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
[email protected]. 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 spread of seizures rather than by raising seizure
firing of sodium-dependent action potentials, threshold.
implying blockade of voltage-sensitive sodium
channels. 42, 44, 45 In hippocampal slices, the Toxicology
blockade of penicillin-induced epileptiform
discharges by MHD was diminished when 4- Oxcarbazepine and MHD were well tolerated
aminopyridine (a potassium channel blocker) after short-term administration to mice, rats, and
was added to the bath. 42 In isolated cortical hamsters. 39 Multiple-dose (3- and 6-month)
pyramidal cells, MHD produced a reversible toxicity studies with oxcarbazepine and MHD in
dose-dependent decrease in high-voltage rats and dogs revealed reversible, dose-dependent
activated calcium currents evoked by membrane increases in liver weight considered due to
depolarization.46 centrilobular megalocytosis related to enzyme
Although these mechanisms of action are induction. Oxcarbazepine, but not MHD, caused
similar to those of carbamazepine, the reports of a progressive nephropathy in male rats. 39
patients resistant to carbamazepine who Oxcarbazepine, like carbamazepine, is a
responded to therapy with oxcarbazepine suggest promoter of liver tumors in rodents, but because
that oxcarbazepine may have additional oxcarbazepine and MHD metabolism differs
unrecognized cellular mechanisms of action. 42 substantially between humans and rodents,54 this
There is no evidence that oxcarbazepine or MHD finding probably cannot be generalized to
potentiates g-aminobutyric acid (GABA) humans. In male and female rats, fertility was
neurotransmission or produces substantial unaffected by oxcarbazepine or MHD at doses up
antagonism of the kainate (N-methyl-D-aspartate to 150 mg/kg.39, 40, 55
[NMDA]) or quisqualate subtypes of the
glutamate receptor (data on file, Novartis Clinical Pharmacokinetics
Pharmaceuticals Corp.). Oxcarbazepine demonstrates rapid and almost
complete absorption (> 95%) after oral
Preclinical in Vivo Studies administration.56, 57 It is rapidly metabolized by
reduction to the pharmacologically active
Efficacy
metabolite MHD, but a small proportion (4%) is
Oxcarbazepine was tested in many animal oxidized to a pharmacologically inactive
models of epilepsy, including the maximal dihydroxy derivative. 56, 57 This reduction is
electroshock test, the chronic aluminum foci catalyzed by cytosolic aldo-ketoreductases that
model, and three types of chemically induced are considered practically noninducible
seizure models. The maximal electroshock test enzymes. 58 This predominant pathway of
identifies agents that may prevent the spread of metabolism in humans is only a minor pathway
seizures.47, 48 In rats and mice, oxcarbazepine and in rats and dogs.54 Subsequently, MHD undergoes
MHD blocked maximal electroshock test seizures glucuronidation by a uridinediphospho-
with a potency similar to that of phenytoin and glucuronosyltransferase.
carbamazepine.45, 49, 50 The chronic aluminum It had been reported that the systemic
foci model in rhesus monkeys identifies agents bioavailability of MHD was increased by
potentially effective against posttraumatic and approximately 17% when oxcarbazepine was
partial-onset seizures.39, 51 Both oxcarbazepine taken with food. 59, 60 However, with a newer
and MHD demonstrated efficacy in this model, oxcarbazepine formulation, there was no effect of
although MHD was less potent than food on the bioavailability of MHD (data on file,
oxcarbazepine. 39, 42, 52 The three models of Novartis Pharmaceuticals Corp.). Peak plasma
chemically induced seizures (pentylenetetrazole, concentrations of MHD occurred 4–6 hours after
picrotoxin, and strychnine) are typically used to a single dose of either oxcarbazepine 400 mg or
identify agents that raise seizure threshold. In all oxcarbazepine 600 mg.57, 61 The plasma terminal
three models, oxcarbazepine, like carbamazepine, half-life of oxcarbazepine was between 1 and 2.5
was either ineffective or only weakly effective.39, hours,62 whereas the plasma MHD terminal half-
42, 53
Both MHD enantiomers have similar life averaged 9.3 ± 1.8 hours after administration
anticonvulsant efficacy and tolerability in these of a single dose.63 There was a linear relationship
animal models.42 This activity profile suggests between oral oxcarbazepine dosage and plasma
that oxcarbazepine and MHD, like carbamazepine, MHD concentrations in healthy volunteers and in
exert their anticonvulsant effects by blocking the patients with epilepsy who were receiving
 OXCARBAZEPINE IN THE TREATMENT OF EPILEPSY Glauser 907
Table 1. Summary of AED Interactions with Oxcarbazepine
Influence of Oxcarbazepine Influence of AEDs on
AED or Metabolite on AED Concentration MHD Concentration
Phenytoin 0–40% increase 29–35% decrease
Phenobarbital 14–15% increase 30–31% decrease
Valproic acid No influence 0–18% decrease
Carbamazepine 0–22% decrease 40% decrease
Carbamazepine-epoxide 30% increase Not studied
Clobazam Not studied No influence
Felbamate Not studied No influence
AED = antiepileptic drug; MHD = pharmacologically active 10-monohydroxy derivative.
Data are based on results of clinical studies.

