**TABLE OF CONTENTS**

1 Introduction [3](#introduction)

2 Assessment of Safety of aspirin and other Nonsteroidal
Anti-Inflammatory DrugS (NSAIDs)
[5](#assessment-of-safety-of-aspirin-and-other-nonsteroidal-anti-inflammatory-drugs-nsaids)

2.1 Exposure Data of Aspirin and Other NSAIDs
[6](#exposure-data-of-aspirin-and-other-nsaids)

2.2 Mechanism of Action [6](#mechanism-of-action)

2.3 Prior FDA Findings of Adverse Events
[6](#prior-fda-findings-of-adverse-events)

2.4 Review of Gastrointestinal Adverse Events at Recommended Doses
[7](#review-of-gastrointestinal-adverse-events-at-recommended-doses)

2.4.1 Gastrointestinal Effects at Recommended Doses
[7](#gastrointestinal-effects-at-recommended-doses)

2.5 Safety of Aspirin and Other NSAIDs in Overdose
[10](#safety-of-aspirin-and-other-nsaids-in-overdose)

2.5.1 Aspirin Overdose [11](#aspirin-overdose)

2.5.2 NSAID Overdose [11](#nsaid-overdose)

2.5.3 American Association of Poison Control Centers (AAPCC) Reports of
NSAID Exposures
[11](#american-association-of-poison-control-centers-aapcc-reports-of-nsaid-exposures)

2.6 Comparative Safety Analysis of OTC Available Analgesics
[12](#comparative-safety-analysis-of-otc-available-analgesics)

2.6.1 Excess Mortality from Gastrointestinal Bleeding Associated with
NSAIDs in the United States
[13](#excess-mortality-from-gastrointestinal-bleeding-associated-with-nsaids-in-the-united-states)

2.6.2 Excess Mortality Associated with Acetaminophen Hepatotoxicity in
the United States
[14](#excess-mortality-associated-with-acetaminophen-hepatotoxicity-in-the-united-states)

2.6.3 Comparison of Excess Mortality
[15](#comparison-of-excess-mortality)

2.7 Conclusions [17](#conclusions)

3 CONSUMER MEDICATION USE [18](#consumer-medication-use)

3.1 Introduction [19](#introduction-1)

3.2 Recent Sources of Information About Consumer Medication Use
[19](#recent-sources-of-information-about-consumer-medication-use)

3.2.1 Actual Consumer Medication Use
[19](#actual-consumer-medication-use)

3.2.2 Consumer Attitudes About Medications
[20](#consumer-attitudes-about-medications)

3.3 Patterns of Medication Use From Recent Sources
[20](#patterns-of-medication-use-from-recent-sources)

3.3.1 MediScope^™^ Household Survey [21](#mediscope-household-survey)

3.3.2 Slone Survey of Analgesic Use [23](#slone-survey-of-analgesic-use)

3.4 Assessment of Consumer Medication Use
[25](#assessment-of-consumer-medication-use)

3.5 Conclusions [28](#conclusions-1)

4 McNeil INitiatives and recommendations
[29](#mcneil-initiatives-and-recommendations)

4.1 Introduction [30](#introduction-2)

4.2 Current Labeling Initiatives [30](#current-labeling-initiatives)

4.2.1 McNeil OTC Analgesic Product Labeling Initiatives
[31](#mcneil-otc-analgesic-product-labeling-initiatives)

4.3 Consumer and Healthcare Professional Education Initiatives
[31](#consumer-and-healthcare-professional-education-initiatives)

4.3.1 McNeil Education Initiatives [32](#mcneil-education-initiatives)

4.3.2 Education Initiatives - Professional and Non-Profit Organizations
[34](#education-initiatives---professional-and-non-profit-organizations)

4.4 Ongoing Consumer OTC Analgesic Use Monitoring
[36](#ongoing-consumer-otc-analgesic-use-monitoring)

4.5 Conclusions [36](#conclusions-2)

5 Reference List [37](#reference-list)

# Introduction

McNeil Consumer & Specialty Pharmaceuticals (McNeil), a member of the
Johnson & Johnson family of companies, submits this background package
for the Nonprescription Drugs Advisory Committee (NDAC) meeting
scheduled for September 20, 2002.

McNeil markets St. Joseph^®^ low strength (81 mg) aspirin that is
intended for use by adults only. In addition, McNeil markets Motrin^®^
(ibuprofen) and Tylenol^®^ (acetaminophen) single-ingredient and
combination-ingredient adult and pediatric products.

McNeil's submission provides data and an evidence-based assessment of
the safety of aspirin and other OTC-available NSAIDs.

**KEY POINTS**

-   The risk of aspirin and other NSAID-related gastrointestinal effects
    occurs at recommended doses and is dose-related.

-   Salicylate poisoning, particularly chronic salicylism, has a high
    risk of mortality despite treatment.

-   At OTC recommended doses, ibuprofen appears to have the least risk
    of gastrointestinal toxicity when compared to other NSAIDs.

```{=html}
<!-- -->
```
-   Medication use surveys provide insight regarding consumer behaviors
    that may result in excessive OTC analgesic exposure.

```{=html}
<!-- -->
```
-   McNeil has implemented labeling and educational interventions aimed
    at focusing the attention of OTC medication users on:

```{=html}
<!-- -->
```
-   the product ingredients

-   the proper dosing and proper use of medications

-   the importance of not taking more than the recommended dose

-   the importance of not using two products containing identical
    ingredients or using the same class of analgesic ingredients (eg,
    NSAIDs) during the same period of time

-   the importance of recognizing that all medications have risks,
    particularly when more than the recommended dose is taken.

```{=html}
<!-- -->
```
-   If acetaminophen use were to be restricted, and consequently aspirin
    and other OTC NSAID use increased in the United States, available
    data suggest that more people would die from aspirin and other
    NSAID-related gastrointestinal bleeding than those potentially
    spared from acetaminophen overdose hepatotoxicity.

# Assessment of Safety of aspirin and other Nonsteroidal Anti-Inflammatory DrugS (NSAIDs)

**KEY POINTS**

-   Consumers will self-treat pain and their selection of OTC analgesics
    will depend on availability, accessibility, and effectiveness of
    these products.

-   The risk of aspirin and other NSAID-related gastrointestinal effects
    occurs at recommended doses and is dose-related.

-   Salicylate poisoning, particularly chronic salicylism, has a high
    risk of mortality despite treatment.

-   At OTC recommended doses, ibuprofen appears to have the least risk
    of gastrointestinal toxicity when compared to other NSAIDs.

```{=html}
<!-- -->
```
-   If acetaminophen use were to be restricted, and consequently aspirin
    and other OTC NSAID use increased in the United States, available
    data suggest that more people would die from aspirin and other
    NSAID-related gastrointestinal bleeding than those potentially
    spared from acetaminophen overdose hepatotoxicity.

## Exposure Data of Aspirin and Other NSAIDs

Aspirin and other OTC NSAIDs are widely used throughout the United
States. A recent survey of medication use in the United States reported
that ibuprofen was taken by 17% of adults, aspirin was taken by 17% of
adults, and naproxen was taken by 3.5% of adults in the preceding week
\[Kaufman 2002\]. Based on market data provided by Information
Resources, Inc., it is estimated that in the year 2001, approximately
14.5 billion tablets of OTC single-ingredient aspirin, 12.7 billion
tablets of OTC single-ingredient adult ibuprofen, 2.8 billion tablets of
OTC adult naproxen sodium and 55 million tablets of OTC adult ketoprofen
were purchased.

## Mechanism of Action

Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin
act by inhibiting prostaglandin G/H synthase isoenzymes, also known as
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). These isoenzymes
are responsible for the conversion of arachidonic acid to various tissue
specific prostaglandins and thromboxanes \[FitzGerald 2001; McGeehan
2002\]. COX-1 is constitutively expressed in all tissues and is
responsible for generating prostaglandins that maintain organ function,
protect the integrity of the gastric mucosa and generate
platelet-derived thromboxane responsible for platelet aggregation and
vasoconstriction \[Konstam 2001; Bjorkman 2002\]. During the
inflammatory process COX-2 is induced, generating prostaglandins that
mediate pain and inflammation \[Bombardier 2000\]. COX-2 is also present
constitutively in the kidneys and vascular endothelium \[Hillis 2002\].
Reported adverse experiences with aspirin and other NSAIDs can be
understood on the basis of this mechanism of action.

## Prior FDA Findings of Adverse Events

The agency has published a final rule for professional labeling of
aspirin that highlights concerns that may occur with use of aspirin, and
a proposed monograph for ibuprofen that outlines reasoning behind
proposed labeling changes.

The FDA notice of final rule making (Final Rule) published in the
Federal Register of October 23, 1998 (63 FR 56816) regarding
professional labeling for aspirin describes adverse experiences that
include, but are not limited to, renal insufficiency and failure,
prolonged prothrombin time, acute anaphylaxis, and asthma. Various drug
interactions are noted and general precautions include renal failure,
hepatic insufficiency, and patients on a sodium-restricted diet (eg,
patients with congestive heart failure). Signs/symptoms and management
of overdose are also described.

The FDA published a notice of proposed rule making (Proposed Rule) in
the Federal Register of August 21, 2002 (67 FR 54152) regarding
ibuprofen. Proposed labeling changes include, but are not limited to, an
asthma/allergy warning and other warnings that advise individuals to ask
their doctor if they have gastrointestinal, hematologic, or renal
disorders, or take an anticoagulant, diuretic or another
analgesic/antipyretic. In addition, individuals with hypertension or
other cardiorenal disease or those who are age 65 years or older would
be instructed to consult with a physician before using the product.

In these documents, the agency provides a lengthy list of publications
and literature review to substantiate these labeling changes.

## Review of Gastrointestinal Adverse Events at Recommended Doses

The recommended OTC dose for aspirin is up to 4000 mg/day; for
ibuprofen, up to 1200 mg/day; for naproxen sodium, up to 660 mg/day; and
for ketoprofen, up to 75 mg/day. Most evaluations of NSAID risks involve
prescription products or prescription doses and, therefore, probably
overestimate risks associated with OTC NSAID use. Some consumers take
more than the recommended daily doses of OTC NSAIDs \[Havey 2001\].
Singh \[1999\] noted that 40% of Americans (who had taken NSAIDs at
least twice in the past year for five or more consecutive days)
simultaneously used OTC and prescription NSAIDs. Based on consumer
survey responses \[Kaufman 2002\], and taking into account concurrent
use of two or more NSAIDs \[Slone 2001\], the one-week prevalence of
aspirin and all other NSAID use is estimated as approximately 34%. This
represents 71 million adults (0.34 x 209 million adults in the United
States) \[US Census Bureau 2000\]. Concurrent use of two or more NSAIDs
was reported by 2.7% of all adults in the Slone Survey of Analgesic Use
\[Slone 2001\]. Applying this rate to the adult population in the United
States provides an estimate of up to 5.6 million adults who may
concurrently use two or more NSAIDs. These concurrent users will be at
higher risk for dose-related side effects.

