Download Oxcarbazepine

ADIS DRUG EVALUATION
CNS Drugs 2001; 15 (2): 137-163
1172-7047/01/0002-0137/$22.00/0
© Adis International Limited. All rights reserved.
Oxcarbazepine
An Update of its Efficacy in the Management of Epilepsy
Keri Wellington and Karen L. Goa
Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by:
M. Bialer, Department of Pharmaceutics, The Hebrew University of Jerusalem, Jerusalem, Israel; A.A.
Beydoun, University of Michigan Medical Center, Ann Arbor, Michigan, USA; B.F.D. Bourgeois, Department
of Neurology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; G. Krauss,
Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland, USA; K.M. Matar, Department of
Clinical Pharmacy, King Saud University, Riyadh, Saudi Arabia; E. Perucca, Department of Internal Medicine
and Therapeutics, University of Pavia, Pavia, Italy; K. Vähäkangas, Department of Pharmacology and
Toxicology, University of Oulu, Oulu, Finland.
Data Selection
Sources: Medical literature published in any language since 1992 on oxcarbazepine, identified using Medline and EMBASE, supplemented
by AdisBase (a proprietary database of Adis International, Auckland, New Zealand). Additional references were identified from the reference
lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company
developing the drug.
Search strategy: Medline search terms were ‘oxcarbazepine’. EMBASE search terms were ‘oxcarbazepine’. AdisBase search terms were
‘oxcarbazepine’ or ‘GP-47779’. Searches were last updated 15 Jan 2001.
Selection: Studies in patients with epilepsy who received oxcarbazepine. Inclusion of studies was based mainly on the methods section of
the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic
and pharmacokinetic data are also included.
Index terms: oxcarbazepine, epilepsy, pharmacodynamics, pharmacokinetics, therapeutic use.
Contents
Summary
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . .
2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2 Effects on the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . .
3.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . .
3.3 Special Patient Populations . . . . . . . . . . . . . . . . . . . . . . . .
3.4 Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.1 Interactions Between Oxcarbazepine and Antiepileptic Drugs
3.4.2 Interactions Between Oxcarbazepine and Other Drugs . . . .
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1 In Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.2 Adjunctive Therapy . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 In Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.2 Adjunctive Therapy . . . . . . . . . . . . . . . . . . . . . . . . .
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1 In Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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138
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Wellington & Goa
5.1.1 Monotherapy . . . . . . . . . . . . . . . . . . .
5.1.2 Adjunctive Therapy . . . . . . . . . . . . . . . .
5.2 In Children . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.1 Monotherapy . . . . . . . . . . . . . . . . . . .
5.2.2 Adjunctive Therapy . . . . . . . . . . . . . . . .
5.3 Hyponatraemia . . . . . . . . . . . . . . . . . . . . . .
6. Dosage and Administration . . . . . . . . . . . . . . . . . .
7. Place of Oxcarbazepine in the Management of Epilepsy
7.1 In Adults . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2 In Children . . . . . . . . . . . . . . . . . . . . . . . . .
7.3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . .
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Summary
Abstract
Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide)
is a 10-keto analogue of carbamazepine with anticonvulsant activity.
In newly diagnosed adult patients, oxcarbazepine monotherapy is as effective
as phenytoin and valproic acid at reducing generalised tonic-clonic and partial
seizure frequency. Furthermore, oxcarbazepine 2400 mg/day as monotherapy has
also proved effective in the treatment of refractory partial seizures in adult patients. Oxcarbazepine 600, 1200 and 2400 mg/day as adjunctive therapy significantly reduced seizure frequency compared with placebo in 692 patients with
refractory partial seizures.
The efficacy of oxcarbazepine monotherapy is similar to that of phenytoin in
the treatment of children and adolescents with newly diagnosed partial or generalised tonic-clonic seizures. Additionally, adjunctive therapy with oxcarbazepine was significantly more effective than placebo at reducing seizure frequency
in children and adolescents with refractory partial seizures.
The most commonly reported adverse events associated with oxcarbazepine
monotherapy and/or adjunctive therapy in adults and/or children are somnolence,
dizziness, headache, nausea and vomiting.
Oxcarbazepine monotherapy is better tolerated than phenytoin (in both adults
and children) and valproic acid (in adults), and although 75 to 90% of adult
patients in 5 recent monotherapy studies reported adverse events while receiving
oxcarbazepine, <8% withdrew from treatment because of them.
Acute hyponatraemia, although usually asymptomatic, develops in 2.7% of
patients treated with oxcarbazepine.
Adverse events most likely to resolve upon switching to oxcarbazepine therapy from treatment with carbamazepine are undetermined skin reactions (rashes,
pruritus, eczema), allergic reactions and a combination of malaise, dizziness and
headache.
Although oxcarbazepine does have a clinically significant interaction with
some drugs (e.g. phenytoin and oral contraceptives), it has a lower propensity for
interactions than older antiepileptic drugs (AEDs) because its major metabolic
pathway is mediated by noninducible enzymes.
Conclusion: Oxcarbazepine as monotherapy is a viable alternative to established AEDs in the treatment of partial and generalised tonic-clonic seizures in
adults and children. Furthermore, it is also effective as adjunctive therapy in the
treatment of refractory partial seizures in both age groups. In addition, the drug
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CNS Drugs 2001; 15 (2)
Oxcarbazepine: An Update
139
is tolerated better than the older, established AEDs, and has a lower potential for
drug interactions. These attributes make oxcarbazepine an effective component
in the initial treatment of newly diagnosed partial and generalised tonic-clonic
seizures, and also as an adjunct for medically intractable partial seizures in both
adults and children.
Pharmacodynamic
Properties
Oxcarbazepine is a 10-keto analogue of carbamazepine which appears to exert its
anticonvulsant activity [as its major active metabolite, the monohydroxy derivative (MHD) 10-hydroxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide]
by blocking neuronal ion channels. In vitro studies in rodents showed that the
drug blocks voltage-sensitive sodium channels, thereby stabilising neural membranes, inhibiting repetitive neuronal firing and reducing synaptic impulse activity. In vitro studies have also shown that MHD reduces high voltage–activated
calcium currents in striatal and cortical neurons, thus reducing glutamatergic
transmission at corticostriatal synapses.
Cognitive function and saccadic and smooth-pursuit eye movements were
minimally affected in newly diagnosed patients with epilepsy undergoing short
term oxcarbazepine monotherapy. However, oxcarbazepine was found to stimulate some aspects of psychomotor functioning, such as focused attention and
writing speed, in healthy volunteers after 2 weeks.
Pharmacokinetic
Properties
Oxcarbazepine is rapidly absorbed after oral administration. Maximum plasma
concentrations (Cmax; 1.05 to 1.74 mg/L) are reached within 2 hours after a single
dose of oxcarbazepine 600mg taken after an overnight fast. The Cmax of MHD
(5.44 to 8.85 mg/L) is reached after about 4 to 6 hours and the area under the
plasma concentration-time curve ranges from 80 to 220 mg/L • h.
Steady-state plasma concentrations of MHD are achieved within 2 to 3 days
of implementing a twice daily regimen. Oxcarbazepine pharmacokinetics are
linear and show dosage proportionality over the dosage range 300 to 2400 mg/day.
Approximately 37 to 43% of MHD and 60 to 67% of oxcarbazepine is bound
to plasma proteins.
Once absorbed from the gastrointestinal tract, oxcarbazepine is almost immediately reduced by an hepatic cytosolic arylketone reductase to form the major
active metabolite MHD. Hence, the metabolism of oxcarbazepine is not affected
by autoinduction, as is the case with carbamazepine. The plasma elimination halflife of oxcarbazepine is 1 to 2.5 hours, illustrating its rapid conversion to MHD.
The elimination half-life of MHD in healthy volunteers averages about 8 to 10
hours. The rate of renal clearance of MHD is 0.71 to 1.26 L/h in healthy volunteers. Plasma concentrations of MHD are higher in patients with renal dysfunction
and in the elderly because of reduced renal clearance, and lower in healthy children aged between 2 and 5 years compared with older children and adults because
of increased systemic clearance. Dosage adjustments for these 3 patient groups
are recommended.
Because the metabolism of oxcarbazepine to its active metabolite is mediated
by noninducible enzymes, oxcarbazepine pharmacokinetics are largely unaffected by induction of the microsomal cytochrome P450 (CYP) system. As such, the
potential for interactions with antiepileptic drugs (AEDs) that induce CYP isozymes is reduced. However, there are reports of clinically significant interactions
between oxcarbazepine, phenytoin and lamotrigine.
The efficacy of oral contraceptives may be reduced by oxcarbazepine because of
significant reductions in serum ethinylestradiol and levonorgestrel concentrations
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CNS Drugs 2001; 15 (2)
140
Wellington & Goa
reported in healthy women receiving oral contraceptives and oxcarbazepine concomitantly.
Furthermore, switching to oxcarbazepine therapy from treatment with carbamazepine resulted in a 47 to 200% increase in plasma concentrations of haloperidol, chlorpromazine and clozapine, most probably due to the removal of the
inducing effect of carbamazepine.
Therapeutic Efficacy
Adults. Early studies showed oxcarbazepine monotherapy to be equivalent in
efficacy to carbamazepine in the treatment of generalised tonic-clonic seizures
and partial seizures in adults. In a more recent study, oxcarbazepine 1200 mg/day
significantly reduced seizure frequency by 89.1 vs 37.4% and increased the time
to the first seizure compared with placebo in previously untreated patients.
Two monotherapy trials showed oxcarbazepine to be as effective at reducing
generalised tonic-clonic and partial seizure frequency as valproic acid and phenytoin in patients with newly diagnosed epilepsy. About 57 and 60% of patients
with newly diagnosed epilepsy treated with oxcarbazepine were seizure-free during a 48-week maintenance treatment period. Furthermore, oxcarbazepine and
the other 2 AEDs did not differ significantly in their effects on seizure frequency
during the maintenance period, number of patients discontinuing treatment due
to lack of efficacy, or overall physician and patient evaluation of treatment.
Oxcarbazepine monotherapy has also proved effective in the treatment of
refractory partial seizures. Oxcarbazepine 2400 mg/day significantly reduced
seizure frequency and increased the time to the first seizure compared with placebo or a subtherapeutic dosage of the drug (300 mg/day), in patients with intractable seizures.
Oxcarbazepine 600, 1200 and 2400 mg/day as adjunctive therapy significantly
reduced seizure frequency compared with placebo in 692 patients with refractory
partial seizures.
