Pharmacology

Pharmacology. The exact mechanism of action of oxcarbazepine is not well understood. Blockade of voltage-sensitive sodium channels could contribute to the antiepileptic efficacy of oxcarbazepine. Additional mechanisms of action, eg, an effect on potassium channels, might be clinically important. Oxcarbazepine also inhibits the release of glutamate.

Pharmacokinetics. Important pharmacokinetic features are as follows:

(1) Oxcarbazepine is the 10-keto derivative of carbamazepine. Absorption is about 95% following oral intake, and peak concentrations are reached within 4 to 6 hours.

(2) It is rapidly metabolized to 10,11-dihydro-10-hydroxycarbamepine, which is excreted in the urine as monohydroxy derivative that are in 2 enantiomeric forms: (R)-licarbazepine and (S)-licarbazepine (14).

(3) The elimination half-life of monohydroxy derivative is 8 to 13 hours, and kinetics are linear within the therapeutic dose range.

(4) Only 38% of the monohydroxy derivative is bound to serum proteins, as compared with 67% for the parent compound.

(5) As a neutral lipophilic substance, the active metabolite of oxcarbazepine is able to diffuse rapidly through the various membranes and the blood-brain barrier.

Oral loading of oxcarbazepine suspension was shown to be as effective as tablet and well-tolerated for rapidly achieving therapeutic levels of 10,11-dihydro-10-hydroxycarbazepine, the active metabolite of oxcarbazepine, in patients with epilepsy, particularly in those at high risk of recurrent seizures (13).

A model-based analysis predicted the comparable efficacy of OXC-XR (extended-release oxcarbazepine) qd versus OXC-IR (immediate-release oxcarbazepine) bid at monohydroxy derivative Cmin concentrations at a dose of 1200 to 2400 mg/day as monotherapy or adjunctive therapy (09). Based on this analysis, the U.S. Food and Drug Administration approved OXC-XR for use as monotherapy in adults and children 6 years of age or older with partial-onset seizures, with weight-based dosing in children.

Therapeutic drug monitoring. A bioanalytical method for the simultaneous determination of oxcarbazepine and its pharmacologically active metabolite -- 10, 11-dihydro-10-hydroxycarbamazepine -- in human plasma has been developed using a high-performance liquid chromatography with tandem mass spectrometry and successfully used to monitor plasma concentrations of the drug in a clinical study (19).

Pharmacogenetics/pharmacogenomics. The HLA-B*15:02 genotype is a predictor of the development of Stevens Johnson syndrome as well as toxic epidermal necrolysis as adverse reactions to carbamazepine or oxcarbazepine, and prescreening is recommended (31). The variant allele HLA-A*31:01 is associated with greater risk of maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms, and Stevens Johnson syndrome or toxic epidermal necrolysis in patients treated with carbamazepine (25).

Clinical trials

Numerous clinical trials with oxcarbazepine have been reported during the past decade. Some of the trials in which oxcarbazepine has been used as monotherapy are listed in Table 1. The indication in these trials was partial epilepsy with or without secondarily generalized seizures and generalized tonic-clonic seizures without partial onset.

Table 1. Some Clinical Trials with Oxcarbazepine

Indications

Oxcarbazepine is indicated as a monotherapy for the treatment of partial epilepsy with or without secondary generalization.

Off-label uses

Contraindications

Oxcarbazepine is not recommended in patients with known hypersensitivity to the drug. Oxcarbazepine should not be used in patients with a history of atrioventricular block.

Goals and duration of treatment

The aim is control of seizures; oxcarbazepine can be used both as a monotherapy and combined with other antiepileptic drugs. The initial dose is 300 mg, which is increased until a good therapeutic effect is reached, usually with an average of 900 mg per day in adults. The therapy is continued as long as it is required. A study in China has shown that oxcarbazepine monotherapy does not impair neuropsychologic functions and is safe for use in benign epilepsy with centrotemporal spikes, which is associated with pervasive cognitive deficits and behavior problem (18).

Dosing

The recommended dosage of oxcarbazepine as monotherapy for adults with epilepsy is 600 to 1200 mg orally per day.

Special considerations

Serum sodium estimation should be done at the start of therapy and repeated periodically to detect hyponatremia.

Oxcarbazepine, like other carbamazepine derivatives, should be used with caution for generalized epilepsy as it can exacerbate seizures. Its metabolite (S)-licarbazepine has been shown to exacerbate spike and wave discharges in experimental studies in mice harboring the human γ-aminobutyric acid A receptor γ2(R43Q) mutation (14).