### Gastrointestinal Effects at Recommended Doses

Aspirin and other NSAIDs are associated with a variety of
gastrointestinal effects ranging from mild gastrointestinal discomfort
(such as dyspepsia, heartburn, nausea, and abdominal pain) to more
severe complications, such as gastrointestinal bleeding and ulcers. The
great majority of excess mortality in users of NSAIDs is attributable to
gastrointestinal bleeding \[Report of CIOMS Working Group IV 1998\].
These effects are a result of primarily two mechanisms. The first
mechanism involves direct local damage to the gastric mucosa, which is
especially seen with acidic NSAIDs that are un-ionized in the stomach
(aspirin and the propionic acid derivatives; ibuprofen, naproxen and
ketoprofen). The second mechanism is the result of the inhibition of
cyclooxygenase with the subsequent inhibition of the synthesis of the
protective prostaglandins in the gastrointestinal mucosa \[Dajani
1998\]. In addition, aspirin irreversibly inhibits the formation of
thromboxane A~2~ in platelets \[Hardman 2001\], which may contribute to
aspirin-related gastrointestinal bleeding.

#### NSAIDs in General

Evidence indicates that the gastrointestinal side effects of aspirin and
other NSAIDs are dose-related \[Griffin 1991; Blot 2000\]. Ofman and
colleagues \[2002\] conducted an extensive meta-analysis of severe upper
gastrointestinal complications from NSAIDs. They estimated the risk of
upper gastrointestinal complications (perforations, ulcers and bleeds)
using data from several study designs, concluding that findings from the
cohort designs were the least biased. The pooled relative risk (RR) from
nine cohort studies, comprising over 750,000 person-years of exposure
was 2.7 (95% CI: 2.1, 3.5).

Griffin and colleagues \[Griffin 1991\] evaluated the risk of peptic
ulcer disease associated with the use of NSAIDs in patients 65 years of
age and older. They found a dose-related effect for peptic ulcer disease
increasing from a RR of 2.8 (95% CI: 1.8, 4.3) for the lowest dose to a
RR of 8.0 (95% CI: 4.4, 14.8) for the highest dose category (doses not
specified). Blot and McLaughlin \[Blot 2000\] conducted an independent
analysis of case-control data from a study conducted by the American
College of Gastroenterology. The risk of gastrointestinal bleeding
increased two- to three-fold among recent users of aspirin, ibuprofen
and other NSAIDs at OTC doses, and the risk was also dose-related.
Additionally, Blot and McLaughlin reviewed seven epidemiologic studies
that looked at gastrointestinal bleeding risk associated with aspirin
and other NSAIDs at OTC doses (eg, 3900 mg/day for aspirin and 1200
mg/day for ibuprofen). They reported about a two-fold excess risk of
gastrointestinal complications at doses lower than the maximum
recommended OTC dosage, with four-fold increases at doses near the
maximum, and an increase of six-fold or more at doses higher than the
recommended daily dose on OTC labels \[Blot 2000\].

#### Aspirin

Adverse gastrointestinal effects are a well known risk associated with
the use of aspirin, including low-dose aspirin \[Kurata 1990; Laporte
1991; Levy 1988\] and appear to be dose-related \[Prichard 1987; Weil
1995\]. The United Kingdom-transient ischemic attack (TIA) aspirin trial
\[UK-TIA Study Group 1991\], a randomized, double-blind,
placebo-controlled trial, compared aspirin doses of 300 mg/day (once
daily) and 1200 mg/day (600 mg twice daily) with placebo in 2435
patients (following a recent TIA or minor ischemic stroke) with a mean
follow-up of about four years. There was a dose-related increase in
gastrointestinal hemorrhage with 3% and 5% of the patients assigned to
300 mg of aspirin and 1200 mg of aspirin, respectively, reporting
gastrointestinal hemorrhage compared with 1% of placebo patients.

Weil et al \[1995\] evaluated the risk for peptic ulcer with
prophylactic aspirin therapy at doses of 75 mg, 150 mg, and 300 mg daily
and reported odds ratios (OR) that increased with daily dose: 2.3 (95%
CI: 1.2, 4.4) for 75 mg, 3.2 (95% CI: 1.7, 6.5) for 150 mg, and 3.9 (95%
CI: 2.5, 6.3) for 300 mg. Prichard and colleagues \[1987\] observed a
significant increase in gastric mucosal bleeding from baseline with a
daily aspirin dose of 75 mg, which increased two-fold at a dose of 300
mg daily (when compared with 75 mg) and increased more than five-fold at
a dose of 1.8 grams/day (when compared with 75 mg).

Derry and Loke \[Derry 2000\] conducted a meta-analysis of 24 randomized
controlled trials that evaluated almost 66,000 patients. They
specifically evaluated the effect of aspirin dose and formulation on the
occurrence of gastrointestinal hemorrhage. Gastrointestinal hemorrhage
occurred in 2.47% of patients taking aspirin compared with 1.42% of
patients taking placebo (OR 1.68; 95% CI: 1.51, 1.88; p\<0.0001). In a
separate analysis of eight trials using aspirin at doses of 50 to 162.5
mg per day, gastrointestinal hemorrhage occurred in 2.30% of patients
taking aspirin compared with 1.45% of patients taking placebo (OR 1.59;
95% CI: 1.40, 1.81; p\<0.0001).

In a case-control study involving 550 incident cases of upper
gastrointestinal bleeding and 1202 population controls \[Kelly 1996\], a
statistically significant increased risk (estimated RR ranging from 2.6
to 3.1, depending on aspirin formulation, ie, plain, enteric-coated, or
buffered) of upper gastrointestinal bleeding was reported for patients
regularly taking [\<]{.underline}325 mg/day of aspirin. An even greater
increased risk (5.8- to 7.0-fold) of upper gastrointestinal bleeding was
associated with regular intake of aspirin at doses above 325 mg/day.

#### Concurrent Aspirin and other NSAID Use Further Increases the Risk of Gastrointestinal Complications 

The risk of gastrointestinal bleeding appears to be doubled or greater
when aspirin is taken concurrently with other NSAIDs. Sorensen and
colleagues \[2000\] studied a cohort in Denmark and evaluated the risk
of hospitalization for upper gastrointestinal bleeding with the use of
low dose aspirin (≤150 mg daily) in 27,694 patients. The standardized
incidence rate ratio (the ratio of the observed to the expected number
of upper gastrointestinal bleeding cases) for upper gastrointestinal
bleeding among users of uncoated low dose aspirin was 2.6 (95% CI: 1.8,
3.5) and for coated aspirin use was 2.6 (95% CI: 2.2, 3.0). More
importantly, however, Sorensen et al found that this rate ratio of upper
gastrointestinal bleeding increased to 5.6 (95% CI: 4.4, 7.0) when
aspirin was used concurrently with other NSAIDs. As the United States
population ages and the prophylactic use of aspirin for cardiovascular
protection increases, the inherent gastrointestinal risks of aspirin
could be compounded by concurrent NSAID use resulting in a dose-related
increase in risk.

#### Ibuprofen

At recommended OTC doses, ibuprofen appears to have a lower risk of
gastrointestinal adverse effects compared with aspirin and other NSAIDs
\[Henry 1996; Straus 2001; Gutthann 1997; Garcia Rodriguez 1998\]. In
recent meta-analyses evaluating the occurrence of gastrointestinal
complications \[Henry 1996; Straus 2001\], ibuprofen was reported to be
the safest of all NSAIDs studied. The crude risk ratios of the other
NSAIDs (including aspirin) that were evaluated ranged up to
approximately four-fold higher than ibuprofen. Henry and colleagues
\[Henry 1996\] noted that adverse gastrointestinal effects for several
of the NSAIDs were dose-related. Low dose ibuprofen (≤ 1200 mg) was
associated with a pooled RR of 1.6 (95% CI: 0.8, 3.2) compared with a
pooled RR of 4.2 (95% CI: 1.8, 9.8) for higher dose ibuprofen (≥ 2400
mg). In another study, Gutthann et al \[1997\] estimated the risk of
complicated ulcer for NSAID users and non-users and found that compared
to users of other NSAIDs, ibuprofen users had the lowest risk of peptic
ulcer (odds ratio, 2.1; 95% CI: 1.1, 4.0).

## Safety of Aspirin and Other NSAIDs in Overdose

The sections that follow review data on the safety of aspirin and other
NSAIDs in overdose. Fatality reports from the American Association of
Poison Control Centers (AAPCC) are also provided. These data indicate
that ibuprofen in overdose is relatively benign and requires supportive
and symptomatic treatment. However, acute overdose with aspirin and
chronic aspirin toxicity (eg, salicylism) are associated with
significant morbidity and mortality.

### Aspirin Overdose

A 16% morbidity rate and a 1% mortality rate are reported with acute
aspirin overdose \[Kreplick 2001\]. Although acute overdose and chronic
salicylism present similarly \[Woolley 1977\], chronic salicylism is
associated with mortality as high as 25% \[Kreplick 2001\]. Chronic
salicylism usually occurs in the course of therapeutic use of aspirin,
when an individual increases the dose and, unknowingly, saturates the
biotransformation and elimination pathways \[Proudfoot 1983\]. As a
result, a small increase in dose can produce a disproportionate increase
in plasma salicylate levels. This can lead to progressive signs of
salicylate intoxication including headache, tinnitus, and confusion
followed by metabolic acidosis and, ultimately, coma, cardiovascular
collapse, and death \[Hardman 2001\]. There is no antidote for
salicylate poisoning and treatment is directed at decreasing absorption,
increasing elimination, and supportive care \[Woolley 1977; Dargan
2002\].

### NSAID Overdose

Symptoms of NSAID overdose are usually mild (eg, gastrointestinal upset,
abdominal pain, vomiting and diarrhea), requiring only supportive
measures; however, 5% to 10% of patients experience convulsions.
Metabolic acidosis is uncommon and is usually associated with large
ingestions. Very rarely, coma, prolonged seizures, apnea, bradycardia,
renal failure and death occur \[Jones 2002\].

### American Association of Poison Control Centers (AAPCC) Reports of NSAID Exposures 

The AAPCC Toxic Exposure Surveillance System (TESS) database includes
reports of human exposures to various substances (eg, pharmaceutical
products, cleaning substances, chemicals, foods, and plants) submitted
by poison control centers \[Litovitz 2001\] across the United States. In
the database, an exposure is defined as a contact to the poison control
center regarding administration of, or contact with a substance, but
does necessarily involve toxicity. Reports are received from consumers
and health care professionals via telephone. Callers typically request
advice and treatment recommendations.

Call information is not verified or clarified by medical record review
or other means. With respect to fatality case reports, poison control
centers provide no causality probability or assessment that the reported
substance(s) contributed directly or indirectly to the fatal outcome.
Nevertheless, TESS is the largest single data set of reported
acetaminophen exposures, and a review of recent data provides a broad
perspective.

