**Meeting Topic: NDAC Meeting on Risks of NSAIDs**

**Background Package Submitted by**

**Wyeth Consumer Healthcare**

# Executive Summary

A joint meeting between the FDA and the Nonprescription Drug Advisory
Committee (NDAC) is scheduled for September 20, 2002. The purpose of the
meeting is to discuss the gastrointestinal (GI) and renal toxicity risks
associated with the use of over-the-counter (OTC) nonsteroidal
anti-inflammatory drugs (NSAIDs) and to determine whether modification
to the current label for these products is necessary to address these
risks.

Wyeth Consumer Healthcare (WCH), the leading manufacturer of OTC
ibuprofen, has prepared an overview of the vast data supporting the
safety and efficacy of OTC ibuprofen. These data show that OTC ibuprofen
has a long history of safe and effective use by consumers, indicating
that the current labeling for OTC ibuprofen has been generally effective
in communicating its appropriate use.

Based on data derived from controlled clinical trials, epidemiology
studies, and safety surveillance data:

-   Not all NSAIDs have the same safety profile;

-   For any NSAID, the risk for developing serious events is related to
    dose and duration of use;

-   Ibuprofen has the most favorable GI safety profile of all NSAIDs;

```{=html}
<!-- -->
```
-   The approved OTC daily dose of ibuprofen (1200 mg/day) is 37.5% of
    the maximum daily prescription dose (3200 mg); the OTC dosing
    regimen of 200 mg to 400 mg has been shown to provide very effective
    analgesia and is designed to allow for flexibility in dosing where
    necessary;

```{=html}
<!-- -->
```
-   When OTC doses of ibuprofen (200-400 mg/dose; 1200 mg/day) are taken
    for acute episodes of pain (i.e., up to 10 days), its GI safety
    profile is even more favorable than at prescription doses, with an
    extremely low risk of causing serious gastrointestinal events;

```{=html}
<!-- -->
```
-   A meta-analysis of epidemiology studies has shown that when
    administered at daily doses of 1500 mg-1800 mg, ibuprofen has a
    relative risk of GI adverse events that is not significantly
    different from that of the general population (RR=1.42, 95% CI 0.93,
    2.15);

-   A case-cohort study specifically designed to estimate the relative
    risk of GI bleeding associated with OTC doses of naproxen sodium and
    ibuprofen evaluated events which occurred within the first 2 weeks
    of dosing among those Medicaid patients whose average daily dose was
    [\<]{.underline} 600 mg/day of naproxen sodium or [\<]{.underline}
    1200 mg/day of ibuprofen. The analysis showed that the incidence of
    GI bleeding associated with both drugs was extremely low (0.012% for
    ibuprofen and 0.026% for naproxen sodium);

-   Over the 18 years that ibuprofen has been available OTC, the Agency
    has received an average of approximately 18 reports per year of GI
    perforations, ulcers or hemorrhage associated with OTC ibuprofen;

```{=html}
<!-- -->
```
-   The frequency of renal side effects with OTC ibuprofen has also been
    shown to be low (less than 2 cases of renal failure per year),
    confirming that nonprescription ibuprofen is well tolerated;

-   Even though for the past eighteen years non-prescription (OTC)
    ibuprofen has been subject to the same post-marketing surveillance
    activities required for prescription drug products, no new,
    significant health risks to the OTC population have been identified;

-   According to data collected and reported by the American Association
    of Poison Control Centers (AAPCC) from 1987 through 2000, ibuprofen
    poses significantly less risk than acetaminophen with respect to
    overdose. Ibuprofen exposures have also resulted in considerably
    less severe outcomes, and many fewer deaths than acetaminophen.

The excellent safety profile of OTC ibuprofen, generated over 18 years
of use by millions of consumers indicates that the current labeling for
OTC ibuprofen has been effective in informing consumers of the
appropriate conditions for using the product. Consumer use data suggests
that the vast majority of consumers follow ibuprofen's label:

-   Data from a 2002 Gallup survey indicate that consumers of OTC
    ibuprofen use an average of only 17.1 pills per month; only 6.5% use
    \> 50 pills/month;

-   In a 1996 Attitude and Usage study conducted over a 10-day period,
    the average number of tablets taken per dose was approximately 2,
    the average number of tablets taken per day was 3.6 (\~720 mg); more
    than 6 tablets per day (\>1200 mg) were taken only 8% of the time.

In preparation for the September NDAC meeting, on August 23, 2002, the
Agency published its review of the GI and renal safety data for
ibuprofen. In their conclusion, the Agency has suggested that
modifications to ibuprofen's label are warranted. On August 21, 2002,
the Agency published a proposal in the Federal Register recommending
that ibuprofen be included in the Tentative Final Monograph for OTC
internal analgesic drug products, thereby recognizing it as being
generally safe and effective. Importantly, the Agency made its
recommendation based on ibuprofen's favorable safety profile, which has
been generated with the **current** OTC label. As part of the Agency's
proposal, they have also provided explicit wording for more specific GI
and renal warnings to the label. As with the label comprehension study
conducted in 1983 prior to the approval of OTC ibuprofen, greater
specificity in the warnings statements may not necessarily prove to be
as effective as the current more general warnings. As such, WCH strongly
recommends that any proposed modifications to the label should be
adequately tested to ensure the proposed changes actually benefit the
consumer. Although WCH has not had sufficient time to consumer test or
evaluate all of the proposed modifications, WCH is fully committed to
working with the Agency on improving the label for all OTC analgesic
products, including ibuprofen, where necessary.

# I. Introduction 

A joint meeting between the FDA and the Nonprescription Drug Advisory
Committee (NDAC) is scheduled for September 20, 2002. The purpose of the
meeting is to discuss the gastrointestinal (GI) and renal toxicity risks
associated with the use of over-the-counter (OTC) nonsteroidal
anti-inflammatory drugs (NSAIDs) and to determine whether modification
to the current label for these products is necessary to address these
risks.

Ibuprofen is a phenylpropionic acid NSAID introduced into the United
States in 1974 as a prescription product intended to treat arthritic
conditions at daily doses of up to 2400 mg. It was subsequently approved
for daily doses of up to 3200 mg/day, and then as a prescription drug to
treat mild to moderate pain in 1978.

Since it became available to consumers in 1984, over 100 billion 200 mg
tablets of ibuprofen have been sold OTC in the United States alone.
Today, consumption of OTC ibuprofen accounts for approximately one third
of the market for OTC analgesics. According to a 2002 study by Kauffman
et al., ibuprofen continues to be one of the most commonly used drugs in
the United States.^1^

In preparation for the September NDAC meeting, on August 23, 2002, the
Agency published its review of the GI and renal safety data for
ibuprofen. In their conclusion, the Agency has suggested that
modifications to ibuprofen's label are warranted. On August 21, 2002,
the Agency published a proposal in the Federal Register to amend the
tentative final monograph (TFM) for OTC internal analgesic, antipyretic
and antirheumatic drug products to include ibuprofen as a generally
recognized safe and effective analgesic/antipyretic active ingredient
for OTC use. The Agency based its recommendation on the very favorable
safety profile of OTC ibuprofen. WCH believes that this long history of
safe and effective use of OTC ibuprofen indicates that the current OTC
labeling has been effective in communicating the appropriate use. As
part of their proposal however, the Agency has recommended the addition
of more specific GI and renal warnings to the label. For the committee's
benefit, WCH has presented the Agency's proposed label changes in this
document as part of the overview of the development of the current OTC
label. WCH looks forward to discussing the proposed changes with the
Agency and welcomes the opportunity to further explore ways to improve
the current label for OTC ibuprofen. As with the label comprehension
study conducted in 1983 prior to the approval of OTC ibuprofen, greater
specificity in the warnings statements may not necessarily prove to be
as effective as the current more general warnings. Accordingly, WCH
believes that prior to implementation, any proposed changes must be
carefully tested to ensure they achieve the desired communication
objective.

Ibuprofen's mode of action, like that of all NSAIDs, is related, in
part, to its ability to inhibit cyclooxygenase, and therefore,
prostaglandin production. Prostaglandins play an important role in
inflammatory processes and pain. They are also involved in maintaining
the integrity of the upper gastrointestinal mucosa, and maintaining
renal function. NSAIDs clearly provide a therapeutic benefit to the vast
majority of individuals. However, in rare instances, usually at
prescription doses, they may also produce GI toxicity, including
bleeding, ulceration, and perforation, and renal side effects, including
renal failure and interstitial nephritis. Accordingly, labeling for all
prescription NSAIDs includes detailed warnings describing these risks.
While it is clear that such class warnings are appropriate for
prescription products, it has become even more clear over the many years
of prescription NSAID use that: a) not all NSAIDs have the same safety
profile; and b) for any given NSAID, the risk for developing serious
events is related to dose and duration of use.

Based primarily on its very favorable GI safety profile at prescription
doses, ibuprofen became the first prescription NSAID to be approved by
the FDA for OTC use as an analgesic in 1984. At the time of the
deliberations that led to its switch, it was anticipated that ibuprofen
would demonstrate an improved GI safety profile when used at lower doses
over brief periods of time. Accordingly, it was approved for use at
single doses of 200-400 mg, up to a maximum of 1200 mg per day. It is
important to note that the OTC dose is 37.5% the minimum daily
prescription dose. Like the other currently marketed monographed
analgesics, the maximum duration for use was limited to 10 days (the
duration of use for prescription NSAIDs is not limited).

Since ibuprofen's approval for consumer use, Wyeth Consumer Healthcare
(WCH), the leading manufacturer of OTC ibuprofen, has continued to
evaluate and assess the efficacy and safety profile of ibuprofen to
expand the knowledge base of the effects and consequences of using
ibuprofen under OTC conditions. Accordingly, WCH has prepared this
document to provide the Agency and the Committee with: a) an overview of
the data supporting the safety and efficacy of OTC ibuprofen, b) a
history of the development of the current OTC label, and c) consumer use
data on OTC ibuprofen.

The data confirm that ibuprofen is the safest prescription NSAID
available, although all NSAIDs demonstrate an increased risk of adverse
events when used chronically at higher prescription doses. More
importantly, as originally expected, when ibuprofen is taken according
to the labeled OTC dose and duration of use, the safety profile is even
better. There are data to show that even at these low doses, OTC
ibuprofen is highly effective in numerous pain states and is more
effective than acetaminophen. The labeled dosing instructions, "take 1
(200 mg) tablet every 4 to 6 hours; if pain or fever does not respond to
1 tablet (200 mg), 2 tablets (400 mg) may be used, but do not exceed 6
tablets in 24 hours" allow for flexibility in dosing where necessary,
and are supported by data demonstrating a dose-response relationship
between 200 mg and 400 mg. As will be shown later in this document,
consumer behavior data confirms that the vast majority of consumers
follow these instructions.

