1 assessment of acetaminophen safety and efficacy fda advisory committees september 19, 2002

1

Assessment of Assessment of AcetaminophenAcetaminophen

Safety and EfficacySafety and Efficacy

FDA Advisory CommitteesFDA Advisory Committees

September 19, 2002September 19, 2002

2

IntroductionIntroduction

Debra L. Bowen, MDDebra L. Bowen, MD

Vice President, R&DVice President, R&D

McNeil Consumer & Specialty McNeil Consumer & Specialty PharmaceuticalsPharmaceuticals

3

ObjectivesObjectives

• 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.

4

Context for ConsiderationContext for Consideration

• Available OTC for over 40 years.

• >100 million users per year in US.

• Harm is rare.

5

Issue StatementIssue 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.

6

Analgesic ScienceAnalgesic Science

• Pharmacology and toxicology

• Clinical and epidemiological data

• Spontaneous reports and cases

• Consumer Use Practices– Underlying attitudes– Reported product use

7

McNeil Actions: OverdoseMcNeil Actions: Overdose

Initiated NAC IND

19781979 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

formulationVoluntarily

added concomitant

use statement and proposed

alcohol warning

1986 19941985

Introduced SAFE-TY-

LOCK

1999

8

McNeil Actions: McNeil Actions: “Unintentional Misuse”“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

9

Today’s Scientific ExpertsToday’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

10

ConclusionsConclusions

• 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.

11

Acetaminophen Metabolism Acetaminophen Metabolism and Pharmacokineticsand Pharmacokinetics

John Slattery, PhDJohn Slattery, PhDProfessor, Department of Professor, Department of

PharmaceuticsPharmaceuticsUniversity of WashingtonUniversity of Washington

12

Acetaminophen Acetaminophen Metabolism and HepatotoxicityMetabolism and Hepatotoxicity

Acetaminophen

OH

O||

HN-C-CH3

O||

HN-C-CH3

Glucuronide

O||

HN-C-CH3

Sulfate

Cysteine & Mercapturic Acid Conjugates

Glutathione

ReactiveMetabolite

(NAPQI)

OH

O||

HN-C-CH3

Cytochrome P450 2E1

Glutathione

Active Repletion Process

25% - 36%47% - 62%

4.8% - 8.0%

13

Acetaminophen Metabolism Acetaminophen Metabolism

• Threshold phenomenon

• Need 70-80% depletion of hepatic glutathione before any toxicity

• Not toxic at recommended doses

14

Acetaminophen Acetaminophen Oxidation to NAPQIOxidation to NAPQI

||||

||NHNH

CH3CH3

CC||

OO

OHOH||||

||NN

CH3CH3

CC||

OO

OO

CYP2E1CYP2E1

CYP1A2CYP1A2CYP3A4CYP3A4

GSHGSH

NAPQINAPQIAPAPAPAP

GSH Conjugates(APAP-3-SR)

GSH Conjugates(APAP-3-SR)

glucuronide, sulfate, catechol metabolitesglucuronide, sulfate, catechol metabolites

15

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

All incubations contained 0.05% v/v methanolAll incubations contained 0.05% v/v methanolaaDDC = 150 µM Diethyldithiocarbamate; DDC = 150 µM Diethyldithiocarbamate; bbFF = 25 µM Furafylline; FF = 25 µM Furafylline; ccTAO = 100 µM TrolcandomycinTAO = 100 µM Trolcandomycin

Acetaminophen conc (mMAcetaminophen conc (mM))

