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Joint Meeting of the Arthritis and Drug Safety Joint Meeting of the Arthritis and Drug Safety and Risk Management Advisory Committeesand Risk Management Advisory Committees

February 16-18, 2005February 16-18, 2005

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Leonard M. Baum, RPhLeonard M. Baum, RPh

Vice President, Regulatory AffairsVice President, Regulatory AffairsBayer HealthCareBayer HealthCare

Consumer Care DivisionConsumer Care Division

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AgendaAgenda

Regulatory Overview Regulatory Overview

NaproxenNaproxen

ADAPT TrialADAPT Trial

Safety EvaluationSafety Evaluation Clinical PharmacologyClinical Pharmacology Clinical Studies Clinical Studies Postmarketing SurveillancePostmarketing Surveillance Observational StudiesObservational Studies

ConclusionsConclusions

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Roche/Bayer Presenters and RespondersRoche/Bayer Presenters and Responders

Presenters:Presenters: Leonard M. Baum, RPhLeonard M. Baum, RPhVice President, Regulatory AffairsVice President, Regulatory Affairs

Bayer HealthCareBayer HealthCare

Martin H. Huber, M.D.Martin H. Huber, M.D.Vice President, Global Head Drug Safety Risk ManagementVice President, Global Head Drug Safety Risk Management

Hoffmann La-Roche Inc.

Responders:Responders:Susan Sacks, Ph.D.Susan Sacks, Ph.D.Global Head, EpidemiologyGlobal Head, Epidemiology

Hoffmann La-Roche Inc.Hoffmann La-Roche Inc.

Bharat Thakrar, Ph.D.Bharat Thakrar, Ph.D.Senior EpidemiologistSenior Epidemiologist

Hoffmann La-Roche Inc.Hoffmann La-Roche Inc.

Ernst Weidmann, M.D.Ernst Weidmann, M.D.Head, Global SafetyHead, Global Safety

Bayer HealthCareBayer HealthCare

Steve Zlotnick, Pharm.DSteve Zlotnick, Pharm.D..Director, Medical AffairsDirector, Medical Affairs Bayer HealthCareBayer HealthCare

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Outside ExpertsOutside Experts

Kay Brune, M.D.Kay Brune, M.D.Professor and ChairmanProfessor and Chairman

Department of Experimental and Clinical Pharmacology and ToxicologyDepartment of Experimental and Clinical Pharmacology and Toxicology

Friedrich-Alexander University Erlangen - NurembergFriedrich-Alexander University Erlangen - Nuremberg

Ian M. Gralnek, M.D., MSHSIan M. Gralnek, M.D., MSHSAssistant Professor of Medicine, Division of Digestive DiseasesAssistant Professor of Medicine, Division of Digestive Diseases

David Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLA

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Regulatory OverviewRegulatory Overview

Naproxen available in the United States since 1976 Prescription currently marketed by multiple manufacturers

for the treatment of RA, OA, ankylosing spondylitis, gout, juvenile RA, dysmenorrhea, tendinitis, bursitis, and pain

Aleve (OTC) approved in 1994 Currently marketed by Bayer HealthCare for temporary

relief of minor aches and pains, and for the temporary reduction of fever

Multiple generic versions

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NaproxenNaproxen

Naproxen, a nonsteroidal anti-inflammatory drug (NSAID), Naproxen, a nonsteroidal anti-inflammatory drug (NSAID), belongs to the chemical class propionic acid derivativesbelongs to the chemical class propionic acid derivatives

Naproxen has anti-inflammatory, analgesic and antipyretic Naproxen has anti-inflammatory, analgesic and antipyretic propertiesproperties

Naproxen known to inhibit platelet aggregationNaproxen known to inhibit platelet aggregation

The major differences between members of the NSAID The major differences between members of the NSAID class are potency and pharmacokineticsclass are potency and pharmacokinetics

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Classes of NSAIDSClasses of NSAIDS Salicylic acid derivativesSalicylic acid derivatives

• Aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisalAspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal Para-aminophenol derivativesPara-aminophenol derivatives

• AcetaminophenAcetaminophen Indole and indene acetic acidsIndole and indene acetic acids

• Indomethacin, sulindacIndomethacin, sulindac Heteroaryl acetic acidsHeteroaryl acetic acids

• Tolmetin, diclofenac, ketorolacTolmetin, diclofenac, ketorolac Propionic acidsPropionic acids

• NaproxenNaproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin Anthranilic acids (fenamates)Anthranilic acids (fenamates)

• Mefenamic acid, meclofenamic acidMefenamic acid, meclofenamic acid Enolic acidsEnolic acids

• Oxicams (piroxicam, meloxicam)Oxicams (piroxicam, meloxicam) AlkanonesAlkanones

