Federal Register / Vol. 68, No. 74 / Thursday, April 17, 2003 / Rules and Regulations 18861

February 26, 1979); and (3) does not DEPARTMENT OF HEALTH AND new drug application (ANDA) is warrant preparation of a Regulatory HUMAN SERVICES October 18, 2004. The compliance dates Evaluation as these routine matters will for all other OTC drug products only affect air traffic procedures and air Food and Drug Administration containing and nonaspirin navigation. It is certified that these salicylates as an active ingredient and proposed rules will not have significant 21 CFR Part 201 marketed under an OTC drug economic impact on a substantial [Docket Nos. 93N–0182 and 82N–0166] monograph (for internal , number of small entities under the , and antirheumatic drug criteria of the Regulatory Flexibility Act. RIN 0910–AA01 products, or for menstrual drug products) will be established when the List of Subjects in 14 CFR Part 71 Labeling for Oral and Rectal Over-the- final monographs for those drug Counter Drug Products Containing products are published in a future issue Airspace, Incorporation by reference, Aspirin and Nonaspirin Salicylates; of the Federal Register. Navigation (air). Reye’s Syndrome Warning FOR FURTHER INFORMATION CONTACT: Ida Adoption of the Amendment AGENCY: Food and Drug Administration, I. Yoder, Center for Drug Evaluation and HHS. Research (HFD–560), Food and Drug ■ Accordingly, pursuant to the authority Administration, 5600 Fishers Lane, delegated to me, the Federal Aviation ACTION: Final rule. Rockville, MD 20857, 301–827–2222. Administration amends part 71 of the SUMMARY: The Food and Drug SUPPLEMENTARY INFORMATION: Federal Aviation Regulations (14 CFR Administration (FDA) is issuing a final part 71) as follows: rule to amend its regulations to revise I. Background PART 71—[AMENDED] the Reye’s syndrome warning required In the Federal Register of May 5, 1993 for oral and rectal over-the-counter (58 FR 26886), FDA published a notice ■ 1. The authority citation for part 71 (OTC) human drug products containing of proposed rulemaking to require a continues to read as follows: aspirin and to require a warning on OTC Reye’s syndrome warning for OTC drug products containing nonaspirin overindulgence drug products that Authority: 49 U.S.C. 106(g), 40103, 40113, salicylates as active ingredients. The contain (the May 40120; E.O. 10854, 24 FR 9565, 3 CFR, 1959– revised warning will inform consumers 1963 Comp., p.389. 1993 proposed rule). The proposed of the symptoms of Reye’s syndrome warning stated: ‘‘Children and teenagers ■ 2. The incorporation by reference in 14 and advise that aspirin and nonaspirin who have or are recovering from CFR 71.1 of Federal Aviation Adminis- salicylate drug products should not be chicken pox, flu symptoms, or flu tration Order 7400.9K, Airspace Designa- given to children or teenagers who have should NOT use this product. If nausea, tions and Reporting Points, dated August or are recovering from chicken pox or , or occur, consult a 30, 2002, and effective September 16, flu-like symptoms. This final rule also doctor because these symptoms could 2002, is amended as follows: finalizes FDA’s notice of proposed be an early sign of Reye syndrome, a rulemaking to require a Reye’s Subpart E—Class E Airspace rare but serious illness.’’ The agency did syndrome warning for orally not propose this warning for OTC * * * * * administered OTC drug products for antidiarrheal drug products that contain relief of symptoms associated with bismuth subsalicylate because bismuth Paragraph 6003 Class E airspace areas overindulgence in food and drink subsalicylate was not a proposed designated as an extension to a Class C (overindulgence drug products) that surface area monograph ingredient for that use at contain bismuth subsalicylate that that time. * * * * * published in the Federal Register of This warning was intended to inform ANE CT E3 Windsor Locks, CT [Revised] May 5, 1993 (58 FR 26886). FDA is consumers of the earliest recognizable Windsor Locks, Bradley International issuing this final rule after considering symptoms of Reye’s syndrome and Airport, CT public comment on the agency’s notices advise that OTC overindulgence drug (Lat. 41°56′20″N, long. 72°41′00″W) of proposed rulemaking and all relevant products containing bismuth CHUPP NDB data and information that have come to subsalicylate should not be used during (Lat. 41°52′39″N., long. 72°45′58″) the agency’s attention. the period when children or teenagers That airspace extending upward from the DATES: have, or are recovering from, the flu or surface within 2.9 miles on each side of the Effective Date: This final rule is chicken pox. The agency mentioned that 225° bearing from the CHUPP NDB extending effective April 19, 2004. it was considering revising the Reye’s from the 5-mile radius of the Bradley Compliance Dates: The compliance syndrome warning currently required International Airport to 8.6 miles southwest date for OTC antidiarrheal and for products containing aspirin in of the airport. This Class E airspace area is overindulgence drug products that § 201.314(h)(1) (21 CFR 201.314(h)(1)) to effective during specific dates and times contain bismuth subsalicylate as an be the same as the proposed warning for established in advance by a Notice to Airman. The effective date and time will active ingredient and have annual sales products containing bismuth thereafter be continuously published in the greater than $25,000 is April 19, 2004. subsalicylate. Airport/Facility Directory. The compliance date for OTC In the Federal Register of October 20, * * * * * antidiarrheal and overindulgence drug 1993 (58 FR 54228), FDA published a products that contain bismuth notice of proposed rulemaking to revise Issued in Burlington, MA, on April 10, subsalicylate as an active ingredient and the Reye’s syndrome warning required 2003. have annual sales less than $25,000 is for OTC drug products containing Thomas R. Davidson, April 18, 2005. The compliance date for aspirin to be consistent with the Manager, Air Traffic Division, New England OTC drug products containing aspirin proposed warning for OTC Region. and nonaspirin salicylates as an active overindulgence drug products [FR Doc. 03–9506 Filed 4–16–03; 8:45 am] ingredient and marketed under a new containing bismuth subsalicylate (the BILLING CODE 4910–13–M drug application (NDA) or abbreviated October 1993 proposed rule). The

VerDate Jan<31>2003 16:20 Apr 16, 2003 Jkt 200001 PO 00000 Frm 00029 Fmt 4700 Sfmt 4700 E:\FR\FM\17APR1.SGM 17APR1 18862 Federal Register / Vol. 68, No. 74 / Thursday, April 17, 2003 / Rules and Regulations

