[Federal Register Volume 68, Number 74 (Thursday, April 17, 2003)]
[Rules and Regulations]
[Pages 18861-18869]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-9382]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket Nos. 93N-0182 and 82N-0166]
RIN 0910-AA01


Labeling for Oral and Rectal Over-the-Counter Drug Products 
Containing Aspirin and Nonaspirin Salicylates; Reye's Syndrome Warning

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
to amend its regulations to revise the Reye's syndrome warning required 
for oral and rectal over-the-counter (OTC) human drug products 
containing aspirin and to require a warning on OTC drug products 
containing nonaspirin salicylates as active ingredients. The revised 
warning will inform consumers of the symptoms of Reye's syndrome and 
advise that aspirin and nonaspirin salicylate drug products should not 
be given to children or teenagers who have or are recovering from 
chicken pox or flu-like symptoms. This final rule also finalizes FDA's 
notice of proposed rulemaking to require a Reye's syndrome warning for 
orally administered OTC drug products for relief of symptoms associated 
with overindulgence in food and drink (overindulgence drug products) 
that contain bismuth subsalicylate that published in the Federal 
Register of May 5, 1993 (58 FR 26886). FDA is issuing this final rule 
after considering public comment on the agency's notices of proposed 
rulemaking and all relevant data and information that have come to the 
agency's attention.

DATES: 
    Effective Date: This final rule is effective April 19, 2004.
    Compliance Dates: The compliance date for OTC antidiarrheal and 
overindulgence drug products that contain bismuth subsalicylate as an 
active ingredient and have annual sales greater than $25,000 is April 
19, 2004. The compliance date for OTC antidiarrheal and overindulgence 
drug products that contain bismuth subsalicylate as an active 
ingredient and have annual sales less than $25,000 is April 18, 2005. 
The compliance date for OTC drug products containing aspirin and 
nonaspirin salicylates as an active ingredient and marketed under a new 
drug application (NDA) or abbreviated new drug application (ANDA) is 
October 18, 2004. The compliance dates for all other OTC drug products 
containing aspirin and nonaspirin salicylates as an active ingredient 
and marketed under an OTC drug monograph (for internal analgesic, 
antipyretic, and antirheumatic drug products, or for menstrual drug 
products) will be established when the final monographs for those drug 
products are published in a future issue of the Federal Register.

FOR FURTHER INFORMATION CONTACT: Ida I. Yoder, Center for Drug 
Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of May 5, 1993 (58 FR 26886), FDA published 
a notice of proposed rulemaking to require a Reye's syndrome warning 
for OTC overindulgence drug products that contain bismuth subsalicylate 
(the May 1993 proposed rule). The proposed warning stated: ``Children 
and teenagers who have or are recovering from chicken pox, flu 
symptoms, or flu should NOT use this product. If nausea, vomiting, or 
fever occur, consult a doctor because these symptoms could be an early 
sign of Reye syndrome, a rare but serious illness.'' The agency did not 
propose this warning for OTC antidiarrheal drug products that contain 
bismuth subsalicylate because bismuth subsalicylate was not a proposed 
monograph ingredient for that use at that time.
    This warning was intended to inform consumers of the earliest 
recognizable symptoms of Reye's syndrome and advise that OTC 
overindulgence drug products containing bismuth subsalicylate should 
not be used during the period when children or teenagers have, or are 
recovering from, the flu or chicken pox. The agency mentioned that it 
was considering revising the Reye's syndrome warning currently required 
for products containing aspirin in Sec.  201.314(h)(1) (21 CFR 
201.314(h)(1)) to be the same as the proposed warning for products 
containing bismuth subsalicylate.
    In the Federal Register of October 20, 1993 (58 FR 54228), FDA 
published a notice of proposed rulemaking to revise the Reye's syndrome 
warning required for OTC drug products containing aspirin to be 
consistent with the proposed warning for OTC overindulgence drug 
products containing bismuth subsalicylate (the October 1993 proposed 
rule). The

