[Federal Register Volume 61, Number 115 (Thursday, June 13, 1996)]
[Proposed Rules]
[Pages 30001-30009]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-14894]
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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; Proposed Amendment to the Tentative
Final Monograph
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of proposed rulemaking.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the tentative final monograph for over-the-counter (OTC) internal
analgesic, antipyretic, and antirheumatic drug products to include the
use of aspirin, buffered aspirin, and aspirin in combination with
antacid to reduce the risk of vascular mortality in people with a
suspected acute myocardial infarction (MI). This proposal is in
response to two citizen petitions and is part of the ongoing review of
OTC drug products conducted by FDA.
DATES: Submit written comments by September 11, 1996. Written comments
on the agency's economic impact determination by September 11, 1996.
The agency is proposing that any final rule that may issue based on
this proposal be effective 12 months after the date of its publication
in the Federal Register.
ADDRESSES: Written comments to the Dockets Management Branch (HFA-305),
Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville,
MD 20857.
FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug
Evaluation and Research (HFD-105), Food and Drug Administration, 5600
Fishers Lane, -Rockville, MD 20857, 301-827-2304.
SUPPLEMENTARY INFORMATION:
I. Introduction
In the Federal Register of November 16, 1988 (53 FR 46204), the
agency published a tentative final monograph (TFM) to establish
conditions under which OTC internal analgesic, antipyretic, and
antirheumatic drug products are generally recognized as safe and
effective and not misbranded (hereinafter referred to as the 1988 TFM).
The 1988 TFM included professional labeling for drug products
containing aspirin, buffered aspirin, and aspirin in combination with
an antacid for certain cardiovascular and cerebrovascular uses to: (1)
Reduce the risk of death and/or nonfatal MI in patients with a previous
infarction or unstable angina pectoris, and (2) reduce 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.
The agency has received two citizen petitions (Refs. 1 and 2),
submitted in accord with Sec. 10.30 (21 CFR 10.30), requesting that the
professional labeling section of the monograph for OTC internal
analgesic, antipyretic, and antirheumatic drug products be amended to
include an indication for the use of aspirin in treating acute MI. One
petition included reports of four studies to support this indication.
The petitions are on public display in the Dockets Management Branch
(address above).
FDA has reviewed the information in the petitions and finds that it
supports the safety and effectiveness of aspirin, buffered aspirin, or
aspirin in combination with antacid to reduce the risk of vascular
mortality in patients with a suspected acute MI. Therefore, the agency
is proposing to amend the professional labeling in Sec. 343.80 of the
1988 TFM for OTC internal analgesic drug products to include
information on aspirin, buffered aspirin, or aspirin in combination
with antacid for this indication. Final agency action on this proposal
will occur in a future issue of the Federal Register.
II. The Citizen Petitions
A. The Agency's Evaluation of the Citizen Petitions
One citizen petition (Ref. 1) included reports of four clinical
trials conducted to evaluate the safety and effectiveness of aspirin in
treating acute MI (Refs. 3 through 6). The petition cited the results
of the Second International Study of Infarct Survival (ISIS-2) (Ref. 3)
as primary support for the safety and effectiveness of aspirin in the
treatment of acute MI to reduce the risk of fatal and nonfatal
cardiovascular and cerebrovascular events.
The ISIS-2 study was undertaken after a pilot study (Ref. 7) of 619
subjects suggested that aspirin was effective in reducing the incidence
of nonfatal reinfarction, death, and stroke in subjects with suspected
acute MI. The ISIS-2 study was a 2 x 2 factorial study of 17,187
subjects (both men and women) with suspected acute MI, randomized so
that 8,592 subjects received a single dose of streptokinase (1.5
million units (MU)) and 8,595 received an intravenous placebo
(hepatitis-B-antigen-free albumin). Streptokinase or placebo was
intravenously infused over about 1 hour in 50 to 200 milliliters of
physiological saline. Of the subjects, 8,587 were also allocated
randomly to receive oral aspirin (162.5 milligrams (mg), enteric-
coated) daily for 1 month (the first dose crushed, sucked, or chewed),
and 8,600 received oral placebo (enteric-coated starch tablets). Thus,
within 24 hours of the onset of symptoms, 4,300 subjects received
streptokinase plus oral placebo, 4,295 received aspirin plus placebo
infusion, 4,292 received both active treatments, and 4,300 received
double placebo. Subjects in whom acute MI was suspected but not
confirmed were eligible for the study if they were entered within 24
hours of the onset of symptoms and had no clear indication for, or
contraindication to, streptokinase or aspirin. Subjects from 417
hospitals in 16 countries were included in the study. Information
collected and recorded prior to randomization included patient
identifiers, age, systolic blood pressure, hours from onset of pain,
aspirin use in the week prior to admission, and details concerning the
planned treatment. Ancillary treatment (including treatment with
aspirin) was not restricted. Electrocardiogram (ECG) results were not
used as a basis for randomization. Once enrolled, subjects remained in
the assigned treatment group for an intent-to-treat analysis of
results.
An ECG done prerandomization was submitted along with information
on compliance with the study treatment, other drug use, and adverse
events. Observers blind to the treatment assignment read the ECG's and
reviewed the deaths. Causes of death were categorized as ``vascular''
or ``nonvascular.'' The protocol defined vascular deaths as those
attributed to cardiac, cerebral, hemorrhagic, other vascular, or
unknown causes. Further details of reports of stroke were collected for
blinded review by a neurologist.
Three primary analyses were conducted to assess the following
effects: (1) Streptokinase on vascular mortality during the first 35
days, (2) streptokinase on vascular mortality during the entire study
period (a median followup of 15 months), and (3) oral daily aspirin on
vascular mortality during the first 35 days. The effects of allocated
treatment on clinical events (reinfarction, cardiac rupture, cardiac
arrest, bleeding, and stroke) and on nonvascular mortality were also
[[Page 30003]]
evaluated. Although not specified in the protocol, subgroup analysis on
vascular mortality in days 0 to 35 was performed for certain
parameters, such as age, gender, diabetes, and systolic blood pressure.
Results were presented as absolute changes and as changes in the
odds of death. The report states: ``* * * a change from 10 percent dead
(odds 10/90) to 8 percent dead (odds 8/92) involves an odds ratio of 8/
92 divided by 10/90, or 0.78, and is therefore described as a 22
percent reduction in the odds of death (rather than as a 20 percent
reduction in the risk of death).'' (A change from 10 percent dead (risk
10/100) to 8 percent dead (risk 8/100) would represent a 20 percent
reduction in risk of death.)
