**EXECUTIVE SUMMARY**

This is McNeil\'s background package on acetaminophen for the September
19, 2002 Nonprescription Drugs Advisory Committee Meeting that was
announced in the *Federal Register* of August 20, 2002. This submission
provides data and an evidence-based assessment of acetaminophen efficacy
and safety.

Our assessment demonstrates the following key points:

-   Access to OTC pain reliever and fever reducer medicines provides
    major benefit to millions of Americans.

-   Each week, nearly 50 million adults in the United States take
    acetaminophen-containing products.

-   Acetaminophen, at currently recommended doses, is used safely by
    adults, pediatric and elderly patients, as well as by patients with
    chronic renal disease or chronic stable liver disease.

-   Review of metabolism, pharmacokinetic, and prospective clinical
    trial data confirms that there is no increased risk of toxicity at
    currently recommended doses of acetaminophen.

```{=html}
<!-- -->
```
-   The optimal effective adult analgesic dose of acetaminophen is 1000
    mg every four to six hours, up to 4000 mg per 24 hours. This dosing
    frequency is supported by pharmacokinetic, clinical, and consumer
    use data.

-   The AERS spontaneous reporting system serves as a signal generating
    system for rare, unexpected adverse events in marketed products. It
    cannot be used to determine event rates, dose, or intentionality.

-   Case reports are the source of serious hepatic events associated
    with acetaminophen exposure. These reports are observational and
    therefore cannot be used to establish causality.

-   Recent medication use surveys suggest that the vast majority of
    consumers use analgesics within the recommended OTC daily dose.

-   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.

In summary,

-   Acetaminophen, at currently recommended OTC doses, is safe and
    effective for adults and children, including the elderly and people
    with liver or kidney disease. Case reports, including AERS data, do
    not undermine this conclusion.

```{=html}
<!-- -->
```
-   As has been known for many years, a substantial untreated
    acetaminophen overdose can lead to serious health consequences.

```{=html}
<!-- -->
```
-   Through labeling changes and educational programs, McNeil is
    committed to minimizing any product misuse leading to overdose.

```{=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.

**TABLE OF CONTENTS**

[1 INTRODUCTION 4](#introduction)

[2 efficacy of Acetaminophen in the treatment of pain
9](#efficacy-of-acetaminophen-in-the-treatment-of-pain)

[2.1 Benefits of Pain Treatment 10](#benefits-of-pain-treatment)

[2.2 Well-Established Efficacy 11](#well-established-efficacy)

[2.2.1 Comparative Efficacy of Acetaminophen 1000 mg Versus 500 mg --
From Individual Clinical Trials
11](#comparative-efficacy-of-acetaminophen-1000-mg-versus-500-mg-from-individual-clinical-trials)

[2.2.2 Comparative Efficacy of Acetaminophen 1000 mg Versus 600/650 mg
-- From Systematic Review and Meta-Analysis
12](#comparative-efficacy-of-acetaminophen-1000-mg-versus-600650-mg-from-systematic-review-and-meta-analysis)

[2.2.3 Comparative Efficacy of Acetaminophen 1000 mg Versus 650 mg --
From Individual Clinical Trials
13](#comparative-efficacy-of-acetaminophen-1000-mg-versus-650-mg-from-individual-clinical-trials)

[2.2.4 Comparative Efficacy of Acetaminophen 1000 mg Versus 2000 mg --
From An Individual Clinical Trial
13](#comparative-efficacy-of-acetaminophen-1000-mg-versus-2000-mg-from-an-individual-clinical-trial)

[2.3 Pharmacokinetic-Pharmacodynamic Model
13](#pharmacokinetic-pharmacodynamic-model)

[2.3.1 Modeling Reveals Effective Concentration for Analgesic Response
14](#modeling-reveals-effective-concentration-for-analgesic-response)

[2.3.2 The 1000-mg Dose Yields Acetaminophen Concentrations Needed to
Provide Adequate Pain Relief
14](#the-1000-mg-dose-yields-acetaminophen-concentrations-needed-to-provide-adequate-pain-relief)

[2.3.3 Data on Frequency of Dosing 17](#data-on-frequency-of-dosing)

[2.4 Implication of Modifying Acetaminophen Dosing Regimen
19](#implication-of-modifying-acetaminophen-dosing-regimen)

[2.5 Added Effectiveness for Acetaminophen-Containing Prescription
Combination Products
19](#added-effectiveness-for-acetaminophen-containing-prescription-combination-products)

[2.5.1 Rationale for an Acetaminophen Combination Product
20](#rationale-for-an-acetaminophen-combination-product)

[2.5.2 Efficacy and Safety of an Acetaminophen Combination Product
20](#efficacy-and-safety-of-an-acetaminophen-combination-product)

[2.6 Conclusions 23](#conclusions)

[3 ACETAMINOPHEN PHARMACOLOGY and toxicology
24](#acetaminophen-pharmacology-and-toxicology)

[3.1 Acetaminophen Mechanism of Action
25](#acetaminophen-mechanism-of-action)

[3.2 Acetaminophen Metabolism 25](#acetaminophen-metabolism)

[3.3 Acetaminophen Pharmacokinetics 27](#acetaminophen-pharmacokinetics)

[3.3.1 Overview 27](#overview)

[3.3.2 Single-Dose Pharmacokinetics at Recommended Therapeutic Doses
27](#single-dose-pharmacokinetics-at-recommended-therapeutic-doses)

[3.3.3 Single-Dose Pharmacokinetics up to Nine Grams
29](#single-dose-pharmacokinetics-up-to-nine-grams)

[3.3.4 Single-Dose Pharmacokinetics at Very High Doses
31](#single-dose-pharmacokinetics-at-very-high-doses)

[3.3.5 Relationship of Dose to Pharmacokinetics
32](#relationship-of-dose-to-pharmacokinetics)

[3.3.6 Repeat- or Multiple-Dose Pharmacokinetics at 4 and 6 g/Day
33](#repeat--or-multiple-dose-pharmacokinetics-at-4-and-6-gday)

[3.4 Acetaminophen Toxicology 37](#acetaminophen-toxicology)

[3.4.1 Pharmacodynamics of Toxicity 37](#pharmacodynamics-of-toxicity)

[3.4.2 Estimation of the Acute Hepatotoxic Dose of Acetaminophen
38](#estimation-of-the-acute-hepatotoxic-dose-of-acetaminophen)

[3.4.3 Development of the Nomogram to Manage Acute Overdose Treatment
39](#development-of-the-nomogram-to-manage-acute-overdose-treatment)

[3.4.4 Hepatotoxic Potential is Less for Divided Doses of Acetaminophen
40](#hepatotoxic-potential-is-less-for-divided-doses-of-acetaminophen)

[3.5 Summary 41](#summary)

[4 Assessment of Acetaminophen Safety
42](#assessment-of-acetaminophen-safety)

[4.1 Use of Recommended Doses in the General Population
43](#use-of-recommended-doses-in-the-general-population)

[4.2 Use of Recommended Doses in Selected Populations
44](#use-of-recommended-doses-in-selected-populations)

[4.2.1 Elderly Adults 44](#elderly-adults)

[4.2.2 Patients with Renal Disease 45](#patients-with-renal-disease)

[4.2.3 Patients with Liver Disease 46](#patients-with-liver-disease)

[4.2.4 Pediatric Patients with Liver Disease
47](#pediatric-patients-with-liver-disease)

[4.2.5 Obese Adults 47](#obese-adults)

[4.2.6 Conclusions 48](#conclusions-1)

[4.3 Metabolic Alterations Theorized to Increase Risk
48](#metabolic-alterations-theorized-to-increase-risk)

[4.3.1 Situations In Which Cytochrome P-450 2E1 Might Be Induced
48](#situations-in-which-cytochrome-p-450-2e1-might-be-induced)

[4.3.2 Concomitant Use of Drugs That Induce Other Cytochrome P-450
Isoenzymes
50](#concomitant-use-of-drugs-that-induce-other-cytochrome-p-450-isoenzymes)

[4.3.3 Situations Affecting Glucuronidation
52](#situations-affecting-glucuronidation)

[4.3.4 Fasting and UDP-Glucuronic Acid or Precursor Depletion
52](#fasting-and-udp-glucuronic-acid-or-precursor-depletion)

[4.3.5 Gilbert's Syndrome and UDP-Glucuronosyltransferase Depletion
52](#gilberts-syndrome-and-udp-glucuronosyltransferase-depletion)

[4.3.6 Glutathione 53](#glutathione)

[4.3.7 Conclusion 55](#conclusion)

[4.4 Clinical Characteristics of Acute Acetaminophen Overdose
55](#clinical-characteristics-of-acute-acetaminophen-overdose)

[4.5 Situations of Potential Acetaminophen Overdose and
Misadministration
56](#situations-of-potential-acetaminophen-overdose-and-misadministration)

[4.5.1 Acute Intentional Overdose in Adults -- Suicide Gestures or
Attempts
56](#acute-intentional-overdose-in-adults-suicide-gestures-or-attempts)

[4.5.2 Repeated Supratherapeutic Overdose in Adults
56](#repeated-supratherapeutic-overdose-in-adults)

[4.5.3 Acute Accidental Overdose in Pediatric Patients
57](#__RefHeading___Toc18717605)

[4.5.4 Repeated Supratherapeutic Overdose in Pediatric Patients
58](#repeated-supratherapeutic-overdose-in-pediatric-patients)

[4.6 Data Sources Available to Assess Misadministration and Overdose
58](#data-sources-available-to-assess-misadministration-and-overdose)

[4.6.1 Quality of Data 59](#quality-of-data)

[4.6.2 Spontaneous Reports Selected by the FDA for Evaluating the
Hepatotoxicity of Acetaminophen (FDA AERS Data Set)
61](#spontaneous-reports-selected-by-the-fda-for-evaluating-the-hepatotoxicity-of-acetaminophen-fda-aers-data-set)

[4.6.3 Poison Control Center Data Sets
74](#poison-control-center-data-sets)

[4.6.4 Drug Abuse Warning Network (DAWN)
79](#drug-abuse-warning-network-dawn)

[4.6.5 Published Data On Liver Transplant Centers' Experience and Acute
Liver Failure Registry
81](#published-data-on-liver-transplant-centers-experience-and-acute-liver-failure-registry)

[4.6.6 Conclusions Concerning Data Sources Available to Assess
Misadministration and Overdose
82](#conclusions-concerning-data-sources-available-to-assess-misadministration-and-overdose)

[4.7 Comparative Safety Analysis with NSAIDs
83](#comparative-safety-analysis-with-nsaids)

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

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

[4.7.3 Comparison of Excess Mortality
86](#comparison-of-excess-mortality)

[4.7.4 Conclusion 88](#conclusion-1)

[5 COnsumer Medication USE 89](#consumer-medication-use)

[5.1 Introduction 90](#introduction-1)

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

[5.2.1 Actual Consumer Medication Use
90](#actual-consumer-medication-use)

[5.2.2 FDA-Selected AERS Data Set of Acetaminophen Reports
91](#fda-selected-aers-data-set-of-acetaminophen-reports)

[5.2.3 Consumer Attitudes About Medications
91](#consumer-attitudes-about-medications)

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

[5.3.1 MediScope^™^ Household Survey 92](#mediscope-household-survey)

[5.3.2 Slone Survey of Analgesic Use 95](#slone-survey-of-analgesic-use)

[5.3.3 FDA-Selected AERS Data Set 96](#fda-selected-aers-data-set)

[5.4 Assessment of Consumer Medication Use
97](#assessment-of-consumer-medication-use)

[5.5 Conclusions 101](#conclusions-2)

[6 McNeil Initiatives and recommendations
102](#mcneil-initiatives-and-recommendations)

[6.1 Introduction 104](#introduction-2)

[6.2 McNeil's Previous Initiatives 104](#mcneils-previous-initiatives)

[6.2.1 Chronology of Previous Initiatives
104](#chronology-of-previous-initiatives)

[6.2.2 Previous Initiatives: Programs to Reduce Misadministration of
Pediatric Acetaminophen Products
105](#previous-initiatives-programs-to-reduce-misadministration-of-pediatric-acetaminophen-products)

[6.3 McNeil's Current Initiatives 107](#mcneils-current-initiatives)

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

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

[6.3.3 Current Consumer OTC Analgesic Use Monitoring
120](#current-consumer-otc-analgesic-use-monitoring)

[6.4 Conclusions 121](#conclusions-3)

[7 Attachments 122](#attachments)

[8 Reference List 128](#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 19, 2002.

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

**KEY POINTS**

**Efficacy**

-   Treatment of pain provides tremendous benefit to many consumers.
    Consumers will self-treat pain and their selection of OTC analgesics
    will depend on availability, accessibility, and effectiveness of
    these products.

-   A recent acute pain dose-response study demonstrates superior
    efficacy of acetaminophen 1000 mg compared to both acetaminophen 500
    mg and placebo.

-   Pharmacokinetic-pharmacodynamic modeling predicts that plasma
    concentrations following a 1000-mg dose of acetaminophen are
    consistently at or above the EC~50~ needed for optimal pain relief.
    Although development of the model was not based on a 650-mg dose of
    acetaminophen, plasma concentrations of a 650-mg dose of
    acetaminophen consistently fall below the EC~50~. These findings,
    integrated with the data from the meta-analysis and
    placebo-controlled studies demonstrate that the optimal effective
    adult analgesic dosing of acetaminophen is 1000 mg every four to six
    hours, up to 4000 mg per 24 hours.

-   A dosing frequency for acetaminophen of every four to six hours up
    to 4000 mg daily is supported by pharmacokinetic, clinical and
    consumer use data indicating both that the majority of subjects
    remedicate in this time frame and that the analgesic duration effect
    lasts between three to five hours.

**Pharmacokinetics**

-   Acetaminophen pharmacokinetics, which have been thoroughly
    characterized by prospective well-controlled studies, are consistent
    and predictable over a wide range of single doses. Therefore, the
    amount of acetaminophen in the body (and plausible corresponding
    doses) can be reliably estimated from a plasma concentration(s)
    measured at a known time following acute acetaminophen ingestion.

-   Prospective pharmacokinetic studies show that with repeat doses of 1
    and 1.5 g (4 and 6 g/day) acetaminophen plasma concentrations reach
    steady-state levels within 10 to 15 hours and do not accumulate to
    higher levels with continued dosing. These results are consistent
    with the short elimination half-life of two to three hours for
    acetaminophen and the recommended dosing interval of four to six
    hours.

**Metabolism**

-   Acetaminophen is primarily metabolized by the liver via three
    pathways: glucuronidation, sulfation, and oxidation. All resulting
    *conjugates* from these pathways are inactive and nontoxic. Only the
    sulfation pathway is capacity-limited, as the glucuronide pathway
    does not saturate, even following a substantial acute acetaminophen
    overdose.

-   The oxidative intermediate, NAPQI, which is mainly generated by
    CYP2E1 oxidation, is not measurable due to its high reactivity and
    *instantaneous conjugation with glutathione*. NAPQI may potentially
    cause hepatotoxicity after a substantial acute overdose; however,
    glutathione is present in sufficient quantities to conjugate the
    small amount of NAPQI following therapeutic acetaminophen doses.
    Additionally, the body continuously replenishes glutathione. As a
    result, liver toxicity does not occur at normal therapeutic doses.

-   With repeat doses of 0.65 and 1 g acetaminophen every six hours,
    steady-state concentrations of the glucuronide conjugate are higher,
    and those for the sulfate, cysteine, and mercapurate conjugates are
    all lower than what would be predicted from single dose data. These
    findings indicate time-dependent changes in acetaminophen metabolism
    during repeat dosing, which may reflect up- and/or down-regulation
    of the different enzymatic pathways.

**Special Populations**

-   Acetaminophen, at currently recommended doses, is used safely by
    adults, pediatric and elderly patients, as well as by patients with
    chronic renal disease or chronic stable liver disease. Review of
    metabolism pathways suggests that there is not an increased risk of
    toxicity at currently recommended doses of acetaminophen.

    **Serious Adverse Event Reports**

```{=html}
<!-- -->
```
-   The AERS spontaneous reporting system serves as a signal generating
    system for rare, unexpected adverse events in marketed products. It
    cannot be used to determine event rates, dose, or intentionality.

```{=html}
<!-- -->
```
-   Case reports are the source of serious hepatic events associated
    with acetaminophen exposure. These reports are observational and
    therefore cannot be used to establish causality.

```{=html}
<!-- -->
```
-   The number of serious reports for acetaminophen products at the FDA
    is disproportionately large relative to other monograph analgesics
    because: a) FDA regulations do not require AERS reporting for OTC
    monograph drug products, and b) McNeil has submitted serious reports
    for all single-ingredient acetaminophen products and reports of
    death for acetaminophen combination products, including published
    literature and fatalities from AAPCC.

```{=html}
<!-- -->
```
-   Data from AAPCC, DAWN and liver transplant centers are consistent,
    and show that intentional suicide is the most frequent reason for
    adult acetaminophen overdose.

    **Consumer Medication Use**

-   Recent medication use surveys suggest that the vast majority of
    consumers use analgesics within the recommended OTC daily dose.

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

-   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.

**Risk Management Initiatives**

-   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}
<!-- -->
```
-   McNeil is also sponsoring an ongoing survey of consumer behaviors to
    monitor changes in consumer OTC analgesic use behaviors.

```{=html}
<!-- -->
```
-   Pediatric misadministration rarely results in serious outcome. Rare
    events could be further prevented by permitting dosage information
    for children under two on the product label.