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

2.02.0

43 ± 443 ± 452 ± 152 ± 1

7 ± 0.27 ± 0.2

53 ± 453 ± 416 ± 916 ± 9 4 ± 54 ± 5

0.10.1

35 ± 335 ± 344 ± 344 ± 312 ± 812 ± 8

37 ± 137 ± 112 ± 112 ± 1 8 ± 48 ± 4

Target CYPTarget CYP

2E12E11A21A23A43A4

2E12E11A21A23A43A4

InhibitorInhibitor

DDCDDCaa

FFFFbb

TAOTAOcc

DDCDDCFFFF

TAOTAO

LiverLiver

H105H105

H108H108

16

Omeprazole on Caffeine and Omeprazole on Caffeine and AcetaminophenAcetaminophen

**P P < 0.001< 0.001

• Omeprazole, 40 mg/d for 7 days

– 4 rapid, 4 slow mephenytoin metabolizers by phenotype and CYP2C19

• No alcohol for 1 week before to study end

Caffeine Cl,L/kg/hr

Clf, APAPthiols, 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 MetabolizersRapid Metabolizers Slow MetabolizersSlow Metabolizers

17

Rifampin on Rifampin on AcetaminophenAcetaminophen

• Rifampin 600 mg/d for 7 days– Alcohol for 1 week before and to end of study

• n = 8

Clf, APAP thiols, L/kg/hr

- Rifampin

0.036 ± 0.011

+ Rifampin

0.040 ± 0.012

18

Disulfiram on Disulfiram on AcetaminophenAcetaminophen

• 500 mg disulfiram 10 hr before APAP– No alcohol 1 week before to 1 week after study

• n = 8

P P < 0.01< 0.01

Clf, APAP thiols, L/kg/hr

- Disulfiram

0.039 ± 0.023

+ Disulfiram

0.010 ± 0.003

19

Concomitant DrugsConcomitant DrugsP450 IsoenzymesP450 Isoenzymes

• CYP2E1 is primarily responsible for conversion of acetaminophen to NAPQI

• CYP3A4 and CYP1A2 play negligible roles in metabolism of acetaminophen

20

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

SSSS

SS

II

++II II

II

21

Time-Course: Inhibition & Induction Time-Course: Inhibition & Induction

NAPQI Formation by EthanolNAPQI Formation by Ethanol

00 55 1010 1515 2020 2525

Time (hr)Time (hr)

Cl(t)

Clo

Cl(t)

Clo

1.61.6

1.41.4

1.21.2

0.60.6

100 mg/dLEtOH

100 mg/dLEtOH

1.01.0

0.20.2

0.40.4

0.80.8

7 & 37 hr7 & 37 hr

15 & 79 hr15 & 79 hr

CYP2E1 t ½CYP2E1 t ½

22

Gilbert’s Syndrome: Genetic Gilbert’s Syndrome: Genetic deficiency of UGT1A1deficiency of UGT1A1

• UGT1A6 is predominant in acetaminophen glucuronidation– Km = 2.2 mM (Cmax @ ~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

23

Acetaminophen Multiple-Dose Acetaminophen Multiple-Dose Pharmacokinetics and MetabolismPharmacokinetics 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

24

Acetaminophen Time Course 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)

25

Fraction of Dose in Urine Fraction of Dose in Urine

-60

-40

-20

0

20

40

60

APAP Dose per Day

% ChangeRelative

to 4 g/Day

6 g 8 g

0.0

0.2

0.4

0.6

0.8

4 g 6 g 8 gAPAP Dose per Day

Fractionof Dosein Urine

G S T A G S T A G S T A

G S T A G S T A

26

Formation Clearances Formation Clearances

-60

-40

-20

0

20

40

60

APAP Dose per Day

% ChangeRelative

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

27

Summary: Acetaminophen Summary: Acetaminophen

Metabolism and PharmacokineticsMetabolism 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

28

Assessment of Assessment of Acetaminophen SafetyAcetaminophen Safety

Richard C. Dart, MD, PhDRichard C. Dart, MD, PhDDirector, Rocky Mountain Poison and Drug CenterDirector, Rocky Mountain Poison and Drug Center

Professor, Surgery, Medicine, and PharmacyProfessor, Surgery, Medicine, and PharmacyUniversity of Colorado University of Colorado

29

Today’s TopicsToday’s Topics

• Acute Substantial Acetaminophen Overdose

• Data Sets of Reported Overdose and Misadministrations

• Chronic Alcohol Use

• Repeated Supratherapeutic Overdose

30

Single Large Overdoses: Single Large Overdoses: Up to 9.1 GramsUp to 9.1 Grams

Study

Christophersen [2002]

