volume 29, issue 6 march 2014 - university of florida

PharmaNote Volume 29 Issue 6 March 2014 1

ajordepressivedisorder(MDD)isacom-monandprevailingmentaldisorderthataffectsanindividual’soverallhealth,qualityoflifeandproductivity.Thean-

nualandlifetimeprevalenceofMDDinUnitedStatesis6.7%and16.5%oftheadultpopulation,respectively,and50%to80%willexperiencean-otherdepressiveepisode.1,2MDDalsocarriesasigni icanteconomicburdeninUnitedStates,con-tributing$83.1billioninhealthcareandproduc-tivitycostsin2000.3Theexactpathophysiologyisstillunknownbutlikelymulti-factorialandasso-ciatedwithdifferentneurotransmitterpathways.4

Longtermtreatmentwithantidepressantscanreducereoccurrenceupto70%.5However,upto40%ofaffectedindividualsdonotreceivetreatment.6ForindividualsreceivingtreatmentforMDDtherearemanyoptions.Pharmacologictreatmentoptionsincludeserotonin-norepinephrinereuptakeinhibitors(SNRIs),se-lectiveserotoninreuptakeinhibitors(SSRIs),ser-otoninmodulators,atypicalantidepressants,monoamineoxidaseinhibitorsandtricyclicanti-depressants.7Inspiteoftheavailableoptions,MDDcontinuestobedif iculttotreat.Majorob-staclesincludedelayedtherapeuticeffect,highnon-responserateduetoheterogeneoustreat-mentresponses,adverseeffects,andconsequent

lowcompliance.8Inresponsetothesetreatmentissuesandamultifactorialpathophysiology,new-erantidepressantstargetdifferentbutcomple-mentarytherapeuticmechanismofactions.

Vortioxetine(Brintellixa)isoneofthenewmulti-modalantidepressants.OnSeptember30,2013,theFDAapprovedvortioxetineformajordepressivedisorderinadults.Itwasjointlymar-ketedbyLundbeckandTakedaPharmaceuticalsIncorporated.Theobjectivesofthispaperaretoreviewthepharmacology,pharmacokinetics,per-tinentclinictrials,safetyanddosingofvortiox-etine.

P P

VortioxetineisaSSRIthatbindstothepre-

synapticserotoninreuptakesite,increasingthelevelofserotonin(5-HT)intheneuronalsynapse,aswellasselectivelybindingtoavarietyofotherserotoninreceptors.Itselectivelybindstoandactsasanantagonistto5-HT3,5-HT1D,and5-HT7receptors,partialagonistto5-HT1Breceptors,andagonistto5-HT1Areceptors(Table1).8Althougheachserotoninreceptorsubtypeisassociatedwithdifferentfunctions,theclinicaleffectsofthesereceptoractivitymodulationsinvortiox-etinearestillunknown(Table2).9,10Its5-HT1A

Volume 29, Issue 6 March 2014

®

Vortioxetine(Brintellix®):AReview

Qian Ya Lensa Zeng, PharmD Candidate

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VortioxetinewasgrantedapprovalintheUnitedStatesbasedonsixshort-termtrialsandonemaintenancestudyinadultpatientswithDi-agnosticandStatisticalManualofMentalDisor-ders,FourthEdition,TextRevision(DSM-IV-TR)majordepressivedisorder.9,13,17-21Thesetrialswererandomized,multi-center,double-blinded,placebo-controlled, ixed-dosetrials.Approxi-matelyhalfofthesestudieswerepresentedasab-stractsattheAmericanPsychiatricAssociationannualmeetingandhavenotyetbeenpublishedorpeer-reviewed.Theexclusioncriteriavariedbetweenstudiesbutgenerallyexcludedpartici-pantswithahistoryofapsychiatric,neurologic,orsubstanceabusedisorderbesidesdepression,clinicallysigni icantmedicalcomorbidities,con-sideredatriskofsuicidalbehavior,

agonistactivitymaysupplementtheantidepres-santactivitysimilartotheproposedmechanismforbuspironeandvilazodone.9,11,12In-vivostud-iesfoundvortioxetinewasassociatedwithin-creasedlevelsotherneurotransmitters,suchasdopamine,norepinephrine,acetylcholineandhis-tamine,inadditiontoserotonin.13Vortioxetineiscurrentlybeinginvestigatedforitsanxiolyticandpotentialprocognitiveeffects,whichmaybeduetothereceptoractivitymodulations.

Inclinicaltrials,vortioxetinedisplayedalineardose-responserelationshipwithahalf-lifeof66hours.Therelativelylonghalf-lifeallowsoncedailydosingandmaypossiblyreducethereboundandwithdrawaleffectsfrommissingdosesorstoppingthedrug.Afteroraladministra-tion,peakplasmaconcentrationswereachievedin7to11hoursandvortioxetinedisplayed75%bioavailability.Sincefooddidnothaveanob-servedeffect,vortioxetinecanbetakenwithoutregardstofood.9

VortioxetineisprimarilymetabolizedbythecytochromeP450(CYP)pathwayintheliver.AlthoughvortioxetineisasubstrateformanyCYPenzymes,CYP2D6istheprimaryenzyme,whichmetabolizesvortioxetinetoapharmacologicallyinactivemetabolite.Thus,dosingadjustmentmaybenecessaryforpeopletakingstrongCYP2D6in-hibitorsorinducersconcomitantlywithvortiox-etine.9Noadjustmentisneededforrenalimpair-mentormildtomoderatehepaticimpairment.Nodoseadjustmentsareneededforagealthoughvortioxetinehasnotbeenstudiedinthepediatricpopulation.

