鹽酸美金剛緩釋膠囊說明書

NDA22525HIGHLIGHTSOFPRESCRIBINGINFORMATIONThesehighlightsdonotincludealltheinformationneededtouseNAMENDAXRcapsulessafelyandeffectively.SeefullprescribinginformationforNAMENDAXRcapsules.NAMENDAXR(memantinehydrochlorideextendedreleasecapsulesInitialU.S.Approval:2003------------------------INDICATIONSANDUSAGE-------------------------NAMENDAXRcontainsmemantineHCl,anNMDAreceptorantagonistindicatedforthetreatmentofmoderatetoseveredementiaoftheAlzheimer’stype.(1---------------------DOSAGEANDADMINISTRATION-------------------InitialDose7mgNAMENDAXRoncedaily(2.1MaintenanceDose28mgNAMENDAXRoncedaily(2.1Aminimumof1weekoftreatmentwiththepreviousdoseshouldbeobservedbeforeincreasingthedose.(2.1Atargetdoseof14mgoncedailyisrecommendedinpatientswithsevererenalimpairment.(2.1-------------------DOSAGEFORMSANDSTRENGTHS-----------------NAMENDAXRisavailableasanextended-releasecapsule(3.1inthefollowingstrengths:7mg,14mg,21mg,28mg(3.1,3.2FULLPRESCRIBINGINFORMATION:CONTENTS*--------------------------------CONTRAINDICATIONS------------------------------NAMENDAXRiscontraindicatedinpatientswithknownhypersensitivitytomemantinehydrochlorideortoanyexcipientsusedintheformulation.(4.1------------------------WARNINGSANDPRECAUTIONS-----------------------ConditionsthatraiseurinepHmaydecreasetheurinaryeliminationofmemantineresultinginincreasedplasmalevelsofmemantine.(5.1---------------------------------ADVERSEREACTIONS----------------------------Themostcommonlyobservedadversereactionsoccurringatafrequencyofatleast5%andgreaterthanplacebowithadministrationofNAMENDAXR28mg/daywereheadache,diarrheaanddizziness.Otherlesscommonandsometimesseriousadverseeventshavebeenreported.(6ToreportSUSPECTEDADVERSEREACTIONS,ContactForestLaboratories,Inc.at1-800-678-1605orFDAat1-800-FDA-1088or/medwatch.---------------------------------DRUGINTERACTIONS-----------------------------UsewithotherNMDAantagonists(amantadine,ketamine,anddextromethorphanhasnotbeensystematicallyevaluatedandsuchuseshouldbeapproachedwithcaution.(7.1------------------------USEINSPECIFICPOPULATIONS-----------------------PediatricUse:ThesafetyandeffectivenessofNAMENDAXRinpediatricpatientshavenotbeenestablished.(8.3--------------------PATIENTCOUNSELINGINFORMATION------------------SeeSection17forPATIENTCOUNSELINGINFORMATIONANDFDAapprovedpatientlabeling.REVISED:[06/2010]1.INDICATIONSANDUSAGE7.4DrugsEliminatedviaRenalMechanisms2.DOSAGEANDADMINISTRATION7.5DrugsthatMaketheUrineAlkaline2.1RecommendedDosing7.6DrugsHighlyBoundtoPlasmaProteins3.DOSAGEFORMSANDSTRENGTHS7.7UsewithCholinesteraseInhibitors3.1DosageForm8.USEINSPECIFICPOPULATIONS3.2DosageStrengths8.1Pregnancy4.CONTRAINDICATIONS8.3NursingMothers4.1Hypersensitivity8.4PediatricUse5.WARNINGSANDPRECAUTIONS9.DRUGDEPENDENCE5.1GenitourinaryConditions10.OVERDOSAGE5.2Seizures11.DESCRIPTION6.ADVERSEREACTIONS12.CLINICALPHARMACOLOGY6.1ClinicalTrialDataSources12.1MechanismofAction6.2Pharmacodynamics6.3MostCommonAdverseReactions12.3Pharmacokinetics6.4VitalSignChanges12.4PharmacokineticsinSpecialPopulations6.5LaboratoryChanges13.NONCLINICALTOXICOLOGY6.6ECGChanges13.1Carcinogenesis,Mutagenesis,ImpairmentofFertility6.7OtherAdverseReactionsObservedDuringClinicalTrialsofNamendaXR13.2AnimalToxicology6.8MemantineImmediateReleaseClinicalTrialandPostMarketingSpontaneousReports14.CLINICALSTUDIES7.DRUGINTERACTIONS16