According to the AAPCC annual report \[Litovitz 2001\], 52 deaths
involving single-ingredient aspirin were reported in the year 2000,
representing a mortality rate of 0.5% (based on the number of exposures
in which the outcome was known). Twenty-five percent (25%) of patients
where the outcome was known experienced moderate or major effects.
Table 2-1 provides a summary of aspirin and ibuprofen exposure data,
based on the AAPCC 2000 annual report \[Litovitz 2001\]. Deaths were
much fewer with ibuprofen (n= 5), although total ibuprofen exposures
were reported approximately three times more often.

Table 2‑1. Aspirin and Ibuprofen Exposure Data Based on the AAPCC 2000
Annual Report

+----------+-------+----+----+----+----------+-------+-------+-------+
| Product  | Total | A  |    |    | Reason   |       | Ou    |       |
|          | Expo  | ge |    |    | for      |       | tcome |       |
|          | sures | in |    |    | exposure |       | (     |       |
|          |       | Y  |    |    | (%)^b^   |       | %)^c^ |       |
|          |       | ea |    |    |          |       |       |       |
|          |       | rs |    |    |          |       |       |       |
|          |       | (% |    |    |          |       |       |       |
|          |       | )^ |    |    |          |       |       |       |
|          |       | a^ |    |    |          |       |       |       |
+----------+-------+----+----+----+----------+-------+-------+-------+
|          |       | \  | 6- | \> | Unint    | I     | Major | Death |
|          |       | <6 | 19 | 19 | entional | ntent |       |       |
|          |       |    |    |    |          | ional |       |       |
+----------+-------+----+----+----+----------+-------+-------+-------+
| *        | 1     |    |    |    |          |       |       |       |
| *Aspirin | 6,649 |    |    |    |          |       |       |       |
| alone**  |       |    |    |    |          |       |       |       |
+----------+-------+----+----+----+----------+-------+-------+-------+
| > Adult  | 5,283 | 31 | 32 | 35 | 49.8     | 47.9  | 1.4   | 0.4   |
| > for    |       | .6 | .6 | .8 |          |       |       |       |
| mulation |       |    |    |    |          |       |       | n=13  |
+----------+-------+----+----+----+----------+-------+-------+-------+
| > P      | 589   | 74 | 15 | 10 | 90.3     | 8.0   | 0     | 0     |
| ediatric |       | .5 | .0 | .5 |          |       |       |       |
| > for    |       |    |    |    |          |       |       | n=0   |
| mulation |       |    |    |    |          |       |       |       |
+----------+-------+----+----+----+----------+-------+-------+-------+
| >        | 1     | 19 | 36 | 44 | 35.4     | 62.7  | 3.6   | 0.6   |
|  Unknown | 0,777 | .1 | .2 | .7 |          |       |       |       |
| > for    |       |    |    |    |          |       |       | n=39  |
| mulation |       |    |    |    |          |       |       |       |
+----------+-------+----+----+----+----------+-------+-------+-------+
| **Ibu    | 5     | 57 | 21 | 21 | 71.4     | 26.9  | 1.0   | 0.02  |
| profen** | 7,876 | .3 | .6 | .1 |          |       |       |       |
|          |       |    |    |    |          |       |       | n=5   |
+----------+-------+----+----+----+----------+-------+-------+-------+

a: Age -- expressed as % of all exposures in which the age was known for
each formulation.

b: Reason for exposure -- expressed as % of all exposure cases in which
the reason was known for each formulation.

c: Outcome -- expressed as % of all exposures cases with a known outcome
for each formulation.

## Comparative Safety Analysis of OTC Available Analgesics

Acetaminophen is the most commonly used OTC analgesic and any actions
that effectively limit its use, or the availability of optimal dosages
that are currently available, may increase the use of aspirin, other OTC
NSAIDs and prescription analgesics, among other pain and fever
treatments. Comparing acetaminophen safety to that of aspirin and other
NSAIDs at recommended doses suggests that an increase in aspirin and
other NSAID use could increase the overall morbidity and mortality
associated with therapeutic OTC analgesic use. The potential public
health impact for the American consumer merits consideration.

For perspective, excess mortality from gastrointestinal bleeding, the
factor that dominates the overall risk profile of aspirin and other
NSAIDs, that occurs at recommended doses and is dose-related, is
compared with excess mortality from hepatotoxicity from overdose with
acetaminophen in the following sections.

### Excess Mortality from Gastrointestinal Bleeding Associated with NSAIDs in the United States

Epidemiologic evidence suggests that 99% of the excess mortality from
NSAID use was attributable to gastrointestinal complications \[Report of
CIOMS Working Group IV 1998\]. Annually, 1% to 2% of people taking
NSAIDs on a regular basis experience serious gastrointestinal
complications that result in hospitalization \[Singh 2000\]. Estimates
of the number of deaths from NSAID-related gastrointestinal bleeding
vary widely.

Singh \[2000\] estimated that 103,000 individuals are hospitalized
annually in the United States for NSAID-related serious gastrointestinal
complications at a cost in excess of two billion dollars. In addition,
Singh \[2000\] estimated that 16,500 NSAID-related deaths occur each
year in the United States among patients with rheumatoid arthritis and
osteoarthritis. Presumably, these estimates are based primarily on
prescription NSAIDs used for longer time periods than the OTC label
recommends, but as noted earlier, some individuals may use OTC NSAIDs in
excess of the OTC recommended dose or take two or more OTC NSAIDs
concurrently.

A more conservative estimate came from Blot and McLaughlin \[personal
communication McLaughlin 2001\] who estimated that 9400 Americans, age
25 years or older, die from upper gastrointestinal bleeding per year.
This is based on United States mortality data from the National Center
for Health Statistics from 1990 through 1999[^1].

Using the pooled relative risk of upper gastrointestinal bleeding from
cohort studies determined by Ofman \[Ofman 2002\] of 2.7 (95% CI: 2.1,
3.5), McNeil estimated that the number of excess deaths per year from
gastrointestinal bleeding secondary to NSAID use among adults in the
United States is 3443 (95% CI; 2559, 4319). The point estimate of the
number of excess deaths was calculated as follows. Estimates for the
upper and lower 95% confidence interval were calculated in the same
manner.

-   Deaths per year attributable to NSAIDs in the United States

> = deaths per year from gastrointestinal bleeding (9400)
>
> x proportion attributable to NSAIDs (0.3662864)
>
> = 3443 deaths per year

-   Proportion attributable to NSAIDs

> = [prevalence of NSAID use (0.34) x \[relative risk of GI bleed (2.7)
> -- 1\]]{.underline}
>
> prevalence of NSAID use (0.34) x \[relative risk of GI bleed (2.7) --
> 1\] + 1
>
> = 0.3662864

Based on the Slone Survey of American adults \[Kaufman 2002\], the
prevalence of use for acetaminophen was estimated to be 23%. Based on
consumer survey responses \[Kaufman 2002\], and taking into account
concurrent use of two or more NSAIDs \[Slone 2001\], the one-week
prevalence of aspirin and all other NSAID use is estimated as
approximately 34%. If half of OTC acetaminophen users switched to
NSAIDs, this would increase the prevalence of NSAID use to 45.5% (34%
plus 11.5%). Using the formulas provided above and an Excel spreadsheet,
this would result in an estimated 4100 deaths per year due to
gastrointestinal bleeding from NSAID use, ie, 657 additional deaths over
the current estimate of 3443. If all acetaminophen users switched to
NSAIDs, it is estimated that there would be 1183 additional deaths due
to gastrointestinal bleeding from NSAID use, with a total of 4626
(Figure 2-1). Thus, for each percentage point switch of acetaminophen
use (eg, from 23% to 22%, or from 1% to 0%) to aspirin or other NSAIDs,
an additional 42 to 64 deaths due to gastrointestinal bleeding are
projected. This concern is compounded by the fact that dyspeptic
symptoms do not serve to warn of impending and serious gastrointestinal
complications among patients taking NSAIDs. As many as 81% of patients
who had serious gastrointestinal complications had no prior
gastrointestinal symptoms \[Singh 1996\].

### Excess Mortality Associated with Acetaminophen Hepatotoxicity in the United States

Hepatotoxicity with acute liver failure following very large overdoses
is the most prominent serious adverse event associated with
acetaminophen. Although there are no surveillance programs or national
statistics, one personal unverified estimate is that 2000 individuals
develop acute liver failure annually in the United States, and 38% of
cases may be attributable to acetaminophen \[Lee 2001\]. A 72% survival
rate has been estimated \[Larson 2000\]. Little has been published about
these cases so it is unclear how the attribution to acetaminophen was
made or whether these estimates are accurate. However, in the absence of
alternative estimates, McNeil used this information for a worst-case
scenario of deaths from acetaminophen overdose: 213 per year
(Figure 2-1).

### Comparison of Excess Mortality

Figure 2-1 illustrates that the excess mortality from NSAID-related
gastrointestinal bleeding at therapeutic doses far exceeds that from
acute liver failure associated with acetaminophen overdoses. Even a
modest shift from acetaminophen to aspirin or other NSAID use would be
associated with a significant increase in the number of drug-related
deaths.

Figure 2‑1. Estimated Annual Excess Mortality Associated with Analgesic
Use in the United States

![](media/image1.wmf){width="5.583333333333333in"
height="4.801388888888889in"}

\* Personal unverified estimate of 2000 cases/year of acute liver
failure, of which 38% (760) may be attributable to acetaminophen \[Lee
2001\]. A 72% survival rate has been estimated \[Larson 2000\]. 760 x
0.28 = 213.

\*\* Estimated number of deaths per year attributable to NSAIDs in the
US = deaths per year from upper GI bleeding (9400) x proportion
attributable to NSAIDs (0.3662864) = 3443 deaths per year. The
proportion attributable to NSAIDs was calculated as the {prevalence of
NSAID use (0.34) x \[relative risk of gastrointestinal bleed \[Ofman
2002\] (2.7) -- 1\]} divided by {prevalence of NSAID use (0.34) x
\[relative risk of GI bleed (2.7) -- 1\] + 1} which equals 0.3662864.

\*\*\* Prevalence of use for acetaminophen was estimated to be 23%
\[Kaufman 2002\] and of NSAIDs to be 34% \[Slone 2001\]. If half of OTC
acetaminophen users switched to NSAIDS, this would increase the
prevalence of NSAID use to 45.5% (34% + 11.5%). This would result in an
estimated 4100 deaths per year due to gastrointestinal bleeding from
NSAID use, ie, 657 additional deaths over the current estimate of 3443.
If all acetaminophen users switched to NSAIDs, it is estimated that
there would be 1183 additional deaths due to gastrointestinal bleeding
from NSAID use, with a total of 4626.

## Conclusions

The risk of aspirin and other NSAID-related gastrointestinal effects
occurs at recommended doses and is dose-related. At OTC recommended
doses, ibuprofen appears to have the least risk of gastrointestinal
toxicity when compared to other NSAIDs.