oxcarbazepine monotherapy or polytherapy.61, 62, was thought to be due to age-related decreases in

64
The volume of distribution of MHD ranged creatinine clearance.60, 71
from 0.7–0.8 L/kg, consistent with distribution
into total body water.39, 56 The in vivo protein Drug interactions
binding of MHD was 40%. 65, 66 It was mainly
bound to albumin, and its binding was independent Oxcarbazepine and AEDs
of serum concentration within the therapeutically In vitro studies revealed that both oxcarbazepine
relevant range.39 No autoinduction or accumulation and MHD were competitive inhibitors of
occurred with oxcarbazepine therapy in healthy cytochrome P450 (CYP) 2C19.40, 72 Inhibition
volunteers.56, 61, 67 occurred at Ki values that were low enough to
Most of an orally administered dose of oxcar- produce potentially clinically relevant
bazepine is excreted as either the glucuronide pharmacokinetic interactions, if high dosages of
derivative of MHD (49%) or unchanged MHD oxcarbazepine are used in patients taking AEDs
(27%).57 Renal excretion is the major route of metabolized by the same isoenzyme (e.g.,
oxcarbazepine elimination.56, 57 Mild to moderate phenytoin, phenobarbital).40, 72, 73 Oxcarbazepine
renal impairment in adults has little effect on and MHD appear to have little or no capacity to
plasma MHD concentrations. However, in function as inhibitors of other human CYP
patients with renal failure (creatinine clearance isoenzymes.40
< 30 ml/min/1.73 m2), the elimination half-life of The in vivo interactions between oxcarbazepine
MHD is prolonged, the area under the curve and other AEDs that occurred in controlled
(AUC) is increased 2-fold, and significant clinical trials are shown in Table 1. The addition
increases in plasma MHD concentrations can of oxcarbazepine to phenytoin produced a 0–40%
occur unless the dosage is adjusted.68 Mild to increase in serum phenytoin concentrations. In
moderate hepatic impairment does not appear to contrast, oxcarbazepine combined with
affect MHD pharmacokinetics (data on file, phenobarbital resulted in only a 14–15% increase
Novartis Pharmaceuticals Corp.). in phenobarbital concentrations. Although
Mean dose-normalized, steady-state plasma oxcarbazepine cotreatment with carbamazepine
MHD concentrations in children and adolescents showed a 0–22% decrease in carbamazepine
(aged 6–18 yrs) adjusted for body weight were concentrations, there was a 30% increase in
comparable to those in adults.60 However, the carbamazepine-epoxide concentrations that
dose-normalized AUC values of MHD in children could result in the appearance of carbamazepine-
aged 2–5 years were 30% lower than those in related adverse effects. When CYP isoenzyme-
children aged 6–12 years after single inducing AEDs (e.g., phenytoin, phenobarbital,
administration of 5-mg/kg and 15-mg/kg doses of carbamazepine) are added to oxcarbazepine,
oxcarbazepine (data on file, Novartis plasma MHD concentrations decrease 29–40%,
Pharmaceuticals Corp.). Thus, higher doses of which may require an increase in oxcarbazepine
oxcarbazepine may be required in children dosage to maintain constant MHD levels. The
younger than 6 years. 69, 70 In contrast, peak mechanism of this heteroinduction is unclear.
plasma MHD concentrations and AUC values of Oxcarbazepine does not appear to have any
MHD were significantly higher in elderly patients clinically significant interactions with valproic
(aged 60–82 yrs) than in younger adults, which 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 thus reduced contraceptive efficacy, was seen in
oxcarbazepine for an enzyme-inducing AED some studies when oxcarbazepine was added to a
(e.g., phenobarbital, primidone, phenytoin, stable regimen of oral contraceptives.78, 79 These
carbamazepine) may result in clinically relevant interactions may be due to a selective induction
increases in plasma concentrations of the of specific isoenzymes of the CYP3A subgroup
remaining AEDs.74–76 In these situations, careful (CYP3A4 and CYP3A5), which is involved in
attention should be paid to concomitant AED ethinylestradiol metabolism.78, 80 Therefore, low-
plasma concentrations after substitution with or mini-dose oral contraceptives may be less
oxcarbazepine.40, 72 reliable in patients receiving oxcarbazepine.81
Therapy with oxcarbazepine caused a 28%
Oxcarbazepine and Non-AEDs relative reduction in the bioavailability of
felodipine, but plasma levels of felodipine
Therapy with oxcarbazepine may decrease the remained within the recommended therapeutic
effectiveness of hormonal contraceptives. When range.39, 78, 82 There was no interaction between
oxcarbazepine treatment was started in women oxcarbazepine and erythromycin, 83 dextro-
who were also receiving oral contraceptives, the propoxyphene, 84 cimetidine, 85 or warfarin. 86
bioavailability of both ethinylestradiol and Minor, probably clinically insignificant, inter-
levonorgestrel decreased (48% and 32%, actions were reported between oxcarbazepine
respectively). 77, 78 Breakthrough bleeding, a and verapamil, 78, 87 and oxcarbazepine and
marker of reduced hormone bioavailability 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

have a “therapeutic failure” design in which AED
Overview efficacy was assessed by comparing two
The efficacy and safety of oxcarbazepine were treatment groups based on the percentage of
assessed in 10 large, controlled trials (Table patients meeting predefined exit criteria or the
2). 28–37 All were randomized, double-blind, time to meet predefined exit criteria.89, 90 Efficacy
controlled, parallel-design studies involving of oxcarbazepine in monotherapy, comparative
patients with partial-onset seizures with or trials was assessed by comparing the proportion
without secondarily generalized seizures. In the of seizure-free patients in the oxcarbazepine
monotherapy trials, patients had either partial group with that in the standard AED groups. In
seizures or generalized tonic-clonic seizures the adjunctive, placebo-controlled trials, efficacy
without partial onset. Four basic study designs of oxcarbazepine was determined by comparing
were used: monotherapy placebo-controlled (i.e., the percentage change in seizure frequency
monotherapy oxcarbazepine vs monotherapy during double-blind treatment compared with
placebo, two studies), monotherapy substitution baseline for the oxcarbazepine and placebo
dose-controlled (i.e., high-dose oxcarbazepine vs groups. All trials had statistical significance
low-dose oxcarbazepine, two studies), monotherapy levels set at p values less than 0.05.