Children. The efficacy of oxcarbazepine monotherapy is similar to that of
phenytoin in the treatment of previously untreated children and adolescents with
partial or generalised tonic-clonic seizures. In a well designed clinical trial, 60%
of evaluable patients treated with oxcarbazepine 450 to 2400 mg/day were seizure-free during the maintenance period. Similarly, 60% of the patients treated
with phenytoin 150 to 800 mg/day were also free of seizures. After accounting
for baseline seizure frequencies, there was no significant difference in seizure
frequency between the 2 treatment groups.
Adjunctive therapy with oxcarbazepine was significantly more effective than
placebo at reducing seizure frequency in children and adolescents with refractory
partial seizures. Reductions in seizure frequency of 35% from baseline were reported for oxcarbazepine-treated patients compared with 9% for children receiving placebo.
Tolerability
Adults. The most commonly reported adverse events associated with oxcarbazepine monotherapy in adults (in ≥5% of patients) are somnolence, headache, dizziness, nausea, vomiting, fatigue, rash and diplopia. Although 75 to 90%
of patients in 5 recent monotherapy studies who received at least one dose of
oxcarbazepine reported adverse events, <8% withdrew from treatment because
of them. Reasons for discontinuing treatment prematurely included rash, postictal
psychosis, ataxia, oxcarbazepine intoxication, headache and dizziness.
The time to premature discontinuation of treatment due to adverse events was
significantly in favour of oxcarbazepine compared with phenytoin in one study,
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CNS Drugs 2001; 15 (2)
Oxcarbazepine: An Update
141
but there was no significant difference compared with valproic acid in another
study. However, oxcarbazepine was better tolerated than phenytoin (particularly
with respect to gum hyperplasia, tremor, diplopia and nystagmus), and valproic
acid (particularly with respect to tremor, weight gain, alopecia and headache).
The most commonly reported adverse events among adult patients receiving
oxcarbazepine adjunctive therapy are dizziness, somnolence, sedation, headache,
fatigue, nausea, vomiting, ataxia, nystagmus and abnormal gait.
In 757 patients with severe partial and/or generalised seizures, as few as 110
adverse events were reported and only 1.3% of patients discontinued treatment
because of them. The majority of these patients were treated for 2 to 6 years with
a dosage of 150 to 3600 mg/day and along with dizziness, headache, nausea and
vomiting, hyponatraemia was also a common adverse event.
In 164 patients switched to oxcarbazepine (monotherapy and adjunctive therapy were not differentiated) from carbamazepine therapy because of adverse
events and/or intolerability while receiving carbamazepine, 18% became free of
adverse events, and in 60% of the patients, symptoms became tolerable. The
adverse events most likely to resolve upon switching to oxcarbazepine were undetermined skin reactions (rashes, pruritus, eczema), allergic reactions and a combination of malaise, dizziness and headache.
In a large well designed clinical trial where oxcarbazepine 600, 1200 or 2400
mg/day was administered to patients taking up to 3 concomitant AEDs the highest
dosage was associated with >65% of patients discontinuing treatment, mainly
because of CNS-related adverse events. However, treatment was well tolerated
in patients receiving oxcarbazepine 1200 mg/day.
Children. Common adverse events in previously untreated children receiving
oxcarbazepine monotherapy are similar to those in adults: somnolence, headache,
dizziness, nausea, apathy and rash. Oxcarbazepine was tolerated better than
phenytoin, particularly with respect to nervousness, dizziness, gum hyperplasia,
hypertrichosis and ataxia. Furthermore, the time to premature discontinuation of
treatment due to adverse events was significantly in favour of oxcarbazepine.
The most common adverse events experienced by children and adolescents
receiving oxcarbazepine adjunctive therapy were somnolence, headache, dizziness, vomiting, nausea, diplopia, fever and ataxia.
Hyponatraemia. Acute hyponatraemia (serum sodium level <125 mmol/L),
although usually asymptomatic, develops in 2.7% of patients receiving oxcarbazepine treatment. In a large retrospective evaluation of the records of 1966
patients who had been enrolled in 14 controlled monotherapy and adjunctive
therapy trials conducted to date, and who were treated for about 20 months with
oxcarbazepine 600 to 1800 mg/day, the incidence of acute hyponatraemia was
found to be low (2.7%).
Dosage and
Administration
In the US and the UK, orally administered oxcarbazepine is approved for use as
monotherapy or adjunctive therapy in the treatment of partial seizures in adults
and as adjunctive therapy in the treatment of partial seizures in children (aged ≥4
years in the US and ≥6 years in the UK). In the UK, the drug is also approved for
use as monotherapy in children ≥6 years of age.
The manufacturer recommends that initiation of monotherapy in adults should
begin with a dosage of 600 mg/day and be titrated to 1200 mg/day. However, in
practice a lower initial dosage may be better tolerated. Adult patients being
switched to oxcarbazepine monotherapy from treatment with other AEDs can
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CNS Drugs 2001; 15 (2)
142
Wellington & Goa
receive ≤2400 mg/day after a 4-week titration period starting at 600 mg/day.
Adjunctive therapy with oxcarbazepine in adults should not exceed the recommended dosage of 1200 mg/day because of intolerability at higher dosages.
Adjunctive therapy in children aged 4 to 16 years can begin with a daily dosage
of 8 to 10 mg/kg (but not exceed 600 mg/day). The target maintenance dosage
(median ≈30 mg/kg/day) should be reached within 2 weeks and is dependent upon
patient bodyweight. Children <8 years of age have an increased clearance (by
about 30 to 40%) compared with older children and adults and, therefore, may
need higher maintenance dosages to achieve effective seizure control.
During the titration phase, patients need to be observed closely and plasma
concentrations of the concomitant AEDs should be monitored, as they may be
altered, especially at oxcarbazepine dosages >1200 mg/day.
The measurement of serum sodium levels should be considered during treatment with oxcarbazepine, especially if the patient is receiving concomitant
medication known to decrease serum sodium levels or if the symptoms of hyponatraemia appear.
There is a 25 to 30% chance that patients with a history of hypersensitivity to
carbamazepine will also experience hypersensitivity reactions to oxcarbazepine.
As such, oxcarbazepine treatment must be discontinued immediately if signs of
hypersensitivity develop.
1. Introduction
Oxcarbazepine (10,11-dihydro-10-oxo-5Hdibenz[b,f]azepine-5-carboxamide) is a 10-keto
analogue of carbamazepine with anticonvulsant activity. The pharmacology and clinical use of oxcarbazepine in epilepsy, trigeminal neuralgia and affective disorders were previously discussed by
Grant and Faulds in Drugs.[1] This review re-examines the role of oxcarbazepine in the management
of epilepsy in the light of more recent data.
2. Pharmacodynamic Properties
There have been few pharmacological studies
on oxcarbazepine reported since the earlier review[1] and, therefore, this section is a general overview of the previous data updated with a small
number of subsequent reports in animals and humans. Oxcarbazepine showed activity in standard
animal models of tonic-clonic and partial seizures
but not in a rat model of absence seizures.[1]
2.1 Mechanism of Action
The actual mechanism of action of oxcarbazepine
remains unknown but its major active metabolite,
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the monohydroxy derivative (MHD) 10-hydroxy10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide,
appears to affect neuronal ion channels.[2-4] The anticonvulsant profiles of oxcarbazepine and MHD
are very similar to that of carbamazepine.[5] Table
I summarises in vitro and in vivo pharmacodynamic
studies with oxcarbazepine. The 3 major proposed
mechanisms of activity for new antiepileptic drugs
(AEDs) are the modulation of voltage-dependent
ionic conductances, enhancement of inhibitory processes [mainly those mediated by γ-aminobutyric
acid (GABA)] and reduction of synaptic excitatory
transmission.[6,15] While there have been no direct
results from studies in the human brain, in vitro
studies in rodents showed that voltage-sensitive
sodium channels are blocked by oxcarbazepine,
thereby stabilising neural membranes, suppressing
repetitive neuronal firing (table I) and reducing synaptic impulse activity.[3] This in vitro activity parallels the ability of the drug to reduce partial and
generalised tonic-clonic seizures clinically (see section 4) and, thus, limitation of the firing rate could
contribute to blocking the spread of seizure activity
from an epileptogenic focus.
There is also in vitro evidence that calcium
CNS Drugs 2001; 15 (2)
Oxcarbazepine: An Update
channels could be involved in the anticonvulsant
mechanism of oxcarbazepine through the ability of
the drug to reduce excitatory synaptic transmission
(table I). In vitro studies showed that MHD reduces
high voltage–activated calcium currents in striatal
and cortical neurons, thus reducing glutamatergic
transmission at corticostriatal synapses.[4,7]
2.2 Effects on the CNS
Recently, studies in humans have evaluated the
effects of oxcarbazepine on the CNS.[16-19] Cognitive function was minimally affected in newly diagnosed patients with epilepsy undergoing oxcarbazepine monotherapy.[17,19] After short term
treatment (4 months) with oxcarbazepine 900 to
1200 mg/day, cognitive function was unimpaired
in 10 adult patients with partial or generalised seizures.[19] In a study of longer duration, both oxcarbazepine and phenytoin showed minimal impediment of memory, attention and simple motor
speed in 29 patients who received oxcarbazepine
(n = 14) or phenytoin (n = 15) for 1 year. Dosages
Table I. Summary of results from in vitro and in vivo pharmacodynamic studies of oxcarbazepine in animal models
In vitro
Suppresses high frequency repetitive firing of sodium dependent
action potentials in cultured mouse spinal cord neurons[2,3]
Acts directly on rat corticostriatal terminals to reduce the release
of excitatory amino acids, probably by inhibiting high
voltage–activated calcium currents[4,6-8]
Inhibits the electrically and chemically induced release of
excitatory amino acids in rat cortical and striatal slices[9,10]
Inhibits penicillin-induced epileptiform discharges in rat
hippocampal slices; an effect attenuated by the addition of the
potassium channel blocker 4-aminopyridine[2]
In vivo
Marked inhibitory effect in the hippocampal discharge test in
cats, inhibits photomyoclonic seizures in the baboon and inhibits
electrically and chemically induced seizures in rats[11]
Significantly inhibits pilocarpine-induced status epilepticus, at
clinically relevant doses, in rats compared with control animals
(p = 0.001)[12]
Inhibits the tonic phase of metrazol-induced generalised
tonic-clonic seizures in a dose-dependent manner in rats[13]
Does not suppress the release of excitatory amino acids elicited
by the normal ongoing electrical activity of the glutamatergic and
aspartatergic neurons in rats[14]
 Adis International Limited. All rights reserved.