agency also proposed to extend the the rule must comply with the rule However, these studies lacked sufficient warning to OTC drug products regardless of the date that the product subjects to adequately evaluate such an containing nonaspirin salicylates, such was initially introduced or initially association. as choline salicylate, magnesium delivered for introduction into interstate The PHS pilot study (Ref. 2) reported salicylate, and sodium salicylate, but commerce. an association between Reye’s syndrome did not specify whether the warning and salicylate use, but did not II. The Agency’s Conclusions on the would apply to products containing differentiate between aspirin and other Comments salicylates used as inactive ingredients. salicylates. In the main study (Ref. 3), In response to the two proposals, the (Comment 1) One comment supported the independent risk of Reye’s agency received comments from two the agency’s proposal to require a Reye’s syndrome with nonaspirin salicylates manufacturers and two professional syndrome warning on products could not be assessed because only two associations. These comments are on containing nonaspirin salicylates. Other cases were not exposed to aspirin. The public display in the Dockets comments asserted that there are no Ohio Department of Health study (Ref. Management Branch (HFA–305), Food scientific data establishing an 1) reported a significant association and Drug Administration, 5630 Fishers association between nonaspirin between aspirin use and Reye’s Lane, rm. 1061, Rockville, MD 20852 salicylates and Reye’s syndrome. The syndrome (relative risk 11.5; confidence under Docket No. 82N–0166 or 93N– comments argued that numerous interval 2.7 - 48.4; p < 0.001). Further 0182. epidemiological studies of the etiology analysis (Ref. 7) of data from the second The agency has determined that the of Reye’s syndrome have failed to year of this study and the PHS pilot two proposals should be combined so suggest an association with nonaspirin study showed that the Ohio study had that all Reye’s syndrome warnings salicylates. One comment included a higher percentage of nonaspirin appear in one place (§ 201.314(h)(1)), published reports of the Ohio salicylate use in the Reye’s syndrome with an appropriate cross reference in Department of Health study (Ref. 1), the cases than in the controls (25 percent the individual ingredient monographs. Public Health Service (PHS) pilot and versus 16.8 percent), whereas the Thus, there is no need for a separate main studies (Refs. 2 and 3), and the findings for the PHS pilot study were rule for overindulgence drug products Yale study (Ref. 4) and cited two reports mixed (14.8 percent versus 21.1, 31.6, containing bismuth subsalicylate. This from Australia published in 1987 (Ref. and 12.7 percent). None of these Reye’s syndrome warning also applies 5) and 1990 (Ref. 6). The comment also findings were significant. to OTC antidiarrheal drug products included unpublished data (Ref. 7) The agency notes that the Yale study containing bismuth subsalicylate based on the Ohio Department of Health (Ref. 4) investigated the validity of the because bismuth subsalicylate is a study and the PHS pilot study. reported association of aspirin and monograph ingredient for this use at The comments contended that the low Reye’s syndrome by evaluating potential this time. incidence of Reye’s syndrome, in spite bias associated with earlier studies. The In the proposed rules to amend parts of widespread use of nonaspirin authors concluded that there is a strong 201 and 257 (21 CFR parts 201 and 357), salicylates and the presence of naturally association between aspirin and Reye’s the agency advised that any final rule occurring salicylates in food, strongly syndrome, as reported in other studies, based on the proposals will be effective argues against an association with but the study did not evaluate the 6 months and 12 months, respectively, nonaspirin salicylates. The comments association of nonaspirin salicylates and after the date of publication in the added that the case reports associating Reye’s syndrome. The two Australian Federal Register. The agency is setting Reye’s syndrome with the use of studies mentioned by the comment the effective date for this final rule at 12 bismuth subsalicylate, calcium (Refs. 5 and 6) did not show an months, but is establishing varying salicylate, and choline salicylate cited association between salicylate ingestion compliance dates for this final rule. (See in the proposal provided insufficient (including aspirin) and Reye’s Compliance Dates in the DATES section detail to support such an association. syndrome. and section II, comment 11 of this The comments also criticized the in The agency is aware of a number of document.) Any OTC drug product that vitro data cited by the agency and reports linking bismuth subsalicylate- is subject to this final rule that is questioned whether mitochondrial containing products to Reye’s syndrome initially introduced or initially swelling, seen in the presence of (Ref. 8). As of May 1999, the agency delivered for introduction into interstate salicylates in the studies, is relevant to found 27 cases of potential neurologic commerce after the compliance dates for the pathogenesis of Reye’s syndrome. reaction for these products reported the rule will be considered misbranded One comment suggested that aspirin’s from 1989 through 1997 in its under sections 201(n) and 502(a) and (f) acetylation mechanism may be Spontaneous Reporting System (SRS). of the Federal Food, Drug, and Cosmetic responsible for the association between Fifteen of these cases had a possible Act (the act) (21 U.S.C. 321(n) and aspirin and Reye’s syndrome. diagnosis of Reyes syndrome, and most 352(a) and (f)) if it does not contain the The agency has reviewed the of these were children. The remaining new warning required by this final rule. epidemiologic studies submitted by the 12 cases (6 pediatric and 6 adult) Further, any OTC drug product subject comment and agrees that they did not included a variety of neurological to this final rule that is repackaged or find an association between nonaspirin disorders. Table 1 summarizes the 15 relabeled after the compliance dates of salicylates and Reye’s syndrome. reports.

TABLE 1.—CASE REPORTS OF REYE’S SYNDROME OR SUSPECTED REYE’S SYNDROME IN PEOPLE WHO TOOK BISMUTH SUBSALICYLATE

FDA Number1 Age2 Gender3 Event (year) Other drugs4 Outcome5

578534 and 725706 6Y F 1989 APAP (only) D 823003 P M U U 8230071 P U 1985 or 1986 U U 824682 P F 1989 U D

VerDate Jan<31>2003 16:20 Apr 16, 2003 Jkt 200001 PO 00000 Frm 00030 Fmt 4700 Sfmt 4700 E:\FR\FM\17APR1.SGM 17APR1 Federal Register / Vol. 68, No. 74 / Thursday, April 17, 2003 / Rules and Regulations 18863

TABLE 1.—CASE REPORTS OF REYE’S SYNDROME OR SUSPECTED REYE’S SYNDROME IN PEOPLE WHO TOOK BISMUTH SUBSALICYLATE—Continued

FDA Number1 Age2 Gender3 Event (year) Other drugs4 Outcome5

824683 12Y F U D 8304791 between 8 and 15Y U 1978 ASA H 830513 U U 1989 U U 8305161 between 8 and 15Y U 1978 ASA H 952481 6Y M 1991 NR D 957562 12Y F 1992 ASA, D D 958922 34M F 1992 NR D 947149 3Y F 1993 NR D 15020571 14Y M 1994 APAP, CC H 1623073 4Y F 1995 APAP, D D 1855719 2Y M 1996 NR D 1 Also literature report 2 M = months, Y = years, P = pediatric, U = unknown 3 F = female, M = male, U = unknown 4 ASA = aspirin, APAP = acetaminophen, CC = cough/cold preparation, D = diphenhydrmine, NR = none reported, U = unknown 5 D = died, H = hospitalized, U = unknown

