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Current role of carbamazepine and oxcarbazepine in the management of epilepsy

      Highlights

      • The role of carbamazepine & oxcarbazepine relative to newer antiepileptic’s is reviewed.
      • Guidelines list both drugs as 1st/2nd-line options for focal or generalized seizures.
      • The effectiveness of both drugs has measured up to the newer antiepileptic drugs.
      • Carbamazepine and oxcarbazepine remain the mainstay of antiepileptic drug treatment.
      • Therapeutic drug monitoring and genetic testing to be encouraged for optimal outcome.

      Abstract

      Epilepsy is one of the most common neurological disorders, affecting approximately 50 million people worldwide. Despite a dramatic increase in treatment options over the past 30 years, it still ranks fourth in the world’s disease burden. There are now close to 30 antiepileptic drugs (AEDs), with more than two thirds introduced to the market after carbamazepine (CBZ) and one third after its derivative, oxcarbazepine (OXC). Following the introduction of these newer AEDs, the role of CBZ and OXC in the therapeutic armamentarium for seizure control and effective epilepsy management needs to be reviewed. The main guidelines list both CBZ and OXC as first-line options or second-line alternatives for the treatment of focal-onset epilepsy and primary generalized tonic-clonic seizures. While evidence suggests that overall AEDs have similar efficacy, some newer AEDs may be better tolerated than CBZ. In line with this, there have been changes in treatment patterns, with many variations across different countries. However, CBZ remains among the two or three most prescribed drugs for focal epilepsy in many countries, and is widely used across Europe, Africa, South America, and Asia, where it represents a good compromise between cost, availability, and effectiveness. OXC is among the first-choice options for the initial treatment of focal-onset seizures in several countries, including the US and China, where the oral suspension is commonly prescribed. This review provides guidance on the optimal use of these two drugs in clinical practice, including in children, the elderly, and in pregnancy.

      Abbreviations:

      AED (antiepileptic drug), CBZ (carbamazepine), CBZ-CR (carbamazepine controlled-release formulation), CBZ-IR (carbamazepine immediate-release formulation), IPD (individual participant data), OXC (oxcarbazepine), RCT (randomized clinical trials), QOL (quality of life), RWE (real-world evidence)

      Keywords

      1. Introduction

      Approximately 50 million people worldwide have epilepsy, which makes it one of the most common neurological diseases globally, ranking fourth in the world’s disease burden [
      • World Health Organisation (WHO)
      ,
      • Beghi E.
      Addressing the burden of epilepsy: many unmet needs.
      ]. Nearly 80% of people with epilepsy live in low- and middle-income countries, with a lifetime prevalence varying from 5.8 per 1000 (developed countries) to 15.4 per 1000 (rural studies in developing countries) [
      • Beghi E.
      Addressing the burden of epilepsy: many unmet needs.
      ,
      • Ngugi A.K.
      • Bottomley C.
      • Kleinschmidt I.
      • Sander J.W.
      • Newton C.R.
      Estimation of the burden of active and life-time epilepsy: a meta-analytic approach.
      ]. A substantial treatment gap remains despite dramatic changes in the epilepsy treatment landscape over the past 30 years. In 1990, only the first generation anti-epileptic drugs (AEDs), namely carbamazepine (CBZ), phenytoin, phenobarbital, primidone, and valproate, were commonly used for focal–onset seizures, and secondarily generalized seizures, while ethosuximide and valproate were used for generalized onset seizures [
      • Pellock J.M.
      Treatment of epilepsy in the new millennium.
      ]. Currently, close to 30 AEDs are available, with some new generation AEDs presenting advantages in terms of tolerability, which has led to changing trends in the choice of the initial AED [
      • Pickrell W.O.
      • Lacey A.S.
      • Thomas R.H.
      • Lyons R.A.
      • Smith P.E.M.
      • Rees M.I.
      Trends in the first antiepileptic drug prescribed for epilepsy between 2000 and 2010.
      ,
      • Shih J.J.
      • Whitlock J.B.
      • Chimato N.
      • Vargas E.
      • Karceski S.C.
      • Frank R.D.
      Epilepsy treatment in adults and adolescents: Expert opinion, 2016.
      ].
      Nevertheless, given their well-established efficacy and safety profiles, older AEDs are still widely prescribed. CBZ, with 38 million patient years exposure, belongs to the WHO model list of essential medicines, and is still considered the standard of care and the most prescribed initial treatment for focal epilepsy [
      • MSdA Campos
      • Ayres L.R.
      • Morelo M.R.S.
      • Marques F.A.
      • Pereira L.R.L.
      Efficacy and tolerability of antiepileptic drugs in patients with focal epilepsy: systematic review and network meta-analyses.
      ].
      Oxcarbazepine (OXC), a structural analogue of CBZ, was developed in an effort to avoid side effects from CBZ and its active metabolites and obtain a more suitable patient profile. The objective was to improve the tolerability and pharmacokinetic profile of the drug while decreasing its potential for drug-drug interactions [
      • Ambrósio A.F.
      • Soares-Da-Silva P.
      • Carvalho C.M.
      • Carvalho A.P.
      Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BIA 2-024.
      ]. OXC was evaluated in four head-to-head comparative trials with CBZ, valproate, and phenytoin, in adults (three trials) and children (one trial vs phenytoin) with newly diagnosed epilepsy. The results showed a similar efficacy between all drugs, with OXC better tolerated than CBZ and phenytoin [
      • Smith P.E.
      • Board UKOA
      Clinical recommendations for oxcarbazepine.
      ,
      • Wellington K.
      • Goa K.L.
      Oxcarbazepine: an update of its efficacy in the management of epilepsy.
      ]. A Cochrane review also concluded that OXC and CBZ appear to be similarly effective and well tolerated [
      • Koch M.W.
      • Polman S.K.
      Oxcarbazepine versus carbamazepine monotherapy for partial onset seizures.
      ] (since the efficacy results are based on a single study, a potential difference cannot be ruled out). OXC currently has 8.4 million patient years exposure.
      The present review aims to investigate the place of these two agents in the epilepsy treatment landscape, using current guidelines, the most recent clinical evidence, and real-world practice, including consideration of geographical variation. We will aim to evaluate and address the benefit/risk ratio of CBZ and OXC in the treatment of epilepsy following the emergence of newer treatment options. This review also intends to provide guidance on the optimal use of these two drugs in clinical practice, including special populations.

      2. Main characteristics and guidelines

      2.1 Main characteristics of CBZ and OXC

      There are close to 30 AEDs available in the US and a similar number available in the EU, including more than two thirds which have become available since the introduction of CBZ in 1963, and one third since the introduction of OXC in 2000 [
      • Vossler D.G.
      • Weingarten M.
      • Gidal B.E.
      American Epilepsy Society Treatments C. Summary of Antiepileptic Drugs Available in the United States of America: Working toward a world without epilepsy.
      ,
      • Patsalos P.N.
      • Spencer E.P.
      • Berry D.J.
      Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update.
      ]. The timing of the introduction of CBZ and OXC relative to the introduction of the other first, second and third generation AEDs is shown in Table 1.
      Table 1AEDs available in the EU
      • Patsalos P.N.
      • Spencer E.P.
      • Berry D.J.
      Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update.
      ,
      • Baftiu A.
      • Johannessen Landmark C.
      • Nikaj V.
      • Neslein I.L.
      • Johannessen S.I.
      • Perucca E.
      Availability of antiepileptic drugs across Europe.
      .
      1st generation

      Approved before 1989
      2nd generation

      Approved from 1989
      3rd generation

      Approved after 2005
      1Phenobarbital11Vigabatrin22Rufinamide
      2Phenytoin12Lamotrigine23Stiripentol
      3Primidone13Gabapentin24Lacosamide
      4Ethosuximide14Felbamate25Eslicarbazepine* acetate
      5Sulthiame15Topiramate26Perampanel
      6Carbamazepine16Fosphenytoin27Brivaracetam
      7Diazepam17Tiagabine28Cannabidiol
      8Valproate18Oxcarbazepine
      9Clonazepam19Levetiracetam
      10Clobazam20Pregabalin
      .21Zonisamide
      * Note that eslicarbazepine, which like oxcarbazepine is a derivative of carbamazepine, is not the main focus of this review as it is a 3rd generation drug with limited clinical experience, and the present review aims at reassessing the role of older drugs in light of the emergence of new treatment options (including eslicarbazepine).
      Whilst there is only a small difference in structure between CBZ and OXC, their mechanisms of action and their metabolic pathways are substantially different [
      • Schmidt D.
      • Elger C.E.
      What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic drugs?.
      ,
      • Beydoun A.
      • Kutluay E.
      Oxcarbazepine.
      ]. Both drugs are strong sodium channel blockers, but they modulate different types of calcium channels [
      • Wellington K.
      • Goa K.L.
      Oxcarbazepine: an update of its efficacy in the management of epilepsy.
      ,
      • Schmidt D.
      • Elger C.E.
      What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic drugs?.
      ,
      • Beydoun A.
      • Kutluay E.
      Oxcarbazepine.
      ]. Furthermore, while CBZ is oxidized by the cytochrome P-450 system and is a potent inducer of most of the isozymes of cytochrome P-450, OXC is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite (monohydroxy derivative [MHD]). MHD, which is primarily responsible for the pharmacological effect of OXC, is subsequently metabolized by conjugation with glucuronic acid in the liver. As a result, OXC was shown to be a substantially weaker inducer of hepatic enzymes and is significantly less prone to drug-drug interactions compared with CBZ [
      • Wellington K.
      • Goa K.L.
      Oxcarbazepine: an update of its efficacy in the management of epilepsy.
      ].

      2.2 CBZ and OXC in current guidelines

      Guidelines have evolved to reflect the evolution of the AED landscape. The main guidelines list CBZ and OXC as first-line options or second-line alternatives for the treatment of focal onset and primary generalized tonic-clonic seizures (Table 2).
      Table 2Place of CBZ and OXC in current guidelines.
      YearGuidelinesFocal-onset seizuresGeneralized tonic-clonic seizures
      2012NICE
      • National Institute for Health and Clinical Excellence (NICE)
      The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care.
      ,
      • Nevitt S.J.
      • Sudell M.
      • Weston J.
      • Tudur Smith C.
      • Marson A.G.
      Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.
      First line:First line:
      • CBZ or lamotrigine for children, young people and adults;
      • Alternatively OXC, valproate or levetiracetam if CBZ and lamotrigine are not appropriate
      • Valproate (or lamotrigine if valproate unsuitable) for children, young people and adults;
      • CBZ and OXC may also be considered depending on risk of exacerbating myoclonic or absence seizures
      2004−2018AAN
      • Kanner A.M.
      • Ashman E.
      • Gloss D.
      • Harden C.
      • Bourgeois B.
      • Bautista J.F.
      • et al.
      Practice guideline update summary: efficacy and tolerability of the new antiepileptic drugs I: treatment of new-onset epilepsy: report of the American Epilepsy Society and the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.
      ,
      • French J.A.
      • Kanner A.M.
      • Bautista J.
      • Abou-Khalil B.
      • Browne T.
      • Harden C.L.
      • et al.
      Efficacy and tolerability of the new antiepileptic drugs, I: treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.
      ,
      • Kanner A.M.
      • Ashman E.
      • Gloss D.
      • Harden C.
      • Bourgeois B.
      • Bautista J.F.
      • et al.
      Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
      First line:
      • Choice can be standard AEDs such as CBZ, phenytoin, valproic acid, phenobarbital, and new AEDs, lamotrigine, gabapentin, OXC, or topiramate
      • Insufficient evidence to consider gabapentin, OXC, or topiramate instead of CBZ.
      No high-quality studies exist for 16 AEDs (including OXC) but:
      • OXC extended release 2,400 mg/d is possibly effective for treating treatment-resistant focal epilepsy in adults (class II)
      • OXC only drug with class I evidence for the treatment of newly diagnosed focal onset seizures in children
      • OXC recommended for treatment-resistant focal epilepsy in infants and children of 1 month to 4 years (add-on therapy)
      2013ILAE
      • Glauser T.
      • Ben-Menachem E.
      • Bourgeois B.
      • Cnaan A.
      • Guerreiro C.
      • Kälviäinen R.
      • et al.
      Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes.
      • CBZ and phenytoin listed as AEDs with level A evidence of efficacy/effectiveness in adults, in addition to levetiracetam and zonisamide
      2015CAAE
      • China Association Against Epilepsy (CAAE)
      Guidelines on the diagnosis and treatment of epilepsy.
      First line:First line:
      • CBZ, lamotrigine and levetiracetam for adults
      • OXC for children
      • Valproate
      • Alternatively CBZ and OXC (for patients with generalized tonic-clonic seizures only), lamotrigine, levetiracetam and phenytoin
      2015Japanese guidelines
      • Tsuji S.
      Clinical guidelines for epilepsy.
      ,
      • Jin K.
      Treatment strategy for adult epilepsy: a current approach.
      • First line: CBZ
      • First line: valproate
      • New AEDs recommended as add-on therapy or for special groups
      AAN: American Academy of Neurology; AED: antiepileptic drug; CAAE: China Association Against Epilepsy; ILAE: International League Against Epilepsy; CBZ: carbamazepine; NICE: National Institute for Health and Clinical Excellence; OXC: oxcarbazepine.
      Results of randomized clinical trials (RCTs) and recently published network analyses and systematic reviews complement guidelines recommendations and provide additional guidance towards evidence-based treatment choice.

