56802 Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations salicylate, , , DEPARTMENT OF HEALTH AND men who have had transient ischemia of , HUMAN SERVICES the brain due to fibrin platelet emboli, sodium, and . and for reducing the risk of death and/ ‘‘ Warning’’ [heading in boldface Food and Drug Administration or nonfatal myocardial infarction (MI) in type]: ‘‘If you consume 3 or more patients with a previous infarction or 21 CFR Part 343 alcoholic drinks every day, ask your unstable angina pectoris. The agency doctor whether you should take [insert [Docket No. 77N±094A] also proposed professional labeling for the use of carbaspirin calcium, choline acetaminophen and one nonsteroidal RIN 0910±AA01 anti-inflammatory / salicylate, magnesium salicylate, or active ingredient—including, but not Internal Analgesic, Antipyretic, and sodium salicylate for rheumatologic limited to , carbaspirin calcium, Antirheumatic Drug Products for Over- diseases. Interested persons were choline salicylate, magnesium The-Counter Human Use; Final Rule invited to submit new data or file written comments, objections, or salicylate, or sodium salicylate] or other for Professional Labeling of Aspirin, requests for oral hearing before the relievers/ reducers. Buffered Aspirin, and Aspirin in Combination With Antacid Drug Commissioner of Food and Drugs [Acetaminophen and (insert one regarding the proposal. nonsteroidal anti-inflammatory Products In response to the TFM, the agency analgesic/antipyretic ingredient— AGENCY: Food and Drug Administration, received four comments and three including, but not limited to aspirin, HHS. citizen petitions related to the carbaspirin calcium, choline salicylate, ACTION: Final rule. professional labeling of aspirin for magnesium salicylate, or sodium cardiovascular and cerebrovascular uses salicylate] may cause liver damage and SUMMARY: The Food and Drug (Ref. 1). No comments were received on stomach bleeding.’’ Administration (FDA) is issuing as a the professional use of aspirin drug (b) Requirements to supplement final rule professional labeling for over- products for rheumatologic diseases. In approved application. Holders of the-counter (OTC) internal analgesic, response to two of the petitions, the approved applications for OTC drug antipyretic, and antirheumatic drug agency proposed to amend the products that contain internal analgesic/ products containing aspirin, buffered professional labeling section of the TFM antipyretic active ingredients that are aspirin, and aspirin in combination with for OTC internal analgesic, antipyretic, subject to the requirements of paragraph an antacid. This portion of the final and antirheumatic drug products to monograph is being issued prior to the (a) of this section must submit include an indication for aspirin for entire monograph so that the supplements under § 314.70(c) of this suspected acute MI (61 FR 30002, June professional labeling of these products chapter to include the required warning 13, 1996). In response to the proposed will reflect the latest information on amendment, the agency received 10 in the product’s labeling. Such labeling cardiovascular, cerebrovascular, and comments (Ref. 2). may be put into use without advance rheumatologic uses. FDA is issuing this In the TFM for OTC internal approval of FDA provided it includes final rule after considering comments on analgesic, antipyretic, and the exact information included in the agency’s proposed regulation for antirheumatic drug products (53 FR paragraph (a) of this section. OTC internal analgesic, antipyretic, and 46204 at 46205), and in the proposed (c) Any drug product subject to this antirheumatic drug products, a amendment to the TFM (61 FR 30002), section that is not labeled as required proposed amendment to the regulation, the agency proposed that any final rule and that is initially introduced or and data and information that have that may issue based on the proposal initially delivered for introduction into come to the agency’s attention. will be effective 12 months after the interstate commerce after April 23, EFFECTIVE DATE: October 25, 1999. date of publication in the Federal 1999, is misbranded under section 502 FOR FURTHER INFORMATION CONTACT: Ida Register. Therefore, on or after October of the Federal Food, Drug, and Cosmetic I. Yoder, Center for Drug Evaluation and 25, 1998, the dissemination of Act (21 U.S.C. 352) and is subject to Research (HFD–560), Food and Drug professional labeling that does not regulatory action. Administration, 5600 Fishers Lane, comply with this final rule may result Rockville, MD 20857, 301–827–2222. in regulatory action against the product, Dated: July 22, 1998. SUPPLEMENTARY INFORMATION: the marketer, or both. Manufacturers are Michael A. Friedman, encouraged to comply voluntarily with Acting Commissioner of Food and Drugs. I. Background this final rule at the earliest possible Donna E. Shalala, In the Federal Register of November date. Secretary of Health and Human Services. 16, 1988 (53 FR 46204), FDA published, The labeling in this final rule for [FR Doc. 98–28520 Filed 10–21–98; 10:58 under 21 CFR 330.10(a)(7), a notice of professional use of aspirin drug am] proposed rulemaking, in the form of a products contains complete information BILLING CODE 4160±01±F tentative final monograph (TFM), that on certain professional uses of aspirin, would establish conditions in part 343 including information for professionals (21 CFR part 343) under which OTC on the treatment of the signs and internal analgesic, antipyretic, and symptoms of rheumatologic disease. antirheumatic drug products are The labeling is organized and presented generally recognized as safe and in a manner similar to that required of effective and not misbranded. In the prescription drug products under TFM (53 FR 46204 at 46258 and 46259), §§ 201.56 and 201.57 (21 CFR 201.56 the agency proposed professional and 201.57). The labeling in this final labeling in § 343.80 for the use of rule also includes an optional highlights aspirin for rheumatologic diseases, for section that summarizes the reducing the risk of recurrent transient professional indications and the ischemic attacks (TIA’s) or stroke in recommended dosage and Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations 56803 administration for each professional individuals at low risk of having a heart also had evidence of an old MI. The indication. attack who would be treated long term. exact number of cases with prior MI in The Committee unanimously agreed the entire study population at the time II. The Agency’s Conclusions on the that patients should ask their doctor of randomization is not known. Comments before beginning prophylactic therapy. Therefore, it is not possible to determine A. Comments to the TFM The agency has considered the with assurance how much of the effect 1. One comment requested that Committee’s views in conjunction with of aspirin attributed to prevention of a aspirin be approved for use as a the additional data that have been primary MI was really prevention of a prophylaxis for primary (first) MI under subsequently submitted to FDA. reinfarction. The agency does not consider the The U.S. Physicians’ Health Study a physician’s supervision. The comment results of the aspirin component of the also found a statistically significant based its request on the preliminary U.S. Physicians’ Health Study adequate reduction in the risk of fatal acute MI in report of a large, highly statistically to support the effectiveness of aspirin in the aspirin group, but no overall effect significant, reduction (47 percent) in the decreasing the risk of MI in healthy on survival. The agency does not risk of total (fatal and nonfatal) MI in individuals without evidence of consider this finding persuasive. subjects taking aspirin in the U.S. coronary artery disease because of Assessing cause-specific mortality is Physicians’ Health Study (Ref. 3). A concerns about the revised primary usually difficult and the finding of final report was published later (Ref. 4). endpoint, the study population, and the benefit is of uncertain meaning in the The agency also considered the results of the British Doctors Study. face of equivalent total cardiovascular British Doctors Study, by Peto et al. The primary endpoint described in mortality (the original primary (Ref. 5), that was similar in many the protocol for the aspirin component endpoint). Thus, the decrease in acute respects to the U.S. Physicians’ Health of the U.S. Physicians’ Health Study MI deaths in the aspirin group were Study. It randomized 5,139 apparently was total cardiovascular mortality. On almost matched by an increase in healthy male doctors, to 500 milligrams interim evaluations, however, it became sudden deaths, not an obviously (mg) aspirin daily, or to no aspirin, to clear to the Data Monitoring Board worthwhile effect. Redefinition of see whether aspirin would reduce the (DMB) for the study that the aspirin arm endpoints would, in any case, require incidence of, and mortality from, stroke, of the study had little chance of adjustment for multiplicity, but it is MI, or other vascular conditions. The showing a survival effect before the year difficult to describe the appropriate British Doctors Study, despite its 2000, if then, because the mortality rate adjustment, as the number of possible similarity to the U.S. Physicians’ Health was far lower than expected and the secondary endpoints is unspecified. The Study, does not support the use of study did not show even a positive nominally significant decrease of fatal aspirin to prevent an initial MI. After 6 trend for this endpoint. There were 81 MI (p = 0.004) thus needs considerable years of followup, there were 23.5 deaths in the aspirin group and 83 in upward adjustment and would not be confirmed nonfatal MI reports per 1,000 the placebo group (p = 0.87). The DMB close to the significance level needed at participants in the aspirin group and 24 also took note of the reductions in total an interim point (p < 0.0027). per 1,000 in the no-aspirin group. When (fatal and nonfatal) MI, a finding they In addition, some of the cause of possible MI reports were added, the considered persuasive. Because the death assignments are questionable. The total was 30 per 1,000 for the aspirin study had little hope of showing an agency evaluated the deaths in the study group and 26.4 per 1,000 for the no- effect on the primary endpoint and attributed to fatal acute MI (10 in the aspirin group. From a safety viewpoint, because of the reduction in MI, the DMB aspirin group and 28 in the placebo disabling stroke was significantly more recommended early termination of the group) and to ‘‘sudden death’’ (22 in the frequent in the aspirin group than the aspirin component of the trial (Ref. 3). aspirin group and 12 in the placebo no-aspirin group (19.1 versus 7.4 per The early stopping rule stated in the group) and found that one death in the 10,000 man years, p < 0.05). In addition, grant proposal (but not in the protocol) placebo group attributed to acute MI expected gastrointestinal (GI) events was that the trial would continue unless was due to stroke. Another placebo (e.g., nonfatal peptic ulcers, bleeding, chi-square tests comparing treatments subject classified as MI had no evidence dyspepsia) occurred in the aspirin reached an extreme value, such as 9.0 of MI, but could have been classified as group. (i.e., if p < 0.0027). The proposal did not a ‘‘sudden death.’’ Thus the number of On October 6, 1989, FDA’s state explicitly which endpoint was the confirmed MI’s in the placebo group Cardiovascular and Renal Drugs basis for the early stopping rule. It is not decreases from 28 to 26, and the number Advisory Committee (the Committee) clear which endpoint served as the basis of ‘‘sudden deaths’’ increases from 12 to considered a claim for aspirin for the for the early stopping rule. Thus, it is 13. prevention of primary (first) heart attack not clear how the reported p values On the other hand, the autopsy report based on the findings of the U.S. should be adjusted retrospectively of one aspirin subject categorized under Physicians’ Health Study (Refs. 3 and 4). although some adjustment would be ‘‘sudden death’’ listed acute MI as the The Committee was aware of the required. cause of death. Another aspirin subject, findings of the British Doctors Study, The finding of a reduction in risk of in the sudden death category, but only the findings from the U.S. MI in the U.S. Physicians’ Health Study experienced chest pain and vomiting Physicians’ Health Study were is further weakened because some of the before collapsing, and the autopsy presented in detail. The Committee study patients had a prior MI, and showed ‘‘moderate to severe 3-vessel recommended (by a 5 to 3 vote) that, aspirin is already known to reduce the atherosclerosis with apparent although some claim should be risk of recurrent MI in such patients. myocardial ischemia in a patient with considered for some high-risk group of According to the study protocol, right and left myocardial hypertension patients, aspirin should not be used subjects should not have had an MI and extensive old septal scarring.’’ It is routinely in patients without risk factors before randomization. However, based likely that this patient’s death was due or in women, until such patients had on the agency’s inspection of the to acute MI. Thus, if 2 of the 22 deaths been studied. The Committee minority subjects’ records, at least 40 (about 8 in the aspirin group classified as was concerned about the toxicity of percent) of the 512 subjects who ‘‘sudden death’’ had been classified as aspirin and the number of normal suffered a nonfatal MI during the study confirmed acute MI (increasing that 56804 Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations total from 10 to 12), the ‘‘sudden death’’ In at least some people at higher risk 2. One comment asked that the total would be decreased from 22 to 20. (people who have had an acute MI or professional labeling in proposed The cause of death could not be have TIA’s), aspirin is known to provide § 343.80(b) for aspirin for TIA include established with certainty in most a net benefit. There may be other both men and women, not just men. The subjects. All subjects in the ‘‘sudden populations in whom the net effect of comment cited results from the Second death’’ category for whom relevant aspirin is favorable, but the U.S. International Study of Infarct Survival information was available had a history Physicians’ Health Study does not (ISIS–2) (Ref. 7), based on an analysis of of atherosclerotic cardiovascular define such groups. The investigators a subset of data for men and women disease, peripheral vascular disease, or did not identify any group in which separately, to support its request. The hypertension. Therefore, all of the cases aspirin could reduce the incidence of absolute decrease in mortality for the of sudden death could have resulted fatal and nonfatal heart attack without aspirin group compared to placebo was from an acute MI. Thus, there could increasing the incidence of other causes 2.4 percent for men and 2.6 percent for have been 32 cases (12 identified, 20 of death or disability. women. The comment concluded that possible) of fatal MI in the aspirin group The Steering Committee of the U.S. this study showed that, up to 5 weeks, versus 39 (26 identified, 13 possible) in Physicians’ Health Study Research mortality was significantly reduced (p < the placebo group. This difference is not Group (Ref. 4) suggested that aspirin is 0.01) in both men and women who had statistically significant (p > 0.50). This beneficial in prevention of the first heart suffered acute MI and were treated for analysis could be considered a ‘‘worst attack (at least in men over 50), but 1 month with aspirin. The comment case’’ analysis of the fatal MI finding, stated: ‘‘Although the short-term benefit added that this study also showed that but it illustrates the difficulty of cause- of aspirin in these populations appears aspirin reduced the incidence of specific mortality findings. to outweigh its risks, the long-term nonfatal stroke and nonfatal MI in both The agency also does not believe the advantage and toxicity of the drug men and women. reported 18 percent reduction in the remain uncertain.’’ In a more recent The comment complained that the endpoint of nonfatal MI, nonfatal stroke, review article (Ref. 6) by several study (Ref. 8) supporting the use of and total cardiovascular mortality can members of the U.S. Physicians’ Health aspirin only in men to reduce the risk be taken as significant. For the Study Research Group, members of the of recurrent TIA or stroke was only one combined endpoint, there were 307 Steering Committee, and others, small trial with a marginally significant subjects in the aspirin group and 370 in concerning primary prevention of MI, overall result. The comment mentioned that the results of this study were the placebo group (relative risk 0.82; p the authors concluded the following: = 0.01). The reported p value of 0.01 is subdivided by gender, and a data- ‘‘Any decision to use aspirin well above the stopping rule p value of dependent subgroup analysis suggested prophylaxis should be made on an 0.0027. Therefore, the study did not an effect only in men. Such subgroup individual basis and, in general, should provide persuasive evidence that aspirin analysis, the comment contended, is be considered only for those whose has a beneficial effect on the combined frequently unreliable. The comment absolute risk of a first MI is sufficiently endpoint. In addition, the isolated suggested that the ISIS–2 study results, high to warrant accepting the potential finding of a statistically significant which showed reduced mortality in adverse effects of long-term aspirin effect on nonfatal MI is not persuasive. both men and women given aspirin use.’’ Of note is the fact that the British following acute MI, should ‘‘illuminate’’ Doctors Study completely failed to In summary, the U.S. Physicians’ data from trials in a different occlusive replicate this finding. Health Study failed to show a vascular disease (TIA). The reduction in incidence of fatal significant effect, or even a beneficial The agency is in substantial and nonfatal MI was also accompanied trend, on the specified primary study agreement with the comment that there by an increase in strokes, especially endpoint of total cardiovascular is no reason to distinguish between severe, fatal, hemorrhagic stroke, and by mortality. The study was stopped early genders with respect to using aspirin to a greater incidence of sudden death and and multiple secondary endpoints were reduce the risk of recurrent TIA or ‘‘other’’ cardiovascular deaths. Thus, evaluated. The effects of aspirin on fatal stroke. Although subset differences are there was no overall benefit or favorable acute MI and on the combined endpoint known to occur, in general, results are trend on mortality. Cerebral hemorrhage of nonfatal MI, nonfatal stroke, and total considered applicable to the whole as a cause of stroke was reported more cardiovascular mortality were not group unless there is reason not to do often in the aspirin group than in the statistically significant when so (Ref. 9). In the present case there was, placebo group (23 versus 12). The adjustments were made for early initially, reason to limit the TIA claim incidence of ulcers, ‘‘other stopping. There was an isolated finding to males. The indication in proposed noninfectious diseases of the digestive of a statistically significant effect on § 343.80(b) was based on results of the tract,’’ bleeding problems, and the need nonfatal MI (a secondary endpoint), but Canadian Cooperative Study Group trial for transfusion, also was significantly the value of this finding is questionable (Ref. 8) and the Fields study (Ref. 10). increased, and one aspirin subject died in the face of adverse trends on stroke In these studies, there seemed to be a from GI bleeding. Although these side and causes of death other than acute MI. difference in response with gender effects would not prevent the use of Of note is the fact that the British when subset analyses were done. aspirin if its net benefit on coronary Doctors Study completely failed to However, there were very few women in artery and cerebrovascular events were replicate this finding on nonfatal MI. the trials and the number of events favorable, the effects are not trivial. Thus, the agency concludes that the reported was small. It seems probable that the net benefit available data do not support the Data from subsequent trials do not of aspirin is critically dependent on the professional labeling of aspirin for the substantiate a gender difference in the underlying risk for coronary and prevention of first MI. The U.S. effect of aspirin on cerebrovascular cerebral events, and that use of aspirin Physicians’ Health Study (Refs. 3 and 4), events, and trends in women have been requires knowing more about its effects in particular, did not show a statistically similar to results seen in men. The UK– in various populations. In people at low significant effect when all deaths as well TIA aspirin trial (Ref. 11), in which 25 risk for acute MI, the increased risk of as nonfatal MI and stroke were percent of the subjects were women, stroke may result in a net disadvantage. combined. showed favorable trends for the Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations 56805 endpoint of major stroke, MI, or death. results of 25 randomized clinical trials in parallel with a 1,200 mg dose. The The AICLA study (Ref. 12), which of the prolonged treatment with drugs primary endpoints of most of these reportedly showed an effect of aspirin that inhibit platelet aggregation. The studies were combined events, for secondary cerebral events in a group comment stated that when the trials are including strokes (fatal and nonfatal) that included 30 percent women, viewed together: (1) The benefits of and death. In some of the studies, TIA showed no significant difference antiplatelet treatment are about the or MI was also included in the primary between men and women. Although the same in cardiac patients (unstable endpoint. The Trialists’ group (Ref. 16) study was small, subset analysis showed angina and MI) as in cerebral patients did a meta-analysis suggesting the a trend favoring women, with a (TIA and stroke thought to be effectiveness of lower doses of aspirin numerically larger effect on stroke in occlusive), and (2) the various (less than 160 to 324 mg per day) in women than in men. The study by treatments used, including 300 mg of reducing combined events (nonfatal Sivenius et al. (Ref. 13) included a larger aspirin daily, were comparable. The stroke, MI, or vascular death), but all proportion of women (42 percent in the comment mentioned that aspirin studies except the UK–TIA study intent-to-treat analysis and 44 percent in gastrotoxicity is dose-related, and cited involved subjects with a history of MI the explanatory analysis), and the the UK–TIA trial (Ref. 11) in which or angina rather than a history of investigators reported a statistically more GI symptoms (indigestion, nausea, cerebrovascular events. significant effect in women. That study heartburn, or vomiting) occurred with In a subsequent publication (Ref. 20), did not include an aspirin-only arm, but 1,200 mg than 300 mg daily aspirin (a the Trialists’ group provided some there is little evidence that difference of 9.4 percent (2p < 0.001)). support for the role of antiplatelet dipyridamole contributes to the effect of Another comment asked the agency to therapy in prevention of nonfatal the aspirin plus dipyridamole consider lower doses of aspirin for strokes in subjects with prior stroke or combination (Refs. 12 and 14); thus, this maintenance therapy. The comment TIA. Among the 10 trials that used study provides some support for an described several serious nasal aspirin alone, dosages ranged from 50 to effect of aspirin in women. The Swedish hemorrhages that occurred when taking 1,300 mg per day. Three of these trials Cooperative study (Ref. 15) failed to maintenance therapy of ‘‘one half (UK–TIA, Danish Very-Low-Dose, and show an effect for aspirin overall, in aspirin tablet (strength not stated) Swedish Aspirin Low-Dose Trial men or in women. daily.’’ The comment also mentioned a (SALT)) used comparatively low doses The agency believes the available data number of instances of sustained of aspirin (Refs. 11, 21, and 22). support the conclusion that women bleeding from shaving nicks, bleeding The UK–TIA study (Ref. 11) alone with a history of TIA should benefit after accidents, bleeding ulcers, and showed no difference in effectiveness from aspirin therapy. Early evidence complications during surgery based on between the 300 mg and the 1,200 mg supporting this use of aspirin came from personal experience or the experiences aspirin daily dose in a TIA population, studies that included mostly men, but of friends or neighbors who were taking but the incidence of side effects, studies since the Canadian and Fields aspirin for maintenance therapy. The especially GI, was greater for the 1,200 studies show numerically similar results comment concluded that the proposed mg dose. The beneficial effect of aspirin for men and women. Favorable trends FDA dosage is several times the dosage on major stroke alone and on the have generally been seen in women as needed for most maintenance therapy composite events, disabling stroke or well as men. Therefore, the agency is and that FDA should lower the dosage. vascular death, was not sufficient to revising the professional labeling in The agency has considered the dosage show a significant difference between § 343.80 for cerebrovascular uses so that of aspirin for cardiovascular and aspirin and placebo, but it did show a the indication is for ‘‘patients’’ rather cerebrovascular conditions and trend in favor of aspirin. For the than for ‘‘men.’’ concludes that specific doses for combined endpoint of all death, 3. One comment asked that the dosage specific uses of aspirin, supported by nonfatal major stroke, and nonfatal MI, for aspirin for TIA in proposed appropriate data, are necessary for an the study showed an 18-percent (95 § 343.80(b) be reduced from 1,300 mg to optimum benefit to the user, and, in percent confidence interval, 2 to 31 300 mg a day. The comment contended general, that a minimum effective dose percent) reduction by aspirin (combined that data from many different trials of established for a given indication 300 and 1,200 mg groups). The Danish antiplatelet treatments in many different should be used to minimize dose-related Very-Low-Dose Study (Ref. 21) used occlusive vascular conditions could be adverse effects. The agency has aspirin doses ranging from 50 to 100 mg viewed together. The comment stated determined that the ISIS–2 study (Ref. per day in subjects with TIA, stroke, or that this approach could be used 7) supports the professional labeling of acute MI who had recently undergone because, no matter what the prior aspirin in the treatment of suspected carotid endarterectomies. The study medical condition may have been, the acute MI at a dosage of 160 to 162.5 mg showed no significant effect of aspirin chief diseases to be prevented (occlusive daily. However, the ISIS–2 study did and side effects were minimal. In the stroke and coronary artery occlusion) not show, nor was it intended to show, SALT study (Ref. 22), 75 mg aspirin may be much the same. The comment the effect of aspirin on subjects with daily reduced the risk of stroke and explained that aspirin doses of only 100 TIA or other cerebrovascular events. death by 18 percent in subjects who to 200 mg daily inhibit cyclo-oxygenase- The Trialists’ report (Ref. 16) previously had TIA, minor ischemic dependent platelet aggregation so evaluated antiplatelet treatment of stroke, or retinal artery occlusion. The completely that little extra effect would subjects with a range of symptoms (e.g., agency also considered the findings of result from higher daily doses. The TIA, occlusive stroke, unstable angina, the second European Stroke Prevention comment cited the ISIS–2 study (Ref. 7) and MI) using a number of antiplatelet Study (ESPS–2) (Ref. 23) in which 50 as showing that 160 mg aspirin daily agents, not only aspirin. Some of the mg daily aspirin had a significant was highly protective in preventing studies (Refs. 8, 10 through 12, 15, and beneficial effect on the combined risk of death (p < 0.01) and in reducing 17 through 19) used aspirin alone and stroke or death in subjects with a prior nonfatal stroke and nonfatal MI in included cerebrovascular subjects given TIA or ischemic stroke. (See section subjects who suffered an acute MI. dosages ranging from 990 to 1,500 mg II.A, comment 4 of this document.) The comment also cited the Trialists’ daily, except one arm of the UK–TIA The proposed indication for aspirin to report (Ref. 16), a meta-analysis of the study that used a dosage of 300 mg daily reduce the risk of recurrent TIA or 56806 Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations stroke in subjects with TIA, at a dosage many adverse reactions due to aspirin endpoint of stroke and death. The of 1,300 mg daily, was based primarily ingestion are dose related. agency considered reviews by the on two small studies (Refs. 8 and 10). In summary, there is clinical trial Antiplatelet Trialists’ group (Refs. 16 Other, more recently published studies support for a lower dose of aspirin for and 20) and Matchar et al. (Ref. 24), but (Refs. 11, 12, 22, and 23) have shown a subjects with a history of TIA or did not include combination arms (e.g., significant effect or trend in favor of cerebral ischemia and considerable aspirin and dipyridamole) and studies aspirin in a population with evidence supporting lower doses in of post-endarterectomy subjects (e.g., cerebrovascular events. The agency has patients with MI. It is also clear that the Danish Very-Low-Dose Study) (Ref. 21). reevaluated the available studies and effect of aspirin on platelet function is The following studies met the criteria: the overall outcome of the available complete at lower doses. The positive SALT (Ref. 22), AICLA (Ref. 12), studies, looking at the role of aspirin on findings at lower dosages (e.g., 50, 75, Canadian Cooperative (Ref. 8), AITIA the endpoint of stroke alone and the and 300 mg daily), along with the higher (Ref. 10), Danish Cooperative (Ref. 18), broader composite endpoint of stroke incidence of side effects expected at the Swedish Cooperative (Ref. 15), and UK– and death, both individually and higher dosage (e.g., 1,300 mg daily), are TIA (Ref. 11). The agency evaluated the collectively. (See section II.A, comment sufficient reason to lower the dosage of available data in the published reports, 4 of this document.) aspirin for subjects with TIA and which in some cases differed from the Although there is more evidence for ischemic stroke. The agency believes a data listing in the Trialists’ reports effectiveness of aspirin for subjects with dose of 50 to 325 mg is an effective daily (Refs. 16 and 20), because of their TIA or cerebral ischemia at higher doses dose for subjects with TIA or cerebral independent review of outcomes. (900 to 1,500 mg daily) than at lower ischemia. Therefore, in this final rule, doses (Ref. 24), the ESPS–2 (50 mg daily the agency is providing for a dosage of The SALT study (Ref. 22) compared aspirin) (Ref. 23), the SALT study (75 50 to 325 mg aspirin daily. aspirin (75 mg daily) and placebo in mg aspirin daily) (Ref. 22), and UK–TIA 4. One comment suggested the 1,360 subjects with a TIA, minor study (300 mg versus 1,200 mg aspirin following indication for low-dose ischemic stroke, or retinal artery daily) (Ref. 11), lend support for a lower aspirin: ‘‘For reduction of the risk of MI, occlusion. Subjects were excluded if dose. Certain adverse reactions, such as stroke, and vascular death among men they had any of the following: (1) A excessive bleeding described by one of or women with a history of occlusive potential cardiac source of emboli, the comments, occur in some cerebral vascular or cardiovascular including an MI, within 3 months prior individuals taking aspirin, but there are disease. The optimal dose is not known, to entry; (2) planned carotid surgery; (3) generally fewer such reactions at lower but there is no good evidence that doses contraindications to aspirin; or (4) the doses than higher doses. This is above 300 mg/day are necessary.’’ need for long-term anticoagulation. The supported by the UK–TIA study (Ref. The agency reviewed a number of median duration of followup was 32 12). The benefit/risk must be taken into published reports (individually and months. The primary outcome measure account for each indication. In this collectively) to further evaluate the was all-cause mortality and stroke of regard, the agency proposed a warning effects of aspirin in subjects with any severity. The following were in § 343.50(c)(1)(v)(B) of the TFM to premonitory cerebrovascular events. planned secondary analyses: (1) All alert people who have bleeding The agency evaluated studies that: (1) strokes (fatal and nonfatal), (2) stroke or problems not to take aspirin unless Compared aspirin alone to placebo in two or more TIA’s within 1 week directed by a doctor (53 FR 46204 at subjects with a history of necessitating a change in therapy, and 46256). Also, the professional labeling cerebrovascular events, and (2) (3) all MI’s (fatal and nonfatal). The in this final rule lists GI bleeding in the evaluated and adequately presented the primary and secondary outcome events adverse reactions section and notes that endpoint of stroke and the composite are listed in Table 1 of this document.