During the first 35 days, there were 804 (9.4 percent) vascular
deaths in the 8,587 subjects randomized to receive oral aspirin, and
1,016 (11.8 percent) vascular deaths in the 8,600 subjects randomized
to placebo. These results represent an absolute reduction of 2.4
percent in the mean 35-day vascular mortality attributable to aspirin
and a highly significant (23 percent) reduction in the odds of vascular
death (2p < 0.00001,="" confidence="" interval="" 15="" to="" 30="" percent).="" although="" not="" an="" endpoint="" specified="" in="" the="" protocol,="" an="" effect="" of="" aspirin="" was="" still="" present="" after="" the="" median="" 15-month="" followup="" was="" completed,="" with="" a="" total="" reduction="" of="" early="" and="" late="" vascular="" mortality="" of="" 1.9="" percent,="" highly="" significant="" (2p="">< 0.001).="" the="" number="" of="" nonvascular="" deaths="" in="" subjects="" allocated="" to="" receive="" aspirin="" was="" not="" significantly="" different="" from="" subjects="" receiving="" placebo="" for="" the="" 15-month="" median="" followup.="" one="" nonvascular="" death="" occurred="" before="" 5="" weeks,="" and="" 24="" deaths="" occurred="" after="" 5="" weeks="" in="" the="" aspirin="" group,="" compared="" to="" 7="" and="" 32,="" respectively,="" in="" the="" placebo="" group.="" total="" mortality="" (vascular="" plus="" nonvascular)="" was="" reduced="" at="" both="" 35="" days="" (9.4="" percent="" versus="" 11.9="" percent,="" odds="" ratio="" 0.77)="" and="" after="" 15="" months="" median="" followup="" (16.0="" percent="" versus="" 18.1="" percent="" odds="" ratio="" 0.87)="" for="" the="" aspirin="" group="" and="" placebo="" group).="" the="" reduction="" in="" all-cause="" mortality="" was="" highly="" significant="" (2p="">< 0.001)="" at="" both="" times.="" the="" beneficial="" effects="" of="" aspirin="" on="" vascular="" mortality="" in="" days="" 0="" to="" 35="" was="" found="" to="" be="" independent="" of="" streptokinase="" infusion.="" (see="" table="" 1.)="" table="" 1.--beneficial="" effects="" of="" aspirin="" on="" vascular="" mortality="" in="" days="" 0="" to="" 35="" ----------------------------------------------------------------------------------------------------------------="" percent="" percent="" treatment\1\="" tablet/infusion="" vascular="" deaths/no.="" of="" subjects="" percent="" absolute="" reduction="" in="" change="" odds="" of="" death="" ----------------------------------------------------------------------------------------------------------------="" a/s+a/p="" 804/8,587\2\="" 9.4="" vs="" p/s+p/p="" 1,016/8,600\3\-="" 11.8="" -2.4="" 23=""><0.00001) a/p="" 461/4,295="" 10.7="" vs="" p/p="" 568/4,300="" 13.2="" -2.5-="" 21=""><0.001) a/s="" 343/4,292="" 8.0="" vs="" p/s="" 448/4,300="" 10.4="" -2.4="" 25=""><0.001) a/s="" 343/4,292="" 8.0="" vs="" p/p="" 568/4,300="" 13.2="" -5.2-="" 42=""><0.00001) a/s="" 343/4,292="" 8.0="" vs="" a/p="" 461/4,295="" 10.7="" -2.7-="" 28=""><0.0001) p/s="" 448/4,300="" 10.4="" vs="" p/p-="" 568/4,300="" 13.2="" -2.8="" 23=""><0.0001) a/s+p/s="" 791/8,592\4\-="" 9.2="" vs="" a/p+p/p="" 1,029/8,595\5\="" 12.0="" -2.8="" 25=""><0.00001) ----------------------------------------------------------------------------------------------------------------="" \1\="" a="aspirin," s="streptokinase," and="" p="placebo." \2\="" inludes="" 4,295="" allocated="" aspirin="" tablets="" +="" placebo="" infusion="" and="" 4,292="" allocated="" aspirin="" tablets="" +="" streptokinase="" infusion.="" \3\="" includes="" 4,300="" allocated="" placebo="" tablets="" +="" placebo="" infusion="" and="" 4,300="" allocated="" placebo="" tablets="" +="" streptokinase="" infusion.="" \4\includes="" 4,292="" allocated="" aspirin="" tablets="" +="" placebo="" infusion="" and="" 4,300="" allocated="" streptokinase="" infusion="" +="" placebo="" tablets.="" \5\includes="" 4,295="" allocated="" aspirin="" tablets="" +="" placebo="" infusion="" and="" 4,300="" allocated="" placebo="" tablets="" +="" placebo="" infusion.="" each="" subject="" received="" one="" tablet="" and="" one="" infusion="" (e.g.,="" each="" subject="" was="" allocated="" either="" a="" single="" active="" ingredient="" plus="" placebo,="" both="" active="" ingredients,="" or="" two="" placebos).="" aspirin="" reduced="" the="" odds="" of="" death="" within="" 35="" days="" by="" 25="" percent="" (standard="" deviation="" (sd)="" 6)="" in="" people="" who="" were="" also="" given="" streptokinase="" infusion,="" and="" by="" 21="" percent="" (sd="" 6)="" in="" people="" given="" a="" placebo="" infusion="" (2p="">< 0.001).="" thus,="" aspirin="" was="" effective="" in="" reducing="" mortality="" both="" in="" the="" presence="" and="" absence="" of="" streptokinase.="" similarly,="" there="" were="" significantly="" fewer="" deaths="" in="" the="" streptokinase="" group="" compared="" to="" the="" placebo="" both="" in="" the="" presence="" and="" absence="" of="" aspirin.="" the="" effect="" of="" the="" combined="" therapy="" of="" aspirin="" plus="" streptokinase="" was="" approximately="" additive.="" the="" 35-day="" vascular="" mortality="" of="" the="" group="" that="" received="" aspirin="" plus="" streptokinase="" was="" 8="" percent="" compared="" to="" 13.2="" percent="" for="" the="" double-placebo="" group.="" these="" results="" represent="" an="" absolute="" reduction="" of="" 5.2="" percent="" and="" a="" 42-percent="" reduction="" in="" odds="" of="" death="" in="" [[page="" 30004]]="" the="" aspirin="" plus="" streptokinase="" group="" (2p="">< 0.00001).="" -when="" specific="" clinical="" events="" (fatal="" plus="" nonfatal)="" that="" occurred="" in="" the="" hospital="" were="" evaluated="" separately,="" statistically="" significant="" absolute="" reductions="" favoring="" aspirin="" were="" found="" for="" reinfarction="" (1.5="" percent="" absolute="" reduction,="" 45="" percent="" odds="" reduction,="" 2p="">< 0.00001),="" cardiac="" arrest="" (1.2="" percent="" absolute="" reduction,="" 14.2="" percent="" odds="" reduction,="" 2p="">< 0.01),="" and="" total="" stroke="" (0.4="" percent="" absolute="" reduction,="" 41.5="" percent="" odds="" reduction,="" 2p="">< 0.01).="" moreover,="" the="" effect="" of="" aspirin="" over="" and="" above="" its="" effect="" on="" mortality="" was="" evidenced="" by="" small,="" but="" significant,="" reductions="" in="" vascular="" morbidity="" in="" those="" subjects="" who="" were="" discharged.="" -the="" combination="" of="" streptokinase="" infusion="" and="" daily="" aspirin="" was="" significantly="" better="" than="" either="" active="" treatment="" alone="" for="" vascular="" mortality="" (see="" table="" 1).="" the="" differences="" in="" favor="" of="" aspirin="" plus="" streptokinase="" compared="" to="" double="" placebo="" for="" specific="" clinical="" events="" were="" 1.1="" percent="" in="" reinfarction,="" 2.5="" percent="" in="" cardiac="" arrest,="" and="" 0.5="" percent="" (2p="0.02)" in="" total="" stroke.="" the="" effects="" of="" aspirin="" and="" aspirin="" in="" combination="" with="" streptokinase="" on="" major="" clinical="" events="" that="" occurred="" in="" a="" hospital="" is="" shown="" in="" table="" 2.="" table="" 2.