[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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.
11. Davies, E. F. and G. S. Avery, ``Ibuprofen: A Review of Its
Pharmacological Properties and Therapeutic Efficacy in Rheumatic
Disorders,'' Drugs, 2:257-408, 1971.
12. Adams, S. S. et al., ``Absorption, Distribution, and
Toxicity of Ibuprofen,'' Toxicology and Applied Pharmacology,
15:310-330, 1969.
13. Neupert, W. et al., ``Effects of Ibuprofen Enantiomers and
Its Coenzyme a Thioester on Human Prostaglandin Endoperoxide
Synthases,'' British Journal of Pharmacology, 122:487-92, 1997.
14. Abernathy, D. R. and D. J. Greenblatt, ``Ibuprofen
Disposition in Obese Individuals,'' Arthritis and Rheumatism,
28:1117-21, 1985.
15. Adams, S. S., P. Bresloff, and C. G. Mason,
``Pharmacological Differences Between the Optical Isomers of
Ibuprofen, Evidence for Metabolic Inversion of the (-)-Isomer,''
Journal of Pharmacy and Pharmacology, 28:256-257, 1976.
16. Geisslinger, G. et al., ``Pharmacological Differences
Between the R(-)- and S(+)-Ibuprofen,'' Agents and Actions, 27:455-
457, 1989.
17. Cheng, H. et al., ``Pharmacokinetics and Bioinversion of
Ibuprofen Enantiomers in Humans,'' Pharmaceutical Research, 11:824-
830, 1994.
18. Cox, S. R., ``Effect of Route of Administration on the
Chiral Inversion of R(-)-Ibuprofen'' (abstract), Clinical
Pharmacology and Therapeutics, 43:146, 1988.
19. Jamali, F. et al., ``Human Pharmacokinetics of Ibuprofen
Enantiomers Following Different Doses and Formulations: Intestinal
Chiral Inversion,'' Journal of Pharmaceutical Sciences, 81:221-225,
1992.
20. Davies, N. M., ``Clinical Pharmacokinetics of Ibuprofen,''
Clinical Pharmacokinetics, 34:101-154, 1998.
21. Gillespie, W. R. et al., ``Relative Bioavailability of
Commercially Available Ibuprofen Oral Dosage Forms in Humans,''
Journal of Pharmaceutical Sciences, 71:1034-1038, 1982.
22. Adams, S. S. and J. Warwick-Buckler, ``Ibuprofen and
Flurbiprofen,'' Clinical Rheumatic Diseases, 5:359-378, 1979.
23. Verbeeck, R. K., ``Pathophysiologic Factors Affecting the
Pharmacokinetics of Nonsteroidal Anti-Inflammatory Drugs,'' Journal
of Rheumatology, 15 (suppl. 17):44-57, 1988.
24. Jamali, F. and D. R. Brocks, ``Clinical Pharmacokinetics of
Ketoprofen and Its Enantiomers,'' Clinical Pharmacokinetics, 19:197-
217, 1990.
25. Whitlam, J. B. and K. F. Brown, ``Ultrafiltration in Serum
Protein Binding Determinations,'' Journal of Pharmaceutical
Sciences, 70:146-50, 1981.
26. Vowles, D. T. and B. Marchant, ``Protein Binding of
Ibuprofen and Its Relationship to Drug Interactions,'' British
Journal of Clinical Practice, 1 (Symp. Suppl.):13-19, 1980.
27. Albert, K. S. and C. M. Gernaat, ``Pharmacokinetics of
Ibuprofen,'' American Journal of Medicine, 23:40-46, 1984.
28. Wanwimolruk, S., D. J. Birkett, and P. M. Brooks, ``Protein
Binding of Some Nonsteroidal Anti-Inflammatory Drugs in Rheumatoid
Arthritis,'' Clinical Pharmacokinetics, 7:85-92, 1982.
29. Greenblatt, D. J. et al., ``Absorption and Disposition of
Ibuprofen in the Elderly,'' Arthritis and Rheumatology, 27:1066-
1069, 1984.
30. Leeman, T. D. et al., ``A Major Role for Cytochrome P450TB
(CYP23) Subfamily in the Actions of Non-Steroidal Anti-Inflammatory
Drugs,'' Drugs Under Experimental and Clinical Research, 19:189-195,
1993.
