal clearance of free salicylate increases from < 5 percent to 
> 80 percent. Alkalinization of the urine is a key concept in the 
management of salicylate overdose. (See Overdosage.) Following 
therapeutic doses, approximately 10 percent is found excreted in the 
urine as salicylic acid, 75 percent as salicyluric acid, as the 
phenolic and acyl glucuronides, respectively.
    Pharmacodynamics: Aspirin affects platelet aggregation by 
irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect 
lasts for the life of the platelet and prevents the formation of the 
platelet aggregating factor thromboxane A2. Non-acetylated 
salicylates do not inhibit this enzyme and have no effect on 
platelet aggregation. At somewhat higher doses, aspirin reversibly 
inhibits the formation of prostaglandin I2 
(prostacyclin), which is an arterial vasodilator and inhibits 
platelet aggregation.
    At higher doses aspirin is an effective anti-inflammatory agent, 
partially due to inhibition of inflammatory mediators via cyclo-
oxygenase inhibition in peripheral tissues. In vitro studies suggest 
that other mediators of inflammation may also be suppressed by 
aspirin administration, although the precise mechanism of action has 
not been elucidated. It is this non-specific suppression of cyclo-
oxygenase activity in peripheral tissues following large doses that 
leads to its primary side effect of gastric irritation. (See Adverse 
Reactions.)

CLINICAL STUDIES

    Ischemic Stroke and Transient Ischemic Attack (TIA): In clinical 
trials of subjects with TIA's due to fibrin platelet emboli or 
ischemic stroke, aspirin has been shown to significantly reduce the 
risk of the combined endpoint of stroke or death and the combined 
endpoint of TIA, stroke, or death by about 13-18 percent.
    Suspected Acute Myocardial Infarction (MI): In a large, multi-
center study of aspirin, streptokinase, and the combination of 
aspirin and streptokinase in 17,187 patients with suspected acute 
MI, aspirin treatment produced a 23-percent reduction in the risk of 
vascular mortality. Aspirin was also shown to have an additional 
benefit in patients given a thrombolytic agent.
    Prevention of Recurrent MI and Unstable Angina Pectoris: These 
indications are supported by the results of six large, randomized, 
multi-center, placebo-controlled trials of predominantly male post-
MI subjects and one randomized placebo-controlled study of men with 
unstable angina pectoris. Aspirin therapy in MI subjects was 
associated with a significant reduction (about 20 percent) in the 
risk of the combined endpoint of subsequent death and/or nonfatal 
reinfarction in these patients. In aspirin-treated unstable angina 
patients the event rate was reduced to 5 percent from the 10 percent 
rate in the placebo group.
    Chronic Stable Angina Pectoris: In a randomized, multi-center, 
double-blind trial designed to assess the role of aspirin for 
prevention of MI in patients with chronic stable angina pectoris, 
aspirin significantly reduced the primary combined endpoint of 
nonfatal MI, fatal MI, and sudden death by 34 percent. The secondary 
endpoint for vascular events (first occurrence of MI, stroke, or 
vascular death) was also significantly reduced (32 percent).
    Revascularization Procedures: Most patients who undergo coronary 
artery revascularization procedures have already had symptomatic 
coronary artery disease for which aspirin is indicated. Similarly, 
patients with lesions of the carotid bifurcation sufficient to 
require carotid endarterectomy are likely to have had a precedent 
event. Aspirin is recommended for patients who undergo 
revascularization procedures if there is a preexisting condition for 
which aspirin is already indicated.
    Rheumatologic Diseases: In clinical studies in patients with 
rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing 
spondylitis and osteoarthritis, aspirin has been shown to be 
effective in controlling various indices of clinical disease 
activity.

ANIMAL TOXICOLOGY

    The acute oral 50 percent lethal dose in rats is about 1.5 g/
kilogram (kg) and in mice 1.1 g/kg. Renal papillary necrosis and 
decreased urinary concentrating ability occur in rodents chronically 
administered high doses. Dose-dependent gastric mucosal injury 
occurs in rats and humans. Mammals may develop aspirin toxicosis 
associated with GI symptoms, circulatory effects, and central 
nervous system depression. (See Overdosage.)