TABLE 1.ÐPRIMARY AND SECONDARY OUTCOME EVENTS IN THE SALT STUDY

Number of Subjects Primary events Aspirin Placebo (n=676) (n=684)

Primary events Nonfatal stroke Cerebral infarction, minor 55 68 Cerebral infarction, major 17 30 Intracerebral hemorrhage 4 3 Subarachnoid hemorrhage 1 1 Fatal stroke Cerebral infarction, major 10 7 Intracerebral hemorrhage 4 0 Subarachnoid hemorrhage 2 0 Unknown 0 3 Nonstroke deaths MI 18 28 Other vascular deaths 14 12 Malignant disorders 10 15 Other (infection, diabetes, trauma) 1 3 Unknown 2 1 Total primary outcome events 138 171 Secondary events Stroke (fatal and nonfatal) 93 112 Stroke or > 2 TIA's within 1 week, necessitating change in therapy 101 128 Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations 56807

TABLE 1.ÐPRIMARY AND SECONDARY OUTCOME EVENTS IN THE SALT STUDYÐContinued

Number of Subjects Primary events Aspirin Placebo (n=676) (n=684)

MI (fatal and nonfatal) 54 68

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

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

TABLE 3.ÐSTUDY 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) 56808 Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations

TABLE 3.ÐSTUDY CRITERIA OF CEREBROVASCULAR TRIALSÐContinued

Aspirin Months Study Entry Criteria n mg/day followup

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

TABLE 4.ÐOUTCOME 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 problems. The collective results of the reduced in the aspirin only arm trends in favor of aspirin for the six other studies (without SALT) compared to placebo. endpoint of stroke, and five of seven for confirmed the finding (see Table 4 of Thus, the SALT study and the ESPS– the composite endpoint of stroke and this document). The composite 2 study provide primary support for an death, although most of them did not endpoint of stroke and death in the indication for aspirin to reduce the independently show a statistically studies evaluated includes those deaths combined risk of death or nonfatal significant difference between aspirin attributed to cerebral, MI, and other fatal stroke in subjects with TIA or ischemic and placebo. Of the studies evaluated, events. stroke. The collective results of the six only the AICLA study (Ref. 12) additional studies lend further support On January 23, 1997, the independently provides statistically for this indication. Therefore, the Cardiovascular and Renal Drugs significant results in favor of aspirin for agency is revising the indication as the endpoint of stroke alone. The agency Advisory Committee and the follows: ‘‘To reduce the combined risk notes that the AICLA study was a small Nonprescription Drugs Advisory of death and nonfatal stroke in patients study that, when compared to the other Committee (the Joint Advisory who have had ischemic stroke or studies, showed an unusually large Committee) met to consider professional transient ischemia of the brain due to magnitude of effect on stroke as an labeling for cardiovascular uses of fibrin platelet emboli.’’ endpoint. A detailed report of the study aspirin. The Joint Advisory Committee 5. One comment recommended that was not submitted to the agency for unanimously recommended an the agency allow consumer-directed review. Without a detailed report, the indication for aspirin for subjects with OTC labeling for the TIA, MI, unstable agency cannot draw definitive prior occlusive stroke (both major and angina, and other thromboembolic conclusions on the effect of aspirin on minor), pending the outcome of the indications, with complete information the endpoint of stroke alone based on agency’s evaluation of the ESPS–2 (Ref. on warnings, recommended dosages, this small study. However, the 23). The agency subsequently evaluated and side effects, provided the product is collective evaluation of all the studies, data from the aspirin (50 mg daily) and not advertised to the general public. The including SALT, showed a statistically placebo arms of that study (Ref. 25). The comment also recommended that such significant effect in favor of aspirin for study was a randomized, double blind, labeling for these uses should be the endpoint of stroke alone. multicenter trial of about 6,600 subjects separate from any labeling for the For the composite endpoint of stroke to show the effect of antiplatelet agents analgesic, antipyretic, and and death, the SALT study on subjects that had experienced TIA or antirheumatic uses of aspirin. The independently showed a statistically completed ischemic stroke. After 2 years comment stated that aspirin is already significant effect of aspirin compared to of treatment, the risk of stroke and the widely used in the treatment of these placebo in subjects with cerebrovascular combined risk of stroke or death were non-analgesic conditions, and that it Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations 56809 would be harmful to the public for the ongoing management of the medical clarified that they were requesting an information not to be included in the conditions being treated. Any prolonged aspirin indication, at a maintenance consumer labeling. use of aspirin has certain possible risks, dose of at least 75 to 81 mg per day, Section 502(f) of the Federal Food, e.g., increased or prolonged bleeding, GI only for those patients who have already Drug, and Cosmetic Act (the act) (21 hemorrhage, and ulceration. An increase been diagnosed as having had some U.S.C. 352(f)) states that a drug shall be in hemorrhagic stroke has also been occlusive arterial disease and who deemed misbranded: ‘‘Unless its reported (Refs. 4 and 5). It is not currently have no special labeling bears (1) adequate directions for possible, in OTC drug product labeling, contraindications to low-dose aspirin. use; and (2) such adequate warnings to provide adequate directions and The petition also included information against use in those pathological warnings to enable the layperson to on the use of aspirin for subjects with conditions * * * where its use may be make a reasonable self assessment of chronic stable angina pectoris. The dangerous to health, or against unsafe these factors. Therefore, safe and agency evaluated the petition and dosage or methods or duration of effective use of aspirin to influence the presented its review of the petition at a administration or application, in such risk of vascular events requires medical meeting on April 25, 1996. Minutes of manner and form, as are necessary for supervision by a practitioner licensed to that meeting, including the agency’s the protection of users * * *.’’ The prescribe drugs. review of the petition, are on file in the directions for use or the warnings may An OTC drug, such as aspirin, may Dockets Management Branch (Ref. 26). be inadequate if the labeling refers to have some uses that can be properly The petition cited published reports of uses or conditions for which the drug labeled for direct consumer use and two studies as support for an indication can be safely used only under the other uses that cannot be adequately for chronic stable angina pectoris. The supervision of a practitioner licensed by labeled for direct consumer use. first study was the Swedish Angina law (see 21 CFR 201.5). The agency Professional labeling should be Pectoris Aspirin Trial (SAPAT) (Ref. considers the conditions and uses of provided only to practitioners licensed 27), and the second study was an aspirin that are the subject of this final to prescribe drugs, but not to the general assessment of those male physicians rule to require the supervision of a public. who entered the U.S. Physicians’ Health physician (or other practitioner licensed 6. The agency also received a citizen Study with chronic stable angina (Ref. to prescribe drugs) to ensure safe use. petition (CP12) (Ref. 1) that requested an 28). The agency therefore disagrees with the amendment to the professional labeling The SAPAT study was a randomized, comment’s recommendation. for aspirin in secondary prevention of multicenter, double-blind, prospective Consumers are not in a position to cardiovascular morbidity and mortality study designed to assess the role of determine when they need to take in men and women at elevated risk for aspirin for prevention of MI in 2,035 aspirin to prevent vascular events, such cardiovascular events. The petition’s subjects with chronic stable angina as stroke, MI, or cardiovascular death, requests for professional labeling for pectoris. Subjects were randomized to and other thromboembolic conditions. aspirin included indications for: (1) receive daily doses of either 75 mg of The need for drug therapy and the safety Patients undergoing coronary, cerebral, aspirin plus sotalol (aspirin group) or of indicating it, for this purpose, is or peripheral arterial revascularization placebo plus sotalol (placebo group) dependent on a variety of factors, procedures; (2) patients with chronic daily. The primary endpoint of the including a person’s medical history, nonvalvular atrial fibrillation; (3) study was the combined rates of first age, gender, lifestyle, and concomitant patients requiring hemodialysis access fatal or nonfatal MI or sudden death. . Medical intervention with a fistula or shunt; and (4) other Secondary endpoints were vascular aimed at reducing the risk of any of patients deemed to be at elevated risk events (first occurrence of nonfatal MI, these vascular events is both due to some form of vascular disease or nonfatal stroke, or vascular death), multifaceted and long term. In addition, other condition implying an increased vascular death, all-cause mortality, and intervention by a practitioner licensed risk of occlusive vascular disease. The stroke. Primary and secondary endpoint to prescribe drugs is required for the authors of the petition subsequently data appear in Table 5 of this document.