**Impact of Risk Management Initiatives**

-   Evaluation of acetaminophen risks, as with evaluation of NSAID
    risks, should include all doses that may be self-administered given
    consumer utilization patterns for OTC-available analgesics.

```{=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.

# efficacy of Acetaminophen in the treatment of pain

**Key Points**

-   Treatment of pain provides tremendous benefit to many consumers.

-   A recent acute pain dose-response study demonstrates superior
    efficacy of acetaminophen 1000 mg compared to both acetaminophen 500
    mg and placebo.

-   In addition to individual study data which demonstrate acetaminophen
    1000 mg has superior efficacy when compared to acetaminophen 650 mg
    and 500 mg, the results of a systematic review and meta-analysis
    demonstrate the statistically significant superior efficacy of
    acetaminophen 1000 mg over acetaminophen 600/650 mg in the relief of
    pain.

-   Pharmacokinetic-pharmacodynamic modeling predicts that plasma
    concentrations following a 1000-mg dose of acetaminophen are
    consistently at or above the EC~50~ needed for optimal pain relief.
    Although development of the model was not based on a 650-mg dose of
    acetaminophen, plasma concentrations of a 650-mg dose of
    acetaminophen consistently fall below the EC~50~. These findings,
    integrated with the data from the meta-analysis and
    placebo-controlled studies demonstrate that the optimal effective
    adult analgesic dosing of acetaminophen is 1000 mg every four to six
    hours, up to 4000 mg per 24 hours.

-   A dosing frequency for acetaminophen of every four to six hours up
    to 4000 mg daily is supported by pharmacokinetic, clinical and
    consumer use data indicating both that the majority of subjects
    remedicate in this time frame and that the analgesic duration effect
    lasts between three to five hours.

-   Acetaminophen in prescription combination medications provides added
    effectiveness over the individual components given separately.

## Benefits of Pain Treatment

Pain is widely recognized as a condition that merits appropriate
pharmacological and non-pharmacological treatment. Recent guidelines and
standards for the assessment and treatment of pain have been issued,
including those by accrediting organizations \[JCAHO 2001\]; state,
federal, and international agencies[^1]; and medical associations[^2].
These guidelines and standards are predicated upon the acceptance of the
individual's right to receive appropriate assessment and treatment for
their pain.

This recent emphasis on appropriate pain treatment is fueled by a
substantial body of research demonstrating that under-treatment of pain
results in considerable costs to patients[^3] (eg, the deterioration of
physical and psychological health), families (eg, increased social
isolation and caregiver distress) \[Snelling 1994; Miaskowski 1997\],
and healthcare institutions[^4] (eg, substantial healthcare utilization
and costs). Research also documents the staggering costs of pain borne
by society. In a survey examining the impact of pain in the American
workplace, investigators found that painful conditions accounted for 50
million sick days per year at an annual cost of \$3 billion in excess
wages \[Louis Harris 1996\]. Additional costs include wages required to
replace absent workers, and disability and worker's compensation claims.
The most common types of pain resulting in absenteeism were headaches
and menstrual pain (each affecting 40 million workers), low back pain
(affecting 36 million workers), muscle pain (affecting 24 million
workers), and neck pain (affecting 20 million workers). As a result, the
socioeconomic ramifications of these "everyday" types of pain are
extensive and affect the society at large.

Given these extensive patient, family, healthcare institution and
socioeconomic costs, a U.S. Federal law was passed in 2001 (U.S., H.R.
3244 Title VI, Sec. 1603), which provided for the \"Decade of Pain
Control and Research\" to begin January 1, 2001. This Congressionally
declared \"Decade\" (the second medical decade in U.S. history ever to
be declared by Congress), is heralded by both pain specialists and
advocates alike as bringing a much-needed focus on pain control to both
the public and private sectors, and as the first step in stimulating
further progress in pain-related research, education and clinical
treatment.

As such, it is very important for the everyday aches and pains
experienced by people in all walks of life to be adequately treated.
Acetaminophen, at doses up to 4000 mg per day, is considered to be
beneficial in the treatment of mild to moderate pain due to its
favorable efficacy and safety profile \[Amadio 1984\].

## Well-Established Efficacy 

The efficacy of acetaminophen for the temporary relief of aches and
pains and for the reduction of fever has been well established in over
150 placebo-controlled clinical trials. These studies examined a variety
of pain, using these models: dental pain (n=76), surgical pain (n=38),
headache/migraine pain (n=19), osteoarthritis (n=3), menstrual pain
(n=2), and other painful conditions (n=13). In 1977, the Advisory Review
Panel on OTC Internal Analgesic, Antipyretic and Antirheumatic Products
concluded that acetaminophen was a safe and effective OTC analgesic when
taken in an adult dosage of up to 1000 mg, not to exceed 4000 mg in 24
hours for no longer than ten days. This same dose was reaffirmed in
1988, when FDA published the Tentative Final Monograph (TFM) for OTC
Internal Analgesic, Antipyretic and Antirheumatic Products.

Important to this review is a discussion of the appropriate dose of
acetaminophen. Several dosage levels have been studied. The most common
regimen is 1000 mg given every four to six hours up to four doses (4000
mg) per day. The next most common regimen is 650 mg given every four
hours up to six doses (3900 mg) per day. Data demonstrate that consumers
get more effective pain relief of a longer duration with single doses of
1000 mg compared to a dose of 650 mg or to a dose of 500 mg.

### Comparative Efficacy of Acetaminophen 1000 mg Versus 500 mg -- From Individual Clinical Trials

A recent acute dose-response study was performed in a postoperative
dental pain model that demonstrated the superior efficacy of
acetaminophen 1000 mg compared to acetaminophen 500 mg \[Nick 2002\].
The primary efficacy endpoint, TOTPAR4[^5], for acetaminophen 1000 mg
was significantly superior to acetaminophen 500 mg (p\<0.0001) and
revealed that approximately 42% more pain relief was provided by the
1000-mg dose compared to the 500-mg dose. The superiority of
acetaminophen 1000 mg compared to acetaminophen 500 mg was also
demonstrated with all other endpoints.

Three other studies utilizing post-oral surgery pain models \[Seymour
1996; Nystrom 1988; Quiding 1984\] and one study utilizing a
post-orthopedic surgery pain model \[McQuay 1986\] also demonstrate the
superior efficacy of acetaminophen 1000 mg compared to acetaminophen 500
mg.

### Comparative Efficacy of Acetaminophen 1000 mg Versus 600/650 mg -- From Systematic Review and Meta-Analysis

An important review of acetaminophen, comparing the relative efficacy of
various acetaminophen doses, is a meta-analysis conducted by the
University of Oxford. In a recent publication, McQuay et al \[McQuay
2002\] identified 46 randomized, placebo-controlled clinical trials of
subjects with postoperative pain of moderate-to-severe intensity
evaluated over a four- to six-hour treatment period. An overall estimate
of the efficacy of two acetaminophen doses (600/650 mg and 1000 mg) was
provided. In these trials, 2561 subjects received acetaminophen and 1625
subjects received placebo \[McQuay 2002\]. The number-needed-to-treat
(NNT) was one of the endpoints used for this meta-analysis and was
defined as the number of subjects required to receive a particular
acetaminophen dose in order for one subject to achieve at least 50% pain
relief at that dose compared with placebo over a four- to six-hour
treatment period. The lower the NNT, the more effective the
acetaminophen dose.

Table 2-. Meta-Analysis Results for Single-Dose Efficacy of
Acetaminophen 1000 mg and 600/650 mg Compared with Placebo \[McQuay
2002\]

+------------+----------+--------------+--------------+---------------+
| Number of  | Dose     | At least 50% |              | NNT           |
| Trials     | (mg)     | pain relief  |              |               |
|            |          | with         |              | (95% CI)      |
+------------+----------+--------------+--------------+---------------+
|            |          | A            | Placebo      |               |
|            |          | cetaminophen |              |               |
|            |          |              | N            |               |
|            |          | N            |              |               |
|            |          |              | (%)          |               |
|            |          | (%)          |              |               |
+------------+----------+--------------+--------------+---------------+
| 23         | 1000     | 701/1527     | 197/1032     | 3.7 (3.3 -    |
|            |          |              |              | 4.3)          |
|            |          | \(46\)       | \(19\)       |               |
+------------+----------+--------------+--------------+---------------+
| 18         | 600/650  | 250/614      | 131/593      | 5.4 (4.2 -    |
|            |          |              |              | 7.4)          |
|            |          | \(41\)       | \(22\)       |               |
+------------+----------+--------------+--------------+---------------+

As shown in Table 2-, the NNT for acetaminophen 1000 mg is 3.7 and the
NNT for acetaminophen 600/650 mg is 5.4, indicating that acetaminophen
1000 mg has superior efficacy compared to 650 mg. Although the
confidence intervals overlap slightly for the two doses, the NNT values
for acetaminophen 1000 mg and 600/650 mg are significantly different (z
= 2.59 and p = 0.009). The marginal overlap of the confidence intervals
in this comparison of more than 3700 subjects underscores the difficulty
of showing significant dose-response differences between doses at less
than two-fold increments with oral analgesics in small individual
clinical trials.

### Comparative Efficacy of Acetaminophen 1000 mg Versus 650 mg -- From Individual Clinical Trials

Three placebo-controlled studies specifically compared acetaminophen
doses of 1000 mg and 650 mg \[Hopkinson 1974; McNeil 1972; Yuan 1998\].
These trials report greater efficacy of acetaminophen 1000 mg compared
to acetaminophen 650 mg. Two of these studies \[Hopkinson 1974; McNeil
1972\] were submitted to the FDA as part of Amendment 1, dated December
19, 1972, to NDA 17-053 for Extra Strength Tylenol acetaminophen 500 mg,
and were the two clinical trials which were the basis of FDA approval
for the NDA. These three studies were not included in the meta-analysis
conducted by McQuay et al \[McQuay 2002\].

### Comparative Efficacy of Acetaminophen 1000 mg Versus 2000 mg -- From An Individual Clinical Trial

The efficacy of acetaminophen 1000 mg has also been demonstrated
compared to acetaminophen 2000 mg. One placebo-controlled post oral
surgery pain study comparing acetaminophen 1000 mg to 2000 mg did not
show statistically significantly greater pain relief of acetaminophen
2000 mg compared to acetaminophen 1000 mg \[Skoglund 1991\]. This study
suggests that there is no significant analgesia benefit beyond an
acetaminophen 1000 mg single dose.

## Pharmacokinetic-Pharmacodynamic Model

Pharmacokinetic-pharmacodynamic (PK-PD) modeling predicts that a 1000-mg
dose of acetaminophen yields plasma concentrations consistently above
the EC50[^6] that is needed to provide optimal pain relief. These PK-PD
results are consistent with the meta-analysis \[McQuay 2002\] of
acetaminophen efficacy studies and placebo-controlled studies
\[Hopkinson 1974; Yuan 1998\] that reported greater efficacy of 1000 mg
acetaminophen compared with lower single doses.

A substantial body of research documents acetaminophen's pharmacokinetic
properties and clinical efficacy. Integrating these study data with
acetaminophen PK/PD modeling demonstrates that the optimal effective
adult analgesic dosing of acetaminophen is 1000 mg every four to six
hours, up to 4000 mg per 24 hours.

### Modeling Reveals Effective Concentration for Analgesic Response

The PK-PD relationship of acetaminophen was determined for postoperative
analgesia in adults following molar extraction. A population PK-PD model
\[Hutcheson 1993\] was developed using data from 114 outpatients, who
received a single dose of 1000 mg acetaminophen (either caplet or
effervescent solution) or placebo, at the onset of significant pain
following surgical extraction of impacted third molars. The other PK-PD
model \[Gelotte 1995\] used data from a bioavailability and dental pain
study in male subjects, who received either two doses of 650 mg
immediate-release acetaminophen four hours apart or one dose of 1300 mg
extended-release acetaminophen.

Similar to other analgesics, both studies found that the analgesic
effect (pain relief and pain intensity scores) of acetaminophen lags
behind plasma concentrations over time. Thus, an \"effect\" compartment
was used to link pharmacokinetic and pharmacodynamic models. This effect
compartment adjusts for the chronological aspects of acetaminophen
effect, which may depend on physicochemical (eg, diffusion,
partitioning) and/or physiological (eg, perfusion, receptor binding)
processes that relate drug in plasma to drug at its site of action.

Estimates of the pharmacodynamic parameters obtained for acetaminophen
analgesia were essentially the same for both studies. In particular the
EC50 (effectiveness concentration that elicits 50% of the maximum drug
response) was estimated at 15.2 g/mL \[Hutcheson 1993\] and 16.55 g/mL
\[Gelotte 1995\] for acetaminophen.

### The 1000-mg Dose Yields Acetaminophen Concentrations Needed to Provide Adequate Pain Relief

To further assess the relationship between acetaminophen dose and
resultant plasma concentrations needed to elicit analgesic response, the
EC~50~ from the PK-PD models was considered with regard to plasma data
from 18 PK studies[^7] for the 650- and 1000-mg doses. Figure 2- shows
the mean C[max]{.smallcaps} values for both doses relative to the EC~50~
for acetaminophen. These findings support that the 1000-mg dose of
acetaminophen yields optimal plasma concentrations needed to provide
adequate pain relief.

Figure 2-. Study Mean C[max]{.smallcaps} By Dose Relative to EC50 for
Adult Analgesia

![](media/image1.wmf){width="5.23125in" height="3.4833333333333334in"}

Factors such as body size, age, and physiology lead to differences in
plasma concentrations among adults at a given dose. For example, maximum
plasma concentrations of acetaminophen for the 1000-mg dose can fall
below the EC50 threshold in larger adults, which is illustrated in
Figure 2- with individual C[max]{.smallcaps} values from patients in a
dental pain study \[Hutcheson 1993\]. In addition, the lowest measured
C[max]{.smallcaps} values in this study were associated with the lower
pain relief scores as seen in Figure 2-. Based on the linear
relationship between dose and C[max]{.smallcaps}, the 650-mg
acetaminophen dose is expected to result in similarly scattered
C[max]{.smallcaps} values with a greater percentage below EC50.

Figure 2-. Individual C[max]{.smallcaps} by Weight After a 1000-mg
Acetaminophen Dose in a Dental Pain Study \[Hutcheson 1993\]

![](media/image2.wmf){width="5.261805555555555in"
height="3.441666666666667in"}

Figure 2-. Individual C[max]{.smallcaps} and Maximum Pain Relief After a
1000-mg Acetaminophen Dose in a Dental Pain Study \[Hutcheson 1993\]

![](media/image3.wmf){width="5.301388888888889in"
height="3.4590277777777776in"}

Pharmacokinetic-pharmacodynamic modeling predicts that plasma
concentrations following a 1000-mg dose of acetaminophen are
consistently at or above the EC~50~ needed for optimal pain relief.
Although development of the model was not based on a 650-mg dose of
acetaminophen, plasma concentrations of a 650-mg dose of acetaminophen
consistently fall below the EC~50~. These findings, integrated with the
data from the meta-analysis and placebo-controlled studies demonstrate
that the optimal effective adult analgesic dosing of acetaminophen is
1000 mg every four to six hours, up to 4000 mg per 24 hours.

### Data on Frequency of Dosing

#### Dosing of Acetaminophen 1000 mg Every Four to Six Hours

It is important to consider dosing interval when discussing the efficacy
of acetaminophen, because the need for pain relief often extends beyond
the initial acetaminophen dose of 1000 mg. The four- to six-hour dosing
interval for acetaminophen 1000 mg included in McNeil's current label is
supported by pharmacokinetic and clinical data.

In a post oral surgery pain study, 59% of patients receiving
acetaminophen 1000 mg remedicated within four hours, and 76% remedicated
within six hours \[Quiding 1984\]. In addition, data from post oral
surgery pain studies indicate that a large percentage of patients
receiving an initial acetaminophen dose of 1000 mg required remedication
four to five hours after the initial dose \[Nystrom 1988; Quiding 1984;
Gustafsson 1983; Pigeon 1992; Kiersch 1994; Mehlisch 1995\]. The
duration of a single dose of analgesia ranged from 3.1 to 4.8 hours in
patients taking the acetaminophen 1000-mg dose in these studies.

The four-to-six hour dosing interval provides consumers with a practical
and flexible dosing regimen to meet their pain relief needs within a
variety of daily living schedules. Use of a four-to-six hour dosing
interval provides the flexibility needed to conveniently coincide with
most waking/breakfast, lunch, dinner, and bedtime medication use
schedules. There are situations (eg, toothache or after oral procedures)
in which additional analgesic relief may be needed as early as four
hours after an initial dose. With this dosing regimen, consumers can be
assured of both effective and consistent pain control.

#### Efficacy of Acetaminophen 4000 mg Per Day for Multiple Days for Recurrent Pain

Adult OTC acetaminophen product labeling includes the following
statement concerning duration of use: Stop use and ask a doctor if pain
gets worse or lasts for more than ten days, if fever gets worse or lasts
for more than three days, or if sore throat persists for more than two
days. Clinical trials studying acetaminophen use for pain can be divided
into those with a duration of less than ten days or greater than ten
days. Safety and efficacy data from studies of longer duration (greater
than ten days) are available to support the use of acetaminophen for
prolonged periods as directed by a health care professional.

Multiple doses of acetaminophen 1000 mg taken for three to ten days have
shown superior efficacy compared to placebo in a variety of models
including post oral surgery pain \[Seymour 1983; Skjelbred 1979;
Skjelbred 1984\], arthritis pain \[Altman 1999; Zoppi 1995\], painful
conditions \[Nielsen 1991; Wade 1982\], and dysmenorrhea \[Haack 1986\].
Acetaminophen was well tolerated and no serious adverse events were
reported in any of the studies.

The safety and efficacy of acetaminophen when compared to placebo or
NSAIDs for the treatment of pain for extended time periods has been
demonstrated in five osteoarthritis trials involving a total of 896
patients \[Amadio 1983, Haack 1986, Bradley 1991, Lee 1998, Geba 2002\].
These studies show that acetaminophen, when taken at the recommended
daily dose of up to 4000 mg per day, demonstrated efficacy and an
acceptable safety profile. The number of subjects and duration of
acetaminophen therapy (25 subjects for three weeks \[Amadio 1983\], 99
subjects for 4 weeks \[Haack 1986\], 61 subjects for 4 weeks \[Bradley
1991\], 52 subjects for 8 weeks \[Lee 1998\], and 94 subjects for 6
weeks \[Geba 2002\]) support the safe use of acetaminophen for extended
periods of time. Results demonstrated that acetaminophen was superior to
placebo and comparable to NSAIDs (such as ibuprofen, celecoxib, and
naproxen) regardless of the number of participants or duration of
therapy.

In addition, current clinical practice guidelines support acetaminophen
use in adults at a dosage up to 4000 mg per day. In 1995, the American
College of Rheumatology (ACR), and in 2000, the European League Against
Rheumatism (EULAR) issued guidelines recommending acetaminophen, in
daily doses up to 4000 mg, as the first line of pharmacologic therapy in
the treatment of osteoarthritis pain \[Hochberg 1995; Pendleton 2000\].
Subsequently in 2000, the ACR issued the results of a detailed
evidence-based-medicine approach used to develop updated recommendations
for the medical treatment of osteoarthritis; this update provided
continued support for acetaminophen use. The ACR approach gave the
strongest weight to data from controlled trials and accommodated expert
opinion as well \[ACR Subcommittee on OA Guidelines 2000\]. Also, the
American Geriatrics Society Clinical Practice Guidelines for the
Management of Chronic Pain in Older Persons recommended acetaminophen as
the drug of choice for relieving mild to moderate musculoskeletal pain
\[AGS 1998\], and it remains the drug of choice in the current
guidelines \[AGS 2002\].

## Implication of Modifying Acetaminophen Dosing Regimen

Consumers take analgesic medications in single doses that provide them
with adequate pain relief. For acetaminophen that dose is 1000 mg. It is
the only approved dose in the United Kingdom. Products that provide this
dose account for approximately 90% of products sold in the United
States. If a dose lower than 1000 mg was the only approved dose, data
suggest that analgesia would be inadequate or of limited duration for
many individuals. Consequently, these individuals may re-dose, and if
pain persists, take repeated doses, which compounds the identified
existing consumer misuse behavior of individuals who may choose to
ignore the maximum recommended dosage and continue to titrate to maximum
analgesic effect \[Carr 2002\]. Alternatively, if consumers consistently
find that the medication they are using does not provide adequate
relief, they may switch to an alternative medication. This switch could
have unintended negative public health consequences (see Section 4,
Assessment of Acetaminophen Safety).

Reduction of the maximum 1000 mg acetaminophen single dose would be
contradictory to the clinical and pharmacokinetic-pharmacodynamic data
presented that demonstrate that the efficacy of acetaminophen is
dose-related between 500 mg and 1000 mg and that acetaminophen 1000 mg
is significantly more efficacious than acetaminophen 650 mg or 500 mg.

## Added Effectiveness for Acetaminophen-Containing Prescription Combination Products

A number of prescription medications contain acetaminophen in
combination with other analgesics. The use of a combination oral
analgesic offers several benefits over the use of the individual
components given separately. Combining analgesics into a single product
may facilitate prescribing and compliance by reducing the total number
of medications that a patient must take. Furthermore, combining products
with different mechanisms of action provides multimodal coverage of the
underlying pain pathophysiology allowing efficacy in a broad spectrum of
pain syndromes as the individual agents act in an additive or
synergistic fashion. Additionally, in terms of safety, lower doses of
each individual analgesic used in the combination may result in a lower
incidence of adverse effects attributable to an individual analgesic
component. An example of this can be demonstrated in the case of the
tramadol/acetaminophen combination product.

### Rationale for an Acetaminophen Combination Product

Tramadol hydrochloride (tramadol) is a centrally-acting analgesic that
is widely marketed throughout the world. Tramadol has been shown to be
effective in treating a wide variety of pain conditions, including the
management of both nociceptive and neuropathic pain, when treatment with
strong opioids is not required. The pharmacokinetic and pharmacodynamic
profile of tramadol shows peak activity in two to three hours with an
elimination half-life and duration of analgesia of about six hours.
Acetaminophen yields peak plasma concentrations between 0.4 and 1 hour
and has an elimination half-life of two to three hours. Combination of
tramadol with a rapid-onset and short-acting analgesic such as
acetaminophen, provides substantial patient benefit over either
component alone. The clinical positioning of the tramadol/acetaminophen
combination is for the treatment of moderate to moderately-severe pain
with dosing as needed where rapid onset combined with prolonged
analgesia is desirable.

ULTRACET contains 37.5 mg of tramadol hydrochloride and 325 mg of
acetaminophen in a single tablet and is made by Ortho-McNeil
Pharmaceutical, another member of the Johnson & Johnson family of
companies. As of August 15, 2001, ULTRACET was approved for marketing in
the United States for the short-term (5 days or less) management of
acute pain, with a dosing regimen of two tablets every four to six hours
as needed for pain relief, up to a maximum of eight tablets per day.

### Efficacy and Safety of an Acetaminophen Combination Product

Three single-dose dental pain studies \[RW Johnson 1999a, 1999b, 1999c\]
that included subjects with multiple molar impactions demonstrated the
analgesic efficacy of the combination product in the treatment of
moderate to moderately-severe pain. In each of these trials,
tramadol/acetaminophen was statistically superior to placebo and to each
component alone for the three summary efficacy variables: areas under
the curve of pain relief against time, of pain intensity difference
against time, and of pain relief plus pain intensity difference against
time at the 0 to 8 hour interval. Figure 2- displays the mean pain
relief scores from one of the single-dose oral surgery pain studies and
demonstrates the added effectiveness of the tramadol/acetaminophen
combination. The time course of activity for tramadol/acetaminophen can
be described by a rapid onset and steady rise in pain relief to peak
effect, generally within two to three hours, followed by prolonged
analgesic activity (pain relief persists throughout dosing interval).
This pattern is clearly a composite of the time-effect curves associated
with each of the components in the combination.

The tramadol/acetaminophen combination was well tolerated in subjects
with acute pain and had an adverse event profile that was consistent
with the known side effects of the individual components. There were no
clinically meaningful changes in clinical laboratory tests, vital signs,
or physical examination findings.

Figure 2-. Mean Hourly Pain Relief Scores[^8] Demonstrating Added
Efficacy of the Tramadol/Acetaminophen Combination

![](media/image4.wmf)

Examination of all available information indicates that the combination
of tramadol and acetaminophen is a superior treatment for acute pain
because its complementary modes of action provide rapid and long-lasting
pain relief, with an excellent safety profile. Furthermore, the
concurrent administration of tramadol and acetaminophen in a single,
fixed-dose combination tablet facilitates patient compliance,
particularly where repeated dosing is necessary.

Within the construct of the WHO Analgesic Ladder \[WHO 1996; Sorge
2000\], Ultracet is well suited as a Step II agent, where the use of a
weak opioid analgesic in combination with an adjuvant or non-opioid
analgesic is recommended for moderate pain. Therefore, the significant
advantage offered by this combination is that it spares the use of
strong opioids. The tramadol/acetaminophen combination offers several
advantages over tramadol alone, including a faster onset of analgesic
activity, greater effectiveness in the treatment of moderate to severe
pain, and improved tolerability. The advantages of
tramadol/acetaminophen over acetaminophen alone include longer duration
of analgesic effect and enhanced relief of moderate to severe pain. This
incremental benefit of the combination product over its individual
components is relevant for a single dose or for each dose of a repeated,
as needed dosing regimen in the relief of pain.

## Conclusions

The data provided in this section demonstrate that the optimal effective
and safe adult analgesic dosing schedule of acetaminophen is 1000 mg
every four to six hours, up to 4000 mg per 24 hours.

-   Results from a recent acute pain dose-response study, individual
    clinical trials and a systematic review and meta-analysis
    demonstrate significantly superior efficacy of acetaminophen 1000 mg
    over lower doses (500 mg and 650 mg). No apparent increase in
    analgesic benefit of acetaminophen 2000 mg compared to acetaminophen
    1000 mg was demonstrated in a single-dose, placebo-controlled dental
    pain study

-   Pharmacokinetic-pharmacodynamic modeling predicts that plasma
    concentrations following a 1000-mg dose of acetaminophen are
    consistently at or above the EC~50~ needed for optimal pain relief.
    Although development of the model was not based on a 650-mg dose of
    acetaminophen, plasma concentrations of a 650-mg dose of
    acetaminophen consistently fall below the EC~50~.

-   Controlled clinical trials of acetaminophen 4000 mg per day taken
    for multiple days or weeks consistently demonstrate efficacy with a
    good safety profile.

Any reduction in the currently approved single or daily acetaminophen
dose would decrease effectiveness and encourage consumers to disregard
labeled dosages or switch to alternative analgesics with consequent
public health implications (see Section 2.4, Implication of Modifying
Acetaminophen Dosing Regimen). Acetaminophen in prescription combination
medications provides added effectiveness over the individual components
given separately.

# ACETAMINOPHEN PHARMACOLOGY and toxicology

**KEY POINTS**

-   Acetaminophen pharmacokinetics, which have been thoroughly
    characterized by prospective well-controlled studies, are consistent
    and predictable over a wide range of single doses. Therefore, the
    amount of acetaminophen in the body (and plausible corresponding
    doses) can be reliably estimated from a plasma concentration(s)
    measured at a known time following acute acetaminophen ingestion.

-   Prospective pharmacokinetic studies show that with repeat doses of 1
    and 1.5 g (4 and 6 g/day) acetaminophen plasma concentrations reach
    steady-state levels within 10 to 15 hours and do not accumulate to
    higher levels with continued dosing. These results are consistent
    with the short elimination half-life of two to three hours for
    acetaminophen and the recommended dosing interval of four to six
    hours.

-   Acetaminophen is primarily metabolized by the liver via three
    pathways: glucuronidation, sulfation, and oxidation. All resulting
    *conjugates* from these pathways are inactive and nontoxic. Only the
    sulfation pathway is capacity-limited, as the glucuronide pathway
    does not saturate, even following a substantial acute acetaminophen
    overdose.

-   The oxidative intermediate, NAPQI, which is mainly generated by
    CYP2E1 oxidation, is not measurable due to its high reactivity and
    *instantaneous conjugation with glutathione*. NAPQI may potentially
    cause hepatotoxicity after a substantial acute overdose; however,
    glutathione is present in sufficient quantities to conjugate the
    small amount of NAPQI following therapeutic acetaminophen doses.
    Additionally, the body continuously replenishes glutathione. As a
    result, liver toxicity does not occur at normal therapeutic doses.

-   With repeat doses of 0.65 and 1 g acetaminophen every six hours,
    steady-state concentrations of the glucuronide conjugate are higher,
    and those for the sulfate, cysteine, and mercapurate conjugates are
    all lower than what would be predicted from single dose data. These
    findings indicate time-dependent changes in acetaminophen metabolism
    during repeat dosing, which may reflect up- and/or down-regulation
    of the different enzymatic pathways.

## Acetaminophen Mechanism of Action

Acetaminophen is both an analgesic and antipyretic drug with weak
anti-inflammatory properties. Although the precise mechanism of action
is not totally understood, recent work by Boutaud et al \[2002\]
suggests acetaminophen is an inhibitor of the peroxidase portion of
cyclooxygenase (prostaglandin H synthase inhibitor). Depending on the
redox state and substrate concentrations surrounding the enzymes,
acetaminophen may or may not have a significant inhibitory effect. This
accounts for its selective activity on pain and fever with little
anti-inflammatory effect \[Ouellet 2001\]. These findings do not exclude
the possibility that acetaminophen exerts some effect on pain and fever
other than through its effect on prostaglandin H synthase.

Assessment of pain threshold of flexion reflex is generally accepted as
an appropriate index of central pain modulation in human subjects
\[Willer 1977; Willer 1983\]. The pain threshold may be assessed by both
a visual analog scale and the nociceptive flexion reflex. In response to
transcutaneous electrical stimulation, the pain threshold in healthy
subjects was significantly raised by 1000 mg intravenous acetaminophen
\[Piletta 1991\]. Additional studies in healthy adults indicate a
dose-response relationship and a close association between the
subjective and objective pain measures and the area under the
concentration-time curves for 500, 1000, and 2000 mg of acetaminophen
\[Desmeules 1995; Piguet 1998\].

Acetaminophen reduces fever by blocking the formation and release of
prostaglandins at the hypothalamic thermoregulatory centers \[Milton
1976\]. A cyclooxygenase-3 enzyme located in the brain has been recently
hypothesized to be the target for the analgesic and antipyretic effects
of acetaminophen \[Botting 2000; Simmons 1999; Simmons 2000\]. However,
these findings may be accounted for by the action on the peroxidase
portion of cyclooxygenases \[Ouellet 2001\]. Acetaminophen exerts its
analgesic and antipyretic effects in the brain in which peroxide levels
are not high; whereas, acetaminophen is not anti-inflammatory because
peroxide levels are elevated in peripheral tissues.

## Acetaminophen Metabolism

Acetaminophen is primarily metabolized by the liver via three major
parallel pathways: glucuronidation, sulfation, and oxidation \[Miners
1983; Slattery 1989; Lee 1992; Miners 1992\]. Both the glucuronic and
oxidative pathways adhere to a first-order rate process, which means the
concentration of acetaminophen metabolized increases as the
concentration in the liver increases. The sulfate pathway adheres to
Michaelis-Menten kinetics, which means the concentration of
acetaminophen metabolized remains constant once the concentration in the
liver increases above a saturation level.

A schematic of acetaminophen metabolism is shown in Figure 3-1. Less
than 9% of a therapeutic dose is excreted unchanged in the urine
\[Miners 1992\]. The major metabolic pathway is glucuronidation, where
47% to 62% of the acetaminophen dose conjugates with glucuronide. These
glucuronide conjugates are inactive and nontoxic \[Koch-Weser 1976\],
and are secreted in bile and eliminated in the urine. Glucuronide
conjugation is catalyzed primarily by one isoform of
glucuronyltransferase (UGT1A6) \[Court 2001\] with uridine
5'-diphosphoglucuronic acid as an essential cofactor.

The second major pathway of acetaminophen metabolism is sulfation, where
25% to 36% of the dose conjugates with sulfate. These sulfate ester
conjugates are also inactive and nontoxic \[Koch-Weser 1976\], and are
readily excreted in the urine. Sulfation is mediated by
sulfotransferases, which are heterogeneous cytosolic enzymes, and
3'-phosphoadenosine 5'-phosphate is a cofactor. Sulfotransferase
activity rather than sulfate depletion is the rate‑controlling factor of
acetaminophen sulfation \[Blackledge 1991\].

The third pathway is oxidation, where 5% to 8% of the acetaminophen dose
is metabolized via the cytochrome P-450 enzyme system. The cytochrome
P-450 isoenzyme that is primarily responsible for acetaminophen
metabolism is CYP2E1 \[Manyike 2000\]. When acetaminophen is metabolized
by CYP2E1, it forms a highly reactive intermediate,
N-acetyl-p-benzoquinoneimine (NAPQI). Because NAPQI is highly reactive,
it cannot be measured outside the liver nor can it accumulate. This
intermediate is rapidly inactivated by hepatocellular stores of
glutathione to form cysteine and mercapturate conjugates, which are both
inactive and nontoxic \[Koch-Weser 1976\]. These conjugates are excreted
in the urine \[Mitchell 1974\].

Figure 3‑1. Acetaminophen Metabolism

![](media/image5.wmf){width="5.3493055555555555in" height="3.6375in"}

## Acetaminophen Pharmacokinetics

### Overview

The pharmacokinetics of acetaminophen have been thoroughly
characterized, and are supported by data from numerous prospective,
well-controlled studies reported in the literature for children (19
studies), healthy adults (over 40 studies), elderly (11 studies),
pregnant women (1 study), renal-impaired adults (6 studies), and
hepatic-impaired children (2 studies) and adults (8 studies).
Pharmacokinetic results for special populations, including potential
drug interactions, are reviewed in Section 4, Assessment of
Acetaminophen Safety, within the context of clinical use and safety.
Results from studies primarily in healthy adults are summarized in this
section to provide the basic principles for understanding
acetaminophen's single- and multiple-dose pharmacokinetics.

### Single-Dose Pharmacokinetics at Recommended Therapeutic Doses

Oral acetaminophen is rapidly and completely absorbed by passive
diffusion from the small intestine. Peak plasma concentrations occur
within 0.4 to 1 hour, depending on the product formulation. Although
high-fat foods delay the time to peak concentration for up to an hour
\[Wessels 1992\], the dose is completely absorbed.

Mean peak concentrations of acetaminophen reported for a 650-mg dose
range from 6 to 12 g/mL, and for a 1000-mg dose from 17 to 24 g/mL.
Generally, the maximum concentration of most drugs is inversely related
to body weight for a given dose. Thus, for a 110-lb person, 1000 mg
acetaminophen corresponds to 13 mg/kg and a higher peak, whereas the
same dose for a 165-lb person corresponds to 8.7 mg/kg and a lower peak.

Acetaminophen is uniformly distributed throughout most body fluids, but
not in fatty tissue. As a result, the volume of distribution in adults
ranges between 0.8 and 1.0 L/kg \[Forrest 1982; Ameer 1983\]. Because
acetaminophen has low protein binding in plasma of only 10% to 25%
\[Levy 1981; Milligan 1994\], it does not compete with drugs that are
highly protein bound.

Acetaminophen undergoes first-order elimination from the body, and has a
short plasma half-life (t½) that ranges from 2 to 3 hours in healthy
young and elderly adults[^9] and from 1.5 to 2.9 hours in children[^10].
Elimination is only slightly longer in neonates (2.8 to 3.5 hours)
\[Levy 1975; Hopkins 1990; Autret 1993\], the frail elderly (3.4 and 3.8
hours) \[Ellmers 1990; Wynne 1990\], and patients with mild-to-moderate
liver disease (2.2 to 3.4 hours) \[Forrest 1979; Benson 1983;
Jorup-Ronstrom 1986\]. Because acetaminophen clears rapidly from the
body, it requires dosing every four to six hours in order to maintain
therapeutic levels. Because of its rapid clearance, repeated doses do
not lead to accumulation of acetaminophen plasma concentrations \[McNeil
1992\].

### Single-Dose Pharmacokinetics up to Nine Grams

Acetaminophen pharmacokinetics in excess of the recommended therapeutic
single doses[^11] of 0.65 and 1 g have been studied. Researchers
conducting the studies[^12] intended to simulate acute overdoses using
single doses from 2.8 to 9.1 g within a well-controlled study
environment in order to assess differences in absorption between dosage
forms \[Stork 1996; Douglas 1996\] and with various overdose
interventions \[Rose 1991; Vance 1992; Hassig 1993; Green 2001;
Christophersen 2002\]. Only pharmacokinetic results for the control
groups without absorption interventions (eg, activated charcoal and
lavage) are highlighted in this section, because they provide
information about those instances when a consumer or patient takes more
than a 1 g dose of acetaminophen.

Differences in acetaminophen absorption between immediate-release and
extended-release caplets were assessed in two studies of healthy men and
women, who received 75 mg/kg (3.8 to 7.2 g, and 4.2 to 7.8 g) as a
single acute dose \[Stork 1996; Douglas 1996\]. In both studies, the
supratherapeutic doses were well tolerated, and adverse events (nausea,
headache, and light-headedness) were minor and transient. In another
study, single doses of 5 g were administered to healthy adults on four
occasions, three of which included coadministration of activated
charcoal as an intervention \[Rose 1991\], and they were well tolerated.
Similar studies using single-doses of 3.6 or 4 g acetaminophen on four
occasions were also reported. Changes in absorption were determined when
activated charcoal, without \[Green 2001\] and with lavage \[Hassig
1993; Christophersen 2002\], was coadministered with the dose.

The effect of different body positions on absorption was assessed in
healthy men and women, who ingested 80 mg/kg (4.1 to 9.1 g) on five
occasions with a three-day washout between each administration \[Vance
1992\]. Subjects were required to swallow within 60 seconds the entire
quantity of tablets, which ranged from 26 to 57 tablets of 160‑mg
acetaminophen each. These repeated exposures above the recommended dose
were well tolerated, with no adverse events or discontinuations
reported.

The collective pool of 80 subjects in the above crossover studies
ingested from 2.8 to 9.1 g of acetaminophen on more than one occasion,
which totaled 152 exposures of single supratherapeutic doses. An
additional 120 exposures included coadministration with activated
charcoal. All doses were well tolerated, and no patterns in the
pharmacokinetic curves indicative of significant metabolic saturation at
these doses were found.

Mean pharmacokinetic data for the control groups in the studies are
summarized in Table 3-1. Acetaminophen pharmacokinetics at
supratherapeutic doses are similar to those at recommended doses.
Additionally, peak acetaminophen concentrations and t½ are consistent
with linear pharmacokinetics and are, therefore, predictable within this
range of supratherapeutic single doses.

Table 3‑1. Mean (sd) Pharmacokinetics Data for Doses Up to Nine Grams

+----------+------------+-----+----+-------+------+-----+----+----+
| Citation | Study      | Gen | We | Dose  | AUC[ | C[m | T[ | t½ |
|          | D          | der | ig | (g)   | inf] | ax] | ma |    |
|          | escription |     | ht |       | {.sm | {.s | x] | \  |
|          |            | M / |    | (R    | allc | mal | {. | (h |
|          |            | F   | (k | ange) | aps} | lca | sm | \) |
|          |            |     | g) |       |      | ps} | al |    |
|          |            |     |    |       | (g·h |     | lc |    |
|          |            |     |    |       | /mL) | (g/ | ap |    |
|          |            |     |    |       |      | mL) | s} |    |
|          |            |     |    |       |      |     |    |    |
|          |            |     |    |       |      |     | \  |    |
|          |            |     |    |       |      |     | (h |    |
|          |            |     |    |       |      |     | \) |    |
+==========+============+=====+====+=======+======+=====+====+====+
| Christ   | Control^a^ | 5 / | 71 | 3     | 190  | 42  | 1  | 2  |
| ophersen | vs         | 7   | .8 | .6^b^ |      |     | .7 | .2 |
| \[2002\] | Charcoal/  |     |    |       |      |     |    |    |
|          | Lavage     |     |    | 2.8   |      |     |    |    |
|          |            |     |    | to    |      |     |    |    |
|          |            |     |    | 5.3   |      |     |    |    |
+----------+------------+-----+----+-------+------+-----+----+----+
| Green    | Control^a^ | 7 / | 77 | 4.0   | 221  | 66  | \  | 2  |
|          | vs         | 3   | .4 |       |      |     | -- | .3 |
| \[2001\] | Charcoal   |     |    | (na)  | \(   | \(2 |    |    |
|          |            |     |    |       | 54\) | 7\) |    | (  |
|          |            |     |    |       |      |     |    | 0. |
|          |            |     |    |       |      |     |    | 6) |
+----------+------------+-----+----+-------+------+-----+----+----+
| Hassig   | Control^a^ | 12  | \  | 4.0   | \--  | 70  | \  | \  |
|          | vs         |     | -- |       |      |     | -- | -- |
| \[1993\] | Charcoal/  |     |    | (na)  |      | (7  |    |    |
|          | Lavage     |     |    |       |      | .4) |    |    |
+----------+------------+-----+----+-------+------+-----+----+----+
| Rose     | Control^a^ | 10  | 73 | 5.0   | 347  | 64  | 1  | 2  |
|          | vs         | / 0 |    |       |      |     | .4 | .6 |
| \[1991\] | Charcoal   |     |    | (na)  | \(   | \(1 |    |    |
|          |            |     |    |       | 73\) | 4\) | (0 | (  |
|          |            |     |    |       |      |     | .5 | 0. |
|          |            |     |    |       |      |     | 2) | 3) |
+----------+------------+-----+----+-------+------+-----+----+----+
| Douglas  | BA         | 7 / | 67 | 5     | 419  | 100 | 0  | 2  |
|          | Comp       | 7   | .8 | .6^b^ |      |     | .9 | .6 |
| \[1996\] | arative^c^ |     |    |       | \(   | \(2 |    |    |
|          |            |     |    | 4.2   | 98\) | 5\) | (  | (  |
|          |            |     |    | to    |      |     | 0. | 0. |
|          |            |     |    | 7.8   |      |     | 6) | 4) |
+----------+------------+-----+----+-------+------+-----+----+----+
| Stork    | BA         | 7 / | 73 | 5     | 432  | 94  | 0  | 2  |
|          | Comp       | 3   |    | .7^b^ |      |     | .8 | .6 |
| \[1996\] | arative^c^ |     |    |       | \(1  | \(2 |    |    |
|          |            |     |    | 3.8   | 32\) | 4\) | (  | (  |
|          |            |     |    | to    |      |     | 0. | 0. |
|          |            |     |    | 7.2   |      |     | 5) | 9) |
+----------+------------+-----+----+-------+------+-----+----+----+
| Vance    | BA in Five | 6 / | \  | 6     | \--  | \-- | \  | \  |
|          | Body       | 6   | -- | .1^b^ |      |     | -- | -- |
| \[1992\] | Positions  |     |    |       |      |     |    |    |
|          |            |     |    | 4.1   |      |     |    |    |
|          |            |     |    | to    |      |     |    |    |
|          |            |     |    | 9.1   |      |     |    |    |
+----------+------------+-----+----+-------+------+-----+----+----+

a: control group data reported.

b: study average dose.

c: immediate-release data reported.

Abbreviations: BA = bioavailability; na = not applicable

Figure 3-2 depicts the mean pharmacokinetic profiles for the 5.6 g
(75 mg/kg) acetaminophen dose \[Douglas 1996\] and the recommended
therapeutic dose of 1 g (15 mg/kg) \[McNeil 98-054\]. This is drawn
relative to the risk line for hepatotoxicity and treatment line of the
nomogram used to manage acute overdoses. The mean plasma concentrations
for this supratherapeutic dose are well below the risk and treatment
lines of the nomogram at all times during the study, which further
support the safety findings.

Figure 3‑2. Mean Data for a Standard (1 g, 15 mg/kg) and Higher (5.6 g,
75 mg/kg) Dose Relative to Risk and Treatment Lines of the Acetaminophen
Nomogram

![](media/image6.wmf){width="5.540972222222222in"
height="3.7416666666666667in"}

### Single-Dose Pharmacokinetics at Very High Doses

A phase I study \[Kobrinsky 1996\] provided prospective data on the
pharmacokinetics of acetaminophen at very high, potentially toxic doses.
Nineteen patients with advanced cancer were given high doses (154 to
1007 mg/kg) of acetaminophen chemotherapy followed eight hours later by
an intravenous N-acetylcysteine[^13] (NAC) regimen. It was anticipated
that very high doses of acetaminophen would cause toxicity, but that the
coadministration of NAC would selectively protect normal cells versus
malignant cells from the toxic effects. Minimal-to-no liver damage
occurred in these patients, even when the acetaminophen-NAC regimens
were given on more than one occasion. This reaffirms that acetaminophen
toxicity does not occur when NAC is administered on a timely basis,
despite the very high, potentially toxic doses.

Serum acetaminophen concentrations from 60 nonvomited courses of therapy
in the cancer patients were available to determine distribution volume
(0.87 0.31 L/kg) and oral clearance (0.21 0.10 L/kg•h). The mean t½ of
3.6 1.4 h was determined with data from 71 courses of therapy. These
pharmacokinetic results at very high doses are similar to those reported
in healthy adults for single doses up to six grams.

### Relationship of Dose to Pharmacokinetics

Acetaminophen pharmacokinetics have been studied over a wide range of
single doses, and are consistent and predictable for half-life, time to
peak concentration, and distribution volume. Furthermore, the peak or
maximum concentration (C[max]{.smallcaps}) is linearly related to dose
within this range, which is illustrated in Figure 3-3 with data from
several published single-dose studies[^14]. This means that the peak
concentration increases proportionally with increasing dose.

Figure 3‑3. Linear-Dose Relationship of Study Mean C[max]{.smallcaps} Up
to Six Grams

![](media/image7.wmf){width="5.5375in" height="3.417361111111111in"}

The apparent bioavailability of acetaminophen increases slightly with
dose due to the saturation of first-pass metabolism \[Rawlins 1977\],
which includes presystemic metabolism in the gastrointestinal
epithelium. Figure 3-4 contains mean values for the area under the curve
(AUC[inf]{.smallcaps}) by dose level from the published single-dose
studies described above. The nonlinear increase in the amount of
acetaminophen absorbed for doses ranging from 325 to 5700 mg reflects
saturation of first-pass metabolism.

Figure 3‑4. Nonlinear-Dose Relationship of Study Mean
AUC[inf]{.smallcaps} Up to Six Grams

![](media/image8.wmf){width="5.499305555555556in"
height="3.3881944444444443in"}

### Repeat- or Multiple-Dose Pharmacokinetics at 4 and 6 g/Day

The multiple-dose pharmacokinetics of acetaminophen have been studied at
4 and 6 g daily in healthy adults \[Sajahawalla 1991; McNeil 1992;
McNeil 2002\] and at 4 g daily in hepatic-impaired adults \[Benson
1983\]. Multiple-dose studies permit further assessment of
pharmacokinetic linearity and determination of chronic or time-dependent
drug effects, such as enzyme self-induction or unusual accumulation.
Drugs with linear pharmacokinetics generally reach steady-state plasma
concentrations or are eliminated from the body after five half-lives
(t½). Therefore, acetaminophen with a t½ of two to three hours achieves
steady-state plasma concentrations after only 10 to 15 hours of repeat
dosing. Additionally, the short t½ and recommended dosing interval of
four to six hours results in minimal acetaminophen accumulation between
doses.

In one study of healthy adults \[Sajahawalla 1991\], acetaminophen
pharmacokinetics for five doses were determined in saliva samples for
325, 650, 825, and 1000 mg doses administered every six hours.
Acetaminophen concentrations in saliva are reported to be virtually
equivalent to those in serum. The multiple-dose pharmacokinetic profiles
were consistent with drugs that show minimal accumulation due to a short
t½. Specifically, mean maximum concentrations at steady state
(C[max,ss)]{.smallcaps} for each dose level differed by only 1 to 2 g/mL
from the initial dose.

In a study of healthy subjects \[McNeil 1992\], plasma acetaminophen
concentrations were determined after repeated doses of 1000 mg every six
hours for two days (4 g / day), and they are shown in Figure 3-5. As
predicted by acetaminophen's short t½ and the dosing interval, there is
minimal accumulation and acetaminophen is almost completely eliminated
from the plasma at 12 hours following the last dose. The mean
C[max,ss]{.smallcaps} at steady state with repeat doses of 1000 mg every
six hours is 11.4 3.8 g/mL.

Figure 3‑5. Repeat-Dose Profile for 1000 mg Every Six Hours (4 g / day)
in Healthy Subjects \[McNeil 1992\]

![](media/image9.wmf){width="5.182638888888889in"
height="3.2694444444444444in"}

The multiple-dose pharmacokinetics of acetaminophen were also determined
in adults with stable chronic liver disease \[Benson 1983\]. Safety was
assessed by monitoring for adverse events and/or the deterioration of
laboratory liver function tests. The dose regimens of 4 g per day for
five days during a pilot study with six subjects and for 13 days during
the full study with 20 subjects were well tolerated, with no clinical or
laboratory adverse event related to acetaminophen observed. The mean t½
of 3.4 hours (2.1 to 5.8 hours) for the hepatic-impaired adults is
consistent with the lack of evidence of acetaminophen accumulation noted
by Benson \[1983\].

In a recent placebo-controlled study \[McNeil 2002\], the tolerability
and multiple-dose pharmacokinetics and metabolic profile of 4 and 6 g
per day, dosed as 1 and 1.5 g acetaminophen every six hours for three
days, were determined in healthy adults. Safety was monitored by daily
measurements of liver function tests (aspartate aminotransferase - AST
and alanine aminotransferase - ALT) during both dosing periods and
during a baseline and two washout intervals of three days each. Results
of daily liver function tests for subjects taking 4 and 6 g per day of
acetaminophen and placebo were all well within normal limits for the
duration of the study. Ranges of individual interday variations for both
enzymes during the drug administration and washout phases are listed in
Table 3-2. They were the same for both groups and reflect the expected
day-to-day and time-of-day biological variations in adults.

Table 3‑2. Ranges of Subjects' Interday Variation in Liver Function
Tests

  ---------------------- ------------------------ ------------------------
  Study Group            AST                      ALT

  Acetaminophen (n = 12) 7% to 17%                7% to 25%

  Placebo (n = 6)        5% to 17%                6% to 20%
  ---------------------- ------------------------ ------------------------

The multiple-dose pharmacokinetic profile for 1.5 g acetaminophen taken
every six hours for three days (totaling 6 g/day) is shown in Figure 3-6
and, as predicted from single-dose data and the short elimination t½,
steady-state concentrations were reached by the third dose.

Figure 3‑6. Repeat-Dose Profile for 1500 mg Every Six Hours (6 g / day)
in Four Healthy Subjects \[McNeil 2002\]

![](media/image10.wmf){width="4.779861111111111in"
height="3.4055555555555554in"}

Plasma metabolite concentrations were also measured during the three
days of repeat dosing \[McNeil 2002\]. The data revealed that the
formation of glucuronide conjugates increased over time to a higher
steady-state level than what would be predicted from glucuronide
concentrations following the first dose. In contrast, formation of
sulfate conjugates and also the cysteine and mercapturate conjugates
decreased over time to lower steady-state plasma concentrations than
what would be predicted from the first dose. These results indicate
time-dependent changes in acetaminophen metabolism during repeat dosing,
which may reflect up- and/or down-regulation of the different enzymatic
pathways. The same pattern of change in the rates of metabolite
formation (higher glucuronide and lower sulfate) was originally reported
by Hendrix-Treacy et al \[1986\] following repeat doses of 650 mg
acetaminophen every six hours for five doses. Moreover, a recent study
in mice \[Shayiq 1999\] demonstrated a down-regulation of CYP2E1 and a
potentiated hepatocyte proliferative response with repeat doses of
acetaminophen over nine days, which led to protection against a
subsequent challenge with a lethal acetaminophen dose in the same mice.

These study results do not support the hypothesis that recurrent or
chronic dosing with acetaminophen at ≥5 g / day would be expected to
result in hepatic toxicity.

## Acetaminophen Toxicology

### Pharmacodynamics of Toxicity

Following acute ingestion of very high acetaminophen doses, there is
clinical evidence that *glucuronidation of acetaminophen is not readily
saturated*, even among those who have taken massive overdoses \[Prescott
1983; 1984\]. The fractional urinary excretion of glucuronide
metabolites reported in the literature ranges from 47% to 62% for
therapeutic doses and from 41% to 75% for very high doses (above 137
mg/kg) \[Davis 1976, Prescott 1980\]. By contrast, *sulfate conjugation
is capacity-limited at very high doses* \[Slattery 1979\] as evidenced
by a decrease in the fractional urinary excretion of sulfate
metabolites. The excretion ranges from 25% to 36% for therapeutic doses
and from 9% to 16% for very high doses (above 137 mg/kg) \[Davis 1976;
Prescott 1980\].

Only the sulfation pathway is saturated following a substantial acute
acetaminophen overdose and, as a result, the fraction of dose
metabolized by both the predominant glucuronide pathway and the
oxidative CYP2E1 pathway increases. More of the oxidative intermediate,
NAPQI, is generated, which conjugates instantaneously with glutathione
to produce more inactive cysteine and mercapturate metabolites. NAPQI
has the potential to cause hepatotoxicity after a substantial acute
overdose if the rate of glutathione consumption by NAPQI exceeds the
rate of glutathione synthesis so that the amount of glutathione
available in the liver becomes insufficient to conjugate with and
detoxify NAPQI.

If NAPQI is not inactivated by glutathione under these specific
conditions, it can cause hepatotoxicity by binding with proteins in
hepatocytes \[Mitchell 1973\]. The exact mechanism of liver cell damage
is not known, but it is a threshold effect, signaled by a significant
rise in serum aminotransferase values. Liver dysfunction occurs with
increasing hepatocellular necrosis and, in severe overdose cases without
the use of N-acetylcysteine (NAC) treatment, acute centrilobular liver
failure can result.

Data analyses demonstrate that hepatic glutathione is present in
sufficient quantities to conjugate the small amount of NAPQI that is
generated by CYP2E1 oxidation following therapeutic acetaminophen doses
\[Rumack 2002\]. Additionally, the body continuously replenishes hepatic
glutathione at an estimated rate of 1.62 mmol/h for a 70 kg person
\[Lauterburg 1987\]. As a result, liver toxicity does not occur at
normal therapeutic doses.

### Estimation of the Acute Hepatotoxic Dose of Acetaminophen

The actual rates of consumption and synthesis of hepatic glutathione in
response to the interaction of glutathione with NAPQI have not been
determined in humans. Theoretical estimates that about 70% to 90% of
hepatic glutathione stores need to be consumed to cause hepatotoxicity
in humans following an *acute dose* were originally extrapolated from
mice and hamster *acute dose* data \[Mitchell 1973\]. In a study of
adults, Mitchell et al \[1974\] determined that the amount of
glutathione conjugates formed with 900, 1200, and 1800 mg doses of
radiolabeled acetaminophen was 4%, and used these data to estimate the
threshold acute dose of hepatotoxicity. Assuming the same level of 70%
depletion of glutathione as mice and assuming that the average 1.5-L
liver for a 70 kg person contains 6 mmol of glutathione, at least 4 mmol
of NAPQI would be necessary to cause liver injury in humans. Therefore,
the amount of acetaminophen estimated to generate this much NAPQI[^15]
is 15 g taken all at once: (4 mmol)(acetaminophen 151.2 mg/mmol) / 4%.

The theoretical estimate of 15 g acetaminophen for the acute hepatotoxic
dose in humans by Mitchell et al \[1974\] does not account for the
dynamics of hepatic glutathione turnover. There is a prompt increase in
glutathione synthesis signaled by the consumption of hepatic glutathione
stores. In mice, the rate of synthesis became faster than the rate of
consumption at 90 minutes following the 300 mg/kg acetaminophen
\[Mitchell 1973\]. A study in adults by Lauterburg and Mitchell
\[Lauterburg 1987\] showed that single doses up to 1200 mg acetaminophen
stimulate the turnover of cysteine and glutathione. The researchers
estimate that the hepatic production of glutathione in humans is
approximately 1.62 mmol/h for a liver weight of 1500 g. Therefore,
theoretically, an additional 1.62 mmol of hepatic glutathione would be
produced each hour, which would be available to consume the amount of
NAPQI that may be generated from an additional 6 g acetaminophen.

Adding together the original 15 g acetaminophen based on the assumption
that 70% depletion of hepatic glutathione stores leads to
hepatotoxicity, and the 6 g from the stimulation of cysteine and
glutathione turnover rates, the estimated acute dose for acetaminophen
hepatotoxicity is approximately 21 g taken all at once for a 70 kg
person (and 15 g for a 50 kg person). These theoretical estimates are
comparable to those estimated by Prescott \[1983\] from clinical
overdose outcomes.

Prescott \[1983\] estimated the threshold acetaminophen dose for
hepatotoxicity from a collection of overdose cases in which patients
were cared for using supportive therapy. He estimated the amount of
acetaminophen absorbed by multiplying the plasma acetaminophen measured
at three hours after ingestion with the volume of distribution (0.8L/kg)
and paired the doses with liver damage ratings for all cases. The
results indicate that the threshold dose for hepatotoxicity in humans is
approximately 250 mg/kg taken all at once, which corresponds to 12.5 and
17.5 g for a 50 and 70 kg person, respectively.

### Development of the Nomogram to Manage Acute Overdose Treatment

Current understanding of acetaminophen pharmacokinetics at very high,
toxic doses is based mainly on case reports and case series of
substantial acute overdoses. The acetaminophen overdose nomogram was
developed by Rumack and Matthew \[Rumack 1975\] by plotting data from 30
previously published cases \[Prescott 1971\] and an additional 34
unpublished cases. Investigators plotted the line that best
discriminated between patients who subsequently showed hepatotoxicity
(defined as aspartate aminotransferase levels above 1000 IU) at any time
during hospitalization and those who did not \[Rumack 2002\]. The
resulting overdose risk line began at four hours after acute ingestion
at 200 g/mL and intersected 50 g/mL at 12 hours. The slope of the line
happened to represent a 4-h half-life, and was not based on
acetaminophen pharmacokinetics \[Rumack 2002\].

N‑acetylcysteine (NAC) is used clinically to treat acute acetaminophen
overdose, and acts by interacting with the oxidative intermediate,
NAPQI. During the development of NAC in the early 1980s, the treatment
line, which was drawn 25% below the original line, was added to
conservatively manage the acute overdose cases. This line connects the
level of 150 g/mL at four hours with 37.5 g/mL at 12 hours. The nomogram
is used to estimate the likelihood that a plasma concentration relative
to the time postingestion will result in hepatotoxicity and, therefore,
whether NAC therapy should be administered.

Smilkstein et al \[1988\] published a national multicenter study on the
efficacy of NAC in which a risk analysis nomogram was used in the
analysis. In addition to the original Rumack-Matthew nomogram line and
the treatment line (25% lower), this risk analysis nomogram included a
third line (50 % higher) that began at four hours after acute ingestion
of acetaminophen at 300 g/mL. This third line was considered the lower
limit for high risk of hepatotoxicity due to substantial acute
acetaminophen overdose \[Smilkstein 1988\].

The amount of acetaminophen present in a person (body burden) at a
specific time after a substantial acute overdose can also be estimated
from a single measurement of plasma concentration and the distribution
volume (0.8 to 1 L/kg in adults). Using the following equation based on
the fundamentals of pharmacokinetics, body burden at a given time after
ingestion may be calculated:

Plasma Concentration (g/mL) at Time (t)

Amount in Body at Time (t) =
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

Distribution Volume (L/kg)

### Hepatotoxic Potential is Less for Divided Doses of Acetaminophen

In considering the appropriate total daily dose of acetaminophen, the
hepatotoxic potential needs to be distinguished between the amount taken
all at once (or over a short interval such as eight hours) and the
amount divided over the whole day (repeat dosing every four to six
hours). Based on the body of scientific evidence provided by prospective
pharmacokinetic, metabolic, and clinical data, acetaminophen doses over
a ten-fold range that are taken all at once are not hepatotoxic. In
addition, pharmacokinetic studies of the wide range of doses taken all
at once further support safety, because resulting acetaminophen
concentrations were well below the probable-risk threshold of 200 g/mL
at four hours postingestion determined for substantial acute overdose
(Rumack-Matthew Nomogram).

The body of scientific evidence provided by prospective pharmacokinetic,
metabolic, and clinical data, indicates that the hepatotoxic potential
would be less for a 12 g acetaminophen dose, for example, when the dose
is divided over the whole day than when it is taken all at once.
Specifically, plasma concentrations would not reach as high levels for
the divided doses. Also, exposure to several repeat doses of
acetaminophen appears to down-regulate the oxidative pathway of
acetaminophen metabolism in mice \[Shayiq 1999\] and adults \[McNeil
2002\], and to up-regulate the predominant glucuronide pathway in adults
\[McNeil 2002; Hendrix-Treacy 1986\]. In addition, because the total
daily dose is not taken all at once but rather as divided doses
throughout the day, continuous glutathione synthesis provides an
additional 1.62 mmol of hepatic glutathione per hour[^16] to the pool
available for conjugation with the reactive NAPQI intermediate of
acetaminophen \[Lauterburg 1987\].

## Summary

The pharmacokinetics of acetaminophen at recommended single and multiple
doses have been well characterized. Additionally, the pharmacokinetics
of single acute doses up to ten times the recommended level without NAC
administration have been described in several studies, and up to 15 to
100 times the recommended level with NAC administration has been
reported in one study of patients with cancer. Collectively, these data
allow for a substantially complete characterization of potential acute
toxic doses, and provide a framework for considering risk levels for
repeated supratherapeutic doses of acetaminophen. (See Section 4,
Assessment of Acetaminophen Safety.)

# Assessment of Acetaminophen Safety

**KEY POINTS**

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

-   Evaluation of acetaminophen risks, as with evaluation of NSAID
    risks, should include all doses that may be self-administered given
    consumer utilization patterns for OTC-available analgesics.