[[Page 18862]]

agency also proposed to extend the warning to OTC drug products 
containing nonaspirin salicylates, such as choline salicylate, 
magnesium salicylate, and sodium salicylate, but did not specify 
whether the warning would apply to products containing salicylates used 
as inactive ingredients.
    In response to the two proposals, the agency received comments from 
two manufacturers and two professional associations. These comments are 
on public display in the Dockets Management Branch (HFA-305), Food and 
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852 
under Docket No. 82N-0166 or 93N-0182.
    The agency has determined that the two proposals should be combined 
so that all Reye's syndrome warnings appear in one place (Sec.  
201.314(h)(1)), with an appropriate cross reference in the individual 
ingredient monographs. Thus, there is no need for a separate rule for 
overindulgence drug products containing bismuth subsalicylate. This 
Reye's syndrome warning also applies to OTC antidiarrheal drug products 
containing bismuth subsalicylate because bismuth subsalicylate is a 
monograph ingredient for this use at this time.
    In the proposed rules to amend parts 201 and 257 (21 CFR parts 201 
and 357), the agency advised that any final rule based on the proposals 
will be effective 6 months and 12 months, respectively, after the date 
of publication in the Federal Register. The agency is setting the 
effective date for this final rule at 12 months, but is establishing 
varying compliance dates for this final rule. (See Compliance Dates in 
the DATES section and section II, comment 11 of this document.) Any OTC 
drug product that is subject to this final rule that is initially 
introduced or initially delivered for introduction into interstate 
commerce after the compliance dates for the rule will be considered 
misbranded under sections 201(n) and 502(a) and (f) of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(n) and 352(a) and 
(f)) if it does not contain the new warning required by this final 
rule. Further, any OTC drug product subject to this final rule that is 
repackaged or relabeled after the compliance dates of the rule must 
comply with the rule regardless of the date that the product was 
initially introduced or initially delivered for introduction into 
interstate commerce.

II. The Agency's Conclusions on the Comments

    (Comment 1) One comment supported the agency's proposal to require 
a Reye's syndrome warning on products containing nonaspirin 
salicylates. Other comments asserted that there are no scientific data 
establishing an association between nonaspirin salicylates and Reye's 
syndrome. The comments argued that numerous epidemiological studies of 
the etiology of Reye's syndrome have failed to suggest an association 
with nonaspirin salicylates. One comment included published reports of 
the Ohio Department of Health study (Ref. 1), the Public Health Service 
(PHS) pilot and main studies (Refs. 2 and 3), and the Yale study (Ref. 
4) and cited two reports from Australia published in 1987 (Ref. 5) and 
1990 (Ref. 6). The comment also included unpublished data (Ref. 7) 
based on the Ohio Department of Health study and the PHS pilot study.
    The comments contended that the low incidence of Reye's syndrome, 
in spite of widespread use of nonaspirin salicylates and the presence 
of naturally occurring salicylates in food, strongly argues against an 
association with nonaspirin salicylates. The comments added that the 
case reports associating Reye's syndrome with the use of bismuth 
subsalicylate, calcium salicylate, and choline salicylate cited in the 
proposal provided insufficient detail to support such an association. 
The comments also criticized the in vitro data cited by the agency and 
questioned whether mitochondrial swelling, seen in the presence of 
salicylates in the studies, is relevant to the pathogenesis of Reye's 
syndrome. One comment suggested that aspirin's acetylation mechanism 
may be responsible for the association between aspirin and Reye's 
syndrome.
    The agency has reviewed the epidemiologic studies submitted by the 
comment and agrees that they did not find an association between 
nonaspirin salicylates and Reye's syndrome. However, these studies 
lacked sufficient subjects to adequately evaluate such an association.
    The PHS pilot study (Ref. 2) reported an association between Reye's 
syndrome and salicylate use, but did not differentiate between aspirin 
and other salicylates. In the main study (Ref. 3), the independent risk 
of Reye's syndrome with nonaspirin salicylates could not be assessed 
because only two cases were not exposed to aspirin. The Ohio Department 
of Health study (Ref. 1) reported a significant association between 
aspirin use and Reye's syndrome (relative risk 11.5; confidence 
interval 2.7 - 48.4; p < 0.001). Further analysis (Ref. 7) of data from 
the second year of this study and the PHS pilot study showed that the 
Ohio study had a higher percentage of nonaspirin salicylate use in the 
Reye's syndrome cases than in the controls (25 percent versus 16.8 
percent), whereas the findings for the PHS pilot study were mixed (14.8 
percent versus 21.1, 31.6, and 12.7 percent). None of these findings 
were significant.
    The agency notes that the Yale study (Ref. 4) investigated the 
validity of the reported association of aspirin and Reye's syndrome by 
evaluating potential bias associated with earlier studies. The authors 
concluded that there is a strong association between aspirin and Reye's 
syndrome, as reported in other studies, but the study did not evaluate 
the association of nonaspirin salicylates and Reye's syndrome. The two 
Australian studies mentioned by the comment (Refs. 5 and 6) did not 
show an association between salicylate ingestion (including aspirin) 
and Reye's syndrome.
    The agency is aware of a number of reports linking bismuth 
subsalicylate-containing products to Reye's syndrome (Ref. 8). As of 
May 1999, the agency found 27 cases of potential neurologic reaction 
for these products reported from 1989 through 1997 in its Spontaneous 
Reporting System (SRS). Fifteen of these cases had a possible diagnosis 
of Reyes syndrome, and most of these were children. The remaining 12 
cases (6 pediatric and 6 adult) included a variety of neurological 
disorders. Table 1 summarizes the 15 reports.

