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

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

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

MI (fatal and nonfatal) 54 68 ----------------------------------------------------------------------------------------------------------------

Log-rank analysis of stroke-free survival showed that aspirin was significantly superior to placebo (p = 0.02). Analysis of the same outcomes by ``accumulated number of events''during the followup period showed a significant (p = 0.05) risk reduction of 18 percent (relative risk 0.82, 95 percent confidence interval 0.67 to 0.99) for nonfatal stroke or death. The risk reduction was similar in men and women (19 percent and 17 percent, respectively). More deaths were attributed to nonstroke events than to stroke in both the aspirin and placebo arms. Most of the nonstroke deaths in this study were attributed to MI, other vascular deaths, and malignant disorders. Fatal hemorrhagic stroke occurred in six subjects in the aspirin group and none in the placebo group (p = 0.03). Overall, more adverse effects were reported in the aspirin group than in the placebo group, particularly bleeding events (see Table 2 of this document).

Table 2.--Adverse Effects of Aspirin in the SALT Study ---------------------------------------------------------------------------------------------------------------- Number (%) of Subjects ----------------------------------------------------- Aspirin Placebo ---------------------------------------------------------------------------------------------------------------- Gastrointestinal (excluding bleeding) Total 85 (12.5) 73 (10.7) Severe or causing discontinuation of study drug 21 (3.1) 18 (2.6) Bleeding Total 49 (7.2) 22 (3.2) Gastrointestinal 11 (1.6) 4 (0.6) Intracranial 10 (1.5) 3 (0.4) Other 28 (4.1) 15 (2.2) Severe bleeding, or causing discontinuation of study drug 20 (3.0) 9 (1.3) Gastrointestinal 9 (1.3) 4 (0.6) Intracranial 10 (1.5) 3 (0.4) Other 1 (0.1) 2 (0.3) Other adverse effects Total 31 (4.6) 42 (6.1) Severe, or causing discontinuation of study drug 9 (1.3) 11 (1.6) Total number of subjects with adverse effects1 147 (21.7) 123 (18.0) ---------------------------------------------------------------------------------------------------------------- \1\ Some subjects had more than one adverse effect.

The SALT study (Ref. 22) is generally a well-controlled and carefully done study that supports the use of low-dose aspirin to reduce the risk of death or stroke in subjects with TIA or minor ischemic stroke (see section II.A, comment 3 of this document). The six additional studies identified were relatively small, except for the UK-TIA study. The Danish Cooperative study (Ref. 18) studied the effect of aspirin in subjects with reversible cerebral ischemic attack. The primary endpoint was stroke or death. TIA, reversible ischemic neurologic disability, and nonfatal MI were also monitored. The AICLA, Canadian Cooperative, AITIA, Swedish Cooperative, and UK-TIA studies are discussed in section II.A, comments 2 and 3 of this document. The Canadian Cooperative study and the AITIA study were also discussed in comment 49 of the TFM (53 FR 46204 at 46228 to 46230). FDA performed a statistical analysis and tabulated the endpoints of all strokes and strokes plus death for these seven studies. The agency considered the overall combined results and estimated a common odds ratio for the selected set of available data. The SALT study was considered an independently positive study for the composite endpoint of stroke and death. To see whether that finding was substantiated by other data, the agency did a combined analysis for that endpoint that included all the studies except SALT. A summary of the entry criteria for the seven studies appears in Table 3 of this document.

Table 3.--Study Criteria of Cerebrovascular Trials -------------------------------------------------------------------------------------------------------------------------------------------------------- Aspirin Months Study Entry Criteria n ------------------------------------- mg/day followup -------------------------------------------------------------------------------------------------------------------------------------------------------- SALT TIA, retinal artery occlusion, or minor stroke 1,360 75 32 AICLA Cerebral or retinal ischemic event 402 990 36 Canadian TIA or partial nonprogressing stroke 283 1,300 26 Fields TIA 178 1,300 6 to 24 UK-TIA TIA or minor ischemic stroke 2,435 1,200 or 300 48 (mean)

Danish Reversible cerebral ischemic attack 203 1,000 43 (mean 24) Swedish Minor or major stroke due to cerebral infarction 505 1,500 24 --------------------------------------------------------------------------------------------------------------------------------------------------------

The estimated odds ratios and 95 percent confidence intervals for aspirin versus placebo for the composite endpoint stroke and death (includes vascular and nonvascular) and for all strokes (includes fatal and nonfatal) are summarized in Table 4 of this document.

