Transition from oxcarbazepine to eslicarbazepine acetate: A single center study

B ain and Beha io . 2017;7:e00634.   | 1 o 6 h ps://doi.o g/10.1002/b b3.634 wileyonlinelib a y.com/jou nal/b b3 Recei ed:2Decembe 2016 | Accep ed:12Decembe 2016 DOI:10.1002/b b3.634 ORIGINAL RESEARCH T ansi ion om oxca bazepine o eslica bazepine ace a e: A single cen e s udy Jussi Mäkinen1 | Si pa Rainesalo1 | Jukka Pel ola2 Thisisanopenaccessa icleunde  he e mso  heC ea i eCommonsA ibu ionLicense,whichpe mi suse,dis ibu ionand ep oduc ioninanymedium, p o ided heo iginalwo kisp ope lyci ed. ©2017TheAu ho s.B ain and Beha io publishedbyWileyPe iodicals,Inc. 1Depa men o Neu ology,Tampe e Uni e si yHospi al,Tampe e,Finland 2Depa men o Neu ology,Uni e si yo  Tampe eandTampe eUni e si yHospi al, Tampe e,Finland Co espondence JussiMäkinen,Depa men o Neu ology, Tampe eUni e si yHospi al,Tampe e, Finland. Email:Jussi.M[email p o ec ed] Funding in o ma ion Thiss udywassuppo edbyanun es ic ed educa ionalg an awa dedbyEisaiL d oUni e si yo Tampe e,Finlandandby Compe i i eEVO-Fundingo Pi kanmaa Hospi alRes ic . Abs ac Objec i es: The eislimi edclinicale idence o compa isonbe weenoxca bazepine (OXC)andeslica bazepineace a e(ESL)in e mso  ole abili y,o how oexecu e he change omOXC oESL.We epo  hep ocesso  ansi ioningpa ien swi h ocal epilepsy omp e iousOXC ea men  oESLdue o ole abili yp oblems.The a ion- ale o change omOXCis epo ed,and heou comewi h espec i e o his a ionale isanalyzedin e mso  ole abili yande icacy. Ma e ials and Me hods: Thesubjec swe e ansi ionedo e nigh  omOXC oESLin ahospi alinpa ien se ing.Ane alua iono  hee ec so  he ansi ionwasmade a e 1and3mon hs.Allad e see en s(AEs)we e eco ded ollowing he ansi ion pe iod.Subjec swe eclassi iedbyou comein e mso AEs. Resul s: Twen y- h eesubjec swe e ansi ioned omOXC oESL.Fi eenpa ien s OXC- ela edAEs educedsigni ican lya e  ansi ion.Pa icula ly,mos o (93%) he AEsp esen edin hemo ning esol eda e  ansi ion oESL.Nopa ien hadanin- c easeinseizu e equency ollowing he ansi ion.Theincidenceo ESL- ela edAEs was39%a 1mon hand13%a 3mon h ollow-up;howe e ,allpa ien scon inued ESL h oughou  hes udype iod. Conclusions: Thiss udydemons a es ha pa ien ssu e ing omOXC- ela edAEs imp o ein e mso  ole abili ya e aswi ch oESLwi hmain ainingseizu econ ol. Thisimp o emen ismo ep onouncedi  heOXC- ela edAEsa emos e iden  ol- lowingmo ningdosingo OXC.T ansi ioncanbesa elyexecu edinanou pa ien  se ing. KEYWORDS epilepsy,eslica bazepineace a e,oxca bazepine, ole abili y, ea men  ansi ion 1 | INTRODUCTION Epilepsyhasanannualincidenceo abou 50pe 100,000andp e - alence be ween 5 and 10 pe  1,000 (Sande , 2003). Mono he apy wi hanan iepilep icd ug(AED)issu icien  oachie eseizu econ- olwi hou in ole ablead e see en s(AEs)app oxima elyin60%o  pa ien s(S ephen&B odie,2012).AEs ela ed oAEDsimpac nega- i elyonheal h- ela edquali yo li e,causeasigni ican sou ceo dis- abili y,andmaylead olowadhe ence o he ea men o  ea men  discon inua ion(S ephen&B odie,2012). Inadul s(>18yea s),o