 Table 1.--Case Reports of Reye's Syndrome or Suspected Reye's Syndrome
                in People Who Took Bismuth Subsalicylate
------------------------------------------------------------------------
     FDA                                Event      Other
  Number\1\     Age\2\    Gender\3\    (year)    drugs\4\    Outcome\5\
------------------------------------------------------------------------
578534 and    6Y         F            1989      APAP        D
 725706                                          (only)
823003        P          M            ........  U           U
823007\1\     P          U            1985 or   U           U
                                       1986
824682        P          F            1989      U           D

[[Page 18863]]

 
824683        12Y        F            ........  U           D
830479\1\     between 8  U            1978      ASA         H
               and 15Y
830513        U          U            1989      U           U
830516\1\     between 8  U            1978      ASA         H
               and 15Y
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
1502057\1\    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 available on these cases, it is 
not certain that bismuth subsalicylate was the cause of Reye's 
syndrome. However, most of the reports identified bismuth subsalicylate 
use only prior to the diagnosis of Reye's syndrome. Death was reported 
in 60 percent of the cases.
    The agency notes that a recent report by Orlowski (Ref. 9) 
suggested that many people originally diagnosed with Reye's syndrome 
may have had metabolic disorders. To test this hypothesis, Orlowski 
evaluated the medical records of subjects in the Australian studies 
(Refs. 5 and 6) that had not shown an association with aspirin or 
salicylate ingestion and Reye's syndrome. The medical records of 26 
people who were originally diagnosed with Reye's syndrome and survived 
were reassessed using more precise diagnostic criteria. Eighteen (69 
percent) of these were subsequently diagnosed as having other diseases 
(15 with inborn errors of metabolism). The most common metabolic 
disorder was medium-chain acyl-coenzyme-A dehydrogenase deficiency. 
Orlowski speculated that the disappearance of Reye's syndrome in the 
1980s may be more related to the discovery of, and ability to diagnose, 
inborn errors of metabolism that mimic Reye's syndrome clinically, 
biochemically, and pathologically than to warning labels and the 
reduced use of aspirin. Although some people previously diagnosed with 
Reye's syndrome have been found to have metabolic disorders that may 
meet the criteria for a diagnosis of Reye's syndrome, and some people 
with metabolic disorders may be predisposed to developing Reye's 
syndrome, the agency finds there is no definitive evidence at this time 
that Reye's syndrome can generally be attributed to metabolic 
disorders. As discussed previously, other studies (Refs. 1, 2, and 3) 
have shown an association with aspirin ingestion and Reye's syndrome.
    The agency notes one comment's statement that the incidence of 
Reye's syndrome is low despite many foods with naturally occurring 
salicylates. Salicylates occur in many foods at low concentrations and 
in certain foods at relatively high concentrations. For instance, a few 
herbs and spices contain as much as 200 milligrams salicylate per 100 
grams (Ref. 10). However, these food products are generally consumed in 
small amounts. The agency has no information to suggest that 
salicylates in food are associated with Reye's syndrome. Although 