Table 4.--Outcome Events of Cerebrovascular Trials -------------------------------------------------------------------------------------------------------------------------------------------------------- Number of Events Study -------------------------------------------------- Odds Ratio 95% Confidence Interval Aspirin Placebo -------------------------------------------------------------------------------------------------------------------------------------------------------- Strokes and Deaths AICLA 27/198 36/204 0.74 0.43, 1.26 Canadian 26/144 30/139 0.80 0.45, 1.44 Fields 13/88 19/90 0.65 0.30, 1.40 UK-TIA 382/1,621 220/814 0.83 0.68, 1.01 Danish 21/101 17/102 1.04 0.65, 2.65 Swedish 57/253 55/252 1.04 0.68, 1.58 All Studies 526/2,405 377/1,601 0.86 0.73, 0.999 All Strokes SALT 93/676 112/684 0.82 0.61, 1.10 AICLA 17/198 31/204 0.53 0.29, 0.98 Canadian 22/144 20/139 1.07 0.56, 2.06 Fields 11/88 14/90 0.78 0.33, 1.81 UK-TIA 163/1,621 98/814 0.81 0.62, 1.07 Danish 17/101 11/102 1.66 0.75, 3.68 Swedish 32/253 32/252 1.00 0.59, 1.68 All Studies 355/3,081 318/2,285 0.84 0.71, 0.99 --------------------------------------------------------------------------------------------------------------------------------------------------------

Four of the seven studies showed trends in favor of aspirin for the endpoint of stroke, and five of seven for the composite endpoint of stroke and death, although most of them did not independently show a statistically significant difference between aspirin and placebo. Of the studies evaluated, only the AICLA study (Ref. 12) independently provides statistically significant results in favor of aspirin for the endpoint of stroke alone. The agency notes that the AICLA study was a small study that, when compared to the other studies, showed an unusually large magnitude of effect on stroke as an endpoint. A detailed report of the study was not submitted to the agency for review. Without a detailed report, the agency cannot draw definitive conclusions on the effect of aspirin on the endpoint of stroke alone based on this small study. However, the collective evaluation of all the studies, including SALT, showed a statistically significant effect in favor of aspirin for the endpoint of stroke alone. For the composite endpoint of stroke and death, the SALT study independently showed a statistically significant effect of aspirin compared to placebo in subjects with cerebrovascular problems. The collective results of the six other studies (without SALT) confirmed the finding (see Table 4 of this document). The composite endpoint of stroke and death in the studies evaluated includes those deaths attributed to cerebral, MI, and other fatal events. On January 23, 1997, the Cardiovascular and Renal Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee (the Joint Advisory Committee) met to consider professional labeling for cardiovascular uses of aspirin. The Joint Advisory Committee unanimously recommended an indication for aspirin for subjects with prior occlusive stroke (both major and minor), pending the outcome of the agency's evaluation of the ESPS-2 (Ref. 23). The agency subsequently evaluated data from the aspirin (50 mg daily) and placebo arms of that study (Ref. 25). The study was a randomized, double blind, multicenter trial of about 6,600 subjects to show the effect of antiplatelet agents on subjects that had experienced TIA or completed ischemic stroke. After 2 years of treatment, the risk of stroke and the combined risk of stroke or death were reduced in the aspirin only arm compared to placebo. Thus, the SALT study and the ESPS-2 study provide primary support for an indication for aspirin to reduce the combined risk of death or nonfatal stroke in subjects with TIA or ischemic stroke. The collective results of the six additional studies lend further support for this indication. Therefore, the agency is revising the indication as follows: ``To reduce the combined risk of death and nonfatal stroke in patients who have had ischemic stroke or transient ischemia of the brain due to fibrin platelet emboli.'' 5. One comment recommended that the agency allow consumer-directed OTC labeling for the TIA, MI, unstable angina, and other thromboembolic indications, with complete information on warnings, recommended dosages, and side effects, provided the product is not advertised to the general public. The comment also recommended that such labeling for these uses should be separate from any labeling for the analgesic, antipyretic, and antirheumatic uses of aspirin. The comment stated that aspirin is already widely used in the treatment of these non-analgesic conditions, and that it

