[Federal Register Volume 67, Number 162 (Wednesday, August 21, 2002)]
[Proposed Rules]
[Pages 54139-54159]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-21122]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 343

[Docket No. 77N-094I]
RIN 0910-AA01


Internal Analgesic, Antipyretic, and Antirheumatic Drug Products 
for Over-the-Counter Human Use; Proposed Amendment of the Tentative 
Final Monograph, and Related Labeling

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
the tentative final monograph (TFM) for over-the-counter (OTC) internal 
analgesic, antipyretic, and antirheumatic (IAAA) drug products to 
include ibuprofen as a generally recognized safe and effective 
analgesic/antipyretic active ingredient for OTC use. FDA is also 
proposing to amend its regulations to include consistent allergy 
warnings for OTC IAAA drug products containing nonsteroidal anti-
inflammatory active ingredients. These proposals are in response to a 
citizen petition (Ref. 1) and to a comment submitted in response to 
that petition (Ref. 2) and are part of the ongoing review of OTC drug 
products conducted by FDA.

DATES: Submit written or electronic comments by November 19, 2002. 
Submit written or electronic comments on the agency's economic impact 
determination by November 19, 2002. Please see section XII of this 
document for the effective date of any final rule that may publish 
based on this proposal.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

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:

Table of Contents

I. Background
II. Comment in Opposition to the Citizen Petition
III. The Agency's Evaluation of the Citizen Petition
    A. Use for a Material Time and to a Material Extent
    B. Safety
    C. Effectiveness
    D. Labeling
IV. The Agency's Tentative Conclusions and Proposals
V. Summary of Proposed Agency Changes
VI. Labeling Guidance
VII. Implementation
VIII. Analysis of Impacts
IX. Paperwork Reduction Act of 1995
X. Environmental Impact
XI. Request for Comments
XII. Proposed Effective Date
XIII. References

I. Background

    Ibuprofen is benzeneacetic acid, -methyl-4-(2-
methylpropyl), ()-, a member of the propionic acid class of 
nonsteroidal anti-inflammatory drugs (NSAIDs). The commercially 
available drug is a racemic mixture of two optical isomers (S-[+] and 
R-[-] ibuprofen). The racemic mixture is recognized in the U.S. 
Pharmacopeia (U.S.P.) (Ref. 3). Ibuprofen has been available as a 
prescription drug for the treatment of osteoarthritis and rheumatoid 
arthritis at a dose of 1,200 to 3,200 milligrams (mg) per (/) day since 
1974 in the United States and since 1969 in the United Kingdom. 
Ibuprofen has also been marketed by prescription and OTC in numerous 
countries throughout the world (Ref. 4).
    Safety and effectiveness data submitted to the agency to support 
the approval of the OTC marketing of a 200-mg ibuprofen tablet were 
considered by the Arthritis Advisory Committee (AAC)

[[Page 54140]]

at its August 18, 1983, meeting. Based on the available data, the AAC 
concluded that a 200-mg ibuprofen product could be used safely and 
effectively OTC, without the supervision of a physician (Ref. 5). It 
has been available on the OTC market for use in adults and children 12 
years and older since 1984 through the new drug application (NDA) 
process. It is marketed at a 200-mg dosage strength, for the relief of 
minor aches and pains and for fever reduction. A single OTC dose is 200 
to 400 mg with a maximum daily dose of 1,200 mg.
    The AAC suggested warnings and precautions that it believed should 
appear in labeling to alert individuals to certain risks, especially 
those individuals who should not use ibuprofen without the supervision 
of a physician. The AAC was concerned that the promotion of OTC 
ibuprofen not counteract a warning regarding ibuprofen's cross-
reactivity with aspirin (Ref. 5). The agency's approved labeling for 
ibuprofen includes warnings for aspirin sensitive individuals and 
people taking other OTC pain reliever/fever reducer products (Ref. 6).
    On October 17, 1983, a citizen petition (Ref. 7) was submitted that 
requested the agency to reopen the administrative record for OTC IAAA 
drug products to amend the proposed monograph to include ibuprofen as 
an internal analgesic ingredient in a 200-mg tablet with a maximum 
1,200-mg total daily dose. The agency denied the petition on May 18, 
1984 (Ref. 8) for several reasons, one of which (use for a material 
time and to a material extent) is discussed in section III.A of this 
document.
    In the Federal Register of November 16, 1988 (53 FR 46204), the 
agency published a TFM to establish conditions under which OTC IAAA 
drug products are generally recognized as safe and effective, and not 
misbranded. The TFM proposed acetaminophen, aspirin, carbaspirin 
calcium, choline salicylate, magnesium salicylate, and sodium 
salicylate as generally recognized as safe and effective IAAA active 
ingredients for OTC use and appropriate labeling for OTC drug products 
containing these ingredients. Ibuprofen was not discussed in the TFM.
    Subsequent to the TFM, the agency received a citizen petition (Ref. 
1) requesting that the TFM be amended to include racemic ibuprofen in 
an oral dosage form, as a single active ingredient. The petition 
recommended a minimum effective dose of 200 mg ibuprofen for use by 
adults and children 12 years and older. The petition requested the same 
indications as proposed for other monograph IAAA active ingredients in 
Sec.  343.50(b)(1) (21 CFR 343.50(b)(1)): ``For the temporary relief of 
minor aches and pains associated with a cold, sore throat, headache, 
toothache, muscular aches, backache, premenstrual and menstrual cramps 
(dysmenorrhea), and for the minor pain from arthritis, and to reduce 
fever.''
    The petition requested warnings specific for the OTC use of 
ibuprofen, including the following warning, in this form, or in a 
different format conveying the same information:
    ASPIRIN SENSITIVE PATIENTS: Although this product does not contain 
aspirin, it may cause a severe reaction in people allergic to aspirin. 
Do not take ibuprofen if you have had any of the following reactions to 
any pain reliever/fever reducer:
     allergic reaction
     shock
     hives
     difficulty breathing
     asthma
     swelling
    If you are under a doctor's care for any serious condition, consult 
a doctor before taking this product. As with aspirin and acetaminophen, 
if you have any condition which requires you to take prescription drugs 
or if you have had any problems or serious side effects from taking any 
nonprescription pain reliever, do not take this product without first 
discussing it with your doctor. IF YOU EXPERIENCE ANY SYMPTOMS WHICH 
ARE UNUSUAL OR SEEM UNRELATED TO THE CONDITION FOR WHICH YOU TOOK 
IBUPROFEN, CONSULT A DOCTOR BEFORE TAKING ANY MORE OF IT. Although 
ibuprofen is indicated for the same conditions as aspirin and 
acetaminophen, it should not be taken with them except under a doctor's 
direction. Do not combine this product with any other ibuprofen-
containing product.
    The petition also suggested the following directions for use:
    Adults: Take 200 mg every 4 to 6 hours while symptoms persist. If 
pain or fever does not respond to 200 mg, 400 mg may be used but do not 
exceed 1,200 mg in 24 hours, unless directed by a doctor. The smallest 
effective dose should be used. Take with food or milk if occasional and 
mild heartburn, upset stomach, or stomach pain occurs with use. Consult 
a doctor if these symptoms are more than mild or if they persist. 
Children: Do not give this product to children under 12 years of age 
except under the advice and supervision of a doctor.
    The petition asserted that ibuprofen has been marketed for a 
material time and to a material extent. To support this statement, the 
petition presented information indicating that from May 1984 (when 
ibuprofen first became available OTC in the United States) through 1996 
over 90 billion 200-mg tablet doses were sold (Ref. 1). The petition 
noted that more than 20 companies now market OTC ibuprofen drug 
products and provided information to show that the sale of OTC 
ibuprofen in the United States is comparable to that of aspirin and 
acetaminophen. Thus, the petitioner said, given the enormous volume of 
sales and more than 13 years of marketing, ibuprofen has been available 
as an OTC drug product for a material time and to a material extent, is 
now generally recognized as safe and effective, and is no longer a new 
drug. The petition did not request monograph status for ibuprofen for 
children under 12 years of age.
    The petition (Ref. 1) included a summary of safety and 
effectiveness data (through 1982) previously submitted to FDA to 
support the prescription-to-OTC switch of ibuprofen. That summary 
included effectiveness data for ibuprofen for analgesic (dysmenorrhea, 
dental, musculoskeletal, postpartum and postsurgical pain, and 
headache), antipyretic, and anti-inflammatory use and a safety overview 
of specific organ systems, special populations, and postmarketing data. 
The petition (Ref. 1) also included the results from a search of the 
worldwide medical literature from 1983 through August 1996 of adverse 
events associated with ibuprofen, mostly in the OTC dosage range.
    The published studies and case reports included in the petition 
involved mainly OTC doses of ibuprofen (less than or equal to 1,200 mg/
day) for an OTC-indicated duration (less than 10 days use for pain, or 
3 days for fever) that occurred in generally healthy individuals, 12 
years of age or older. The agency's comments on the citizen petition 
are on file in the Dockets Management Branch (Ref. 9). The petitioner 
subsequently submitted additional information in support of ibuprofen's 
safety profile (Ref. 10), which included publications from 1990 through 
1998, generated from a number of databases.
    The agency also received a comment opposing the petition's request 
to include ibuprofen in the TFM (Ref. 2). The petition, related 
correspondence, additional information, and the opposing comment are on 
public

[[Page 54141]]

display in the Dockets Management Branch (see ADDRESSES).

II. Comment in Opposition to the Citizen Petition

    One comment (Ref. 2), opposing the petition's request, stated there 
is: (1) A lack of a general recognition of safety and effectiveness of 
all oral ibuprofen dosage forms, (2) a significant potential for use of 
OTC ibuprofen products at prescription dosage levels, and (3) a 
continued need for adverse event reporting and other marketing 
controls. Therefore, the comment contended, ibuprofen (200 mg) should 
remain subject to the NDA process.
    The comment suggested that allowing marketing of ibuprofen (200 mg) 
in any ``suitable'' oral dosage form (as provided for in the TFM) 
creates a potential for consumer harm. As examples, the comment 
mentioned several risks if ibuprofen would be included in the 
monograph: (1) Changes in product composition and manufacturing methods 
that would not be subject to prior FDA review, and (2) possible misuse 
of ibuprofen products due to the concurrent marketing of ibuprofen 
suspensions (one marketed under a monograph for adults and the other 
marketed under the new drug approval process and labeled for children).
    The comment also criticized the data included in the petition. The 
comment observed that although data on adverse events in prescription 
dosages is relevant to the consideration of whether an ingredient is 
appropriate for inclusion in the monograph, the petition submitted only 
information on adverse effects at OTC doses. The comment asserted that 
ingestion of larger doses (2,400 to 3,600 mg) has not been seen due to 
the relative expense of the OTC tablets. The comment contended that the 
lowered prices that would result from monograph status of ibuprofen 
(200 mg) could increase the potential for harm because prescription 
ibuprofen users may be enticed to switch to OTC drug products and self-
medicate at prescription dose levels without a doctor's supervision. 
The comment did not provide any data to support its assertions.
    The agency agrees with the opposing comment (Ref. 2) that ibuprofen 
is not generally recognized as safe and effective in all dosage forms. 
For instance, ibuprofen in suspension formulation for adult use has not 
been marketed OTC, and children's formulations have been marketed OTC 
less than 5 years. Thus, these formulations are not generally 
recognized as safe and effective for OTC use. In some studies 
evaluating the effectiveness of ibuprofen, capsule formulations were 
used as a means of blinding the studies. However, ibuprofen has been 
marketed OTC for adult use almost entirely in tablet formulations 
(i.e., tablets, caplets, and gelcaps (a tablet dosage form)) throughout 
its marketing history. Thus, current evidence for ibuprofen to be 
generally recognized as safe and effective for OTC use is only 
sufficient for tablet formulations. This proposal does not include 
liqui-gel formulations (ibuprofen solubilized in a gel matrix).
    The comment raised a concern about the potential for OTC ibuprofen 
to be used at prescription-dose levels. Currently approved NDA and 
abbreviated new drug application (ANDA) labeling for OTC ibuprofen drug 
products contains directions for appropriate OTC dosing. Products 
marketed under an OTC drug monograph will contain the same directions. 
Further, both the NDA/ANDA and the proposed monograph labeling alert 
consumers of the hazards associated with improper use and when to seek 
the advice of a physician. Given that the comment did not include any 
data to support its concern, the agency finds no basis to believe that 
the potential for misuse of these OTC ibuprofen drug products will be 
greater if their marketing status is changed from an NDA/ANDA to OTC 
drug monograph.
    The agency appreciates the comment's concern for the need for 
continued adverse event reporting and other marketing controls. The 
safety of ibuprofen has been monitored since it was first marketed in 
the United States under the new drug approval process (as a 
prescription drug in 1974 and as an OTC drug in 1984) and as a generic 
drug (for prescription use in 1985 and for OTC use in 1986). The agency 
monitors the quality of products marketed under OTC drug monographs 
through its current good manufacturing practice regulations in part 211 
(21 CFR part 211) and its inspection authority. Based on the available 
data, the agency finds the safety profile of ibuprofen to be comparable 
to that of other OTC internal analgesics (e.g., aspirin and 
acetaminophen) that have been proposed as generally recognized to be 
safe for OTC use.
    During ibuprofen's extensive OTC marketing history significant 
formulation and manufacturing issues have not arisen. The agency does 
not anticipate any potential problems if ibuprofen, in specific tablet 
formulations, is included in the monograph for adult use. 
Specifications for ibuprofen tablets are recognized in the U.S.P. (Ref. 
3). Although there is some degree of risk associated with the use of 
any OTC drug, whether marketed through the NDA/ANDA process, as a 
generic drug, or under an OTC drug monograph, the agency believes 
ibuprofen 200 mg in a tablet dosage form for adult use has been 
marketed safely OTC for a sufficient time and extent that it can be 
generally recognized as safe and effective for OTC use.