--effects="" of="" aspirin="" and="" aspirin="" plus="" streptokinase="" on="" major="" clinical="" events="" in="" hospital="" ----------------------------------------------------------------------------------------------------------------="" aspirin="" aspirin="" plus="" streptokinase="" -----------------------------------------------------------------------------------------------="" percent="" placebo="" percent="" asprin="" tablets="" placebo="" absolute="" aspirin="" and="" infusion="" and="" absolute="" tablets="" change="" streptokinase="" tablet="" change="" ----------------------------------------------------------------------------------------------------------------="" number="" randomized="" 8,587="" 8,600="" 4,292="" 4,300="" number="" discharged="" alive="" 8,492="" 8,489="" 4,239="" 4,238="" reinfarction="" (any)="" 156="" 284="" 1.5="" 77="" 123="" 1.1="" (any="" discharged="" alive)="" 83="" 170="" 1.0="" 46="" 61="" 0.4="" cardiac="" rupture="" (any)="" 69="" 81="" 0.1="" 31="" 38="" 0.2="" (any="" discharged="" alive)="" 7="" 5="" 0.0="" 2="" 1="" 0.0="" cardiac="" arrest="" (any)="" 690-="" 793="" 1.2="" 311="" 417="" 2.5="" (any="" discharged="" alive)="" 259="" 289="" 0.4="" 133="" 129="" -0.1="" stroke="" (any)-="" 47="" 81="" 0.4="" 25="" 45="" 0.5="" (fatal)="" 20="" 30="" 0.1="" 12="" 18="" 0.1="" (disabled)="" 17="" 23="" 0.1="" 9="" 15="" 0.1="" (not="" disabled)="" 10="" 28="" 0.2="" 4="" 12="" 0.2="" (hemorrhagic)="" 5="" 2="" 0.0="" 5="" 0="" -0.1="" (any="" discharged="" alive)="" 27="" 51="" 0.3="" 13="" 27="" 0.3="" major="" bleeds="" (transfused)="" 31-="" 33="" 0.0-="" 24="" 11="" -0.3="" minor="" bleeds="" (not="" transfused)="" 215="" 163="" -0.6="" 167="" 33="" -3.2="" ----------------------------------------------------------------------------------------------------------------="" subgroup="" analysis="" was="" done="" for="" 35-day="" vascular="" mortality="" for="" 3,945="" women="" assigned="" to="" either="" aspirin="" (1,994)="" or="" oral="" placebo="" (1,951),="" and="" for="" 13,125="" men="" assigned="" to="" aspirin="" (6,540)="" or="" oral="" placebo="" (6,585).="" vascular="" mortality="" was="" higher="" in="" women="" than="" men="" in="" both="" the="" placebo="" and="" the="" aspirin="" group,="" but="" the="" absolute="" reduction="" of="" risk="" of="" vascular="" death="" was="" 2.6="" percent="" for="" women="" and="" 2.4="" percent="" for="" men,="" representing="" a="" 19="" percent="" (p="0.018)" odds="" reduction="" for="" women="" and="" a="" 25="" percent="" (p="">< 0.0001)="" odds="" reduction="" for="" men.="" these="" data="" suggest="" that="" beneficial="" effects="" of="" aspirin="" may="" be="" expected="" in="" treating="" both="" men="" and="" women="" for="" an="" acute="" mi.="" subgroup="" analyses="" suggest="" that="" all="" age="" groups="" analyzed="" benefited="" from="" aspirin.="" there="" were="" 1="" percent="" fewer="" vascular="" deaths="" recorded="" for="" 3,870="" subjects="" under="" 60="" years="" of="" age="" who="" received="" aspirin="" than="" for="" 3,850="" subjects="" who="" received="" oral="" placebo="" (18="" percent="" relative="" risk="" reduction).="" in="" subjects="" 60="" to="" 69="" years="" old,="" 3.1="" percent="" fewer="" vascular="" deaths="" were="" recorded="" for="" 2,999="" subjects="" who="" received="" aspirin="" than="" for="" 3,057="" subjects="" who="" received="" placebo="" (22="" percent="" relative="" risk="" reduction).="" subjects="" over="" 70="" years="" old="" (1,718="" on="" aspirin="" versus="" 1,693="" on="" placebo)="" appeared="" to="" have="" the="" greatest="" (4.7="" percent)="" absolute="" reduction="" in="" vascular="" death.="" the="" relative="" risk="" reduction="" in="" subjects="" over="" 70="" years="" old="" was="" 21="" percent="" for="" those="" who="" received="" aspirin.--="" however,="" the="" agency="" agrees="" with="" the="" investigators'="" conclusion="" that="" more="" weight="" should="" be="" placed="" on="" the="" overall="" results="" than="" on="" any="" particular="" subgroup="" of="" people.="" the="" agency="" has="" determined="" that="" the="" evidence="" is="" insufficient="" at="" present="" to="" validate="" efficacy="" results="" in="" particular="" subsets="" of="" patients="" with="" suspected="" acute="" mi.="" the="" principal="" entry="" criterion="" for="" subjects="" in="" the="" isis-2="" study="" was="" that="" the="" responsible="" physician="" suspected="" acute="" mi="" based="" on="" clinical="" presentation.="" the="" protocol="" did="" not="" require="" that="" mi="" be="" documented="" in="" those="" entering="" the="" study.="" the="" agency="" notes="" that="" the="" only="" preliminary="" indications="" of="" an="" mi="" are="" chest="" pain="" and="" changes="" in="" the="" ecg.="" the="" report="" did="" not="" indicate="" how="" many="" of="" the="" subjects="" actually="" had="" an="" acute="" mi.="" in="" a="" retrospective="" analysis,="" about="" 98="" percent="" of="" the="" subjects="" admitted="" to="" the="" study="" had="" some="" ecg="" abnormality.="" aspirin="" produced="" similar-sized="" reductions="" in="" vascular="" mortality="" among="" subjects="" treated="" early="" and="" treated="" late="" after="" the="" onset="" of="" symptoms="" (odds="" reductions="" at="" 0="" to="" 4,="" 5="" to="" 12,="" and="" 13="" to="" 24="" hours="" were="" 25="" percent,="" 21="" percent,="" and="" 21="" percent,="" respectively).="" the="" effects="" of="" streptokinase="" appeared="" to="" be="" greatest="" among="" those="" treated="" earliest.="" when="" comparing="" subjects="" who="" received="" both="" aspirin="" and="" streptokinase="" to="" subjects="" who="" received="" double="" placebo,="" the="" odds="" of="" death="" were="" more="" reduced="" among="" those="" subjects="" randomized="" 0="" to="" 4="" hours="" (53="" percent="" odds="" reduction;="" 2p="">< 0.00001)="" after="" the="" onset="" of="" pain="" than="" those="" randomized="" later:="" 5="" to="" 12="" hours="" (32="" percent="" odds="" reduction;="" 2p="">< 0.0001),="" and="" 13="" to="" 24="" hours="" (38="" percent="" odds="" reduction;="" 2p="">< 0.01).="" the="" aspirin="" regimen="" was="" well="" tolerated.="" there="" was="" no="" difference="" in="" the="" incidence="" of="" major="" bleeding="" (bleeds="" requiring="" transfusion)="" between="" the="" two="" groups="" (0.4="" percent="" for="" aspirin;="" 0.4="" percent="" for="" placebo).="" there="" was="" a="" small="" but="" statistically="" significant="" 0.6="" percent="" (sd="0.2," 2p="">< 0.01)="" increase="" in="" minor="" bleeding="" in="" people="" taking="" aspirin="" compared="" to="" placebo="" (2.5="" versus="" 1.9="" [[page="" 30005]]="" percent).="" no="" other="" significant="" adverse="" effects="" were="" reported.="" although="" there="" were="" five="" confirmed="" cerebral="" hemorrhages="" in="" the="" aspirin="" group="" compared="" with="" two="" in="" the="" placebo="" group,="" this="" difference="" was="" not="" statistically="" significant.="" as="" discussed="" above,="" the="" incidence="" of="" stroke="" of="" any="" cause="" was="" lower="" in="" subjects="" taking="" aspirin="" when="" compared="" to="" those="" on="" oral="" placebo="" (47="" versus="" 81),="" a="" 0.4="" percent="" absolute="" reduction="" and="" a="" 41.5="" percent="" reduction="" in="" odds="" of="" stroke="" (2p="">< 0.01)="" in="" subjects="" taking="" aspirin.="" the="" second="" study="" (ref.="" 4)="" was="" a="" study="" of="" low="" dose="" aspirin="" (75="" mg="" daily)="" and="" intravenous="" heparin="" in="" 945="" men="" with="" unstable="" coronary="" artery="" disease,="" defined="" as="" non-q-wave="" mi="" or="" increasing="" angina="" within="" the="" previous="" 4="" weeks="" associated="" with="" ischemia="" (deficiency="" of="" oxygen="" supply="" to="" the="" heart="" muscle,="" due="" to="" the="" constriction="" or="" obstruction="" of="" a="" blood="" vessel)="" in="" a="" resting="" ecg="" or="" during="" a="" predischarge="" exercise="" test.="" the="" subjects="" were="" randomized="" within="" 72="" hours="" after="" admission="" to="" coronary="" care="" units="" to="" receive="" bolus="" intravenous="" injections="" of="" heparin="" (10,000="" units="" 4="" times="" a="" day="" for="" 1="" day="" and="" 7,500="" units="" 4="" times="" a="" day="" for="" 4="" additional="" days)="" or="" placebo="" (saline)="" for="" 5="" days,="" and="" oral="" aspirin="" (75="" mg="" daily)="" or="" placebo="" for="" 1="" year.="" the="" study="" was="" stopped="" early="" after="" publication="" of="" the="" isis-2="" study.="" as="" a="" result,="" the="" minimum="" period="" of="" randomized="" treatment="" was="" reduced="" to="" 3="" months.="" a="" detailed="" report="" of="" this="" study="" has="" not="" been="" submitted="" to="" the="" agency="" for="" review.="" one="" hundred="" and="" forty-nine="" subjects="" were="" excluded="" from="" the="" study="" (115="" with="" no="" evidence="" of="" myocardial="" ischemia="" after="" an="" exercise="" test,="" and="" 34="" with="" an="" anterior="" q-wave="" mi="" before="" recruitment).