comparative (i.e., oxcarbazepine vs standard
AED, four studies), and adjunctive placebo- Monotherapy, Placebo-Controlled Trials
controlled (i.e., oxcarbazepine adjunctive therapy In two separate trials, a monotherapy, placebo-
vs placebo adjunctive therapy, two studies) controlled design was used to evaluate the safety
Monotherapy, placebo-controlled trials and and efficacy of oxcarbazepine. One of these trials
910 PHARMACOTHERAPY Volume 21, Number 8, 2001

enrolled outpatients with recent-onset partial (another secondary efficacy variable) were all
seizures,28 whereas the other involved hospitalized statistically significant in favor of oxcarbazepine
patients with treatment-resistant partial seizures.29 (p=0.0001).29
In the first trial, oxcarbazepine monotherapy
with 1200 mg/day was compared with placebo Monotherapy, Substitution Dose-Controlled
monotherapy in 67 previously untreated adults, Trials
adolescents, and children (aged 8–69 yrs) with
newly diagnosed partial seizures.28 In this trial, a The first oxcarbazepine monotherapy,
56-day baseline phase was followed by a 90-day substitution dose-controlled trial included 143
double-blind treatment phase and an open-label, adult and adolescent patients (aged 12–65 yrs)
long-term extension phase. To qualify for the with treatment-resistant partial seizures who
study, patients with recent-onset partial seizures were receiving carbamazepine monotherapy at a
had to experience at least two documented stable dosage of 800–1600 mg/day.30 The trial
seizures/month during the baseline phase and consisted of five phases: (1) a 56-day screening
were not permitted any AED intake within 90 phase during which patients were maintained on
days before randomization. carbamazepine monotherapy, (2) a 28-day open-
The time to the first seizure after randomization label conversion phase during which patients
(the study’s primary efficacy variable) was were converted to oxcarbazepine monotherapy,
significantly longer for the oxcarbazepine group (3) a 56-day open-label baseline phase during
compared with the placebo group (p=0.0457). which patients were maintained on monotherapy
The median time to the first seizure was 11.7 with oxcarbazepine 2400 mg/day, (4) a 126-day
days for patients in the oxcarbazepine group double-blind treatment phase during which
compared with 3.2 days in the placebo group. patients were randomly assigned to either
The median percentage reduction from baseline oxcarbazepine 300 mg/day or oxcarbazepine
in seizure frequency/28 days (the study’s 2400 mg/day, and (5) an open-label, long-term
secondary efficacy variable) was significantly extension phase.
greater for the oxcarbazepine group compared Patients either completed the entire 126-day
with the placebo group (89.1% vs 37.4%, double-blind treatment phase or exited the phase
respectively, p=0.033).28 by meeting any one of four patient-specific exit
The second monotherapy, placebo-controlled criteria: a 2-fold increase in any 28-day seizure
trial was performed in 102 adults and adolescents frequency relative to baseline, a 2-fold increase in
(aged 11–62 yrs) with treatment-resistant partial the highest consecutive 2-day seizure frequency, a
seizures who had completed an inpatient new-onset generalized seizure, or prolongation of
presurgical diagnostic evaluation.29 Patients were generalized seizure. Both the time to meet one of
eligible if they were not being treated with AEDs four exit criteria (the primary efficacy variable)
and experienced 2–10 partial seizures within 48 and the percentage of patients who met one of
hours before randomization. The trial consisted the exit criteria (the secondary efficacy variable)
of a 48-hour baseline phase followed by a 10-day, were statistically significant in favor of the
double-blind treatment phase and an open-label oxcarbazepine 2400-mg/day group (p=0.0001
extension phase. Lorazepam was permitted for and p=0.01, respectively). The median time to
48 hours before randomization and for the first meet one of the exit criteria was significantly
24 hours after randomization. longer in the oxcarbazepine 2400-mg/day group
In the oxcarbazepine therapy arm, patients compared with the oxcarbazepine 300-mg/day
received oxcarbazepine 1500 mg/day on day 1 group (68 vs 28 days, respectively, p=0.0001).