III. The Agency's Evaluation of the Citizen Petition

A. Use for a Material Time and to a Material Extent

    In 1984, the agency denied a petition (Ref. 7) to include ibuprofen 
in the OTC IAAA monograph because the request was for a new dosage 
strength (200 mg) which the agency determined had not been used to a 
material extent and for a material time in the United States and, thus, 
was considered a new drug within the meaning of section 201(p) of the 
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(p)). The 
petitioner had contended that ibuprofen had been available in the 
United States since 1974 as a prescription drug with more than 18.8 
billion cumulative 400-mg doses of the drug distributed worldwide 
through August 1982, and that the drug is currently the fourth largest 
prescription drug by volume in the United States. In its denial letter 
(Ref. 8), the agency pointed out that experience with ibuprofen at 
prescription strength is pertinent to the drug's safety, but such 
experience cannot support general recognition that the product, at a 
different strength and daily dose, can be used safely and effectively 
by the patient alone. The agency concluded that the petition ignored 
the lack of experience with the proposed single 200-mg tablet dose as 
an OTC drug product.
    Since that time, the current petition (Ref. 1) points out that from 
May 1984 (when ibuprofen 200-mg first became available OTC in the 
United States) through 1996 over 90 billion 200-mg tablet doses were 
sold. That number has substantially increased since 1996. The agency 
has determined that ibuprofen's 17 years of OTC marketing with over 100 
billion doses of 200-mg tablets sold shows that the drug at this dosage 
and in this dosage form as an internal analgesic and antipyretic has 
been used for a material time and to a material extent to qualify it 
for inclusion in an OTC drug monograph.

[[Page 54142]]

B. Safety

1. Preclinical
    a. Toxicity. The toxicity of ibuprofen has been extensively studied 
in a number of animal species (Refs. 11 and 12) and well characterized. 
The LD50 in the mouse was 800 mg/kilogram (kg) orally and 
320 mg/kg intraperitoneally. In rats, the LD50 was 1,600 mg/
kg orally and 1,300 mg/kg subcutaneously. In dogs, adverse effects were 
observed after a single oral dose of 125 mg/kg. There were no apparent 
ill effects after a single 20 or 50 mg/kg dose. Ibuprofen in lethal 
doses depressed the central nervous system of rodents, and was 
ulcerogenic in rodents and nonrodents.
    Newly weaned male and female rats were given 180, 60, 20, and 7.5 
mg/kg/day ibuprofen by oral gavage for 26 weeks (Ref. 12) . Rats 
receiving ibuprofen grew normally except for male rats receiving the 
180-mg/kg/day dose which gained significantly less weight than 
controls. When examined hematologically in the final week of dosing, 
both males and females on the 180 mg/kg/day dose were anemic as 
evidenced by low erythrocyte counts, hemoglobin concentrations, and 
hematocrits. Significant increases in the weights of the kidney, liver, 
and spleen occurred in both sexes. Histologic examination of the 
tissues revealed no significant changes except for one male and three 
female rats in the 180-mg dose group (10 animals/sex/group) that had 
intestinal ulcers.
    In a followup experiment (Ref. 12) to determine if the changes 
observed in the 26-week study were reversible, male and female rats 
were given 180, 60, and 20 mg/kg/day for 13 weeks. The day after dosing 
ended, half the animals in each group were sacrificed and the rest were 
kept undosed for 3 weeks. Generally, the results from this experiment 
were supportive of the 26-week study. Males given 180 mg/kg/day had 
enlarged kidneys, spleen, and testes. A dose-dependant enlargement of 
the kidney occurred in females. An enlargement of the liver and ovaries 
occurred in females on 180 mg/kg/day, and of the spleen and ovaries in 
females on 60 mg/kg/day. None of the enlarged organs were 
histologically abnormal. These changes were found to be reversible 3 
weeks after the end of dosing.
    No significant hematological or biochemical alterations were 
observed in dogs (two dogs/sex/group) given 16, 4, or 2 mg/kg/day 
ibuprofen (administered as two doses 6 hours apart) for 26 weeks (Ref. 
12). In the eighth week of dosing, female dogs in the high-dose group 
showed gross signs of gastrointestinal (GI) disturbance characterized 
by frequent vomiting, diarrhea (with occasional passage of fresh 
blood), and loss of blood. Occult blood was irregularly detected in 
fecal samples obtained from all dogs in the high-dose group from day 8 
on. At autopsy, organ weights were normal and pathologic changes were 
limited to ulcerative lesions of the GI tract.
    The effects of ibuprofen on reproduction have been studied in rats 
and rabbits (Ref. 12). Rats were administered 180, 60, 20, or 7.5 mg/
kg/day ibuprofen on days 1 through 20 of pregnancy. All litters were of 
normal size and weight. No difference in the incidence of fetal 
malformations was found between the treated and control groups.
    A reproduction study in rabbits (Ref. 12) at doses of 60, 20, or 
7.5 mg/kg/day was conducted on days 1 through 29 of pregnancy. Female 
rabbits given 60 mg/kg/day had fewer live fetuses per litter than did 
controls, but there was no significant difference in the number of dead 
and resorbed rabbits per litter. However, there was a reduction in the 
ratio of implants to corpora lutea, which suggested that the decrease 
in live litter size was due to interruption of early pregnancy. The 
average fetal weight was normal. At the lower doses, the litter size 
was unaffected. Apart from four young in one litter (60 mg/kg/day) with 
multiple malformations characteristic of cyclopia, there was no 
consistent pattern of dose-related malformations. The authors concluded 
that ibuprofen is not teratogenic but may reduce fertility by affecting 
early pregnancy at the high dose.
    The labeling of ibuprofen drug products currently marketed under an 
NDA/ANDA includes the general pregnancy/breast-feeding warning in 
Sec. 201.63(a) (21 CFR 201.63(a)) advising that a health professional 
should be consulted before use. It also includes a statement like that 
required for aspirin drug products in Sec. 201.63(e), which warns that 
it is especially important not to use the product during the third 
trimester of pregnancy because it could cause problems in the unborn 
child and complications during delivery. The agency is proposing to 
expand the warning in Sec. 201.63(e) to include ibuprofen. (See section 
V, number 1 of this document.)
    b. Pharmacokinetics. Ibuprofen's mode of action is not completely 
understood, but it may be related to its ability to inhibit 
prostaglandin synthetase (Ref. 13). Following oral dosing, ibuprofen 
has been found in synovial fluid, which is the proposed site of action 
for ibuprofen in patients with rheumatoid arthritis (Ref. 14). The 
pharmacologic activity of ibuprofen has been attributed mostly to the 
S-[+]-enantiomer (Refs. 15 and 16). After administration of racemic 
ibuprofen, the inactive R-[-]-enantiomer is slowly and incompletely (60 
percent) converted to the biologically active S-[+]-enantiomer, 
primarily through both presystemic and systemic chiral inversion (Refs. 
17, 18, and 19).
    The pharmacokinetics of ibuprofen have been well documented (Ref. 
20). The absorption of orally administered ibuprofen is rapid and 
approximately 80 percent of the dose is absorbed from the GI tract. 
Peak plasma levels in humans are reached between 45 and 90 minutes 
after administration of a single oral dose on an empty stomach, 
depending upon the formulation (Ref. 21). The extent of absorption is 
unchanged when ibuprofen is taken with meals (Ref. 22).
    Following oral administration, the apparent plasma volume of 
distribution has been reported to be between 0.1 to 0.2 liter (L)/kg, 
which approximates plasma volume and suggests minimal tissue binding is 
present (Refs. 23 and 24). Ibuprofen is extensively bound (more than 98 
percent) to whole human plasma and purified serum albumin at 
therapeutic concentrations, and may participate in plasma protein 
binding displacement reactions (Refs. 25 and 26). The apparent volume 
of distribution, based on total concentration, increases significantly 
with dose, but there is no attendant change in free drug volume of 
distribution (Ref. 27). The protein binding of ibuprofen is similar 
between normal individuals and people with osteoarthritis and 
rheumatoid arthritis and is not influenced by age or gender (Refs. 28 
and 29).
    Plasma concentrations of ibuprofen appear to decline in a biphasic 
manner with a plasma half-life of 2 to 4 hours for the racemate (Ref. 
20). Ibuprofen is metabolized via oxidation by the cytochrome P-450 
enzyme CYP 2C9 to form two inactive metabolites, hydroxy- and 
carboxypropyl-phenylpropionic acid (Refs. 30 and 31). These metabolites 
(or their glucuronide conjugates) are excreted in the urine and account 
for about 50 to 60 percent of the oral dose administered (Refs. 32 and 
33). Less than 10 percent of the drug is excreted in urine unchanged 
(Ref. 32). The remainder is eliminated in the feces, as metabolites and 
unabsorbed drug. Excretion of ibuprofen is essentially complete within 
24 hours following oral administration of a single dose (Ref. 33). 
While total clearance may be affected by age, no dosage adjustment is 
needed in the elderly (Ref.

[[Page 54143]]

34). Ibuprofen does not appear in the breast milk of mothers to any 
appreciable extent (i.e.,  0.0008 percent of the plasma level) (Ref. 
35).
    Ibuprofen is neither an inducer or an inhibitor of cytochrome P-450 
mediated metabolism. At doses above those recommended for OTC use 
(1,200 mg daily, in divided doses), ibuprofen may decrease the renal 
excretion of some drugs due to ibuprofen's ability to interfere with 
renal prostaglandin synthesis necessary for normal renal function. This 
interference in the renal elimination of other drugs can be estimated 
by following the net reduction in creatinine clearance. Ibuprofen can 
cause an increase in blood pressure in hypertensive patients being 
treated with diuretics alone or diuretics combined with other agents 
(Ref. 36).
2. Clinical Data
    The petition (Ref. 1) and a subsequent submission (Ref. 10) 
provided extensive published clinical data on the safety of OTC use of 
ibuprofen. The data provide a safety profile typical of other OTC drugs 
in the NSAID class.
    a. Gastrointestinal. The GI tract is one of the major organ systems 
commonly affected by NSAID-induced drug toxicity. This resulted in a GI 
warning in the prescription labeling for these drugs (Refs. 37 and 38). 
At the August 18, 1983, AAC meeting, data submitted in support of the 
NDA for ibuprofen 200 mg to be marketed as an OTC drug product 
suggested that, of all NSAIDs available at that time, ibuprofen caused 
the least amount of GI irritation (Ref. 39).
    Additional support in favor of ibuprofen's overall gastric 
tolerability was generated in a recent study by Moore et al. (Ref. 40), 
which evaluated the tolerability of ibuprofen (1,200 mg/day) and 
acetaminophen (up to 3 grams (g)/day) to that of aspirin (up to 3 g/
day). This study was a large, blinded, randomized, multicenter, 7-day 
analgesic study conducted in France in 8,677 adults with mild to 
moderate pain due to a variety of conditions. Although the incidence 
for significant (serious, severe, or moderate) adverse events 
(including all body systems) for the ibuprofen treated group (13.7 
percent) was comparable to that of the acetaminophen treated group 
(14.5 percent), both drugs were shown to be significantly better 
tolerated than aspirin (18.7 percent; p  0.001 via a one-sided 96.5 
percent confidence interval (CI)). A total of six subjects reported 
having GI bleeds during this study, four from the acetaminophen group 
and two from the aspirin group, one of whom developed peptic ulcer. 
Overall, treatment with ibuprofen was associated with fewer significant 
adverse GI events than aspirin (p  0.001) or acetaminophen (p  0.02). 
The incidences of abdominal pain and dyspepsia were both significantly 
lower in the ibuprofen group as compared with the aspirin (p  0.001) or 
acetaminophen (p  0.02) groups. Although this study was designed to 
approximate the general population who would use OTC doses and 
durations of these three analgesics, its selection criteria prohibited 
any individual with known risk factors for GI bleeding from 
participating. Thus, selection bias may have been introduced and 
resulted in a lower incidence of GI adverse events than what may be 
seen in the general population at risk.
    In a retrospective, nested, case-controlled study of Medicaid 
enrollees, Griffin et al. (Ref. 41) compared the relative risk (RR) for 
the development of peptic ulcer disease (PUD) in 1,415 subjects 65 
years and older who were current nonaspirin NSAID users to nonusers. 
Eighty-three of the 1,415 subjects who were hospitalized due to PUD 
during the period studied were identified as having been exposed to OTC 
doses (1,200 mg) of ibuprofen. The overall RR for the development of 
PUD in this group was found to be 2.3 (95 percent CI: 1.8 to 3.0). 
Further examination by dose revealed that in 70 subjects exposed to 
doses less than 2,400 mg ibuprofen the RR for the development of PUD 
was 2.2 (95 percent CI: 1.7 to 2.9), and in 13 subjects exposed to 
2,400 mg or greater the RR increased to 3.3 (95 percent CI: 1.7 to 
6.5).
    Bradley et al. (Ref. 42) conducted a 4-week, double-blind, 
randomized trial in 184 subjects comparing the effectiveness and safety 
of the maximum approved OTC daily dose of 1,200 mg of ibuprofen (number 
of subjects (n) = 62) to that of a prescription dose of 2,400 mg/day (n 
= 61), and to 4,000 mg/day of acetaminophen (n = 59) for the treatment 
of osteoarthritis. While there were no significant differences in the 
number of side effects reported during this study, the study 
demonstrated a trend towards a dose-dependent increase in minor GI 
adverse events (nausea and dyspepsia) associated with higher doses of 
ibuprofen (1,200 mg/day: 7/62 or 11.3 percent; versus 2,400 mg/day: 14/
61 or 23 percent). In addition, two subjects treated with 2,400 mg/day 
of ibuprofen became positive for occult blood while participating in 
the study.
    Although these studies (Refs. 41 and 42) demonstrate that a dose-
dependent relationship exists for ibuprofen-induced gastrotoxicity, the 
number of subjects exposed to OTC doses of ibuprofen (1,200 mg or less 
a day) is too small to draw valid conclusions. Further, the study 
results may also be confounded since the studies did not control for 
other risk factors (i.e., smoking, alcoholism, concomitant use of 
corticosteroids and anticoagulants, advanced age, prior history of PUD, 
or deteriorated general health status) which are known to increase the 
risk of developing GI bleeding while using NSAIDs. In addition, the 
results of the retrospective study (Ref. 41) may be biased because the 
exposure data from that study were generated from records of 
prescriptions written for both the study and control populations rather 
than what was actually used by the subjects.
    In a matched, case-controlled, international study of upper 
gastrointestinal bleeding (UGIB), Kaufman et al. (Ref. 43) evaluated 
the association between regular and occasional NSAID use and the risk 
of major UGIB in subjects hospitalized with their first major UGIB. 
Subjects were asked about their history of NSAID use, and details of 
timing, duration, frequency, and the daily dose of each episode of use. 
The focus of the data analysis was on NSAID use in the week immediately 
before the day of onset of bleeding. Exposure was defined as any use in 
the week before the index day. No evidence of an association of gastric 
bleeding with either regular use (n = 9; RR: 1.0 [95 percent, 0.4 to 
2.6]) or occasional use (n = 14; RR 1.1 [95 percent, 0.5 to 2.4]) of 
ibuprofen was identified in this study. Among the cases of gastric 
bleeding, the median ibuprofen dose was 2,332 mg. The RR for developing 
a duodenal bleed with regular use (n = 7) of ibuprofen was 2.4 (95 
percent, 0.5 to 11), the median daily ibuprofen dose ingested was 1,074 
mg.
    Strom et al. (Ref. 44) did a retrospective, case-controlled study 
in a Medicaid population generated database and evaluated the risk of 
developing GI bleeding associated with the use of OTC-simulated doses 
of naproxen sodium (600 mg/day or less) versus ibuprofen (1,200 mg/day 
or less). (At the time of the study, naproxen sodium was not yet 
approved for OTC use.) Although this study demonstrated that the 
overall incidence of UGIB associated with either the use of naproxen 
sodium [0.026 percent (95 percent CI, 0.017 percent to 0.038 percent)] 
or ibuprofen [0.012 percent (95 percent CI, 0.008 percent to 0.017 
percent)] at simulated OTC doses was relatively low, the RR for 
developing an UGIB was approximately twofold higher for the

