Oxcarbazepine

Drug Evaluation

2002 © Ashley Publications Ltd ISSN 1465-6566 59

Ashley Publicationswww.ashley-pub.com

1. Introduction

2. Pharmacodynamic properties

3. Pharmacokinetic properties

4. Therapeutic efficacy

5. Safety and tolerability

6. Effects of OXC on

neuropsychological and PNS

functions

7. Expert opinion

OxcarbazepineAhmad Beydoun & Ekrem KutluayUniversity of Michigan Medical Center, Ann Arbor 48109, USA

Oxcarbazepine is one of the recently introduced anti-epileptic drugs (AEDs)in the US. This drug has demonstrated efficacy as adjunctive therapy in adultsand children, and as monotherapy in adults for the treatment of seizures ofpartial onset. There is also convincing evidence of its efficacy in patients withnewly diagnosed and refractory trigeminal neuralgia. In addition, the initialefficacy results of oxcarbazepine in other neuropathic pain conditions and inbipolar disorders are encouraging. In this review, recommendations on theoptimal clinical use of oxcarbazepine are given based on its pharmacokineticprofile, efficacy and tolerability in those various conditions.

Keywords: bipolar disorders, efficacy, epilepsy, mania, neuropathic pain, oxcarbazepine, partial seizures, pharmacokinetics, safety, tolerability, trigeminal neuralgia

Expert Opin. Pharmacother. (2001) 3(1):59-71

1. Introduction

Oxcarbazepine (OXC) (Trileptal®, Novartis), with a chemical structure of 10,11-dihydro-10-oxo-5H-dibenz[b,f ]azepine-5-carboxamide, is already registered in morethan 50 countries and is one of the recently approved AEDs in the US. It is currentlyindicated as monotherapy in adults with partial epilepsy and as adjunctive therapy inadults and children aged 4 - 16 years with partial or secondarily generalised seizures.Although OXC is the parent molecule, most of the pharmacological effects of thedrug are derived from its active metabolite, referred to as monohydroxy derivative(MHD). The clinical development of OXC for the treatment of epilepsy was impres-sive not only because of the number of randomised clinical trials (RCTs) but alsobecause of the concordance of efficacy results in various patient populations rangingfrom the newly diagnosed to the highly refractory patient with seizures of partialonset. As for some other AEDs, there is an interest in evaluating the potential efficacyof OXC in conditions beside epilepsy, including neuropathic pain, migraine prophy-laxis and psychiatric disorders. In this paper we will review the preclinical and clinicaldata of OXC in epilepsy and other conditions focusing on the pivotal clinical trialsand extrapolate issues of clinical relevance when using this drug from their results.

2. Pharmacodynamic properties

2.1 Mechanisms of actionOXC and its active MHD metabolite must have multiple mechanisms of action,some of which are still undetermined, to account for the efficacy of OXC in epi-lepsy, pain management and psychiatric disorders. In vitro studies have shown thatone of the mechanisms of action of OXC is similar to that of carbamazepine (CBZ)and consists of the inhibition of sustained, high frequency, repetitive firing of volt-age-sensitive sodium channels (Figure 1) [1-3]. However, unlike CBZ which modu-lates L-type calcium channels, OXC has been shown to inhibit the high-voltageactivated N-type calcium channels [4-6]. This results in dose-dependent inhibition ofpostsynaptic excitatory glutamatergic potentials on striatal neurones [4-6]. Both ofthose mechanisms of action could partially account for the efficacy of OXC in treat-ing neuropathic pain. In addition, MHD was shown to reduce burst firing fre-quency in rat hippocampal slices by increasing current through voltage-sensitivepotassium channels, suggesting an additional anticonvulsant effect [2].

Oxcarbazepine

60 Expert Opin. Pharmacother. (2002) 3(1)

Table 1. Anticonvulsant ED50 of OXC and MHD.

Anticonvulsant ED50 (mg/kg p.o.)

MES model PTZ model Strychnine and picrotoxin model

Mouse Rat Mouse Mouse

OXC 11 - 14 10 - 13.5 23 - 30 150 - 250

MHD 20 - 20.5 17 - 20 52 150 - 250

ED50: Median effective dose; MES: Maximal electroshock model; MHD: Monohydroxy derviative; OXC: Oxcarbazepine; PTZ: Pentylenetetrazole model.

Figure 1. Effects of OXC, MHD and CBZ on sustained repetitive firing of the sodium ion channels. CBZ: Carbamazepine;MHD: Monohydroxy derivative; OXC: Oxcarbazepine; SRF: Sustained repetitive firing. Data from [2].

Perc

enta

ge S

RF

Log [compound] M

CBZ

OXC

MHD

0C -10 -9 -8 -7 -6 -5 -4

12 10 6

100

80

60

40

20

33

24

10

10

10 6

10

10

11

6

6 10

1010

1010

20

10

2.2 Animal models of epilepsyOXC and MHD were found to have strong anticonvulsantefficacy in various chemically- and electrically-induced sei-zures (Table 1). Both were found to inhibit the tonic phase ofgeneralised tonic-clonic seizures in the maximal electroshockmodel in mice [3,7]. Although efficacy was shown in the penty-lenetetrazole model in mice, it required higher doses thanthose in the electroshock test [7]. OXC was also shown to haveefficacy against metrazol-induced motor seizures in rats [8]. Inthe aluminium foci model in rhesus monkeys, believed to cor-respond to partial and post-traumatic seizures in man, bothOXC and MHD were found to have anticonvulsant proper-ties [7]. The anticonvulsant effect of OXC and MHD were lessprominent in other animal models tested, with a weak effectagainst picrotoxin- and strychnine-induced seizures [7,9].

