Transition from oxcarbazepine to eslicarbazepine acetate: A single center study

Brain and Behavior. 2017;7:e00634.   | 1 of 6 https://doi.org/10.1002/brb3.634 wileyonlinelibrary.com/journal/brb3 Received:2December2016 | Accepted:12December2016 DOI:10.1002/brb3.634 ORIGINAL RESEARCH Transition from oxcarbazepine to eslicarbazepine acetate: A single center study Jussi Mäkinen1 | Sirpa Rainesalo1 | Jukka Peltola2 ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsuse,distributionandreproductioninanymedium, providedtheoriginalworkisproperlycited. ©2017TheAuthors.Brain and BehaviorpublishedbyWileyPeriodicals,Inc. 1DepartmentofNeurology,Tampere UniversityHospital,Tampere,Finland 2DepartmentofNeurology,Universityof TampereandTampereUniversityHospital, Tampere,Finland Correspondence JussiMäkinen,DepartmentofNeurology, TampereUniversityHospital,Tampere, Finland. Email:Jussi.M[email protected] Funding information Thisstudywassupportedbyanunrestricted educationalgrantawardedbyEisaiLtd toUniversityofTampere,Finlandandby CompetitiveEVO-FundingofPirkanmaa HospitalRestrict. Abstract Objectives: Thereislimitedclinicalevidenceforcomparisonbetweenoxcarbazepine (OXC)andeslicarbazepineacetate(ESL)intermsoftolerability,orhowtoexecutethe changefromOXCtoESL.Wereporttheprocessoftransitioningpatientswithfocal epilepsyfrompreviousOXCtreatmenttoESLduetotolerabilityproblems.TherationaleforchangefromOXCisreported,andtheoutcomewithrespectivetothisrationale isanalyzedintermsoftolerabilityandefficacy. Materials and Methods: ThesubjectsweretransitionedovernightfromOXCtoESLin ahospitalinpatientsetting.Anevaluationoftheeffectsofthetransitionwasmade after1and3months.Alladverseevents(AEs)wererecordedfollowingthetransition period.SubjectswereclassifiedbyoutcomeintermsofAEs. Results: Twenty-threesubjectsweretransitionedfromOXCtoESL.Fifteenpatients OXC-relatedAEsreducedsignificantlyaftertransition.Particularly,mostof(93%)the AEspresentedinthemorningresolvedaftertransitiontoESL.Nopatienthadanincreaseinseizurefrequencyfollowingthetransition.TheincidenceofESL-relatedAEs was39%at1monthand13%at3monthfollow-up;however,allpatientscontinued ESLthroughoutthestudyperiod. Conclusions: ThisstudydemonstratesthatpatientssufferingfromOXC-relatedAEs improveintermsoftolerabilityafteraswitchtoESLwithmaintainingseizurecontrol. ThisimprovementismorepronouncediftheOXC-relatedAEsaremostevidentfollowingmorningdosingofOXC.Transitioncanbesafelyexecutedinanoutpatient setting. KEYWORDS epilepsy,eslicarbazepineacetate,oxcarbazepine,tolerability,treatmenttransition 1 | INTRODUCTION Epilepsyhasanannualincidenceofabout50per100,000andprevalence between 5 and 10 per 1,000 (Sander, 2003). Monotherapy withanantiepilepticdrug(AED)issufficienttoachieveseizurecontrolwithoutintolerableadverseevents(AEs)approximatelyin60%of patients(Stephen&Brodie,2012).AEsrelatedtoAEDsimpactnegativelyonhealth-relatedqualityoflife,causeasignificantsourceofdisability,andmayleadtolowadherencetothetreatmentortreatment discontinuation(Stephen&Brodie,2012). Inadults(>18years),oraleslicarbazepineacetate(ESL)isapproved intheEUasanadjunctivetherapywithpartialonsetseizureswithor 2 of 6 | MÄKINEN Et al. withoutsecondarilygeneralizationandintheUSasamonotherapyor adjunctivetreatmentofpartial-onsetseizures(Aptiom®;Zebinix®). ESLisathird-generationmemberofthedibenzazepinefamily,which alsoincludescarbamazepine(CBZ)andoxcarbazepine(OXC;Keating, 2014; Zaccara, Giovanelli, Cincotta, & Verrotti, 2015). Blockade of voltage-gated sodium channel (VGSC) is the proposed mechanism ofactionforCBZ,OXC,andESL(Keating,2014),butESLhasbeen showntohaveamodulatingactionandinhibitstheslowactivation ofVGSC(Hebeisenetal.,2015)andalsoaneffectonCav3.2T-type Ca2+channels(Doeseretal.,2015).ESLisaprodrugthatismetabolizedto