R EVIEWS _F T HERAPEUTICS

Oxcarbazepine in the Treatment of Epilepsy

Tracy A. Glauser, M.D.

Oxcarbazepine is a new antiepileptic drug (AED) that has been registered in

more than 50 countries worldwide since 1990 and recently received approval
in the United States and the European Union. Oxcarbazepine is a keto analog
of carbamazepine and has a more favorable pharmacokinetic profile. It is
rapidly absorbed after oral administration and undergoes rapid and almost
complete reductive metabolism to form the pharmacologically active
10-monohydroxy derivative. Oxcarbazepine exhibits linear pharmaco-
kinetics, no autoinduction, and minimal interaction with other AEDs. Ten
controlled trials demonstrated that oxcarbazepine is safe and efficacious in the
treatment of partial seizures across a wide range of ages (children to adults),
situations (recent onset to treatment-resistant epilepsy), and uses
(monotherapy and adjunctive therapy). The most common treatment-
emergent adverse events are related to the central nervous system. Treatment-
emergent hyponatremia (defined as serum sodium level < 125 mEq/L)
occurred in 3% of patients treated with oxcarbazepine in clinical trials.
According to the efficacy and safety profile established in the controlled trials,
oxcarbazepine represents an important new treatment option indicated for
monotherapy and adjunctive therapy in adults with partial seizures and as
adjunctive therapy in children aged 4 years or older with partial seizures.
Although structurally similar to carbamazepine, significant differences exist in
the pharmacokinetics, drug interaction potential, adverse-effect profile, and
dosage and titration between these two agents, and they should be considered
distinct therapeutic agents.
(Pharmacotherapy 2001;21(8):904–919)

OUTLINE Clinical Pharmacokinetics

Chemistry Drug Interactions
Preclinical in Vitro Studies Clinical Efficacy
Preclinical in Vivo Studies Overview
Monotherapy, Placebo-Controlled Trials
Efficacy
Monotherapy, Substitution Dose-Controlled Trials
Toxicology
Monotherapy, Comparative Trials
From the Department of Neurology, Children’s Adjunctive, Placebo-Controlled Trials
Comprehensive Epilepsy Program, Children’s Hospital
Clinical Tolerability
Medical Center, Cincinnati, Ohio.
Supported in part by an unrestricted educational grant Overview
from Novartis Pharmaceuticals Corporation, East Hanover, Adverse-Event Profile from Controlled Clinical
New Jersey. Trials
Address reprint requests to Tracy A. Glauser, M.D., Serious Adverse Reactions
Children’s Comprehensive Epilepsy Program, Department of
Neurology, OSB-5, Children’s Hospital Medical Center, 3333 Laboratory Abnormalities
Burnet Avenue, Cincinnati, OH 45229-3039; e-mail: Dosage, Titration, and Conversion from Other AEDs
glauser@chmcc.org. Conclusion
 OXCARBAZEPINE IN THE TREATMENT OF EPILEPSY Glauser 905

