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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 343

[Docket No. 77N-094A]

RIN 0910-AA01

Internal Analgesic, Antipyretic, and Antirheumatic Drug Products

for Over-The-Counter Human Use; Final Rule for Professional Labeling of

Aspirin, Buffered Aspirin, and Aspirin in Combination With Antacid Drug

Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing as a final

rule professional labeling for over-the-counter (OTC) internal

analgesic, antipyretic, and antirheumatic drug products containing

aspirin, buffered aspirin, and aspirin in combination with an antacid.

This portion of the final monograph is being issued prior to the entire

monograph so that the professional labeling of these products will

reflect the latest information on cardiovascular, cerebrovascular, and

rheumatologic uses. FDA is issuing this final rule after considering

comments on the agency's proposed regulation for OTC internal

analgesic, antipyretic, and antirheumatic drug products, a proposed

amendment to the regulation, and data and information that have come to

the agency's attention.

EFFECTIVE DATE: October 25, 1999.

FOR FURTHER INFORMATION CONTACT: Ida I. Yoder, Center for Drug

Evaluation and Research (HFD-560), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of November 16, 1988 (53 FR 46204), FDA

published, under 21 CFR 330.10(a)(7), a notice of proposed rulemaking,

in the form of a tentative final monograph (TFM), that would establish

conditions in part 343 (21 CFR part 343) under which OTC internal

analgesic, antipyretic, and antirheumatic drug products are generally

recognized as safe and effective and not misbranded. In the TFM (53 FR

46204 at 46258 and 46259), the agency proposed professional labeling in

Sec. 343.80 for the use of aspirin for rheumatologic diseases, for

reducing the risk of recurrent transient ischemic attacks (TIA's) or

stroke in men who have had transient ischemia of the brain due to

fibrin platelet emboli, and for reducing the risk of death and/or

nonfatal myocardial infarction (MI) in patients with a previous

infarction or unstable angina pectoris. The agency also proposed

professional labeling for the use of carbaspirin calcium, choline

salicylate, magnesium salicylate, or sodium salicylate for

rheumatologic diseases. Interested persons were invited to submit new

data or file written comments, objections, or requests for oral hearing

before the Commissioner of Food and Drugs regarding the proposal.

In response to the TFM, the agency received four comments and three

citizen petitions related to the professional labeling of aspirin for

cardiovascular and cerebrovascular uses (Ref. 1). No comments were

received on the professional use of aspirin drug products for

rheumatologic diseases. In response to two of the petitions, the agency

proposed to amend the professional labeling section of the TFM for OTC

internal analgesic, antipyretic, and antirheumatic drug products to

include an indication for aspirin for suspected acute MI (61 FR 30002,

June 13, 1996). In response to the proposed amendment, the agency

received 10 comments (Ref. 2).

In the TFM for OTC internal analgesic, antipyretic, and

antirheumatic drug products (53 FR 46204 at 46205), and in the proposed

amendment to the TFM (61 FR 30002), the agency proposed that any final

rule that may issue based on the proposal will be effective 12 months

after the date of publication in the Federal Register. Therefore, on or

after October 25, 1998, the dissemination of professional labeling that

does not comply with this final rule may result in regulatory action

against the product, the marketer, or both. Manufacturers are

encouraged to comply voluntarily with this final rule at the earliest

possible date.

The labeling in this final rule for professional use of aspirin

drug products contains complete information on certain professional

uses of aspirin, including information for professionals on the

treatment of the signs and symptoms of rheumatologic disease. The

labeling is organized and presented in a manner similar to that

required of prescription drug products under Secs. 201.56 and 201.57

(21 CFR 201.56 and 201.57). The labeling in this final rule also

includes an optional highlights section that summarizes the

professional indications and the recommended dosage and

[[Page 56803]]

administration for each professional indication.

II. The Agency's Conclusions on the Comments

A. Comments to the TFM

1. One comment requested that aspirin be approved for use as a

prophylaxis for primary (first) MI under a physician's supervision. The

comment based its request on the preliminary report of a large, highly

statistically significant, reduction (47 percent) in the risk of total

(fatal and nonfatal) MI in subjects taking aspirin in the U.S.

Physicians' Health Study (Ref. 3). A final report was published later

(Ref. 4).

The agency also considered the British Doctors Study, by Peto et

al. (Ref. 5), that was similar in many respects to the U.S. Physicians'

Health Study. It randomized 5,139 apparently healthy male doctors, to

500 milligrams (mg) aspirin daily, or to no aspirin, to see whether

aspirin would reduce the incidence of, and mortality from, stroke, MI,

or other vascular conditions. The British Doctors Study, despite its

similarity to the U.S. Physicians' Health Study, does not support the

use of aspirin to prevent an initial MI. After 6 years of followup,

there were 23.5 confirmed nonfatal MI reports per 1,000 participants in

the aspirin group and 24 per 1,000 in the no-aspirin group. When

possible MI reports were added, the total was 30 per 1,000 for the

aspirin group and 26.4 per 1,000 for the no-aspirin group. From a

safety viewpoint, disabling stroke was significantly more frequent in

the aspirin group than the no-aspirin group (19.1 versus 7.4 per 10,000

man years, p 0.50). This analysis could be considered

a ``worst case'' analysis of the fatal MI finding, but it illustrates

the difficulty of cause-specific mortality findings.