      3. Efficacy/effectiveness

      In epilepsy, effectiveness often refers to the proportion of patients who remain on the allocated AED for a period of time. This provides a combined measure of efficacy (seizure control) and tolerability, with the ultimate goal of epilepsy treatment being lasting freedom from seizures without adverse effects [
      • Perucca E.
      • Tomson T.
      The pharmacological treatment of epilepsy in adults.
      ].

      3.1 Randomized controlled trials and other studies

      Although there is evidence of efficacy under controlled research conditions for newer AEDs, their clinical effectiveness has been poorly studied [
      • Brodie M.J.
      • Kwan P.
      Newer drugs for focal epilepsy in adults.
      ], and previous RCTs have limitations in informing the choice between all different AEDs [
      • Marson A.G.
      • Al-Kharusi A.M.
      • Alwaidh M.
      • Appleton R.
      • Baker G.A.
      • Chadwick D.W.
      • et al.
      The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.
      ]. Several large trials conducted after 2006 have nevertheless provided some limited information on their relative efficacy.
      The Standard and New Antiepileptic Drugs (SANAD) study was a non-blinded RCT comparing CBZ, gabapentin, lamotrigine, OXC, and topiramate in focal epilepsy, conducted in 1721 hospital-based outpatient clinics in the UK [
      • Marson A.G.
      • Al-Kharusi A.M.
      • Alwaidh M.
      • Appleton R.
      • Baker G.A.
      • Chadwick D.W.
      • et al.
      The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.
      ]. In this study, CBZ was superior to gabapentin for time to 12-month remission and had a non-significant advantage over lamotrigine, topiramate, and OXC. However, for time to treatment failure, lamotrigine was superior to all other AEDs except for OXC.
      It is important to note that the oldest head-to-head trials with CBZ (as is the case for SANAD) used the immediate-release formulation (CBZ-IR) on a BID schedule. Evidence indicates that CBZ is better tolerated with the controlled-release formulation (CBZ-CR), as suggested by studies conducted in the elderly population. For example, in a multicenter study comparing CBZ-IR with lamotrigine, the latter was significantly better tolerated than CBZ-IR [
      • Brodie M.J.
      • Overstall P.W.
      • Giorgi L.
      Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group.
      ]; however, an identical study comparing lamotrigine with CBZ-CR did not find any significant difference in tolerability between the two drugs [
      • Saetre E.
      • Perucca E.
      • Isojärvi J.
      • Gjerstad L.
      • Group LAMS
      An international multicenter randomized double-blind controlled trial of lamotrigine and sustained-release carbamazepine in the treatment of newly diagnosed epilepsy in the elderly.
      ].
      More recently, the efficacy and tolerability of a number of the newer AEDs, including levetiracetam, zonisamide, lacosamide, and eslicarbazepine were evaluated in head-to-head trials against CBZ-CR in adults with newly diagnosed epilepsy [
      • Baulac M.
      • Brodie M.J.
      • Patten A.
      • Segieth J.
      • Giorgi L.
      Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial.
      ,
      • Baulac M.
      • Rosenow F.
      • Toledo M.
      • Terada K.
      • Li T.
      • De Backer M.
      • et al.
      Efficacy, safety, and tolerability of lacosamide monotherapy versus controlled-release carbamazepine in patients with newly diagnosed epilepsy: a phase 3, randomised, double-blind, non-inferiority trial.
      ,
      • Trinka E.
      • Ben-Menachem E.
      • Kowacs P.A.
      • Elger C.
      • Keller B.
      • Löffler K.
      • et al.
      Efficacy and safety of eslicarbazepine acetate versus controlled-release carbamazepine monotherapy in newly diagnosed epilepsy: a phase III double-blind, randomized, parallel-group, multicenter study.
      ,
      • Brodie M.J.
      • Perucca E.
      • Ryvlin P.
      • Ben-Menachem E.
      • Meencke H.J.
      Levetiracetam Monotherapy Study G. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy.
      ]. No significant differences in efficacy or tolerability were observed.
      Effectiveness, however, should not be the only factor to consider. The impact on quality of life (QOL) is another important variable, as not all adverse events (AEs) affecting QOL lead to drug discontinuation. This was suggested by the results of an open-label, single-arm study of patients aged ≥12 years with focal onset seizures, whereby patients who switched to OXC monotherapy due to lack of efficacy or poor tolerability on their current AED had significant and clinically relevant improvement in QOL [
      • Sachdeo R.C.
      • Gates J.R.
      • Bazil C.W.
      • Barkley G.L.
      • Tatum W.
      • D’Souza J.
      • et al.
      Improved quality of life in patients with partial seizures after conversion to oxcarbazepine monotherapy.
      ].
      Recent network meta-analyses and Cochrane Reviews, based on individual participant data (IPD), presented below shed further light on how CBZ and OXC compare with other treatments.

      3.2 Systematic reviews/network analyses

      Several network meta-analyses have recently been published that provide direct and indirect comparisons for all available AEDs (see Table 3a for a summary of the results).
      Table 3aSummary of meta-analyses results.
      YearStudies includedAEDsTolerability / Time to withdrawalSeizure control
      2019

      • Lattanzi S.
      • Zaccara G.
      • Giovannelli F.
      • Grillo E.
      • Nardone R.
      • Silvestrini M.
      • et al.
      Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis.
      4 head-to-head trials involving 2856 participants with newly diagnosed

      focal epilepsy
      CBZ-CR vs levetiracetam, zonisamide, lacosamide, or eslicarbazepine
      • No difference in treatment-emergent AEs between CBZ-CR and any of the four AEDs tested
      • Lacosamide was associated with lower discontinuation rate than CBZ‐CR
      • Rates of 6- and 12-month seizure freedom were similar between CBZ-CR and any of the four AEDs tested
      2014
      • Li Z.
      • Gao Z.
      • Jin C.
      • Guo Q.
      • Wang L.
      • Wang S.
      • et al.
      The efficacy of leviteracetam versus carbamazepine for epilepsy: a meta-analysis.
      3 trials in 1696 newly diagnosed patients or patients with focal or generalized epilepsyCBZ vs leviteracetam
      • Levetiracetam led to depression more frequently than CBZ, while CBZ caused rash more frequently
      • Rates of seizure freedom were similar between CBZ and levetiracetam
      2017
      • Nevitt S.J.
      • Sudell M.
      • Weston J.
      • Tudur Smith C.
      • Marson A.G.
      Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.
      36 trials including IPD for 12,391 participants with focal onset seizures or generalized tonic clonic seizures10 AEDs currently used as monotherapy for focal onset seizures or focal to bilateral tonic-clonic seizuresTime to withdrawal (focal seizures):Time to 12-month remission:
      • CBZ performed significantly better than gabapentin and phenobarbitone (high quality evidence) and worse than levetiracetam and lamotrigine
      • CBZ performed better than levetiracetam for individuals with partial seizures
      2016
      • MSdA Campos
      • Ayres L.R.
      • Morelo M.R.S.
      • Marques F.A.
      • Pereira L.R.L.
      Efficacy and tolerability of antiepileptic drugs in patients with focal epilepsy: systematic review and network meta-analyses.
      Tolerability analysis: 43 trials with 12,886 patients

      Efficacy analysis: 18 studies, comprising 5951 patients with focal epilepsy
      17 available AEDs used as monotherapy (analyses done on focal epilepsy for efficacy, and all types of epilepsy for tolerability)Withdrawal due to adverse reactions:Seizure freedom and withdrawal due to therapeutic inefficacy:
      • CBZ performed better than phenobarbital and primidone
      • Newer AEDs, including clobazam, gabapentin, lamotrigine, OXC, valproate, and vigabatrin had lower risk of withdrawal vs CBZ
      • CBZ performed better than the older drugs, primidone and phenobarbital, which were associated with a lower chance of patients becoming seizure-free, and better than pregabalin
      • Clobazam, levetiracetam, lamotrigine, OXC, sulthiame, topiramate, and valproate, which had the best efficacy profiles, demonstrated no evidence of superiority vs CBZ
      Results of one of the largest and most recent network meta-analysis of IPD published in the Cochrane database of systematic reviews are in line with NICE guidelines, concluding that CBZ and lamotrigine are suitable first-line treatment options for individuals with focal onset seizures [
      • Nevitt S.J.
      • Sudell M.
      • Weston J.
      • Tudur Smith C.
      • Marson A.G.
      Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.
      ]. In addition, levetiracetam was listed among the most suitable alternatives. Generally, most AEDS in the network performed similarly in terms of seizure control, but older drugs performed worse in terms of long-term retention compared with the newer drugs, such as lamotrigine and levetiracetam (Table 3a).
      Another large systematic review and network meta-analysis compared the relative efficacy and tolerability of 17 available AEDs used as monotherapy for the treatment of epilepsy (analyses done on focal epilepsy for efficacy, and all types of epilepsy for tolerability) [
      • MSdA Campos
      • Ayres L.R.
      • Morelo M.R.S.
      • Marques F.A.
      • Pereira L.R.L.
      Efficacy and tolerability of antiepileptic drugs in patients with focal epilepsy: systematic review and network meta-analyses.
      ]. The tolerability analyses again showed that newer drugs performed better than the oldest AEDs in terms of treatment withdrawal due to AEs, with CBZ ranking somewhat in the middle. In the efficacy analyses, CBZ performed better than the older drugs, primidone and phenobarbital, which were associated with a lower chance of achieving seizure freedom, and better than pregabalin in terms of withdrawals due to lack of therapeutic efficacy. No AED showed a significant improvement in any efficacy outcomes compared with CBZ, and OXC was listed among the drugs with the best efficacy profiles.
      Taken together, these result indicate that while some new AEDs appear to be better tolerated than CBZ, none were more effective and some (primidone, phenobarbital, pregabalin) were less effective than CBZ based on certain efficacy measures. In several studies, levetiracetam showed comparable efficacy, and in one analysis, showed lower efficacy than CBZ in terms of seizure control [
      • MSdA Campos
      • Ayres L.R.
      • Morelo M.R.S.
      • Marques F.A.
      • Pereira L.R.L.
      Efficacy and tolerability of antiepileptic drugs in patients with focal epilepsy: systematic review and network meta-analyses.
      ,
      • Nevitt S.J.
      • Sudell M.
      • Weston J.
      • Tudur Smith C.
      • Marson A.G.
      Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.
      ].
      These overall findings are generally in line with results of pairwise comparisons based on IPD, as published in a series of Cochrane Reviews (Table 3b) [
      • Nevitt S.J.
      • Marson A.G.
      • Tudur Smith C.
      Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.
      ,
      • Nevitt S.J.
      • Marson A.G.
      • Tudur Smith C.
      Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review.
      ,
      • Nevitt S.J.
      • Sudell M.
      • Tudur Smith C.
      • Marson A.G.
      Topiramate versus carbamazepine monotherapy for epilepsy: an individual participant data review.
      ,
      • Nevitt S.J.
      • Tudur Smith C.
      • Marson A.G.
      Oxcarbazepine versus phenytoin monotherapy for epilepsy: an individual participant data review.
      ,
      • Nevitt S.J.
      • Tudur Smith C.
      • Weston J.
      • Marson A.G.
      Lamotrigine versus carbamazepine monotherapy for epilepsy: an individual participant data review.
      ].
      Table 3bResults summary of pairwise comparisons based on IPD from series Cochrane Reviews.
      YearStudies includedAEDsTolerability / Time to withdrawalSeizure control
      2018
      • Nevitt S.J.
      • Tudur Smith C.
      • Marson A.G.
      Oxcarbazepine versus phenytoin monotherapy for epilepsy: an individual participant data review.
      3 trials with IPD available for 480 patients with focal onset seizures or generalized tonic-clonic seizuresOXC vs phenytoin
      • Treatment failure due to AEs occurs significantly later with OXC than with phenytoin monotherapy (high quality evidence)
      • OXC may be superior to phenytoin in focal onset seizures in terms of treatment failure for any reason, seizure recurrence, and seizure remission (moderate quality evidence)
      2018
      • Nevitt S.J.
      • Marson A.G.
      • Tudur Smith C.
      Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.
      13 trials with IPD available for 836 patients with focal onset or generalized onset tonic-clonic seizuresCBZ vs phenobarbitone
      • CBZ is likely to be a more effective drug than phenobarbitone in terms of treatment retention (moderate-quality evidence)
      2018
      • Nevitt S.J.
      • Tudur Smith C.
      • Weston J.
      • Marson A.G.
      Lamotrigine versus carbamazepine monotherapy for epilepsy: an individual participant data review.
      13 trials with IPD available for 2572 patients with focal onset or generalized onset tonic-clonic seizuresCBZ vs lamotrigine
      • Treatment failure for any reason related to treatment or due to AEs occurs significantly earlier with CBZ than with lamotrigine
      • CBZ may be associated with earlier remission and later seizure recurrence vs lamotrigine (moderate quality evidence)
      2019
      • Nevitt S.J.
      • Marson A.G.
      • Tudur Smith C.
      Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review.
      12 trials with IPD available for 595 patients with focal onset or generalized onset tonic-clonic seizuresCBZ vs phenytoin
      • No difference between CBZ and phenytoin in terms of effectiveness (retention)
      • No difference between CBZ and phenytoin in terms of seizure recurrence and seizure remission (moderate quality evidence)
      2019
      • Nevitt S.J.
      • Sudell M.
      • Tudur Smith C.
      • Marson A.G.
      Topiramate versus carbamazepine monotherapy for epilepsy: an individual participant data review.
      3 trials with IPD were available for 1151 patients with focal onset seizuresCBZ vs topiramate
      • CBZ is less likely to be withdrawn than topiramate (moderate quality evidence)
      • 12-month remission achieved earlier with CBZ than topiramate (high quality evidence)
      AED: antiepileptic drug; CBZ: carbamazepine; CBZ-CR: carbamazepine controlled-release formulation; IPD: individual participant data; OXC: oxcarbazepine.