and 2400 mg/day thereafter. Patients either The second substitution dose-controlled study
completed the entire 10-day double-blind had a simpler design.31 Patients enrolled in this
treatment phase or exited the phase by meeting study were receiving prior treatment with one or
any one of the exit criteria: four partial seizures, two AEDs (not just carbamazepine). After giving
two new-onset secondarily generalized seizures, written informed consent, patients entered a 56-
serial seizures, or status epilepticus. Analysis of day baseline period during which they were
the time to meeting one of the exit criteria (the maintained on stable dosages of their current
primary efficacy variable), percentage of patients AED(s). To continue in the study, patients had to
meeting one of the exit criteria (a secondary experience 2–40 seizures during each 28-day
efficacy variable), and the total partial seizure period of the 56-day baseline period. Qualifying
frequency/9 days during double-blind treatment patients then entered a 126-day double-blind
 OXCARBAZEPINE IN THE TREATMENT OF EPILEPSY Glauser 911

treatment phase during which they were mg/day. The primary efficacy variable in each
randomly assigned to either oxcarbazepine 300 study was the proportion of seizure-free patients
mg/day or oxcarbazepine 2400 mg/day. In the during the 48-week maintenance period for each
2400 mg/day therapy arm, patients received group.
oxcarbazepine 1200 mg/day on days 1–7, 1800 All three trials had similar efficacy results:
mg/day on days 8–14, and 2400 mg/day on days oxcarbazepine efficacy was similar to the
15–126. This period consisted of a 14-day comparator AED. The oxcarbazepine-valproic
titration phase and a 112-day maintenance phase. acid comparative study included 249 adults and
Patients were converted from their current AEDs adolescents (aged 15–65 yrs). Patients in this
to oxcarbazepine monotherapy during the first study received a mean maintenance daily dose of
42 days of this phase. Patients could enter an oxcarbazepine 1053 mg (range 600–2400 mg) or
open-label, long-term extension phase either by valproic acid 1146 mg (range 600–2700 mg).
completing the entire 126-day double-blind There was no difference in the proportion of
treatment phase or by exiting the phase if they seizure-free patients during the 48-week
met any one of the predetermined exit criteria. maintenance period between the oxcarbazepine
Overall, 87 adult and adolescent patients (aged group (57%) and the valproic acid group
11–66 yrs) with treatment-resistant partial (54%). 32 One oxcarbazepine-phenytoin
seizures were enrolled. Although almost half comparative study included 287 adults and
(49%) were taking carbamazepine at study adolescents (aged 15–91 yrs). Patients in this
enrollment, many patients were taking phenytoin study received a mean maintenance daily dose of
(24%), valproic acid (14%), lamotrigine (14%), oxcarbazepine 1028 mg (range 600–2100 mg) or
or gabapentin (13%). The percentage of patients phenytoin 313 mg (range 100–650 mg). There
meeting one of the exit criteria (the primary was no difference in the proportion of seizure-
efficacy variable) was significantly lower and the free patients during the 48-week maintenance
time to exit (the secondary efficacy variable) was period between the oxcarbazepine group (59%)
significantly longer in the group receiving and the phenytoin group (58%). 33 The other
oxcarbazepine 2400 mg/day than in the group oxcarbazepine-phenytoin comparative trial
receiving oxcarbazepine 300 mg/day (p<0.0001 included 193 children and adolescents (aged
and p=0.0001, respectively).31 5–17 yrs), who received mean maintenance
dosages of oxcarbazepine 18.8 mg/kg/day (672
Monotherapy, Comparative Trials mg/day, range 300–1350 mg) or phenytoin 5.8
mg/kg/day (226 mg/day, 100–400 mg). In this
Four double-blind, parallel-group, monotherapy trial, there was no difference in the proportion of
trials were conducted with oxcarbazepine. Three seizure-free patients during the 48-week
similarly designed comparative trials examined maintenance period between the oxcarbazepine
the efficacy and tolerability of oxcarbazepine group (61%) and the phenytoin group (60%).34
monotherapy against either valproic acid (one A fourth monotherapy, comparative trial,
study) or phenytoin (two studies, one in children conducted by the Scandinavian Oxcarbazepine
and one in adults) in patients with recent-onset Study Group in the late 1980s, examined the
partial seizures or generalized tonic-clonic efficacy and tolerability of oxcarbazepine and
seizures.32–34 Eligible patients had two or more carbamazepine as initial monotherapy in 235
seizures in the previous 6 months and no prior patients with newly diagnosed and previously
AED therapy. Each study was a randomized (1:1 untreated epilepsy that consisted of either partial-
oxcarbazepine:comparator AED), double-blind, onset seizures (with or without secondarily
parallel-group trial consisting of a 14-day generalized seizures) or generalized tonic-clonic
screening phase followed by a 56-week double- seizures. 35 The design was a randomized,
blind treatment period (8-wk flexible titration double-blind, parallel-group trial beginning with
phase followed by a 48-wk maintenance phase). a 4-week baseline period followed by a double-
The initial starting dosages were oxcarbazepine blind, 4–8-week flexible titration phase, and
300 mg/day, valproic acid 300 mg/day, and concluding with a 48-week maintenance phase.
phenytoin 100 mg/day. Each patient’s AED The initial starting dosages were oxcarbazepine
dosage was titrated to an optimum dosage based 300 mg/day and carbamazepine 200 mg/day.
