# Presentation: 217065

## Assessment of AcetaminophenSafety and Efficacy

**FDA Advisory Committees**
**September 19, 2002**

## Introduction

- Debra L. Bowen, MD
- Vice President, R&D
- McNeil Consumer & Specialty Pharmaceuticals

## Objectives

**Provide context for committee consideration of acetaminophen safety.**
**Provide the science supporting McNeil’s view that acetaminophen is safe at recommended doses for the general population and special populations.**
**Provide data and databases that underscore acetaminophen safety.**
**Review steps we are taking to minimize very rare unintentional product misuse****.**

## Context for Consideration

**Available OTC for over 40 years.**
**>100 million users per year in US.**
**Harm is rare.**

## Issue Statement

**Hepatotoxicity may result from  very high doses when not treated early with the antidote, NAC.**
** **
**In very rare cases, consumers inadvertently overuse acetaminophen products.**

## Analgesic Science

**Pharmacology and toxicology**
**Clinical and epidemiological data**
**Spontaneous reports and cases**
**Consumer Use Practices**
**Underlying attitudes**
**Reported product use**

## McNeil Actions: Overdose

**Initiated NAC IND**

**1978**

**1979 to present**

**Funded support for Poison Center and developed OD treatment information**

**Tamper-evident packaging**

**1982**

**Funded support for development of NAC**

**Replaced capsules with tamper-resistant caplet formulation**

**Voluntarily added concomitant use statement and proposed alcohol warning**

**1986**

**1994**

**1985**

**Introduced SAFE-TY-LOCK**

**1999**

## McNeil Actions: “Unintentional Misuse”

**Labeling Changes**
**Prescription and OTC products**
**Pediatric products**
**Consumer Education **
**“****Know Your Medicine”**
**“****Be MedWise” Grant**
**Healthcare Professional Education**
**American Academy of Family Physicians**
**American Pharmaceutical Association**

## Today’s Scientific Experts

**John Slattery, PhD****	****    ****	****	****	****Metabolism and ****	****	**
**Professor of Pharmaceutics****	****	****	**** Pharmacokinetics**
**Richard Dart, MD, PhD****    ****	****	****	****Acetaminophen Safety**
**Professor, Surgery, Medicine, and Pharmacy**
**Director, Rocky Mountain Poison & Drug Center**
**Raymond Koff, MD****	****    ****	****	****	****Use in Liver Disease**
**Professor, Medicine and Director, ****Clinical Hepatology Research**
**Daniel Carr, MD****	****    ****	****     ****	****	****Analgesic Benefit****	**
**Professor, Pain Research**
**Anthony Temple, MD****	****     ****	****	****Questions & Answers **
**Vice President, Medical and Regulatory Sciences****McNeil Consumer and Specialty Pharmaceuticals**
**	**

## Conclusions

**Data from many sources support the safety of acetaminophen.**
**Science completely supports the current recommended dose. **
**True for both general and special populations.**
**Current recommended dose is needed for safety and efficacy.**
**Risk management interventions must focus on misuse, and consider health outcomes of changes in utilization.**

## Acetaminophen Metabolism and Pharmacokinetics

**John Slattery, PhD**
**Professor, Department of Pharmaceutics**
**University of Washington**

## Acetaminophen Metabolism and Hepatotoxicity 

**Acetaminophen**

**OH**

**O**
**||**
**HN-C-CH****3**

**O**
**||**
**HN-C-CH****3**

**Glucuronide**

**O**
**||**
**HN-C-CH****3**

**Sulfate**

**Cysteine & Mercapturic Acid Conjugates**

**Glutathione**

**Reactive**
**Metabolite**
**(NAPQI)**

**OH**

**O**
**||**
**HN-C-CH****3**

**Cytochrome P450 2E1**

**Glutathione**

**Active Repletion Process**

**25% - 36%**

**47% - 62%**

**4.8% - 8.0%**

## Acetaminophen Metabolism 

**Threshold phenomenon**
**Need 70-80% depletion of hepatic glutathione before any toxicity**
**Not toxic at recommended doses**