      3.3 Cost-effectiveness

      The question of cost-effectiveness does not have a straightforward answer, as costs cannot be generalized worldwide. In addition, indirect costs are also an important factor to be taken into account and high quality cost-effectiveness studies are lacking [
      • Brodie M.J.
      • Kwan P.
      Newer drugs for focal epilepsy in adults.
      ].
      A cost-minimization analysis investigated the costs of treatment with lamotrigine, CBZ, phenytoin, and valproate in 12 European countries, taking into account each drug's side-effect and tolerability profiles. In each country considered, lamotrigine was twofold to threefold more expensive than the other drugs [
      • Heaney D.C.
      • Shorvon S.D.
      • Sander J.W.
      • Boon P.
      • Komarek V.
      • Marusic P.
      • et al.
      Cost minimization analysis of antiepileptic drugs in newly diagnosed epilepsy in 12 European countries.
      ].
      A more recent study reviewing the scant health economic data on CBZ suggested that the use of this drug in epilepsy is cost-effective in certain contexts [
      • Heaney D.
      • Sander J.W.
      Cost-effectiveness of carbamazepine in epilepsy.
      ]. However, evidence from a prospective, randomized, controlled trial is lacking and uncertainty persists. In particular, cost-effectiveness remains to be demonstrated when used in certain patient subgroups, including the elderly, women of childbearing potential, and patients with learning difficulties. In the developing world, cheaper options such as phenytoin and phenobarbital should be considered. Furthermore, the economic effect on long-term side effects (particularly the potential effects on bone metabolism) drug-drug interactions, and teratogenicity was not incorporated into the analysis.
      In spite of these uncertainties, the latest NICE guidelines, which included cost utility analyses of AEDs, concluded that lamotrigine was the most cost-effective monotherapy, but noted that CBZ may be as cost-effective [
      • National Institute for Health and Clinical Excellence (NICE)
      The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care.
      ].

      3.4 Real-world evidence

      Guideline recommendations and clinical trial outcomes only partly reflect the place of AEDs in the epilepsy armamentarium. Real-world evidence studies and geographical variations in the use of AEDs in clinical practice are an important part of the picture, especially as they take into account essential factors, such as availability and cost in real-world settings. The authors of this review identified several studies conducted in different parts of the world that may help shed light on various clinical practices across countries. It should, however, be kept in mind that these examples are not full reflections of the situation in the countries considered. A summary of the findings is included in Table 4.
      Table 4Geographical variation in AED use and evidence of effectiveness: results of observational studies.
      Region/ CountryStudyFindings
      A

      S

      I

      A
      China11 tertiary hospitals across China including 1603 outpatients
      • Yu P.
      • Zhou D.
      • Liao W.
      • Wang X.
      • Wang Y.
      • Wang T.
      • et al.
      An investigation of the characteristics of outpatients with epilepsy and antiepileptic drug utilization in a multicenter cross-sectional study in China.
      • OXC 26% and valproic acid 39% most commonly prescribed monotherapy for patients with focal seizures and generalized seizures, respectively
      3069 southern Chinese outpatients with epilepsy (conducted 2003–2015)
      • Du Y.
      • Lin J.
      • Shen J.
      • Ding S.
      • Ye M.
      • Wang L.
      • et al.
      Adverse drug reactions associated with six commonly used antiepileptic drugs in southern China from 2003 to 2015.
      • CBZ and OXC are among the six most widely used AEDs along with valproate, lamotrigine, topiramate and levetiracetam
      6547 patients in rural western China
      • Hu J.
      • Si Y.
      • Zhou D.
      • Mu J.
      • Li J.
      • Liu L.
      • et al.
      Prevalence and treatment gap of active convulsive epilepsy: a large community-based survey in rural West China.
      • Only one third (34%) of patients received appropriate AED medication, which consisted of phenytoin (15%), CBZ (10%), phenobarbital (9%), and valproate (6%)
      CBZ vs valproate in 584 patients with focal seizures followed for 10 years in a tertiary epilepsy center in China
      • Hu Y.
      • Huang Y.
      • Quan F.
      • Hu Y.
      • Lu Y.
      • Wang X.-F.-F.
      Comparison of the retention rates between carbamazepine and valproate as an initial monotherapy in Chinese patients with partial seizures: a ten-year follow-up, observational study.
      • First 6 months to 2 years: patients treated with CBZ (vs valproate) were more likely to discontinue treatment due to lack of efficacy, but were less likely to discontinue due to AEs
      • Long-term treatment: CBZ appeared to be more effective in terms of five-year remission and clinical control vs valproate
      Follow up study focusing on OXC and newer AEDs
      • H-c Kang
      • Hu Q.
      • X-y Liu
      • Z-g Liu
      • Zeng Z.
      • J-l Liu
      • et al.
      A follow-up study on newer anti-epileptic drugs as add-on and monotherapy for partial epilepsy in China.
      • OXC, lamotrigine and topiramate all showed good efficacy and tolerability for focal epilepsy, with efficacy maintained for at least one year
      OXC in 102 adult patients from the Epilepsy Clinic of West China Hospital
      • Zou X.-M.-M.
      • Chen J.-N.-N.
      • An D.-M.-M.
      • Hao N.-Y.-Y.
      • Hong Z.
      • Hao N.-Y.-T.
      • et al.
      Efficacy of low to moderate doses of oxcarbazepine in adult patients with newly diagnosed partial epilepsy.
      • OXC at low to moderate doses was effective for the treatment of Chinese adult patients with newly diagnosed, previously untreated, focal epilepsy
      OXC oral suspension:
      • 531 Chinese children aged 2–5 years with focal and/or generalized tonic-clonic seizures
        • Qin J.
        • Wang Y.
        • Huang X.-F.-F.
        • Zhang Y.-Q.-Q.
        • Fang F.
        • Chen Y.-B.-B.
        • et al.
        Oxcarbazepine oral suspension in young pediatric patients with partial seizures and/or generalized tonic-clonic seizures in routine clinical practice in China: a prospective observational study.
      • More than 80% of children achieving complete seizure remission
      • 912 children aged 2–16 years with focal and/or generalized tonic-clonic seizures
        • Wang Y.
        • Chen Y.-B.-B.
        • Zhang Y.-Q.-Q.
        • Luo R.
        • Wang H.
        • Lv J.-L.-L.
        • et al.
        Oxcarbazepine oral suspension in pediatric patients with partial seizures and/or generalized tonic-clonic seizures: a multi-center, single arm, observational study in China.
      • 82%, 7%, and 4% of patients became controlled, significantly improved, and improved, respectively, after 26 weeks of treatment
      • The efficacy of OXC was not affected by seizure types, age, or gender
      India972 patients in South India
      • Radhakrishnan K.
      • Nayak S.D.
      • Kumar S.P.
      • Sarma P.S.
      Profile of antiepileptic pharmacotherapy in a tertiary referral center in South India: a pharmacoepidemiologic and pharmacoeconomic study.
      • CBZ was the most frequently used AED, followed by diphenylhydantoin, valproate, and phenobarbitone
      BangladeshHospital-based study of low-cost AEDs in 854 Bangladeshi people years
      • Habib M.
      • Khan S.U.
      • Hoque A.
      • Mondal B.A.
      • Hasan A.T.M.H.
      • Chowdhury R.N.
      • et al.
      Antiepileptic drug utilization in Bangladesh: experience from Dhaka Medical College Hospital.
      • CBZ (67%) was the most frequently prescribed AED, followed by valproate (43%), phenobarbital (17%), and phenytoin (8%)
      • CBZ was prescribed in 37% of patients as monotherapy, followed by valproate in 21% and phenobarbital in 8%
      • Newer generation drugs (e.g. lamotrigine and topiramate) were used only as add-on therapy in combination with CBZ or valproate in 2% of patients
      Outcomes:
      • Treatment retention rates for AED monotherapy varied between 86% and 91% and were highest for CBZ, followed by valproate
      • Reduction of seizure frequency was highest for phenytoin (100%) and phenobarbital (98%), followed by CBZ (96%) and valproate (95%)
      • Phenytoin (64%) was the most common drug to cause adverse drug reaction, while CBZ was the least likely drug to be associated with AEs (12%)
      • Phenobarbital and phenytoin were the cheapest of all AEDs (42 I$ and 56 I$/ year respectively); the cost of CBZ and valproate were two times higher and lamotrigine and topiramate were six to eight times higher
      Middle EastJordan694 pediatric patients from specialized clinics
      • Albsoul-Younes A.
      • Gharaibeh L.
      • Murtaja A.A.
      • Masri A.
      • Alabbadi I.
      • Al-Qudah A.A.
      Patterns of antiepileptic drugs use in epileptic pediatric patients in Jordan.
      • Most frequently prescribed as a monotherapy: Valproic acid 235 (51%) and CBZ 155 (33%).
      • The most common combination in dual therapy was valproic acid with CBZ 28 (17%).
      E

      U

      R

      O

      P

      E
      43 EU countriesSurvey conducted in 43 European chapters of the ILAE
      • Baftiu A.
      • Johannessen Landmark C.
      • Nikaj V.
      • Neslein I.L.
      • Johannessen S.I.
      • Perucca E.
      Availability of antiepileptic drugs across Europe.
      • Large differences in AED availability across European countries, especially between high-income countries and the other countries
      • None of the newest (3rd generation) AEDs were available in any of the 12 non-high-income countries, the main reasons including lack of regulatory approval, high prices, and reimbursement restrictions
      • CBZ was the only drug available in all 43 countries studied
      • Among older AEDs, phenobarbital, has been withdrawn in three countries, and ethosuximide was not marketed in 11 countries, including 3 high-income countries
      • Among new AEDs, OXC was available in 34 countries and had the greatest variation in availability, from 91% in high-income countries to 50% in upper-middle-income countries and 15% in lower-middle/low-income countries
      GermanyClaims data years (2007–2014) of 34,422 patients with focal epilepsy
      • Groth A.
      • Wilke T.
      • Borghs S.
      • Gille P.
      • Joeres L.
      Real life pharmaceutical treatment patterns for adult patients with focal epilepsy in Germany: a longitudinal and cross-sectional analysis of recently approved anti-epileptic drugs.
      • Most prescribed in 2007: CBZ (40% of patients); that percentage decreased to 21% in 2014
      • Most prescribed in 2014: Levetiracetam (36% of patients) and CBZ fell into third position (21%) after valproate (26%)
      • In 2014, OXC is in fifth position (7%) after lamotrigine (20%)
      • 3rd generation AEDs are prescribed in a small proportion of patients only (<6%)
      4,115,705 AED prescriptions (2009)
      • Hamer H.M.
      • Dodel R.
      • Strzelczyk A.
      • Balzer-Geldsetzer M.
      • Reese J.P.
      • Schöffski O.
      • et al.
      Prevalence, utilization, and costs of antiepileptic drugs for epilepsy in Germany--a nationwide population-based study in children and adults.
      • Prevalence and prescribing patterns changed with age
      • OXC and sultiame were popular with pediatricians
      • Elderly patients frequently received phenytoin and primidone
      SwedenNational register (2007–2013) including 27,772 patients treated for epilepsy
      • Bolin K.
      • Berggren F.
      • Berling P.
      • Morberg S.
      • Gauffin H.
      • Landtblom A.M.
      Patterns of antiepileptic drug prescription in Sweden: a register-based approach.
      • The most common first monotherapies were CBZ, valproate, and lamotrigine
      • CBZ dropped from almost 40% in 2007 to 24% in 2013 (while valproate dropped from 23% to 14%, and lamotrigine monotherapy rose slightly from 18% to almost 21%)
      • The most common second-line monotherapy was levetiracetam
      MacedoniaSurvey of neurologists
      • Cvetkovska E.
      • Kuzmanovski I.
      • Boshkovski B.
      Brief communication of assessment of clinical practice regarding pharmacological treatment of epilepsy: a survey of neurologists in Republic of Macedonia.
      • CBZ and lamotrigine were the most frequently prescribed first-line drugs for focal seizures (note that Macedonia is listed as upper-middle-income countries in the European survey above mentioned)
      A