TABLE 5.ÐPRIMARY AND SECONDARY ENDPOINTS IN THE SAPAT STUDY

Aspirin + Sotalol Placebo + Sotalol Endpoint n=1,009 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 <.001 vascular deaths 51 70 -26 .114 all cause mortality 82 106 -22 .103 stroke 28 38 -25 .246 hemorrhagic 5 2 nonhemorrhagic 23 36

The SAPAT study supports the use of MI and sudden death, and the component of the primary endpoint, 75 mg aspirin daily in subjects with secondary endpoint of vascular events nonfatal MI. Although the decreases in chronic stable angina pectoris. The (first occurrence of MI, stroke, or vascular deaths and all cause mortality study showed a significant reduction in vascular death). The study also showed were not statistically significant, there the primary endpoint of fatal or nonfatal a significant overall reduction in a major was a favorable trend in the aspirin 56810 Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations group for both of these endpoints and a with coronary artery disease that show PTCA procedures have an underlying weakly favorable trend for stroke. There reduced risk for similar endpoints, condition for which aspirin is indicated. were more reports of serious bleeds in specifically patients with a prior MI. Similarly, the agency believes subjects the aspirin group than in the placebo The dosage range is also revised from with lesions of the carotid bifurcation group, but the difference was not ‘‘300 to 325 mg daily’’ to ‘‘75 to 325 mg sufficient to require carotid significant. As in many other studies, daily,’’ to include the lower dose used endarterectomy are likely to have had a however, there were more hemorrhagic in the SAPAT study, and the ‘‘Clinical TIA or stroke, and may also have strokes in the aspirin group than the Studies’’ section of the professional coexisting coronary artery disease (Ref. placebo group. All the subjects in the labeling includes information on this 34). Therefore, the agency is adding an SAPAT study were treated with sotalol. study. indication to the professional labeling Therefore, the question arises as to The agency has considered the for subjects who have had specific whether it can be concluded that aspirin petition’s request for an indication for arterial revascularization procedures is effective in angina patients not aspirin for subjects who have undergone (i.e., CABG, PTCA, or carotid receiving sotalol (or some other beta revascularization procedures including endarterectomy). Likewise, the agency blocker). Although there are not specific coronary artery bypass graft (CABG), believes it is reasonable to recommend data on this point, the ability of aspirin percutaneous transluminal coronary the standard dosages being used in to decrease the rate of thrombotic angioplasty (PTCA), carotid clinical practice (Refs. 35 through 37) vascular events in various settings has endarterectomy, peripheral artery grafts, during the preoperative period. The not required or, to date, been related to, peripheral arterial fistula or shunt, or following dosages are included in this the presence or absence of beta blockers. peripheral angioplasty. The agency final rule: CABG, 325 mg daily, starting Therefore, the agency concludes that the considered the published reports 6 hours post-procedure and continued 1 SAPAT study supports the use of submitted by the petitioner that year; PTCA, 325 mg 2 hours presurgery, aspirin in patients with chronic stable evaluated aspirin alone in one arm followed by maintenance therapy of 160 angina, with or without sotalol. versus a placebo or other active to 325 mg daily; and carotid The agency presented a summary of ingredient, and additional information endarterectomy, 80 mg daily to 650 mg its findings for the SAPAT study at the from the report of the Fourth American twice daily preoperatively and meeting of the Joint Advisory College of Chest Physicians (ACCP) continued indefinitely. Committee on January 23, 1997. The Consensus Conference on The issue of an indication for aspirin Joint Advisory Committee unanimously Antithrombotic Therapy (Ref. 29). The for subjects with peripheral arterial agreed that the SAPAT study supports agency concluded (Ref. 26) that there disease was also considered by the Joint the use of aspirin in subjects with was insufficient evidence, based on the Advisory Committee. The Joint chronic stable angina pectoris, and that published studies, to support the Advisory Committee concluded that the an indication for low-dose aspirin professional labeling of aspirin alone in trials that used aspirin alone showed no should be extended to that population. patients who have undergone effect on subjects with peripheral Ridker et al. (Ref. 28) assessed those revascularization procedures, although arterial disease, despite a sizable data subjects with chronic stable angina who some studies have suggested benefit in base in which to examine this effect. By entered the U.S. Physicians’ Health these patients (Refs. 30 through 34). a vote of 11 to 4, the members Study (Ref. 4). The authors concluded The issue of aspirin use in patients recommended not to label aspirin for that aspirin therapy reduced the risk of who have undergone revascularization the indication. The agency agrees with first MI among patients with chronic procedures was considered by the Joint the Committee and concludes that there stable angina. However, the agency Advisory Committee on January 23, is insufficient data to support found that some of the subjects entered 1997. The panel members concluded professional labeling for aspirin alone in into the U.S. Physicians’ Health Study that specific studies have not been subjects with peripheral arterial disease, had evidence of a previous MI. Thus, it presented to show effectiveness of including subjects with and without is possible that in the subgroup of aspirin for this population. However, peripheral artery grafts or peripheral subjects with chronic stable angina they noted that almost all patients who angioplasty. pectoris, some subjects may also have undergo coronary revascularization The petitioner has withdrawn the had a previous MI. Aspirin has already procedures have already had request for an indication for aspirin for been shown to be effective in subjects symptomatic coronary disease, such as subjects requiring hemodialysis access with a previous MI and, therefore, some stable or unstable angina or MI. The with a fistula or shunt, and for subjects of the positive results found in the Joint Advisory Committee with atrial fibrillation (Ref. 38). Ridker study may in part be due to recommended unanimously that aspirin aspirin’s demonstrated effectiveness in be recommended for subjects who have B. Comments to the Proposal to Include patients with previous MI. Nevertheless, undergone revascularization procedures Acute MI in Professional Labeling of the results of the Ridker study are such as CABG or PTCA if there is a Aspirin consistent with the findings in the preexisting condition for which aspirin 7. The agency received four comments SAPAT study, and lend some additional is already indicated. However, the Joint (Ref. 2) that addressed the need for support for an indication for aspirin for Advisory Committee made no specific additional warnings relating to the use subjects with chronic stable angina recommendation regarding the use of of aspirin for cardiovascular and pectoris. aspirin in subjects who have undergone cerebrovascular indications. Two The agency is, therefore, extending carotid endarterectomy. comments recommended that additional the indication for aspirin for The agency agrees with the Joint information about adverse events be cardiovascular uses in proposed Advisory Committee’s recommendation included in the professional and § 343.80(c) to include reducing the that the professional labeling of aspirin consumer labeling. Two comments combined risk of MI and sudden death should include subjects who have argued against the need for additional in patients with chronic stable angina undergone revascularization procedures warnings. pectoris. This conclusion is also for symptomatic coronary artery disease. One comment recommended that supported by substantial additional It is a reasonable assumption that, in professional aspirin labeling be revised controlled trials in other populations general, subjects who have had CABG or to provide the following: (1) Information Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations 56811 for physicians on the risk of adverse GI all of the professional uses of aspirin document. The agency will address effects associated with the long-term use into a single labeling format. The final consumer aspirin labeling in the final of low-dose aspirin, and (2) advice to aspirin professional labeling also rule for internal analgesic, antipyretic, physicians concerning appropriate includes an optional highlights section and antirheumatic drug products, which analgesic and antipyretic use in their that summarizes the professional will be published in a future issue of the patients who are taking long-term low- indications for aspirin and the Federal Register. dose aspirin for cardiovascular recommended dosage and 9. One comment asked the agency to indications. The comment further administration for each indication. The consider several proposed wording recommended that consumer aspirin highlights section, if disseminated, must changes. The comment suggested labeling should be revised to: (1) Alert accompany the required professional changing the proposed sentence ‘‘a dose consumers to the signs and symptoms of labeling as provided in § 343.80(a). of 162.5 mg/day, started as soon as adverse events that might occur with Dissemination of the highlights section, possible after a suspected infarction’’ to therapeutic (labeled) doses of aspirin, however, is not required. ‘‘a dose of 162.5 mg/day, started as soon This professional labeling also and (2) advise patients that they should as possible during’ a suspected includes complete information on consult their physician prior to any infarction.’’ The comment suggested adverse reactions. The labeling states, analgesic use for pain or fever relief if that the current wording is misleading they are taking low-dose aspirin under ‘‘Many adverse reactions due to aspirin and implies that treatment not be a physician’s care for cardiovascular ingestion are dose-related.’’ Among the initiated until a diagnosis of infarction indications. The comment asserted that adverse reactions listed are GI bleeding, is established. adverse GI effects are present with ulceration, and perforation, as requested aspirin in doses as low as 30 mg per day by the comment. Also, this labeling The agency agrees that the dosing and that the risk of adverse GI events warns against concurrent use of aspirin information for suspected acute MI increases as the aspirin dose increases. with other with similar should be revised to emphasize the In support of this position, the comment adverse drug event profiles because this immediate use of aspirin for suspected included literature articles (Refs. 4, 11, may result in an increase in adverse acute MI. However, the agency believes 22, and 39 through 46). drug reactions, and it includes a that instructions for the initial dose of Another comment acknowledged that warning regarding bleeding risks aspirin to be administered ‘‘as soon as adverse events from aspirin use have associated with chronic, heavy use of an MI is suspected’’ better conveys the been carefully studied and alcohol. (See the final rule published need for immediate action and has characterized, and stated that even at elsewhere in this issue of the Federal included this information in the the highest doses studied, 1,500 mg per Register entitled ‘‘Over-the-Counter professional labeling for suspected acute day, the incidence of serious adverse Drug Products Containing Analgesic/ MI. events is small. The comment noted that Antipyretic Active Ingredients for 10. One comment recommended a the internal analgesic TFM proposes a Internal Use; Required Alcohol dosage range of 162.5 to 325 mg aspirin total daily aspirin dose of 4,000 mg for Warning’’.) per day for suspected acute MI. In acute pain management. The comment The agency does not believe that this support of its request, the comment concluded that none of the studies cited labeling will interfere with a physician’s cited the results of the ISIS–2 and ISIS by the first comment demonstrate that a guidance to a patient. Rather, both the pilot studies. The comment suggested person taking 75 to 325 mg per day of content and the format of the labeling is that this dosage range for suspected aspirin is at risk of adverse events other expected to enhance appropriate acute MI is more consistent with agency than those already labeled if additional choices. dosing recommendations for other The agency will address consumer aspirin is taken for short-term analgesic professional labeling indications for aspirin labeling in the final rule for or antipyretic use. The comment aspirin, e.g., 300 to 325 mg aspirin for internal analgesic, antipyretic, and concluded that labeling should not be the prevention of a second heart attack. proposed which could interfere with a antirheumatic drug products, which physician’s guidance to a patient, and will be published in a future issue of the In the preamble to the proposed rule that aspirin should not be singled out Federal Register. for the use of aspirin, buffered aspirin, for special consideration. One comment 8. One comment asked the agency to and aspirin/antacid combinations to noted that professional labeling already include an indication for acute MI in reduce the risk of vascular mortality in includes information concerning OTC consumer drug labeling. The people with suspected acute MI (61 FR adverse reactions and no further comment stated that a significant 30002), the agency discussed the basis changes are necessary. number of people who die of heart for its conclusions on the effective dose The agency agrees that physicians attacks do so beyond the reach of of aspirin for this use. The results of the should be provided information on health-care providers. The comment ISIS–2 study (162.5 mg aspirin per day) potential adverse events from long-term argued that by limiting the proposed (Ref. 7) were accepted by the agency as low-dose aspirin use. The agency indication to professional labeling, the the primary support for the indication. believes this information should not be agency neglects consumers at risk for Concerning the ISIS pilot study (Ref. limited to potential adverse GI events, heart attack. The comment said that this 47), the agency noted that a 325 mg but that professional labeling should population needs to know that a half an aspirin dose every other day produced: include complete prescribing aspirin can reduce their risk of (1) A nonsignificant reduction in information for practitioners licensed to cardiovascular morbidity and mortality. nonfatal reinfarction, (2) a significantly prescribe drugs. Therefore, the agency The comment also recommended a lower rate of in-hospital deaths (all has developed aspirin professional warning stating that patients should causes), and (3) similar rates of post- labeling containing the type of seek immediate diagnosis and treatment hospital deaths (61 FR 30005). prescribing information included in by a doctor. Therefore, the ISIS pilot study does not prescription drug labeling in a format The issue of whether consumer provide a basis to support a 325 mg similar to that required for prescription labeling is appropriate for an indication aspirin dose for suspected acute MI and drugs under §§ 201.56 and 201.57. In such as acute MI is addressed generally this dose is not included in this final addition, the agency has consolidated in section II.A, comment 5 of this rule. 56812 Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations

III. Summary of Changes professional labeling only for those (7) ISIS–2 (Second International Study Of Infarct Survival) Collaborative Group, 1. The TFM for OTC analgesic, products that meet USP dissolution and drug release standards in § 343.90. ‘‘Randomized Trial of Intravenous antipyretic, and antirheumatic drug Streptokinase, Oral Aspirin, Both, or Neither products included an indication for the 5. In the TFM, the agency proposed professional labeling indications for TIA Among 17,187 Cases of Suspected Acute professional use of aspirin, carbaspirin Myocardial Infarction: ISIS–2,’’ Lancet, calcium, magnesium salicylate, or and rheumatologic diseases for aspirin 2:349–360, 1988. sodium salicylate for rheumatologic and buffered aspirin drug products (8) The Canadian Cooperative Study diseases (53 FR 46204 at 46244). The identified in § 343.10(b), except those Group, ‘‘A Randomized Trial of Aspirin and indication was based on the buffered with sodium. The TFM did not in Threatened Stroke,’’ New England Journal of Medicine, 299:53–59, recommendations of the Panel made in include these indications for aspirin in combination with antacids identified in 1978. 1977. No comments were received in (9) Yusef, S., ‘‘Analysis and Interpretation response to the TFM concerning this § 343.20(b)(3). The agency is expanding the professional labeling indications for of Treatment Effects in Subgroups of Patients indication. The indication for the use of in Randomized Clinical Trials,’’ Journal of aspirin in rheumatologic diseases has TIA and rheumatologic diseases in this the American Medical Association, 266:93– been updated. For completeness, the final rule to include aspirin drug 98, 1991. agency has included full prescribing products buffered with sodium and (10) Fields, W. S. et al., ‘‘Controlled Trial information for the professional uses of aspirin in combination with antacid. of Aspirin in Cerebral Ischemia,’’ Stroke, 8:301–316, 1977. aspirin, including full information for The agency has taken this action based on: (1) The additional prescribing (11) UK–TIA Study Group, ‘‘United the treatment of the signs and symptoms Kingdom Transient Ischaemic Attack (UK– of rheumatologic disease. However, information included in this final rule on the use of sodium-containing TIA) Aspirin Trial: Interim Results,’’ British professional labeling on the use of other Medical Journal, 296:316–320, 1988. Category I salicylates for rheumatologic products in patients who need to restrict (12) Bousser, M. G. et al., ‘‘‘AICLA’ diseases has not been included and will their sodium intake; (2) data that show Controlled Trial of Aspirin and Dipyridamole be addressed in the final rule for OTC there is no significant difference in the Secondary Prevention of Athero- internal analgesic, antipyretic, and between the plasma aspirin levels Thrombotic Cerebral Ischemia,’’ Stroke, 14:5– antirheumatic drug products to be obtained with aspirin, buffered aspirin, 14, 1983. (13) Sivenius, J. et al., ‘‘The European published in a future issue of the and aspirin in combination with antacids (Refs. 48 and 49); (3) the lower Stroke Prevention Study: Results According Federal Register. to Sex,’’ Neurology, 41:1189–1192, 1991. 2. To allow for the codification of the dosage of aspirin for TIA; and (4) the physician’s routine practice of titrating (14) The American-Canadian Co-Operative professional labeling, the agency is: (1) Study Group, ‘‘Persantine Aspirin Trial in Finalizing certain sections of the the dosage of aspirin to an effective Cerebral Ischemia Part II: Endpoint Results,’’ proposed rule pertaining to scope, blood level for rheumatologic diseases. Stroke, 16:406–415, 1985. 6. Portions of the proposed rule definitions, and testing procedures that (15) A Swedish Cooperative Study, ‘‘High- would have amended 21 CFR 310.201, apply to both OTC and professional Dose Acetylsalicylic Acid after Cerebral 369.20, and 369.21. This final rule is labeling; (2) adding definitions in Infarction,’’ Stroke, 18:325–334, 1987. one segment of the proposed rule and (16) Antiplatelet Trialists’ Collaboration, § 343.3; and (3) adding §§ 343.12, 343.13 does not affect these sections. The other ‘‘Secondary Prevention of Vascular Disease and 343.22 which include portions of the proposed rule will be by Prolonged Antiplatelet Treatment,’’ British cardiovascular and rheumatologic active discussed in a future issue of the Medical Journal, 296:320–331, 1988. ingredients and permitted combinations Federal Register. (17) Fields, W. S. et al., ‘‘Controlled Trial of active ingredients. of Aspirin in Cerebral Ischemia. Part II: 3. The heading for § 343.90 under IV. References Surgical Group,’’ Stroke, 9:309–318, 1978. (18) Sorensen, P. S. et al., ‘‘Acetylsalicylic ‘‘Testing Procedures’’ has been changed The following references are on from ‘‘Dissolution testing’’ to Acid in the Prevention of Stroke in Patients display in the Dockets Management with Reversible Cerebral Ischemic Attacks. A ‘‘Dissolution and drug release testing’’ Branch (address above) and may be seen to include the current United States Danish Cooperative Study,’’ Stroke, 14:15– by interested persons between 9 a.m. 22, 1983. Pharmacopeia (USP) terminology for and 4 p.m., Monday through Friday. (19) Reuther, R., and W. Dorndorf, testing delayed-release products. The (1) Comment Nos. C146, C153, C154, C155, ‘‘Aspirin in Patients with Cerebral Ischemia agency has updated the dissolution tests CP9, CP10, and CP12, Docket No. 77N–0094, and Normal Angiograms. The Results of a in § 343.90 from those contained in USP Dockets Management Branch. Double Blind Trial,’’ in Acetylsalicylic Acid XXI, which were in effect when the (2) Comment Nos. C1–C10, Docket No. in Cerebral Ischaemic and Coronary Artery TFM was published, to those currently 77N–0094A, Dockets Management Branch. Disease, edited by Breddin, K. et al., in effect in USP 23. The dissolution (3) Steering Committee of the Physicians’ Schatauer Verlag, Stuttgart Germany, pp. 97– testing procedures have been added for Health Study Research Group, ‘‘Preliminary 106, 1978. aspirin, alumina, and magnesium oxide Report: Findings from the Aspirin (20) Antiplatelet Trialists’ Collaboration, Component of the Ongoing Physicians’ ‘‘Collaborative Overview of Randomized tablets and aspirin effervescent tablets Health Study,’’ New England Journal of Trials of Antiplatelet Therapy—I: Prevention for oral solution in § 343.90(f) and (g), Medicine, 318:262–264, 1988. of Death, Myocardial Infarction, and Stroke respectively. (A monograph for these (4) Steering Committee of the Physicians’ by Prolonged Antiplatelet Therapy in Various products were included in the USP after Health Study Research Group, ‘‘Final Report Categories of Patients,’’ British Medical publication of the TFM.) Proposed on the Aspirin Component of the Ongoing Journal, 308:81–106, 1994. § 343.90(f) for buffered aspirin tablets is Physicians’ Health Study,’’ New England (21) Boysen, G. et al., ‘‘Danish Very-Low- now § 343.90(h). Journal of Medicine, 321:129–135, 1989. Dose Aspirin after Carotid Endarterectomy 4. The minimum dosages for the (5) Peto, R. et al., ‘‘Randomized Trial of Trial,’’ Stroke, 19:1211–1215, 1988. vascular indications in this final rule are Prophylactic Daily Aspirin in British Male (22) The SALT Collaborative Group, Doctors,’’ British Medical Journal, 296:313– ‘‘Swedish Aspirin Low-Dose Trial (SALT) of lower than those proposed in the TFM. 316, 1988. 75 mg Aspirin as Secondary Prophylaxis after The agency is concerned about the (6) Manson, J. E. et al., ‘‘Medical Progress: Cerebrovascular Ischaemic Events,’’ Lancet, impact of formulation on the The Primary Prevention of Myocardial 338:1345–1349, 1991. effectiveness of the lower-dose aspirin. Infarction,’’ New England Journal of (23) Diener, H. C. et al., ‘‘European Stroke Therefore, this final rule allows Medicine, 326:1406–1416, 1992. Prevention Study 2. Dipyridamole and Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations 56813