## Acetaminophen Oxidation to NAPQI

- ||

- |

- N

- CH3

- C

- |

- O

- O

- CYP2E1

- CYP1A2

- CYP3A4

- GSH

- NAPQI

- APAP

- GSH Conjugates
- (APAP-3-SR)

- glucuronide, sulfate, catechol metabolites

## Contribution of CYP2E1, 1A2 and 3A4 to the Formation of NAPQI in Human Liver Microsomes

**All incubations contained 0.05% v/v methanol**
**a****DDC = 150 μM Diethyldithiocarbamate; ****b****FF = 25 μM Furafylline; ****c****TAO = 100 μM Trolcandomycin**

**Acetaminophen conc (mM*****)***

***(% Inhibition of NAPQI Formation******)***

**2.0**
**43 ± 4**
**52 ± 1**
**     ****7 ± 0.2**
**53 ± 4**
**16 ± 9**
**  ****4 ± 5**

**0.1**
**35 ± 3**
**44 ± 3**
**12 ± 8**
**37 ± 1**
**12 ± 1**
**  ****8 ± 4**

**Target CYP**
**2E1**
**1A2**
**3A4**
**2E1**
**1A2**
**3A4**

**Inhibitor**
**DDC****a**
**FF****b**
**TAO****c**
**DDC**
**FF**
**TAO**

**Liver**
**H105**
**H108**

## Omeprazole on Caffeine and Acetaminophen

********P  *****< 0.001**

**Omeprazole, 40 mg/d for 7 days**
**4 rapid, 4 slow mephenytoin metabolizers by phenotype and *****CYP2*****C19**
**No alcohol for 1 week before to study end**** **

**Caffeine Cl,****L/kg/hr**
**Cl****f****, APAP****thiols, L/kg/hr**

**- Omep**
**0.13 ± 0.03**
**0.019 ± 0.005**

**+ Omep**
**0.13 ± 0.02**
**0.019 ± 0.005**

**- Omep**
**0.08 ± 0.01**
**0.014 ± 0.002**

**+ Omep**
**0.14* ± 0.01**
**0.015 ± 0.002**

**Rapid Metabolizers**

**Slow Metabolizers**

## Rifampin on Acetaminophen

**Rifampin 600 mg/d for 7 days**
**Alcohol for 1 week before and to end of study**
**n = 8**

**Cl****f****, APAP thiols, L/kg/hr**

**- Rifampin**
**0.036 ± 0.011 **

**+ Rifampin**
**0.040 ± 0.012**

## Disulfiram on Acetaminophen

**500 mg disulfiram 10 hr before APAP**
**No alcohol 1 week before to 1 week after study**
**n = 8**

***P *****< 0.01**

**Cl****f****, APAP thiols, L/kg/hr**

**- Disulfiram**
**0.039 ± 0.023**

**+ Disulfiram**
**0.010 ± 0.003**

## Concomitant DrugsP450 Isoenzymes

**CYP2E1 is primarily responsible for conversion of acetaminophen to NAPQI**
**CYP3A4 and CYP1A2 play negligible roles in metabolism of acetaminophen**

## Induction of CYP2E1 Stabilization Through Occupation of Active Site

**Induction of CYP2E1 Stabilization Through Occupation of Active Site**

- S

- S

- S

- I

- +

- I

- I

- I

## Time-Course: Inhibition & Induction NAPQI Formation by Ethanol

**Time-Course: Inhibition & Induction ****NAPQI Formation by Ethanol**

- 0

- 5

- 10

- 15

- 20

- 25

- Time (hr)