INDICATIONS AND USAGE

    Vascular Indications (Ischemic Stroke, TIA, Acute MI, Prevention 
of Recurrent MI, Unstable Angina Pectoris, and Chronic Stable Angina 
Pectoris): Aspirin is indicated to: (1) Reduce the combined risk of 
death and nonfatal stroke in patients who have had ischemic stroke 
or transient ischemia of the brain due to fibrin platelet emboli, 
(2) reduce the risk of vascular mortality in patients with a 
suspected acute MI, (3) reduce the combined risk of death and 
nonfatal MI in patients with a previous MI or unstable angina 
pectoris, and (4) reduce the combined risk of MI and sudden death in 
patients with chronic stable angina pectoris.
    Revascularization Procedures (Coronary Artery Bypass Graft 
(CABG), Percutaneous Transluminal Coronary Angioplasty (PTCA), and 
Carotid Endarterectomy): Aspirin is indicated in patients who have 
undergone revascularization procedures (i.e., CABG, PTCA, or carotid 
endarterectomy) when there is a preexisting condition for which 
aspirin is already indicated.
    Rheumatologic Disease Indications (Rheumatoid Arthritis, 
Juvenile Rheumatoid Arthritis, Spondyloarthropathies, 
Osteoarthritis, and the Arthritis and Pleurisy of Systemic Lupus 
Erythematosus (SLE)): Aspirin is indicated for the relief of the 
signs and symptoms of rheumatoid arthritis, juvenile rheumatoid 
arthritis, osteoarthritis, spondyloarthropathies, and arthritis and 
pleurisy associated with SLE.

CONTRAINDICATIONS

    Allergy: Aspirin is contraindicated in patients with known 
allergy to nonsteroidal anti-inflammatory drug products and in 
patients with the syndrome of asthma, rhinitis, and nasal polyps. 
Aspirin may cause severe urticaria, angioedema, or bronchospasm 
(asthma).
    Reye's Syndrome: Aspirin should not be used in children or 
teenagers for viral infections, with or without fever, because of 
the risk of Reye's syndrome with concomitant use of aspirin in 
certain viral illnesses.

WARNINGS

    Alcohol Warning: Patients who consume three or more alcoholic 
drinks every day should be counseled about the bleeding risks 
involved with chronic, heavy alcohol use while taking aspirin.
    Coagulation Abnormalities: Even low doses of aspirin can inhibit 
platelet function leading to an increase in bleeding time. This can 
adversely affect patients with inherited (hemophilia) or acquired 
(liver disease or vitamin K deficiency) bleeding disorders.
    GI Side Effects: GI side effects include stomach pain, 
heartburn, nausea, vomiting, and gross GI bleeding. Although minor 
upper GI symptoms, such as dyspepsia, are common and can occur 
anytime during therapy, physicians should remain alert for signs of 
ulceration and bleeding, even in the absence of previous GI 
symptoms. Physicians should inform patients about the signs and 
symptoms of GI side effects and what steps to take if they occur.
    Peptic Ulcer Disease: Patients with a history of active peptic 
ulcer disease should avoid using aspirin, which can cause gastric 
mucosal irritation and bleeding.

[[Page 56816]]

PRECAUTIONS

General

    Renal Failure: Avoid aspirin in patients with severe renal 
failure (glomerular filtration rate less than 10 mL/minute).
    Hepatic Insufficiency: Avoid aspirin in patients with severe 
hepatic insufficiency.
    Sodium Restricted Diets: Patients with sodium-retaining states, 
such as congestive heart failure or renal failure, should avoid 
sodium-containing buffered aspirin preparations because of their 
high sodium content.
    Laboratory Tests: Aspirin has been associated with elevated 
hepatic enzymes, blood urea nitrogen and serum creatinine, 
hyperkalemia, proteinuria, and prolonged bleeding time.