Acetylsalicylic Acid in the Secondary Analgesics,’’ Archives of Internal Medicine, final rule is not a significant regulatory Prevention of Stroke,’’ Journal of 148:281–285, 1988. action as defined by the Executive Order Neurological Sciences, 143:1–13, 1996. (42) The Dutch TIA Trial Study Group, ‘‘A and, thus, is not subject to review under (24) Matchar, D. B. et al., ‘‘Medical Comparison of Two Doses of Aspirin (30 mg the Executive Order. This rule also does Treatment for Stroke Prevention,’’ Annals of vs. 283 mg a Day) in Patients after a Transient Internal Medicine, 121:41–53, 1994. Ischemic Attack or Minor Ischemic Stroke,’’ not trigger the requirement for a written (25) FDA evaluation of ESPS–2 data, OTC New England Journal of Medicine, 325:1261– statement under section 202(a) of the Volume 03BFMP, Docket No. 77N–0094, 1266, 1991. Unfunded Mandates Reform Act Dockets Management Branch. (43) Weil, J. et al., ‘‘Prophylactic Aspirin because it does not impose a mandate (26) Minutes of Meeting between and Risk of Peptic Ulcer Bleeding,’’ British that results in an expenditure of $100 representatives of FDA and The Aspirin Medical Journal, 310:827–830, 1995. million or more by State, local, and Strategy Group, on April 25, 1996, Coded (44) Kelly, J. P. et al., ‘‘Risk of Aspirin- tribal governments in the aggregate, or MM21, Docket No. 77N–0094, Dockets Associated Major Upper-Gastrointestinal by the private sector, in any 1 year. Management Branch. Bleeding with Enteric-Coated or Buffered Product,’’ Lancet, 348–1413–1416, 1996. If a rule would have a significant (27) Juul-Mo¨ller, S. et al., ‘‘Double-Blind impact on a substantial number of small Trial of Aspirin in Primary Prevention of (45) Soll, A. H. et al., ‘‘Nonsteroidal Myocardial Infarction in Patients with Stable Antiinflammatory Drugs and Peptic Ulcer entities, the Regulatory Flexibility Act Chronic Angina Pectoris,’’ Lancet, 340:1421– Disease,’’ Annals of Internal Medicine, requires agencies to analyze regulatory 1425, 1992. 114:307–319, 1991. options that would minimize the impact (28) Ridker, P. M. et al., ‘‘Low-Dose Aspirin (46) Fuster, V. et al., ‘‘Aspirin as a of the rule on small entities. This final Therapy for Chronic Stable Angina,’’ Annals Therapeutic Agent in Cardiovascular rule will impose direct one-time costs of Internal Medicine, 114:835–839, 1991. Disease,’’ Circulation, 87(2):659–675, 1993. associated with changing professional (29) Dalen, J. E., and J. Hirsh, (Guest (47 ) ISIS Pilot Study Investigators, labeling to reflect current information. Editors), Fourth ACCP Consensus Conference ‘‘Randomized Factorial Trial of High-Dose Intravenous Streptokinase, of Oral Aspirin, In the June 13, 1996 (61 FR 30002 at on Antithrombotic Therapy, Chest, 30007), amendment to the TFM, the 108:225S–522S, October 1995 (Supplement). and of Intravenous Heparin in Acute (30) Goldman, S. et al., ‘‘Improvement in Myocardial Infarction,’’ European Heart agency certified that the rule would not Early Saphenous Vein Graft Patency after Journal, 8:634–642, 1987. have a significant economic impact on Coronary Artery Bypass Surgery with (48) Itthipanichpong, C. et al., ‘‘The Effect a substantial number of small entities, Antiplatelet Therapy: Results of a Veterans of Antacid on Aspirin Pharmacokinetics in based on the fact that few manufacturers Administrative Cooperative Study,’’ Healthy Thai Volunteers,’’ Drug Metabolism of aspirin products appear to distribute Circulation, 77:1324–1332, 1988. and Drug Interaction, 10:213–228, 1992. professional labeling for their products (49) Vigano, G. et al., ‘‘Pharmacokinetic (31) Goldman, S. et al., ‘‘Saphenous Vein and that manufacturers who do Graft Patency 1 Year after Coronary Artery Study of a New Oral Buffered Acetylsalicylic Acid (ASA) Formulation in Comparison with distribute such professional labeling Bypass Surgery and Effects of Antiplatelet will have 1 year after publication of this Therapy: Results of a Veterans Plain ASA in Healthy Volunteers,’’ International Journal for Clinical final rule to implement this relabeling. Administration Cooperation Study,’’ Pharmacological Research, 11:129–135, Circulation, 80:1190–1197, 1989. The economic impact of this final rule 1991. (32) Lorenz, R. L. et al., ‘‘Improved on manufacturers appears to be Aortocoronary Bypass Patency by Low-Dose V. Analysis of Impacts minimal. The agency did not receive Aspirin (100 mg Daily),’’ Lancet, pp. 1261– any comments challenging the basis for 1263, 1984. An analysis of the costs and benefits its initial proposed certification. (33) Brown, G. B. et al., ‘‘Improved Graft of this regulation conducted under Accordingly, the agency certifies that Patency in Patients Treated with Platelet- Executive Order 12291 was discussed in the final rule will not have a significant inhibiting Therapy after Coronary Bypass the TFM for OTC internal analgesic, economic impact on a substantial Surgery,’’ Circulation, 72:138–146, 1985. antipyretic, and antirheumatic drug number of small entities. Therefore, (34) Kretschmer, G. et al., ‘‘Antiplatelet products (53 FR 46204 at 46254). No Treatment Prolongs Survival after Carotid under the Regulatory Flexibility Act, no comments on the economic impact further analysis is required. Bifurcation Endarterectomy,’’ Annals of related to professional labeling for Surgery, 211:317–322, 1990. VI. Paperwork Reduction Act of 1995 (35) Stein, P. D. et al., ‘‘Antithrombotic aspirin were received in response to the Therapy in Patients with Saphenous Vein agency’s request for specific comment FDA concludes that the labeling and Internal Mammary Artery Bypass on the economic impact of this requirements in this final rule are not Grafts,’’ Chest, 108:424S–430S, 1995. rulemaking. Executive Order 12291 has subject to review by the Office of (36) Popma, J. J. et al., ‘‘Antithrombotic been superseded by Executive Order Management and Budget because they Therapy in Patients Undergoing Coronary 12866. do not constitute a ‘‘collection of Angioplasty,’’ Chest, 108:486S–501S, 1995. FDA has examined the impacts of the information’’ under the Paperwork (37) Clagett, P. G. et al., ‘‘Antithrombotic final rule under Executive Order 12866, Reduction Act of 1995 (44 U.S.C. 3501 Therapy in Peripheral Arterial Occlusive the Regulatory Flexibility Act (5 U.S.C. et seq.). Rather, the labeling statements Disease,’’ Chest, 108:431S–443S, 1995. 601–612), and the Unfunded Mandates (38) Letter from C. H. Hennekens, are a ‘‘public disclosure of information Chairman Aspirin Strategy Group, to W. E. Reform Act of 1995 (Pub. L. 104–4). originally supplied by the Federal Gilbertson, FDA, coded LET134, Docket No. Executive Order 12866 directs agencies Government to the recipient for the 77N–0094, Dockets Management Branch. to assess all costs and benefits of purpose of disclosure to the public’’ (5 (39) Kurata, J. H., and D. E. Abbey, ‘‘The available regulatory alternatives and, CFR 1320.3(c)(2)). Effect of Chronic Aspirin Use on Duodenal when regulation is necessary, to select and Gastric Ulcer Hospitalization,’’ Journal of regulatory approaches that maximize VII. Environmental Impact Clinical Gastroenterology, 12:260–266, 1990. net benefits (including potential The agency has determined under 21 (40) Laporte, J. R. et al., ‘‘Upper economic, environmental, public health CFR 25.24(c)(6) that this action is of a Gastrointestinal Bleeding in Relation to and safety, and other advantages; type that does not individually or Previous Use of Analgesics and Nonsteroidal Antiinflammatory Drugs,’’ Lancet, 337:85–89, distributive impacts; and equity). The cumulatively have a significant effect on 1991. agency believes that this final rule is the human environment. Therefore, (41) Levy, M. et al., ‘‘Major Upper consistent with the regulatory neither an environmental assessment Gastrointestinal Tract Bleeding: Relation to philosophy and principles identified in nor an environmental impact statement Use of Aspirin and Other Nonnarcotic the Executive Order. In addition, the is required. 56814 Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations

List of Subjects in 21 CFR Part 343 Subpart BÐActive Ingredients standards for dissolution or drug release in § 343.90.) Labeling, Over-the-counter drugs. § 343.10 [Reserved] (1) The labeling contains the Therefore, under the Federal Food, § 343.12 Cardiovascular active following prescribing information under Drug, and Cosmetic Act and under ingredients. the heading ‘‘Comprehensive Prescribing Information’’ and the authority delegated to the Commissioner (a) Aspirin. subheadings ‘‘Description,’’ ‘‘Clinical of Food and Drugs, 21 CFR Chapter I is (b) Buffered aspirin. Aspirin Pharmacology,’’ ‘‘Clinical Studies,’’ amended as follows: identified in paragraph (a) of this ‘‘Animal Toxicology,’’ ‘‘Indications and 1. Part 343 is added to read as follows: section may be buffered with any Usage,’’ ‘‘Contraindications,’’ antacid ingredient(s) identified in ‘‘Warnings,’’ ‘‘Precautions,’’ ‘‘Adverse PART 343ÐINTERNAL ANALGESIC, § 331.11 of this chapter provided that Reactions,’’ ‘‘Drug Abuse and ANTIPYRETIC, AND ANTIRHEUMATIC the finished product contains at least Dependence,’’ ‘‘Overdosage,’’ ‘‘Dosage DRUG PRODUCTS FOR OVER±THE± 1.9 milliequivalents of acid-neutralizing and Administration,’’ and ‘‘How COUNTER HUMAN USE capacity per 325 milligrams of aspirin as Supplied’’ in the exact language and the measured by the procedure provided in Subpart AÐGeneral Provisions exact order provided as follows: the United States Pharmacopeia 23/ Sec. National Formulary 18. COMPREHENSIVE PRESCRIBING 343.1 Scope. INFORMATION § 343.13 Rheumatologic active 343.3 Definitions. ingredients. DESCRIPTION Subpart BÐActive Ingredients (a) Aspirin. (Insert the proprietary name and the established name (if any) of the drug, type of 343.10 [Reserved] (b) Buffered aspirin. Aspirin dosage form (followed by the phrase ‘‘for oral 343.12 Cardiovascular active ingredients. identified in paragraph (a) of this administration’’), the established name(s) 343.13 Rheumatologic active ingredients. section may be buffered with any and quantity of the active ingredient(s) per 343.20 [Reserved] antacid ingredient(s) identified in dosage unit, the total sodium content in 343.22 Permitted combinations of active § 331.11 of this chapter provided that milligrams per dosage unit if the sodium ingredients for cardiovascular- the finished product contains at least content of a single recommended dose is 5 rheumatologic use. 1.9 milliequivalents of acid-neutralizing milligrams or more, the established name(s) capacity per 325 milligrams of aspirin as (in alphabetical order) of any inactive Subpart CÐLabeling measured by the procedure provided in ingredient(s) which may cause an allergic hypersensitivity reaction, the 343.50 [Reserved] the United States Pharmacopeia 23/ pharmacological or therapeutic class of the 343.60 [Reserved] National Formulary 18. drug, and the chemical name(s) and 343.80 Professional labeling. structural formula(s) of the drug.) Aspirin is § 343.20 [Reserved] Subpart DÐTesting Procedures an odorless white, needle-like crystalline or § 343.22 Permitted combinations of active powdery substance. When exposed to 343.90 Dissolution and drug release ingredients for cardiovascular- moisture, aspirin hydrolyzes into salicylic testing. rheumatologic use. and acetic acids, and gives off a vinegary- Authority: 21 U.S.C. 321, 351, 352, 353, odor. It is highly lipid soluble and slightly Combinations containing aspirin must soluble in water. 355, 360, 371. meet the standards of an acceptable Subpart AÐGeneral Provisions dissolution test, as set forth in § 343.90. CLINICAL PHARMACOLOGY The following combinations are Mechanism of Action: Aspirin is a more § 343.1 Scope. permitted: Aspirin identified in potent inhibitor of both synthesis and platelet aggregation than other (a) An over-the-counter analgesic- §§ 343.12 and 343.13 may be combined with any antacid ingredient identified derivatives. The differences in antipyretic drug product in a form activity between aspirin and salicylic acid suitable for oral administration is in § 331.11 of this chapter or any are thought to be due to the acetyl group on generally recognized as safe and combination of antacids permitted in the aspirin molecule. This acetyl group is effective and is not misbranded if it accordance with § 331.10(a) of this responsible for the inactivation of cyclo- meets each of the conditions in this part chapter provided that the finished oxygenase via acetylation. product meets the requirements of in addition to each of the general PHARMACOKINETICS § 331.10 of this chapter and is marketed conditions established in § 330.1 of this Absorption: In general, immediate release chapter. in a form intended for ingestion as a solution. aspirin is well and completely absorbed from (b) References in this part to the gastrointestinal (GI) tract. Following regulatory sections of the Code of Subpart CÐLabeling absorption, aspirin is hydrolyzed to salicylic Federal Regulations are to chapter I of acid with peak plasma levels of salicylic acid title 21 unless otherwise noted. § 343.50 [Reserved] occurring within 1–2 hours of dosing (see Pharmacokinetics—Metabolism). The rate of § 343.3 Definitions. § 343.60 [Reserved] absorption from the GI tract is dependent upon the dosage form, the presence or As used in this part: § 343.80 Professional labeling. absence of food, gastric pH (the presence or Analgesic-antipyretic drug. An agent The labeling of an over-the-counter absence of GI antacids or buffering agents), drug product written for health and other physiologic factors. Enteric coated used to alleviate pain and to reduce aspirin products are erratically absorbed from fever. professionals (but not for the general public) shall consist of the following: the GI tract. Distribution: Salicylic acid is widely Cardiovascular drug. An agent used to (a) For products containing aspirin prevent ischemic events. distributed to all tissues and fluids in the identified in §§ 343.12 and 343.13 or body including the central nervous system Rheumatologic drug. An agent used permitted combinations identified in (CNS), breast milk, and fetal tissues. The for the treatment of rheumatologic § 343.22. (These products must meet highest concentrations are found in the disorders. United States Pharmacopeia (USP) plasma, liver, renal cortex, heart, and lungs. Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations 56815