salicylates are present in a wide range of foods, the amount consumed 
from foods is generally lower than the therapeutic doses in drugs.
    The references submitted by the comment that suggested that the 
acetylation mechanism of aspirin may be responsible for Reye's syndrome 
did not provide adequate information to support this suggestion. The 
references included discussion of the hydrolysis of acetylsalicylic 
acid into acetyl and salicylic acid moieties and the further hydrolysis 
of the acetyl moiety to acetate, which is ultimately metabolized to 
carbon dioxide. Up to 50 percent of orally administered doses of 
acetylsalicylic acid are hydrolyzed before they reach the blood stream 
because of esterases located in the gut wall and the clearance of the 
compound by the liver (Ref. 11). Packham (Ref. 12) noted that the 
acetyl moiety can rapidly acetylate cyclo-oxygenase in platelets at 
micromolar concentration. However, it may not remain in the circulation 
long enough to acetylate other proteins to an extent that alters their 
function. Salicylic acid is the circulating drug form which is shared 
by all salicylate products. It undergoes direct renal excretion and 
hepatic biotransformation through several enzymatic systems.
    As noted in the October 1993 proposed rule (58 FR 54228 at 54229) 
there are some in vitro biochemical data that suggest salicylate may 
contribute to mitochondrial injury that is characteristic of Reye's 
syndrome. Based on a more recent in vitro study, Trost and Lemasters 
(Ref. 13) suggested that induction of the mitochondrial permeability 
transition (MPT) is a common pathophysiological mechanism causing 
mitochondrial injury in Reye's syndrome. In that study, MPT induction 
by aspirin required alkaline hydrolysis. Because aspirin spontaneously 
decomposes to salicylate, the authors said it is likely that 
salicylate, rather than acetylsalicylate, is the primary inducer of 
MPT.
    While some in vitro studies (Refs. 14 and 15) suggest salicylate is 
responsible for mitochondrial injury that may be responsible for the 
pathogenesis of Reye's syndrome, the agency agrees with the comment 
that the evidence is not sufficient to show the salicylate moiety is 
responsible for Reye's syndrome. The pathogenesis of Reye's syndrome is 
not known. None of the submitted references link Reye's syndrome to 
either the salicylate or acetyl drug moiety.
    Although the agency does not have definitive evidence that drugs 
containing nonaspirin salicylates significantly increase the risk of 
Reye's syndrome, a number of case reports (Ref. 8) suggest an 
association. Because of the serious consequences of Reye's syndrome, 
the agency has determined, in the interest of safe use of OTC drug

[[Page 18864]]

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

[[Page 18865]]

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

[[Page 18866]]

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

III. The Agency's Final Conclusions

    The agency has determined that the Reye's syndrome warning should 
apply to all oral and rectal OTC drug products containing salicylates 
as active ingredients, regardless of their intended use. Therefore, the 
requirement for a Reye's syndrome warning for aspirin and nonaspirin 
salicylates (including bismuth subsalicylate) will appear in one 
location (Sec.  201.314(h)). A reference to this warning is included in 
Sec.  335.50(c)(2)(i)(A) (21 CFR 335.50(c)(2)(i)(A)) of the final 
monograph for OTC antidiarrheal drug products. A reference will also be