Epilepsy, a disease characterized by recurrent, reactions; and cost.25–27

unprovoked seizures, afflicts an estimated 50 Since oxcarbazepine (Trileptal; Novartis
million people worldwide, including 2.3 million Pharmaceuticals Corp., East Hanover, NJ) was
Americans (approximately 1% of the total introduced in 1990, it has been registered in
population of the United States).1, 2 Partial-onset more than 50 countries worldwide and recently
seizures are the most common form of seizures in was approved for use in both the U.S. and the
children, adolescents, and adults, with an European Union. Ten randomized, double-blind,
incidence of 20/100,000 from infancy through parallel-design, controlled trials established that
age 65 years. 3 Two landmark multicenter oxcarbazepine is efficacious and well tolerated as
Veterans Administration (VA) cooperative studies monotherapy or as adjunctive therapy in adults,
established carbamazepine and phenytoin as adolescents, and children with newly diagnosed
first-line antiepileptic drugs (AEDs) for adults or treatment-resistant partial-onset seizures, with
with partial seizures. 4–6 The first VA study or without secondary generalization.28–37
demonstrated that carbamazepine and phenytoin
were more effective and better tolerated over time Chemistry
than primidone and phenobarbital in the
Oxcarbazepine (10,11-dihydro-10-oxo-5H-
treatment of complex partial seizures.4 All four
dibenz[b,f]azepine-5-carboxamide) is a 10-keto
of these AEDs were equally effective as
analog of carbamazepine (Figure 1). 38 It is a
monotherapy for secondarily generalized tonic-
neutral lipophilic compound with a molecular
clonic seizures. 7 The second VA cooperative
weight of 252.27 daltons 39, 40 and very low
study demonstrated that carbamazepine was
solubility in water.41 Although oxcarbazepine is
superior to valproic acid in the treatment of
pharmacologically active in humans, it undergoes
complex partial seizures and that valproic acid
rapid and almost complete reductive metabolism
and carbamazepine were equivalent in the
of its keto group to form the pharmacologically
management of secondarily generalized tonic-
active 10-monohydroxy derivative (MHD; 10,11-
clonic seizures.5
dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-
In both VA cooperative studies, only 25–45%
carboxamide).42 The reduction of oxcarbazepine
of patients were seizure free after 12 months of
to MHD results in the formation of both the S-
therapy.4, 5 This “therapeutic gap” has important (+)-MHD (80%) and the R-(-)-MHD (20%)
ramifications because continued seizures prevent enantiomers.43
a patient from leading a normal life and result in
increased risk of injury and death. 8–10 These
Preclinical in Vitro Studies
studies did not address the treatment of partial
seizures in children or generalized seizures (e.g., In vitro, oxcarbazepine and MHD have been
myoclonic, atonic) in adults or children. During shown to modulate several different ionic
the past decade, many new AEDs (including channels. In cultured mouse central neurons,
felbamate, gabapentin, lamotrigine,
levetiracetam, tiagabine, topiramate, and
zonisamide) have been approved for use in the
U.S. and around the world. All have shown
efficacy as adjunctive therapy in adults with O
refractory partial seizures,11–16 and some have
proved effective as monotherapy in adults with
partial seizures17–21 or as adjunctive therapy in
children with refractory partial seizures.22–24 In
addition to proven efficacy, the new AEDs
possess several pharmacokinetic advantages
compared with their older counterparts.
However, neurologists have not yet accepted
these newer agents as first-line therapy for a
variety of reasons, including long experience
N
with older AEDs; insufficient postmarketing
experience to assess relative efficacy (especially
by seizure type or epilepsy syndrome) or CONH2
tolerability, or likelihood of idiosyncratic Figure 1. Chemical structure of oxcarbazepine.
906 PHARMACOTHERAPY Volume 21, Number 8, 2001
oxcarbazepine and MHD limited the frequency of
firing of sodium-dependent action potentials,
implying blockade of voltage-sensitive sodium
channels. 42, 44, 45 In hippocampal slices, the
blockade of penicillin-induced epileptiform
discharges by MHD was diminished when 4-
aminopyridine (a potassium channel blocker)
was added to the bath. 42 In isolated cortical
pyramidal cells, MHD produced a reversible
dose-dependent decrease in high-voltage
activated calcium currents evoked by membrane
depolarization.46
Although these mechanisms of action are
similar to those of carbamazepine, the reports of
patients resistant to carbamazepine who
responded to therapy with oxcarbazepine suggest
that oxcarbazepine may have additional
unrecognized cellular mechanisms of action. 42
There is no evidence that oxcarbazepine or MHD
potentiates g-aminobutyric acid (GABA)
neurotransmission or produces substantial
antagonism of the kainate (N-methyl-D-aspartate
[NMDA]) or quisqualate subtypes of the
glutamate receptor (data on file, Novartis
Pharmaceuticals Corp.).
Preclinical in Vivo Studies
Efficacy
Oxcarbazepine was tested in many animal
models of epilepsy, including the maximal
electroshock test, the chronic aluminum foci
model, and three types of chemically induced
seizure models. The maximal electroshock test
identifies agents that may prevent the spread of
seizures.47, 48 In rats and mice, oxcarbazepine and
MHD blocked maximal electroshock test seizures
with a potency similar to that of phenytoin and
carbamazepine.45, 49, 50 The chronic aluminum
foci model in rhesus monkeys identifies agents
potentially effective against posttraumatic and
partial-onset seizures.39, 51 Both oxcarbazepine
and MHD demonstrated efficacy in this model,
although MHD was less potent than
oxcarbazepine. 39, 42, 52 The three models of
chemically induced seizures (pentylenetetrazole,
picrotoxin, and strychnine) are typically used to
identify agents that raise seizure threshold. In all
three models, oxcarbazepine, like carbamazepine,
was either ineffective or only weakly effective.39,
42, 53
Both MHD enantiomers have similar
anticonvulsant efficacy and tolerability in these
animal models.42 This activity profile suggests
that oxcarbazepine and MHD, like carbamazepine,
exert their anticonvulsant effects by blocking the
spread of seizures rather than by raising seizure
threshold.
Toxicology
Oxcarbazepine and MHD were well tolerated
after short-term administration to mice, rats, and
hamsters. 39 Multiple-dose (3- and 6-month)
toxicity studies with oxcarbazepine and MHD in
rats and dogs revealed reversible, dose-dependent
increases in liver weight considered due to
centrilobular megalocytosis related to enzyme
induction. Oxcarbazepine, but not MHD, caused
a progressive nephropathy in male rats. 39
Oxcarbazepine, like carbamazepine, is a
promoter of liver tumors in rodents, but because
oxcarbazepine and MHD metabolism differs
substantially between humans and rodents,54 this
finding probably cannot be generalized to
humans. In male and female rats, fertility was
unaffected by oxcarbazepine or MHD at doses up
to 150 mg/kg.39, 40, 55
Clinical Pharmacokinetics
Oxcarbazepine demonstrates rapid and almost
complete absorption (> 95%) after oral
administration.56, 57 It is rapidly metabolized by
reduction to the pharmacologically active
metabolite MHD, but a small proportion (4%) is
oxidized to a pharmacologically inactive
dihydroxy derivative. 56, 57 This reduction is
catalyzed by cytosolic aldo-ketoreductases that
are considered practically noninducible
enzymes. 58 This predominant pathway of
metabolism in humans is only a minor pathway
in rats and dogs.54 Subsequently, MHD undergoes
glucuronidation by a uridinediphospho-
glucuronosyltransferase.
It had been reported that the systemic
bioavailability of MHD was increased by
approximately 17% when oxcarbazepine was
taken with food. 59, 60 However, with a newer
oxcarbazepine formulation, there was no effect of
food on the bioavailability of MHD (data on file,
Novartis Pharmaceuticals Corp.). Peak plasma
concentrations of MHD occurred 4–6 hours after
a single dose of either oxcarbazepine 400 mg or
oxcarbazepine 600 mg.57, 61 The plasma terminal
half-life of oxcarbazepine was between 1 and 2.5
hours,62 whereas the plasma MHD terminal half-
life averaged 9.3 ± 1.8 hours after administration
of a single dose.63 There was a linear relationship
between oral oxcarbazepine dosage and plasma
MHD concentrations in healthy volunteers and in
patients with epilepsy who were receiving
 OXCARBAZEPINE IN THE TREATMENT OF EPILEPSY Glauser
Table 1. Summary of AED Interactions with Oxcarbazepine
Influence of Oxcarbazepine
AED or Metabolite on AED Concentration
Phenytoin 0–40% increase
Phenobarbital 14–15% increase
Valproic acid No influence
Carbamazepine 0–22% decrease
Carbamazepine-epoxide 30% increase
Clobazam Not studied
Felbamate Not studied
AED = antiepileptic drug; MHD = pharmacologically active 10-monohydroxy derivative.
Data are based on results of clinical studies.
oxcarbazepine monotherapy or polytherapy.61, 62,
64
The volume of distribution of MHD ranged
from 0.7–0.8 L/kg, consistent with distribution
into total body water.39, 56 The in vivo protein
binding of MHD was 40%. 65, 66 It was mainly
bound to albumin, and its binding was independent
of serum concentration within the therapeutically
relevant range.39 No autoinduction or accumulation
occurred with oxcarbazepine therapy in healthy
volunteers.56, 61, 67
Most of an orally administered dose of oxcar-
bazepine is excreted as either the glucuronide
derivative of MHD (49%) or unchanged MHD
(27%).57 Renal excretion is the major route of
oxcarbazepine elimination.56, 57 Mild to moderate
renal impairment in adults has little effect on
plasma MHD concentrations. However, in
patients with renal failure (creatinine clearance
< 30 ml/min/1.73 m2), the elimination half-life of
MHD is prolonged, the area under the curve
(AUC) is increased 2-fold, and significant
increases in plasma MHD concentrations can
occur unless the dosage is adjusted.68 Mild to
moderate hepatic impairment does not appear to
affect MHD pharmacokinetics (data on file,
Novartis Pharmaceuticals Corp.).
Mean dose-normalized, steady-state plasma
MHD concentrations in children and adolescents
(aged 6–18 yrs) adjusted for body weight were
comparable to those in adults.60 However, the
dose-normalized AUC values of MHD in children
aged 2–5 years were 30% lower than those in
children aged 6–12 years after single
administration of 5-mg/kg and 15-mg/kg doses of
oxcarbazepine (data on file, Novartis
Pharmaceuticals Corp.). Thus, higher doses of
oxcarbazepine may be required in children
younger than 6 years. 69, 70 In contrast, peak
plasma MHD concentrations and AUC values of
MHD were significantly higher in elderly patients
(aged 60–82 yrs) than in younger adults, which
907
Influence of AEDs on
MHD Concentration
29–35% decrease
30–31% decrease
0–18% decrease
40% decrease
Not studied
No influence
No influence
was thought to be due to age-related decreases in
creatinine clearance.60, 71
Drug interactions
Oxcarbazepine and AEDs
In vitro studies revealed that both oxcarbazepine
and MHD were competitive inhibitors of
cytochrome P450 (CYP) 2C19.40, 72 Inhibition
occurred at Ki values that were low enough to
produce potentially clinically relevant
pharmacokinetic interactions, if high dosages of
oxcarbazepine are used in patients taking AEDs
metabolized by the same isoenzyme (e.g.,
phenytoin, phenobarbital).40, 72, 73 Oxcarbazepine
and MHD appear to have little or no capacity to
function as inhibitors of other human CYP
isoenzymes.40
The in vivo interactions between oxcarbazepine
and other AEDs that occurred in controlled
clinical trials are shown in Table 1. The addition
of oxcarbazepine to phenytoin produced a 0–40%
increase in serum phenytoin concentrations. In
contrast, oxcarbazepine combined with
phenobarbital resulted in only a 14–15% increase
in phenobarbital concentrations. Although
oxcarbazepine cotreatment with carbamazepine
showed a 0–22% decrease in carbamazepine
concentrations, there was a 30% increase in
carbamazepine-epoxide concentrations that
could result in the appearance of carbamazepine-
related adverse effects. When CYP isoenzyme-
inducing AEDs (e.g., phenytoin, phenobarbital,
carbamazepine) are added to oxcarbazepine,
plasma MHD concentrations decrease 29–40%,
which may require an increase in oxcarbazepine
dosage to maintain constant MHD levels. The
mechanism of this heteroinduction is unclear.
Oxcarbazepine does not appear to have any
clinically significant interactions with valproic
acid.40
908 PHARMACOTHERAPY Volume 21, Number 8, 2001
Table 2. Major Controlled Trials Assessing Oxcarbazepine Efficacy, Safety, and Tolerability in Patients with Partial-Onset
Seizures
Nature of Age Range No. of
Study Design Dosage Regimen Seizure (yrs) Patients
Monotherapy Oxcarbazepine 1200 mg/d vs placebo Recent onset 8–69 67
placebo-controlled28
Monotherapy Oxcarbazepine 400 mg/d vs placebo Refractory 11–62 102
placebo-controlled29
Monotherapy Oxcarbazepine 2400 vs 300 mg/d Refractory 12–65 143
substitution
dose-controlled30
Monotherapy Oxcarbazepine 2400 vs 300 mg/d Refractory 11–66 87
substitution
dose-controlled31
Monotherapy Oxcarbazepine 2400 mg/d vs Recent onset 15–65 249
comparative32 valproic acid 2400 mg/d (max. dosages)