The agency also does not believe the reported 18 percent reduction

in the endpoint of nonfatal MI, nonfatal stroke, and total

cardiovascular mortality can be taken as significant. For the combined

endpoint, there were 307 subjects in the aspirin group and 370 in the

placebo group (relative risk 0.82; p = 0.01). The reported p value of

0.01 is well above the stopping rule p value of 0.0027. Therefore, the

study did not provide persuasive evidence that aspirin has a beneficial

effect on the combined endpoint. In addition, the isolated finding of a

statistically significant effect on nonfatal MI is not persuasive. Of

note is the fact that the British Doctors Study completely failed to

replicate this finding.

The reduction in incidence of fatal and nonfatal MI was also

accompanied by an increase in strokes, especially severe, fatal,

hemorrhagic stroke, and by a greater incidence of sudden death and

``other'' cardiovascular deaths. Thus, there was no overall benefit or

favorable trend on mortality. Cerebral hemorrhage as a cause of stroke

was reported more often in the aspirin group than in the placebo group

(23 versus 12). The incidence of ulcers, ``other noninfectious diseases

of the digestive tract,'' bleeding problems, and the need for

transfusion, also was significantly increased, and one aspirin subject

died from GI bleeding. Although these side effects would not prevent

the use of aspirin if its net benefit on coronary artery and

cerebrovascular events were favorable, the effects are not trivial.

It seems probable that the net benefit of aspirin is critically

dependent on the underlying risk for coronary and cerebral events, and

that use of aspirin requires knowing more about its effects in various

populations. In people at low risk for acute MI, the increased risk of

stroke may result in a net disadvantage. In at least some people at

higher risk (people who have had an acute MI or have TIA's), aspirin is

known to provide a net benefit. There may be other populations in whom

the net effect of aspirin is favorable, but the U.S. Physicians' Health

Study does not define such groups. The investigators did not identify

any group in which aspirin could reduce the incidence of fatal and

nonfatal heart attack without increasing the incidence of other causes

of death or disability.

The Steering Committee of the U.S. Physicians' Health Study

Research Group (Ref. 4) suggested that aspirin is beneficial in

prevention of the first heart attack (at least in men over 50), but

stated: ``Although the short-term benefit of aspirin in these

populations appears to outweigh its risks, the long-term advantage and

toxicity of the drug remain uncertain.'' In a more recent review

article (Ref. 6) by several members of the U.S. Physicians' Health

Study Research Group, members of the Steering Committee, and others,

concerning primary prevention of MI, the authors concluded the

following: ``Any decision to use aspirin prophylaxis should be made on

an individual basis and, in general, should be considered only for

those whose absolute risk of a first MI is sufficiently high to warrant

accepting the potential adverse effects of long-term aspirin use.''

In summary, the U.S. Physicians' Health Study failed to show a

significant effect, or even a beneficial trend, on the specified

primary study endpoint of total cardiovascular mortality. The study was

stopped early and multiple secondary endpoints were evaluated. The

effects of aspirin on fatal acute MI and on the combined endpoint of

nonfatal MI, nonfatal stroke, and total cardiovascular mortality were

not statistically significant when adjustments were made for early

stopping. There was an isolated finding of a statistically significant

effect on nonfatal MI (a secondary endpoint), but the value of this

finding is questionable in the face of adverse trends on stroke and

causes of death other than acute MI. Of note is the fact that the

British Doctors Study completely failed to replicate this finding on

nonfatal MI. Thus, the agency concludes that the available data do not

support the professional labeling of aspirin for the prevention of

first MI. The U.S. Physicians' Health Study (Refs. 3 and 4), in

particular, did not show a statistically significant effect when all

deaths as well as nonfatal MI and stroke were combined.

2. One comment asked that the professional labeling in proposed

Sec. 343.80(b) for aspirin for TIA include both men and women, not just

men. The comment cited results from the Second International Study of

Infarct Survival (ISIS-2) (Ref. 7), based on an analysis of a subset of

data for men and women separately, to support its request. The absolute

decrease in mortality for the aspirin group compared to placebo was 2.4

percent for men and 2.6 percent for women. The comment concluded that

this study showed that, up to 5 weeks, mortality was significantly

reduced (p 2 TIA's within 1 week, necessitating change in therapy 101 128

[[Page 56807]]

MI (fatal and nonfatal) 54 68

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Log-rank analysis of stroke-free survival showed that aspirin was

significantly superior to placebo (p = 0.02). Analysis of the same

outcomes by ``accumulated number of events''during the followup period

showed a significant (p = 0.05) risk reduction of 18 percent (relative

risk 0.82, 95 percent confidence interval 0.67 to 0.99) for nonfatal

stroke or death. The risk reduction was similar in men and women (19

percent and 17 percent, respectively). More deaths were attributed to

nonstroke events than to stroke in both the aspirin and placebo arms.

Most of the nonstroke deaths in this study were attributed to MI, other

vascular deaths, and malignant disorders. Fatal hemorrhagic stroke

occurred in six subjects in the aspirin group and none in the placebo

group (p = 0.03). Overall, more adverse effects were reported in the

aspirin group than in the placebo group, particularly bleeding events

(see Table 2 of this document).