# Efficacy of Ibuprofen 200-400 mg

Over its 24-year history of prescription and OTC use, ibuprofen has been
studied in numerous clinical analgesic trials encompassing a wide
variety of pain conditions including oral surgery pain, general surgery
pain, minor arthritic pain, orthopedic pain, muscle aches, sore throat,
tension headache, migraine headache and dysmenorrhea. The OTC dosage
regimen of 200-400 mg has been evaluated in many of these studies.

Studies in several pain models have shown that ibuprofen 200-400 mg
demonstrates a clinically meaningful, as well as statistically
significant dose-response relationship (Figures 1-3).^2-5^ Both doses
provide effective concentrations (EC~50~) of 6-10 ug/mL ^6,7^ within the
first 30 minutes and reach peak effects in approximately 1-2 hours. The
400 mg dose provides enhanced analgesia that is reflected in both a
greater peak effect and a slightly longer duration of effect compared to
the 200 mg dose. The peak analgesic effect appears to be at or near 400
mg (Figure 4).^7^ When evaluating the switch of ibuprofen from
prescription to OTC status, an important consideration in assessing the
benefit/risk of ibuprofen was evaluating efficacy above the traditional
400 mg dose. A review of the data substantiates that 400 mg of ibuprofen
achieves the maximum peak analgesic effect, as higher doses only
slightly enhance its duration of action. ^7-9^

Figure 1

![](media/image2.wmf)

Figure 2

![](media/image2.wmf)

Figure 3

![](media/image2.wmf)

Figure 4

![](media/image2.wmf)

Many of the acute pain studies evaluating ibuprofen have been performed
with the Dental Impaction Pain Model. This model is widely accepted by
expert analgesiologists as the most sensitive, valid and reliable
paradigm for assessing relative efficacy and dose-response of NSAID
analgesics. Briefly, these studies demonstrate that:

-   Ibuprofen 400 mg is significantly more efficacious than both aspirin
    650 mg^2,10^ and acetaminophen 1000 mg ^11^ (Figures 1-2); its
    benefit is even more impressive in subjects with severe baseline
    pain^12^;

-   Ibuprofen 400 mg is significantly superior to 1000 mg of
    acetaminophen while the 200 mg dose of ibuprofen has been shown to
    be equianalgesic ^3^ (Figure 2);

-   Ibuprofen 400 mg has been shown to provide significantly better
    efficacy than acetaminophen combined with codeine,^13,14^ and to
    provide comparable efficacy to other commonly used narcotic
    combinations: ^15,16^

-   Ibuprofen 400 mg is comparable to rofecoxib 50 mg and has
    statistically significant and clinically superior efficacy compared
    to celecoxib 200 mg over the first 4-6 hours^17,18^ (Figure 5);

-   Ibuprofen is unsurpassed by other NSAIDs (diclofenac,^19^
    ketoprofen,^20^ naproxen sodium^21,22^) at their indicated analgesic
    doses.

In addition to the aforementioned trials in the oral surgery pain model,
ibuprofen 200- 400 mg has also been shown to be highly effective, and
significantly superior to aspirin or acetaminophen in headache
pain,^23,24^ sore throat,^25^ sports injuries^26^ and episiotomy
pain.^27,28^

Figure 5

![](media/image2.wmf)

Ibuprofen has been proven efficacious for a broad variety of painful
conditions. It has a positive dose-response with a higher analgesic
ceiling than either aspirin or acetaminophen. These characteristics
allow for a flexible dosing regimen so that drug exposure can be
titrated to the intensity and duration of the pain being treated.

# III. Ibuprofen Safety

The safety data that have been generated since ibuprofen became
available as an OTC analgesic in 1984 are derived from the following
sources:

-   Clinical trials conducted by Wyeth Consumer Healthcare (WCH);

-   Published literature on the safety and efficacy of ibuprofen;

-   Post-marketing surveillance databases;

-   Exposure data from the American Association of Poison Control
    Centers.

It is important to note that the post-marketing safety surveillance
database for OTC ibuprofen is quite extensive. Given ibuprofen's NDA
status, all adverse drug experience reports received by the manufacturer
since its approval OTC in 1984 have been submitted to FDA. In contrast,
because aspirin and acetaminophen are monographed drugs, their
manufacturers are not required to submit adverse event reports to the
Agency.

## **A. [Gastrointestinal Safety]{.underline}**

> At the time of the deliberations that led to the switch of ibuprofen
> from prescription to OTC status in 1984, the gastrointestinal (GI)
> safety of the drug was thoroughly reviewed and has remained under
> close surveillance ever since. There is a vast body of evidence,
> including data from controlled clinical trials, epidemiology studies,
> and actual consumer use spanning 18 years, which show that: a) while
> there is an increased risk of experiencing serious GI events when
> ibuprofen is taken at prescription doses on a chronic basis, ibuprofen
> has the most favorable GI safety profile of all prescription NSAIDs;
> b) when administered at OTC doses and for a short duration for use
> (i.e., up to 10 days), the GI safety profile of ibuprofen is even more
> favorable, with an extremely low risk of causing serious
> gastrointestinal events, and c) despite close surveillance, no new GI
> adverse effect trends have been identified since ibuprofen became
> available for OTC use in 1984.
>
> **[Controlled Clinical Studies]{.underline}**
>
> The safety of ibuprofen administered at OTC doses (up to 1200 mg/day)
> for up to a maximum of 10 days has recently been studied in three
> prospective, randomized, double-blind clinical trials. While these
> studies had limited power to detect rare, significant adverse events,
> they were useful in evaluating the incidence of more frequently
> occurring, non-serious side effects associated with NSAID use, such as
> "GI upset". The designs of these studies are summarized in Table 1.
>
> The PAIN study, which was conducted by Moore, et al., was designed to
> compare the safety of ibuprofen (1200 mg/day), with aspirin (3000
> mg/day) and acetaminophen (3000 mg/day) in the treatment of acute pain
> in 8677 patients for up to seven days. ^29^
>
> In that trial:

-   Ibuprofen was associated with a significantly lower rate of GI
    complaints compared to both aspirin and acetaminophen (Figure 1);

-   There were no serious GI events with ibuprofen, compared to an
    incidence rate of 0.14% for aspirin, and 0.1% for acetaminophen;

-   The rate of discontinuation was low for all three treatments, and
    lowest for ibuprofen (Figure 2).

> WCH has conducted two Multiple Use Safety and Efficacy Studies (MUST I
> and II), which evaluated the safety of ibuprofen administered at the
> maximum daily OTC dose (1200 mg/day) and duration for use (10
> consecutive days) in subjects representative of the OTC analgesic
> consumer population.^30,31^ MUST study I compared the GI safety
> profile of OTC ibuprofen to placebo in over 1200 subjects, while MUST
> study II compared OTC ibuprofen to celecoxib 200 mg/day, as well as
> placebo, and enrolled over 2200 subjects. As an indirect measure of
> blood loss, fecal samples were collected in both studies and analyzed
> for occult blood. The results from these trials are as follows:

-   The incidence of GI symptoms for ibuprofen was no different from
    placebo in both studies (Figure 6). In addition, the incidence of GI
    symptoms for celecoxib was similar to that of ibuprofen (MUST II).

-   There was one serious GI event in each study;

```{=html}
<!-- -->
```
-   in MUST I, there was one report of GI ulcer, bleeding and
    diverticulitis with ibuprofen. These events were considered
    unrelated to ibuprofen because it was subsequently learned that the
    subject did not take any study medication;

-   in MUST II, there was one report of diverticulitis in a subject who
    had received ibuprofen during the trial. The event was considered
    unrelated to the drug since it occurred 7 days after the completion
    of the study;

```{=html}
<!-- -->
```
-   In both trials, the incidence of subject withdrawal due to an
    adverse event was low, and there were no significant differences
    between treatment groups (Figure 7);

-   In both studies, only 0.5 -- 1.4% of the subjects tested positive
    for fecal occult blood. There were no significant differences among
    the treatments.

Table 1 Overview of Multiple Dose Clinical Trials Evaluating OTC
Ibuprofen Safety

+-----------+-----------+----------+-----------------+------+--------+
| Trial     | P         | Design   | Treatment       | Dura | Sample |
|           | opulation |          | Groups          | tion | Size   |
+-----------+-----------+----------+-----------------+------+--------+
| PAIN      | Patients  | Ran      | ASA 500 mg; up  | 1-7  | 2753   |
| Study^29^ | 18-75     | domized, | to 3000mg/day   | days |        |
|           | requiring | doubl    |                 |      | 2743   |
|           | short     | e-blind, | APAP 500 mg; up |      |        |
|           | term      | parallel | to 3000 mg/day  |      | 2737   |
|           | treatment | group,   |                 |      |        |
|           | for mild  | out      | IBU 200 mg; up  |      |        |
|           | to        | patient, | to 1200 mg/day  |      |        |
|           | moderate  | multiple |                 |      |        |
|           | pain      | dose     |                 |      |        |
+-----------+-----------+----------+-----------------+------+--------+
| MUST      | Consumers | Ran      | IBU tablets     | 10   | 415    |
| Study     | of OTC    | domized, | 1200 mg/day     | days |        |
| I^30^     | a         | doubl    |                 |      | 418    |
|           | nalgesics | e-blind, | IBU liquigels   |      |        |
|           |           | parallel | 1200 mg/day     |      | 413    |
|           |           | group,   |                 |      |        |
|           |           | out      | PBO             |      |        |
|           |           | patient, |                 |      |        |
|           |           | multiple |                 |      |        |
|           |           | dose     |                 |      |        |
+-----------+-----------+----------+-----------------+------+--------+
| MUST      | Consumers | Ran      | IBU 1200 mg/day | 10   | 908    |
| Study     | of OTC    | domized, |                 | days |        |
| II^31^    | a         | doubl    | CBX 200 mg/day  |      | 891    |
|           | nalgesics | e-blind, |                 |      |        |
|           |           | parallel | PBO             |      | 450    |
|           |           | group,   |                 |      |        |
|           |           | out      |                 |      |        |
|           |           | patient, |                 |      |        |
|           |           | multiple |                 |      |        |
|           |           | dose     |                 |      |        |
+-----------+-----------+----------+-----------------+------+--------+