      F

      R

      I

      C

      A
      UgandaSurvey of 305 households having patients with epilepsy
      • Rutebemberwa E.
      • Ssemugabo C.
      • Tweheyo R.
      • Turyagaruka J.
      • Pariyo G.W.
      Biomedical drugs and traditional treatment in care seeking pathways for adults with epilepsy in Masindi district, Western Uganda: a household survey.
      • Patients use modern medicine, traditional herbs and prayers interchangeably
      • A significant proportion of patients do not access biomedical treatment (37% of patients did not receive AEDs during first contact care)
      • Drugs prescribed were phenobarbitone, CBZ and phenytoin with a few other drugs
      RwandaSurvey of 1137 patients
      • Sebera F.
      • Munyandamutsa N.
      • Teuwen D.E.
      • Ndiaye I.P.
      • Diop A.G.
      • Tofighy A.
      • et al.
      Addressing the treatment gap and societal impact of epilepsy in Rwanda--Results of a survey conducted in 2005 and subsequent actions.
      • 43% indicated that they received no treatment and 25% received solely some form of traditional treatment, resulting in a treatment gap of 68%
      • The three most frequently used AEDS were valproic acid (44%) and CBZ (44%), followed by phenobarbital (33%)
      • 49% of respondents taking AEDs managed to take their medication on a regular basis
      A

      M

      E

      R

      I

      C

      A
      MexicoSurvey including 306 physicians and 21,476 patients
      • Alva E.
      Recommendations and clinical use of oxcarbazepine for focal epilepsy treatment: mexican national survey: P195.
      • OXC was the first treatment option in newly diagnosed focal epilepsy in children and adults, followed by CBZ and valproic acid
      • The add-on therapy most often used with OXC was valproic acid, but phenytoin, phenobarbital and lamotrigine were also tolerable
      • The study concluded that OXC was a good option in Mexican neurologists' experience
      BrazilSurvey of 54,102 people in South-East Brazil
      • Noronha A.L.
      • Borges M.A.
      • Marques L.H.
      • Zanetta D.M.
      • Fernandes P.T.
      • de Boer H.
      • et al.
      Prevalence and pattern of epilepsy treatment in different socioeconomic classes in Brazil.
      • 38% of patients with active epilepsy were inadequately treated, including 19% on no medication, with similar rates across socioeconomic classes
      • Urgent need for education in Brazil to inform people that epilepsy is a treatable, as well as a preventable, condition
      ArgentinaCommunity-based survey
      • Melcon M.O.
      • Kochen S.
      • Vergara R.H.
      Prevalence and clinical features of epilepsy in Argentina. A community-based study.
      • Phenobarbital and CBZ were the most common AEDs used individually
      • Phenobarbital and phenytoin were the most common AEDs used in polytherapy
      USSurvey of 42 physicians specialised in epilepsy
      • Shih J.J.
      • Whitlock J.B.
      • Chimato N.
      • Vargas E.
      • Karceski S.C.
      • Frank R.D.
      Epilepsy treatment in adults and adolescents: Expert opinion, 2016.
      • OXC, lamotrigine and levetiracetam are considered as the drugs of choice for initial treatment of focal seizures
      • Compared with similar surveys conducted in 2001 and 2005, preference for the use of levetiracetam and lamotrigine appears to have increased, at the expense of that of phenytoin, gabapentin, phenobarbital and CBZ
      • CBZ was usually considered appropriate or first-line for focal seizures
      AED: antiepileptic drug; CBZ: carbamazepine; OXC: oxcarbazepine.

      3.4.1 Asia

      It appears that for initial monotherapy of focal seizures in China, OXC has become the most prescribed AED in tertiary hospitals [
      • Yu P.
      • Zhou D.
      • Liao W.
      • Wang X.
      • Wang Y.
      • Wang T.
      • et al.
      An investigation of the characteristics of outpatients with epilepsy and antiepileptic drug utilization in a multicenter cross-sectional study in China.
      ]. In rural areas, CBZ is listed among the top two AEDs, although the treatment gap in these is large compared with epilepsy centers [
      • Hu J.
      • Si Y.
      • Zhou D.
      • Mu J.
      • Li J.
      • Liu L.
      • et al.
      Prevalence and treatment gap of active convulsive epilepsy: a large community-based survey in rural West China.
      ] (Table 4). In terms of outcomes, there are favorable real-world evidence efficacy data in China for both CBZ and OXC in focal epilepsy [
      • Hu Y.
      • Huang Y.
      • Quan F.
      • Hu Y.
      • Lu Y.
      • Wang X.-F.-F.
      Comparison of the retention rates between carbamazepine and valproate as an initial monotherapy in Chinese patients with partial seizures: a ten-year follow-up, observational study.
      ,
      • H-c Kang
      • Hu Q.
      • X-y Liu
      • Z-g Liu
      • Zeng Z.
      • J-l Liu
      • et al.
      A follow-up study on newer anti-epileptic drugs as add-on and monotherapy for partial epilepsy in China.
      ,
      • Zou X.-M.-M.
      • Chen J.-N.-N.
      • An D.-M.-M.
      • Hao N.-Y.-Y.
      • Hong Z.
      • Hao N.-Y.-T.
      • et al.
      Efficacy of low to moderate doses of oxcarbazepine in adult patients with newly diagnosed partial epilepsy.
      ]. In addition, OXC oral suspension is used in Chinese children for focal and generalized tonic-clonic seizures with substantial evidence for efficacy and safety [
      • Qin J.
      • Wang Y.
      • Huang X.-F.-F.
      • Zhang Y.-Q.-Q.
      • Fang F.
      • Chen Y.-B.-B.
      • et al.
      Oxcarbazepine oral suspension in young pediatric patients with partial seizures and/or generalized tonic-clonic seizures in routine clinical practice in China: a prospective observational study.
      ,
      • Wang Y.
      • Chen Y.-B.-B.
      • Zhang Y.-Q.-Q.
      • Luo R.
      • Wang H.
      • Lv J.-L.-L.
      • et al.
      Oxcarbazepine oral suspension in pediatric patients with partial seizures and/or generalized tonic-clonic seizures: a multi-center, single arm, observational study in China.
      ] (Table 4). However, while OXC is approved in China for generalized onset tonic-clonic seizures in children it should be noted that it is not the case in some other countries including the US [
      • Qin J.
      • Wang Y.
      • Huang X.-F.-F.
      • Zhang Y.-Q.-Q.
      • Fang F.
      • Chen Y.-B.-B.
      • et al.
      Oxcarbazepine oral suspension in young pediatric patients with partial seizures and/or generalized tonic-clonic seizures in routine clinical practice in China: a prospective observational study.
      ].
      CBZ, a commonly used AED in rural hospitals in India [
      • Das S.
      • Fleming D.H.
      • Mathew B.S.
      • Winston A.B.
      • Prabhakar A.T.
      • Alexander M.
      Determination of serum carbamazepine concentration using dried blood spot specimens for resource-limited settings.
      ], was also the most frequently used AED in a tertiary referral center in South India [
      • Radhakrishnan K.
      • Nayak S.D.
      • Kumar S.P.
      • Sarma P.S.
      Profile of antiepileptic pharmacotherapy in a tertiary referral center in South India: a pharmacoepidemiologic and pharmacoeconomic study.
      ] and in Bangladesh [
      • Habib M.
      • Khan S.U.
      • Hoque A.
      • Mondal B.A.
      • Hasan A.T.M.H.
      • Chowdhury R.N.
      • et al.
      Antiepileptic drug utilization in Bangladesh: experience from Dhaka Medical College Hospital.
      ] (Table 4). This is despite CBZ being a relatively expensive option in these countries, and it may be explained by its favorable safety profile versus cheaper alternatives [
      • Habib M.
      • Khan S.U.
      • Hoque A.
      • Mondal B.A.
      • Hasan A.T.M.H.
      • Chowdhury R.N.
      • et al.
      Antiepileptic drug utilization in Bangladesh: experience from Dhaka Medical College Hospital.
      ] (Table 4).
      In part of the Middle East, CBZ appears to be the second most frequently prescribed drug as a monotherapy in children after valproic acid, as suggested by a study conducted in Jordan [
      • Albsoul-Younes A.
      • Gharaibeh L.
      • Murtaja A.A.
      • Masri A.
      • Alabbadi I.
      • Al-Qudah A.A.
      Patterns of antiepileptic drugs use in epileptic pediatric patients in Jordan.
      ] (Table 4).

      3.4.2 Europe

      A survey conducted in 43 European ILAE chapters found large differences in AED availability across European countries, especially between high-income countries and the other countries [
      • Baftiu A.
      • Johannessen Landmark C.
      • Nikaj V.
      • Neslein I.L.
      • Johannessen S.I.
      • Perucca E.
      Availability of antiepileptic drugs across Europe.
      ]. CBZ was the only AED available in each of the 43 countries studied. OXC was available in 34 of the 43 countries and had the greatest variation in availability between high and low income countries (Table 4).
      Although its prevalence has decreased since 2007, CBZ seems to remain among the two or three most prescribed drugs for epilepsy in Eastern and Western Europe, as suggested by studies conducted in Macedonia, Germany, and Sweden [
      • Bolin K.
      • Berggren F.
      • Berling P.
      • Morberg S.
      • Gauffin H.
      • Landtblom A.M.
      Patterns of antiepileptic drug prescription in Sweden: a register-based approach.
      ,
      • Hamer H.M.
      • Dodel R.
      • Strzelczyk A.
      • Balzer-Geldsetzer M.
      • Reese J.P.
      • Schöffski O.
      • et al.
      Prevalence, utilization, and costs of antiepileptic drugs for epilepsy in Germany--a nationwide population-based study in children and adults.
      ,
      • Groth A.
      • Wilke T.
      • Borghs S.
      • Gille P.
      • Joeres L.
      Real life pharmaceutical treatment patterns for adult patients with focal epilepsy in Germany: a longitudinal and cross-sectional analysis of recently approved anti-epileptic drugs.
      ]. OXC appears to be more commonly prescribed in the pediatric population [
      • Bolin K.
      • Berggren F.
      • Berling P.
      • Morberg S.
      • Gauffin H.
      • Landtblom A.M.
      Patterns of antiepileptic drug prescription in Sweden: a register-based approach.
      ] (Table 4).