aleslica bazepineace a e(ESL)isapp o ed in heEUasanadjunc i e he apywi hpa ialonse seizu eswi ho  2 o 6 | MÄKINEN E al. wi hou seconda ilygene aliza ionandin heUSasamono he apyo  adjunc i e ea men o pa ial-onse seizu es(Ap iom®;Zebinix®). ESLisa hi d-gene a ionmembe o  hedibenzazepine amily,which alsoincludesca bamazepine(CBZ)andoxca bazepine(OXC;Kea ing, 2014; Zacca a, Gio anelli, Cinco a, & Ve o i, 2015). Blockade o  ol age-ga ed sodium channel (VGSC) is he p oposed mechanism o ac ion o CBZ,OXC,andESL(Kea ing,2014),bu ESLhasbeen shown oha eamodula ingac ionandinhibi s heslowac i a ion o VGSC(Hebeisene al.,2015)andalsoane ec onCa 3.2T- ype Ca2+channels(Doese e al.,2015).ESLisap od ug ha isme abo- lized o i s majo ac i eme aboli e eslica bazepine(S-lica bazepine) and o hemino ac i eme aboli es(R)-lica bazepineandOXC,which a emainlyelimina edby enalexc e ion(bo hunchangedandglucu o- nideconjuga e o ms;Kea ing,2014).Hal -li e e minalelimina iono  ESLinplasmaconcen a ions a iesbe ween20–24h allowingonce- dailyadminis a ion egimen(Pe uccae al.,2011).Maximumplasma concen a ions o  ESL we e eached in median 2.0–2.5h  (Almeida &Soa es-Da-sil a,2004).S eadys a eis eachedin4–5days(Elge , Halász,Maia,Almeida,&Soa es-Da-sil a,2009). Eslica bazepine ace a e is e icacious and well ole a ed as ad- junc i e he apyind ug- esis an  ocalepilepsiesa doseso 800and 1,200mgonce-daily(Ben-Menacheme al.,2010;Elge e al.,2009; Gil-Nagel, Lopes-Lima,Almeida, Maia,&Soa es-Da-sil a,2009; Gil- Nagele al.,2013;Spe linge al.,2015).Dizziness, e igo,abno mal coo dina ion, a axia, diplopia, a igue, somnolence, and headache a emos o en epo edand equen AEsincon olledclinical ials (Spe linge al.,2015)and oalesse deg eewhenusedas heonly adjunc i eAED(Hol kamp,McMu ay,Bagul,Sousa,&Kockelmann, 2016).I wasno edinones udy ha swi ching omOXC oESL(dose a io1:1)wasassocia edwi hbe e  ole abili ydu ingESL ea men  (Villanue ae al., 2014).Recen me a-analysiscompa ed he ole a- bili yo ESL,OXC,andlacosamide(LCM)showing ha pa ien swi h OXCwi hd ew om he ea men mo e equen ly hanpa ien swi h ESLo LCM (Zacca a,Gio anelli,Ma a ea, Fadda,&Ve o i,2013). Fu he mo e,someside-e ec s(diplopia,a axia,abno malcoo dina- ion)we esigni ican lymo e equen inOXC- ea edpa ien scom- pa ed oESLandLCM.ESL- ela edhypona emia a ies om1.2% o 8.8%be weendi e en s udies(Halasze al.,2010; Hu nagele al., 2013; Villanue a e al., 2014; Zacca a e al., 2013). The di e ence canbeexplainedin e mso dosageused,popula ioncha ac e is ics, and cu -o  used o de ine hypona emia. These da a sugges , ha  ESLmigh sha esimila e icacycompa ed oOXC,bu wi hlessAEs. Se e al dose-dependen  neu ological AEs occu  in e mi en ly and appea almos alwaysa ewhou sa e OXCadminis a ion(S iano e al.,2006).I seems easonable o ela eAEs oOXCpeakconcen- a ion a he  han o heac i eme aboli eeslica bazepine,whichle - elsinc easemo eslowly(Kea ing,2014).ESLisdi ec lyme abolized o eslica bazepinewi hmino concen a ionso  -lica bazepineandOXC (Almeida&Soa es-Da-sil a,2007). A  p esen , he eis