Table 2.--Adverse Effects of Aspirin in the SALT Study

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Number (%) of Subjects

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Aspirin Placebo

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Gastrointestinal (excluding bleeding)

Total 85 (12.5) 73 (10.7)

Severe or causing discontinuation of study drug 21 (3.1) 18 (2.6)

Bleeding

Total 49 (7.2) 22 (3.2)

Gastrointestinal 11 (1.6) 4 (0.6)

Intracranial 10 (1.5) 3 (0.4)

Other 28 (4.1) 15 (2.2)

Severe bleeding, or causing discontinuation of study drug 20 (3.0) 9 (1.3)

Gastrointestinal 9 (1.3) 4 (0.6)

Intracranial 10 (1.5) 3 (0.4)

Other 1 (0.1) 2 (0.3)

Other adverse effects

Total 31 (4.6) 42 (6.1)

Severe, or causing discontinuation of study drug 9 (1.3) 11 (1.6)

Total number of subjects with adverse effects1 147 (21.7) 123 (18.0)

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\1\ Some subjects had more than one adverse effect.

The SALT study (Ref. 22) is generally a well-controlled and

carefully done study that supports the use of low-dose aspirin to

reduce the risk of death or stroke in subjects with TIA or minor

ischemic stroke (see section II.A, comment 3 of this document).

The six additional studies identified were relatively small, except

for the UK-TIA study. The Danish Cooperative study (Ref. 18) studied

the effect of aspirin in subjects with reversible cerebral ischemic

attack. The primary endpoint was stroke or death. TIA, reversible

ischemic neurologic disability, and nonfatal MI were also monitored.

The AICLA, Canadian Cooperative, AITIA, Swedish Cooperative, and UK-TIA

studies are discussed in section II.A, comments 2 and 3 of this

document. The Canadian Cooperative study and the AITIA study were also

discussed in comment 49 of the TFM (53 FR 46204 at 46228 to 46230).

FDA performed a statistical analysis and tabulated the endpoints of

all strokes and strokes plus death for these seven studies. The agency

considered the overall combined results and estimated a common odds

ratio for the selected set of available data. The SALT study was

considered an independently positive study for the composite endpoint

of stroke and death. To see whether that finding was substantiated by

other data, the agency did a combined analysis for that endpoint that

included all the studies except SALT. A summary of the entry criteria

for the seven studies appears in Table 3 of this document.

Table 3.--Study Criteria of Cerebrovascular Trials

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Aspirin Months

Study Entry Criteria n -------------------------------------

mg/day followup

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SALT TIA, retinal artery occlusion, or minor stroke 1,360 75 32

AICLA Cerebral or retinal ischemic event 402 990 36

Canadian TIA or partial nonprogressing stroke 283 1,300 26

Fields TIA 178 1,300 6 to 24

UK-TIA TIA or minor ischemic stroke 2,435 1,200 or 300 48 (mean)

[[Page 56808]]

Danish Reversible cerebral ischemic attack 203 1,000 43 (mean 24)

Swedish Minor or major stroke due to cerebral infarction 505 1,500 24

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The estimated odds ratios and 95 percent confidence intervals for

aspirin versus placebo for the composite endpoint stroke and death

(includes vascular and nonvascular) and for all strokes (includes fatal

and nonfatal) are summarized in Table 4 of this document.

Table 4.--Outcome Events of Cerebrovascular Trials

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Number of Events

Study -------------------------------------------------- Odds Ratio 95% Confidence Interval

Aspirin Placebo

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Strokes and Deaths

AICLA 27/198 36/204 0.74 0.43, 1.26

Canadian 26/144 30/139 0.80 0.45, 1.44

Fields 13/88 19/90 0.65 0.30, 1.40

UK-TIA 382/1,621 220/814 0.83 0.68, 1.01

Danish 21/101 17/102 1.04 0.65, 2.65

Swedish 57/253 55/252 1.04 0.68, 1.58

All Studies 526/2,405 377/1,601 0.86 0.73, 0.999

All Strokes

SALT 93/676 112/684 0.82 0.61, 1.10

AICLA 17/198 31/204 0.53 0.29, 0.98

Canadian 22/144 20/139 1.07 0.56, 2.06

Fields 11/88 14/90 0.78 0.33, 1.81

UK-TIA 163/1,621 98/814 0.81 0.62, 1.07

Danish 17/101 11/102 1.66 0.75, 3.68

Swedish 32/253 32/252 1.00 0.59, 1.68

All Studies 355/3,081 318/2,285 0.84 0.71, 0.99

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Four of the seven studies showed trends in favor of aspirin for the

endpoint of stroke, and five of seven for the composite endpoint of

stroke and death, although most of them did not independently show a

statistically significant difference between aspirin and placebo. Of

the studies evaluated, only the AICLA study (Ref. 12) independently

provides statistically significant results in favor of aspirin for the

endpoint of stroke alone. The agency notes that the AICLA study was a

small study that, when compared to the other studies, showed an

unusually large magnitude of effect on stroke as an endpoint. A

detailed report of the study was not submitted to the agency for

review. Without a detailed report, the agency cannot draw definitive

conclusions on the effect of aspirin on the endpoint of stroke alone

based on this small study. However, the collective evaluation of all

the studies, including SALT, showed a statistically significant effect

in favor of aspirin for the endpoint of stroke alone.

For the composite endpoint of stroke and death, the SALT study

independently showed a statistically significant effect of aspirin

compared to placebo in subjects with cerebrovascular problems. The

collective results of the six other studies (without SALT) confirmed

the finding (see Table 4 of this document). The composite endpoint of

stroke and death in the studies evaluated includes those deaths

attributed to cerebral, MI, and other fatal events.