No antidote is available for aspirin or ibuprofen overdose. Acute
overdose and chronic aspirin toxicity (eg, salicylism) are associated
with significant morbidity and mortality (as high as 25%). In contrast,
overdose with ibuprofen is relatively benign and requires supportive and
symptomatic treatment only.

If acetaminophen use were to be restricted, and consequently aspirin and
other OTC NSAID use increased in the United States, available data
suggest that more people would die from aspirin and other NSAID-related
gastrointestinal bleeding than those potentially spared from
acetaminophen overdose hepatotoxicity. Even a modest shift from
acetaminophen to aspirin or other NSAID use would be associated with a
significant net increase in the number of drug-related deaths. This net
public health impact should be taken into consideration in the
formulation of any regulatory policy pertaining to OTC analgesics.

# CONSUMER MEDICATION USE

**KEY POINTS**

-   Acetaminophen, ibuprofen, and aspirin are the most commonly used
    analgesic medications in the adult population of the United States.
    In any given week, some 23% of adults (48.1 million people) report
    using acetaminophen-containing products. The estimated prevalence of
    aspirin use is 17% and ibuprofen use is 17%. Naproxen use is 3.5%
    during this same time.

-   Medication use surveys provide insight regarding consumer analgesic
    use behaviors that may result in excessive OTC analgesic exposure.

```{=html}
<!-- -->
```
-   McNeil has implemented labeling and educational interventions aimed
    at focusing the attention of OTC medication users on:

```{=html}
<!-- -->
```
-   the product ingredients

-   the proper dosing and proper use of medications

-   the importance of not taking more than the recommended dose

-   the importance of not using two products containing identical
    ingredients or using the same class of analgesic ingredients (eg,
    NSAIDs) during the same period of time

-   the importance of recognizing that all medications have risks,
    particularly when more than the recommended dose is taken.

## Introduction

Aspirin and other OTC NSAIDs are widely used throughout the United
States. A recent survey of medication use in the United States estimated
that ibuprofen was taken by 17% of adults, aspirin was taken by 17% of
adults, and naproxen was taken by 3.5% of adults in the preceding week
\[Kaufman 2002\]. This section will examine recent data on consumer
medication use behaviors and information regarding misuse of OTC
analgesics. Based on this review, specific actions, directed at focusing
the consumer on proper medication use, are discussed in Section 4,
McNeil Initiatives and Recommendations.

## Recent Sources of Information About Consumer Medication Use

### Actual Consumer Medication Use

**Slone Survey of Medication Use** -- an ongoing population-based
telephone survey of medication use conducted by the Slone Epidemiology
Unit (Slone) of Boston University School of Public Health \[Kaufman
2002\]. The survey provides recent information on use of all
medications, including prescription and OTC drugs, vitamins and
minerals, and herbal preparations/supplements during the 1-week period
preceding a telephone interview. This survey represents a random sample
of the ambulatory adult (18 years of age and older) population in the 48
continental states and the District of Columbia. As part of the
interview, the participant is asked to gather the relevant bottles or
packages on all medications taken during the preceding seven days.

At the request of McNeil, Slone conducted a specific analysis of
utilization patterns of OTC and prescription analgesic products
containing acetaminophen, aspirin, ibuprofen and naproxen based on the
Survey of Medication Use. This supplemental analysis of analgesics
includes a total of 6,279 participants interviewed during the time
period of February 1998 through August 2001. Herein, this analysis is
referred to as "Slone Survey of Analgesic Use" \[Slone 2001\].

**The MediScope**^™^ **Household Survey** -- a diary-based survey of
United States households demographically balanced to match US Census
data provided by a market research service. Consumers are instructed to
record every use of nonprescription medicine by all household members,
regardless of age, for a four-week period. The data collected includes
the product name, the reason for using the product, the dose amount, and
the number of doses taken. Survey data is available for approximately
6700 households over a two-year time period from September 1999 through
September 2001 \[McNeil 2002\].

### Consumer Attitudes About Medications

**McNeil Habits & Practices Survey** -- a telephone survey of consumer
attitudes and behavior regarding use of both OTC and prescription
analgesic medications conducted by a market research service. A random
sample of US consumers was surveyed to identify OTC products they
regularly use and their understanding of product ingredients and safety.
The survey was conducted in September 2001 and sampled 410 male and
female adults between the ages of 18 and 65 who had used OTC analgesics
in the past six months \[McNeil 2001\].

**National Council on Patient Information and Education (NCPIE)
Survey** - a market research telephone survey of consumers and health
professionals to track their opinions about the use of OTC medicines.
The survey was conducted between October 25 and November 11, 2001 and
consisted of two polls: one of 1011 adults 18 years of age and older and
the other involving 451 pharmacists, nurses and general practice
physicians. Interview questions focused on the general term of
"non-prescription medicines", but did not specifically address the
category of OTC pain relievers. Survey results were released to the
public in January 2002 as part of the "Be Medwise" campaign \[NCPIE
2002\].

## Patterns of Medication Use From Recent Sources

This section provides a description and perspective about patterns of
use of OTC analgesics from recent sources.

According to the Slone Survey of Medication Use \[Kaufman 2002\], in the
United States 61% of adults recall using some analgesic in the previous
week. Some 23% of adults (48.1 million people) report using
acetaminophen-containing products. The prevalence of aspirin use is 17%
and ibuprofen use is 17%. These data are depicted in Figure 3-2.
Naproxen use is 3.5% during this same time period.

Figure 3‑2. One-Week Prevalence of Most Commonly Used Analgesic Products
in the United States Adult Population (n= 209 million) From Slone Survey
of Medication Use \[Kaufman 2002\]

![](media/image2.wmf){width="5.996527777777778in"
height="3.2020833333333334in"}

### MediScope^™^ Household Survey

The MediScope Household Survey provides additional detail about OTC
medication use by adults. When the daily OTC analgesic tablet
consumption by consumers is analyzed, the data in Table 3-2 show that
the overwhelming majority of consumers use analgesics within the
recommended OTC dose. However, a small percentage of analgesic users
exceed the recommended maximum daily dose; these usage rates are 1% for
acetaminophen, 6% for ibuprofen, and 13.5% for naproxen.

For aspirin, 92.4% of daily usage was 1 to 2 tablets. These data may not
represent typical consumer usage of aspirin for pain relief, since
approximately 52% of reportage usage was for the prevention of heart
attack or stroke, situations where low-strength aspirin is recommended.