143
were individualised to achieve serum oxcarbazepine or phenytoin concentrations of 30 to 120 µmol/L
and 40 to 80 µmol/L, respectively.[17] Similarly,
oxcarbazepine 600 mg/day produced negligible effects on saccadic and smooth-pursuit eye movements
in healthy volunteers.[16] In another study, oxcarbazepine 600 mg/day was found to stimulate some
aspects of psychomotor functioning, such as focused attention and increased writing speed, in healthy
volunteers over a 2-week treatment period.[18]
3. Pharmacokinetic Properties
The pharmacokinetic properties of oxcarbazepine in healthy volunteers and in patients with epilepsy have been comprehensively reviewed recently.[20-24] This section provides a brief overview
of these data, with additional information from
other patient groups and healthy volunteers.
3.1 Absorption and Distribution
Oxcarbazepine is rapidly absorbed after oral administration. In fasting healthy volunteers, maximum
plasma concentrations (Cmax) ranging from 1.05 to
1.74 mg/L are reached within 2 hours (tmax) after a
single dose of oxcarbazepine 600mg (table II).[25-28]
The area under the plasma concentration-time
curve (AUC) ranges from 5.10 to 6.84 mg/L • h
(table II). The Cmax of MHD (5.44 to 8.85 mg/L) is
reached after about 4 to 6 hours and the AUC is
about 16- to 32-fold higher than for the parent drug
(table II). Food has no effect on the rate or extent
of absorption of oxcarbazepine.[35]
Steady-state plasma concentrations of MHD are
achieved within 2 to 3 days of implementing a twice
daily regimen. Oxcarbazepine pharmacokinetics are
linear and show dose proportionality over the dosage range 300 to 2400 mg/day.[35]
MHD is distributed equally between plasma and
red blood cells but, at steady state, plasma concentrations of MHD were found to be 3 to 5 times higher than corresponding saliva concentrations, indicating that drug monitoring by saliva sampling
is inappropriate.[37] Approximately 37 to 43% of MHD
and 60 to 67% of oxcarbazepine is bound to plasma proteins.[29,33] Because only a relatively small
CNS Drugs 2001; 15 (2)
144
Wellington & Goa
Table II. Overview of the pharmacokinetic properties of oxcarbazepine and its active metabolite monohydroxy derivative
(MHD) in healthy volunteers after oral administration of a single
600mg dose
Parameter
Oxcarbazepine
MHD
Cmax (mg/L)
1.05-1.74[25-28]
5.44-8.85[25-30]
tmax (h)
1.0-2.0[25-28]
4.0-6.6[25-30]
AUC (mg/L • h)
5.10-6.84[25-28]
80-220[25-31]
[32,33]
Plasma protein binding (%) 60-67
37-43[22,29,34]
Vdss (L)
49[35]
Vdss adjusted for
bodyweight (L/kg)
0.7-0.8[32]
t1⁄2β (h)
1.0-2.5[22]
0.71-1.26[30,36]
CLR (L/h)
Excretion (% of dose)
a
6.5-24.3[25,28-31]
>96% in urinea;
<4% in faeces[35]
The majority of the administered dose is excreted as the inactive glucuronide conjugates of MHD (49%) and oxcarbazepine (9%) and unchanged MHD (27%).
AUC = area under the plasma concentration-time curve; Cmax =
maximum plasma concentration; CLR = renal clearance; t1⁄2β =
elimination half-life; tmax = time to reach Cmax; Vdss = volume of
distribution at steady state.
proportion of MHD is protein bound, the potential
for clinically relevant competitive plasma protein
binding with other AEDs is unlikely.[38]
The ratio between the concentration of MHD in
breast milk and that in maternal plasma is 0.5,[39]
therefore the active moiety is excreted in breast
milk (see section 6).
3.2 Metabolism and Elimination
Once absorbed from the gastrointestinal tract, oxcarbazepine is almost immediately reduced by an
hepatic cytosolic arylketone reductase (there is
also some evidence of placental metabolism[40,41])
to form the major active metabolite MHD (fig. 1).[21]
This is in contrast to the metabolism of carbamazepine, in which oxidative attack of the double bond
at C-10 and C-11 by an epoxidase forms the intermediate carbamazepine-10,11-epoxide (fig. 1). This
conversion, unlike that of oxcarbazepine to MHD,
requires microsomal cytochrome P450 (CYP) isozymes, which are inducible. Hence, the metabolism of oxcarbazepine is not affected by autoinduction, which is a feature of treatment with
carbamazepine.
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The metabolic reduction of the 10-keto group of
oxcarbazepine results in the formation of an asymmetric carbon and, therefore, a chiral molecule.
Hence, MHD is formed as an enantiomeric pair
(fig. 1), with both the S- and R-enantiomers (formed in the ratio of 80% to 20%, respectively) demonstrating equivalent potency in several animal
models for anticonvulsant activity.[30] Because
both enantiomers have equivalent anticonvulsant
potency, studies determining the efficacy of oxcarbazepine have been nonstereospecific with regard to MHD, despite both enantiomers having different pharmacokinetic properties (table III).[30]
The majority of the administered dose of oxcarbazepine is excreted by the kidneys as the inactive glucuronide conjugates of MHD (49%) and
oxcarbazepine (9%) and unchanged MHD (27%).
Less than 1% of the administered dose is excreted
as unchanged oxcarbazepine.[32,35] A small proportion (4 to 7%) of MHD undergoes further metabolism to the inactive dihydroxy derivative 10,11dihydro-10,11-trans-dihydroxycarbamazepine.[32]
This is the only conversion that requires inducible
CYP isozymes. However, this induction is less pronounced than the induction associated with carbamazepine.[21] This has been shown in studies in patients with epilepsy in whom, upon replacement of
carbamazepine treatment with oxcarbazepine, altered levels of serum lipids associated with induction of the CYP system were normalised.[43-46]
The plasma elimination half-life (t1⁄2β) of oxcarbazepine is 1 to 2.5 hours (table II), illustrating its
rapid conversion to MHD.[22] The t1⁄2β of MHD in
healthy volunteers averages about 8 to 10 hours,[35,47]
although t1⁄2β values between 6.5 and 24.3 hours
have been reported (table II).[25,28-31]
The rate of renal clearance of MHD is 0.71 to
1.26 L/h in healthy volunteers.[30,36]
3.3 Special Patient Populations
The pharmacokinetics of oxcarbazepine have
been studied in healthy elderly patients and children, and in patients with impaired renal function. Because 96% of the total administered dose of oxcarbazepine is eliminated renally, hepatic impairment
CNS Drugs 2001; 15 (2)
Oxcarbazepine: An Update
145
has no apparent effect on the pharmacokinetics of
oxcarbazepine or its metabolites, although patients
with severe hepatic dysfunction have not been
studied.[22,35] However, plasma concentrations of
MHD are significantly increased in patients with impaired renal function [creatinine clearance (CLCR)
<1.8 L/h] and dosage reductions are recommended
in these patients (section 6).[36,47] The Cmax and
AUC of MHD are significantly higher in healthy
elderly volunteers (60 to 82 years) than in younger
adults, probably because of the effects of aging on
renal function. Conversely, plasma concentrations
of MHD are lower in healthy children aged between 2 and 5 years than in older children and
adults because systemic clearance is higher.[22,48]
Dosage adjustments for both of these patient
groups are recommended (section 6).
3.4 Drug-Drug Interactions
3.4.1 Interactions Between Oxcarbazepine and
Antiepileptic Drugs
Patients undergoing adjunctive therapy with
carbamazepine and concomitant AEDs may experience complicated pharmacokinetic drug interactions due to the propensity of various drugs to induce CYP isozymes, resulting in important changes
in serum concentrations of concomitant AEDs. However, because the metabolism of oxcarbazepine to
its active metabolite is mediated by noninducible
enzymes, the pharmacokinetic properties of the
HO HO
OH
HOOC
O
HO
O
Cytosolic
arylketone
reductase
10 11
Glucuronyl
transferase
N
O
O
N
NH2
O
Oxcarbazepine
(active)
N
NH2
O
MHD
(active)
NH2
10,11-Dihydro-10-hydroxycarbamazepine glucuronide
(inactive)
CYP
O
HO
Epoxide
hydrolase
10 11
CYP
N
O
N
N
NH2
Carbamazepine
(active)
OH
O
NH2
Carbamazepine-10,11-epoxide
(active)
O
NH2
10,11-Dihydro-10, 11-transdihydroxycarbamazepine
(inactive)
Fig. 1. Metabolic pathway of oxcarbazepine and carbamazepine. MHD (monohydroxy derivative) is formed as a pair of enantiomers
in the ratio of 80% (S+) to 20% (R–), both of which are active and undergo elimination upon conjugation with a microsomal glucuronyl
transferase. A minor amount (4-7%) is oxidised to an inactive 10,11-trans-dihydroxy derivative common to both oxcarbazepine and
carbamazepine.[2,42] CYP = cytochrome P450.
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CNS Drugs 2001; 15 (2)
146
Wellington & Goa
Table III. Mean pharmacokinetic parameters of the R- and S-enantiomers of monohydroxy derivative (MHD), the main active metabolite of oxcarbazepine. Values are calculated from serum data
obtained after a single 600mg dose of oxcarbazepine in 12 healthy
Chinese volunteers[30]
Parameter
S-MHD
R-MHD
Cmax (mg/L)
4.49
0.99*
tmax (h)
6.0
5.5
AUC (mg/L • h)
129.8
26.3*
t1⁄2 (h)
13.0
11.9
MRT (h)
22.9
20.9**
AUC = area under the plasma concentration-time curve; Cmax =
maximum plasma concentration; MRT = mean residence time; t1⁄2
= half life; tmax = time to reach Cmax; *p < 0.001, **p < 0.02 vs S-MHD.
drug are largely unaffected by induction of the CYP
system. For this reason, the potential for interactions with AEDs that induce CYP isozymes is reduced during oxcarbazepine therapy compared
with carbamazepine therapy.[49]
Carbamazepine reduced the median AUC of
MHD by 15 to 35% in 3 double-blind, placebocontrolled studies involving 531 adults and 138
children.[31,50] Serum carbamazepine concentrations
were decreased (by ≈15%) by oxcarbazepine, although not to a clinically significant level.[50]
There is no evidence of a significant interaction
between oxcarbazepine and valproic acid or felbamate (table IV).[28,31,51] However, there was a statistically significant interaction between oxcarbazepine and phenobarbital (table IV).[28] The
AUC of MHD after a single dose of oxcarbazepine
600mg was 25% lower in patients with epilepsy
being treated with phenobarbital, than in healthy
controls receiving oxcarbazepine alone.[28] Plasma
phenobarbital concentrations increased by 14% in
adults and in children receiving concomitant oxcarbazepine. These changes, however, are unlikely
to be of clinical significance.[50]
Oxcarbazepine inhibits the CYP2C19 isozyme
which is involved in the human metabolism of
phenytoin.[35] This inhibition can lead to an increase in serum phenytoin concentrations. As such,
up to a 40% increase in plasma phenytoin concentrations in adult patients receiving a higher dosage
of oxcarbazepine (>1200 mg/day) has been repor Adis International Limited. All rights reserved.