Pregnancy. A significant decrease of plasma concentration of 10-monohydroxy derivate of oxcarbazepine is associated with deterioration of seizure control during treatment of pregnant women (24). A potential risk to the fetus exists during pregnancy. Oxcarbazepine should be used only if the benefits outweigh the risks. The mother should receive supplementation with folic acid during pregnancy to reduce the risk of neural tube malformations of the offspring. Because oxcarbazepine and its active metabolite are secreted in the mother's milk, breast feeding of the newborn should be avoided.

Pediatric. Safety in pediatric use has been demonstrated by clinical trials. A prospective study has shown that oxcarbazepine can be considered an effective and well-tolerated first-line drug for long-term monotherapy in children with epilepsy, both for idiopathic and symptomatic/cryptogenic forms (10).

The “Warnings and Precautions” section of the prescribing information for oxcarbazepine tablets and oral suspension, indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children ages 4 to 16 years with epilepsy, describes serious dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis that have been reported in both children and adults in association with oxcarbazepine use.

Geriatric. In elderly patients with renal insufficiency, the dose may need to be reduced. The elderly show a higher frequency of adverse effects.

Anesthesia. There are no special precautions for anesthesia.

Hepatic porphyria. Most antiepileptic drugs, except gabapentin, are known to precipitate clinically latent porphyria by inducing hepatic metabolism. Because of low induction of hepatic enzymes, oxcarbazepine can also be successfully administered to patients with hepatic porphyria and focal epilepsy who do not respond to treatment with gabapentin.

Interactions

Because of the lack of hepatic enzyme-inducing properties, oxcarbazepine has little or no interaction with other antiepileptic drugs. Concomitant use of carbamazepine, sodium valproate, and phenytoin in epileptic patients showed no clinically relevant interactions, indicating that oxcarbazepine can be used as an add-on therapy with other antiepileptic drugs. Interactions with other drugs are modest. However, oxcarbazepine reduces plasma concentrations of estrogen and progestogen components of steroid oral contraceptives, leading to decreased efficacy of contraception. Combination with monoamine oxidase inhibitors should be avoided because oxcarbazepine has structural similarities with tricyclic antidepressants.

Adverse effects

A meta-analysis of literature and systematic review of clinical studies reveals no evidence that oxcarbazepine administration has any significant effect on serum levels of homocysteine, vitamin B12, and folate in epileptic patients (26).

Although oxcarbazepine has a lower risk of cutaneous adverse drug reactions than carbamazepine, an association of HLA-B*40:02 and HLA-DRB1*04:03 alleles with oxcarbazepine hypersensitivity, manifesting as susceptibility to maculopapular eruption or more severe Stevens-Johnson syndrome and toxic epidermal necrolysis has been demonstrated in Korean patients (23).

Most of the adverse effects are minor and transient. These usually occur at the start of the therapy and subside during the therapy. Ataxia, dizziness, fatigue, nausea, somnolence, and diplopia have been significantly associated with oxcarbazepine. Analysis of a drug safety database shows that the occurrence of adverse events in patients on oxcarbazepine therapy is significantly dependent on the serum level of mono-hydroxy-carbazepine, the main metabolite of oxcarbazepine, rather than the dosage of the drug (28).

Hyponatremia associated with oxcarbazepine is usually benign and can be managed with water restriction. Acute water intoxication may occur rarely and may require drug discontinuation. Possible mechanisms of hyponatremia include a direct effect of oxcarbazepine on the renal collecting tubules or an enhancement of their responsiveness to circulating antidiuretic hormone. Serum sodium level should be monitored during oxcarbazepine therapy.

Oxcarbazepine-induced oculogyric crises occur rarely and can be relieved by vagus nerve stimulation, which has been used as a treatment for epilepsy.

Psychotic side effects have been reported following oxcarbazepine therapy in a patient with coexistent Parkinson disease and epilepsy, possibly because of its dopaminergic effect, and caution is recommended in its use in such patients (15).

Oxcarbazepine has been reported to aggravate seizures in Jeavons syndrome, which is a distinct clinical syndrome manifested by eyelid myoclonia, photosensitivity, and EEG paroxysms, which may be associated with absence (22). A child with complex partial seizures developed infantile spasms, developmental regression, and hypsarrhythmia (West syndrome) during the 2 weeks directly following initiation of oxcarbazepine, and the symptoms resolved within a few days after discontinuation of therapy (32). A patient with Rasmussen syndrome with seizures resistant to valproic acid developed frequent absence seizures after starting oxcarbazepine as add-on therapy but disappeared after oxcarbazepine was discontinued (05).

Retrospective analysis of adverse effects of ingestions of oxcarbazepine overdose reported to United States poison centers over a period of 13 years showed that serious outcomes were infrequent (less than 1% in the pediatric patients) (30). Even in adults with intentional ingestion of oxcarbazepine, there were few neurologic and cardiovascular complications.