[[Page 54144]]

naproxen sodium cohort [2.0 (95 percent CI, 1.1 to 3.8)] as compared to 
the ibuprofen cohort. The study also showed that the RR for developing 
UGIB is increased in subjects who ingest multiple NSAIDs at OTC doses 
[4.1 (95 percent CI, 1.2 to 13.8)].
    Endoscopic data (Refs. 45 and 46) demonstrated that while ibuprofen 
produced less GI mucosal toxicity or gastric injury than other NSAIDs, 
low doses of ibuprofen produced lesions in some subjects. In a study by 
Bergmann et al. (Ref. 45), endoscopic lesions of 12 healthy volunteers 
were evaluated after the administration of single doses of ketoprofen 
(25 mg), ibuprofen (200 mg), and aspirin (500 mg), and rated on a scale 
of 0 to 4. Endoscopic scores for ketoprofen were comparable to those 
for ibuprofen. After a single dose of ibuprofen 200 mg, eight subjects 
had endoscopic scores of 0, one had a score of 1, and three had scores 
of 2. For ketoprofen, nine subjects had a score of 0, two had a score 
of 2, and one had a score of 3.
    Lanza (Ref. 46) conducted an endoscopic study of normal volunteers 
without histories of PUD. Subjects were prohibited from using alcohol 
and other NSAIDs for the week before and during the study. Ingestion of 
1,200 mg/day of ibuprofen for 7 days produced a gastric injury score of 
0.46 (on a scale of 0 to 4) and a 0 ulcer incidence rate in the 13 
subjects studied. However, an increase in the ibuprofen dose to 1,600 
mg/day for 7 days under the same conditions produced ulcers in 5 out of 
the 55 (9.1 percent) subjects studied, and an injury score of 1.24.
    A chromium 51-labeled fecal blood loss study (Ref. 47) indicated 
that after 5 days of treatment with either ibuprofen 1,500 mg/day, 
aspirin 1,500 mg/day, lysine clonixinate 375 mg/day, or placebo, the 
fecal blood loss in subjects treated with ibuprofen was significantly 
less than the aspirin treated group. Nevertheless, treatment with 
ibuprofen lead to a small increase in mean daily blood loss of +0.52 
milliliter (mL)/day.
    These studies indicate that ibuprofen, at OTC doses, has a low 
level of GI toxicity but is not entirely devoid of such toxicity. The 
agency believes that even this low level of toxicity could increase the 
risk of GI bleeding in people who have other risk factors for 
developing GI bleeding. Therefore, the agency is proposing including a 
warning in the labeling of OTC ibuprofen to alert individuals at risk 
for GI problems associated with the use of the product. The warning 
would include: ``Ask a doctor before use if you have:  stomach 
problems that last or come back, such as heartburn, upset stomach, or 
pain  ulcers  bleeding problems''.
    b. Renal. NSAIDs affect renal physiology by inhibiting cyclo-
oxygenase and the synthesis of vasodilatory prostaglandins resulting in 
acute intrarenal hemodynamic changes that can cause reversible 
deterioration in the renal function of susceptible individuals (Ref. 
48). Thus, in individuals with decreased renal blood flow, impaired 
renal function, or hypovolemia, the use of NSAIDs can produce an 
increase in serum creatinine concentrations and a decrease in 
creatinine clearance that may progress to acute renal failure, but 
which is reversible by stopping the drug (Ref. 48). This has 
necessitated precaution statements in the labeling of prescription 
NSAIDs directed at the management of patients who use these drugs, 
despite having prostaglandin-dependent states such as renal disease, 
heart failure, liver dysfunction, concomitant diuretic therapy, and 
advanced age that put them at risk for developing this type of 
nephrotoxicity (Ref. 38). Although the class labeling for prescription 
NSAIDs also mentions idiosyncratic forms of nephrotoxicity, such as 
papillary necrosis, acute interstitial nephritis, and nephrotic 
syndrome that may develop with long-term use of these drugs, these 
cases are usually not associated with any identifiable risk factor and 
are rare in occurrence (Ref. 49).
    The petition (Ref. 1) included a summary package that was prepared 
for the August 18, 1983, AAC meeting in which ibuprofen 200 mg was 
considered for OTC marketing. The summary included safety data 
generated from clinical trials and supportive evidence from a review of 
then-published case reports of ibuprofen-associated nephrotoxicity. The 
summary concluded that although ibuprofen does cause cyclo-oxygenase 
mediated renal toxicity like other members of the NSAID class, the 
reversibility of this condition is dependent upon its recognition and 
the discontinuation of the drug, particularly when it occurs in those 
at risk, such as the chronically ill or the elderly (Ref. 39).
    In support of ibuprofen's renal safety profile, four studies (Refs. 
50 through 53) that evaluated the prostaglandin-mediated effects of OTC 
doses of ibuprofen ( 1,200 mg a day) on renal function were 
reviewed. In a crossover study, Farquhar (Ref. 50) evaluated the renal 
effects of ibuprofen (1,200 mg daily) and acetaminophen (4 g daily) 
versus a placebo in 12 healthy men (n = 6) and women (n = 6) who were 
subjected to progressive renal stress. Subjects were on a low-sodium 
diet, on limited exercise, and given a drug or placebo for 3 days and 
the morning of day four. On day four, the participants were subjected 
to treadmill exercise, in the heat, to cause dehydration. The combined 
stressors caused decreases in effective renal plasma flow, glomerular 
filtration rate (GFR), and sodium excretion. Baseline GFR (range 118 to 
123 mL/minute (min) decreased to 73  5, 78  4, 
and 82  5 mL/min, post-exercise, in the ibuprofen, 
acetaminophen, and placebo groups, respectively, with a significantly 
greater decrease in GFR for ibuprofen than placebo (p  0.05). The 
decrease in GFR for the acetaminophen group was not significantly 
different from placebo. The authors attributed the lower GFR that 
occurred in the ibuprofen arm of the study to renal prostaglandin 
inhibition by the drug.
    In a randomized, disease-controlled study, Ciabattoni et al. (Ref. 
51) evaluated the prostacyclin-mediated effects on GFR and renal blood 
flow of 20 women with chronic glomerular disease versus 19 normal 
healthy control subjects following 7 days of treatment with ibuprofen 
(1,200 mg daily) versus sulindac (400 mg daily). In the 10 subjects 
with renal insufficiency who were given ibuprofen, the serum creatinine 
level was increased by about 40 percent and the creatinine and para-
aminohippurate clearances were decreased by 28  7 and 35 
 8 percent, respectively, during treatment (p  0.01). Renal 
function returned to baseline values after ibuprofen was discontinued, 
although the serum creatinine and creatinine clearance were still 
significantly altered up to 5 days after ibuprofen was stopped.
    Welton et al. (Ref. 52) evaluated the renal effects of ibuprofen 
(800 mg three times daily), piroxicam (20 mg daily), and sulindac (200 
mg twice daily) in an 11-day, randomized, triple crossover study of 12 
women with asymptomatic, mild, stable, chronic renal failure with serum 
creatinine ranging from 130 to 270 micromoles (mol)/L. 
Although all the subjects were able to complete courses of treatment 
with piroxicam and sulindac, three subjects developed acute decreases 
in renal function with an elevation in their renal parameters that met 
the study criteria for stopping (defined as an increase in serum 
creatinine of 130 mol/L or more, or a serum potassium value of 
more than 6 millimole/L (mmol/L)) by the eighth day of treatment with 
ibuprofen. When these three subjects were rechallenged with ibuprofen, 
400 mg three times a day, two again developed acute deterioration of 
renal function. The authors

[[Page 54145]]

concluded that a brief course of nonprescription ibuprofen may result 
in the precipitous decrease in the renal function of people with 
asymptomatic, mild, chronic renal failure.
    In contrast, Furey et al. (Ref. 53) did a 7-day, double-blind, 
randomized study comparing the renovascular effects of ibuprofen (400 
mg three times daily) versus that of aspirin (650 mg three times daily) 
and acetaminophen (650 mg three times daily) in 25 elderly subjects 
with mild renal insufficiency, and hypertension controlled with 
thiazide diuretics. Although the mean baseline serum creatinine levels 
for all three treatment groups were comparable, the mean baseline serum 
creatinine clearances were higher in both the acetaminophen (78.9 
 8.3 mL/min) and aspirin (67.1  6.4 mL/min) 
treatment groups as compared to the ibuprofen group (56.3  
5.3 mL/min). On analysis, this was not found to be statistically 
different. This study failed to demonstrate any statistically 
significant changes in the five renal parameters (serum creatinine, 
creatinine clearance, blood urea nitrogen (BUN), serum potassium and 
sodium) evaluated in any of the three treatment groups.
    The three studies by Farquhar (Ref. 50), Ciabattoni et al. (Ref. 
51), and Welton et al. (Ref. 52) demonstrated that, at an OTC dose of 
ibuprofen (1,200 mg daily), hemodynamic changes in the kidney do occur 
in subjects with prostaglandin-dependent states, which can lead to 
diminished renal function. The inability of the study by Furey et al. 
(Ref. 53) to demonstrate any significant deterioration in any of the 
renal parameters studied may be due to the fact that the subjects who 
participated in this study may not have had severe enough renal disease 
as manifested by the mildly elevated range of their baseline mean serum 
creatinine from 1.4  0.08 mg/deciliter (dL) to 1.5 
 0.07 mg/dL to demonstrate ibuprofen's prostaglandin-
dependent renal effects. Thus, despite their histories of hypertension 
and the concomitant use of diuretics, these subjects may also have had 
adequate renal reserves to compensate for any ibuprofen-mediated 
decreases in their renal function.
    The largest study involving an OTC dose of ibuprofen that included 
monitoring of renal function was the 4-week study by Bradley et al. 
(Ref. 42). This study compared the effectiveness of low-dose (1,200 mg 
daily) and high-dose (2,400 mg daily) ibuprofen and acetaminophen 
(4,000 mg daily) in the treatment of osteoarthritis in 184 subjects. 
Side effects were similar in all three groups. The serum creatinine 
level increased by more than 17 mol/L (0.2 mg/dL) in four of 
the subjects receiving low-dose ibuprofen, six receiving high-dose 
ibuprofen, and one receiving acetaminophen. As a group, the serum 
creatinine concentration increased only slightly (2.7 mol/L) 
in the high-dose ibuprofen group (p = 0.04), but there was no increase 
in the low-dose group. Although this trial is the only study which 
compared a low-dose (i.e., OTC dose) to a high-dose (i.e., 
prescription-strength dose) ibuprofen and could possibly be interpreted 
as a dose-ranging study for the renal effects of ibuprofen-mediated 
prostaglandin inhibition, the subjects who were entered into this trial 
were healthy with a mean age of 55.7  13.7 to 57.2 
 11.7 years. Exclusion criteria prohibited participation by 
subjects with medical conditions that contraindicated the use of the 
study medications. Thus, the study subjects were not reflective of the 
population identified at risk for developing this type of 
nephrotoxicity.
    The petition included numerous case reports (Refs. 54 through 61) 
of renal failure associated with the use of OTC doses of ibuprofen in 
people with normal renal function. Four cases (Refs. 54 through 57) 
described the syndrome of acute flank pain with reversible renal 
failure following short-term doses of 1,200 mg, or less, of ibuprofen. 
One (Ref. 54) of these four cases was confounded by the concomitant use 
of alcohol, and one (Ref. 55) used alcohol and acetaminophen, both of 
which can cause nephrotoxicity. Four reports (Ref. 58 through 61) 
described cases of idiosyncratic drug-induced types of renal failure. 
One of the cases (Ref. 61) discussed a case of idiosyncratic 
hypersensitivity reaction in an elderly man who experienced acute renal 
failure twice; once after taking ibuprofen orally and, again, a few 
years later, after using a topical formulation of ibuprofen. Renal 
function returned to normal in all eight people after medical therapy. 
The agency is aware of additional case reports of patients who 
developed renal toxicity after taking ibuprofen (Refs. 62 through 66).
    In 1996, the National Kidney Foundation published a position paper 
in which it recommended that consumer labeling of OTC analgesic drug 
products contain warnings directed to the population at risk for the 
development of nephrotoxicity associated with the use of these products 
(Ref. 67). These recommendations were based on the review of a database 
that contained 556 articles on aspirin, acetaminophen, aspirin/
acetaminophen combinations, and NSAID-related renal disease by an ad 
hoc group of expert investigators and clinicians. This committee 
suggested the following consumer warning for OTC NSAID-containing 
products:
      DO NOT TAKE THIS PRODUCT WITHOUT PHYSICIAN SUPERVISION IF: (1) 
You are allergic to aspirin; (2) you are under a physician's care for 
asthma or stomach problems (such as heartburn); (3) you take diuretic 
medicine; (4) you have heart disease, high blood pressure, kidney 
disease, or liver disease; (5) you are over 65 years of age.
    The information contained in the literature review and case reports 
submitted in support of this petition confirms that OTC doses of 
ibuprofen can exert a variety of renal adverse effects, particularly in 
those who are predisposed by prostaglandin-dependent states. Although 
the sporadic nature of the idiosyncratic drug-induced type of ibuprofen 
nephrotoxicity makes it impossible to predict which group of 
individuals is at risk for developing this type of adverse event, this 
is not the case with individuals who experience prostaglandin-driven 
hemodynamic changes in renal function. The latter, if recognized, is 
reversible following discontinuation of the drug. Thus, based on the 
information reviewed, the agency concurs with the recommendations made 
by the National Kidney Foundation that the consumer labeling for OTC 
ibuprofen should have a warning directed at those at risk for the 
development of acute renal failure associated with the use of the 
product. The agency is proposing a warning that includes: ``Ask a 
doctor before use if you have:  high blood pressure, heart or 
kidney disease, are taking a diuretic, or are over 65 years of age''.
    c. Hepatic. The petition (Ref. 1) contained only one case report 
(Ref. 68) from the literature of biopsy-proven drug-induced hepatitis 
that occurred in a person taking 1,200 mg daily ibuprofen and 
cefadrine. The authors concluded that the liver lesion was induced by 
drug hypersensitivity. The supplemental submission (Ref. 10) included 
one case report (Ref. 69) of drug-induced vanishing bile duct syndrome 
secondary to ibuprofen. Similarly, the authors of this report concluded 
that the reaction was induced by a drug hypersensitivity.
    In a retrospective, crossover cohort study, Garcia-Rodriguez et al. 
(Ref. 70) evaluated the risk of developing serious, acute, 
noninfectious liver injury associated with the use of NSAIDs. One of 
the 16 subjects was identified as having NSAID-induced hepatitis: A 93-
year-old male who developed cholestatic jaundice after taking 1,200