3. Pharmacokinetic properties

Although OXC is a keto analogue of CBZ and is structurallyvery similar, this slight modification in molecular structureresults in major differences in biotransformation and pharma-cokinetics. Unlike CBZ, which is oxidised by the cytochromeP450 (CYP) oxidase system, OXC is rapidly reduced bycytosolic enzymes to MHD, which is responsible for most ofits anticonvulsant effect [1,9-11] (Figure 2). As a result, one of

the active metabolites of CBZ, the 10,11-epoxide, which con-tributes to the adverse effect of the drug, is not produced. Fol-lowing oral administration OXC is rapidly absorbed, withmaximum plasma concentrations (Cmax) of OXC and MHDreached in 2 and 4 - 6 h, respectively. In healthy individuals,the half-lives of OXC and MHD are ~ 2 and 9 h, respectively[10,12]. Both the parent compound and its metabolite exhibitlinear pharmacokinetics at daily dosages of 300 - 2400 mg[Novartis, data on file]. Since only 40% of MHD is bound toprotein, mainly albumin [11], it is unlikely that clinically rele-vant displacement will occur with the concomitant adminis-tration of other highly protein-bound drugs. The percentageof MHD that is bound to protein is independent of its serumconcentration. It has a volume of distribution of 0.7 - 0.8 l/kg[1] with an equal distribution in red blood cells (RBCs) andplasma [13]. Because of the linear relationship between plasmaand RBC concentrations, routine RBC concentrations are notnecessary for dosage adjustment [14]. MHD is mainly elimi-nated by direct renal excretion (~ 96%) either unchanged oras glucuronide conjugates. Hydroxylation to a pharmacologi-cally inactive dihydroxy derivative contributes to 3% of itselimination [Trileptal Package Insert] [15].

It was shown that the bioavailability and pharmacokineticsof OXC are not altered by food intake. Poor absorptionthrough the rectal mucosa and an inability to attain thera-

Beydoun & Kutluay

Expert Opin. Pharmacother. (2002) 3(1) 61

peutic serum levels with this mode of administration meansit is unlikely that rectal administration of OXC will be clini-cally useful [16].

Although the early studies using OXC doses of up to600 mg/day failed to demonstrate any hepatic enzyme induc-ing effect [17], it was shown that OXC does interact with thehepatic mono-oxygenase enzymes when used at higher dos-ages [Trileptal Package Insert]. It is a weak inhibitor ofCYP2C19 and a weak inducer of CYP3A4/5.

When crossing the placenta [18], OXC is metabolised intoMHD [19]. The serum levels of OXC and MHD are comparablein the new-born and mother [19]. The concentration of MHD inmaternal milk is 50% of the serum concentration, consistentwith the unbound MHD fraction [Novartis, data on file].

3.1 Clinical implications of OXC pharmacokineticsOXC can be administered on a twice-daily schedule, MHDsteady-state levels being achievable within 2 - 3 days. OXCcan be ingested before or after meals since food intake was notfound to either alter the pharmacokinetics of the drug or itstolerability [Trileptal Package Insert].

Since urinary excretion is the main elimination pathway ofMHD, adjustment of the dose will be needed for patientswith moderately severe-to-severe renal impairment. In a studyof patients with creatinine clearances of < 30 ml/min, thehalf-life of MHD was prolonged with a 2-fold increase in thearea under the concentration-time curve (AUC) [20]. The doseof OXC should therefore be decreased by 50% for patientswith creatinine clearance < 30 ml/min. It is not necessary toadjust the dose of OXC for patients with mild-to-moderatehepatic impairment. There is also no need for dose adjust-ment in elderly patients unless their renal functions are signif-icantly altered [Trileptal Package Insert].

The clearance of OXC is higher for young children; a studyin children with epilepsy showed that the normalised AUC

for MHD are 30% lower in children aged 2 - 5 years com-pared to those aged 6 - 12 years [21]. It is therefore recom-mended that the daily dose be increased by 30% (compared tothe dose for older children on a mg/kg basis) when OXC isadministered to children aged 2 - 5 years.

Unlike CBZ, the metabolism of which can be decreasedby concomitant administration of CYP system oxidativeenzyme inhibitors with resulting carbamazepine toxicity,there are no clinically relevant drug-drug interactionsbetween OXC and dextropropoxyphene, erythromycin orcimetidine. Verapamil causes a 20% decrease in MHDplasma levels (Table 2) [22,23] [Trileptal Package Insert]. Inaddition, OXC can be safely administered to patients onwarfarin therapy because of the lack of induction of the lat-ter in the presence of OXC [24]. Unlike CBZ, OXC does notundergo autoinduction [15]. The metabolism of OXC isenhanced by 30 - 40% in the presence of hepatic enzymeinducers, such as CBZ, phenytoin or barbiturates.

Because OXC is a much weaker inducer of the CYP sys-tem, the substitution of OXC for CBZ or other hepaticenzyme inducers can result in de-induction of liver enzymes.This can have clinically relevant consequences for patients onpolytherapy. These effects will be discussed later with theclinical implications for various conditions. The enzymaticinduction of the 3A family can result in enhanced metabo-lism of dihydopyridine calcium antagonists [25]. The samemechanism accounts for the interaction of OXC with oralcontraceptives containing ethinyloestradiol and levonorg-estrel. A study in healthy women showed that in the presenceof OXC, the systemic exposure to ethinyloestradiol and lev-onorgestel was reduced by 52% [26]; it is therefore importantthat women on OXC take higher doses of oral contraceptivesor use an additional contraceptive method in order to pre-vent unwanted pregnancies [27,28]. The administration ofOXC had no significant effect on the sex hormone-binding

Figure 2. Molecular structures and metabolic pathways of OXC and CBZ. CBZ: Carbamazepine; MHD: Monohydroxy derivative;OXC: Oxcarbazepine.

No autoinduction

AutoinductionN

NH2 O

OHOH

N

NH2 O

N

NH2 O

O

Oxidation Hydrolysis

CBZ 10,11-epoxide diol

OXC MHD

N

GlucO

O NH2

N

OH

O NH2

N

O

O NH2

Reduction Conjugation

Oxcarbazepine


globulins [29] or on the development of puberty in girls withepilepsy [30]. In addition, OXC did not influence the serumlevels of androgens in men [17].

The inhibition of CYP2C19 isoform by high dose OXCcan result in an increase of phenytoin and phenobarbitalserum levels since those drugs are partially metabolised viathis isozyme [31,32]. This is of special importance when OXC isadministered to patients already on high-dose phenytoin ther-apy, which exhibits non-linear pharmacokinetics. In thosepatients, the serum level of phenytoin can increase by up to40% and result in phenytoin toxicity [33].

4. Therapeutic efficacy

4.1 OXC in epilepsyThe safety, tolerability and efficacy of OXC for patients withpartial epilepsy were extensively evaluated in a number ofclinical trials. Of the ten pivotal trials in epilepsy, two wereadd-on studies conducted in adults and children with medi-cally refractory epilepsy, and eight were monotherapy studiesconducted in adults and children with newly diagnosed par-tial epilepsy and in adults with medically-refractory partial-onset seizures (Table 3).