Table1|ReceptorPro ilesfortheNewMulti‐ModalAntidepressantsComparedwithCom‐monlyUsedSSRIsandSNRIs8,23

Class Drug 5‐HT1A 5‐HT1B 5‐HT2C 5‐HT3 5‐HT7SERTinhibition

NETinhibition

DATinhibition

SSRI Citalopram +++

Fluoxetine ++ +++

SNRI Duloxetine +++ +++ +

Venlafaxine +++ ++

Vilazodone +++ +++

Vortioxetine +++ +++ +++ +++ +++

DAT:dopaminetransporter;NET:norepinephrinetransporter;SERT:serotonintransporter;+:weakaf inity;++:moder-ateaf inity;+++:strongaf inity.AdaptedfromRichelsonetal.8

Multi‐modal

Table 2 | Loca on and Clinically Relevant Func-on of Selected Serotonin Subtype Receptors10

Receptor Subtype

Loca on Func on

5-HT1A CNS Neuronal inhibi on, behavioral effects (sleep, feeding, thermoregula on, and anxiety)

CNS Presynap c inhibi on, behavioral effects

Vascular Pulmonary vasoconstric on

5-HT1D Unknown Unknown

5-HT3 GI tract Sensory and enteric nerves, emesis

5-HT7 CNS, blood vessels, GI tract

Unknown

5‐HT: serotonin; CNS: central nervous system; GI: Gastroin‐tes nal. Adapted from Mohammad‐Zadeh et al.10

5-HT1B


mild-to-moderatedepressionortreatment-resistantdepression.ThemeanbaselineMADRSorHDRS-24scoreacrossallthesixshort-termtrialswasapproximately30,re lectingahighmoderatetoseveredepressionpatientpopula-tion.14,15Theprimaryendpointofallthestudieswaschangeintotalscoreofavalidateddepres-sionscalefrombaselinecomparedtoplacebo.AllthestudiesusedMontgomery-AsbergDepressionRatingScale(MADRS)excepttwostudiesusedHamiltonDepressionScale(HDRS-24).AlthoughHDRS-24hasbeenmorecommonlyusedinclini-caltrials,thereisahighcorrelationbetweenthetwoscales.16Forbothscales,ahigherscoreisas-sociatedwithincreasedseverity.

Fiveoftheshort-termclinicaltrialswereconductedinadultsbetweentheagesof18to75yearsdiagnosedwithMDD(Table3).17-21Thesetrialswereapproximately6to8weekslongandthreeofthe ivestudieswereconductedoutsideoftheUnitedStatesandmostlyinEurope.Collec-tively,theparticipantswererandomizedtooneofthetreatmentgroups(vortioxetine5mg,10mg,15mgor20mg)orplacebooncedaily.Partici-pantsassignedto15mgor20mgweretitratedfrom10mgwithin1week.AlvarezetalandBou-lengeretalusedvenlafaxineXR225mgdailyastheactivecontrolforassaysensitivitytovalidatetheir indings.16,17Itisunknownwhethertheoth-erthreetrialsusedanactivecontrolsincetheyhavenotbeenpublished.Ineachofthe ivetrials,atleastoneofthevortioxetinearmshadstatisti-callysigni icantchangesindepressionscorescomparedtoplacebo(Table3).Ofnote,thestatis-ticallysigni icantdifferencesindepressionscorefromplaceborangedfrom-4.1to-7.1inthenon-USstudiesand-2.8to-3.6intheUSstudies.Thecauseandsigni icanceofthenon-USstudiescon-sistentlyachievingahigherreductioninseverityscoreshavenotbeendetermined.Possiblerea-sonsaredifferencesincompliance,reportingre-sponses,anddifferencesinweightbetweenEuro-peanandAmericanpopulations.

Katonaetalconductedan8-week,multi-centertrialin453elderlypatientswithMDDwhorangedbetween64and88yearsoldinsevencountries,includingtheUnitedStates.Partici-pantswererandomlyassignedtovortioxetine5mg,placebo,orduloxetine60mg,whichwasthe

activecontrol.13Participantswereconsideredre-spondersiftheyhad50%orgreaterreductionintotalHDRS-24scoreatendpointcomparedtotheirbaselinescore.Signi icantlymorepartici-pantsinthevortioxetinegroupwereresponderscomparedtoplacebo(53.2%versus35.2%,P<0.05)(Table3).Nauseawasthesolesideeffectsigni icantlymoreprevalentinthetreatmentarmcomparedtoplacebo(21.8%versus8.3%,P<0.01).Inaddition,cognitiveeffectsindependentoftheantidepressanteffectwereexploredbyas-sessingchangesinscoresforReyAuditoryVerbalLearningTest(RAVLT)andTheDigitSymbolSub-stitutionTest(DSST).Bothduloxetineandvorti-oxetinewereassociatedwithanimprovementinverballearningbutonlyvortioxetinewasassoci-atedwithanimprovementinmemoryandpro-cessingspeedcomparedtoplacebo.Theinvesti-gatorsconcludedthatvortioxetineisbothsafeandef icaciousinelderlypatientsandmayhavepro-cognitiveeffects.

Inadditiontotheshort-termclinicaltrials,a52-weekrelapsepreventionstudywasconduct-edtoassessthelongtermef icacyinpatientwithmoderatetosevereMDDandatleastonepriordepressiveepisode.22Severitywasre lectedinthemeanbaselineMADRStotalscoreof32.5.Thisstudywasconductedin17countries,butwasnotconductedintheUnitedStates.Thestudypopula-tionconsistedof396oftheinitial639partici-pantsbetweentheagesof18and75yearsthatwerediagnosedtobeinremissionbyendofanopen-label, lexibledosingacutetreatmentphase.Remissionwasde inedasaMADRStotalscoreof10orless.Theeligibleparticipantswererandom-izedtoreceiveindividualized ixedtreatmentdose(5mgor10mg)orplacebofor24to46weeks.Theprimaryoutcomewastimetorelapsewithinthe irst24weeksofthedouble-blindphasewhererelapsewasde inedasaMADRSscoreof22orgreater.Thetimetorelapsewastwiceaslongwithvortioxetinecomparedtopla-cebo(HR=2.01,p=0.0035).Therelapserateofthevortioxetinegroupwas13%comparedto26%oftheplacebogroup(p=0.0013).Thedis-continuationrateduetosideeffectswas8%intheopen-label, lexibledosingphasethatallowedeither5mgor10mgtreatmentdoses.Inthedou-ble-blindphase,thediscontinuationrateswere


8%inthevortioxetinegroupand3%intheplace-bogroup.Theinvestigatorsconcludedvortiox-etinesigni icantlyreducestheriskofrecurrentdepressiveepisodescomparedtoplaceboandiswelltoleratedforlong-termuse.