ted, suggesting dosage adjustments of phenytoin
may be necessary in these patients.[50]
Oxcarbazepine had a significant inducing effect
on lamotrigine, although this was smaller than that
of carbamazepine. The Cmax of lamotrigine was reduced by 29% with oxcarbazepine (table IV) and
54% with carbamazepine.[52] However, oxcarbazepine in conjunction with valproic acid (a CYP inhibitor) increased serum lamotrigine concentrations by 111%, compared with 211% with valproic
acid alone. This implies that the inhibiting effect of
valproic acid dominates the inducing effect of oxcarbazepine, and that removal of oxcarbazepine
therapy in patients coadministered valproic acid
and lamotrigine would cause a 50% increase in serum lamotrigine concentrations.[52]
3.4.2 Interactions Between Oxcarbazepine and
Other Drugs
Oxcarbazepine induces specific isozymes of the
CYP3A group (CYP3A4 and CYP3A5) which are
involved in the metabolism of oral contraceptives
and dihydropyridine calcium antagonists.[23,57]
Oxcarbazepine decreased the AUCs of ethinylestradiol and levonorgestrel by about 47 and 36%,
respectively, in healthy women receiving an oral
contraceptive (table IV).[54,55] Breakthrough bleeding in women taking oxcarbazepine with an oral
contraceptive has also been reported.[58] Hence, the
efficacy of oral contraceptives may be reduced by
oxcarbazepine.
Furthermore, repeated administration of oxcarbazepine 900 mg/day reduced the AUC and
Cmax of the calcium antagonist felodipine by 28 and
34%, respectively, in 7 healthy volunteers (table
IV).[56] However, this reduction is considerably
less than that seen when felodipine is coadministered with carbamazepine, which has been shown
to reduce the bioavailability of felodipine by up to
94%,[59] and plasma felodipine concentrations
remained within the recommended therapeutic
range.[56]
Although viloxazine was shown to moderately
increase plasma MHD concentrations in 6 patients
with partial seizures stabilised on a mean dosage of
CNS Drugs 2001; 15 (2)
Oxcarbazepine: An Update
147
oxcarbazepine 1500 mg/day (table IV), this interaction is unlikely to be of clinical significance.[53]
Studies have shown a lack of statistically significant interactions between oxcarbazepine 600
mg/day and cimetidine 400 mg/day or erythromycin 500 mg/day (table IV).[26,27] Similarly, oxcarbazepine (600mg once daily and 900mg twice
daily) did not affect the anticoagulant activity of
warfarin in 7 healthy volunteers.[60]
The disappearance of induction of hepatic metabolism after substitution of oxcarbazepine for
carbamazepine can cause an increase in the serum
concentration of concomitant medications. Switching to oxcarbazepine therapy from treatment with
carbamazepine in 12 patients receiving concomitant clozapine resulted in a 47% increase in plasma
clozapine concentrations.[61] Furthermore, serum con-
centrations of haloperidol, chlorpromazine and
clozapine increased by 50 to 200% upon switching
to oxcarbazepine from carbamazepine in 7 patients
with schizophrenia or organic psychosis.[62] In 2
further case reports, plasma citalopram concentrations increased to usual therapeutic concentrations
after replacing carbamazepine with oxcarbazepine
in 2 patients with comorbid epilepsy, depression
and panic disorder.[63]
4. Therapeutic Efficacy
Previous studies[64-68] found oxcarbazepine to
be effective at reducing seizure frequency in patients with generalised tonic-clonic seizures or partial seizures with or without secondary generalisation. Since the earlier review,[1] clinical experience
Table IV. Pharmacokinetic drug interactions involving oxcarbazepine and other drugs
Coadministered drug regimen
(no. of participants)
Oxcarbazepine Effect of coadministered drug
dosage (mg/day) on MHD pharmacokinetics
Cmax
In combination with antiepileptic drugs
Carbamazepine 400-2000 mg/day (12)a[31]
900
Felbamate 2400 mg/day (18)b[51]
1200
Lamotrigine 6.5-1000 mg/day (14)a[52]
2057 (mean)
Phenobarbital (phenobarbitone) 100-150 mg/day (8)c[28]
600
Phenytoin 250-500 mg/day (12)a[31]
900
Valproic acid 1000-2000 mg/day (8)c[28]
600
Valproic acid 400-2800 mg/day (12)a[31]
900
AUC
Effect of oxcarbazepine
on coadministered drug
pharmacokinetics
Cmax
AUC
↓35%†
↓2%
↓2%
↓9%
↔
↔
↓29%*
↓20%
↓25%†
↓32%
↓11%
↑10%
↓4%
↓13%
↔
In combination with hepatic microsomal enzyme inhibitors
Cimetidine 400 mg/day (8)b[27]
600
↑1%
↑6%
Erythromycin 500 mg/day (8)b[26]
600
↓8%
↑2%
Viloxazine 200 mg/day (6)a[53]
1500 (mean)
↑11%††
In combination with other drugs
Ethinylestradiol 50 µg/day (22)b[54]
1200
↓35%***
↓47%***
Ethinylestradiol 30-40 µg/day (10)b[55]
900
↓25%***
↓47%***
Felodipine 10 mg/day (7)b[56]
900
↓34%**
↓28%**
Levonorgestrel 250 µg/day (22)b[54]
1200
↓25%***
↓47%***
Levonorgestrel 50-125 µg/day (10)b[55]
900
↓7%
↓36%***
a
Patients with epilepsy.
b
Healthy volunteers.
c
Patients with epilepsy and healthy volunteers as control.
AUC = area under the plasma concentration-time curve; Cmax = maximum plasma concentration; MHD = monohydroxy derivative; ↑ indicates
increase; ↓ indicates decrease; ↔ indicates no effect; † p < 0.05, †† p < 0.003 vs oxcarbazepine alone; * p < 0.05, ** p < 0.01, *** p < 0.006
vs coadministered drug alone.
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CNS Drugs 2001; 15 (2)
148
Wellington & Goa
Table V. Efficacy of oxcarbazepine (OXC) as monotherapy in the treatment of adults with epilepsy: results of randomised, double-blind,
multicentre studies
Reference
No. of patients
Treatment regimen
evaluated/randomised (mg/day) [duration]
Seizure frequency at
Results
baseline (mean/median seizure frequency
per week)
during maintenance
period (mean/median
per week, unless
otherwise stated)
In patients with previously untreated partial and/or generalised seizures
Bill et al.[70] 118/143
OXC 600-2100
0.98/0.20
(mean 1028.4)
[48wk]
Christe
et al.[71]
0.08/0
70 (59.3%)
NA
119/144
PHT 100-650
(mean 313.4)
[48wk]
0.84/0.23
0.06/0
69 (58.0%)
NA
106/128
OXC 600-2400
(mean 1052.8)
[48wk]
0.58/0.13
0.17/0
60 (56.6%)
NA
106/121
VPA 200-2700
(mean 1146.2)
[48wk]
1.09/0.25
0.40/0
57 (53.8%)
NA
NR/2.63
NR
5 (12%)b
14 (41%)*
In patients with refractory partial seizures
Beydoun
34/41
OXC 2400
et al.[73]
[18wk]
Schachter
et al.[72]
no. of
no. of
patients
patients
seizure free meeting ≥1
exit criteriona
45/46
OXC 300
[18wk]
NR/1.63
NR
0b
42 (93%)
51/51
OXC 2400
[9d]
4.9/NRc
NR/2 (per 9d)**
13 (25%)
24 (47%)***
51/51
PL
[9d]
4.4/NRc
NR/31 (per 9d)
1 (2%)
43 (84%)
a
In the study by Beydoun et al.,[73] exit criteria included a 2-fold increase in partial seizure frequency in any 28-day period or a 2-fold increase in the highest consecutive 2-day seizure frequency relative to baseline, a new-onset secondarily generalised seizure, worsening of generalised seizure duration or frequency requiring investigator intervention. In the study by Schachter et al.,[72] patients exited
the treatment phase by experiencing 4 partial seizures, 2 new-onset secondarily generalised seizures, serial seizures or status epilepticus.
b
These figures are based on the intent-to-treat population (i.e randomised).
c
Existing treatment with antiepileptic drugs was stopped 48 hours prior to randomisation, during which time partial seizure frequency was
recorded (i.e. baseline results are mean frequency per 48h).
NA = not assessed; NR = not reported; PHT = phenytoin; PL = placebo; VPA = valproic acid; * p < 0.0001 vs OXC 300 mg/day; ** p = 0.0001,
*** p ≤ 0.0001 vs PL.
with oxcarbazepine in the treatment of epilepsy has
increased, both in children and in adults.
4.1 In Adults
4.1.1 Monotherapy
Early studies,[64,65] as discussed previously,[1]
showed oxcarbazepine monotherapy to be equivalent in efficacy to carbamazepine in the treatment
of generalised tonic-clonic seizures and partial seizures. Subsequently, 5 well designed clinical trials
have been published, 3 of which examined the ther Adis International Limited. All rights reserved.
apeutic potential of oxcarbazepine in previously
untreated patients with partial and/or generalised
seizures.[69-71] The other 2 investigated the efficacy
of oxcarbazepine in patients with refractory partial
seizures.[72,73] Each trial was of randomised, double-blind, parallel-group design.
In most studies, assessment of efficacy was
based on the number of patients who became seizurefree, the reduction in seizure frequency and the
number of discontinuations due to unsatisfactory
therapeutic effect. Exclusion criteria in the trials
CNS Drugs 2001; 15 (2)
Oxcarbazepine: An Update
In Previously Untreated Patients
Oxcarbazepine was as effective as phenytoin[70]
and valproic acid[71] at reducing generalised tonicclonic and partial seizure frequency in 2 large trials
of similar design (table V). About 57 and 60% of
patients with newly diagnosed epilepsy treated
with oxcarbazepine were seizure-free during a 48week maintenance treatment period, a proportion
similar to that observed with phenytoin and valproic acid. Oxcarbazepine and the other 2 AEDs
also did not differ significantly in their effects on
seizure frequency during the maintenance period
(table V), number of patients discontinuing treatment due to lack of efficacy, or overall physician
and patient evaluation of treatment[70,71] (1 trial[71]
used a 4-point scale to assess this latter parameter).
Oxcarbazepine was as effective as phenytoin and
valproic acid in reducing both partial and generalised seizures (fig. 2); for all drugs there appeared to be a slightly higher efficacy rate in patients with generalised seizures than in those with
partial seizures.