="" the="" remaining="" 796="" subjects="" were="" randomized="" to="" either="" double="" placebo="" (199),="" heparin="" and="" aspirin="" (210),="" aspirin="" and="" placebo="" (189),="" or="" heparin="" and="" placebo="" (198).="" the="" combined="" rate="" of="" mi="" or="" death="" in="" subjects="" on="" aspirin="" (aspirin="" with="" placebo="" and="" aspirin="" with="" heparin)="" was="" 9.1="" percent="" and="" 10.6="" percent="" lower="" at="" 1="" and="" 3="" months,="" respectively,="" than="" the="" combined="" rate="" for="" subjects="" receiving="" placebo="" (double="" placebo="" or="" placebo="" with="" heparin),="" a="" risk="" reduction="" of="" 68="" percent="" at="" 1="" month="" (p="0.0001)" and="" 62="" percent="" at="" 3="" months="" (p="0.0001)." heparin="" alone="" did="" not="" appear="" to="" affect="" the="" rate="" of="" death="" or="" mi.="" however,="" the="" combination="" of="" heparin="" and="" aspirin="" was="" the="" only="" regimen="" that="" significantly="" reduced="" the="" risk="" of="" mi="" during="" the="" first="" 5="" days="" in="" the="" hospital.="" thus,="" the="" authors="" suggested="" that="" reduction="" of="" events="" in="" the="" aspirin="" treated="" group="" may="" have="" been="" influenced="" by="" initial="" simultaneous="" treatment="" with="" heparin.="" a="" few="" side="" effects="" were="" reported="" with="" the="" daily="" aspirin="" dose="" used="" in="" this="" study,="" although="" details="" were="" not="" provided.="" hematological="" side="" effects="" were="" reported="" to="" be="" rare="" and="" minor.="" gastrointestinal="" side="" effects="" were="" similar="" in="" the="" aspirin="" and="" placebo="" groups="" at="" 1="" month,="" but="" were="" more="" frequent="" with="" aspirin="" (5.2="" percent="" to="" 6.5="" percent)="" than="" with="" placebo="" (0.7="" percent="" to="" 1.9="" percent)="" at="" 3="" months.="" this="" study="" primarily="" involved="" the="" use="" of="" aspirin="" in="" subjects="" with="" unstable="" angina.="" the="" agency="" has="" already="" accepted="" the="" benefits="" of="" aspirin="" in="" unstable="" angina="" and="" has="" included="" that="" indication="" in="" sec.="" 343.80(c).="" the="" third="" study="" (ref.="" 5)="" compared="" the="" effect="" of="" aspirin="" (100="" mg="" daily)="" to="" placebo="" for="" 3="" months="" on="" infarct="" size,="" death,="" reinfarction,="" unstable="" angina,="" and="" revascularization="" in="" 100="" subjects="" with="" early="" symptoms="" of="" first="" anterior="" wall="" acute="" mi.="" all="" subjects="" also="" received="" subcutaneous="" heparin="" until="" they="" were="" mobilized.="" in="" addition,="" those="" subjects="" who="" were="" less="" than="" 70="" years="" of="" age="" and="" had="" symptoms="" for="" less="" than="" 4="" hours="" when="" recruited="" (24="" subjects="" on="" aspirin="" and="" 26="" subjects="" on="" placebo)="" also="" received="" thrombolysis="" therapy="" (intravenous="" streptokinase).="" the="" study="" was="" randomized="" for="" aspirin="" but="" not="" for="" thrombolysis.="" the="" primary="" endpoint="" was="" infarct="" size="" in="" the="" first="" 72="" hours.="" the="" size="" of="" the="" infarct="" was="" determined="" by="" the="" cumulative="" release="" of="" serum="" lactate="" dehydrogenase="" (ldh)="" in="" the="" first="" 72="" hours.="" secondary="" endpoints="" were="" death,="" reinfarction,="" unstable="" angina,="" and="" revascularization.="" the="" results="" showed="" a="" 10="" percent="" difference="" in="" infarct="" size="" (1,431=""> 782 versus 1,592 1,082 LDH units per liter)
for the aspirin versus placebo group. This difference was not
statistically significant (p = 0.35). Of the secondary endpoints
evaluated, only reinfarction was significantly lower in the aspirin
than the placebo group (4 percent versus 18 percent, p < 0.03)="" at="" 3="" months.="" mortality="" rate="" was="" 20="" percent="" in="" subjects="" given="" aspirin="" compared="" to="" 24="" percent="" in="" those="" given="" placebo.="" this="" difference="" was="" not="" statistically="" significant="" (p="0.65)." the="" significant="" reduction="" in="" incidence="" of="" reinfarction="" in="" this="" study="" is="" surprising="" because="" of="" the="" small="" size="" of="" the="" study="" and="" may="" depend="" on="" an="" atypical="" incidence="" of="" reinfarction="" in="" the="" control="" group="" (18="" percent="" at="" 3="" months).="" this="" was="" much="" higher="" than="" in="" the="" control="" group="" of="" the="" isis-2="" study="" (approximately="" 3="" percent="" at="" 35="" days).="" followup="" for="" this="" third="" study="" was="" longer="" than="" for="" the="" isis-2="" study="" (3="" months="" versus="" 35="" days).="" only="" subjects="" with="" early="" signs="" of="" first="" anterior="" wall="" infarction="" were="" eligible="" for="" entry="" in="" the="" third="" study,="" while="" in="" the="" isis-2="" study="" subjects="" with="" only="" ``suspected="" acute="" mi''="" were="" eligible.="" the="" more="" stringent="" entry="" criteria="" and="" the="" longer="" followup="" period="" may="" account="" for="" the="" higher="" incidence="" of="" reinfarction="" in="" the="" control="" group="" and="" the="" significant="" effect="" of="" aspirin="" on="" reinfarction="" in="" the="" third="" study.="" a="" detailed="" report="" of="" this="" study="" was="" not="" submitted="" to="" the="" agency.="" based="" on="" the="" information="" provided,="" this="" study="" provides="" little="" additional="" evidence="" of="" the="" effectiveness="" of="" aspirin="" in="" treating="" acute="" mi.="" the="" fourth="" study="" (ref.="" 6)="" was="" an="" uncontrolled="" study="" to="" evaluate="" infarct="" vessel="" patency="" in="" subjects="" started="" on="" both="" aspirin="" (325="" mg/day)="" and="" dipyridamole="" (75="" mg/day)="" after="" thrombolytic="" therapy="" with="" streptokinase.="" in="" the="" absence="" of="" a="" control="" group,="" the="" study="" cannot="" provide="" any="" information="" on="" the="" effectiveness="" of="" aspirin="" in="" treating="" acute="" mi.="" the="" second="" petition="" (ref.="" 2)="" also="" requested="" the="" agency="" to="" approve="" professional="" labeling="" for="" aspirin="" for="" prevention="" of="" fatal="" and="" nonfatal="" cardiovascular="" events="" in="" patients="" with="" suspected="" acute="" mi.="" the="" petition="" requested="" approval="" of="" an="" initial="" dose="" of="" ``at="" least="" 162="" mg="" aspirin''="" during="" the="" 24="" hours="" following="" acute="" mi,="" with="" continued="" treatment="" for="" at="" least="" the="" subsequent="" 30-day="" followup="" period="" at="" the="" minimum="" dose="" of="" 162="" mg/day.="" the="" petition="" relied="" primarily="" on="" the="" results="" of="" isis-2="" (ref.="" 3)="" to="" support="" the="" labeling="" claim.="" data="" from="" that="" study="" are="" summarized="" above.="" in="" addition="" to="" isis-2,="" the="" petition="" included="" results="" of="" four="" published="" efficacy="" studies="" of="" aspirin="" in="" acute="" mi="" (refs.="" 5,="" 7,="" 8,="" and="" 9).="" the="" study="" by="" verheugt="" et="" al.="" (ref.="" 5)="" was="" also="" submitted="" in="" the="" first="" petition="" and="" is="" discussed="" above.="" in="" the="" isis-2="" pilot="" study="" (ref.="" 7),="" there="" was="" a="" nonsignificant="" reduction="" in="" nonfatal="" reinfarction="" in="" 313="" subjects="" who="" received="" 325="" mg="" aspirin="" on="" alternate="" days="" compared="" with="" 306="" subjects="" who="" received="" placebo.="" in-hospital="" death="" (all="" causes)="" was="" reported="" to="" be="" significantly="" lower="" in="" the="" aspirin-treated="" group.="" postdischarge="" death="" was="" reported="" at="" a="" similar="" rate="" in="" both="" the="" aspirin="" and="" placebo="" subjects.="" elwood="" and="" williams="" (ref.