[[Page 54146]]

mg of ibuprofen along with other hepatotoxic drugs. Causality could not 
be directly associated with ibuprofen in this case due to the 
concomitant use of other hepatotoxic drugs.
    In a review of FDA postmarketing data of NSAID-induced 
hepatotoxicity, Katz et al. (Ref. 71) noted that while ibuprofen is 
known to cause idiosyncratic metabolic toxicity of the liver, ibuprofen 
and ketoprofen were found to have the lowest reported calculated 
incidences of hepatotoxicity (0.55 percent and 0.56 percent 
respectively) of all NSAIDs evaluated at that time. Due to the 
limitations of FDA's reporting requirements, the authors were unable to 
estimate separately the incidence of this phenomena associated with OTC 
doses of ibuprofen. Given the available information, the agency sees no 
need to propose a hepatitis warning at this time.
    d. Blood. Three case reports from the literature described 
hematological events attributed to ibuprofen (Refs. 72, 73, and 74). 
Two of these (Refs. 72 and 73) involved individuals taking OTC doses of 
ibuprofen who developed thrombocytopenia and white-cell aplasia with 
bone marrow plasmacytosis. The duration of ibuprofen use was not stated 
in the second case report. The third individual (Ref. 74), taking an 
undisclosed dose of ibuprofen (by prescription), developed Pelger-Huet 
syndrome due to a complement-dependent immunoglobulin G (IgG) antibody 
that prevented bone marrow production of myeloid stem cells. Ibuprofen 
is known to reversibly inhibit platelet aggregation (Ref. 75). Further, 
ibuprofen has been shown to potentiate the effects of warfarin. As a 
result, the agency believes consumers who are taking anticoagulants 
should be alerted to check with a health professional before taking 
ibuprofen because of the potential for bleeding. Thus, the agency is 
proposing a warning that includes: ``Ask a doctor or pharmacist before 
use if you are:  taking a prescription drug for anticoagulation 
(blood thinning)''.
    e. Immune system. Ibuprofen has been associated with some 
hypersensitivity reactions. The petition (Ref. 1) included 14 case 
reports (Refs. 76 through 86) from the worldwide literature that 
described hypersensitivity and anaphylactic reactions to ibuprofen. The 
reports of ibuprofen-associated hypersensitivity (Refs. 76 through 80) 
included six individuals with underlying histories of asthma (one (Ref. 
78) of whom also had a known allergy to aspirin). Three of the 
individuals with asthma died following hypersensitivity reactions that 
were attributed to ibuprofen (Refs. 76, 77, and 78). One report (Ref. 
86) included five patients with Sjogren's syndrome who developed 
symptomatic drug allergies after taking ibuprofen.
    Hypersensitivity reactions were also reported in one individual 
(Ref. 80) with general allergies (including a known aspirin 
sensitivity), in one individual (Ref. 82) with systemic lupus 
erythematosus, and in three individuals (Refs. 83, 84, and 85) with no 
apparent underlying illnesses (one (Ref. 84) had taken aspirin just 
prior to the reaction). The petition also included an abstract of a 
report of challenge testing with ibuprofen (Ref. 87) in 42 people with 
histories of allergies to various analgesic agents. Five people 
experienced anaphylactic reactions to incremental doses of up to 500 mg 
of ibuprofen. Eleven of 33 subjects had similar reactions to aspirin. 
The agency is proposing an ``Allergy alert'' warning and additional 
allergy warning statements for all OTC drug products containing NSAID 
IAAA active ingredients. (See section IV of this document.)
    f. Nervous system. The petition (Ref. 1) included 20 literature 
citations (Refs. 82 and 88 through 106) that described 21 individuals 
with aseptic meningitis associated with the use of ibuprofen. Twelve of 
these individuals (Refs. 82, 88 through 95, 98, and 100) had underlying 
histories of systemic lupus erythematosus or other immune disorders, 3 
(Ref. 96) had histories of arthritis, 1 (Ref. 97) had a history of 
spontaneous recurrent aseptic meningitis, and 5 (Refs. 100 through 104) 
reportedly had no underlying medical problems. The supplemental 
submission (Ref. 10) included several review articles (Refs. 107 
through 110) that described the spectrum of central nervous system side 
effects reported to be associated with NSAIDs, as well as case reports 
(Refs. 111 through 115) of aseptic meningitis associated with the use 
of a variety of NSAIDs. Although there has been an increase in 
availability and use of NSAIDs in general, the overall number of 
aseptic meningitis cases reported to be associated with the use of 
these agents since 1978 is only about 35. Most of the case reports 
(Refs. 111, 112, and 114) involved individuals with underlying collagen 
vascular disorders (i.e., systemic lupus erythematosus and rheumatoid 
arthritis). Several cases (Refs. 111, 113, and 115) established direct 
causality by histories of positive dechallenge-rechallenge with the 
suspected NSAID. While other NSAIDs were sometimes implicated, 
ibuprofen was the most commonly reported. The agency does not believe a 
nervous system warning is needed at this time.
    g. Skin. There were a total of seven case reports (Refs. 116 
through 122) and two articles (Refs. 123 and 124) on the results of 
provocative skin testing with ibuprofen. The seven case reports 
describe episodes of fixed drug reactions (Ref. 116), erythema nodosum 
(Ref. 117), a bullous drug eruption (Ref. 118), various cases of 
urticaria (Ref. 119), exacerbations of psoriasis (Refs. 120 and 121), 
and the occurrence of dermatitis herpetiformis (Ref. 122). The doses of 
ibuprofen involved in these cases, when reported, were 800 mg daily. 
The two articles (Refs. 123 and 124) described the results of 
provocative testing with a variety of drugs including ibuprofen. Of the 
169 patients tested, 11 had positive skin reactions to ibuprofen. As 
stated above, the agency is proposing allergy warnings for OTC drug 
products containing NSAIDs. (See section IV of this document.)
    h. Special senses. There were three case reports (Refs. 125, 126, 
and 127) and one adverse event, which occurred during a clinical trial 
(Ref. 128), that mentioned ibuprofen's effects on the visual 
parameters. The reports involved macular hemorrhage in people with age-
related maculopathy (Ref. 126), vortex keratopathy (Ref. 127), 
iridocyclitis (Ref. 125), and depressed contrast sensitivity (Ref. 128) 
associated with total daily doses of ibuprofen ranging from 800 to 
2,400 mg. Given the available information, the agency sees no need to 
propose a special senses warning at this time.
3. Spontaneous Reporting System (SRS) and Adverse Event Reporting 
System (AERS) Data
    The petition analyzed adverse event data from the FDA SRS for all 
single-ingredient OTC ibuprofen drug products marketed in the United 
States for the time period from May 1984 through July 1996. Adverse 
reaction reports associated with a generic OTC ibuprofen drug product 
marketed under an ANDA or prescription ibuprofen drug products used at 
OTC doses were excluded from this analysis. A total of 8,168 case 
reports associated with 16,627 adverse events in the SRS database 
attributed to the use of single-ingredient, nongeneric OTC ibuprofen 
were thus identified. The total number of adverse events was greater 
than the total number of case reports because some case reports 
included more than one adverse reaction associated with the use of the 
drug.
    The petitioner screened the electronic records of all case reports 
for confounding factors. Reports were

[[Page 54147]]

considered confounded if they included the coadministration of at least 
one other medication (drug confounder), the administration of ibuprofen 
in a dose greater than 1,200 mg/day (dose confounder), the 
administration of ibuprofen for more than 10 days (duration 
confounder), or if the subject was less than 12 years of age (age 
confounder). Reports with missing or unreliable data were included in 
the analysis. Screening for confounders yielded 3,540 nonconfounded 
case reports which generated 6,197 adverse events. Case reports were 
then reviewed to identify serious reports associated with OTC 
ibuprofen. Of the 3,540 nonconfounded case reports, 592 were considered 
to be serious in nature. FDA's definition of a serious outcome is an 
event that results in death or hospitalization, is life threatening, 
produces permanently disability or congenital anomaly, or one in which 
medical intervention is required. However, the case report forms for 
these serious reactions were not included in the petition. The petition 
(Ref. 1) submitted information on case reports from the SRS associated 
with the use of OTC ibuprofen, reported by COSTART (Coding Symbols for 
Thesaurus of Adverse Reaction Terms) body system terminology. The 
information is summarized in table 1 of this document and represents 
the number of case reports that included at least one adverse event 
associated with the COSTART term.

Table 1.--Summary of Cases Associated With the Use of OTC Ibuprofen in the FDA Spontaneous Reporting System From
                                       May 1984 Through July 1996 (Ref. 1)
----------------------------------------------------------------------------------------------------------------
                                                               No. of Nonconfounded          No. of Serious
          COSTART Term             No. of Cases Reported              Cases               Nonconfounded Cases
----------------------------------------------------------------------------------------------------------------
Allergic reaction/ anaphylaxis.            461                        261                         72
Body as a whole................          3,686                      1,786                        236
Cardiovascular system..........            795                        293                        127
Digestive system...............          2,445                        916                        236
Endocrine system...............             32                         12                          8
Hematological/lymphatic systems            679                        141                         92
 (blood).......................
Liver..........................            165                         35                          9
Metabolic and nutritional                  757                        176                         71
 system........................
Musculoskeletal system.........            163                         49                          7
Nervous system.................          1,447                        577                        101
Respiratory system.............            629                        250                         81
Skin and appendages............          1,339                        589                         71
Special senses.................            479                        188                         29
Urogenital system..............            716                        176                         61
----------------------------------------------------------------------------------------------------------------