ASA = Aspirin; APAP = Acetaminophen; IBU = Ibuprofen; CBX = Celecoxib

Figure 6

![](media/image3.wmf){width="5.748611111111111in" height="3.4375in"}

Figure 7

![](media/image4.wmf){width="5.397916666666666in"
height="3.509027777777778in"}

> Taken together, the PAIN and MUST studies show that the GI
> tolerability of low dose, short term ibuprofen use is very favorable.
> While the MUST Studies demonstrated that GI tolerability was
> comparable to placebo, the PAIN study indicated that the GI
> tolerability of ibuprofen was superior to aspirin, and comparable to
> acetaminophen. Although OTC ibuprofen is perceived by the medical
> community (perhaps due to their experience with prescription NSAIDs)
> to cause GI upset, these studies clearly demonstrate that this is not
> the case. Although individually, these trials had limited power to
> evaluate the incidence of serious events because of their limited
> sample sizes, taken together, with over 4400 subjects receiving
> ibuprofen, they do provide supportive data that the incidence of
> serious GI events with OTC ibuprofen is very rare and there is an
> absence of occult bleeding.
>
> In addition to ibuprofen's widespread use in adults, it also has a
> long history of safe use in children. Ibuprofen was originally
> approved as a prescription drug for children in 1989, and was switched
> OTC in 1995. In support of its OTC switch, two large scale clinical
> trials were conducted, the Children's Analgesic Medicine Project
> (CAMP),^32^ and the Boston Fever Study.^33^ Both studies focused on
> examining the potential risk of rare, serious events, including GI
> bleeding and renal failure in children treated with ibuprofen. In
> these two studies, over 76,000 of the 114,359 children were treated
> with ibuprofen, while the remaining received acetaminophen. Both
> studies demonstrated that there were no significant differences
> between ibuprofen and acetaminophen in the observed risk of GI
> bleeding, indicating that the treatment of children with ibuprofen for
> acute pain and fever is not associated with an increased risk over
> acetaminophen of serious GI adverse events.
>
> In addition to the clinical trials cited above, ibuprofen has been
> evaluated in hundreds of other clinical trials. It has been one of the
> most thoroughly studied drugs on the market today. Accordingly, over
> the years, there have been four meta-analyses of the safety data from
> numerous single-dose and/or multiple-dose, randomized, double-blind
> clinical trials evaluating OTC doses of ibuprofen in adults.^34-37^
> These evaluations are summarized in Table 2. While there may have been
> some overlap in the data included in these various analyses, which
> consisted anywhere from 878 to 3111 ibuprofen-treated patients, they
> provide additional data indicating that OTC ibuprofen has an excellent
> safety profile in multiple-dose, as well as single-dose use. The
> analyses consistently show that OTC doses of ibuprofen have a
> frequency of GI events similar to placebo, or acetaminophen.

Table 2 Overview of Meta-Analyses of Controlled Clinical Trials to
Evaluate the Safety Profile of OTC Ibuprofen

+------------+---------------+--------------------+-------------------+
| Author     | Scope of      | Treatments (sample | Results           |
|            | Analysis      | size)              |                   |
+------------+---------------+--------------------+-------------------+
| Furey, et  | 15            | IBU 200--400 mg    | Incidence of GI   |
| al.^34^    | double-blind, | (n=878)            | AEs was           |
| (1992)     | randomized,   |                    | comparable for    |
|            | placebo       | APAP 650-1000 mg   | all 3 treatments  |
|            | controlled,   | (n=849)            |                   |
|            | single dose   |                    | IBU=0.9%          |
|            | trials        | PBO (n=852)        |                   |
|            |               |                    | APAP=1.1%         |
|            |               |                    |                   |
|            |               |                    | PBO=0.9%          |
|            |               |                    |                   |
|            |               |                    | No serious GI AEs |
|            |               |                    | reported          |
|            |               |                    |                   |
|            |               |                    | No renal AEs      |
|            |               |                    | reported          |
+------------+---------------+--------------------+-------------------+
| DeArmond,  | 19            | IBU 200-400 mg     | Most Common GI    |
| et al.^35^ | double-blind, | (n=1574)           | AE: Nausea        |
| (1995)     | randomized,   |                    |                   |
|            | single-dose   | PBO (n=1061)       | IBU=2.2%          |
|            | and           |                    |                   |
|            | multiple-dose |                    | PBO=2.1%          |
|            | trials which  |                    |                   |
|            | included IBU  |                    | No serious GI or  |
|            | as comparator |                    | Renal AEs         |
|            |               |                    | reported          |
+------------+---------------+--------------------+-------------------+
| Rainsford, | 96            | IBU (n=3111)       | Incidence of GI   |
| et al.^36^ | double-blind, |                    | AEs with IBU was  |
| (1997)     | randomized,   | APAP (n=5958)      | comparable to     |
|            | single-dose   |                    | APAP              |
|            | and multiple  |                    |                   |
|            | dose trials   |                    | No serious GI or  |
|            |               |                    | renal AEs         |
|            |               |                    | reported          |
+------------+---------------+--------------------+-------------------+
| Kellstein, | 8 randomized, | IBU 800-1200       | Incidence of GI   |
| et al.^37^ | m             | mg/day (n=1094)    | AEs with IBU was  |
| (1999)     | ultiple-dose, |                    | comparable to PBO |
|            | placebo       | PBO (n=1093)       |                   |
|            | controlled    |                    | IBU=12.1%         |
|            | multiple-dose |                    |                   |
|            | trials        |                    | PBO=11.0%         |
|            |               |                    |                   |
|            |               |                    | No renal AEs      |
|            |               |                    | reported          |
+------------+---------------+--------------------+-------------------+

IBU = Ibuprofen; APAP = Acetaminophen; PBO = Placebo

> **[Epidemiology Studies]{.underline}**
>
> Because of their widespread use, there have been many epidemiological
> studies evaluating the relationship between NSAIDs and serious GI
> events. Henry, et. al. recently completed a comprehensive
> meta-analysis of controlled epidemiological studies which used
> **prescription** drug databases to evaluate the relationship between
> NSAID use and hospital admissions for serious GI events.^38^ The
> analyses included 36 case control trials and 8 controlled cohort
> studies which had been completed through June 2001.

-   Sixteen of the case control studies included ibuprofen. The pooled
    relative risk of developing a serious GI event for ibuprofen in
    these studies was 1.81 (95% CI = 1.34, 2.43);

-   Nine of the 16 studies had relative risk 95% confidence intervals
    which included unity;

-   Figure 8 presents the results of pooling the studies which compared
    ibuprofen to a specific NSAID. Using ibuprofen as the reference,
    naproxen, diclofenac, indomethacin, ketoprofen, and piroxicam all
    had a significantly higher relative risk than ibuprofen. Although
    aspirin was shown to be no different from ibuprofen in this
    analysis, it should be noted that in the majority of studies,
    aspirin was taken in low doses for cardioprotection;

```{=html}
<!-- -->
```
-   Seven studies evaluated the relative risks associated with low doses
    and high doses of prescription NSAIDs. Five of these studies
    evaluated ibuprofen. The pooled results from these 5 trials are
    presented in Figure 9 and indicate that the relative risk for
    ibuprofen at lower doses, (defined as [\<]{.underline} 1500 mg in
    some studies, and [\<]{.underline} 1800 mg in others; RR =1.42, 95%
    CI 0.93, 2.15) is significantly reduced compared to higher ibuprofen
    doses (defined in some studies as [\>]{.underline}1500 mg and in
    others as [\>]{.underline}1800 mg; RR = 4.40, 95% CI 2.79, 6.92).
    These results showed that lower doses of ibuprofen were not
    associated with an increased risks of serious GI adverse events,
    which is especially impressive since:

```{=html}
<!-- -->
```
-   The "low doses" of ibuprofen defined in these studies
    ([\<]{.underline} 1500 mg/day in some studies, and [\<]{.underline}
    1800 mg/day in others) were higher than the OTC dose of 1200 mg/day;

-   These studies evaluated data from prescription databases, which
    probably included patients who were chronically taking ibuprofen,
    and who were also likely to have had confounding underlying disease.

Figure 8

![](media/image5.wmf){width="6.450694444444444in"
height="3.509027777777778in"}

  ---------------- -------- ---------- -------- --------- -------- ---------
  \# Studies in    11       18         13       18        13       15
  meta-analysis                                                   

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

 Each Comparison was based on a meta analyses of controlled
epidemiological studies which simultaneously evaluated the drug with IBU

\^ Majority of aspirin use was as intermittent low-doses in analgesia,
or low-dose prophylaxis in CV disease

\*Significantly worse than ibuprofen at 0.05 level

Figure 9

![](media/image6.wmf){width="5.995138888888889in"
height="3.4444444444444446in"}

> Using a prescription database known as ARAMIS (Arthritis, Rheumatism,
> and Aging Medical Information System), Singh, et al. concluded that
> there is an overall increased risk of developing serious GI toxicity
> with OTC doses of NSAIDs.^39^ Even within this dataset based on
> chronic prescription use in patients with significant underlying
> disease, ibuprofen was reported to have a rate of GI hospitalization
> (per 100 patient years) of 0.65, with the 95% confidence interval
> included zero (95% CI 0.0, 1.38).
>
> Blot and McLaughlin published an analysis of the American College of
> Gastroenterology (ACG) bleeding registry to evaluate the potential
> risks of gastrointestinal bleeding associated with OTC NSAIDs. The ACG
> bleeding registry was generated in 1995 by having members of the ACG
> participate in a mail survey, where they provided information in a
> non-randomized, non-blinded manner on up to 10 patients with GI
> bleeding and 10 procedure-matched patients without GI bleeding.^40^ Of
> those patients in the registry who developed GI bleeding, 10.1%
> reported taking OTC doses of ibuprofen, compared to 5.8% of controls.
> The odds ratios were related to the dose of ibuprofen as follows:
> [\<]{.underline} 600 mg per day had a ratio of 1.8 (95% CI 0.8, 4.1),
> while [\<]{.underline} 1200 mg per day had a ratio of 3.5 (95% CI 1.2,
> 10.7). The relevance of these data to true OTC use of ibuprofen is
> unknown, since critical information regarding duration of use was not
> collected, and since the survey was conducted in an uncontrolled,
> non-randomized, non-blinded manner.
>
> To WCH's knowledge, there are no epidemiology studies which have
> specifically evaluated the relative risk of OTC doses of ibuprofen
> administered under OTC conditions (i.e., [\<]{.underline} 10 days).
> This is probably because most databases do not track use of OTC
> products; therefore, the data are not accessible. However, a
> case-cohort study by Strom et al, was specifically designed to
> estimate the relative risk of GI bleeding associated with OTC doses of
> naproxen sodium and ibuprofen by evaluating events which occurred
> within the first 2 weeks of dosing among those Medicaid patients whose
> average daily dose was [\<]{.underline} 600 mg/day of naproxen sodium
> or [\<]{.underline} 1200 mg/day of ibuprofen.^41^

-   The incidence of GI bleeding associated with ibuprofen was 0.012%,
    and 0.026% for naproxen sodium;

-   Compared to ibuprofen, the adjusted relative risk for those using
    naproxen sodium was significantly higher, 2.0 (95% CI 1.1, 3.8).