On January 23, 1997, the Cardiovascular and Renal Drugs Advisory

Committee and the Nonprescription Drugs Advisory Committee (the Joint

Advisory Committee) met to consider professional labeling for

cardiovascular uses of aspirin. The Joint Advisory Committee

unanimously recommended an indication for aspirin for subjects with

prior occlusive stroke (both major and minor), pending the outcome of

the agency's evaluation of the ESPS-2 (Ref. 23). The agency

subsequently evaluated data from the aspirin (50 mg daily) and placebo

arms of that study (Ref. 25). The study was a randomized, double blind,

multicenter trial of about 6,600 subjects to show the effect of

antiplatelet agents on subjects that had experienced TIA or completed

ischemic stroke. After 2 years of treatment, the risk of stroke and the

combined risk of stroke or death were reduced in the aspirin only arm

compared to placebo.

Thus, the SALT study and the ESPS-2 study provide primary support

for an indication for aspirin to reduce the combined risk of death or

nonfatal stroke in subjects with TIA or ischemic stroke. The collective

results of the six additional studies lend further support for this

indication. Therefore, the agency is revising the indication as

follows: ``To reduce the combined risk of death and nonfatal stroke in

patients who have had ischemic stroke or transient ischemia of the

brain due to fibrin platelet emboli.''

5. One comment recommended that the agency allow consumer-directed

OTC labeling for the TIA, MI, unstable angina, and other thromboembolic

indications, with complete information on warnings, recommended

dosages, and side effects, provided the product is not advertised to

the general public. The comment also recommended that such labeling for

these uses should be separate from any labeling for the analgesic,

antipyretic, and antirheumatic uses of aspirin. The comment stated that

aspirin is already widely used in the treatment of these non-analgesic

conditions, and that it

[[Page 56809]]

would be harmful to the public for the information not to be included

in the consumer labeling.

Section 502(f) of the Federal Food, Drug, and Cosmetic Act (the

act) (21 U.S.C. 352(f)) states that a drug shall be deemed misbranded:

``Unless its labeling bears (1) adequate directions for use; and (2)

such adequate warnings against use in those pathological conditions * *

* where its use may be dangerous to health, or against unsafe dosage or

methods or duration of administration or application, in such manner

and form, as are necessary for the protection of users * * *.'' The

directions for use or the warnings may be inadequate if the labeling

refers to uses or conditions for which the drug can be safely used only

under the supervision of a practitioner licensed by law (see 21 CFR

201.5). The agency considers the conditions and uses of aspirin that

are the subject of this final rule to require the supervision of a

physician (or other practitioner licensed to prescribe drugs) to ensure

safe use. The agency therefore disagrees with the comment's

recommendation.

Consumers are not in a position to determine when they need to take

aspirin to prevent vascular events, such as stroke, MI, or

cardiovascular death, and other thromboembolic conditions. The need for

drug therapy and the safety of indicating it, for this purpose, is

dependent on a variety of factors, including a person's medical

history, age, gender, lifestyle, and concomitant medications. Medical

intervention aimed at reducing the risk of any of these vascular events

is both multifaceted and long term. In addition, intervention by a

practitioner licensed to prescribe drugs is required for the ongoing

management of the medical conditions being treated. Any prolonged use

of aspirin has certain possible risks, e.g., increased or prolonged

bleeding, GI hemorrhage, and ulceration. An increase in hemorrhagic

stroke has also been reported (Refs. 4 and 5). It is not possible, in

OTC drug product labeling, to provide adequate directions and warnings

to enable the layperson to make a reasonable self assessment of these

factors. Therefore, safe and effective use of aspirin to influence the

risk of vascular events requires medical supervision by a practitioner

licensed to prescribe drugs.

An OTC drug, such as aspirin, may have some uses that can be

properly labeled for direct consumer use and other uses that cannot be

adequately labeled for direct consumer use. Professional labeling

should be provided only to practitioners licensed to prescribe drugs,

but not to the general public.

6. The agency also received a citizen petition (CP12) (Ref. 1) that

requested an amendment to the professional labeling for aspirin in

secondary prevention of cardiovascular morbidity and mortality in men

and women at elevated risk for cardiovascular events. The petition's

requests for professional labeling for aspirin included indications

for: (1) Patients undergoing coronary, cerebral, or peripheral arterial

revascularization procedures; (2) patients with chronic nonvalvular

atrial fibrillation; (3) patients requiring hemodialysis access with a

fistula or shunt; and (4) other patients deemed to be at elevated risk

due to some form of vascular disease or other condition implying an

increased risk of occlusive vascular disease. The authors of the

petition subsequently clarified that they were requesting an aspirin

indication, at a maintenance dose of at least 75 to 81 mg per day, only

for those patients who have already been diagnosed as having had some

occlusive arterial disease and who currently have no special

contraindications to low-dose aspirin. The petition also included

information on the use of aspirin for subjects with chronic stable

angina pectoris. The agency evaluated the petition and presented its

review of the petition at a meeting on April 25, 1996. Minutes of that

meeting, including the agency's review of the petition, are on file in

the Dockets Management Branch (Ref. 26). The petition cited published

reports of two studies as support for an indication for chronic stable

angina pectoris. The first study was the Swedish Angina Pectoris

Aspirin Trial (SAPAT) (Ref. 27), and the second study was an assessment

of those male physicians who entered the U.S. Physicians' Health Study

with chronic stable angina (Ref. 28).

The SAPAT study was a randomized, multicenter, double-blind,

prospective study designed to assess the role of aspirin for prevention

of MI in 2,035 subjects with chronic stable angina pectoris. Subjects

were randomized to receive daily doses of either 75 mg of aspirin plus

sotalol (aspirin group) or placebo plus sotalol (placebo group) daily.