would be harmful to the public for the information not to be included in the consumer labeling. Section 502(f) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352(f)) states that a drug shall be deemed misbranded: ``Unless its labeling bears (1) adequate directions for use; and (2) such adequate warnings against use in those pathological conditions * * * where its use may be dangerous to health, or against unsafe dosage or methods or duration of administration or application, in such manner and form, as are necessary for the protection of users * * *.'' The directions for use or the warnings may be inadequate if the labeling refers to uses or conditions for which the drug can be safely used only under the supervision of a practitioner licensed by law (see 21 CFR 201.5). The agency considers the conditions and uses of aspirin that are the subject of this final rule to require the supervision of a physician (or other practitioner licensed to prescribe drugs) to ensure safe use. The agency therefore disagrees with the comment's recommendation. Consumers are not in a position to determine when they need to take aspirin to prevent vascular events, such as stroke, MI, or cardiovascular death, and other thromboembolic conditions. The need for drug therapy and the safety of indicating it, for this purpose, is dependent on a variety of factors, including a person's medical history, age, gender, lifestyle, and concomitant medications. Medical intervention aimed at reducing the risk of any of these vascular events is both multifaceted and long term. In addition, intervention by a practitioner licensed to prescribe drugs is required for the ongoing management of the medical conditions being treated. Any prolonged use of aspirin has certain possible risks, e.g., increased or prolonged bleeding, GI hemorrhage, and ulceration. An increase in hemorrhagic stroke has also been reported (Refs. 4 and 5). It is not possible, in OTC drug product labeling, to provide adequate directions and warnings to enable the layperson to make a reasonable self assessment of these factors. Therefore, safe and effective use of aspirin to influence the risk of vascular events requires medical supervision by a practitioner licensed to prescribe drugs. An OTC drug, such as aspirin, may have some uses that can be properly labeled for direct consumer use and other uses that cannot be adequately labeled for direct consumer use. Professional labeling should be provided only to practitioners licensed to prescribe drugs, but not to the general public. 6. The agency also received a citizen petition (CP12) (Ref. 1) that requested an amendment to the professional labeling for aspirin in secondary prevention of cardiovascular morbidity and mortality in men and women at elevated risk for cardiovascular events. The petition's requests for professional labeling for aspirin included indications for: (1) Patients undergoing coronary, cerebral, or peripheral arterial revascularization procedures; (2) patients with chronic nonvalvular atrial fibrillation; (3) patients requiring hemodialysis access with a fistula or shunt; and (4) other patients deemed to be at elevated risk due to some form of vascular disease or other condition implying an increased risk of occlusive vascular disease. The authors of the petition subsequently clarified that they were requesting an aspirin indication, at a maintenance dose of at least 75 to 81 mg per day, only for those patients who have already been diagnosed as having had some occlusive arterial disease and who currently have no special contraindications to low-dose aspirin. The petition also included information on the use of aspirin for subjects with chronic stable angina pectoris. The agency evaluated the petition and presented its review of the petition at a meeting on April 25, 1996. Minutes of that meeting, including the agency's review of the petition, are on file in the Dockets Management Branch (Ref. 26). The petition cited published reports of two studies as support for an indication for chronic stable angina pectoris. The first study was the Swedish Angina Pectoris Aspirin Trial (SAPAT) (Ref. 27), and the second study was an assessment of those male physicians who entered the U.S. Physicians' Health Study with chronic stable angina (Ref. 28). The SAPAT study was a randomized, multicenter, double-blind, prospective study designed to assess the role of aspirin for prevention of MI in 2,035 subjects with chronic stable angina pectoris. Subjects were randomized to receive daily doses of either 75 mg of aspirin plus sotalol (aspirin group) or placebo plus sotalol (placebo group) daily. The primary endpoint of the study was the combined rates of first fatal or nonfatal MI or sudden death. Secondary endpoints were vascular events (first occurrence of nonfatal MI, nonfatal stroke, or vascular death), vascular death, all-cause mortality, and stroke. Primary and secondary endpoint data appear in Table 5 of this document.

Table 5.--Primary and Secondary Endpoints in the SAPAT Study -------------------------------------------------------------------------------------------------------------------------------------------------------- Aspirin + Placebo + Endpoint Sotalol n=1,009 Sotalol n=1,026 Percent Change p -------------------------------------------------------------------------------------------------------------------------------------------------------- Primary: 81 124 -34 .003 nonfatal MI 47 78 -3.9 .006 fatal MI 15 15 0 sudden death 19 31 -38 .097 Secondary: vascular events 108 161 -32 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.

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

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

[GRAPHIC] [TIFF OMITTED] TR23OC98.025

(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