    The 592 serious nonconfounded case reports included 7 deaths 
associated with the use of OTC ibuprofen (2 GI, 1 hematological 
effects, 2 anaphylaxis, 1 miscarriage, and 1 in utero exposure 
resulting in the postpartum death of an encephalic infant). As shown 
above in table 1 of this document, the largest number of adverse events 
involved the GI system. Of the 236 nonconfounded serious case reports 
related to the GI system, 94 were GI hemorrhage, 52 were various 
ulcerations, 32 were melena, 25 were abdominal pain, and 20 were 
hematemesis. This additional evidence supports the need for a GI tract 
warning in the consumer labeling of OTC ibuprofen drug products.
    FDA queried its AERS database for reports of renal failure in 
adults, over 16 years of age, associated with the use of OTC doses of 
ibuprofen for the period extending from the time of initial approval 
for OTC marketing (May 18, 1984) through August 10, 1999 (Ref. 129). 
For completeness, a search of the AERS database was also done for 
reports of renal failure in people 16 years of age and under. Fourteen 
cases of renal failure were identified in this population. In 8 of the 
14 cases, a children's suspension formulation was used while, in the 
remaining 6 cases, 200-mg tablets were reportedly ingested. After 
excluding cases involving prescription dosages, overdoses, or 
duplication, there were a total of 80 cases of renal failure in adults 
over 16 years of age associated with the use of 1,200 mg, or less, of 
ibuprofen a day. Although 37 of these 80 cases had positive 
dechallenges with the discontinuation of ibuprofen (which is supportive 
of the reversibility of this drug-induced adverse event), 9 cases 
required dialysis treatment. Of these 80 cases, 56 were severe enough 
to require hospitalization, with 9 reported deaths, out of which 5 
listed ibuprofen-induced renal failure as a contributing cause of 
death. Hypertension (16), pre-existing renal insufficiency (8), 
diabetes (7), other cardiac problems (8), alcoholism (3), and hepatic 
disease (2) were some of the most commonly concurrent medical disorders 
reported. In addition, 15 people were reported to have been taking 
diuretics prior to developing renal failure. These cases further 
support the need for consumer labeling directed at those individuals 
with predisposing medical conditions for the development of ibuprofen-
induced prostaglandin-dependent renal toxicity. (See section III.B.2.b 
of this document.)
4. American Association of Poison Control Center (AAPCC) Data
    The petition (Ref. 1) also included data on ibuprofen from the 
Toxic Exposure Surveillance System (TESS) collected by the AAPCC from 
1987 to 1996. During that time, TESS reported only 9 fatalities from 
163,948 OTC ibuprofen exposures compared to 450 fatalities from 312,618 
acetaminophen exposures, and 401 fatalities from 153,495 aspirin 
exposures. The supplemental submission (Ref. 10) included additional 
information on the nine deaths, reports of seven additional deaths 
related to OTC ibuprofen in 1997, and three other deaths related to OTC 
or prescription-strength ibuprofen that occurred in 1996.
    Of these 19 deaths, 14 were classified as intentional suicides. One 
person ingested 165 tablets of 200-mg strength ibuprofen and the other 
13 ingested other drugs in combination with OTC ibuprofen. Of the 
remaining five cases, one was classified as a therapeutic error in a 
person with a history of alcoholism and hepatic disease waiting for a 
liver transplant, who reportedly took ``excessive'' amounts of 
acetaminophen and ibuprofen for pain. This person's death was 
attributed to chronic hepatic failure associated with ethanol and

[[Page 54148]]

acetaminophen toxicity, chronic pancreatitis, and gastritis.
    Another case was reported as intentional misuse in a patient with a 
history of chronic alcoholism, cirrhosis, and portal hypertension who 
developed acute liver failure following the chronic use of ibuprofen 
and acetaminophen. Another case of reported intentional misuse involved 
a patient with a history of drug abuse who reportedly ingested 27 
tablets containing 100 mg propoxyphene napsylate and 650 mg 
acetaminophen and 50 tablets of ibuprofen (strength not specified) over 
a 16- to 48-hour period. The remaining two cases were listed as adverse 
drug reactions in young children. Thus, a large majority of the deaths 
were suicidal overdoses or intentional abuse associated with the 
concomitant use of other drugs, and should not be directly attributed 
to ibuprofen. A few of the cases could have been due to allergic 
reactions related to ibuprofen use. An allergy warning is required to 
appear in the labeling of OTC ibuprofen drug products marketed under an 
NDA/ANDA to alert consumers of that risk.
5. Drug-Drug Interactions
    The petition (Ref. 1) included eight journal articles (Refs. 53 and 
130 through 135) that described clinical trials involving a variety of 
antihypertensive agents (i.e., calcium channel blockers, angiotensin 
converting enzyme inhibitors, and triamterene-hydrochlorothiazide) in 
chronically treated and elderly hypertensive patients with renal 
insufficiency who took OTC doses of ibuprofen. The studies did not 
demonstrate any diminished antihypertensive effectiveness when these 
drugs were coadministered with ibuprofen. This is in contrast to the 
diminution in the effectiveness of a variety of antihypertensive 
medications such as beta-blockers, ACE inhibitors, hydralazine, and 
diuretic agents in patients who use prescription doses of NSAIDs (Ref. 
136).
6. Tentative Conclusion on the Safety of Ibuprofen
    Based on the evaluation of available information, the agency 
concludes ibuprofen is generally recognized as safe for OTC use by 
adults and children 12 years of age and older, if the labeling includes 
appropriate warnings and directions for use. The agency is proposing to 
include warnings to alert individuals of the potential for renal and GI 
problems associated with the use of ibuprofen. For consistency in 
labeling, the agency is also proposing to include the same allergy 
alert warning statements in the labeling of all OTC NSAID products.

C. Effectiveness

    The reports of clinical effectiveness trials submitted in the 
petition (Ref. 1) compared OTC doses of ibuprofen to aspirin, 
acetaminophen, and/or codeine-containing analgesic compounds. The 
petition identified a number of double-blind, randomized clinical 
trials, either placebo or active controlled. Most of the studies are 
generally applicable to the indications proposed in Sec.  343.50 of the 
TFM for other OTC internal analgesic/antipyretic drug products (e.g., 
dental pain, pain of arthritis, dysmenorrhea, headache, and sore 
throat). Nineteen studies (Refs. 137 through 155) were placebo-
controlled, and the reports concluded that ibuprofen, at the OTC doses 
studied, was a more effective analgesic agent than placebo. The authors 
of these studies (Refs. 137 through 155) and three active-controlled 
trials (Refs. 156, 157, and 158) also reported that, at the OTC doses 
studied, ibuprofen was either comparable to or more effective than 
aspirin, acetaminophen, and various strengths of codeine-containing 
analgesics or other NSAIDs tested. The pain models included in the 
studies were dental, headache, episiotomy, sore throat, and 
dysmenorrhea. One report (Ref. 159) described the results of two 
randomized, double-blind, parallel studies that compared the 
antipyretic effectiveness of ibuprofen to aspirin in adults, which 
showed effectiveness of both the 200- and 400-mg doses of ibuprofen.
    The only dosage forms used in the trials and identified in the 
reports were tablets, caplets, and capsules. Some of the reports did 
not identify the dosage form. Table 2 of this document summarizes the 
placebo-controlled and active-controlled trials the agency reviewed to 
demonstrate the effectiveness of OTC doses of ibuprofen for various 
pain and fever models.

        Table 2.--Trials to Demonstrate the Effectiveness of Ibuprofen for Various Pain and Fever Models
----------------------------------------------------------------------------------------------------------------
   Investigator(s) (reference         Type of Pain                            Treatment\2\
             number)                    Measured           Dosage Form       (dosage in mg)    Reported Results
----------------------------------------------------------------------------------------------------------------
Cooper (137)....................  Dental.............  Tablets............  I 400; AP 600;    I more effective
                                                                             AP300 + C 30;     than AP 600, AP
                                                                             AP 600 + C 60;    300 + C 30, and P
                                                                             P                 (p values not
                                                                                               given)
Cooper (138)....................  Dental.............  Tablets............  I 400; C 60; A    I 400 more
                                                                             650; A 650 + C    effective than A
                                                                             60; I 400 + C     (p0.05) and C
                                                                             60; P             (p0.001); I + C
                                                                                               more effective
                                                                                               than A + C
                                                                                               (p0.05)
Cooper (139)....................  Dental.............  N.S.\1\............  I 200; AP 650; P  I more effective
                                                                                               than P (p0.05); I
                                                                                               comparable to AP
Cooper (140)....................  Dental.............  N.S.\1\............  I 200; I 400; AP  I 200 and I 400
                                                                             1000; P           comparable to AP;
                                                                                               all more
                                                                                               effective than P
                                                                                               (p values not
                                                                                               given)
Cooper (141)....................  Dental.............  N.S.\1\............  I 200; I 400; AP  I 200 and I 400
                                                                             1000; P           comparable to AP;
                                                                                               all more
                                                                                               effective than P
                                                                                               (p values not
                                                                                               given)
Cooper (142)....................  Dental.............  N.S.\1\............  I 200; AP 650; I  I more effective
                                                                             200 + AP 650; P   than AP (p0.05)
                                                                                               and P (p0.025); I
                                                                                               + AP more
                                                                                               effective than AP
                                                                                               (p0.05) and P (p
                                                                                               value not given)
Cooper et al. (143).............  Dental.............  N.S.\1\............  I 400; AP 1000;   I more effective
                                                                             P                 than AP (p0.05)
                                                                                               and P (p0.001)
Forbes et al. (144).............  Dental.............  Capsule............  I 400; AP 600;    I, K 10 and K 20
                                                                             AP 600 + C 60;    not significantly
                                                                             K 10; K 20; P     different; I more
                                                                                               effective (p0.05)
                                                                                               than AP and AP +
                                                                                               C; all more
                                                                                               effective than P
                                                                                               (p0.01)

[[Page 54149]]

 
Forbes et al. (145).............  Dental.............  Capsule............  I 400; A 650; B   I more effective
                                                                             5; B 10; B 25;    (p0.01) than A, B
                                                                             P                 5, and B 10; I
                                                                                               comparable to B
                                                                                               25; all more
                                                                                               effective than P
                                                                                               (p0.01 to p0.05)
Forbes et al. (146).............  Dental.............  Capsule............  I 400; A 650; B   I more effective
                                                                             10; B 25; B 50;   than A (p0.01); B
                                                                             B 100; P          25 and B 100 more
                                                                                               effective than I
                                                                                               (p0.01); all more
                                                                                               effective than P
                                                                                               (p0.01)
Giles et al. (147)..............  Dental.............  N.S.\1\............  1 200; C 15; I    I comparable to A
                                                                             200 + C 15; A     and I + C, and
                                                                             600; P            more effective
                                                                                               (p0.05) than C
                                                                                               and P; I + C
                                                                                               comparable to A
                                                                                               and more
                                                                                               effective (p0.05)
                                                                                               than C and P
Jain et al. (148)...............  Dental.............  Tablet.............  I 100; I 200; I   I (all doses) and
                                                                             400; A 650; P     A more effective
                                                                                               than P (p0.001);
                                                                                               no consistent
                                                                                               significant
                                                                                               difference among
                                                                                               active groups
Mehlisch et al. (149)...........  Dental.............  Tablet or caplet ..  I 400; AP 1000;   I more effective
                                                                             P                 (p0.001) than AP
                                                                                               and P; AP more
                                                                                               effective than P
                                                                                               (p0.001)
Ngan et al. (150)...............  Dental.............  Capsule............  I 400; A 650; P   I more effective
                                                                                               (p0.05) than A
                                                                                               and P; A more
                                                                                               effective than P
                                                                                               (p0.05)
Diamond (151)...................  Headache...........  Tablet.............  I 400; I 800; A   No statistically
                                                                             650; P            significant
                                                                                               difference among
                                                                                               active drugs; all
                                                                                               active drugs more
                                                                                               effective than P
                                                                                               (p = 0.02 to p =
                                                                                               0.018)
Schachtel et al. (152)..........  Headache...........  Capsule............  I 400; AP 1000;   I more effective
                                                                             P                 (p0.01) than AP
                                                                                               and P; AP more
                                                                                               effective than P
                                                                                               (p0.01)
Nebe et al. (153)...............  Headache...........  Tablet.............  I 200; A 500; P   I at least as
                                                                                               effective as A; I
                                                                                               and A more
                                                                                               effective than P
                                                                                               (p = 0.002 and
                                                                                               0.046,
                                                                                               respectively)
Schachtel et al. (154)..........  Episiotomy.........  N.S.\1\............  I 400; AP 1000;   I more effective
                                                                             P                 (p0.05) than AP
                                                                                               and P; AP more
                                                                                               effective than P
                                                                                               (p0.05)
Schachtel et al. (155)..........  Sore throat........  N.S.\1\............  I 400; AP 1000;   I more effective
                                                                             P                 (p0.01) than AP
                                                                                               and P; AP more
                                                                                               effective than P
                                                                                               (p0.01)
Habib et al. (156)..............  Dental.............  Enteric coated       I 400; DHC 30; A  I comparable to AP
                                                        tablets.             600 + CA 60       + C + CA (p>0.05)
                                                                             (soluble); AP     and A + CA
                                                                             1000 + C 16 +     (p>0.05); All
                                                                             CA 60             more effective
                                                                             (dispersible)     than DHC (p0.001
                                                                                               in each case)
Noyelle et al. (157)............  Headache...........  Capsule............  I 400; A 650; A   I comparable to A
                                                                             1000; AP 1000     1000; I more
                                                                                               effective
                                                                                               (p>0.01) than A
                                                                                               650 and AP 1000
Milsom and Andersch (158).......  Dysmenorrhea.......  N.S.\1\............  I 400; N 250; AP  I reduced pain
                                                                             500               (p0.05); I more
                                                                                               effective than N
                                                                                               and AP (no p
                                                                                               value given); N
                                                                                               and AP no
                                                                                               significant
                                                                                               reduction in pain
Gaitonde et al. (159)...........  Fever..............  Capsule............  I 200; A 300      I 200 and I 400
                                                                             (Study 1), I      effective as
                                                                             400; A 600        antipyretics; I
                                                                             (Study 2)         200 comparable to
                                                                                               A 300 (p>0.05); I
                                                                                               400 comparable to
                                                                                               A 600 (p>0.05)
----------------------------------------------------------------------------------------------------------------
\1\ N.S. = Not stated.
\2\ A = aspirin; AP = acetaminophen; B = bromfenac; CA = caffeine; C = codeine; DHC = dihydrocodeine; I =
  ibuprofen; K = ketorolac; N = naproxen sodium; P = placebo.

    The agency has evaluated the reports and agrees that the studies 
support the effectiveness of ibuprofen as an OTC drug product for a 
variety of pain and fever models. These studies support the general 
recognition of racemic ibuprofen as an effective internal analgesic/
antipyretic drug at a minimum dose of 200 mg every 4 to 6 hours.
D. Labeling
    Internal analgesic/antipyretic drug products containing ibuprofen 
have been marketed for OTC use under the NDA/ANDA process for many 
years with indications for use and warnings similar to those proposed 
in Sec. 343.50(b) and (c) of the TFM for other OTC internal analgesic/
antipyretic drug products. In the Federal Register of March 17, 1999 
(64 FR 13254), FDA established a standardized format and standardized 
content for the labeling of OTC drug products (Sec. 201.66 (21 CFR 
201.66)). Table 3 of this document shows parts of the approved labeling 
for currently marketed OTC ibuprofen drug products for adults under the 
NDA process, using the new ``Drug Facts'' labeling format in 
Sec. 201.66.