The primary endpoint of the study was the combined rates of first fatal

or nonfatal MI or sudden death. Secondary endpoints were vascular

events (first occurrence of nonfatal MI, nonfatal stroke, or vascular

death), vascular death, all-cause mortality, and stroke. Primary and

secondary endpoint data appear in Table 5 of this document.

Table 5.--Primary and Secondary Endpoints in the SAPAT Study

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Aspirin + Placebo +

Endpoint Sotalol n=1,009 Sotalol n=1,026 Percent Change p

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Primary: 81 124 -34 .003

nonfatal MI 47 78 -3.9 .006

fatal MI 15 15 0

sudden death 19 31 -38 .097

Secondary:

vascular events 108 161 -32 g/mL)), approximately 90 percent of plasma salicylate is

bound to albumin while at higher concentrations (> 400 g/

mL), only about 75 percent is bound. The early signs of salicylic

overdose (salicylism), including tinnitus (ringing in the ears),

occur at plasma concentrations approximating 200 g/mL.

Severe toxic effects are associated with levels > 400 g/mL.

(See Adverse Reactions and Overdosage.)

Metabolism: Aspirin is rapidly hydrolyzed in the plasma to

salicylic acid such that plasma levels of aspirin are essentially

undetectable 1-2 hours after dosing. Salicylic acid is primarily

conjugated in the liver to form salicyluric acid, a phenolic

glucuronide, an acyl glucuronide, and a number of minor metabolites.

Salicylic acid has a plasma half-life of approximately 6 hours.

Salicylate metabolism is saturable and total body clearance

decreases at higher serum concentrations due to the limited ability

of the liver to form both salicyluric acid and phenolic glucuronide.

Following toxic doses (10-20 grams (g)), the plasma half-life may be

increased to over 20 hours.

Elimination: The elimination of salicylic acid follows zero

order pharmacokinetics; (i.e., the rate of drug elimination is

constant in relation to plasma concentration). Renal excretion of

unchanged drug depends upon urine pH. As urinary pH rises above 6.5,

the renal clearance of free salicylate increases from 80 percent. Alkalinization of the urine is a key concept in the

management of salicylate overdose. (See Overdosage.) Following

therapeutic doses, approximately 10 percent is found excreted in the

urine as salicylic acid, 75 percent as salicyluric acid, as the

phenolic and acyl glucuronides, respectively.

Pharmacodynamics: Aspirin affects platelet aggregation by

irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect

lasts for the life of the platelet and prevents the formation of the

platelet aggregating factor thromboxane A2. Non-acetylated

salicylates do not inhibit this enzyme and have no effect on

platelet aggregation. At somewhat higher doses, aspirin reversibly

inhibits the formation of prostaglandin I2

(prostacyclin), which is an arterial vasodilator and inhibits

platelet aggregation.

At higher doses aspirin is an effective anti-inflammatory agent,

partially due to inhibition of inflammatory mediators via cyclo-

oxygenase inhibition in peripheral tissues. In vitro studies suggest

that other mediators of inflammation may also be suppressed by

aspirin administration, although the precise mechanism of action has

not been elucidated. It is this non-specific suppression of cyclo-

oxygenase activity in peripheral tissues following large doses that

leads to its primary side effect of gastric irritation. (See Adverse

Reactions.)

CLINICAL STUDIES

Ischemic Stroke and Transient Ischemic Attack (TIA): In clinical

trials of subjects with TIA's due to fibrin platelet emboli or

ischemic stroke, aspirin has been shown to significantly reduce the

risk of the combined endpoint of stroke or death and the combined

endpoint of TIA, stroke, or death by about 13-18 percent.

Suspected Acute Myocardial Infarction (MI): In a large, multi-

center study of aspirin, streptokinase, and the combination of

aspirin and streptokinase in 17,187 patients with suspected acute

MI, aspirin treatment produced a 23-percent reduction in the risk of

vascular mortality. Aspirin was also shown to have an additional

benefit in patients given a thrombolytic agent.

Prevention of Recurrent MI and Unstable Angina Pectoris: These

indications are supported by the results of six large, randomized,

multi-center, placebo-controlled trials of predominantly male post-

MI subjects and one randomized placebo-controlled study of men with

unstable angina pectoris. Aspirin therapy in MI subjects was

associated with a significant reduction (about 20 percent) in the

risk of the combined endpoint of subsequent death and/or nonfatal

reinfarction in these patients. In aspirin-treated unstable angina

patients the event rate was reduced to 5 percent from the 10 percent

rate in the placebo group.

Chronic Stable Angina Pectoris: In a randomized, multi-center,

double-blind trial designed to assess the role of aspirin for

prevention of MI in patients with chronic stable angina pectoris,

aspirin significantly reduced the primary combined endpoint of

nonfatal MI, fatal MI, and sudden death by 34 percent. The secondary

endpoint for vascular events (first occurrence of MI, stroke, or

vascular death) was also significantly reduced (32 percent).

Revascularization Procedures: Most patients who undergo coronary

artery revascularization procedures have already had symptomatic

coronary artery disease for which aspirin is indicated. Similarly,

patients with lesions of the carotid bifurcation sufficient to

require carotid endarterectomy are likely to have had a precedent

event. Aspirin is recommended for patients who undergo

revascularization procedures if there is a preexisting condition for

which aspirin is already indicated.

Rheumatologic Diseases: In clinical studies in patients with

rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing

spondylitis and osteoarthritis, aspirin has been shown to be

effective in controlling various indices of clinical disease

activity.