31. Hamman, M. A., G. A. Thompson, and S. D. Hall,
``Regioselective and Stereoselective Metabolism of Ibuprofen by
Human Cytochrome P450 2C,'' Biochemical Pharmacology, 54:33-41 1997.
32. Evans, A. M. et al., ``The Relationship Between the
Pharmacokinetics of Ibuprofen Enantiomers and the Dose of Racemic
Ibuprofen in Humans,'' Biopharmaceutics and Drug Disposition,
11:507-518, 1990.
33. Rudy, A. C. et al., ``Stereoselective Metabolism of
Ibuprofen in Humans: Administration of R-, S- and Racemic
Ibuprofen,'' Journal of Pharmacology and Experimental Therapeutics,
259:1133-1139, 1991.
34. Albert, K. S. et al., ``Effects of Age on the Clinical
Pharmacokinetics of Ibuprofen,'' American Journal of Medicine, 6:47-
50, 1984.
35. Walter, K. and C. Dilger, ``Ibuprofen in Human Milk,''
British Journal of Clinical Pharmacology, 44:211-212 1997.
36. Gurwitz, J. H. et al., ``The Impact of Ibuprofen on the
Efficacy of Antihypertensive Treatment With Hydrochlorthiazide in
Elderly Patients,'' Journal of Gerontology, 51A: M74-M79, 1996.
37. Agency Letter to Prescription NSAID Manufacturers/Sponsors,
OTC Vol. 03BTFM(I), Docket No. 77N-094I, Dockets Management Branch.
38. Motrin (prescription) Label, Physicians' Desk Reference,
54th ed., Directory Services edited by David W. Sifton, Medical
Economics Co., Inc., Montvale, NJ, pp. 1684-1687, 2000.
39. ``Summary of Safety and Efficacy Data From the Advil New
Drug Application (1983),'' Appendix C, Comment No. CP13, Docket No.
77N-0094, Dockets Management Branch.
40. Moore, N. et al., ``The PAIN Study: Paracetamol, Aspirin,
and Ibuprofen, New Tolerability Study. A Large-Scale, Randomized
Clinical Trial Comparing the Tolerability of Aspirin, Ibuprofen, and
Paracetamol for Short-Term Analgesia,'' Clinical Drug
Investigations, 18:89-98, 1999.
41. Griffin, M. R. et al., ``Nonsteroidal Anti-Inflammatory Drug
Use and Increased Risk for Peptic Ulcer Disease in Elderly
Persons,'' Annals of Internal Medicine, 114:257, 1991.
42. Bradley, J. D. et al., ``Comparison of an Anti-Inflammatory
Dose of Ibuprofen, An Analgesic Dose of Ibuprofen, and Acetaminophen
in the Treatment of Osteoarthritis of the Knee,'' New England
Journal of Medicine, 325:87-91, 1991.
43. Kaufman, D. W. et al., ``Nonsteroidal Anti-Inflammatory Drug
Use in Relation to Major Upper Gastrointestinal Bleeding,'' Clinical
Pharmacology and Therapy, 53:485, 1993.
44. Strom, B. L. et al., ``Gastrointestinal Tract Bleeding
Associated With Naproxen Sodium Versus Ibuprofen,'' Archives of
Internal Medicine, 157:2626-2631, 1997.
45. Bergmann, J. F. et al., ``Endoscopic Evaluation of the
Effect of Ketoprofen, Ibuprofen, and Aspirin on the Gastroduodenal
Mucosa,'' European Journal of Clinical Pharmacology, 42:685, 1992.
46. Lanza, F. L., ``A Review of Gastric Ulcer and
Gastrointestinal Injury in Normal Volunteers Receiving Aspirin and
Other Nonsteroidal Anti-Inflammatory Drugs,'' Scandinavian Journal
of Gastroenterology, 24 (Suppl. 163):24-31, 1989.
[[Page 54156]]
47. Bidlingmaier, A. et al. ``Gastrointestinal Blood Loss
Induced by Three Different Nonsteroidal Anti-Inflammatory Drugs,''
Arzneim Forsch, 45:491-493, 1995.