onlyone s udydocumen ing ha  o e nigh  swi ch omOXC oESLseemed obesa eand esul insigni ican im- p o emen sinAEs,quali yo li e,andale ness(Schmide al.,2016). Howe e , ha s udy ocusedonacu ee ec s ollowing he ansi ion lea inglong- e me ec so such ansi ion ela ed o ole abili yand e icacys illunclea . We p o ide 3mon h ollow-up da a when ansi ioning pa ien s wi h ocalepilepsy omp e iousOXC ea men  oESLinas anda d- izedclinicalse ing.The a ionale o change omOXCis epo ed,and 3mon hou comewi h espec i e o his a ionaleisanalyzedin e ms o  ole abili y( hemainobjec i e)ande icacy( heseconda yobjec i e). 2 | MATERIAL AND METHODS Weiden i iedall hepa ien s(agea leas 18yea s)wi h ocalepi- lepsy ollowedin heDepa men o Neu ologyinTampe eUni e si y Hospi al, Finland om he pa ien  egis y. Following inclusion c i- e iawe eapplied:(1)cu en  ea men wi hOXC;(2)OXC- ela ed mode a eo se e e ole abili yp oblemswhicha ec eddailyli e;(3) ansi ion omOXC oESLwaspe o meddue oOXC- ela edAEs; and (4) ansi ion was unde aken be o e 30 No embe  2015. The dosageso concomi an AEDs emainedunchangeddu ing he ansi- ionpe iod.Allsubjec swe eonimmedia e- eleaseOXCasex ended- elease OXC is no  a ailable in Finland. In o ma ion on he pa ien  cha ac e is icswasob ained e ospec i ely om hemedical eco ds. Tole abili y p oblems ela ed o OXC we e ca ego ized as in e- cen me a-analysis(Zacca ae al.,2013)add essingneu ologicalAEs o  new gene a ion sodium-blocke s (somnolence, dizziness, e igo, a axia/coo dina ion abno mal, diplopia, nys agmus, a igue, emo , headache, nausea, omi ing). Pa ien s we e classi ied acco ding o ILAEguidelines o empo al, on al,pa ie al,occipi al,mul i ocal,o  unclassi iable epilepsies based on seizu e cha ac e is ics, EEG and imaging indingsand o somepa ien sonic al ideo-EEG eco dings (CoCaTo ILA, 1989).Thee iologieswe edi idedin o emo esymp- oma icandunknown.Theseizu e equency om hep e iousyea  was eco ded;seizu e- eepa ien sdidno ha eanyseizu esdu ing he p e ious yea . Re ac o y epilepsy was de ined as ha ing pe - sis en seizu esa e  ialso a leas  woAEDswi hmaximally ole - a eddoses(sequen iallyo incombina ion he apy). Pa ien swe e ansi ionedo e nigh  omOXC oESLinahospi al inpa ien se ingon hedayo a i aland hepa ien swe e ollowed up o3mon hsbyclinicians.The a ge doseo ESLwascalcula ed usinganOXC:ESLdose a io1:1dependingon hep e ansi ionOXC dose.I  he1:1dose a iodidno co espond oanexac ESLdose, hen hecloses lowe ESLdosewasused.Thelas in akeo OXCwas hemo ningdose ollowedby he i s in akeo ESLin hee ening o  hesameday.A e 1and3mon hsane alua iono  hee ec so  he ansi ionwasmadein e mso  ole abili y,whichwasmainpu - poseo  hiss udy.E icacyin e mso seizu echangewase alua ed a 1and3mon hsa e  ansi ioning.AllAEsand hei in ensi y(mild, mode a e,se e e)we e eco dedand epo ed ollowing he ansi- ioningpe iod.Mildwasde inedasasymp omno in e e ingwi h dailyac i i ies,mode a easin e e ingbu no p e en ingdailyli e ac i i iesandse e easincapaci a inga leas pa o dailyac i i ies. Pa ien swe edicho omiedbyou comein e mso AEsa e swi ched omOXC oESL. | 3 o 6 MÄKINEN E al. Thiswasanonin asi e, e ospec i es udy,whichdoesno oblige e hics commi ee app o al acco ding o Finnish Law on Resea ch. Access opa ien  eco dsbasedondecisionmadebyHeado Science Cen e,Tampe eUni e si yHospi al esea chandinno a ionse ices, ScienceCen e . 