ANIMAL TOXICOLOGY

The acute oral 50 percent lethal dose in rats is about 1.5 g/

kilogram (kg) and in mice 1.1 g/kg. Renal papillary necrosis and

decreased urinary concentrating ability occur in rodents chronically

administered high doses. Dose-dependent gastric mucosal injury

occurs in rats and humans. Mammals may develop aspirin toxicosis

associated with GI symptoms, circulatory effects, and central

nervous system depression. (See Overdosage.)

INDICATIONS AND USAGE

Vascular Indications (Ischemic Stroke, TIA, Acute MI, Prevention

of Recurrent MI, Unstable Angina Pectoris, and Chronic Stable Angina

Pectoris): Aspirin is indicated to: (1) Reduce the combined risk of

death and nonfatal stroke in patients who have had ischemic stroke

or transient ischemia of the brain due to fibrin platelet emboli,

(2) reduce the risk of vascular mortality in patients with a

suspected acute MI, (3) reduce the combined risk of death and

nonfatal MI in patients with a previous MI or unstable angina

pectoris, and (4) reduce the combined risk of MI and sudden death in

patients with chronic stable angina pectoris.

Revascularization Procedures (Coronary Artery Bypass Graft

(CABG), Percutaneous Transluminal Coronary Angioplasty (PTCA), and

Carotid Endarterectomy): Aspirin is indicated in patients who have

undergone revascularization procedures (i.e., CABG, PTCA, or carotid

endarterectomy) when there is a preexisting condition for which

aspirin is already indicated.

Rheumatologic Disease Indications (Rheumatoid Arthritis,

Juvenile Rheumatoid Arthritis, Spondyloarthropathies,

Osteoarthritis, and the Arthritis and Pleurisy of Systemic Lupus

Erythematosus (SLE)): Aspirin is indicated for the relief of the

signs and symptoms of rheumatoid arthritis, juvenile rheumatoid

arthritis, osteoarthritis, spondyloarthropathies, and arthritis and

pleurisy associated with SLE.

CONTRAINDICATIONS

Allergy: Aspirin is contraindicated in patients with known

allergy to nonsteroidal anti-inflammatory drug products and in

patients with the syndrome of asthma, rhinitis, and nasal polyps.

Aspirin may cause severe urticaria, angioedema, or bronchospasm

(asthma).

Reye's Syndrome: Aspirin should not be used in children or

teenagers for viral infections, with or without fever, because of

the risk of Reye's syndrome with concomitant use of aspirin in

certain viral illnesses.

WARNINGS

Alcohol Warning: Patients who consume three or more alcoholic

drinks every day should be counseled about the bleeding risks

involved with chronic, heavy alcohol use while taking aspirin.

Coagulation Abnormalities: Even low doses of aspirin can inhibit

platelet function leading to an increase in bleeding time. This can

adversely affect patients with inherited (hemophilia) or acquired

(liver disease or vitamin K deficiency) bleeding disorders.

GI Side Effects: GI side effects include stomach pain,

heartburn, nausea, vomiting, and gross GI bleeding. Although minor

upper GI symptoms, such as dyspepsia, are common and can occur

anytime during therapy, physicians should remain alert for signs of

ulceration and bleeding, even in the absence of previous GI

symptoms. Physicians should inform patients about the signs and

symptoms of GI side effects and what steps to take if they occur.

Peptic Ulcer Disease: Patients with a history of active peptic

ulcer disease should avoid using aspirin, which can cause gastric

mucosal irritation and bleeding.

[[Page 56816]]

PRECAUTIONS

General

Renal Failure: Avoid aspirin in patients with severe renal

failure (glomerular filtration rate less than 10 mL/minute).

Hepatic Insufficiency: Avoid aspirin in patients with severe

hepatic insufficiency.

Sodium Restricted Diets: Patients with sodium-retaining states,

such as congestive heart failure or renal failure, should avoid

sodium-containing buffered aspirin preparations because of their

high sodium content.

Laboratory Tests: Aspirin has been associated with elevated

hepatic enzymes, blood urea nitrogen and serum creatinine,

hyperkalemia, proteinuria, and prolonged bleeding time.

Drug Interactions

Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic

and hypotensive effects of ACE inhibitors may be diminished by the

concomitant administration of aspirin due to its indirect effect on

the renin-angiotensin conversion pathway.

Acetazolamide: Concurrent use of aspirin and acetazolamide can

lead to high serum concentrations of acetazolamide (and toxicity)

due to competition at the renal tubule for secretion.

Anticoagulant Therapy (Heparin and Warfarin): Patients on

anticoagulation therapy are at increased risk for bleeding because

of drug-drug interactions and the effect on platelets. Aspirin can

displace warfarin from protein binding sites, leading to

prolongation of both the prothrombin time and the bleeding time.

Aspirin can increase the anticoagulant activity of heparin,

increasing bleeding risk.

Anticonvulsants: Salicylate can displace protein-bound phenytoin

and valproic acid, leading to a decrease in the total concentration

of phenytoin and an increase in serum valproic acid levels.

Beta Blockers: The hypotensive effects of beta blockers may be

diminished by the concomitant administration of aspirin due to

inhibition of renal prostaglandins, leading to decreased renal blood

flow, and salt and fluid retention.

Diuretics: The effectiveness of diuretics in patients with

underlying renal or cardiovascular disease may be diminished by the

concomitant administration of aspirin due to inhibition of renal

prostaglandins, leading to decreased renal blood flow and salt and

fluid retention.