      3.4.3 Africa

      In many African countries, access is a key factor determining AED use. Multiplicity of health providers, reliance on traditional herbs and prayers, and no clear guidance as to who provides the primary care in epilepsy further limit the use of AEDs in these countries, where the treatment gap (defined as the number of people with active epilepsy not on treatment or on inadequate treatment) may be very significant (Table 4). Findings from two African-based studies indicate that CBZ, valproate, phenobarbital and phenytoin rank among the most prescribed drugs [
      • Rutebemberwa E.
      • Ssemugabo C.
      • Tweheyo R.
      • Turyagaruka J.
      • Pariyo G.W.
      Biomedical drugs and traditional treatment in care seeking pathways for adults with epilepsy in Masindi district, Western Uganda: a household survey.
      ,
      • Sebera F.
      • Munyandamutsa N.
      • Teuwen D.E.
      • Ndiaye I.P.
      • Diop A.G.
      • Tofighy A.
      • et al.
      Addressing the treatment gap and societal impact of epilepsy in Rwanda--Results of a survey conducted in 2005 and subsequent actions.
      ].
      Overall the findings suggest that there is room for greater private sector engagement in providing AEDs for refill, improving patient access, and decreasing patient financial burden associated with traveling [
      • Rutebemberwa E.
      • Ssemugabo C.
      • Tweheyo R.
      • Turyagaruka J.
      • Pariyo G.W.
      Biomedical drugs and traditional treatment in care seeking pathways for adults with epilepsy in Masindi district, Western Uganda: a household survey.
      ,
      • Sebera F.
      • Munyandamutsa N.
      • Teuwen D.E.
      • Ndiaye I.P.
      • Diop A.G.
      • Tofighy A.
      • et al.
      Addressing the treatment gap and societal impact of epilepsy in Rwanda--Results of a survey conducted in 2005 and subsequent actions.
      ]. They also highlight the continued effort required from the government to close the treatment gap through education and ensuring availability of classic AEDs, including CBZ, but also phenobarbital, phenytoin, and valproate in central pharmacies.

      3.4.4 South America

      A systematic review of the epilepsy treatment gap in developing countries in 2009 suggested that it was larger in Asia (64%) and Latin America (55%) compared with Africa (49%) [
      • Mbuba C.K.
      • Ngugi A.K.
      • Newton C.R.
      • Carter J.A.
      The epilepsy treatment gap in developing countries: a systematic review of the magnitude, causes, and intervention strategies.
      ]. The treatment gap in Brazil [
      • Noronha A.L.
      • Borges M.A.
      • Marques L.H.
      • Zanetta D.M.
      • Fernandes P.T.
      • de Boer H.
      • et al.
      Prevalence and pattern of epilepsy treatment in different socioeconomic classes in Brazil.
      ] and AED use in Argentina [
      • Melcon M.O.
      • Kochen S.
      • Vergara R.H.
      Prevalence and clinical features of epilepsy in Argentina. A community-based study.
      ] and in Mexico [
      • Alva E.
      Recommendations and clinical use of oxcarbazepine for focal epilepsy treatment: mexican national survey: P195.
      ] are shown in Table 4. The Argentinean survey indicated that CBZ and phenobarbital were the two most prescribed AEDs as monotherapy in 2007 in Argentina while the Mexican study concluded that OXC was a good first-choice option for newly diagnosed focal epilepsy, according to the experience of Mexican neurologists.

      3.4.5 US

      A recent survey of 42 US physicians specialized in epilepsy considered OXC, along with lamotrigine and levetiracetam, as a drug of choice for initial treatment of focal seizures [
      • Shih J.J.
      • Whitlock J.B.
      • Chimato N.
      • Vargas E.
      • Karceski S.C.
      • Frank R.D.
      Epilepsy treatment in adults and adolescents: Expert opinion, 2016.
      ]. While the survey highlighted a decrease in the preference for the use of CBZ since 2001 and 2005, CBZ was usually considered appropriate or first-line for focal onset seizures [
      • Shih J.J.
      • Whitlock J.B.
      • Chimato N.
      • Vargas E.
      • Karceski S.C.
      • Frank R.D.
      Epilepsy treatment in adults and adolescents: Expert opinion, 2016.
      ] (Table 4)
      Overall, the real-world-evidence data indicate that although disparities exist in terms of clinical management of epilepsy and drug availability, CBZ remains one of the most frequently prescribed AEDs, balancing effectiveness, availability, and cost. Across Asia, Africa, and South America, but in Europe also (although its prevalence there is decreasing), CBZ still plays an important role, remaining among the top two or three AEDs used in many countries. OXC is commonly used for focal epilepsy in China and is among the first-choice options in other countries, including the US, for initial treatment of focal onset seizures; the oral suspension formulation is commonly prescribed in children. Increasing the availability of classic AEDs, including CBZ, in some developing countries is still needed to close the treatment gap.

      4. Pharmacokinetic profile and treatment optimization

      Reducing the burden of epilepsy through treatment with CBZ or OXC, whenever these options are the most appropriate, necessitates following evidence-based treatment recommendations and guidelines to optimize efficacy and minimize side effects [
      • French J.A.
      • Kanner A.M.
      • Bautista J.
      • Abou-Khalil B.
      • Browne T.
      • Harden C.L.
      • et al.
      Efficacy and tolerability of the new antiepileptic drugs, I: treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.
      ]. CBZ is available in multiple dosage forms including tablets (IR 100, 200 and 400 mg and CR 200 and 400 mg), chewable tablets (100 mg), oral suspension (100 mg/5 ml) and suppositories (125 and 250 mg). OXC is available as tablets (150, 300 and 600 mg) and oral suspension (60 mg/mL). The pharmacokinetic parameters and serum reference ranges of the two drugs are provided in Table 5.
      Table 5Pharmacokinetic parameters and serum reference ranges of CBZ and OXC.
      AEDMetabolic pathwayTime to

      steady

      state (days)
      Plasma

      protein

      binding

      (%)
      Half-life

      (hours)
      Pharmaco-logically

      active metabolites
      Plasma reference range
      CBZCYP4502–4†758–20epoxide-CBZ*4–12 mg/L (17–51 μ mol/L)
      OXCCytosolic enzymes glucuronic acid2–3408–15MHD3–35 mg/L (12–139 μ mol/L)
      CBZ: carbamazepine; MHD: 10-monohydroxy derivative; OXC: oxcarbazepine. †Patients on chronic therapy after autoinduction has completed—values are much longer after a single dose. All values refer to the active metabolite MHD. *There are clinical settings where monitoring of epoxide-CBZ, in addition to CBZ, is warranted, particularly when a co-medication occurs with an inhibitor of epoxide-CBZ metabolism. When CBZ-CR tablets are administered singly and repeatedly, they yield about 25% lower peak concentrations of active substance in plasma than the conventional tablets; the peaks are attained within 24 h. The CBZ-CR tablets provide a statistically significant decreased fluctuation index, but not a significant decreased Cmin at steady state. The fluctuation of the plasma concentrations with a twice-daily dosage regimen is low. The bioavailability of CBZ-CR tablets is about 15% lower than that of the other oral dosage forms [
      • Das S.
      • Fleming D.H.
      • Mathew B.S.
      • Winston A.B.
      • Prabhakar A.T.
      • Alexander M.
      Determination of serum carbamazepine concentration using dried blood spot specimens for resource-limited settings.
      ,
      • Patsalos P.N.
      • Zugman M.
      • Lake C.
      • James A.
      • Ratnaraj N.
      • Sander J.W.
      Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: a comparison of free non-protein-bound concentrations.
      ,
      • Eeg-Olofsson O.
      • Nilsson H.L.
      • Tonnby B.
      • Arvidsson J.
      • Grahn P.A.
      • Gylje H.
      • et al.
      Diurnal variation of carbamazepine and carbamazepine-10,11-epoxide in plasma and saliva in children with epilepsy: a comparison between conventional and slow-release formulations.
      ].

      4.1 CBZ

      CBZ is a powerful inducer of hepatic enzymes (including both hetero and auto-induction) and is extensively metabolized in the liver (primarily by CYP3A4), causing numerous clinically relevant drug-drug interactions [
      • Das S.
      • Fleming D.H.
      • Mathew B.S.
      • Winston A.B.
      • Prabhakar A.T.
      • Alexander M.
      Determination of serum carbamazepine concentration using dried blood spot specimens for resource-limited settings.
      ] (Table 5). Auto-induction, in particular, results in nonlinear, time-dependent kinetics, with CBZ metabolism becoming more efficient as the duration of treatment increases; the steady-state concentration of CBZ is reduced by as much as 50% after 3 weeks of drug administration. As a result, during the introduction of CBZ, dose increases do not correlate with corresponding increases in the plasma levels and half-life of CBZ decreases with long-term use and polytherapy.
      Not only does CBZ dose correlate poorly with blood levels, but also using the same dose, blood levels vary depending on gender, race, or age (e.g., women, children, or patients of African extraction often need higher doses than Caucasian men to reach similar blood concentrations). Following dosing recommendations and monitoring drug levels is thus critical to minimize drug interactions as well as early intolerance and subsequent reduced efficacy due to auto-induction (see Table 6 for recommendations on treatment optimization including management of side effects, such as rash and hyponatremia).
      Table 6Recommendations for treatment optimization with CBZ or OXC.
      CBZ

      [
      • Patsalos P.N.
      • Spencer E.P.
      • Berry D.J.
      Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update.
      ,
      • French J.A.
      • Kanner A.M.
      • Bautista J.
      • Abou-Khalil B.
      • Browne T.
      • Harden C.L.
      • et al.
      Efficacy and tolerability of the new antiepileptic drugs, I: treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.
      ,
      • Das S.
      • Fleming D.H.
      • Mathew B.S.
      • Winston A.B.
      • Prabhakar A.T.
      • Alexander M.
      Determination of serum carbamazepine concentration using dried blood spot specimens for resource-limited settings.
      ,
      • Arroyo S.
      • Sander J.W.
      Carbamazepine in comparative trials: pharmacokinetic characteristics too often forgotten.
      ]
      OXC