Therearekeylimitationstothedatafromthesestudies.Althoughhavinganactivecontrolincreasesthevalidityoftheresults,noneofthestudieswerepoweredtodirectlycomparevorti-oxetinetotheactivecontrol.Moreimportantly,similartomostclinicaltrials,generalizabilityof

thedataislimitedsincethetrialsexcludedpa-tientsthatarerepresentativeofthegeneralpa-tientpopulationtreatedinclinicalpractice,suchastreatment-resistantpatientsandpatientswithmultiplecomorbidities.Inaddition,itisunclearofthesigni icanceofthevaryingresultsbetweennon-USpopulationandUS-population.FurtherstudiesconductedintheUSassessingvortiox-etineinpeoplewithtreatment-resistancedepres-sionorwhohaveotherconcomitantdisordersareneeded.

Table3|SummaryofPrimaryOutcomeResultsofthe6to8weekClinicalTrials9,13,17,18,19,20,21

ClinicalTrialLocation

TreatmentGroup Numberofpatients

PrimaryMeasureDepressionRatingScale

MeanBase‐lineScore

LSMeanChangefromBase‐line(SE)

Placebo‐subtractedDifference(95%CI)

Alvarezetal17Non‐USStudy

Vortioxetine5mg/day

Vortioxetine10mg/dayPlacebo

108

100105

MADRS 34.1(2.6)

34.0(2.8)33.9(2.7)

-20.4(1.0)

-20.2(1.0)-14.5(1.0)

-5.9

(-8.6,-3.2)

-5.7

(-8.5,-2.9)

Henigsbergetal18Non‐USStudy

Vortioxetine5mg/day

Vortioxetine10mg/day

Placebo

139

139

139

HAMD-24 32.2(5.0)

33.1(4.8)

32.7(4.4)

-15.4(0.7)

-16.2(0.8)

-11.3(0.7)

-4.1

(-6.2,-2.1)-4.9

(-7.0,-2.9)

Boulengeretal19Non‐USStudy


Vortioxetine20mg/dayPlacebo

149

151158

MADRS 31.8(3.4)

31.2(3.4)31.5(3.6)

-17.2(0.8)

-18.8(0.8)-11.7(0.8)

-5.5

(-7.7,-3.4)

-7.1

(-9.2,-5.0)

Mahable‐shwarkaretal20USStudy



Placebo

145

147

153

MADRS 31.9(4.1)

32.0(4.4)

31.5(4.2)

-14.3(0.9)

-15.6(0.9)

-12.8(0.8)

-1.5

(-3.9,0.9)

-2.8

(-5.1,-0.4)

Jacobsenetal21USStudy



Placebo

154

148

155

MADRS 32.2(4.5)

32.5(4.3)

32.0(4.0)

-13.0(0.8)

-14.4(0.9)

-10.8(0.8)

-2.2

(-4.5,0.1)

-3.6

(-5.9,-1.4)

Katonaetal13USandNon‐USStudyElderly

Vortioxetine5mg/day

Placebo

155

145

HAMD-24 29.2(5.0)

29.1(5.1)

-13.7(0.7)

-10.3(0.8)

-3.3

(-5.3,-1.3)

AdaptedfromBrintellix(vortioxetine)packageinsert9


A E D I

Manyofvortioxetine’sreportedadverseeffectsanddruginteractionsareexpected.Itsmostcommonsideeffectsaregastrointestinalandneurological,suchasnausea,diarrhea,consti-pation,dizzinessandabnormaldreams.OthercommonsideeffectsarelistedinTable4.9Ifpa-tientsexperienceintolerablesideeffects,lower-ingtheinitialdosemaybebene icial.

Ararebutserioussideeffectcharacteristicofallantidepressantsthatmodulateserotoninreuptakeisincreasedriskofsuicide.Short-termtrialsindicatethatonlyparticipantsyoungerthan24yearsoldtakingvortioxetinewereobservedtobeatrisk,butallpatientsshouldbecloselymoni-tored.9Otherserioussideeffectsthatrequiremonitoringincludehypersensitivity,angioedema,andmaniaorhypomania.Thus,patientsshouldbescreenedforriskofbipolardisorderpriortoinitiatingvoritioxetine.9Currentlyavailabledatasuggestsvortioxetineisweightneutral.Onlythemaleparticipantstakingvortioxetinereportedahigherincidenceofsexualdysfunctioncomparedtotheircounterpartstakingplacebo(Table5).9SimilartootherSSRIsandSNRIs,hyponatremiahasbeenreported;patientsconcomitantlytakingdiureticsandelderlypatientsmaybeathigherrisk.Nootherclinicalimportantchangesinlabor-atorytestsandvitalsigns,includingbloodpres-sureandheartrate,havebeenobserved.

Vortioxetinehassomekeydruginterac-tions.PatientsconcomitantlytakingNSAIDS,aspi-rin,oranticoagulantssuchaswarfarinareatin-creasedbleedingrisk.Vortioxetineuseiscontra-indicatedwiththefollowingmedicationsduetoanincreaseriskofserotoninsyndrome:MAOin-hibitors,linezolidandintravenousmethyleneblue.Cautionshouldbeexercisedinpatientscon-comitantlytakingvortioxetineandserotonergicagents;bothmedicationsshouldbediscontinuedifserotoninsyndromedevelops.Sincevortiox-etineisprimarilymetabolizedbytheCYP2D6en-zyme,itsserumdruglevelsmaychangewhentak-enwithmedicationsthatinduceorinhibitCYP2D6.Therecommendedmaximumdoseisreducedby50%to10mgdailyinknownCYP2D6poormetabolizersorpatientsconcomitantlytak-ingastrongCYP2D6inhibitor,suchasbupropion,

luoxetine,paroxetine,orquinidine.Ofnote,con-comitantuseof luoxetineorparoxetinewithvor-tioxetinemayincreaseriskofserotoninsyndromeinadditiontoserumvortioxetineconcentration.Conversely,adoseincreasemaybewarrantedinpatientstakingastrongCYP2C6inducer,suchasrifampin,carbamazepine,orphenytoin,forgreat-erthan14days.9

D

Itisrecommendedthatpatientsinitially

startwith10mgorallyoncedailywithoutregardstofoodandtitrateastolerated.Patientsshouldbetitrateddownto5mgdailyiftheyexperiencein-tolerablesideeffects.Themaximumrecommend-eddoseis20mgdaily.However,forpoorCYP2D6metabolizersorpatientsconcomitantlytakingastrongCYP2C6inhibitor,themaximumrecom-mendeddoseis10mgdaily.Doseincreasesupto