BILLING CODE 4160-01-S

[[Page 54150]]

[GRAPHIC] [TIFF OMITTED] TP21AU02.014

BILLING CODE 4160-01-C

[[Page 54151]]

    In addition to the indications approved for currently marketed OTC 
ibuprofen 200-mg products, the proposed labeling in the TFM for other 
internal analgesic/antipyretic drug products includes an indication for 
sore throat in Sec. 343.50(b)(1). The agency will discuss the proposed 
sore throat indication for all of these drug products in a future issue 
of the Federal Register. Currently marketed ibuprofen for adult use 
does not include an indication for sore throat. Thus, the agency is not 
including a sore throat claim for ibuprofen in this current proposal.
    The approved labeling of OTC drug products containing aspirin, 
ibuprofen, ketoprofen, and naproxen sodium as active ingredients, 
marketed under the NDA/ANDA process, includes an ``Allergy alert'' 
warning and additional allergy warning statements under the headings 
``Do not use'' and ``Stop use and ask a doctor if'' (see table 3 of 
this document). These allergy warning statements are similar to the 
allergy warnings requested in the petition. Proposed labeling for OTC 
drug products containing aspirin ingredients in Sec. 343.10(b) and (c) 
(21 CFR 343.10(b) and (c)) of the TFM also includes an allergy warning 
in Sec. 343.50(c)(1)(iv), which states: ``Do not take this product if 
you are allergic to aspirin or if you have asthma unless directed by a 
doctor.'' For those products containing salicylate active ingredients 
in Sec. 343.10(d) through (f) the proposed warning in 
Sec. 343.50(c)(1)(vi) of the TFM states: ``Do not take this product if 
you are allergic to salicylates (including aspirin) unless directed by 
a doctor.''
    The Advisory Review Panel on OTC Internal Analgesic and 
Antirheumatic Drug Products (the Panel) proposed allergy warnings for 
aspirin. In discussing the safety of OTC aspirin use (42 FR 35346 at 
35397 through 35399, July 8, 1977), the Panel concluded that in 
sensitive individuals aspirin produces allergic type reactions, that 
include: (1) Rash, (2) swelling, (3) hives and giant hives, (4) 
shortness of breath to severe asthma attacks, and (5) anaphylactic 
shock involving laryngeal swelling and a precipitous drop in blood 
pressure. The Panel provided a detailed discussion of the importance of 
an aspirin hypersensitivity warning (42 FR 35346 at 35397). The Panel 
noted that the incidence of hypersensitivity reactions (dermal and 
pulmonary) has been estimated to be about 0.2 percent of the general 
population, but that as much as 20 percent is found in some subgroups 
(asthmatics and people with chronic urticaria). Thus, the Panel 
concluded that these adverse effects occur in a significant proportion 
of the population and they can be serious and even life-threatening in 
some instances.
    The Panel suggested an asthmatic response to aspirin is 
nonimmunologic and related to the inhibition of prostaglandin 
synthesis, and noted that cross-sensitivity is commonly seen with other 
prostaglandin synthesis inhibitors including indomethacin, flufenamic 
acid, mefenamic acid, ibruprofen, and phenylbutazone. The Panel 
suggested dermal hypersensitivity is an immunologic response, and that 
these individuals also appear to be susceptible to anaphylaxis and more 
susceptible to cross-sensitivity to salicylic acid and acetaminophen 
(42 FR 35346 at 35398). The Panel concluded, based on the known risk of 
aspirin and salicylate hypersensitivity in a significant portion of the 
general population, that these products should bear warnings alerting 
consumers who are allergic to these products to consult a doctor before 
using the products (42 FR 35346 at 35499). The agency has determined 
that a consistent approach is needed for all OTC NSAID drug products. 
As discussed in section IV of this document, the agency is proposing 
standardized allergy alert and warning statements for all OTC NSAID 
IAAA drug products.
    In the safety discussion above (sections III.B.2.a, III.B.2.b, 
III.B.2.d, and III.B.3), the agency noted that the use of ibuprofen has 
some risk for certain individuals. GI bleeding may be increased for 
certain at-risk individuals (i.e., people with ulcers). For people 
taking anticoagulants, the risk for GI bleeding is already increased, 
and the use of ibuprofen by those individuals is likely to further 
increase that risk. Individuals with certain medical conditions are at 
increased risk for developing renal failure. The agency believes 
individuals need to be alerted to these risks. The agency is proposing 
that the labeling of ibuprofen include warnings related to GI bleeding, 
use of anticoagulant drugs, and medical conditions that predispose 
individuals to renal failure, using the standardized labeling format 
for OTC drug products.

IV. The Agency's Tentative Conclusions and Proposals

    After reviewing the information submitted and other relevant 
information, FDA has determined that ibuprofen 200-mg tablets have been 
used for a material time and to a material extent to qualify for 
inclusion in an OTC drug monograph. Therefore, FDA is proposing that 
ibuprofen, in 200-mg tablet formulation, be generally recognized as 
safe and effective as an OTC IAAA drug for adults and children 12 years 
of age and older. The safety and effectiveness of ibuprofen are further 
supported by the data the agency evaluated in two NDAs in 1983, the 
findings of the AAC in 1983, and the subsequent marketing history of 
ibuprofen for OTC use. The agency believes ibuprofen can be marketed 
OTC under the monograph system for the indications previously approved 
under the NDA/ANDA process for adult formulations if labeled with the 
appropriate warnings and directions for use. The agency agrees with the 
petition that the proposed labeling should only include adults and 
children 12 years of age and older. The agency is proposing to amend 
the TFM for OTC IAAA drug products to include ibuprofen 200 mg, in 
tablet formulation, in Sec.  343.10(g) as a safe and effective 
ingredient for the relief of pain and fever in adults and children 12 
years of age and older, and to include specific warnings and directions 
for use in Sec.  343.50(c) and (d), similar to those suggested by the 
petition and those approved by FDA for currently marketed OTC ibuprofen 
drug products under the new drug review process. The proposed labeling 
is in a different format than that requested by the petition. However, 
the format is consistent with the new OTC labeling format in 
Sec. 201.66, which was issued after the petition was submitted. In 
addition to the warnings already included in the labeling for OTC 
ibuprofen drug products under the NDA/ANDA process, the agency is 
proposing warning statements related to GI and renal problems and use 
of anticoagulant drugs.
    The agency also tentatively concludes that, for consistency, the 
``Allergy alert'' and additional allergy warning statements required 
for ibuprofen, ketoprofen, and naproxen sodium should be extended to 
all OTC NSAID IAAA drug products, whether marketed under an OTC drug 
monograph or an NDA/ANDA. These standardized allergy alert and warning 
statements (in proposed Sec. 201.324) would provide the following 
information:
    (a) Allergy alert: [insert name of active ingredient (first 
letter of first word for ingredient in uppercase)] may cause a 
severe allergic reaction which may include:  hives  
facial swelling  asthma (wheezing)  shock
    (b) Do not use:  if you have ever had an allergic 
reaction to any other pain reliever/fever reducer [This statement 
appears as the first warning under the subheading ``Do not use.'']
    (c) Stop use and ask a doctor if:  an allergic reaction 
occurs. Seek medical help right away. [These statements appear as 
the first warning under the subheading ``Stop use and ask a doctor 
if.'']

[[Page 54152]]

    Should this proposed amendment to part 201 relating to allergy 
warning statements for OTC IAAA drug products be published as a final 
rule, then the proposed allergy warnings in Secs. 343.50(c)(1)(iv)(A), 
(c)(1)(vi), (c)(2)(iv)(A), and (c)(2)(vi) will be replaced with a 
reference to the allergy warning requirements in proposed Sec. 201.324. 
Final agency action on this proposal will occur in a future issue of 
the Federal Register.

V. Summary of Proposed Agency Changes

Section 201.63
    1. The agency is proposing to amend the third-trimester pregnancy 
warning to include OTC drug products containing ibuprofen.
Section 201.324 (proposed)
    2. The agency is proposing to require an ``Allergy alert'' and 
additional allergy warning statements for all OTC drug products 
containing NSAID IAAA active ingredients--including, but not limited 
to, aspirin, carbaspirin calcium, choline salicylate, ibuprofen, 
ketoprofen, magnesium salicylate, naproxen sodium, and sodium 
salicylate. (See section III of this document.)
Part 343 (21 CFR Part 343)
    3. The agency is proposing to add a definition for ibuprofen in 
Sec. 343.3.
    4. The agency is proposing to add Sec. 343.10(g) to include 
ibuprofen as an active ingredient.
    5. The agency is proposing to reword the statements in Sec.  
343.20(b)(2) providing for the combination of any analgesic/antipyretic 
in Sec. 343.10 and cough-cold products and in Sec. 343.20(b)(4) 
providing for the combination of any analgesic in Sec. 343.10 and 
diuretic drug products to provide for combinations with specific IAAA 
active ingredients (but not including ibuprofen). The petition did not 
include data for the safety and effectiveness of ibuprofen in 
combination with these ingredients, nor did it request ibuprofen, as a 
combination drug product, to be included in the TFM.
    6. The agency is proposing to revise the headings in proposed 
Sec. 343.50(b)(1), (c)(1)(i), and (c)(2)(i) from ``For products 
containing any ingredient in Sec. 343.10.'' to ``For products 
containing any ingredient in Sec.  343.10(a) through (f)'' to limit 
those paragraphs to specific active ingredients (not including 
ibuprofen).
    7. The agency is proposing to add Sec. 343.50(b)(5) to include 
indications for ibuprofen.
    8. The agency is proposing to revise the phrase related to allergy 
in the allergy/asthma warning for adults in proposed 
Sec. 343.50(c)(1)(iv)(A) to read as follows: ``Do not use this product 
if you have asthma unless directed by a doctor''. Similarly, for 
products labeled for children in Sec. 343.50(c)(2)(iv)(A) the agency is 
proposing to revise the warning to read as follows: ``Do not give this 
product to children who have asthma unless directed by a doctor''.
    9. The agency is proposing to revise the warning in proposed 
Sec. 343.50(c)(1)(iv)(B) to reference the pregnancy/breast-feeding 
warnings in Sec. 201.63(a) and (e).
    10. The agency is proposing to revise the warnings in 
Sec. 343.50(c)(1)(iv)(A), (c)(1)(vi), (c)(2)(iv)(A), and (c)(2)(vi) for 
adults and children, respectively, to require the allergy warning 
statements in proposed Sec. 201.324 for products containing any 
ingredient in Sec. 343.10(b) through (g). (The allergy part of the 
previously proposed allergy/asthma warning in Sec. 343.50(c)(1)(iv)(A) 
is now covered by proposed Sec. 201.324.)
    11. The agency is proposing the following warnings for drug 
products containing ibuprofen in Sec. 343.10(g) labeled for use by 
adults:
    (a) The ``Allergy alert'' warnings in proposed Sec. 201.324(a), 
(b), and (c).
    (b) The alcohol warning in Sec. 201.322(a)(2).
    (c) The following statements after the subheading ``Ask a doctor 
before use if you have:
     problems or serious side effects from taking pain 
relievers or fever reducers
     stomach problems that last or come back, such as 
heartburn, upset stomach, or pain
     ulcers
     bleeding problems
     high blood pressure, heart or kidney disease, are taking a 
diuretic, or are over 65 years of age''.
    (d) The following statements after the subheading ``Ask a doctor or 
pharmacist before use if you are:
     under a doctor's care for a serious condition
     taking any other product that contains ibuprofen, or any 
other pain reliever/fever reducer
     taking a prescription drug for anticoagulation (blood 
thinning)
     taking any other drug''.
    (e) The following statement after the subheading ``When using this 
product take with food or milk if stomach upset occurs''.
    (f) The following statements after the subheading ``Stop use and 
ask a doctor if:
     an allergic reaction occurs. Seek medical help right away.
     pain gets worse or lasts more than 10 days
     fever gets worse or lasts more than 3 days
     stomach pain or upset gets worse or lasts
     redness or swelling is present in the painful area
     any new symptoms appear''.
    (g) The pregnancy/breast-feeding warning in Sec. 201.63 of this 
chapter.
    (h) The ``Keep out of reach of children'' warning in Sec. 330.1(g).
    12. The agency is proposing the following directions for ibuprofen 
in Sec. 343.10(g):
    `` do not take more than directed [in bold type]
     adults and children 12 years and over:
     200 milligrams\3\ every 4 to 6 hours while symptoms 
persist
     if pain or fever does not respond to 200 milligrams\3\, 
400 milligrams\3\ may be used
     do not exceed 1,200 milligrams\3\ in 24 hours, unless 
directed by a doctor
     the smallest effective dose should be used
     children under 12 years: ask a doctor''.
\3\Convert number of milligrams to proper dosage.

VI. Labeling Guidance

    In the Federal Register of March 17, 1999 (64 FR 13254), the agency 
published a final rule for standardized format and content requirements 
for OTC drug product labeling under Sec. 201.66. An example of some 
aspects of the required format for labeling of OTC IAAA drug products 
containing ibuprofen appears in table 3 of this document. The ibuprofen 
labeling in the proposed amendment to the TFM (see the codified section 
of this document) appears in the new format.

VII. Implementation

    Ibuprofen may be marketed only under an approved drug application 
prior to completion of a final rule for OTC IAAA drug products.
    The agency encourages manufacturers to comply voluntarily with the 
provisions of this proposed rule for the labeling of OTC NSAID IAAA 
drug products that do not contain ibuprofen and that are marketed under 
an OTC drug TFM prior to the completion of a final rule, despite the 
fact that revisions in the requirements may occur in the final rule in 
response to submitted comments. Such labeling may be disseminated 
pending issuance of a final rule, subject to the risk that the agency 
may, in the final rule, adopt a different position that could require 
relabeling, recall, or other regulatory action. Should any manufacturer 
choose to adopt the labeling described in this proposed rule, and 
should any revisions occur in the final rule, the agency will permit 
the use of existing stocks of

[[Page 54153]]

labels for those products labeled according to this proposed rule for a 
period of 18 months following the publication of the final rule. Those 
manufacturers who do not wish to revise the labeling in accordance with 
this proposal may continue to use the labeling proposed in the 1988 TFM 
(53 FR 46204 at 46258 through 46260) until a final rule becomes 
effective.