its majoractivemetabolite eslicarbazepine(S-licarbazepine) andtotheminoractivemetabolites(R)-licarbazepineandOXC,which aremainlyeliminatedbyrenalexcretion(bothunchangedandglucuronideconjugateforms;Keating,2014).Half-lifeterminaleliminationof ESLinplasmaconcentrationsvariesbetween20–24hrallowingonce- dailyadministrationregimen(Peruccaetal.,2011).Maximumplasma concentrations of ESL were reached in median 2.0–2.5hr (Almeida &Soares-Da-silva,2004).Steadystateisreachedin4–5days(Elger, Halász,Maia,Almeida,&Soares-Da-silva,2009). Eslicarbazepine acetate is efficacious and well tolerated as adjunctivetherapyindrug-resistantfocalepilepsiesatdosesof800and 1,200mgonce-daily(Ben-Menachemetal.,2010;Elgeretal.,2009; Gil-Nagel, Lopes-Lima,Almeida, Maia,&Soares-Da-silva,2009; Gil- Nageletal.,2013;Sperlingetal.,2015).Dizziness,vertigo,abnormal coordination, ataxia, diplopia, fatigue, somnolence, and headache aremostoftenreportedandfrequentAEsincontrolledclinicaltrials (Sperlingetal.,2015)andtoalesserdegreewhenusedastheonly adjunctiveAED(Holtkamp,McMurray,Bagul,Sousa,&Kockelmann, 2016).ItwasnotedinonestudythatswitchingfromOXCtoESL(dose ratio1:1)wasassociatedwithbettertolerabilityduringESLtreatment (Villanuevaetal., 2014).Recentmeta-analysiscomparedthe tolerabilityofESL,OXC,andlacosamide(LCM)showingthatpatientswith OXCwithdrewfromthetreatmentmorefrequentlythanpatientswith ESLorLCM (Zaccara,Giovanelli,Maratea, Fadda,&Verrotti,2013). Furthermore,someside-effects(diplopia,ataxia,abnormalcoordination)weresignificantlymorefrequentinOXC-treatedpatientscomparedtoESLandLCM.ESL-relatedhyponatremiavariesfrom1.2%to 8.8%betweendifferentstudies(Halaszetal.,2010; Hufnageletal., 2013; Villanueva etal., 2014; Zaccara etal., 2013). The difference canbeexplainedintermsofdosageused,populationcharacteristics, and cut-off used to define hyponatremia. These data suggest, that ESLmightsharesimilarefficacycomparedtoOXC,butwithlessAEs. Several dose-dependent neurological AEs occur intermittently and appearalmostalwaysafewhoursafterOXCadministration(Striano etal.,2006).ItseemsreasonabletorelateAEstoOXCpeakconcentrationratherthantotheactivemetaboliteeslicarbazepine,whichlevelsincreasemoreslowly(Keating,2014).ESLisdirectlymetabolizedto eslicarbazepinewithminorconcentrationsofr-licarbazepineandOXC (Almeida&Soares-Da-silva,2007). At present,thereis onlyone studydocumenting that overnight switchfromOXCtoESLseemedtobesafeandresultinsignificantimprovementsinAEs,qualityoflife,andalertness(Schmidetal.,2016). However,thatstudyfocusedonacuteeffectsfollowingthetransition leavinglong-termeffectsofsuchtransitionrelatedtotolerabilityand efficacystillunclear. We provide 3month follow-up data when transitioning patients withfocalepilepsyfrompreviousOXCtreatmenttoESLinastandardizedclinicalsetting.TherationaleforchangefromOXCisreported,and 3monthoutcomewithrespectivetothisrationaleisanalyzedinterms oftolerability(themainobjective)andefficacy(thesecondaryobjective). 2 | MATERIAL AND METHODS Weidentifiedallthepatients(ageatleast18years)withfocalepilepsyfollowedintheDepartmentofNeurologyinTampereUniversity Hospital, Finland from the patient registry. Following inclusion criteriawereapplied:(1)currenttreatmentwithOXC;(2)OXC-related moderateorseveretolerabilityproblemswhichaffecteddailylife;(3) transitionfromOXCtoESLwasperformedduetoOXC-relatedAEs; and (4) transition was undertaken before 30 November 2015. The dosagesofconcomitantAEDsremainedunchangedduringthetransitionperiod.Allsubjectswereonimmediate-releaseOXCasextended- release OXC is not available in Finland. Information on the patient characteristicswasobtainedretrospectivelyfromthemedicalrecords. Tolerability problems related to OXC were categorized as in