on clinical response. The dosage ranges allowed Each patient was titrated to an optimum AED
were oxcarbazepine 450–2400 mg/day, valproic dosage. The maximum dosages reached were
acid 900–2400 mg/day, and phenytoin 150–800 oxcarbazepine 1800 mg/day and carbamazepine
912 PHARMACOTHERAPY Volume 21, Number 8, 2001

1400 mg/day. In 165 patients considered baseline phase was followed by a 16-week
evaluable for efficacy, three variables were double-blind treatment phase (2-wk titration
examined: changes in seizure frequency, changes period, 14-wk maintenance period). Patients
in electroencephalographic tracings, and could then enter the open-label, long-term
investigator’s global evaluation of efficacy. There extension phase. The initial oxcarbazepine
were no differences between the oxcarbazepine dosage was 10 mg/kg/day, which was steadily
monotherapy arm and the carbamazepine increased every 2–3 days to a maximum target
monotherapy arm in any of these outcome dosage of 30–46 mg/kg/day. The percentage
variables. There was no difference in the change in partial seizure frequency/28 days in the
proportion of seizure-free patients during the double-blind treatment phase relative to the
maintenance period between the oxcarbazepine baseline phase (the primary efficacy variable) was
group (52%) and the carbamazepine group greater in the oxcarbazepine adjunctive therapy
(60%).35 arm (p=0.0001). The response rate (i.e., the
percentage of patients with ≥ 50% reduction in
Adjunctive, Placebo-Controlled Trials seizure frequency/28 days relative to the baseline
phase) was 41% in the oxcarbazepine adjunctive
Two randomized, double-blind, placebo- arm compared with 22% in the placebo
controlled, parallel-group trials of oxcarbazepine adjunctive arm (p=0.0005). The percentage
adjunctive therapy were completed. The first reduction in secondarily generalized seizure
was a four-arm, dose-ranging trial in 692 patients frequency was 78% in the oxcarbazepine
(aged 15–65 yrs) designed to evaluate the safety adjunctive group compared with 33% in the
and efficacy of oxcarbazepine 600, 1200, and placebo adjunctive group (p=0.0012).37
2400 mg/day adjunctive therapy compared with
placebo adjunctive therapy in patients with Clinical Tolerability
treatment-resistant partial seizures.36 An 8-week
baseline phase was followed by a 26-week Overview
double-blind treatment phase (2-wk titration The tolerability of an AED involves consideration
period, 24-wk maintenance period). Patients of the “incidence, severity, and impact”91 of dose-
could then enter an open-label, long-term related adverse effects (e.g., cognitive or motor)
extension phase. Eligible patients had to be on along with the risk of severe idiosyncratic
stable dosages of one to three concomitant AEDs reactions. Objectively evaluating the tolerability
and had to experience four or more partial onset of an AED is more difficult than assessing its
seizures in each 4-week segment of the 8-week efficacy. Analysis of withdrawal rates from AED
baseline period. The percentage change in the therapy due to intolerable or life-threatening
partial seizure frequency/28 days relative to the adverse reactions is objective evidence of a new
baseline phase (the primary efficacy variable) was AED’s tolerability if withdrawal rates are a
in favor of oxcarbazepine (p=0.0001). The primary outcome variable in a randomized,
median percentage reduction from baseline in controlled, monotherapy design.91 Even if it is
partial seizure frequency was 26%, 40%, and 50% not a primary outcome variable, a new AED’s
in the 600-, 1200- and 2400-mg/day groups, withdrawal rate from a study may still be useful
respectively, compared with 8% in the placebo in giving a general indication of its tolerability.
group (each p≤0.0001). The response rate (i.e., Trial designs that provide the best insight into an
percentage of patients with ≥ 50% reduction in AED’s tolerability are (in decreasing order of
seizure frequency/28 days relative to the baseline importance) monotherapy placebo-controlled
phase) in the 600-, 1200-, and 2400-mg/day trials, monotherapy comparative trials,
groups was 27%, 41%, and 50%, respectively, monotherapy dose-controlled trials, and finally,
compared with 13% in the placebo group (each adjunctive placebo-controlled trials.