```{=html}
<!-- -->
```
-   Acetaminophen, at currently recommended doses, is used safely by
    adults, pediatric and elderly patients, as well as by patients with
    chronic renal disease or chronic stable liver disease. Review of
    metabolism pathways suggests that there is not an increased risk of
    toxicity at currently recommended doses of acetaminophen.

```{=html}
<!-- -->
```
-   The AERS spontaneous reporting system serves as a signal generating
    system for rare, unexpected adverse events in marketed products. It
    cannot be used to determine event rates, dose, or intentionality.

```{=html}
<!-- -->
```
-   Case reports are the source of serious hepatic events associated
    with acetaminophen exposure. These reports are observational and
    therefore cannot be used to establish causality.

```{=html}
<!-- -->
```
-   The number of serious reports for acetaminophen products at the FDA
    is disproportionately large relative to other monograph analgesics
    because: a) FDA regulations do not require AERS reporting for OTC
    monograph drug products, and b) McNeil has submitted serious reports
    for all single-ingredient acetaminophen products and reports of
    death for acetaminophen combination products, including published
    literature and fatalities from AAPCC.

-   Data from AAPCC, DAWN and liver transplant centers are consistent,
    and show that intentional suicide is the most frequent reason for
    adult acetaminophen overdose.

-   Pediatric misadministration rarely results in serious outcome. Rare
    events could be further prevented by permitting dosage information
    for children under two on the product label.

```{=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.

## Use of Recommended Doses in the General Population 

Acetaminophen is widely available and used throughout the United States.
The TFM for Over-the-Counter Internal Analgesic, Antipyretic, and
Antirheumatic Products provides for an "adult acetaminophen dose up to
1000 mg, not to exceed 4000 mg in 24 hours for not more than ten days."

A recent survey of medication use in the United States reported that
acetaminophen was used by 23% of adults in the preceding week \[Kaufman
2002\]. Market data from AC Nielsen Home Scan estimate that 40,250,000
households in the United States bought an OTC single-ingredient adult
acetaminophen product during the 12-month period ending June 2002. Over
the same time period, an estimated 28,000,000 United States households
bought an OTC combination ingredient adult acetaminophen product. Based
on data provided by Information Resources, Inc., it is estimated that in
2001 approximately 11 billion tablets of OTC single-ingredient adult
acetaminophen were purchased, as well as nine billion tablets of OTC
combination-ingredient adult acetaminophen. In regard to prescription
products, IMS Health market data report that 155,000,000 prescriptions
were filled for acetaminophen-containing prescription analgesic products
in the year 2001.

At least 500 published and unpublished controlled clinical trials in
adults and children have evaluated acetaminophen for the relief of pain
or fever. These studies include single and multiple dose treatments.
Most studies were less than 14 days in duration, although the longest
study duration was two years. At least 31,500 study participants were
exposed to acetaminophen with approximately 1800 subjects exposed for 14
days or more. No significant safety issues were reported in any of these
studies. In particular, there have been no published reports of serious
renal or hepatic adverse events at therapeutic doses of up to 4000 mg
per day in divided doses used for two weeks \[McGuiness 1969, Choffray
1987, Lequesne 1997\], three weeks \[Amadio 1983; Kroner 1991\], four
weeks \[Hickey 1982; Kjaersgaard-Anderson 1990; Bradley 1991\], five
weeks \[Stein 1996\], six weeks \[Matts 1983; Geba 2002\], 12 weeks
\[Ertuck 1998\] or as long as two years \[Williams 1993\].

Moreover, at recommended doses, acetaminophen has not been shown to
increase the risk of developing renal diseases \[Prescott 1996; Prescott
1990; Edwards 1971; Rexrode 2001\] or upper gastrointestinal
ulceration/bleeding \[Hoftiezer 1982; Johnson 1981; Peura 1997; Singh
2000; Langman 1994\]. This observation is consistent with its minimal
inhibitory effect on peripheral prostaglandin synthesis \[Jackson 1984\]
and on gastric prostaglandin synthesis \[personal communication Cryer
2002\].

In addition to these studies, Lesko and Mitchell \[Lesko 1995\] enrolled
more than 84,000 febrile children in a randomized, double-blind,
acetaminophen-controlled trial to assess the risk of rare but serious
adverse events following the use of pediatric ibuprofen. Of the children
included in the analysis, 28,130 received acetaminophen and none
experienced anaphylaxis, or serious hepatic, gastrointestinal or renal
effects.

## Use of Recommended Doses in Selected Populations

Some authors have theorized that metabolic or pharmacokinetic
alterations in certain populations require a dose reduction of
acetaminophen to avoid potential increased risk for toxicity. However,
results of well-designed clinical studies indicate that a dose reduction
is not necessary for elderly adults, patients with chronic renal
disease, adult and pediatric patients with chronic, stable liver
disease, and obese adults. Each of these population groups is discussed
in the following sections.

### Elderly Adults

The pharmacokinetics of acetaminophen have been well characterized in
the elderly population. Ten studies included 145 elderly adults, ranging
in age from 65 to 92 years, and 97 young adults. As shown in Table 4-1,
no differences in the elimination half-life of acetaminophen between
young and elderly adults were observed. Two of the studies also included
a subgroup of 35 elderly adults who were receiving continuous hospital
care for chronic disabling conditions \[Ellmers 1990; Wynne 1990\]. The
mean half-lives reported for these *frail* elderly adults (3.4 and 3.7
h) were only slightly prolonged.

Small differences in acetaminophen clearance were reported in some
studies (Table 4-); however, in a comprehensive metabolic study by
Miners et al \[1988\], the formation clearance of glucuronide and
glutathione conjugates were the same in young and elderly adults. This
finding provides prospective scientific data that the amount of
acetaminophen metabolized via the oxidative pathway, from which the
highly reactive intermediate, NAPQI, is generated, does not increase
with age. Only the formation clearance of the sulfate conjugates was
less in elderly adults \[Miners 1988\], which may contribute to the
slightly lower clearance of acetaminophen.

**Table 4-**. Acetaminophen Pharmacokinetics in Elderly Adults (Study
Means)

+--------+---------------+--------------+-----------------------------+
| Study  | Elimination   | Clearance    | References                  |
| Group  |               |              |                             |
|        | Half-Life (h) | (mL/min/kg)  |                             |
+--------+---------------+--------------+-----------------------------+
| E      | 2.7; 2.8;     | 3.7; 3.3;    | Bannwarth \[2001\];         |
| lderly | 2.5; 2.2;     | 5.1; 4.2;    | Bedjaoui \[1984\]; Briant   |
| Adults | 2.8; 2.5;     | 3.7; 3.9;    | \[1976\]; Divoll            |
|        | 2.6; 2.2;     | 3.4; 5.7;    | \[1982a,b,c\]; Triggs       |
| (n =   | 2.2; 2.7; 2.4 | 5.6; 3.7     | \[1975\]; Miners \[1988\];  |
| 145)   |               |              | Ellmers \[1990\]; Wynne     |
|        |               |              | \[1990\]                    |
+--------+---------------+--------------+-----------------------------+
| Young  | 2.1; 1.8;     | 7.8; 5.7;    | Bedjaoui \[1984\]; Briant   |
| Adults | 2.6; 2.6;     | 4.6; 5.1;    | \[1976\]; Divoll            |
|        | 2.7; 1.8;     | 4.1; 6.8;    | \[1982a,b,c\]; Triggs       |
| (n =   | 2.1; 2.1      | 6.1; 4.7     | \[1975\]; Miners \[1988\];  |
| 97)    |               |              | Wynne \[1990\]              |
+--------+---------------+--------------+-----------------------------+

Recently, Bannwarth et al \[2001\] evaluated the multiple-dose
pharmacokinetics of acetaminophen in elderly adults (89 4 y). After
seven days of repeat dosing, acetaminophen did not accumulate in the
plasma, and the elimination half-life (2.8 0.3 h) was the same as that
reported for young adults. In conclusion, acetaminophen is safe for use
in the elderly population as currently labeled.

### Patients with Renal Disease

Well-controlled, prospective data summarized below indicate that
acetaminophen can be used in patients with moderate-to-severe renal
failure, with no dosage adjustment. This favorable view on the renal
safety profile of acetaminophen is shared also by the National Kidney
Foundation, which recommends acetaminophen as the non-narcotic analgesic
of choice for episodic use in patients with underlying renal disease
\[Henrich 1996\].

Martin and colleagues \[Martin 1991\] found that patients with chronic
renal failure had slightly higher plasma concentrations of inactive
glucuronide and sulfate metabolites than healthy subjects during
repeated dosing up to ten days. The metabolites rapidly cleared when
acetaminophen was discontinued. In patents maintained with hemodialysis
\[Martin 1993\], the same researchers found that plasma acetaminophen
metabolites were more rapidly cleared compared to healthy subjects. They
concluded that use of recommended doses of acetaminophen was safe in
patients with moderate-to-severe renal failure.

Several single-dose studies demonstrate accumulation of acetaminophen
metabolites in patients with moderate chronic renal failure and in
anephric patients \[Lowenthal 1976; Chan 1997; Prescott 1989\] for whom
hemodialysis appeared to be the major route of elimination \[Oie 1975\].
However, accumulation of these inactive and nontoxic metabolites has no
implications for safety \[Lowenthal 1976\]. Furthermore, metabolism
appears unaltered, since the percentage of urinary metabolites was
similar to that of healthy volunteers \[Prescott 1989\].

Data demonstrate that there is no risk of acetaminophen toxicity at
currently recommended doses in patients with moderate-to-severe renal
failure and that a dosage adjustment is unnecessary in this patient
population.

### Patients with Liver Disease

Slower metabolism of acetaminophen, increased activity of the cytochrome
P-450 enzyme system, or depleted glutathione stores are cited as
theoretical risk factors for acetaminophen hepatotoxicity in patients
with chronic liver disease. However, acetaminophen has been studied in
both adults and children with a wide variety of liver diseases including
various types of cirrhosis, hepatitis, nodular transformation,
congenital hepatic fibrosis, and ~1~-antitrypsin deficiency. In none of
these conditions is there evidence of an increased risk for
hepatotoxicity at currently recommended acetaminophen doses.

Andreasen \[1979\] evaluated the pharmacokinetics of acetaminophen in
patients with and without liver disease. Both a single dose (1000 mg),
and five days of acetaminophen (1000 mg three times per day) were
studied in patients with biopsy-confirmed cirrhosis. There was no
accumulation of acetaminophen during five days of therapy, nor were
there any clinical or biochemical signs of hepatotoxicity.

Forrest and associates \[Forrest 1979\] compared acetaminophen
metabolism following a single 1500 mg dose to normal subjects, patients
with mild liver disease, and patients with severe liver disease. There
were no significant differences between groups in overall 24-hour
urinary excretion of acetaminophen and its glucuronide, sulfate,
cysteine, and mercapturic acid conjugates, evidence that acetaminophen
metabolism was similar to that in normal subjects.

Benson \[1983\] conducted a double-blind, two-period crossover study of
4000 mg/day of acetaminophen for 13 days in patients with stable chronic
liver disease. Acetaminophen did not accumulate and the pharmacokinetics
were similar to that reported in healthy subjects.

In a placebo-controlled study \[Dargere 2000\], French patients with
chronic hepatitis C were given three grams of acetaminophen daily or
placebo for seven days. Transaminase and viral loads were unaffected by
treatment. The authors concluded that recommended doses of acetaminophen
could be used for patients with chronic hepatitis C. \[Note: The
recommended daily dose of acetaminophen in France at the time this study
was conducted was three grams per day. It is now four grams per day.\]

A study in patients with acute viral hepatitis (A, B, nonA/nonB)
compared the changes in pharmacokinetics of acetaminophen during the
acute and recovery phases of the disease \[Jorup-Ronstrom 1986\]. The
mean half-life was 3.2 and 2.1 h for the acute and recovery phases,
respectively. Although the elimination rate was slightly prolonged, the
researchers conclude that acetaminophen may be given in conventional
doses to patients with hepatitis.

Based on results of these studies, acetaminophen may safely be used in
adults with existing liver disease at the currently recommended doses,
without exacerbation of these underlying conditions.

### Pediatric Patients with Liver Disease

Acetaminophen has also been studied in pediatric patients with liver
disease (ages seven months to 12 years). Following a single (10 mg/kg)
acetaminophen dose, the pharmacokinetic profiles in pediatric patients
with mild, moderate, or severe liver disease were not significantly
different \[al-Obaidy 1996\]. In another study \[Careddu 1961\],
acetaminophen elimination of a 10 mg/kg dose by children experiencing an
acute phase of infectious hepatitis was determined. The mean half-life
of 2.96 h was slightly prolonged compared with 2.24 h for healthy
control children. Elimination half-lives in four children were
redetermined during the recovery phase, and were found to decrease to
control values. Data demonstrate that acetaminophen may be safely used
in children with existing liver disease at recommended doses.

### Obese Adults

There has been a suggestion that obesity may increase the risk of
acetaminophen hepatotoxicity. O'Shea et al \[1994\] studied the
pharmacokinetics of chlorzoxazone (a putative probe for CYP2E1 activity)
to evaluate the effect of obesity on CYP2E1 activity. Based on
chlorzoxazone urinary metabolite data, the authors concluded that CYP2E1
is induced in obese adults and that this could impact the metabolic
pathway of a number of drugs metabolized by CYP2E1, including
acetaminophen. None of these other drugs were investigated in this
study. However, acetaminophen pharmacokinetic data have been
investigated in obese adults \[Abernethy 1982\]. In this prospective
study, 650 mg acetaminophen was administered intravenously to obese men
(297 lb), obese women (193 lb), control men (155 lb), and control women
(121 lb). Acetaminophen distribution volume per total body weight was
slightly lower in the obese adults but, more importantly, the half-life
and metabolic clearance per total body weight did not differ among
groups.

### Conclusions

Available data demonstrate that the use of recommended acetaminophen
doses in the general population does not result in hepatic,
gastrointestinal or renal toxicity. Furthermore, patient populations
theorized to have impaired metabolism that might put them at special
risk for toxicity, such as the elderly, patients with renal or hepatic
impairment, pediatric patients with liver disease, and obese patients
are not at increased risk of toxicity from acetaminophen. There is no
evidence to support the need for a dosage adjustment in these patients.

## Metabolic Alterations Theorized to Increase Risk

Genetic or induced metabolic alterations theoretically might increase
the risk for hepatotoxicity with acetaminophen use or overdose. Examples
include CYP2E1 or other isoenzyme induction, glucuronidation disorders
(UGDP deficiency), or glutathione deficiency or depletion. Available
data on each of these are summarized in the following sections, and
support the safe use of currently recommended doses of acetaminophen in
these situations.

### Situations In Which Cytochrome P-450 2E1 Might Be Induced

Approximately 5% to 8% of an acetaminophen dose is metabolized via the
cytochrome P-450 isoenzyme, CYP2E1. The contribution of other isoenzymes
is negligible \[Manyike 2000\], so only CYP2E1-inducing drugs have any
potential for an interaction with acetaminophen via this pathway. Two
agents have been shown in man to induce CYP2E1, long-term alcohol intake
and prolonged isoniazid therapy \[Omiecinski 1999\].

***Acute Alcohol Use.*** Acute alcohol ingestion refers to the
occasional or intermittent use of alcohol. The amount of alcohol
considered to be an acute ingestion can range from one or two drinks to
a weekend "binge." Binge drinkers have been theorized to be a patient
population that may have potential for increased risk of acetaminophen
hepatotoxicity. However, when taken together, alcohol competes with
acetaminophen for CYP2E1. CYP2E1 accepts alcohol more readily than
acetaminophen; therefore, less NAPQI is produced \[Sato 1981; Altomare
1984; Banda 1982\]. In the presence of alcohol, it is possible that
acetaminophen may be diverted to the glucuronidation and sulfation
pathways. Consequently, the overall result is that in the presence of
alcohol, a smaller percentage of acetaminophen may be expected to be
metabolized to the toxic intermediate (NAPQI) than would otherwise be
the case \[Rumack 2002\].

In a study by Thummel \[2000\], the fraction of acetaminophen dose
presumptively converted to NAPQI (measured as urinary cysteine and
mercapturic conjugates) was modestly increased when alcohol was infused
over the course of one evening. Nonetheless, this increase was
clinically insignificant, and the authors concluded that the maximum
recommended dose of acetaminophen (4 grams/day) can be safely consumed
by healthy adults after ingestion of alcohol.

***Chronic Alcohol Use.*** Prolonged excessive alcohol use may induce
the amount of CYP2E1 \[Lieber 1999\]. Thus, chronic heavy alcohol
abusers might be at increased risk of liver toxicity following excessive
acetaminophen use. While some \[Makin 2000\] have found no correlation
between alcohol consumption and the severity of hepatotoxicity following
acetaminophen overdose, others suggest that alcoholics may be at
increased risk from recommended doses. Available case reports usually
involve cases of severe chronic alcoholics and the dosages most often
exceed recommended doses or involve substantial overdose \[Schiodt 1997;
Seeff 1986; Zimmerman 1995\]. Even so, these case reports are
problematic with regard to drug histories. Chronic alcoholics and drug
overdose patients most often cannot provide a reliable history of the
medications or amounts they have taken \[Broughan 2000; Matsika 1999;
Montague 2001; Pohjola-Sintonen 2000\].

The only prospective data available \[Kuffner 1997, 2001\] demonstrate
that chronic alcoholics can take recommended doses of acetaminophen (up
to four grams per day) without added risk of liver injury. In these
prospective, placebo-controlled studies, the researchers evaluated an
actively drinking group of alcoholics with a high prevalence of
malnourishment. The study participants abruptly stopped their daily
alcohol intake and took acetaminophen the next day. This should
theoretically make them vulnerable to acetaminophen injury because their
CYP2E1 would be maximally induced from the alcohol and there would be no
alcohol present in the body to compete with acetaminophen for metabolism
by CYP2E1. However, there was no statistically significant difference in
mean values for AST, ALT, or International Normalized Ratio for
alcoholics given four grams per day of acetaminophen compared to those
given placebo. Additionally, the investigators performed an analysis of
the malnourished patients that showed there was no increase in AST or
ALT levels in these patients.

Other studies using single acetaminophen doses (up to 20 mg/kg) in
chronic alcohol abusers did not show an increase in the production of
the mercapturic metabolite \[Critchley 1982, 1983; Skinner 1990;
Villeneuve 1983\]. This finding is additional evidence that chronic
alcohol use does not significantly alter acetaminophen metabolism or
risk for hepatotoxicity with recommended doses. However, the caution to
have anyone who consumes three or more alcoholic drinks every day talk
with their doctor before using acetaminophen or other pain relievers
remains appropriate, and the need to strongly urge chronic alcoholics
not to exceed the recommended dose is very important.

***Isoniazid.*** Isoniazid is primarily metabolized by CYP2E1 \[Lieber
1997; Omiecinski 1999\] and induces CYP2E1 \[Bray 1992; Parkinson 1996;
Lieber 1997; Manyike 2000\]. Studies in healthy subjects clearly
demonstrate that isoniazid blocks the formation of the toxic metabolite,
NAPQI, \[Epstein 1991; Zand 1993\]. Thus, concomitant use of isoniazid
is unlikely to potentiate the risk of acetaminophen-induced
hepatotoxicity at recommended doses. In fact, it has been postulated,
but not demonstrated, that concurrent use of isoniazid may protect
against hepatotoxicity in an acute acetaminophen overdose \[Epstein
1991; Zand 1993\]. The isoniazid induction of CYP2E1 is short-lived,
lasting only 12 to 48 hours after the discontinuation of isoniazid
\[Zand 1993; Chien 1997\], so theoretically only during this period
would one consider whether there may be potentiation of a substantial
acetaminophen overdose.

### Concomitant Use of Drugs That Induce Other Cytochrome P-450 Isoenzymes

When evaluating the possibility of a potential interaction between
acetaminophen and drugs that induce cytochrome P-450 isoenzymes other
than CYP2E1, it is important to remember that only a small amount (5% to
8%) of acetaminophen is metabolized by cytochrome P-450. The CYP2E1
isoenzyme is primarily responsible for the conversion of acetaminophen
to NAPQI, whereas CYP3A4 and CYP1A2 play negligible roles, if any, in
the metabolism of acetaminophen \[Manyike 2000\].

Some reports have suggested that patients taking long-term
anticonvulsant therapy (eg, phenobarbital, phenytoin, or carbamazepine),
who overdose on acetaminophen may be at increased risk for
hepatotoxicity as a result of enhanced acetaminophen metabolism due to
induction of CYP3A4 and CYP1A2 \[Wright 1973; Mitchell 1974; Perucca
1979; Miners 1984; Bray 1992\]. Table 4- lists the effect of each of
these drugs on CYP2E1 and provides a list of the other cytochrome P-450
isoenzymes involved in their metabolism. Additionally, a review of the
published medical literature clearly indicates that patients on
long-term anticonvulsant therapy are not at increased risk of
hepatotoxicity when acetaminophen is taken at recommended therapeutic
doses \[Kampffmeyer 1969; Kampffmeyer 1971; Neuvonen 1979; Prescott
1981; Makin 1995\].

Table 4-. Effect of Concomitant Use of Drugs That Induce Cytochrome
P-450 Isoenzymes

+-------------+-------+-----------------------+-----------------------+
| Drug        | E     | Cytochrome P-450      | References            |
|             | ffect | Isoenzyme(s) Induced  |                       |
|             | On    |                       |                       |
|             | C     |                       |                       |
|             | YP2E1 |                       |                       |
+-------------+-------+-----------------------+-----------------------+
| **Antico    |       |                       |                       |
| nvulsants** |       |                       |                       |
+-------------+-------+-----------------------+-----------------------+
| Ph          | None  | CYP2B6                | \[Parkinson 1996;     |
| enobarbital |       |                       | Chang 1997; Anderson  |
|             |       | CYP2C8, CYP2C9        | 1998; Omiecinski      |
|             |       |                       | 1999; Fuhr 2000\]     |
|             |       | CYP1A2, CYP3A4        |                       |
+-------------+-------+-----------------------+-----------------------+
| Phenytoin   | None  | CYP2C9                | \[Prescott 1981;      |
|             |       |                       | Anderson 1998\]       |
|             |       | CYP3A4                |                       |
+-------------+-------+-----------------------+-----------------------+
| Ca          | None  | CYP2C9                | \[Parkinson 1996;     |
| rbamazepine |       |                       | Tomlinson 1996;       |
|             |       | CYP3A4                | Anderson 1998\]       |
+-------------+-------+-----------------------+-----------------------+
| **Other     |       |                       |                       |
| Drugs**     |       |                       |                       |
+-------------+-------+-----------------------+-----------------------+
| Rifampin    | None  | CYP3A4                | \[Pichard 1990;       |
|             |       |                       | Parkinson 1996; Chang |
|             |       | CYP2B6                | 1997; Anderson 1998;  |
|             |       |                       | Lehmann 1998; Thummel |
|             |       | CYP2C8, CYP2C9,       | 1998; Omiecinski      |
|             |       | CYP2C19               | 1999; Fuhr 2000\]     |
+-------------+-------+-----------------------+-----------------------+
| Omeprazole  | None  | CYP1A2                | Diaz 1990; Rost 1992; |
|             |       |                       | Parkinson 1996;       |
|             |       |                       | Sarich 1997;          |
|             |       |                       | Omiecinski 1999\]     |
+-------------+-------+-----------------------+-----------------------+

Other drugs metabolized by CYP1A2 and CYP3A4 include rifampin and
omeprazole. Manyike and colleagues \[Manyike 2000\] found that rifampin
pretreatment had no significant effects on the formation of NAPQI or the
recovery of thiol metabolites formed by the conjugation of NAPQI with
glutathione, suggesting that even when induced, the contribution of
CYP3A4 to NAPQI formation is negligible. This study also provided
convincing evidence of the predominance of CYP2E1 in NAPQI formation in
humans, and suggests that the contribution of CYP3A4 is minor.

Omeprazole has been shown to induce the activity of CYP1A2 in humans
\[Diaz 1990; Rost 1992; Parkinson 1996; Sarich 1997; Omiecinski 1999\].
However, data demonstrate that CYP1A2 induction by omeprazole is not
clinically significant, and since CYP1A2 has a negligible role in
acetaminophen metabolism, it is unlikely to increase the risk of
acetaminophen-induced hepatotoxicity \[Xiadong 1994; Sarich 1997\].

### Situations Affecting Glucuronidation 

In humans, the major metabolic pathway of acetaminophen is
glucuronidation, accounting for 47% to 62% of a dose \[Koch-Weser
1976\]. These glucuronide conjugates are inactive and nontoxic (see
Section 3.2, Acetaminophen Metabolism). Addressed below are theoretical
concerns that decreased glucuronidation capacity may alter the
pharmacokinetics of acetaminophen and increase risk of hepatotoxicity.

