01-02-2001 | Adis Drug Evaluation
Oxcarbazepine
An Update of its Efficacy in the Management of Epilepsy
Published in: CNS Drugs | Issue 2/2001
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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 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 half-life 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 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, 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 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.