[[Page 18867]]

included in 21 CFR part 343 in the final monograph for OTC internal 
analgesic, antipyretic, and antirheumatic drug products and in part 
357, subpart J, in the final monograph for OTC overindulgence drug 
products, when the monographs for those products are finalized. Other 
labeling that was proposed in Sec.  357.950 for drug products for the 
relief of symptoms associated with overindulgence in food and drink 
will be finalized in a future issue of the Federal Register. The OTC 
drug product labeling format and content requirements in Sec.  
201.66(c)(5)(ii)(A) state that the warning in Sec.  201.314(h)(i) shall 
follow the subheading ``Reye's syndrome:''.
    Mandating warnings in an OTC drug monograph does not require a 
finding that any or all of the OTC drug products covered by the 
monograph actually caused an adverse event, and FDA does not so find. 
Nor does FDA's requirement of warnings repudiate the prior OTC drug 
monographs and monograph rulemakings under which the affected drug 
products have been lawfully marketed. Rather, as a consumer protection 
agency, FDA has determined that warnings are necessary to ensure that 
these OTC drug products continue to be safe and effective for their 
labeled indications under ordinary conditions of use as those terms are 
defined in the Federal Food, Drug, and Cosmetic Act. This judgment 
balances the benefits of these drug products against their potential 
risks (see 21 CFR 330.10(a)).
    FDA's decision to act in this instance need not meet the standard 
of proof required to prevail in a private tort action (Glastetter v. 
Novartis Pharmaceuticals, Corp., 252 F.3d 986, 991 (8th Cir. 2001)). To 
mandate warnings, or take similar regulatory action, FDA need not show, 
nor do we allege, actual causation. For an expanded discussion of case 
law supporting FDA's authority to require such warnings, see Labeling 
of Diphenhydramine-Containing Drug Products for Over-the-Counter Human 
Use, final rule, 67 FR 72555 (December 6, 2002).

IV. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, if a rule has a significant economic impact on a 
substantial number of small entities, an agency must analyze regulatory 
options that would minimize any significant impact of the rule on small 
entities. Section 202(a) of the Unfunded Mandates Reform Act of 1995 
requires that agencies prepare a written statement of anticipated costs 
and benefits before proposing any rule that may result in an 
expenditure in any one year by State, local, and tribal governments, in 
the aggregate, or by the private sector of $100 million (adjusted 
annually for inflation). The rules that led to the development of this 
final rule were published in 1993, before the Unfunded Mandates Reform 
Act of 1995 was enacted. The agency explains in this final rule that 
the final rule will not result in an expenditure in any one year by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100 million.
    The agency concludes that this final rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
This final rule is not a significant regulatory action as defined by 
the Executive order and so is not subject to review under the Executive 
order. The Unfunded Mandates Reform Act does not require FDA to prepare 
a statement of costs and benefits for this final rule, because the 
final rule is not expected to result in any 1-year expenditure that 
would exceed $100 million adjusted for inflation. The current inflation 
adjusted statutory threshold is about $110 million.
    The purpose of this final rule is to revise the Reye's syndrome 
warning that is already required for OTC drug products that contain 
aspirin for use by children and adolescents and to extend the 
requirement to those products that contain nonaspirin salicylates 
(including bismuth subsalicylate) as active ingredients. The revised 
warning is similar to the voluntary warning already included on some 
OTC antidiarrheal and overindulgence drug products that contain bismuth 
subsalicylate. This final rule is intended to bring uniformity and 
consistency to the labeling of OTC drug products containing aspirin and 
nonaspirin salicylates.

A. Benefits

    The revised warning will inform consumers of the symptoms of Reye's 
syndrome and advise that aspirin or nonaspirin salicylate (including 
bismuth subsalicylate) drug products should not be given to children or 
teenagers who have or are recovering from chicken pox or flu-like 
symptoms. As stated in the October 1993 proposed rule (58 FR 54228), 
the agency has reconsidered the need to include all OTC drug products 
containing salicylates in this required warning. Fifteen adverse drug 
reports linking bismuth subsalicylate with Reye's syndrome have been 
entered into the agency's database since March 1991, when the first 
Reye's syndrome death associated with bismuth subsalicylate was 
reported to the agency (Refs. 8 and 18). Most of these cases occurred 
in children, and deaths were reported in the majority of these cases.
    FDA cannot quantify the expected benefits of this rule, because it 
lacks the data to conduct a quantitative risk assessment. The agency 
notes, however, that in most disease surveillance systems, reported 
cases are recognized to represent only a fraction of the actual total. 
Reye's syndrome is manifested by a change in mental status ranging from 
lethargy to delirium, seizures, and respiratory arrest (Ref. 19). 
Mortality is related to the stage of coma at the time of hospital 
admission and has been estimated to be as high as 40 percent (Ref. 19). 
It has been estimated that 30 percent of Reye's syndrome patients who 
deteriorate to the stage of neurologic seizure, and survive, develop 
serious neurologic sequelae. Thus, alerting consumers to the early 
symptoms of Reye's syndrome is essential so that prompt medical 
treatment can be obtained, with a better prognosis for the patient.