3 | RESULTS Weiden i ied23pa ien s,whowe e ansi ioned omOXC oESL because o  OXC- ela ed AEs. Demog aphic and medical cha ac e - is ico  he subjec s a e p esen ed in Table1. Th ee mos common concomi an  AEDs we e le e i ace am, opi ama e, and clobazam. AEs ela ed oOXCbe o e ansi ion oESLa edesc ibedinFigu e1. Fi een(65.2%)pa ien sOXC- ela edAEs esol eda e  ansi iona  3mon hs ollow-upand hiswas hecasein14pa ien sa 1mon h ollow-up.Fu he mo e, he imingo  heAEso e  hedaywi h e- spec  o hei  pe sis ency was analyzed and he esul s a e shown inFigu e2.Two hi ds(66.5%)o  heAEsoccu edin hemo ning andmos o  hem(93.4%) esol eda e  ansi ioning OXC oESL. AEsp esen ingalldayo e ening ended obemo epe sis en a e  ansi ion. Themos in ole ablesingleOXC- ela edAEswe esomnolence, dizziness, and diplopia. Fa ique, somnolence, emo , diplopia, andnauseamos ly esol eda e  ansi ion.Aclea  endency ha  someAEswouldha ebeenmo epe sis en  hano he s,especially in he mo ning,wasno obse ed.Howe e ,dizziness and coo - dina ion p oblems we e he commones AEs ha  pe sis ed a e  ansi ion. Thee ec so  he ansi ion omOXC oESLonseizu e equency a e summa ized inTable2.AEs occu ing a e  ansi ion ela ed o ESLa eshowninFigu e3.Theincidenceo AEswashighe a 1mon h (39.1%[9/23]) hana 3mon h ollow-up(13.0%[3/23]).Howe e ,no ea men discon inua ions occu edand all pa ien scon inuedESL h oughou  hes udype iod.Mos o  heAEsa ibu ed oESLwe e mildandsomemode a einin ensi y.Thedose-dependen inc easein AEs equencywasno no iced. Changes in seizu e equency o  du a ion we e no  obse ed du ing he ansi ion pe iod in a hospi al inpa ien  se ing.Two pa- ien s epo ed headache du ing he hospi aliza ion, bu  a  1 and 3mon h ollow-up hisAE was no  obse ed in hese pa ien s any mo e.Noneo  hosepa ien swhohadAEsdu ing he ollow-updid epo  ole abili yp oblemsdu ing hehospi aliza ion. TABLE1 Demog aphicandmedicalcha ac e is icso  hepa ien s Numbe o pa ien s 23 Sex Female,N(%) 14(60.9) Male,N(%) 9(39.1) Meanage;yea s( ange) 41.8(22–69) Meandu a iono epilepsy;yea s( ange) 14.4(2–62) E iology Remo esymp oma ic,N(%) 17(73.9) Unknown,N(%) 6(26.1) Re ac o yepilepsy,N(%) 18(78.2) Seizu e equency Seizu e ee(du ingp e iousyea ),N(%) 11(47.8) Pe sis en seizu es,N(%) 12(52.2) MeanOXCdose;mg/day( ange) 1,152(600–1,800) FinalESLdose;mg/day( ange) 1,095(800–2,000) Numbe o concomi an AEDs,N(%) 03(13.0) 19(39.2) 210(43.5) 31(4.3) Numbe o p io AEDs,N(%) 13(13.0) 25(21.8) 36(26.1) 43(13.0) ≥5 6(26.1) AEDs,an iepilep icd ugs;ESL,eslica bazepineace a e;OXC,oxca bazepine. FIGURE1 Ad e se-e en s ela ed o oxca bazepine.Oneo mo ead e se-e en  canbep esen onasinglesubjec 0 10 20 30 40 50 60 Pe cen age (%) 4 o 6 | MÄKINEN E al. 4 | DISCUSSION Themainobjec i eo  hiss udy