+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Table |       |       |       |       |       |       |       |       |
|  3‑2. |       |       |       |       |       |       |       |       |
| Rep   |       |       |       |       |       |       |       |       |
| orted |       |       |       |       |       |       |       |       |
| Di    |       |       |       |       |       |       |       |       |
| strib |       |       |       |       |       |       |       |       |
| ution |       |       |       |       |       |       |       |       |
| of    |       |       |       |       |       |       |       |       |
| Daily |       |       |       |       |       |       |       |       |
| OTC   |       |       |       |       |       |       |       |       |
| Anal  |       |       |       |       |       |       |       |       |
| gesic |       |       |       |       |       |       |       |       |
| T     |       |       |       |       |       |       |       |       |
| ablet |       |       |       |       |       |       |       |       |
| C     |       |       |       |       |       |       |       |       |
| onsum |       |       |       |       |       |       |       |       |
| ption |       |       |       |       |       |       |       |       |
| in an |       |       |       |       |       |       |       |       |
| Av    |       |       |       |       |       |       |       |       |
| erage |       |       |       |       |       |       |       |       |
| 4     |       |       |       |       |       |       |       |       |
| -Week |       |       |       |       |       |       |       |       |
| P     |       |       |       |       |       |       |       |       |
| eriod |       |       |       |       |       |       |       |       |
| Expr  |       |       |       |       |       |       |       |       |
| essed |       |       |       |       |       |       |       |       |
| as a  |       |       |       |       |       |       |       |       |
| Perce |       |       |       |       |       |       |       |       |
| ntage |       |       |       |       |       |       |       |       |
| of    |       |       |       |       |       |       |       |       |
| Usage |       |       |       |       |       |       |       |       |
| Days  |       |       |       |       |       |       |       |       |
| (     |       |       |       |       |       |       |       |       |
| based |       |       |       |       |       |       |       |       |
| on    |       |       |       |       |       |       |       |       |
| Medi  |       |       |       |       |       |       |       |       |
| Scope |       |       |       |       |       |       |       |       |
| Hous  |       |       |       |       |       |       |       |       |
| ehold |       |       |       |       |       |       |       |       |
| S     |       |       |       |       |       |       |       |       |
| urvey |       |       |       |       |       |       |       |       |
| Data  |       |       |       |       |       |       |       |       |
| from  |       |       |       |       |       |       |       |       |
| 9/99  |       |       |       |       |       |       |       |       |
| --    |       |       |       |       |       |       |       |       |
| 9/01  |       |       |       |       |       |       |       |       |
| \[M   |       |       |       |       |       |       |       |       |
| cNeil |       |       |       |       |       |       |       |       |
| 20    |       |       |       |       |       |       |       |       |
| 02\]) |       |       |       |       |       |       |       |       |
| ^a,b^ |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | Ace   |       | As    |       | Ibup  |       | Nap   |       |
|       | tamin |       | pirin |       | rofen |       | roxen |       |
|       | ophen |       |       |       |       |       | S     |       |
|       |       |       | (500  |       | (6x   |       | odium |       |
|       | (8x - |       | mg    |       | --    |       |       |       |
|       | 500   |       | t     |       | 200   |       | (3x   |       |
|       | mg    |       | ablet |       | mg    |       | --    |       |
|       | ta    |       | equi  |       | table |       | 220   |       |
|       | blets |       | valen |       | ts/da |       | mg    |       |
|       | /day) |       | t)^e^ |       | y)^c^ |       | table |       |
|       | ^c,d^ |       |       |       |       |       | ts/da |       |
|       |       |       |       |       |       |       | y)^c^ |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| No.   | \%    | Cumul | \%    | Cumul | \%    | Cumul | \%    | Cumul |
| of    | Usage | ative | Usage | ative | Usage | ative | Usage | ative |
| Ta    | Days  | Usage | Days  | Usage | Days  | Usage | Days  | Usage |
| blets |       | %     |       | %     |       | %     |       | %     |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| 1     | 19.0  | 19.0  | 76.6  | 76.6  | 18.9  | 18.9  | 33.3  | 33.3  |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| 2     | 41.6  | 60.6  | 15.8  | 92.4  | 36.4  | 55.3  | 48.1  | 81.4  |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| 3     | 10.1  | 70.7  | 3.4   | 95.8  | 10.3  | 65.6  | 5.1   | 86.5  |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| 4     | 14.4  | 85.1  | 2.8   | 98.6  | 18.5  | 84.1  | **1   | **9   |
|       |       |       |       |       |       |       | 1.5** | 8.0** |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| 5     | 1.2   | 86.3  | 0.3   | 98.9  | 1.2   | 85.3  | **    | **9   |
|       |       |       |       |       |       |       | 0.1** | 8.1** |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| 6     | 8.2   | 94.5  | 0.7   | 99.6  | 8.7   | 94.0  | **    | **9   |
|       |       |       |       |       |       |       | 1.3** | 9.4** |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| 7     | 0.6   | 95.1  | 0.1   | 99.6  | **    | **9   | **    | **9   |
|       |       |       |       |       | 0.6** | 4.6** | 0.1** | 9.5** |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| 8     | 3.8   | 99.0  | 0.3   | 99.9  | **    | **9   | **    | **9   |
|       |       |       |       |       | 2.4** | 7.0** | 0.3** | 9.8** |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| 9 to  | **    | **9   | 0.1   | 100.0 | **    | **9   | **\-  | **9   |
| 12    | 0.9** | 9.9** |       |       | 2.7** | 9.7** | \--** | 9.8** |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| 13 to | **    | **9   | 0     | 100.0 | **    | **9   | **\-  | **9   |
| 16    | 0.1** | 9.9** |       |       | 0.2** | 9.0** | \--** | 9.8** |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| 17 to | **\<  | **10  | 0     | 100.0 | **0   | **10  | **    | **10  |
| 20    | 0.1** | 0.0** |       |       | .03** | 0.0** | 0.2** | 0.0** |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| \%    | **    | **\-  | Not   | \--   | **    | **\-  | **1   | *     |
| days  | 1.0** | \--** | appli |       | 6.0** | \--** | 3.5** | **\-\ |
| \>    |       |       | cable |       |       |       |       | --*** |
| max.  |       |       | since |       |       |       |       |       |
| daily |       |       | use   |       |       |       |       |       |
| OTC   |       |       | not   |       |       |       |       |       |
| anal  |       |       | only  |       |       |       |       |       |
| gesic |       |       | for   |       |       |       |       |       |
| dose  |       |       | pain  |       |       |       |       |       |
|       |       |       | r     |       |       |       |       |       |
|       |       |       | elief |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| a:    |       |       |       |       |       |       |       |       |
| Adult |       |       |       |       |       |       |       |       |
| si    |       |       |       |       |       |       |       |       |
| ngle- |       |       |       |       |       |       |       |       |
| ingre |       |       |       |       |       |       |       |       |
| dient |       |       |       |       |       |       |       |       |
| anal  |       |       |       |       |       |       |       |       |
| gesic |       |       |       |       |       |       |       |       |
| pr    |       |       |       |       |       |       |       |       |
| epara |       |       |       |       |       |       |       |       |
| tions |       |       |       |       |       |       |       |       |
| (incl |       |       |       |       |       |       |       |       |
| uding |       |       |       |       |       |       |       |       |
| PM    |       |       |       |       |       |       |       |       |
| pro   |       |       |       |       |       |       |       |       |
| duct) |       |       |       |       |       |       |       |       |
| among |       |       |       |       |       |       |       |       |
| users |       |       |       |       |       |       |       |       |
| 12    |       |       |       |       |       |       |       |       |
| years |       |       |       |       |       |       |       |       |
| of    |       |       |       |       |       |       |       |       |
| age   |       |       |       |       |       |       |       |       |
| and   |       |       |       |       |       |       |       |       |
| o     |       |       |       |       |       |       |       |       |
| lder. |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       |       |       |
| b:    |       |       |       |       |       |       |       |       |
| Bold  |       |       |       |       |       |       |       |       |
| indi  |       |       |       |       |       |       |       |       |
| cates |       |       |       |       |       |       |       |       |
| usage |       |       |       |       |       |       |       |       |
| days  |       |       |       |       |       |       |       |       |
| exce  |       |       |       |       |       |       |       |       |
| eding |       |       |       |       |       |       |       |       |
| the   |       |       |       |       |       |       |       |       |
| r     |       |       |       |       |       |       |       |       |
| ecomm |       |       |       |       |       |       |       |       |
| ended |       |       |       |       |       |       |       |       |
| ma    |       |       |       |       |       |       |       |       |
| ximum |       |       |       |       |       |       |       |       |
| daily |       |       |       |       |       |       |       |       |
| OTC   |       |       |       |       |       |       |       |       |
| anal  |       |       |       |       |       |       |       |       |
| gesic |       |       |       |       |       |       |       |       |
| dose. |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       |       |       |
| c:    |       |       |       |       |       |       |       |       |
| Total |       |       |       |       |       |       |       |       |
| n     |       |       |       |       |       |       |       |       |
| umber |       |       |       |       |       |       |       |       |
| of    |       |       |       |       |       |       |       |       |
| t     |       |       |       |       |       |       |       |       |
| ablet |       |       |       |       |       |       |       |       |
| s/day |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| equal |       |       |       |       |       |       |       |       |
| the   |       |       |       |       |       |       |       |       |
| r     |       |       |       |       |       |       |       |       |
| ecomm |       |       |       |       |       |       |       |       |
| ended |       |       |       |       |       |       |       |       |
| ma    |       |       |       |       |       |       |       |       |
| ximum |       |       |       |       |       |       |       |       |
| daily |       |       |       |       |       |       |       |       |
| OTC   |       |       |       |       |       |       |       |       |
| anal  |       |       |       |       |       |       |       |       |
| gesic |       |       |       |       |       |       |       |       |
| dose. |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       |       |       |
| d:    |       |       |       |       |       |       |       |       |
| A     |       |       |       |       |       |       |       |       |
| ctual |       |       |       |       |       |       |       |       |
| mg    |       |       |       |       |       |       |       |       |
| usage |       |       |       |       |       |       |       |       |
| (     |       |       |       |       |       |       |       |       |
| based |       |       |       |       |       |       |       |       |
| upon  |       |       |       |       |       |       |       |       |
| i     |       |       |       |       |       |       |       |       |
| ntake |       |       |       |       |       |       |       |       |
| of    |       |       |       |       |       |       |       |       |
| 325,  |       |       |       |       |       |       |       |       |
| 500,  |       |       |       |       |       |       |       |       |
| or    |       |       |       |       |       |       |       |       |
| 625   |       |       |       |       |       |       |       |       |
| mg)   |       |       |       |       |       |       |       |       |
| st    |       |       |       |       |       |       |       |       |
| andar |       |       |       |       |       |       |       |       |
| dized |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| 5     |       |       |       |       |       |       |       |       |
| 00-mg |       |       |       |       |       |       |       |       |
| ta    |       |       |       |       |       |       |       |       |
| blet. |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       |       |       |
| e:    |       |       |       |       |       |       |       |       |
| A     |       |       |       |       |       |       |       |       |
| ctual |       |       |       |       |       |       |       |       |
| mg    |       |       |       |       |       |       |       |       |
| usage |       |       |       |       |       |       |       |       |
| (     |       |       |       |       |       |       |       |       |
| based |       |       |       |       |       |       |       |       |
| upon  |       |       |       |       |       |       |       |       |
| i     |       |       |       |       |       |       |       |       |
| ntake |       |       |       |       |       |       |       |       |
| of    |       |       |       |       |       |       |       |       |
| 325   |       |       |       |       |       |       |       |       |
| or    |       |       |       |       |       |       |       |       |
| 500   |       |       |       |       |       |       |       |       |
| mg)   |       |       |       |       |       |       |       |       |
| st    |       |       |       |       |       |       |       |       |
| andar |       |       |       |       |       |       |       |       |
| dized |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| 5     |       |       |       |       |       |       |       |       |
| 00-mg |       |       |       |       |       |       |       |       |
| ta    |       |       |       |       |       |       |       |       |
| blet. |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+

On days that individuals used acetaminophen, 99% of usage was 4000 mg
(eight tablets) of acetaminophen or less per day. Another 0.9% of
acetaminophen usage was between \>4000 mg and up to 6000 mg per day.
Very rarely do individuals report using more than 8000 mg acetaminophen
daily.

For comparison, 94% of ibuprofen daily usage was of doses of up to 1200
mg (six tablets) while 6% of daily usage exceeded 1200 mg (\>6 tablets).
Some 0.23% exceeded an ibuprofen dose of 2400 mg per day, while \<0.03%
exceeded the maximum prescription ibuprofen dose of 3200 mg per day. For
consumers who use naproxen sodium, daily doses of up to 660 mg (3
tablets) represent 86.5% of naproxen sodium use, while 13.5% reported
exceeding the maximum OTC daily dose, with 1.9% of the total exceeded
the prescription naproxen sodium dose of 1100 mg daily. In summary,
while the majority of analgesic usage is within the recommended OTC
doses, a small percentage of consumers take substantially more that the
recommended doses despite product labeling.

### Slone Survey of Analgesic Use

In the Slone Survey of Analgesic Use, 79% of all aspirin users reported
using a single-ingredient product \[Slone 2001\]. A large group (41%) of
aspirin users reported a daily dose of 325 mg or less with a median
duration of use of three years. This long duration is consistent with
cardiovascular prophylaxis being the most frequently reported reason for
aspirin use (48%). Another aspect of the aspirin usage was a pattern of
concurrent use with other NSAIDs. Aspirin was used concurrently with
ibuprofen, naproxen, or ibuprofen plus naproxen by a total 2.5% of
subjects in the survey.

Few aspirin users reported a daily dose with their use of an OTC aspirin
combination product or with use of two aspirin products concurrently. A
total of 67% of OTC aspirin combination product users reported an
unknown dose and 73% of those who used a single-ingredient plus a
combination aspirin product reported an unknown dose (Table 3-3).

+------------+------------------+----------------+--------------------+
| Table 3‑3. |                  |                |                    |
| Average    |                  |                |                    |
| Daily      |                  |                |                    |
| Aspirin    |                  |                |                    |
| Exposure   |                  |                |                    |
| (mg) by    |                  |                |                    |
| Type of    |                  |                |                    |
| Aspirin    |                  |                |                    |
| Product    |                  |                |                    |
| Taken      |                  |                |                    |
| (Slone     |                  |                |                    |
| Survey of  |                  |                |                    |
| Analgesic  |                  |                |                    |
| Use)       |                  |                |                    |
| \[Slone    |                  |                |                    |
| 2001\]     |                  |                |                    |
+------------+------------------+----------------+--------------------+
|            | \- - - - - % of  |                |                    |
|            | Product Category |                |                    |
|            | Taking Dose      |                |                    |
|            | Within the       |                |                    |
|            | Stated           |                |                    |
|            | Range - - - - -  |                |                    |
+------------+------------------+----------------+--------------------+
|            | Use of One       |                | Use of Two         |
|            | Product Only     |                | Products           |
+------------+------------------+----------------+--------------------+
| Daily      | OTC              | OTC            | OTC                |
|            | s                | combination    | single-ingredient  |
| Aspirin    | ingle-ingredient |                | plus               |
| Exposure   |                  | (n= 239)       |                    |
| (mg)       | (n= 951)^a^      |                | OTC combination    |
|            |                  |                |                    |
|            |                  |                | (n= 11)            |
+------------+------------------+----------------+--------------------+
| 325 or     | 50%              | 8%             | 0%                 |
| less       |                  |                |                    |
+------------+------------------+----------------+--------------------+
| 326 to     | 17%              | 19%            | 9%                 |
| 1000       |                  |                |                    |
+------------+------------------+----------------+--------------------+
| 1001 to    | 4%               | 6%             | 18%                |
| 4000^b^    |                  |                |                    |
+------------+------------------+----------------+--------------------+
| More than  | 0.1%             | 0%             | 0%                 |
| 4000       |                  |                |                    |
+------------+------------------+----------------+--------------------+
| Unknown    | 29%              | 67%            | 73%                |
| dose       |                  |                |                    |
+------------+------------------+----------------+--------------------+
| a: Total   |                  |                |                    |
| number of  |                  |                |                    |
| users      |                  |                |                    |
| within the |                  |                |                    |
| specified  |                  |                |                    |
| category.  |                  |                |                    |
|            |                  |                |                    |
| b: Maximum |                  |                |                    |
| r          |                  |                |                    |
| ecommended |                  |                |                    |
| daily OTC  |                  |                |                    |
| analgesic  |                  |                |                    |
| dose       |                  |                |                    |
| indicated  |                  |                |                    |
+------------+------------------+----------------+--------------------+