- 1.6

- 1.4

- 1.2

- 0.6

- 100 mg/dL
- EtOH

- 1.0

- 0.2

- 0.4

- 0.8

*CYP2*E1 t 1⁄2

## Gilbert’s Syndrome: Genetic deficiency of UGT1A1

**UGT1A6 is predominant in acetaminophen glucuronidation**
**K****m**** = 2.2 mM (C****max**** @ ****~****20g dose), **
**1A1 and 1A9 are minor ****(Court et al, JPET 2001)**** **
**If UGT1A1 is gone ****(****@**** 0.5 mM, or ****~ 5g dose)**
**NAPQI increases from 6.4% of dose to 7.3%**** **
**Overall APAP-G formation variability in 56 HLM was 15 fold**

## Acetaminophen Multiple-Dose Pharmacokinetics and Metabolism

**Healthy adults 4, 6 or 8 grams per day for three days (divided at 6 hr intervals)**
**n = 12/group active, 6/group placebo**

**Notes:**
 h intervals)

## Acetaminophen Time Course 

**4 g/day**

**8 g/day**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**Time (h)**

**APAP **
**(********g/mL)**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**Time (h)**

**APAP **
**(********g/mL)**

## Fraction of Dose in Urine 

**-60**

**-40**

**-20**

**0**

**20**

**40**

**60**

**APAP Dose per Day**

**% Change****Relative****to 4 g/Day**

**6 g**

**8 g**

**0.0**

**0.2**

**0.4**

**0.6**

**0.8**

**4 g**

**6 g**

**8 g**

**APAP Dose per Day**

**Fraction**
**of Dose**
**in Urine**

**G**

**S**

**T**

**A**

**G**

**S**

**T**

**A**

**G**

**S**

**T**

**A**

**G**

**S**

**T**

**A**

**G**

**S**

**T**

**A**

## Formation Clearances 

**Formation Clearances **

**-60**

**-40**

**-20**

**0**

**20**

**40**

**60**

**APAP Dose per Day**

**% Change****Relative****to 4 g/Day**

**6 g**

**8 g**

**0.24**
**0.20**
**0.16**
**0.12**
**0.08**
**0.04**
**0.00**

**4 g**

**6 g**

**8 g**

**APAP Dose per Day**

**Clearance****(L/h/kg)**

**G**

**S**

**T**

**A**

**G**

**S**

**T**

**A**

**G**

**S**

**T**

**A**

**G**

**S**

**T**

**A**

**G**

**S**

**T**

**A**

## Summary: Acetaminophen Metabolism and Pharmacokinetics 

**NAPQI formed by CYP2E1**
**Modulation of other CYPs is unimportant **
**Toxicity follows substantial GSH depletion**
**Mitochondrial pool is critical**
**Absence of UGT1A1 (Gilbert’s) is not a significant risk factor **
**Does not accumulate on multiple doses up to 8 g/d**

## Assessment of Acetaminophen Safety

**Richard C. Dart, MD, PhD**
**Director, Rocky Mountain Poison and Drug Center**
**Professor, Surgery, Medicine, and Pharmacy**
**University of Colorado **

## Today’s Topics

**Acute Substantial Acetaminophen Overdose**
**Data Sets of Reported Overdose and Misadministrations**
**Chronic Alcohol Use**
**Repeated Supratherapeutic Overdose**** **

## Single Large Overdoses: Up to 9.1 Grams

**Study**
**Christophersen ****[2002]**
**Green ****[2001]**
**Hassig ****[1993]**
**Rose ****[1991]**
**Douglas ****[1996]**
**Stork ****[1996]**
**Vance ****[1992]**

**Gender****M/F**
**5/7**
**7/3**
**12**
**10/0**
**7/7**
**7/3**
**6/6**

**Weight****(kg)**
**71.8**
**77.4**
**N/A**
**73**
**67.8**
**73**
**N/A**

**Dose (g)****(Range)**
**3.6****(2.8****–5.3)**
**4.0****(na****)**
**4.0****(na****)**
**5.0****(na****)**
**5.6****(4.2****–7.8)**
**5.7****(3.8****–7.2)**
**6.1****(4.1****–9.1)**