48. Insel, P. A., ``Analgesic-Antipyretic and Anti-Inflammatory
Agents and Drugs Employed in the Treatment of Gout'' (Chapter 27),
Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th
ed., Hardman, J. G., and L. E. Limbird, Editors-in-Chief, McGraw-
Hill, Health Professions Division, New York, NY, pp. 617-657, 1996.
49. Kirschenbaum, M. A. and G. A. Shah, ``Nephropathy of
Nonsteroidal Anti-Inflammatory Agents,'' Textbook of Nephrology,
3rd. ed., edited by Massry, S. G. and R. J. Glassock, Williams and
Wilkins, Baltimore, MD, pp. 940-947, 1995.
50. Farquhar, W. B. et al., ``Effects of Acetaminophen and
Ibuprofen on Renal Function in the Stressed Kidney,'' Journal of
Applied Physiology, 86:598-604, 1999.
51. Ciabottoni, G. et al., ``Effects of Sulindac and Ibuprofen
in Patients With Chronic Glomerular Disease: Evidence for the
Dependence of Renal Function on Prostacyclin,'' New England Journal
of Medicine, 310:279-283, 1984.
52. Whelton, A. et al., ``Renal Effects of Ibuprofen, Piroxicam,
and Sulindac in Patients With Asymptomatic Renal Failure:
Prospective, Randomized, Crossover Comparison,'' Annals of Internal
Medicine, 112:568-576, 1990.
53. Furey, S. A., R. Vargas, and F. G. McMahan, ``Renovascular
Effects of Nonprescription Ibuprofen in Elderly Hypertensive
Patients With Mild Renal Impairment,'' Pharmacotherapy, 13:143-148,
1993.
54. Elsasser, G. N., L. Lopez, and E. Evans, ``Reversible Acute
Renal Failure Associated With Ibuprofen Ingestion and Binge
Drinking,'' Journal of Family Practice, 27:221, 1988.
55. Johnson, G. and S. F. Wen, ``Syndrome of Flank Pain and
Acute Renal Failure After Binge Drinking and Nonsteroidal Anti-
Inflammatory Drug Ingestion,'' Journal of the American Society of
Nephrology, 5:1647, 1995.
56. McIntire, S. C. et al., ``Acute Flank Pain and Reversible
Renal Dysfunction Associated With Nonsteroidal Anti-Inflammatory
Drug Use,'' Pediatrics, 92:459-460, 1993.
57. Wattad, A., T. Feehan, and F. M. Shepard, ``A Unique
Complication of Nonsteroidal Anti-Inflammatory Drug Use,''
Pediatrics, 93:693, 1993.
58. Moss, A. H. et al., ``Over-the-Counter Ibuprofen and Renal
Failure,'' Annals of Internal Medicine, 105:303, 1986.
59. Corwin, H. L. and J. V. Bonventure, ``Renal Insufficiency
Associated With Nonsteroidal Anti-Inflammatory Drugs,'' American
Journal of Kidney Disease, 4:147-152, 1984.
60. Marasco, W. A., P. W. Gikas, and R. Azziz-Baumgartener,
``Ibuprofen-Associated Renal Dysfunction, Pathophysiologic
Mechanisms of Acute Renal Failure Hyperkalemia, Tubular Necrosis,
and Proteinuria,'' Archives of Internal Medicine, 147:2107, 1987.
61. Fernando, A. H. N. et al., ``Renal Failure After Topical Use
of NSAID's,'' British Medical Journal, 308:533, 1994.
62. Spierto, T. J., M. B. Kaufman, and C. A. Stoukedes, ``Acute
Renal Failure Associated With the Use of Over-the-Counter
Ibuprofen,'' The Annals of Pharmacotherapy, 26:714, 1992.
63. Atkinson, L. K., G. H. Goodship, and M. K. Ward, ``Acute
Renal Failure Associated With Acute Pyelonephritis and Consumption
of Non-Steroidal Anti-Inflammatory Drugs,'' British Medical Journal,
292:97-98, 1986.
64. Sheiner, P. A. et al., ``Acute Renal Failure Associated With
the Use of Ibuprofen in Two Liver Transplant Recipients on FK506,''
Transplant, 57:1132-1133, 1994.
65. Rault, R. M., ``Case Report: Hyponatremia Associated With
Non-Steroidal Anti-Inflammatory Drugs,'' American Journal of Medical
Science, 305:318-320, 1993.