Green [2001]

Hassig [1993]

Rose [1991]

Douglas [1996]

Stork [1996]

Vance [1992]

GenderM/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)

T½ (hrs)

2.2

2.3(0.6)

N/A

2.6(0.3)

2.6(0.4)

2.6(0.9)

N/A

31

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

0

40

80

120

160

200

0 2 4 6 8 10 12 14 16Time (h)

AP

AP

(m

cg/m

L)

Risk Line Treatment Line

Douglas [1996] BE Study 98-054

75 mg/ kg

15 mg/ kg

32

FDA-Selected AERS Data Set 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

33

Limitations to Case ReportsLimitations 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)

34

Expert Review PanelExpert 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

35

Expert Review PanelExpert Review Panel

281 FDA AERs CasesAdults

281 FDA AERs CasesAdults

Panel TrainingStandardized Data Collection Instrument

Panel TrainingStandardized Data Collection Instrument

Panel Case Review – Clinical JudgementPanel Case Review – Clinical Judgement

Panel Consensus MeetingAssigned Probability of Association with APAP:

Definite, Probably, Possibly, Unlikely, Definitely Not, Insufficient Information

Panel Consensus MeetingAssigned Probability of Association with APAP:

Definite, Probably, Possibly, Unlikely, Definitely Not, Insufficient Information

36

Consensus Probabilities Consensus Probabilities Expert Review Panel Expert Review Panel

3

74

4753

27

73

3 10

20

40

60

80

Defin

itely

Proba

bly

Possi

bly

Unlike

ly

Defin

itely

not

Data a

re in

suffi

cien

t

Not e

valu

able

No co

nsen

sus

Numberof reports

Probability Category

N = 281 adult reports

37

Expert Panel Review Expert Panel Review FDA AERS Adult ReportsFDA 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.

38

Pediatric Reports Pediatric Reports FDA AERS Data SetFDA 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

39

Putative Risk SubsetsPutative Risk Subsets

• History of Liver Disease

• Co-ingestion of Hepatotoxic Medications

• Ethanol Use

40

Chronic Alcohol UseChronic Alcohol UseKuffner and Dart 2001Kuffner 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

41

Repeated Supratherapeutic Repeated Supratherapeutic Ingestion (RSI): Prospective StudyIngestion (RSI): Prospective Study

O’Malley 2000, Daly submitted

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

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

Acute Single Exposuren=7021

Acute Single Exposuren=7021

Repeated Supratherapeutic Ingestionn=277

Repeated Supratherapeutic Ingestionn=277

Enrolled249

Enrolled249

Declinedn=28

Declinedn=28

Acetaminophen level > 10 mg/LAST > 50 IU/L

Acetaminophen level > 10 mg/LAST > 50 IU/L

YesTreat with Aceytlcysteine

YesTreat with Aceytlcysteine

NoDischarge

NoDischarge

Followup Over 72 hoursValidation of History

Followup Over 72 hoursValidation of History

42

Outcome of RSI StudyOutcome of RSI StudyAST

Level, IU/L

Age,

yrs

Dose, Mean, g/24h

Duration, Median,

hrs

Outcome

< ULN* 95% CI

38 35 - 41

10.6 9.4 - 11.7

34

N = 126: 109 well, 17 lost f/u

50 – 1000 95% CI

40 35 - 45

11.7 9.6 - 13.8

48

N = 40: 37 well, 3 lost f/u

> 1000 95% CI

44 36 - 46

12.6 10.3 - 14.9

72

N = 44: 37 well, 7 died or

transplant Not Done 95% CI

36 31 - 42

7.6 6.6 - 8.6

24

N = 39: 21 well, 18 lost f/u

*ULN = Upper Limits of Normal

43

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

0

2

4

6

8

10

12

14

< ULN 50 - 1000 > 1000

Dose (g/24 hr)

Duration (24 hr periods)