Table4|CommonAdverseReactionsOccur‐ringin≥2%ofPatientsTreatedwithanyVor‐tioxetineDoseandatLeast2%MoreFre‐quentlythanIncidenceinPlacebo‐treatedPa‐tientsinthe6to8WeekPlacebo‐ControlledStudies9

DoseofVortioxetine

5mgperday

10mgperday

15mgperday

20mgperday

N=1013(%)

N=699(%)

N=449(%)

N=455(%)

Gastrointestinaldisorders

Nausea 21 26 32 32

Diarrhea 7 7 10 7

Drymouth 7 7 6 8

Constipation 3 5 6 6

Vomiting 3 5 6 6

Flatulence 1 3 2 1

Nervoussystemdisorders

Dizziness 6 6 8 9

Psychiatricdisorders

Abnormaldreams

6 6 8 9

Pruritus 1 2 3 3

Skinandsubcutaneoustissuedisorders


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GuidelinefortheTreatmentofPatientsWithMajorDe-pressiveDisorder.3rded.Arlington,VA:AmericanPsy-chiatricAssociation;2010.AmericanPsychiatricAssoci-ation.

8. RichelsonE.Multi-modality:anewapproachforthetreatmentofmajordepressivedisorder.IntJNeuropsy-chopharmacol.2013July;16(6):1433–1442.

9. Brintellix(vortioxetine)packageinsert.Deer ield,IL:TakedaPharmacueticalsAmerica,Inc.;2013Sept.

10. Mohammad-Zadeh,L.F.,Moses,L.,Gwaltney-Brant,S.M.Serotonin:areview.JVetPharmacolTher.2008Jun;31(3):187-99.

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13. KatonaC,HansenT,OlsenCK.Arandomized,double-blind,placebo-controlled,duloxetine-referenced, ixed-dosestudycomparingtheef icacyandsafetyofLuAA21004inelderlypatientswithmajordepressivedis-order.IntClinPsychopharmacol.2012Jul;27(4):215-23.

14. FrankE,PrienRF,JarrettRB,KellerMB,KupferDJ,La-voriPW,RushAJ,WeissmanMM:Conceptualizationandrationaleforconsensusde initionsoftermsinmajordepressivedisorder.Remission,recovery,relapse,andrecurrence.ArchGenPsychiatry1991;48:851–5.

15. SnaithRP,HarropFM,NewbyPA,TealeC.GradescoresoftheMontgomery-Asbergdepressionandtheclinicalanxietyscales.BrJPsychiatry.1986;148:599–601.

16. FoodandDrugAdministration.DescriptionoftheHam-iltonDepressionRatingScale(HAMD)andtheMont-gomery-AsbergDepressionRatingScale(MADRS)http://www.fda.gov/ohrms/dockets/ac/07/brie ing/2007-4273b1_04-descriptionofmadrshamddepressionr%281%29.pdf.AccessedNovember172013.

17. AlvarezE,PerezV,DragheimM,LoftH,ArtigasF.Adou-ble-blind,randomized,placebo-controlled,activerefer-encestudyofLuAA21004inpatientswithmajorde-pressivedisorder.IntJNeuropsychopharmacol.2012Jun;15(5):589-600.

18. HenigsbergN,MahableshwarkarAR,JacobsenP,ChenY,ThaseME.Arandomized,double-blind,placebo-controlled8-weektrialoftheef icacyandtolerabilityofmultipledosesofLuAA21004inadultswithmajorde-pressivedisorder.JClinPsychiatry.2012;73:953-959.

19. BoulengerJP,LoftH,OlsenCK.Arandomized,double-blind,placebo-controlled,duloxetine-referencedstudyoftheef icacyandsafetyofvortioxetineinacutetreat-mentofMDD.Programandabstractsofthe166thAn-nualAmericanPsychiatricAssociationMeeting;May18-22,2013;SanFrancisco,California.PosterNR3-054.

20. MahableshwarkarAR,JacobsenPL,SerenkoM,ChenY,TrivediM.Arandomized,double-blind,parallelgroupstudycomparingtheef icacyandsafetyof2dosesofvortioxetineinadultswithmajordepressivedisorder.

threetimestheoriginaldosemaybeconsideredinpatientstakingastrongCYP2D6inducerforgreaterthan14days.Nodoseadjustmentsarerecommendedforgeriatricpatients,renalimpair-mentandmildtomoderatehepaticfailure.

S

Vortioxetineisanewmultimodalantide-

pressantindicatedforMDDinadults.InadditiontobeingaSSRI,vortioxetinehasmodulatingactiv-ityofavarietyofserotoninreceptors.Speci ically,itactsasanantagonistto5-HT3,5-HT1D,and5-HT7receptors,partialagonistat5-HT1Breceptors,andagonistat5-HT1Areceptorsbuttheclinicaleffectsremainsunknown.Itisanewoptionforacuteandlong-termtreatment.However,majori-tyoftheclinicaltrialsusedtosupportitsapprovalwereshort-term,conductedoutsidetheUnitedStatesandexcludedpatientsthatarecommonlyseeninclinicalpractice.Patientsshouldbestart-edon10mgdailyandcanbetitratedupto20mgdaily;somepatientsexperiencingsideeffectsmaybene itfromhavingtheirinitialdosereducedto5mgdaily.Vortioxetinecanbetakenwithoutre-gardtomealsandnodoseadjustmentsareneed-edforage,renalfunctionormildtomoderatehe-paticimpairment.However,thereispotentialfordruginteractions,patientstakingstrongCYP2D6inhibitorsorinducersmayrequiredoseadjust-ments.

R

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ty,andcomorbidityof12-monthDSM-IVdisordersintheNationalComorbiditySurveyReplication.ArchGenPsychiatry.2005;62(6):617–627.

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tion.Witheachadditionalmedicationaddedtotheregimen,thesideeffectpro ileincreases,withaboutaquarterofallepilepticpatientsexperienc-ingunnecessarysideeffects.6Inadequatecontrolandsideeffectscontributetoaneconomicandsocialburdenthatmayjeopardizedthequalityoflifeformanypatients.7Thus,researcherscontin-uetostrivefordevelopingAEDsthatpossessesbothhighef icacyandtolerability.