4.1.1 Adjunctive therapy trialsTwo multi-centre, placebo-controlled, parallel-group RCTsevaluated the efficacy and tolerability of adjunctive therapywith OXC for adults and children with medically-refractorypartial epilepsy.

In the adult trial, eligible patients were 15 - 65 years oldexperiencing at least four partial-onset seizures per monthwhile maintained on 1 - 3 AEDs during an 8-week baselinephase [33]. During the double-blind phase (2-week titrationperiod and fixed dose period of 24 weeks) patients were ran-domised to adjunctive treatment with placebo or OXCadministered as 600, 1200 or 2400 mg/day administered intwo daily doses. The titration schedule was quite aggressive,since patients randomised to the 2400 mg group were titratedto 600 mg over 2 days, 1200 mg over 6 days and to 2400 mgon day 14. The primary efficacy variable was the percentagechange in seizure frequency per 28 days during the double-blind treatment phase compared to baseline.

A total of 694 patients participated in this trial. At baseline,the median seizure frequency across all groups ranged between

9 - 10 seizures per 28 days. In the OXC groups, 74% ofpatients were maintained on at least two AEDs at baseline.The most common baseline AED was CBZ, which was usedby 74% of patients across all randomised groups. An intent-to-treat (ITT) analysis demonstrated a significant reductionin seizure frequency for all three OXC groups compared toplacebo. A dose-response relationship was also shown withmedian reductions in seizure frequency of 26, 40 and 50% forthe OXC 600, 1200 and 2400 mg groups, respectively, com-pared to 8% for placebo (Figure 3). A similar dose-responserelationship was reported for the 50% responder and seizure-free rates. The seizure-free rates were 10 and 22% for theOXC 1200 and 2400 mg groups, respectively, compared to0.6% for placebo-treated patients (Figure 3). The efficacyresults were essentially similar when the analysis only includedpatients treated with CBZ at baseline or only the subgroup ofpatients who completed the double-blind phase of the trial[33]. The discontinuation rates because of significant adverseevents (AEs) were also proportional to the doses with 12, 36and 67% withdrawing from the OXC 600, 1200 and2400 mg groups, respectively, compared to 9% for placebo.More than 80% of those discontinuations occurred within3 weeks of initiating treatment with OXC. The most com-mon dose-related AEs experienced in this trial consisted ofdizziness, diplopia, somnolence, vomiting, nausea and ataxia.

The paediatric trial randomised 267 children aged 3 -17 years with refractory partial epilepsy to 112 days double-blind treatment, which consisted of 14 days titration and 98days maintenance period [34]. Patients experiencing a mini-mum of eight partial-onset seizures during an 8-week baselinephase while maintained on constant doses of one or twoAEDs were randomised to placebo or OXC. Treatment wasinitiated at 10 mg/kg/day and titrated over two weeks to adose of 30 - 46 mg/kg/day administered in two daily doses.The efficacy parameters were similar to those analysed in theadult adjunctive trial. The baseline seizure frequency per 28days was 12 - 13, with 40% of children experiencing second-arily generalised tonic-clonic seizures. The median daily doseof OXC administered during the maintenance phase was31.4 mg/kg. CBZ was the most common baseline AED, fol-lowed by valproate, lamotrigine and phenytoin. The resultsdemonstrated significant improvement in seizure frequencyfor OXC treated patients with median reductions of 35 and9% in the OXC and placebo groups, respectively. Theresponder rates were also significantly in favour of OXC

Table 2. Effects of different drugs on oxcarbazepine and carbamazepine plasma levels.

Oxcarbazepine Carbamazepine

Warfarin None None

Verapamil ↓ in MHD levels ↑

Erythromycin None ↑

Cimetidine None ↑

Table 3. Oxcarbazepine in monotherapy trials.

Monotherapy trial designs Number of trials

Active-controlled (new onset) 4

Dose-controlled (refractory) 2

Placebo-controlled (recent onset) 1

Placebo-controlled (pre-surgical) 1

Total 8

Beydoun & Kutluay


treated patients, with 41 and 22% of patients in the OXC andplacebo groups, respectively, experiencing ≥ 50% improve-ment in seizure frequency compared to baseline. The dropoutrates because of AEs were 10% in the OXC group and 3% inthe placebo group. Vomiting, somnolence, headache, dizzi-ness and nausea were the most common AEs [34].

4.1.2 Clinical implications of the adjunctive trialsThe results of the adjunctive trials clearly demonstrated thatadd-on treatment with OXC is efficacious in significantlyimproving seizure control in adults and children with refrac-tory partial epilepsy. It is important to note that CBZ was themost common baseline AED in both trials and that a sub-group analysis of those patients demonstrated that adjunctivetherapy with OXC led to efficacy results comparable to thoseobtained from all randomised patients [33]. This suggests thatthe anticonvulsant effects of CBZ and OXC are at least par-tially mediated by different mechanisms. From a clinical per-spective, these results indicate that adding OXC therapy topatients incompletely controlled on CBZ can be an effica-cious regimen for adults and children with medically refrac-tory partial epilepsy. It also suggests that patients whopreviously failed treatment with CBZ might achieve betterseizure control with the addition of OXC. The substantialdropout rate in the OXC 2400 mg group, with the vastmajority of patients withdrawing during the first 3 weeksafter treatment initiation, is most likely the result of theaggressive and forced titration that did not allow for adjust-ment of the dose of the baseline AEDs. In addition, it couldbe the result of the total AED load that patients were sub-jected to and the pharmacodynamic interactions betweenOXC and the baseline AEDs. It is therefore important whenOXC is used as adjunctive therapy to initiate treatment at alower dose and to gradually increase the dose to efficacy inorder to minimise those side effects. Based on clinical experi-

ence, a better-tolerated titration schedule consists of a initiat-ing treatment with OXC at a dose of 150 mg b.i.d. withweekly increases of 300 mg and a target dose of 1200 mg/day. Depending on the efficacy and tolerability, the dose ofOXC can be subsequently increased up to 2400 mg/day orhigher. In the event of AEs, the treating physician shouldconsider lowering the dose of the baseline AEDs because oftheir potential pharmacodynamic interactions with OXC.Some patients treated with high dose OXC who are experi-encing AEs tolerate the drug better when the dose is giventhrice-daily. For patients on phenytoin experiencing sideeffects with the addition of OXC, it is important to check aphenytoin level because of the potential pharmacokineticinteractions between the two drugs (see Section 3). Althoughthe adult adjunctive clinical trial demonstrated a dose-response relationship, there was no relationship between effi-cacy and the serum levels of MHD. Therefore, a so-called‘therapeutic serum range’ for MHD has not yet been estab-lished. The dose can usually be titrated to efficacy or tolera-bility according to the clinical response. If a serum levelneeds to be checked, for instance to document compliance orto establish an efficacious trough serum level for patients whoachieve seizure control, it is important to check the MHDlevel. Ordering a CBZ level for patients on OXC will resultin undetectable serum levels.