> It should be noted that the absolute risk for serious GI bleeding was
> extremely low for both drugs.
>
> In addition to the Strom study, the effect of the increased
> availability of OTC NSAIDs on the hospitalization and mortality rates
> from gastrointestinal bleeding and peptic ulcer disease was evaluated
> by Lewis, et al.^42^ As presented in the table below, the
> hospitalization and mortality rates due to these conditions have not
> increased concurrently with the increasing sale of NSAIDs over the
> years.

Table 3 Correlations Between NSAID Sale and Rate of Hospitalization and
Mortality for Peptic Ulcer Disease and GI Bleeding

  ------------- -------------- ----------------- -------------- -----------------
                Mortality from Hospitalization   Mortality from Hospitalization
                Peptic Ulcer   from Peptic Ulcer GI Bleeding    from GI Bleeding
                Disease        Disease                          -

  NSAIDs        -0.17, p=0.65  0.14, p=0.38      -0.67, p=0.96  -0.67, p=0.96

  Aspirin       -0.31, p=0.77  0.33, p=0.21      -0.62,p=0.94   -0.74, p=0.98

  NSAIDs +      -0.24, p=0.71  0.31, p=0.23      -0.81, p=0.99  -0.88, p=0.99
  Aspirin                                                       
  ------------- -------------- ----------------- -------------- -----------------

> In the aggregate, the vast amount of epidemiological data indicates
> that ibuprofen is quite safe, even at prescription doses. More
> importantly, from the epidemiological data that approximates OTC use,
> it appears that the incremental risk of serious GI events from OTC
> ibuprofen is extremely low relative to the background incidence of GI
> bleeds.
>
> **[Ibuprofen GI Safety Surveillance Data]{.underline}**
>
> Data from FDA's spontaneous reporting system for all single ingredient
> ibuprofen products from the period May 1984 through March 2002 have
> been reviewed. The data presented here include only the reports of
> adverse events associated with the administration of ibuprofen for ten
> days or less, at doses of 1200 mg/day or less, and in subjects 12
> years of age or older, with no use of concomitant drugs reported
> (reports where any information was missing were also included). Note:
> The Agency's review of ibuprofen GI safety surveillance data (provided
> to the public on August 23, 2002) was limited to the cases reported to
> FDA from January 1, 1998 through December 31, 2001.
>
> Over the 18-year period, a total of 5042 adverse event reports have
> been received for ibuprofen. Of these, 15.2% (n = 768) were serious,
> and of the serious reports, 42% (n = 324) possessed at least one GI
> system term (\~ 18 serious GI events/year). Clinically significant
> reports, such as GI bleeding and perforation (n = 71) were infrequent
> over the 18-year reporting period. Of the 324 serious GI reports
> received during this 18-year period, an outcome of death was noted in
> four, presumably due to GI bleeding. Three of those who died were
> between the ages of 72-94. The age of the fourth individual was not
> provided. One patient had been taking 1200 mg/day of ibuprofen for an
> unknown period at the time of death. Dosing information for the other
> three deaths was not available.

When data including those who took concomitant medication were examined,
there was a total of 62 deaths involving GI bleeding (including the 4
patients cited above). Twenty-five of these patients had been taking
ibuprofen 1200 mg/day or less, 19 males and 6 females. Most of these
patients (n=18) were [\>]{.underline} 65 years of age, and seven had
been taking aspirin concomitantly. For the remaining 37 cases, ibuprofen
dosing information was not provided. Nine of these patients were male,
15 were female, and the gender of 13 patients was not provided. Of the
25 patients whose age was provided, 20 were [\>]{.underline} 65 years
old. Twelve of the 37 patients had also been taking low dose aspirin
and/or another NSAID (in addition to ibuprofen).

> Two decades of postmarketing experience in the United States have
> established that the reporting frequency of serious GI events has
> remained consistently low during this time, suggesting that OTC
> ibuprofen is well tolerated in the general population.

## **B. [Renal Safety]{.underline}**

All NSAIDs can produce a variety of adverse effects on the kidney. While
there is little threat of renal insult with NSAIDs in normal, healthy
individuals, risks may be increased in the elderly, in those who are
dehydrated, and in those with underlying renal disease. The risk of
certain types of renal toxicity may increase with the dose and duration
of NSAID use.

Almost three decades of postmarketing experience with
prescription-strength ibuprofen in the United States and worldwide,
during which over 100 billion doses have been administered, has shown
the \[reporting\] frequency of renal side effects to be low. Post
marketing experience with non-prescription ibuprofen confirms its safety
in the general population. Safety data from controlled clinical trials
add further assurance that non-prescription doses of ibuprofen are well
tolerated by the kidneys.

The foregoing publicly-available information has been extracted from the
original Citizen's Petition to request monograph status for ibuprofen
(July 1997), and two updates (through 2001). The published OTC
experience of ibuprofen during the past 18 years is consistent with a
very safe profile with respect to the renal system. Despite the National
Kidney Foundation's first consensus statement published in 1984, a more
recent statement in 1996, and a public FDA feedback meeting on the
subject, the dire renal consequences which were forecasted with the OTC
availability and use of ibuprofen have not materialized. When used as
directed, the potential of OTC ibuprofen to cause renal problems is
extremely low.

**[Controlled Clinical Trials]{.underline}**

> **Prescription Doses**

As shown in the following table, several studies indicate that under
prescription use, ibuprofen is not commonly associated with adverse
renal function in those without underlying renal disease. These findings
suggest that, even at higher doses and longer duration of use, ibuprofen
therapy is not commonly associated with adverse renal effects.

Table 4. Controlled Clinical Trials with Ibuprofen in Patients without
known Underlying Renal Disease

+-------------+----------+-----------+---------------+-----------------+
| **Au        | **No.    | **Daily   | **Duration**  | **Outcome**     |
| thor/Year** | Pa       | Dose**    |               |                 |
|             | tients** |           |               |                 |
+-------------+----------+-----------+---------------+-----------------+
| Bradley,    | 62       | 1200 mg   | 4 weeks       | No significant  |
| 1991^43^    |          |           |               | effect on renal |
|             |          |           |               | function        |
+-------------+----------+-----------+---------------+-----------------+
| Cummings    | 52       | 1600 mg   | 6 weeks       | No significant  |
| 1988^44^    |          |           |               | effect on renal |
|             | (63-87   |           |               | function        |
|             | years)   |           |               |                 |
+-------------+----------+-----------+---------------+-----------------+
| Fox,        | 8412     | Rx doses  | in-patients = | No significant  |
| 1984^45^    |          |           | 12 days       | effect on renal |
|             |          |           |               | function        |
|             |          |           | out-patients  |                 |
|             |          |           | ≥ 5 Rx/yr     |                 |
+-------------+----------+-----------+---------------+-----------------+
| Bonney,     | 182      | 1200-2400 | Up to 1 year  | 2 reports of    |
| 1986^46^    |          | mg        |               | elevated BUN or |
|             |          |           |               | creatinine:     |
|             |          |           |               | clinically      |
|             |          |           |               | asymptomatic    |
+-------------+----------+-----------+---------------+-----------------+

> **OTC Doses**

As previously discussed under the GI Safety section of this document,
the safety of ibuprofen administered at OTC doses (up to 1200 mg/day)
for up to a maximum of 10 days was studied in three independent,
prospective, randomized, double-blind clinical trials (the PAIN Study,
MUST I and MUST II Studies).^29-31^ While these studies individually had
limited power to detect rare, significant adverse events, taken
together, 4478 individuals received ibuprofen, without a single incident
of a serious renal event. Similarly, in the two large scale studies that
were conducted in children (CAMP and the Boston Fever Study), where over
76,000 children received ibuprofen, there was no occurrence of acute
renal failure.^32,33^

In addition, there have been several studies conducted on the safety of
OTC ibuprofen in those at risk for developing renal effects. These
studies are presented in Table 5 and show that renal effects, if any,
were reversible after discontinuation of drug.