66. Wachtel, A. et al., ``Non-Steroidal Anti-Inflammatory Agents
and Acute Renal Failure,'' Mayo Clinic Proceedings, 57:601, 1982
(Letters).
67. Henrich, W. L. et al., ``Analgesic and the Kidney: Summary
and Recommendations to the Scientific Advisory Board of the National
Kidney Foundation From an Ad Hoc Committee of the National Kidney
Foundation,'' American Journal of Kidney Diseases, 27:162-165, 1996.
68. Fukui, M. et al., ``A Case of Drug-Induced Hepatitis With
Multinuclear Giant Hepatic Cells in Adult,'' Kanzo, 26:500-505,
1985.
69. Alam, I., L. D. Ferrell, and M. Bass, ``Vanishing Bile Duct
Syndrome Temporarily Associated With Ibuprofen Use,'' American
Journal of Gastroenterology, 91:1626-1630, 1996.
70. Garcia-Rodriguez, L.A. et al., ``The Role of Non-Steroidal
Anti-Inflammatory Drugs in Acute Liver Injury,'' British Medical
Journal, 305:865-868, 1992.
71. Katz, L. M., and P. Y. Love, ``NSAIDs and the Liver,''
Therapeutic Applications of NSAIDs (chapter 12), edited by J. P.
Famaey and H. E. Paulus, Marcel Dekker, Inc., New York, NY, pp. 247-
263, 1992.
72. Jain, S., ``Ibuprofen-Induced Thrombocytopenia,'' British
Journal of Clinical Practice, 48:51, 1994.
73. Manus, S. W. et al., ``Ibuprofen Associated Pure White-Cell
Aplasia,'' Archives of Internal Medicine, 314:624, 1986.
74. Deutsch P. H. and G. L. Mandell, ``Reversible Pelger-Huet
Anomaly Associated With Ibuprofen Therapy,'' Archives of Internal
Medicine, 145:166, 1985.
75. Wittkowsky, A. K., ``Thrombosis,'' Applied Therapeutics: The
Clinical Use of Drugs, 6th ed., edited by Young, L. Y., and M. A.
Koda-Kimble, Applied Therapeutics, Inc., Vancouver, WA, ch. 12, pp.
20-21, 1995.
76. Mathur, S. L., ``Ibuprofen in Bronchial Asthma,'' Journal of
the Association of Physicians of India, 36:523, 1988.
77. Ayers, J. G., D. M. Flemming, and R. M. Whittington,
``Asthma Death Due to Ibuprofen,'' Lancet, 1:1082, 1987.
78. Anderson, J. S. and H. Guldager, ``Ibuprofen-Triggered
Asthma Attack in a Patient With Known Aspirin Hypersensitivity,''
Ugeske Laeger, 151:1885, 1989.
79. Antonicelli, L. and A. Tagliabracci, ``Asthma Death Induced
by Ibuprofen,'' Monaldi Archives for Chest Disease, 50:276-278,
1995.
80. Jamil, A. S. and F. S. Majd, ``Life-Threatening Asthma and
Anti-Inflammatory Drugs,'' Journal of Kuwaiti Medical Association,
22:165, 1988.
81. Sharma, S. K., ``Ibuprofen (Brufen) Induced Bronchial
Asthma,'' Journal of the Association of Physicians of India, 32:843,
1984.
82. Mandell, B. F. and Raps, E. C., ``Severe Systemic
Hypersensitivity Reaction to Ibuprofen Occurring After Prolonged
Therapy,'' American Journal of Medicine, 82:817-820, 1987.
83. Lee, R. P., E. G. King, and A. S. Russell, ``Ibuprofen: A
Severe Reaction,'' Canadian Medical Association Journal, 61:463,
1986.
84. Harman Fridrich, H., G. A. Zach, and K. L. Fridrich,
``Aspirin-Intolerance Syndrome: Report of a Case,'' Oral Surgery,
Oral Medicine, and Oral Pathology, 61:463-465, 1986.
85. Butterfield H. et al., ``Severe Generalized Reaction to
Ibuprofen: Report of a Case,'' Journal of Rheumatology, 13:649,
1986.
86. Katz, J. et al., ``Drug Allergy in Sjogren's Syndrome,''
Lancet, 337:239, 1991.