Although children tolerated a starting OXC dose of 10 mg/kg/day, a more conservative approach would be to initiatetreatment at 5 mg/kg/day with weekly increments of 5 mg/kg/day and a target dose range of 30 - 50 mg/kg/day based onefficacy and tolerability. Since the clearance of OXC is higherin children < 5 years, the maintenance dose of OXC in thatgroup will need to be on the higher end of the target doserange. The FDA recently approved a 6% oral suspension for-mulation (60 mg/ml) with approval expected in Europe at thebeginning of 2002.

Figure 3. Seizure free and 50% responder rates in patients taking oxcarbazepine versus placebo. ITT: Intent-to-treat;OXC: Oxcarbazepine. Data from [33].

Perc

ent o

f pat

ient

s

50% seizure reduction

Seizure-free

Response to treatment (ITT)

Placebo OXC600 mg/day

OXC1200 mg/day

OXC2400 mg/day

0

10

20

30

40

50

p = 0.008

p = 0.0001

p = 0.0001

41.2%

50%

26.8%

13%0.6% 3% 10% 22%

60

Oxcarbazepine


4.2 Monotherapy trialsThe eight monotherapy trials with OXC in epilepsy weredivided into two major clinical trial designs. Four of the trialswere therapeutic failure designs aimed at unequivocally dem-onstrating the efficacy of OXC as monotherapy and satisfy-ing the US regulatory agencies. The therapeutic failuredesign trials have incorporated specific exit criteria to mini-mise risks to patients. The typical efficacy parameters inthose trials include time to exit across the various randomisa-tion groups and the completer rate, which refers to the per-centage of patients in each group who completed the double-blind phase of the trial without fulfilling one or more of thepredefined exit criteria. The other four monotherapy trialswere active control trial designs aimed at evaluating the rela-tive efficacy and tolerability of OXC as monotherapy com-pared to those of the standard AEDs.

4.2.1 Therapeutic failure design trialsA multi-centre, double-blind RCT conducted in adultpatients with refractory partial epilepsy admitted to the hospi-tal for continuous closed circuit television-electroencephalo-gram (CCTV-EEG) monitoring as part of their presurgicalwork-up was done to evaluate the short-term efficacy and tol-erability of OXC as monotherapy [35]. A total of 102 patientsalready tapered off their baseline AEDs were randomised toplacebo or OXC. OXC was rapidly loaded with a starting doseof 1500 mg on day 1 and 2400 mg on day 2, administered ona twice-daily schedule. Patients remained in the trial for atotal of 10 days but had to exit if they satisfied specific exitcriteria consisting of a total of four partial-onset seizures, twonew-onset secondarily generalised seizures, serial seizures orstatus epilepticus. Seizure frequency was assessed throughoutthe trial by CCTV-EEG monitoring and direct observation.The results demonstrated statistically significant differencesfor time to exit and completer rate in favour of OXC-treatedpatients, with 47% of patients randomised to OXC meetingan exit criterion compared to 84% of placebo-treated patients.In addition, 25% of OXC-treated patients remained seizure-free throughout the double-blind phase compared to only 2%in the placebo group. Despite the aggressive dose initiationwith OXC, only two patients exited the trial because of AEs.The most common AEs were nausea, headache, pruritus, diz-ziness and somnolence.

Two multi-centre, randomised, dose-controlled mono-therapy trials were conducted in out-patients at least 12 yearsold with refractory partial epilepsy [36,37]. In the first trial,patients with 2 - 40 seizures per 28 days while maintained onconstant doses of one or two AEDs during a 56-day baselinephase were randomised to OXC 300 or 2400 mg/day groups[36]. Patients randomised to the 300 mg/day group received adosage of 300 mg throughout the 126-day double-blindphase. Those randomised to the OXC 2400 mg groupreceived 1200 mg/day during the first 7 days, 1800 mg/dayon days 8 - 14 and 2400 mg/day starting on day 15. Patientswere tapered and discontinued from their baseline AEDs over

a 6-week period beginning on day 1. The exit criteria wereindividualised based on each patient’s seizure frequency duringthe baseline phase. Patients had to exit the trial if they experi-enced a 2-fold increase in seizure frequency during any 28-dayperiod compared to baseline, a 2-fold increase in the highestconsecutive 2-day seizure frequency compared to baseline,occurrence of a single generalised tonic-clonic seizure if noneoccurred in the 6 months prior to randomisation, or a clini-cally relevant prolongation or worsening of seizure duration orfrequency. A total of 87 patients were randomised in the trialwith a median of eight seizures per 28 days during the baselinephase. The most common baseline AEDs were CBZ (49% ofpatients) followed by phenytoin and valproic acid. The per-centage of patients meeting one of the exit criteria was signifi-cantly higher in the OXC 300 mg group (93%) compared tothe OXC 2400 mg group (41%). The time to exit was alsosignificantly in favour of the high dose OXC group (Figure 4).An ITT analysis showed that, compared to baseline, 42 and12% of patients randomised to the OXC 2400 mg group wereresponders (≥ 50% improvement in seizure frequency com-pared to baseline) or seizure-free, respectively (Figure 5). Thecorresponding values for the OXC 300 mg group were 7 and0%, respectively. The drop-out rate because of significant AEswas 15% in the high-dose group. All of those discontinuationsoccurred prior to reaching OXC monotherapy during taperingof the baseline AEDs. The most common AEs were dizziness,fatigue, somnolence and nausea [36].