p≤0.0008).36 Four of the major oxcarbazepine-controlled
The second adjunctive therapy trial was clinical trials were designed to formally assess
designed to evaluate the efficacy and safety of tolerability. 32–35 All were monotherapy
adjunctive oxcarbazepine therapy compared with comparative trials. In the valproic acid study32
placebo adjunctive therapy in 267 adolescents and the two phenytoin studies,33, 34 the primary
and children (aged 2–17 yrs) with treatment- tolerability outcome variable was the time to
resistant partial seizures who were receiving premature discontinuation due to adverse
stable dosages of one or two AEDs.37 An 8-week experiences. In both phenytoin studies, this time
 OXCARBAZEPINE IN THE TREATMENT OF EPILEPSY Glauser 913
Table 3. Frequency of Most Common Treatment-Emergent Adverse Eventsa
Adjunctive Therapy or
Monotherapy Substitution Studies Initiation of Monotherapy
Oxcarbazepine Placebo Oxcarbazepine Placebo
Adverse Eventa (N=1272) (N=353) (N=440) (N=66)
Any adverse event 86.3 75.6 82.5 74.2
Fatigue 13.4 6.8 8.6 12.1
Headache 26.7 21.0 37.5 12.1
Dizziness 25.6 10.8 19.5 4.5
Somnolence 25.4 10.8 21.6 6.1
Ataxia 11.4 4.2 1.8 0.0
Nausea 18.2 7.4 13.2 12.1
Vomiting 16.9 8.2 6.6 6.1
Diplopia 17.2 2.5 0.5 0.0
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 safety database from all controlled
oxcarbazepine monotherapy arm than that for clinical trials provides an overview of the adverse
patients in the phenytoin monotherapy arm experience profile of oxcarbazepine. There are
(p=0.0233 and p=0.002,34 respectively). These two distinct oxcarbazepine safety databases: the
results imply that oxcarbazepine monotherapy is primary database, which includes all post-1991
better tolerated than phenytoin monotherapy for clinical trials, and the secondary database, which
all age ranges. In contrast, there was no includes all pre-1991 trials along with all named-
significant difference between oxcarbazepine patient programs and oxcarbazepine post-
monotherapy and valproic acid monotherapy in marketing experience (data on file, Novartis
the time to premature discontinuation due to Pharmaceutical Corp.). The primary database
adverse experiences.32 (2327 patients exposed to oxcarbazepine) is
There were two primary tolerability outcome smaller than the secondary database (4363
variables in the Scandinavian oxcarbazepine- patients). The secondary database contains
carbamazepine study 35 : the percentage of information on 2886 patients in a named-patient
patients with an adverse experience and the program. Most patients (72%) in the primary
percentage of patients with a severe adverse database were adults, whereas 26% were children
experience requiring withdrawal from the trial. and adolescents (aged 2–17 yrs) and 2% were
Although no difference was noted between the elderly patients (> 65 yrs). The exposure to
oxcarbazepine monotherapy arm and oxcarbazepine in the primary database was 12
carbamazepine monotherapy arm in the months or less for 62% of patients, 12–24
percentage of patients with an adverse months for 24%, and more than 24 months for
experience, there was a significant difference in 14%.
favor of oxcarbazepine in the percentage of A profile of treatment-emergent adverse events
patients with a severe adverse experience that resulting from dosages of 300–2400 mg/day for
required withdrawal from the trial (p=0.04). 1712 patients treated with oxcarbazepine in
Although not specifically stated by the lead controlled clinical trials is shown in Table 3 (data
investigators, this implies that oxcarbazepine on file, Novartis Pharmaceuticals Corp). These
monotherapy was better tolerated than data were derived from oxcarbazepine
carbamazepine monotherapy in this population. monotherapy placebo-controlled studies,
oxcarbazepine monotherapy dose-controlled
Adverse Event Profile from Controlled Clinical studies, and oxcarbazepine adjunctive placebo-
controlled trials. In general, the most commonly
Trials
reported treatment-emergent adverse events were
All oxcarbazepine clinical trials collected data related to the central nervous system, and most
on potential adverse effects of oxcarbazepine for were rated as mild or moderate in severity.
descriptive purposes. Analysis of the Novartis Across the trials, eight treatment-emergent
914 PHARMACOTHERAPY Volume 21, Number 8, 2001

adverse events (considered to be at least possibly experienced a recurrence with oxcarbazepine

related to study drug) occurred in at least 10% of treatment.93 A large Danish retrospective survey
oxcarbazepine-treated patients: fatigue, of 947 patients found that 6% of patients treated
headache, dizziness, somnolence, ataxia, nausea, with oxcarbazepine developed a rash, but half of
vomiting, and diplopia. Each of these adverse those patients had experienced a previous allergic
events, with the exception of headache, occurred reaction to carbamazepine.94
more frequently in patients treated with No single, randomized, controlled trial or
oxcarbazepine adjunctive therapy than in group of trials can provide enough information to
patients treated with oxcarbazepine monotherapy. make definitive conclusions about the risk of
The frequency of ataxia, vomiting, and diplopia severe idiosyncratic reactions. Instead, postmarketing
was at least 2 times greater in patients receiving experience is necessary to fully evaluate the
oxcarbazepine adjunctive therapy than in frequency and severity of idiosyncratic reactions.
patients receiving oxcarbazepine monotherapy, As of March 1, 2000, there were over 200,000
placebo monotherapy, or placebo adjunctive patient-years of postmarking experience with
therapy. The frequency of adverse events was oxcarbazepine (data on file, Novartis
related to total concomitant AED load rather than Pharmaceuticals Corp.). No association appears
any specific oxcarbazepine-AED interaction.37 to exist between oxcarbazepine and severe
idiosyncratic reactions such as hepatic failure,
Serious Adverse Reactions pancreatitis, aplastic anemia, Steven-Johnson
syndrome, or toxic epidermal necrolysis.92
During clinical trials, the most common Scattered cases of overdose with oxcarbazepine
potentially significant (as judged by have occurred; the maximum dose taken was
investigators) oxcarbazepine-related adverse approximately 24,000 mg. Symptoms of
effects were disorders of balance, gait, or oxcarbazepine overdose were somnolence,
coordination; hyponatremia; convulsions; and dizziness, nausea, vomiting, hypokinesia,
rash (data on file, Novartis Pharmaceutical hyponatremia, ataxia, and nystagmus. All
Corp.). In oxcarbazepine monotherapy trials, the patients who experienced an overdose with
frequency of severe adverse events was 8.2% for oxcarbazepine recovered with symptomatic
oxcarbazepine-treated patients, 7.6% for patients treatment (data on file, Novartis Pharmaceuticals
receiving placebo, 9.9% for patients receiving Corp.).