="" 8)="" found="" no="" evidence="" of="" reduced="" mortality="" in="" males="" or="" females="" evaluated="" up="" to="" 28="" days="" after="" a="" single="" 300="" mg="" dose="" of="" aspirin.="" aspirin="" or="" placebo="" was="" administered="" to="" 2,530="" subjects,="" upon="" first="" suspicion="" of="" acute="" mi.="" analysis="" was="" [[page="" 30006]]="" confined="" to="" 1,705="" subjects="" in="" whom="" acute="" mi="" was="" subsequently="" confirmed.="" husted="" et="" al.="" (ref.="" 9)="" compared="" aspirin="" 100="" mg/day,="" aspirin="" 1,000="" mg/day,="" and="" placebo="" in="" 293="" subjects="" with="" suspected="" acute="" mi.="" an="" intent-="" to-treat="" analysis="" showed="" no="" significant="" difference="" between="" groups.="" a="" significant="" benefit="" of="" 100="" mg/day="" (but="" not="" 1,000="" mg/day)="" on="" the="" combined="" incidence="" of="" cardiac="" death="" and="" nonfatal="" mi="" was="" found="" when="" subjects="" who="" withdrew="" from="" the="" study="" were="" excluded="" from="" the="" analysis.="" no="" conclusions="" were="" drawn="" as="" to="" the="" reasons="" for="" the="" difference="" in="" effect="" between="" a="" 100="" mg="" and="" 1,000="" mg="" daily="" dose.="" the="" agency="" received="" additional="" comments="" that="" raised="" other="" issues="" related="" to="" professional="" labeling="" of="" aspirin="" for="" cardiovascular="" use.="" those="" issues="" will="" be="" addressed="" in="" a="" future="" issue="" of="" the="" federal="" register.="" b.="" summary="" of="" the="" agency's="" evaluation="" the="" agency="" has="" determined="" that="" the="" isis-2="" study="" (ref.="" 3)="" supports="" the="" use="" of="" aspirin="" at="" a="" dose="" of="" 162.5="" mg/day,="" started="" as="" soon="" as="" possible="" after="" an="" infarction="" and="" continued="" for="" at="" least="" 30="" days="" to="" reduce="" the="" risk="" of="" fatal="" and="" nonfatal="" cardiovascular="" and="" cerebrovascular="" events="" in="" subjects="" with="" a="" suspected="" acute="" mi.="" the="" study="" also="" shows="" that="" the="" effect="" of="" aspirin="" is="" not="" diminished="" with="" concomitant="" early="" treatment="" with="" a="" thrombolytic="" (i.e.,="" an="" immediate="" 1-="" hour,="" single-dose,="" infusion="" of="" 1.5="" million="" units="" of="" streptokinase).="" aspirin="" treatment="" should="" be="" started="" as="" soon="" as="" the="" physician="" suspects="" an="" mi,="" rather="" than="" delaying="" treatment="" until="" definitive="" testing="" can="" be="" done.="" a="" significant="" benefit="" of="" aspirin="" in="" reducing="" the="" risk="" of="" vascular="" death="" was="" seen="" in="" isis-2="" for="" aspirin="" alone="" compared="" to="" placebo="" as="" well="" as="" for="" aspirin="" plus="" streptokinase="" compared="" to="" streptokinase="" alone,="" representing,="" in="" effect,="" two="" separate="" studies="" showing="" a="" benefit="" of="" aspirin.="" this="" internal="" replication="" supports="" the="" indication="" for="" treatment="" of="" acute="" mi.="" the="" large="" number="" of="" investigators="" involved="" in="" the="" study="" and="" the="" consistency="" of="" results="" among="" countries="" lend="" further="" credibility="" to="" the="" results="" of="" this="" single="" study.-="" the="" benefit="" of="" aspirin="" is="" evident="" for="" both="" all-cause="" mortality="" and="" vascular="" mortality="" for="" aspirin="" alone="" and="" for="" aspirin="" in="" addition="" to="" early="" thrombolytic="" treatment.="" although="" the="" most="" important="" effect="" of="" aspirin="" in="" acute="" mi="" is="" the="" reduction="" in="" mortality,="" small,="" but="" statistically="" significant,="" decreases="" in="" nonfatal="" reinfarction="" and="" stroke="" were="" also="" found.="" overall,="" the="" other="" studies="" included="" in="" the="" petitions="" are="" consistent="" with="" a="" favorable="" effect="" of="" aspirin="" in="" the="" acute="" and="" subacute="" mi="" setting,="" but="" do="" not="" provide="" substantial="" support="" for="" isis-2.="" while="" the="" dosage="" in="" the="" isis-2="" study="" was="" 162.5="" mg="" enteric-="" coated="" aspirin="" daily,="" the="" agency="" believes="" one-half="" of="" a="" conventional="" 325-mg="" tablet="" or="" two="" 80-="" or="" 81-mg="" tablets="" are="" also="" reasonable="" doses="" (i.e.,="" a="" range="" of="" 160="" to="" 162.5="" mg).="" in="" the="" 1988="" tfm="" (53="" fr="" 46204="" at="" 46229="" and="" 46231),="" the="" agency="" proposed="" (in="" sec.="" 343.20(b)(3))="" that="" aspirin,="" buffered="" aspirin,="" and="" aspirin="" in="" combination="" with="" antacids="" are="" effective="" to="" treat="" patients="" with="" tia,="" a="" previous="" mi,="" or="" unstable="" angina="" pectoris.="" that="" proposal="" was="" based="" on="" recommendations="" of="" the="" peripheral="" and="" central="" nervous="" system="" drugs="" advisory="" committee,="" the="" agency's="" review="" of="" data="" submitted="" to="" show="" that="" buffered="" aspirin="" would="" be="" expected="" to="" have="" similar="" effects,="" and="" on="" the="" data="" from="" an="" unstable="" angina="" trial="" that="" used="" a="" highly="" buffered="" aspirin="" solution.="" based="" on="" those="" data,="" the="" agency="" is="" proposing="" that="" aspirin,="" buffered="" aspirin,="" or="" aspirin="" in="" combination="" with="" an="" antacid="" may="" be="" used="" to="" treat="" patients="" with="" a="" suspected="" acute="" mi.="" after="" the="" 30-="" day="" recommended="" treatment="" with="" aspirin="" for="" acute="" mi,="" physicians="" should="" consider="" further="" therapy="" based="" on="" the="" labeling="" for="" dosage="" and="" administration="" of="" aspirin="" for="" prevention="" of="" recurrent="" mi="" (reinfarction).="" based="" on="" the="" above="" discussion,="" the="" agency="" is="" now="" proposing="" several="" changes="" in="" the="" professional="" labeling="" proposed="" in="" sec.="" 343.80(c)="" for="" otc="" drug="" products="" containing="" aspirin="" proposed="" in="" sec.="" 343.10(b)="" or="" permitted="" combinations="" proposed="" in="" sec.="" 343.20(b)(3)="" as="" follows:="" (1)="" add="" information="" for="" treatment="" of="" a="" suspected="" acute="" mi,="" and="" (2)="" revise="" some="" of="" the="" previously="" proposed="" text="" based="" on="" additional="" information="" from="" the="" isis-2="" study="" (ref.="" 8).="" iii.="" summary="" of="" agency="" changes="" in="" summary,="" the="" agency="" is="" proposing="" to="" add="" the="" following="" to="" the="" professional="" labeling="" in="" sec.="" 343.80(c):="" an="" indication="" for="" aspirin="" to="" reduce="" the="" risk="" of="" vascular="" mortality="" in="" patients="" with="" a="" suspected="" acute="" mi;="" the="" findings="" of="" the="" isis-2="" study="" under="" ``clinical="" trials;''="" a="" dosage="" of="" 160="" to="" 162.5="" mg="" for="" a="" suspected="" acute="" mi="" taken="" as="" soon="" as="" the="" infarct="" is="" suspected="" and="" then="" daily="" for="" at="" least="" 30="" days;="" and="" a="" statement="" that="" this="" use="" of="" aspirin="" applies="" to="" both="" solid,="" oral="" dosage="" forms="" and="" buffered="" aspirin="" in="" solution.="" to="" add="" the="" findings="" of="" the="" isis-2="" study="" and="" to="" improve="" readability,="" the="" agency="" is="" also="" proposing="" the="" following:="" change="" the="" heading="" from="" ``indication''="" to="" ``indications;''="" add="" the="" subheadings,="" ``recurrent="" mi="" (reinfarction)="" or="" unstable="" angina="" pectoris''="" and="" ``suspected="" acute="" mi,''="" under="" the="" headings="" ``indications,''="" ``clinical="" trials,''="" and="" ``dosage="" and="" administration;''="" revise="" the="" text="" under="" ``gastrointestinal="" reactions''="" and="" change="" from="" 300="" mg="" aspirin="" to="" 160="" mg="" aspirin="" daily="" the="" dosage="" level="" at="" which="" subjects="" should="" have="" biochemical="" measurements="" assessed;="" add="" a="" subheading,="" ``bleeding,''="" under="" the="" heading="" ``adverse="" reactions''="" (after="" ``gastrointestinal="" reactions'');="" renumber="" existing="" reference="" (8)="" as="" reference="" (9);="" and="" add="" a="" new="" reference="" (8).