Because of the limited information attributed to metabolic disorders. As extent that alters their function. available on these cases, it is not certain discussed previously, other studies Salicylic acid is the circulating drug that bismuth subsalicylate was the cause (Refs. 1, 2, and 3) have shown an form which is shared by all salicylate of Reye’s syndrome. However, most of association with aspirin ingestion and products. It undergoes direct renal the reports identified bismuth Reye’s syndrome. excretion and hepatic biotransformation subsalicylate use only prior to the The agency notes one comment’s through several enzymatic systems. diagnosis of Reye’s syndrome. statement that the incidence of Reye’s As noted in the October 1993 was reported in 60 percent of the cases. syndrome is low despite many foods proposed rule (58 FR 54228 at 54229) The agency notes that a recent report with naturally occurring salicylates. there are some in vitro biochemical data by Orlowski (Ref. 9) suggested that Salicylates occur in many foods at low that suggest salicylate may contribute to many people originally diagnosed with concentrations and in certain foods at mitochondrial injury that is Reye’s syndrome may have had relatively high concentrations. For characteristic of Reye’s syndrome. Based metabolic disorders. To test this instance, a few herbs and spices contain on a more recent in vitro study, Trost hypothesis, Orlowski evaluated the as much as 200 milligrams salicylate per and Lemasters (Ref. 13) suggested that medical records of subjects in the 100 grams (Ref. 10). However, these induction of the mitochondrial Australian studies (Refs. 5 and 6) that food products are generally consumed permeability transition (MPT) is a had not shown an association with in small amounts. The agency has no common pathophysiological mechanism aspirin or salicylate ingestion and information to suggest that salicylates in causing mitochondrial injury in Reye’s Reye’s syndrome. The medical records food are associated with Reye’s syndrome. In that study, MPT induction of 26 people who were originally syndrome. Although salicylates are by aspirin required alkaline hydrolysis. diagnosed with Reye’s syndrome and present in a wide range of foods, the Because aspirin spontaneously survived were reassessed using more amount consumed from foods is decomposes to salicylate, the authors precise diagnostic criteria. Eighteen (69 generally lower than the therapeutic said it is likely that salicylate, rather percent) of these were subsequently doses in drugs. than acetylsalicylate, is the primary diagnosed as having other diseases (15 The references submitted by the inducer of MPT. with inborn errors of metabolism). The comment that suggested that the While some in vitro studies (Refs. 14 most common was acetylation mechanism of aspirin may and 15) suggest salicylate is responsible medium-chain acyl-coenzyme-A be responsible for Reye’s syndrome did for mitochondrial injury that may be dehydrogenase deficiency. Orlowski not provide adequate information to responsible for the pathogenesis of speculated that the disappearance of support this suggestion. The references Reye’s syndrome, the agency agrees Reye’s syndrome in the 1980s may be included discussion of the hydrolysis of with the comment that the evidence is more related to the discovery of, and acetylsalicylic acid into acetyl and not sufficient to show the salicylate ability to diagnose, inborn errors of salicylic acid moieties and the further moiety is responsible for Reye’s metabolism that mimic Reye’s syndrome hydrolysis of the acetyl moiety to syndrome. The pathogenesis of Reye’s clinically, biochemically, and acetate, which is ultimately metabolized syndrome is not known. None of the pathologically than to warning labels to carbon dioxide. Up to 50 percent of submitted references link Reye’s and the reduced use of aspirin. orally administered doses of syndrome to either the salicylate or Although some people previously acetylsalicylic acid are hydrolyzed acetyl drug moiety. diagnosed with Reye’s syndrome have before they reach the blood stream Although the agency does not have been found to have metabolic disorders because of esterases located in the gut definitive evidence that drugs that may meet the criteria for a wall and the clearance of the compound containing nonaspirin salicylates diagnosis of Reye’s syndrome, and some by the (Ref. 11). Packham (Ref. 12) significantly increase the risk of Reye’s people with metabolic disorders may be noted that the acetyl moiety can rapidly syndrome, a number of case reports predisposed to developing Reye’s acetylate cyclo-oxygenase in platelets at (Ref. 8) suggest an association. Because syndrome, the agency finds there is no micromolar concentration. However, it of the serious consequences of Reye’s definitive evidence at this time that may not remain in the circulation long syndrome, the agency has determined, Reye’s syndrome can generally be enough to acetylate other proteins to an in the interest of safe use of OTC drug

VerDate Jan<31>2003 16:20 Apr 16, 2003 Jkt 200001 PO 00000 Frm 00031 Fmt 4700 Sfmt 4700 E:\FR\FM\17APR1.SGM 17APR1 18864 Federal Register / Vol. 68, No. 74 / Thursday, April 17, 2003 / Rules and Regulations

products containing nonaspirin any data supporting an association of information for consumers’ safe and salicylates, these products should bear a Reye’s syndrome with salicylate effective use of an OTC drug product. warning to alert consumers that inactive ingredients. The concentration The comment suggested that knowledge children and teenagers recovering from of salicylates contained as inactive of Reye’s syndrome symptoms may be chicken pox or flu-like symptoms ingredients in OTC drug products is important for the safe use of OTC drug should not use these products. generally low and the mechanism of products containing bismuth (Comment 2) Several comments action responsible for the development subsalicylate, but it is not needed for the contended that requiring a Reye’s of Reye’s syndrome is unknown. safe and effective use of aspirin. Noting syndrome warning on the large number Therefore, the agency does not have the agency’s rejection of a of drug products containing salicylates sufficient data and information at this recommendation to include symptoms as inactive ingredients would reduce its time to require a Reye’s syndrome in the Reye’s syndrome warning in effectiveness for products such as warning on OTC drug products current § 201.314(h)(1) (see the March 7, aspirin for which the warning is containing salicylates as inactive 1986, final rule (51 FR 8180 at 8181)), justified. The comments noted that ingredients. In the event additional data the comment suggested that the agency’s salicylates are commonly used as become available on the association of rationale still applies today. The flavorings in many OTC drugs, salicylates, as inactive ingredients, with comment further suggested that the including mouth rinses, toothpastes, Reye’s syndrome, the agency will listing of symptoms in the warning may cough , stomach remedies, reconsider this position. cause consumers to believe that the laxatives, stool softeners, and other (Comment 3) Several comments common symptoms of nausea and mint-flavored oral medications. These asserted that the use of the same vomiting or fever should prompt a call flavorings impart a distinctive warning for OTC drug products to a doctor. characteristic that cannot be readily containing bismuth subsalicylate and Another comment suggested that the duplicated using other ingredients. aspirin is inappropriate. The comments addition of nausea, vomiting, and fever The comments added that salicylates stated that the purpose of the current to the Reye’s syndrome warning is are used as buffers, stabilizing agents, voluntary warning on OTC redundant because consumers are and preservatives. Replacing salicylates overindulgence drug products already familiar with these common with alternative excipients as buffering containing bismuth subsalicylate is symptoms of flu. Pointing out that the agents does not provide comparable different from that for aspirin- labeling type size is already small due hydrogen-ion concentration (pH) containing OTC drug products, in that it to the amount of required label control, thereby increasing the risk of is intended to discourage attempts to information, the comment asserted that microbial contamination. Further, self-treat symptoms (nausea and this additional verbiage would decrease alternative buffering agents do not vomiting) that may be early signs of label readability and the provide adequate suspension of the Reye’s syndrome. Because the intended conspicuousness of the warning. active ingredient, potentially leading to uses for aspirin (minor aches and pains The agency disagrees with the misdosing. The comments contended and fever) are different, the comments comment’s assertion that including the that practical replacements for salicylate contended that the warnings should be symptoms in the warning is beyond the excipients do not exist. different. scope of traditional or appropriate OTC One comment concluded that the The agency agrees that the warning on drug label warnings. Warnings for widespread presence of salicylates in bismuth subsalicylate products that certain ingredients caution consumers prescription and OTC drugs, and foods, mentions nausea and vomiting is to consult a doctor or to discontinue use together with the very low reported helpful in discouraging self-treatment of of the product if specific symptoms incidence of Reye’s syndrome in recent symptoms that may be early signs of appear. For example, the warning in years, strongly suggests that exposure to Reye’s syndrome and in encouraging § 340.50(c)(1) (21 CFR 340.50(c)(1)) nonaspirin salicylate inactive prompt medical attention. Likewise, alerts consumers of the specific ingredients is not a risk factor for people who take an aspirin product for symptoms of excessive caffeine developing Reye’s syndrome. The aches and pains and fever related to the consumption, stating in part: ‘‘* * * too comment argued that a Reye’s syndrome flu could also have nausea and much caffeine may cause nervousness, warning is not needed for drug products vomiting. Regardless of the product’s irritability, sleeplessness, and, containing nonaspirin salicylates as indication, the warning statement is occasionally, rapid heart beat.’’ A inactive ingredients unless the products intended to alert consumers when they proposed warning for products could be used to self-treat symptoms should not use the products and that containing aspirin and other salicylates such as nausea, diarrhea, and vomiting prompt medical attention should be states: ‘‘If ringing in the ears or a loss (which may be early signs of Reye’s sought if certain symptoms are present. of hearing occurs, consult a doctor syndrome). The comment projected a Therefore, based on the information before taking any more of this product.’’ significant economic impact in the cost available suggesting that Reye’s (See 53 FR 46204 at 46256, November of relabeling drugs containing syndrome is associated with both 16, 1988.) Thus, symptoms have salicylates as inactive ingredients. aspirin and nonaspirin salicylates, the traditionally been included in warnings The agency discussed one report in agency has determined that the warning for certain OTC drug products. the October 1993 proposed rule (58 FR statement in this final rule should be the As one comment noted, the agency 54228 at 54229) of Reye’s syndrome same for all OTC drug products rejected a recommendation for associated with a drug product containing salicylates as an active including symptoms in the Reye’s containing a nonaspirin salicylate as an ingredient. syndrome warning in 1986. FDA has inactive ingredient. This case resulted (Comment 4) One comment urged the reconsidered this position, and now in the death of a child treated with a agency not to include Reye’s syndrome recognizes increased value in theophylline drug product that symptoms on aspirin-containing information on the symptoms of Reye’s contained calcium salicylate as an products, asserting that this additional syndrome that can be particularly emulsifying agent. The report provided language is beyond the scope of helpful to alert consumers of the minimal information. Other than this traditional or appropriate label potential situations where problems case report, the agency is not aware of warnings, i.e., providing sufficient could arise with the use of these