B. Costs

    Based on information in the agency's drug listing system, there are 
between 900 and 1,500 manufacturers and distributors that together 
produce about 5,000 OTC drug products containing salicylates as an 
active ingredient that will be affected by this final rule. Over 90 
percent of these products are internal analgesic, antipyretic, and 
antirheumatic drug products, which may have more than one stock keeping 
unit (SKU) (individual products, packages, and sizes). Because the 
majority of the products already include a warning statement that is 
similar to the labeling required by this final rule, most changes will 
be minor. Further, the cost to implement the new warning statement 
should be negligible because the agency is providing that the warning 
can be coordinated with the other labeling changes that will be 
included in a future final monograph for those products.
    As discussed elsewhere in this issue of the Federal Register, about 
8 percent

[[Page 18868]]

(400) of the affected products are antidiarrheal drug products that 
contain bismuth subsalicylate as the active ingredient. The cost to 
implement the new Reye's syndrome warning for those products is 
significantly mitigated because the warning will be incorporated into 
the new labeling for those products as a result of publication of the 
final monograph for OTC antidiarrheal drug products.
    The remaining 2 percent (100) of affected products includes OTC 
drug products containing aspirin and nonaspirin salicylates marketed 
under an NDA or ANDA or marketed under the tentative final monograph 
for OTC overindulgence drug products. A number of the overindulgence 
drug products that contain bismuth subsalicylate as the active 
ingredient also bear antidiarrheal claims and, thus, will need to be 
relabeled as a result of publication of the final monograph for those 
drug products. The cost to add a warning to product labeling generally 
averages about $2,000 to $3,000 per SKU. Thus, the cost for these 
products to be relabeled is estimated to be between $200,000 and 
$300,000.

C. Small Business Impacts

    Census data provide aggregate industry statistics on the total 
number of manufacturers for Standardized Industrial Classification Code 
2384 Pharmaceutical Preparations by establishment size, but do not 
distinguish between manufacturers of prescription and OTC drug 
products. According to the U.S. Small Business Administration (SBA) 
designations for this industry, however, over 92 percent of the roughly 
700 establishments and over 87 percent of the 650 firms are small. 
(Because census size categories do not correspond to the SBA 
designation of 750 employees, these figures are based on 500 
employees.)
    The agency's drug listing system indicates that between 900 and 
1,500 marketers will need to relabel as the result of this final rule. 
Thus, the agency believes that many of the manufacturers affected by 
this final rule would be small. However, the cost of relabeling of 
private label products is incurred by the private label manufacturers, 
not the individual small marketers. The effect on individual firms will 
vary with the number of the firm's SKUs that require relabeling and the 
size and cost of the firm's labeling inventory. Most small firms will 
not incur significant regulatory costs because they manufacture few 
affected SKUs and use less expensive labeling stock. Because most firms 
will be able to incorporate these required changes when incorporating 
other regulatory requirements, this final rule should have a minimal 
economic impact on small entities.