="" 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="" no.="" cp9,="" docket="" no.="" 77n-0094,="" dockets="" management="" branch.="" (2)="" comment="" no.="" cp10,="" docket="" no="" 77n-0094,="" dockets="" management="" branch.="" (3)="" 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.="" (4)="" risc="" group,="" ``risk="" of="" myocardial="" infarction="" and="" death="" during="" treatment="" with="" low="" dose="" aspirin="" and="" intravenous="" heparin="" in="" men="" with="" unstable="" coronary="" artery="" disease,''="" lancet,="" 336:827-830,="" 1990.="" (5)-="" verheugt,="" f.="" w.="" et="" al.,="" ``effects="" of="" early="" intervention="" with="" low-dose="" aspirin="" (100="" mg)="" on="" infarct="" size,="" reinfarction="" and="" mortality="" in="" anterior="" wall="" acute="" myocardial="" infarction,''="" american="" journal="" of="" cardiology,="" 66:267-270,="" 1990.="" (6)-="" hays,="" l.="" j.="" et="" al.,="" ``short-term="" infarct="" vessel="" patency="" with="" aspirin="" and="" dipyridamole="" started="" 24="" to="" 36="" hours="" after="" intravenous="" streptokinase,''="" american="" heart="" journal,="" 115:717-721,="" 1988.="" (7)="" 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.="" (8)="" elwood,="" p.="" c.,="" and="" w.="" o.="" williams,="" ``a="" randomized="" controlled="" trial="" of="" aspirin="" in="" the="" prevention="" of="" early="" mortality="" in="" myocardial="" infarction,''="" journal="" of="" the="" royal="" college="" of="" general="" practitioners,="" 29:413-416,="" 1979.="" (9)="" husted,="" s.="" e.="" et="" al.,="" ``acetylsalicylic="" acid="" 100="" mg="" and="" 1,000="" mg="" daily="" in="" acute="" myocardial="" infarction="" suspects:="" a="" placebo-="" controlled="" trial,''="" journal="" of="" internal="" medicine,="" 226:303-310,="" 1989.="" v.="" enforcement="" policy="" the="" agency="" is="" allowing="" the="" proposed="" professional="" labeling="" to="" be="" used="" prior="" to="" the="" completion="" of="" a="" final="" rule="" for="" otc="" internal="" analgesic,="" antipyretic,="" and="" antirheumatic="" drug="" products.="" this="" decision="" is="" based="" on="" the="" substantial="" data="" [[page="" 30007]]="" supporting="" the="" safety="" and="" effectiveness="" of="" aspirin="" for="" suspected="" acute="" mi="" and="" on="" the="" importance="" of="" early="" dissemination="" of="" this="" information="" to="" health="" professionals.="" manufacturers="" who="" disseminate="" this="" information="" must="" use="" the="" exact="" professional="" labeling="" set="" forth="" in="" this="" proposal.="" such="" labeling="" may="" be="" disseminated="" pending="" issuance="" of="" a="" final="" rule,="" subject="" to="" the="" risk="" that="" the="" agency="" may,="" in="" the="" final="" rule,="" adopt="" a="" different="" position="" that="" could="" require="" relabeling,="" recall,="" or="" other="" regulatory="" action.="" those="" manufacturers="" who="" do="" not="" wish="" to="" revise="" the="" professional="" labeling="" in="" accordance="" with="" this="" proposal="" may="" continue="" to="" disseminate="" the="" labeling="" proposed="" in="" the="" 1988="" tfm="" (53="" fr="" 46204="" at="" 46258="" through="" 46260)="" until="" a="" final="" rule="" becomes="" effective.="" dissemination="" of="" professional="" labeling="" that="" is="" not="" in="" accord="" with="" the="" labeling="" in="" the="" 1988="" tfm="" or="" with="" this="" proposed="" amendment="" to="" the="" 1988="" tfm="" may="" result="" in="" regulatory="" action="" against="" the="" product,="" the="" marketer,="" or="" both.="" vi.="" analysis="" of="" impacts="" fda="" has="" examined="" the="" impacts="" of="" the="" proposed="" rule="" under="" executive="" order="" 12866="" and="" the="" regulatory="" flexibility="" act="" (pub.="" l.="" 96-354).="" 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="" proposed="" rule="" is="" consistent="" with="" the="" regulatory="" philosophy="" and="" principles="" identified="" in="" the="" executive="" order.="" in="" addition,="" the="" proposed="" rule="" is="" not="" a="" significant="" regulatory="" action="" as="" defined="" by="" the="" executive="" order="" and="" so="" is="" not="" subject="" to="" review="" under="" the="" executive="" order.="" the="" regulatory="" flexibility="" act="" requires="" agencies="" to="" analyze="" regulatory="" options="" that="" would="" minimize="" any="" significant="" impact="" of="" a="" rule="" on="" small="" entities.="" if="" this="" proposed="" rule="" becomes="" a="" final="" rule,="" direct="" one-time="" costs="" associated="" with="" changing="" professional="" labeling="" will="" be="" imposed.="" that="" cost="" is="" estimated="" to="" be="" less="" than="" $1="" million.="" also,="" there="" appears="" to="" be="" a="" limited="" number="" of="" aspirin="" products="" involved="" because="" many="" manufacturers="" of="" these="" products="" do="" not="" distribute="" professional="" labeling="" for="" their="" products.="" manufacturers="" who="" do="" distribute="" such="" professional="" labeling="" will="" have="" an="" additional="" claim="" to="" make="" for="" their="" product(s)="" and="" will="" have="" 1="" year="" after="" publication="" of="" the="" final="" rule="" to="" implement="" this="" relabeling.="" accordingly,="" the="" agency="" certifies="" that="" the="" proposed="" 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.="" the="" agency="" invites="" public="" comment="" regarding="" any="" substantial="" or="" significant="" economic="" impact="" that="" this="" rulemaking="" would="" have="" on="" the="" professional="" labeling="" of="" otc="" internal="" analgesic,="" antipyretic,="" and="" antirheumatic="" drug="" products="" that="" contain="" aspirin,="" buffered="" aspirin,="" or="" aspirin="" in="" combination="" with="" antacid.="" types="" of="" impact="" may="" include,="" but="" are="" not="" limited="" to,="" costs="" associated="" with="" relabeling.="" comments="" regarding="" the="" impact="" of="" this="" rulemaking="" on="" these="" otc="" drug="" products="" should="" be="" accompanied="" by="" appropriate="" documentation.="" the="" agency="" will="" evaluate="" any="" comments="" and="" supporting="" data="" that="" are="" received="" and="" will="" reassess="" the="" economic="" impact="" of="" this="" rulemaking="" in="" the="" preamble="" to="" the="" final="" rule.="" vii.="" paperwork="" reduction="" act="" of="" 1995="" fda="" tentatively="" concludes="" that="" the="" labeling="" requirements="" proposed="" in="" this="" document="" 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="" proposed="" 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)).="" viii.="" 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.="" ix.="" request="" for="" comments="" interested="" persons="" may,="" on="" or="" before="" september="" 11,="" 1996,="" submit="" to="" the="" dockets="" management="" branch="" (address="" above)="" written="" comments="" regarding="" this="" proposal.="" written="" comments="" on="" the="" agency's="" economic="" impact="" determination="" may="" be="" submitted="" on="" or="" before="" september="" 11,="" 1996.="" three="" copies="" of="" all="" comments="" are="" to="" be="" submitted,="" except="" that="" individuals="" may="" submit="" one="" copy.="" comments="" are="" to="" be="" identified="" with="" the="" docket="" number="" found="" in="" brackets="" in="" the="" heading="" of="" this="" document="" and="" may="" be="" accompanied="" by="" a="" supporting="" memorandum="" or="" brief.="" received="" comments="" may="" be="" seen="" in="" the="" office="" above="" between="" 9="" a.m.="" and="" 4="" p.m.,="" monday="" through="" friday.