      • Smith P.E.
      • Board UKOA
      Clinical recommendations for oxcarbazepine.
      ,
      • Wellington K.
      • Goa K.L.
      Oxcarbazepine: an update of its efficacy in the management of epilepsy.
      ,
      • Beydoun A.
      • Kutluay E.
      Oxcarbazepine.
      ,
      • French J.A.
      • Kanner A.M.
      • Bautista J.
      • Abou-Khalil B.
      • Browne T.
      • Harden C.L.
      • et al.
      Efficacy and tolerability of the new antiepileptic drugs, I: treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.
      ,
      • Kern R.
      Oxcarbazepine - profile of a new anticonvulsant.
      ,
      • Dam M.
      Practical aspects of oxcarbazepine treatment.
      Dosing recommendations
      • Unless the CBZ-CR formulation is used, a twice or thrice a day dosing regimen is necessary
      • Low initial dose and slow titration: 100 mg/day starting dose with 100 mg increments at weekly intervals (more likely to succeed than starting at 200 mg/day, as in many trials) up to 600 mg/day
      • Children: start 5–10 mg/kg/day up to 20 mg/kg/day
      • Similarly to CBZ, a slower introduction is preferable (e.g. 150 mg on Day one, then 300 mg daily, and increased by 300 mg weekly) both for monotherapy and adjuvant therapy
      • The recommended dose of OXC as monotherapy for adults with epilepsy is 600–1,200 mg orally per day but may be higher in patients with refractory seizures and in those requiring combination therapy
      • Children: start 10–20 up to 45 mg/kg/day
      • Owing to individual variations in CBZ enzyme auto-induction, overnight switching (using CBZ/OXC ratio of 1/1.5) is advised only for patients on CBZ < 800 mg daily; otherwise, slower switching over a period of 2–4 weeks is recommended to minimize side effects
      Drug interactions
      • Enhances its own metabolism (auto-induction)
      • CYP3A4 inducers/inhibitors decrease/increase CBZ levels
      • Decrease levels of drugs metabolized by CYP3A4 including many commonly used medications such as warfarin, oral contraceptives, calcium channel antagonists, and chemotherapeutic agents, etc.
      • Modest, dose-dependent induction of CYP 3A4 may reduce effectiveness of oral contraceptives.
      • Inhibition of CYP2C19 may result in increases in phenytoin plasma concentrations
      TDM
      • Perform TDM routinely if possible, or 14 days after equilibration and in case of interactions with other drugs, doubt on compliance or unexplained side effects
      • The “therapeutic range” derived from the relationships among plasma level, seizure control, and emergence of side effects, is often set between 4 and 12 mg/L
      • Setting a plasma level target on both CBZ and its metabolite, epoxide-CBZ, may help to achieve an optimum therapeutic response
        • Chbili C.
        • Hassine A.
        • Laouani A.
        • Amor S.B.
        • Nouira M.
        • Ammou S.B.
        • Saguem S.
        The relationship between pharmacokinetic parameters of carbamazepine and therapeutic response in epileptic patients.
      • Drug concentration may be measured in saliva instead of blood, with the advantage of easier collection and access to levels of the free, non-protein-bound compound, which is the form entering the brain (saliva monitoring is widely practiced in the US)
        • Patsalos P.N.
        • Spencer E.P.
        • Berry D.J.
        Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update.
      • Plasma range for monitoring of MHD: 3–35 mg/L
      • As per CBZ, MHD is secreted into saliva, which may be used for TDM in place of blood
        • Patsalos P.N.
        • Spencer E.P.
        • Berry D.J.
        Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update.
      Rash
      • Major AE that leads to CBZ discontinuation
      • Wide range of frequency (2.3%–19%)
      • A low initial CBZ dose and slow titration have been shown to substantially reduce the likelihood of rash
        • Arroyo S.
        • Sander J.W.
        Carbamazepine in comparative trials: pharmacokinetic characteristics too often forgotten.
      Hyponatremia
      • Hyponatremia may develop with both CBZ or OXC, but is more frequent with OXC
        • Perucca E.
        • Tomson T.
        The pharmacological treatment of epilepsy in adults.
      • Sodium monitoring recommended in case of concomitant administration of sodium depleting drug or renal disease
        • Schmidt D.
        • Arroyo S.
        • Baulac M.
        • Dam M.
        • Dulac O.
        • Friis M.L.
        • et al.
        Recommendations on the clinical use of oxcarbazepine in the treatment of epilepsy: a consensus view.
      • It is often asymptomatic, but may be more frequent than suggested by clinical studies, especially in the elderly
        • Perucca E.
        • Tomson T.
        The pharmacological treatment of epilepsy in adults.
        – one fourth of patients taking CBZ and almost half of those taking OXC in a recent RWE study (hyponatremia was severe in 7% and 22% of patients, respectively)
        • Berghuis B.
        • van der Palen J.
        • de Haan G.J.
        • Lindhout D.
        • Koeleman B.P.C.
        • Sander J.W.
        Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy.
      • In a population-based study, CBZ use was associated with a higher risk of hospitalization with hyponatremia within 30 days of drug initiation in people older than 65 years
        • Gandhi S.
        • McArthur E.
        • Mamdani M.M.
        • Hackam D.G.
        • McLachlan R.S.
        • Weir M.A.
        • et al.
        Antiepileptic drugs and hyponatremia in older adults: two population-based cohort studies.
      • To prevent this, the EpiPGX Consortium recommend a low threshold of suspicion, and to routinely check sodium levels in people taking either of these drugs
      • Children are also at risk of developing electrolyte disturbances, and the level of sodium, at least, should also be measured in the pediatric population
        • Borusiak P.
        • Korn-Merker E.
        • Holert N.
        • Boenigk H.E.
        Hyponatremia induced by oxcarbazepine in children.
      • In any case, if symptoms of hyponatremia, such as headache, general malaise, gait disturbance, and somnolence, are suspected, the serum sodium level should be measured
        • Lin C.H.
        • Lu C.H.
        • Wang F.J.
        • Tsai M.H.
        • Chang W.N.
        • Tsai N.W.
        • et al.
        Risk factors of oxcarbazepine-induced hyponatremia in patients with epilepsy.
      • Mild hyponatremia can be treated with fluid restriction
      • In case of severe hyponatremia, the introduction of an alternative AED with the gradual withdrawal of CBZ/OXC is recommended
      Hormonal contraception
      • Due to its inducing effect, CBZ at common dosage decreases levels of contraceptive steroids, which has been shown to increase breakthrough bleeding and permit ovulation if low dose of oral contraceptives are used
        • Davis A.R.
        • Westhoff C.L.
        • Stanczyk F.Z.
        Carbamazepine coadministration with an oral contraceptive: effects on steroid pharmacokinetics, ovulation, and bleeding.
      • OXC may also reduce the effectiveness of hormonal contraception
        • Wellington K.
        • Goa K.L.
        Oxcarbazepine: an update of its efficacy in the management of epilepsy.
        ,
        • Kern R.
        Oxcarbazepine - profile of a new anticonvulsant.
      Genotyping
      • The Dutch Pharmacogenetics Working Group (DPWG) recommend avoiding the use of CBZ and selecting an alternative, if possible, for individuals positive for HLA-B*1502, HLA-A*3101, and HLA-B*1511
        • Dean L.
        Carbamazepine therapy and HLA genotype.
      • In the US, genotyping is recommended prior to commencing CBZ treatment in patients with susceptible ancestry, with supportive evidence of its cost-effectiveness
        • Choi H.
        • Mohit B.
        Cost-effectiveness of screening for HLA-B*1502 prior to initiation of carbamazepine in epilepsy patients of Asian ancestry in the United States.
      • Chinese guidelines recommend testing all patients who are ethnically Chinese
        • Guideline Development Group HKES
        The Hong Kong epilepsy guideline 2009.
      AED: antiepileptic drug; CBZ: carbamazepine; MHD: monohydroxy derivative; OXC: oxcarbazepine; RWE, real world evidence.
      These recommendations include low initial dose and slow titration, as well as routine therapeutic drug monitoring (TDM) of CBZ to adjust the dose based on drug concentrations (using plasma reference range, Table 5) in order to optimize clinical outcome [
      • Patsalos P.N.
      • Spencer E.P.
      • Berry D.J.
      Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update.
      ,
      • Das S.
      • Fleming D.H.
      • Mathew B.S.
      • Winston A.B.
      • Prabhakar A.T.
      • Alexander M.
      Determination of serum carbamazepine concentration using dried blood spot specimens for resource-limited settings.
      ]. TDM also helps to ensure compliance and to establish which level is suitable for a patient. However, in the experience of the authors of the present report, many centers only clinically follow patients and perform TDM in cases of specific indications rather than routinely (e.g. development of side effects or seizure occurrence).

      4.1.1 Genotyping

      It is now recognized that some of the potential side effects of CBZ may be avoided through targeted genotyping. The HLA-B*1502 allele, which occurs with varying frequency among Asians (e.g. 10–20% Chinese in Hong Kong), is associated with a dramatically increased risk of CBZ-induced potentially life-threatening cutaneous reactions, such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (from 1 to 6 per 10000 in Caucasian users to 10 times higher in some Asian countries) [
      • Guideline Development Group HKES
      The Hong Kong epilepsy guideline 2009.
      ,
      • Dean L.
      Carbamazepine therapy and HLA genotype.
      ,
      Carbamazepine summary of product characteristics.
      ]. Other alleles, including HLA-A*3101 and HLA-B*1511, have been linked with cutaneous reactions, and CBZ dosing guidelines based on HLA genotype have been published by different groups (Table 6).
      In particular, the presence of HLA-A*3101 allele in European descent and Japanese populations may increase the risk for CBZ-induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of Northern European ancestry, whereas its absence may reduce the risk from 5.0%–3.8% [
      Carbamazepine summary of product characteristics.
      ].
      However, HLA typing is expensive and labor-intensive. Despite guideline recommendations and proven cost-effectiveness [
      • Choi H.
      • Mohit B.
      Cost-effectiveness of screening for HLA-B*1502 prior to initiation of carbamazepine in epilepsy patients of Asian ancestry in the United States.
      ], in the experience of the authors of this review, the rate of genotyping is ‘low’, including in children. In China, no routine testing is currently performed (partly due to examination fees and patient compliance); however, awareness is increasing, especially among Chinese pediatricians, and tests are suggested to most patients in epilepsy centers, especially in tertiary hospitals. Determining genetic variants in individual patients could prove invaluable by allowing drug selection and dosing according to genotype [
      • Patsalos P.N.
      • Spencer E.P.
      • Berry D.J.
      Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update.
      ].

      4.2 OXC

      Many patients are successfully managed using OXC based on the Prescribing Information-recommended titration schedule [
      • Smith P.E.
      • Board UKOA
      Clinical recommendations for oxcarbazepine.
      ,
      • Beydoun A.
      • Kutluay E.
      Oxcarbazepine.
      ]. Evolving clinical experience however suggests a number of additional treatment recommendations (Table 6). Recommendations on switching to OXC follow the results of the multicentre Italian PRIMO study [
      • Albani F.
      • Baruzzi A.
      • Group P.S.
      Oxcarbazepine long-term treatment retention in patients switched over from carbamazepine.
      ]. While that it is not advisable to switch a patient with focal epilepsy stabilized on CBZ, switching to OXC in case of poor tolerability or scant clinical efficacy of CBZ was well tolerated in the vast majority of patients (87% still on OXC after one year). Retention rate was similar regardless of the reason of the switch (insufficient clinical efficacy or poor tolerability) suggesting that OXC can play a role in both scenarios, although it should be noted that significantly more patients needed combination therapy when switched due to poor efficacy. The CBZ/OXC ratio of 1/1.5 appears to be close to the optimal for the switch from CBZ to OXC, at least for patients treated with CBZ monotherapy.
      As with other AEDs, including CBZ, TDM is a valuable adjunct in individualizing OXC treatment due to large individual differences in dose to plasma concentration relationship. Since OXC is rapidly transformed to its metabolite MHD, it is now routine practice to monitor only MHD concentration [
      • Patsalos P.N.
      • Spencer E.P.
      • Berry D.J.
      Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update.
      ].
      In terms of AEs, there is a higher risk of hyponatremia with OXC compared with CBZ [
      • Perucca E.
      • Tomson T.
      The pharmacological treatment of epilepsy in adults.
      ]. For both drugs the overall incidence varies greatly depending on the population studied and definition of hyponatremia (from 33% to 73% for OXC vs 5%–40% for CBZ) [
      • Van Amelsvoort T.
      • Bakshi R.
      • Devaux C.B.
      • Schwabe S.
      Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review.
      ]. More recent studies of clinical trial data and experience reported rates of OXC-induced hyponatremia (serum sodium <135 mmol/l) of around 25% [
      • Schmidt D.
      • Arroyo S.
      • Baulac M.
      • Dam M.
      • Dulac O.
      • Friis M.L.
      • et al.
      Recommendations on the clinical use of oxcarbazepine in the treatment of epilepsy: a consensus view.
      ] and 30% (vs 13% for CBZ-induced hyponatremia) [
      • Dong X.
      • Leppik I.E.
      • White J.
      • Rarick J.
      Hyponatremia from oxcarbazepine and carbamazepine.
      ], and 3% for severe hyponatremia (serum sodium <125 mmol/l) [
      • Schmidt D.
      • Arroyo S.
      • Baulac M.
      • Dam M.
      • Dulac O.
      • Friis M.L.
      • et al.
      Recommendations on the clinical use of oxcarbazepine in the treatment of epilepsy: a consensus view.
      ]. Although hyponatremia is usually asymptomatic, routine serum sodium monitoring is recommended if relevant risk factors exist, including renal disease, or sodium-depleting comedications [
      • Smith P.E.
      • Board UKOA
      Clinical recommendations for oxcarbazepine.
      ,
      • Wellington K.
      • Goa K.L.
      Oxcarbazepine: an update of its efficacy in the management of epilepsy.
      ,
      • Beydoun A.
      • Kutluay E.
      Oxcarbazepine.
      ,
      • Schmidt D.
      • Arroyo S.
      • Baulac M.
      • Dam M.
      • Dulac O.
      • Friis M.L.
      • et al.
      Recommendations on the clinical use of oxcarbazepine in the treatment of epilepsy: a consensus view.
      ,
      • Kern R.
      Oxcarbazepine - profile of a new anticonvulsant.
      ,
      • Dam M.
      Practical aspects of oxcarbazepine treatment.
      ]. It should also be noted that the authors of a recent real-world evidence study, including the EpiPGX Consortium [
      • Berghuis B.
      • van der Palen J.
      • de Haan G.J.
      • Lindhout D.
      • Koeleman B.P.C.
      • Sander J.W.
      Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy.
      ] found a higher risk than previously reported. Specific recommendations on the management of hyponatremia are included in Table 6.
      Although, as mentioned above, drug interactions are less frequent with OXC compared with CBZ, OXC may reduce the effectiveness of hormonal contraception [
      • Wellington K.
      • Goa K.L.
      Oxcarbazepine: an update of its efficacy in the management of epilepsy.
      ,
      • Kern R.
      Oxcarbazepine - profile of a new anticonvulsant.
      ].

      5. Specific populations

      All existing guidelines emphasize the need to consider individual patient characteristics when selecting an AED, including childbearing potential, age, and comorbidities.

      5.1 Pediatric

      The epilepsies of childhood are a heterogeneous group of disorders that include several different types of seizure with different causes, treatments, and outcomes [
      • Appleton R.E.
      • Freeman A.
      • Cross J.H.
      Diagnosis and management of the epilepsies in children: a summary of the partial update of the 2012 NICE epilepsy guideline.
      ].