Eslicarbazepineacetate(ESL),manufac-turedbySunovionPharmaceuticalsandmarketedunderthetrademarknameAptiom®,wasap-provedbytheFDAonNovember8th,2013asad-junctivetreatmentforpartial-onsetseizures.8Thisarticlewilldiscussthepharmacology,phar-macokinetics,ef icacy,dosing,andsafetyofESL.

P P

Eslicarbazepineacetatepossessesafew

uniquecharacteristicswhencomparedtootherAEDs.Thoughtheexactmechanismofactionisunknown,ESLisbelievedtocompetitivelyblockinactivehigh-frequencyvoltage-gatedsodiumchannelsatreceptorsite2.Thisprolongsthein-activationperiod,therebyreducingtheabilityofneuronsto ireathighfrequencies.Inaddition,ESLismoreselectiveforrapidly iringneuronsversusrestingneurons,showingathreefoldloweraf inityforrestingsodiumchannelswhencom-paredtocarbamazepine(CBZ).ESLisstructurallysimilartoCBZandoxcarbazepine(OXC)becauseitsharesadibenzazepinenucleus.9However,un-likeCBZ,ESLisnotmetabolizedtoatoxicepoxideduetothemoleculardifferenceofESLatthe10,11-positiononthemolecule.Becauseofthismo-leculardifference,ESLhasmodestenzymeinduc-ingpropertiesand,unlikeCBZ,willnotinduceitsownmetabolism.Additionally,incontrasttoOXC,ESLisaprodrugmetabolizedintoasingleenanti-omerwhereasOXCismetabolizedtobothR-andS-licarbazepine.Thissingleenantiomerisbe-lievedtobemoreef icacious,possessfewersideeffects,andcrossthebloodbrainbarriermoreef icientlythantheR-licarbazepine.10

Table1providesasummaryofseveralim-portantpharmacokineticpropertiesofESL.Themetabolite,eslicarbazepine,isresponsibleforthepharmacologicalactivityofESL.Atdosesof400-1200mg/day,ESLhaslinear,dosedependent

Programandabstractsofthe166thAnnualAmericanPsychiatricAssociationMeeting;May18-22,2013;SanFrancisco,California.PosterNR9-02.

21. JacobsenPL,MahableshwarkarAR,SerenkoM,ChenY,TrivediM.Arandomized,double-blind,placebo-controlledstudyoftheef icacyandsafetyofvortiox-etine10mgand20mginadultswithmajordepressivedisorder.Programandabstractsofthe166thAnnualAmericanPsychiatricAssociationMeeting;May18-22,2013;SanFrancisco,California.PosterNR9-06.

22. BoulengerJP,LoftH,FloreaI.ArandomizedclinicalstudyofLuAA21004inthepreventionofrelapseinpatientswithmajordepressivedisorder.JPsychophar-macol.2012;26(11):1408–1416.

23. Prozac( luoxetine)packageinsert.EliLillyandCompa-ny.Indianaplis,IN;1987.

pilepsyisacommonneurologicaldisor-derthatimpactsthelivesofmany,withanage-adjustedincidenceof44per100,000andaprevalenceof6-8per

1000.1,2Thoughmanyoftheantiepilepticdrugshaveadvancedthetreatmentofepilepsy,manyindividualssufferfrominadequateseizurecontroland/orundesirablesideeffects.Epilepsyisdivid-edintotwocategories:generalizedandpartialseizures.Generalizedseizuresoccurinbothhemi-spheresofthebrainandusuallyresultsinalossofconsciousness.Conversely,partialepilepsyislocalizedtoonehemisphereofthebrain,doesnotleadtoalossofconsciousness,andaccountsfornearly60%ofpeoplewithepilepsy.Partialepi-lepsyencompassessimplepartialseizures,com-plexpartialseizures,andsecondarygeneralizedseizures.3,4

Seizuresarisefromavarietyofcomplexmechanismsthatarenotcompletelyunderstood.Alterationsinionchannels,genetics,andneuro-transmitterimbalancesarebelievedtocontributetothepathophysiologyofseizures.5Antiepilepticdrugs(AEDs)arethemainstayintreatmentforpartialseizures.However,approximately30%oftreatedpatientswithepilepsyhavesuboptimalcontrolandwillberequiredtotakebetween2-4concomitantmedicationstomanagethiscondi-


Aptiom®(Eslicarbazepineacetate):

AReview John Chichetto, PharmD, Candidate

E

CYP2A6,CYP2B6,CYP2D6,CYP2E1,andCYP3A4,butESLhasbeenshowntohavemoderateinhibi-toryeffectonCYP2C19.Inmild-to-moderatehe-paticinsuf iciency,nodosereductionisneeded,butESLisnotrecommendedinpatientswithse-verehepaticdysfunction.8

AftermultipledosesofESL(800mg/day),92%ofESLwasexcretedinurineaseslicarbaze-pine,inwhich67%wasunchanged,33%asglucu-ronideconjugates,andtheother8%wasexcretedinurineas(R)-licarbazepine,OXC,andglucu-ronideconjugates.ClearanceofESLreliesonre-nalfunctionandacreatinineclearance(CrCl)<50mL/minwillwarrantsoundclinicaljudgmentandappropriatedoseadjustmentsthatarediscussedinthedosingandadministrationsection.Thehalf-life(t1/2)isapproximately13-20hours.8