### Fasting and UDP-Glucuronic Acid or Precursor Depletion

Acetaminophen is metabolized to acetaminophen glucuronide by
glucuronosyltransferase, with uridine diphosphoglucuronic acid (UDP-GA)
as a necessary co-factor. A theoretical concern is that a deficiency in
the precursors for UDP-GA may decrease glucuronidation capacity and
shift acetaminophen metabolism to other pathways, ie, microsomal
oxidation, via CYP2E1. In 1994, Whitcomb and Block published a case
series and suggested that hepatotoxicity following acetaminophen
overdose is enhanced by fasting \[Whitcomb 1994\]. Presumptively,
fasting depletes precursors for glucuronidation and shifts metabolism to
the cytochrome pathway. Although severe caloric restriction can deplete
UDP-GA precursors in laboratory animals, no clinical data indicate
conclusively that this occurs in humans or that a decrease in
glucuronidation would lead to an increase in the microsomal oxidation
pathway of acetaminophen metabolism \[Price 1988\].

Additional studies have evaluated the effect of fasting on acetaminophen
disposition. A recent clinical study found that there was no change in
urinary metabolites and unaltered liver function tests with use of a
single two-gram dose of acetaminophen in obese, fasting
caloric-restricted adults \[Schenker 2001\]. Another study showed no
difference in acetaminophen pharmacokinetics between fasting and
nonfasting patients \[Kohli 1982\]. Taken together, these studies
indicate that fasting does not lead to decreased glucuronidation that
would shift acetaminophen metabolism toward the microsomal oxidation
pathway.

### Gilbert's Syndrome and UDP-Glucuronosyltransferase Depletion

The primary enzymatic deficiency in Gilbert's is in uridine
diphosphoglucuronosyltransferase (UDP-GT) activity, specifically the
isoform UGT1A1. This deficiency leads to hyperbilirubinemia \[De Morais
1992; Bosma 1995; Radu 2001\]. Acetaminophen glucuronidation involves a
different UDP-GT isoform, UGT1A6 (and to a lesser extent UGT1A9) \[Bock
1993; Court 2001\].

Concern has been expressed that glucuronidation is decreased in patients
with Gilbert's syndrome, which would lead to more acetaminophen
undergoing oxidation by cytochrome P-450, resulting in more NAPQI being
formed at therapeutic doses.

Studies of acetaminophen metabolism in patients with Gilbert's syndrome
show little or no reduction in glucuronidation capacity for
acetaminophen metabolism \[Schmid 1959; Ullrich 1987\]. Others have
shown a slight decrease in glucuronidation capacity accompanied by a
modest increase in the proportion of glutathione-derived metabolites,
but only in the subset of Gilbert's syndrome patients with less than 50%
glucuronidation \[Esteban 1999\]. This amount of increase in
glutathione-derived metabolites is unlikely to have clinical
significance.

Court and colleagues \[Court 2001\] confirmed the results of a previous
study \[Bock 1993\] indicating that UGT1A6 was the primary isoform
involved in the glucuronidation of acetaminophen, with UGT1A9
contributing a lesser extent. UGT1A1 contributed to a small extent. In
addition, Court also found that UGT1A1 activity varied considerably
among human livers, enough to overshadow any changes that might be seen
in Gilbert's syndrome.

Available data suggest that UGT1A6, and to a lesser extent, UGT1A9 are
the most important isoforms for acetaminophen glucuronidation in humans
(not UGT1A1), so there is no support for an increased risk of
hepatotoxicity in these patients who take acetaminophen at recommended
doses. Additional human data might be informative to determine if there
is any risk with higher than recommended single doses (eg, 3- or 4-gram
single doses).

### Glutathione

Glutathione plays an important role in detoxifying intermediary
metabolites of multiple analgesics, namely, NSAIDs, morphine and
acetaminophen. It follows that individuals with hepatic glutathione
deficiency or with a deficiency in glutathione synthetase (the enzyme
responsible for coupling NAPQI with glutathione) may be theorized to be
at increased risk for acetaminophen toxicity.

#### Glutathione Synthetase Deficiency

In vitro studies \[Spielberg 1981; 1985\] on cells from patients with
glutathione synthetase deficiency and from heterozygotes for the
disorder suggest the possibility of decreased ability to detoxify the
reactive metabolite of acetaminophen. To our knowledge, no one, either
heterozygous or homozygous for the deficiency, has taken acetaminophen
and thus, there are no reports of in vivo toxicity. Glutathione
synthetase deficiency is an extremely rare inborn error of metabolism.
In fact, there are under one dozen known pedigrees in the world. These
patients are easily identified as they typically have clinical symptoms
such as hemolytic anemia, severe acidosis and 5-oxoproline in the urine.
Patients with glutathione synthetase deficiency and their parents are
routinely instructed by their healthcare provider to avoid
acetaminophen-containing products \[personal communication Spielberg
2002\].

#### Disorders in Which Glutathione Might be Depleted

***Glutathione Levels in Alcoholics.*** Chronic alcoholics have been
reported to have decreased intrahepatic glutathione stores \[Jewell
1986\]. The extent to which glutathione is actually depleted in
alcoholics is uncertain. However, as previously reviewed,
well-controlled, prospective studies \[Kuffner 1997; 2000\] demonstrate
that therapeutic doses of acetaminophen do not cause liver injury in
chronic alcoholics. The impact of this in cases of substantial overdose
is not determined.

***Use of Acetaminophen in HIV-infected Patients.*** HIV-infected adults
and children appear to show a progressive decrease of glutathione in
peripheral blood lymphocytes at different stages of the disease. The
degree of correlation between blood and hepatic glutathione is unclear.
It has been suggested that drugs that deplete glutathione may make
glutathione-deficient individuals more susceptible to toxicity
\[Herzenberg 1997\]. Nevertheless, there are no human data suggesting
that acetaminophen depletes total body or plasma glutathione stores,
when taken at recommended therapeutic doses in patients infected with
HIV.

**Use of Acetaminophen in Patients with Hepatitis C.** Chronic hepatitis
C infection can lead to a decrease in glutathione levels \[Lauterburg
2002\]. This decrease appears not to alter acetaminophen safety and at
least one prospective trial showed that hepatitis C patients can use
therapeutic doses of acetaminophen without clinical evidence of liver
injury \[Dargere 2000\].

**Use of Acetaminophen in Patients with Cirrhosis of the Liver.**
Patients who have cirrhosis of the liver reportedly have decreased
glutathione levels, possibly resulting from the impaired formation of
the precursor amino acid cysteine from methionine \[Lauterburg 2002;
Rumack 2002\]. However, the activity of the CYP2E1 isoenzyme that
metabolizes acetaminophen to NAPQI is also decreased in patients with
cirrhosis \[Lauterburg 2002; Rumack 2002\]. Importantly, prospective
data indicate that currently recommended doses of acetaminophen may be
used in adults with cirrhosis, and this use will not exacerbate their
condition \[Benson 1983\].

### Conclusion

These data support that use of recommended doses of acetaminophen in
certain subpopulations believed to have glutathione deficiency provides
no increased risk of hepatotoxicity and does not require a dosage
adjustment. Additionally, patients with glutathione synthetase
deficiency are exceedingly rare, easily identified and should be
instructed by their physicians to avoid the use of acetaminophen.

## Clinical Characteristics of Acute Acetaminophen Overdose

Hepatic injury is the principal toxic effect of a substantial
acetaminophen overdose. Signs and symptoms of acetaminophen overdose
show a consistent pattern, and the clinical course generally occurs in a
three-phase sequential pattern. The first phase begins shortly after
ingestion of an overdose and lasts for 12 to 24 hours. The patient may
manifest signs of gastrointestinal irritability, nausea, vomiting,
anorexia, diaphoresis, and pallor. Many patients with early symptoms
never progress beyond the first phase and recover without sequela.

If toxicity continues or is to ensue, there is a latent phase of up to
48 hours. During this second phase, initial symptoms abate and the
patient may feel better. However, hepatic enzymes, bilirubin, and
prothrombin time or International Normalized Ratio values will
progressively rise, with hepatic enzymes often rising to striking
levels. Right upper quadrant pain may develop as the liver becomes
enlarged and tender. Most patients do not progress beyond this phase,
especially if given N-acetylcysteine (NAC) treatment early in the
course.

Signs and symptoms of the third phase depend on the severity of hepatic
damage and usually occur from three to five days following overdose
ingestion. Symptoms may be limited to anorexia, nausea, general malaise,
and abdominal pain in less severe cases or may progress to confusion,
stupor, and sequelae of hepatic necrosis including jaundice, coagulation
defects, hypoglycemia, and encephalopathy, as well as renal failure and
cardiomyopathy. Death, if it occurs, is generally the result of
complications associated with fulminant hepatic failure. Mortality rates
in patients with toxic plasma levels who do not receive antidote therapy
range from 3% to 4%. In nonfatal cases, serial liver biopsies and liver
function tests have shown prompt resolution with no significant residual
functional or architectural alterations of the liver.

## Situations of Potential Acetaminophen Overdose and Misadministration

Untreated acetaminophen overdoses (single doses of 15 grams) can produce
hepatotoxicity. Acetaminophen hepatotoxicity occurs as a threshold
effect and is characterized by a lack of toxicity at lower/therapeutic
doses. Acetaminophen hepatotoxicity occurs after major depletion of
glutathione, an endogenous detoxifying substance. Once the threshold is
exceeded, increasing acetaminophen doses may produce increasing degrees
of hepatotoxicity, unless NAC (antidote) is administered. This threshold
is not likely to be reached at single doses of less than 15 grams of
acetaminophen \[Mitchell 1974\].

Situations in which acetaminophen overdose and resultant hepatotoxicity
may occur include acute intentional overdose and repeated
supratherapeutic overdose in adults and acute accidental ingestion or
overdose and repeated supratherapeutic overdose in children. These
situations are summarized in the following sections.

### Acute Intentional Overdose in Adults -- Suicide Gestures or Attempts

Adult and adolescent intentional overdoses, either as a suicide gesture
or attempt (whether successful or unsuccessful), cause most of the
serious cases of acetaminophen hepatotoxicity. This conclusion is based
on data sources summarized in detail in Section 4.6, Data Sources
Available to Assess Misadministration and Overdose. The frequency of
suicide as a reason for overdose may be higher than reported since
suicidal intent is difficult to confirm. Disclosure of suicidal intent
may be of concern given possible repercussions (eg, loss of insurance
coverage, privacy, social stigma and family impact). An effective
antidote treatment (NAC) and strategy for treating cases of
acetaminophen overdose have greatly reduced morbidity and mortality from
intentional and unintentional overdose.

### Repeated Supratherapeutic Overdose in Adults

Another form of overdose is that of repeated supratherapeutic ingestion.
In these cases, consumers report repeat doses of multiple products
containing acetaminophen or repeat dosing of more than the recommended
single dose of acetaminophen. These practices may result in a
substantial and serious acetaminophen overdose.

Two case series of repeated supratherapeutic overdoses have been
recently reported, one from the United States \[Dart 2000\] and the
second from the United Kingdom \[Dargan 2002\]. These cases were
evaluated to identify if and when therapeutic interventions for
acetaminophen overdose might be required. The United States case series
\[Dart 2000\] identified two groups of patients based upon clinical
presentation: 1) those with elevated liver function tests on
presentation; and 2) those with normal liver function. Patients
presenting with normal liver function tests were not treated with a
course of NAC, and there was no subsequent evidence of hepatotoxicity.
Among the patients presenting with abnormal liver function tests, all
were started on NAC therapy and 32.5% of these patients with abnormal
liver function tests developed liver failure; one patient required a
liver transplant and four patients died. The authors concluded that
patients who present after repeated supratherapeutic overdoses with
normal liver function may not need treatment with NAC.

In the United Kingdom case series \[Dargan 2002\], the mean reported
acetaminophen dose ingested was 17.7 grams and the mean time from the
first acetaminophen dose to presentation was 32 hours. Seventeen of the
19 cases received NAC; two cases did not. Notably, in this case series
none of the 19 patients developed serious sequelae.

### Acute Accidental Overdose in Pediatric Patients

Acute accidental ingestion or overdose may occur in young children
because of the widespread availability of acetaminophen in American
households. Reports from the AAPCC indicate that even though there are
large numbers of exposures to pediatric dosage forms, very little
toxicity follows from such exposures. Even accidental ingestion of adult
dosage forms of acetaminophen in children infrequently produces
toxicity, in part because the dose actually absorbed is usually below
the threshold for toxicity.

In a recent five-year period (1996-2000), AAPCC reported 217,170
exposures to acetaminophen-containing products in children less than six
years of age. There were three fatalities in children less than six
years of age and one fatality in an 11-year-old child \[Litovitz 1997;
Litovitz 1998; Litovitz 1999; Litovitz 2000; Litovitz 2001\]. McNeil
obtained additional details from the AAPCC for 1997 and learned that of
49,873 exposures to acetaminophen-containing products in children less
than six years of age, there were 256 exposures in which NAC treatments
were reportedly administered \[personal communication from AAPCC,
September 27, 2001\]. These more serious exposures represent about 0.5%
of the reported exposures in children that year. Toxicity is rare
following acute accidental overdose in children.

### Repeated Supratherapeutic Overdose in Pediatric Patients

Repeated supratherapeutic overdose in pediatric patients has been
described when parents or caregivers repeatedly gave more than the
recommended acetaminophen dose, resulting in a substantial acetaminophen
overdose. Most of these cases are unintentional and most serious cases
involve parents administering adult products to children or incorrect
doses to children under age two. We are concerned about these potential
cases of inadvertent overdose. As such, in 1999 McNeil submitted a
Citizen's Petition to the FDA requesting an expansion of the OTC
labeling of pediatric acetaminophen products to include dosing
instructions for children under 2 years of age.

## Data Sources Available to Assess Misadministration and Overdose

This section summarizes the FDA AERS Data Set and other data.

-   Case reports are the source of serious hepatic events associated
    with acetaminophen exposure. These reports are observational and
    therefore cannot be used to establish causality.

-   The number of serious reports for acetaminophen products at the FDA
    is disproportionately large relative to other monograph analgesics
    because: a) FDA regulations do not require AERS reporting for OTC
    monograph drug products, and b) McNeil has submitted serious reports
    for all single-ingredient acetaminophen products and reports of
    death for acetaminophen combination products, including published
    literature and fatalities from AAPCC.

The data sources available to assess the misadministration and overdose
situations described in Section 4.5, Situations of Potential
Acetaminophen Overdose and Misadministration, include spontaneous
reports submitted to the FDA's Adverse Event Reporting System (AERS),
poison control center reports, the Drug Abuse Warning Network (DAWN),
and reports from liver transplant centers. These data sources are
descriptive in nature and consist of case reports. This section places
the case reports in the hierarchy of medical evidence, reviews the data
from the available sources, and summarizes inferences from these data.

### Quality of Data

The ability to accurately assess risk depends on the quality of the data
available for evaluation. The quality of medical evidence can be
categorized as being from analytical studies (randomized controlled
trials, cohort studies, case-control studies) or from descriptive
studies (correlational studies, cross-sectional surveys, case series,
and case reports) \[Hennekens 1987\]. Information from analytical
studies is more likely to be useful in establishing causal associations
than information from descriptive studies, from which causation cannot
be assessed. Spontaneous reports sent to manufacturers and regulatory
authorities are useful for signaling the possibility of rare unexpected
adverse drug reactions that are not detected during pre-marketing
testing, and for providing potential patient risk factors (such as drug
interaction, age) associated with drug reactions \[Faich 1986; Stang
1992\]. Properly designed epidemiological studies may be useful to
evaluate potential signals suggested by spontaneous reports and for
quantifying relative risk associated with specific drug exposures. While
randomized controlled trials are unlikely to include a sufficient number
of subjects for detection of rare adverse drug events, they are useful
for exploring specific causal relationships.

Spontaneous adverse event reports have limitations that are well
recognized (see below). AERS, the FDA's database for spontaneous adverse
drug experience, is referenced, where appropriate. Lack of reliable dose
information and the intentionality in overdose, as identified below, are
applicable not only to spontaneous reports, but also to data from most
case reports and liver transplant centers.

**Causality Assessment.** Causality assessment is impeded by the limited
quality \[Goldman 1998\] and incompleteness of data in spontaneous
reports, despite diligent efforts by manufacturers to obtain follow-up
information from reporters. Spontaneous reports rely on retrospective
data collection and as such are often missing important clinical
information and laboratory results.

**Dose Information and Intentionality in Overdose.** Dosing information
provided in spontaneous reports relies on the reporter's ability to
recall information conveyed to the reporter by healthcare professionals
during the reporting process, and the reporter's motivation to correctly
report. The lack of precise dose information and uncertain reliability
regarding intent of drug use (overdose, misuse, therapeutic intent, etc)
make it impossible to assess the relationship between dose and drug
reaction. This is of particular concern with acetaminophen because
dosage information is key to assessing the likelihood of drug toxicity,
and whether a plausible threshold for overdose was exceeded. OTC
analgesics are often taken on an as-needed basis by consumers who do not
typically keep a record and accurately report how much or how often they
take their medications. Even when the reports originate from healthcare
professionals, the dosing information comes ultimately from consumers or
the family members of affected individuals. In addition, even if plasma
levels are available, the absence of a reliable time interval between
acute ingestion of acetaminophen and blood drawing limits the utility of
acetaminophen levels. When reported, very high plasma concentrations may
refute the reported dose and suggest that a large overdose was taken.
Given the social stigma associated with suicide attempts and concerns
regarding insurance coverage in the United States, intentional overdose
may be reported as accidental.

**Reporting Bias.** Safety signal detection as proposed by International
Committee on Harmonization is based on review of individual reports, or
on the reporting frequency of a given adverse event relative to a
reference (either all drugs in the entire database or a select few for
the same indications). The frequency of reporting of a given adverse
event can be skewed by numerous factors including publicity through
educational efforts, media and literature, as well as the reporting
practices of various manufacturers \[Stang 1992\]. Spontaneous reports
are an unreliable measure of risk, since they may reflect the relative
awareness of specific toxic effects among reporters \[Miwa 1997\]. As an
example, an apparent differential risk of gastrointestinal and
dermatological events for NSAIDs suggested by a review of spontaneous
reports was not corroborated by epidemiologic studies.

Manufacturers of monograph OTC analgesics are not required by FDA
regulation to submit adverse event reports to AERS. Any manufacturer
electing to submit such reports could create a false signal by doing so.
OTC ibuprofen and naproxen sodium analgesic products are marketed under
the NDA process and therefore have more stringent adverse event
reporting requirements than aspirin or acetaminophen, which are marketed
under the Tentative Final Monograph for Internal Analgesic, Antipyretic
and Antirheumatic products. While not required under the monograph
process to submit adverse event reports for regular or extra-strength
acetaminophen (monograph products), as an NDA holder of extended release
acetaminophen, McNeil submits to the FDA serious reports for all
single-ingredient acetaminophen products; McNeil also voluntarily
submits to the FDA reports of death for all monograph Tylenol
combination products. McNeil scans the world literature for reports of
acetaminophen events, regardless of brand name, dosage form, country of
origin, or case verification. McNeil also reports AAPCC annual fatality
table cases as individual case reports. Furthermore, McNeil submits any
consumer reported event, whether or not the event is verified. Thus, the
number of serious reports for acetaminophen products at the FDA is
disproportionately large relative to other monograph analgesics.

**Underreporting.** Reports in spontaneous reporting systems are either
submitted to the manufacturer and subsequently, to regulators, or
voluntarily reported directly to regulators. It is generally believed by
regulatory authorities that there is an underreporting of adverse events
\[Goldman 1998\]. This may be more pronounced for OTC products marketed
under the monograph process, for which there are no regulatory reporting
requirements. Thus, the incidence of drug-related adverse events cannot
be determined from spontaneous reporting systems \[Goldman 1998\], and
the number of reports in such a database do not reflect the incidence of
the event in the population exposed.

In summary, case reports are limited by their anecdotal and
retrospective nature, quality and incompleteness of data, reliance on
patient's ability to recall information on dosing and the true intention
of overdose, and the effects of reporting bias and underreporting. For
acetaminophen, this is further complicated by the fact that
acetaminophen toxicity occurs only after a threshold dose has been
exceeded, so that an accurate, reliable dosage history is critical for
any evaluation.

###  Spontaneous Reports Selected by the FDA for Evaluating the Hepatotoxicity of Acetaminophen (FDA AERS Data Set)

#### Background

FDA has identified a set of AERS reports with serious outcome reported
during the time period January 1998 through March 2001 that include
selected \"hepatic\" adverse event terms and acetaminophen as a suspect
drug. Stated exclusions were reports from foreign sources and duplicate
reports; reports with hepatic cancer terms, reports with suicide or
intentional overdose terms; reports with concomitant drugs that were
removed from the market for hepatotoxicity; and those reports with more
than two non-acetaminophen suspect drugs. This specific FDA-selected
AERS Data Set was developed in an attempt to determine the circumstances
that led to hepatotoxicity. A total of 307 reports, identified by FDA
from AERS over this time period, were provided to the Consumer
Healthcare Products Association (CHPA) under a Freedom of Information
request. McNeil subsequently obtained the MedWatch forms from CHPA.

#### Analysis of FDA-Selected Reports

McNeil has reviewed and analyzed the FDA-selected AERS Data Set. McNeil
noted discrepancies regarding stated exclusion criteria. One report did
not involve acetaminophen as a suspect drug. There was one report of
intentional self-injury and four reports were apparently from foreign
sources, indicated by the term paracetamol as the suspect medication,
describing intravenous NAC protocols or intravenous acetaminophen, a
formulation not available in the United States. The manufacturer's
received date ranged from November 28, 1994 to August 2, 2001.
Additionally, reports were included from the AAPCC TESS database dating
back to 1987. At least one third of the events occurred during the time
period from 1979 through 1997. To put in perspective these events that
took place over 25 years, it should be noted that in 2001 purchases of
OTC single-ingredient adult acetaminophen tablets were approximately 11
billion, of OTC combination-ingredient adult acetaminophen tablets were
approximately nine billion, and approximately three billion prescription
were filled for acetaminophen-containing products;
purchases/perscriptions in earlier years were less.

The FDA-selected AERS Data Set (306 reports) is referred to herein as
the "FDA AERS Data Set". The 281 adult reports are discussed in Section
4.6.2.2.1, FDA AERS Data Set -- Adult Reports, and the 25 pediatric
reports are discussed in Section 4.6.2.2.2, FDA AERS Data Set --
Pediatric Reports.

##### FDA AERS Data Set -- Adult Reports

This AERS Data Set was selected by FDA to understand reports that may
reflect inadvertent adverse outcomes or misuse. FDA intended to exclude
obvious suicide, usually associated with very large drug ingestions.
Thus, the reported dosage (which could only be estimated in 48% of the
reports in the data set) is skewed significantly toward labeled
directions for use, consistent with reports of inadvertent use or
misuse.

This selective data set cannot be used to determine an acetaminophen
toxicity threshold for any condition (ie, concomitant drug, alcohol
history, or pre-existing concomitant disease) or to establish intent.

Table 4- provides a summary of the distribution of the 281 adult reports
in the FDA-selected Data Set by product category, ie, the type of
acetaminophen-containing product, (single-ingredient, multiple
ingredient, OTC, and prescription) used. Use of acetaminophen-containing
prescription combination analgesics accounted for 37% of the reports.

Table 4-. Distribution of Reports by Product Category

+----------------------------------------------+---------+-------------+
| Drug Product Category                        | Number  | \% of Total |
|                                              |         | Reports     |
|                                              | of      |             |
|                                              | Reports |             |
+----------------------------------------------+---------+-------------+
| OTC Acetaminophen Single Ingredient alone    | 153     | 54.4%       |
+----------------------------------------------+---------+-------------+
| OTC Acetaminophen Combos + OTC Acetaminophen | 14      | 5.0%        |
| Single                                       |         |             |
+----------------------------------------------+---------+-------------+
| OTC Acetaminophen Combos                     | 9       | 3.2%        |
+----------------------------------------------+---------+-------------+
| Rx Acetaminophen Combos                      | 57      | 20.3%       |
+----------------------------------------------+---------+-------------+
| Rx Acetaminophen Combos + OTC Acetaminophen  | 48      | 17.1%       |
| Single                                       |         |             |
+----------------------------------------------+---------+-------------+

Overall, 24.5% of the reports involved the concurrent ingestion of two
or more acetaminophen-containing products. The majority of these reports
were found in the two categories identified in Table 4- with an
asterisk. In addition, other reports of concurrent ingestion were
included in this percentage, eg, use of multiple OTC single-ingredient
acetaminophen products, use of multiple Rx acetaminophen combination
products.

The quality of these reports with respect to the presence or absence of
important data elements that could be used to infer drug relationship to
reported hepatotoxicity was evaluated. One hundred sixty-eight (168)
reports did not have sufficient information to allow for an estimate of
the dose taken. Eighty-eight percent (88%) of these reports did not
contain liver pathology information. Seventy-eight percent (78%) of
these reports did not report viral hepatitis testing; of the 61 that
did, 48% (29) were positive for hepatitis A, B, or C. In addition, 38%
(108) of the reports did not contain AST or ALT levels. Reported alcohol
use or abuse among the cases was frequent. Among the 281 reports, 116
contained information on alcohol use or blood alcohol level, 76 of which
had a history of chronic alcohol ingestion up through the time of
ingesting acetaminophen.

*FDA Subsets.* FDA theorized that three factors, ethanol use,
underlying/history of liver disease, and potentially hepatotoxic
co-suspect medications, increase susceptibility to
acetaminophen-associated hepatotoxicity at lower than expected doses.
For these report subsets, FDA calculated the mean and median
acetaminophen reported dose separately for cases with and without the
factor. These factors, however, appear to be groupings in which lower
doses of acetaminophen use may be coincidentally associated with reports
of hepatotoxicity from other causes, or, in some cases, reports in which
the reported dose grossly underestimates actual acetaminophen exposure
in some cases. A more-detailed description is provided below.

-   *Ethanol Use.* It is well known that the alcoholic person
    underreports alcohol use \[Broughan 2000\] and may experience
    short-term memory deficits. Recall of other drug use may also be
    inaccurate. The excessive use of ethanol may also extend into
    excessive use of other substances, including acetaminophen. (See
    Section 4.3.1, Situations in Which Cytochrome P-450 2E1 Might Be
    Induced, for a discussion of alcohol-related issues.) Nevertheless,
    the caution to have anyone who consumes three or more alcoholic
    drinks every day talk with their doctor before using acetaminophen
    or other pain relievers remains appropriate and the need to strongly
    urge chronic alcoholics not to exceed the recommended dose is very
    important.

```{=html}
<!-- -->
```
-   *Underlying or History of Liver Disease.* Underlying liver disease
    also confounds attribution, since pathophysiology of the underlying
    disease progression and accompanying discomfort may lead an
    individual to self-medicate with OTC analgesics, including
    acetaminophen. In fact, one would expect confounding by indication.
    Frequency of therapeutic acetaminophen use would be expected to be
    higher in persons with liver disease because other analgesics are
    frequently contraindicated. In particular, individuals who take
    acetaminophen for their pain and have underlying liver disease are
    likely to be using recommended doses and would be expected to
    accurately report a lower average dose. This association is not
    causal. The pathophysiology of their underlying liver disease
    progression or liver failure, however, may be unrelated to the use
    of acetaminophen.

```{=html}
<!-- -->
```
-   *Potentially Hepatotoxic Co-Suspect Medications.* Many of these
    cases were submitted to FDA primarily for the co-suspect drug and
    patients were taking acetaminophen to treat symptoms associated with
    their underlying illness. This association is not causal.

While we believe that it is impossible to determine accurate dose from
case reports and disagree with relying upon an analysis of acetaminophen
dose from case reports, we explored FDA's analysis of acetaminophen dose
for the subsets of cases with alcohol use and liver disease history.

We calculated the mean and median acetaminophen dose (mg/day) by alcohol
use group (yes, no, or unknown) and found no statistically significant
difference among the groups (ANOVA p= 0.85). Further, when the "unknown"
alcohol use group was alternately combined with the "yes" and "no"
alcohol use categories, again, there were no statistically significant
differences between the groups (unknown combined with yes, p= 0.57;
unknown combined with no, p= 0.82).

We performed the same analysis for underlying liver disease. We
calculated the mean and median acetaminophen dose (mg/day) by underlying
liver disease group (yes, no, or unknown) and found no statistically
significant difference among the groups (ANOVA p= 0.54). Further, when
the "unknown" underlying liver disease group was alternately combined
with the "yes" and "no" underlying liver disease categories, again,
there were no statistically significant differences between the groups
(unknown combined with yes, p= 0.78; unknown combined with no, p= 0.32).

In summary, we believe that it is impossible to determine accurate dose
from case reports and disagree with relying upon an analysis of
acetaminophen dose from case reports. Further, our statistical analysis
demonstrates that the trends FDA reported with these data are not
systematic and no relationship between these factors and the reported
acetaminophen dose is evident. For all of these reasons, these analyses
do not support the theory that these factors increase susceptibility to
acetaminophen-associated hepatotoxicity.

#####  {#section .unnumbered}

*Expert Review Panel Causality Attribution of Adult Reports.* Case
reports are descriptive and cannot be used to establish causality. To
prevent evaluation bias and to assist identification of important
signals contained in this dataset, McNeil undertook to assess the nature
of identifiable factors among these reports. To do this, McNeil convened
a group of nine outside medical experts, representing toxicology,
hepatology, and emergency medicine to review the 281 adult reports.
Attachment 1 contains the complete listing of the names and affiliations
for each member of the Expert Review Panel. The panel of medical experts
was asked to determine if each report was evaluable, and if so, the
likelihood that the reported hepatic event was related to acetaminophen.
Reports were considered evaluable if there was mention of acetaminophen
use anywhere in the report and the case findings indicated or
demonstrated any degree of liver injury or disease. All but three of the
cases were considered to be evaluable.

After considering criteria used by others to evaluate adverse drug
reactions, the panel developed their own causality data collection
instrument \[see Attachment 2\] since existing methodologies (The
Roussel Uclaf Causality Assessment Method and the Clinical Diagnostic
Scale) require more data than are available on the FDA 3500A MedWatch
reports, and were not directly applicable to acetaminophen overdose
toxicology.

Each medical expert reviewed all 281 reports independently, assigned a
probability category, and submitted a report assessment sheet for each
case, noting the basis for their judgement. This was done by all
participants prior to a final consensus meeting. At the consensus
meeting, the panel reviewed each report as a group, and reached a
consensus regarding the probability category for each report.
Additionally, the panel was asked to provide overall observations on the
process and data set. Table 4- provides a summary of the number of
reports classified into each of the categories. As shown in Table 4-, 73
(26%) reports did not contain sufficient information for determination.
Of the 205 reports with sufficient information, 38% were considered to
have more than a 50% likelihood (probably or definitely categories) of
being related to acetaminophen exposure.

Table 4-. Summary of Expert Review Panel Consensus Probabilities of
Acetaminophen Exposure Being Related to Hepatic Events in the FDA Data
Set

  ------------------------------------- ---------------------------------
  Probability category                  Number of Reports

  Definitely                            3

  Probably                              74

  Possibly                              47

  Unlikely                              53

  Definitely not                        27

  Data are insufficient                 73

  Not evaluable                         3

  No consensus                          1

  Total number of reports               281
  ------------------------------------- ---------------------------------

McNeil further evaluated all reports with an Expert Review Panel
designation of 50% probability of acetaminophen related liver
abnormality (Definitely and Probably). We evaluated these reports for
identification of descriptive factors that could, taken together with
consumer medication usage information, lead to effective interventions
and reduction in adverse outcomes (as described later in Section 6,
McNeil Initiatives and Recommendations). These reports were also
classified against FDA's severity criteria (FDA Briefing Document.
Nonprescription Drugs Advisory Committee Meeting, September 19 -- 20,
2002; <http://www.fda.gov/ohrms/dockets/ac/02/briefing/3882b1.htm>,
access confirmed August 30, 2002), Categories 1 to 4, and found to be
positively correlated (0.24, p\<0.001).

As shown in Table 4-, the cases assessed by the Expert Review Panel to
be definite or probable (n= 77) included individuals who were younger
and had reported a history of alcohol use or alcohol abuse (alcoholism)
when compared with the remaining reports (n=204).

Table 4-. Demographic Characteristics of FDA-Selected AERS Data Set\
Grouped by Expert Review Panel-Probability Categories

+------------------------------+-------------+---------------+--------+
|                              | Defini      | All Other     | p-Va   |
|                              | te/Probable | Cases         | lue^b^ |
|                              | Cases^a^    |               |        |
|                              |             | (N = 204)     |        |
|                              | (N = 77)    |               |        |
+------------------------------+-------------+---------------+--------+
| Mean age, years              | 40.1        | 45.2          | 0.0192 |
|                              |             |               | **\*** |
+------------------------------+-------------+---------------+--------+
| Gender, no. (%)              | 53 (68.8)   | 119 (58.3)    | 0.1947 |
|                              |             |               |        |
| Female                       | 24 (31.2)   | 78 (38.2)     |        |
|                              |             |               |        |
| Male                         | 0 (0)       | 7 (3.4)       |        |
|                              |             |               |        |
| Unknown                      |             |               |        |
+------------------------------+-------------+---------------+--------+
| Product type, no. (%)        | 41 (53.2)   | 112 (54.9)    | 0.7983 |
|                              |             |               |        |
| OTC APAP single ingredient   | 4 (5.2)     | 5 (2.4)       |        |
|                              |             |               |        |
| OTC APAP combination         | 4 (5.2)     | 10 (4.9)      |        |
|                              |             |               |        |
| OTC APAP combination + OTC   | 14 (18.2)   | 43 (21.1)     |        |
| APAP                         |             |               |        |
|                              | 14 (18.2)   | 34 (16.7)     |        |
| Rx APAP combination          |             |               |        |
|                              |             |               |        |
| Rx APAP combination + OTC    |             |               |        |
| APAP                         |             |               |        |
+------------------------------+-------------+---------------+--------+
| History of alcoholism or     | 40 (51.9)   | 56 (27.4)     | 0.0087 |
| alcohol, no.(%)              |             |               | **\*** |
|                              | 7 (9.1)     | 32 (15.7)     |        |
| Yes                          |             |               |        |
|                              | 30 (39.0)   | 116 (56.9)    |        |
| No                           |             |               |        |
|                              |             |               |        |
| Unknown                      |             |               |        |
+------------------------------+-------------+---------------+--------+
| Pre-existing liver disease,  | 15 (19.5)   | 32 (15.7)     | 0.3279 |
| no. (%)                      |             |               |        |
|                              | 6 (7.8)     | 22 (10.8)     |        |
| Yes                          |             |               |        |
|                              | 56 (72.7)   | 150 (73.5)    |        |
| No                           |             |               |        |
|                              |             |               |        |
| Unknown                      |             |               |        |
+------------------------------+-------------+---------------+--------+
| Pre-existing kidney disease, | 1 (1.3)     | 8 (3.9)       | 0.4392 |
| no. (%)                      |             |               |        |
|                              | 6 (7.8)     | 20 (9.8)      |        |
| Yes                          |             |               |        |
|                              | 70 (90.9)   | 176 (86.3)    |        |
| No                           |             |               |        |
|                              |             |               |        |
| Unknown                      |             |               |        |
+------------------------------+-------------+---------------+--------+
| Human immune deficiency      | 0 (0)       | 4 (2.0)       | 0.3044 |
| status, no. (%)              |             |               |        |
|                              | 6 (7.8)     | 22 (10.8)     |        |
| Yes                          |             |               |        |
|                              | 71 (92.2)   | 178 (87.3)    |        |
| No                           |             |               |        |
|                              |             |               |        |
| Unknown                      |             |               |        |
+------------------------------+-------------+---------------+--------+
| a: Cases ranked by Expert    |             |               |        |
| Review Panel as being 50%    |             |               |        |
| attributable.                |             |               |        |
|                              |             |               |        |
| b: ANOVA for age, chi-square |             |               |        |
| test for all other           |             |               |        |
| comparisons (unknowns not    |             |               |        |
| included).                   |             |               |        |
+------------------------------+-------------+---------------+--------+

The type of products used in both groups was similar; approximately half
of the reports included use of an OTC single-ingredient acetaminophen
product. Both groups were comprised of more women than men (58.3% to
68.8%). As expected with these types of incomplete reports, all
categories contain some "unknowns."

