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Oxcarbazepine

A Review of its Use in Children with Epilepsy

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Summary

Abstract

Oxcarbazepine (Trileptal®, Timox®) is structurally related to carbamazepine and has anticonvulsant activity. Studies suggest that the anticonvulsant activity of oxcarbazepine is mediated via the blocking of neuronal ion channels.

In patients aged <18 years, the efficacy of oxcarbazepine monotherapy was similar to that of phenytoin in children with partial onset or generalized tonic-clonic seizures in a 48-week trial. Additional supporting findings demonstrated that 43–71% of patients with partial onset, generalized or undetermined epilepsy were seizure free after oxcarbazepine monotherapy (mean dosage 27.7–50 mg/kg/day; duration 1–5 years). In contrast, one small nonblind trial showed more patients treated with oxcarbazepine monotherapy than with carbamazepine monotherapy had recurrent seizures during 16 months of therapy (although the conclusions that can be drawn from this trial are limited).

As adjunctive therapy, oxcarbazepine was significantly better than placebo at reducing seizure frequency in children and adolescents with refractory partial onset seizures with or without secondary generalization: the median percentage change in partial onset seizure frequency was 35% vs 9%, respectively, during 16 weeks of therapy. In noncomparative trials of adjunctive oxcarbazepine (mean dosage of 34.5–56.7 mg/kg/day), 7–11 % of patients with partial onset or generalized seizures were seizure free during treatment, and 20–54% had seizure reductions of ≥50%.

Oxcarbazepine was generally well tolerated during monotherapy and adjunctive therapy; 2.5% and 10% of patients withdrew from well controlled trials of oxcarbazepine monotherapy and adjunctive therapy. Oxcarbazepine monotherapy was better tolerated than phenytoin and events observed in oxcarbazepine-treated patients were transient.

Oxcarbazepine metabolism is largely unaffected by induction of the cytochrome (CYP) P450 system. However, oxcarbazepine can inhibit CYP2C19 and induce CYP3A4 and CYP3A5, thereby interfering with the metabolism of other drugs (e.g. phenytoin). In addition, oxcarbazepine decreases plasma levels of oral contraceptives and alternative contraceptive methods should be used.

In conclusion, oxcarbazepine (as both monotherapy and adjunctive therapy) has shown efficacy in the treatment of partial onset seizures in children with epilepsy. Nevertheless, the generally favorable tolerability profile and relatively low potential for drug interactions of oxcarbazepine make it a valuable option in the treatment of childhood epilepsy.

Pharmacodynamic Properties

Oxcarbazepine is structurally related to carbamazepine. The specific mechanism of action is unknown; however, in vitro rodent studies suggest that the anticonvulsant activity of oxcarbazepine and its major active metabolite, the monohydroxy derivative (MHD) 10-hydroxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, occurs primarily through blocking neuronal ion channels. In particular, oxcarbazepine and MHD have been shown to block voltage-sensitive sodium channels, thereby stabilizing neural membranes, inhibiting repetitive neuronal firing and reducing synaptic impulse propagations. Limited studies also suggest that high-voltage calcium channels may be involved in the anticonvulsant activity of oxcarbazepine through the ability of the drug to reduce excitatory synaptic transmission.

Cognitive function was minimally affected in healthy volunteers and adult patients with newly-diagnosed epilepsy after short-term (2 weeks) and longer-term (4 months) oxcarbazepine treatment, respectively. There are no comparable data in children.

Oxcarbazepine therapy affected endocrine function in girls aged 8–18 years. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were higher than in control patients, and pubertal development was delayed, although the study was small and retrospective.

Pharmacokinetic Properties

Oxcarbazepine is rapidly and almost completely (≥96%) absorbed after oral administration. In children aged 2.3–12.5 years, specific (values divided by administered dose) peak plasma concentrations (Cmax spe) of 0.46–0.6 µmol/L were reached approximately 1 hour after administration of oxcarbazepine 5 or 15 mg/kg and the Cmax spe of MHD (2.72–4.48 µnol/L) was reached after 3–4 hours.

The area under the plasma concentration-time curve (AUC) of MHD increases significantly with age; patients aged 2–6 years have AUC levels 30% lower than older children and adults.

Steady-state concentrations of MHD are achieved 2–3 days after implementation of a twice-daily administration regimen. The relationship between oxcarbazepine dosage and steady-state MHD concentrations is log-linear in children aged 1–16 years.

MHD is distributed equally between plasma and red blood cells, and the apparent volume of distribution is 0.7–0.8 L/kg. Plasma protein binding is 37–43% for MHD and 60–67% for oxcarbazepine. Reduction of oxcarbazepine by cytosolic arylketone reductase forms the major active metabolite MHD (as an enantiomeric pair with equivalent anticonvulsant activity).

Most of an administered dose of oxcarbazepine is excreted via the kidneys. The plasma elimination half-life (t½β) in healthy adults is 1–2.5 hours for oxcarbazepine, and 8–10 hours for MHD. In children, the t½β of MHD increases with age (quantitative data not reported). The rate of renal clearance of MHD is 0.71–1.26 L/h in healthy volunteers and is prolonged in patients with renal failure because of reduced renal clearance. Systemic clearance is higher in children aged ≤8 years than in older children and adults.

Oxcarbazepine is metabolized by noninducible enzymes; thus, minimal interactions occur between oxcarbazepine and antiepileptic drugs that induce CYP isozymes. However, oxcarbazepine can inhibit CYP2C19 and induce CYP3A4 and CYP3A5, so can interfere with the metabolism of other drugs including phenytoin.