Oxcarbazepine significantly reduced seizure
frequency, and increased the time to the first seizure, in previously untreated patients compared
with placebo in a study reported as an abstract.[69]
67 previously untreated patients with recent-onset
partial seizures received either oxcarbazepine
1200 mg/day (600mg twice daily) or placebo for
90 days after a 56-day baseline phase. During the
double-blind treatment phase, the median time to
the first partial seizure was 12 days in the oxcarbazepine group (n = 32) compared with 3 days in
placebo recipients (n = 35; p = 0.0457). The seizure
frequency per 28 days was reduced by a median
 Adis International Limited. All rights reserved.
89.1% from baseline in the oxcarbazepine group
compared with 37.4% in the placebo group (p =
0.033).[69]
In Patients with Refractory Seizures
Oxcarbazepine significantly reduced seizure
frequency and increased the time to the first seizure
in patients with refractory partial seizures compared with patients receiving placebo. In a study of
short duration,[72] 102 hospitalised patients (who
had undergone evaluation for epilepsy surgery)
ranging in age from 11 to 62 years with refractory
partial seizures including simple, complex and secondarily generalised seizures, were randomised to
receive oxcarbazepine 2400 mg/day or placebo for
Oxcarbazepine
Phenytoin
Valproic acid
a
80
58
46
84 98
60
40
Patients free of seizures (%)
included a history of status epilepticus, progressive
neurological disorder and significant organic disease. Among the trials in refractory patients, exclusion criteria also featured the use of barbiturates,
benzodiazepines, calcium antagonists or monoamine oxidase inhibitors (MAOIs) and the use of
felbamate 30 days prior to randomisation.[72,73] The
study by Schachter et al.[72] also excluded patients
with hypersensitivity to carbamazepine or lorazepam.
149
20
0
b
80
52
43
60
76 78
40
20
0
Patients with
partial seizures
Patients with
generalised seizures
Fig. 2. Control of partial and generalised seizures with oxcarbazepine, phenytoin or valproic acid as monotherapy. Percentage of adult patients who presented with newly diagnosed
partial seizures (with or without secondary generalisation) or
generalised seizures (without partial onset) and were seizurefree throughout the 48-week treatment period in 2 randomised,
double-blind, multicentre studies.[70,71] Patients treated with oxcarbazepine received a mean dosage of 1028.4 mg/day vs
phenytoin or 1052.8 mg/day vs valproic acid. Patients randomised to phenytoin[71] (a) or valproic acid[70] (b) received
mean dosages of 313.4 and 1146.2 mg/day, respectively. Numbers above the bars indicate the number of patients with the
seizure type at randomisation.
CNS Drugs 2001; 15 (2)
150
Wellington & Goa
9 days. The primary efficacy variable detailed the
time taken for a patient to meet one of the exit
criteria. Patients exited the trial after experiencing
4 partial seizures, 2 new-onset secondarily generalised seizures, serial seizures or status epilepticus, whichever came first. Seizure monitoring did
not begin until day 2, once the full dosage level was
achieved. During the first day, lorazepam 8mg was
administered to 45 and 47 patients in the oxcarbazepine and placebo groups, respectively, to maintain an acceptable seizure frequency.[72]
Within 4.5 days, approximately 25% of the
oxcarbazepine-treated patients versus 75% of the
patients given placebo, excluding 5 who dropped
out, exited from the trial according to the defined
criteria. In the 9-day study period, 47% of the
oxcarbazepine–treated patients met one of the exit
criteria compared with 84% of the placebo group
(p < 0.0001; fig. 3). The median seizure frequency
for the oxcarbazepine-treated group was also significantly lower than that of the placebo group (table V). Additionally, oxcarbazepine significantly
reduced the number of patients experiencing secondarily generalised partial seizures compared with
placebo (8 vs 47%, p = 0.0006).[72]
In a dose comparison study in 87 patients, oxcarbazepine 2400 mg/day, administered in 2 daily
doses for 16 weeks (after a 2-week titration period),
was significantly more effective (p < 0.0001) at seizure control than a low dosage of oxcarbazepine
(300 mg/day) [table V].[73] Given that the lower dosage of oxcarbazepine is subtherapeutic (see section
6), this result is to be expected.
4.1.2 Adjunctive Therapy
Oxcarbazepine 600, 1200 or 2400 mg/day was
significantly more effective than placebo as adjunctive therapy in adult patients with refractory partial
seizures.[74,75] 692 randomised patients who had
experienced ≥4 partial seizures per month during the
baseline period while taking 1, 2 or 3 other AEDs
(actual AEDs not reported) in optimum dosages received oxcarbazepine 600, 1200 or 2400 mg/day or
placebo for a 26-week double-blind treatment period (including an initial 2-week titration phase).
All 3 active treatment groups experienced significant reductions in seizure frequency compared
with the placebo group (fig. 4).[74,75] Furthermore,
22, 10 and 3% of patients in the oxcarbazepine
2400, 1200 and 600 mg/day groups, respectively,
were free of seizures during the treatment phase compared with 0.6% of patients in the placebo group.[74]
Oxcarbazepine
Placebo
6
2
16
53*
47
n = 51
76
n = 51
Responders to treatment
Exited because of experiencing 4 partial seizures
Exited because of experiencing serial seizures
Exited because of experiencing new-onset secondarily generalised seizures
Fig. 3. Efficacy of oxcarbazepine 2400 mg/day versus placebo as monotherapy in 102 adults with refractory partial seizures. The
proportion of patients (%) who responded to treatment and, thus, remained in the trial throughout the 9-day randomised, double-blind
treatment phase and the percentage of patients who experienced 1 of 4 exit criteria. No patients experienced status epilepticus, the
fourth exit criterion.[72] * p < 0.0001 vs placebo.
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CNS Drugs 2001; 15 (2)
Oxcarbazepine: An Update
Median reduction in partial seizure
frequency from baseline (%)
OXC
2400mg
(n = 174)
151
OXC
1200mg
(n = 177)
OXC
600mg
(n = 168)
Placebo
(n = 173)
0
−10
−20
−30
*
−40
*
−50
*
−60
Fig. 4. Efficacy of 3 daily dosages of oxcarbazepine (OXC) as
adjunctive therapy compared with placebo in patients with refractory seizures. Median percentage reduction from baseline
in partial seizure frequency in 4 groups of patients receiving 3
different dosages of oxcarbazepine or placebo for 24 weeks;
results from a randomised, double-blind trial in 692 patients
receiving optimal dosages of ≤3 concomitant antiepileptic
drugs.[74,75] * p = 0.0001 vs placebo.
4.2 In Children
of whom experienced partial seizures) who were
treated with oxcarbazepine 20 to 55 mg/kg/day for
a mean duration of 35 months, became seizurefree. A further 11 patients had a ≥50% reduction in
seizure frequency, and 18 experienced no improvement.[81]
The 2 well designed trials, 1 investigating oxcarbazepine monotherapy[76] and the other adjunctive therapy,[77] included patients under the age of
18 years diagnosed with generalised tonic-clonic
seizures without partial onset and/or partial seizures with or without secondary generalisation.
Exclusion criteria in both trials included a history
of status epilepticus, progressive neurological disorder or significant organic disease. The study
involving oxcarbazepine adjunctive therapy excluded patients who had recently used calcium antagonists or MAOIs, who were hypersensitive to
carbamazepine or who had used felbamate within
90 days of randomisation.[77]
4.2.1 Monotherapy
Recently, 2 randomised, double-blind, multicentre trials evaluating the efficacy of oxcarbazepine have been conducted in young patients,[76,77]
but the majority of studies performed in children
and adolescents with epilepsy are retrospective
postmarketing analyses.[11,78-81] All the studies of
oxcarbazepine as adjunctive therapy found the
drug to be effective in reducing seizure frequency
among children under the age of 18 years.[11,78-80]
In these studies, children (including those with intellectual disability[78,79]) who had intractable partial or generalised epilepsy received oxcarbazepine
in conjunction with at least one other AED. The
mean duration of treatment was 18.4 months with
dosages ranging from 18 to 123 mg/kg/day. Patient
numbers ranged from 40 to 67 among the 4 studies.
There have also been a number of noncomparative retrospective analyses involving patients under the age of 18 years receiving oxcarbazepine as
monotherapy, but these did not supply separate results for monotherapy and adjunctive therapy.[11,33,79]
In the one retrospective, postmarketing study that
specifically investigated monoherapy, 71 of the
100 patients aged 3 months to 4 years (the majority
 Adis International Limited. All rights reserved.
The efficacy of oxcarbazepine was similar to
that of phenytoin in the treatment of previously
untreated children and adolescents with partial seizures with or without secondary generalisation, or
generalised tonic-clonic seizures, in a randomised,
double-blind, multicentre clinical trial (table VI).[76]
After a retrospective baseline phase, 193 children
aged 5 to 17 years (mean, 10 years) with newly diagnosed partial seizures (78%) or generalised tonicclonic seizures (22%) were randomised to receive
either oxcarbazepine (n = 97) or phenytoin (n = 96)
for 56 weeks (starting with an 8-week titration
phase).
During the 48-week maintenance phase, 4 patients receiving oxcarbazepine and 3 phenytointreated patients withdrew because of lack of efficacy, and 16 patients (2 receiving oxcarbazepine
and 14 receiving phenytoin) exited because of adverse events, (see section 5). These patients were,
however, included in the efficacy analysis. Among
the 158 evaluable patients, the same proportion in
each group (60%) were seizure-free during the
maintenance period and there were no significant
differences in seizure frequency (table VI). 60% of
CNS Drugs 2001; 15 (2)
152
Wellington & Goa
Table VI. Efficacy of oxcarbazepine (OXC) as monotherapy and adjunctive therapy in the treatment of children and adolescents with epilepsy:
results of randomised, double-blind, multicentre trials
Reference
No. of pts Treatment regimen
evaluated/ (mg/day) [duration]
randomised
As monotherapy
Guerreiro
81/97
et al.[76]
77/96
As adjunctive therapya
Glauser
136/138
et al.[77]
128/129
Seizure frequency
at baseline
(mean/median per
week)
Results
no. of pts
seizure-free
seizure
frequency
(mean/median
per week)
% reduction
from baseline in
median seizure
frequency/28d
% of pts with
≥50% seizure
reduction
OXC 450-2400
[48wk]
0.68/0.25
49 (60%)
0.07/0
NR
NR
PHT 150-800
[48wk]
0.66/0.33
46 (60%)
0.04/0
NR
NR
OXC 30-46
mg/kg/day
[16wk]
Medianb 12/28d
5
NR
35**
41*
PL [16wk]
Medianb 13/28d
1
NR
9
22
a
Patients were receiving 1 or 2 other antiepileptic drugs concomitantly.
b
Partial seizures.