ansi ioningpa ien swi h ocalepi- lepsy omOXC oESLdue o ypicalOXC- ela edAEswas oe alu- a e he ole abili ydu ingsu icien lylong ollow-uppe iod.Ou s udy demons a es ha pa ien sa is ac ionimp o edsigni ican lyin e ms o  educedAEsa e swi ching omOXC oESLin65%o  hesub- jec swi hou inc easeinseizu e equency.This indingissimila  oa p e iouss udydemons a ing ha 15o 26pa ien swhowe e an- si ioned omOXC oESLdue oOXC- ela edAEsnolonge hadAEs a e  hechange(Villanue ae al., 2014). Fu he mo e, we showed ha i  heOXC- ela edAEsa emos e iden in hemo ning( ollowing mo ningdosing),nea lyallo  hem(93%)dissol eda e  ansi ion o ESLindica inga ela ion oOXCpeakce eb ospinal luidandplasma concen a ion as sugges ed ea lie  (Kea ing, 2014). These indings migh helpclinicianine e ydayp ac ice oassesswhe he pa ien ’s complain so neu ologicalAEs ela ed oOXC,especiallyincomplex si ua ions; se e al AEDs, como bidi ies (e.g. dep ession, sleeping p oblems)and,pe sis en seizu es. Theseconda yobjec i ewas oassess he e icacyo ESL.The esul s o  his s udy indica ed ha  when swi ched om OXC, ESL wase ec i eandwell ole a eddu ing3mon hs ollow-up.Du ing p e iousyea 12pa ien shadpe sis en seizu esanda e changing omOXC oESLinonepa ien seizu e equency educedby50% andinano he pa ien by30%.Mo eo e ,in wopa ien sseizu edu- a ionsho enedwi hou changeinseizu e equency.Al oge he  ou  pa ien so  12 achie ed educ ioninseizu e equency o du a ion. Ne e heless, he ac  ha noneo  hepa ien shadinc easedseizu e equencyisa leas asimpo an asseizu e educ ioninsmallp opo - iono  hepa ien s. Ea lie expe g oup′sopinionhypo hesized he emigh besi u- a ionsinwhichi maybe easonable ocon e pa ien s omOXC o ESL; mos  app op ia ely hosewho expe ience OXC- ela edAEs o ha epoo compliancewi h wice-dailyOXCdosing(Pel olae al., 2015).Recen s udybySchmide al.(2016)demons a ed ha o e - nigh swi ching omOXC oESLwassa eandsuccess ulwi h ega d oe icacyconce ning heacu eandimmedia ee ec son ole abili y andseizu eissues.O he majo  indingis heabsenceo seizu e e- la edo o he p oblemsdu ing he ansi ioninanyo ou pa ien s which gi e added alue o he publica ion by Schmid e al. (2016). Fu he mo e, we did no  ind any speci ic conce ns,why ansi ion omOXC oESLshouldbedonenecessa ilyinaninpa ien se ingas TABLE2 Thee ec o  ansi ion omoxca bazepine oeslica bazepineace a eonseizu e equencyin3mon h ollow-up Pa ien Baseline SF (p e ious mon h) 1s mon h SF 2nd mon h SF 3 d mon h SF Ou come 1–11 Seizu e ee Noseizu es Noseizu es Noseizu es S illseizu e ee 12 1SGS,31SPS,4CPS 30SPS,3CPS 32SPS,4CPS 31SPS,6CPS Nosigni ican changeinSF 13 In equen seizu esaNoseizu es Noseizu es Noseizu es Nosigni ican changeinSF 14 1SGS,5CPS 2CPS Noseizu es 1CPS 50% educ ioninseizu e equency 15 1SPS,2CPS 2SPS,2CPS 1SPS,3CPS 1SPS,2CPS Nosigni ican 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,seizu edu a ionsho ened 18 1CPS Noseizu es 1CPS Noseizu es 30% educ ioninseizu e equency 19 In equen seizu esbNoseizu es Noseizu es Noseizu es Nosigni ican 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seizu