The design of the second trial was slightly different. In thattrial, patients experiencing 2 - 40 seizures per 28 days whilemaintained on monotherapy treatment with CBZ at dailydoses of 800 - 1600 mg were converted to OXC monotherapyat 2400 mg/day [37]. This open-label conversion phase lasted28 days, with initiation of OXC treatment at 600 mg/day onday 1, 1200 mg/day on day 7, 1800 mg/day on day 14 and2400 mg/day on day 21. The CBZ dose was tapered by 25,50, 75 and 100% (discontinued) on days 1, 7, 14 and 21,respectively. Following an additional 7-day treatment withOXC at 2400 mg/day, patients were maintained on OXC at2400 mg/day during a 56-day baseline period to establish abaseline seizure frequency. Patients completing the open-labelbaseline phase were then randomised to continue on OXCtreatment at 2400 mg/day or be tapered to OXC at 300 mg/day over the first 42 days of the 126-day double-blind treat-ment phase. Patients met the efficacy end points by complet-ing the double-blind phase or by meeting individualised exitcriteria that were similar to those listed in the previous trialrelative to the 56-day baseline phase. There were 143 patientsenrolled in the trial with a mean baseline CBZ dose of1300 mg/day. Of those, 96 patients were randomised in thedouble-blind phase, with 24 patients (17%) exiting because ofAEs during the conversion phase. The most common AEsduring the conversion phase were dizziness, headache, fatigueand nausea. The efficacy results were significantly in favour ofthe high dosage group, with median times to exit of 28 and68 days for the OXC 300 and 2400 mg/day groups, respec-

Beydoun & Kutluay


tively. The percentage of patients meeting one of the exit cri-teria was also significantly in favour of patients randomised tothe high-dose OXC group. There was no discontinuation dueto AEs throughout the double-blind treatment phase.

Another monotherapy trial was conducted in patients withuntreated, recently diagnosed partial epilepsy [38]. This was amulti-centre, double-blind, placebo-controlled parallel groupRCT that randomised patients ≥ 10 years with at least twopartial seizures per month during a 56-day retrospective base-line period. Eligible patients were randomised to OXC(titrated to 1200 mg/day) or placebo over 6 days, followed byan 84-day maintenance period. A total of 67 patients wererandomised in this trial with a median of five seizures per 28days. The primary efficacy variable, time to first seizure, wassignificantly in favour of patients randomised to OXC(p = 0.0457). The median percent reductions in seizure fre-quency compared to baseline were 89.1% and 37.4% for theOXC- and placebo-treated group, respectively [38]. There werethree patients in the OXC group and two in the placebogroup who discontinued the trial because of an AE.

4.2.2 Active control trialsAll four active-control comparative trials had a similar design[39-42]. They were multi-centre, double-blind RCTs consisting

of a titration phase lasting 4 - 8 weeks followed by a 48-weekmaintenance period. Eligible patients were those with newly-diagnosed or previously untreated epilepsy with a minimumof two seizures separated by at least 8 h within the 6 monthsprior to enrolment in the study. The primary efficacy variablewas the percentage of patients remaining seizure-free through-out the 48-week maintenance period. One trial compared therelative efficacy and tolerability of OXC compared to CBZ inadults [42], another to valproate in adults [41] and the last twowere comparative trials of OXC versus phenytoin in adults [39],children and adolescents [40]. During the titration period,OXC and active comparators were titrated to the dose, whichin the opinion of the investigators was the most effective. Thestarting dose of OXC in all adult trials was 300 mg/day(150 mg/day in the paediatric trial) with a mean daily doseduring the maintenance phase of 1028 - 1053 mg (18.8 mg/kg/day in the paediatric trial) (Table 4). The doses of the activecomparators were consistent with clinical practice (Table 4).None of the four trials showed substantial differences betweenOXC and the active comparator, with seizure-free rates onOXC between 52 - 61%. However, OXC was substantiallybetter tolerated than CBZ and phenytoin both in adults andchildren, as shown by significantly lower exit rates due to sig-nificant AEs (Figure 6).

Figure 4. Time to exit and dose relationship in OXC monotherapy trial. OXC: Oxcarbazepine. Data from [36].

Patie

nts

not m

eetin

gon

e of

the

exit

crite

riaOXC 2400 mg/day (n = 41)

OXC 300 mg/day (n = 46)

0

Time to exit versus control (days)

20

40

60

80

100

0

p = 0.0001

12010080604020

Figure 5. Response to treatment in patients taking low- and high-dose OXC. §Responders refers to patients with at least a 50%improvement in seizure frequency compared to baseline. OXC: Oxcarbazepine. Data from [36].

42

712

00

10

20

30

40

50

Responders§ Seizure free

OXC 2400 mg/day

OXC 300 mg/day

Perc

ent o

f pat

ient

s

Oxcarbazepine


4.2.3 Clinical significance of the monotherapy trialsA number of clinically relevant points were learned from themonotherapy trials in partial epilepsy. To begin with, OXCunequivocally demonstrated significant efficacy as mono-therapy in various populations ranging from newly diagnosedpatients to those with highly refractory partial epilepsy.Refractory patients will most likely transition from polyther-apy to monotherapy. In that regard, the results of the in-patient trial indicate that it is possible to load patients admit-ted to the hospital for presurgical monitoring starting withOXC at 1500 mg/day on day 1 with a maintenance dose of2400 mg/day on day 2. For out-patients with refractory par-tial epilepsy already maintained on one or more AEDs theresults of the two out-patient trials indicate that is possible toconvert them to monotherapy by initially adding OXC totheir regimen then tapering the dosages of the baseline AEDs.This conversion can result in improved seizure control sinceconverting patients maintained on up to two AEDs resultedin a ≥ 50% improvement in seizure frequency in 42% and sei-zure freedom in 12% of patients [36]. It also indicates that asubstantial proportion of patients who previously failed treat-ment with CBZ monotherapy will obtain significantly betterseizure control on OXC. The transition phase might be diffi-cult to tolerate for some patients since all patients who exitedthe conversion to monotherapy trials did so at a time whenthey were on a combination of OXC and baseline AEDs[36,37]. For those patients, a strategy similar to the one sug-gested for patients on adjunctive therapy works best with astarting OXC dose of 150 mg b.i.d. and weekly increments of300 mg until a target OXC dose of 900 - 1200 mg/day isreached. At that point, the dose of the baseline AED can betapered by 25 - 33% weekly while concomitantly increasingthe OXC dose by 300 mg every week until the baseline AEDsare discontinued. Obviously, this suggested conversion regi-men could be carried out more quickly or slowly dependenton seizure control and tolerability. Another way suitable forpatients treated with carbamazepine is to perform an immedi-ate switch [43]. Although this conversion method was nottested in the pivotal clinical trials, it is an attractive optionbecause of its swiftness. The conversion ratio between CBZ

and OXC is 1.2 - 1.5 mg of OXC for each milligram of CBZ.An overnight conversion is best performed over a weekend byreplacing the evening dose of CBZ with OXC on a Friday, fol-lowed by the full equivalent dose of OXC the next day. Theadvantage of performing the conversion over a weekend is tominimise the impact of potential drowsiness, fatigue, GIsymptoms and somnolence for patients who hold a job.