.HOWSUPPLIED/STORAGEANDHANDLING7.1UsewithOtherN-methyl-D-aspartateAntagonists17.PATIENTCOUNSELINGINFORMATION7.2EffectofMemantineontheMetabolismofOtherDrugs7.3EffectofOtherDrugsonMemantine*Sectionsorsubsectionsomittedfromthefullprescribinginformationarenotlisted.FULLPRESCRIBINGINFORMATION1INDICATIONSANDUSAGENAMENDAXR(memantinehydrochlorideextended-releasecapsulesareindicatedforthetreatmentofmoderatetoseveredementiaoftheAlzheimer’stype.2DOSAGEANDADMINISTRATION2.1RecommendedDosingThedosageofNAMENDAXRshowntobeeffectiveinacontrolledclinicaltrialis28mgoncedaily.TherecommendedstartingdoseofNAMENDAXRis7mgoncedaily.Therecommendedtargetdoseis28mgoncedaily.Thedoseshouldbeincreasedin7mgincrementsto28mgoncedaily.Theminimumrecommendedintervalbetweendoseincreasesisoneweek,andonlyifthepreviousdosehasbeenwelltolerated.Themaximumrecommendeddoseis28mgoncedaily.NAMENDAXRcanbetakenwithorwithoutfood.NAMENDAXRcapsulescanbetakenintactormaybeopened,sprinkledonapplesauce,andtherebyswallowed.TheentirecontentsofeachNAMENDAXRcapsuleshouldbeconsumed;thedoseshouldnotbedivided.Exceptwhenopenedandsprinkledonapplesauce,asdescribedabove,NAMENDAXRshouldbeswallowedwhole.NAMENDAXRcapsulesshouldnotbedivided,chewed,orcrushed.SwitchingfromNAMENDATabletstoNAMENDAXRCapsules:PatientstreatedwithNAMENDAtabletsmaybeswitchedtoNAMENDAXRcapsulesasfollows:Itisrecommendedthatapatientwhoisonaregimenof10mgtwicedailyofNAMENDAtabletsbeswitchedtoNAMENDAXR28mgoncedailycapsulesthedayfollowingthelastdoseofa10mgNAMENDAtablet.Thereisnostudyaddressingthecomparativeefficacyofthese2regimens.Inapatientwithsevererenalimpairment,itisrecommendedthatapatientwhoisonaregimenof5mgtwicedailyofNAMENDAtabletsbeswitchedtoNAMENDAXR14mgoncedailycapsulesthedayfollowingthelastdoseofa5mgNAMENDAtablet.SpecialPopulations:HepaticImpairmentNodosageadjustmentisrecommendedinpatientswithmildormoderatehepaticimpairment.NAMENDAXRshouldbeadministeredwithcautiontopatientswithseverehepaticimpairment.RenalImpairmentNodosageadjustmentisrecommendedinpatientswithmildormoderaterenalimpairment.Atargetdoseof14mg/dayisrecommendedinpatientswithsevererenalimpairment(creatinineclearanceof5–29mL/min,basedontheCockroft-Gaultequation.3DOSAGEFORMSANDSTRENGTHS3.1DosageFormCapsule:Eachcapsulecontains7mg,14mg,21mgor28mgofmemantineHCl.The7mgcapsulesareayellowopaque#4sizecapsule,with“FLI7mg”blackimprint.The14mgcapsulesareayellowcapanddarkgreenopaquebody#4sizecapsule,with“FLI14mg”blackimprintontheyellowcap.The21mgcapsulesareawhitetooff-whitecapanddarkgreenopaquebody#4sizecapsule,with“FLI21mg”blackimprintonthewhitetooff-whitecap.The28mgcapsulesareadarkgreenopaque#3sizecapsule,with“FLI28mg”whiteimprint.3.2DosageStrengths?Each7mgcapsulecontains7mgmemantineHCl.?Each14mgcapsulecontains14mgmemantineHCl.?Each21mgcapsulecontains21mgmemantineHCl.?Each28mgcapsulecontains28mgmemantineHCl.Forafulllistofexcipients,seeDescription(11.4CONTRAINDICATIONS4.1HypersensitivityNAMENDAXRiscontraindicatedinpatientswithknownhypersensitivitytomemantinehydrochlorideortoanyexcipientsusedintheformulation[seeDescription(11].5WARNINGSANDPRECAUTIONS5.1GenitourinaryConditionsConditionsthatraiseurinepHmaydecreasetheurinaryeliminationofmemantineresultinginincreasedplasmalevelsofmemantine.5.2SeizuresNAMENDAXRhasnotbeensystematicallyevaluatedinpatientswithaseizuredisorder.Inclinicaltrialsofmemantine,seizuresoccurredin0.3%ofpatientstreatedwithmemantineand0.6%ofpatientstreatedwithplacebo.6ADVERSEREACTIONS6.1ClinicalTrialDataSourcesNAMENDAXRwasevaluatedinadouble-blindplacebo-controlledtrialtreatingatotalof676patientswithmoderatetoseveredementiaoftheAlzheimer’stype(341patientstreatedwithNAMENDAXR28mg/daydoseand335patientstreatedwithplaceboforatreatmentperiodupto24weeks.Becauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereactionratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreflecttheratesobservedinpractice.6.2AdverseReactionsLeadingtoDiscontinuationIntheplacebo-controlledclinicaltrialofNAMENDAXR(seeClinicalStudies(14,whichtreatedatotalof676patients,theproportionofpatientsintheNAMENDAXR28mg/daydoseandplacebogroupswhodiscontinuedtreatmentduetoadverseeventswere10.0%and6.3%,respectively.ThemostcommonadversereactionintheNAMENDAXRtreatedgroupthatledtotreatmentdiscontinuationinthisstudywasdizzinessatarateof1.5%.6.3MostCommonAdverseReactionsThemostcommonlyobservedadversereactionsseeninpatientsadministeredNAMENDAXRinthecontrolledclinicaltrial,definedasthoseoccurringatafrequencyofatleast5%intheNAMENDAXRgroupandatahigherfrequencythanplacebowereheadache,diarrheaanddizziness.Table1liststreatment-emergentadversereactionsthatwereobservedatanincidenceof≥2%intheNAMENDAXRtreatedgroupandoccurredatarategreaterthanplacebo.Table1:Adversereactionsobservedwithafrequencyof≥2%andoccurringwitharategreaterthanplaceboAdversereactionPlacebo(n=335%NAMENDAXR28mg(n=341%GastrointestinalDisordersAbdominalpain12InfectionsandinfestationsInvestigationsWeight,increased13MusculoskeletalandconnectivetissuedisordersBackpain13NervoussystemdisordersTable1:Adversereactionsobservedwithafrequencyof≥2%andoccurringwitharategreaterthanplaceboAdversereactionPlacebo(n=335%NAMENDAXR28mg(n=341%PsychiatricdisordersRenalandurinarydisordersUrinaryincontinence12Vasculardisorders6.4VitalSignChangesNAMENDAXRandplacebogroupswerecomparedwithrespectto(1meanchangefrombaselineinvitalsigns(pulse,systolicbloodpressure,diastolicbloodpressure,andweightand(2theincidenceofpatientsmeetingcriteriaforpotentiallyclinicallysignificantchangesfrombaselineinthesevariables.TherewerenoclinicallyimportantchangesinvitalsignsinpatientstreatedwithNAMENDAXR.AcomparisonofsupineandstandingvitalsignmeasuresforNAMENDAXRandplaceboinAlzheimer’spatientsindicatedthatNAMENDAXRtreatmentisnotassociatedwithorthostaticchanges.6.5LaboratoryChangesNAMENDAXRandplacebogroupswerecomparedwithrespectto(1meanchangefrombaselineinvariousserumchemistry,hematology,andurinalysisvariablesand(2theincidenceofpatientsmeetingcriteriaforpotentiallyclinicallysignificantchangesfrombaselineinthesevariables.TheseanalysesrevealednoclinicallyimportantchangesinlaboratorytestparametersassociatedwithNAMENDAXRtreatment.6.6ECGChangesNAMENDAXRandplacebogroupswerecomparedwithrespectto(1meanchangefrombaselineinvariousECGparametersand(2theincidenceofpatientsmeetingcriteriaforpotentiallyclinicallysignificantchangesfrombaselineinthesevariables.TheseanalysesrevealednoclinicallyimportantchangesinECGparametersassociatedwithNAMENDAXRtreatment.6.7OtherAdverseReactionsObservedDuringClinicalTrialsofNAMENDAXRFollowingisalistoftreatment-emergentadversereactionsreportedfrom750patientstreatedwithNAMENDAXRforperiodsupto52weeksindouble-blindoropen-labelclinicaltrials.ThelistingdoesnotincludethoseeventsalreadylistedinTable1,thoseeventsforwhichadrugcausewasremote,thoseeventsforwhichdescriptivetermsweresolackinginspecificityastobeuninformative,andthoseeventsreportedonlyoncewhichdidnothaveasubstantialprobabilityofbeingimmediatelylifethreatening.Eventsarecategorizedbybodysystem.BloodandLymphaticSystemDisorders:anemia.CardiacDisorders:bradycardia,myocardialinfarction.GastrointestinalDisorders:fecalincontinence,nausea.GeneralDisorders:asthenia,fatigue,gaitdisturbance,irritability,peripheraledema,pyrexia.InfectionsandInfestations:bronchitis,nasopharyngitis,pneumonia,upperrespiratorytractinfection,urinarytractinfection.Injury,PoisoningandProceduralComplications:fall.Investigations:weightdecreased.MetabolismandNutritionDisorders:anorexia,dehydration,decreasedappetite,hyperglycemia.MusculoskeletalandConnectiveTissueDisorders:arthralgia,paininextremity.NervousSystemDisorders:convulsion,dementiaAlzheimer'stype,syncope,tremor.PsychiatricDisorders:agitation,confusionalstate,delirium,delusion,disorientation,hallucination,insomnia,restlessness.Respiratory,ThoracicandMediastinalDisorders:cough,dyspnea.6.8MemantineImmediateReleaseClinicalTrialandPostMarketingSpontaneousReportsThefollowingadditionaladversereactionshavebeenidentifiedfrompreviousworldwideexperiencewithmemantine(immediatereleaseuse.Theseadversereactionshavebeenchosenforinclusionbecauseofacombinationofseriousness,frequencyofreporting,orpotentialcausalconnectiontomemantineandhavenotbeenlistedelsewhereinlabeling.However,becausesomeoftheseadversereactionswerereportedvoluntarilyfromapopulationofuncertainsize,itisnotalwayspossibletoreliablyestimatetheirfrequencyorestablishacausalrelationshipbetweentheiroccurrenceandtheadministrationofmemantine.Theseeventsinclude:BloodandLymphaticSystemDisorders:agranulocytosis,leukopenia(includingneutropenia,pancytopenia,thrombocytopenia.thromboticthrombocytopenicpurpura.CardiacDisorders:atrialfibrillation,atrioventricularblock(including2ndand3rddegreeblock,cardiacfailure,orthostatichypotension,andtorsadesdepointes.EndocrineDisorders:inappropriateantidiuretichormonesecretion.Gastrointestinaldisorders:colitis,pancreatitis.Generaldisordersandadministrationsiteconditions:malaise,suddendeath.HepatobiliaryDisorders:hepatitis(includingabnormalhepaticfunctiontest,cytolyticandcholestatichepatitis,hepaticfailure.Infectionsandinfestations:sepsis.Investigations:electrocardiogramQTprolonged,internationalnormalizedratioincreased.MetabolismandNutritionDisorders:hypoglycaemia,hyponatraemia.NervousSystemDisorders:convulsions(includinggrandmal,cerebrovascularaccident,dyskinesia,extrapyramidaldisorder,hypertonia,lossofconsciousness,neurolepticmalignantsyndrome,Parkinsonism,tardivedyskinesia,transientischemicattack.PsychiatricDisorders:hallucinations(bothvisualandauditory,restlessness,suicidalideation.RenalandUrinaryDisorders:acuterenalfailure(includingabnormalrenalfunctiontest,urinaryretention.SkinDisorders:rash,StevensJohnsonsyndrome.VascularDisorders:pulmonaryembolism,thrombophlebitis,deepvenousthrombosis.Thefollowingadverseeventshavebeenreportedtobetemporallyassociatedwithmemantinetreatmentandarenotdescribedelsewhereintheproductlabeling:aspirationpneumonia,bonefracture,carpaltunnelsyndrome,cerebralinfarction,chestpain,cholelithiasis,claudication,depressedlevelofconsciousness(includingrarereportsofcoma,dysphagia,encephalopathy,gastritis,gastroesophagealreflux,intracranialhemorrhage,hyperglycemia,hyperlipidemia,ileus,impotence,lethargy,myoclonus,supraventriculartachycardia,andtachycardia.However,thereisagainnoevidencethatanyoftheseadditionaladverseeventsarecausedbymemantine.7DRUGINTERACTIONSNodrug-druginteractionstudieshavebeenconductedwithNAMENDAXR,specifically,7.1UsewithotherN-methyl-D-aspartate(NMDAAntagonistsThecombineduseofNAMENDAXRwithotherNMDAantagonists(amantadine,ketamine,anddextromethorphanhasnotbeensystematicallyevaluatedandsuchuseshouldbeapproachedwithcaution.7.2EffectofMemantineontheMetabolismofOtherDrugsInvitrostudiesconductedwithmarkersubstratesofCYP450enzymes(CYP1A2,-2A6,-2C9,-2D6,-2E1,-3A4showedminimalinhibitionoftheseenzymesbymemantine.Inaddition,invitrostudiesindicatethatatconcentrationsexceedingthoseassociatedwithefficacy,memantinedoesnotinducethecytochromeP450isozymesCYP1A2,-2C9,-2E1and-3A4/5.Nopharmacokineticinteractionswithdrugsmetabolizedbytheseenzymesareexpected.Pharmacokineticstudiesevaluatedthepotentialofmemantineforinteractionwithdonepezil(SeeSection7.7UsewithCholinesteraseInhibitorsandbupropion.CoadministrationofmemantinewiththeAChEinhibitordonepezilHCldoesnotaffectthepharmacokineticsofeithercompound.MemantinedidnotaffectthepharmacokineticsoftheCYP2B6substratebupropionoritsmetabolitehydroxybupropion.7.3EffectofOtherDrugsonMemantineMemantineispredominantlyrenallyeliminated,anddrugsthataresubstratesand/orinhibitorsoftheCYP450systemarenotexpectedtoalterthepharmacokineticsofmemantine.Aclinicaldrug-druginteractionstudyindicatedthatbupropiondidnotaffectthepharmacokineticsofmemantine.7.4DrugsEliminatedviaRenalMechanismsBecausememantineiseliminatedinpartbytubularsecretion,coadministrationofdrugsthatusethesamerenalcationicsystem,includinghydrochlorothiazide(HCTZ,triamterene(TA,metformin,cimetidine,ranitidine,quinidine,andnicotine,couldpotentiallyresultinalteredplasmalevelsofbothagents.However,coadministrationofmemantineandHCTZ/TAdidnotaffectthebioavailabilityofeithermemantineorTA,andthebioavailabilityofHCTZdecreasedby20%.Inaddition,coadministrationofmemantinewiththeantihyperglycemicdrugGlucovance?(glyburideandmetforminHCldidnotaffectthepharmacokineticsofmemantine,metforminandglyburide.Furthermore,memantinedidnotmodifytheserumglucoseloweringeffectofGlucovance?,indicatingtheabsenceofapharmacodynamicinteraction.7.5DrugsThatMaketheUrineAlkalineTheclearanceofmemantinewasreducedbyabout80%underalkalineurineconditionsatpH8.Therefore,alterationsofurinepHtowardsthealkalineconditionmayleadtoanaccumulationofthedrugwithapossibleincreaseinadverseeffects.UrinepHisalteredbydiet,drugs(e.g.carbonicanhydraseinhibitors,sodiumbicarbonateandclinicalstateofthepatient(e.g.renaltubularacidosisorsevereinfectionsoftheurinarytract.Hence,memantineshouldbeusedwithcautionundertheseconditions.7.6DrugsHighlyBoundtoPlasmaProteinsBecausetheplasmaproteinbindingofmemantineislow(45%,aninteractionwithdrugsthatarehighlyboundtoplasmaproteins,suchaswarfarinanddigoxin,isunlikely[seeSection7.].7.7UsewithCholinesteraseInhibitorsCoadministrationofmemantinewiththeAChEinhibitordonepezilHCldidnotaffectthepharmacokineticsofeithercompound.Ina24-weekcontrolledclinicalstudyinpatientswithmoderatetosevereAlzheimer’sdisease,theadverseeventprofileobservedwithacombinationofmemantineimmediate-releaseanddonepezilwassimilartothatofdonepezilalone.8.USEINSPECIFICPOPULATIONS8.1PregnancyPregnancyCategoryB:Therearenoadequateandwell-controlledstudiesofNAMENDAXRinpregnantwomen.NAMENDAXRshouldbeusedduringpregnancyonlyifthepotentialbenefitjustifiesthepotentialrisktothefetus.Memantinegivenorallytopregnantratsandpregnantrabbitsduringtheperiodoforganogenesiswasnotteratogenicuptothehighestdosestested(18mg/kg/dayinratsand30mg/kg/dayinrabbits,whichare6and21times,respectively,themaximumrecommendedhumandose[MRHD]onamg/m2basis.Slightmaternaltoxicity,decreasedpupweightsandanincreasedincidenceofnon-ossifiedcervicalvertebraewereseenatanoraldoseof18mg/kg/dayinastudyinwhichratsweregivenoralmemantinebeginningpre-matingandcontinuingthroughthepostpartumperiod.Slightmaternaltoxicityanddecreasedpupweightswerealsoseenatthisdoseinastudyinwhichratsweretreatedfromday15ofgestationthroughthepost-partumperiod.Theno-effectdosefortheseeffectswas6mg/kg,whichis2timestheMRHDonamg/m2basis.8.3NursingMothersItisnotknownwhethermemantineisexcretedinhumanmilk.Becausemanydrugsareexcretedinhumanmilk,cautionshouldbeexercisedwhenmemantineisadministeredtoanursingmother.8.4PediatricUseThesafetyandeffectivenessofmemantineinpediatricpatientshavenotbeenestablished.9DRUGABUSEANDDEPENDENCEMemantineisnotacontrolledsubstance.MemantineisalowtomoderateaffinityuncompetitiveNMDAantagonistthatdidnotproduceanyevidenceofdrug-seekingbehaviororwithdrawalsymptomsupondiscontinuationin3,254patientswhoparticipatedinclinicaltrialsattherapeuticdoses.Postmarketingdata,outsidetheU.S.,retrospectivelycollected,hasprovidednoevidenceofdrugabuseordependence.10OVERDOSAGESignsandsymptomsmostoftenaccompanyingoverdosagewithotherformulationsofmemantineinclinicaltrialsandfromworldwidemarketingexperience,aloneorincombinationwithotherdrugsand/oralcohol,includeagitation,asthenia,bradycardia,confusion,coma,dizziness,ECGchanges,increasedbloodpressure,lethargy,lossofconsciousness,psychosis,restlessness,slowedmovement,somnolence,stupor,unsteadygait,visualhallucinations,vertigo,vomiting,andweakness.Thelargestknowningestionofmemantineworldwidewas2gramsinanindividualwhotookmemantineinconjunctionwithunspecifiedantidiabeticmedications.Thispersonexperiencedcoma,diplopia,andagitation,butsubsequentlyrecovered.OnepatientparticipatinginaNAMENDAXRclinicaltrialunintentionallytook112mgofNAMENDAXRdailyfor31daysandexperiencedanelevatedserumuricacid,elevatedserumalkalinephosphatase,andlowplateletcount.Nofatalitieshavebeennotedwithoverdosesofmemantinealone.Afataloutcomehasveryrarelybeenreportedwhenmemantinehasbeeningestedaspartofoverdosingwithmultipledrugs;inthoseinstances,therelationshipbetweenmemantineandafataloutcomehasbeenunclear.Becausestrategiesforthemanagementofoverdosearecontinuallyevolving,itisadvisabletocontactapoisoncontrolcentertodeterminethelatestrecommendationsforthemanagementofanoverdoseofanydrug.Asinanycasesofoverdose,generalsupportivemeasuresshouldbeutilized,andtreatmentshouldbesymptomatic.Eliminationofmemantinecanbeenhancedbyacidificationofurine.11DESCRIPTIONNAMENDAXRisanorallyactiveNMDAreceptorantagonist.Thechemicalnameformemantinehydrochlorideis1-amino-3,5-dimethyladamantanehydrochloridewiththefollowingstructuralformula:NH2.HClH3CH3ThemolecularformulaisC12H21N?HClandthemolecularweightis215.76.MemantineHCloccursasafinewhitetooff-whitepowderandissolubleinwater