="" 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,="" it="" is="" proposed="" that="" 21="" cfr="" part="" 343="" (proposed="" in="" the="" federal="" register="" of="" november="" 16,="" 1988,="" 53="" fr="" 46204)="" be="" amended="" as="" follows:="" part="" 343--internal="" analgesic,="" antipyretic,="" and="" antirheumatic="" drug="" products="" for="" over-the-counter="" human="" use="" 1.="" the="" authority="" citation="" for="" 21="" cfr="" part="" 343="" continues="" to="" read="" as="" follows:="" -authority:="" secs.="" 201,="" 501,="" 502,="" 503,="" 505,="" 510,="" 701="" of="" the="" federal="" food,="" drug,="" and="" cosmetic="" act="" (21="" u.s.c.="" 321,="" 351,="" 352,="" 353,="" 355,="" 360,="" 371).="" 2.="" section="" 343.80="" is="" amended="" by="" revising="" paragraph="" (c)="" to="" read="" as="" follows:="" sec.="" 343.80="" professional="" labeling.="" *="" *="" *="" *="" *-="" (c)="" for="" products="" containing="" aspirin="" identified="" in="" sec.="" 343.10(b)="" or="" permitted="" combinations="" identified="" in="" sec.="" 343.20(b)(3).="" the="" labeling="" states,="" under="" the="" heading="" ``aspirin="" for="" myocardial="" infarction,''="" the="" following:="" indications:="" recurrent="" myocardial="" infarction="" (mi)="" (reinfarction)="" or="" unstable="" angina="" pectoris="" aspirin="" is="" indicated="" to="" reduce="" the="" risk="" of="" death="" and/or="" nonfatal="" mi="" in="" patients="" with="" a="" previous="" mi="" or="" unstable="" angina="" pectoris.="" suspected="" acute="" mi="" aspirin="" is="" indicated="" to="" reduce="" the="" risk="" of="" vascular="" mortality="" in="" patients="" with="" a="" suspected="" acute="" mi.="" clinical="" trials:="" recurrent="" mi="" (reinfarction)="" and="" unstable="" angina="" pectoris="" the="" indication="" is="" supported="" by="" the="" results="" of="" six="" large,="" randomized="" multicenter,="" placebo-controlled="" studies="" involving="" 10,816,="" predominantly="" male,="" post-mi="" subjects="" and="" one="" randomized="" placebo-="" controlled="" study="" of="" 1,266="" men="" with="" unstable="" angina="" (1-7).="" therapy="" with="" aspirin="" was="" begun="" at="" intervals="" after="" the="" onset="" of="" acute="" mi="" varying="" from="" less="" than="" 3="" days="" to="" more="" than="" 5="" years="" and="" continued="" for="" periods="" of="" from="" less="" than="" 1="" year="" to="" 4="" years.="" in="" the="" unstable="" angina="" study,="" treatment="" was="" started="" within="" 1="" month="" after="" the="" onset="" of="" unstable="" angina="" and="" continued="" for="" 12="" weeks,="" and="" patients="" with="" complicating="" conditions="" such="" as="" congestive="" heart="" failure="" were="" not="" included="" in="" the="" study.="" aspirin="" therapy="" in="" mi="" subjects="" was="" associated="" with="" about="" a="" 20-="" percent="" reduction="" in="" the="" risk="" of="" subsequent="" death="" and/or="" nonfatal="" reinfarction,="" a="" median="" absolute="" decrease="" of="" 3="" percent="" from="" the="" 12-="" to="" 22-percent="" event="" rates="" in="" the="" placebo="" groups.="" in="" aspirin-treated="" unstable="" angina="" patients="" the="" reduction="" in="" risk="" was="" about="" 50="" percent,="" a="" [[page="" 30008]]="" reduction="" in="" the="" event="" rate="" of="" 5-percent="" from="" the="" 10-percent="" rate="" in="" the="" placebo="" group="" over="" the="" 12-weeks="" of="" the="" study.="" daily="" dosage="" of="" aspirin="" in="" the="" post-mi="" studies="" was="" 300="" milligrams="" in="" one="" study="" and="" 900="" to="" 1,500="" milligrams="" in="" five="" studies.="" a="" dose="" of="" 325="" milligrams="" was="" used="" in="" the="" study="" of="" unstable="" angina.="" suspected="" acute="" mi="" the="" use="" of="" aspirin="" in="" patients="" with="" a="" suspected="" acute="" mi="" is="" supported="" by="" the="" results="" of="" a="" large,="" multicenter="" 2="" x="" 2="" factorial="" study="" of="" 17,187="" subjects="" with="" suspected="" acute="" mi="" (8).="" subjects="" were="" randomized="" within="" 24="" hours="" of="" the="" onset="" of="" symptoms="" so="" that="" 8,587="" subjects="" received="" oral="" aspirin="" (162.5="" milligrams,="" enteric-coated)="" daily="" for="" 1="" month="" (the="" first="" dose="" crushed,="" sucked,="" or="" chewed)="" and="" 8,600="" received="" oral="" placebo.="" of="" the="" subjects,="" 8,592="" were="" also="" randomized="" to="" receive="" a="" single="" dose="" of="" streptokinase="" (1.5="" million="" units)="" infused="" intravenously="" for="" about="" 1="" hour,="" and="" 8,595="" received="" a="" placebo="" infusion.="" thus,="" 4,295="" subjects="" received="" aspirin="" plus="" placebo,="" 4,300="" received="" streptokinase="" plus="" placebo,="" 4,292="" received="" aspirin="" plus="" streptokinase,="" and="" 4,300="" received="" double="" placebo.="" vascular="" mortality="" (attributed="" to="" cardiac,="" cerebral,="" hemorrhagic,="" other="" vascular,="" or="" unknown="" causes)="" occurred="" in="" 9.4="" percent="" of="" the="" subjects="" in="" the="" aspirin="" group="" and="" in="" 11.8="" percent="" of="" the="" subjects="" in="" the="" oral="" placebo="" group="" in="" the="" 35-day="" followup.="" this="" represents="" an="" absolute="" reduction="" of="" 2.4="" percent="" in="" the="" mean="" 35-day="" vascular="" mortality="" attributable="" to="" aspirin="" and="" a="" 23-percent="" reduction="" in="" the="" odds="" of="" vascular="" death="" (2p="">< 0.00001).="" significant="" absolute="" reductions="" in="" mortality="" and="" corresponding="" reductions="" in="" specific="" clinical="" events="" favoring="" aspirin="" were="" found="" for="" reinfarction="" (1.5="" percent="" absolute="" reduction,="" 45="" percent="" odds="" reduction,="" 2p="">< 0.00001),="" cardiac="" arrest="" (1.2="" percent="" absolute="" reduction,="" 14.2="" percent="" odds="" reduction,="" 2p="">< 0.01),="" and="" total="" stroke="" (0.4="" percent="" absolute="" reduction,="" 41.5="" percent="" odds="" reduction,="" 2p="">< 0.01).="" the="" effect="" of="" aspirin="" over="" and="" above="" its="" effect="" on="" mortality="" was="" evidenced="" by="" small,="" but="" significant,="" reductions="" in="" vascular="" morbidity="" in="" those="" subjects="" who="" were="" discharged.="" the="" beneficial="" effects="" of="" aspirin="" on="" mortality="" were="" present="" with="" or="" without="" streptokinase="" infusion.="" aspirin="" reduced="" vascular="" mortality="" from="" 10.4="" to="" 8.0="" percent="" for="" days="" 0="" to="" 35="" in="" subjects="" given="" streptokinase="" and="" reduced="" vascular="" mortality="" from="" 13.2="" to="" 10.7="" percent="" in="" subjects="" given="" no="" streptokinase.="" the="" effects="" of="" aspirin="" and="" thrombolytic="" therapy="" with="" streptokinase="" in="" this="" study="" were="" approximately="" additive.="" subjects="" who="" received="" the="" combination="" of="" streptokinase="" infusion="" and="" daily="" aspirin="" had="" significantly="" lower="" vascular="" mortality="" at="" 35="" days="" than="" those="" who="" received="" either="" active="" treatment="" alone="" (combination="" 8.0="" percent,="" aspirin="" 10.7="" percent,="" streptokinase="" 10.4="" percent,="" and="" no="" treatment="" 13.2="" percent).="" while="" this="" study="" demonstrated="" that="" aspirin="" has="" an="" additive="" benefit="" in="" patients="" given="" streptokinase,="" there="" is="" no="" reason="" to="" restrict="" its="" use="" to="" that="" specific="" thrombolytic.="" adverse="" reactions:="" gastrointestinal="" reactions="" doses="" of="" 1,000="" milligrams="" per="" day="" of="" aspirin="" caused="" gastrointestinal="" symptoms="" and="" bleeding="" that="" in="" some="" cases="" were="" clinically="" significant.="" in="" the="" aspirin="" myocardial="" infarction="" study="" (amis)="" (4)="" with="" 4,500="" post-infarction="" subjects,="" the="" percentage="" incidences="" of="" gastrointestinal="" symptoms="" for="" the="" aspirin="" (1,000="" milligrams="" of="" a="" standard,="" solid-tablet="" formulation)="" and="" placebo-="" treated="" subjects,="" respectively,="" were:="" stomach="" pain="" (14.5="" percent,="" 4.4="" percent);="" heartburn="" (11.9="" percent,="" 4.8="" percent);="" nausea="" and/or="" vomiting="" (7.6="" percent,="" 2.1="" percent);="" hospitalization="" for="" gastrointestinal="" disorder="" (4.8="" percent,="" 3.5="" percent).