Therapeutic Efficacy

The efficacy of oxcarbazepine monotherapy was similar to that of phenytoin in the treatment of children and adolescents with partial onset seizures or generalized tonic-clonic seizures in a large randomized, double-blind study. Approximately 60% of patients treated with either oxcarbazepine or phenytoin were seizure free during the 48-week maintenance period and seizure type did not appear to have a marked affect on response rate. In addition, oxcarbazepine monotherapy was less effective than carbamazepine therapy in one small nonblind study.

In a noncomparative, nonblind, prospective study and retrospective monotherapy analyses 43–71% of patients with partial, generalized or undetermined epilepsy receiving oxcarbazepine were seizure free at completion of therapy (1–5 years). Oxcarbazepine treatment also improved health-related quality-of-life evaluations (emotional well-being, the ability to carry out everyday activities, including cognitive functions) in one trial (significance not reported).

As adjunctive therapy, oxcarbazepine was significantly better than placebo at reducing seizure frequency in children and adolescents with uncontrolled partial onset or secondary generalized seizures. During the large well designed 16-week trial, the median percentage change in seizure frequency per 28 days was 4-fold greater in oxcarbazepine than in placebo recipients (35% vs 9% decrease). Furthermore 3-fold more patients were seizure-free in the oxcarbazepine group (3.6% vs 0.8%, respectively), and the number of patients with ≥50% reduction in seizure frequency was approximately 40% with oxcarbazepine and was twice as high as with placebo.

In three additional studies, oxcarbazepine (mean dosage 44.7–56 mg/kg/day) reduced seizure frequency by ≥50% in 20–54% of patients with partial onset and generalized seizures, and 7–11% were seizure free.

Tolerability

Oxcarbazepine was generally well tolerated as both monotherapy and adjunctive therapy in children aged <18 years: common adverse events included somnolence, headache, dizziness, and vomiting. Oxcarbazepine monotherapy was better tolerated than both phenytoin (including nervousness [2.1% vs 11.7%], dizziness [9.4% vs 22.3%], and gum hyperplasia [2.1% vs 25.5%]) and carbamazepine (overall 31% vs 61%) and events observed in oxcarbazepine-treated patients were transient in several studies.

During adjunctive therapy, 91% and 82% of patients receiving oxcarbazepine or placebo, respectively, reported adverse events and 10% of patients receiving oxcarbazepine withdrew from treatment compared with 3% in the placebo group. Nausea, vomiting, dizziness headache and somnolence were each reported by >20% of patients in a large well designed study.

Altered laboratory values, including hyponatremia and abnormal liver enzyme levels, were also observed in a small number of patients.

Dosage and Administration

Oxcarbazepine is approved for use as adjunctive therapy in the treatment of partial onset seizures in children aged ≥4 years in the US and Canada, and as monotherapy or adjunctive therapy in the treatment of partial onset seizures in children aged ≥6 years in the EU, Central and Latin America and the majority of Asia.

Oxcarbazepine monotherapy in children should be initiated with a dosage of 8–10 mg/kg/day in two divided doses. This may be increased by weekly increments of up to 10 mg/kg/day to a maintenance dosage not exceeding 46 mg/kg/day. Administration of oxcarbazepine as adjunctive treatment in children aged 4–16 years should be initiated at a daily dosage of 8–10 mg/kg (not exceeding 600 mg/day). The target maintenance dose should be achieved after 2 weeks and is dependent on patient bodyweight. Children aged <8 years have increased clearance rates (by approximately 30–40%) compared with older children and adults and may therefore require higher oxcarbazepine dosages to achieve effective seizure control.

Dosage adjustment is generally not required in patients with mild to moderate hepatic dysfunction; however, in patients with impaired renal function (creatinine clearance <1.8 L/h [<30 mL/min]), oxcarbazepine therapy should be initiated at half the usual dosage and slowly increased to achieve the desired clinical response.

Dosage adjustment (and alternative forms of contraception) may be required in patients receiving oral contraceptives and concomitant oxcarbazepine therapy.

Care should be taken when administering oxcarbazepine to patients with hypersensitivity to carbamazepine as hypersensitive patients have a 25–30% chance of also experiencing a reaction to oxcarbazepine. If hypersensitivity is suspected, oxcarbazepine treatment must be discontinued immediately.

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Corresponding author

Correspondence to Lynne M. Bang.

Additional information

Various sections of the manuscript reviewed by: M. Brodie, Epilepsy Unit, Western Infirmary, Glasgow, Scotland; S. Crecco, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts, USA; E. Faught, Department of Neurology, University of Alabama School of Medicine, Birmingham, Alabama, USA; E. Gaily, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland; M. Kalis, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts, USA; D. Schmidt, Epilepsy Research Group, Berlin, Germany; P.E. Smith, Epilepsy Unit, University Hospital of Wales, Cardiff, Wales; E. Tecoma, UCSD Epilepsy Center, University of California, San Diego, California, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on oxcarbazepine, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). 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’ and ([‘children’ or ‘childhood’ or ‘pediatric’ or ‘infants’] and [‘epilepsy’ or ‘epilepsies’ or ‘epileptic’]). EMBASE search terms were ‘oxcarbazepine’ and ([‘children’ or ‘infants’ or ‘pediatric’ or ‘paediatric] and ‘epilepsy’). AdisBase search terms were ‘oxcarbazepine’ or ‘GP-47680’ and ([‘children’ or ‘childhood’ or ‘infants’ or ‘pediatric’ or ‘paediatric’] and [‘epilepsy’ or ‘epilepsies’]). Searches were last updated 18 July 2003.

Selection: Studies in children with epilepsy who received oxcarbazepine therapy. 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, children, pharmacodynamics, pharmacokinetics, therapeutic use.

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Bang, L.M., Goa, K.L. Oxcarbazepine. Pediatr-Drugs 5, 557–572 (2003). https://doi.org/10.2165/00148581-200305080-00006

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