There was no significant difference between the definite or probable
reports and all other reports for pre-existing liver or kidney disease
or HIV. In addition, there are well-controlled prospective data
indicating that in individuals with liver or kidney disease,
acetaminophen can be used safely with no dose adjustment (see Section
4.2, Use of Recommended Doses in Selected Populations).

However, history of alcoholism appears to have been reported more
frequently in the definite or probable groupings. The only prospective
data available \[Kuffner 1997, 2001\] demonstrate that chronic
alcoholics can take recommended doses of acetaminophen (up to four grams
per day) without added risk of liver injury. The caution to have anyone
who consumes three or more alcoholic drinks every day talk with their
doctor before using acetaminophen or other pain relievers remains
appropriate, and the need to strongly urge chronic alcoholics not to
exceed the recommended dose is very important.

Table 4- provides a summary of the demographic characteristics for those
cases assessed by the Expert Review Panel to be definite or probable and
included a single-ingredient OTC acetaminophen product (n= 41) and
definite or probable cases that included a prescription acetaminophen
combination product (n= 28) as a suspect drug. Both groups of reports
had more women than men (67.9% to 70.7%). As expected with case reports,
all categories contain some "unknowns." Mean age was significantly lower
in the OTC single-ingredient group when compared to the prescription
product group.

Of the OTC single-ingredient acetaminophen products, 52% had no dose or
dosage form specified, 37% were 500 mg dosage forms, 10% were 325 mg and
a single report listed 650 mg extended release. This is consistent with
the most widely distributed dosage form, 500 mg. In these cases, other
suspect drugs listed were alcohol (7) and cocaine/opiates/phenobarbital/
benzodiazepine (6).

Of the prescription acetaminophen combination products, 50% were used
with single-ingredient acetaminophen products and 50% were used alone.
In the prescription combination product only category, two reports
described non-therapeutic use of large doses of the prescription
ingredient, leading to acetaminophen overdose. When additional
acetaminophen was taken along with the prescription acetaminophen
combination, the additional acetaminophen product was infrequently
specified as to dosage strength. Prescription combination product
ingredients included hydrocodone (9) codeine (9) oxycodone (5)
propoxyphene (5).

Table 4-. Demographic Characteristics for OTC Single Ingredient and
Prescription Acetaminophen Product Subcategories of Expert Review
Panel-Ranked Definite/ Probable Cases^a^ from FDA-Selected AERS Data Set

+----------------------------+----------------+--------------+---------+
|                            | OTC Single     | Prescription | p-V     |
|                            | Ingredient     | Product^b^   | alue^c^ |
|                            | Product        |              |         |
|                            |                | (N = 28)     |         |
|                            | (N = 41)       |              |         |
+----------------------------+----------------+--------------+---------+
| Mean age, years            | 38.1           | 44.9         | 0.0448  |
+----------------------------+----------------+--------------+---------+
| Gender, no. (%)            | 29 (70.7)      | 19 (67.9)    | 0.7970  |
|                            |                |              |         |
| Female                     | 12 (29.3)      | 9 (32.1)     |         |
|                            |                |              |         |
| Male                       |                |              |         |
+----------------------------+----------------+--------------+---------+
| History of alcoholism or   | 21 (51.2)      | 13 (46.4)    | 1.000   |
| alcohol, no.(%)            |                |              |         |
|                            | 4 (9.8)        | 3 (10.7)     |         |
| Yes                        |                |              |         |
|                            | 16 (39.0)      | 12 (42.9)    |         |
| No                         |                |              |         |
|                            |                |              |         |
| Unknown                    |                |              |         |
+----------------------------+----------------+--------------+---------+
| Pre-existing liver         | 7 (17.1)       | 6 (21.4)     | 0.6285  |
| disease, no. (%)           |                |              |         |
|                            | 2 (4.9)        | 4 (14.3)     |         |
| Yes                        |                |              |         |
|                            | 32 (78.0)      | 18 (64.3)    |         |
| No                         |                |              |         |
|                            |                |              |         |
| Unknown                    |                |              |         |
+----------------------------+----------------+--------------+---------+
| a: Cases ranked by Expert  |                |              |         |
| Review Panel as being 50%  |                |              |         |
| attributable.              |                |              |         |
|                            |                |              |         |
| b: Includes use of a       |                |              |         |
| prescription acetaminophen |                |              |         |
| combination product alone  |                |              |         |
| or together with an        |                |              |         |
| acetaminophen OTC product. |                |              |         |
|                            |                |              |         |
| c: ANOVA for age,          |                |              |         |
| Fischer's Exact test for   |                |              |         |
| all other comparisons      |                |              |         |
| (unknowns not included).   |                |              |         |
+----------------------------+----------------+--------------+---------+

Only three of the 205 reports (1.5%) were considered by the medical
experts to be definitely related to acetaminophen. All had a history of
self-abusive behavior - an apparent bulimic and two alcoholics. All
appeared to involve substantial overdoses, but intentionality could not
be determined. A brief description of these three cases follows.

One of the reports involved ingestion of 14.5 grams in one day by a
16-year-old female to induce nausea/vomiting. She had a five-to-seven
day history of inducing nausea/vomiting. She was treated with NAC and
was discharged.

The second report involved a consumer with a history of drinking six to
eight beers in an average day. Over the week prior to admission, he took
approximately 110 Sinutab and acetaminophen 500-mg tablets combined.
Sinutab tablets contain 500 mg of acetaminophen. He was treated with NAC
and received a liver transplant. He developed septicemia following the
transplant and died.

The third report was a 62-year-old female with a history of chronic
alcohol use (estimated 60 grams per day for 40 years) and hepatitis C,
who reportedly ingested 1 to 1.5 grams per day of acetaminophen for
shoulder pain during the four days preceding admission. However, at an
unspecified time post-ingestion, the plasma acetaminophen level was
reportedly 158.9 ug/mL. Assuming her weight was 60 kg and the volume of
distribution was 1 L/kg, this would equate to a body burden of 9.5
grams, consistent with a substantial overdose. She was treated with NAC,
gradually improved and was discharged.

Dose cannot be verified in this data set. Fifteen (15) reports were
considered by the experts to have a 50% likelihood of attribution to
acetaminophen with a reported dose of less than 8 grams per day. When
available, however, plasma levels did not confirm the reported doses,
often suggesting a body burden vastly in excess of the reported dose.

##### Conclusions from the FDA Selected AERS Data Set of Adult Reports

Despite significant limitations to the reports in the FDA selected AERS
Data Set, the available information supports the following conclusions:

-   The AERS spontaneous reporting system serves as a signal generating
    system for rare, unexpected adverse events in marketed products. It
    cannot be used to determine event rates, dose, or intentionality.

```{=html}
<!-- -->
```
-   The three AERS reports that McNeil's Expert Review Panel found to be
    definitively associated with acetaminophen involved substantial
    overdose in individuals with self-abusive behaviors (alcohol abuse,
    bulimia).

-   McNeil's Expert Review Panel concluded that most of the cases with a
    50% likelihood of attribution to acetaminophen use were associated
    with substantial overdoses.

-   Hepatic effects, although reported at recommended therapeutic doses
    in the FDA-selected Data Set, were impossible to confirm given the
    limitations of the available information.

-   Formulations most commonly reported were OTC single-ingredient and
    Rx combination acetaminophen products. OTC acetaminophen combination
    products were rarely reported.

-   Alcohol and alcohol abuse were reported more often in reports
    assigned a 50% probability of acetaminophen attribution.

##### FDA AERS Data Set -- Pediatric Reports

Twenty-five of the total of 307 reports identified by FDA from AERS were
pediatric reports. Of these 25 pediatric reports, four involved an
unintentional single ingestion in which an unsupervised child ingested
an acetaminophen product and three reports were of maternal overdoses.
Because these seven reports were not reports of misadministration to
children, they are not described further.

The remaining 18 reports were divided into two categories:

-   Those reports involving the ingestion of one *single-ingredient
    acetaminophen product (n = 16)*.

-   Those reports involving the ingestion of two
    *acetaminophen-containing products (n = 2).*

Each category of reports is described below.

*Reports Involving the Ingestion of One Single-Ingredient Acetaminophen
Product.* Sixteen of the 18 reports involved the ingestion of one
single-ingredient acetaminophen product.

Twelve of the 16 reports involved children less than two years of age.

-   In seven reports, infant drops were administered using a device
    other than the supplied dropper and resulted in unintended overdose.
    Five of the 12 resulted in death; six recovered, and in one the
    outcome is unknown. In four of the five cases that resulted in
    death, the acetaminophen dose reported was in excess of the
    recommended dose. The remaining fatality reported use of
    acetaminophen at a dose "normal dose for his weight," however, the
    reporter indicated that the child's primary physician did not
    attribute the death to acetaminophen. When the reported doses were
    converted to daily exposure by weight, the doses ranged from 233 to
    375 mg/kg/day given for periods from less than one day to four days.
    However, in some instances, the dose was not clearly defined or the
    duration not specified.

The four remaining reports were in children between two and eight years
of age.

-   One report was of an eight-year-old whose mother admitted to giving
    the child "at least 10 double strength Tylenol^®^ tablets within
    less than 24 hours". This would exceed the recommended dose for an
    adult. Extra Strength Tylenol^®^ is not labeled for use in children
    under 12 years of age.

```{=html}
<!-- -->
```
-   Three of these four reports involved the use of single-ingredient
    acetaminophen at recommended dose, but other potentially hepatotoxic
    medications (Dilantin^®^ and Zithromax^®^) were also being given.
    There was no clinical evidence that the reported events were
    causally related to the acetaminophen use.

*Reports Involving the Ingestion of Two Acetaminophen-Containing
Products.* Two of these 18 reports involved the ingestion of two
acetaminophen-containing products. Neither of the two cases had dosing
information available.

-   One involved a three-year-old child who was given both OTC and
    prescription formulations containing acetaminophen for four to five
    days. A drug screen was positive for pseudoephedrine,
    dextromethorphan, and codeine. The child died three days after
    presentation to the hospital.

-   One involved an 11-month-old infant given acetaminophen as a
    suspension, in suppositories, and as part of a multi-symptom cold
    remedy. The infant received a 72-hour course of NAC therapy and
    progressed to a full recovery.

#####  {#section-1 .unnumbered}

*Previous Summary of FDA SRS and AERS - Pediatric Misadministration
Reports.* At FDA's request, McNeil provided to the FDA in December 2000
a report on all pediatric cases of misadministration (domestic and
international) that were previously reported to the FDA for the period
January 1, 1992 through August 31, 2000. During the more than eight-year
period, there were 117 reports of misadministration in children.
Eighty-six (86) of the 117 reports involved misadministration of
pediatric dosage forms, usually in children less than two years of age
for which dosing information is not on the label. Fifty (50) of the 86
reports involved misuse of the more concentrated infants' drops in place
of the less concentrated children's liquid \[McNeil Submission to FDA
12/20/00\]. McNeil's introduction in 1999 of the SAFE-TY-LOCK integrated
infant dropper/bottle helps prevent dispensing of infant drops in
teaspoons or similar imprecise dosing devices. The effect of this
dropper/bottle innovation on the number of such reports is described in
Section 6.2.2, Previous Initiatives: Programs to Reduce
Misadministration of Pediatric Acetaminophen Products.

##### Conclusions From the FDA AERS Data Set of Pediatric Reports

An analysis of the FDA AERS Data Set of pediatric reports clearly
indicates that the majority of cases involved situations where the child
was given substantial overdoses of a single-ingredient pediatric
acetaminophen product. The most frequently involved dosage form was the
acetaminophen drops formulation for which McNeil has implemented a risk
management plan (see Section 6.2.2, Previous Initiatives: Programs to
Reduce Misadministration of Pediatric Acetaminophen Products). Eleven of
the 12 reports involving the acetaminophen single-ingredient products
were in children less than two years of age. In 1999, McNeil submitted a
Citizen's Petition to FDA requesting labeled dosing for children less
than two years of age on pediatric liquid formulations.

###  Poison Control Center Data Sets

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.
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. In addition to the general data published by AAPCC, we also
obtained a year's worth of case-specific information about pediatric
misadministration reports from two poison control centers in an effort
to understand causal factors that might contribute and be amenable to
intervention.

Our review found the following:

-   Among acetaminophen alone exposure with known outcome, 96% did not
    result in major effects, and less than 0.5% of these reported
    exposures (including suicidal overdose) were known to result in
    death.

-   Half of the exposure reports pertain to single-ingredient
    acetaminophen products and the other half to combination
    acetaminophen products.

-   Although about half of the single-ingredient acetaminophen exposure
    reports pertain to children six years of age or younger, there was
    less than 1 known death per year for the period of 1996 to 2000.

-   Pediatric misadministration rarely results in serious outcome. Rare
    events could be further prevented by permitting dosage information
    for children under two on the product label.

#### AAPCC TESS Data Set

In the AAPCC TESS database, an exposure is defined as a call to the
poison control center regarding administration of, or contact with, a
substance, but does not necessarily involve toxicity. Reasons for
exposure are coded using categories that include intentional exposure
(suspected suicidal, intentional abuse, intentional misuse or
intentional unknown), unintentional exposure (unintentional general,
therapeutic error, unintentional misuse, or unintentional unknown), and
adverse reaction. Medical outcomes are also coded by category: unknown,
no effect, minor effect, moderate effect, major effect, and death
\[Litovitz 2001\]. Major effect involves signs or symptoms that are
life-threatening or an outcome of significant disability or
disfigurement.

As shown in Table 4- , in the year 2000 \[Litovitz 2001\], 108,066
acetaminophen exposures in adults and children were reported to 63
poison control centers serving a population of 270.6 million in the
United States. For single-ingredient acetaminophen products alone, there
were 856 exposures in adults and children with a major effect (3.4% of
25,101 exposures with known outcomes). Ninety-nine (99) deaths were
reported to be associated with single-ingredient acetaminophen products.
One hundred and eleven (111) deaths were reported associated with
acetaminophen combination products (85 episodes were associated with
opioid-containing acetaminophen products, representing 40% of all
acetaminophen-associated deaths).

Table 4- . Acetaminophen Exposure Data Based On AAPCC 2000 Annual Report

  ------------------- ----------- -------- ------ ------ ---------------- -------------- --------- -------
  Product             Total       Age in                 Reason for                      Outcome   
                      Exposures   Years                  exposure (%)^b^                 (%)^c^    
                                  (%)^a^                                                           

                                  \<6      6-19   \>19   Unin-tentional   Inten-tional   Major     Death

  **Acetaminophen     56, 371     47.1     26.7   26.2   65               35             3.41      0.39
  only**                                                                                           

  Adult formulation   28,009      22.8     37.2   40.0   46.5             52.5           3.62      0.37

  Pediatric           20,629      89.0     9.6    1.4    97.6             1.9            0.41      0.02
  formulation                                                                                      

  Unknown formulation 7,733       22.5     34.3   43.2   41.1             57.7           6.15      0.90

  **Acetaminophen in  51,695      15.7     20.9   63.4   38.1             57.1           4.2       0.4
  combination with                                                                                 
  other drugs**                                                                                    
  ------------------- ----------- -------- ------ ------ ---------------- -------------- --------- -------

a: Age -- expressed as % of all exposure cases in which the age was
known for each acetaminophen formulation

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

c: Outcome -- expressed as % of all exposure cases with known outcome
for each dose formulation

**Pediatric Data - AAPCC.** As shown in Table 4- , also in 2000,
children six years of age or younger accounted for 47.1% and 15.7% of
the reported exposures to single-ingredient acetaminophen and
acetaminophen combination products, respectively. In a recent five-year
period (1996-2000), the AAPCC reported 217,170 exposures to
acetaminophen-containing products in children less than six years of
age. There were three fatalities in children less than six years of age
and one fatality in an 11-year-old child \[Litovitz 1997; Litovitz 1998;
Litovitz 1999; Litovitz 2000; Litovitz 2001\]. McNeil has obtained
additional detail from the AAPCC for 1997 and found that of 49,873
exposures to acetaminophen-containing products in children there were
256 exposures in which NAC was reportedly administered to children under
six years of age \[personal communication from AAPCC, September 27,
2001\]. This represents 0.5% of childhood acetaminophen exposures that
led to hospitalization and treatment with NAC. These data suggest that
while pediatric exposures are common, the actual proportion of cases
where there is a need for other than routine induction of emesis or
similar measures is rare.

In a separate analysis of TESS data for acetaminophen-associated
episodes in children less than six years of age (data not shown above),
it is noted that of the 117,892 episodes received during the period 1998
to 2000, over 99% were unintentional overdose. Sixty-five (65) episodes
(0.055%) were associated with major adverse effects.

**Intentionality of Overdose Exposure -- Five-Year AAPCC Data.** AAPCC
annual report data for single-ingredient acetaminophen during a recent
five-year period (1996-2000) were reviewed. Table 4- provides a summary
of the 213 fatal outcomes reported to AAPCC involving single-ingredient
acetaminophen during a recent five-year period (1996-2000), the
percentage reporting unintentional exposure reasons was small.

Approximately 16% of 190 reports that specified a reason reported
unintentional reasons (therapeutic error or unintentional unknown).
During this period, the frequency of intentional overdose (intentional
misuse, intentional abuse, intentional unknown) was 32% and of
intentional suicide was 52%. Thus, intentional overdose accounted for
84% of overdose with known intentionality. This is consistent with data
from the National Hospital Discharge Survey for the period 1990 to 1999.
In this survey, acetaminophen overdose was intentional in 74% of the
patients, and intention was unknown in 18% of the patients.

Table 4-. Exposure Reasons for the 213 Single Ingredient Acetaminophen
Fatality Reports (1996-2000 AAPCC reports)

+--------------------+------------+------------+----------+----------+
| > Reason for       | Ace        | Aceta      | Total    | \% of    |
| > exposure         | taminophen | minophen + |          | Total    |
|                    | alone      | alcohol    | N        |          |
|                    |            |            |          |          |
|                    | N          | N          |          |          |
+--------------------+------------+------------+----------+----------+
| > Unknown          | 21         | 2          | 23       | NA       |
+--------------------+------------+------------+----------+----------+
|                    |            |            |          |          |
+--------------------+------------+------------+----------+----------+
| > Intentional      | 11         | 1          | 12       | 6.3      |
| > unknown          |            |            |          |          |
+--------------------+------------+------------+----------+----------+
| > Intentional      | 88         | 10         | 98       | 51.6     |
| > suicide          |            |            |          |          |
+--------------------+------------+------------+----------+----------+
| > Intentional      | 33         | 12         | 45       | 23.7     |
| > misuse           |            |            |          |          |
+--------------------+------------+------------+----------+----------+
| > Intentional      | 2          | 2          | 4        | 2.1      |
| > abuse            |            |            |          |          |
+--------------------+------------+------------+----------+----------+
|                    |            |            |          |          |
+--------------------+------------+------------+----------+----------+
| > Unintentional    | 3          | 0          | 3        | 1.6      |
| > unknown (exact   |            |            |          |          |
| > reason unknown)  |            |            |          |          |
+--------------------+------------+------------+----------+----------+
| > Therapeutic      | 20         | 7          | 27       | 14.2     |
| > error            |            |            |          |          |
+--------------------+------------+------------+----------+----------+
|                    |            |            |          |          |
+--------------------+------------+------------+----------+----------+
| > Adverse reaction | 1          | 0          | 1        | 0.5      |
| > (adverse event   |            |            |          |          |
| > occurred at      |            |            |          |          |
| > recommended dose |            |            |          |          |
| > regardless of    |            |            |          |          |
| > causality)       |            |            |          |          |
+--------------------+------------+------------+----------+----------+

**Discussion of Intentionality**. When serious outcomes or death follow
a drug overdose, intentionality is difficult to confidently determine.
Spooner \[1993\] cautioned that coroners in the United Kingdom are
reluctant to categorize a death as suicide unless there is hard
evidence, such as a suicide note. In the absence of such evidence,
accidental death is more likely to be the determined cause, even when
there is strong suspicion of deliberate overdose. Physicians also may be
reluctant to attribute self-harmful or suicidal intent if the patient is
too ill to communicate or because of the impact on privacy, insurance
coverage, or family relationships. Therefore, it seems likely that
acetaminophen suicidal overdose intent is underreported in AAPCC
fatality data.

Spooner also pointed out errors in attributing deaths to acetaminophen.
Among 547 deaths in 1990 in England and Wales attributed to
acetaminophen, only 27% were considered to be probably related. His
assessment considered liver histopathology, identified causes other than
liver necrosis, and the time course of death following acute suicidal
ingestion. In the absence of similar close attention to clinical and
pathologic details, the number of deaths causally attributed to
acetaminophen, because of its incidental use in a large percentage of
the population (23% in the past week), may be grossly exaggerated. The
widespread prevalence of acetaminophen exposure and awareness that
acetaminophen can produce hepatotoxicity (albeit at massive overdoses)
may also contribute to misclassification by healthcare professionals of
deaths as being acetaminophen related.

#### Selected Poison Control Center Data for Evaluating Pediatric Misadministration

Annual national AAPCC reports do not provide case details. To better
understand the frequency, severity, and outcomes of pediatric
acetaminophen misadministration, McNeil obtained 12 months of data (for
the year 2000) from two regional AAPCC-certified poison centers (one in
the west and one on the east coast) that serve large base populations.
Together, the two centers received 3.4% of AAPCC exposure reports.

During 2000, these two centers received 74,417 calls of which 1730 calls
reported exposure to an acetaminophen-containing product in children 0
to 11 years of age. Of these, 500 reports were coded as being
therapeutic error, unintentional misuse, intentional misuse or
intentional abuse. None reported a serious adverse outcome ("moderate"
or "major" effect or "death"). Six reports were of children who received
an acetaminophen dose in excess of the recommended daily dose of 75
mg/kg/day. Of these six reports, outcomes were classified as minor
effects (3) and no effects (3). A majority of the reports (66.6%)
involved scenarios where the caller contacted the poison control center
for reassurance after realizing that they had mistakenly administered an
incorrect dose or after they had inadvertently administered an
acetaminophen-containing medication twice, 21% involved the
administration of an inappropriate formulation or concentration, and 4%
involved a single episode of concomitant administration of more than one
acetaminophen-containing product.

Twenty-eight (28) of the 500 reports involved the use of the wrong
dosing device to administer the acetaminophen-containing product.
Twenty-one (21) of the 28 reports involved single-ingredient
acetaminophen. Of these, 18 reports involved the ingestion of the
concentrated acetaminophen drops formulation, of which 13 reports
involved children less than two years of age for which dosing
information is not presently permitted on the product label. None of
these reports resulted in serious outcomes. The other three reports
involved misadministration of children's liquid acetaminophen
formulations; all of these reports involved children greater than two
years of age. The remaining seven reports involved infants' (3) or
children's (4) cough/cold products. Most of these reports involved
mistaken use, and there were no serious outcomes.

From these data we conclude that pediatric misadministration rarely
results in serious outcome. Rare events could be further prevented by
permitting dosage information for children under two on the product
label.

### Drug Abuse Warning Network (DAWN)

To assess the nature of emergency department visits in the United States
related to analgesic uses, data from the Drug Abuse Warning Network
(DAWN) available online was used: http://www.samhsa.gov/oas/dawn.htm\].
DAWN is an ongoing drug abuse data collection system sponsored by
Substance Abuse & Mental Health Services Administration (SAMHSA) Office
of Applied Studies. It collects data from: 1) hospital emergency
departments and 2) medical examiners. The hospital emergency department
component of DAWN relies mainly on a nationally representative sample of
hospital emergency departments in 21 metropolitan areas to produce
information on the number and characteristics of drug abuse-related
visits to such hospital emergency departments in the United States.

An episode report is submitted to the DAWN system for each individual
who visits a DAWN emergency department and meets **all** of the
following criteria:

-   The individual was age 6 to 97 and was treated in the hospital\'s
    emergency department;

```{=html}
<!-- -->
```
-   The presenting problem(s) (ie, the reason for the emergency
    department visit) was induced by or related to drug use, regardless
    of when the drug use occurred;

-   The episode involved the use of an illegal drug or the use of a
    legal drug or other chemical substance for nonmedical purposes; and
    the reason for using the substance(s) was dependence, suicide
    attempt or gesture, and/or psychic effects.

In addition to drug overdoses, reportable emergency department episodes
may result from the chronic effects of habitual drug use or from
unexpected reactions. DAWN cases do **not** include accidental ingestion
or inhalation of a substance with no intent of abuse, or adverse
reactions to prescription or over-the-counter medications taken as
prescribed.

The percentage of total drug-related episodes for various products
containing either acetaminophen or NSAIDs for the year 2000 are provided
in Table 4- in descending order. Drug-related episodes for OTC available
NSAIDs, OTC acetaminophen, and prescription acetaminophen products
accounted for 6.2%, 6.0% and 4.6% of the emergency room visits,
respectively. This is an estimated percentage because patients could
have experienced drug-related episodes after use of multiple drugs, and
the actual percentages could be lower because each drug is reported
separately.

Table 4‑. Percentage of Emergency Department Visits Associated with
Analgesics Containing Either Acetaminophen or NSAIDs in the Year 2000 --
DAWN data

  ------------------------------ ----------------------------------------
  Product                        Percent of Total Drug-related Episodes

  Acetaminophen                  5.5

  Ibuprofen                      3.1

  Acetaminophen-hydrocodone      2.9

  Aspirin                        1.8

  Acetaminophen-oxycodone        1.1

  Naproxen                       0.8

  Acetaminophen-codeine          0.6

  Acetaminophen/ASA/caffeine     0.5
  ------------------------------ ----------------------------------------

The 1997 DAWN data, the most recent available for downloading, were
analyzed further. Of the 164,056 reports, 6,554 reported use of
acetaminophen. Of the 6,544 acetaminophen exposures, 2,766 (42%) were
reported to involve ingestion of single-ingredient acetaminophen
(acetaminophen alone), while the rest involved acetaminophen plus other
drugs (acetaminophen combination products or the coadministration of
other drugs). The age distribution for these two groups was similar;
93.8% and 90.4% of the acetaminophen alone exposures and the
acetaminophen plus other drugs exposures, respectively, were between the
ages of 12 to 44.

The primary reason for presentation to the emergency department was drug
overdose in 87.5% of the acetaminophen exposures and in 85.3% of the
acetaminophen plus other drugs exposures. There were no reported deaths
in the acetaminophen alone group and two reported deaths in the
acetaminophen plus other drugs group. As shown in Table 4-, suicide was
the predominant motive for consumption of acetaminophen-containing
products that resulted in hospital emergency department visits.

Table 4‑. Distribution of DAWN Reports by Drug Use Motive

  -------------------- ----------------------- ---------------------------
  Drug Use Motive      \% of Total             \% of Total\
                       (Acetaminophen Alone    (Acetaminophen + Other
                       Exposures )             Drugs)

  Suicide              77.1%                   79.0%

  Psychic Effects      14.0%                   9.8%

  Dependence           0.4%                    2.7%

  Recreational Use     0.9%                    1.8%

  Other                1.1%                    0.7%

  Missing              6.6%                    5.9%
  -------------------- ----------------------- ---------------------------

In summary, the frequency of hospital emergency department visits
attributable to OTC available NSAIDs was similar to that of OTC
acetaminophen. Suicide was the motive and overdose was the reason for
most emergency department visits that resulted from ingestion of
acetaminophen-containing products. Death was rare.

### Published Data On Liver Transplant Centers' Experience and Acute Liver Failure Registry

The most serious cases of acetaminophen hepatotoxicity may be referred
to a hepatologist or liver transplant unit. As a result, these experts
and centers see the most seriously ill patients. Experiences at two
transplant centers have been published and are summarized in the
following sections.

#### United Kingdom Experience

Makin \[1995\] retrospectively reviewed 560 medical records that
indicated acetaminophen overdose during the period January 1, 1987 to
December 31, 1993. Half (50%) of the patients reported taking an
overdose after a financial, employment or personal event (eg, breakup of
a relationship), 30% reported depression, and 38% reported at least one
previous suicide attempt. Only 8% of the patients denied suicidal intent
and reported an unintended overdose. Of those denying suicidal intent,
25% had a history of previous overdose attempt and 62% were heavy
alcohol users; in these patients the median reported acetaminophen dose
was 40 grams (range, 5 to 210 grams), with 71% taking more than 24
grams. Sixty-two percent (62%) of reportedly therapeutic overdoses were
of more than 24 grams of acetaminophen; the authors reported that the
acetaminophen dose was staggered over a number of hours or days.
Forty-five (45) patients (8% of the 560 patients) alleged taking less
then 12 grams, and none reported taking four grams or less. However, 35
(78%) of the 45 patients had a dose history of questionable reliability
(17 had a history of deliberate acetaminophen overdose, eight were
undergoing psychiatric treatment for depression, ten were consuming in
excess of 40 units of alcohol per week, and five had serum acetaminophen
concentrations that were inappropriately high for the alleged dose of
acetaminophen taken). In addition, alcohol or anticonvulsant consumption
did not affect overall clinical outcome.

#### Liver Failure Registry Experience

Lee and colleagues (the Acute Liver Failure Study Group) described their
transplant case series to a varying degree in different sources. These
sources include a review article \[Lee 2001\], an abstract and
presentation at an FDA co-sponsored meeting (Drug-Induced Liver Disease:
A National and Global Problem, February 12-13, 2001, Chantilly, VA) by
Lee \[FDA 2001\], and in abstracts \[Ostapowicz 2000; Larson 2000\]. We
have been unable to identify a peer-reviewed publication that provides a
comprehensive and detailed description of the participating centers,
data collection methods and findings. Further, requests to Dr. Lee for
access to these data have been denied. Therefore, we have used the most
comprehensive information from the FDA website and the Larson abstract
in the following discussion.

These sources provide 203 cases of acute liver failure during
approximately two years (January 1998 to April 2000). Of these, 79 cases
(38%) were reported to be associated with acetaminophen overdose (27
reported taking acetaminophen-opiate prescription products); the overall
survival rate among these patients was 72% (67% spontaneous survival and
6% received a liver transplant). Seventy-seven percent (77%) of these
patients were female and the average age was 37 years. Sixty percent
(60%) were classified as "accidental" overdose and 40% as suicidal
overdose. The frequency of antidepressant use was similar between those
who claimed suicidal overdose (35%) and those who claimed accidental
overdose (37%). The prevalence of antidepressant use in the accidental
overdose group was at least six times higher than expected since the
percentage of United States adults who receive pharmacotherapy and/or
psychotherapy for depression is 5.8% \[Olfson 2002\]. This suggests
either that those who took antidepressants were more prone to
"accidental" overdose, or perhaps, some of the "accidental" overdose
cases were not truly unintentional. Given the prominent role of
depression in suicidal overdose \[McMahon 2001\], one would not expect
the frequency of antidepressant use in the two groups to be similar.

### Conclusions Concerning Data Sources Available to Assess Misadministration and Overdose

The data sources we have used to assess the misadministration and
overdose situations include spontaneous reports submitted to the FDA's
Adverse Event Reporting System (AERS), poison control center reports,
the Drug Abuse Warning Network (DAWN), and reports from liver transplant
centers. These data sources are descriptive in nature and consist only
of reports. In addition to our conclusions for AERS adult reports
(Section 4.6.2.2.3, Conclusions from the FDA Selected AERS Data Set of
Adult Reports), we conclude:

-   Data from AAPCC, DAWN and liver transplant centers are consistent,
    and show that intentional suicide is the most frequent reason for
    adult acetaminophen overdose.

-   Pediatric misadministration rarely results in serious outcome. Rare
    events could be further prevented by permitting dosage information
    for children under two on the product label.

## Comparative Safety Analysis with NSAIDs

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 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 NSAIDs
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 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

The more common serious risks of aspirin and other NSAIDs are
gastrointestinal bleeding, renal failure and congestive heart failure.
Epidemiologic evidence suggests that 99% of the excess mortality from
NSAID use is attributable to gastrointestinal complications \[Report of
CIOMS Working Group IV 1998\]. Thus, the remaining discussion concerning
NSAID risks in this section is limited to gastrointestinal
complications.

The risk of gastrointestinal bleeding increases with NSAID dose \[Blot
2000\]. 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 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)
and 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 recommended on OTC labels \[Blot
2000\].

Evaluation of NSAID risks should not be limited to OTC doses. 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). 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.

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 the
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).

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.

A more conservative estimation came from Blot and McLaughlin (personal
communication November 12, 2001) who estimated that 9,400 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[^17].

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 4-1). 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 \[Singh 1996\].

As the overall United States population ages, an increase in the
prophylactic use of aspirin for cardiac protection is anticipated. Thus,
more American adults will be exposed to aspirin and other NSAIDs
concurrently. This combination could potentially increase the risk of
gastrointestinal bleeding due to the additional antiplatelet effect of
aspirin. Concurrent use of aspirin with NSAIDs has been shown to
increase the risk of gastrointestinal bleeding when compared with use of
aspirin alone \[Sorensen 2000\].

### Excess Mortality Associated with Acetaminophen and 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
4-1).

### Comparison of Excess Mortality

Figure 4-1 illustrates that the excess mortality from NSAID-related
gastrointestinal bleeding at recommended 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 4-1. Estimated Annual Excess Mortality Associated with
Analgesic Use in the United States**

![](media/image11.wmf){width="5.573611111111111in"
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.