="" symptoms="" and="" signs="" of="" gastrointestinal="" irritation="" were="" not="" significantly="" increased="" in="" subjects="" treated="" for="" unstable="" angina="" with="" 325="" milligrams="" buffered="" aspirin="" in="" solution.="" bleeding="" in="" the="" amis="" and="" other="" trials,="" aspirin-treated="" subjects="" had="" increased="" rates="" of="" gross="" gastrointestinal="" bleeding.="" in="" the="" isis-2="" study="" (8),="" there="" was="" no="" significant="" difference="" in="" the="" incidence="" of="" major="" bleeding="" (bleeds="" requiring="" transfusion)="" between="" 8,587="" subjects="" taking="" 162.5="" milligrams="" aspirin="" daily="" and="" 8,600="" subjects="" taking="" placebo="" (31="" versus="" 33="" subjects).="" there="" were="" five="" confirmed="" cerebral="" hemorrhages="" in="" the="" aspirin="" group="" compared="" with="" two="" in="" the="" placebo="" group,="" but="" the="" incidence="" of="" stroke="" of="" all="" causes="" was="" significantly="" reduced="" from="" 81="" to="" 47="" for="" the="" placebo="" versus="" aspirin="" group="" (0.4="" percent="" absolute="" change).="" there="" was="" a="" small="" and="" statistically="" significant="" excess="" (0.6="" percent)="" of="" minor="" bleeding="" in="" people="" taking="" aspirin="" (2.5="" percent="" for="" aspirin,="" 1.9="" percent="" for="" placebo).="" no="" other="" significant="" adverse="" effects="" were="" reported.-="" (other="" applicable="" warnings="" related="" to="" the="" use="" of="" aspirin="" as="" described="" in="" sec.="" 343.50(c)="" may="" also="" be="" included="" here.)="" cardiovascular="" and="" biochemical="" in="" the="" amis="" trial="" (4),="" the="" dosage="" of="" 1,000="" milligrams="" per="" day="" of="" aspirin="" was="" associated="" with="" small="" increases="" in="" systolic="" blood="" pressure="" (bp)="" (average="" 1.5="" to="" 2.1="" millimeters="" hg)="" and="" diastolic="" bp="" (0.5="" to="" 0.6="" millimeters="" hg),="" depending="" upon="" whether="" maximal="" or="" last="" available="" readings="" were="" used.="" blood="" urea="" nitrogen="" and="" uric="" acid="" levels="" were="" also="" increased,="" but="" by="" less="" than="" 1.0="" milligram="" percent.="" subjects="" with="" marked="" hypertension="" or="" renal="" insufficiency="" had="" been="" excluded="" from="" the="" trial="" so="" that="" the="" clinical="" importance="" of="" these="" observations="" for="" such="" subjects="" or="" for="" any="" subjects="" treated="" over="" more="" prolonged="" periods="" is="" not="" known.="" it="" is="" recommended="" that="" patients="" placed="" on="" long-term="" aspirin="" treatment,="" even="" at="" doses="" of="" 160="" milligrams="" per="" day,="" be="" seen="" at="" regular="" intervals="" to="" assess="" changes="" in="" these="" measurements.="" sodium="" in="" buffered="" aspirin="" for="" solution="" formulations:="" one="" tablet="" daily="" of="" buffered="" aspirin="" in="" solution="" adds="" 553="" milligrams="" of="" sodium="" to="" that="" in="" the="" diet="" and="" may="" not="" be="" tolerated="" by="" patients="" with="" active="" sodium-retaining="" states="" such="" as="" congestive="" heart="" or="" renal="" failure.="" this="" amount="" of="" sodium="" adds="" about="" 30="" percent="" to="" the="" 70-="" to="" 90-milliequivalent="" intake="" suggested="" as="" appropriate="" for="" dietary="" treatment="" of="" essential="" hypertension="" in="" the="" ``1984="" report="" of="" the="" joint="" national="" committee="" on="" detection,="" evaluation,="" and="" treatment="" of="" high="" blood="" pressure''="" (9).="" dosage="" and="" administration:="" recurrent="" mi="" (reinfarction)="" and="" unstable="" angina="" pectoris="" although="" most="" of="" the="" studies="" used="" dosages="" exceeding="" 300="" milligrams,="" two="" trials="" used="" only="" 300="" milligrams,="" and="" pharmacologic="" data="" indicate="" that="" this="" dose="" inhibits="" platelet="" function="" fully.="" therefore,="" 300="" milligrams="" or="" a="" conventional="" 325="" milligram="" aspirin="" dose="" is="" a="" reasonable,="" routine="" dose="" that="" would="" minimize="" gastrointestinal="" adverse="" reactions.="" this="" use="" of="" aspirin="" applies="" to="" both="" solid,="" oral="" dosage="" forms="" (buffered="" and="" plain="" aspirin)="" and="" buffered="" aspirin="" in="" solution.="" suspected="" acute="" mi="" the="" recommended="" dose="" of="" aspirin="" to="" treat="" suspected="" acute="" mi="" is="" 160="" to="" 162.5="" milligrams="" taken="" as="" soon="" as="" the="" infarct="" is="" suspected="" and="" then="" daily="" for="" at="" least="" 30="" days.="" (one-half="" of="" a="" conventional="" 325-milligram="" aspirin="" tablet="" or="" two="" 80-="" or="" 81-milligram="" aspirin="" tablets="" may="" be="" taken.)="" this="" use="" of="" aspirin="" applies="" to="" both="" solid,="" oral="" dosage="" forms="" (buffered,="" plain,="" and="" enteric-coated="" aspirin)="" and="" buffered="" aspirin="" in="" solution.="" if="" using="" a="" solid="" dosage="" form,="" the="" first="" dose="" should="" be="" crushed,="" sucked,="" or="" chewed.="" after="" the="" 30-day="" treatment,="" physicians="" should="" consider="" further="" therapy="" based="" on="" the="" labeling="" for="" dosage="" and="" administration="" of="" aspirin="" for="" prevention="" of="" recurrent="" mi="" (reinfarction).="" (1)="" elwood,="" p.="" c.="" et="" al.,="" ``a="" randomized="" controlled="" trial="" of="" acetylsalicylic="" acid="" in="" the="" secondary="" prevention="" of="" mortality="" from="" myocardial="" infarction,''="" british="" medical="" journal,="" 1:436-440,="" 1974.="" (2)="" the="" coronary="" drug="" project="" research="" group,="" ``aspirin="" in="" coronary="" heart="" disease,''="" journal="" of="" chronic="" diseases,="" 29:625-642,="" 1976.="" (3)="" breddin,="" k.="" et="" al.,="" ``secondary="" prevention="" of="" myocardial="" infarction:="" a="" comparison="" of="" acetylsalicylic="" acid,="" phenprocoumon="" or="" placebo,''="" homeostasis,="" 470:263-268,="" 1979.="" (4)="" aspirin="" myocardial="" infarction="" study="" research="" group,="" ``a="" randomized,="" controlled="" trial="" of="" aspirin="" in="" persons="" recovered="" from="" myocardial="" infarction,''="" journal="" of="" the="" american="" medical="" association,="" 243:661-669,="" 1980.="" (5)="" elwood,="" p.="" c.,="" and="" p.="" m.="" sweetnam,="" ``aspirin="" and="" secondary="" mortality="" after="" myocardial="" infarction,''="" lancet,="" ii:1313-1315,="" december="" 22-29,="" 1979.="" (6)="" the="" persantine-aspirin="" reinfarction="" study="" research="" group,="" ``persantine="" and="" aspirin="" in="" coronary="" heart="" disease,''="" circulation,="" 62:449-461,="" 1980.="" (7)="" lewis,="" h.="" d.="" et="" al.,="" ``protective="" effects="" of="" aspirin="" against="" acute="" myocardial="" infarction="" and="" death="" in="" men="" with="" unstable="" angina,="" results="" of="" a="" veterans="" administration="" cooperative="" study,''="" new="" england="" journal="" of="" medicine,="" 309:396-403,="" 1983.="" (8)="" 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,="" august="" 13,="" 1988.="" [[page="" 30009]]="" (9)="" ``1984="" report="" of="" the="" joint="" national="" committee="" on="" detection,="" evaluation,="" and="" treatment="" of="" high="" blood="" pressure,''="" united="" states="" department="" of="" health="" and="" human="" services="" and="" united="" states="" public="" health="" service,="" national="" institutes="" of="" health,="" publication="" no.="" nih="" 84-1088,="" 1984.="" dated:="" june="" 5,="" 1996.="" william="" k.="" hubbard,="" associate="" commissioner="" for="" policy="" coordination.="" [fr="" doc.="" 96-14894="" filed="" 6-12-96;="" 8:45="" am]="" billing="" code="" 4160-01-f="">