It is important to pay attention to the potential effect of de-induction when CBZ or other hepatic enzyme inducers arereplaced by CBZ. This is of importance if patients are main-tained on other drugs that were induced by CBZ and canresult in side effects due to the elevation in serum levels of thebaseline AEDs. For example, patients maintained on CBZand lamotrigine (or CBZ and valproate) might require reduc-tion of the daily valproate or lamotrigine doses when switch-ing from CBZ or phenytoin to OXC.

For the newly diagnosed patient with partial epilepsy, it hasbeen shown that the efficacy of OXC does not differ substan-tially from that of the standard AEDs but that it is signifi-cantly better tolerated than the first-line agents phenytoin andCBZ. This makes OXC an attractive drug for patients withnewly diagnosed partial epilepsy. The median daily OXC dosefrom all three adult comparative trials was ~ 1 g/day, whichresulted in seizure free rates of 52 - 61% throughout the 48-week double-blind phase. This indicates that a target OXCdose of 900 - 1200 mg/day (15 - 25 mg/kg/day in children) isappropriate for the newly diagnosed patient. For the patientwith isolated seizures, a starting dose of 300 mg taken as150 mg b.i.d. (2.5 mg/kg/day b.i.d. in children) with weeklyincrements of 300 mg (5 mg/kg/day) is the best tolerated. Incase of frequent seizures, the patient can be started on 300 mgb.i.d. (5 mg/kg b.i.d. in children) with the dose increased by300 mg increments (5 mg/kg in children) at 4 - 5 day inter-vals to the most effective dose.

Although OXC was not evaluated in patients with general-ised epilepsies its use, especially as monotherapy, is not recom-mended in patients suffering from primarily generalisedseizures, such as absence or atypical absence seizures.

4.3 OXC treatment in affective disordersThe efficacy of some AEDs in general and CBZ in particularfor the treatment of psychiatric conditions led to an interestin the evaluation of OXC for the treatment of bipolar disor-ders. The first trial was a small double-blind, placebo-con-trolled, cross-over clinical study in six patients with acutemania [44]. Treatment with OXC at daily dosages between1800 - 2100 mg resulted in a 50% improvement in themania scale. These encouraging results led to two multi-cen-tre active-control trials that compared the relative efficacyand tolerability of OXC versus haloperidol and lithium inpatients with acute mania [44].

In the trial comparing OXC to haloperidol, 38 patientswere randomised to a starting OXC dose of 900 mg/day(300 mg t.i.d.) and titrated to a mean daily dose of 2400 mg.Haloperidol was initiated at 5 mg t.i.d. and titrated to a mean

Table 4. OXC dosage in active-control monotherapy trials.

Comparator (n) MDD (mg/day) Range (mg/day) Ref.

OXC (143)PHT (144)

1028313

600 - 2100100 - 650

[39]

OXC (97)PHT (96)

672226

300 - 1350100 - 400

[40]

OXC (128)VPA (121)

10531146

600 - 2400600 - 2700

[41]

OXC (94)CBZ (100)

1040684

300 - 800300 - 1400

[42]

CBZ: Carbamazepine; MDD: Mean daily dose during maintenance phase;OXC: Oxcarbazepine; PHT: Phenytoin; VPA: Valproate.

Beydoun & Kutluay


daily dose of 42 mg. The study showed that both drugsresulted in a statistically significant improvement in the maniarating scales compared to baseline, with no significant differ-ence in efficacy between the groups. However, OXC was sub-stantially better tolerated as the frequency of AEs was morethan 3-fold higher for haloperidol-treated patients. In addi-tion, the treating physicians rated the tolerability of OXC aspoor in 6% of patients, compared to 25% of those ran-domised to the haloperidol group [44].

Fifty-two patients were randomised in a multi-centre trialof OXC versus lithium. In this study, the mean daily dose ofOXC was 1400 mg compared to 1100 mg of lithium. At theend of the 15-day trial there was significant improvement inthe mania rating scale compared to baseline for both treat-ment groups, with no significant difference in efficacy acrossthe two groups. In addition, the frequency of AEs and thephysician’s global evaluation of tolerability were comparableacross the two groups [44].

4.3.1 Clinical implicationsAlthough the comparative trials of OXC in acute mania arerelatively small in scale and no firm conclusion of efficacy canbe derived from them, the suggestion of no substantial differ-ence in efficacy between lithium or haloperidol and OXC forthe management of acute mania is encouraging. If confirmedin larger trials the results are clinically significant, as manypatients with psychiatric disorders are treated with polyther-apy and OXC is associated with substantially fewer drug-druginteractions with other psychotropic drugs than CBZ. Forexample, CBZ is known to increase the clearance of valproate,lamotrigine, haloperidol, tricyclic antidepressants, benzodi-azepines, buproprion, clonazepam, clozapine and olanzapine[45] (Table 5). This increase in clearance is clinically important.For example, it is difficult to achieve high trough valproatelevels in the presence of CBZ; in addition, the clearance ofclozapine can be increased by 65 - 85% in the presence ofCBZ, which can result in a substantial reduction in the effi-cacy of clozapine.

Conversely, fluoxetine, nefadozone and valproate inhibit themetabolism of CBZ, which can lead to CBZ toxicity (Table 5).

Concomitant administration of CBZ and lithium can result inlithium toxicity with resultant symptoms, such as nausea,vomiting, sedation and tremors [46]. Since OXC causes fewerdrug-drug interactions, it is especially important to pay atten-tion to the effect of de-induction when OXC is substituted forCBZ. For example, since OXC dose not alter the clearance ofvalproate, the serum level of the latter will increase substan-tially when OXC is substituted for carbamazepine. Similarly, itwas shown that plasma concentration of clozapine increased by47% when OXC was switched for CBZ. Other documentedelevations of serum levels include haloperidol, chlorpromazineand citalopram. No clinically relevant interactions wereobserved between OXC and the tricyclic antidepressants[Novartis, data on file] or viloxazine [47].