#### Comparison of Aspirin and Ibuprofen to Acetaminophen

Aspirin and ibuprofen are the two most commonly used NSAIDs in the
United States. Using CIOMS estimation of mortality rates with short-term
use \[Report of CIOMS Working Group IV 1998\] and the Slone Survey
prevalence and use data for specific OTC NSAIDs \[Kaufman 2002\], one
can estimate the number of deaths per year from gastrointestinal
bleeding among short-term aspirin and ibuprofen users as 3013 and 795
(total of 3808), respectively. The total excess mortality (3808) from
these two NSAIDs is comparable to the estimate (3443) for NSAIDs as a
class as reported in Section 4.7.1, Excess Mortality from
Gastrointestinal Bleeding Associated with NSAIDs in the United States.

### Conclusion

In the choice of OTC analgesics, it is important to balance the
therapeutic benefit against both the risk in therapeutic use, and the
risk and available antidote treatment in overdose. Acetaminophen is the
safest OTC analgesic at therapeutic doses. Massive acetaminophen
overdose can lead to a high risk of hepatotoxicity, but the antidote NAC
is widely available and prevents hepatic damage when administered early
in the course. In contrast, serious adverse drug reactions occur more
frequently with NSAIDs at therapeutic doses, are dose-related, and there
is no antidote available for NSAID overdose.

The excess mortality from NSAID-related gastrointestinal bleeding at
recommended doses (estimated as 3443 deaths per year) far exceeds that
from acute liver failure associated with acetaminophen overdoses
(estimated as 213 deaths per year). 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.

Any change in the access or availability of any currently available OTC
analgesics must be balanced against the risks presented by each of them.
Consumers will self-treat pain and their selection of OTC analgesics
will depend on the availability, accessibility, and effectiveness of
these products.

# 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.

-   Recent medication use surveys suggest that the vast majority of
    consumers use analgesics within the recommended OTC daily dose.

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

-   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

Acetaminophen-containing products are widely used throughout the United
States. A recent survey of medication use in the United States estimated
the some 23% of adults (48.1 million people) report taking
acetaminophen-containing products in the preceding week \[Kaufman
2002\]. Information in this section demonstrates that consumers almost
invariably take acetaminophen at the recommended OTC doses. As with any
product available for direct use, acetaminophen can be misused. The
misuse can be intentional or inadvertent. 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 6, 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 an 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. The supplemental analysis of analgesics
includes a total of 6279 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^SM^ 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 \[McNeil 2002\].

### FDA-Selected AERS Data Set of Acetaminophen Reports

In Section 4, Assessment of Acetaminophen Safety, clusters of common
factors are identified in spontaneously reported cases that have been
submitted to the FDA Adverse Event Reporting System (AERS). FDA has
identified a set of AERS reports with serious outcomes for the time
period of January 1998 through March 2001 involving acetaminophen as a
suspect drug. Only those reports with "hepatic" adverse event terms
selected by the FDA were included. Of 306 reports in this data set,
there were 281 adult (Section 4.6.2.1, FDA AERS Data Set -- Adult
Reports) and 25 pediatric (Section 4.6.2.2, FDA AERS Data Set --
Pediatric Reports) case reports. These 306 reports are referred herein
as the "FDA AERS Data Set".

### Consumer Attitudes About Medications

**McNeil Habits & Practices Survey** -- 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 United States 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 or 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 5-7.
Naproxen use is 3.5% during this same time period.

Figure 5‑7. 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/image12.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 5-3 show that
the 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 sodium.

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 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 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.

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 vast majority of analgesic usage by consumers is
within the recommended OTC daily dose, a small percentage of consumers
take substantially more that the recommended doses despite product
labeling.

+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Table |       |       |       |       |       |       |       |       |
|  5‑3. |       |       |       |       |       |       |       |       |
| 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. |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+

### Slone Survey of Analgesic Use

In this survey, 81% of acetaminophen users reported taking one OTC
acetaminophen product and 11% reported taking one prescription product
containing acetaminophen \[Slone 2001\]. Of all acetaminophen users, 75%
identified a specific acetaminophen dose and 25% reported an unknown
dose. Of those who reported a dose, ninety-nine percent (99%) reported a
dose of no more than the maximum OTC recommended daily acetaminophen
dose of 4000 mg, whereas, 1% reported taking more than 4000 mg daily. A
somewhat higher percentage, 13%, of all ibuprofen users reported a dose
of more than the maximum recommended OTC dose of 1200 mg per day, and 1%
reported taking more than 3200 mg daily. Comparable survey information
for naproxen was not collected \[Slone 2001\].

Regarding aspirin, 79% of all users of aspirin reported using a
single-ingredient product. 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 its 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.

The Slone Survey also provides additional insight regarding the use of
other types of acetaminophen-containing products by consumers. Low
percentages of acetaminophen users reported combined use of a
single-ingredient OTC acetaminophen product with either an OTC
acetaminophen containing combination (5%) or a prescription
acetaminophen-containing combination (2%).

A small fraction of OTC analgesic use is greater than the recommended
dose. Table 5-4 provides a summary of the reported average daily
acetaminophen exposure by type of OTC or prescription (Rx) acetaminophen
product taken by consumers. In this survey a single individual reported
taking more than the recommended dose of acetaminophen from among those
who used only one OTC single-ingredient acetaminophen product. Among
individuals taking only one Rx acetaminophen-containing analgesic, two
reported taking from 4001 mg to up to 8000 mg per day and one reported
taking more than 8000 mg daily. However, in this category of
prescription products a high proportion (49%) of unknown dose was
reported \[Slone 2001\].

When two OTC products containing acetaminophen were being used, 5%
reported taking more than 4000 mg to 6000 mg and 3% reported taking more
than 6000 mg to 8000 mg. When taking both an Rx and an OTC analgesic
containing acetaminophen, 3% reported taking more than 4000 mg daily.
For all users of two products containing acetaminophen, no individuals
reported using more than 8000 mg per day of acetaminophen. Users of two
acetaminophen-containing type products reported high proportions, 42%
and 47%, of unknown dose.

+-------------+-----------+----------+------+------------+----------+
| Table 5‑4.  |           |          |      |            |          |
| Average     |           |          |      |            |          |
| Daily       |           |          |      |            |          |
| Ac          |           |          |      |            |          |
| etaminophen |           |          |      |            |          |
| Exposure    |           |          |      |            |          |
| (mg) by     |           |          |      |            |          |
| Type of     |           |          |      |            |          |
| Ac          |           |          |      |            |          |
| etaminophen |           |          |      |            |          |
| Product     |           |          |      |            |          |
| Taken       |           |          |      |            |          |
| (Slone      |           |          |      |            |          |
| Survey of   |           |          |      |            |          |
| Analgesic   |           |          |      |            |          |
| Use)        |           |          |      |            |          |
| \[Slone     |           |          |      |            |          |
| 2001\]      |           |          |      |            |          |
+-------------+-----------+----------+------+------------+----------+
|             | \         |          |      |            |          |
|             | - - - - - |          |      |            |          |
|             | % of      |          |      |            |          |
|             | Product   |          |      |            |          |
|             | Category  |          |      |            |          |
|             | Taking    |          |      |            |          |
|             | Dose      |          |      |            |          |
|             | Within    |          |      |            |          |
|             | the       |          |      |            |          |
|             | Stated    |          |      |            |          |
|             | Rang      |          |      |            |          |
|             | e - - - - |          |      |            |          |
|             | -         |          |      |            |          |
+-------------+-----------+----------+------+------------+----------+
|             | Use of    |          |      | Use of Two |          |
|             | One       |          |      | Products   |          |
|             | Product   |          |      |            |          |
|             | Only      |          |      |            |          |
+-------------+-----------+----------+------+------------+----------+
| Daily       | OTC       | OTC      | Rx   | OTC plus   | Rx plus  |
|             | Single-i  | Com      |      | OTC        | OTC      |
| Ac          | ngredient | bination | (n=  | c          | products |
| etaminophen |           |          | 158) | ombination |          |
|             | (         | (n=405)  |      |            | (n=30)   |
| Exposure    | n=720)^a^ |          |      | (n=65)     |          |
| (mg)        |           |          |      |            |          |
+-------------+-----------+----------+------+------------+----------+
| Less than   | 72%       | 85%      | 43%  | 37%        | 27%      |
| 2000        |           |          |      |            |          |
+-------------+-----------+----------+------+------------+----------+
| 2001 to     | 4%        | 3%       | 6%   | 14%        | 23%      |
| 4000^b^     |           |          |      |            |          |
+-------------+-----------+----------+------+------------+----------+
| 4001 to     | 0.1%      | 0%       | 1%   | 5%         | 0%       |
| 6000        |           |          |      |            |          |
+-------------+-----------+----------+------+------------+----------+
| 6001 to     | 0%        | 0%       | 0%   | 3%         | 3%       |
| 8000        |           |          |      |            |          |
+-------------+-----------+----------+------+------------+----------+
| More than   | 0%        | 0%       | 0.6% | 0%         | 0%       |
| 8000        |           |          |      |            |          |
+-------------+-----------+----------+------+------------+----------+
| Unknown     | 24%       | 12%      | 49%  | 42%^c^     | 47%      |
| dose        |           |          |      |            |          |
+-------------+-----------+----------+------+------------+----------+

a: Total number of users within the specified category

b: Maximum recommended daily OTC analgesic dose

c: One subject reported using more than 4000 mg daily (actual dose not
specified)

### FDA-Selected AERS Data Set

Case reports are limited by their anecdotal and retrospective nature.
For acetaminophen and hepatic events, the majority of reports contained
in the AERS database are overdose cases. Section 4.6, Data Sources
Available to Assess Misadministration and Overdose, describes some
clusters of common factors in the FDA selected AERS data set of 307
cases. Of the adult reports, these common factors involve taking more
than the recommended dose, either by exceeding the recommended daily
dose of single-ingredient acetaminophen products or by taking multiple
acetaminophen-containing medications.

The majority of the pediatric case reports involved situations where the
child was given substantial overdoses of a single ingredient pediatric
acetaminophen product. Most of these reports involve children less than
two years of age for which dosing is not permitted on the OTC package
label.

## 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 prescription pain relievers containing acetaminophen plus
single-ingredient OTC acetaminophen products \-- consumers taking both
products at the same time may take enough acetaminophen to exceed the
currently recommended total daily dose.**

Review of recent data suggest possible reasons for this behavior:

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

-   Not knowing that either the prescription pain reliever or both pain
    relievers contain the same active ingredient

-   Not understanding that products containing the same active
    ingredient should not be taken simultaneously to avoid exceeding the
    maximum recommended single or daily dose.

-   Abusive use patterns in the intake of one or more pain relievers

-   Intentional self-harm.

The McNeil Habits and Practices Survey provides relevant data. This
survey demonstrates that consumers did not know or could not recall what
certain prescription products contained. Only one of 61 consumers who
were taking Vicodin, Percocet, or Endocet knew that the product
contained acetaminophen. None knew what the other active ingredient was
in any of these products. Reasons reported by respondents who reported
taking a prescription pain reliever and some other type of
non-prescription pain reliever at the same time included, "symptoms not
relieved" (26%), "have multiple symptoms" (21%), "have severe symptoms"
(19%) and "told by doctor to take multiple products" (17%).

**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. Specifically, 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.

Again, some respondents in the Habits and Practices survey expressed a
lack of concern when taking two OTC products if they knew the two
products contained the same pain reliever. When queried, the most
frequent responses included: "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%). The survey did not
include questions specifically addressing consumer attitudes about
exceeding the maximum daily dose. However, 88% of respondents agreed
that adverse side effects were possible if more than the recommended
dose of an OTC pain reliever were used on a regular basis. Again,
cautious interpretation is warranted because a perception of "safe" may
relate to one time use.

**When using pediatric products -- caregivers may not adhere to or
access proper dosing directions**

Information from review of recent sources suggest some reasons for this
behavior:

-   Lack of clarity about dosage for children under two years of age

-   Giving an adult dose to a child

-   Confusion regarding pediatric dosage forms

-   Extra, possibly inadvertent, dosing by multiple caregivers.

In the McNeil Habits and Practices Survey, when parents of children
under the age of 12 years were asked if they [ever]{.underline} gave a
child an adult medicine, 17% responded "yes". Of those who reported
giving a child an adult formulation, 19% followed a doctor's instruction
and 26% used the dosing instructions for children on the label or used a
lower dose.

Some parents (30%) of children less than two years of age reported
having difficulty determining what the correct dose should be when
giving a pain reliever or fever reducer product to their child. They
reported calling their doctor (67%) or consulting a doctor's reference
chart (6%) or another health professional (8%) to determine the correct
dose \[McNeil 2001\]. This information suggests that, in most cases,
precautions are taken by consumers to administer an appropriate dose to
children.

## Conclusions

Recent medication use surveys suggest that the vast majority of
consumers use analgesics analgesic use within the recommended OTC daily
dose. They also provide insight regarding consumer analgesic use
behaviors that may result in excessive OTC analgesic exposure.

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}
<!-- -->
```
-   Prior McNeil initiatives include introduction of tamper-resistant
    product formulations and packaging, an educational program for
    Children's Tylenol products, development of the SAFE-TY-LOCK
    integrated dropper and bottle for Infants' Tylenol Concentrated
    Suspension Drops, and voluntary compliance with FDA proposed rules
    (Alcohol Warning and Drug Facts Labeling) in advance of the Final
    Rules.

-   Prior McNeil requests pending at FDA include a Citizen's Petition
    filed with the agency in 1999 to expand dosing directions on OTC
    pediatric acetaminophen product labeling to include children under
    two years of age.

```{=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}
<!-- -->
```
-   McNeil is also sponsoring an ongoing survey of consumer behaviors to
    monitor changes in consumer OTC analgesic use behaviors.

## Introduction

> Medication use surveys provide insight regarding consumer behaviors
> that may result in excessive OTC analgesic exposure. These behaviors
> affect the use of:

-   OTC single-ingredient adult analgesic products;

-   Prescription pain relievers with single-ingredient OTC analgesics;

-   OTC combination (cough/cold) products plus single-ingredient OTC
    analgesics;

-   OTC pediatric analgesics (administered by parents to their
    children).

In this section, we describe previous and recently implemented
interventions to promote the safe use of OTC analgesics in general, and
acetaminophen in particular to help reduce the occurrence of excessive
OTC analgesic exposure or overdose.

## McNeil's Previous Initiatives

### Chronology of Previous Initiatives

In an effort to promote the safe and appropriate use of OTC medicines,
McNeil:

-   Initiated the N-acetylcysteine (NAC) IND for the treatment of
    acetaminophen overdose (1978).

-   Funded support for Rocky Mountain Poison Center to handle calls
    related to acetaminophen overdose (1979 to present).

-   Provided detailed acetaminophen overdose management guidelines;
    including fundamental information published in Physicians' Desk
    Reference (1979 to present) and more detailed information in the
    Guidelines for the Management of Acute Acetaminophen Overdose (1979
    to present).

-   Developed tamper-evident packaging (1982).

-   Funded support for the development of NAC, for the treatment of
    acetaminophen overdose (1985).

-   Replaced capsules with a tamper-resistant caplet formulation in
    response to product tampering (1986).

-   Voluntarily added a concomitant use statement to the Warnings
    section of acetaminophen labeling (1994).

-   Voluntarily added the proposed alcohol warning to all Tylenol
    products in 1994 in advance of the final rule published in 1998.

-   Initiated an education program for Children's Tylenol products,
    focusing on the use of the proper dosage device (1997).

-   Implemented an easier to read format on Tylenol labeling (1998) in
    advance of the **Drug Facts** final rule (1999).

-   Introduced the SAFE-TY-LOCK system for Infants' Tylenol Suspension
    Drops to promote proper administration of infants' concentrated
    acetaminophen drops (1999).

An example of a successful McNeil-initiated intervention and ongoing
monitoring program is presented below for infants' acetaminophen
concentrated drops.

### Previous Initiatives: Programs to Reduce Misadministration of Pediatric Acetaminophen Products

Liquid single-ingredient acetaminophen products are available in two
concentrations. For children at least two years old, products are
formulated to contain acetaminophen at a concentration of 160 mg per 5
mL. For infants, a concentrated suspension drops product contains
acetaminophen, 80 mg/0.8mL, to provide medication in a volume suitable
for infants.

Based on a few manufacturer reports of parents using a dosing device
other than the enclosed dropper to administer acetaminophen infants'
concentrated drops, McNeil has instituted several interventions. These
include dosing instructions, revised labeling, and an integrated dropper
system.

[Dosing Instruction]{.underline}

In 1983, McNeil developed acetaminophen-dosing schedules based on age
and weight, to supplement the labeling instructions as published in the
1977 proposed rule \[Temple 1983\]. These schedules were made available
to healthcare professionals through the Physicians' Desk Reference (PDR)
and through professional materials. McNeil submitted in 1999 a Citizen's
Petition to the FDA requesting an expansion of the OTC labeling of
pediatric acetaminophen products to include dosing instructions for
children under two years of age (down to two months of age for infants'
drops and to four months of age for children's liquids) to make the
information available to all consumers. Additionally, as of an August
2002 (report on file) survey, 84% of pediatricians believe that dosing
for children less than 2‑years-old should be provided on the label of
the infants' drops products.

[Revised Labeling]{.underline}

In 1997, McNeil added the words "concentrated drops" to our infants'
drops labeling to highlight the difference between the drops and other
children's products. The warning section was revised to include the
statements, "Do not exceed recommended dose. Taking more than the
recommended dose (overdose) may not provide more pain or fever relief
and could cause serious health problems." There was also an increased
emphasis on the importance of using the proper dosing device (included
in the package).

[Integrated Dropper System]{.underline}

In 1999, McNeil introduced the SAFE-TY-LOCK, with its unique safety
barrier inside the bottle designed to prevent pouring the concentrated
infants' drops product out of the bottle. The barrier works for
suspension formulations because they are viscous. This design reduces
the risk of misadministration that results from using a dosing device
other than the provided dropper and also makes it difficult for a child
to accidentally ingest medicine from an open, unattended bottle.

After the introduction of the SAFE-TY-LOCK in 1999, the number of
misadministration cases associated with the infants' concentrated drops
product reported to McNeil declined notably (Figure 6-8). In 1998,
McNeil received eight reports of misadministration associated with the
use of the infants' concentrated drops product. The number of reports
has steadily declined after the introduction of the SAFE-TY-LOCK. There
were no reported cases in 2001 and a single report in the first quarter
2002 for which little information has been provided except that released
by the media. McNeil continues its efforts to obtain additional
understanding of the details surrounding this report.

These initiatives related to the infants' concentrated drops products
facilitate the safe use of the product that is integral to the treatment
of pain and fever in young children. An August 2002 survey (report on
file) indicates that 86% of pediatricians state that acetaminophen
concentrated drops are the preferred product for infants (6 months of
age) with a fever.

Figure 6-8. Acetaminophen Concentrated Suspension Drops
Misadministration Cases Reported to McNeil

![](media/image14.wmf){width="5.6375in" height="3.3027777777777776in"}

## McNeil's Current Initiatives

### McNeil OTC Analgesic Product Labeling Initiatives

Appropriate consumer medication use requires knowledge of the safe and
effective dose, as well as adherence to labeled contraindications to
use, warnings about use in special circumstances, and directions when
ingestion exceeds the recommended dose. McNeil's current acetaminophen
labeling explicitly warns consumers against concurrent use of multiple
acetaminophen-containing 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 or
combination-ingredient analgesics. Results from the McNeil Habits and
Practices survey \[McNeil 2001\] indicate that respondents generally
were not aware that cough/cold products also contained an analgesic. In
addition, some consumers may not be aware or may disregard the maximum
recommended single-dose or maximum recommended total 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.

Consequently, McNeil has revised its product labeling to direct the
attention and enhance awareness of consumers to key label information
that may reduce the occurrence of excessive acetaminophen exposure.
Revisions are being implemented for McNeil's monograph single-ingredient
and cough/cold-combination products containing acetaminophen. McNeil has
also requested revisions to the labeling for its NDA single-ingredient
pain relievers. In addition, McNeil has worked with in-pharmacy
prescription label producers to revise labeling on all prescription
products that contain acetaminophen. These efforts are described below.

#### Monograph Labeling of OTC Single-Ingredient and Combination Products

Specific labeling revisions include those of language and format that
stress key information. These revisions will appear on cartons, bottle
labels, and blister cards.

Revisions to packaging include changes that are not currently required
by FDA regulation. The changes include: 1) increasing the type size of
active ingredient(s) on the principal display panel for all
single-ingredient products; 2) adding active ingredient names to the
principal display panel for all cough/cold-combination products; and 3)
presenting the first letter of the name of active ingredient(s) in upper
case type with the remainder in lower case type. These revisions are
illustrated in the package examples that follow.

Previous Labeling for Tylenol^®^ --Principal Display Panel of Carton

![](media/image15.png){width="5.4in" height="2.8534722222222224in"}

New Labeling --Principal Display Panel of Carton: Increased Prominence
of Active Ingredient and Addition of Flag (upper left)

![](media/image16.png){width="5.4in" height="2.8618055555555557in"}

Previous Labeling Tylenol^®^ Cold --Principal Display Panel of Carton

![](media/image17.png){width="3.1902777777777778in"
height="3.329861111111111in"}

New Labeling --Principal Display Panel of Carton: Active Ingredients
Prominently Displayed with Concomitant Use Statement on Side of Box

![](media/image18.wmf){width="3.8402777777777777in"
height="3.2354166666666666in"}

Revisions to the back panel (or **Drug Facts**) are not shown and
include highlighting the active ingredient(s), creation of a distinct
**Overdose warning** section that is separated from the "Keep out of
reach of children" statement and reference to the **Overdose warning**
in the **Directions** section of the labeling. The **Overdose warning**
reads as follows:

> **Overdose warning:** Taking more than the recommended dose (overdose)
> could cause serious health problems. In case of overdose, get medical
> help or contact a Poison Control Center right away. Quick medical
> attention is critical for adults as well as for children even if you
> do not notice any signs or symptoms.

Revisions to the bottle label on Tylenol brand products also include a
prominently displayed concomitant use warning, a more prominent active
ingredients listing on the front principal display panel, and at the top
of the principal display panel near the lid - a "Read The Label"
message. An example of the bottle label revisions is presented below:

![](media/image19.png){width="5.929861111111111in"
height="2.4944444444444445in"}Previous Tylenol^®^ Labeling -- Bottle

![](media/image20.png){width="5.999305555555556in"
height="2.270138888888889in"}New Labeling -- Bottle: Addition of
Concomitant Use Warning, Increased Prominence of Active Ingredients,
Added "Read The Label" Message

A detailed summary of the specific labeling revisions being made to the
outer carton and bottle label of monograph single-ingredient
acetaminophen products is provided in Table 6-5. Table 6-6 provides a
summary of revisions relevant to cough/cold-combination products
containing acetaminophen.

Table 6‑5. Summary of McNeil OTC Labeling Revisions Implemented for
Tylenol Brand Single-Ingredient Products Marketed under the Monograph
System

+-----------------------------------------------------------------------+
| Labeling Revisions                                                    |
+-----------------------------------------------------------------------+
| [Outer carton and bottle label]{.underline}:                          |
+-----------------------------------------------------------------------+
| Increased type size and prominence of the active ingredient on the    |
| PDP\* and added the word "contains" before the ingredient.            |
+-----------------------------------------------------------------------+
| Presented the first letter of the active ingredient name in upper     |
| case type with the remainder in lower case type.                      |
+-----------------------------------------------------------------------+
| Highlighted the ***Active ingredient*** section of the ***Drug        |
| Facts*** box (carton) and the bottle label in yellow contrasting      |
| color.                                                                |
+-----------------------------------------------------------------------+
| Created a distinct **Overdose warning** section, separating it from   |
| "**Keep out of reach of children**" and revised the existing overdose |
| warning language:                                                     |
|                                                                       |
| **Overdose warning**: Taking more than the recommended dose           |
| (overdose) could cause serious health problems. In case of overdose,  |
| get medical help or contact a Poison Control Center right away. Quick |
| medical attention is critical for adults as well as for children even |
| if you do not notice any signs or symptoms.                           |
+-----------------------------------------------------------------------+
| Added to the ***Directions*** section of both the ***Drug Facts***    |
| box (carton) and bottle label:                                        |
|                                                                       |
| "**do not take more than directed (see overdose warning)**"           |
+-----------------------------------------------------------------------+
| [Outer carton only]{.underline}:                                      |
+-----------------------------------------------------------------------+
| Added a flag "NEW LABEL INFORMATION" to the upper corner of the PDP   |
| in contrasting color that will be included for a minimum of 6 months. |
+-----------------------------------------------------------------------+
| [Bottle label only]{.underline}:                                      |
+-----------------------------------------------------------------------+
| Added "DO NOT USE WITH OTHER MEDICINES CONTAINING ACETAMINOPHEN" to   |
| the PDP.                                                              |
+-----------------------------------------------------------------------+
| Added "READ THE LABEL" to the PDP.                                    |
+-----------------------------------------------------------------------+
| Abbreviations: PDP = principal display panel.                         |
+-----------------------------------------------------------------------+

Table 6‑6. Summary of McNeil OTC Labeling Revisions Implemented for
Tylenol Brand Cough/Cold-Combination Products Marketed under the
Monograph System

+-----------------------------------------------------------------------+
| Labeling Revisions                                                    |
+-----------------------------------------------------------------------+
| [Outer carton]{.underline}:                                           |
+-----------------------------------------------------------------------+
| Added active ingredient names to the PDP\* in prominent type size,    |
| with the first letter of the ingredient in upper case type and the    |
| remainder in lower case type.                                         |
+-----------------------------------------------------------------------+
| Added "contains ([number of]{.underline}) ingredients" to the PDP.    |
+-----------------------------------------------------------------------+
| Created a distinct **Overdose warning** section, separating it from   |
| "**Keep out of reach of children**" and revised the existing overdose |
| warning language:                                                     |
|                                                                       |
| **Overdose warning:** Taking more than the recommended dose           |
| (overdose) could cause serious health problems. In case of overdose,  |
| get medical help or contact a Poison Control Center right away. Quick |
| medical attention is critical for adults as well as for children even |
| if you do not notice any signs or symptoms.                           |
+-----------------------------------------------------------------------+
| -   Added to the ***Directions*** section of the ***Drug Facts*** box |
|     in bold type:                                                     |
|                                                                       |
| **"do not take more than directed (see overdose warning)"**           |
+-----------------------------------------------------------------------+
| Added a flag "NEW LABEL INFORMATION" to the upper corner of the PDP   |
| in contrasting color that will be included for a minimum of 6 months. |
+-----------------------------------------------------------------------+
| Added "DO NOT USE WITH OTHER MEDICINES CONTAINING ACETAMINOPHEN" on   |
| the side flap of the box opened by the consumer and added "OPEN FROM  |
| OTHER SIDE" on the opposite flap of the box.                          |
+-----------------------------------------------------------------------+
| Highlighted the ***Active ingredient*** section of the ***Drug        |
| Facts*** box (carton) in yellow contrasting color.                    |
+-----------------------------------------------------------------------+
| [Blister cards]{.underline}:                                          |
+-----------------------------------------------------------------------+
| Added "CONTAINS ACETAMINOPHEN" to all blister cards.                  |
+-----------------------------------------------------------------------+
| Abbreviations: PDP = principal display panel.                         |
+-----------------------------------------------------------------------+

#### Labeling of Prescription Acetaminophen-Containing Products

The McNeil Habits and Practices Survey indicates that consumers did not
know or could not recall what certain prescription analgesic products
contained. Only one of 61 consumers who were taking Vicodin, Percocet,
or Endocet knew that the product contained acetaminophen. None knew what
the other active ingredient was in any on these products. We hypothesize
that excessive acetaminophen exposure can occur with prescription
products if individuals are not aware that acetaminophen is present in
their prescription analgesic product. Additionally, despite information
on current OTC labels, some consumers may not be aware or may disregard
the potential for acetaminophen overdose when taking concomitant OTC and
prescription products containing acetaminophen.

To address these issues, McNeil sought to revise the labeling
information provided on prescription products containing acetaminophen.
McNeil identified one of the major companies that provides drug label
database services to most of the pharmacy market, including several of
the largest chains and has advised them of the rationale for revising
labeling on all prescription acetaminophen-containing products. Based on
this information, beginning March 11, 2002, the company independently
created and added to the labeling database two new auxiliary warning
labels (ie, those labels placed directly on prescription bottles)
specific to acetaminophen:

-   This medicine contains ACETAMINOPHEN. Taking more ACETAMINOPHEN than
    recommended may cause serious liver problems.

-   Do not take other ACETAMINOPHEN containing products at the same time
    without first checking with your Doctor. Check all medicine labels
    carefully.

An additional revision has been implemented, that specifically spells
out "acetaminophen" instead of using an abbreviation. For example, the
generic name "codeine phosphate/APAP" is now printed as "codeine
phosphate/acetaminophen" on the bottle label.

These revisions are being introduced throughout the United States. All
pharmacies using this label database service will have the new revisions
in place by the end of 2002.

###  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.

#### Education Targeting Consumers: McNeil's "Know Your Medicine" Initiative

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 seeks 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 the 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, in 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 with consumers in the McNeil
    database following requests for additional information.

-   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 the following figure.
It shows the emphasis upon warning against use of multiple products
containing the same analgesic and helping consumers to identify where
that might be a problem.

![](media/image21.png){width="4.5625in" height="4.53125in"}Figure 6-9.
McNeil's Know Your Medicine Brochure (Front)

**Figure 6-4. Know Your Medicine Brochure (Back)**

![](media/image22.png){width="4.5625in" height="4.510416666666667in"}

#### Educational Interventions Targeting Healthcare Providers and Professional and Non-Profit Organizations

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

In January 2002, 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, and 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 US 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 an 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 developed with an educational grant from McNeil.
They were distributed to all 93,000 AAFP members and 30,000 other
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 use in pharmacist
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.

### Current 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.

This 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 products that
contain acetaminophen.

## 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 group 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 \[personal communication Carr 2002\]. McNeil has
initiated interventions that include pediatric labeling and dosing
device modifications, and labeling revisions to OTC single and
combination products as well as prescription acetaminophen-containing
analgesics. Implemented McNeil initiatives include consumer and
healthcare educational programs and an ongoing consumer OTC analgesic
use monitoring survey.

# Attachments

**Attachment 1: Academic Affiliations for each Member of the Expert
Review Panel**

[Expert Review Panel]{.underline}

[Member Names and Academic Affiliations]{.underline}

[Gordon D. Benson, MD]{.underline}

Professor of Medicine, Associate Dean

Robert Wood Johnson Medical School

Camden, NJ

[Martin Caravati, MD]{.underline}

Medical Director

Division of Emergency Medicine

University of Utah

Salt Lake City, UT

[Richard C. Dart, MD, PhD]{.underline}

Director

Rocky Mountain Poison & Drug Center

Denver, CO

[Raymond S. Koff, MD]{.underline}

Director of Clinical Hepatology Research

University of Massachusetts Memorial Medical Center

Worcester, MA

[Victor J. Navarro, MD]{.underline}

Clinical Professor of Medicine

Thomas Jefferson University

Philadelphia, PA

[Kent R. Olson, MD]{.underline}

Medical Director

Poison Control Center of San Francisco General Hospital

San Francisco, CA

[Barry H. Rumack, MD]{.underline}

Clinical Professor of Pediatrics

Director Emeritus

Rocky Mountain Poison & Drug Center

Denver, CO

[Donna Seger, MD]{.underline}

Assistant Professor of Emergency Medicine

Vanderbilt University Medical Center

Nashville, TN

[K. V. Speeg, MD, PhD]{.underline}

Professor, Department of Medicine

University of Texas Health Science Center

San Antonio, TX

**Attachment 2: Causality Data Form**

**Mfr. Report Number (see 9 on MedWatch) \_\_\_\_\_\_\_\_\_\_\_\_\_
Reviewer's Name\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**ACETAMINOPHEN HEPATOTOXICITY CAUSALITY DATA COLLECTION INSTRUMENT**

1.  **Does case include adequate information for evaluation?**

> To be considered a case must include BOTH of the following:

-   A history of acetaminophen ingestion or a serum level with
    acetaminophen present.

-   Evidence of liver injury of any type

> **Should case be evaluated?** Yes \_\_\_\_ No \_\_\_\_

**If NO, STOP HERE!**

2.  **Working Definition of Acetaminophen Causation**

A case of acetaminophen induced hepatic injury may have occurred when
evidence of liver injury is present in a patient with acetaminophen
exposure in the absence of an equally or more likely alternative cause.

1.  **Is evidence of acetaminophen ingestion present?**

> Check all that apply:

-   History of acetaminophen ingestion? Y N ?

```{=html}
<!-- -->
```
-   Positive serum acetaminophen level?

> What was first serum acetaminophen level reported? (mcg/ml or mg/L) Y
> N ?
>
> What was time of level post ingestion? Circle one:
>
> Admission, Not Reported, or \_\_\_\_ hrs post ingestion

2.  **Is evidence of liver injury present?**

> Check all that apply:

-   AST or ALT greater than 500 IU/L at any time Y N ?

-   Evidence of clinical signs of acute liver injury or failure Y N ?

-   Statement of "liver failure" or similar comment (e.g. liver
    histopathology showing

injury) is present Y N ?

3.  **Is there an equally or more likely alternative cause in the
    report?**

> Check all that apply:

-   Infectious liver disease? Y N ?

-   Inconsistent liver histopathology or presence of other anatomical
    liver conditions (e.g. Budd-Chiari syndrome)? Y N ?