Monotherapy Oxcarbazepine 2400 mg/d vs Recent onset 15–91 287

comparative33 phenytoin 800 mg/d (max. dosages)

Monotherapy Oxcarbazepine 2400 mg/d vs Recent onset 5–17 193

comparative34 phenytoin 800 mg/d (max. dosages)

Monotherapy Oxcarbazepine 1800 mg/d vs Recent onset 14–63 235

comparative35 carbamazepine 1400 mg/d (max. dosages)

Adjunctive Oxcarbazepine 600, 1200, 2400 mg/d vs Refractory 15–65 692

placebo-controlled36 placebo
Adjunctive Oxcarbazepine 30–46 mg/kg/d vs placebo Refractory 2–17 267
placebo-controlled37
NA = not applicable, since no tolerability primary outcome variable was identified for statistical analysis. In this study, only descriptive adverse
event data were presented.

In patients on AED polytherapy, substitution of
oxcarbazepine for an enzyme-inducing AED
(e.g., phenobarbital, primidone, phenytoin,
carbamazepine) may result in clinically relevant
increases in plasma concentrations of the
remaining AEDs.74–76 In these situations, careful
attention should be paid to concomitant AED
plasma concentrations after substitution with
oxcarbazepine.40, 72
Oxcarbazepine and Non-AEDs
Therapy with oxcarbazepine may decrease the
effectiveness of hormonal contraceptives. When
oxcarbazepine treatment was started in women
who were also receiving oral contraceptives, the
bioavailability of both ethinylestradiol and
levonorgestrel decreased (48% and 32%,
respectively). 77, 78 Breakthrough bleeding, a
marker of reduced hormone bioavailability and
thus reduced contraceptive efficacy, was seen in
some studies when oxcarbazepine was added to a
stable regimen of oral contraceptives.78, 79 These
interactions may be due to a selective induction
of specific isoenzymes of the CYP3A subgroup
(CYP3A4 and CYP3A5), which is involved in
ethinylestradiol metabolism.78, 80 Therefore, low-
or mini-dose oral contraceptives may be less
reliable in patients receiving oxcarbazepine.81
Therapy with oxcarbazepine caused a 28%
relative reduction in the bioavailability of
felodipine, but plasma levels of felodipine
remained within the recommended therapeutic
range.39, 78, 82 There was no interaction between
oxcarbazepine and erythromycin, 83 dextro-
propoxyphene, 84 cimetidine, 85 or warfarin. 86
Minor, probably clinically insignificant, inter-
actions were reported between oxcarbazepine
and verapamil, 78, 87 and oxcarbazepine and
viloxazine.78, 88
 OXCARBAZEPINE IN THE TREATMENT OF EPILEPSY Glauser 909
Table 2. Major Controlled Trials Assessing Oxcarbazepine Efficacy, Safety, and Tolerability in Patients with Partial-Onset
Seizures (continued)

Efficacy Tolerability Primary Efficacy (E) and Tolerability (T) Variable

Oxcarbazepine > placebo NA (E) Time to first seizure
(p=0.0457)
Oxcarbazepine > placebo NA (E) Time to meeting one of the exit criteria
(p=0.0001)
Oxcarbazepine 2400 > NA (E) Time to meeting one of the exit criteria
300 mg/d (p=0.0001)

Oxcarbazepine 2400 > NA (E) % of patients meeting one of the exit criteria
300 mg/d (p<0.0001)