*ULN = Upper Limits of Normal

44

Distribution of APAP-Associated Distribution of APAP-Associated Deaths by Liver ConditionDeaths by Liver Condition

58

31861

Acute liver toxicity

Chronic liver diseases

No liverdisease reported

21

Other

Acetaminophen-associated deaths (FDA Estimate from

NMCD files)

458

45

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

Intentional Unintentional

Accidental overdoseand therapeutic misuse2830

Total = 58

46

Relative Risk of Serious GI Hospitalization Relative Risk of Serious GI Hospitalization For OTC Pain Relievers, As Compared to For OTC Pain Relievers, As Compared to ‘No Drug’ Group‘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 3.423.92

Singh, unpublished

47


• 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

48

Acetaminophen: Safe Acetaminophen: Safe Use in Liver DiseaseUse in Liver Disease

Raymond S. Koff, MDRaymond S. Koff, MD Professor of MedicineProfessor of Medicine

University of Massachusetts Medical SchoolUniversity of Massachusetts Medical School Director, Clinical Hepatology Research Director, Clinical Hepatology Research

UMass Memorial Medical Center UMass Memorial Medical Center

49

AcetaminophenAcetaminophen

• Current recommended dose (4 Current recommended dose (4 g/day) is safe to use in patients g/day) is safe to use in patients with liver diseasewith liver disease

• Supportive evidenceSupportive evidence– prospective single dose studiesprospective single dose studies– prospective multiple dose studiesprospective multiple dose studies– clinical experienceclinical experience

• Concerns of increased risk for Concerns of increased risk for hepatotoxicity: based on anecdotal hepatotoxicity: based on anecdotal case reportscase reports

50

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

SulfateSulfate

3333±1.2±1.2

2929±1.9±1.9

3535±3.1±3.1

24-hour urinary recovery24-hour urinary recovery

Single doseSingle dose

Normal subjects (n=8); mild disease (n=8); severe disease Normal subjects (n=8); mild disease (n=8); severe disease (n=7)(n=7)

*Forrest et al, 1979*Forrest et al, 1979

Normal Normal subjectssubjects

Mild liver Mild liver diseasedisease

Severe liver Severe liver diseasedisease

GlucuronideGlucuronide

5454±1.4±1.4

2929±2.3±2.3

5050±3.7±3.7

CysteineCysteine

3.83.8±0.1±0.1

4.44.4±0.6±0.6

4.24.2±0.9±0.9

MercapturateMercapturate

4.84.8±0.2±0.2

4.34.3±0.7±0.7

4.24.2±0.6±0.6

51

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

Body Plasma Body Plasma clearanceclearance weight (kg) Ascites T weight (kg) Ascites T 1/2 (h) (mL/min)1/2 (h) (mL/min)

Cirrhosis (N=11) 60+/-9 7 3.7+/-0.8 162+/-Cirrhosis (N=11) 60+/-9 7 3.7+/-0.8 162+/-5151

Controls (N=12) 60+/-10 0 2.1+/-0.6 355+/-Controls (N=12) 60+/-10 0 2.1+/-0.6 355+/-6868

*Andreasen and Hutters, 1979*Andreasen and Hutters, 1979

• No changes in ALT, prothrombin, bilirubin, alkaline No changes in ALT, prothrombin, bilirubin, alkaline p’tase and no clinical signs of hepatotoxicity in p’tase and no clinical signs of hepatotoxicity in patients treated with 3 g daily for 5 dayspatients treated with 3 g daily for 5 days

• No accumulation of acetaminophen No accumulation of acetaminophen • PK unchanged (day 1 vs. day 5)PK unchanged (day 1 vs. day 5)

52

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

*Benson 1983*Benson 1983

Double-blind crossover design; n = 20Double-blind crossover design; n = 20

Values are for end of baseline and treatment Values are for end of baseline and treatment periods periods

Baseline Baseline periodperiod

1.31.3±0.8±0.80.7±0.60.7±0.6

42.542.5±26.3±26.3

58.658.6±55.7±55.7

Laboratory test Laboratory test (normal range)(normal range)