```{=html}
<!-- -->
```
-   Potential confounding drug or drug interaction ? Y N ?

-   Hypotension or shock or severe hypoxemia present during course? Y N
    ?

-   Serum acetaminophen level that is inconsistent with reported
    history? Y N ?

-   Other inconsistency of clinical course or plausible alternative
    cause of liver injury

that questions relationship Y N ?

-   Evidence of hypersensitivity reaction? Y N ?

**Mfr. Report Number (see 9 on MedWatch) \_\_\_\_\_\_\_\_\_\_\_\_\_
Reviewer's Name\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

**FINAL ASSESSMENT (Check one)**

**Evaluable Case:**

**Sufficient information is available INSUFFICIENT**

**Case is consistent with APAP toxicity No DEFINITELY NOT APAP**

**Alternative diagnosis more likely Yes UNLIKELY**

**(No more likely diagnosis)**

**Still Absent "key" Information Yes POSSIBLE**

**(Sufficient "key" data)**

**More than 50 % clinical probability Yes PROBABLE**

**Nearly 100% clinical probability Yes DEFINITE**

**Acetaminophen [definitely]{.underline} caused liver injury \_\_\_\_**

(Nearly 100% certainty that APAP was the cause of liver injury)

**Acetaminophen [probably]{.underline} caused liver injury \_\_\_\_**

(Greater than 50% clinical certainty that APAP was the cause of liver
injury)

**Acetaminophen [possibly]{.underline} caused liver injury \_\_\_\_**

(Case is consistent with APAP as cause, but other confounders or
alternative explanations are present; less than 50% clinical certainly
that APAP was cause of liver injury)

**Acetaminophen was [unlikely]{.underline} the cause of liver injury
\_\_\_\_**

(Alternative explanation seems clinically more likely than APAP)

**Acetaminophen [was not]{.underline} cause of liver injury \_\_\_\_**

(Nearly 100% certainty that APAP was NOT the cause of liver injury)

**Data available are [insufficient]{.underline} to determine causality
\_\_\_\_**

(Even if the case may be consistent with APAP cause, crucial data are
simply not present.)

**DOSE ASSESSMENT**

**What is the body burden of acetaminophen (see table)** \_\_\_\_

**If a serum acetaminophen level is available (timed or untimed), is the
body burden consistent with the reported dose?**

1.  **Yes**

2.  **No. Please Explain
    \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

3.  **Can't evaluate**

# Reference List

The reference materials are listed in alphabetical order by section.

**[Section 2: Efficacy of Acetaminophen in the Treatment of
Pain]{.underline}**

Agency for Healthcare Research and Quality. [Management of Cancer Pain.
\[]{.underline}Summary\] Rockville, MD: AHRQ, January 2001; Evidence
Report/Technology Assessment: Number 35. AHRQ Publication No. 01-E033.

[]{.mark}

Altman RD. Ibuprofen, acetaminophen and placebo in osteoarthritis of the
knee: A six-day double-blind study. [Advances in OA
Therapeutics]{.underline} 1999 \[abstract\].

Amadio P Jr, Cummings DM: Evaluation of acetaminophen in the management
of osteoarthritis of the knee. [Curr Ther Res]{.underline} 1983
Jul;34(1):59-66.

Amadio P Jr. Peripherally acting analgesics. [Am J Med]{.underline} 1984
Sep 10; 17-26.

Ameer B, Divoll M, Abernethy DR, et al. Absolute and relative
bioavailability of oral acetaminophen preparations. [J Pharm
Sci]{.underline} 1983 Aug;72(8):955-958.

American Academy of Orthopaedic Surgeons/American Association of
Neurological Surgeons/American College of Physical Medicine and
Rehabilitation/American College of Rheumatology. [Clinical guideline on
hip pain]{.underline} 1996.

American Academy of Pediatrics/Canadian Paediatric Society. Prevention
and management of pain and stress in the neonate. 2000 Feb.

American College of Radiology (ACR) Expert Panel on Neurologic Imaging.
[ACR Appropriateness Criteria™: Acute low back
pain---Radiculopathy]{.underline}. Reston, VA: ACR, 1999.

American College of Rheumatology Subcommittee on Osteoarthritis
Guidelines. Recommendations for the medical management of osteoarthritis
of the hip and knee: 2000 update. [Arthritis Rheum]{.underline} 2000
Sep;43(9):1905-1915.

American Geriatrics Society (AGS) Panel on Chronic Pain in Older
Persons. The management of chronic pain in older persons. [J Am Geriatr
Soc]{.underline} 1998 May;46(5):635-651.

American Geriatrics Society (AGS) Panel on Persistent Pain in Older
Persons. The management of persistent pain in older persons. [J Am
Geriatr Soc]{.underline} 2002 Jun:50(S6) (supplement).

American Medical Directors Association (AMDA). [Chronic Pain Management
in the Long-Term Care Setting.]{.underline} Columbia MD: AMDA, 1999.

American Pain Society (APS). [Guideline for the Management of Acute and
Chronic Pain in Sickle Cell Disease]{.underline}. Glenview, IL: APS,
1999.

American Society of Anesthesiologists Task Force on Pain Management,
Chronic Pain Section. Practice Guidelines for Chronic Pain Management.
[Anesthesiology]{.underline} 1997 Apr;86(4):995-1004.

Bedjaoui A, Demotes-Mainard F, Raynal F, et al. Influence de l'âge et du
sexe sur la pharmacocinétique du paracétamol \[Influence of age and sex
on the pharmacokinetics of paracetamol\]. [Thérapie]{.underline}
1984;39:353-359.

BenDebba M, Torgerson WS, Long DM. Personality traits, pain duration and
severity, functional impairment, and psychological distress in patients
with persistent low back pain. [Pain]{.underline} 1997;72:115-125.

Borin MT, Ayres JW. Single dose bioavailability of acetaminophen
folllowing oral administration. [Int J Pharm]{.underline}
1989;54:199-209.

Bradley JD, Brandt KD, Katz BP, et al: Comparison of an antiinflammatory
dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in
the treatment of patients with osteoarthritis of the knee. [N Engl J
Med]{.underline} 1991 Jul 11;325(2):87-91.

Carr AJ. Beyond disability: Measuring the social and personal
consequences of osteoarthritis. [Osteoarthritis Cartilage]{.underline}
1999;7(2):230-238.

Carr D, Chao S, Polomano R, et al. Restricting dosage or availability of
OTC analgesics: A model for analysis. 2002 (unpublished).

Casten RJ, Parmelee PA, Kleban MH, et al. The relationships among
anxiety, depression, and pain in a geriatric institutionalized sample.
[Pain]{.underline} 1995;61:271-276.

Christophersen AB, Levin D, Hoegberg LC, et al. Activated charcoal alone
or after gastric lavage: A simulated large paracetamol intoxication. [Br
J Clin Pharmacol]{.underline} 2002 Mar;53(3):312-317.

Cousins M. Acute and postoperative pain. In: Wall PD, Melzack R, eds.
[Textbook of Pain, 3^rd^ ed.]{.underline} New York: Churchill
Livingstone, 1994:357-385.

Desbiens NA, Mueller-Rizner N, Connors AF Jr, et al. HELP Investigators:
Pain in the oldest-old during hospitalization and up to one year later.
[J Am Geriatr Soc]{.underline} 1997 Oct;45(10):1167-1172.

Divoll M, Abernathy DR, Ameer B, et al. Acetaminophen kinetics in the
elderly. [Clin Pharmacol Ther]{.underline} 1982; 31:151-156.

Divoll M, Ameer B, Abernathy DR, et al. Age does not alter acetaminophen
absorption. [J Am Geriatrics Soc]{.underline} 1982;30:240-244.

Divoll M, Greenblatt DJ, Ameer B, et al. Effect of food on acetaminophen
absorption in young and elderly subjects. [J Clin Pharmacol]{.underline}
1982 Nov/Dec;22:571-576.

Douglas, DR, Sholar, JB, Smilkstein MJ. A pharmacokinetic comparison of
acetaminophen products (Tylenol® Extended Relief vs Regular Tylenol®).
[Acad Emerg Med]{.underline} 1996 Aug;3:740-744.

Dworkin RH. Which individuals with acute pain are most likely to develop
a chronic pain syndrome? [Pain Forum]{.underline} 1997;6:127-36.

Ferrell BR, Griffith H. Cost issues related to pain management: Report
from the cancer pain panel of the agency for health care policy and
research. [J Pain Symptom Manage]{.underline} 1994 May;9(4):221-234.

Foley KM. Pain relief into practice: Rhetoric without reform. [J Clin
Oncol]{.underline} 1995 Sep;13(9):2149-2151 (editorial).

Furdon SA, Eastman M, Benjamin K, et al. Outcome measures after
standardized pain management strategies in postoperative patients in the
neonatal intensive care unit. [J Perinat Neonatal Nurs]{.underline} 1998
Jun;12(1):58-69.

Geba GP, Weaver AL, Polis AB, et al. Efficacy of rofecoxib, celecoxib,
and acetaminophen in osteoarthritis of the knee: A randomized trial.
[JAMA]{.underline} 2002 Jan 2;287(1):64-71.

Gelotte CK. Cross-study pharmacokinetic and pharmacodynamic modeling of
acetaminophen: comparison of Tylenol Extended Relief Caplets with
Regular-Strength Tylenol Caplets. Fort Washington, PA: McNeil Consumer &
Specialty Pharmaceuticals; 1995. Submitted to NDA 19-872 as Phase IV
Commitment.

Gottschalk A, Smith DS, Jobes DR, et al. Preemptive epidural analgesia
and recovery from radical prostatectomy: A randomized controlled trial.
[JAMA]{.underline} 1998 Apr 8;279(14):1076-1082.

Grant M, Ferrell BR, Rivera LM, et al. Unscheduled readmissions for
uncontrolled symptoms: A health care challenge for nurses. [Nurs Clin
North Am]{.underline} 1995 Dec;30(4):673-682.

Grattan T, Hickman R, Darby-Dowman A, et al. A five way crossover human
volunteer study to compare the pharmacokinetics of paracetamol following
oral administration of two commercially available paracetamol tablets
and three development tablets containing paracetamol in combination with
sodium bicarbonate or calcium carbonate. [Eur J Pharm
Biopharm]{.underline} 2000;49:225-229

Green R, Grierson R, Sitar DS, et al. How long after drug ingestion is
activated charcoal still effective? [Clinical Toxicology]{.underline}
2001;31(6):601-605

Gureje O, Von Korff M, Simon GE, et al. Persistent pain and well-being:
A World Health Organization study in primary care. [JAMA]{.underline}
1998 Jul;280(2):147-151.

Gustafsson I, Nystrom E, Quiding H. Effects of preoperative paracetamol
on pain after oral surgery. [Eur J Clin Pharmacol]{.underline}
1983;24:63-65.

Haack DG. A phase IV collaborative multi-clinic, double-blind study to
compare efficacy of and side effects profile of acetaminophen and
ibuprofen in the treatment of pain secondary to osteoarthritis. Stat Rpt
72. Protocol 3-277, Unpublished Report 192, September 1986.

Heim HM, Oei TP. Comparison of prostate cancer patients with and without
pain. [Pain]{.underline} 1993;53:159-162.

Hindmarsh KW, Mayers DJ, Wallace SM, et al. Increased serum sulfate
concentrations in man due to environmental factors: Effects on
acetaminophen metabolism. [Vet Hum Toxicol]{.underline} 1991
Oct;33(5):441-445.

Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical
management of osteoarthritis. [Arthritis Rheum]{.underline}
1995;38:1535-1546.

Hopkinson JH, Smith MT, Bare WW, et al. Acetaminophen (500 mg) versus
acetaminophen (325 mg) for the relief of pain in episiotomy patients.
[Curr Ther Res]{.underline} 1974 Mar;16(3):194-200.

Hutcheson SJ, Mason WD. Pharmacodynamic modeling of the analgesic
properties of specific non-opioid analgesics using the dental pain
model. 1993 (abstract).

Joint Commission on Accreditation of Healthcare Organizations Pain
Standards, 2001.

Jorup-Rönström C, Beermann B, Wählin-Boll E, et al. Reduction of
paracetamol and aspirin metabolism during viral hepatitis. [Clin
Pharmacokinet]{.underline} 1986;11:250-256.

Katz J. Pre-emptive analgesia: Evidence, current status and future
directions. [Eur J Anaesthesiol]{.underline} 1995;12 (Suppl. 10):8-13.

Katz J, Jackson M, Kavanagh BP, et al. Acute pain after thoracic surgery
predicts long-term post-thoracotomy pain. [Clin J Pain]{.underline}
1996;12(1):50-55.

Kiersch TA, Halladay SC, Hormel PC. A single-dose, double-blind
comparison of naproxen sodium, acetaminophen, and placebo in
postoperative dental pain. [Clin Ther]{.underline} 1994;16(3):394-404.

Kohli U, Sharma SK, Agarwal SS, et al. Influence of nutritional status
on acetaminophen metabolism in man. [Indian J Med Res]{.underline} 1982
Feb;75:265-273.

Lee SH, Kim SI, Yoo WH, et al. The comparison of the efficacy and
gastrointestinal side effects of Tylenol-ER (extended relief) and
naproxen in patients with osteoarthritis of the knee: Multicenter
clinical trial. [J Korean Rheum Arthritis Soc]{.underline} 1998
Nov;5(2):211-220.

Liebeskind JC. Pain *can* kill. [Pain]{.underline} 1991;44:3-4 (guest
editorial).

Linton SJ. Overlooked and undertreated? The role of acute pain intensity
in the development of chronic low back pain problems. [Pain
Forum]{.underline} 1997;6:145-7.

Liu S, Carpenter RL, Neal JM. Epidural Anesthesia and Analgesia: Their
role in postoperative outcome. [Anesthesiology]{.underline} 1995
Jun;82(6):1474-1506 (review).

Louis Harris & Associates. Pain and Absenteeism in the Workplace.
[Business and Health]{.underline} 1996. Available at
http://208.153.7.109/resources/reports/related_news_0301.html (accessed
8/29/02).

McCaffrey M, Pasero BR. [Pain: Clinical Manual]{.underline}. 1999. St
Louis: Mosby.

McNeil Laboratories. [NDA 170-53: Amendment No 1: Clinical Study
Data]{.underline} 1972 December 19.

McQuay HJ, Poppleton P, Carroll D, et al. Ketorolac and acetaminophen
for orthopedic postoperative pain. [Clin Pharmacol Ther]{.underline}
1986;39(1):89-93.

McQuay HJ, Edwards JF, Moore RA. Evaluating analgesia: The challenges.
[Am J Ther]{.underline} 2002;9(3):179-187.

Mehlisch DR, Jasper RD, Brown P, et al. Comparative study of ibuprofen
lysine and acetaminophen in patients with postoperative dental pain.
[Clin Ther]{.underline} 1995;17(5):852-860.

Miaskowski C, Kragness L, Dibble S, et al. Differences in mood states,
health status, and caregiver strain between family caregivers of
oncology outpatients with and without cancer-related pain. [J Pain
Symptom Manage]{.underline} 1997;13:138-147.

Miners JO, et al. Comparison of paracetamol metabolism in young adult
and elderly males. [Eur J Clin Pharmacol]{.underline} 1988:35:157-160.

Mitchell MC, Hanew T, Meredith CG, et al. Effects of oral contraceptive
steroids on acetaminophen metabolism and elimination. [Clin Pharmacol
Ther]{.underline} 1983 Jul;34(1):48-53.

Nick JB. A single-dose, double-blind, placebo-controlled study of the
relative efficacy and safety of acetaminophen at doses of 500mg and
1000mg in postoperative dental pain. McNeil Consumer & Specialty
Pharmaceuticals Protocol 02-156. Data on file. 2002

Nielsen JC, Bjerring P, Arendt-Nielsen L. A comparison of the
hypoanalgesic effect of paracetamol in slow-release and plain tablets on
laser-induced pain. [Br J Clin Pharmacol]{.underline} 1991;31:267-270.

Nystrom E, Gustafsson I, Quiding H. The pain intensity at analgesic
intake and the efficacy of diflunisal in single doses and effervescent
acetaminophen in single and repeated doses.
[Pharmacotherapy]{.underline} 1988;8(3):201-209.

Page GG. The medical necessity of adequate pain management. [Pain
Forum]{.underline} 1996;5:227-31.

Parier JL, Pichard O, Bonhomme L, et al. Bioavailability of paracetamol
according to pharmaceutical form. [J Pharm Belg]{.underline}
1988;43(3):287-291.

Pendleton A, Arden N, Dougados M, et al. EULAR recommendations for the
management of knee osteoarthritis: Report of a task force of the
Standing Committee for International Clinical Studies Including
Therapeutic Trials (ESCISIT). [Ann Rheum Dis]{.underline}
2000;59:936-944.

Pigeon JG, Nick JB. A comparative study using a single dose of
acetaminophen, acetaminophen/pseudoephedrine, pseudoephedrine alone, and
placebo in dental pain. CSR 163. Protocol 91-123, Unpublished Report
289, November 1992.

Quiding H, Oikarinen V, Sane J, et al. Analgesic efficacy after single
and repeated doses of codeine and acetaminophen. [J Clin
Pharmacol]{.underline} 1984;24(1):27-34.

Rawlins MD, Henderson DB, Hijab AR, et al. Pharmacokinetics of
paracetamol (acetaminophen) after intravenous and oral administration.
[Eur J Clin Pharmacol]{.underline} 1977;11:283-286.

Riley LA. Pain management facilitates early postoperative recovery.
[Prog Cardiovasc Nurs]{.underline} 1996;11(1):47-48.

RW Johnson Pharmaceutical Research Institute Clinical Study Report
1999a: Evaluation of the efficacy and safety of tramadol/APAP in oral
surgical pain. Protocol TRAMAP-ANAG. Unpublished report 3996. 1999 July.

RW Johnson Pharmaceutical Research Institute Clinical Study Report
1999b: Evaluation of the efficacy and safety of tramadol/APAP in oral
surgical pain. Protocol TRAMAP-ANAG. Unpublished report 3997. 1999 July.

RW Johnson Pharmaceutical Research Institute Clinical Study Report
1999c: Evaluation of the efficacy and safety of tramadol/APAP in oral
surgical pain. Protocol TRAMAP-ANAG. Unpublished report 3999. 1999 July.

Sajahawalla CG, Ayres JW. Multiple-dose acetaminophen pharmacokinetics.
[J Pharm Sci]{.underline} 1991 Sept;80(9):855-860.

Seymour RA. Efficacy of paracetamol in reducing post-operative pain
after periodontal surgery. [J Clin Periodontal]{.underline}
1983;10:311-316

Seymour RA, Kelly PJ, Hawkesford JE. The efficacy of ketoprofen and
paracetamol (acetaminophen) in postoperative pain after third molar
surgery. [Brit J Clin Pharmacol]{.underline} 1996;41(6):581-585.

Sheehan J, McKay J, Ryan M, et al. What cost chronic pain? [Ir Med
J]{.underline} 1996 Nov/Dec;89(6):218-219.

Silberstein EB, Taylor AT for the Society of Nuclear Medicine,
[Procedure Guideline for Bone Pain Treatment 2.0]{.underline}, Reston,
VA: 1999 Feb. available at [www.snm.org](http://www.snm.org/).

Skjelbred P, Løkken P. Paracetamol versus placebo: Effects on
post-operative course. [Eur J Clin Pharmacol]{.underline} 1979;15:27-33.

Skjelbred P, Løkken P, Skoglund LA. Postoperative administration of
acetaminophen to reduce swelling and other inflammatory events. [Curr
Thera Res]{.underline} 1984 Mar;35(3):377-385.

Skoglund LA, Skjelbred P, Fyllingen G. Analgesic efficacy of
acetaminophen 1000 mg, acetaminophen 2000 mg, and the combination of
acetaminophen 1000 mg and codeine phosphate 60 mg versus placebo in
acute postoperative pain. [Pharmacotherapy]{.underline}
1991;11(5):364-369.

Snelling J. The effect of chronic pain on the family unit. [J Adv
Nurs]{.underline} 1994;19:543-551.

Sorge J. The lesson from cancer pain. [Eur J Pain]{.underline} 2000:A
(suppl A);3-7

Stork, CM, Rees S, Howland MA et al. Pharmacokinetics of extended relief
versus regular release Tylenol in simulated human overdose. [Clin
Toxicol]{.underline} 1996;34(2):157-162.

Tasmuth T, von Smitten K, Hietanen P, et al. Pain and other symptoms
after different treatment modalities of breast cancer. [Ann
Oncol]{.underline} 1995;6:453-459.

Veterans Health Administration/Department of Defense (VHA/DOD). [VHA/DOD
clinical practice guideline for the management of low back pain or
sciatica in the primary care setting]{.underline}. Washington, D.C.: VHA
Headquarters, May 1999; Contract number: V101(93)P-1633.

Wade AG, Ward PJ. A double-blind comparison of meptazinol versus
paracetamol and placebo in acute and chronic painful conditions
presenting to the general practitioner. [Curr Med Res Opin]{.underline}
1982;8(3):191-196.

Washington State Department of Labor and Industries/ Washington State
Medical Association. [Fibromyalgia]{.underline}. 1999.

World Health Organization. Cancer pain relief: A guide to opioid
availability. 2^nd^ ed. Geneva: World Health Organization, 1996.

World Health Organization Expert Committee on Cancer Pain Relief and
Active Supportive Care. [Cancer Pain Relief and Palliative
Care]{.underline}. Geneva: World Health Organization, 1990; WHO
Technical Report Series 804.

Yiamouyiannis CA, Harris A, Sanders RA. Paracetamol Pharmacokinetics are
independent of caloric intake and physical activity. [Drug
Invest]{.underline} 1994; 8(6):361-368.

Yuan CS, Karrison T, Wu JA, et al. Dose-related effects of oral
acetaminophen on cold-induced pain: A double-blind, randomized,
placebo-controlled trial. [Clin Pharmacol Ther]{.underline}
1998;63(3):379-383

Zoppi M, Perett G, Boccard E. Paracetamol and arthritis:
Placebo-controlled study of the analgesic efficacy of an effervescent
formulation of 500 mg paracetamol in arthritis of the knee or hip. [Eur
J Pain]{.underline} 1995;16(1-2):42-48.

**[Section 3: Acetaminophen Pharmacology and Toxicology]{.underline}**

Ameer B, Divoll M, Abernethy DR, et al. Absolute and relative
bioavailability of oral acetaminophen preparations. [J Pharm
Sci]{.underline} 1983 Aug;72(8):955-958

Autret E, Dutertre J-P, Bretau M, et al. Pharmacokinetics of paracetamol
in the neonate and infant after administration of propacetamol
chlorhydrate. [Dev Pharmacol Ther]{.underline} 1993;20:129-134.

Bannwarth B, Netter P, Lapicque F, et al. Plasma and cerebrospinal fluid
concentrations of paracetamol after a single intravenous dose of
propacetamol. [Br J Clin Pharmacol]{.underline} 1992;34:79-81.

Bedjaoui A, Demotes-Mainard F, Raynal F, et al. Influence de l'âge et du
sexe sur la pharmacocinétique du paracétamol \[Influence of age and sex
on the pharmacokinetics of paracetamol\]. [Thérapie]{.underline}
1984;39:353-359.

Benson GD. Acetaminophen in chronic liver disease. [Clin Pharmacol
Ther]{.underline} 1983 Jan;33(1):95-101.

Blackledge HM, O'Farrell J, Minton NA, et al. The effect of therapeutic
doses of paracetamol on sulphur metabolism in man. [Hum Exp
Toxicol]{.underline} 1991 May; 10(3): 159-65.

Borin MT, Ayres JW. Single dose bioavailability of acetaminophen
folllowing oral administration. [Int J Pharm]{.underline}
1989;54:199-209.

Botting RM. Mechanism of action of acetaminophen: Is there a
cyclooxygenase 3? [Clin Infect Dis]{.underline} 2000;31(Supp
5):S202-S210.

Boutaud O, Aronoff DM, Richardson JH, et al. Determinants of the
cellular specificity of acetaminophen as an inhibitor of prostaglandin
H~2~ synthases. [PNAS]{.underline} 2002;99(10):7130-7135.

Briant RH, Dorrington RE, Cleal J, et al. The rate of acetaminophen
metabolism in the elderly and the young. [J Am Geriatr Soc]{.underline}
1976 Aug; 24(6):359-361.

Brown RD, Wilson JT, Kearns GL, et al. Single-dose pharmacokinetics of
ibuprofen and acetaminophen in febrile children. [J Clin
Pharmacol]{.underline} 1992 Mar;32(3):231-241.

Christophersen AB, Levin D, Hoegberg LC, et al. Activated charcoal alone
or after gastric lavage: A simulated large paracetamol intoxication. [Br
J Clin Pharmacol]{.underline} 2002 Mar;53(3):312-317.

Court MH, Duan SX, Von Moltke LL, et al. Interindividual variability in
acetaminophen glucuronidation by human liver microsomes: Identification
of relevant acetaminophen UDP-glucuronosyltransferase isoforms. [J
Pharmacol Exp Ther]{.underline} 2001;299(3):998-1006.

Davis M, Simmons CJ, Harrison NG, et al. Paracetamol overdose in man:
Relationship between pattern of urinary metabolites and severity of
liver damage. [Quarterly Journal of Medicine New Series XLV]{.underline}
1976 Apr;178:181-191.

Desmeules J, Piguet V, Dayer P. Nociceptive flexion reflex (R-III) as a
tool to assess the antinociceptive effect of central analgesics. [Clin
Pharm Ther]{.underline} 1995 Feb;57(3):139.

Divoll M, Abernathy DR, Ameer B, et al. Acetaminophen kinetics in the
elderly. [Clin Pharmacol Ther]{.underline} 1982a; 31:151-156.

Divoll M, Ameer B, Abernathy DR, et al. Age does not alter acetaminophen
absorption. [J Am Geriatrics Soc]{.underline} 1982b;30:240-244.

Divoll M, Greenblatt DJ, Ameer B, et al. Effect of food on acetaminophen
absorption in young and elderly subjects. [J Clin Pharmacol]{.underline}
1982c Nov/Dec;22:571-576.

Douglas, DR, Sholar, JB, Smilkstein MJ. A pharmacokinetic comparison of
acetaminophen products (Tylenol Extended Relief vs Regular Tylenol).
[Acad Emerg Med]{.underline} 1996 Aug;3:740-744.

Ellmers SE, Parker, LRC, Notarianni LJ, et al. Excretion of paracetamol
in fit and frail elderly people. [Br J Clin Pharmacol]{.underline} 1990
May;31(5):596P-597P (abstract).

Forrest JA, Adriaenssens P, Finlayson ND, Prescott LF. Paracetamol
metabolism in chronic liver disease. [Eur J Clin Pharmacol]{.underline}
1979;15:427-431.

Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of
paracetamol. [Clin Pharmacokinet]{.underline} 1982;7:93-107.

Grattan T, Hickman R, Darby-Dowman A, et al. A five way crossover human
volunteer study to compare the pharmacokinetics of paracetamol following
oral administration of two commercially available paracetamol tablets
and three development tablets containing paracetamol in combination with
sodium bicarbonate or calcium carbonate. [Eur J Pharm
Biopharm]{.underline} 2000;49:225-229.

Green R, Grierson R, Sitar DS, et al. How long after drug ingestion is
activated charcoal still effective? [Clinical Toxicology]{.underline}
2001;31(6):601-605

Hassig SR, Linscheer WG, Murthy UK, et al. Effects of PEG-electrolyte
(colyte) lavage on serum acetaminophen concentrations: A model for
treatment of acetaminophen overdose. [Dig Dis Sci]{.underline} 1993
Aug;38(8):1395-1401.

Hendrix-Treacy, Wallace SM, Hindmarsh KW, et al. The effect of
acetaminophen administration on its disposition and body stores of
sulphate. [Eur J Clin Pharmacol]{.underline} 1986;30:273-278.

Hindmarsh KW, Mayers DJ, Wallace SM, et al. Increased serum sulfate
concentrations in man due to environmental factors: Effects on
acetaminophen metabolism. [Vet Hum Toxicol]{.underline} 1991
Oct;33(5):441-445.

Hopkins CS, Underhill S, Booker PD. Pharmacokinetics of paracetamol
after cardiac surgery. [Arch Dis Child]{.underline} 1990;65:971-976.

Jorup-Rönström C, Beermann B, Wählin-Boll E, et al. Reduction of
paracetamol and aspirin metabolism during viral hepatitis. [Clin
Pharmacokinet]{.underline} 1986;11:250-256.

Kelley MT, Walson PD, Edge JH, et al. Pharmacokinetics and
pharmacodynamics of ibuprofen isomers and acetaminophen in febrile
children. [Clin Pharmacol Ther]{.underline} 1992 Aug;52(2):181-189.

Kobrinsky NL, Hartfield D, Horner H, et al. Treatment of advanced
malignancies with high-dose acetaminophen and *N*-acetylcysteine rescue.
[Cancer Invest]{.underline} 1996;14(3):202-210.

Koch-Weser J. Medical Intelligence: Drug Therapy. [N Engl J
Med]{.underline} 1976 Dec 2;295(23):1297-1300.

Kohli U, Sharma SK, Agarwal SS, et al. Influence of nutritional status
on acetaminophen metabolism in man. [Indian J Med Res]{.underline} 1982
Feb;75:265-273.

Lauterberg BH, Mitchell JR. Therapeutic doses of acetaminophen stimulate
the turnover of cysteine and glutathione in man. [J Hepat]{.underline}
1987;4:206-211

Lee HS, Ti TY, Koh, YK, et al. Paracetamol elimination in Chinese and
Indians in Singapore. [Eur J Clin Pharmacol]{.underline} 1992;43:81-84.

Levy G, Khanna NN, Soda DM, et al. Pharmacokinetics of acetaminophen in
the human neonate: Formation of acetaminophen glucuronide and sulfate in
relation to plasma bilirubin concentration and D-glucaric acid
excretion. [Pediatrics]{.underline} 1975 June;55(6):818-825.

Levy G. Comparative Pharmacokinetics of aspirin and acetaminophen. [Arch
Intern Med]{.underline} 1981 Feb 23;141:279.

Manyike PT, Kharasch ED, Kalhorn TF, et al. Contribution of CYP2E1 and
CYP3A to acetaminophen reactive metabolite formation. [Clin Pharmacol
Ther]{.underline} 2000 Mar;67(3):275-282.

McNeil Consumer Healthcare Bioequivalence Study Report for Protocol
89-956 (BS-92): A comparison of sustained-release AC caplet formulation
and a conventional tablet formulation under multiple dose conditions.
Fort Washington, PA: McNeil Consumer Healthcare, July 1990. Submitted to
NDA 19-872 Amendment No. 4 on October 29, 1992.

McNeil Consumer Healthcare Bioequivalence Study Report for Protocol
98-054: Bioequivalence determination of extra strength Tylenol gelcaps
and caplets with extra strength Tylenol tablets. Fort Washington PA:
McNeil Consumer Healthcare, May 2001.

McNeil Consumer and Specialty Pharmaceuticals Pharmacokinetic Study for
Protocol 02-161: Tolerability and multiple-dose pharmacokinetics of
acetaminophen (paracetamol) at and above the currently recommended
maximum daily dose. Fort Washington, PA, July 2002 . Data on file.

Milligan TP, Morris HC, Hammond PM, et al. Studies on paracetamol
binding to serum proteins. [Ann Clin Biochem]{.underline} 1994;
31:492-496

Milton AS. Modern views on the pathogenesis of fever and the mode of
action on antipyretic drugs. [J Pharm Pharmacol]{.underline}
1976;28:393-399.

Miners JO, Atwood J, Birkett DJ. Influence of sex and oral contraceptive
steroids on paracetamol metabolism. [Br J Clin Pharmacol]{.underline}
1983;16:503-509

Miners JO, et al. Comparison of paracetamol metabolism in young adult
and elderly males. [Eur J Clin Pharmacol]{.underline} 1988:35:157-160.

Miners JO, Osborne NJ, Tonkin AL, et al. Perturbation of paracetamol
urinary metabolic ratios by urine flow rate. [Br J Clin
Pharmacol]{.underline} 1992;34:359-362.

Mitchell JB, Jollow DJ, Potter WZ. Acetaminophen-induced hepatic
necrosis: I. Role of drug metabolism. [J Pharmacol Exp
Therapeut]{.underline} 1973 Oct;187:185-194.

Mitchell JR, Thorgeirsson SS, Potter WZ, et al. Acetaminophen-induced
injury: Protective role of glutathione in man and rationale for therapy.
[Clin Pharmacol Ther]{.underline} 1974;16:676-684.

Mitchell MC, Hanew T, Meredith CG, et al. Effects of oral contraceptive
steroids on acetaminophen metabolism and elimination. [Clin Pharmacol
Ther]{.underline} 1983 Jul;34(1):48-53.

Nahata MC, Powell DA, Durell DE. Acetaminophen (APAP) kinetics in
infants and children after single and repeated doses. [Eur J Clin
Pharmacol]{.underline} 1984;27:57-59.

Ouellet M, Percival MD. Mechanisms of acetaminophen inhibiton of
cyclooxygenase isoforms. [Archives of Biochemistry and
Biophysics]{.underline} 2001;3987(2):273-280.

Parier JL, Pichard O, Bonhomme L, et al. Bioavailability of paracetamol
according to pharmaceutical form. [J Pharm Belg]{.underline}
1988;43(3):287-291.

Piguet V, Desmeules J, Dayer P. Lack of acetaminophen ceiling effect on
R-III nociceptive flexion reflex. [Eur J Clin Pharmacol]{.underline}
1998 Jan;53(5):321-324.

Piletta P, Porchet HC, Dayer P. Pharmacodynamics and drug action:
Central analgesic effect of acetaminophen but not of aspirin. [Clin
Pharmacol Ther]{.underline} 1991 Apr;49(4):350-354.

Prescott LF. Drug conjugation in clinical toxiology. [Biochem Soc
Trans]{.underline} 1984 Feb;12(1):96-99.

Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. [Br
J Clin Pharmacol]{.underline} 1980;10:291S-298S.

Prescott LF. Paracetamol overdosage: Pharmacological considerations and
clinical management. [Drugs]{.underline} 1983 Mar 25(3):290-314.

[]{.mark}

Prescott LF, Wright N, Roscoe P, et al. Plasma-paracetamol half life and
hepatic necrosis in patients with paracetamol overdosage.
[Lancet]{.underline} 1971 Mar 13;519-522.

Rawlins MD, Henderson DB, Hijab AR, et al. Pharmacokinetics of
paracetamol (acetaminophen) after intravenous and oral administration.
[Eur J Clin Pharmacol]{.underline} 1977;11:283-286.

Rømsing J, Ostergaard D, Senderovitz T, et al. Pharmacokinetics of oral
diclofenac and acetaminophen in children after surgery. [Paediatr
Anaesth]{.underline} 2001 Mar;11(2):205-213.

Rose SR, Gorman RL, Oderda GM, et al. Simulated acetaminophen overdose:
Pharmacokinetics and effectiveness of activated charcoal. [Ann Emerg
Med]{.underline} 1991; 20: 1064-1068.

Rumack BH, Matthews H. Acetaminophen poisoning and toxicity.