Oxcarbazepine = Oxcarbazepine = (E) % of seizure-free patients during maintenance therapy

valproic acid valproic acid (T) Time to premature discontinuation of drug due to adverse
experience
Oxcarbazepine = Oxcarbazepine > (E) % of seizure-free patients during maintenance therapy
phenytoin phenytoin (p=0.02) (T) Time to premature discontinuation of drug due to adverse
experience
Oxcarbazepine = Oxcarbazepine > (E) % of seizure-free patients during maintenance therapy
phenytoin phenytoin (p=0.002) (T) Time to premature discontinuation of drug due to adverse
experience
Oxcarbazepine = Oxcarbazepine = (E) % of seizure-free patients during maintenance therapy
carbamazepine carbamazepine (T1) (T1) % of patients with adverse experience
Oxcarbazepine > (T2) % of patients with severe adverse experience requiring
carbamazepine (T2) withdrawal from trial
Oxcarbazepine > placebo NA (E) % change in partial seizure frequency/28 d
(p=0.0001)
Oxcarbazepine > placebo NA (E) % change in partial seizure frequency/28 d
(p=0.0001)

Clinical Efficacy monotherapy, substitution dose-controlled trials

Overview
The efficacy and safety of oxcarbazepine were
assessed in 10 large, controlled trials (Table
2). 28–37 All were randomized, double-blind,
controlled, parallel-design studies involving
patients with partial-onset seizures with or
without secondarily generalized seizures. In the
monotherapy trials, patients had either partial
seizures or generalized tonic-clonic seizures
without partial onset. Four basic study designs
were used: monotherapy placebo-controlled (i.e.,
monotherapy oxcarbazepine vs monotherapy
placebo, two studies), monotherapy substitution
dose-controlled (i.e., high-dose oxcarbazepine vs
low-dose oxcarbazepine, two studies), monotherapy
comparative (i.e., oxcarbazepine vs standard
AED, four studies), and adjunctive placebo-
controlled (i.e., oxcarbazepine adjunctive therapy
vs placebo adjunctive therapy, two studies)
Monotherapy, placebo-controlled trials and
have a “therapeutic failure” design in which AED
efficacy was assessed by comparing two
treatment groups based on the percentage of
patients meeting predefined exit criteria or the
time to meet predefined exit criteria.89, 90 Efficacy
of oxcarbazepine in monotherapy, comparative
trials was assessed by comparing the proportion
of seizure-free patients in the oxcarbazepine
group with that in the standard AED groups. In
the adjunctive, placebo-controlled trials, efficacy
of oxcarbazepine was determined by comparing
the percentage change in seizure frequency
during double-blind treatment compared with
baseline for the oxcarbazepine and placebo
groups. All trials had statistical significance
levels set at p values less than 0.05.
Monotherapy, Placebo-Controlled Trials
In two separate trials, a monotherapy, placebo-
controlled design was used to evaluate the safety
and efficacy of oxcarbazepine. One of these trials
910 PHARMACOTHERAPY Volume 21, Number 8, 2001
enrolled outpatients with recent-onset partial
seizures,28 whereas the other involved hospitalized
patients with treatment-resistant partial seizures.29
In the first trial, oxcarbazepine monotherapy
with 1200 mg/day was compared with placebo
monotherapy in 67 previously untreated adults,
adolescents, and children (aged 8–69 yrs) with
newly diagnosed partial seizures.28 In this trial, a
56-day baseline phase was followed by a 90-day
double-blind treatment phase and an open-label,
long-term extension phase. To qualify for the
study, patients with recent-onset partial seizures
had to experience at least two documented
seizures/month during the baseline phase and
were not permitted any AED intake within 90
days before randomization.
The time to the first seizure after randomization
(the study’s primary efficacy variable) was
significantly longer for the oxcarbazepine group
compared with the placebo group (p=0.0457).
The median time to the first seizure was 11.7
days for patients in the oxcarbazepine group
compared with 3.2 days in the placebo group.
The median percentage reduction from baseline
in seizure frequency/28 days (the study’s
secondary efficacy variable) was significantly
greater for the oxcarbazepine group compared
with the placebo group (89.1% vs 37.4%,
respectively, p=0.033).28
The second monotherapy, placebo-controlled
trial was performed in 102 adults and adolescents
(aged 11–62 yrs) with treatment-resistant partial
seizures who had completed an inpatient
presurgical diagnostic evaluation.29 Patients were
eligible if they were not being treated with AEDs
and experienced 2–10 partial seizures within 48
hours before randomization. The trial consisted
of a 48-hour baseline phase followed by a 10-day,
double-blind treatment phase and an open-label
extension phase. Lorazepam was permitted for
48 hours before randomization and for the first
24 hours after randomization.
In the oxcarbazepine therapy arm, patients
received oxcarbazepine 1500 mg/day on day 1
and 2400 mg/day thereafter. Patients either
completed the entire 10-day double-blind
treatment phase or exited the phase by meeting
any one of the exit criteria: four partial seizures,
two new-onset secondarily generalized seizures,
serial seizures, or status epilepticus. Analysis of
the time to meeting one of the exit criteria (the
primary efficacy variable), percentage of patients
meeting one of the exit criteria (a secondary
efficacy variable), and the total partial seizure
frequency/9 days during double-blind treatment
(another secondary efficacy variable) were all
statistically significant in favor of oxcarbazepine
(p=0.0001).29
Monotherapy, Substitution Dose-Controlled
Trials
The first oxcarbazepine monotherapy,
substitution dose-controlled trial included 143
adult and adolescent patients (aged 12–65 yrs)
with treatment-resistant partial seizures who
were receiving carbamazepine monotherapy at a
stable dosage of 800–1600 mg/day.30 The trial
consisted of five phases: (1) a 56-day screening
phase during which patients were maintained on
carbamazepine monotherapy, (2) a 28-day open-
label conversion phase during which patients
were converted to oxcarbazepine monotherapy,
(3) a 56-day open-label baseline phase during
which patients were maintained on monotherapy
with oxcarbazepine 2400 mg/day, (4) a 126-day
double-blind treatment phase during which
patients were randomly assigned to either
oxcarbazepine 300 mg/day or oxcarbazepine
2400 mg/day, and (5) an open-label, long-term
extension phase.
Patients either completed the entire 126-day
double-blind treatment phase or exited the phase
by meeting any one of four patient-specific exit
criteria: a 2-fold increase in any 28-day seizure
frequency relative to baseline, a 2-fold increase in
the highest consecutive 2-day seizure frequency, a
new-onset generalized seizure, or prolongation of
generalized seizure. Both the time to meet one of
four exit criteria (the primary efficacy variable)
and the percentage of patients who met one of
the exit criteria (the secondary efficacy variable)