In this survey, 98% of consumers who used ibuprofen reported taking only
one ibuprofen product. Of this group, approximately 28% of users
reported using one prescription product containing ibuprofen. Of all
ibuprofen users, 34% reported an unknown dose and 66% identified a
specific ibuprofen dose. Of those who reported a dose, eighty-seven
percent (87%) reported a dose of no more than the maximum OTC
recommended dose of 1200 mg daily. A total of 13% of ibuprofen users
reported using more than the maximum recommended daily OTC dose of 1200
mg ibuprofen and 1% reported taking more than 3200 mg daily.

Some consumers do report taking more than the recommended OTC dose of
ibuprofen. Table 3-4 provides a summary from the Slone Survey of
Analgesic Use of the reported average daily ibuprofen exposure by type
of OTC or prescription (Rx) ibuprofen product taken by consumers \[Slone
2001\]. In this survey, 4% of ibuprofen users taking an OTC
single-ingredient ibuprofen product reported taking from more than 1200
mg to 3200 mg. For individuals taking an Rx ibuprofen product, 2%
reported taking more than 3200 mg per day. In users of OTC and Rx single
ingredient products, high proportions of unknown doses were reported,
31% and 42% respectively.

+------------+-------------+---------+-----------------+-------------+
| Table 3‑4. |             |         |                 |             |
| Average    |             |         |                 |             |
| Daily      |             |         |                 |             |
| Ibuprofen  |             |         |                 |             |
| Exposure   |             |         |                 |             |
| (mg) by    |             |         |                 |             |
| Type of    |             |         |                 |             |
| Ibuprofen  |             |         |                 |             |
| Product    |             |         |                 |             |
| Taken      |             |         |                 |             |
| (Slone     |             |         |                 |             |
| Survey of  |             |         |                 |             |
| Analgesic  |             |         |                 |             |
| Use)       |             |         |                 |             |
| \[Slone    |             |         |                 |             |
| 2001\]     |             |         |                 |             |
+------------+-------------+---------+-----------------+-------------+
|            | \- - - - -  |         |                 |             |
|            | % of        |         |                 |             |
|            | Product     |         |                 |             |
|            | Category    |         |                 |             |
|            | Taking Dose |         |                 |             |
|            | Within the  |         |                 |             |
|            | Stated      |         |                 |             |
|            | Ra          |         |                 |             |
|            | nge - - - - |         |                 |             |
|            | -           |         |                 |             |
+------------+-------------+---------+-----------------+-------------+
|            | Use of One  |         | Use of Two      | Unknown     |
|            | Product     |         | Products        | Product     |
|            | Only        |         |                 |             |
+------------+-------------+---------+-----------------+-------------+
| Daily      | OTC         | Rx      | Rx + OTC        | Unknown     |
|            | single      |         | si              | type        |
| Ibuprofen  | -ingredient | (n=     | ngle-ingredient |             |
| Exposure   |             | 277)    |                 | (n= 17)     |
| (mg)       | (n= 682)^a^ |         | (n= 5)          |             |
+------------+-------------+---------+-----------------+-------------+
| 800 or     | 58%         | 30%     | 0%              | 77%         |
| less       |             |         |                 |             |
+------------+-------------+---------+-----------------+-------------+
| 801 to     | 7%          | 10%     | 0%              | 0%          |
| 1200^b^    |             |         |                 |             |
+------------+-------------+---------+-----------------+-------------+
| 1201 to    | 4%          | 17%     | 40%             | 6%          |
| 3200       |             |         |                 |             |
+------------+-------------+---------+-----------------+-------------+
| More than  | 0.1%        | 2%      | 20%             | 0%          |
| 3200       |             |         |                 |             |
+------------+-------------+---------+-----------------+-------------+
| Unknown    | 31%^c^      | 42%     | 40%             | 18%         |
| dose       |             |         |                 |             |
+------------+-------------+---------+-----------------+-------------+
| a: Total   |             |         |                 |             |
| number of  |             |         |                 |             |
| users      |             |         |                 |             |
| within the |             |         |                 |             |
| specified  |             |         |                 |             |
| category.  |             |         |                 |             |
|            |             |         |                 |             |
| b: Maximum |             |         |                 |             |
| r          |             |         |                 |             |
| ecommended |             |         |                 |             |
| daily OTC  |             |         |                 |             |
| analgesic  |             |         |                 |             |
| dose.      |             |         |                 |             |
|            |             |         |                 |             |
| c: One     |             |         |                 |             |
| subject    |             |         |                 |             |
| reported   |             |         |                 |             |
| using more |             |         |                 |             |
| than 1200  |             |         |                 |             |
| mg daily   |             |         |                 |             |
| (actual    |             |         |                 |             |
| dose not   |             |         |                 |             |
| s          |             |         |                 |             |
| pecified). |             |         |                 |             |
+------------+-------------+---------+-----------------+-------------+

Of consumers who reported using naproxen, 65% used an OTC product, 14%
used an Rx product, 2% used two naproxen products, and 19% used an
unknown naproxen product. This survey did not collect naproxen dosing
\[Slone 2001\].

## Assessment of Consumer Medication Use

Labels of OTC medications contain adequate information for safe use of a
product when read and followed by a consumer. Yet reports of consumer
misuse are available. McNeil is not aware of any definitive studies that
examine the association between consumer medication use behaviors and
increased risk, but it seems possible that some reported consumer
practices, described below (in bold), may be reduced with labeling
changes and dissemination of more widespread and pervasive consumer and
healthcare professional education programs.

**When using single-ingredient OTC analgesic products \-- consumers may
ingest amounts that exceed recommended dosing.**

Review of recent data suggest possible reasons for this behavior:

-   Pain may be so severe that extra medicine was taken for relief

-   Not understanding that two products containing the same analgesic
    (acetaminophen or NSAID) should not be taken together in a higher
    than recommended single or daily dose

-   Failure to read dosing instructions and warnings

-   Failure to heed label warnings

-   Not believing that harm could occur from taking too much medication,
    despite warning language

-   Ingestion of alcohol or other substances that impair reasoning or
    judgment

-   Intentional self-harm.

Even though actual medication use data indicated that excess use over
the maximum daily dose is rare, in the McNeil Habits and Practices
Survey 23% of consumers reported usually taking more than the OTC
recommended single dose when taking the [first]{.underline} dose of a
non-prescription pain reliever. Of these respondents, the most frequent
reasons why they usually take more than the recommended single dose were
reported as "have multiple symptoms" (49%), "want faster relief" (19%),
"have severe pain" (11%) and "told by doctor" (10%).

Similarly, among NCPIE survey respondents asked about taking more than
the recommended dose of a non-prescription medicine, 33% recalled having
ever taken more than the recommended dose. Sixty-eight percent (68%) of
the respondents, who recalled ever taking more than the recommended
dose, reported doing so because they had severe symptoms.

In the McNeil OTC Habits and Practices survey, when consumers reported
using two OTC products containing the same pain reliever, they were
asked why they were not concerned about this practice. Some of their
responses suggest that they thought it was safe to do so: "It's safe
because it is the same medicine" (27%); "I never experienced side
effects" (14%), "it's safe to take together" (8%); or "OTCs are not
strong enough" (5%) \[McNeil 2001\]. However, when asked in the survey
if they think any adverse effects are possible if more than the
recommended dose is used on a regular basis, 88% said that they believed
adverse side effects are possible.

These responses require cautious interpretation since they may reflect a
lack of concern by consumers regarding a one-time or occasional use
beyond the recommended dose.

**When using single-ingredient OTC analgesic products \-- consumers may
take concurrently more than one OTC NSAID.**

Review of recent data suggest possible reasons for this behavior:

-   Not knowing the ingredients of OTC pain relievers

-   Not knowing that different pain relievers contain similar
    ingredients

-   Severe pain states causing consumers to take additional pain
    relievers to relieve residual pain.

Some insights about consumer knowledge of pain reliever active
ingredients is found in the McNeil OTC Habits and Practices survey. When
consumers were asked what active ingredient is contained in certain
brands of pain reliever, the percentage of respondents who answered
correctly was 68% for Bayer, 42% for Advil, 42% for Motrin, 41% for
Tylenol and 10% for Aleve. In regards to concurrent use, the Slone
Survey of Analgesic Use documents patterns of concurrent use of two or
three different OTC NSAIDs \[Slone 2001\].

**When using OTC combination (cough/cold) products plus
single-ingredient OTC pain reliever products containing the same
analgesic (acetaminophen or NSAID) \-- consumers may take two (or more)
OTC products for multiple symptoms, thus taking increased doses of some
ingredients.**

Review of recent data suggest possible reasons for this behavior:

-   Not recognizing that some multi-symptom relief products contain a
    pain reliever

-   Not recognizing the risk of taking two products containing the same
    active ingredient (acetaminophen or NSAID).

The McNeil Habits and Practices survey provides insight regarding these
behaviors. Respondents generally were not aware that cough/cold products
also contained an analgesic. Sixty-six percent (66%) of consumers knew
that Tylenol Cold^^, 47% knew Vick's Nyquil^^, 40% knew Alka-Seltzer
Plus Cold^^, and 35% knew Sudafed Cold & Cough^^, respectively,
contained a pain-relief ingredient (acetaminophen). For
ibuprofen-containing products 69% knew that Motrin^®^ Sinus/Headache and
62% knew that Advil^®^ Cold & Flu contained a pain-relief ingredient. It
appears that using the tradename of an analgesic (eg Tylenol or Motrin)
within the name of a combination product increases consumer awareness of
the analgesic component of these combination products.

## Conclusions

Recent medication use surveys provide insight into consumer analgesic
use behaviors that may result in excessive OTC analgesic exposure and,
possibly, an increase in dose-related adverse effects or overdose.