87. Ekert, F. et al, ``Anaphylactoid Reactions Due to
Ibuprofen'' (abstract), Journal of Allergy and Clinical Immunology,
89:347, 1992.
88. Grimm, A. M. and J. E. Wolf, ``Aseptic Meningitis Associated
With Nonprescription Ibuprofen Use'' (letter to the editor), DICP,
The Annals of Pharmacotherapy, 23:712, 1989.
89. Katona, B. G. et al., ``Aseptic Meningitis From Over-the-
Counter Ibuprofen,'' Lancet, 1:59, 1988 (letters).
90. Durback, M. A., J. Freeman, and V. R. Schumacher,
``Recurrent Ibuprofen-Induced Aseptic Meningitis: Third Episode
After Only 200 mg of Generic Ibuprofen,'' Arthritis and
Rheumatology, 31:813-815, 1988.
91. Agus, B. et al., ``Acute Central Nervous System Symptoms
Caused by Ibuprofen in Connective Tissue Disease,'' Journal of
Rheumatology, 17:1094-1096, 1990.
92. Ewert, B. H., ``Ibuprofen-Associated Meningitis in a Woman
With Only Serologic Evidence of a Rheumatologic Disorder,'' American
Journal of Medical Science, 287:326-327, 1989.
93. Lortholary, A. et al., ``Generalized Status Epilepticus
After Ingestion of Ibuprofen (Brufen) Disclosing Lupus
Erythematosus,'' LaRevue de Medicine Interne, 11:243-244, 1990.
94. Treves, R. et al., ``Aseptic Meningitis and Acute Renal
Failure Induced by Ibuprofen During the Treatment of Systemic Lupus
Erythematosus,'' Revue de Rheumatisme, 50:75-76, 1983.
95. Colamarino, R., M. Soubrier, and M. Zenut-Leaud, ``Aseptic
Meningitis Due to Ibuprofen (Nuprofen) in Cases of Connective-Tissue
Disease,'' Therapie, 48:516-518, 1993.
96. Perera, D. R., A. K. Seiffert, and H. M. Greeley,
``Ibuprofen and Meningoencephalitis,'' Southern Medical Journal,
100:619, 1984.
[[Page 54157]]
97. Thilman, A. F. et al., ``Recurrent Aseptic Meningitis
(Mollaret Meningitis)--Spontaneous and Drug-Induced Appearance,''
Fortschritte der Neurologie-Psychiatrie (Stuttgart), 59:493-497,
1991.
98. Gilbert, G. J. and H. W. Eichenbaum, ``Ibuprofen-Induced
Meningitis in an Elderly Patient With Systemic Lupus
Erythematosus,'' Southern Medical Journal, 82:514-515, 1989.
99. Hanson, L. and H. J. Morgan, ``Ibuprofen-Induced Aseptic
Meningitis,'' Journal of Tennessee Medical Association, 87:58, 1994.
100. Lawson, J. M. and M. J. Grady, ``Ibuprofen-Induced Aseptic
Meningitis in a Previously Healthy Patient,'' Western Journal of
Medicine, 143:386-387, 1985.
101. Quinn, J. P., R. A. Weinstein, and L. R. Caplan,
``Eosinophilic Meningitis and Ibuprofen Therapy,'' Neuorology,
34:108-109, 1984.
102. Mifsud, A. J., ``Drug-Related Recurrent Meningitis,''
Journal of Infection, 17:151-153, 1988.
103. Van der Zwan, A. and J. G. Van Dam, ``Side Effects of
Medicinal Agents--Ibuprofen Meningitis,'' Ned Tijdschr Geneeskd,
136:1613-1614, 1992.
104. Chez, M. et al., ``Ibuprofen-Induced Meningitis: Detection
of Intrathecal IgG Synthesis and Immune Complexes,'' Neurology,
39:1578-1580, 1989.
105. Bouland, D. L., N. L. Specht, and D. R. Hegstad,
``Ibuprofen and Aseptic Meningitis,'' Annals of Internal Medicine,
104:731, 1986.
106. Davis, B. J. et al., ``Drug-Induced Aseptic Meningitis
Caused by Two Medications,'' Neurology, 44:984-985, 1994.