.NAMENDAXRcapsulesaresuppliedfororaladministrationas7,14,21and28mgcapsules(seeHowSuppliedSection16.EachcapsulecontainsextendedreleasebeadswiththelabeledamountofmemantineHClandthefollowinginactiveingredients:sugarspheres,polyvinylpyrrolidone,hypromellose,talc,polyethyleneglycol,ethylcellulose,ammoniumhydroxide,oleicacid,andmediumchaintriglyceridesinhardgelatincapsules.12CLINICALPHARMACOLOGY12.1MechanismofActionPersistentactivationofcentralnervoussystemN-methyl-D-aspartate(NMDAreceptorsbytheexcitatoryaminoacidglutamatehasbeenhypothesizedtocontributetothesymptomatologyofAlzheimer’sdisease.Memantineispostulatedtoexertitstherapeuticeffectthroughitsactionasalowtomoderateaffinityuncompetitive(open-channelNMDAreceptorantagonistwhichbindspreferentiallytotheNMDAreceptor-operatedcationchannels.ThereisnoevidencethatmemantinepreventsorslowsneurodegenerationinpatientswithAlzheimer’sdisease.12.2PharmacodynamicsMemantineshowedlowtonegligibleaffinityforGABA,benzodiazepine,dopamine,adrenergic,histamineandglycinereceptorsandforvoltage-dependentCa2+,Na+orK+channels.Memantinealsoshowedantagonisticeffectsatthe5HT3receptorwithapotencysimilartothatfortheNMDAreceptorandblockednicotinicacetylcholinereceptorswithone-sixthtoone-tenththepotency.Invitrostudieshaveshownthatmemantinedoesnotaffectthereversibleinhibitionofacetylcholinesterasebydonepezil,galantamine,ortacrine.12.3PharmacokineticsMemantineiswellabsorbedafteroraladministrationandhaslinearpharmacokineticsoverthetherapeuticdoserange.Itisexcretedpredominantlyunchangedinurineandhasaterminaleliminationhalflifeofabout60-80hours.Inastudycomparing28mgoncedailyNAMENDAXRto10mgtwicedailyNAMENDACmaxandAUC0-24valueswere48%and33%higherfortheXRdosageregimen,respectively.AbsorptionAftermultipledoseadministrationofNAMENDAXR,memantinepeakconcentrationsoccuraround9-12hourspostdose.ThereisnodifferenceintheabsorptionofNAMENDAXRwhenthecapsuleistakenintactorwhenthecontentsaresprinkledonapplesauce.Thereisnodifferenceinmemantineexposure,basedonCmaxorAUC,forNAMENDAXRwhetherthatdrugproductisadministeredwithfoodoronanemptystomach.However,peakplasmaconcentrationsareachievedabout18hoursafteradministrationwithfoodversusapproximately25hoursafteradministrationonanemptystomach.DistributionThemeanvolumeofdistributionofmemantineis9-11L/kgandtheplasmaproteinbindingislow(45%.MetabolismMemantineundergoespartialhepaticmetabolism.ThehepaticmicrosomalCYP450enzymesystemdoesnotplayasignificantroleinthemetabolismofmemantine.EliminationMemantineisexcretedpredominantlyintheurine,unchanged,andhasaterminaleliminationhalflifeofabout60-80hours.About48%ofadministereddrugisexcretedunchangedinurine;theremainderisconvertedprimarilytothreepolarmetaboliteswhichpossessminimalNMDAreceptorantagonisticactivity:theN-glucuronideconjugate,6-hydroxymemantine,and1-nitroso-deaminatedmemantine.Atotalof74%oftheadministereddoseisexcretedasthesumoftheparentdrugandtheN-glucuronideconjugate.RenalclearanceinvolvesactivetubularsecretionmoderatedbypHdependenttubularreabsorption.12.4PharmacokineticsinSpecialPopulationsHepaticImpairmentMemantinepharmacokineticswereevaluatedfollowingtheadministrationofsingleoraldosesof20mgin8subjectswithmoderatehepaticimpairment(Child-PughClassB,score7-9and8subjectswhowereage-,gender-,andweight-matchedtothehepatically-impairedsubjects.Therewasnochangeinmemantineexposure(basedon