The protein binding of salicylate is endpoint of stroke or death and the combined nonfatal stroke in patients who have had concentration-dependent, i.e., non-linear. At endpoint of TIA, stroke, or death by about ischemic stroke or transient ischemia of the low concentrations (< 100 micrograms/ 13–18 percent. brain due to fibrin platelet emboli, (2) reduce µ milliliter ( g/mL)), approximately 90 percent Suspected Acute Myocardial Infarction the risk of vascular mortality in patients with of plasma salicylate is bound to albumin (MI): In a large, multi-center study of aspirin, a suspected acute MI, (3) reduce the µ while at higher concentrations (> 400 g/mL), streptokinase, and the combination of aspirin combined risk of death and nonfatal MI in only about 75 percent is bound. The early and streptokinase in 17,187 patients with patients with a previous MI or unstable signs of salicylic overdose (salicylism), suspected acute MI, aspirin treatment angina pectoris, and (4) reduce the combined including tinnitus (ringing in the ears), occur produced a 23-percent reduction in the risk risk of MI and sudden death in patients with at plasma concentrations approximating 200 of vascular mortality. Aspirin was also µg/mL. Severe toxic effects are associated shown to have an additional benefit in chronic stable angina pectoris. with levels > 400 µg/mL. (See Adverse patients given a thrombolytic agent. Revascularization Procedures (Coronary Reactions and Overdosage.) Prevention of Recurrent MI and Unstable Artery Bypass Graft (CABG), Percutaneous Metabolism: Aspirin is rapidly hydrolyzed Angina Pectoris: These indications are Transluminal Coronary Angioplasty (PTCA), in the plasma to salicylic acid such that supported by the results of six large, and Carotid Endarterectomy): Aspirin is plasma levels of aspirin are essentially randomized, multi-center, placebo-controlled indicated in patients who have undergone undetectable 1–2 hours after dosing. Salicylic trials of predominantly male post-MI subjects revascularization procedures (i.e., CABG, acid is primarily conjugated in the liver to and one randomized placebo-controlled PTCA, or carotid endarterectomy) when there form salicyluric acid, a phenolic glucuronide, study of men with unstable angina pectoris. is a preexisting condition for which aspirin an acyl glucuronide, and a number of minor Aspirin therapy in MI subjects was is already indicated. metabolites. Salicylic acid has a plasma half- associated with a significant reduction (about Rheumatologic Disease Indications life of approximately 6 hours. Salicylate 20 percent) in the risk of the combined (Rheumatoid Arthritis, Juvenile Rheumatoid metabolism is saturable and total body endpoint of subsequent death and/or nonfatal Arthritis, Spondyloarthropathies, clearance decreases at higher serum reinfarction in these patients. In aspirin- Osteoarthritis, and the Arthritis and Pleurisy concentrations due to the limited ability of treated unstable angina patients the event of Systemic Lupus Erythematosus (SLE)): the liver to form both salicyluric acid and rate was reduced to 5 percent from the 10 Aspirin is indicated for the relief of the signs phenolic glucuronide. Following toxic doses percent rate in the placebo group. (10–20 grams (g)), the plasma half-life may be Chronic Stable Angina Pectoris: In a and symptoms of rheumatoid arthritis, increased to over 20 hours. randomized, multi-center, double-blind trial juvenile rheumatoid arthritis, osteoarthritis, Elimination: The elimination of salicylic designed to assess the role of aspirin for spondyloarthropathies, and arthritis and acid follows zero order pharmacokinetics; prevention of MI in patients with chronic pleurisy associated with SLE. (i.e., the rate of drug elimination is constant stable angina pectoris, aspirin significantly CONTRAINDICATIONS in relation to plasma concentration). Renal reduced the primary combined endpoint of excretion of unchanged drug depends upon nonfatal MI, fatal MI, and sudden death by Allergy: Aspirin is contraindicated in urine pH. As urinary pH rises above 6.5, the 34 percent. The secondary endpoint for patients with known allergy to nonsteroidal renal clearance of free salicylate increases vascular events (first occurrence of MI, anti-inflammatory drug products and in from < 5 percent to > 80 percent. stroke, or vascular death) was also patients with the syndrome of asthma, Alkalinization of the urine is a key concept significantly reduced (32 percent). rhinitis, and nasal polyps. Aspirin may cause in the management of salicylate overdose. Revascularization Procedures: Most severe urticaria, angioedema, or (See Overdosage.) Following therapeutic patients who undergo coronary artery bronchospasm (asthma). doses, approximately 10 percent is found revascularization procedures have already Reye’s Syndrome: Aspirin should not be excreted in the urine as salicylic acid, 75 had symptomatic coronary artery disease for used in children or teenagers for viral percent as salicyluric acid, as the phenolic which aspirin is indicated. Similarly, infections, with or without fever, because of and acyl glucuronides, respectively. patients with lesions of the carotid the risk of Reye’s syndrome with Pharmacodynamics: Aspirin affects bifurcation sufficient to require carotid concomitant use of aspirin in certain viral platelet aggregation by irreversibly inhibiting endarterectomy are likely to have had a illnesses. prostaglandin cyclo-oxygenase. This effect precedent event. Aspirin is recommended for lasts for the life of the platelet and prevents patients who undergo revascularization WARNINGS the formation of the platelet aggregating procedures if there is a preexisting condition Alcohol Warning: Patients who consume factor A2. Non-acetylated for which aspirin is already indicated. three or more alcoholic drinks every day salicylates do not inhibit this enzyme and Rheumatologic Diseases: In clinical studies should be counseled about the bleeding risks have no effect on platelet aggregation. At in patients with rheumatoid arthritis, somewhat higher doses, aspirin reversibly juvenile rheumatoid arthritis, ankylosing involved with chronic, heavy alcohol use while taking aspirin. inhibits the formation of prostaglandin I2 spondylitis and osteoarthritis, aspirin has (), which is an arterial been shown to be effective in controlling Coagulation Abnormalities: Even low vasodilator and inhibits platelet aggregation. various indices of clinical disease activity. doses of aspirin can inhibit platelet function At higher doses aspirin is an effective anti- leading to an increase in bleeding time. This inflammatory agent, partially due to ANIMAL TOXICOLOGY can adversely affect patients with inherited inhibition of inflammatory mediators via The acute oral 50 percent lethal dose in (hemophilia) or acquired (liver disease or cyclo-oxygenase inhibition in peripheral rats is about 1.5 g/kilogram (kg) and in mice vitamin K deficiency) bleeding disorders. tissues. In vitro studies suggest that other 1.1 g/kg. Renal papillary necrosis and GI Side Effects: GI side effects include mediators of inflammation may also be decreased urinary concentrating ability occur stomach pain, heartburn, nausea, vomiting, suppressed by aspirin administration, in rodents chronically administered high and gross GI bleeding. Although minor upper although the precise mechanism of action has doses. Dose-dependent gastric mucosal injury GI symptoms, such as dyspepsia, are not been elucidated. It is this non-specific occurs in rats and humans. Mammals may common and can occur anytime during suppression of cyclo-oxygenase activity in develop aspirin toxicosis associated with GI therapy, physicians should remain alert for peripheral tissues following large doses that symptoms, circulatory effects, and central signs of ulceration and bleeding, even in the leads to its primary side effect of gastric nervous system depression. (See absence of previous GI symptoms. Physicians irritation. (See Adverse Reactions.) Overdosage.) should inform patients about the signs and CLINICAL STUDIES INDICATIONS AND USAGE symptoms of GI side effects and what steps Ischemic Stroke and Transient Ischemic Vascular Indications (Ischemic Stroke, to take if they occur. Attack (TIA): In clinical trials of subjects TIA, Acute MI, Prevention of Recurrent MI, Peptic Ulcer Disease: Patients with a with TIA’s due to fibrin platelet emboli or Unstable Angina Pectoris, and Chronic history of active peptic ulcer disease should ischemic stroke, aspirin has been shown to Stable Angina Pectoris): Aspirin is indicated avoid using aspirin, which can cause gastric significantly reduce the risk of the combined to: (1) Reduce the combined risk of death and mucosal irritation and bleeding. 56816 Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations

PRECAUTIONS Carcinogenesis, Mutagenesis, Impairment may have difficulty perceiving tinnitus. In General of Fertility: Administration of aspirin for 68 these patients, tinnitus cannot be used as a weeks at 0.5 percent in the feed of rats was clinical indicator of salicylism. Renal Failure: Avoid aspirin in patients not carcinogenic. In the Ames Salmonella Urogenital: Interstitial nephritis, papillary with severe renal failure (glomerular assay, aspirin was not mutagenic; however, necrosis, proteinuria, renal insufficiency and filtration rate less than 10 mL/minute). aspirin did induce chromosome aberrations failure. Hepatic Insufficiency: Avoid aspirin in in cultured human fibroblasts. Aspirin patients with severe hepatic insufficiency. inhibits ovulation in rats. (See Pregnancy.) DRUG ABUSE AND DEPENDENCE Sodium Restricted Diets: Patients with Pregnancy: Pregnant women should only Aspirin is non-narcotic. There is no known sodium-retaining states, such as congestive take aspirin if clearly needed. Because of the potential for addiction associated with the heart failure or renal failure, should avoid known effects of NSAID’s on the fetal use of aspirin. sodium-containing buffered aspirin cardiovascular system (closure of the ductus OVERDOSAGE preparations because of their high sodium arteriosus), use during the third trimester of content. pregnancy should be avoided. Salicylate Salicylate toxicity may result from acute Laboratory Tests: Aspirin has been products have also been associated with ingestion (overdose) or chronic intoxication. associated with elevated hepatic enzymes, alterations in maternal and neonatal The early signs of salicylic overdose blood urea nitrogen and serum creatinine, hemostasis mechanisms, decreased birth (salicylism), including tinnitus (ringing in hyperkalemia, proteinuria, and prolonged weight, and with perinatal mortality. the ears), occur at plasma concentrations bleeding time. Labor and Delivery: Aspirin should be approaching 200 µg/mL. Plasma µ Drug Interactions avoided 1 week prior to and during labor and concentrations of aspirin above 300 g/mL delivery because it can result in excessive are clearly toxic. Severe toxic effects are Angiotensin Converting Enzyme (ACE) blood loss at delivery. Prolonged gestation associated with levels above 400 µg/mL. (See Inhibitors: The hyponatremic and and prolonged labor due to prostaglandin Clinical Pharmacology.) A single lethal dose hypotensive effects of ACE inhibitors may be inhibition have been reported. of aspirin in adults is not known with diminished by the concomitant Nursing Mothers: Nursing mothers should certainty but death may be expected at 30 g. administration of aspirin due to its indirect avoid using aspirin because salicylate is For real or suspected overdose, a Poison effect on the renin-angiotensin conversion excreted in breast milk. Use of high doses Control Center should be contacted pathway. may lead to rashes, platelet abnormalities, immediately. Careful medical management is Acetazolamide: Concurrent use of aspirin and bleeding in nursing infants. essential. and acetazolamide can lead to high serum Pediatric Use: Pediatric dosing Signs and Symptoms: In acute overdose, concentrations of acetazolamide (and recommendations for juvenile rheumatoid severe acid-base and electrolyte disturbances toxicity) due to competition at the renal arthritis are based on well-controlled clinical may occur and are complicated by tubule for secretion. studies. An initial dose of 90–130 mg/kg/day and dehydration. Respiratory Anticoagulant Therapy (Heparin and in divided doses, with an increase as needed alkalosis occurs early while hyperventilation Warfarin): Patients on anticoagulation for anti-inflammatory efficacy (target plasma is present, but is quickly followed by therapy are at increased risk for bleeding salicylate levels of 150–300 µg/mL) are metabolic acidosis. because of drug-drug interactions and the effective. At high doses (i.e., plasma levels of Treatment: Treatment consists primarily of effect on platelets. Aspirin can displace greater than 200 mg/mL), the incidence of supporting vital functions, increasing warfarin from protein binding sites, leading toxicity increases. salicylate elimination, and correcting the to prolongation of both the prothrombin time acid-base disturbance. Gastric emptying and/ and the bleeding time. Aspirin can increase ADVERSE REACTIONS or lavage is recommended as soon as possible the anticoagulant activity of heparin, Many adverse reactions due to aspirin after ingestion, even if the patient has increasing bleeding risk. ingestion are dose-related. The following is a vomited spontaneously. After lavage and/or Anticonvulsants: Salicylate can displace list of adverse reactions that have been emesis, administration of activated charcoal, protein-bound phenytoin and valproic acid, reported in the literature. (See Warnings.) as a slurry, is beneficial, if less than 3 hours leading to a decrease in the total Body as a Whole: Fever, hypothermia, have passed since ingestion. Charcoal concentration of phenytoin and an increase thirst. adsorption should not be employed prior to in serum valproic acid levels. Cardiovascular: Dysrhythmias, emesis and lavage. Beta Blockers: The hypotensive effects of hypotension, tachycardia. Severity of aspirin intoxication is beta blockers may be diminished by the Central Nervous System: Agitation, determined by measuring the blood salicylate concomitant administration of aspirin due to , coma, confusion, dizziness, level. Acid-base status should be closely inhibition of renal , leading to , subdural or intracranial followed with serial blood gas and serum pH decreased renal blood flow, and salt and hemorrhage, lethargy, seizures. measurements. Fluid and electrolyte balance fluid retention. Fluid and Electrolyte: Dehydration, should also be maintained. Diuretics: The effectiveness of diuretics in hyperkalemia, metabolic acidosis, respiratory In severe cases, hyperthermia and patients with underlying renal or alkalosis. hypovolemia are the major immediate threats cardiovascular disease may be diminished by Gastrointestinal: Dyspepsia, GI bleeding, to life. Children should be sponged with the concomitant administration of aspirin ulceration and perforation, nausea, vomiting, tepid water. Replacement fluid should be due to inhibition of renal prostaglandins, transient elevations of hepatic enzymes, administered intravenously and augmented leading to decreased renal blood flow and hepatitis, Reye’s Syndrome, pancreatitis. with correction of acidosis. Plasma salt and fluid retention. Hematologic: Prolongation of the electrolytes and pH should be monitored to Methotrexate: Salicylate can inhibit renal prothrombin time, disseminated promote alkaline diuresis of salicylate if clearance of methotrexate, leading to bone intravascular coagulation, coagulopathy, renal function is normal. Infusion of glucose marrow toxicity, especially in the elderly or thrombocytopenia. may be required to control hypoglycemia. renal impaired. Hypersensitivity: Acute anaphylaxis, Hemodialysis and peritoneal dialysis can Nonsteroidal Anti-inflammatory Drugs angioedema, asthma, bronchospasm, be performed to reduce the body drug (NSAID’s): The concurrent use of aspirin laryngeal edema, urticaria. content. In patients with renal insufficiency with other NSAID’s should be avoided Musculoskeletal: Rhabdomyolysis. or in cases of life-threatening intoxication, because this may increase bleeding or lead to Metabolism: Hypoglycemia (in children), dialysis is usually required. Exchange decreased renal function. hyperglycemia. transfusion may be indicated in infants and Oral Hypoglycemics: Moderate doses of Reproductive: Prolonged pregnancy and young children. aspirin may increase the effectiveness of oral labor, stillbirths, lower birth weight infants, hypoglycemic drugs, leading to antepartum and postpartum bleeding. DOSAGE AND ADMINISTRATION hypoglycemia. Respiratory: Hyperpnea, pulmonary Each dose of aspirin should be taken with Uricosuric Agents (Probenecid and edema, tachypnea. a full glass of water unless patient is fluid Sulfinpyrazone): Salicylates antagonize the Special Senses: Hearing loss, tinnitus. restricted. Anti-inflammatory and analgesic uricosuric action of uricosuric agents. Patients with high frequency hearing loss dosages should be individualized. When Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations 56817 aspirin is used in high doses, the Carotid Endarterectomy: Doses of 80 mg greater than 200 mg/mL), the incidence of development of tinnitus may be used as a once daily to 650 mg twice daily, started toxicity increases. clinical sign of elevated plasma salicylate presurgery, are recommended. Continue HOW SUPPLIED levels except in patients with high frequency therapy indefinitely. hearing loss. Rheumatoid Arthritis: The initial dose is 3 (Insert specific information regarding, Ischemic Stroke and TIA: 50–325 mg once g a day in divided doses. Increase as needed strength of dosage form, units in which the a day. Continue therapy indefinitely. for anti-inflammatory efficacy with target dosage form is generally available, and Suspected Acute MI: The initial dose of plasma salicylate levels of 150–300 µg/mL. information to facilitate identification of the 160–162.5 mg is administered as soon as an At high doses (i.e., plasma levels of greater dosage form as required under § 201.57(k)(1), MI is suspected. The maintenance dose of than 200 mg/mL), the incidence of toxicity (k)(2), and (k)(3).) Store in a tight container 160–162.5 mg a day is continued for 30 days increases. at 25 °C (77 °F); excursions permitted to 15– post-infarction. After 30 days, consider Juvenile Rheumatoid Arthritis: Initial dose 30 °C (59–86 °F). further therapy based on dosage and is 90–130 mg/kg/day in divided doses. administration for prevention of recurrent REV: (insert date of publication in the Increase as needed for anti-inflammatory MI. Federal Register.) efficacy with target plasma salicylate levels Prevention of Recurrent MI: 75–325 mg µ once a day. Continue therapy indefinitely. of 150–300 g/mL. At high doses (i.e., plasma (2) In addition to, and immediately Unstable Angina Pectoris: 75–325 mg once levels of greater than 200 mg/mL), the preceding, the labeling required under a day. Continue therapy indefinitely. incidence of toxicity increases. paragraph (a)(1) of this section, the Chronic Stable Angina Pectoris: 75–325 mg Spondyloarthropathies: Up to 4 g per day professional labeling may contain the once a day. Continue therapy indefinitely. in divided doses. following highlights of prescribing CABG: 325 mg daily starting 6 hours post- Osteoarthritis: Up to 3 g per day in divided information in the exact language and procedure. Continue therapy for 1 year post- doses. exact format provided, but only when procedure. Arthritis and Pleurisy of SLE: The initial accompanied by the comprehensive PTCA: The initial dose of 325 mg should dose is 3 g a day in divided doses. Increase prescribing information required in be given 2 hours pre-surgery. Maintenance as needed for anti-inflammatory efficacy with paragraph (a)(1) of this section. dose is 160–325 mg daily. Continue therapy target plasma salicylate levels of 150–300 µg/ indefinitely. mL. At high doses (i.e., plasma levels of BILLING CODE 4160±01±F 56818 Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations 56819

(b) [Reserved] DEPARTMENT OF DEFENSE coordinate as they implement its provisions. Subpart DÐTesting Procedures Office of the Secretary This rule defines the criteria for determining whether an institution of § 343.90 Dissolution and drug release 32 CFR Part 216 higher education has a policy or testing. RIN 0790±AG42 practice prohibiting or preventing the (a) [Reserved] Secretary of Defense from maintaining, establishing, or efficiently operating a (b) Aspirin capsules. Aspirin capsules Military Recruiting and Reserve Officer Senior ROTC unit; or has a policy of must meet the dissolution standard for Training Corps Program Access to Institutions of Higher Education denying military recruiting personnel aspirin capsules as contained in the entry to campuses, access to students on United States Pharmacopeia (USP) 23 at AGENCY: Department of Defense. campuses, or access to directory page 132. ACTION: Final rule. information on students. The Acts (c) Aspirin delayed-release capsules establish that institutions of higher and aspirin delayed-release tablets. SUMMARY: The Department of Defense education having such policies or Aspirin delayed-release capsules and promulgates the rule addressing military practices are ineligible for certain aspirin delayed-release tablets must recruiting and Reserve Officer Training Federal funding. meet the drug release standard for Corps program access at institutions of The criterion of ‘‘efficiently operating aspirin delayed-release capsules and higher education. This rule implements a Senior ROTC unit’’ refers generally to the National Defense Authorization Act aspirin delayed-release tablets as an expectation that the ROTC for Fiscal Year 1995, the National contained in USP 23 at pages 133 and Department would be treated on a par Defense Authorization Act for Fiscal with other academic departments; as 136 respectively. Year 1996, and the Omnibus such, it would not be singled out for (d) Aspirin tablets. Aspirin tablets Consolidated Appropriations Act, 1997 unreasonable actions that would impede must meet the dissolution standard for (the Acts). access to students (and vice versa) or aspirin tablets as contained in USP 23 The Acts state that no funds available restrict its operations. at page 134. under appropriations acts for any fiscal This rule also defines the procedures (e) Aspirin, alumina, and magnesia year for the Departments of Defense, that would be followed in evaluating tablets. Aspirin in combination with Transportation (with respect to military reports that a covered school has not met requirements defined in this rule. alumina and magnesia in a tablet dosage recruiting), Labor, Health and Human When a component of the Department of form must meet the dissolution standard Services, Education, and Related Agencies may be provided by contract Defense (DOD Component) believes that for aspirin, alumina, and magnesia or grant (including a grant of funds to policies or practices of an institution of tablets as contained in USP 23 at page be available for student aid) to a covered higher education might require such an 138. school that has a policy or practice evaluation, that component is required (f) Aspirin, alumina, and magnesium (regardless of when implemented) that to confirm the institution’s policy in oxide tablets. Aspirin in combination either prohibits, or in effect prevents, consultation with the institution. If that with alumina, and magnesium oxide in the Secretary of Defense from obtaining, exchange suggests that the policy or a tablet dosage form must meet the for military recruiting purposes, entry to practice could trigger a denial of dissolution standard for aspirin, campuses, access to students on funding, as required by the Acts, the alumina, and magnesium tablets as campuses, access to directory supporting facts would be forwarded contained in USP 23 at page 139. information on students, or that has an through Department of Defense anti-ROTC policy. channels to the decision authority, who (g) Aspirin effervescent tablets for oral is the Assistant Secretary of Defense for EFFECTIVE DATE: March 29, 1997. solution. Aspirin effervescent tablets for Force Management Policy (ASD(FMP)). oral solution must meet the dissolution FOR FURTHER INFORMATION CONTACT: The Department of Defense received standard for aspirin effervescent tablets William J. Carr, (703) 697–8444. and considered comments relating to for oral solution as contained in USP 23 SUPPLEMENTARY INFORMATION: On April this rule. Those comments frequently at page 137. 8, 1997 the Department of Defense related to the interplay between the Acts (h) Buffered aspirin tablets. Buffered published an interim rule to implement and Family Educational Rights and aspirin tablets must meet the the Acts, and invited public comments Privacy Act of 1974, as amended dissolution standard for buffered aspirin by July 7, 1997 (62 FR 16691). (FERPA), 20 U.S.C. 1232g. Commenters Consistent with the Acts, the interim have inquired whether release of tablets as contained in USP 23 at page rule took effect on March 29, 1997. student information in response to a 135. Public comments were received and request from a military recruiter would Dated: October 19, 1998. appropriate adjustments were made as violate FERPA. Commenters pointed out William B. Schultz, reflected in this final rule. that ‘‘directory information’’ is a term of Deputy Commissioner for Policy. The Secretary is committed to art under FERPA that triggers particular [FR Doc. 98–28519 Filed 10–21–98; 10:59 establishing sound procedures to responsibilities of the institution am] implement current statutes, while regarding the confidentiality of student keeping the regulatory burden to the information. Depending on the policy of BILLING CODE 4160±01±C minimum necessary to carry out the a particular institution, that term may congressional intent. To that end, the not necessarily refer to the same Department has finalized this rule in information that may be requested by a consultation with other Federal military recruiter. Commenters also agencies, including the Departments of pointed out that FERPA provides a Education, Labor, Transportation, and mandatory opportunity for a student to Health and Human Services. Agencies object to release of ‘‘directory affected by this rule will continue to information’’ designated by an