Drug Interactions

    Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic 
and hypotensive effects of ACE inhibitors may be diminished by the 
concomitant administration of aspirin due to its indirect effect on 
the renin-angiotensin conversion pathway.
    Acetazolamide: Concurrent use of aspirin and acetazolamide can 
lead to high serum concentrations of acetazolamide (and toxicity) 
due to competition at the renal tubule for secretion.
    Anticoagulant Therapy (Heparin and Warfarin): Patients on 
anticoagulation therapy are at increased risk for bleeding because 
of drug-drug interactions and the effect on platelets. Aspirin can 
displace warfarin from protein binding sites, leading to 
prolongation of both the prothrombin time and the bleeding time. 
Aspirin can increase the anticoagulant activity of heparin, 
increasing bleeding risk.
    Anticonvulsants: Salicylate can displace protein-bound phenytoin 
and valproic acid, leading to a decrease in the total concentration 
of phenytoin and an increase in serum valproic acid levels.
    Beta Blockers: The hypotensive effects of beta blockers may be 
diminished by the concomitant administration of aspirin due to 
inhibition of renal prostaglandins, leading to decreased renal blood 
flow, and salt and fluid retention.
    Diuretics: The effectiveness of diuretics in patients with 
underlying renal or cardiovascular disease may be diminished by the 
concomitant administration of aspirin due to inhibition of renal 
prostaglandins, leading to decreased renal blood flow and salt and 
fluid retention.
    Methotrexate: Salicylate can inhibit renal clearance of 
methotrexate, leading to bone marrow toxicity, especially in the 
elderly or renal impaired.
    Nonsteroidal Anti-inflammatory Drugs (NSAID's): The concurrent 
use of aspirin with other NSAID's should be avoided because this may 
increase bleeding or lead to decreased renal function.
    Oral Hypoglycemics: Moderate doses of aspirin may increase the 
effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.
    Uricosuric Agents (Probenecid and Sulfinpyrazone): Salicylates 
antagonize the uricosuric action of uricosuric agents.
    Carcinogenesis, Mutagenesis, Impairment of Fertility: 
Administration of aspirin for 68 weeks at 0.5 percent in the feed of 
rats was not carcinogenic. In the Ames Salmonella assay, aspirin was 
not mutagenic; however, aspirin did induce chromosome aberrations in 
cultured human fibroblasts. Aspirin inhibits ovulation in rats. (See 
Pregnancy.)
    Pregnancy: Pregnant women should only take aspirin if clearly 
needed. Because of the known effects of NSAID's on the fetal 
cardiovascular system (closure of the ductus arteriosus), use during 
the third trimester of pregnancy should be avoided. Salicylate 
products have also been associated with alterations in maternal and 
neonatal hemostasis mechanisms, decreased birth weight, and with 
perinatal mortality.
    Labor and Delivery: Aspirin should be avoided 1 week prior to 
and during labor and delivery because it can result in excessive 
blood loss at delivery. Prolonged gestation and prolonged labor due 
to prostaglandin inhibition have been reported.
    Nursing Mothers: Nursing mothers should avoid using aspirin 
because salicylate is excreted in breast milk. Use of high doses may 
lead to rashes, platelet abnormalities, and bleeding in nursing 
infants.
    Pediatric Use: Pediatric dosing recommendations for juvenile 
rheumatoid arthritis are based on well-controlled clinical studies. 
An initial dose of 90-130 mg/kg/day in divided doses, with an 
increase as needed for anti-inflammatory efficacy (target plasma 
salicylate levels of 150-300 g/mL) are effective. At high 
doses (i.e., plasma levels of greater than 200 mg/mL), the incidence 
of toxicity increases.

ADVERSE REACTIONS

    Many adverse reactions due to aspirin ingestion are dose-
related. The following is a list of adverse reactions that have been 
reported in the literature. (See Warnings.)
    Body as a Whole: Fever, hypothermia, thirst.
    Cardiovascular: Dysrhythmias, hypotension, tachycardia.
    Central Nervous System: Agitation, cerebral edema, coma, 
confusion, dizziness, headache, subdural or intracranial hemorrhage, 
lethargy, seizures.
    Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic 
acidosis, respiratory alkalosis.
    Gastrointestinal: Dyspepsia, GI bleeding, ulceration and 
perforation, nausea, vomiting, transient elevations of hepatic 
enzymes, hepatitis, Reye's Syndrome, pancreatitis.
    Hematologic: Prolongation of the prothrombin time, disseminated 
intravascular coagulation, coagulopathy, thrombocytopenia.
    Hypersensitivity: Acute anaphylaxis, angioedema, asthma, 
bronchospasm, laryngeal edema, urticaria.
    Musculoskeletal: Rhabdomyolysis.
    Metabolism: Hypoglycemia (in children), hyperglycemia.
    Reproductive: Prolonged pregnancy and labor, stillbirths, lower 
birth weight infants, antepartum and postpartum bleeding.
    Respiratory: Hyperpnea, pulmonary edema, tachypnea.
    Special Senses: Hearing loss, tinnitus. Patients with high 
frequency hearing loss may have difficulty perceiving tinnitus. In 
these patients, tinnitus cannot be used as a clinical indicator of 
salicylism.
    Urogenital: Interstitial nephritis, papillary necrosis, 
proteinuria, renal insufficiency and failure.