were statistically significant in favor of the
oxcarbazepine 2400-mg/day group (p=0.0001
and p=0.01, respectively). The median time to
meet one of the exit criteria was significantly
longer in the oxcarbazepine 2400-mg/day group
compared with the oxcarbazepine 300-mg/day
group (68 vs 28 days, respectively, p=0.0001).
The second substitution dose-controlled study
had a simpler design.31 Patients enrolled in this
study were receiving prior treatment with one or
two AEDs (not just carbamazepine). After giving
written informed consent, patients entered a 56-
day baseline period during which they were
maintained on stable dosages of their current
AED(s). To continue in the study, patients had to
experience 2–40 seizures during each 28-day
period of the 56-day baseline period. Qualifying
patients then entered a 126-day double-blind
 OXCARBAZEPINE IN THE TREATMENT OF EPILEPSY Glauser
treatment phase during which they were
randomly assigned to either oxcarbazepine 300
mg/day or oxcarbazepine 2400 mg/day. In the
2400 mg/day therapy arm, patients received
oxcarbazepine 1200 mg/day on days 1–7, 1800
mg/day on days 8–14, and 2400 mg/day on days
15–126. This period consisted of a 14-day
titration phase and a 112-day maintenance phase.
Patients were converted from their current AEDs
to oxcarbazepine monotherapy during the first
42 days of this phase. Patients could enter an
open-label, long-term extension phase either by
completing the entire 126-day double-blind
treatment phase or by exiting the phase if they
met any one of the predetermined exit criteria.
Overall, 87 adult and adolescent patients (aged
11–66 yrs) with treatment-resistant partial
seizures were enrolled. Although almost half
(49%) were taking carbamazepine at study
enrollment, many patients were taking phenytoin
(24%), valproic acid (14%), lamotrigine (14%),
or gabapentin (13%). The percentage of patients
meeting one of the exit criteria (the primary
efficacy variable) was significantly lower and the
time to exit (the secondary efficacy variable) was
significantly longer in the group receiving
oxcarbazepine 2400 mg/day than in the group
receiving oxcarbazepine 300 mg/day (p<0.0001
and p=0.0001, respectively).31
Monotherapy, Comparative Trials
Four double-blind, parallel-group, monotherapy
trials were conducted with oxcarbazepine. Three
similarly designed comparative trials examined
the efficacy and tolerability of oxcarbazepine
monotherapy against either valproic acid (one
study) or phenytoin (two studies, one in children
and one in adults) in patients with recent-onset
partial seizures or generalized tonic-clonic
seizures.32–34 Eligible patients had two or more
seizures in the previous 6 months and no prior
AED therapy. Each study was a randomized (1:1
oxcarbazepine:comparator AED), double-blind,
parallel-group trial consisting of a 14-day
screening phase followed by a 56-week double-
blind treatment period (8-wk flexible titration
phase followed by a 48-wk maintenance phase).
The initial starting dosages were oxcarbazepine
300 mg/day, valproic acid 300 mg/day, and
phenytoin 100 mg/day. Each patient’s AED
dosage was titrated to an optimum dosage based
on clinical response. The dosage ranges allowed
were oxcarbazepine 450–2400 mg/day, valproic
acid 900–2400 mg/day, and phenytoin 150–800
911
mg/day. The primary efficacy variable in each
study was the proportion of seizure-free patients
during the 48-week maintenance period for each
group.
All three trials had similar efficacy results:
oxcarbazepine efficacy was similar to the
comparator AED. The oxcarbazepine-valproic
acid comparative study included 249 adults and
adolescents (aged 15–65 yrs). Patients in this
study received a mean maintenance daily dose of
oxcarbazepine 1053 mg (range 600–2400 mg) or
valproic acid 1146 mg (range 600–2700 mg).
There was no difference in the proportion of
seizure-free patients during the 48-week
maintenance period between the oxcarbazepine
group (57%) and the valproic acid group
(54%). 32 One oxcarbazepine-phenytoin
comparative study included 287 adults and
adolescents (aged 15–91 yrs). Patients in this
study received a mean maintenance daily dose of
oxcarbazepine 1028 mg (range 600–2100 mg) or
phenytoin 313 mg (range 100–650 mg). There
was no difference in the proportion of seizure-
free patients during the 48-week maintenance
period between the oxcarbazepine group (59%)
and the phenytoin group (58%). 33 The other
oxcarbazepine-phenytoin comparative trial
included 193 children and adolescents (aged
5–17 yrs), who received mean maintenance
dosages of oxcarbazepine 18.8 mg/kg/day (672
mg/day, range 300–1350 mg) or phenytoin 5.8
mg/kg/day (226 mg/day, 100–400 mg). In this
trial, there was no difference in the proportion of
seizure-free patients during the 48-week
maintenance period between the oxcarbazepine
group (61%) and the phenytoin group (60%).34
A fourth monotherapy, comparative trial,
conducted by the Scandinavian Oxcarbazepine
Study Group in the late 1980s, examined the
efficacy and tolerability of oxcarbazepine and
carbamazepine as initial monotherapy in 235
patients with newly diagnosed and previously
untreated epilepsy that consisted of either partial-
onset seizures (with or without secondarily
generalized seizures) or generalized tonic-clonic
seizures. 35 The design was a randomized,
double-blind, parallel-group trial beginning with
a 4-week baseline period followed by a double-
blind, 4–8-week flexible titration phase, and
concluding with a 48-week maintenance phase.
The initial starting dosages were oxcarbazepine
300 mg/day and carbamazepine 200 mg/day.
Each patient was titrated to an optimum AED
dosage. The maximum dosages reached were
oxcarbazepine 1800 mg/day and carbamazepine
912 PHARMACOTHERAPY Volume 21, Number 8, 2001
1400 mg/day. In 165 patients considered
evaluable for efficacy, three variables were
examined: changes in seizure frequency, changes
in electroencephalographic tracings, and
investigator’s global evaluation of efficacy. There
were no differences between the oxcarbazepine
monotherapy arm and the carbamazepine
monotherapy arm in any of these outcome
variables. There was no difference in the
proportion of seizure-free patients during the
maintenance period between the oxcarbazepine
group (52%) and the carbamazepine group
(60%).35
Adjunctive, Placebo-Controlled Trials
Two randomized, double-blind, placebo-
controlled, parallel-group trials of oxcarbazepine
adjunctive therapy were completed. The first
was a four-arm, dose-ranging trial in 692 patients
(aged 15–65 yrs) designed to evaluate the safety
and efficacy of oxcarbazepine 600, 1200, and
2400 mg/day adjunctive therapy compared with
placebo adjunctive therapy in patients with
treatment-resistant partial seizures.36 An 8-week
baseline phase was followed by a 26-week
double-blind treatment phase (2-wk titration
period, 24-wk maintenance period). Patients
could then enter an open-label, long-term
extension phase. Eligible patients had to be on