McNeil has implemented labeling and educational interventions aimed at
focusing the attention of OTC medication users on:

-   the product ingredients

-   the proper dosing and proper use of medications

-   the importance of not taking more than the recommended dose

-   the importance of not using two products containing identical
    ingredients or using the same class of analgesic ingredients (eg,
    NSAIDs) during the same period of time

-   the importance of recognizing that all medications have risks,
    particularly when more than the recommended dose is taken.

# McNeil INitiatives and recommendations

**KEY POINTS**

-   Based on review of surveys regarding consumer behaviors and other
    available data regarding misuse of OTC analgesics, McNeil proposes
    that labeling and educational interventions for enhancing proper
    consumer behaviors should be aimed at focusing the attention of all
    OTC medication users on:

```{=html}
<!-- -->
```
-   the product ingredients

-   the proper dosing and proper use of medications

-   the importance of not taking more than the recommended dose

-   the importance of not using two products containing identical
    ingredients or using the same class of analgesic ingredients (eg,
    NSAIDs) during the same period of time

-   the importance of recognizing that all medications have risks,
    particularly when more than the recommended dose is taken.

```{=html}
<!-- -->
```
-   Medication use surveys provide insight to formulate risk management
    initiatives to reduce excessive OTC analgesic exposure.

```{=html}
<!-- -->
```
-   McNeil has implemented changes to its product labeling to 1)
    increase the type size of active ingredient(s) on the principal
    display panel for all single-ingredient and combination products;
    and 2) present the first letter of the name of active ingredient(s)
    in upper case type with the remainder in lower case type. McNeil
    recommends these changes for all OTC analgesics.

-   McNeil encourages the FDA to require labeling changes for
    aspirin-containing products that are consistent with those
    recommended for ibuprofen in the proposed amendment of the tentative
    final monograph (TFM) for internal analgesic, antipyretic, and
    antirheumatic drug products for over-the-counter (OTC) human use (67
    FR 54139). McNeil recommends these changes for all OTC NSAIDs.

## Introduction

> Medication use surveys provide some insight regarding consumer
> behaviors that could result in excessive OTC analgesic exposure and,
> possibly, an increase in dose-related adverse effects or overdose.
> These behaviors affect the use of:

-   Single-ingredient OTC analgesic products

-   More than one OTC NSAID analgesic product concurrently

-   Concurrent use of OTC single-ingredient and combination analgesic
    products

-   Concurrent use of an aspirin- or other NSAD-containing combination
    prescription pain reliever and an OTC pain reliever containing
    aspirin or other NSAIDs

McNeil has implemented several educational initiatives to promote the
safe use of OTC analgesics. In this section, we describe ongoing and
proposed risk management interventions that seek to reduce the
occurrence of excessive OTC analgesic exposure and potential adverse
effects.

## Current Labeling Initiatives

Appropriate consumer medication use requires knowledge of the safe and
effective dose, as well as following the labeled contraindications,
warnings about use in special circumstances, and directions when
ingestion exceeds the recommended dose. Current OTC analgesic labeling
explicitly warns consumers about concurrent use of multiple analgesic
products, warns against taking an overdose, and provides instructions in
the event of accidental overdose.

Despite these efforts, some consumers may not be aware of the specific
active ingredient contained in OTC single-ingredient analgesics. In
addition, some consumers may not be aware or may disregard the maximum
recommended dose per administration or maximum recommended daily dose.
According to results from the McNeil Consumer Habits and Practices
Survey, respondents were not concerned about this practice. These
responses require cautious interpretation since they may reflect a lack
of concern by consumers regarding a one-time or occasional use beyond
the recommended dose.

The objective of the following current McNeil initiatives and
recommendations is to direct the attention and enhance awareness of
consumers to key information that may reduce the occurrence of excessive
analgesic exposure.

### McNeil OTC Analgesic Product Labeling Initiatives

McNeil has revised its product labeling to further promote appropriate
use of its OTC monograph acetaminophen products. McNeil has also made
revisions to the labeling for its OTC Motrin^®^ (ibuprofen) products and
its St. Joseph^®^ aspirin products.

Changes to labeling include 1) increasing the type size of active
ingredient(s) on the principal display panel for all products; and 2)
presenting the first letter of the name of active ingredient(s) in upper
case type with the remainder in lower case type. McNeil recommends these
changes for all OTC analgesics.

In light of the FDA notice of a proposed amendment of the tentative
final monograph (TFM) for internal analgesic, antipyretic, and
antirheumatic drug products for over-the-counter (OTC) human use (67 FR
54139), McNeil proposes that appropriate warning and precaution language
also be incorporated into all ibuprofen products marketed under the NDA
process as well.

McNeil encourages the FDA to require labeling changes for
aspirin-containing products that are consistent with those recommended
for ibuprofen in the proposed amendment of the tentative final monograph
(TFM) for internal analgesic, antipyretic, and antirheumatic drug
products for over-the-counter (OTC) human use (67 FR 54139). McNeil
recommends these changes for all OTC NSAIDs.

## Consumer and Healthcare Professional Education Initiatives

Some consumers may not be aware of the specific active ingredient
contained in single-ingredient analgesics. To highlight the proper use
of OTC analgesics, maximize compliance with labeling recommendations,
enhance understanding of the medications consumers are using, and to
caution against the use of multiple analgesics, McNeil has instituted or
participated in several consumer education initiatives.

### McNeil Education Initiatives

In March 2002, McNeil launched its "Know Your Medicine" campaign to
complement another major campaign developed by the National Council on
Patient Information and Education (NCPIE, described below). This
initiative aims to encourage proper dosing and awareness of OTC
analgesic products using three key messages:

-   Read the label

-   Know what's in your medicine

-   Count the doses.

Consumer "touch points" for delivery of these key messages include print
and radio advertising, direct mail, retail outlets, the Internet,
pharmacies, and doctors' offices. Key education partners in the McNeil
"Know Your Medicine" initiative include the American Academy of Family
Physicians (AAFP) and the American Pharmacist Association (APhA), in
addition to NCPIE. McNeil is currently identifying additional potential
partnership opportunities, including other OTC manufacturers, retailers,
and third party professional organizations, to further help educate
consumers.

Examples of specific activities related to the "Know Your Medicine"
initiative include the following:

-   Distribution of over 11 million "Know Your Medicine" consumer
    education brochures, in English and Spanish, via retail stores, by
    direct mail, at pharmacy counters, and doctors' offices through
    2002.

-   Retailer partnerships established to develop retailer-branded
    brochures that incorporate the "Know Your Medicine" message (eg,
    CVS, Target, Walgreens, and Walmart).

-   Placement of a home page promotional module on McNeil brand web
    sites and a link to the NCPIE Be MedWise web site.

-   A direct mail and e-mail correspondence to consumers in the McNeil
    database following requests for additional information.

-   Establishment of a professional plan for professional education.

-   Use of doctors' offices to distribute additional tip cards,
    brochures, and sheets from patient education tear pads.

-   Creation of print advertisements of pediatric dosing in English and
    Spanish in publications with strong parent readership.

-   A campaign targeted directly to Hispanic consumers (with television,
    print, and radio ads).

An example of the educational content is seen in Figure 4-3 and Figure
4-4. It shows the emphasis on warning against the use of multiple
products containing the same analgesic and helping consumers to identify
where that might be a problem.

Figure 4‑3. McNeil's Know Your Medicine Brochure (Front)

![](media/image5.png){width="4.5625in" height="4.53125in"}

Figure 4‑4. McNeil's Know Your Medicine Brochure (Back)

![](media/image6.png){width="4.5625in" height="4.510416666666667in"}

### Education Initiatives - Professional and Non-Profit Organizations

**NCPIE's "Be MedWise" Campaign**

In January 2002, the National Council on Patient Information and
Education (NCPIE) launched the nationwide "Be MedWise" program, a
multi-media effort to increase public awareness of OTC product
ingredients and their uses. The program was developed by NCPIE through
an educational grant from McNeil. It was designed to attract support
from other manufacturers as well. This effort has proven successful. On
August 15, 2002, Proctor and Gamble announced its support with a \$1
million educational grant toward the "Be MedWise" campaign. McNeil is
optimistic that additional sponsors will participate.

The program includes television and print advertisements, as well as an
Internet web site ([www.bemedwise.org](http://www.bemedwise.org/)). Many
of the materials have been developed in cooperation with the FDA. For
example, NCPIE has a television advertisement aimed at avoiding the use
of more than one medication containing the same active ingredient. The
ad has already reached 70% of the population and has been seen over one
billion times. It features a man, who, on the advice of his wife, reads
the labels of the drugs he is taking and discovers that he is taking two
drugs with the same active ingredient for the same indication.

The "Be MedWise" website has been featured on CNN. Key website
communication points include:

-   "Know What's in Your Medicine" - designed to encourage consumers to
    read medication labels to understand the active ingredient(s) in the
    OTC product they have purchased.

-   "How to Read a Drug Label" - designed to encourage consumers to read
    medication labels and to help them understand the safety and use
    information present on the label.

Phase II of the campaign, launched on May 16, 2002, features an expanded
consumer-friendly website, advertisement in two issues of TIME magazine,
and expanded media outreach.

**Other Professional Organization Education Initiatives**

McNeil initiatives include efforts to promote physicians', pharmacists',
and other healthcare professionals' awareness of tools to reduce the
occurrence of inappropriate OTC analgesic use. Working in cooperation
with various professional organizations, McNeil has sponsored materials
directed towards this objective.

For example, the American Association of Family Physicians (AAFP) has
developed a monograph entitled "Appropriate Use of Common OTC Analgesics
and Cough and Cold Medications" \[Montauk 2002\] and supporting patient
education tools. This includes "Knowing What's in the Medicine You
Take," a guide to using OTC pain relievers and prescription medicines.
These materials were sponsored by an educational grant from McNeil. They
were distributed to all 93,000 AAFP members and 30,000 high-prescribing
primary care physicians.

In an effort to improve pharmacist awareness, McNeil has sponsored a
National Association of Chain Drug Stores (NACDS) memo containing
extensive information on the importance of proper dosing to be included
in the Chain Pharmacist Practice Memo. Building on a previously
established partnership with the American Pharmaceutical Association
(APhA), McNeil is developing several monographs for continuing education
including "The Pharmacist's Role in Assuring OTC Medication Use,"
Achieving Optimal Therapeutic Outcomes with Nonprescription Analgesics,"
and "Health Communication in Culturally Diverse Patient Populations."
These monographs will be sent to over 55,000 pharmacists in the US.

## Ongoing Consumer OTC Analgesic Use Monitoring

McNeil is dedicated to evaluating the impact of its current labeling and
education interventions described above on reported consumer behavior
and awareness. To this end, McNeil has entered into an agreement with
the Slone Epidemiology Center to expand their ongoing telephone survey
of consumer behaviors regarding medications \[Kaufman 2002\].

Slone is adding questions to monitor changes in reported consumer
behavior and to allow adjustments to OTC analgesic use-related consumer
education and labeling initiatives (ie, to examine the impact of these
initiatives on consumer behaviors). Data collection began in mid-June
2002. Consumers are asked about usage of any OTC analgesic product
during the previous week. Respondents are asked about the dosages taken
for each OTC analgesic used and sources they use to obtain information
about these products. In addition, respondents are asked about their
knowledge of product ingredient(s), the recommended labeled dose and
knowledge of multiple-products with the same analgesic ingredient.