DRUG ABUSE AND DEPENDENCE

    Aspirin is non-narcotic. There is no known potential for 
addiction associated with the use of aspirin.

OVERDOSAGE

    Salicylate toxicity may result from acute ingestion (overdose) 
or chronic intoxication. The early signs of salicylic overdose 
(salicylism), including tinnitus (ringing in the ears), occur at 
plasma concentrations approaching 200 g/mL. Plasma 
concentrations of aspirin above 300 g/mL are clearly toxic. 
Severe toxic effects are associated with levels above 400 
g/mL. (See Clinical Pharmacology.) A single lethal dose of 
aspirin in adults is not known with certainty but death may be 
expected at 30 g. For real or suspected overdose, a Poison Control 
Center should be contacted immediately. Careful medical management 
is essential.
    Signs and Symptoms: In acute overdose, severe acid-base and 
electrolyte disturbances may occur and are complicated by 
hyperthermia and dehydration. Respiratory alkalosis occurs early 
while hyperventilation is present, but is quickly followed by 
metabolic acidosis.
    Treatment: Treatment consists primarily of supporting vital 
functions, increasing salicylate elimination, and correcting the 
acid-base disturbance. Gastric emptying and/or lavage is recommended 
as soon as possible after ingestion, even if the patient has vomited 
spontaneously. After lavage and/or emesis, administration of 
activated charcoal, as a slurry, is beneficial, if less than 3 hours 
have passed since ingestion. Charcoal adsorption should not be 
employed prior to emesis and lavage.
    Severity of aspirin intoxication is determined by measuring the 
blood salicylate level. Acid-base status should be closely followed 
with serial blood gas and serum pH measurements. Fluid and 
electrolyte balance should also be maintained.
    In severe cases, hyperthermia and hypovolemia are the major 
immediate threats to life. Children should be sponged with tepid 
water. Replacement fluid should be administered intravenously and 
augmented with correction of acidosis. Plasma electrolytes and pH 
should be monitored to promote alkaline diuresis of salicylate if 
renal function is normal. Infusion of glucose may be required to 
control hypoglycemia.
    Hemodialysis and peritoneal dialysis can be performed to reduce 
the body drug content. In patients with renal insufficiency or in 
cases of life-threatening intoxication, dialysis is usually 
required. Exchange transfusion may be indicated in infants and young 
children.

DOSAGE AND ADMINISTRATION

    Each dose of aspirin should be taken with a full glass of water 
unless patient is fluid restricted. Anti-inflammatory and analgesic 
dosages should be individualized. When

[[Page 56817]]