C T

InthreephaseIIItrialsperformedin23

countries,theef icacyandsafetyofESLwasas-sessedasanadjunctivetherapyinpatientswithpartial-onsetseizures.Allthreestudiesweremul-ticentered,randomized,placebo-controlled,anddouble-blinded.Thechiefenrollmentcriteriain-cludedpatientstreatedwithonetothreeAEDsandwithatleastfoursimpleorcomplexpartial-onsetseizuresovera28dayperiod.Eachofthethreestudiesrequiredaneightweekbaselinepe-riod,atwoweektitrationperiod,anda12weektreatmentperiod.12Ben-MenachemetalandElgeretalusedthreeESLdosegroupstoassesstheef icacyandsafety(400mg,800mg,and1200mg),whileGil-NageletalonlyaddressedtwoESLdosesof800mgand1200mg.6,13,14Inthesetri-als,69%ofpatientswereusingtwoconcomitantAEDsand28%ofthepatientswereusingoneconcomitantAED.Carbamazepine(50%),lamotrigine(24%),valproicacid(21%),andle-vetiracetam(18%)werethemostcommonlyusedAEDsinthesetrials.BecauseOXCsharescommonmetaboliteswithESL,OXCwasnotallowedasaconcomitantAED.InallthreephaseIIIstudies,ESLatdosesof800mgand1200mgonceaday,demonstratedeffectivenessandwaswelltolerat-edbypatients.Theinclusionandexclusioncrite-riavariedbetweenthethreestudies,butthedif-ferenceswerenotsigni icant.Additionally,base-

pharmacokinetics.Themeanpeakplasmaconcen-trations(Cmax)inthefedstatewas12.8,whiletheCmaxwas11.3inthefastingstate.8Peakplasmaconcentrationsoccurapproximately2-3hourspostdoseandsteadystateconcentrationsarereachedin4-5days.9,11Because90%oftheESLdoseisrecoveredinurine,thebioavailabilityofESLisconsideredhigh.ESLplasmaproteinbind-ingislow(<40%)andnoclinicallysigni icantin-teractionhasbeenobservedwheninthepresenceofwarfarin,digoxin,phenytoin,ortolbutamide.Usingpopulationpharmacokineticparameters,thevolumeofdistributionwasdeterminedtobe61L.8

Eslicarbazepineacetateisrapidlyandsig-ni icantlymetabolizedintothemajoractiveme-taboliteeslicarbazepinebyhydrolytic irst-pass.8Becauseofthisrapidconversion,ESLplasmacon-centrationsremainbelowquanti icationandatherapeuticplasmalevelhasnotbeendeterminedforESL.9,11Thisactivemetaboliteaccountsfor91%ofplasmaconcentrationswiththeminorac-tivemetabolites,R-licarbazepineandOXC,ac-countingfor5%and1%,respectively.ESLhasnoclinicallyrelevantinhibitoryeffectsoncyto-chrome(CYP)P450enzymessuchasCYP1A2,


Table1|PharmacokineticInformationforEslicarbazepineacetate(ESL)8,10

Parameter Measurement

PeakPlasmaConcentration

(Cmax)

2-3h

Eliminationt1/2 13-20h

Bioavailability High

PlasmaClearance 20-30mL/min

Metabolism Hydrolysis(Cytochrome

P450enzymesandUDP-

glucuronyltransferases)

VolumeofDistribution 61L

Excretion >90%inurineasESLand

inactiveglucuronide

conjugates

ProteinBinding <40%

Cmax=maximumconcentrationESL:Eslicarbazepine

linecharacteristicsdidnotdiffersigni icantlybe-tweenthetrials.12

Theprimaryef icacyendpointforallthreetrialswasseizurefrequencyduringthe12weekmaintenanceperiod,whilerelativereductioninseizurefrequency,andresponderrate(≥50%re-ductioninseizurefrequency)wereanalyzedassecondaryendpoints.Ef icacyendpointswereanalyzedusinganintentiontotreatanalysis,whichincludedallpatientsrandomizedandthatreceivedatleastonedoseofESL.AllthreetrialsassessedtheimpactofESLonreducingthenum-berofseizures,whilecontrollingforothervaria-blessuchasconcomitantAEDsandbaselinesei-zurefrequency.Secondaryendpointswereper-formedperprotocolandincludedallpatientsthatcompletedthestudy.12

Elgeretalrandomized402patients,ofwhich102patientswereassignedtotheplacebogroup,100patientswereassignedtoESL400mg/day,98patientswereassignedtoESL800mg/day,and102patientswereassignedtoESL1200mg/day.6Ofthe402patientsthatenteredthetreatmentphase,330(82%)completedthestudy.Ofthe72(18%)patientsthatwerelosttofollow-up,themostcommonreasonwasduetoadverseevents(AEs).Overthe12weektreat-mentphase,theseizurefrequencywasfoundtobesigni icantlylowerintheESL800mg/dayarm

(LeastSquare(LS)Mean5.66,p=0.0028)andintheESL1200mg/dayarm(LSMean5.35,p=0.0003),comparedtotheplacebogroup(LSMean7.64).TheESL400mg/dayarmandplace-bodidnothaveastatisticallysigni icantdifferentLSMean.TheLSMeanseizurefrequencywasad-justedperfourweektimeperiod.Theresponderrate(patientswith≥50%decreaseinseizurefre-quencies)wassigni icantlyhigherintheESL800mg/day(34%,p=0.0359)andintheESL1200mg/dayarm(43%,p=0.009)thanintheplacebogroup(20%).Theincidencesofmild-to-moderateAEsincreasedwithincreasingdoses,andthefrequencyofseriousAEswassimilaracrossallgroupsinthetrial.Theauthorsconclud-edthatboththeESL800mg/dayand1200mg/dayarewelltoleratedandeffectiveinpatientsthathaverefractorypartial-onsetseizures.6

Gil-Nageletalstudiedtheef icacyandsafetyofdailydosesofESL800mgand1200mgasadjunctivetreatmentinpatientswithpartial-onsetseizures.13Afteran8-weekbaselineperiod,253patientswererandomizedintothreearms.Theplacebogroupcontained88patients,theESL800mg/dayarmhad85participants,andtheESL1200mg/daygrouphad80patients.Afteratwoweektitrationperiod,patientsentereda12weekmaintenanceperiod.Thepopulationwasana-lyzedusinganintention-to-treatmethod.The


Table2|SummaryofESLphaseIIITrials

Author/Year StudyDesignESLdose(mg/

day)ResponderRate(%)

MedianRela‐tiveRiskRe‐ductioninsei‐zurefrequen‐cy(%)