VerDate Jan<31>2003 16:20 Apr 16, 2003 Jkt 200001 PO 00000 Frm 00032 Fmt 4700 Sfmt 4700 E:\FR\FM\17APR1.SGM 17APR1 Federal Register / Vol. 68, No. 74 / Thursday, April 17, 2003 / Rules and Regulations 18865

products. Listing the early symptoms of association with aspirin. Further, such a study on which it relied for scientific Reye’s syndrome will help alert warning is inconsistent with the justification for the warning consumers to contact a doctor during message repeatedly given to the public requirement. The comment asserted that the early stages of the syndrome, when that aspirin should not be used for the adding the word ‘‘flu’’ would provide a better outcome is expected. symptoms of flu or chicken pox. no new information and may confuse (Comment 5) Noting that the medical The comment stated that the studies consumers who are unable to literature demonstrates that fever is not used by FDA to support the regulation differentiate ‘‘flu’’ from flu symptoms. a symptom of Reye’s syndrome, two provide no evidence that aspirin taken The other comment recommended that comments recommended that the while recovering from chicken pox or the words ‘‘flu symptoms’’ not be agency modify the proposed warning by flu (but not for chicken pox or flu included in the warning because they deleting ‘‘fever’’ from the list of Reye’s symptoms themselves) increases the risk are redundant and likely to confuse syndrome symptoms. The comments of Reye’s syndrome. Unless further consumers. The comment recommended also cited a conclusion from the studies show that there is a risk in that the agency use only one of these in National Institutes of Health Consensus taking aspirin for situations other than the warning. Development Conference (Ref. 16) that the symptoms of flu or chicken pox, the The agency disagrees with the ‘‘neither fever nor is usually comment contended there is no basis for comments that use of the words ‘‘flu present’’ as a symptom of Reye’s the proposed change. Any use of aspirin symptoms’’ along with the word ‘‘flu’’ is syndrome. while ‘‘recovering from’’ these illnesses redundant, but agrees that including One comment stated that the would be for residual symptoms of both in the warning may confuse some proposed list of Reye’s syndrome chicken pox or flu and therefore would consumers who may be unable to symptoms is incomplete because be covered by the current warning. differentiate ‘‘flu’’ from ‘‘flu symptoms.’’ important symptoms (e.g., lethargy, The agency disagrees with the Therefore, the agency is replacing ‘‘flu’’ , aggressiveness) were not comment. As stated in the agency’s May and ‘‘flu symptoms’’ with ‘‘flu-like included. The comment noted that by 1993 proposed rule (58 FR 26886 to symptoms,’’ as this description omitting some important symptoms 26887), Reye’s syndrome most broadens the warning to help consumers from the list, parents may not seek commonly occurs following , who may not be sure the symptoms are emergency treatment for a child with chicken pox, and several other common due to the flu. Reye’s syndrome. The comment added viral infections. As symptoms of the (Comment 8) One comment asserted that the proposal overwarns by initial viral illness begin to diminish or that the proposed amendment would including fever, and parents may call a clear, the dramatic symptoms of Reye’s remove the reference to consult a doctor whenever a fever is present. syndrome (i. e., intractable vomiting, doctor, and would significantly Fever is not a generally recognized lethargy, or delirium) begin (Ref. 17). It undermine a doctor’s ability to prescribe symptom of Reye’s syndrome. Thus, the is not clear that aspirin or other aspirin under certain circumstances term ‘‘fever’’ is being deleted from the salicylate use in children is safe at any despite the reported risk of Reye’s proposed warning. While nausea and time from onset to complete recovery syndrome. The comment stated that the vomiting are easily recognizable, early from the initial viral illness. Some of the proposed warning simply directs symptoms of Reye’s syndrome, the residual symptoms, including fever, children and teenagers not to use the agency agrees with the comment that associated with the initial viral illness drug, whereas the current warning adding other associated symptoms may still be present at the time that cautions against use ‘‘before a doctor is would more accurately reflect the symptoms of Reye’s syndrome develop. consulted about Reye’s syndrome.’’ situation in which parents and young Although fever is not usually a Further, while there may be no people need to be concerned about the symptom of Reye’s syndrome and conditions for which bismuth possibility of Reye’s syndrome. The aspirin is not used to treat the subsalicylate should be used in children agency has also considered that label symptoms of Reye’s syndrome, it may or teenagers having chicken pox or flu space is limited and believes the broad be used to treat lingering symptoms of symptoms, aspirin has other important term ‘‘changes in behavior’’ is the initial viral illness in some people. uses that might justify a physician’s understood by consumers and covers Thus, the agency believes it is important recommendation that it be used, despite the symptoms mentioned by the that aspirin and other salicylates not be the warning. The comment explained comment. When changes in behavior are given to children and teenagers when that if a doctor believes that a child associated with nausea and vomiting it flu symptoms are present or when the suffering from the pain and disability of is important to seek medical care as symptoms are disappearing and the juvenile rheumatoid arthritis should use soon as possible. Therefore, the warning child seems to be recovering from the aspirin, and the benefits outweigh the statement includes the phrase, ‘‘if illness (58 FR 26886 at 26887). The risks, the doctor should be able to make changes in behavior with nausea and warning for OTC aspirin drug products a patient-specific assessment of risks, vomiting occur.’’ should be consistent with that for other and consumers should not be afraid to (Comment 6) One comment salicylates and include a broad warning follow the doctor’s advice. The contended that there is no scientific not to use the product both during the comment concluded that without evidence of an association between illness and during recovery. Therefore, justification, it is inappropriate to Reye’s syndrome and the use of aspirin the agency is retaining the proposed reverse the reasoned position held by by children and teenagers who ‘‘are phrase ‘‘who have or are recovering the agency in 1982 (47 FR 57886 at recovering from’’ chicken pox, flu, or flu from’’ in this final rule. 57895, December 28, 1982) in which the symptoms. The comment stated that (Comment 7) Two comments suggested warning against salicylate use while a warning about the recovery recommended that the word ‘‘flu’’ not in children did not apply to all period from a preceding illness may be be included in the proposed Reye’s circumstances, but included the phrase appropriate for products used to treat, syndrome warning. One comment noted ‘‘unless directed by a doctor.’’ The and possibly mask, the early symptoms that, in issuing the current aspirin label agency stated that the possible benefits of Reye’s syndrome, such a warning on regulation in 1988, FDA refused to of salicylates might outweigh the risk of aspirin is not supported by the studies expand the warning beyond ‘‘chicken Reye’s syndrome in certain cases such that have been reported to show an pox or flu symptoms,’’ based on the PHS as juvenile rheumatoid arthritis.