edu a ion sho ened 21 1SGS,3SPS,1CPS 1SGS,3SPS,3 CPS 2SPS,2CPS 1SGS,3SPS,1 CPS Nosigni ican changeinSF 22 2SGS,7CPS 3SGS,8CPS 2SGS,11CPS 3SGS,6CPS Nosigni ican changeinSF 23 1SGS,4CPS 1CPS 4CPS 2SGS,4CPS Nosigni ican changeinSF CPS,complexpa ialseizu e;SF,seizu e equency;SGS,seconda ygene alized onic-clonicseizu e;SPS,simplepa ialseizu e. a1SGSdu ingp e iousyea . b1CPSdu ingp e iousyea . FIGURE2 Diu nal a ia ionand3mon hou comeo  oxca bazepine- ela edad e see en sa e  ansi ion o eslica bazepineace a e 0 10 20 30 40 50 60 70 Mo ningE ening No diu nal a ia ion Pe cen age (%) Pe sis ed Resol ed | 5 o 6 MÄKINEN E al. doneea lie inou cen e .T ansi ion omOXC oESLcanbesa ely doneinanou pa ien se ing. The ewe esligh di e enceshow hep omp swi ch omOXC o ESLwasconduc edinou cen e incompa ison o hep e iouss udy bySchmide al.(2016).In ha s udy helas in akeo OXCwas he e eningdose ollowedby i s in akeo ESLin hee eningo nex day, whe easinou cen e  helas in akeo OXCwas hemo ningdose ollowedby he i s in akeo ESLal eadyin hee eningo  hesame day.The ewe enodi e encesbe ween hese wos udies onhow heini ia iono ESLwaspe o medin e mso  a ge dosingasbo h s udiesaspi ed ousea a ioo 1:1o OXCandESL. Conside ing he limi a ions, his was e ospec i e uncon olled ollow-up s udy and he ela i e numbe  o  ou  pa ien  is no  high. Howe e ,whenconside ing he esul sandconclusionseme ging om ou s udy henumbe o pa ien sisjus i iedasi s’p esen  o m.The mainconclusionis ha suchOXC- ela edneu ologicalside-e ec s ha  appea a e inges iono  hemo ningdoseo OXCdisappea in he as  majo i y(o e 90%)o  hepa ien swhensubs i u edwi hESL,whe eas i  hesesymp omsexis ei he a e e eningdoseo wi hou diu nal a i- a ion hesubs i u ionislesshelp ul.Thisassocia ionissos ong ha  hecu en numbe o pa ien sissu icien  op o ide heconclusion. Inconclusion,ou  indingssuppo  heno ion ha pa ien scu - en ly ecei ingOXC andexpe iencingin ole ableAEsbene i  om swi ching o ESL in o de  o main ain seizu e con ol and imp o e AED ole abili y.Thisispa icula ly uei  heseAEsa emos e iden  ollowingmo ningdosing.Ou da aalsosugges  ha  ansi ion om OXC oESLcanbepe o medsa elyinanou pa ien se ingins ead o o e nigh hospi aliza ion o cos e ec i enessandpa ien com o . ACKNOWLEDGMENTS All au ho s mee  he In e na ional Commi ee o  Medical Jou nals Edi o s(ICMJE)c i e ia o au ho shipandha egi en inalapp o al o hemanusc ip  obepublished. CONFLICT OF INTEREST JussiMäkinenhas ecei edsuppo  o  a elcong esses omBiogen- Idec,Boeh inge -Ingelheim,Eisai,andO ionPha ma; ecei edspeake  hono a ia om Boeh inge -Ingelheim; ecei ed esea ch und- ing om Finnish Epilepsy Associa ion; and pa icipa ed in ad iso y boa d o Eisai.Si paRainesalohas ecei edspeake hono a ia om FennoMedical,O ionPha ma,UCBand ecei edsuppo  o  a el o cong esses omAbb ieandUCB.JukkaPel olahaspa icipa edin clinical ials o Eisai,UCB,andBial; ecei ed esea chg an s om Eisai, Med onic, UCB, and Cybe onics; ecei ed speake  hono a ia omCybe onics,Eisai,Med onic,O ionPha ma,andUCB; ecei ed suppo  o  a