D. Alternatives

    The agency considered and rejected a more costly alternative that 
would have required all products to be relabeled within 12 to 18 months 
of publication of this final rule in the Federal Register, with a 
multimillion dollar cost to industry based on the potential number of 
affected products. Because 80 percent of the products (a number of 
which have multiple SKUs) already have a Reye's syndrome warning on 
their label, the agency concluded that the incremental benefits of a 
reworded warning did not outweigh the costs. As discussed in section 
II, comment 11 of this document, the agency has set the implementation 
date of this final rule for the Reye'syndrome warning for OTC 
antidiarrheal drug products that contain bismuth subsalicylate as an 
active ingredient to coincide with the compliance dates for the final 
monograph for those drug products. The agency considers this a 
reasonable time for manufacturers to implement these final rules, and 
the costs associated with implementation will be less for one label 
change than for two label changes. The agency has also set the 
compliance dates for the majority of the products (internal analgesic, 
antipyretic, and antirheumatic) affected by this final rule to coincide 
with the final monograph for those drug products, to be published in 
the future. The agency encourages manufacturers to relabel their 
products voluntarily, if new labeling is implemented before that final 
monograph publishes.
    The agency considered, but rejected, an exemption from coverage for 
small entities because the new labeling information is also needed by 
consumers who purchase products marketed by those entities. However, 
longer compliance dates are being provided for antidiarrheal and 
overindulgence drug products containing bismuth subsalicylate with 
annual sales less than $25,000 (an additional 12 months) and for 
products containing aspirin and nonaspirin salicylates marketed under 
an NDA or ANDA (an additional 6 months).

E. Conclusion

    The Unfunded Mandates Reform Act does not require FDA to prepare a 
statement of costs and benefits for this final rule, because the final 
rule is not expected to result in any 1-year expenditure that would 
exceed $100 million adjusted for inflation. The current inflation 
adjusted statutory threshold is about $110 million.
    This analysis shows that the agency has considered the burden to 
small entities and provided compliance dates that should significantly 
reduce the burden. Thus, the agency certifies that this final rule will 
not have a significant impact on a substantial number of small 
entities.

V. Paperwork Reduction Act of 1995

    FDA concludes that the warning statement set forth in this final 
rule is not subject to review by the Office of Management and Budget 
because it does not constitute a ``collection of information'' under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, 
the required labeling is a ``public disclosure of information 
originally supplied by the Federal government to the recipient for the 
purpose of disclosure to the public'' (5 CFR 1320.3(c)(2)).

VI. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

VIII. References

    The following references are on display in the Dockets Management 
Branch (see section I of this document) and may be seen by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday.

    1. Halpin, T. et al., ``Reye's Syndrome and Medication Use,'' 
Journal of the American Medical Association, 248:687-723, 1982.
    2. Hurwitz, E. et al., ``Public Health Service Study of Reye's 
Syndrome and Medications: Report of the Pilot Study,'' New England 
Journal of Medicine, 313:849-857, 1985.

[[Page 18869]]