VerDate Jan<31>2003 16:20 Apr 16, 2003 Jkt 200001 PO 00000 Frm 00033 Fmt 4700 Sfmt 4700 E:\FR\FM\17APR1.SGM 17APR1 18866 Federal Register / Vol. 68, No. 74 / Thursday, April 17, 2003 / Rules and Regulations

The agency disagrees with the The agency agrees with the comment labeling revisions required by those comment that a doctor’s advice to take that health care professionals play final monographs and the new Reye’s an aspirin-containing drug in limited important roles in delivering clinical syndrome warning can be implemented circumstances will be undermined or services directly to consumers and may at the same time. The agency currently that consumers will be frightened from sometimes serve as primary medical expects those final monographs or using the drug at the direction of a care providers. However, because of the portions of the final monographs to doctor if the revised Reye’s syndrome serious consequences of Reye’s publish within the next 18 to 24 warning is used in the product’s syndrome the agency believes that a months. Thus, any economic hardship labeling. Salicylates (including aspirin) doctor should be consulted if symptoms on manufacturers of these products is should not be given to, or used by, associated with Reye’s syndrome (e.g., greatly reduced or eliminated. children and teenagers who have or are changes in behavior with nausea and Manufacturers of OTC antidiarrheal recovering from certain viral illnesses. vomiting) occur after taking a salicylate. drug products have 12 or 24 months to In most conditions for which aspirin is In addition, the agency believes that the implement the new Reye’s syndrome indicated there are alternative use of the term ‘‘doctor’’ is consistent warning, which will be done medications that doctors can with other OTC drug product labeling concurrently with implementation of recommend. In rare instances where warnings. As discussed in the OTC the labeling in the final monograph for other medications are contraindicated, a labeling requirements final rule (64 FR those drug products, published patient’s doctor may determine that the 13254 at 13261, March 17, 1999), the elsewhere in this issue of the Federal benefits of aspirin use outweigh the agency determined that questions Register. Because the Reye’s syndrome risks. In those cases, it is still possible related to certain conditions and warning is only one small part of the for the doctor to override the label symptoms are best answered by a doctor labeling for OTC antidiarrheal drug warning if, in his or her judgment, who is trained and licenced specifically products containing bismuth aspirin should be used. The agency to make a differential diagnosis and to subsalicylate, the agency is requiring all believes the revised warning continues treat disease entities. Therefore, the labeling for those products to be to reflect the agency’s 1982 position. agency is retaining the term ‘‘doctor’’ in implemented at the same time. (Comment 9) One comment the warning. Manufacturers of OTC overindulgence recommended that the agency modify (Comment 11) Two comments stated drug products also have 12 or 24 the proposed warning to include ‘‘while that due to economic hardship, 6 months to implement the new Reye’s using this ’’ as follows: ‘‘If months was too short to revise labels, syndrome warning. Because the agency nausea, vomiting, or fever occur while dispose of existing label stock, relabel does not currently expect the final rule using this medication, consult a doctor product, and initiate the distribution for those products to publish in the next because these symptoms could be an process. Therefore, one comment 18 to 24 months, it is requiring those early sign of Reye’s syndrome, a rare but requested that the agency consider an products to include the Reye’s serious illness.’’ The comment stated 18-month implementation date instead syndrome warning before the final that reference to indications and adverse of the proposed 6 months. Another monograph is published. There are a effects that are similar may be confusing comment requested 12 months. One limited number of affected products in to consumers, who may assume that the comment stated that labeling changes this product category, and any economic presence of nausea, vomiting, or fever could be made more efficiently if costs for manufacturers of those alone is an absolute indication of Reye’s multiple rulings for similar products products should be minimal. All syndrome. The comment suggested this become effective simultaneously. The manufacturers are encouraged to change would convey a clearer message comment suggested that the agency incorporate this new warning that this drug, when used to treat the incorporate all revisions into the final information into product labeling if they symptoms of a viral illness in children monograph for OTC internal analgesic print new labeling before the required and teenagers, may precipitate Reye’s drug products to decrease costs. implementation times. syndrome. The agency agrees with the comments Although this final rule may have an The agency does not believe the that 6 months may not be a reasonable economic impact on a few proposed warning suggests that any amount of time for manufacturers to manufacturers, the agency concludes individual symptom is an absolute implement the required warning for that the potential benefits of the rule, indication of Reye’s syndrome. salicylate-containing drug products. The including reduced risk of adverse However, the agency has deleted labeling for most OTC drug products effects, override these economic ‘‘fever’’ and added ‘‘changes in (those containing aspirin) covered by concerns. (See section II, comment 1 of behavior’’ to the list of symptoms to this final rule already includes a Reye’s this document.) more accurately reflect the symptoms syndrome warning similar to the III. The Agency’s Final Conclusions associated with the development of warning in this final rule, and most Reye’s syndrome. (See section II, manufacturers would need to make only The agency has determined that the comment 5 of this document.) The minor labeling revisions. Because of the Reye’s syndrome warning should apply agency is adding the phrase ‘‘when large number of affected products and to all oral and rectal OTC drug products using this product’’ to convey a clearer because many of these products are containing salicylates as active message that the drug, when used to internal that contain aspirin ingredients, regardless of their intended treat the symptoms of a viral illness, and already have a Reye’s syndrome use. Therefore, the requirement for a may precipitate Reye’s syndrome. warning, the agency is providing that Reye’s syndrome warning for aspirin (Comment 10) Noting that pediatric the compliance dates for those products and nonaspirin salicylates (including nurse practitioners have been a source to incorporate the new warning will be bismuth subsalicylate) will appear in of primary health care to children and established when the final monographs one location (§ 201.314(h)). A reference teens for over 25 years, one comment for OTC internal analgesic, antipyretic, to this warning is included in suggested amending the proposed and antirheumatic drug products and § 335.50(c)(2)(i)(A) (21 CFR Reye’s syndrome warning by replacing OTC menstrual drug products are 335.50(c)(2)(i)(A)) of the final ‘‘doctor’’ with ‘‘health-care published in a future issue of the monograph for OTC antidiarrheal drug professional.’’ Federal Register. Thus, all of the products. A reference will also be