Bilirubin (mg/dL)Bilirubin (mg/dL) Total (0.2-1.2)Total (0.2-1.2) Direct (0.0-0.3 Direct (0.0-0.3))

AST (2-18U)AST (2-18U)

ALT (0-18U)ALT (0-18U)

Acetaminophen4 Acetaminophen4 g/d: 13 daysg/d: 13 days

1.41.4±1.1±1.10.7±0.80.7±0.8

39.539.5±23.1±23.1

53.353.3±48.8±48.8

PlaceboPlacebo13 days13 days

1.41.4±1.0±1.00.7±0.80.7±0.8

55.055.0±71.6±71.6

77.377.3±126.2±126.2

53

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

ALT (IU/L)ALT (IU/L)

Before End of 3 days Before End of 3 days afterafter treatment (D0) treatment (D7) treatment treatment (D0) treatment (D7) treatment (D10)(D10)

Placebo 149+/-75 141+/-70 137+/-Placebo 149+/-75 141+/-70 137+/-6262

(N = 17)(N = 17)

Acetaminophen 123+/-48 115+/-44 119+/-Acetaminophen 123+/-48 115+/-44 119+/-48 48

(N = 17)(N = 17)

*Dargere, 2000*Dargere, 2000

Prospective, randomized studyProspective, randomized study No change in HCV RNA levelNo change in HCV RNA level

54

Use of Acetaminophen in Use of Acetaminophen in Chronic Hepatitis C PatientsChronic Hepatitis C Patients

• Over a decade of experience using Over a decade of experience using acetaminophen to acetaminophen to

ameliorate the flu-like symptoms ameliorate the flu-like symptoms associated with alpha interferon therapy. associated with alpha interferon therapy.

• Continues to be used in Continues to be used in clinical trialsclinical trials and and inin practicepractice to treat flu-like effects of to treat flu-like effects of pegylated-interferonspegylated-interferons

• No evidence of hepatotoxicity in routinely No evidence of hepatotoxicity in routinely monitored patientsmonitored patients

• Free of adverse effects on Free of adverse effects on platelet platelet functionfunction

55


• Acetaminophen at Acetaminophen at recommended doses is the OTC recommended doses is the OTC analgesic of choice for patients analgesic of choice for patients with liver diseasewith liver disease

• No dosage adjustment is No dosage adjustment is needed for patients with needed for patients with – liver disease liver disease – altered liver functionaltered liver function

56

Analgesic BenefitAnalgesic Benefit

Daniel B. Carr, MDDaniel B. Carr, MD

Professor of Pain ResearchProfessor of Pain Research

Department of AnesthesiologyDepartment of Anesthesiology

Tufts New England Medical CenterTufts New England Medical Center

57

The Right to Pain Treatment 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”

58

““Everyday Pain”: Everyday Pain”: Public Health BurdenPublic 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)

PotentialAdverse Events



SELF MANAGEMENT:

OTC

PAIN

MEDICAL MANAGEMENT:

Rx

NO TREATMENT

SELF MANAGEMENT:

ETOH /ILLICIT DRUGS


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


PATIENTS

QualityOf Life

HealthStatus

62

In Everyday Practice... 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

63

Summary and Q&ASummary and Q&A

Anthony R. Temple, MDAnthony R. Temple, MD

Vice President, Medical & Regulatory SciencesVice President, Medical & Regulatory Sciences

McNeil Consumer & Specialty PharmaceuticalsMcNeil Consumer & Specialty Pharmaceuticals

64

InsightsInsights

• 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

65

Assessment 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

66

AssessmentAssessment

• 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

67

McNeil InterventionsMcNeil 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

68

McNeil Continuing ScienceMcNeil 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

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Committee ConsiderationsCommittee Considerations

• Is AERS an appropriate surveillance system for an old drug with a well-known safety profile?

• If AERS reported doses are inaccurate, 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?

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• 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?

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• 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?

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QuestionsQuestions

1 assessment of acetaminophen safety and efficacy fda advisory committees september 19, 2002

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