**T****1⁄2**** (hrs)**
**2.2**
**2.3****(0.6)**
**N/A**
**2.6****(0.3)**
**2.6****(0.4)**
**2.6****(0.9)**
**N/A**

## Dose Relative to Risk and Treatment Lines of Acetaminophen Nomogram 

## FDA-Selected AERS Data Set 

**FDA identified set of AERS reports **
**January 1998 through March 2001 **
**Acetaminophen as suspect therapy **
**Hepatic adverse events with serious outcome**
**Events occurred over approximately 25 years**
**307 reports identified**
**281 adult reports**
**25 pediatric reports**
**1 report did not involve acetaminophen**

## Limitations to Case Reports

**Causality cannot be ascertained using retrospective data**
**History of dose is often inaccurate**
**Inherent clinical bias**
**to omit intentional overdose**
**to report unusual cases (e.g. low reported dose) **
**to  truncate evaluation (e.g. work-up bias)**

## Expert Review Panel

**Richard Dart, MD, PhD****	****EM, Toxicology**
**Gordon Benson, MD****	****Hepatology**
**Martin Caravati, MD****	****EM, Toxicology**
**Raymond Koff, MD****	****	****Hepatology**
**Victor Navarro, MD****	****	****Hepatology**
**Kent Olson, MD****	****	****EM, Toxicology**
**Barry Rumack, MD****	****	****Peds, Toxicology**
**Donna Seger, MD****	****	****EM, Toxicology**
**K.V. Speeg, MD, PhD****	****Hepatology**

## Expert Review Panel

**281 FDA AERs Cases**
**Adults**

**Panel Training**
**Standardized Data Collection Instrument**

**Panel Case Review – Clinical Judgement**

**Panel Consensus Meeting**
**Assigned Probability of Association with APAP:**
**Definite, Probably, Possibly, Unlikely, Definitely Not, Insufficient Information**

## Consensus Probabilities Expert Review Panel 

**Number****of reports**

**Probability Category**

**N = 281 adult reports**

## Expert Panel Review FDA AERS Adult Reports

**Most definite/probable cases were considered to be associated with substantial overdoses.**
**More often, definite/probable cases spontaneously reported alcohol and alcohol abuse.**

## Pediatric Reports FDA AERS Data Set

**25 reports identified by FDA AERS were pediatric reports**
**4 involved unintentional single ingestion**
**3 involved maternal overdoses**
**18 involved misadministration; most reported children < 2 years of age **

## Putative Risk Subsets

**History of Liver Disease**
**Co-ingestion of Hepatotoxic Medications**
**Ethanol Use **

## Chronic Alcohol UseKuffner and Dart 2001

**Randomized, double-blinded, ****placebo-controlled trial**
**Alcoholic patients received acetaminophen 1000 mg or placebo 4 times daily for 2 days**
**All currently drinking by history **** **
**50% drinking >20 yrs**
**1/3 with low body mass index**
**No statistically significant differences in mean AST, ALT or INR at 2 and 4 days for acetaminophen group compared to placebo**
**Additional study underway**