VerDate Jan<31>2003 16:20 Apr 16, 2003 Jkt 200001 PO 00000 Frm 00034 Fmt 4700 Sfmt 4700 E:\FR\FM\17APR1.SGM 17APR1 Federal Register / Vol. 68, No. 74 / Thursday, April 17, 2003 / Rules and Regulations 18867

included in 21 CFR part 343 in the final and safety, and other advantages; teenagers who have or are recovering monograph for OTC internal analgesic, distributive impacts; and equity). Under from chicken pox or flu-like symptoms. antipyretic, and antirheumatic drug the Regulatory Flexibility Act, if a rule As stated in the October 1993 proposed products and in part 357, subpart J, in has a significant economic impact on a rule (58 FR 54228), the agency has the final monograph for OTC substantial number of small entities, an reconsidered the need to include all overindulgence drug products, when the agency must analyze regulatory options OTC drug products containing monographs for those products are that would minimize any significant salicylates in this required warning. finalized. Other labeling that was impact of the rule on small entities. Fifteen adverse drug reports linking proposed in § 357.950 for drug products Section 202(a) of the Unfunded bismuth subsalicylate with Reye’s for the relief of symptoms associated Mandates Reform Act of 1995 requires syndrome have been entered into the with overindulgence in food and drink that agencies prepare a written agency’s database since March 1991, will be finalized in a future issue of the statement of anticipated costs and when the first Reye’s syndrome death Federal Register. The OTC drug product benefits before proposing any rule that associated with bismuth subsalicylate labeling format and content may result in an expenditure in any one was reported to the agency (Refs. 8 and requirements in § 201.66(c)(5)(ii)(A) year by State, local, and tribal 18). Most of these cases occurred in state that the warning in § 201.314(h)(i) governments, in the aggregate, or by the children, and were reported in shall follow the subheading ‘‘Reye’s private sector of $100 million (adjusted the majority of these cases. syndrome:’’. annually for inflation). The rules that FDA cannot quantify the expected Mandating warnings in an OTC drug led to the development of this final rule benefits of this rule, because it lacks the monograph does not require a finding were published in 1993, before the data to conduct a quantitative risk that any or all of the OTC drug products Unfunded Mandates Reform Act of 1995 assessment. The agency notes, however, covered by the monograph actually was enacted. The agency explains in that in most disease surveillance caused an adverse event, and FDA does this final rule that the final rule will not systems, reported cases are recognized not so find. Nor does FDA’s requirement result in an expenditure in any one year to represent only a fraction of the actual of warnings repudiate the prior OTC by State, local, and tribal governments, total. Reye’s syndrome is manifested by drug monographs and monograph in the aggregate, or by the private sector, a change in mental status ranging from rulemakings under which the affected of $100 million. lethargy to delirium, , and drug products have been lawfully The agency concludes that this final (Ref. 19). Mortality is marketed. Rather, as a consumer rule is consistent with the principles set related to the stage of at the time protection agency, FDA has determined out in Executive Order 12866 and in of hospital admission and has been that warnings are necessary to ensure these two statutes. This final rule is not estimated to be as high as 40 percent that these OTC drug products continue a significant regulatory action as defined (Ref. 19). It has been estimated that 30 to be safe and effective for their labeled by the Executive order and so is not percent of Reye’s syndrome patients indications under ordinary conditions subject to review under the Executive who deteriorate to the stage of of use as those terms are defined in the order. The Unfunded Mandates Reform neurologic , and survive, develop Federal Food, Drug, and Cosmetic Act. Act does not require FDA to prepare a serious neurologic sequelae. Thus, This judgment balances the benefits of statement of costs and benefits for this alerting consumers to the early these drug products against their final rule, because the final rule is not symptoms of Reye’s syndrome is potential risks (see 21 CFR 330.10(a)). expected to result in any 1-year essential so that prompt medical FDA’s decision to act in this instance expenditure that would exceed $100 treatment can be obtained, with a better need not meet the standard of proof million adjusted for inflation. The prognosis for the patient. required to prevail in a private tort current inflation adjusted statutory B. Costs action (Glastetter v. Novartis threshold is about $110 million. Pharmaceuticals, Corp., 252 F.3d 986, The purpose of this final rule is to Based on information in the agency’s 991 (8th Cir. 2001)). To mandate revise the Reye’s syndrome warning that drug listing system, there are between warnings, or take similar regulatory is already required for OTC drug 900 and 1,500 manufacturers and action, FDA need not show, nor do we products that contain aspirin for use by distributors that together produce about allege, actual causation. For an children and adolescents and to extend 5,000 OTC drug products containing expanded discussion of case law the requirement to those products that salicylates as an active ingredient that supporting FDA’s authority to require contain nonaspirin salicylates will be affected by this final rule. Over such warnings, see Labeling of (including bismuth subsalicylate) as 90 percent of these products are internal Diphenhydramine-Containing Drug active ingredients. The revised warning analgesic, antipyretic, and Products for Over-the-Counter Human is similar to the voluntary warning antirheumatic drug products, which Use, final rule, 67 FR 72555 (December already included on some OTC may have more than one stock keeping 6, 2002). antidiarrheal and overindulgence drug unit (SKU) (individual products, products that contain bismuth packages, and sizes). Because the IV. Analysis of Impacts subsalicylate. This final rule is intended majority of the products already include FDA has examined the impacts of the to bring uniformity and consistency to a warning statement that is similar to final rule under Executive Order 12866, the labeling of OTC drug products the labeling required by this final rule, the Regulatory Flexibility Act (5 U.S.C. containing aspirin and nonaspirin most changes will be minor. Further, the 601–612), and the Unfunded Mandates salicylates. cost to implement the new warning Reform Act of 1995 (2 U.S.C. 1501 et statement should be negligible because seq.). Executive Order 12866 directs A. Benefits the agency is providing that the warning agencies to assess all costs and benefits The revised warning will inform can be coordinated with the other of available regulatory alternatives and, consumers of the symptoms of Reye’s labeling changes that will be included when regulation is necessary, to select syndrome and advise that aspirin or in a future final monograph for those regulatory approaches that maximize nonaspirin salicylate (including products. net benefits (including potential bismuth subsalicylate) drug products As discussed elsewhere in this issue economic, environmental, public health should not be given to children or of the Federal Register, about 8 percent