Methotrexate: Salicylate can inhibit renal clearance of

methotrexate, leading to bone marrow toxicity, especially in the

elderly or renal impaired.

Nonsteroidal Anti-inflammatory Drugs (NSAID's): The concurrent

use of aspirin with other NSAID's should be avoided because this may

increase bleeding or lead to decreased renal function.

Oral Hypoglycemics: Moderate doses of aspirin may increase the

effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.

Uricosuric Agents (Probenecid and Sulfinpyrazone): Salicylates

antagonize the uricosuric action of uricosuric agents.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Administration of aspirin for 68 weeks at 0.5 percent in the feed of

rats was not carcinogenic. In the Ames Salmonella assay, aspirin was

not mutagenic; however, aspirin did induce chromosome aberrations in

cultured human fibroblasts. Aspirin inhibits ovulation in rats. (See

Pregnancy.)

Pregnancy: Pregnant women should only take aspirin if clearly

needed. Because of the known effects of NSAID's on the fetal

cardiovascular system (closure of the ductus arteriosus), use during

the third trimester of pregnancy should be avoided. Salicylate

products have also been associated with alterations in maternal and

neonatal hemostasis mechanisms, decreased birth weight, and with

perinatal mortality.

Labor and Delivery: Aspirin should be avoided 1 week prior to

and during labor and delivery because it can result in excessive

blood loss at delivery. Prolonged gestation and prolonged labor due

to prostaglandin inhibition have been reported.

Nursing Mothers: Nursing mothers should avoid using aspirin

because salicylate is excreted in breast milk. Use of high doses may

lead to rashes, platelet abnormalities, and bleeding in nursing

infants.

Pediatric Use: Pediatric dosing recommendations for juvenile

rheumatoid arthritis are based on well-controlled clinical studies.

An initial dose of 90-130 mg/kg/day in divided doses, with an

increase as needed for anti-inflammatory efficacy (target plasma

salicylate levels of 150-300 g/mL) are effective. At high

doses (i.e., plasma levels of greater than 200 mg/mL), the incidence

of toxicity increases.

ADVERSE REACTIONS

Many adverse reactions due to aspirin ingestion are dose-

related. The following is a list of adverse reactions that have been

reported in the literature. (See Warnings.)

Body as a Whole: Fever, hypothermia, thirst.

Cardiovascular: Dysrhythmias, hypotension, tachycardia.

Central Nervous System: Agitation, cerebral edema, coma,

confusion, dizziness, headache, subdural or intracranial hemorrhage,

lethargy, seizures.

Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic

acidosis, respiratory alkalosis.

Gastrointestinal: Dyspepsia, GI bleeding, ulceration and

perforation, nausea, vomiting, transient elevations of hepatic

enzymes, hepatitis, Reye's Syndrome, pancreatitis.

Hematologic: Prolongation of the prothrombin time, disseminated

intravascular coagulation, coagulopathy, thrombocytopenia.

Hypersensitivity: Acute anaphylaxis, angioedema, asthma,

bronchospasm, laryngeal edema, urticaria.

Musculoskeletal: Rhabdomyolysis.

Metabolism: Hypoglycemia (in children), hyperglycemia.

Reproductive: Prolonged pregnancy and labor, stillbirths, lower

birth weight infants, antepartum and postpartum bleeding.

Respiratory: Hyperpnea, pulmonary edema, tachypnea.

Special Senses: Hearing loss, tinnitus. Patients with high

frequency hearing loss may have difficulty perceiving tinnitus. In

these patients, tinnitus cannot be used as a clinical indicator of

salicylism.

Urogenital: Interstitial nephritis, papillary necrosis,

proteinuria, renal insufficiency and failure.

DRUG ABUSE AND DEPENDENCE

Aspirin is non-narcotic. There is no known potential for

addiction associated with the use of aspirin.

OVERDOSAGE

Salicylate toxicity may result from acute ingestion (overdose)

or chronic intoxication. The early signs of salicylic overdose

(salicylism), including tinnitus (ringing in the ears), occur at

plasma concentrations approaching 200 g/mL. Plasma

concentrations of aspirin above 300 g/mL are clearly toxic.

Severe toxic effects are associated with levels above 400

g/mL. (See Clinical Pharmacology.) A single lethal dose of

aspirin in adults is not known with certainty but death may be

expected at 30 g. For real or suspected overdose, a Poison Control

Center should be contacted immediately. Careful medical management

is essential.

Signs and Symptoms: In acute overdose, severe acid-base and

electrolyte disturbances may occur and are complicated by

hyperthermia and dehydration. Respiratory alkalosis occurs early

while hyperventilation is present, but is quickly followed by

metabolic acidosis.

Treatment: Treatment consists primarily of supporting vital

functions, increasing salicylate elimination, and correcting the

acid-base disturbance. Gastric emptying and/or lavage is recommended

as soon as possible after ingestion, even if the patient has vomited

spontaneously. After lavage and/or emesis, administration of

activated charcoal, as a slurry, is beneficial, if less than 3 hours

have passed since ingestion. Charcoal adsorption should not be

employed prior to emesis and lavage.

Severity of aspirin intoxication is determined by measuring the

blood salicylate level. Acid-base status should be closely followed

with serial blood gas and serum pH measurements. Fluid and

electrolyte balance should also be maintained.