## Repeated Supratherapeutic Ingestion (RSI): Prospective Study

**O’Malley 2000, Daly submitted**

**Call to RMPDC (n=194,927)**
**Acetaminophen calls (n=7298)**

**Acute Single Exposure**
**n=7021**

**Repeated Supratherapeutic Ingestion**
**n=277**

**Enrolled**
**249**

**Declined**
**n=28**

**Acetaminophen level > 10 mg/L**
**AST > 50 IU/L**

**Yes**
**Treat with Aceytlcysteine**

**No**
**Discharge**

**Followup Over 72 hours**
**Validation of History**

## Outcome of RSI Study

***ULN = Upper Limits of Normal**

## RSI Study: Dose and Duration are  Related to Peak AST Level

**Dose (g/24 hr)**
**Duration ****(24 hr periods)**

***ULN = Upper Limits of Normal**

## Distribution of APAP-Associated Deaths by Liver Condition

**58**

**318**

**61**

**Acute liver toxicity**

**Chronic ****liver diseases**

**No liver**
**disease reported**

**21**

**Other**

**Acetaminophen**
**-associated deaths **
**(FDA Estimate from NMCD files)**
**458**

## Distribution of APAP-Associated Deaths with Acute Liver Toxicity by Intentionality 

**Intentional**

**Unintentional**

**Accidental overdose**
**and therapeutic misuse**

**28**

**30**

**Total = 58**

## Relative Risk of Serious GI Hospitalization For OTC Pain Relievers, As Compared to ‘No Drug’ Group

***(error bars represent 95% lower C.I.s based on one-tailed test)***

**Relative risk****(vs. no drug)**

**No Drug**

**APAP**

**ASA****

**IBU***

**NAP***

**Any** NSAID**

**5**

**4**

**3**

**2**

**1**

**0**

***  p =.05**
****p = .01**

**0.76**

**4.14**

**3.50**

**3.42**

**3.92**

**Singh, unpublished**

## Conclusions

**Prospective studies indicate no toxicity at or near the recommended dose**
**Serious hepatotoxicity occurs following substantial overdose (single dose ~15 g or multiple days, ~12 g/day)**
**Chronic alcoholics may safely take current recommended doses of acetaminophen; therefore no need for dose reduction**

## Acetaminophen: Safe Use in Liver Disease	

**  ****Raymond S. Koff, MD**
**  ****Professor of Medicine**
**University of Massachusetts Medical School**
**  ****Director, Clinical Hepatology Research  **
**  ****UMass Memorial Medical Center **

## Acetaminophen	

**Current recommended dose (4 g/day) is safe to use in patients with liver disease**
**Supportive evidence**
**prospective single dose studies**
**prospective multiple dose studies**
**clinical experience**
**Concerns of increased risk for hepatotoxicity: based on anecdotal case reports**

## Chronic Liver Disease: No Change in Acetaminophen Metabolism after 1.5 g*

**Sulfate**
**33****±1.2**
**29****±1.9**
**35****±3.1**

**  ****24-hour urinary recovery**
**  ****Single dose**
**  ****Normal subjects (n=8); mild disease (n=8); severe disease (n=7)**

***Forrest et al, 1979**

**Normal subjects**
**Mild liver disease**
**Severe liver disease**

**Glucuronide**
**54****±1.4**
**29****±2.3**
**50****±3.7**

**Cysteine**
**3.8****±0.1**
**4.4****±0.6**
**4.2****±0.9**

**Mercapturate**
**4.8****±0.2**
**4.3****±0.7**
**4.2****±0.6**

## Acetaminophen Does Not Cause Liver Injury: in Biopsy-confirmed Cirrhosis (3 g/day)*

- 		     **Body                                      Plasma clearance**
**                          ****weight (kg)  Ascites    T ****1/2 (h)     (mL/min)**

** ****Cirrhosis (N=11)  60+/-9           7        3.7+/-0.8     162+/-51**
** ****Controls (N=12)   60+/-10         0        2.1+/-0.6     355+/-68**
** **

***Andreasen and Hutters, 1979**

**No changes in ALT, prothrombin, bilirubin, alkaline p’tase and no  clinical signs of hepatotoxicity in patients treated with 3 g daily for 5 days**
**No accumulation of acetaminophen **
**PK unchanged (day 1 vs. day 5)**

## Acetaminophen Does Not Cause Liver Injury in Chronic Liver Disease (4 g/day)*

***Benson 1983**

**  ****Double-blind crossover design; n = 20**
** ****Values are for end of baseline and treatment periods  **

**Baseline period**
**1.3****±0.8****0.7±0.6**
**42.5****±26.3**
**58.6****±55.7**

**Laboratory test (normal range)**
**Bilirubin (mg/dL)****    ****Total  (0.2-1.2)****    Direct (0.0-0.3****)**
**AST (2-18U)**
**ALT (0-18U)**