stable dosages of one to three concomitant AEDs
and had to experience four or more partial onset
seizures in each 4-week segment of the 8-week
baseline period. The percentage change in the
partial seizure frequency/28 days relative to the
baseline phase (the primary efficacy variable) was
in favor of oxcarbazepine (p=0.0001). The
median percentage reduction from baseline in
partial seizure frequency was 26%, 40%, and 50%
in the 600-, 1200- and 2400-mg/day groups,
respectively, compared with 8% in the placebo
group (each p≤0.0001). The response rate (i.e.,
percentage of patients with ≥ 50% reduction in
seizure frequency/28 days relative to the baseline
phase) in the 600-, 1200-, and 2400-mg/day
groups was 27%, 41%, and 50%, respectively,
compared with 13% in the placebo group (each
p≤0.0008).36
The second adjunctive therapy trial was
designed to evaluate the efficacy and safety of
adjunctive oxcarbazepine therapy compared with
placebo adjunctive therapy in 267 adolescents
and children (aged 2–17 yrs) with treatment-
resistant partial seizures who were receiving
stable dosages of one or two AEDs.37 An 8-week
baseline phase was followed by a 16-week
double-blind treatment phase (2-wk titration
period, 14-wk maintenance period). Patients
could then enter the open-label, long-term
extension phase. The initial oxcarbazepine
dosage was 10 mg/kg/day, which was steadily
increased every 2–3 days to a maximum target
dosage of 30–46 mg/kg/day. The percentage
change in partial seizure frequency/28 days in the
double-blind treatment phase relative to the
baseline phase (the primary efficacy variable) was
greater in the oxcarbazepine adjunctive therapy
arm (p=0.0001). The response rate (i.e., the
percentage of patients with ≥ 50% reduction in
seizure frequency/28 days relative to the baseline
phase) was 41% in the oxcarbazepine adjunctive
arm compared with 22% in the placebo
adjunctive arm (p=0.0005). The percentage
reduction in secondarily generalized seizure
frequency was 78% in the oxcarbazepine
adjunctive group compared with 33% in the
placebo adjunctive group (p=0.0012).37
Clinical Tolerability
Overview
The tolerability of an AED involves consideration
of the “incidence, severity, and impact”91 of dose-
related adverse effects (e.g., cognitive or motor)
along with the risk of severe idiosyncratic
reactions. Objectively evaluating the tolerability
of an AED is more difficult than assessing its
efficacy. Analysis of withdrawal rates from AED
therapy due to intolerable or life-threatening
adverse reactions is objective evidence of a new
AED’s tolerability if withdrawal rates are a
primary outcome variable in a randomized,
controlled, monotherapy design.91 Even if it is
not a primary outcome variable, a new AED’s
withdrawal rate from a study may still be useful
in giving a general indication of its tolerability.
Trial designs that provide the best insight into an
AED’s tolerability are (in decreasing order of
importance) monotherapy placebo-controlled
trials, monotherapy comparative trials,
monotherapy dose-controlled trials, and finally,
adjunctive placebo-controlled trials.
Four of the major oxcarbazepine-controlled
clinical trials were designed to formally assess
tolerability. 32–35 All were monotherapy
comparative trials. In the valproic acid study32
and the two phenytoin studies,33, 34 the primary
tolerability outcome variable was the time to
premature discontinuation due to adverse
experiences. In both phenytoin studies, this time
 OXCARBAZEPINE IN THE TREATMENT OF EPILEPSY Glauser
Table 3. Frequency of Most Common Treatment-Emergent Adverse Eventsa
Adjunctive Therapy or
Monotherapy Substitution Studies
Oxcarbazepine Placebo Oxcarbazepine
Adverse Eventa (N=1272) (N=353)
Any adverse event 86.3 75.6
Fatigue 13.4 6.8
Headache 26.7 21.0
Dizziness 25.6 10.8
Somnolence 25.4 10.8
Ataxia 11.4 4.2
Nausea 18.2 7.4
Vomiting 16.9 8.2
Diplopia 17.2 2.5
N = total number of patients. Data are percentages.
Data on file with Novartis Pharmaceutical Corporation.
a
Experienced by at least 10% of patients in any group.
frame was significantly longer for patients in the
oxcarbazepine monotherapy arm than that for
patients in the phenytoin monotherapy arm
(p=0.0233 and p=0.002,34 respectively). These
results imply that oxcarbazepine monotherapy is
better tolerated than phenytoin monotherapy for
all age ranges. In contrast, there was no
significant difference between oxcarbazepine
monotherapy and valproic acid monotherapy in
the time to premature discontinuation due to
adverse experiences.32
There were two primary tolerability outcome
variables in the Scandinavian oxcarbazepine-
carbamazepine study 35 : the percentage of
patients with an adverse experience and the
percentage of patients with a severe adverse
experience requiring withdrawal from the trial.
Although no difference was noted between the
oxcarbazepine monotherapy arm and
carbamazepine monotherapy arm in the
percentage of patients with an adverse
experience, there was a significant difference in
favor of oxcarbazepine in the percentage of
patients with a severe adverse experience that
required withdrawal from the trial (p=0.04).
Although not specifically stated by the lead
investigators, this implies that oxcarbazepine
monotherapy was better tolerated than
carbamazepine monotherapy in this population.
Adverse Event Profile from Controlled Clinical
Trials
All oxcarbazepine clinical trials collected data
on potential adverse effects of oxcarbazepine for
descriptive purposes. Analysis of the Novartis
913
Initiation of Monotherapy
Placebo
(N=440) (N=66)
82.5 74.2
8.6 12.1
37.5 12.1
19.5 4.5
21.6 6.1
1.8 0.0
13.2 12.1
6.6 6.1
0.5 0.0
oxcarbazepine safety database from all controlled
clinical trials provides an overview of the adverse
experience profile of oxcarbazepine. There are
two distinct oxcarbazepine safety databases: the
primary database, which includes all post-1991
clinical trials, and the secondary database, which
includes all pre-1991 trials along with all named-
patient programs and oxcarbazepine post-
marketing experience (data on file, Novartis
Pharmaceutical Corp.). The primary database
(2327 patients exposed to oxcarbazepine) is
smaller than the secondary database (4363
patients). The secondary database contains
information on 2886 patients in a named-patient
program. Most patients (72%) in the primary
database were adults, whereas 26% were children
and adolescents (aged 2–17 yrs) and 2% were
elderly patients (> 65 yrs). The exposure to
oxcarbazepine in the primary database was 12
months or less for 62% of patients, 12–24
months for 24%, and more than 24 months for
14%.
A profile of treatment-emergent adverse events
resulting from dosages of 300–2400 mg/day for
1712 patients treated with oxcarbazepine in
controlled clinical trials is shown in Table 3 (data
on file, Novartis Pharmaceuticals Corp). These
data were derived from oxcarbazepine
monotherapy placebo-controlled studies,
oxcarbazepine monotherapy dose-controlled