In severe cases, hyperthermia and hypovolemia are the major

immediate threats to life. Children should be sponged with tepid

water. Replacement fluid should be administered intravenously and

augmented with correction of acidosis. Plasma electrolytes and pH

should be monitored to promote alkaline diuresis of salicylate if

renal function is normal. Infusion of glucose may be required to

control hypoglycemia.

Hemodialysis and peritoneal dialysis can be performed to reduce

the body drug content. In patients with renal insufficiency or in

cases of life-threatening intoxication, dialysis is usually

required. Exchange transfusion may be indicated in infants and young

children.

DOSAGE AND ADMINISTRATION

Each dose of aspirin should be taken with a full glass of water

unless patient is fluid restricted. Anti-inflammatory and analgesic

dosages should be individualized. When

[[Page 56817]]

aspirin is used in high doses, the development of tinnitus may be

used as a clinical sign of elevated plasma salicylate levels except

in patients with high frequency hearing loss.

Ischemic Stroke and TIA: 50-325 mg once a day. Continue therapy

indefinitely.

Suspected Acute MI: The initial dose of 160-162.5 mg is

administered as soon as an MI is suspected. The maintenance dose of

160-162.5 mg a day is continued for 30 days post-infarction. After

30 days, consider further therapy based on dosage and administration

for prevention of recurrent MI.

Prevention of Recurrent MI: 75-325 mg once a day. Continue

therapy indefinitely.

Unstable Angina Pectoris: 75-325 mg once a day. Continue therapy

indefinitely.

Chronic Stable Angina Pectoris: 75-325 mg once a day. Continue

therapy indefinitely.

CABG: 325 mg daily starting 6 hours post-procedure. Continue

therapy for 1 year post-procedure.

PTCA: The initial dose of 325 mg should be given 2 hours pre-

surgery. Maintenance dose is 160-325 mg daily. Continue therapy

indefinitely.

Carotid Endarterectomy: Doses of 80 mg once daily to 650 mg

twice daily, started presurgery, are recommended. Continue therapy

indefinitely.

Rheumatoid Arthritis: The initial dose is 3 g a day in divided

doses. Increase as needed for anti-inflammatory efficacy with target

plasma salicylate levels of 150-300 g/mL. At high doses

(i.e., plasma levels of greater than 200 mg/mL), the incidence of

toxicity increases.

Juvenile Rheumatoid Arthritis: Initial dose is 90-130 mg/kg/day

in divided doses. Increase as needed for anti-inflammatory efficacy

with target plasma salicylate levels of 150-300 g/mL. At

high doses (i.e., plasma levels of greater than 200 mg/mL), the

incidence of toxicity increases.

Spondyloarthropathies: Up to 4 g per day in divided doses.

Osteoarthritis: Up to 3 g per day in divided doses.

Arthritis and Pleurisy of SLE: The initial dose is 3 g a day in

divided doses. Increase as needed for anti-inflammatory efficacy

with target plasma salicylate levels of 150-300 g/mL. At

high doses (i.e., plasma levels of greater than 200 mg/mL), the

incidence of toxicity increases.

HOW SUPPLIED

(Insert specific information regarding, strength of dosage form,

units in which the dosage form is generally available, and

information to facilitate identification of the dosage form as

required under Sec. 201.57(k)(1), (k)(2), and (k)(3).) Store in a

tight container at 25 deg.C (77 deg.F); excursions permitted to

15-30 deg.C (59-86 deg.F).

REV: (insert date of publication in the Federal Register.)

(2) In addition to, and immediately preceding, the labeling

required under paragraph (a)(1) of this section, the professional

labeling may contain the following highlights of prescribing

information in the exact language and exact format provided, but only

when accompanied by the comprehensive prescribing information required

in paragraph (a)(1) of this section.

BILLING CODE 4160-01-F

[[Page 56818]]

[GRAPHIC] [TIFF OMITTED] TR23OC98.025

[[Page 56819]]

(b) [Reserved]

Subpart D--Testing Procedures

Sec. 343.90 Dissolution and drug release testing.

(a) [Reserved]

(b) Aspirin capsules. Aspirin capsules must meet the dissolution

standard for aspirin capsules as contained in the United States

Pharmacopeia (USP) 23 at page 132.

(c) Aspirin delayed-release capsules and aspirin delayed-release

tablets. Aspirin delayed-release capsules and aspirin delayed-release

tablets must meet the drug release standard for aspirin delayed-release

capsules and aspirin delayed-release tablets as contained in USP 23 at

pages 133 and 136 respectively.

(d) Aspirin tablets. Aspirin tablets must meet the dissolution

standard for aspirin tablets as contained in USP 23 at page 134.

(e) Aspirin, alumina, and magnesia tablets. Aspirin in combination

with alumina and magnesia in a tablet dosage form must meet the

dissolution standard for aspirin, alumina, and magnesia tablets as

contained in USP 23 at page 138.

(f) Aspirin, alumina, and magnesium oxide tablets. Aspirin in

combination with alumina, and magnesium oxide in a tablet dosage form

must meet the dissolution standard for aspirin, alumina, and magnesium

tablets as contained in USP 23 at page 139.

(g) Aspirin effervescent tablets for oral solution. Aspirin

effervescent tablets for oral solution must meet the dissolution

standard for aspirin effervescent tablets for oral solution as

contained in USP 23 at page 137.

(h) Buffered aspirin tablets. Buffered aspirin tablets must meet

the dissolution standard for buffered aspirin tablets as contained in

USP 23 at page 135.

Dated: October 19, 1998.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 98-28519 Filed 10-21-98; 10:59 am]

BILLING CODE 4160-01-C