Table 5. Controlled Studies Evaluating Renal Safety of OTC Ibuprofen in
At-Risk Individuals

+--------+------------+----------+--------+--------------------------+
| **Aut  | **Age/Sex  | **Daily  | **Dura | **Comments/Outcome**     |
| hor/** | or \# of   | Dose**   | tion** |                          |
|        | patients** |          |        |                          |
| **     |            |          |        |                          |
| Year** |            |          |        |                          |
+--------+------------+----------+--------+--------------------------+
| Stosic | 55         | 1200 mg  | 7 days | Ibuprofen caused a       |
|        | patients   |          |        | significant decrease in  |
| 19     | with hx of |          |        | GFR and renal plasma     |
| 95^47^ | reduced    |          |        | flow.                    |
|        | renal      |          |        |                          |
|        | function   |          |        |                          |
+--------+------------+----------+--------+--------------------------+
| Furey  | 8 elderly  | 1200 mg  | 7 days | No change in renal       |
|        | patients   |          |        | function.                |
| 19     |            |          |        |                          |
| 93^48^ |            |          |        |                          |
+--------+------------+----------+--------+--------------------------+
| Fa     | 12         | 1200 mg  | 1 day  | Ibuprofen had a small,   |
| rquhar | healthy,   |          |        | but statistically        |
|        | exercised  |          |        | significant effect on    |
| 19     | induced    |          |        | glomerular filtration    |
| 99^49^ | kidney     |          |        | rate compared to placebo |
|        | stress     |          |        | (73.5 ± 5 vs 82 ± 5      |
|        |            |          |        | mL/min, respectively).   |
+--------+------------+----------+--------+--------------------------+
| S      | 18/F       | 4        | 2 days | Reduced creatinine       |
| heiner |            | tablets  |        | clearance which reversed |
|        |            | (        |        | after drug was           |
| 19     |            | unknown) |        | discontinued             |
| 94^50^ |            |          |        |                          |
+--------+------------+----------+--------+--------------------------+
|        | 17/F       | 1200 mg  | 1 day  | Eleveated creatinine,    |
|        |            |          |        | oliguric. Reversed after |
|        |            |          |        | ibuprofen was            |
|        |            |          |        | discontinued.            |
+--------+------------+----------+--------+--------------------------+

**[Meta Analyses of Controlled Clinical trials]{.underline}**

> **Prescription Doses**
>
> A comparison of adverse renovascular experiences among 8460
> osteoarthritis patients treated with the selective COX-2 inhibitor
> rofecoxib 25-12.5 mg/day or ibuprofen 2400 mg/day (n=1902) established
> that rofecoxib was generally similar to ibuprofen.^51^ In that trial,
> the relative rates of renal events per 100 patient months of exposure
> (with 95% CI) in those who received ibuprofen were as follows:

-   Acute renal failure: 0.1 (0.0, 0.2)

-   Elevated serum creatinine: 0.5 (0.2, 0.8)

-   Incidence of hypertension AEs: 1.3 (0.8,1.8)

-   Incidence of lower extremity edema AEs: 1.7 (1.1, 2.3)

A recently published meta analysis of 14 trials by the Cochrane group
reviewed the effect of NSAIDs on post-operative renal function in normal
adults. The authors concluded that NSAIDs should not be withheld from
adults with normal pre-operative renal function because of concerns
about post-operative renal impairment.^52^

> **OTC Doses**
>
> As was discussed under the GI Safety section of this document, there
> have been 4 meta-analyses of the safety data from numerous single-dose
> and/or multiple-dose, randomized, double-blind clinical trials
> evaluating OTC doses of ibuprofen in adults.^34-37^ These analyses are
> summarized in Table 2. There were no instances of serious renal
> effects reported in any of these analyses, providing additional data
> indicating that OTC ibuprofen has an excellent renal safety profile in
> short term, multiple-dose, as well as single-dose use.

**[Case Reports]{.underline}**

To WCH's knowledge, the literature contains very few case reports of
renal dysfunction associated with ibuprofen administered at OTC dosage
and duration in those without underlying renal disease.

As presented in Table 6, there are 7 case reports of renal dysfunction
in patients without underlying renal illness who had taken ibuprofen,
but the dosage that had been taken was either higher or longer than the
OTC dose. Following appropriate medical management, normal renal
function was restored in all of these patients.

Table 6. Case Reports of Renal Dysfunction in Those Without Underlying
Disease Who Had Taken Ibuprofen

  ------------------ ------------- ------------ -------------- ---------------------------------
  **Author/Year**    **Age/Sex**   **Dose**     **Duration**   **Comments/Outcome**

  Elasser,1998^53^   19/F          1600 mg/day  6 days         Elevated BUN, creatinine.
                                                               Decreased urine output.
                                                               Improvement seen after d/c
                                                               ibuprofen, spironolactone.

  Johnson,1995^54^   22/F          1200 mg      single dose    Elevated BUN, creatinine. Acute
                                   (heavy                      renal failure was reversed.
                                   alcohol                     
                                   intake the                  
                                   evening                     
                                   prior)                      

  Moss, 1986^55^     43/M          600 mg/day   2 days         Acute renal failure treated with
                                                               hemodialysis, prednisone.

  Marasco, 1987^56^  45/M          800 mg/day   \~ 5 weeks     Tubulointerstitial nephritis
                                                               reversed after d/c ibuprofen with
                                                               hemodialysis,methylprednisolone
                                                               tx.

  McIntire, 1993^57^ 12/F          600 mg, then Unknown        Acute renal failure. Reversed.
                                   200 mg q6h                  

  Wattad, 1994^58^   14/F          600 mg       Single dose    Nonoliguric acute renal failure.
                                                               Reversed after prednisone
                                                               treatment.

  Fernando, 1994^59^ 76/M          4 tablets    Single dose    Acute anuric renal failure.
                                   (unknown)                   Recovered after hemodialysis

                                   Topical      Single dose    Acute anuric renal failure.
                                                               Recovered with hemodialysis and
                                                               methylprednisolone treatments
  ------------------ ------------- ------------ -------------- ---------------------------------

Table 7 presents two summaries of case reports and two individual case
reports wherein a total of 14 patients with underlying renal disease
experienced various additional renal functional abnormalities and
changes associated with OTC doses of ibuprofen.

Table 7. Case Reports of Adverse Renal Effects with OTC Ibuprofen in
Those With Underlying Renal Disease

+--------+----------+-------+-------+--------------------------------+
| **Aut  | *        | **    | **    | **Comments/Outcome**           |
| hor/** | *Age/Sex | Daily | Durat |                                |
|        | or \# of | D     | ion** |                                |
| **     | pa       | ose** |       |                                |
| Year** | tients** |       |       |                                |
+--------+----------+-------+-------+--------------------------------+
| S      | 73/M     | 600mg | 1     | Acute renal failure with       |
| pierto |          |       | week  | digoxin toxicity. Reversed     |
|        |          |       |       | after discontinuation of drug. |
| 19     |          |       |       |                                |
| 92^60^ |          |       |       |                                |
+--------+----------+-------+-------+--------------------------------+
| At     | 22/F     | 1200  | 6     | Elevated creatinine, acute     |
| kinson |          | mg    | days  | renal failure. Reversed after  |
|        |          |       |       | ibuprofen was discontinued.    |
| 19     |          |       |       |                                |
| 86^61^ |          |       |       |                                |
+--------+----------+-------+-------+--------------------------------+
| W      | 2        | 2400  | 11    | Elevated creatinine levels,    |
| helton | patients | mg    | days  | acute renal failure,           |
|        |          |       |       | asymptomatic, reversed after   |
| 19     |          |       |       | ibuprofen was discontinued.    |
| 90^62^ |          |       |       |                                |
+--------+----------+-------+-------+--------------------------------+
| Ciab   | 10       | 1200  | 1     | Elevated mean creatinine,      |
| ottoni | patients | mg    | week  | decreased mean creatinine      |
|        |          |       |       | clearance. Reversed after      |
| 19     |          |       |       | ibuprofen was discontinued.    |
| 84^63^ |          |       |       |                                |
+--------+----------+-------+-------+--------------------------------+

**[Epidemiology Studies]{.underline}**

Many of the epidemiological studies report on NSAIDs as a class and do
not report specific data for ibuprofen. Studies that specifically
mention ibuprofen generally provide little information on dose or
duration of use. For example, Sandler, et al. and Perneger, et al.
included NSAIDs in their case control studies to examine renal
dysfunction and end-stage renal disease, respectively.^64,65^ Neither
study provided specific data on dose or duration of ibuprofen use.

A study by Rexrode, et al. examined whether analgesic use is associated
with a risk of renal dysfunction.^66^ This cohort study included 11,032
previously healthy men who provided blood samples and a self-report of
analgesic consumption. The main outcome measures during this 14-year
study of men 40-84 years were elevated creatinine levels( ≥1.5 mg/dL), a
reduced creatinine clearance (≤55 mL/min), and self-reported use of
acetaminophen, aspirin, and NSAIDs (never \[\<12 pills\], 12-1499 pills,
1500-2499 pills, and ≥ 2500 pills). Mean creatinine levels and clearance
were similar between the groups that used analgesics and those who did
not, even in use \>2500 pills. Multivariate analysis (adjusted for age,
body mass, history of hypertension, elevated cholesterol, diabetes,
cardiovascular disease, physical activity, use of other analgesics)
indicated that the relative risks of elevated creatinine levels
associated with intake of ≥ 2500 pills were 0.83 (95% C.I. 0.50-1.39)
for acetaminophen, 0.98 (95% C.I. 0.53-1.81) for aspirin, and 1.07 (95%
C.I. 0.71-1.64) for other NSAIDs. No association was observed between
analgesic use and reduced creatinine clearance. The authors concluded
that the moderate use of analgesics in a cohort of initially healthy men
was not associated with increased risk of renal dysfunction.

Griffin, et al., reviewed the records of 1,799 patients [\>]{.underline}
65 years old enrolled in the Tennesse Medicaid program from 1987-1991
who had acute renal failure.^67^ Of the 1,799 patients, 18.1% were
current users of NSAIDs. Ibuprofen accounted for 35% of the NSAID users.
The associated risk of acute renal failure in ibuprofen users was
evidenced by increasing odds ratios by dose [\<]{.underline}1200 mg
(0.94), \>1200 mg-[\<]{.underline}2400 mg (1.89), \>2400 mg (2.32).

Murray, et al. conducted a cohort study of 1908 prescription ibuprofen
users and 3933 acetaminophen users from the medical records system of
Indiana University Hospital during 1975-1986.^68^ The authors included a
population with multiple concomitant medical problems in an attempt to
identify subgroups who might be at increased risk. Blood creatinine
levels \>20 mg/L developed in 0.9% of the group receiving prescription
ibuprofen. There was no significant difference in the incidence of renal
impairment between acetaminophen and ibuprofen users except in those ≥
65 years of age (relative risk = 1.3 in ibuprofen users, 95% C.I.=
1.1-1.7).

Radford conducted a retrospective chart review of the Mayo Clinic
records for the years 1975-1995 to investigate the frequency of
membranous nephropathy associated with NSAID use. ^69^ Of 125 patients
identified with the early stages of this condition, the three that were
taking ibuprofen had a duration of use from one to nine months, which
far exceeds the recommended duration of OTC use.

Pospishil studied the renal biopsies of previously normal patients who
developed renal complications after treatment with NSAIDs including OTC
ibuprofen.^70^ While information on dosages was not provided, the
authors noted that the patients who developed renal symptoms had, in
general, used NSAIDs for prolonged periods of time, ranging from 3
months to seven years.

**[Safety Surveillance Data]{.underline}**

As mentioned previously, data from FDA's spontaneous reporting system
for all single ingredient ibuprofen products from the period May 1984
through March 2002 have been reviewed. The data presented here include
only the reports of adverse events associated with the administration of
ibuprofen for ten days or less, at doses of 1200 mg/day or less, and in
subjects 12 years of age or older, with no use of concomitant drugs
reported (reports where any information was missing were also included).
Note: The data that was included in the Agency's review of ibuprofen
renal safety surveillance data (provided to the public on August 23,
2002) included reports submitted to FDA from May 1984 through August 9,
1999.