107. Chaudhry, H. J. and B. A. Cunha, ``Drug-Induced Aseptic
Meningitis,'' Postgraduate Medicine, 90:65-70, 1991.
108. Morgan, A. and D. Clark, ``CNS Adverse Effects of
Nonsteroidal Anti-Inflammatory Drugs,'' CNS Drugs, 4:281-290, 1998.
109. Hoppmann, R. A., J. G. Peden, and S. K. Ober, ``Central
Nervous System Side Effects of Nonsteroidal Anti-Inflammatory
Drugs,'' Archives of Internal Medicine, 151:1309-1313, 1991.
110. Perlman, D. M., ``Ibuprofen-Induced Aseptic Meningitis in
Individuals With HIV,'' Abstract of International Conference on
AIDS, 119, 1992.
111. Horn, A. C. and S. W. Jarrett, ``Ibuprofen-Induced Aseptic
Meningitis in Rheumatoid Arthritis,'' Annals of Pharmacotherapy,
31:1009-1011, 1997.
112. Eustace, S. and B. Buff, ``Magnetic Resonance Imaging in
Drug-Induced Meningitis,'' Canadian Association of Radiology
Journal, 45:463-465, 1994.
113. Greenberg, G. N., ``Recurrent Sulindac-Induced Aseptic
Meningitis in a Patient Tolerant to Other Nonsteroidal Anti-
Inflammatory Drugs,'' Southern Medical Journal, 11:1463-1464, 1998.
114. Jensen, S. et al., ``Ibuprofen-Induced Meningitis in a Male
With Systemic Lupus Erythematosus,'' Acta Medica Scandinavica,
221:509-511, 1987.
115. Rottach, K. et al., ``Mollaret's Meningitis: A New
Aetiologic Feature,'' European Neurology, 36:172-173, 1996.
116. Bharija, S. C. and M. S. Belhaj, ``Fixed Drug Eruption on
Three Independent Sites Induced by Chemically Unrelated Drugs,''
Dermatologica, 181:237, 1990.
117. Khan, A. R., ``Erythema Nodosum After Ibuprofen,'' British
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.
125. Kaplan, B. H. et al., ``Aseptic Meningitis and
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.
128. Ridder III, W. H. and A. Tomlinson, ``Effect of Ibuprofen
on Contrast Sensitivity,'' Optometry and Vision Science, 69:652-655,
1992.
129. FDA's evaluation of data in its Adverse Event Reporting
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.
134. Pancera, P. et al., ``Changes in Peripheral Hemodynamics
and Vasodilating Prostaglandins After High-Dose Short-Term Ibuprofen
in Chronically Treated Hypertensive Patients,'' Prostaglandins,
Leukotrienes and Essential Fatty Acids, 54:217-222, 1996.
135. Halawa, B., ``Effect of Indomethacin and Ibuprofen on the
Blood Pressure of Patients Treated With Nifedipine or Captopril,''
Polski Tygodnik Lekarsi, 48:313-315, 1993.
136. Brater, D. G., ``Drug-Drug and Drug-Disease Interactions
With Nonsteroidal Anti-Inflammatory Drugs,'' American Journal of
Medicine, 80 (supplement 1A):62-77, 1986.
137. Cooper, S. A., ``Five Studies on Ibuprofen for Postsurgical
Dental Pain (Study 2),'' American Journal of Medicine, 77:70-77,
1984.
138. Cooper, S. A., ``Five Studies on Ibuprofen for Postsurgical
Dental Pain (Study 5),'' American Journal of Medicine, 77:70-77,
1984.
139. Cooper, S. A., ``The Relative Effectiveness of Ibuprofen in
Dental Pain (Study 3),'' Compendium of Continuing Education
University of Pennsylvania School of Dental Medicine, 7:578-588,
1986.
140. Cooper, S. A., ``The Relative Effectiveness of Ibuprofen in
Dental Pain (Study 4),'' Compendium of Continuing Education
University of Pennsylvania School of Dental Medicine, 7:578-588,
1986.
141. Cooper, S. A., ``The Relative Effectiveness of Ibuprofen in
Dental Pain (Study 5),'' Compendium of Continuing Education
University of Pennsylvania School of Dental Medicine, 7:578-588,
1986.
142. Cooper, S. A., ``The Relative Effectiveness of Ibuprofen in
Dental Pain (Study 2),'' Compendium of Continuing Education
University of Pennsylvania School of Dental Medicine, 7:578-588,
1986.