VIII. Analysis of Impacts

    FDA has examined the impacts of this proposed 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 agency believes that this proposed rule is consistent with the 
principles set out in the Executive order and in these two statutes. 
OMB has determined that the proposed rule is a significant regulatory 
action as defined by the Executive order. This economic analysis, 
together with other relevant sections of this document, serves as the 
agency's initial regulatory flexibility analysis, as required under the 
Regulatory Flexibility Act.
    The Unfunded Mandates Reform Act does not require FDA to prepare a 
statement of costs and benefits for this proposed rule, because the 
proposed 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 proposed rule is to include ibuprofen in the 
monograph for OTC IAAA drug products and to require consistent 
``Allergy alert'' and additional allergy warning statements in the 
labeling of all OTC NSAID IAAA products. As most OTC NSAID IAAA 
products will be marketed under the final OTC IAAA monograph, these 
products will not have to include the allergy warnings in this proposal 
in product labeling until the final monograph is issued and becomes 
effective.
    Current manufacturers of OTC 200-mg ibuprofen drug products should 
incur only minor one-time costs to relabel their products to meet the 
monograph. These costs may be offset by the elimination of the cost to 
maintain a market application, such as filing annual reports and 
submitting manufacturing supplements. Other manufacturers who may wish 
to market OTC 200-mg ibuprofen drug products would be able to enter the 
marketplace without the costs associated with obtaining an approved 
NDA/ANDA. Their costs would be those associated with the standard 
startup of any OTC drug marketed under the monograph system.
    This proposed rule amends part 201 (21 CFR part 201) and will 
require relabeling for many OTC drug products containing NSAID IAAA 
ingredients. Most manufacturers that market such products under an 
approved NDA/ANDA already include the proposed ``Allergy alert'' and 
allergy warning statements in the product's labeling. Some 
manufacturers of these products, however, would have to revise the 
``Allergy alert'' and allergy warning statements to conform to the 
proposed labeling. In addition, manufacturers of monograph products 
containing NSAID IAAA ingredients will have to relabel and include the 
revised allergy warnings in accord with the compliance dates specified 
in the IAAA products final rule. However, these allergy warnings are 
only one part of the overall labeling changes that will occur at that 
time when IAAA products are required to implement the standardized 
format and content requirements in Sec. 201.66. The agency does not 
believe the proposed revised warnings will have a measurable impact on 
product usage.
    The agency's analysis of impacts in the final rule that established 
the labeling requirements in Sec. 201.66 applied only to products 
covered by the final OTC drug monographs or approved product 
applications (64 FR 13254 at 13283). Because these relabeling costs for 
OTC IAAA products have not been accounted for in earlier rules, the 
agency is presenting them here. The following discussion addresses the 
cost of product relabeling under Sec. 201.66 that will result from the 
IAAA final monograph, which includes, in part, the labeling in this 
proposal.
    Based on information in the agency's Drug Listing System, there are 
approximately 102 manufacturers and 322 distributors that together 
account for 2,000 to 2,400 OTC NSAID IAAA products. Assuming an average 
of 3 individual stockkeeping units (SKUs) (individual products, 
packages, and sizes) per product, up to 7,200 SKUs would require the 
allergy warnings. Estimates of relabeling costs for the type of changes 
required by the IAAA final monograph vary greatly and range from $500 
to $15,000 per SKU depending on whether the products are nationally 
branded or private label. Because of the large number of products 
affected, the agency used the same weighted average cost to relabel 
(i.e., $3,600 per SKU)\1\ that was used to estimate the cost of the 
standardized format and content requirements for OTC drug products in 
Sec. 201.66 (64 FR 13254 at 13279 to 13281). Therefore, the estimated 
one-time cost to relabel these products is $25.9 million ($3,600 x 
7,200 SKUs).
---------------------------------------------------------------------------

    \1\ The average weighted cost to relabel was calculated by using 
midpoint estimates of the cost to redesign labels and value of 
inventory losses of old labels by type of product and firm. The 
midpoint estimate for labeling design for large nationally branded 
SKUs is $10,000 per SKU, the midpoint estimate for smaller branded 
SKUs is $4,500 per SKU, and the cost to relabel private label SKUs 
is $1,261. About 10 percent of the SKUs are nationally branded 
goods, 20 percent are smaller branded products, and 70 percent of 
the SKUs are private label goods. The average label inventory loss 
is about $2,968 per SKU for nationally branded products and about 
$576 per SKU for smaller branded products and private label goods. 
(($10,000 x 0.10) + ($4,500 x 0.20) + ($1,261 x 0.70) + ($2,968 x 
0.10) + ($576 x 0.90) = $3,598)
---------------------------------------------------------------------------

    In addition to the above costs, some manufacturers may incur one-
time and annually recurring costs if they need to increase the size of 
the label and/or package size of some SKUs because of the additional 
information required by this proposed rule. The agency had estimated 
that about 6,400 of the almost 100,000 marketed OTC drug SKUs may 
require increased label and/or package sizes to comply with the final 
labeling rule (64 FR 13254). As many of these 6,400 SKUs were for 
products subject to this final rule, much of the costs for increasing 
label and/or package sizes may have already been accounted for in the 
agency's impact analysis of that broader rule. The agency estimates 
that the additional lines of labeling required by this proposed rule 
could compel an additional 5 percent of the approximately 7,200 
affected SKUs to increase their label size and/or package size.\2\
---------------------------------------------------------------------------

    \2\ FDA has assumed tht all 7,200 SKUs will need to be relabeled 
to accommodate the standardized format and content requirements in 
Sec. 201.66 and the proposed warning. When calculating the cost of 
the standardized format and content requirements, FDA included the 
cost to increase the size of the label or the package size to 
accommodate the standardized format. As a result of this proposal, 
the warning adds additional lines of text to the label. FDA 
estimates that 5 percent of the 7,200 SKUs may require larger labels 
or package sizes to accommodate the additional text.

---------------------------------------------------------------------------

[[Page 54154]]

    Because of the large number of products affected by this rule, the 
agency assumes that the average cost per SKU to increase label and/or 
package sizes would be similar to that previously estimated by FDA for 
its analysis of the standardized format and content requirements for 
OTC drug products in Sec. 201.66 (64 FR 13254). The model used to 
estimate the cost to change label/package sizes for that rule was 
developed by Eastern Research Group, Inc. (ERG), a private economics 
consulting firm under contract to FDA (Ref. 160). ERG assigned 
probabilities to several options for package changes, including adding 
a carton (if not already present), adding a fifth panel, increasing the 
size of the packaging or switching to a nonstandard form of labeling 
such as peel-back or accordion labels. Where applicable, the cost for 
changing a container size included container inventory loss, adjustment 
of the packaging line, and stability testing. Based on this model, FDA 
had estimated that the cost to increase label/package sizes to comply 
with the standardized format and content requirements for OTC drug 
products in Sec. 201.66 was $38.1 million for 6,313 SKUs, with an 
annual recurring cost of $11.5 million. Consequently the average per 
SKU one-time cost was $6,038, and the average per SKU recurring cost 
was $1,820. Under the same assumptions, this proposed rule would impose 
additional one-time costs for increasing label/package sizes of $2.2 
million (0.05 x 7,200 SKUs x $6,038), with annual recurring costs of 
$0.7 million (0.05 x 7,200 SKUs x $1,820). Thus, FDA estimates the 
overall costs of the OTC IAAA final monograph, which would include the 
labeling in this proposed rule, and the labeling required under 
Sec. 201.66 to be $28.1 million in one-time costs and $0.7 million in 
annual recurring costs.
    The proposed rule would not require any new reporting and 
recordkeeping activities, and no additional professional skills are 
needed. The March 17, 1999, standardized format and content 
requirements final rule for OTC drug product labeling in Sec. 201.66 
(64 FR 13254) will have an effect on the labeling of most of these 
products. There are no Federal rules that duplicate, overlap, or 
conflict with the proposed rule.
    This proposed rule should not have a significant economic impact on 
a substantial number of small entities. However, the agency lacks sales 
information for the affected companies to quantify the impact. The 
Small Business Administration has determined that a small firm in this 
industry employs fewer than 750 employees. Approximately 70 percent of 
the 102 manufacturers affected by this proposed rule are estimated to 
be small. (Note: The cost to relabel private label goods are usually 
bourne by the manufacturer rather than the distributor.) The economic 
impact on any particular small firm is difficult to measure, because it 
will vary with the number of products affected, the number of SKUs per 
product, and the number of label and/or package sizes that require 
changing. For example, if a small manufacturer must relabel three 
products, or nine SKUs, the total one-time cost would be $32,400 
assuming $3,600 as the average cost to relabel. Another small 
manufacturer of private label products may also need to relabel 3 
products, with 3 SKUs per product, but for 20 customers. Its cost would 
be $648,000. If either of these manufacturers had to increase the label 
and/or package sizes of their SKUs, the costs would be even higher. 
However, the total cost will primarily result from relabeling OTC IAAA 
drug products in accord with the future final monograph for those 
products and the standardized format and content requirements for 
labeling OTC drug products in Sec. 201.66 (64 FR 13254) at the same 
time. The agency invites small firms to address this economic impact. 
(See section XI of this document--request for comments.)
    Concerning the allergy alert warning, the agency considered but 
rejected the following alternatives: (1) Voluntary relabeling, and (2) 
longer implementation period. The agency does not consider either of 
these approaches acceptable because they do not ensure that consumers 
will have the most updated information needed for the safe and 
effective use of OTC drug products containing NSAID IAAA active 
ingredients. Concerning ibuprofen, the agency considered: (1) Not 
including ibuprofen in the monograph, and (2) marketing before a final 
rule is issued. The option to not include ibuprofen in the monograph 
was rejected because the agency considers the data presented supportive 
of monograph status. The agency is not allowing marketing under the 
monograph to occur prior to a final rule because of a number of new 
labeling statements being proposed. Not allowing marketing under this 
proposed rule does not interrupt current OTC marketing of products 
containing ibuprofen and will allow the agency to consider comments on 
the additional labeling for OTC ibuprofen drug products before 
finalizing the monograph labeling. The agency does not consider an 
exemption for small entities who wish to market ibuprofen to be 
necessary because those manufacturers or distributors can enter the 
marketplace under the monograph at any time after a final rule issues.
    The agency invites public comment regarding any substantial or 
significant economic impact that this rulemaking would have on OTC drug 
products that contain ibuprofen or other NSAID IAAA active ingredients. 
Comments regarding the impact of this rulemaking on these OTC drug 
products should be accompanied by appropriate documentation. The agency 
will evaluate any comments and supporting data that are received and 
will reassess the economic impact of this rulemaking in the preamble to 
the final rule.

IX. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling requirements in this 
proposal are not subject to review by the Office of Management and 
Budget because they do not constitute a ``collection of information'' 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). 
Rather, the proposed 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)).

X. 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.

XI. Request for Comments

    Interested persons may submit to the Dockets Management Branch 
(address above) written or electronic comments regarding this proposal 
by November 19, 2002. Submit written comments on the agency's economic 
impact determination by November 19, 2002. Three copies of all written 
comments are to be submitted. Individuals submitting written comments 
or anyone submitting electronic comments may submit one copy. Comments 
are to be identified with the docket number found in brackets in the 
heading of this

[[Page 54155]]

document and may be accompanied by a supporting memorandum or brief. 
Received comments may be seen in the office above between 9 a.m. and 4 
p.m., Monday through Friday.

XII. Proposed Effective Date

    FDA is proposing that any final rule based on this proposal become 
effective 12 months after the date of its publication in the Federal 
Register or at a later date if stated in the final rule. The compliance 
date for products with annual sales less than $25,000 would be 24 
months after the date of publication of a final rule in the Federal 
Register or at a later date if stated in the final rule.