NR = not reported; PHT = phenytoin; PL = placebo; pts = patients; * p = 0.0005, ** p = 0.0001 vs PL.
the oxcarbazepine-treated patients with partial seizures were seizure-free during the maintenance period compared with 62% in the phenytoin group.
59 and 54% of patients with generalised seizures
who were treated with oxcarbazepine and phenytoin, respectively, were seizure-free throughout the
48-week period.
4.2.2 Adjunctive Therapy
Adjunctive therapy with oxcarbazepine was significantly more effective than placebo at reducing
seizure frequency in children and adolescents in a
randomised, double-blind, multicentre trial[77] and
a noncomparative, nonblind extension study.[82]
In the well designed study by Glauser et al.,[77]
267 patients between the ages of 3 and 17 years
with refractory partial seizures (including simple,
complex and partial seizures with secondary generalisation) received either oxcarbazepine 30 to 46
mg/kg/day or placebo, administered twice daily,
for a period of 14 weeks after a preliminary titration period of 2 weeks in which the initial dosage
was 10 mg/kg/day. Children were eligible for randomisation if they had experienced at least 8 partial
seizures during the 56-day baseline period, were
being treated with 1 or 2 concomitant AEDs and had
a serum sodium level ≥130 mmol/L.[77]
 Adis International Limited. All rights reserved.
During the maintenance period, the reduction in
median seizure frequency per 28 days (the primary
efficacy variable) and the percentage of patients
with ≥50% seizure reduction were significantly
greater in patients treated with oxcarbazepine than
in patients who received placebo (table VI). Furthermore, the median percentage reduction in seizure frequency for the 2 partial seizure subtypes, and
also for secondarily generalised seizures, was significantly greater (p = 0.0012) in oxcarbazepinetreated patients than placebo recipients. The median
reduction in simple and complex partial seizure
frequency among the oxcarbazepine-treated patients
was 45 and 42%, respectively, compared with 16 and
10% among the placebo group. The median reduction
in secondarily generalised seizure frequency was
78% in the oxcarbazepine group compared with 33%
in placebo recipients.[77]
In the noncomparative nonblind extension
study, reported as an abstract,[82] 13 children aged
between 4 and 14 years with undefined seizure
types received oxcarbazepine 18 to 45 (mean 34.5)
mg/kg/day for 28 days in addition to at least one
other AED (mainly carbamazepine). This was followed by an additional 28-day period with the oxcarbazepine dosage increased to 32 to 71 (mean 56)
mg/kg/day and included a switch to oxcarbazepine
CNS Drugs 2001; 15 (2)
Oxcarbazepine: An Update
monotherapy in 5 children. In the first 28-day period, 1 patient was seizure-free, 4 had a decrease
of >50% and 4 patients had an increase in seizure
frequency. Seizure control increased in the second
treatment phase: 9 patients had a reduction in seizure frequency of >25%; 7 of these had a decrease
of >50%, although it was not reported which 5 patients received oxcarbazepine as monotherapy.[82]
5. Tolerability
In the previous review in Drugs,[1] there were
limited data from which to draw definitive conclusions about the incidence of adverse events associated with oxcarbazepine therapy compared with
other AEDs. However, oxcarbazepine was shown
to have a similar tolerability profile to carbamazepine, although oxcarbazepine was associated with
a lower incidence of serious adverse events, especially allergic reactions.
In the ensuing years there have been a number
of clinical trials examining both the efficacy (see
section 4) and the tolerability of oxcarbazepine in
comparison with placebo or other active therapies,[70-73,76,77] as well as studies that concentrated
solely on tolerability.[18,83-87] There have also been
a number of clinician case reports.[88-91]
5.1 In Adults
5.1.1 Monotherapy
The most commonly reported adverse events associated with oxcarbazepine monotherapy in
adults (in ≥5% of patients) are somnolence, headache, dizziness, nausea, vomiting, fatigue, rash and
diplopia.[11,33,35,70-72,83,87,91] There are also reports
of abdominal pain, acne, agitation, alopecia, apathy, ataxia, convulsions, diarrhoea, gum hyperplasia, hyponatraemia, memory complaints, nervousness, respiratory distress, tremor and weight
gain.[33,35,70-72,85-87]
Oxcarbazepine was well tolerated in the 5 clinical trials involving oxcarbazepine monotherapy
(table VII).[69-73] Although 75 to 90% of the 388
patients who received at least one dose of oxcarbazepine reported adverse events, <8% withdrew
from treatment because of them. Reasons for dis Adis International Limited. All rights reserved.
153
continuing treatment prematurely included rash,[69-72]
postictal psychosis,[72,73] ataxia,[73] oxcarbazepine
intoxication after attempted suicide,[70] headache
and dizziness.[71,92] However, in the study by Beydoun et al.[73] all dropouts (15%) occurred during
a tapering phase (before monotherapy was reached) in which concomitant AEDs were phased out.
The time to premature discontinuation of treatment due to adverse events was significantly in
favour of oxcarbazepine compared with phenytoin
(p = 0.02) in one study,[70] but there was no significant difference compared with valproic acid in another.[71] However, oxcarbazepine was better tolerated than phenytoin (particularly with respect to
gum hyperplasia, tremor, diplopia and nystagmus;
table VII), and valproic acid (particularly with respect to tremor, weight gain, alopecia and headache; table VII).[70,71]
As few as 33% of oxcarbazepine recipients reported adverse events, with 18% discontinuing
treatment prematurely, in a retrospective analysis
of the records of 947 patients with epilepsy.[11] The
majority of patients (93%) were aged ≥15 years
and received oxcarbazepine at an average dosage
of 18 mg/kg/day as monotherapy (n = 597) or adjunctive therapy (n = 350) for a mean duration of
23 months. Among the patients who received oxcarbazepine as monotherapy, rash (7%), fatigue
(5%), dizziness (4%) and sedation (4%) were most
prevalent, although half of the patients who experienced rash had previously had allergic reactions
to carbamazepine. CNS-related adverse events associated with oxcarbazepine monotherapy were
usually moderate in severity and were less frequent
than those in patients receiving adjunctive therapy
(fig. 5), yet they were more often rated as severe
(in 26 vs 15% of patients). However, discontinuation of treatment due to adverse events was similar
in both groups.[11]
5.1.2 Adjunctive Therapy
The most commonly reported adverse events
among adult patients receiving oxcarbazepine adjunctive therapy are dizziness, somnolence, sedation, headache, fatigue, nausea, vomiting, ataxia,
nystagmus and abnormal gait.[11,74,83]
CNS Drugs 2001; 15 (2)
154
Wellington & Goa
Table VII. Tolerability profile [percentage of patients (> 5%) experiencing adverse events] of oxcarbazepine (OXC) monotherapy compared
with phenytoin (PHT), valproic acid (VPA) and placebo (PL). Results of randomised, multicentre clinical trials
Adverse event
Reference
Beydoun et al.[73]
Bill et al.[70]
Christe et al.[71]
Guerreiro et al.[76]
Schachter et al.[72]
OXC 2400a
n = 41
OXC 300a
n = 46
OXCb
n = 136
PHTb
n = 142
OXCc
VPAc
n = 128 n = 121
OXCd
n = 96
PHTd
n = 94
OXCe
n = 51
Somnolence
29.3
4.3
30.1
28.9
14.8
19.8
25.0
29.8
16
0
Headache
22.0
8.7
14.7
19.0
10.2
17.4
13.5
14.9
20
20
Dizziness
46.3
8.7
13.2
15.5
10.2
11.6
9.4
22.3
18
12
Nausea
29.3
8.7
9.6
11.3
8.6
11.6
5.2
7.4
20
6
Vomiting
22.0
4.3
0
5.3
10
4
4.2
5.3
2.1
25.5
2.1
11.7
11.5
10.6
5.2
4.3
Fatigue
39.0
8.7
Rash
12.2
4.3
12.5
8.8
11.3
Gum hyperplasia
1.5
12.7
Tremor
2.9
7.0
Diplopia
19.5
0
Nervousness
0.7
7.7
1.5
6.3
3.9
15.7
Weight gain
Alopecia
Abnormal vision
17.1
2
18f
8f
12
0
6.3
7.4
12.5
21.5
8.6
17.4
2.2
Nystagmus
a
10
15.7
Apathy
Abdominal pain
PL
n = 51
2.2
5.6
OXC 2400 or 300 mg/day in adults with refractory partial and/or generalised seizures.
b
OXC 600 to 2100 mg/day or PHT 100 to 650 mg/day in previously untreated adults with partial seizures.
c
OXC 600 to 2400 mg/day or VPA 200 to 2700 mg/day in previously untreated adults with partial seizures.
d
OXC 450 to 2400 mg/day or PHT 150 to 800 mg/day in previously untreated children with partial and/or generalised seizures.
e
OXC 2400 mg/day or PL in patients with refractory partial and/or generalised seizures.
f
These patients experienced pruritus.
Oxcarbazepine was well tolerated in 2 retrospective studies, 1 reported as an abstract,[83] involving the long term use of oxcarbazepine adjunctive
therapy.[11,83] In 757 patients (aged 7 to 91 years)
with severe partial (66%) and/or generalised seizures,[83] as few as 110 adverse events were reported which were severe in 0.9% of patients, and only
10 patients (1.3%) discontinued treatment because
of them. The majority of patients were treated for
2 to 6 years with a dosage of 150 to 3600 mg/day.
Specific concomitant AED medication was not reported. Along with dizziness, headache, nausea and
vomiting, hyponatraemia was also a common adverse event (see section 5.3).
In a long term monitoring study,[33] 164 patients
who had previously been treated with carbamazepine were switched to oxcarbazepine therapy (monotherapy and adjunctive therapy were not differentiated in the report) because of adverse events
 Adis International Limited. All rights reserved.
and/or intolerability while receiving carbamazepine. 18% became free of adverse events and in
60% of the patients, symptoms became tolerable. The
adverse events most likely to resolve upon switching to oxcarbazepine were undetermined skin reactions (rashes, pruritus, eczema), allergic reactions and
a combination of malaise, dizziness and headache.[33]
In a large (n = 692) randomised, double-blind
trial,[74] the highest dosage of oxcarbazepine (2400
mg/day) was associated with a high proportion of
patients (>65%) discontinuing treatment, mainly
because of CNS-related adverse events. However,
treatment was well tolerated in patients receiving
oxcarbazepine 1200 mg/day.[74]
5.2 In Children
5.2.1 Monotherapy
Common adverse events in previously untreated
children receiving oxcarbazepine monotherapy are
CNS Drugs 2001; 15 (2)
Oxcarbazepine: An Update
155
similar to those in adults: somnolence, headache,
dizziness, nausea, apathy and rash.[35,76,81] Oxcarbazepine was tolerated better than phenytoin,
particularly with respect to nervousness, dizziness,
gum hyperplasia (table VII), hypertrichosis (0 vs
8.5%) and ataxia (0 vs 13.8%).[76] Furthermore, the
time to premature discontinuation of treatment due
to adverse events was significantly in favour of
oxcarbazepine (p = 0.002). 82.3% of patients reported adverse events while receiving oxcarbazepine compared with 89.4% of the phenytoin group.