143. Cooper, S. A. et al., ``Ibuprofen and Acetaminophen in the
Relief of Acute Pain: A Randomized, Double-Blind, Placebo-Controlled
Study,'' Journal of Clinical Pharmacology, 29:1026-1030, 1989.
144. Forbes, J. A. et. al., ``Evaluation of Ketorolac,
Ibuprofen, Acetaminophen, and an Acetaminophen-Codeine Combination
in Post-Operative Oral Surgery Pain,'' Pharmacotherapy, 10 (Suppl.
6):94S-105S, 1990.
145. Forbes, J. A. et al., ``Evaluation of Bromfenac, Aspirin,
and Ibuprofen in Postoperative Oral Surgery Pain,'' Pharmacotherapy,
11:64-70, 1991.
146. Forbes, J. A. et al., ``Analgesic Efficacy of Bromfenac,
Ibuprofen, and Aspirin in Postoperative Oral Surgery Pain,''
Clinical Pharmacology, 51:343-352, 1992.
147. Giles, A. D. et al., ``A Single-Dose Assessment of an
Ibuprofen/Codeine Combination in Post-Operative Dental Pain,''
International Journal of Oral Maxillofacillary Surgery, 15:727-732,
1986.
148. Jain, A. K. et al., ``Analgesic Efficacy of Low-Dose
Ibuprofen in Dental Extraction Pain,'' Pharmacotherapy, 6:318-322,
1986.
149. Mehlisch, D. R. et al., ``Multi-Center Clinical Trial of
Ibuprofen and Acetaminophen in the Treatment of Postoperative Dental
Pain,'' Journal of American Dental Association, 121:257-263, 1990.
150. Ngan, P. et al., ``The Effect of Ibuprofen on the Level of
Discomfort in Patients Undergoing Orthodontic Treatment,'' American
Journal of Orthodontics and Dentofacial Orthopedics, 106:88-95,
1994.
151. Diamond, S., ``Ibuprofen Versus Aspirin and Placebo in the
Treatment of
[[Page 54158]]
Muscle Contraction Headache,'' Headache, 23:206-210, 1983.
152. Schachtel, B. P., S. A. Furey, and W. R. Thoden,
``Nonprescription Ibuprofen and Acetaminophen in the Treatment of
Tension-Type Headache,'' Journal of Clinical Pharmacology, 36:1120-
1125, 1996.
153. Nebe, J., M. Heier, and H. C. Diener, ``Low-Dose Ibuprofen
in Self-Medication of Mild to Moderate Headache: A Comparison With
Acetylsalicylic Acid and Placebo,'' Cephalalgia, 5:531-535, 1995.
154. Schachtel, B., W. R. Thoden, and R. I. Baybutt, ``Ibuprofen
and Acetaminophen in the Relief of Postpartum Episiotomy Pain,''
Journal of Clinical Pharmacology, 29:550-553, 1989.
155. Schachtel, B. P. et al., ``Sore Throat Pain in the
Evaluation of Mild Analgesics,'' Clinical Pharmacology and
Therapeutics, 44:704-711, 1988.
156. Habib, S. et al., ``A Study of the Comparative
Effectiveness of Four Common Analgesics in the Control of Post-
Surgical Dental Pain,'' Oral Surgery, Oral Medicine, and Oral
Pathology, 70:559-563, 1990.
157. Noyelle, R. M. et al., ``Ibuprofen, Aspirin, and
Paracetamol Compared in a Community Study,'' Pharmaceutical Journal,
238:561-564, 1987.
158. Milsom, I. and B. Andersch, ``Effect of Ibuprofen, Naproxen
Sodium, and Paracetamol on Intrauterine Pressure and Menstrual Pain
in Dysmenorrhea,'' British Journal of Obstetrics and Gynecology,
91:1129-1135, 1984.
159. Gaitonde, B. B. et al., ``Antipyretic Activity of Ibuprofen
(Brufen),'' Journal of the Association of Physicians in India,
21:579-584, 1973.
160. Eastern Research Group, Inc., ``Cost Impacts of the Over-
the-Counter Pharmaceutical Labeling Rule,'' OTC Vol. 28FR, Docket
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