**Acetaminophen4 g/d: 13 days**
** ****1.4****±1.1****0.7±0.8**
**39.5****±23.1**
**53.3****±48.8**

**Placebo****13 days**
**1.4****±1.0****0.7±0.8**
**55.0****±71.6**
**77.3****±126.2**

## Acetaminophen Does Not Affect ALT or Viral Load in Chronic Hepatitis C Patients Not Receiving Antiviral Therapy (3 g/day)*

- 			         **ALT (IU/L)**
**                         ****Before                   End of                3 days after**
**                      ****treatment (D0)    treatment (D7)  treatment (D10)**

** ****Placebo               149+/-75             141+/-70          137+/-62**
**  ****(N = 17)**
** ****Acetaminophen  123+/-48             115+/-44          119+/-48 **
**  ****(N = 17)**

***Dargere, 2000**

** ****Prospective, randomized study**
** ****No change in HCV RNA level**

## Use of Acetaminophen in Chronic Hepatitis C Patients

**Over a decade of experience using       ****	****	****     acetaminophen to ameliorate the flu-like symptoms associated with alpha interferon therapy. **
**Continues to be used in **_**clinical trials**_** and **_**in**__** **__**practice**_** to treat flu-like effects of pegylated-interferons**
**No evidence of hepatotoxicity in routinely monitored patients**
**Free of adverse effects on ****platelet function**

## Conclusions

**Acetaminophen at recommended doses is the OTC analgesic of choice for patients with liver disease**
**No dosage adjustment is needed for patients with **
**liver disease **
**altered liver function**

## Analgesic Benefit

**Daniel B. Carr, MD**
**Professor of Pain Research**
**Department of Anesthesiology**
**Tufts New England Medical Center**

## The Right to Pain Treatment   

**Guidelines, standards and position papers**
**Federal Agencies: *****AHRQ, JCAHO***
**International Organizations: *****WHO***
**Medical Associations: *****AAP, AAOS, APS, AAPM***
**Healthcare Institutions : *****VA***
**Consumer Groups:****  *****AAPM, ACPA***** **
**Federal law: “Decade of Pain Control and Research”**

## “Everyday Pain”: Public Health Burden

**Highly prevalent**
**Tension headache: 38% past year ****(Schwartz et al., 1998) **
**Non-inflammatory low back pain: 22% past month ****(Hagen et al., 1997)**
**Costly  **
**50 million sick days per year ****(Louis Harris, 1996)**
**$3 billion excess wages ****(Louis Harris, 1996)**
**OTC analgesic use widespread**
**$3 billion spent annually on OTC analgesics ****(Sheftell, 1997)**
**One week usage: acetaminophen (23%), aspirin (17%), OTC NSAIDS (17%) ****(Kaufman et al., 2002)**