el cong esses om Cybe onics, Eisai, Med onic, andUCB;andpa icipa edinad iso y boa ds o Cybe onics,Eisai, Med onic,UCB,andP ize . REFERENCES Almeida, L., & Soa es-Da-sil a, P. (2004). Sa e y, ole abili y, and pha - macokine ic p o ile o  BIA 2-093, a no el pu a i e an iepilep ic, in a ising mul iple-dose in young heal hy humans. Jou nal o Clinical Pha macology,44,906–918. Almeida, L., & Soa es-Da-sil a, P. (2007). Eslica bazepine ace a e (BIA 2-093). Neu o he apeu ics: The Jou nal o he Ame ican Socie y o Expe imen al Neu oThe apeu ics,4,88–96. Ap iom®.P esc ibing In o ma ion. (2013).Re ie ed omh p://www.ap- iom.com/Ap iom-P esc ibing-In o ma ion.pd Ben-Menachem, E., Gabbai, A. A., Hu nagel, A., Maia, J., Almeida, L., & Soa es-Da-sil a,P.(2010).Eslica bazepineace a easadjunc i e he apy inadul pa ien swi hpa ialepilepsy.Epilepsy Resea ch,89,278–285. CoCaTo ILA,E.(1989).P oposal o  e isedclassi ica iono epilepsiesand epilep icsynd omes.Commissiononclassi ica ionand e minologyo  hein e na ionalleagueagains epilepsy.Epilepsia,30,389–399. Doese ,A.,Dickho ,G.,Rei ze,M.,Uebachs,M.,Schaub,C.,Pi es,N.M., …Beck,H.(2015).Ta ge ingpha maco esis an epilepsyandepilep o- genesiswi hadual-pu posean iepilep icd ug.B ain,138,371–387. Elge , C., Halász, P., Maia, J., Almeida, L., & Soa es-Da-sil a, P. (2009). BIA-2093-301 In es iga o s S udy G oup. E icacy and sa e y o  FIGURE3 Du a iono eslica bazepine ace a e- ela edad e see en s 0 2 4 6 8 10 12 14 16 18 20 Headache Dia hea Somnolence NauseaVe igoDizziness Diplopia Pe cen age (%) 3 mon hs 1 mon h 6 o 6 | MÄKINEN E al. eslica bazepine ace a e as adjunc i e ea men  in adul s wi h  e ac o y pa ial-onse  seizu es: A andomized, double-blind, placebo-con olled,pa allel-g oupphaseIIIs udy.Epilepsia,50,454– 463. Gil-Nagel, A., Elge , C., Ben-Menachem, E., Halász, P., Lopes-Lima, J., Gabbai,A.A.,…Soa es-Da-Sil a,P.(2013).E icacyandsa e yo esli- ca bazepineace a easadd-on ea men inpa ien swi h ocal-onse  seizu es:In eg a edanalysiso pooledda a omdouble-blindphaseIII clinicals udies.Epilepsia,54,98–107. Gil-Nagel, A., Lopes-Lima, J., Almeida, L., Maia, J., & Soa es-Da-sil a, P. (2009).BIA-2093-303In es iga o sS udyG oup.E icacyandsa e y o  800 and 1,200 mg eslica bazepine ace a e as adjunc i e ea - men inadul swi h e ac o ypa ial-onse seizu es.Ac a Neu ologica Scandina ica,120,281–287. Halász,P.,C ame ,J.,Hodoba,D.,Członkowska,A.,Guekh ,A.,Maia,J.,… Soa es-da-Sil a,P.(2010).Long- e me icacyandsa e yo eslica baze- pineace a e:Resul so a1-yea open-labelex ensions udyinpa ial- onse seizu esinadul swi hepilepsy.Epilepsia,51,1963–1969. Hebeisen,S.,Pi es,N.,Lou ei o,A.I.,Boni ácio,M.J.,Palma,N.,Whymen , A.,…Soa es-da-Sil a,P.(2015).Eslica bazepineand heenhancemen  o  ol age-ga edsodiumchannels:Acompa isonwi hca bamazepine, oxca bazepineandlacosamide.Neu opha macology,89,122–135. Hol kamp,M.,McMu ay,R.,Bagul,M.,Sousa,R.,&Kockelmann,E.(2016). Real-wo ldda aoneslica bazepineace a easadd-on oan iepilep ic mono he apy.Ac a Neu ologica Scandina ica,134,76–82.doi:10.1111/ ane.12574 Hu nagel,A.,Ben-Menachem,E.,Gabbai,A.A.,Falcao,A.,Almeida,L.,& Soa es-Da-sil a,P.