• NabumetoneNabumetone CoxibsCoxibs

• Celecoxib, valdecoxib, rofecoxib (withdrawn)Celecoxib, valdecoxib, rofecoxib (withdrawn)

Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10Source: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10 thth edition edition

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Relevance of Naproxen DataRelevance of Naproxen Data

The safety profile for naproxen is well knownThe safety profile for naproxen is well known

Naproxen is a reference drug for many analgesic clinical Naproxen is a reference drug for many analgesic clinical trialstrials

Naproxen and other non-selective NSAIDs, are important treatment options for a broad range of patients and conditions

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Naproxen Exposure Data (Rx and OTC)Naproxen Exposure Data (Rx and OTC)

550,000,000 550,000,000 courses of courses of therapy*therapy*

110,000,000 pts110,000,000 ptsPost-marketingPost-marketing

----> 80,000 pts> 80,000 ptsObservational Observational StudiesStudies

> 8,000 pts> 8,000 pts> 10,000 pts> 10,000 ptsClinical TrialsClinical TrialsOTCOTCRXRX

*courses of therapy (2 tab x 10 days)*courses of therapy (2 tab x 10 days)

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The ADAPT TrialThe ADAPT Trial

NIH sponsored studyNIH sponsored study

Bayer provided naproxen sodium for investigational use Bayer provided naproxen sodium for investigational use

Study DesignStudy Design Naproxen sodium 220 mg bidNaproxen sodium 220 mg bid Celecoxib 200 mg bidCelecoxib 200 mg bid Placebo Placebo

Patient Population Patient Population 2400 patients, age 70 years or older, for prevention of 2400 patients, age 70 years or older, for prevention of

Alzheimer’s diseaseAlzheimer’s disease

Study DurationStudy Duration Began in 2001, planned for 7 years, suspended after 3 yearsBegan in 2001, planned for 7 years, suspended after 3 years

Sources: NIH News Dec 20, 2004; Washingtonpost.com Feb 1, 2005, written by Woloshin S et al.Sources: NIH News Dec 20, 2004; Washingtonpost.com Feb 1, 2005, written by Woloshin S et al.

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Publicly Reported Events Leading to the Publicly Reported Events Leading to the Suspension of ADAPTSuspension of ADAPT

DSMB review on Dec. 10, 2004 did not recommend DSMB review on Dec. 10, 2004 did not recommend stopping the study stopping the study

The APC study was suspended due to indications of an The APC study was suspended due to indications of an increase in cardiovascular and cerebrovascular risk of increase in cardiovascular and cerebrovascular risk of celecoxib vs. placebo (Dec. 17, 2004)celecoxib vs. placebo (Dec. 17, 2004)

NIA announced ADAPT trial suspension (Dec. 20, 2004)NIA announced ADAPT trial suspension (Dec. 20, 2004)

Information released to public by study group, were based Information released to public by study group, were based on preliminary findings, not through peer-reviewed journals on preliminary findings, not through peer-reviewed journals

Sources: Celebrex News Release Dec 17, 2004; NIH News Dec 20, 2004; Sources: Celebrex News Release Dec 17, 2004; NIH News Dec 20, 2004; Washingtonpost.com Feb 1, 2005, written by Woloshin S et al.Washingtonpost.com Feb 1, 2005, written by Woloshin S et al.

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SummarySummary

Naproxen is a non-selective COX-1 / COX-2 inhibitorNaproxen is a non-selective COX-1 / COX-2 inhibitor

Widely used Widely used

Established safety profileEstablished safety profile

Reference standardReference standard

Unadjudicated preliminary findings of ADAPT needs to be looked at in context of the wide body of data on naproxen

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Martin H. Huber, MDMartin H. Huber, MD

Global Head, Drug SafetyGlobal Head, Drug SafetyHoffmann-La Roche Inc.Hoffmann-La Roche Inc.

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Safety EvaluationSafety Evaluation

Clinical PharmacologyClinical Pharmacology

Clinical Studies Clinical Studies

Post-Marketing Safety SurveillancePost-Marketing Safety Surveillance

Post-Marketing Clinical StudiesPost-Marketing Clinical Studies

Observational StudiesObservational Studies

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Pharmacological Difference between Pharmacological Difference between Naproxen and COX-2 InhibitorsNaproxen and COX-2 Inhibitors

Naproxen is a non-selective COX-1 /COX-2 Naproxen is a non-selective COX-1 /COX-2 inhibitorinhibitor

Naproxen is known to inhibit platelet Naproxen is known to inhibit platelet aggregation and thus, is not expected to have aggregation and thus, is not expected to have an increased risk of myocardial infarctionan increased risk of myocardial infarction

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Clinical Trials and Post-Marketing Clinical Trials and Post-Marketing SurveillanceSurveillance