VerDate Jan<31>2003 16:20 Apr 16, 2003 Jkt 200001 PO 00000 Frm 00035 Fmt 4700 Sfmt 4700 E:\FR\FM\17APR1.SGM 17APR1 18868 Federal Register / Vol. 68, No. 74 / Thursday, April 17, 2003 / Rules and Regulations

(400) of the affected products are incorporating other regulatory current inflation adjusted statutory antidiarrheal drug products that contain requirements, this final rule should threshold is about $110 million. bismuth subsalicylate as the active have a minimal economic impact on This analysis shows that the agency ingredient. The cost to implement the small entities. has considered the burden to small new Reye’s syndrome warning for those entities and provided compliance dates D. Alternatives products is significantly mitigated that should significantly reduce the because the warning will be The agency considered and rejected a burden. Thus, the agency certifies that incorporated into the new labeling for more costly alternative that would have this final rule will not have a significant those products as a result of publication required all products to be relabeled impact on a substantial number of small of the final monograph for OTC within 12 to 18 months of publication entities. antidiarrheal drug products. of this final rule in the Federal Register, The remaining 2 percent (100) of with a multimillion dollar cost to V. Paperwork Reduction Act of 1995 affected products includes OTC drug industry based on the potential number FDA concludes that the warning products containing aspirin and of affected products. Because 80 percent statement set forth in this final rule is nonaspirin salicylates marketed under of the products (a number of which have not subject to review by the Office of an NDA or ANDA or marketed under multiple SKUs) already have a Reye’s Management and Budget because it does the tentative final monograph for OTC syndrome warning on their label, the not constitute a ‘‘collection of overindulgence drug products. A agency concluded that the incremental information’’ under the Paperwork number of the overindulgence drug benefits of a reworded warning did not Reduction Act of 1995 (44 U.S.C. 3501 products that contain bismuth outweigh the costs. As discussed in et seq.). Rather, the required labeling is subsalicylate as the active ingredient section II, comment 11 of this a ‘‘public disclosure of information also bear antidiarrheal claims and, thus, document, the agency has set the originally supplied by the Federal will need to be relabeled as a result of implementation date of this final rule government to the recipient for the publication of the final monograph for for the Reye’syndrome warning for OTC purpose of disclosure to the public’’ (5 those drug products. The cost to add a antidiarrheal drug products that contain CFR 1320.3(c)(2)). warning to product labeling generally bismuth subsalicylate as an active averages about $2,000 to $3,000 per ingredient to coincide with the VI. Environmental Impact SKU. Thus, the cost for these products compliance dates for the final The agency has determined under 21 to be relabeled is estimated to be monograph for those drug products. The CFR 25.31(a) that this action is of a type between $200,000 and $300,000. agency considers this a reasonable time that does not individually or for manufacturers to implement these C. Small Business Impacts cumulatively have a significant effect on final rules, and the costs associated with the human environment. Therefore, Census data provide aggregate implementation will be less for one neither an environmental assessment industry statistics on the total number of label change than for two label changes. nor an environmental impact statement manufacturers for Standardized The agency has also set the compliance is required. Industrial Classification Code 2384 dates for the majority of the products Pharmaceutical Preparations by (internal analgesic, antipyretic, and VII. Federalism establishment size, but do not antirheumatic) affected by this final rule FDA has analyzed this final rule in distinguish between manufacturers of to coincide with the final monograph for accordance with the principles set forth prescription and OTC drug products. those drug products, to be published in in Executive Order 13132. FDA has According to the U.S. Small Business the future. The agency encourages determined that the rule does not Administration (SBA) designations for manufacturers to relabel their products contain policies that have substantial this industry, however, over 92 percent voluntarily, if new labeling is direct effects on the States, on the of the roughly 700 establishments and implemented before that final relationship between the National over 87 percent of the 650 firms are monograph publishes. Government and the States, or on the small. (Because census size categories The agency considered, but rejected, distribution of power and do not correspond to the SBA an exemption from coverage for small responsibilities among the various designation of 750 employees, these entities because the new labeling levels of government. Accordingly, the figures are based on 500 employees.) information is also needed by agency has concluded that the rule does The agency’s drug listing system consumers who purchase products not contain policies that have indicates that between 900 and 1,500 marketed by those entities. However, federalism implications as defined in marketers will need to relabel as the longer compliance dates are being the Executive order and, consequently, result of this final rule. Thus, the agency provided for antidiarrheal and a federalism summary impact statement believes that many of the manufacturers overindulgence drug products is not required. affected by this final rule would be containing bismuth subsalicylate with small. However, the cost of relabeling of annual sales less than $25,000 (an VIII. References private label products is incurred by the additional 12 months) and for products The following references are on private label manufacturers, not the containing aspirin and nonaspirin display in the Dockets Management individual small marketers. The effect salicylates marketed under an NDA or Branch (see section I of this document) on individual firms will vary with the ANDA (an additional 6 months). and may be seen by interested persons number of the firm’s SKUs that require E. Conclusion between 9 a.m. and 4 p.m., Monday relabeling and the size and cost of the through Friday. firm’s labeling inventory. Most small The Unfunded Mandates Reform Act firms will not incur significant does not require FDA to prepare a 1. Halpin, T. et al., ‘‘Reye’s Syndrome and Medication Use,’’ Journal of the American regulatory costs because they statement of costs and benefits for this Medical Association, 248:687–723, 1982. manufacture few affected SKUs and use final rule, because the final rule is not 2. Hurwitz, E. et al., ‘‘Public Health Service less expensive labeling stock. Because expected to result in any 1-year Study of Reye’s Syndrome and Medications: most firms will be able to incorporate expenditure that would exceed $100 Report of the Pilot Study,’’ New England these required changes when million adjusted for inflation. The Journal of Medicine, 313:849–857, 1985.

