[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]



=======================================================================
-----------------------------------------------------------------------

[[Page 30002]]

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.

-----------------------------------------------------------------------

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       
                                                                                                    (2p<0.00001)
                                                                                                                
A/P                             461/4,295                              10.7                                     
vs                                                                                                              
P/P                             568/4,300                              13.2            -2.5-      21 (2p<0.001) 
                                                                                                                
A/S                             343/4,292                               8.0                                     
vs                                                                                                              
P/S                             448/4,300                              10.4            -2.4       25 (2p<0.001) 
                                                                                                                
A/S                             343/4,292                               8.0                                     
vs                                                                                                              
P/P                             568/4,300                              13.2            -5.2-           42       
                                                                                                    (2p<0.00001)
                                                                                                                
A/S                             343/4,292                               8.0                                     
vs                                                                                                              
A/P                             461/4,295                              10.7            -2.7-      28 (2p<0.0001)
                                                                                                                
P/S                             448/4,300                              10.4                                     
vs                                                                                                              
P/P-                            568/4,300                              13.2            -2.8       23 (2p<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       
                                                                                                    (2p<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 
<plus-minus> 782 versus 1,592 <plus-minus> 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