Clinical trials in the prescription and OTC naproxen NDAs Clinical trials in the prescription and OTC naproxen NDAs did not provide any evidence of an increased risk of did not provide any evidence of an increased risk of myocardial infarction or stroke myocardial infarction or stroke

A review of postmarketing surveillance data showed no A review of postmarketing surveillance data showed no signal for MI or cerebrovascular accident with exposures signal for MI or cerebrovascular accident with exposures to prescription naproxen of more than 110,000,000 to prescription naproxen of more than 110,000,000 patients patients

A review OTC postmarketing surveillance data did not A review OTC postmarketing surveillance data did not identify a signal for MI or CVA with an estimate of identify a signal for MI or CVA with an estimate of 550,000,000 courses of therapy550,000,000 courses of therapy

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Proportional Reporting Rate (PRR)Proportional Reporting Rate (PRR)

EventEvent PRRPRR Significance (P value)Significance (P value)

Ischemic coronary Ischemic coronary artery disorders (high-artery disorders (high-level term)level term)

0.160.16 <<0.050.05

MI (preferred terms)MI (preferred terms) 0.180.18 <<0.050.05

CNS hemorrhages CNS hemorrhages and cerebrovascular and cerebrovascular accidents (high level accidents (high level term)term)

0.160.16 << 0.05 0.05

Source: Evans S et al. Pharmacoepidemiology and Drug Safety 2001; 10: 483-86Source: Evans S et al. Pharmacoepidemiology and Drug Safety 2001; 10: 483-86

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Post-Marketing Clinical TrialsPost-Marketing Clinical Trials

VIGORVIGOR Randomized RA patients Randomized RA patients ≥ 50 yo (or ≥ 40 yo and ≥ 50 yo (or ≥ 40 yo and

receiving long-term glucocorticoid therapy) into either receiving long-term glucocorticoid therapy) into either rofecoxib 50mg qd (N=4,047) or naproxen 500mg bid rofecoxib 50mg qd (N=4,047) or naproxen 500mg bid (N=4,029)(N=4,029)

Overall rate of cardiovascular events reported in Overall rate of cardiovascular events reported in association with naproxen is consistent with that association with naproxen is consistent with that expected in this population expected in this population

MI: Rofecoxib (0.4%) vs. naproxen (0.1%)MI: Rofecoxib (0.4%) vs. naproxen (0.1%) Ischemic cerebrovascular events: 0.2% in both armsIschemic cerebrovascular events: 0.2% in both arms

Source: Bombardier C et al. NEJM 2000; 343:1520-8Source: Bombardier C et al. NEJM 2000; 343:1520-8

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Post-Marketing Clinical TrialsPost-Marketing Clinical Trials

TARGETTARGET Randomized OA patients Randomized OA patients ≥ 50 yo into either lumiracoxib ≥ 50 yo into either lumiracoxib

400mg qd (N=9,156), naproxen 500mg bid (N=4,754) or 400mg qd (N=9,156), naproxen 500mg bid (N=4,754) or ibuprofen 800mg tid (N=4,415)ibuprofen 800mg tid (N=4,415)

Naproxen arm showed lower rates for cerebrovascular Naproxen arm showed lower rates for cerebrovascular events and MI:events and MI:

• Stroke: Lumiracoxib (0.34%) vs. naproxen (0.25%)Stroke: Lumiracoxib (0.34%) vs. naproxen (0.25%)• Ischemic stroke: Lumiracoxib (0.32%) vs. naproxen Ischemic stroke: Lumiracoxib (0.32%) vs. naproxen

(0.23%)(0.23%)• Hemorrhagic stroke: 0.02% in both armsHemorrhagic stroke: 0.02% in both arms• Acute MI: Lumiracoxib (0.38%) vs. naproxen (0.23%)Acute MI: Lumiracoxib (0.38%) vs. naproxen (0.23%)

Source: Farkouh ME et al. Lancet 2004; 364: 675-84Source: Farkouh ME et al. Lancet 2004; 364: 675-84

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Post-Marketing Clinical TrialsPost-Marketing Clinical Trials TARGET (cont.)TARGET (cont.)