[Pediatrics]{.underline}1975 Jun; 55(6):871-6.

Rumack BH. Acetaminophen hepatotoxicity: The first 35 years. [Clinical
Toxicology]{.underline} 2002;40(1):3-20.

Sajahawalla CG, Ayres JW. Multiple-dose acetaminophen pharmacokinetics.
[J Pharm Sci]{.underline} 1991 Sept;80(9):855-860.

Shayiq RM, Roberts DW, Rothstein K, et al. Repeat exposure to
incremental doses of acetaminophen provides protection against
acetaminophen-induced lethality in Mice: An explanation for high
acetaminophen dosage in humans without hepatic injury.
[Hepatology]{.underline} 1999 Feb;29(2):451-463.

Simmons DL, Botting RM, Robertson PM. Induction of an
acetaminophen-sensitive cyclooxygenase with reduced sensitivity to
nonsteroid antiinflammatory drugs. [Proc Natl Acad Sci]{.underline} USA
1999 Mar;96:3275-3280.

Simmons DL. Wagner D, Westover K. Nonsteroidal anti-inflammatory drugs,
acetaminophen, cyclooxygenase2, and fever. [Clin Infect Dis]{.underline}
2000;31(Suppl 5):S211-S218.

Slattery JT, Levy G. Acetaminophen kinetics in acutely poisoned
patients. [Clin Pharmacol Ther]{.underline} 1979 Feb;25(2):184-95.

Slattery JT, McRorie TI, Reynolds R, et al. Lack of effect of cimetidine
on acetaminophen disposition in humans. [Clin Pharmacol
Ther]{.underline} 1989 Nov;46(5):591-597.

Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral
N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of
the national multicenter study (1976 to 1985[). N Engl J
Med]{.underline} 1988 Dec 15;319(24):1557-62.

Stork, CM, Rees S, Howland MA et al. Pharmacokinetics of extended relief
versus regular release Tylenol in simulated human overdose. [Clin
Toxicol]{.underline} 1996;34(2):157-162.

Triggs EJ, Nation RL, Long A, et al. Pharmacokinetics in the Elderly.
[Eur J Clin Pharmaco]{.underline}l 1975;8:55-62.

Vance MV, Selden BS, Clark RF. Optimal patient position for transport
and initial management of toxic ingestions. [Ann Emerg Med]{.underline}
1992 Mar;21(3):243-246.

Walson PD, Galletta G, Braden NJ, et al. Ibuprofen, acetaminophen, and
placebo treatment of febrile children. [Clin Pharmacol Ther]{.underline}
1989 Jul;46(1):9-17.

Wessels JC, Koeleman HA, Boneschans B, et al. The influence of different
types of breakfast on the absorption of paracetamol among members of an
ethnic group. [Int J Clin Pharm Ther Tox]{.underline}
1992;30(6):208-213.

Willer, J C. Comparative study of perceived pain and nociceptive flexion
reflex in man. [Pain]{.underline} 1977;3:69-80.

Willer, J.C. Nociceptive flexion reflexes as a tool for pain research in
man. In: Desmedt JE, Ed. [Advances in neurology: Motor control
mechanisms in health and disease]{.underline}. New York: Raven Press,
1983;809-827.

Wynne HA, Cope LH, Herd B, et al. The association of age and frailty
with paracetamol conjugation in man. [Age Ageing]{.underline} 1990
Nov;19(6):419-424.

Yiamouyiannis CA, Harris A, Sanders RA. Paracetamol Pharmacokinetics are
independent of caloric intake and physical activity. [Drug
Invest]{.underline} 1994; 8(6):361-368.

**[Section 4: Assessment of Acetaminophen Safety]{.underline}**

AAPCC. Toxic Exposure Surveillance System (TESS): TESS exposures treated
with NAC-PO, 1997: Medical outcomes by age (adults lumped). 2001
September 27.

Abernethy DR, Divoll M, Greenblatt DJ, et al. Obesity, sex and
acetaminophen disposition. [Clin Pharmacol Ther]{.underline} June
1982;31(6):783-790.

Al-Obaidy SS, McKiernan PJ, Li Wan Po A, et al. Metabolism of
paracetamol in children with chronic liver disease. [Eur J Clin
Pharmacol]{.underline} 1996;50:69-76.

Altomare E, Leo MA, Sato C, et al. Interaction of ethanol with
acetaminophen metabolism in the baboon. [Biochem Pharmacol]{.underline}
1984;33(14):2207-2212.

Amadio P Jr, Cummings DM: Evaluation of acetaminophen in the management
of osteoarthritis of the knee. [Curr Ther Res]{.underline} 1983
Jul;34(1):59-66.

Anderson GD: A mechanistic approach to antiepileptic drug interactions.
[Ann Pharmacother]{.underline} 1998 May;32:554-563.

Andreasen PB, Hutters L: Paracetamol (acetaminophen) clearance in
patients with cirrhosis of the liver. [Acta Med Scand]{.underline} 1979;
Suppl 624:99-105.

Banda PW, Quart BD. The effect of mild alcohol consumption in the
metabolism of acetaminophen in man. [Res Commun Chem Pathol
Pharmacol]{.underline} 1982 Oct;38(1):57-70.

Bannwarth B, Pehourcq F, Lagrange F, et al. Single and multiple dose
pharmacokinetics of acetaminophen (paracetamol) in polymedicated very
old patients with rheumatic pain. [J Rheumatol]{.underline}
2001;28:182-184.

Bedjaoui A, Demotes-Mainard F, Raynal F, et al. Influence de l'âge et du
sexe sur la pharmacocinétique du paracétamol \[Influence of age and sex
on the pharmacokinetics of paracetamol\]. [Thérapie]{.underline}
1984;39:353-359.

Benson GD. Acetaminophen in chronic liver disease. [Clin Pharmacol
Ther]{.underline} 1983 Jan;33(1):95-101.

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.

Bock KW, Forster A, Gscgaidmeier H, et al. Paracetamol glucuronidation
by recombinant rat and human phenol UDP-glucuronosyltransferases.
[Biochem Pharmacol 1993;]{.underline}45(9):1809-1814.

Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the
reduced expression of bilirubin UDP-glucurononsyltransferase 1 in
Gilbert's Syndrome. N Engl J Med 1995;333(18):1171-1175.

Bradley JD, Brandt KD, Katz BP, et al: Comparison of an antiinflammatory
dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in
the treatment of patients with osteoarthritis of the knee. [N Engl J
Med]{.underline} 1991 Jul 11;325(2):87-91.

Bray GP, Harrison PM, O'Grady JG, et al. Long-term anticonvulsant
therapy worsens outcome in paracetamol-induced fulminant hepatic
failure. [Hum Exp Toxicol]{.underline} 1992;11:265-270.

Briant RH, Dorrington RE, Cleal J, et al. The rate of acetaminophen
metabolism in the elderly and the young. [J Am Geriatr Soc]{.underline}
1976 Aug; 24(6):359-361.

Broughan TA, Soloway RD. Acetaminophen hepatoxcity. [Dig Dis
Sci]{.underline} 2000 Aug;45(8):1553-1558.

Careddu P, Mereu T, Apollonio T. Studies on glucuroconjugation in
infectious hepatitis: Half-life of NAPA as a test of liver function.
[Minerva Pediatr]{.underline} 1961;13:1619 (translation).

Chan MTV, et al. Single-dose pharmacokinetics of paracetamol and its
conjugates in Chinese non-insulin-dependent diabetic patients with renal
impairment. [Eur J Clin Pharmacol]{.underline} 1997;52:285-288.

Chang TK, Yu L, Maurel P, et al. Enhanced cyclophosphamide and
ifosfamide activation in primary human hepatocyte cultures : Response to
cytochrome P-450 inducers and autoinduction by oxazaphosphorines.
[Cancer Res]{.underline} 1997 May;57:1946-1954.

Chien JY, Peter RM, Nolan CM, et al. Influence of polymorphic
N-acetyltransferase phenotype on the inhibition and induction of
acetaminophen bioactivation with long-term isoniazid. [Clin Pharmacol
Ther]{.underline} 1997;61:24-34.

Choffray DU, Crielaard JM, Albert A, et al. Comparative study of high
bioavailability glaphenine and paracetamol in cervical and lumbar
arthrosis. [Clin Rheumatol]{.underline} 1987;6(4):518-525.

Court MH, Duan SX, Von Moltke LL, et al. Interindividual variability in
acetaminophen glucuronidation by human liver microsomes: Identification
of relevant acetaminophen UDP-glucuronosyltransferase isoforms. [J
Pharmacol Exp Ther]{.underline} 2001;299(3):998-1006.

Critchley JA, Cregeen RJ, Balali-Mood M, et al. Paracetamol metabolism
in heavy drinkers. [Br J Clin Pharmacol]{.underline} 1982;13:276P-277P.

Critchley JA, Dyson EH, Scott AW, et al. Is there a place for cimetidine
or ethanol in the treatment of paracetamol poisoning?
[Lancet]{.underline} 1983 Jun;1:1375-1376.

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.

Dargere S, Collet T, Crampon D, et al. Lack of toxicity of acetaminophen
in patients with chronic hepatitis C: A randomized controlled trial.
[Gastroenterology]{.underline} 2000; 118 (4,Suppl.2);A947.

Dart RC, Kuffner EK, Rumack BH. Treatment of pain or fever with
paracetamol (acetaminophen) in the alcoholic patient: A systematic
review. [Am J Therap.]{.underline} 2000;7:123-134.

De Morais SMF, Uetrecht JP, Wells PG. Decreased glucuronidation and
increased bioactivation of acetaminophen in Gilbert's Syndrome.
[Gastroenterology]{.underline} 1992 February;102(2):577-586.

Diaz D, Fabre I, Daujay M, et al. Liver, pancreas, and biliary tract:
Omeprazole in an aryl hydrocarbon-like inducer of human hepatic
cytochrome P450. [Gastroenterology]{.underline} 1990 Sep;99(3):737-747.

Divoll M, Abernathy DR, Ameer B, et al. Acetaminophen kinetics in the
elderly. [Clin Pharmacol Ther]{.underline} 1982a; 31:151-156.

Divoll M, Ameer B, Abernathy DR, et al. Age does not alter acetaminophen
absorption. [J Am Geriatrics Soc]{.underline} 1982b;30:240-244.

Divoll M, Greenblatt DJ, Ameer B, et al. Effect of food on acetaminophen
absorption in young and elderly subjects. [J Clin Pharmacol]{.underline}
1982c Nov/Dec;22:571-576.

Edwards OM, Edwards P, Huskisson RT, et al. Paracetamol and renal
damage. [Br Med J]{.underline} 1971 Apr 10;2:87-89.

Ellmers SE, Parker LRC, Notarianni LJ, et al. Excretion of paracetamol
in fit and frail elderly people. [Proceedings of the BPS]{.underline}
1990:596p-597p.

Epstein MM, Nelson SD, Slattery JT, et al. Inhibition of the metabolism
of paracetamol by isoniazid. [Br J Clin Pharmacol]{.underline}
1991;31:139-142.

Erturk H, Celiker R, Aydin M, et al. Comparison of efficacy of
tolerability of acemetacin and acetaminophen in the treatment of knee
osteoarthritis. [J Rheumatol Med Rehab]{.underline} 1998;9(3):157-161
(translation).

Esteban A, Pérez-Mateo M. Heterogeneity of paracetamol metabolism in
Gilbert's syndrome. [Eur J Drug Metab Pharmacokinet]{.underline}
1990;24(1):9-13.

Faich, GA. Adverse drug reaction monitoring. [N Engl J Med]{.underline}
1986 Jun 12;314(24):1589-1592.

Food and Drug Administration. Drug Induced Liver Toxicity. 2001.
Available at <http://www.fda.gov/cder/livertox/default.html> (accessed
8/29/02).

Forrest JA, Adriaenssens P, Finlayson ND, Prescott LF. Paracetamol
metabolism in chronic liver disease. [Eur J Clin Pharmacol]{.underline}
1979;15:427-431.

Fuhr U. Induction of drug metabolising enzymes: Pharmacokinetic and
toxicological consequences in humans. [Clin Pharmacokinet]{.underline}
2000 Jun;38(6):493-504.

Geba GP, Weaver AL, Polis AB, et al. Efficacy of rofecoxib, celecoxib,
and acetaminophen in osteoarthritis of the knee: A randomized trial.
[JAMA]{.underline} 2002 Jan 2;287(1):64-71.

Goldman SA. Limitations and strengths of spontaneous reports data. [Clin
Ther]{.underline} 1998;20(suppl C):C40-C44.

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.

Hennekens CH, Buring JE. [Epidemiology in Medicine]{.underline}. Boston:
Little, Brown and Company, 1987:16-29.

Henrich WL, Agodoa LE, Barrett B, et al. Analgesics and the kidney:
Summary and recommendations to the Scientific Advisory Board of the
National Kidney Foundation from an Ad Hoc Committee of the National
Kidney Foundation. [Am J Kidney Dis]{.underline} 1996 Jan;27(1):162-165.

Herzenberg LA, DeRosa SC, Dubs JG, et al. Glutathione deficiency is
associated with impaired survival in HIV disease. [Proc Natl Acad Sci
USA]{.underline} 1997 Mar 4;94(5):1967-72.

Hickey RFJ. Chronic low back pain: A comparison of diflunisal with
paracetamol. [N Z Med J]{.underline} 1982;95:312-314.

Hoftiezer JW, O'Laughlin JC, Ivey KJ. Effects of 24 hours of aspirin,
Bufferin, paracetamol and placebo on normal gastroduodenal mucosa.
[Gut]{.underline} 1982;23:692-697.

Jackson CH, MacDonald NC, Cornett JWD. Acetaminophen: A practical
pharmacologic overview. [Can Med Assoc J]{.underline} 1984 Jul
1;131:25-32.

Jewell SA, DiMonte D, Gentile A. Decreased hepatic glutathione in
chronic alcoholic patients. J Hepatol 1986;3:1-6.

[]{.mark}

Johnson PC, Driscoll T. Comparison of plain and buffered aspirin with
acetaminophen in regard to gastrointestinal bleeding. [Current
Therapeutic Research]{.underline} 1981 July;30(1):79-84.

Jorup-Rönström C, Beermann B, Wählin-Boll E, et al. Reduction of
paracetamol and aspirin metabolism during viral hepatitis. [Clin
Pharmacokinet]{.underline} 1986;11:250-256.

Kampffmeyer HG. Failure to detect increased elimination rate of
phenacetin in man after treatment with phenobarbitol. [Klin
Wehr]{.underline} 1969;1237-1238.

Kampffmeyer HG. Elimination of phenacetin and phenazone by man before
and after treatment with phenobarbitol\*. [Eur J Clin
Pharmacol]{.underline} 1971;3(2):113-118.

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 Jan 16;287(3):337-344.

Kjaersgaard-Andersen P, Nafei A, Skov O, et al. Codeine plus paracetamol
versus paracetamol in longer-term treatment of chronic pain due to
osteoarthritis of the hip: A randomised, double-blind, multi-center
study. [Pain]{.underline} 1990;43(3):309-318.

Koch-Weser J. Medical Intelligence: Drug Therapy. [N Engl J
Med]{.underline} 1976 Dec 2;295(23):1297-1300.

Kohli U, Sharma SK, Agarwal SS, et al. Influence of nutritional status
on acetaminophen metabolism in man. [Indian J Med Res]{.underline} 1982
Feb;75:265-273.

Kroner K, Hansen TB, Harving S, et al. Individually dosed codeine plus
paracetamol versus paracetamol in long-treatment of chronic pain due to
arthrosis of the hip: A randomised, double-blind, multicenter study.
[Acta Orthop Scand]{.underline} 1991;62(suppl 246):43.

Kuffner EK, Bogdan GM, Dart RC. Evaluation of hepatotoxicity in
alcoholics from therapeutic dosing of acetaminophen. [J
Toxicol]{.underline} 1997;35(5):561.

Kuffner EK, Dart RC, Bogdan GM, et al. Effect of maximal daily doses of
acetaminophen on the liver of alcoholic patients: A randomized,
double-blind, placebo-controlled trial. [Arch Intern Med]{.underline}
2001 Oct 8;161(18):2247-2252.

Langman MJS, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer
associated with individual non-steroidal anti-inflammatory drugs.
[Lancet]{.underline} 1994 April 30;343:1075-1078

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.

Lauterberg BH. Analgesics and glutathione. [Am J Ther]{.underline}
2002;9(3):225-233.

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

Lehmann JM, McKee DD, Watson MA, et al. The human orphan nuclear
receptor PXR is activated by compounds that regulate CYP3A4 gene
expression and cause drug interactions. J Clin Invest 1998 Sept;
102(5):1016-1023.

Lesko SM, Mitchell AA. An assessment of the safety of pediatric
ibuprofen: A practitioner-based randomized clinical trial.
[JAMA]{.underline} 1995 Mar 22/29;273(12):929-933.

Lequensne M, Fannius J, Reginster JY, et al. Floctafenin versus
acetaminophen for pain control in patients with osteoarthritis in the
lower limbs. [Rev Rhumatis]{.underline} 1997;64(5):327-333.

Lieber CS. Cytochrome *P*-4502E1: Its physiological and pathological
role. [Physiol Rev]{.underline} 1997 Apr;77(2):517-544.

Lieber CS: Microsomal ethanol-oxidizing system (MEOS): The first 30
years (1968-1998) \-- A review. [Alcohol Clin Exp Res]{.underline}.
1999;23(6):991-1007.

Litovitz TL, Klein-Schwartz W, Caravati EM, et al. 1998 annual report of
the American Association of Poison Control Centers Toxic Exposure
Surveillance System. [Am J Emerg Med]{.underline} 1999 Sep;17(5):435-87.

Litovitz TL, Klein-Schwartz W, Dyer KS, et al. 1997 annual report of the
American Association of Poison Control Centers Toxic Exposure
Surveillance System. [Am J Emerg Med]{.underline} 1998
Sep;16(5):443-497.

Litovitz TL, Klein-Schwartz W, White S, et al. 1999 annual report of the
American Association of Poison Control Centers Toxic Exposure
Surveillance System. [Am J Emerg Med]{.underline} 2000
Sep;18(5):517-574.

[]{.mark}

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

[]{.mark}

Litovitz TL, Smilken M, Felberg L, et al. 1996 annual report of the
American Association of Poison Control Centers Toxic Exposure
Surveillance System. [Am J Emerg Med]{.underline} 1997
Sep;15(5):447-500.

[]{.mark}

Lowenthal DT, Øie S, Van Stone JC, et al. Pharmacokinetics of
acetaminophen elimination by anephric patients. [J Pharmacol Exp
Ther]{.underline} 1976;196(3):570-578.

Makin AJ, Wendon J, Williams R. A 7-year experience of severe
acetaminophen-induced hepatotoxicity (1987-1993).
[Gastroenterology]{.underline} 1995;109:1907-1916.

Makin A, Williams R. Paracetamol hepatotoxicity and alcohol consumption
in deliberate and accidental overdose. [Quarterly Journal of
Medicine.]{.underline} 2000;93(6):341-349.

Manyike PT, Kharasch ED, Kalhorn TF, et al. Contribution of CYP2E1 and
CYP3A to acetaminophen reactive metabolite formation. [Clin Pharmacol
Ther]{.underline} 2000 Mar;67(3):275-282.

Martin U, et al. The disposition of paracetamol and the accumulation of
its glucuronide and sulphate conjugates during multiple dosing in
patients with chronic renal failure. [Eur J Clin Pharmacol]{.underline}
1991; 1:43-46.

Martin U, et al. The disposition of paracetamol and its conjugates
during multiple dosing in patients with end-stage renal failure
maintained on haemodialysis. [Eur J Clin Pharmacol]{.underline}
1993;45:141-145.

Matsika MD, Moore N. Intentional drug overdoses: Validity of the
information sources on drugs in comparison with plasma data.
[Thérapie]{.underline} 1999;54:273 (abstract).

Matts SGF, Boston PF. Paracetamol plus metoclopramide (Paramex) as an
adjunct analgesic in the treatment of arthritis. [Curr Med Res
Opin]{.underline} 1983;8(8):547-552.

McGuinness BW, Lloyd-Jones M, Fowler PD. A double-blind comparative
trial of Parazolidin and paracetamol. [Br J Clin Prac]{.underline}
1969;23:452-455.

McMahon GT, McGarry K. Deliberate self-poisoning in an Irish county
hospital. [Ir J of Med Sci]{.underline} 2001;170(2):94-97.

McNeil Consumer Healthcare. [NDA 19-872: Correspondence: APAP ADE
Data]{.underline} 2000 December 20.

Miners JO, Atwood J, Birkett DJ. Determinants of acetaminophen
metabolism: Effect of inducers and inhibitors of drug metabolism on
acetaminophen's metabolic pathways. [Clin Pharmacol Ther]{.underline}
1984 Apr;35(4):480-486.

Miners JO, et al. Comparison of paracetamol metabolism in young adult
and elderly males. [Eur J Clin Pharmacol]{.underline} 1988:35:157-160.

Mitchell JR, Thorgeirsson SS, Potter WZ, et al. Acetaminophen-induced
injury: Protective role of glutathione in man and rationale for therapy.
[Clin Pharmacol Ther]{.underline} 1974;16:676-684.

Miwa LJ, Jones JK, Pathiyal A, et al. Value of epidemiologic studies in
determining the true incidence of adverse events: The non-steroidal
anti-inflammatory drug story. [Arch Intern Med]{.underline} 1997 Oct
13;157(18):2129-36.

Montague RE, Grace, RF, Lewis JH, et al. Urine drug screens in overdose
patients do not contribute to immediate clinical management. [Ther Drug
Monit]{.underline} 2001;23(1):46-50.

Neuvonen PJ, Lehtovaara R, Bardy A, et al. Antipyretic analgesics in
patients on antiepileptic drug therapy. [Eur J Clin
Pharmacol]{.underline} 1979;15:263-268.

O'Shea D, Davis SN, Kim RB, et al. Effect of fasting and obesity in
humans on the 6-hydroxylation of chlorzoxazone: a putative probe of
CYP2E1 activity. [Clin Pharmacol Th]{.underline}er 1994 Oct;56(4):359-67

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

Øie S, Lowenthal DT, Briggs WA, et al. Effect of hemodialysis on
kinetics of acetaminophen elimination by anephric patients. [Clin
Pharmacol Ther]{.underline} 1975 Dec;18(6):680-686.

Olfson M, Marcus S, Druss B, et al. National trends in the outpatient
treatment of depression. [JAMA]{.underline} 2002;287:203-209

Omiecinski CJ, Remmel RP, Hosagrahara VP. Concise review of cytochrome
P450s and their roles in toxicology. [Toxicological
Sciences]{.underline} 1999;48:151-156.

Ostapowicz G, Fontana RJ, Navarro VJ, et al. Use of liver
transplantation in patients with acute liver failure.
[Hepatology]{.underline} 2000;32(4 pt 2):215A.

Parkinson A. Biotransformation of xenobiotics. In: Klaassen CD, ed.
[Casarett & Doull's Toxicology: The Basic Science of Poisons. 5^th^
ed]{.underline}. New York: McGraw-Hill; 1996:113-186.

Perucca E, Richens A. Paracetamol disposition in normal subjects and
patients treated with antiepileptic drugs. [Br J Clin
Pharmacol]{.underline} 1979;7:201-206.

Peura DA, Lanza FL, Gostout CJ, et al. The American College of
Gastroenterology bleeding registry: Preliminary findings. [Am J
Gastroenterol]{.underline} 1997 Jun;92(6):924-928.

Pichard L, Fabre I, Fabre G, et al. Cyclosporin A drug interactions:
Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A
oxidase) in primary cultures of human hepatocytes and in liver
microsomes. [Drug Metab Dispos]{.underline} 1990;18:595-606.

Pohjola-Sintonen S, Kivisto KT, Vuori E, et al. Identification of Drugs
ingested in acute poisoning: Correlation of patient history with drug
analyses. [Ther Drug M]{.underline}onit 2000;22(6):749-752.

Prescott L. Paracetamol: A critical bibliographic review. London: Taylor
and Francis, Ltd;1996:231.

Prescott LF, Critchley JH, Balali-Mood M, et al. Effects of microsomal
enzyme induction on paracetamol metabolism in man. [Br J Clin
Pharmacol]{.underline} 1981;12:149-153.

Prescott LF, Mattison P, Menzies DG, et al. The comparative effects of
paracetamol and indomethacin on renal function in healthy female
volunteers. [Br J Clin Pharmacol]{.underline} 1990;29:403-412.

Prescott L, Speirs GC, Critchley JA, et al. Paracetamol disposition and
metabolite kinetics in patients with chronic renal failure. [Eur J Clin
Pharmacol]{.underline} 1989;36:291-297.

Price VF, Jollow DJ. Mechanism of decreased acetaminophen
glucuronidation in the fasted rat. [Biochem Pharmacol]{.underline}
1988;37(6):1067-1075.

Radu P, Atsmon J. Gilbert's Syndrome: Clinical and pharmacological
implications. [IMAJ]{.underline} 2001 August;3:593-598.

Report of CIOMS Working Group IV. Benefit-risk balance for marketed
drugs: evaluating safety signals. 1998.

Rexrode KM, Buring JE, Glynn RJ, et al. Analgesic use and renal function
in men. [JAMA]{.underline} 2001 Jul 18;286(3):315-321.

Rost KL, Brösicke H, Brockmöller J, et al. Increase of cytochrome
P450IA2 activity by omeprazole: Evidence by the
^13^C-\[N-3-methyl\]-caffeine breath test in poor and extensive
metabolizers of *S*-mephenytoin. [Clin Pharmacol Ther]{.underline} 1992
Nov;52(2):170-180.

Rumack BH. Acetaminophen hepatotoxicity: The first 35 years. [Clinical
Toxicology]{.underline} 2002;40(1):3-20.

Sarich T, Kalhorn T, Magee S, et al. The effect of omeprazole
pretreatment on acetaminophen metabolism in rapid and slow metabolizers
of *S*-mephenytoin. [Clin Pharmacol The]{.underline}r 1997
Jul;62(1):21-28.

Sato C, Lieber CS. Mechanism of the preventive effect of ethanol on
acetaminophen-induced hepatotoxicity. [J Pharmacol Exp Ther]{.underline}
1981;218:811-815.

Schenker S, Speeg KV, Perez A, Finch J: The effects of food restriction
in man on hepatic metabolism of acetaminophen. [Clinical
Nutrition]{.underline} 2001;20(2):145-150.

Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an
urban county hospital. [N Engl J Med]{.underline} 1997;337:1112-1117.

Schmid R, Hammaker L. Glucuronide formation in patients with
constitutional hepatic dysfunction (Gilbert's Disease). [N Engl J
Med]{.underline} 1959 June 25;260(26):1310-1314.

Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB.
Acetaminophen hepatotoxicity in alcoholics: a therapeutic misadventure.
[Ann Intern Med]{.underline} 1986;104:399-404.

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, Fries JF. Famotidine to prevent peptic ulcer caused by NSAIDS.
[N Engl J Med]{.underline} 1996 Oct 24;335(17):1322-1323.

Singh G, Triadafilopoulos G. Epidemiology of NSAID induced
gastrointestinal complications. [J Rheumatol Suppl]{.underline}
1999;26(56):18-25.

Skinner MH, Matano R, Hazle W, Blaschke TF. Acetaminophen metabolism in
recovering alcoholics. [Methods Find Exp Clin Pharmacol]{.underline}
1990;12:513-515.

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.

Sorenson HT, Mellamkjer L, Blot WJ, et al. Risk of upper
gastrointestinal bleeding associated with use of low-dose aspirin. [Am J
Gastroenterol]{.underline} 2000 Sep; 95(9): 2218-24.

Spielberg SP. Acetaminophen toxcity in lymphocytes heterozygous for
glutathione synthetase deficiency. [Can J Physiol Pharmacol]{.underline}
1985;63:468-471.

Spielberg SP, Gordon GB. Glutathione synthetase deficient lymphocytes
and acetaminophen toxicity. [Clin Pharmacol Ther]{.underline}
1981;29:51-55.

Spooner JB, Harvey JG. Paracetamol overdose: Facts not misconceptions.
[Pharm J]{.underline} 1993;252:706-707.

Stang PE, Fox JL. Adverse drug events and the Freedom of Information
Act: An apple in Eden. [Ann Pharmacother]{.underline} 1992
Feb;26(2):238-243.

Stein D, Peri T, Edelstein E, et al. The efficacy of amitriptyline and
acetaminophen in the management of acute low back pain.
[Psychosomatics]{.underline} 1996;37(1):63-70.

Thummel KE, Slattery JT, Ro H, Chien JY, Nelson SD, Lown KE, Watkins PB.
Ethanol and production of the hepatotoxic metabolite of acetaminophen in
healthy adults. [Clin Pharmacol Ther]{.underline} 2000;67(6):591-599.

Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions
involving human CYP3A. [Annu Rev Pharmacol Toxicol]{.underline}
1998;38:389-430.

Tomlinson R, Young RP, Ng MCY, et al. Pharmacokinetics and disposition:
Selective liver enzyme induction by carbamazeine and phenytoin in
Chinese epileptics. [Eur J Clin Pharmacol]{.underline} 1996;50:411-415

Triggs EJ, Nation RL, Long A, et al. Pharmacokinetics in the Elderly.
[Eur J Clin Pharmaco]{.underline}l 1975;8:55-62.

Ullrich D, Sieg A, Blume R, et al. Normal pathways for glucuronidation,
sulphation and oxidation of paracetamol in Gilbert's syndrome. [Eur J
Clin Invest]{.underline} 1987;17:237-240.

Villeneuve JP, Raymond G, Bruneau J, Colpron L, Pomier-Layrargues G.
Pharmacokinetics and metabolism of acetaminophen in normal, alcoholic,
and cirrhotic subjects. [Gastroenterol Clin Biol]{.underline}
1983;7:898-902.

Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with
fasting and ethanol use. [JAMA]{.underline} 1994 Dec;272(23):1845-1850.

Williams HJ, Ward JR, Egger MJ, et al. Comparison of naproxen and
acetaminophen in a two-year study of treatment of osteoarthritis of the
knee. [Arthritis Rheum]{.underline} 1993;36(9):1196-1206.

Wright N, Prescott LF. Potentiation by previous drug therapy of
hepatotoxicity following paracetamol overdosage. [Scot Med
J]{.underline} 1973; 18:56-58.

Wynne HA, Cope LH, Herd B, et al. The association of age and frailty
with paracetamol conjugation in man. [Age Ageing]{.underline} 1990
Nov;19(6):419-424.

Xiaodong S, Gatti G, Bartoli A. Omeprazole does not enhance the
metabolism of phenacetin, a marker of CYPIA2 activity, in healthy
volunteers. [Ther Drug Monit]{.underline} 1994;16:248-250.

Zand R, Nelson SD, Slattery JT, et al. Inhibition and induction of
cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. [Clin
Pharmacol Ther]{.underline} 1993; 54:142-149.

Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity
with regular intake of alcohol: analysis of instances of therapeutic
misadventure. [Hepatology]{.underline} 1995;22:767-773.

**[Section 5: Consumer Medication Use Behaviors]{.underline}**

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. 2002 January. (Available at
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 6: McNeil Initiatives and Recommendations]{.underline}**

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

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.

Temple AR. Pediatric Dosing of Acetaminophen. [Pediatric
Pharmacology]{.underline} 1983;3:321-327.

[^1]: Agency for Healthcare Research and Quality \[2001\]; World Health
    Organization \[1990\]; Veterans Health Administration \[1999\];
    Washington State \[1999\].

[^2]: American Academy of Pediatrics \[2000\]; American College of
    Radiology \[1999\]; American Geriatric Society \[1998\]; American
    Medical Directors Association \[1999\]; American Pain Society
    \[1999\]; American Society of Anesthesiologists \[1997\]; American
    Academy of Orthopedic Surgeons \[1996\]; Silberstein \[1999\].

[^3]: BenDebba \[1997\]; Carr \[1999\]; Casten \[1995\]; Cousins
    \[1994\]; Desbiens \[1997\]; Dworkin \[1997\]; Foley \[1995\];
    Gottschalk \[1998\]; Heim \[1993\]; Katz \[1995, 1996\]; Liebeskind
    \[1991\]; Linton \[1997\]; Liu \[1995\]; McCaffrey \[1999\]; Page
    \[1996\]; Sheehan \[1996\]; Tasmuth \[1995\].

[^4]: Ferrell \[1994\]; Furdon \[1998\]; Grant \[1995\]; Gureje
    \[1998\]; Riley \[1996\].

[^5]: Total pain relief over four hours.

[^6]: concentration that elicits 50% of the maximum drug response

[^7]: Bedjaoui \[1984\]; Rawlins \[1977\]; Ameer \[1983\]; Divoll
    \[1982a,b,c\]; Hindmarsh \[1991\]; Grattan \[2000\]; Jorup-Ronstrom
    \[1986\]; Kohli \[1982\]; Miners \[1988\]; Parier \[1988\];
    Yiamouyiannis \[1994\]; Mitchell \[1983\]; Borin \[1989\];
    Sajahawalla \[1991\]; Douglas \[1996\]; Stork \[1996\];
    Christophersen \[2002\]; Green \[2001\].

[^8]: Pain relief rating scale: 0=none; 1=a little; 2=some; 3=a lot;
    4=complete. Displayed scores based on last observation carried
    forward analysis.

[^9]: Triggs \[1975\], Briant \[1976\], Divoll \[1982a,b,c\], Bedjaoui
    \[1984\], Miners \[1988\], Bannwarth \[1992\]

[^10]: Nahata \[1984\], Walson \[1989\], Brown \[1992\], Kelley
    \[1992\], Romsing \[2001\]

[^11]: Therapeutic doses of 650 and 1000 mg correspond by body weight to
    13 and 20 mg/kg, respectively, for a 50 kg (110 lb) person, and 8.7
    and 13.3 mg/kg for an 75 kg person (165 lb).

[^12]: Acetaminophen doses evaluated in the pharmacokinetics studies
    were administered to subjects in one of two ways: (1) a specific
    number of tablets, equal to 5 g for example, which results in a
    range of mg/kg doses, or (2) a specific mg/kg dose, equal to 75
    mg/kg for example, which results in a range of tablets or grams
    based on each subject's body weight.

[^13]: During the 1980s, N-acetylcysteine (NAC) was developed and then
    approved by FDA as an effective treatment for substantial acute
    acetaminophen overdose. NAC works by interacting with the toxic
    intermediate metabolite, NAPQI. The trade name for commercial NAC is
    Mucomyst.

[^14]: Bedjaoui \[1984\], Rawlins \[1977\], Ameer \[1983\], Divoll
    \[1982a,b,c\], Hindmarsh \[1991\], Grattan \[2000\], Jorup-Ronstrom
    \[1986\], Kohli \[1982\], Miners \[1988\], Parier \[1988\],
    Yiamouyiannis \[1994\], Mitchell \[1983\], Borin \[1989\],
    Sajahawalla \[1991\], Douglas \[1996\], Stork \[1996\],
    Christophersen \[2002\], Green \[2001\].

[^15]: Mitchell et al \[1974\] rounded the amount of NAPQI generated
    from 4.2 to 4 mmol in their calculations (70% of 6 mmol equals 4.2
    mmol). In a recent review article by Rumack \[2002\], 4.2 mmol NAPQI
    is used in the same calculations, resulting in a 15.9 g
    acetaminophen dose taken all at once in an overdose.

[^16]: Estimate for a 70 kg person.

[^17]: 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.