96-14894. Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Proposed Amendment to the Tentative Final Monograph  

  • [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
    
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    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="">

Document Information

Published:
06/13/1996
Department:
Food and Drug Administration
Entry Type:
Proposed Rule
Action:
Notice of proposed rulemaking.
Document Number:
96-14894
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.
Pages:
30001-30009 (9 pages)
Docket Numbers:
Docket No. 77N-094A
RINs:
0910-AA01: Over-the-Counter (OTC) Drug Review
RIN Links:
https://www.federalregister.gov/regulations/0910-AA01/over-the-counter-otc-drug-review
PDF File:
96-14894.pdf
CFR: (2)
21 CFR 343.80(c)
21 CFR 343.80