The periodic assessment of consumer behaviors will provide a tool to
measure changes in consumer awareness and reported behaviors that arise
in response to targeted messages from our consumer education programs,
as well as from labeling revisions to OTC and prescription analgesic
products.

## Conclusions

McNeil has reviewed survey and other data that provide insights for the
interventions we have implemented. These interventions are designed to
target the small number of consumers who may inadvertently exceed
recommended doses of OTC analgesics. Excessive doses of an OTC analgesic
may be taken inadvertently because an individual does not pay attention
to the product label, does not understand the product label, or is not
sufficiently concerned about the potential ramifications of exceeding
the recommended dose \[personal communication Carr 2002\]. Implemented
McNeil initiatives include labeling revisions, consumer and healthcare
education programs, and an ongoing consumer OTC analgesic use monitoring
survey.

# Reference List

The reference materials are listed below in alphabetically order by
section.

Section 2 Assessment of Safety of Aspirin and other Nonsteroidal
Anti-Inflammatory Drugs (NSAIDs)

Bjorkman DJ. Commentary: Gastrointestinal safety of coxibs and outcomes
studies: What's the verdict?. [J Pain Symptom Manage]{.underline} 2002
April 23;(4S):S11-S14.

Blot WJ, McLaughlin JK. Over the counter non-steroidal anti-inflammatory
drugs and risk of gastrointestinal bleeding. [J Epidemiol
Biostat]{.underline} 2000;5(2):137-142.

Bombardier C, Laine L, Reicin A, et al. Comparison of upper
gastrointestinal toxicity of rofecoxib and naproxen in patients with
rheumatoid arthritis. [N Engl J Med]{.underline} 2000 Nov
23;343(21):1520-1528.

Dajani ES. Gastrointestinal toxicity of over-the-counter analgesics.
[AJG]{.underline} 1998;93(7):1020-1022.

Dargan PI, Wallace CI, Jones AL. An evidence based flowchart to guide
the management of acute salicylate (aspirin) overdose. [Emerg Med
J]{.underline} 2002;19:206-209.

Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term
use of aspirin: meta-analysis. [BMJ]{.underline} 2000;321:1183-1187.

FitzGerald GA, Patrono C. The coxibs, selective inhibitors of
cyclooxygenase-2. [N Engl J Med]{.underline} 2001 Aug 9;345(6):433-442.
Review.

Garcia Rodriguez LA. Variability in Risk of Gastrointestinal
complications with different nonsteroidal anti-inflammatory drugs. [Am J
Med]{.underline} 1998 Mar 30:104(3A):30S-42S.

Griffin MR, Piper JM, Daugherty JR, et al. Nonsteroidal
anti-inflammatory drug use and increased risk for peptic ulcer disease
in elderly persons. [Ann Intern Med]{.underline} 1991 Feb
15;114(4):257-263.

Gutthann SP, Garcia Rodriguez LA, Raiford DS. Individual nonsteroidal
anti-inflammatory drugs and other risk factors for upper
gastrointestinal bleeding and performation. [Epidemiology]{.underline}
1997;8(1):18-24.

Hardman JG, ed. [Goodman & Gilman\'s The Pharmacological Basis of
Therapeutics]{.underline} 10th ed. New York:McGraw-Hill;2001:700-702.

Havey JM, Hill RE, Robins CW, et al. Supratherapeutic use of
over-the-counter (OTC) analgesics by patients reporting to an urban
dental clinic. [J Toxicol Clin Toxicol]{.underline} 2001;39(5):543
\[abstract\].

Henry D, Lim LLY, Garcia Rodriguez LA, et al. Variability in risk of
gastrointestinal complications with individual non-steroidal
anti-inflammatory drugs: results of a collaborative meta-analysis.
[BMJ]{.underline} 1996;312:1563-1566.

Hillis WS. Areas of emerging interest in analgesia: Cardiovascular
complications. [Am J Ther]{.underline} 2002;9:259-269.

Jones A. Over-the-counter analgesics: A toxicologic perspective. [Am J
Ther]{.underline} 2002;9:245-257.

Kaufman DW, Kelly JP, Rosenberg L, et al. Recent patterns of medication
use in the ambulatory adult population of the United States. The Slone
Survey. [JAMA]{.underline} 2002;287:337-344.

Kelly JP, Kaufman DW, Jurgelon JM, et al. Risk of aspirin-associated
major upper-gastrointestinal bleeding with enteric-coated or buffered
product. [Lancet]{.underline} 1996;348:1413-1415

Konstam MA, Weir MR, Reicin A, et al. Cardiovascular thrombotic events
in controlled, clinical trials of rofecoxib. [Circulation]{.underline}
2001;104:2280-2288.

Kreplick, LW. (2001, June 7). Toxicity, salicylate. [eMedicine
Journal]{.underline}, 2(6), Retrieved August 19, 2002 from
http://www.emedicine.com

Kurata JH, Abbey De. The effect of chronic aspirin use on duodenal and
gastric ulcer hospitalizations. [J Clin Gastroenterol]{.underline}
1990;12(3):260-266.

Laporte JR, Carne X, Vidal X, et al. Upper gastrointestinal bleeding
inrelation to previous use of analgesics and non-steroidal
anti-inflammatory drugs. [Lancet]{.underline} Jan 12 1991;337:85-89.

Larson AM, Ostapowicz G, Fontana RJ, et al. Outcome of
acetaminophen-induced liver failure in the USA in suicidal vs accidental
overdose: Preliminary results of a prospective multi-center trial.
[Hepatology]{.underline} 2000;32(4 pt 2):396A \[abstract\].

Lee WM. Acute liver failure. [Clinical Perspectives in
Gastroenterology]{.underline} 2001 Mar/Apr;101-110.

Levy M, Miller DR, Kaufman DW, et al. Major upper gastrointestinal tract
bleeding relation to the use of aspirin and other nonnarcotic
analgesics. [Arch Intern Med]{.underline} 1988;148:281-285.

Litovitz TL. 2000 annual report of the American Association of Poison
Control Centers Toxic Exposure Surveillance System. [Am J Emerg
Med]{.underline} 2001;19(5):337-395

McGeehan M, Bush RK. The mechanisms of aspirin-intolerant asthma and its
management. [Curr Allergy Asthma Rep]{.underline} 2002;2:117-125.

Ofman JJ, Maclean CH, Straus WL, et al. A metaanalysis of severe upper
gastrointestinal complications of nonsteroidal anti-inflammatory drugs.
[J Rheumatol]{.underline} 2002;29(4):804-812.

Prichard PJ, Kitchingham GK, Hawkey CJ. Gastric mucosal bleeding: What
dose of aspirin is safe? [British Society Gastroenterology]{.underline}
1987:A1401.

Proudfoot AT. Toxicity of salicylates. [Am J Med]{.underline}
1983:99-103.

Report of CIOMS Working Group IV. [Benefit-risk balance for marketed
drugs: Evaluating Safety Signals]{.underline} Geneva:CIOMS;1998:111.

Singh G, Rosen Ramey D, Morfeld D, et al. Gastrointestinal Tract
Complications of nonsteroidal anti-inflammatory drug treatment in
rheumatoid arthritis. [Arch Intern Med]{.underline} 1996;156:1530-1536.

Singh G. Gastrointestinal Complications of Prescription and
over-the-counter nonsteroidal anti-inflammatory drugs: A view from the
ARAMIS database. [Am J Ther]{.underline} 2000;7:115-121.

Singh G, Triadafilopoulos G. Epidemiology of NSAID induced
gastrointestinal complications. [J Rheumatol]{.underline}
1999;26(56):18-24.

Slone Epidemiology Unit. Prepared for McNeil Consumer Healthcare.
Analgesic use in the adult population of the United States:
Acetaminophen, aspirin, ibuprofen and naproxen. Results of a
population-based telephone survey, 1998-2001. Report on file, 2001.

Sorensen HT, Mellemkjaer L, Blot WJ, et al. Risk of upper
gastrointestinal bleeding associated with use of low-does aspirin. [Am J
Gastrointestinal]{.underline} 2000;95(9):2218-2224.

Straus WL, Ofman JJ. Gastrointestinal toxicity associated with
nonsteroidal anti-inflammatory drugs. [Gastroenterol Clin North
Am]{.underline} 2001;30(4):895-920.

UK-TIA Study Group. United Kingdom transient ischaemic attack (UK-TIA)
aspirin trial: Interim results. [JNeurol Neurosurg
Psychiatry]{.underline} 1991;54:1044-1054.

US Census Bureau. Profile of General Demographic Characteristics: 2000.
Available at
<http://factfinder.census.gov/servlet/QTTable?ds_name=D&geo_id=D&qr_name=DEC_2000_SF1_U_DP1&_lang=en>.
(accessed on 08/30/02).

Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk
of peptic ulcer bleeding. [BMJ]{.underline} 1995 Apr 1;310:827-830.

Woolley BH, Temple AR. Toxicology and Poison Prevention.
1977;I(8):41-51.

**Section 3 Consumer Medication Use**

Kaufman DW, Kelly JP, Rosenberg L, et al. Recent patterns of medication
use in the ambulatory adult population of the United States. The Slone
Survey. [JAMA]{.underline} 2002;287:337-344.

McNeil Consumer & Specialty Pharmaceuticals. MediScope
medication-use/symptom diary data analysis. Data on file, 2002.

McNeil Consumer & Specialty Pharmaceuticals. McNeil OTC habits &
practices study. Data on file, 2001.

National Council on Patient Information and Education (NCPIE). Attitudes
and Beliefs About the Use of Over-the-Counter Medicines: A Dose of
Reality. January 2002. (Available on
http:www.bemedwise.org/survey/final_survey.pdf, access confirmed 23 July
2002.)

Slone Epidemiology Unit. Prepared for McNeil Consumer Healthcare.
Analgesic use in the adult population of the United States:
Acetaminophen, aspirin, ibuprofen and naproxen. Results of a
population-based telephone survey, 1998-2001. Report on file, 2001.

**Section 4 McNeil Initiatives and Recommendations**

Kaufman DW, Kelly JP, Rosenberg L, et al. Recent patterns of medication
use in the ambulatory adult population of the United States. The Slone
Survey. [JAMA]{.underline} 2002;287:337-344.

Montauk SL, Rheinstein PH. Appropriate Use of Common OTC Analgesics and
Cough and Cold Medications. American Family Physician Monograph No. 1.
Leawood, KS: American Academy of Family Physicians, 2002.

[^1]: The ICD-9 codes used for calculating this estimate were 531.0,
    531.2, 531.4, 531.6, 532.0, 532.2, 532.4, 532.6, 533.0, 533.2,
    533.4, 533.6, 534.0, 534.2, 534.4, 534.6, and 578.0 -- 578.9.