AuthorsConclu‐sion

Elgeretal.(2009)6

MC,DB,R,PC Placebo4008001200

20.023.034.043.0

16.026.036.045.0

ESL800and1200mg/daywelltoler-atedandeffective

Gil‐Nageletal.(2009)13

MC,DB,R,PC

Placebo8001200

22.634.537.7

17.037.941.9

800and1200mg/dayofESLeffectiveandwelltolerated

Ben‐Menachemetal.(2010)14

MC,DB,R,PC Placebo4008001200

13.017.040.037.1

0.818.732.632.8

ESL800and1200mg/daywelltoler-atedandeffective

DB:Double-blind;MC:Multicenter;R:Randomized;PC:Placebocontrolled;ESL:Eslicarbazepineacetate;Responderrate:percentageofpatientswith≥50%decreaseinseizurefrequency;

standardized(per4week)seizurefrequencywassigni icantlylowerforthe800mg/day(LSMean5.7,p=0.048)and1200mg/day(LSMean5.5,p=0.021)armswhencomparedtoplacebo(LSMean7.3).Theresponderratewas22.6%fortheplaceboarm,34.5%(p=0.106)forthe800mg/dayarm,and37.7%(p=0.020)inthe1200mg/dayarm.Theauthorsconcludedthat800mg/dayand1200mg/dayofESLareeffectiveandwelltolerated.13

Ben-MenachemetalcarriedoutatrialsimilartothatofElgeretal.6,14Afteran8-weekbaselineobservationalperiod,395ofthe503pa-tientsthatenteredthestudywererandomizedtoplacebo(n=100),ESL400mg/day(n=96),ESL800mg/day(n=101),or1200mg/day(n=98).Afteratwoweektitrationperiod,thepatientsen-tereda12-weektreatmentperiodfollowedbyatwoweekdiscontinuationphase.Thedatacollect-edwasanalyzedafterthe14weektreatmentpe-riodandthestandardizedseizurefrequency(per4weeks)wassigni icantlylowerintheESL800mg/day(LSMean7.1,p<0.001)andintheESL1200mg/day(LSMean7.4,p<0.001),comparedtotheplaceboarm.Therewasnostatisticallysig-ni icantdifferenceintheplaceboandESL400mg/daygroups.Inaddition,theresponderrateintheESL800mg/daygroup(40.0%,p<0.001)andintheESL1200mg/day(37.1,p<0.01)wassigni -icantlyhigherthantheplacebogroup.Likeprevi-

Table3|DruginteractionswithESLanddoseadjustments8,15

Drug EffectsofESLondrugEffectofdrugonESL

Doseadjustment

Carbamazepine None 21-33%de-creaseinAUC

MayneedanincreaseESLdose

Phenytoin Increase30-35%inAUC 21-33%de-creaseinAUC

MonitorphenytoinlevelsandmayneedanincreaseinESLdose

Phenobarbital None DecreaseAUC MayneedanincreaseinESLdose

Simvastatin Decrease41-61%inAUC None Increaseinsimvastatindosemayberequired

Rosuvastatin DecreaseinAUC None Increaseinrosuvastatindosemayberequired

Ethinylestradiol Decreaseof37%inAUC None Additionalcontraceptionshouldbeused

Levonorgestrel Decreaseof42%inAUC None Additionalcontraceptionshouldbeused

Warfarin Decreaseof23%in(S)-WarfarinAUC

None MonitorINRclosely

AUC:Areaunderthecurve

Table4|Combinedadversereactionsfromthreeclinicaltrials(Events≥2%ofpatientsinESL800mgand1200mgarms)8

Adversereaction

Placebo(%) ESL800mg ESL1200mg

Dizziness 9 20 28

Nausea 5 10 16

Somnolence 8 11 18

Headache 9 13 15

Diplopia 2 9 11

Vomiting 3 6 10

Fatigue 4 4 7

Ataxia 2 4 6

Blurredvision

1 6 5

Tremor 1 2 4

Vertigo 1 2 6

Rash 1 1 3

Hyperten‐sion

1 1 2

Hypo‐natremia

1 2 2


ous indings,AEsincreasedwithincreasingdosesandthediscontinuationratesduetoAEswere3.0%(placebo),12.5%(400mg),18.8%(800mg),and26.5%(1200mg).ThemostcommonAEsweredizziness,somnolence,headache,nau-sea,anddiplopia.TheauthorsconcludedthattreatmentwithoncedailyESL800mgand1200mgarebothef icaciousandwelltolerated.14Table2summarizestheaforementionedtrials.

D I Manyofthedruginteractionsnotedhave

beenwithconcomitantuseofotherAEDs.Whenphenytoin(PHT)andESLaregivenconcomitant-ly,a30-35%increaseinPHTanda21-33%de-creaseinESLexposureisseen.Similarly,con-comitantlytakingCBZandESLleadstoanin-creaseinCBZplasmaconcentrationsandade-creaseinESLplasmaconcentrations.Therefore,thedoseofPHT,CBZ,andESLmayneedtobead-justedaccordingly.WhenusedconcomitantlywithenzymeinducingAEDs,suchasphenobarbi-talandprimidone,higherdosesofESLmaybeneeded.InteractionswithotherAEDs,suchasle-vetiracetam,valproicacid,andgabapentin,donotappeartobeclinicallyrelevant,notrequiringdoseadjustments.ESLcaninhibitCYP2C19,whichcancauseincreasedplasmaconcentrationsofdrugs,suchasomeprazole,clobazam,andphenytoin.ESLcaninduceCYP3A4,decreasingplasmaconcentrationsofagentsmetabolizedbythisCYPenzyme.Administrationofethyinyles-tradiol/levonorgestrelwithESLleadstoade-creaseof42%inethyinylestradiolanda37%de-creaseinlevonorgestrel.Thisinteractionappearstooccurinadosedependentfashion.Theclinical-lyrelevantinteractions,alongwithappropriatedosingrecommendations,aresummarizedinTa-ble4.15

A E

ESLappearstohaveafavorablesideeffectpro ile.InphaseIIIstudies,mostofthemildtomoderateAEsoccurredmainlyduringtheinitia-tionphaseofESL.Aftersixweeksoftreatment,nosigni icantdifferencesintheoccurrenceofAEswereevidentbetweenESL800mg,1200mg,and

placebogroups.AEsleadingtoattritionduringthetrialswere4.5%intheplaceboarm,8.7%intheESL400mgarm,11.6%intheESL800mgarm,and19.3%intheESL1200mgarm.4Gil-Nageletal,frompooleddata,concludedthat45.3%treatedwithESLreportedtreatmentrelat-edAEs,comparedto24.4%treatedwithplace-bo.12TheoccurrenceofsevereAEs,suchasSte-vens-JohnsonSyndrome,Toxicepidermalnecrol-ysis,andDRESS/MultiorganHypersensitivity,waslowandsimilarineachoftheESLtreatmentarms.Theincidenceofrashwas0.3%inplacebo,0.5%withESL400mg,1.1%withESL800mg,and3.2%withESL1200mg.Hyponatremia,de-inedbyNa+<125mmol/L,wasreportedinfourpatientsand<1%ofthetreatmentarmsexperi-encedbehavioralorpsychiatricAEs.4ThemostcommonAEs,suchasdizziness,nausea,somno-lence,andheadache,aresummarizedinTable4.14