**Potential**
**Adverse Events**

**Potential**
**Adverse Events**

**Potential**
**Adverse Events**

**SELF **
**MANAGEMENT: **
**OTC**

**PAIN**

**MEDICAL **
**MANAGEMENT: **
**Rx**

**NO **
**TREATMENT**

**SELF **
**MANAGEMENT: **
**ETOH /**
**ILLICIT DRUGS**** **

**Potential**
**Adverse Events**

**OUTCOMES**

**Emotional **
**Well-being**

**Social **
**Functioning**

**FAMILY MEMBERS**

**Healthcare Utilization**

**Healthcare **
**Costs**

**HEALTHCARE SYSTEMS**

**Costs for Uninsured**

**Work Productivity**

**SOCIETY**

**OTC acetaminophen**

**OTC **
**aspirin**

**OTC **
**NSAIDs**

**Potential**
**Adverse Events**

**PATIENTS**

**Quality**
**Of Life**

**Health**
**Status**

** **

**Potential**
**Adverse Events**

**Potential**
**Adverse Events**

**Potential**
**Adverse Events**

**SELF **
**MANAGEMENT: **
**OTC**

**PAIN**

**MEDICAL **
**MANAGEMENT: **
**Rx**

**NO **
**TREATMENT**

**SELF **
**MANAGEMENT: **
**ETOH /**
**ILLICIT DRUGS**** **

**Potential**
**Adverse Events**

**OUTCOMES**

**Emotional **
**Well-being**

**Social **
**Functioning**

**FAMILY MEMBERS**

**Healthcare Utilization**

**Healthcare **
**Costs**

**HEALTHCARE SYSTEMS**

**Costs for Uninsured**

**Work Productivity**

**SOCIETY**

**OTC acetaminophen**

**OTC **
**aspirin**

**OTC **
**NSAIDs**

**Potential**
**Adverse Events**

**PATIENTS**

**Quality**
**Of Life**

**Health**
**Status**

**Potential**
**Adverse Events**

**Potential**
**Adverse Events**

**Potential**
**Adverse Events**

**SELF **
**MANAGEMENT: **
**OTC**

**PAIN**

**MEDICAL **
**MANAGEMENT: **
**Rx**

**NO **
**TREATMENT**

**SELF **
**MANAGEMENT: **
**ETOH /**
**ILLICIT DRUGS**** **

**Potential**
**Adverse Events**

**OUTCOMES**

**Emotional **
**Well-being**

**Social **
**Functioning**

**FAMILY MEMBERS**

**Healthcare Utilization**

**Healthcare **
**Costs**

**HEALTHCARE SYSTEMS**

**Costs for Uninsured**

**Work Productivity**

**SOCIETY**

**OTC acetaminophen**

**OTC **
**aspirin**

**OTC **
**NSAIDs**

**Potential**
**Adverse Events**

**PATIENTS**

**Quality**
**Of Life**

**Health**
**Status**

## In Everyday Practice...   

**Patients already self-medicate (+CAM)**
**Patients and families continually make choices **
**Restriction of more appropriate choices invites less appropriate choices**
**Education fosters appropriate decisions**

## Summary and Q&A

**Anthony R. Temple, MD**
**Vice President, Medical & Regulatory Sciences**
**McNeil Consumer & Specialty Pharmaceuticals**

## Insights

**Acetaminophen has been extensively investigated, well described, but the science has not always been fully understood**
**Threshold effect is an important consideration**
**Acetaminophen toxicity is caused by substantial overdose**
**Case reports, like AERS data set, must be subjected to careful scrutiny by experts**

## Assessment 

**Management of common aches and pains is an important consumer benefit**
**Acetaminophen remains the safest OTC pain reliever when used at recommended doses**
**True for both general and special populations**
**Consumers deserve the most effective dose of acetaminophen**

## Assessment

**Consumer attitudes key to understanding misuse **
**Data led us to implement new label changes and education efforts**
**Consumers need to know**
**What is in each medicine**
**The correct dose**
**Not to mix medicines**

## McNeil Interventions

**Labeling Changes**
**Prescription and OTC products**
**Pediatric products **
**Consumer Education **
**“****Know Your Medicine”**
**“****Be MedWise” Grant**
**Healthcare Professional Education**
**American Academy of Family Physicians**
**American Pharmaceutical Association**

## McNeil Continuing Science

**Two long term use studies ****in field today:**
**Study I: placebo controlled, 3 month, OA, 4 g/d, completion mid-year 2003**
**Study II: NSAID control, one year, OA,    4 g/d, completion 2004**

## Committee Considerations

**Is AERS an appropriate surveillance ****system for an old drug with a well-known safety profile?**
**If AERS reported doses are **_***in***_**accurate, ****what conclusions can or should be drawn?**
**Are the assumptions inherent in a system like AERS applicable to acetaminophen, which is most often associated with intentional overdose?**

## Committee Considerations

**Prospective data capture**
**Surveillance system targeted to specific issues, vs. relying on existing, broad and confounded data sources**
**Clinical studies to address specific issues unresolved, such as threshold of toxicity in single and multiple dose in humans**
**Can prospective clinical studies using ****large overdoses of acetaminophen be conducted?**

## Committee Considerations

**What can be done to improve FDA oversight of Rx consumer labeling?**
**What can we do now to establish consensus on pediatric labeling for children under age two?**

## Questions