Rate of MI events was lower for naproxen than Rate of MI events was lower for naproxen than ibuprofen, using lumiracoxib as the reference point ibuprofen, using lumiracoxib as the reference point for both studiesfor both studies

Event*Event* LumiracoxibLumiracoxib IbuprofenIbuprofen

CV CV deathdeath

0.18%0.18% 0.23%0.23%

All MIAll MI 0.11%0.11% 0.16%0.16%

StrokeStroke 0.18%0.18% 0.20%0.20%

Source: Farkouh ME et al. Lancet 2004; 364: 675-84Source: Farkouh ME et al. Lancet 2004; 364: 675-84

* Given in percent of patients with confirmed or probable cardiovascular and cerebrovascular events* Given in percent of patients with confirmed or probable cardiovascular and cerebrovascular events

LumiracoxibLumiracoxib NaproxenNaproxen

0.23%0.23% 0.17%0.17%

0.38%0.38% 0.21%0.21%

0.34%0.34% 0.25%0.25%

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Additional Post-Marketing Clinical TrialsAdditional Post-Marketing Clinical Trials

Alzheimer’s TrialAlzheimer’s Trial Randomized mild to moderate AD patients (mean age: 74 Randomized mild to moderate AD patients (mean age: 74

yo) into either rofecoxib 25mg qd, naproxen sodium 220mg yo) into either rofecoxib 25mg qd, naproxen sodium 220mg bid, or placebobid, or placebo

Source: Aisen PS et al. JAMA 2003; 289: 2819-26Source: Aisen PS et al. JAMA 2003; 289: 2819-26

EventsEvents PlaceboPlacebo

(n=111)(n=111)

Naproxen Naproxen

(N=118)(N=118)

Rofecoxib Rofecoxib

(N=122)(N=122)DeathDeath 11 11 22MIMI 11 00 33Stroke/TIAStroke/TIA 11 33 33

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Trials with CelecoxibTrials with Celecoxib

Pooled analysis of 41 celecoxib clinical trials (White et al)Pooled analysis of 41 celecoxib clinical trials (White et al)

2271 naproxen patients2271 naproxen patients 1 non-fatal stroke 1 non-fatal stroke 1 fatal stroke1 fatal stroke 2 non-fatal MIs2 non-fatal MIs

Naproxen (relative to celecoxib): 4/393 (1.01 per 100 patient years)Naproxen (relative to celecoxib): 4/393 (1.01 per 100 patient years)

Celecoxib (relative to NSAIDs): 56/4,969 (1.13 per 100 patient years)Celecoxib (relative to NSAIDs): 56/4,969 (1.13 per 100 patient years)

Placebo (relative to celecoxib): 3/200 (1.5 per 100 patient years)Placebo (relative to celecoxib): 3/200 (1.5 per 100 patient years)

There is no evidence of an increased risk of MI or stroke compared to There is no evidence of an increased risk of MI or stroke compared to either celecoxib or placeboeither celecoxib or placebo

Source: White et al. Am J Cardiology 2003; 92: 411-18Source: White et al. Am J Cardiology 2003; 92: 411-18

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Observational StudiesObservational Studies

Case control studies and retrospective cohort Case control studies and retrospective cohort studies can be performed in a shorter period of studies can be performed in a shorter period of timetime

Opportunity to detect/evaluate relatively Opportunity to detect/evaluate relatively infrequent eventsinfrequent events

Reflect “real world” use of the drug Reflect “real world” use of the drug More heterogeneous populationsMore heterogeneous populations Concomitant medications, concurrent illnessesConcomitant medications, concurrent illnesses

Value of observational studies increases when Value of observational studies increases when these studies are done in multiple populationsthese studies are done in multiple populations

Source: Strom B, Pharmacoepidemiology 2000; Wiley and SonsSource: Strom B, Pharmacoepidemiology 2000; Wiley and Sons

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Summary of observational studies of Summary of observational studies of naproxen and MInaproxen and MI

Source: Juni et al. Lancet 2004;364:2021-29Source: Juni et al. Lancet 2004;364:2021-29

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Sensitivity Analysis of Observational Sensitivity Analysis of Observational StudiesStudies

Meta-analysis included multiple studies from same Meta-analysis included multiple studies from same databasesdatabases

Performed analysis including only one study from GPRD Performed analysis including only one study from GPRD and one study from Tennessee Medicaidand one study from Tennessee Medicaid

Excluded Jick, Watson, Schlienger studies with GPRD Excluded Jick, Watson, Schlienger studies with GPRD and Ray (Lancet 2002, 359:118-23) study with and Ray (Lancet 2002, 359:118-23) study with Tennessee MedicaidTennessee Medicaid

Resulting pooled RR : 0.87 (0.72-1.03)Resulting pooled RR : 0.87 (0.72-1.03)

No material change in conclusions of Juni et al.No material change in conclusions of Juni et al.

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SummarySummary

A review of the observational studies shows no increased risk of MI with naproxen

A review of the postmarketing surveillance data shows no signal for MI or cerebrovascular events

The published clinical trials do not provide evidence of an increased risk of MI or cerebrovascular events

Unadjudicated preliminary findings of ADAPT are inconsistent with the known data and pharmacologic properties of naproxen

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ConclusionsConclusions

The vast majority of data collected for over 30 years indicates no signal for naproxen and myocardial infarction or cerebrovascular accidents.

Naproxen Rx and Aleve OTC remain safe and effective

Naproxen remains an important treatment option for patients