    3. Hurwitz, E. et al., ``Public Health Service Study of Reye's 
Syndrome and Medications: Report of the Main Study,'' Journal of the 
American Medical Association, 257:1905-1911, 1987.
    4. Forsyth, B. et al., ``New Epidemiologic Evidence Confirming 
that Bias Does Not Explain the Aspirin/Reye's Syndrome 
Association,'' Journal of the American Medical Association, 
261:2517-2524, 1989.
    5. Orlowski, J. et al., ``A Catch in the Reye,'' Pediatrics, 
80:638-642, 1987.
    6. Orlowski, J. et al., ``Reye's Syndrome: A Case Control Study 
of Medication Use and Associated Viruses in Australia,'' Cleveland 
Clinic Journal of Medicine, 57:323-329, 1990.
    7. Biometric Research Institute, ``Analysis of Exposure to Non-
Aspirin Salicylates Among Subjects from the Ohio Department of 
Health Survey and the Public Health Service Pilot Study on Reye 
Syndrome,'' June 13, 1986, in comment C2, Docket No. 93N-0182, 
Dockets Management Branch.
    8. Adverse Drug Reaction Reports, in OTC Vol. 03RSFR, Docket No. 
93N-0182, Dockets Management Branch.
    9. Orlowski, J. P., ``Whatever Happened to Reye's Syndrome? Did 
It Ever Really Exist?'' Critical Care Medicine, 27:1582-1587, 1999.
    10. Swain, A., ``Salicylates in Foods,'' Journal of the American 
Dietetic Association, 85:950-960, 1985.
    11. Reigelman, S., ``The Kinetic Disposition of Aspirin in 
Humans,'' in Aspirin, Platelets, and Stroke (Chapter X), edited by 
W. S. Fields and W. K. Hess, W. H. Green Inc., St. Louis, MO, pp. 
105-114, 1971.
    12. Packham, M., ``Mode of Action of Acetylsalicylic Acid,'' in 
Acetylsalicylic Acid: New Uses for an Old Drug, edited by H. Barnett 
et al., Raven Press, New York, NY, pp. 63-82, 1982.
    13. Trost, L. C., and J. J. Lemasters, ``The Mitochondrial 
Permeability Transition: A New Pathophysiological Mechanism for 
Reye's Syndrome and Toxic Liver Injury,'' The Journal of 
Pharmacology and Therapeutics, 278:1000-1005, 1996.
    14. Martens, M. E., and C. Lee, ``Reye's Syndrome: Salicylates 
and Mitochondrial Functions,'' Biochemical Pharmacology, 33:2869-
2876, 1984.
    15. Yoshida, Y. et al., ``Effect of Salicylic Acid on 
Mitochondrial Peroxisomal Fatty Acid Catabolism,'' Pediatric 
Research, 23:338-341, 1988.
    16. National Institutes of Health, Consensus Conference, 
``Diagnosis and Treatment of Reye's Syndrome,'' Journal of the 
American Medical Association, 246:2441-2444, 1981.
    17. Wolinsky, J. S., ``Reye's Syndrome,'' in Cecil Textbook of 
Medicine, 19th ed., edited by J. B. Wyngaarden et al., W. B. 
Saunders Co., Philadelphia, PA, pp. 2194-2195, 1992.
    18. Adverse Drug Reaction Reports, in OTC Vol. 03RSNPR, Docket 
No. 93N-0182, Dockets Management Branch.
    19. Betts, R., ``Influenza,'' in Principles and Practices of 
Infectious Diseases, 4th ed., edited by G. L. Mandell, J. E. 
Bennett, and R. Dolin, Churchhill Livingston, New York, NY, pp. 
1546-1567, 1995.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
201 is amended as follows:

PART 201--LABELING

0
1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

0
2. Section 201.314 is amended by revising paragraphs (h)(1) and (h)(4) 
to read as follows:


Sec.  201.314  Labeling of drug preparations containing salicylates.

* * * * *
    (h)(1) The labeling of orally or rectally administered over-the-
counter drug products containing aspirin or nonaspirin salicylates as 
active ingredients subject to this paragraph is required to prominently 
bear the following warning: ``Reye's syndrome [subheading in bold 
type]: Children and teenagers who have or are recovering from chicken 
pox or flu-like symptoms should not use this product. When using this 
product, if changes in behavior with nausea and vomiting occur, consult 
a doctor because these symptoms could be an early sign of Reye's 
syndrome, a rare but serious illness.''
* * * * *
    (4) Any product subject to paragraphs (h)(1), (h)(2), and (h)(3) of 
this section that is not labeled as required by these paragraphs and 
that is initially introduced or initially delivered for introduction 
into interstate commerce after the following dates is misbranded under 
sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and 
Cosmetic Act.
    (i) Compliance by October 18, 2004, for OTC drug products 
containing aspirin and nonaspirin salicylates as an active ingredient 
and marketed under a new drug application or abbreviated new drug 
application.
    (ii) Compliance by April 19, 2004, for OTC antidiarrheal and 
overindulgence drug products that contain bismuth subsalicylate as an 
active ingredient and have annual sales greater than $25,000.
    (iii) Compliance by April 18, 2005, for OTC antidiarrheal and 
overindulgence drug products that contain bismuth subsalicylate as an 
active ingredient and have annual sales less than $25,000.
    (iv) Compliance dates for all other OTC drug products containing 
aspirin and nonaspirin salicylates as an active ingredient and marketed 
under an OTC drug monograph (for internal analgesic, antipyretic, and 
antirheumatic drug products, or for menstrual drug products) will be 
established when the final monographs for those products are published 
in a future issue of the Federal Register. In the interim, these 
products should continue to be labeled with the previous Reye's 
syndrome warning that appears in paragraph (h)(1) of this section.

    Dated: March 31, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-9382 Filed 4-16-03; 8:45 am]
BILLING CODE 4160-01-S