[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