      5.1.1 CBZ

      The NICE guidelines recommend CBZ or lamotrigine as first-line treatment in children and young people with newly diagnosed focal onset seizures, with a recommendation to use the controlled-release formulation if CBZ is used [
      • Appleton R.E.
      • Freeman A.
      • Cross J.H.
      Diagnosis and management of the epilepsies in children: a summary of the partial update of the 2012 NICE epilepsy guideline.
      ], In fact, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to CBZ, including focal and generalized tonic-clonic seizures [
      • Dodson WE
      Carbamazepine efficacy and utilization in children.
      ], resulting in CBZ being still heavily utilized for the treatment of epilepsy in children (Djordjevic, Jankovic et al. 2017). When treating children, we should however keep in mind that CBZ can aggravate some seizure types, especially absences (more common in children than in adults), myoclonic seizures, and tonic seizures, and it is contraindicated in Dravet syndrome. In addition, major considerations should be given to age-related pharmacokinetic differences and drug interactions [
      • Dodson WE
      Carbamazepine efficacy and utilization in children.
      ]. On average, children have higher clearance rates of CBZ, shorter half-lives, and higher ratios of epoxide-CBZ to CBZ than adults. Moreover, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions causing intermittent side effects.
      Pharmacokinetics and pharmacodynamics of CBZ in children also depend on genetic and environmental factors; dosing regimens should take these into account to ensure safe and effective use of CBZ in this population [
      • Djordjevic N.
      • Jankovic S.M.
      • Milovanovic J.R.
      Pharmacokinetics and pharmacogenetics of carbamazepine in children.
      ]. Evidence also emphasizes the importance of HLA typing for prediction of adverse drug reactions to CBZ in children.
      Genetic factors also play a part in some early onset epilepsies, in which CBZ has an increasingly important role. Benign familial neonatal epilepsy (BFNE) is a rare genetic condition, which typically presents with recurrent clusters of seizures or status epilepticus in the first days of life leading to prolonged hospitalization. The benefits of using CBZ in such settings is supported by results from a study of 19 infants with BFNE, which showed that seizures promptly respond to low-dose oral CBZ. Early diagnosis and treatment with oral CBZ was associated with dramatically shortened hospitalization with no observed side effects [
      • Sands T.T.
      • Balestri M.
      • Bellini G.
      • Mulkey S.B.
      • Danhaive O.
      • Bakken E.H.
      • et al.
      Rapid and safe response to low-dose carbamazepine in neonatal epilepsy.
      ]. Similar observations were published for genetic epilepsies associated with SCN2A and SNC8A mutations [
      • Wolff M.
      • Brunklaus A.
      • Zuberi S.M.
      Phenotypic spectrum and genetics of SCN2A-related disorders, treatment options, and outcomes in epilepsy and beyond.
      ,
      • Gardella E.
      • Møller R.S.
      Phenotypic and genetic spectrum of SCN8A-related disorders, treatment options, and outcomes.
      ].

      5.1.2 OXC

      OXC is approved for use as adjunctive therapy in the treatment of partial onset seizures in children aged ≥4 years in the US and Canada, and as monotherapy or adjunctive therapy in the treatment of partial onset seizures in children aged ≥6 years in the EU, Central and Latin America, and the majority of Asia [
      • Bang L.M.
      • Goa K.L.
      Spotlight on oxcarbazepine in epilepsy.
      ].
      OXC is in fact the only AED with Class I evidence for efficacy/effectiveness as initial monotherapy for focal-onset seizures in children [
      • Arya R.
      • Glauser T.A.
      Pharmacotherapy of focal epilepsy in children: a systematic review of approved agents.
      ]. In addition, it has Class I efficacy/effectiveness evidence as adjunctive therapy for the treatment of pediatric partial-onset seizures, along with gabapentin, lamotrigine, levetiracetam, oxcarbazepine, and topiramate.
      As is the case with CBZ, children aged <8 years have increased clearance rates of OXC (by approximately 30%–40%) compared with older patients, and may therefore require higher OXC doses to achieve effective seizure control (Bang and Goa 2004). A pharmacokinetic simulation indicates that for most pediatric patients, a dosing regimen of 20–30 mg/kg/d BID may be sufficient to reach the therapeutic range of OXC metabolite [
      • Chen C.-Y.-Y.
      • Zhou Y.
      • Cui Y.-M.-M.
      • Yang T.
      • Zhao X.
      • Wu Y.
      Population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy.
      ]. However, in very young children (1 month to <4 years), a study evaluating the efficacy, safety, and pharmacokinetics of OXC as adjunctive therapy found that high-dose OXC was significantly more effective than low-dose OXC in controlling focal onset seizures (Piña-Garza, Espinoza et al. 2005).

      5.2 Pregnancy

      Women with epilepsy (WWE) have a risk of bearing children with congenital malformations that is approximately twice that of the general population. Almost every AED has been associated with such risk [
      • Yerby MS
      Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation.
      ]. CBZ and OXC, like many other AEDS, cross the placenta, with equivalent maternal blood and cord blood levels [
      • Yerby MS
      Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation.
      ,
      • Kaushik G.
      • Thomas M.A.
      • Aho K.A.
      Psychoactive pharmaceuticals as environmental contaminants may disrupt highly inter-connected nodes in an Autism-associated protein-protein interaction network.
      ,
      • Pynnönen S.
      • Kanto J.
      • Sillanpää M.
      • Erkkola R.
      Carbamazepine: placental transport, tissue concentrations in foetus and newborn, and level in milk.
      ].
      Although several observational studies have confirmed lower rates of major congenital malformations with use of CBZ during pregnancy compared with valproate [
      • Morrow J.
      • Russell A.
      • Guthrie E.
      • Parsons L.
      • Robertson I.
      • Waddell R.
      • et al.
      Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register.
      ,
      • Campbell E.
      • Kennedy F.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Morrison P.J.
      • et al.
      Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy registers.
      ] (Perucca and Tomson 2011), CBZ, like valproate, has been associated specifically with the development of neural tube defects (NTDs), especially spina bifida [
      • Yerby MS
      Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation.
      ]. Even with folate supplementation, women taking CBZ or valproate during pregnancy should avail themselves of prenatal diagnostic ultrasonography to detect NTD in the fetus. Based on the UK/Ireland epilepsy and pregnancy register, the overall major congenital malformations (MCMs) rates seen with exposure to CBZ and lamotrigine were not that different from background, particularly when taken in doses of less than 400 mg/day and 1000 mg/day, respectively [
      • Campbell E.
      • Kennedy F.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Morrison P.J.
      • et al.
      Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy registers.
      ]. However, there seems to be a dose related effect, which is steeper for CBZ than for lamotrigine. CBZ has been associated with a 2% risk when given at <500 mg daily, 3% at 500–1000 mg and 5% at >1000 mg [
      • Campbell E.
      • Kennedy F.
      • Russell A.
      • Smithson W.H.
      • Parsons L.
      • Morrison P.J.
      • et al.
      Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy registers.
      ]. In a recent Cochrane review of 50 studies, CBZ (as well as topimarate and valproate) was associated with higher rates of MCMs than levetiracetam and lamotrigine [
      • Weston J.
      • Bromley R.
      • Jackson C.F.
      • Adab N.
      • Clayton-Smith J.
      • Greenhalgh J.
      • et al.
      Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.
      ]. The same review did not identify any increased risk for MCMs for OXC. These results are in line with findings from a prospective cohort study of the EURAP registry which found that the risks of MCMs associated with OXC (3%), as well as with lamotrigine (2.9%) and levetiracetam (2.8%), were within the range reported in the literature for offsprings unexposed to AEDs [
      • Tomson T.
      • Battino D.
      • Bonizzoni E.
      • Craig J.
      • Lindhout D.
      • Perucca E.
      • et al.
      Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry.
      ]. The rate of MCMs observed in this study for CBZ was 5·5% and was 10·3% for valproate. Thus, overall, epilepsy and pregnancy registers are consolidating data, pointing to the use of lamotrigine, levetiracetam, OXC, and/or CBZ (lower dose) as those AEDs with the lowest risk of MCM [
      • Manford M.
      Recent advances in epilepsy.
      ].
      In addition to congenital malformation, exposure with AEDs during pregnancy has been associated with effects on cognitive functioning in children [
      • Bromley R.L.
      • Baker G.A.
      Fetal antiepileptic drug exposure and cognitive outcomes.
      ] and increased behavioral difficulties [
      • Huber-Mollema Y.
      • Oort F.J.
      • Lindhout D.
      • Rodenburg R.
      Behavioral problems in children of mothers with epilepsy prenatally exposed to valproate, carbamazepine, lamotrigine, or levetiracetam monotherapy.
      ] compared with unexposed children. These, however, were mainly observed with valproate exposure which showed significant differences on social and attention problems and symptoms of ADHD [
      • Huber-Mollema Y.
      • Oort F.J.
      • Lindhout D.
      • Rodenburg R.
      Behavioral problems in children of mothers with epilepsy prenatally exposed to valproate, carbamazepine, lamotrigine, or levetiracetam monotherapy.
      ] compared with lamotrigine-, levetiracetam-, and CBZ‐exposed children. A prospective observational study of 311 children also showed that the IQ at age 6 years was significantly lower after exposure to valproate than to CBZ, lamotrigine, or phenytoin [
      • Meador K.J.
      • Baker G.A.
      • Browning N.
      • Cohen M.J.
      • Bromley R.L.
      • Clayton-Smith J.
      • et al.
      Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study.
      ]. Children exposed to CBZ were not found by the majority of studies to have poorer early development, although there is a lack of evidence regarding specific cognitive skills later in childhood and adolescence [
      • Bromley R.L.
      • Baker G.A.
      Fetal antiepileptic drug exposure and cognitive outcomes.
      ].
      A higher proportion of conduct disorder were found in valproate and levetiracetam-exposed children, and a higher proportion of children exposed to lamotrigine in utero had clinical symptoms of autistic behavior [
      • Huber-Mollema Y.
      • Oort F.J.
      • Lindhout D.
      • Rodenburg R.
      Behavioral problems in children of mothers with epilepsy prenatally exposed to valproate, carbamazepine, lamotrigine, or levetiracetam monotherapy.
      ]. In this study CBZ‐exposed children did not show higher proportions of clinical behavioral problems.
      In a review of contemporary published evidence-based guidelines [
      • Singh S.P.
      • Sankaraneni R.
      • Antony A.R.
      Evidence-based guidelines for the management of epilepsy.
      ], the avoidance of valproate and older AED during pregnancy remains the main focus. Avoidance of valproate and AED polytherapy is recommended during the first trimester to prevent MCM and throughout pregnancy to avoid reduced cognitive outcomes. Avoidance of phenytoin and phenobarbital during pregnancy may also be considered to prevent reduced cognitive outcomes.
      Prescription pattern of AEDs during pregnancy have changed in line with the evolving evidence and guidelines. In Spain, for instance, there is increased use of levetiracetam, slight increased use of lamotrigine and OXC, and diminishing use of older agents, including phenytoin, phenobarbital, and CBZ [
      • Martinez Ferri M.
      • Peña Mayor P.
      • Perez López-Fraile I.
      • Escartin Siquier A.
      • Martin Moro M.
      • Forcadas Berdusan M.
      • et al.
      Comparative study of antiepileptic drug use during pregnancy over a period of 12 years in Spain. Efficacy of the newer antiepileptic drugs lamotrigine, levetiracetam, and oxcarbazepine.
      ]. In a recent worldwide survey of 642 participants in 81 countries, the most common first agents prescribed for young women with focal epilepsy were lamotrigine and levetiracetam, both of which appear to be relatively safe in pregnancy [
      • George I.C.
      • Bartolini L.
      • Ney J.
      • Singhal D.
      Differences in treatment of epilepsy in pregnancy: a worldwide survey.
      ].
      The same survey, however, pointed out differences in treatment of epilepsy in pregnancy across the world, with the choice of first-line agent varying by the economic development status of the respondent's country [
      • George I.C.
      • Bartolini L.
      • Ney J.
      • Singhal D.
      Differences in treatment of epilepsy in pregnancy: a worldwide survey.
      ]. Respondents from countries with developing economies were significantly more likely to prescribe CBZ and less likely to prescribe levetiracetam or lamotrigine. According to the authors, this probably reflects limited availability and prohibitive pricing of newer AEDs in the developing world, rather than better efficacy or safety of the newer AEDs.
      Apart from the cost, there is a potential advantage of CBZ compared with lamotrigine in pregnancy, as it generally requires less frequent drug monitoring. While lamotrigine is known to have greatly increased clearance in pregnancy, CBZ clearance is not substantially affected, making it a relatively safe and cost-effective treatment option for pregnant women with focal epilepsy syndromes [
      • George I.C.
      • Bartolini L.
      • Ney J.
      • Singhal D.
      Differences in treatment of epilepsy in pregnancy: a worldwide survey.
      ,
      • Johnson E.L.
      • Stowe Z.N.
      • Ritchie J.C.
      • Newport D.J.
      • Newman M.L.
      • Knight B.
      • et al.
      Carbamazepine clearance and seizure stability during pregnancy.
      ]. Similarly to lamotrigine, OXC shows an increase in clearance during pregnancy (both AEDs being metabolized primarily by glucuronidation), with a peak in the second trimester to 1.63-fold baseline, and increased values persisting in the third trimester [
      • Voinescu P.E.
      • Park S.
      • Chen L.Q.
      • Stowe Z.N.
      • Newport D.J.
      • Ritchie J.C.
      • et al.
      Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy.
      ]. Therefore, early monitoring and dose adjustment is recommended for MHD to avoid increased seizure frequency [
      • Patsalos P.N.
      • Spencer E.P.
      • Berry D.J.
      Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update.
      ,
      • Voinescu P.E.
      • Park S.
      • Chen L.Q.
      • Stowe Z.N.
      • Newport D.J.
      • Ritchie J.C.
      • et al.
      Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy.
      ].
      In summary, lower doses may be considered when using CBZ in pregnancy to minimize the risks of MCM with the advantage of less frequent monitoring; conversely, OXC requires more frequent dose monitoring but is listed among the safest drugs in terms of MCM.