valproic acid, and 5.8% for patients receiving Oxcarbazepine is considered under the Food
phenytoin.28, 32–34 Thus, the frequency of severe and Drug Administration Pregnancy Category
adverse events with oxcarbazepine monotherapy C.40 Evidence of teratogenic potential was seen
is similar to that of older AEDs and only slightly for oxcarbazepine and MHD at doses of 1.2–4
higher than that for placebo. times the maximum recommended human doses
Allergic rashes have been reported to occur in on a milligram/square meter basis.40 There have
patients treated with oxcarbazepine. In been no controlled studies of the effects of
monotherapy comparative trials, allergic skin oxcarbazepine on the human fetus. Fetal
reactions appeared less frequently with malformations, both congenital and anomalous,
oxcarbazepine than with phenytoin 33 or have been associated with in utero exposure to
carbamazepine,35 but more frequently than with AEDs.81, 95 Carbamazepine is embryotoxic and,
valproic acid.32 Clinical experience suggests that, like valproic acid,96 has been reported to produce
whereas allergic rashes during oxcarbazepine neural tube defects in an estimated 0.5–1% of
therapy do occur, they are uncommon39 and may those exposed.97, 98 One mechanism suggested to
be less frequent than with carbamazepine. 55, 92 account for the teratogenicity of carbamazepine
Cross-sensitivity to oxcarbazepine in patients is the formation of the 10,11-epoxide metabolite
exhibiting allergic sensitivity to carbamazepine in vivo, which may act as a free radical, binding
can occur in up to 30% of patients. In one to proteins and nucleic acids and disrupting
report, 27% of 51 patients experiencing allergic DNA, RNA, and protein synthesis. 95 Unlike
skin reactions to carbamazepine experienced carbamazepine, oxcarbazepine does not form the
allergic cross-reactivity when switched to epoxide but instead undergoes reduction of the
oxcarbazepine.54 A similar study showed that 9 carbonyl group to form MHD, which then
(16%) of 55 patients switched from undergoes glucuronidation.52 Based on animal
carbamazepine to oxcarbazepine because of skin studies and the structural relationship of
reactions or “evidently allergic” reactions oxcarbazepine to carbamazepine, it is likely
 OXCARBAZEPINE IN THE TREATMENT OF EPILEPSY Glauser 915

however that oxcarbazepine is a human Novartis Pharmaceuticals Corp.).

teratogen.40 Antifolate effects are hypothesized to In the Danish retrospective study of 947
be another mechanism responsible for neural patients treated with oxcarbazepine, hyponatremia
tube defects with the established AEDs,95 and (sodium level < 135 mEq/L) was noted in 23% of
folate supplementation is recommended for 350 patients in whom plasma sodium was
pregnant women with epilepsy.81 Seizures in the measured; however, it was the reason for
pregnant patient with epilepsy need to be treated, discontinuation of oxcarbazepine in only 4
and women must be informed of the risks of patients. 94 In a cross-sectional study of 41
pregnancy associated with anticonvulsant use patients receiving oxcarbazepine, approximately
before they become pregnant.81, 95 Oxcarbazepine 50% experienced hyponatremia (serum sodium
should be used in pregnant women only if the level < 135 mEq/L), but no patients were
potential benefits justify the possible risks. symptomatic or discontinued treatment
secondary to hyponatremia. 104 Risk factors
Laboratory Abnormalities associated with the development of hyponatremia
include advanced age (elderly) and dosages
In oxcarbazepine-controlled clinical trials, no above 30 mg/kg/day. 54, 104 In general, serum
clinically significant hematologic or renal sodium concentrations return to normal with
changes were noted over time. Although dosage reduction, discontinuation of oxcarbazepine,
transient changes in liver enzymes were or restriction of water intake.37, 99
observed, investigators did not consider the
changes to be clinically significant.32–34 Decreases
Dosage, Titration, and Conversion from Other
in serum uric acid and thyroxine levels were
noted; however, investigators did not consider AEDs
these to be clinically significant. In adults with partial seizures, the manufacturer
Hyponatremia associated with oxcarbazepine is recommends an initial oxcarbazepine dosage of
usually asymptomatic, 39, 92, 99 but cases of 600 mg/day (given in two divided doses) for
symptomatic hyponatremia have been adjunctive or monotherapy use. 40 Based on
reported.100–102 A review of data from controlled clinical experience, oxcarbazepine adjunctive
clinical trials in the Novartis database included treatment can be initiated at 300 mg/day, given in
2026 oxcarbazepine-treated patients with two divided doses, with or without food. The
baseline and postbaseline serum sodium dosage then may be increased based on clinical
measurements. 103 In this population, the response in increments of 300–600 mg at
frequency of serum sodium level less than 135 approximately weekly intervals. The recommended
mEq/L, less than 130 mEq/L, and less than 125 target dosage for adjunctive therapy is 1200
mEq/L was 24.5%, 10.9%, and 3%, respectively.103 mg/day; if indicated, dosages up to 2400 mg/day
The frequency of serum sodium levels less than may be used but may not be tolerated, mainly
125 mEq/L increased with age, from 0.4% in because of central nervous system effects.40 If
children (≤ 17 yrs) to 3.8% in adults (18–64 yrs) dosages higher than 1200 mg/day are used as
and 7.3% in the elderly (> 65 yrs). 103 adjunctive therapy, patients should be observed
Hyponatremia did not occur in children younger closely and plasma levels of concomitant AEDs
than 6 years and was rare in adolescents. The monitored during the titration period.