recentmeta-analysis(Zaccaraetal.,2013)addressingneurologicalAEs of new generation sodium-blockers (somnolence, dizziness, vertigo, ataxia/coordination abnormal, diplopia, nystagmus, fatigue, tremor, headache, nausea, vomiting). Patients were classified according to ILAEguidelinestotemporal,frontal,parietal,occipital,multifocal,or unclassifiable epilepsies based on seizure characteristics, EEG and imagingfindingsandforsomepatientsonictalvideo-EEGrecordings (CoCaTotILA, 1989).Theetiologiesweredividedintoremotesymptomaticandunknown.Theseizurefrequencyfromthepreviousyear wasrecorded;seizure-freepatientsdidnothaveanyseizuresduring the previous year. Refractory epilepsy was defined as having persistentseizuresaftertrialsofatleasttwoAEDswithmaximallytolerateddoses(sequentiallyorincombinationtherapy). PatientsweretransitionedovernightfromOXCtoESLinahospital inpatientsettingonthedayofarrivalandthepatientswerefollowed upto3monthsbyclinicians.ThetargetdoseofESLwascalculated usinganOXC:ESLdoseratio1:1dependingonthepretransitionOXC dose.Ifthe1:1doseratiodidnotcorrespondtoanexactESLdose, thentheclosestlowerESLdosewasused.ThelastintakeofOXCwas themorningdosefollowedbythefirstintakeofESLintheevening ofthesameday.After1and3monthsanevaluationoftheeffectsof thetransitionwasmadeintermsoftolerability,whichwasmainpurposeofthisstudy.Efficacyintermsofseizurechangewasevaluated at1and3monthsaftertransitioning.AllAEsandtheirintensity(mild, moderate,severe)wererecordedandreportedfollowingthetransitioningperiod.Mildwasdefinedasasymptomnotinterferingwith dailyactivities,moderateasinterferingbutnotpreventingdailylife activitiesandsevereasincapacitatingatleastpartofdailyactivities. PatientsweredichotomiedbyoutcomeintermsofAEsafterswitched fromOXCtoESL. | 3 of 6 MÄKINEN Et al. Thiswasanoninvasive,retrospectivestudy,whichdoesnotoblige ethics committee approval according to Finnish Law on Research. AccesstopatientrecordsbasedondecisionmadebyHeadofScience Centre,TampereUniversityHospitalresearchandinnovationservices, ScienceCenter. 3 | RESULTS Weidentified23patients,whoweretransitionedfromOXCtoESL because of OXC-related AEs. Demographic and medical characteristicofthe subjects are presented in Table1. Three mostcommon concomitant AEDs were levetiracetam, topiramate, and clobazam. AEsrelatedtoOXCbeforetransitiontoESLaredescribedinFigure1. Fifteen(65.2%)patientsOXC-relatedAEsresolvedaftertransitionat 3monthsfollow-upandthiswasthecasein14patientsat1month follow-up.Furthermore,thetimingoftheAEsoverthedaywithrespect to their persistency was analyzed and the results are shown inFigure2.Twothirds(66.5%)oftheAEsoccurredinthemorning andmostof them(93.4%)resolvedaftertransitioning OXCtoESL. AEspresentingalldayoreveningtendedtobemorepersistentafter transition. ThemostintolerablesingleOXC-relatedAEsweresomnolence, dizziness, and diplopia. Fatique, somnolence, tremor, diplopia, andnauseamostlyresolvedaftertransition.Acleartendencythat someAEswouldhavebeenmorepersistentthanothers,especially inthe morning,wasnotobserved.However,dizziness and coordination problems were the commonestAEs that persisted after transition. TheeffectsofthetransitionfromOXCtoESLonseizurefrequency are summarized inTable2.AEs occurring after transition related to ESLareshowninFigure3.TheincidenceofAEswashigherat1month (39.1%[9/23])thanat3monthfollow-up(13.0%[3/23]).However,no treatmentdiscontinuations occurredand all patientscontinuedESL throughoutthestudyperiod.MostoftheAEsattributedtoESLwere mildandsomemoderateinintensity.Thedose-dependentincreasein AEsfrequencywasnotnoticed. Changes in seizure frequency or duration were not observed duringthe transition period in a hospital inpatient setting.Two patients reported headache during the hospitalization, but at 1 and 