Of a total of 768 serious adverse event reports received in the last 18
years of post marketing surveillance for OTC ibuprofen, 93 contained at
least one adverse event term related to the urogenital system. Of these,
there were 26 reports of renal failure. This represents less than two
cases reported each year during the OTC availability of ibuprofen, an
extremely low reporting frequency that supports the adequacy of the
current labeling. Additionally, none of these renal events resulted in
death during this time period.

When data including those who took concomitant medication were examined,
there were 10 deaths involving renal failure, seven females and three
males. Six of the individuals were [\>]{.underline}68 years of age, and
six were taking at least three other medications (in addition to
ibuprofen), at the time of death. Given the limited amount of
information available, it is not clear whether renal failure was a
pre-treatment event, whether it was related to taking the other
medications, related to another medical condition, or related to taking
ibuprofen.

## **C. [Safety in Overdose]{.underline}**

At the time ibuprofen was approved for OTC use, it was generally
recognized that it posed significantly less risk than either
acetaminophen or aspirin with respect to overdose. As is evident by data
collected and reported by the American Association of Poison Control
Centers (AAPCC) from 1987 through 2000, this continues to be the case.
Ibuprofen exposures have resulted in the less severe outcomes, and fewer
deaths, compared to aspirin and acetaminophen. During this timeframe,
there have been only 49 fatalities from 528,396 reports of ibuprofen
overdose (a rate of 0.009%), compared to 769 fatalities resulting from
978,014 reports of acetaminophen overdose (a rate of 0.079%) and 576
fatalities resulting from 221,356 reports of aspirin overdose (a rate of
0.26%).

# IV. Devlopment of Labeling for OTC Ibuprofen

As previously mentioned, the labeling for all prescription NSAIDs
includes detailed warnings about GI and renal toxicity. As the risk of
these toxicities is dependent upon the drug, dose, and duration of use,
ibuprofen was switched from prescription to OTC status based on:

-   its favorable safety profile at prescription doses;

-   the proposed maximum daily OTC dose of 1200 mg per day was less than
    one half of the approved maximum daily prescription dose (3200 mg),
    which was expected to pose minimal risks to consumers;

-   the approved single dose of 200-400 mg was shown to a very effective
    analgesic and was designed to allow for flexibility in dosing where
    necessary

While drugs that are granted OTC status are felt to pose minimal safety
risks to consumers, no drug is entirely safe. Therefore, the labeling
for OTC drugs should clearly communicate the intended target population,
indications for treatment, dosing instructions, populations at risk,
potential harmful outcomes, and what to do should there be a harmful
outcome. At the same time, labels should not be so overloaded with
information as to dilute the information consumers need to read.

Labeling for prescription products (including NSAIDs) is lengthy and
very detailed because it is primarily designed to provide the physician
or learned intermediary with as much information as possible about the
drug so that he/she can select the appropriate drug and provide
appropriate counsel the patient. On the other hand, labeling for OTC
products is intended for the consumer. The current labeling for OTC
ibuprofen is based on data from a study designed by FDA. During the
approval process, there was lengthy consideration by the Agency of
whether potential consumer confusion and associated problems might occur
with the introduction of this entirely new OTC analgesic. FDA took the
unusual step of forming a multi-disciplinary internal task force to
advise on the development of labeling for OTC ibuprofen. During the
group's deliberations, it became evident that there were divergent views
about how to most effectively communicate the warnings and precautions
to consumers. Two different labels were developed reflecting the
disparate views of the task force. One version was more general and
indicated in broad terms when a consumer should consult a physician. The
second version was more specific and listed nearly all the diseases and
conditions that would require a user to consult a physician before use.
Following a protocol developed by the Agency, the labels were tested in
a mall intercept study involving 300 consumers from 13 locations
throughout the US.

Results of the study were discussed in the Medical Officer's Review for
the sponsor NDAs. Interestingly, many of the more general warning
statements were better understood by consumers than the more specific
ones. Subjects receiving the more specific label were more likely to
self-diagnose their medical condition and determine the suitability for
using ibuprofen without consulting a physician. However, those seeing
the more general version were more likely to consult their doctor as a
source of information about using the product rather than make a
decision about taking the drug on their own. Based on the results of the
research, the task force arrived at labeling they believed combined the
better portions of each of the versions. As agreed to with the Agency,
Sponsors provided educational campaigns for consumers and health
professionals to make sure that aspirin sensitive individuals were
suitably informed about OTC ibuprofen. Sponsors also worked with the
Agency to create educational materials to promote safe and effective use
of OTC ibuprofen.

Over the past 18 years, the labeling for OTC ibuprofen has been revised
to include several new warnings. In 1986 when generic ibuprofen products
came on the market, a warning was added to state clearly that the
product should not be used with any other ibuprofen-containing product.
In 1990, the Agency required sponsors to capitalize the statement "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." This was implemented as a precautionary step by the
Agency and, to the best of WCH's knowledge, was not in response to a
specific incident or complaints from health care professionals.

In 1998, the Agency amended its regulations to require a revised allergy
warning for NSAID drug products. OTC ibuprofen had included a warning
for "ASPIRIN SENSITIVE PATIENTS" since the time of approval in 1984.
Under the new regulation, this warning was replaced with the following:

> **Allergy alert:** ibuprofen may cause a severe allergic reaction
> which may include:

-   hives •facial swelling • asthma (wheezing) • shock

> **Do not use** if you have ever had an allergic reaction to any other
> pain reliever/fever reducer.
>
> **Stop use and ask a doctor if** an allergic reaction occurs. Seek
> medical help right away.

Additionally, in 1998, the Agency issued a regulation requiring an organ
specific alcohol warning on all OTC analgesic products. The following
warning was added to OTC ibuprofen labeling:

> **Alcohol warning:** If you consume 3 or more alcoholic drinks every
> day, ask your doctor whether you should take ibuprofen or other pain
> relievers/fever reducers. Ibuprofen may cause stomach bleeding.

In May 2002, the drug facts rulemaking became effective for many OTC
drug products. This rulemaking requires a bulleted format and a standard
order or presentation of information on the label for all OTC products.
Wyeth Consumer Healthcare has revised Advil labeling to the required
format. The "Warnings" and "Directions for Use" sections of the current
label are presented below, and include specific statements that aid the
consumer in using the product safely.

***Warnings***

**Allergy alert:** Ibuprofen may cause a severe allergic reaction which
may include:

> • hives • facial swelling • asthma (wheezing) • shock

**Alcohol warning:** If you consume 3 or more alcoholic drinks every
day, ask your doctor whether you should take ibuprofen

or other pain relievers/fever reducers. Ibuprofen may cause stomach
bleeding.

**Do not use** if you have ever had an allergic reaction to any other
pain reliever/fever reducer

**Ask a doctor before use if you have**

-   had problems or side effects with any pain reliever/fever reducer

-   stomach pain

**Ask a doctor or pharmacist before use if you are**

-   under a doctor's care for any continuing medical condition

-   taking other drugs on a regular basis

-   taking another product containing ibuprofen, or any other pain
    reliever/fever reducer

**When using this product** take with food or milk if stomach upset
occurs

**Stop use and ask a doctor if**

-   an allergic reaction occurs. Seek medical help right away.

-   fever gets worse or lasts more than 3 days

-   pain gets worse or lasts more than 10 days

-   stomach pain occurs with the use of this product

-   the painful area is red or swollen

-   any new or unexpected symptoms occur

**If pregnant or breast-feeding,** ask a health professional before use.
It is especially important not to use ibuprofen 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.

**Keep out of reach of children.** In case of overdose, get medical help
or contact a Poison Control Center right away.

> ***Directions***

-   do not take more than directed

-   adults: take 1 tablet every 4 to 6 hours while symptoms occur

-   if pain or fever does not respond to 1 tablet, 2 tablets may be
    used, but do not

exceed 6 tablets in 24 hours, unless directed by a doctor

-   the smallest effective dose should be used

-   children: do not give to children under 12 unless directed by a
    doctor

As previously mentioned, on August 21, 2002, the Agency published a
proposal in the Federal Register to amend the tentative final monograph
(TFM) for OTC internal analgesic, antipyretic and antirheumatic drugs to
include ibuprofen as a generally recognized safe and effective
analgesic/antipyretic for OTC use. The Agency based its recommendation
on the very favorable safety profile of OTC ibuprofen. Importantly, this
safety profile has been generated from ibuprofen's current OTC label. As
part of their proposal however, the Agency has recommended the addition
of more specific GI and renal warnings to the label as follows:

+-----------------------------------------------------------------------+
| ####### Warnings                                                      |
|                                                                       |
| > **Allergy alert:** Ibuprofen may cause a severe allergic reaction   |
| > which may include:                                                  |
| >                                                                     |
| > • hives • facial swelling • asthma (wheezing) • shock               |
| >                                                                     |
| > **Alcohol warning:** If you consume 3 or more alcoholic drinks      |
| > every day, ask your doctor whether you should take ibuprofen or     |
| > other pain relievers/fever reducers. Ibuprofen may cause stomach    |
| > bleeding.                                                           |
+-----------------------------------------------------------------------+
| > **Do not use** if you have ever had an allergic reaction to any     |
| > other pain reliever/fever reducer                                   |
|                                                                       |
| ########                                                              |
|                                                                       |
| ######## Ask a doctor before use if you have                          |
|                                                                       |
| ######## ~~had~~ problems or [serious]{.unde                          |
| rline} side effects ~~with any~~ [from taking]{.underline} pain relie |
| ver[s]{.underline}~~/~~ [or]{.underline} fever reducer[s]{.underline} |
|                                                                       |
| -   stomach ~~pain~~ [problems that last or come back, such as        |
|     heartburn, upset stomach, or pain]{.underline}                    |
|                                                                       |
| -   [ulcers]{.underline}                                              |
|                                                                       |
| -   [bleeding problems]{.underline}                                   |
|                                                                       |
| -   [high blood pressure, heart or kidney disease, are taking a       |
|     diuretic, or are over 65 years of age]{.underline}                |
|                                                                       |
| #########                                                             |
|                                                                       |
| ######### Ask a doctor or pharmacist before use if you are            |
|                                                                       |
| -   under a doctor's care for ~~any continuing medical~~ [any         |
|     serious]{.underline} condition                                    |
|                                                                       |
| -   ~~taking other drugs on a regular basis~~                         |
|                                                                       |
| -   taking ~~another~~ [any other]{.underline} product                |
|     [that]{.underline} contains~~ing~~ ibuprofen, or any other pain   |
|     reliever/fever reducer                                            |
|                                                                       |
| -   [taking a prescription drug for anticoagulation (blood            |
|     thinning)]{.underline}                                            |
|                                                                       |
| -   [taking any other drug]{.underline}                               |
|                                                                       |
| **When using this product** take with food or milk if stomach upset   |
| occurs                                                                |
|                                                                       |
| ######## 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 [gets worse or lasts]{.underline} ~~occurs with the  |
|     use of this product~~                                             |
|                                                                       |
| -   [redness or swelling is present in]{.underline} the painful area  |
|     ~~is red or swollen~~                                             |
|                                                                       |
| -   any new ~~or unexpected~~ symptoms [appear]{.underline} ~~occur~~ |
|                                                                       |
| > **If pregnant or breast-feeding,** ask a health professional before |
| > use. It is especially important not to use ibuprofen 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.                                      |
|                                                                       |
| **Keep out of reach of children.** In case of overdose, get medical   |
| help or contact a Poison Control Center right away.                   |
|                                                                       |
| > ***Directions***                                                    |
|                                                                       |
| -   **do not take more than directed**                                |
|                                                                       |
| -   adults [and children 12 years and over]{.underline}: take 1       |
|     tablet every 4 to 6 hours while symptoms ~~occur~~                |
|     [persist]{.underline}                                             |
|                                                                       |
| -   if pain or fever does not respond to 1 tablet, 2 tablets may be   |
|     used~~, but do no~~                                               |
|                                                                       |
| -   [do not]{.underline} exceed 6 tablets in 24 hours, unless         |
|     directed by a doctor                                              |
|                                                                       |
| -   the smallest effective dose should be used                        |
|                                                                       |
| ```{=html}                                                            |
| <!-- -->                                                              |
| ```                                                                   |
| -   children [under 12 years:-ask a doctor ~~do not give to children  |
|     under 12 unless directed by a doctor~~]{.underline}               |
+-----------------------------------------------------------------------+

WCH looks forward to working with the Agency to evaluate the current, as
well as alternate proposals for improving the label. As with the label
comprehension study conducted in 1983 prior to the approval of OTC
ibuprofen, greater specificity in the warnings statements may not prove
to be as effective as the current more general warnings.

# V. Consumer Use Data

As previously mentioned, WCH believes its labeling for OTC ibuprofen has
been effective in communicating the appropriate use of this product. In
addition to the very favorable safety profile that has been generated
since it became available OTC, this is also supported by the following
consumer use data which shows that few consumers exceed recommended
doses.

In an Attitude and Usage study conducted over a 10-day period in
1996:^71^

-   the average number of tablets taken per dose was approximately 2

```{=html}
<!-- -->
```
-   consumers took [\>]{.underline} 3 tablets 11% of the time

-   the average number of tablets taken per day was 3.6 (\~720 mg)

-   more than 6 tablets per day (\>1200 mg) were taken only 8% of the
    time.

> In a 30-day actual use study conducted in 3094 individuals with a
> history of using OTC analgesics who were provided with sufficient
> study medication for 10 days (60 pills):^72^

-   1.23% took more than 2 ibuprofen tablets per dose

```{=html}
<!-- -->
```
-   7.5% took more than 6 ibuprofen tablets in 24 hours

-   3.72% took ibuprofen for more than 10 days for pain or for more than
    3 days for fever

Data from a 2002 Gallup survey indicate that consumers of OTC ibuprofen
use an average of 17.1 pills per month.^73^

-   36% use 1-4 pills/month

-   21% use 5-8 pills/month

-   30% use 9-29 pills/month

-   14% use [\>]{.underline} 30 pills/month

```{=html}
<!-- -->
```
-   7.6% use 30- 50 pills/month

-   4.1% use 51-100 pills/month

-   1.6% use 101-180 pills/month

-   0.8% use \> 180 pills/month

Survey data in 2002 indicate that about 65% of Advil's pill volume comes
from those 18 to 49 years of age, and 10% from those 65 years or older.
The major uses of the brand are: 34% for headache, 21% for arthritis
pain, and 16% for muscle aches and pains.

# VI. Conclusions

Since ibuprofen's approval for OTC use in 1984, its safety profile has
continued to be closely investigated, evaluated and assessed by WCH.
While no drug, even if it is OTC, is completely safe, there is a vast
amount of data indicating a very low risk of developing serious GI or
renal toxicity when OTC ibuprofen is used according to the labeled
dosing instructions (i.e. 200-400 mg every 4 -- 6 hours, up to 1200 mg
per day, for up to 10 days). Because it is critical that consumers
follow the labeled dosing instructions for any drug, WCH has worked very
closely with FDA in developing the current label for OTC ibuprofen. WCH
believes that the long history of safe and effective use of OTC
ibuprofen indicates that this labeling has been generally effective in
communicating its appropriate use. We have presented consumer behavior
data confirming that the vast majority of consumers follow the labeled
instructions. While the Agency has recommended that ibuprofen be
included in the Tentative Final Monograph, thereby recognizing it as
being generally safe and effective, they have also proposed the addition
of more specific GI and renal warnings to the label. Although WCH has
not had sufficient time to consumer test or evaluate all of the proposed
modifications, WCH is fully committed to working with the Agency on
improving the label for all OTC analgesic products, including ibuprofen,
where necessary. As in the past, WCH strongly believes that any proposed
modifications to the label should be adequately tested to ensure the
proposed changes actually benefit the consumer.

**[References]{.underline}**

1.  Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent
    Patterns of Medication Use in the Ambulatory Adult Population of the
    United States: The Sloan Survey. JAMA 2002;287(3):337-344.

2.  Cooper SA, Needle SE, Kruger GO. Comparative analgesic potency of
    aspirin and ibuprofen. J Oral Surg 1977;35:898-903.

3.  Beaver WT, Forbes JA, Barkaszl BA, Ragland RN, Hankle JJ. An
    evaluation of ibuprofen and acetaminophen in postoperative oral
    surgery pain. Clin Pharmacol Ther 1987;41:180.

4.  Schou S, Nielson H, Nattestad A, Hillerup S, Ritzau M, Branebjerg
    PE, Bugge C, Skoglund LA. Analgesic dose-response relationship of
    ibuprofen 50, 100, 200 and 400 mg after surgical removal of third
    molars; a single-dose, randomized, placebo-controlled and
    double-blind study of 304 patients. J Clin Pharmacol
    1998;38:447-454.

5.  Codispoti JR, Prior MJ, Fu M, Harte CM, Nelson EB. Efficacy of
    nonprescription doses of ibuprofen for treating migraine headache. A
    randomized controlled trial. Headache 2001;41:665-679.

6.  Lemmens H, Stanski D, Cooper S, Karpow S.
    Pharmacokinetic-pharmacodynmics (PK/PD) of ibuprofen in dental pain.
    J Clin Pharmacol 1996;36:856.

7.  Laska EM, Sunshine A, Marrero I, Olson N, Siegel C, McCormick N. The
    correlation between blood levels of ibuprofen and clinical analgesic
    response. Clin Pharmacol Ther 1986;40:1-7.

8.  Seymour RA, Ward-Booth P, Kelly PJ. Evaluation of different doses of
    soluble ibuprofen and ibuprofen tablets in postoperative dental
    pain. Br J Oral Maxillofac Surg 1996;34:110-114.

9.  Winter L, Bass E, Recant B, Cahaly JF. Analgesic activity of
    ibuprofen (Motrin) in postoperative oral surgery pain. Oral Surg
    Oral Med Oral Path 1978;45:159-166.

10. Forbes JA, Barkaszi BA, Ragland RN, Hankle JJ. Analgesic effect of
    fendosal, ibuprofen and aspirin in postoperative oral surgery pain.
    Pharmacotherapy 1984;4:385-391.

11. Cooper SA, Schachtel BP, Goldman E, Gelb S, Cohn P. Ibuprofen and
    acetaminophen in the relief of acute pain: a randomized,
    double-blind, placebo-controlled study. J Clin Pharmacol
    1989;29:1026-1030.

12. Hersh EV, Levin LM, Cooper SA, Doyle G, Waksman J, Wedell D, Hong D,
    Secreto S. Ibuprofen liquigel for oral surgery pain. Clin Thera
    2000;22:1306-1318.

13. Schachtel BP, Fazio RC, Greene JJ. Ibuprofen 400 mg compared to
    acetaminophen 600 mg with codeine 60 mg for pain relief following
    periodontal surgery. J Clin Pharmacol 1990;30:846.

14. Cooper SA, Greene JJ, Schachtel BP. Ibuprofen 400 mg compared to
    acetaminophen 600 mg with codeine 60 mg. Clin Pharmacol Ther
    1989;45:176.

15. Medve RA, Wang J, Karim K. Tramadol and acetaminophen tablets for
    dental pain. Anesth Prog 2001;48:79-81.

16. Winter L, Bass E, Recant B, Cahaly JF. Analgesic activity of
    ibuprofen (Motrin) in postoperative oral surgical pain. Oral Surg,
    Oral Med, Oral Path. 1978;45:159-166.

17. Doyle G, Jayawardena S, Ashraf E, Cooper SA. Efficacy and
    tolerability of nonprescription ibuprofen versus celecoxib for
    dental pain. J Clin Pharmacol 2002:42;1-8.

18. Malmstrom K, Daniels S, Kotey P, Seidenberg BC, Desjardins PJ.
    Comparison of rofecoxib and celecoxib, two cyclooxygenase-2
    inhibitors, in postoperative dental pain: a randomized, placebo- and
    active-comparator- controlled clinical trial. Clin Thera
    1999:21;1653-1663.

19. Bakshi R, Frenkel G, Dietlein G, Meurer-Witt B, Schneider B,
    Sinterhauf U. A placebo-controlled comparative evaluation of
    diclofenac dispersible versus ibuprofen in postoperative pain after
    third molar surgery. J Clin Pharmacol 1994;34:225-230.

20. Cooper SA, Berrie R, Cohn P. Comparison of ketoprofen, ibuprofen and
    placebo in a dental surgery pain model. Adv Ther 1988;5:43-53.

21. Fricke JR, Halladay SC, Francisco CA. Efficacy and safety of
    naproxen sodium and ibuprofen for pain relief after oral surgery.
    Curr Ther Res 1993;54:619-627.

22. Kiersch TA, Halladay SC, Koschik M. A double-blind, randomized study
    of naproxen sodium, ibuprofen and placebo in postoperative dental
    pain. Clin Ther 1993;15:845-854.

23. Packman B, Packman E, Doyle G, Cooper S, Ashraf E, Koronkiewicz K,
    Jayawardena S. Solubilized ibuprofen: evaluation of onset, relief,
    and safety of a novel formulation in the treatment of episodic
    tension-type headache. Headache 2000;40:561-567.

24. Schachtel B, Furey S, Thoden WR. Nonprescription ibuprofen and
    acetaminophen in the treatment of tension-type headache. J Clin
    Pharmacol 1996;36:1120-1125.

25. Schachtel B, Fillingim JM, Thoden WR, Lane AC, Baybutt RL. Sore
    throat pain in the evaluation of mild analgesics. Clin Pharmacol
    Ther 1988;44:704-711.

26. Muckle DS. Comparative study of ibuprofen and aspirin in soft tissue
    injuries. Rheumato Rehabil 1974;13:141-147.)

27. Sunshine A, Olson NZ, Laska EM, Zighelboim I, De Castro A, De
    Sarrazin C. Ibuprofen, zomepirac, aspirin, and placebo in the relief
    if postepisiotomy pain. Clin Pharmacol Ther 1983:34;254-258.

28. Schachtel B, Thoden WR, Baybutt RI. Ibuprofen and acetaminophen in
    the relief of postpartum episiotomy pain. J Clin Pharmacol
    1989;29:550-553.

29. Moore N, Van Ganse E, Le Parc JM, Wall R, Schneid H, Farhan M,
    Verriere F, Pelen F. The PAIN Study: Paracetamol, Aspirin, and
    Ibuprofen New Tolerability Study. Clin Drug Invest 1999;18:89-97.

30. Gastrointestinal Safety and Tolerance of Ibuprofen at Maximum
    Over-the Counter Dose. Aliment Pharmacol Ther 1999;13:897-906.

31. Data on File. Wyeth Consumer Healthcare, 2000.

32. Ashraf E, Ford L, Geetha R, Cooper S. Safety profile of ibuprofen
    suspension in young children. Inflammopharmacol 1999;7:219-225.

33. Lesko SM, Mitchel AA. Assessment of the Safety of Pediatric
    Ibuprofen. J Am Med Assoc 1996;273:929-933.

34. Furey SA, Waksman JA, Dash BH. Nonprescription ibuprofen: side
    effect profile. Pharmacotherapy 1192;12:403-407.

35. DeArmond B, Francisco CA, Lin JS, Huang F, Halladay S, Bartizek R,
    Skare K. Safety profile of over-the-counter naproxen sodium. Clin
    Ther 1995;17:587-601.

36. Rainsford KD, Roberts SC, Brown S. Ibuprofen and paracetamol:
    relative safety in non-prescription dosages. J Pharm Pharmacol
    1997;49:345-376.

37. Kellstein DE, Waksman JA, Furey SA, Binstock G, Cooper S. The safety
    profile of nonprescription ibuprofen in multiple-dose use: A
    Meta-Analysis. J Clin Pharmacol 1999;39:520-532.

38. Henry D. Epidemiology overview of gastrointestinal and renal
    toxicity. Highlights of the 2002 International Ibuprofen Foundation
    Conference. Supplement to the Int J Clin Practice (In Press)

39. Singh G, Ramey D, Balise R, Triadafilopoulos G. Serious
    gastrointestinal complications of over-the-counter NSAIDS. World
    Congress Gastroenterology Vienna, 1998.

40. Blot WJ, McLaughlin JK. Over the counter non-steroidal
    anti-inflammatory drugs and risk of gastrointestinal bleeding. J
    Epid Biostat 2000;5:137-142.

41. Strom BL, Schinnar R, Bilker WB, Feldman H, Farrar JT, Carson JL.
    Gastrointestinal Tract Bleeding Associated with Naproxen Sodim vs
    Ibuprofen. Ach Intern Med 1997;157:2626-2631.

42. Lewis JD, Bilker WB, Brensinger C, Farrar JT, Strom BL.
    Hospitalization and Mortality Rates from Peptic Ulcer Disease and
    Gastrointestinal Bleeding in the 1990s: Relationship to Sales of
    NSAIDs and Acid Suppression Medications. Am J Gastroenterol (In
    Press)

43. Bradley JD, Brandt KD, Katz BP, et al. Comparison of an
    antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen,
    an acetaminophen in the treatment of patients with osteoarthritis of
    the knee. N Engl J Med 1991;325:87-91.

44. Cummings DM, Amadio P, Nettler S, et al. Office-based evaluation of
    renal function in elderly patients receiving nonsteroidal
    anti-inflammatory drugs. J Am Board Fam Prac 1988;1:77.

45. Fox DA, Jick H. Nonsteroidal antiinflammatory drugs and renal
    disease. J Am Med Assoc 1984;251:1299-1300.

46. Bonney SL. Northington RS, Hedrich DA, et al. Renal safety of two
    analgesics used over the counter: ibuprofen and aspirin. Clin
    Pharmacol Ther 1986;40:373-377.

47. Stosic Z, Sedlak V, Curie S. The effect of ibuprofen with glomerular
    filtration rate and renal plasma flow in patients with
    glomerularnephrites with normal and reduced renal function. Therapie
    1995;(Supp):502.

48. Furey SA, Vargas R, McMahan FG. Renovascular effects of
    nonprescription ibuprofen in elderly hypertensive patients with mild
    renal impairment. Pharmacotherapy 1993;13:143-148.

49. Farquhar WB, Morgan AL, Zambraski EJ, Kenney WL. Effects of
    acetaminophen and ibuprofen on renal function in the stressed
    kidney. J Appl Physiol 1999;86:598-604.

50. Sheiner PA, Mor E, Chodoff L, et al. Acute renal failure associated
    with the use of ibuprofen in two liver transplant recipients on
    FK506. Transplant 1994;57:1132-1133.

51. Gertz BJ, Krupa D, Bolognese JA, Sperling RS, Reicin A. A comparison
    of adverse renovascular experience among osteoarthritis patients
    treated with rofecoxib and comaparator non-selective non-steroidal
    anti-inflammatory agents. Curr Med Res Opinion 2002;18:82-91.

52. Lee A, Cooper MC, Craig JC, Knight JF, Keneally JP: Effects of
    nonsteroidal anti-inflammatory drugs on post-operative renal
    function in normal adults. The Cochrane Library 2002: Issue 2.

53. Elasser GN, Lopez L, Evans E. Reversible acute renal failure
    associated with ibuprofen ingestion and binge drinking. J Fam Pract
    1988;27:221.

54. Johnson GR, Wen SF. Syndrome of flank pain and acute renal failure
    after binge drinking and nonsteroidal inflammatory drug ingestion. J
    Am Soc Neprhol 1995;5:1647.

55. Moss AH, Riley R, Murgo A, Skaff LA. Over-the-counter ibuprofen and
    acute renal failure. Ann Intern Med 1986;105:303.

56. Marasco AW, Gikas PW, Azziz-Baumgartner R. Ibuprofen-associated
    renal dysfunction. Pathphysiologic mechanisms of acute renal
    failure, hyperkalemia, tubular necrosis, and proteinuria. Arch
    Intern Med 1987;147:2107.

57. McIntire SC, Rubenstien RC, Gartner JC, et al. Acute flank pain and
    reversible renal dysfunction associated with nonsteroidal
    anti-inflammatory drug use. Pediatrics 1993;92:459-460.

58. Wattad A, Feehan T, Shepard FM. A unique complication of
    non-steroidal anti-inflammatory drug use. Pediatrics 1994;93:693.

59. Fernando AHN, Thomas S, Temple RM, et al. Renal failure after
    topical use of NSAIDs. Br Med J 1994;308:533.

60. Spierto RJ, Kaufman MB, Stoukides CA. Acute renal failure associated
    with the use of over-the-counter ibuprofen. Ann Pharmacother
    1992;26:714.

61. Atkinson LK, Goodship TH, Ward MK. Acute renal failure associated
    with acute pyelonephritis and consumption of non-steroidal
    anti-inflammatory drugs. Br Med J 1986;292:97-98.

62. Whelton A, Stout RL, Spilman PS, Klassen DK. Renal effects of
    ibuprofen, piroxicam, and sulindac in patients with asymptomatic
    renal failure: prospective, randomized, crossover comparison. Ann
    Intern Med 1990;112:568-576.

63. Ciabottoni G, Cinotti GA, Pierucci A, et al. Effects of sulindac and
    ibuprofen in patients with chronic glomerular disease: evidence for
    the dependence of renal function on prostacyclin. New Eng J Med
    1984;310:279-283.

64. Sandler DP, Burr FR, Weinberg CR. Nonsteroidal anti-inflammatory
    drugs and the risk for chronic renal disease. Ann Intern Med
    1991;115:165-172.

65. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated
    with the use of acetaminophen, aspirin, and nonsteroidal
    antiinflammatory drugs. N Engl J Med 1994;331:1675-1679.

66. Rexrode KM, Buring JE, Glynn RJ, Stampfer MJ, Youngman LD, Gaziano
    JM. Analgesic use and renal function in men. JAMA 2001;286:315-321.

67. Griffin M-R, Yared A, Ray WA. Nonsteroidal antiinflammatory drugs
    and acute renal failure in elderly persons. Am J Epidemiol
    2000;151:488-496.

68. Murray MD, Brater CD, Tierney WM, et al. Ibuprofen-associated renal
    impairment in a large general internal medicine practice. Am J Med
    Sci 1990;299:222-229.

69. Radford MG, Holley KE, Grande JP, et al. Reversible membranous
    nephropathy associated with the use of nonsteroidal
    anti-inflammatory drugs. JAMA 1996;276:466-469.

70. Pospishil YO, Antonovych TM. NSAIDs associated nephropathy. Pol J
    Pathol 1998;49:35-39.

71. Analgesic Attitude and Usage Study, 1996, Sponsored by
    Whitehall-Robins.

72. Summary Basis of Approval for Actron, 1995.

73. Gallup Annual Monitor of Pain Relievers, 2002.