XIII. References

    The following references are on display in the Dockets Management 
Branch (address above), under Docket No. 77N-094I (or 77N-0094, where 
indicated), and may be seen by interested persons between 9 a.m. and 4 
p.m., Monday through Friday.
    1. Comment No. CP13, Docket No. 77N-0094, Dockets Management 
Branch.
    2. Comment No. C233, Docket No. 77N-0094, Dockets Management 
Branch.
    3. The United States Pharmacopeia 24--The National Formulary 19, 
The United States Pharmacopeial Convention, Inc., Rockville, MD, p. 
856, 1999.
    4. Martindale--The Extra Pharmacopeia, 31st ed., edited by J. 
Reynolds, Royal Pharmaceutical Society, London, pp. 50-51, 1996.
    5. Minutes of the Seventeenth Meeting of the Arthritis Advisory 
Committee, OTC Vol. 03BTFM(I), Docket No. 77N-094I, Dockets 
Management Branch.
    6. Summary Basis of Approval for New Drug Application for 
Ibuprofen (200 mg), OTC Vol. 03BTFM(I), Docket No. 77N-094I, Dockets 
Management Branch.
    7. Comment No. CP3, Docket No. 77N-0094, Dockets Management 
Branch.
    8. Comment No. PDN002, Docket No. 77N-0094, Dockets Management 
Branch.
    9. Memoranda of Telecon Between Representatives of Whitehall 
Robins Health Care and FDA on August 6, 1998, and August 26, 1998, 
coded MT12 and MT13, respectively, Docket No. 77N-0094, Dockets 
Management Branch.
    10. Comment No. SUP44, Docket No. 77N-0094, Dockets Management 
Branch.
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AIDS, 119, 1992.
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Meningitis in a Patient Tolerant to Other Nonsteroidal Anti-
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With Systemic Lupus Erythematosus,'' Acta Medica Scandinavica, 
221:509-511, 1987.
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Aetiologic Feature,'' European Neurology, 36:172-173, 1996.
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Three Independent Sites Induced by Chemically Unrelated Drugs,'' 
Dermatologica, 181:237, 1990.
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Medical Journal, 288:1048, 1984.
    118. Laing, V. B. et al., ``Pemphigold-Like Bullous Eruption 
Related to Ibuprofen,'' Journal of the American Academy of 
Dermatology, 19:91-94, 1988.
    119. Shelly, E. D. and W. B. Shelley, ``Ibuprofen Urticaria,'' 
Journal of the American Academy of Dermatology, 17:1057-1058, 1987.
    120. Ben-Chetrit, E. and A. Rubinow, ``Exacerbation of Psoriasis 
by Ibuprofen,'' Cutis, 38:45, 1986.
    121. Pavithran, K., ``Exacerbation of Psoriasis by Ibuprofen,'' 
Indian Journal of Dermatology, Venereology, and Leprology, 53:372-
373, 1987.
    122. Tousignant, J. et al., ``Dermatitis Herpetiformis Induced 
by Nonsteroidal Anti-Inflammatory Drugs,'' International Journal of 
Dermatology, 33:199-200, 1994.
    123. Kanwar, A. J. et al., ``Drugs Causing Fixed Eruptions,'' 
Journal of Dermatology, 11:383-385, 1984.
    124. Kanwar, A. J. et al., ``Ninety-eight Fixed Drug Eruptions 
With Provocation Tests,'' Dermatologica, 177:274-279, 1988.
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Iridocyclitis Related to Ibuprofen,'' American Journal of 
Ophthalmology, 117:119-120, 1994.
    126. Kinshuck, D. and L. Stevenson, ``Complications of NSAID 
Therapy in Patients With Macular Disease,'' Survey of Ophthalmology, 
37:149-150, 1992.
    127. Fitt, A. et al., ``Vortex Keratopathy Associated With 
Ibuprofen Therapy,'' Eye, 10:145-146, 1996.
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on Contrast Sensitivity,'' Optometry and Vision Science, 69:652-655, 
1992.
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System, OTC Vol. 03BTFM(I), Docket No. 77N-094I, Dockets Management 
Branch.
    130. Minuz, P. et al., ``Antihypertensive Activity of Enalapril. 
Effect of Ibuprofen and Different Salt Intakes,'' Journal of 
Clinical Hypertension, 3:645-653, 1987.
    131. Gehr, T. W. B. et al., ``Interaction of Triamterene-
Hydrochlorothiazide (T-H) and Ibuprofen (I),'' Clinical Pharmacology 
& Therapeutics, 47:200, 1990.
    132. Radack, K. L. et. al., ``Ibuprofen Interferes With the 
Efficacy of Antihypertensive Drugs,'' Annals of Internal Medicine, 
107:628-635, 1987.
    133. Minuz, P. et al., ``Amlodipine and Haemodynamic Effects of 
Cyclo-Oxygenase Inhibition,'' British Journal of Clinical 
Pharmacology, 39:45-50, 1995.
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and Vasodilating Prostaglandins After High-Dose Short-Term Ibuprofen 
in Chronically Treated Hypertensive Patients,'' Prostaglandins, 
Leukotrienes and Essential Fatty Acids, 54:217-222, 1996.
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Blood Pressure of Patients Treated With Nifedipine or Captopril,'' 
Polski Tygodnik Lekarsi, 48:313-315, 1993.
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With Nonsteroidal Anti-Inflammatory Drugs,'' American Journal of 
Medicine, 80 (supplement 1A):62-77, 1986.
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Dental Pain (Study 2),'' American Journal of Medicine, 77:70-77, 
1984.
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Dental Pain (Study 5),'' American Journal of Medicine, 77:70-77, 
1984.
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Dental Pain (Study 3),'' Compendium of Continuing Education 
University of Pennsylvania School of Dental Medicine, 7:578-588, 
1986.
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Dental Pain (Study 4),'' Compendium of Continuing Education 
University of Pennsylvania School of Dental Medicine, 7:578-588, 
1986.
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Dental Pain (Study 5),'' Compendium of Continuing Education 
University of Pennsylvania School of Dental Medicine, 7:578-588, 
1986.
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Dental Pain (Study 2),'' Compendium of Continuing Education 
University of Pennsylvania School of Dental Medicine, 7:578-588, 
1986.
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Relief of Acute Pain: A Randomized, Double-Blind, Placebo-Controlled 
Study,'' Journal of Clinical Pharmacology, 29:1026-1030, 1989.
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Ibuprofen, Acetaminophen, and an Acetaminophen-Codeine Combination 
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and Ibuprofen in Postoperative Oral Surgery Pain,'' Pharmacotherapy, 
11:64-70, 1991.
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Ibuprofen, and Aspirin in Postoperative Oral Surgery Pain,'' 
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Ibuprofen/Codeine Combination in Post-Operative Dental Pain,'' 
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1986.
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Ibuprofen in Dental Extraction Pain,'' Pharmacotherapy, 6:318-322, 
1986.
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Ibuprofen and Acetaminophen in the Treatment of Postoperative Dental 
Pain,'' Journal of American Dental Association, 121:257-263, 1990.
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Treatment of

[[Page 54158]]

Muscle Contraction Headache,'' Headache, 23:206-210, 1983.
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in Self-Medication of Mild to Moderate Headache: A Comparison With 
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Evaluation of Mild Analgesics,'' Clinical Pharmacology and 
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No. 96N-0420, Dockets Management Branch.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 343

    Labeling, Over-the-counter drugs.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 201 and 343 be amended as follows:

PART 201--LABELING

    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.

    2. Section 201.63 is amended by revising paragraph (e) to read as 
follows:


Sec. 201.63   Pregnancy/breast-feeding warning.

* * * * *
    (e) The labeling of orally or rectally administered OTC aspirin- 
and ibuprofen-containing products must bear a warning that immediately 
follows the general warning identified in paragraph (a) of this 
section. The warning shall be as follows:
    ``It is especially important not to use'' [select ``aspirin,'' 
``carbaspirin calcium,'' or ``ibuprofen,'' as appropriate] ``during the 
last 3 months of pregnancy unless definitely directed to do so by a 
doctor because it may cause problems in the unborn child or 
complications during delivery.''

    3. Section 201.324 is added to subpart G to read as follows:


Sec. 201.324  Over-the-counter drug products containing internal 
analgesic/antipyretic active ingredients; required allergy warning 
statements.

    The labeling for all over-the-counter (OTC) drug products 
containing nonsteroidal anti-inflammatory internal analgesic/
antipyretic active ingredients--including but not limited to aspirin, 
carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, 
magnesium salicylate, naproxen sodium, and sodium salicylate--whether 
subject to an applicable OTC drug monograph or an approved drug 
application, contains the following allergy warnings under the heading 
``Warnings'':
    (a) ``Allergy alert: [insert name of active ingredient (first 
letter of first word for ingredient in uppercase)] may cause a severe 
allergic reaction which may include: [bullet]\1\  hives [bullet] facial 
swelling [bullet] asthma (wheezing) [bullet] shock''.
---------------------------------------------------------------------------

    \1\ See Sec. 201.66(b)(4) of this chapter for definition of 
bullet symbol.
---------------------------------------------------------------------------

    (b) ``Do not use [insert bullet if more than one warning occurs 
under this subheading] if you have ever had'' or for products labeled 
only for use in children under 12 years of age, ``Do not use [insert 
bullet if more than one warning occurs under this subheading] if your 
child has ever had'' followed by, ``an allergic reaction to any other 
pain reliever/fever reducer''. [This statement appears as the first 
warning under the subheading ``Do not use.'']
    (c) ``Stop use and ask a doctor if [insert bullet if more than one 
warning occurs under this heading] an allergic reaction occurs. Seek 
medical help right away.'' [These statements appear as the first 
warning under the subheading ``Stop use and ask a doctor if.'']

PART 343--INTERNAL ANALGESIC, ANTIPYRETIC, AND ANTIRHEUMATIC DRUG 
PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

    4. The authority citation for 21 CFR part 343 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    5. Section 343.3 is amended by alphabetically adding a definition 
for ibuprofen to read as follows:


Sec. 343.3  Definitions.

* * * * *
    Ibuprofen. A racemic mixture of the S-[+] and R-[-] enantiomers of 
ibuprofen in a tablet formulation for adults and children 12 years and 
older.
* * * * *

    6. Section 343.10, as proposed at 53 FR 46255, November 16, 1988, 
is further amended by adding paragraph (g) to read as follows:


Sec. 343.10  Analgesic-antipyretic active ingredients.

* * * * *
    (g) Ibuprofen 200-milligram tablet.
* * * * *

    7. Section 343.20, as proposed at 53 FR 46255, November 16, 1988, 
is further is amended by revising paragraphs (b)(2) and (b)(4) to read 
as follows:


Sec. 343.20  Permitted combinations of active ingredients.

* * * * *
    (b) * * * 
    (2) Analgesic-antipyretic active ingredients identified in Sec.  
343.10(a) through (f) and cough-cold combinations. See Sec.  341.40 of 
this chapter.
* * * * *
    (4) Analgesic and diuretic combinations. Any analgesic identified 
in Sec.  343.10(a) through (f) or any combination of analgesics 
identified in Sec.  343.20(a) may be combined with any diuretic 
identified in Sec.  357.1012 of this chapter provided the product bears 
labeling indications in accordance with Sec.  357.1060(b) of this 
chapter.

    8. Section 343.50, as proposed at 53 FR 46255, November 16, 1988, 
is further is amended by revising the headings in paragraphs (b)(1), 
(c)(1)(i), and (c)(2)(i); and the text of paragraphs (c)(1)(iv)(A), 
(c)(1)(iv)(B), (c)(1)(vi), (c)(2)(iv)(A), and (c)(2)(vi); and by adding 
paragraphs (b)(5), (c)(1)(ix), and (d)(7) to read as follows:


Sec. 343.50  Labeling of analgesic-antipyretic drug products.

* * * * *
    (b) * * * 

[[Page 54159]]

    (1) For products containing any ingredient identified in Sec.  
343.10(a) through (f). * * * 
* * * * *
    (5)For products containing ibuprofen identified in Sec.  343.10(g). 
The labeling of the product contains any of the indications in Sec.  
343.50(b) except ``sore throat.''
    (c) * * * 
    (1) * * * 
    (i) For products containing any ingredient identified in 
Sec. 343.10(a) through (f). * * * 
* * * * *
    (iv) * * * 
    (A) ``Do not use this product if you have asthma unless directed by 
a doctor''.
    (B) The labeling contains the pregnancy/breast-feeding warnings set 
forth in Sec.  201.63(a) and (e) of this chapter.
* * * * *
    (vi) For products containing any ingredient identified in Sec.  
343.10(b) through (g). The labeling of the product contains the allergy 
warnings set forth in Sec.  201.324(a), (b), and (c) of this chapter.
* * * * *
    (ix) For products containing ibuprofen identified in Sec.  
343.10(g). (A) The alcohol warning set forth in Sec.  201.322(a)(2) of 
this chapter appears after the subheading ``Alcohol warning:.''
    (B) ``Ask a doctor before use if you have: [bullet]\1\  problems or 
serious side effects from taking pain relievers or fever reducers 
[bullet] stomach problems that last or come back, such as heartburn, 
upset stomach, or pain [bullet] ulcers [bullet] bleeding problems 
[bullet] high blood pressure, heart or kidney disease, are taking a 
diuretic, or are over 65 years of age''.
---------------------------------------------------------------------------

    \1\See Sec. 201.66(b)(4) of this chapter for definition of 
bullet symbol.
---------------------------------------------------------------------------

    (C) ``Ask a doctor or pharmacist before use if you are: [bullet] 
under a doctor's care for any serious condition [bullet] taking any 
other product that contains ibuprofen, or any other pain reliever/fever 
reducer [bullet] taking a prescription drug for anticoagulation (blood 
thinning) [bullet] taking any other drug''.
    (D) ``When using this product: [insert bullet if more than one 
warning occurs under this subheading] take with food or milk if stomach 
upset occurs''.
    (E) In addition to the warning required in Sec.  201.324(c) of this 
chapter, the following statements appear after the subheading ``Stop 
use and ask a doctor if: [bullet] pain gets worse or lasts more than 10 
days [bullet] fever gets worse or lasts more than 3 days [bullet] 
stomach pain gets worse or lasts [bullet] redness or swelling is 
present in the painful area [bullet] any new symptoms appear''.
    (F) The labeling contains the pregnancy/breast-feeding warnings set 
forth in Sec.  201.63(a) and (e) of this chapter.
    (2) * * * 
    (i) For products containing any ingredient identified in Sec.  
343.10(a) through (f). * * * 
* * * * *
    (iv) * * * 
    (A) ``Do not give this product to children who have asthma unless 
directed by a doctor''.
* * * * *
    (vi) For products containing any ingredient in Sec.  343.10(b) 
through (g). The labeling contains the allergy warnings set forth in 
Sec.  201.324(a), (b), and (c) of this chapter.
* * * * *
    (d) * * * 
* * * * *
    (7) For products containing ibuprofen identified in Sec.  
343.10(g). The labeling states ``[bullet]\1\  do not take more than 
directed [in bold type] [bullet] adults and children 12 years and over: 
[bullet] 200 milligrams\2\ every 4 to 6 hours while symptoms persist 
[bullet] if pain or fever does not respond to 200 milligrams\2\, 400 
milligrams\2\ may be used [bullet] do not exceed 1,200 milligrams\2\ in 
24 hours, unless directed by a doctor [bullet] the smallest effective 
dose should be used [bullet] children under 12 years: ask a doctor''.
* * * * *
---------------------------------------------------------------------------

    \1\See Sec. 201.66(b)(4) of this chapter for definition of 
bullet symbol.
    \2\ Convert number of milligrams to proper dosage.

    Dated: January 10, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-21122 Filed 8-20-02; 8:45 am]
BILLING CODE 4160-01-S