studies, and oxcarbazepine adjunctive placebo-
controlled trials. In general, the most commonly
reported treatment-emergent adverse events were
related to the central nervous system, and most
were rated as mild or moderate in severity.
Across the trials, eight treatment-emergent
914 PHARMACOTHERAPY Volume 21, Number 8, 2001
adverse events (considered to be at least possibly
related to study drug) occurred in at least 10% of
oxcarbazepine-treated patients: fatigue,
headache, dizziness, somnolence, ataxia, nausea,
vomiting, and diplopia. Each of these adverse
events, with the exception of headache, occurred
more frequently in patients treated with
oxcarbazepine adjunctive therapy than in
patients treated with oxcarbazepine monotherapy.
The frequency of ataxia, vomiting, and diplopia
was at least 2 times greater in patients receiving
oxcarbazepine adjunctive therapy than in
patients receiving oxcarbazepine monotherapy,
placebo monotherapy, or placebo adjunctive
therapy. The frequency of adverse events was
related to total concomitant AED load rather than
any specific oxcarbazepine-AED interaction.37
Serious Adverse Reactions
During clinical trials, the most common
potentially significant (as judged by
investigators) oxcarbazepine-related adverse
effects were disorders of balance, gait, or
coordination; hyponatremia; convulsions; and
rash (data on file, Novartis Pharmaceutical
Corp.). In oxcarbazepine monotherapy trials, the
frequency of severe adverse events was 8.2% for
oxcarbazepine-treated patients, 7.6% for patients
receiving placebo, 9.9% for patients receiving
valproic acid, and 5.8% for patients receiving
phenytoin.28, 32–34 Thus, the frequency of severe
adverse events with oxcarbazepine monotherapy
is similar to that of older AEDs and only slightly
higher than that for placebo.
Allergic rashes have been reported to occur in
patients treated with oxcarbazepine. In
monotherapy comparative trials, allergic skin
reactions appeared less frequently with
oxcarbazepine than with phenytoin 33 or
carbamazepine,35 but more frequently than with
valproic acid.32 Clinical experience suggests that,
whereas allergic rashes during oxcarbazepine
therapy do occur, they are uncommon39 and may
be less frequent than with carbamazepine. 55, 92
Cross-sensitivity to oxcarbazepine in patients
exhibiting allergic sensitivity to carbamazepine
can occur in up to 30% of patients. In one
report, 27% of 51 patients experiencing allergic
skin reactions to carbamazepine experienced
allergic cross-reactivity when switched to
oxcarbazepine.54 A similar study showed that 9
(16%) of 55 patients switched from
carbamazepine to oxcarbazepine because of skin
reactions or “evidently allergic” reactions
experienced a recurrence with oxcarbazepine
treatment.93 A large Danish retrospective survey
of 947 patients found that 6% of patients treated
with oxcarbazepine developed a rash, but half of
those patients had experienced a previous allergic
reaction to carbamazepine.94
No single, randomized, controlled trial or
group of trials can provide enough information to
make definitive conclusions about the risk of
severe idiosyncratic reactions. Instead, postmarketing
experience is necessary to fully evaluate the
frequency and severity of idiosyncratic reactions.
As of March 1, 2000, there were over 200,000
patient-years of postmarking experience with
oxcarbazepine (data on file, Novartis
Pharmaceuticals Corp.). No association appears
to exist between oxcarbazepine and severe
idiosyncratic reactions such as hepatic failure,
pancreatitis, aplastic anemia, Steven-Johnson
syndrome, or toxic epidermal necrolysis.92
Scattered cases of overdose with oxcarbazepine
have occurred; the maximum dose taken was
approximately 24,000 mg. Symptoms of
oxcarbazepine overdose were somnolence,
dizziness, nausea, vomiting, hypokinesia,
hyponatremia, ataxia, and nystagmus. All
patients who experienced an overdose with
oxcarbazepine recovered with symptomatic
treatment (data on file, Novartis Pharmaceuticals
Corp.).
Oxcarbazepine is considered under the Food
and Drug Administration Pregnancy Category
C.40 Evidence of teratogenic potential was seen
for oxcarbazepine and MHD at doses of 1.2–4
times the maximum recommended human doses
on a milligram/square meter basis.40 There have
been no controlled studies of the effects of
oxcarbazepine on the human fetus. Fetal
malformations, both congenital and anomalous,
have been associated with in utero exposure to
AEDs.81, 95 Carbamazepine is embryotoxic and,
like valproic acid,96 has been reported to produce
neural tube defects in an estimated 0.5–1% of
those exposed.97, 98 One mechanism suggested to
account for the teratogenicity of carbamazepine
is the formation of the 10,11-epoxide metabolite
in vivo, which may act as a free radical, binding
to proteins and nucleic acids and disrupting
DNA, RNA, and protein synthesis. 95 Unlike
carbamazepine, oxcarbazepine does not form the
epoxide but instead undergoes reduction of the
carbonyl group to form MHD, which then
undergoes glucuronidation.52 Based on animal
studies and the structural relationship of
oxcarbazepine to carbamazepine, it is likely
 OXCARBAZEPINE IN THE TREATMENT OF EPILEPSY Glauser
however that oxcarbazepine is a human
teratogen.40 Antifolate effects are hypothesized to
be another mechanism responsible for neural
tube defects with the established AEDs,95 and
folate supplementation is recommended for
pregnant women with epilepsy.81 Seizures in the
pregnant patient with epilepsy need to be treated,
and women must be informed of the risks of
pregnancy associated with anticonvulsant use
before they become pregnant.81, 95 Oxcarbazepine
should be used in pregnant women only if the
potential benefits justify the possible risks.
Laboratory Abnormalities
In oxcarbazepine-controlled clinical trials, no
clinically significant hematologic or renal
changes were noted over time. Although
transient changes in liver enzymes were
observed, investigators did not consider the
changes to be clinically significant.32–34 Decreases
in serum uric acid and thyroxine levels were
noted; however, investigators did not consider
these to be clinically significant.
Hyponatremia associated with oxcarbazepine is
usually asymptomatic, 39, 92, 99 but cases of
symptomatic hyponatremia have been
reported.100–102 A review of data from controlled
clinical trials in the Novartis database included
2026 oxcarbazepine-treated patients with
baseline and postbaseline serum sodium
measurements. 103 In this population, the
frequency of serum sodium level less than 135
mEq/L, less than 130 mEq/L, and less than 125
mEq/L was 24.5%, 10.9%, and 3%, respectively.103
The frequency of serum sodium levels less than
125 mEq/L increased with age, from 0.4% in
children (≤ 17 yrs) to 3.8% in adults (18–64 yrs)
and 7.3% in the elderly (> 65 yrs). 103
Hyponatremia did not occur in children younger
than 6 years and was rare in adolescents. The
study noted that although the frequency of
hyponatremia may be higher in elderly patients,