(2013).Long- e msa e yande icacyo eslica ba- zepineace a easadjunc i e he apyin he ea men o pa ial-onse  seizu esinadul swi hepilepsy:Resul so a1-yea open-labelex en- sions udy.Epilepsy Resea ch,103,262–269. Kea ing,G.M.(2014).Eslica bazepineace a e:A e iewo i suseasad- junc i e he apy in e ac o y pa ial-onse  seizu es. CNS D ugs, 28, 583–600. Pel ola, J., Hol kamp, M., Rocamo a, R., Ry lin, P., Sie adzan, K., & Villanue a,V.(2015).P ac icalguidanceandconside a ions o  ansi- ioningpa ien s omoxca bazepineo ca bamazepine oeslica baze- pineace a e—Expe opinion.Epilepsy & Beha io ,50,46–49. Pe ucca,E.,Elge ,C.,Halász,P.,Falcão,A.,Almeida,L.,&Soa es-Da-sil a, P. (2011). Pha macokine ics o  eslica bazepine ace a e a  s eady- s a einadul swi hpa ial-onse seizu es.Epilepsy Resea ch,96,132– 139. Sande , J. W. (2003). The epidemiology o  epilepsy e isi ed. Cu en Opinion in Neu ology,16,165–170. Schmid, E., Kuchukhidze, G., Ki schne , M., Lei inge , M., Hö le , J., Roh ache , A., … T inka, E. (2016). O e nigh  swi ching om oxca - bazepine o eslica bazepine ace a e: An obse a ional s udy. Ac a Neu ologica Scandina ica.doi:10.1111/ane.12645 Spe ling, M. R., Abou-Khalil, B., Ha ey, J., Rogin, J. B., Bi aben, A., Galimbe i, C. A., … Soa es-da-Sil a, P. (2015). Eslica bazepine ace- a easadjunc i e he apyinpa ien swi huncon olledpa ial-onse  seizu es: Resul s o  a phase III, double-blind, andomized, placebo- con olled ial.Epilepsia,56,244–253. S ephen,L.J.,&B odie,M.J.(2012).An iepilep icd ugmono he apy e - suspoly he apy:Pu suingseizu e eedomand ole abili yin adul s. Cu en Opinion in Neu ology,25,164–172. S iano, S., S iano, P., Di Noce a, P., I aliano, D., Fasiello, C., Ruosi, P., … Pisani, F. (2006). Rela ionship be ween se um mono-hyd oxy- ca bazepineconcen a ionsand ad e see ec sin pa ien swi hep- ilepsy on high-dose oxca bazepine he apy. Epilepsy Resea ch, 69, 170–176. Villanue a,V.,Se a osa,J.M.,Guillamón,E.,Ga cés,M.,Gi áldez,B.G., Toledo,M.,…Molins,A.(2014).Long- e msa e yande icacyo es- lica bazepineace a einpa ien swi h ocalseizu es:Resul so  he1- yea ESLIBASE e ospec i es udy.Epilepsy Resea ch,108,1243–1252. Zacca a,G.,Gio anelli,F.,Cinco a,M.,&Ve o i,A.(2015).Clinicalu il- i yo eslica bazepine:Cu en e idence.D ug Design, De elopmen and The apy,9,781–789. Zacca a, G., Gio anelli, F., Ma a ea, D., Fadda, V., & Ve o i, A. (2013). Neu ologicalad e see en so newgene a ionsodiumblocke an ie- pilep ic d ugs. Me a-analysis o  andomized, double-blinded s udies wi heslica bazepine ace a e,lacosamideand oxca bazepine. Seizu e, 22,528–536. Zebinix®. Summa y o p oduc cha ac e is ics. (2012). Re ie ed om h p://www.ema.eu opa.eu/docs/en_GB/documen _lib a y/EPAR_-_ P oduc _In o ma ion/human/000988/WC500047225.pd How o ci e his a icle:MäkinenJ,RainesaloS,Pel olaJ. T ansi ion omoxca bazepine oeslica bazepineace a e: Asinglecen e s udy.B ain Beha . 2017;7:e00634. h ps://doi.o g/10.1002/b b3.634