Of these patients, 2 receiving oxcarbazepine discontinued treatment because of rash and 14 phenytoin recipients were withdrawn from treatment because of hypertrichosis, gingival hypertrophy or
rash.[76]
In a study examining the effects of AEDs on
growth and sexual maturation, oxcarbazepine 14.2
to 33.2 mg/kg/day had no effect on pubertal development and linear growth in 18 prepubescent girls
with epilepsy.[84]
headache, dizziness, vomiting, nausea, diplopia, fever and ataxia.[35,77,80] 91 and 82% of patients receiving oxcarbazepine or placebo, respectively, reported adverse events in a trial involving 267
children between the ages of 3 and 17 years with
refractory partial seizures on 1 or 2 concomitant
AEDs.[77] Figure 6 illustrates the incidence of adverse events that occurred in ≥10% of patients. 14
patients (10%) receiving oxcarbazepine discontinued treatment prematurely (mainly because of nausea, vomiting and rash) compared with 3% of the
patients receiving placebo. Rash occurred in 4% of
the oxcarbazepine group and in 5% of the placebo
group, and of the 4 patients who discontinued oxcarbazepine treatment because of maculopapular
and erythematous rash, 2 were receiving carbamazepine as concomitant medication.[77]
5.3 Hyponatraemia
Hyponatraemia is usually defined as a serum
sodium level <135 mmol/L. The clinical symptoms
of acute hyponatraemia (which normally occur
when the serum sodium level is <125 mmol/L) include headache, nausea, vomiting, tremors, delirium, seizures and decerebrate posturing, and can lead
5.2.2 Adjunctive Therapy
The most common adverse events experienced
by children (aged 1.2 to 17.9 years) undergoing oxcarbazepine adjunctive therapy were somnolence,
12
Monotherapy
Adjunctive therapy
Patients (%)
10
8
6
4
2
o
tig
si
ne
Ve
r
a
a
xi
Am
da
ea
H
At
a
e
ch
nc
ba
ur
st
su
al
di
a/
Vi
se
au
N
e
ng
vo
m
iti
ue
ig
Fa
t
n
io
at
Se
d
D
iz
zi
ne
ss
0
Fig. 5. CNS-related adverse events associated with oxcarbazepine monotherapy and adjunctive therapy. Results from a retrospective study of the records of 947 patients with epilepsy (aged 2 to 90 years) treated with oxcarbazepine as monotherapy (n = 597) or
adjunctive therapy (n = 350). 7% of patients were previously untreated. The most common concomitant antiepileptic drugs were
vigabatrin (in children), valproic acid (in adults) and phenobarbital (phenobarbitone) [in the elderly].[11]
 Adis International Limited. All rights reserved.
CNS Drugs 2001; 15 (2)
156
Wellington & Goa
Oxcarbazepine (n = 138)
Placebo (n = 129)
Somnolence
Headache
Dizziness
Vomiting
Nausea
Diplopia
Fever
Ataxia
Abdominal vision
Viral infection
Fatigue
Rhinitis
Abdominal gait
Nystagmus
Pharyngitis
Abdominal pain
Upper respiratory
tract infection
Anorexia
0
5
10
15
20
25
30
35
40
Incidence of adverse events (%)
Fig. 6. Tolerability of oxcarbazepine adjunctive therapy com-
pared with placebo in children. Incidence of adverse events
reported by ≥10% of 3- to 17-year-old patients with epilepsy
receiving adjunctive treatment with oxcarbazepine 30 to 46
mg/kg/day or placebo for 16 weeks. Patients were taking 1 or 2
concomitant antiepileptic drugs (predominantly carbamazapine, valproic acid, lamotrigine or phenytoin).[77]
to death. The symptoms of chronic hyponatraemia
are more subtle and include anorexia, cramps, personality changes, gait disturbance, stupor, nausea and
vomiting.[87]
While hyponatraemia has been associated with oxcarbazepine therapy, it is usually asymptomatic and
does not lead to discontinuation of the drug.[87,93,94]
The manufacturer’s prescribing information[35]
states that acute hyponatraemia, although usually
asymptomatic, developed in 2.7% of oxcarbazep Adis International Limited. All rights reserved.
ine-treated patients in the 14 controlled monotherapy and adjunctive therapy studies conducted to
date, compared with no patients who received placebo or active controls (carbamazepine, phenobarbital, phenytoin or valproic acid). The evaluation
included records of 1966 patients with epilepsy
aged between 2 and 88 years who had been treated
for 20 months with oxcarbazepine 600 to 1800
mg/day.[35,87] Serum sodium levels were <135 mmol/L
in 423 patients (21.5%) and <125 mmol/L in 54
patients (2.7%). Such low levels were uncommon
in patients aged <18 years (0.5%) and absent among patients <6 years of age. Generally, patients
with hyponatraemia recovered once oxcarbazepine
therapy was stopped. The incidence of symptoms
suggestive of hyponatraemia was similar among all
patients, irrespective of sodium levels and, therefore, most likely due to the treatment milieu rather
than hyponatraemia.[87]
Among recent monotherapy trials which evaluated serum sodium levels,[70-73,76] the incidence of
hyponatraemia was highest in a 10-day study with
a 2-day titration period.[72] 22% of patients receiving oxcarbazepine 2400 mg/day had serum sodium
levels <135 mmol/L, although only one patient
(2%) had a sodium level <125 mmol/L. In contrast,
one patient receiving placebo had sodium levels
<135 mmol/L. One[70,73,76] or 2[71] instances of hyponatraemia were reported in other trials, prompting
treatment discontinuation in one patient.[73] The time
and frequency of serum sampling was often not
reported.[70,71,76]
Although a retrospective study reported serum
sodium levels <135 mmol/L in 9 of 48 children who
received oxcarbazepine as adjunctive therapy (all
were asymptomatic), baseline levels of serum sodium were not measured and neither the age of the
children nor the duration of therapy were reported.[90]
In a study involving 144 randomly selected patients with epilepsy, females were found to have lower serum sodium levels than males (monotherapy:
134 vs 137.6 mmol/L, p < 0.05; adjunctive therapy
131.3 vs 137.9 mmol/L, p < 0.001).[95]
Hyponatraemia was reported in 23% of patients
in a large retrospective study of oxcarbazepine
CNS Drugs 2001; 15 (2)
Oxcarbazepine: An Update
therapy. Friis et al.[11] reported a shift to abnormal
(not defined) serum sodium levels in 23% of the
350 patients (from a total population of 947) with
available laboratory test data. However, only 4 patients (0.4% of the total population) discontinued
treatment because of hyponatraemia.
6. Dosage and Administration
In the US and the UK, oxcarbazepine is approved for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and
as adjunctive therapy in the treatment of partial
seizures in children (aged ≥4 years in the US and
≥6 years in the UK).[35,96] In the UK, the drug is
also approved for use as monotherapy in children
≥6 years of age.[96] Oxcarbazepine is administered
orally, with or without food, and a twice daily regimen is recommended.
The manufacturer recommends that initiation of
monotherapy with oxcarbazepine in adult patients
not currently treated with AEDs should begin with
a dosage of 600 mg/day (given as a twice daily
regimen) and be increased by 300 mg/day every
third day to a dosage of 1200 mg/day.[35] However,
in practice a lower initial dosage may be better tolerated.[97]
Adult patients already being treated with AEDs
can be switched to oxcarbazepine monotherapy by
initiating treatment at a dosage of 600 mg/day
while simultaneously reducing the dosage of the
concomitant AEDs, which should be withdrawn after 3 weeks. Oxcarbazepine should be increased as
clinically indicated by a maximum increment of
600 mg/day at weekly intervals to achieve a dosage
of ≤2400 mg/day.[35]
In adults, adjunctive therapy with oxcarbazepine can begin with a dosage of ≤600 mg/day and,
if clinically indicated, be increased by a maximum
of 600 mg/day at weekly intervals. The manufacturer recommends a daily dosage of 1200 mg/day,
as unpublished results have shown that daily dosages above 1200 mg/day, while more efficacious,
were intolerable in most patients because of adverse
CNS effects.[35] During the titration phase, the patient needs to be observed closely and plasma con Adis International Limited. All rights reserved.
157
centrations of the concomitant AEDs should be
monitored, as they may be altered, especially at oxcarbazepine dosages >1200 mg/day.
Adjunctive therapy in children aged 4 to 16
years can begin with a daily dosage of 8 to 10 mg/kg
(but not exceed 600 mg/day). The target maintenance dose (median ≈30 mg/kg/day) should be
reached within 2 weeks and is dependent upon patient bodyweight (table VIII).[35]
Monotherapy in children can be initiated with a
dosage of 8 to 10 mg/kg/day in 2 divided doses. If
clinically indicated, the dose may be increased by
increments of up to 10 mg/kg/day at approximately
weekly intervals to a maintenance dosage of no
more than 46 mg/kg/day.[96]
Children <8 years of age have an increased
clearance (by about 30 to 40%) compared with
older children and adults and, therefore, may need
higher maintenance dosages to achieve effective
seizure control.[35]
Potential interactions between oxcarbazepine
and other AEDs can result in changes in the concentration of the active metabolite of oxcarbazepine (MHD), reducing the therapeutic effect (section 3.4.1 and table IV). Strong inducers of CYP
isozymes (i.e. carbamazepine, phenytoin and phenobarbital) decrease the plasma concentrations of
MHD by 29 to 40%. Concomitant use of oxcarbazepine at dosages above 1200 mg/day and
phenytoin elevates the plasma concentration of
phenytoin by up to 40%. Therefore, during adjunctive therapy with phenytoin, a lower dose of phenytoin may be required.[35,95]
Coadministration of oxcarbazepine with hormonal contraceptives may reduce the effectiveness
of birth control as oxcarbazepine has been shown
to reduce plasma concentrations of the hormonal
Table VIII. Recommended daily dosage of oxcarbazepine, adjusted for bodyweight, in paediatric patients with epilepsy undergoing adjunctive therapy[35]
Bodyweight (kg)
20-29
Target dosage (mg/day)
900
29.1-39
1200
>39
1800
CNS Drugs 2001; 15 (2)
158
components of oral contraceptives (section 3.4.2
and table IV). Other forms of nonhormonal contraceptives are recommended.[35]
The pharmacokinetics and metabolism of oxcarbazepine are not significantly affected by hepatic
dysfunction (section 3.3) and dose adjustment is
generally not needed in patients with mild to moderate hepatic dysfunction.[35] However, the pharmacokinetics of oxcarbazepine have not been evaluated in patients with severe hepatic impairment.