3month follow-up thisAE was not observed in these patients any more.NoneofthosepatientswhohadAEsduringthefollow-updid reporttolerabilityproblemsduringthehospitalization. TABLE1 Demographicandmedicalcharacteristicsofthepatients Numberofpatients 23 Sex Female,N(%) 14(60.9) Male,N(%) 9(39.1) Meanage;years(range) 41.8(22–69) Meandurationofepilepsy;years(range) 14.4(2–62) Etiology Remotesymptomatic,N(%) 17(73.9) Unknown,N(%) 6(26.1) Refractoryepilepsy,N(%) 18(78.2) Seizurefrequency Seizurefree(duringpreviousyear),N(%) 11(47.8) Persistentseizures,N(%) 12(52.2) MeanOXCdose;mg/day(range) 1,152(600–1,800) FinalESLdose;mg/day(range) 1,095(800–2,000) NumberofconcomitantAEDs,N(%) 03(13.0) 19(39.2) 210(43.5) 31(4.3) NumberofpriorAEDs,N(%) 13(13.0) 25(21.8) 36(26.1) 43(13.0) ≥5 6(26.1) AEDs,antiepilepticdrugs;ESL,eslicarbazepineacetate;OXC,oxcarbazepine. FIGURE1 Adverse-eventsrelatedto oxcarbazepine.Oneormoreadverse-event canbepresentonasinglesubject 0 10 20 30 40 50 60 Percentage (%) 4 of 6 | MÄKINEN Et al. 4 | DISCUSSION ThemainobjectiveofthisstudytransitioningpatientswithfocalepilepsyfromOXCtoESLduetotypicalOXC-relatedAEswastoevaluatethetolerabilityduringsufficientlylongfollow-upperiod.Ourstudy demonstratesthatpatientsatisfactionimprovedsignificantlyinterms ofreducedAEsafterswitchingfromOXCtoESLin65%ofthesubjectswithoutincreaseinseizurefrequency.Thisfindingissimilartoa previousstudydemonstratingthat15of26patientswhoweretransitionedfromOXCtoESLduetoOXC-relatedAEsnolongerhadAEs afterthechange(Villanuevaetal., 2014). Furthermore, we showed thatiftheOXC-relatedAEsaremostevidentinthemorning(following morningdosing),nearlyallofthem(93%)dissolvedaftertransitionto ESLindicatingarelationtoOXCpeakcerebrospinalfluidandplasma concentration as suggested earlier (Keating, 2014). These findings mighthelpclinicianineverydaypracticetoassesswhetherpatient’s complaintsofneurologicalAEsrelatedtoOXC,especiallyincomplex situations; several AEDs, comorbidities (e.g. depression, sleeping problems)and,persistentseizures. Thesecondaryobjectivewastoassess the efficacyofESL.The results of this study indicated that when switched from OXC, ESL waseffectiveandwelltoleratedduring3monthsfollow-up.During previousyear12patientshadpersistentseizuresandafterchanging fromOXCtoESLinonepatientseizurefrequencyreducedby50% andinanotherpatientby30%.Moreover,intwopatientsseizuredurationshortenedwithoutchangeinseizurefrequency.Altogetherfour patientsof 12 achievedreductioninseizurefrequency orduration. Nevertheless,thefactthatnoneofthepatientshadincreasedseizure frequencyisatleastasimportantasseizurereductioninsmallproportionofthepatients. Earlierexpertgroup′sopinionhypothesizedtheremightbesituationsinwhichitmaybereasonabletoconvertpatientsfromOXC to ESL; most appropriately thosewho experience OXC-relatedAEs orhavepoorcompliancewithtwice-dailyOXCdosing(Peltolaetal., 2015).RecentstudybySchmidetal.(2016)demonstratedthatovernightswitchingfromOXCtoESLwassafeandsuccessfulwithregard toefficacyconcerningtheacuteandimmediateeffectsontolerability andseizureissues.Othermajorfindingistheabsenceofseizurerelatedorotherproblemsduring thetransitioninanyofourpatients which give addedvalue to the publication by Schmid etal. (2016). Furthermore, we did not find any specific concerns,why transition fromOXCtoESLshouldbedonenecessarilyinaninpatientsettingas TABLE2 Theeffectoftransitionfromoxcarbazepinetoeslicarbazepineacetateonseizurefrequencyin3monthfollow-up Patient Baseline SF (previous month) 1st month SF 2nd month SF 3rd month SF Outcome 1–11 Seizurefree Noseizures Noseizures Noseizures Stillseizurefree 12 1SGS,31SPS,4CPS 30SPS,3CPS 32SPS,4CPS 31SPS,6CPS NosignificantchangeinSF 13 InfrequentseizuresaNoseizures Noseizures Noseizures NosignificantchangeinSF 