study noted that although the frequency of Clinical trials used an oxcarbazepine
hyponatremia may be higher in elderly patients, monotherapy dosage of 1200–2400 mg/day. 28–35
the sample (41 patients) was too small to draw The lower dosage of 1200 mg/day may be
any conclusion. 103 Most patients who effective in patients receiving monotherapy. In
experienced a serum sodium level less than 125 these patients, treatment can be initiated at 300
mEq/L were taking concomitant sodium- mg/day and increased by 300 mg/day every third
depleting diuretics, and most remained day to a target of 1200 mg/day.
asymptomatic. In patients receiving a fixed In adults receiving other AEDs (including
dosage of oxcarbazepine (300–2400 mg/day), carbamazepine monotherapy) who are converted
there was no significant dose-response to oxcarbazepine monotherapy, oxcarbazepine
relationship in the frequency of treatment- treatment can be initiated while simultaneously
emergent hyponatremia at 1 and 3 months of reducing concomitant AED dosage; concomitant
therapy.103 The frequency of hyponatremia in the AEDs can be withdrawn completely over 3–6
named patient program was 1.1% (data on file, weeks, whereas the target dosage of oxcarbazepine
916 PHARMACOTHERAPY Volume 21, Number 8, 2001

should be attained in about 2–4 weeks. When Conclusion

oxcarbazepine is substituted for carbamazepine, a
Oxcarbazepine is an effective anticonvulsant
suggested oxcarbazepine replacement dose is 300
for the treatment of partial-onset seizures in
mg for each 200 mg of carbamazepine.90
adults, adolescents, and children. Oxcarbazepine
Although the manufacturer recommends an
(and its pharmacologically active derivative
initial oxcarbazepine dosage of 8–10 mg/kg/day
MHD) has a favorable pharmacokinetic profile of
in children (aged 4–16 yrs) with partial seizures
rapid absorption, linear pharmacokinetics, and
who are receiving other AEDs, oxcarbazepine can
minimal interaction with other AEDs. Its
be started at 4–5 mg/kg/day, not to exceed 300
proposed mechanism of action involves
mg/day (150 mg twice/day). In clinical trials, the
modulation of sodium, potassium, and calcium
target maintenance dosage was achieved over 2
channels. The results of the 10 large
weeks and depended on body weight (20–29 kg,
oxcarbazepine clinical trials demonstrated that
900 mg/day; 29.1–39 kg, 1200 mg/day; and > 39
oxcarbazepine monotherapy is safe, effective, and
kg, 1800 mg/day). 40 In clinical practice,
well tolerated in adults, adolescents, and children
oxcarbazepine pediatric dosages have been
with either recent-onset or treatment-resistant
increased by increments of 4–5 mg/kg/day each
partial seizures. Comparative trials have shown
week as tolerated based on clinical response.
that oxcarbazepine monotherapy has efficacy
Oxcarbazepine has potential advantages over
similar to that of phenytoin, valproic acid, and
other AEDs when combined with them or
carbamazepine in partial-onset seizures and
substituted for them because of its more
generalized tonic-clonic seizures in adults,
favorable pharmacokinetic and metabolic profile.
adolescents, and children. The proportions of
In patients receiving carbamazepine (or other
oxcarbazepine-treated patients and standard
enzyme-inducing AEDs), substitution with
AED-treated patients who became seizure free
oxcarbazepine can result in deinduction of
during treatment were approximately 60%.
hepatic CYP enzyme system function,41, 90 with
Oxcarbazepine adjunctive therapy is superior to
subsequent increased serum levels of remaining
placebo adjunctive therapy in treatment-resistant
AEDs.90 Dosage adjustment may be needed in
partial onset seizures in adults, adolescents, and
patients being switched to oxcarbazepine from
children. Among newer AEDs, oxcarbazepine is
AEDs with enzyme-inducing properties.40, 55, 72, 90
suitable for first-line monotherapy use in adults
Patients should be observed closely during
with partial seizures, and it may be a suitable
titration, and plasma levels of concomitant AEDs
first-line therapy for children with partial
can be monitored as clinically indicated. Patients
seizures.105 Overall, oxcarbazepine represents an
with mild to moderate hepatic impairment do not
important new treatment option indicated for
require oxcarbazepine dosage adjustment, but
monotherapy or adjunctive therapy in adults and
patients with impaired renal function (creatinine
as adjunctive therapy in children with partial
clearance < 30 ml/min) should receive one-half
seizures.
the usual starting dosage, which is then increased
slowly to achieve the desired clinical response.40
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