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Click to edit Master title styleClick to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,P-,*,Joint Meeting of the Arthritis and Drug Safety and Risk Management Advisory Committees,February 16-18,2005,P-,1,Leonard M.Baum,RPh,VicePresident,Regulatory Affairs,BayerHealthCare,Consumer Care Division,P-2,Agenda,RegulatoryOverview,Naproxen,ADAPTTrial,Safety Evaluation,Clinical Pharmacology,Clinical Studies,Postmarketing Surveillance,Observational Studies,Conclusions,3,Roche/Bayer Presenters and Responders,Presenters:,LeonardM.Baum,RPh,Vice President,Regulatory Affairs,Bayer HealthCare,MartinH.Huber,M.D.,Vice President,Global HeadDrug Safety Risk Management,Hoffmann La-Roche Inc.,Responders:,Susan Sacks,Ph.D.,GlobalHead,Epidemiology,Hoffmann La-Roche Inc.,BharatThakrar,Ph.D.,SeniorEpidemiologist,Hoffmann La-Roche Inc.,Ernst Weidmann,M.D.,Head,Global Safety,Bayer HealthCare,Steve Zlotnick,Pharm.D,.,Director,Medical Affairs,Bayer HealthCare,4,OutsideExperts,Kay Brune,M.D.,Professor andChairman,Department ofExperimental and Clinical Pharmacology andToxicology,Friedrich-Alexander University Erlangen-Nuremberg,Ian M.Gralnek,M.D.,MSHS,Assistant Professor of Medicine,Divisionof Digestive Diseases,David Geffen School of Medicine atUCLA,5,Regulatory Overview,Naproxen available inthe United States since 1976,Prescription currently marketed bymultiple manufacturers for the treatment of RA,OA,ankylosingspondylitis,gout,juvenileRA,dysmenorrhea,tendinitis,bursitis,and pain,Aleve(OTC)approvedin 1994,Currently marketed byBayerHealthCare fortemporary relief ofminor aches and pains,and for thetemporary reduction of fever,Multiple generic versions,6,Naproxen,Naproxen,a nonsteroidal anti-inflammatorydrug(NSAID),belongs to the chemical class propionic acid derivatives,Naproxen has anti-inflammatory,analgesicand antipyretic properties,Naproxen knownto inhibit plateletaggregation,The major differencesbetween members of the NSAID classare potency and pharmacokinetics,7,Classesof NSAIDS,Salicylic acidderivatives,Aspirin,sodium salicylate,cholinemagnesium trisalicylate,salsalate,diflunisal,Para-aminophenol derivatives,Acetaminophen,Indoleand indene acetic acids,Indomethacin,sulindac,Heteroaryl acetic acids,Tolmetin,diclofenac,ketorolac,Propionic acids,Naproxen,ibuprofen,flurbiprofen,ketoprofen,fenoprofen,oxaprozin,Anthranilic acids(fenamates),Mefenamic acid,meclofenamicacid,Enolicacids,Oxicams(piroxicam,meloxicam),Alkanones,Nabumetone,Coxibs,Celecoxib,valdecoxib,rofecoxib(withdrawn),Source:Goodman and GilmansThe PharmacologicalBasis of Therapeutics,10,th,edition,8,Relevance of NaproxenData,The safety profile for naproxen iswell known,Naproxen is areference drugfor many analgesic clinicaltrials,Naproxen and other non-selective NSAIDs,are important treatment options fora broadrangeof patients and conditions,9,Naproxen Exposure Data(Rx and OTC),550,000,000 courses of therapy*,110,000,000 pts,Post-marketing,-,80,000 pts,Observational Studies,8,000 pts,10,000 pts,Clinical Trials,OTC,RX,*,coursesof therapy(2tab x10 days),10,The ADAPT Trial,NIH sponsoredstudy,Bayer providednaproxen sodium forinvestigational use,Study Design,Naproxen sodium 220 mg bid,Celecoxib 200mg bid,Placebo,PatientPopulation,2400 patients,age 70yearsor older,forprevention ofAlzheimers disease,Study Duration,Began in 2001,planned for 7years,suspended after 3 years,Sources:NIH News Dec20,2004;W Feb 1,2005,written by WoloshinS et al.,11,Publicly Reported Events Leading tothe Suspension of ADAPT,DSMB reviewon Dec.10,2004 did notrecommend stopping thestudy,The APC study wassuspended due to indications of an increase in cardiovascular andcerebrovascular risk ofcelecoxib vs.placebo(Dec.17,2004),NIA announced ADAPT trial suspension(Dec.20,2004),Informationreleased topublicby study group,were based onpreliminaryfindings,not through peer-reviewedjournals,Sources:CelebrexNews ReleaseDec 17,2004;NIHNewsDec 20,2004;,WFeb 1,2005,written byWoloshin Set al.,12,Summary,Naproxen isa non-selective COX-1/COX-2inhibitor,Widelyused,Establishedsafetyprofile,Reference standard,Unadjudicated preliminary findings of ADAPT needs to be looked atin context of thewide body ofdataon naproxen,13,MartinH.Huber,MD,GlobalHead,DrugSafety,Hoffmann-LaRocheInc.,P-14,SafetyEvaluation,Clinical Pharmacology,Clinical Studies,Post-Marketing Safety Surveillance,Post-Marketing ClinicalStudies,Observational Studies,15,Pharmacological Difference between Naproxen andCOX-2Inhibitors,Naproxen isa non-selective COX-1/COX-2 inhibitor,Naproxen isknownto inhibit platelet aggregation andthus,is notexpected tohavean increasedriskof myocardial infarction,16,Clinical Trials and Post-Marketing Surveillance,Clinical trials inthe prescriptionand OTC naproxen NDAs did notprovide anyevidence ofan increasedriskof myocardial infarctionor stroke,A review ofpostmarketing surveillance data showed nosignalfor MI or cerebrovascular accidentwith exposures toprescriptionnaproxen ofmorethan 110,000,000
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