56802 Federal Register / Vol. 63, No. 205 / Friday, October 23, 1998 / Rules and Regulations salicylate, ibuprofen, ketoprofen, DEPARTMENT OF HEALTH AND men who have had transient ischemia of magnesium salicylate, naproxen HUMAN SERVICES the brain due to fibrin platelet emboli, sodium, and sodium salicylate. and for reducing the risk of death and/ ``Alcohol 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 analgesic/antipyretic salicylate, magnesium salicylate, or active ingredientÐincluding, but not Internal Analgesic, Antipyretic, and sodium salicylate for rheumatologic limited to aspirin, 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 pain relievers/fever 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 ingredientÐ 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).