VerDate Jan<31>2003 16:20 Apr 16, 2003 Jkt 200001 PO 00000 Frm 00036 Fmt 4700 Sfmt 4700 E:\FR\FM\17APR1.SGM 17APR1 Federal Register / Vol. 68, No. 74 / Thursday, April 17, 2003 / Rules and Regulations 18869

3. Hurwitz, E. et al., ‘‘Public Health Service ■ Therefore, under the Federal Food, antipyretic, and antirheumatic drug Study of Reye’s Syndrome and Medications: Drug, and Cosmetic Act and under products, or for menstrual drug Report of the Main Study,’’ Journal of the authority delegated to the Commissioner products) will be established when the American Medical Association, 257:1905– 1911, 1987. of Food and Drugs, 21 CFR part 201 is final monographs for those products are 4. Forsyth, B. et al., ‘‘New Epidemiologic amended as follows: published in a future issue of the Evidence Confirming that Bias Does Not Federal Register. In the interim, these Explain the Aspirin/Reye’s Syndrome PART 201—LABELING products should continue to be labeled Association,’’ Journal of the American ■ 1. The authority citation for 21 CFR with the previous Reye’s syndrome Medical Association, 261:2517–2524, 1989. part 201 continues to read as follows: warning that appears in paragraph (h)(1) 5. Orlowski, J. et al., ‘‘A Catch in the of this section. Reye,’’ , 80:638–642, 1987. Authority: 21 U.S.C. 321, 331, 351, 352, 6. Orlowski, J. et al., ‘‘Reye’s Syndrome: A 353, 355, 358, 360, 360b, 360gg–360ss, 371, Dated: March 31, 2003. Case Control Study of Medication Use and 374, 379e; 42 U.S.C. 216, 241, 262, 264. Jeffrey Shuren, Associated Viruses in Australia,’’ Cleveland ■ Assistant Commissioner for Policy. Clinic Journal of Medicine, 57:323–329, 1990. 2. Section 201.314 is amended by 7. Biometric Research Institute, ‘‘Analysis revising paragraphs (h)(1) and (h)(4) to [FR Doc. 03–9382 Filed 4–16–03; 8:45 am] of Exposure to Non-Aspirin Salicylates read as follows: BILLING CODE 4160–01–S Among Subjects from the Ohio Department of Health Survey and the Public Health Service § 201.314 Labeling of drug preparations Pilot Study on Reye Syndrome,’’ June 13, containing salicylates. DEPARTMENT OF HEALTH AND 1986, in comment C2, Docket No. 93N–0182, * * * * * HUMAN SERVICES Dockets Management Branch. (h)(1) The labeling of orally or rectally 8. Adverse Drug Reaction Reports, in OTC administered over-the-counter drug Food and Drug Administration Vol. 03RSFR, Docket No. 93N–0182, Dockets products containing aspirin or Management Branch. 21 CFR Parts 310, 335, and 369 9. Orlowski, J. P., ‘‘Whatever Happened to nonaspirin salicylates as active ingredients subject to this paragraph is Reye’s Syndrome? Did It Ever Really Exist?’’ [Docket No. 78N–036D] Critical Care Medicine, 27:1582–1587, 1999. required to prominently bear the 10. Swain, A., ‘‘Salicylates in Foods,’’ following warning: ‘‘Reye’s syndrome RIN 0910–AA01 Journal of the American Dietetic Association, [subheading in bold type]: Children and 85:950–960, 1985. teenagers who have or are recovering Antidiarrheal Drug Products for Over- 11. Reigelman, S., ‘‘The Kinetic Disposition from chicken pox or flu-like symptoms the-Counter Human Use; Final of Aspirin in Humans,’’ in Aspirin, Platelets, should not use this product. When and (Chapter X), edited by W. S. Monograph using this product, if changes in Fields and W. K. Hess, W. H. Green Inc., St. AGENCY: Food and Drug Administration. Louis, MO, pp. 105–114, 1971. behavior with nausea and vomiting 12. Packham, M., ‘‘Mode of Action of occur, consult a doctor because these ACTION: Final rule. Acetylsalicylic Acid,’’ in Acetylsalicylic symptoms could be an early sign of Acid: New Uses for an Old Drug, edited by Reye’s syndrome, a rare but serious SUMMARY: The Food and Drug H. Barnett et al., Raven Press, New York, NY, illness.’’ Administration (FDA) is issuing a final pp. 63–82, 1982. rule in the form of a final monograph 13. Trost, L. C., and J. J. Lemasters, ‘‘The * * * * * establishing conditions under which (4) Any product subject to paragraphs Mitochondrial Permeability Transition: A over-the-counter (OTC) antidiarrheal (h)(1), (h)(2), and (h)(3) of this section New Pathophysiological Mechanism for drug products (to control the symptoms Reye’s Syndrome and Toxic Liver Injury,’’ that is not labeled as required by these of diarrhea) are generally recognized as The Journal of Pharmacology and paragraphs and that is initially safe and effective and not misbranded. Therapeutics, 278:1000–1005, 1996. introduced or initially delivered for This final rule is part of FDA’s ongoing 14. Martens, M. E., and C. Lee, ‘‘Reye’s introduction into interstate commerce Syndrome: Salicylates and Mitochondrial review of OTC drug products. FDA is after the following dates is misbranded Functions,’’ Biochemical Pharmacology, issuing this final rule after considering under sections 201(n) and 502(a) and (f) 33:2869–2876, 1984. public comments on the agency’s of the Federal Food, Drug, and Cosmetic 15. Yoshida, Y. et al., ‘‘Effect of Salicylic proposed regulation, which was issued Act. Acid on Mitochondrial Peroxisomal Fatty in the form of a tentative final Acid Catabolism,’’ Pediatric Research, (i) Compliance by October 18, 2004, 23:338–341, 1988. for OTC drug products containing monograph (TFM), and all new data and 16. National Institutes of Health, aspirin and nonaspirin salicylates as an information on OTC antidiarrheal drug Consensus Conference, ‘‘Diagnosis and active ingredient and marketed under a products that have come to the agency’s Treatment of Reye’s Syndrome,’’ Journal of new drug application or abbreviated attention. Also, this final rule amends the American Medical Association, the regulation that lists nonmonograph 246:2441–2444, 1981. new drug application. (ii) Compliance by April 19, 2004, for active ingredients by adding those OTC 17. Wolinsky, J. S., ‘‘Reye’s Syndrome,’’ in antidiarrheal active ingredients that Cecil Textbook of Medicine, 19th ed., edited OTC antidiarrheal and overindulgence by J. B. Wyngaarden et al., W. B. Saunders drug products that contain bismuth have been found to be not generally Co., Philadelphia, PA, pp. 2194–2195, 1992. subsalicylate as an active ingredient and recognized as safe and effective. 18. Adverse Drug Reaction Reports, in OTC have annual sales greater than $25,000. DATES: Effective Date: This rule is Vol. 03RSNPR, Docket No. 93N–0182, (iii) Compliance by April 18, 2005, for effective April 19, 2004. Dockets Management Branch. OTC antidiarrheal and overindulgence Compliance Dates: The compliance 19. Betts, R., ‘‘Influenza,’’ in Principles and drug products that contain bismuth date for products with annual sales less Practices of Infectious Diseases, 4th ed., edited by G. L. Mandell, J. E. Bennett, and subsalicylate as an active ingredient and than $25,000 is April 18, 2005. The R. Dolin, Churchhill Livingston, New York, have annual sales less than $25,000. compliance date for all other OTC NY, pp. 1546–1567, 1995. (iv) Compliance dates for all other antidiarrheal drug products is April 19, OTC drug products containing aspirin 2004. List of Subjects in 21 CFR Part 201 and nonaspirin salicylates as an active Comment Date: Comments on specific Drugs, Labeling, Reporting and ingredient and marketed under an OTC labeling items discussed in section IX of recordkeeping requirements. drug monograph (for internal analgesic, the SUPPLEMENTARY INFORMATION section

VerDate Jan<31>2003 16:20 Apr 16, 2003 Jkt 200001 PO 00000 Frm 00037 Fmt 4700 Sfmt 4700 E:\FR\FM\17APR1.SGM 17APR1