aspirin is used in high doses, the development of tinnitus may be 
used as a clinical sign of elevated plasma salicylate levels except 
in patients with high frequency hearing loss.
    Ischemic Stroke and TIA: 50-325 mg once a day. Continue therapy 
indefinitely.
    Suspected Acute MI: The initial dose of 160-162.5 mg is 
administered as soon as an MI is suspected. The maintenance dose of 
160-162.5 mg a day is continued for 30 days post-infarction. After 
30 days, consider further therapy based on dosage and administration 
for prevention of recurrent MI.
    Prevention of Recurrent MI: 75-325 mg once a day. Continue 
therapy indefinitely.
    Unstable Angina Pectoris: 75-325 mg once a day. Continue therapy 
indefinitely.
    Chronic Stable Angina Pectoris: 75-325 mg once a day. Continue 
therapy indefinitely.
    CABG: 325 mg daily starting 6 hours post-procedure. Continue 
therapy for 1 year post-procedure.
    PTCA: The initial dose of 325 mg should be given 2 hours pre-
surgery. Maintenance dose is 160-325 mg daily. Continue therapy 
indefinitely.
    Carotid Endarterectomy: Doses of 80 mg once daily to 650 mg 
twice daily, started presurgery, are recommended. Continue therapy 
indefinitely.
    Rheumatoid Arthritis: The initial dose is 3 g a day in divided 
doses. Increase as needed for anti-inflammatory efficacy with target 
plasma salicylate levels of 150-300 g/mL. At high doses 
(i.e., plasma levels of greater than 200 mg/mL), the incidence of 
toxicity increases.
    Juvenile Rheumatoid Arthritis: Initial dose is 90-130 mg/kg/day 
in divided doses. Increase as needed for anti-inflammatory efficacy 
with target plasma salicylate levels of 150-300 g/mL. At 
high doses (i.e., plasma levels of greater than 200 mg/mL), the 
incidence of toxicity increases.
    Spondyloarthropathies: Up to 4 g per day in divided doses.
    Osteoarthritis: Up to 3 g per day in divided doses.
    Arthritis and Pleurisy of SLE: The initial dose is 3 g a day in 
divided doses. Increase as needed for anti-inflammatory efficacy 
with target plasma salicylate levels of 150-300 g/mL. At 
high doses (i.e., plasma levels of greater than 200 mg/mL), the 
incidence of toxicity increases.

HOW SUPPLIED

    (Insert specific information regarding, strength of dosage form, 
units in which the dosage form is generally available, and 
information to facilitate identification of the dosage form as 
required under Sec. 201.57(k)(1), (k)(2), and (k)(3).) Store in a 
tight container at 25  deg.C (77  deg.F); excursions permitted to 
15-30  deg.C (59-86  deg.F).
    REV: (insert date of publication in the Federal Register.)
    (2) In addition to, and immediately preceding, the labeling 
required under paragraph (a)(1) of this section, the professional 
labeling may contain the following highlights of prescribing 
information in the exact language and exact format provided, but only 
when accompanied by the comprehensive prescribing information required 
in paragraph (a)(1) of this section.

BILLING CODE 4160-01-F

[[Page 56818]]

[GRAPHIC] [TIFF OMITTED] TR23OC98.025



[[Page 56819]]

    (b) [Reserved]

Subpart D--Testing Procedures


Sec. 343.90  Dissolution and drug release testing.

    (a) [Reserved]
    (b) Aspirin capsules. Aspirin capsules must meet the dissolution 
standard for aspirin capsules as contained in the United States 
Pharmacopeia (USP) 23 at page 132.
    (c) Aspirin delayed-release capsules and aspirin delayed-release 
tablets. Aspirin delayed-release capsules and aspirin delayed-release 
tablets must meet the drug release standard for aspirin delayed-release 
capsules and aspirin delayed-release tablets as contained in USP 23 at 
pages 133 and 136 respectively.
    (d) Aspirin tablets. Aspirin tablets must meet the dissolution 
standard for aspirin tablets as contained in USP 23 at page 134.
    (e) Aspirin, alumina, and magnesia tablets. Aspirin in combination 
with alumina and magnesia in a tablet dosage form must meet the 
dissolution standard for aspirin, alumina, and magnesia tablets as 
contained in USP 23 at page 138.
    (f) Aspirin, alumina, and magnesium oxide tablets. Aspirin in 
combination with alumina, and magnesium oxide in a tablet dosage form 
must meet the dissolution standard for aspirin, alumina, and magnesium 
tablets as contained in USP 23 at page 139.
    (g) Aspirin effervescent tablets for oral solution. Aspirin 
effervescent tablets for oral solution must meet the dissolution 
standard for aspirin effervescent tablets for oral solution as 
contained in USP 23 at page 137.
    (h) Buffered aspirin tablets. Buffered aspirin tablets must meet 
the dissolution standard for buffered aspirin tablets as contained in 
USP 23 at page 135.

    Dated: October 19, 1998.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 98-28519 Filed 10-21-98; 10:59 am]
BILLING CODE 4160-01-C