      5.3 Elderly patients

      The incidence of new-onset epilepsy is higher among the elderly than in any other age group [
      • Bergey G.K.
      Initial treatment of epilepsy: special issues in treating the elderly.
      ]. In spite of this, there is relative scarcity of randomized-controlled trials involving older and newer AEDs in the geriatric population [
      • Kaur U.
      • Chauhan I.
      • Gambhir I.S.
      • Chakrabarti S.S.
      Antiepileptic drug therapy in the elderly: a clinical pharmacological review.
      ].
      The elderly population is characterized by altered physiology, decline in organ function, altered plasma protein binding and pharmacodynamics, as well as the presence of comorbidities and polypharmacy. All of these factors increase the chances of drug interactions, thereby making elderly patients with seizure disorder a challenging group to treat, and CBZ with its enzyme-inducing properties not the ideal drug in such a population [
      • Kaur U.
      • Chauhan I.
      • Gambhir I.S.
      • Chakrabarti S.S.
      Antiepileptic drug therapy in the elderly: a clinical pharmacological review.
      ].
      A systematic review and network meta-analysis of AEDs in the elderly showed no significant difference in efficacy across treatments, but CBZ had a poor tolerability profile, leading to higher withdrawal rates compared with levetiracetam and valproate [
      • Lattanzi S.
      • Trinka E.
      • Del Giovane C.
      • Nardone R.
      • Silvestrini M.
      • Brigo F.
      Antiepileptic drug monotherapy for epilepsy in the elderly: a systematic review and network meta-analysis.
      ]. OXC, with its low potential for enzyme induction, appears to be safe to use in elderly patients with evidence indicating that its tolerability in this age group is similar to that of younger adult patients [
      • Bergey G.K.
      Initial treatment of epilepsy: special issues in treating the elderly.
      ,
      • Kutluay E.
      • McCague K.
      • D’Souza J.
      • Beydoun A.
      Safety and tolerability of oxcarbazepine in elderly patients with epilepsy.
      ].
      In spite of this, CBZ is still widely use in the elderly. This is (or was) the case in the UK according to a 2003 survey [
      • Battino D.
      • Croci D.
      • Rossini A.
      • Messina S.
      • Mamoli D.
      • Perucca E.
      Serum carbamazepine concentrations in elderly patients: a case-matched pharmacokinetic evaluation based on therapeutic drug monitoring data.
      ]. In a more recent Irish survey of 736 older adults with intellectual disabilities, the most prescribed drugs were valproic acid (48.7%) and CBZ (46.3%), followed by lamotrigine (27.8%) [
      • O’Dwyer M.
      • Peklar J.
      • Mulryan N.
      • McCallion P.
      • McCarron M.
      • Henman M.C.
      Prevalence and patterns of anti-epileptic medication prescribing in the treatment of epilepsy in older adults with intellectual disabilities.
      ]. Recommendations in terms of careful CBZ dosing and serum monitoring is thus especially valuable in this population [
      • Battino D.
      • Croci D.
      • Rossini A.
      • Messina S.
      • Mamoli D.
      • Perucca E.
      Serum carbamazepine concentrations in elderly patients: a case-matched pharmacokinetic evaluation based on therapeutic drug monitoring data.
      ].
      Optimal use of CBZ in the elderly is dependent on a full understanding of the age-related alterations in pharmacokinetics and pharmacodynamics. Because of considerably lower metabolism rates, older patients require lower CBZ doses to achieve serum concentrations similar to younger adults [
      • Battino D.
      • Croci D.
      • Rossini A.
      • Messina S.
      • Mamoli D.
      • Perucca E.
      Serum carbamazepine concentrations in elderly patients: a case-matched pharmacokinetic evaluation based on therapeutic drug monitoring data.
      ]. A lower starting dose and careful titration according to response are recommended, and lower maintenance doses may be required on average to achieve optimal clinical effects. In case of bone health concerns, endocrine dysfunction, cholesterol, hyponatremia (higher in OXC than in CBZ) an alternative (e.g. lamotrigine, levetiracetam) should be considered [
      • Perucca E.
      • Tomson T.
      The pharmacological treatment of epilepsy in adults.
      ].

      5.4 Comorbidities

      While the main goal of epilepsy treatment is to achieve seizure-freedom, another important aspect to consider is the management of comorbidities including neurological, psychiatric and cognitive comorbidities [
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ]. About one third to one half of patients with epilepsy also suffer from some type of psychiatric and/or neurological comorbidity [
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ]. The most common are mood disorders, anxiety disorders, and migraine, but stroke, dementia, or autistic spectrum disorder are common too. Psychiatric/neurological comorbidities are a greater determinant of QoL than seizure frequency in those with refractory epilepsy [
      • Manford M.
      Recent advances in epilepsy.
      ]. These comorbidities can cause or be caused by the onset of the seizure disorder, and may be influenced by AED treatment. Both AED treatment and treatment of comorbidities must be selected on the basis of the therapeutic or iatrogenic effects they may have with respect to the concomitant disorders.
      Most AEDs are now tested for their prophylactic and analgesic effects in different types of migraine and neuropathic pain; OXC and CBZ have been shown to have some analgesic value in neuralgic pain [
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ]. In addition, CBZ and OXC have psychiatric benefits, acting as mood stabilizer, and anti-depressant and anti-manic therapies. Both drugs can therefore be considered in patients with a current or prior history of mood disorder [
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ]. However, it should be kept in mind that AEDs with enzyme-inducing properties, including CBZ and high dose OXC, can accelerate the clearance of some psychotropic drugs and limit their efficacy. Conversely, several psychotropic drugs (e.g. selective serotonin reuptake inhibitors [SSRI] antidepressants fluoxetine, fluvoxamine and paroxetine, some of the first-generation [haloperidol and loxapine] and second-generation [risperidone, quetiapine] antipsychotic drugs) can inhibit the clearance of some enzyme-inducing AEDs, including CBZ, and should be avoided [
      • Manford M.
      Recent advances in epilepsy.
      ,
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ]. Moreover, SSRIs have been linked to osteopenia and osteoporosis, and SSRIs and serotonin-norepinephrine reuptake Inhibitor (SNRIs) can facilitate the development of hyponatremia, which should also be considered when prescribing CBZ or OXC concomitantly [
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ].
      AEDs with enzyme-inducing properties can also worsen neurological comorbidities. Discontinuation of CBZ has been showed to result in a notable reduction of LDL cholesterol and other lipid parameters, suggesting that enzyme-inducing AEDs including CBZ may increase the risk of cardiovascular and cerebrovascular disease [
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ]. Even OXC (>900 mg day) have been associated with potential atherogenic effect according to one study. However, it should be noted that some AEDs without enzyme-inducing properties have also been associated with such effect, and a history of epilepsy has been linked to an increased risk of stroke [
      • Kanner A.M.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ].
      Most AED taken at high dose have been associated with cognitive disturbances, and psychiatric or behavioral side effects. In a study part of the Columbia and Yale AED Database Project comparing each AED to lamotrigine, CBZ was found to have a significantly lower rate of psychiatric and behavioral side effects [
      • Chen B.
      • Choi H.
      • Hirsch L.J.
      • Katz A.
      • Legge A.
      • Buchsbaum R.
      • et al.
      Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy.
      ]. The cognitive and behavioral long-term effects of AEDs have also been the focus of a recent review [
      • Moavero R.
      • Santarone M.E.
      • Galasso C.
      • Curatolo P.
      Cognitive and behavioral effects of new antiepileptic drugs in pediatric epilepsy.
      ], confirming the benefits of CBZ-CR over lamotrigine in terms of behavioral effects, although lamotrigine may have a more favorable effect on cognitive function. The same review indicated that OXC monotherapy appears to have no adverse effect on cognition and would rather act as a stimulant leading to increased performance on focused attention task. These encouraging results should however be considered with caution and need to be replicated including a wider range of cognitive measures [
      • Curran H.V.
      • Java R.
      Memory and psychomotor effects of oxcarbazepine in healthy human volunteers.
      ,
      • Lee S.A.
      • Lee H.W.
      • Heo K.
      • Shin D.J.
      • Song H.K.
      • Kim O.J.
      • et al.
      Cognitive and behavioral effects of lamotrigine and carbamazepine monotherapy in patients with newly diagnosed or untreated partial epilepsy.
      ].

      6. Summary and conclusion

      Epilepsy is a heterogeneous clinical condition, with expanding treatment options. While the choice of treatment should consider the efficacy and safety profile of the AED for the individual seizure type, treatment decisions should also be individualized based on patient characteristics including age, sex, childbearing potential, genotype, comorbidities, and concomitant medications [
      • Perucca E.
      • Tomson T.
      The pharmacological treatment of epilepsy in adults.
      ,
      • Azar N.J.
      • Abou-Khalil B.W.
      Considerations in the choice of an antiepileptic drug in the treatment of epilepsy.
      ]. Compared with first generation drugs, some newer AEDs may have similar efficacy, but more favorable tolerability profiles. Treatment patterns have undergone minor changes with some decrease in CBZ use observed in the US and some European countries. However, solid evidence and long-term experience have established the effectiveness of CBZ and OXC, which has measured up to all the newer AEDs, and both drugs remain important options in the clinical management of epilepsy.
      According to the recommendations of evidence-based guidelines, CBZ/OXC are first-line options or second-line alternatives for the treatment of focal onset and generalized tonic-clonic seizures. In addition, strong evidence supports the use of OXC as initial monotherapy for focal-onset seizures in children, while CBZ has been increasingly used across various early epilepsy phenotypes.
      No drug is appropriate in all settings and populations, as access and cost play an important role in clinical decision making in many parts of the world. However, in many contexts, CBZ represents a good compromise between cost, availability, efficacy, and tolerability – older drugs being cheaper but not as well tolerated, while newer expensive drugs may not be available or affordable.
      In addition, both CBZ and OXC may present some advantages in people with neuropathic pain or those at risk of psychiatric disorders, including mood and behavior disturbances. However, particular attention should be given to the well-known enzyme-inducing effects when administered concomitantly with other drugs including psychotropic medications, or in people with cardiovascular disease.
      The enzyme-inducing effect of CBZ can be mitigated in patients at risk by using a low initial dose and slow titration, which also reduces the likelihood of rash. Although the OXC-inducing effect is much lower, low starting dose, slow titration, and slow switching from CBZ are also recommended to optimize clinical outcomes. Increased awareness about the importance and cost-effectiveness of HLA typing to identify patients at risk for more serious skin AEs with CBZ should be encouraged. TDM is also important, and valuable for both CBZ and OXC, with recent evidence pointing towards the benefits of monitoring not only CBZ but also its metabolite to optimize therapeutic efficacy. In settings where cost and resource may be an issue, more guidance and support are needed to help implement TDM and HLA tests more routinely in clinical practice.

      Funding

      The development of this publication was organized and funded by Novartis Pharma AG .

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      Marie-Catherine Mousseau (Novartis Ireland Limited, Dublin, Ireland) wrote the first draft and updated subsequent versions under the guidance of the authors. Writing and editorial support was funded by Novartis Pharma AG.

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        Seizure - European Journal of EpilepsyVol. 83
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          We are all creatures of habit. It requires much less mental effort to stick with an established routine than to deviate from it and approach a given task differently. However, as clinicians we must remain prepared to learn throughout our working lives, we have to review the way we manage illness regularly, and we must force ourselves to change when medical knowledge has moved on. While this may not be controversial in principle, the decision whether the time has come to change a well-established treatment method or to stick with a familiar, time-honoured approach is rarely clear-cut.
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