4.4 OXC in the treatment of painful neuropathiesThe efficacy of CBZ for the treatment of trigeminal neuralgiais well established. Three clinical trials that enrolled a total of151 patients documented a 56 - 75% mean improvement inpain during the CBZ phase of the trials compared to 0 - 26%during the placebo phase [48-50]. Those positive results led to anevaluation of the efficacy of OXC in that condition, initially inopen-label series followed by a double-blind comparativeactive-control clinical trial and in three multi-centre trials thatcompared the efficacy of CBZ with that of OXC in patientswith newly diagnosed and refractory trigeminal neuralgia.

In an open-label study, 15 patients refractory to CBZ wereconverted to OXC as monotherapy [51]. The results indicatedthat 67% of patients achieved complete control of their symp-toms on a daily OXC dose of 900 - 1800 mg, with an addi-tional 20% of patients controlled with occasionalexacerbation of the pain. Another open-label study with amean follow-up of 11 months evaluated the efficacy of OXCin 13 patients suffering from trigeminal neuralgia or otherfacial neuralgias [52]. On a mean daily OXC dose of 850 mg(range 400 - 2000 mg), 73% of patients were reportedly verywell controlled and 27% were moderately well controlled. Inan open-label study of six patients refractory or intolerant toCBZ, treatment with OXC at 600 - 2400 mg/day resulted incomplete control of symptoms in all patients within the first

Figure 6: Discontinuation rate due to the AEs in patients taking OXC versus other AEDs. AE: Adverse event; AED: Anti-epilepticdrug; CBZ: Carbamazepine; OXC: Oxcarbazepine; PHT: Phenytoin; VPA: Valproate.

p = 0.002 p = 0.017 p = 0.331 p = 0.04

Perc

ent o

f pat

ient

sdi

scon

tinue

dOXC

PHT

VPA

CBZ

0

5

10

15

20

25

30

2%

18%

4%

13% 14%

10%

14%

26%

Oxcarbazepine


24 h after initiating OXC treatment [53]. The comparativeefficacy of OXC to that of CBZ was evaluated in a double-blind crossover clinical trial [54]. Patients were titrated to OXCat 900 - 2100 mg/day or CBZ at 400 - 1200 mg/day, withefficacy assessed on an 11-point scale. These results showedcomparable analgesic effect for the majority of patients, lead-ing to the conclusion that OXC offers an alternative to CBZfor the treatment of trigeminal neuralgia [54]. Three multi-centre, double-blind clinical trials evaluated the comparativeefficacy of OXC to that of CBZ in patients with newly diag-nosed and refractory patients with trigeminal neuralgia (Bey-doun et al. unpublished data). The trials consisted of a 2- to4-week titration period followed by a 4-week maintenanceperiod. There were no statistical differences for any of the effi-cacy variables between the two groups, including theresponder rates, reduction in pain days, pain during eatingand global assessment. In those trials, the median effectiveOXC dose was 900 - 1200 mg/day for patients with newlydiagnosed trigeminal neuralgia and 1050 - 1200 mg/day forthe refractory patients.

Adjunctive therapy with OXC was also evaluated in a cohortof 55 consecutive patients with various painful neuropathieswho failed to respond to treatment with gabapentin [55]. Theunderlying causes included complex regional pain syndromes,radicular pain, symmetrical painful polyneuropathies and neu-ralgias. The starting dose of OXC was 150 - 300 mg/day,which was gradually titrated by 150 - 300 mg every 3 - 5 daysto a maximum daily dose of 1200 mg. An excellent response(≥ 70% improvement in pain scores) was achieved by 27.3%of patients and a good response (50 - 70% improvement) wasachieved by 45.5% of patients [55]. There is a published casereport of a patient with refractory painful diabetic peripheralneuropathy who responded well to OXC at 1200 mg/day [56].

4.4.1 Clinical implicationsThe pathophysiology of neuropathic pain has been linked tomaladaptive changes in the PNS and CNS following a periph-

eral nerve injury. Peripherally, significant accumulation ofsodium channels at the level of the injury has been docu-mented [57], resulting in a lowering of the nociceptor depolari-sation threshold and ectopic discharges. Central sensitisationof dorsal horn neurones results in lowering of their thresholdsand in ectopic discharges. Some of the mechanisms impli-cated in the development and maintenance of central sensiti-sation include excitatory neurotransmitter release,intracellular calcium influx, induction of early gene expressionand activation of protein kinases. By virtue of its effect on thesodium and high threshold calcium channels, OXC has themechanistic potential to modulate both peripheral and centralsensitisation. There is strong evidence that OXC is efficaciousin the treatment of trigeminal neuralgia at a median dailyeffective dose of 900 - 1200 mg. Its efficacy in other painfulneuropathies, such as painful diabetic neuropathy, is so farbased on clinical experience but not on clinical trial results.This is likely to be temporary since a number of multi-centre,randomised, placebo-controlled clinical trials evaluating thesafety, tolerability and efficacy of OXC as monotherapy in thetreatment of painful diabetic neuropathy are expected to beinitiated later this year.

5. Safety and tolerability

The type and frequency of AEs on OXC therapy depends onthe total daily dose of OXC, whether it is used as mono-therapy or adjunctive therapy and on the age of the patientpopulation being treated. In the comparative trials in patientswith newly diagnosed partial epilepsy, the dropout ratesbecause of significant side effects ranged from 2 - 14% on amean daily dose of ~ 1 g in adults and 672 mg in children[39,40,42]. The most common side effects in those trials con-sisted of somnolence, headache, dizziness and ataxia. In theconversion to monotherapy trials, all of the dropoutsoccurred during the transition phase when patients were onOXC in addition to their baseline AEDs. In those trials, themost common AEs were dizziness, fatigue, somnolence, nau-sea and vomiting. The adjunctive clinical trials showed thatthe frequency and types of AEs differ between adults andchildren treated with OXC. In the adult trial, the dropoutrate because of significant AEs was dose related and consistedof dizziness, headache and somnolence. In children treatedwith adjunctive therapy, OXC was significantly better toler-ated. with vomiting, somnolence, headache and dizzinessbeing the most common AEs.

A rash was reported in ~ 4 - 5% of patients exposed toOXC, with disappearance of the rash in all patients followingthe discontinuation of the drug [Novartis, data on file]. Twocases of exfoliative dermatitis were reported with a similarreaction to CBZ in one of the patients [58]. In addition, threecases of erythema multiforme were filed, all of which recov-ered fully. In a study that evaluated the risk of cross-sensitivitybetween CBZ and OXC, it was found that 27% of 51 patientswith a rash whilst taking CBZ developed an allergic cutaneous

Table 5. Drug-drug interactions between OXC and some psychotropic drugs.