14 1SGS,5CPS 2CPS Noseizures 1CPS 50%reductioninseizurefrequency 15 1SPS,2CPS 2SPS,2CPS 1SPS,3CPS 1SPS,2CPS NosignificantchangeinSF 16 83SPS,8CPS 84SPS,8CPS 83SPS,8CPS 83SPS,8CPS NochangeinSF 17 5CPS 4CPS 5CPS 6CPS NochangeinSF,seizuredurationshortened 18 1CPS Noseizures 1CPS Noseizures 30%reductioninseizurefrequency 19 InfrequentseizuresbNoseizures Noseizures Noseizures NosignificantchangeinSF 20 5SPS,8CPS 5SPS,8CPS 8SPS,11CPS 7SPS,8CPS NochangeinSF,CPSseizureduration shortened 21 1SGS,3SPS,1CPS 1SGS,3SPS,3 CPS 2SPS,2CPS 1SGS,3SPS,1 CPS NosignificantchangeinSF 22 2SGS,7CPS 3SGS,8CPS 2SGS,11CPS 3SGS,6CPS NosignificantchangeinSF 23 1SGS,4CPS 1CPS 4CPS 2SGS,4CPS NosignificantchangeinSF CPS,complexpartialseizure;SF,seizurefrequency;SGS,secondarygeneralizedtonic-clonicseizure;SPS,simplepartialseizure. a1SGSduringpreviousyear. b1CPSduringpreviousyear. FIGURE2 Diurnalvariationand3monthoutcomeof oxcarbazepine-relatedadverseeventsaftertransitionto eslicarbazepineacetate 0 10 20 30 40 50 60 70 MorningEvening No diurnal variation Percentage (%) Persisted Resolved | 5 of 6 MÄKINEN Et al. doneearlierinourcenter.TransitionfromOXCtoESLcanbesafely doneinanoutpatientsetting. TherewereslightdifferenceshowthepromptswitchfromOXCto ESLwasconductedinourcenterincomparisontothepreviousstudy bySchmidetal.(2016).InthatstudythelastintakeofOXCwasthe eveningdosefollowedbyfirstintakeofESLintheeveningofnextday, whereasinourcenterthelastintakeofOXCwasthemorningdose followedbythefirstintakeofESLalreadyintheeveningofthesame day.Therewerenodifferencesbetweenthese twostudies onhow theinitiationofESLwasperformedintermsoftargetdosingasboth studiesaspiredtousearatioof1:1ofOXCandESL. Considering the limitations, this was retrospective uncontrolled follow-up study and the relative number of our patient is not high. However,whenconsideringtheresultsandconclusionsemergingfrom ourstudythenumberofpatientsisjustifiedasits’presentform.The mainconclusionisthatsuchOXC-relatedneurologicalside-effectsthat appearafteringestionofthemorningdoseofOXCdisappearinthevast majority(over90%)ofthepatientswhensubstitutedwithESL,whereas ifthesesymptomsexisteitheraftereveningdoseorwithoutdiurnalvariationthesubstitutionislesshelpful.Thisassociationissostrongthat thecurrentnumberofpatientsissufficienttoprovidetheconclusion. Inconclusion,ourfindingssupportthenotionthatpatientscurrentlyreceivingOXC andexperiencingintolerableAEsbenefitfrom switching to ESL in order to maintain seizure control and improve AEDtolerability.ThisisparticularlytrueiftheseAEsaremostevident followingmorningdosing.Ourdataalsosuggestthattransitionfrom OXCtoESLcanbeperformedsafelyinanoutpatientsettinginstead ofovernighthospitalizationforcosteffectivenessandpatientcomfort. ACKNOWLEDGMENTS All authors meet the International Committee of Medical Journals Editors(ICMJE)criteriaforauthorshipandhavegivenfinalapproval tothemanuscripttobepublished. CONFLICT OF INTEREST JussiMäkinenhasreceivedsupportfortravelcongressesfromBiogen- Idec,Boehringer-Ingelheim,Eisai,andOrionPharma;receivedspeaker honoraria from Boehringer-Ingelheim; received research funding from Finnish Epilepsy Association; and participated in advisory boardforEisai.SirpaRainesalohasreceivedspeakerhonorariafrom FennoMedical,OrionPharma,UCBandreceivedsupportfortravelto congressesfromAbbvieandUCB.JukkaPeltolahasparticipatedin clinicaltrialsforEisai,UCB,andBial;receivedresearchgrantsfrom Eisai, Medtronic, UCB, and Cyberonics; received speaker honoraria fromCyberonics,Eisai,Medtronic,OrionPharma,andUCB;received support for travel congresses from Cyberonics, Eisai, Medtronic, andUCB;andparticipatedinadvisory boardsforCyberonics,Eisai, Medtronic,UCB,andPfizer. 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