the sample (41 patients) was too small to draw
any conclusion. 103 Most patients who
experienced a serum sodium level less than 125
mEq/L were taking concomitant sodium-
depleting diuretics, and most remained
asymptomatic. In patients receiving a fixed
dosage of oxcarbazepine (300–2400 mg/day),
there was no significant dose-response
relationship in the frequency of treatment-
emergent hyponatremia at 1 and 3 months of
therapy.103 The frequency of hyponatremia in the
named patient program was 1.1% (data on file,
915
Novartis Pharmaceuticals Corp.).
In the Danish retrospective study of 947
patients treated with oxcarbazepine, hyponatremia
(sodium level < 135 mEq/L) was noted in 23% of
350 patients in whom plasma sodium was
measured; however, it was the reason for
discontinuation of oxcarbazepine in only 4
patients. 94 In a cross-sectional study of 41
patients receiving oxcarbazepine, approximately
50% experienced hyponatremia (serum sodium
level < 135 mEq/L), but no patients were
symptomatic or discontinued treatment
secondary to hyponatremia. 104 Risk factors
associated with the development of hyponatremia
include advanced age (elderly) and dosages
above 30 mg/kg/day. 54, 104 In general, serum
sodium concentrations return to normal with
dosage reduction, discontinuation of oxcarbazepine,
or restriction of water intake.37, 99
Dosage, Titration, and Conversion from Other
AEDs
In adults with partial seizures, the manufacturer
recommends an initial oxcarbazepine dosage of
600 mg/day (given in two divided doses) for
adjunctive or monotherapy use. 40 Based on
clinical experience, oxcarbazepine adjunctive
treatment can be initiated at 300 mg/day, given in
two divided doses, with or without food. The
dosage then may be increased based on clinical
response in increments of 300–600 mg at
approximately weekly intervals. The recommended
target dosage for adjunctive therapy is 1200
mg/day; if indicated, dosages up to 2400 mg/day
may be used but may not be tolerated, mainly
because of central nervous system effects.40 If
dosages higher than 1200 mg/day are used as
adjunctive therapy, patients should be observed
closely and plasma levels of concomitant AEDs
monitored during the titration period.
Clinical trials used an oxcarbazepine
monotherapy dosage of 1200–2400 mg/day. 28–35
The lower dosage of 1200 mg/day may be
effective in patients receiving monotherapy. In
these patients, treatment can be initiated at 300
mg/day and increased by 300 mg/day every third
day to a target of 1200 mg/day.
In adults receiving other AEDs (including
carbamazepine monotherapy) who are converted
to oxcarbazepine monotherapy, oxcarbazepine
treatment can be initiated while simultaneously
reducing concomitant AED dosage; concomitant
AEDs can be withdrawn completely over 3–6
weeks, whereas the target dosage of oxcarbazepine
916 PHARMACOTHERAPY Volume 21, Number 8, 2001
should be attained in about 2–4 weeks. When
oxcarbazepine is substituted for carbamazepine, a
suggested oxcarbazepine replacement dose is 300
mg for each 200 mg of carbamazepine.90
Although the manufacturer recommends an
initial oxcarbazepine dosage of 8–10 mg/kg/day
in children (aged 4–16 yrs) with partial seizures
who are receiving other AEDs, oxcarbazepine can
be started at 4–5 mg/kg/day, not to exceed 300
mg/day (150 mg twice/day). In clinical trials, the
target maintenance dosage was achieved over 2
weeks and depended on body weight (20–29 kg,
900 mg/day; 29.1–39 kg, 1200 mg/day; and > 39
kg, 1800 mg/day). 40 In clinical practice,
oxcarbazepine pediatric dosages have been
increased by increments of 4–5 mg/kg/day each
week as tolerated based on clinical response.
Oxcarbazepine has potential advantages over
other AEDs when combined with them or
substituted for them because of its more
favorable pharmacokinetic and metabolic profile.
In patients receiving carbamazepine (or other
enzyme-inducing AEDs), substitution with
oxcarbazepine can result in deinduction of
hepatic CYP enzyme system function,41, 90 with
subsequent increased serum levels of remaining
AEDs.90 Dosage adjustment may be needed in
patients being switched to oxcarbazepine from
AEDs with enzyme-inducing properties.40, 55, 72, 90
Patients should be observed closely during
titration, and plasma levels of concomitant AEDs
can be monitored as clinically indicated. Patients
with mild to moderate hepatic impairment do not
require oxcarbazepine dosage adjustment, but
patients with impaired renal function (creatinine
clearance < 30 ml/min) should receive one-half
the usual starting dosage, which is then increased
slowly to achieve the desired clinical response.40
Before beginning oxcarbazepine, patients
should be asked about prior exposure to
carbamazepine. Those with a history of
hypersensitivity to carbamazepine should be
treated cautiously with oxcarbazepine. If
hypersensitivity subsequently occurs in such
patients receiving oxcarbazepine, treatment
should be discontinued promptly.
Measurement of baseline serum sodium levels
should be considered when initiating oxcarbazepine.
Monitoring of serum sodium levels also should
be considered during maintenance therapy,
especially in patients receiving cotreatment
known to cause hyponatremia, 40 if such
cotreatment is added during oxcarbazepine
maintenance therapy, 103 and if symptoms
suggestive of hyponatremia develop.40
Conclusion
Oxcarbazepine is an effective anticonvulsant
for the treatment of partial-onset seizures in
adults, adolescents, and children. Oxcarbazepine
(and its pharmacologically active derivative
MHD) has a favorable pharmacokinetic profile of
rapid absorption, linear pharmacokinetics, and
minimal interaction with other AEDs. Its
proposed mechanism of action involves
modulation of sodium, potassium, and calcium
channels. The results of the 10 large
oxcarbazepine clinical trials demonstrated that
oxcarbazepine monotherapy is safe, effective, and
well tolerated in adults, adolescents, and children
with either recent-onset or treatment-resistant
partial seizures. Comparative trials have shown
that oxcarbazepine monotherapy has efficacy
similar to that of phenytoin, valproic acid, and
carbamazepine in partial-onset seizures and
generalized tonic-clonic seizures in adults,
adolescents, and children. The proportions of
oxcarbazepine-treated patients and standard
AED-treated patients who became seizure free
during treatment were approximately 60%.
Oxcarbazepine adjunctive therapy is superior to
placebo adjunctive therapy in treatment-resistant
partial onset seizures in adults, adolescents, and
children. Among newer AEDs, oxcarbazepine is
suitable for first-line monotherapy use in adults
with partial seizures, and it may be a suitable
first-line therapy for children with partial
seizures.105 Overall, oxcarbazepine represents an
important new treatment option indicated for
monotherapy or adjunctive therapy in adults and
as adjunctive therapy in children with partial
seizures.
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