Drug OXC CBZ

Valproate NCS ↓ VPA↑ CBZ-epoxide

Haloperidol NCS ↓ Haloperidol

ChlorpromazineOlanzapineClozapine

NCS ↓ Chlorpromazine↓ Olanzapine↓ Clozapine

BenzodiazepineTCA

NCS ↓ Benzodiazepine↓ TCA

Lithium NCS Lithium toxicity

Fluoxetine, Nefazadone

NCS ↑ CBZ

CBZ: Carbamazepine; NCS: Not clinically significant; OXC: Oxcarbazepine; TCA: Tricyclic antidepressants; VPA: Valproate.

Beydoun & Kutluay


reaction to OXC. In the majority of those cases the rash onOXC appeared during the first month of treatment [42].

No clinically significant abnormalities involving the hae-matological, hepatic or renal systems were reported withOXC. As with CBZ, treatment with OXC can result inhyponatraemia [59-61]. Sodium levels < 125 mmol/l werereported in 2.5% of patients receiving OXC therapy [TrileptalPackage Insert]. The risk of OXC-induced hyponatraemia isage-dependent, since it is extremely rare in childhood andincreases to ~ 7% in the elderly population. The risk is alsoincreased for patients concomitantly taking natriuretic drugs.There have been a few case reports of hyponatraemia-inducedmorbidity related to OXC therapy [62,63]. A retrospectivestudy from eight epilepsy clinics in Denmark reportedhyponatraemia as a reason for discontinuation in four of 947patients (0.5%) receiving OXC treatment, although theyreported a shift to subnormal sodium levels in 23% of thepatients [61]. Results of double-blind monotherapy trials withlarge patient populations revealed low incidence of significanthyponatraemia [36,39,40,64,65]. Three of these studies did notreport any patients with hyponatraemia [39,40,65]. Beydounet al. reported one patient with a baseline level of 137 mmol/lwho later dropped to 121 mmol/l. However, the patient’ssodium level increased after discontinuation of OXC [36]. Intheir series, Schachter et al. reported 11 of 51 patients withhyponatraemia (< 135 mmol/l) but only one patient had asignificant reduction in the sodium levels (124 mmol/l) [35].

To date the maximum dose of OXC taken was 24 g,although a few other cases of OXC overdose were alsoreported and all cases recovered with symptomatic treatment[Trileptal Package Insert].

5.1 Clinical implicationsAlthough the serum sodium levels tend to decrease on OXCtreatment, hyponatraemia is usually not clinically significantand rarely leads to discontinuation of OXC therapy. A recentunpublished study demonstrated that OXC-inducedhyponatraemia is not due to an increase in antidiuretic hor-mone (ADH) secretion but is most likely due to an OXC-dependent increase in the sensitivity of the renal tubules tocirculating ADH or to a direct effect of OXC on the distaltubules. In clinical practice, chronic hyponatraemia is usuallyasymptomatic until the serum sodium drops to ≤ 125 mEq/l.In those instances, symptoms such as anorexia, dizziness, som-nolence, nausea, cramps and seizures can occur. It mighttherefore be prudent to check a baseline sodium level prior toinitiating therapy, especially in elderly patients or patientsreceiving concomitant sodium-wasting drugs, such as diuret-ics, antipsychotics, antidepressants or NSAIDs. One alsoneeds to be careful about the possibility of hyponatraemia inpatients ingesting high liquid loads, such as those living in hotweather, those with psychogenic polydipsia and postoperativepatients. A follow-up sodium level can be checked 6 - 8 weekslater; if the sodium level is stable, there is no further need tocheck the sodium levels as long as the OXC dose remains sta-

ble. If the level is dropping or the OXC dose is increased, fol-low-up sodium levels every 2 months are advisable until thelevels stabilised. If needed, fluid restriction can be quite effec-tive in some patients in normalising the sodium levels.

6. Effects of OXC on neuropsychological and PNS functions

In a study of 19 patients with newly diagnosed epilepsy, neu-ropsychological assessment performed at baseline and follow-ing 6 and 12 months of treatment did not show anysignificant difference in cognitive functioning between OXC-and phenytoin-treated patients [65]. In focused attention andmanual writing tasks (n = 12), those randomised to OXC at150 or 300 mg/day were reported to perform better thanthose randomised to placebo [66]. However, the OXC dosesused in that study were lower than the doses used in clinicalpractice. Exposure to 400 and 600 mg OXC did not have anyeffect on saccadic and smooth eye movements in healthy vol-unteers [67]. One study evaluated the effects of OXC onperipheral nerve conduction and compared it to CBZ [68].Although treatment with CBZ resulted in significantly slowedmotor conduction velocity at 6 months, there was no signifi-cant slowing following OXC treatment.

7. Expert opinion

OXC is a welcome addition to the AED armamentarium. Forpatients with newly diagnosed partial epilepsy, it offers clini-cally relevant advantages compared to the standard AEDsboth in terms of better tolerability and improved pharmacoki-netic profile. For the 25 - 33% of patients with medicallyrefractory partial epilepsy, OXC can result in improved seizurecontrol when used as adjunctive therapy or as alternativemonotherapy. OXC is usually well-tolerated, especially whenthe titration to efficacy is performed gradually. Hyponatrae-mia can be symptomatic in some patients and it is thereforeuseful to monitor the sodium levels in patients at risk. Todate, the exposure rate to OXC exceeds 400,000 patient-years,which makes it unlikely that new life-threatening AEs to thisdrug will occur.

There is strong data supporting the efficacy of OXC forpatients with trigeminal neuralgia. Three large multi-centre,randomised, placebo-controlled clinical trials are scheduled tostart later this year to evaluate its efficacy for patients withpainful diabetic neuropathy.

Although the numbers of patients randomised in the acutemania trials are relatively small, the early results suggest thatthe efficacy of OXC is comparable to lithium and haloperidol.The advantages of OXC over CBZ in that patient populationinclude better tolerability and fewer drug-drug interactionswith other psychotropic drugs when used as adjunctive ther-apy. Large RCTs will be needed to ascertain the efficacy ofOXC in patients with bipolar disorders.

Oxcarbazepine


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AffiliationAhmad Beydoun & Ekrem KutluayUniversity of Michigan Medical Center,Ann Arbor 48109, USA

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