In patients with impaired renal function (CLCR
<1.8 L/h), clearance is decreased (section 3.3) and
oxcarbazepine therapy should be initiated at 300
mg/day and increased slowly to achieve the desired
clinical response.
Serum sodium levels need to be monitored during treatment with oxcarbazepine, especially if the
patient is receiving concomitant medication known
to decrease serum sodium levels (for example, drugs
that are associated with inappropriate antidiuretic
hormone secretion) or if the symptoms of hyponatraemia (section 5.3) appear.[35]
Patients with a history of hypersensitivity to
carbamazepine should be informed of a 25 to 30%
chance that they will also experience hypersensitivity reactions to oxcarbazepine. If signs of hypersensitivity develop, oxcarbazepine treatment must
be discontinued immediately.[35]
It is not known if oxcarbazepine is a human teratogen, but animal studies have shown an increase
in fetal structural abnormalities at doses close to
the maximum recommended human dose. Therefore, oxcarbazepine should be administered during
pregnancy only if the potential benefit to the patient outweighs the potential risk to the fetus. Oxcarbazepine and its active metabolite are both excreted in human milk and, therefore, a decision to
continue treatment in the nursing mother should
consider the potential for serious adverse reactions
to oxcarbazepine in the infant.[35] It is also recommended that folic acid supplementation be instituted at a dosage of 0.8 to 1 mg/day in women with
epilepsy who are of childbearing age. Higher dosages (4 mg/day) are recommended for women with
a history of child defects.[98]
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Withdrawal of oxcarbazepine, and AEDs in general, is problematic in that the decision to discontinue treatment is often not based on well defined
criteria.[99-102] The Quality Standards Subcommittee of the American Academy of Neurology, after
analysing 53 studies, published a report with recommended guidelines on AED discontinuation in
children and in adults.[103] It is recommended that
adult and paediatric patients with a single type of
partial or generalised seizure who have a normal
neurological examination and IQ, a normalised
EEG with treatment, and who have been seizurefree for 2 to 5 years on AEDs, be withdrawn from
treatment with AEDs. Seizure recurrence should be
<31.2% for children and <39% for adults if the
above conditions are met. Discontinuation of
AEDs may be appropriate in patients not meeting
these criteria even though the risk of relapse may
be higher.[103] To minimise the increased potential
for seizure recurrence, AEDs, including oxcarbazepine, should be withdrawn gradually.[35]
7. Place of Oxcarbazepine in the
Management of Epilepsy
The main objective in epilepsy management is
the control of seizures. Individuals with epilepsy
have a high incidence of depression, anxiety, interpersonal difficulty and lowered self-esteem often
brought about by the social stigma attached to epilepsy and lifestyle limitations imposed by their
condition.[104,105] A successful reduction in seizure
frequency not only lowers the risk of harm to the
patient but also improves the patient’s quality of
life through improved self-image. People with epilepsy have a 2 to 3 times greater risk of death than
those without, and standardised mortality ratios of
≤8 have been reported.[106,107] Causes of death attributed to epilepsy include trauma, suicide and
pneumonia,[106] although the most common seizure-related death is sudden unexpected death in
epilepsy.[107]
Estimates of the prevalence of epilepsy vary but
are in the range of 0.4 to 1% of the world’s population. However, in some developing countries the prevalence is as high as 2%.[108] The incidence rate of
CNS Drugs 2001; 15 (2)
Oxcarbazepine: An Update
unprovoked seizures ranges from 20 to 70 per 100 000
persons in industrialised countries[106,109,110] and in
developing countries may be >100 per 100 000.[106]
Partial epilepsy, which is often symptomatic of an
underlying focal brain injury, accounts for about
60% of all epilepsy cases, whereas generalised seizures account for approximately 30%.[105,110]
Seizures are most common in the first 10 years
of life and then decline until about age 50, whereupon the incidence increases again.[111] About 15
per 100 000 adults ≤50 years of age experience seizures, increasing to approximately 86 and 114 per
100 000 adults by ages 65 and 75 years, respectively.[112]
Identification of the cause of seizures is of paramount importance as treatment, by way of long
term AED therapy, is often not needed. If therapeutic intervention of precipitating factors (for example, metabolic or systemic disorders) is achievable,
specific treatment regimens could be implemented
to correct the underlying cause. Alterations to daily
activities (i.e. reducing stress and intake of alcohol
and caffeine, increasing exercise and improving
sleep) can help reduce seizure frequency,[105] as can
a ketogenic diet.[113]
However, if the underlying cause cannot be determined and seizures recur, long term treatment
with AEDs is warranted.[105] Although the older
AEDs such as carbamazepine, phenytoin and valproic acid are the most common forms of medical
treatment for partial and generalised tonic-clonic
seizures, the use of newer drugs such as oxcarbazepine is becoming more frequent. New anticonvulsants such as oxcarbazepine have been developed because of the high incidence of adverse
events associated with the established AEDs. Furthermore, complex drug interactions due to induction (carbamazepine and phenytoin) or inhibition
(valproic acid) of hepatic microsomal isozymes or
displacement from binding sites, are also a feature
of these drugs. Oxcarbazepine does not interfere
with the metabolism of most other AEDs to a great
extent, although it does have clinically significant
interactions with phenytoin, phenobarbital and
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159
lamotrigine (section 3.4.1) and also reduces the effectiveness of oral contraceptives (section 3.4.2).
Oxcarbazepine has proved effective in the management of partial seizures with or without secondary generalisation and generalised tonic-clonic seizures in adults and children as monotherapy and
adjunctive therapy.
7.1 In Adults
Previous studies[64,65] showed oxcarbazepine
monotherapy to be as effective as carbamazepine
in the treatment of partial and generalised tonicclonic seizures. Moreover, recent comparative data
from monotherapy trials (section 4.1.1) have
shown oxcarbazepine to reduce seizure frequency
as effectively as phenytoin or valproic acid in newly diagnosed patients with partial and/or generalised tonic-clonic seizures. As many as 60% of
patients with newly diagnosed epilepsy treated with
dosages of oxcarbazepine up to 2400 mg/day as
monotherapy can be expected to be free of seizures.
Data from 2 additional trials support the use of
oxcarbazepine monotherapy (2400 mg/day) in the
treatment of adult patients with seizures refractory
to treatment with one or more AEDs (section 4.1.1).
However, treatment response is lower than in patients with newly diagnosed epilepsy (25% of patients receiving oxcarbazepine 2400 mg/day were
seizure-free compared with 2% patients receiving
placebo in one trial).
The most common adverse events associated
with oxcarbazepine therapy in adults are somnolence, dizziness, headache, nausea, vomiting, rash,
diplopia and fatigue. However, in oxcarbazepine
monotherapy trials, <8% of patients withdrew
from treatment because of adverse events. Oxcarbazepine was tolerated better than phenytoin (particularly with respect to gum hyperplasia, tremor,
diplopia and nystagmus; table VII), and valproic
acid (particularly with respect to tremor, weight
gain, alopecia and headache; section 5.1.1).
While monotherapy is the accepted choice for
patients with newly diagnosed epilepsy, adjunctive therapy is important for patients with seizures
CNS Drugs 2001; 15 (2)
160
intractable to medication with only one AED.[114]
Whereas switching medication from one AED to
another is effective in about 40% of patients with
partial seizures refractory to the first-line agent, adjunctive therapy with 2 or 3 drugs may be beneficial in a small minority of patients.[115]
Data from 1 trial (section 4.1.2) showed oxcarbazepine, in conjunction with 1 to 3 AEDs, to
be effective at controlling partial seizures in patients with seizures refractory to optimum dosages
of the concomitant AEDs. However, the highest
dosage of oxcarbazepine (2400 mg/day) was not tolerated well, with >65% of the patients discontinuing treatment because of adverse events (section
5.1.2). Lower dosages were also significantly more
effective than placebo and were well tolerated.
Although usually asymptomatic, acute hyponatraemia (serum sodium level <125 mmol/L) occurs
in about 2.7% of patients receiving oxcarbazepine
treatment. The manufacturer recommends that the
measurement of serum sodium levels be considered, especially if the patient is receiving concomitant medication known to decrease serum sodium
levels or if the symptoms of hyponatraemia appear
(section 6).
7.2 In Children
Between 0.5 and 1% of children have epilepsy
and the onset of seizures usually occurs during
infancy.[116] The decision to initiate AED treatment
in children (as well as adults) involves a riskbenefit analysis including the probability of seizure recurrence.[117] However, the diagnosis of epilepsy in children is problematic and often requires
seizure repetition. For this reason, around 75% of
children with newly diagnosed epilepsy have previously had more than one seizure.[117] AED therapy in children is difficult in that about 25% of
paediatric patients treated with traditional AEDs
remain refractory to treatment and experience troublesome adverse events.[118,119] Therefore, newer
AEDs such as oxcarbazepine are tried.
Oxcarbazepine is effective and well tolerated as
adjunctive therapy in the treatment of children and
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Wellington & Goa
adolescents with refractory partial seizures, as
shown in a placebo-controlled trial (sections 4.2.2 and
5.2.2).
Although data are limited, oxcarbazepine
monotherapy has been shown to be effective in the
treatment of partial seizures and generalised tonicclonic seizures in children and adolescents, achieving seizure control equivalent to that of phenytoin
with significantly fewer adverse events (section
4.2.1). More extensive clinical experience is required to clearly establish efficacy.
7.3 Conclusions
Oxcarbazepine as monotherapy is a viable alternative to established AEDs in the treatment of partial and generalised tonic-clonic seizures in adults
and children. However, additional data are required
to solidify its role as a front-line choice for monotherapy in the treatment of children with epilepsy.
Furthermore, oxcarbazepine is effective as adjunctive therapy in the treatment of refractory partial
seizures in both adults and children. The drug is
tolerated better than the older, established AEDs,
and, while it does have clinically significant interactions with some drugs, it has a lower potential
for drug interactions. These attributes make oxcarbazepine an effective component in the initial
treatment of adults and children with newly diagnosed partial or generalised tonic-clonic seizures,
and also an effective adjunct for medically intractable partial seizures in both adults and children.
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Correspondence: Keri Wellington, Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,
Auckland 10, New Zealand.
E-mail: [email protected]
CNS Drugs 2001; 15 (2)