D A

Eslicarbazepineacetatewillbeavailablein

200mg,400mg,600mg,and800mgtablets.ESLcanbetakenwithoutregardtofoodandcrushedifneeded.8Initialdosesshouldbe400mgbymouthdailyforoneweekandtitratedtotherec-ommendedmaintenancedoseof800mgdaily.Thedosecanbefurthertitratedto1200mgdailybasedontolerabilityandclinicalresponse.9,11Ifthedesireddoseis1200mgdaily,themanufac-turerrecommendsstartingwith400mgdailyforoneweek,thenincreasingto800mgdailyforatleastaweek.8Thoughthishasshowntodecreaseseizurefrequency,cliniciansshouldbeawaretheAEsseenwithESLaredosedependent.11There-fore,clinicalresponseandpatienttolerabilitywillbethemostvaluablemethodforassessingtheef-icacyofESLineachpatient.Inpatientswithcom-promisedrenalfunctionCrCl<50mL/min,thedoseshouldbehalfoftherecommendedmainte-nancedose.Themanufacturerrecommendsstart-ingwith200mgdailyfortwoweeksandthenini-tiateESL400mgdailythereafter.8Doseadjust-mentsarenotavailableforCrCl<30mL/minduetoinadequatedata.15IfdiscontinuationofESLiswarranted,abruptwithdrawalshouldbeavoidedandthedoseshouldbegraduallytaperedoverseveralweekstominimizetheriskofseizures.8


S

Eslicarbazepineacetateisindicatedasanadjuvantforthetreatmentofpartial-onsetsei-zures.ESLwasef icaciousinseveralphaseIIIclinicaltrialsandhasshowngoodtolerabilityinadults,withthemostcommonsideeffectsinclud-ingdizziness,somnolence,headache,nausea,andvomiting.Thoughstructurallysimilartocarbam-azepine,ESLhasamuchlowerpotentialfordrug-druginteractionsandnoautoinduction.Withlessdrug-druginteractions,onceadaydosing,andgoodtolerability,ESLhasthepotentialtoposi-tivelyimpactthelivesofmanypatientssufferingfromseizuresandcontributetoincreasedqualityoflife.

R

1. HauserWA,AnnegersJF,KurlandLT.Incidenceofepi-

lepsyandunprovokedseizuresinRochester,Minneso-ta:1935–1984.Epilepsia.1993;34:453–468.

2. HauserWA,AnnegersJF,KurlandLT.Prevalenceofepi-lepsyinRochester,Minnesota:1940–1980.Epilepsia.1991;32:429–445.

3. Chang,B,Lowenstein,D.Epilepsy.NEngJMed.2003;349:1257-1266.

4. Rauchenzauner,M,Luef,G.Updateontreatmentofpar-tialonsetepilepsy:roleofeslicarbazepine.Neuropsychi‐atricDiseaseandTreatment.2010;6:723-730.

5. Chang,BS,Lowenstein,DH.Mechanismsofdisease:Epi-lepsy.NEnglJMed.2003;349:1257-66.

6. Elger,C,Halasz,P,Almeida,L,etal.Ef icacyandSafetyofeslicarbazepineacetateasadjunctivetreatmentinadultswithrefractorypartial-onsetseizures:arandom-ized,double-blind,placebo-controlled,parallel-groupphaseIIIstudy.Epilepsial.2009;50(3):454-463.

7. Jennum,P,Gyllenborg,J,Kjellberg,J.Thesocialandeco-nomicconsequencesofepilepsy:acontrollednationalstudy.Epilepsia.2011;52(5):949-956.

8. Aptiom®[packageinsert].SunovionPharmaceuticalsInc.November2013.AccessedonDecemeber4,201.http://www.epilepsy.com/pdfs/aptiom_insert.pdf.

9. Almeida,L,Soares-da-Silva,P.Eslocarbazepienacetate(BIA2-093).Neurotherapeutics.2007;4(1):88-96.

10. Singh,R,Asconape,J.Areviewofeslicarbazepineace-tatefortheadjunctivetreatmentofoartial-onsetepi-lepsy.JournalofCentralNervousSystemDisease.2011;3:179-187.

11. Verrotti,A,Loiacono,G,Rossi,A,etal.Eslicarbazepineacetate:anupdateonef icacyandsafetyinepilepsy.EpilepsyRes.(2013),http://dx.doi.org/10.1016/j.eplepsyres.10.005.

12. Gil-Nagel,a,Elger,C,Ben-Menachem,E,etal.Ef icacyandsafetyofeslicarbazepineacetateasadd-ontreat-mentinpatientswithfocal-onsetseizures:integrated

analysisofpooleddatafromdouble-blindphaseIIIclinicalstudies.Epilepsia,2013;54(1):98-107.

13. Gil-Nagel,A,Lopes-Lima,J,Almeida,L,etal.Ef icacyandsafetyof800and1200mgeslicarbazepineacetateasadjunctivetreatmentinadultswithrefractorypar-tial-onsetseizures.ActaNeurolScand.2009;120:281-287.

14. Ben-Menachem,E,Gabbai,AA,Hufnagel,A,etal.Eslicarbazepineacetateasadjunctivetherapyinadultpatientswithpartialepilepsy.EpilepsyResearch.2010;89:278-285.

15. Bialer,M,Soares-da-Silva,P.Pharmacokineticsanddruginteractionsofeslicarbazepineacetate.Epilepsia.2012;53(6):935-946.


John G. Gums PharmD, FCCP

R. Whit Curry, MD

Nicholas Carris PharmD, BCPS

Editor

Associate Editor

Assistant Editor

The PharmaNote is Published by: The Department of Pharmacy Services, UF Family Practice

Residency Program, Departments of Community Health and Family

Medicine and Pharmacotherapy and Translational Research University of Florida

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