Oxcarbazepine is the 10-keto analogue of carbamazepine but has a distinct pharmacokinetic profile. In contrast to the oxidative metabolism of carbamazepine, oxcarbazepine is rapidly reduced to its active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine. With the possible exception of the P450IIIA isozyme of the cytochrome P450 family, neither oxcarbazepine nor its monohydroxy derivative induce hepatic oxidative metabolism.
Direct comparison of oxcarbazepine and carbamazepine has shown no difference in efficacy between these 2 agents in terms of reducing seizure frequency in patients with partial epilepsy with or without secondary generalisation, or with tonic-clonic seizures. Substitution of oxcarbazepine for carbamazepine in multiple antiepileptic drug regimens improved seizure control in some patients with refractory epilepsy; however, the rise in serum concentrations of concurrent antiepileptic agents secondary to elimination of carbamazepine-associated hepatic enzyme induction may have also played a role. Substitution of oxcarbazepine for carbamazepine was associated with improved cognition and alertness in some patients with epilepsy.
Limited data indicate that oxcarbazepine may be a useful alternative to carbamazepine in the management of trigeminal neuralgia. Experience in patients with acute mania is promising, but the value of oxcarbazepine in managing affective disorders, particularly as a prophylactic agent, is not established.
Oxcarbazepine may be better tolerated than carbamazepine; however, the current published database is small and the potential for oxcarbazepine to induce the type of serious idiosyncratic reactions occasionally associated with carbamazepine is unknown. Hyponatraemia has been reported in patients treated with oxcarbazepine. Although apparently asymptomatic, fluid restriction may be deemed necessary in some patients to reduce the risk of precipitating seizures secondary to low serum sodium.
Thus, oxcarbazepine appears to be an effective substitute for carbamazepine in those patients intolerant of this agent, or experiencing significant drug interactions. Wider clinical experience should help clarify the long term efficacy and tolerability of oxcarbazepine. Pharmacokinetic advantages over current antiepileptic drugs, carbamazepine in particular, may then favour oxcarbazepine for consideration as a first-line agent in the management of partial and tonic-clonic epilepsy.
Oxcarbazepine is reduced rapidly after oral absorption to its therapeutically active metabolite 10,11-dihydro-10-hydroxy-carbamazepine. Both compounds have anticonvulsant efficacy similar to carbamazepine in standard seizure models. These in vivo models indicate that oxcarbazepine has therapeutic potential in the management of partial and tonic-clonic, but not absence, seizures. After ingestion of a single dose of oxcarbazepine 600mg by healthy volunteers, maximum plasma concentrations (Cmax) of 10,11-dihydro-10-hydroxy-carbamazepine of approximately 5 mg/L were achieved after 8 hours. Steady-state plasma concentrations of 10,11-dihydro-10-hydroxy-carbamazepine, measured in patients with epilepsy, were 9-fold higher than plasma concentrations of the parent drug, and there was a linear correlation between plasma drug and metabolite concentrations and oxcarbazepine dosage.
Oxcarbazepine and its metabolite are widely distributed within the body. The volume of distribution of 10,11-dihydro-10-hydroxy-carbamazepine is approximately 0.7 to 0.8 L/kg, and 40% is bound to plasma protein. Both oxcarbazepine and 10,11-dihydro-10-hydroxy-carbamazepine cross the placenta and appear in breast milk.
No significant change in the half-life of elimination of either oxcarbazepine or 10,11-dihydro-10-hydroxy-carbamazepine is seen with continued drug administration, in contrast to the autoinduction of metabolism seen with carbamazepine. 96% of a radiolabelled dose of oxcarbazepine can be found in the urine, but < 1% appears as unchanged drug.
The value of monitoring plasma concentrations of oxcarbazepine or 10,ll-dihydro-10-hydroxy-carbamazepine is not established. With the possible exception of hyponatraemia, the appearance of serious adverse effects has not been correlated with a particular plasma drug concentration, nor is there an established ‘therapeutic window’.
In a large controlled study, oxcarbazepine was as effective as carbamazepine in reducing seizure frequency in patients with newly diagnosed epilepsy; 80% of subjects in either group had a ⩾ 50% decrease in the incidence of seizures. Similarly, both agents were equally effective when replacing phenytoin (diphenylhydantoin) in patients with various tonic-clonic or partial seizure types who were refractory to and/or intolerant of phenytoin. Oxcarbazepine was also effective in patients with refractory epilepsy when replacing carbamazepine in multiple drug regimens, but the confounding influence of increased serum concentrations of, for example, concomitantly administered phenytoin or valproic acid (valproate sodium) after withdrawal of carbamazepine on the evaluation of both the efficacy and tolerability of oxcarbazepine must be kept in mind. Several investigators report improved alertness and cognition in patients switched from carbamazepine to oxcarbazepine.
Experience with oxcarbazepine in trigeminal neuralgia has been limited to small numbers of patients intolerant of, or having pain refractory to, carbamazepine. It appears to have equivalent analgesic effects compared with carbamazepine. In patients with acute mania, results of short term comparative trials with haloperidol or lithium indicate similar improvement in mania rating scale values for patients administered oxcarbazepine. In contrast, results of the single available prophylactic trial in 18 patients with affective disorders favour lithium over oxcarbazepine. These results are preliminary and further evaluation in patients with affective disorders is needed to clarify the role of oxcarbazepine in this indication.
Oxcarbazepine may be better tolerated than carbamazepine, although the difference is probably modest. A limited published database precludes accurate estimation of the incidence of adverse effects, most of which involve the central nervous system (e.g. drowsiness, dizziness, ataxia, headache), with additional reports of diarrhoea, nausea and vomiting, and anorexia. Generally these effects are mild and transient. The propensity of oxcarbazepine to induce the idiosyncratic reactions seen occasionally in carbamazepine-treated patients is unknown.
Approximately 75% of patients with skin reactions to carbamazepine tolerate oxcarbazepine, allowing this agent to be substituted in a substantial portion of these patients.
Oxcarbazepine can induce a decrease in plasma sodium level which is greater than the decrease seen with carbamazepine at clinically equivalent dosages. This hyponatraemia appears to be linearly related to oxcarbazepine dosage and plasma concentrations of 10,11-dihydro-10-hydroxy-carbamazepine. Oxcarbazepine-induced hyponatraemia has not been linked to increased seizure activity; however, fluid restriction has been necessary in some patients.
Because hepatic oxidative enzymes play a minor role in the metabolism of oxcarbazepine, enzyme induction is not a problem with this agent. The exception may be the P450IIIA isozyme of the P450 family. As a result, estrogen plasma levels may be decreased in women taking oral contraceptives containing ethinylestradiol with possible breakthrough bleeding and loss of contraceptive efficacy. The metabolism of other antiepileptic drugs is not increased by oxcarbazepine which is in contrast to the effect of carbamazepine. Therefore, serum concentrations of concomitant antiepileptic agents should be monitored during the transition from carbamazepine to oxcarbazepine. Oxcarbazepine has been shown not to interact with warfarin; however, it may decrease systemic availability of felodipine by approximately 30% through induction of the P450IIIA isozyme. The pharmacokinetics of oxcarbazepine are not influenced by erythromycin, cimetidine, or dextropropoxyphene. Coadministration of verapamil produced a 20% decrease in the Cmax and area under the plasma concentration-time curve of 10,11-dihydro-10-hydroxy-carbamazepine in a study of healthy volunteers. The clinical significance of this interaction remains to be determined.
Dosage and Administration
In adults with epilepsy, the recommended dosage of oxcarbazepine is 600 to 1200 mg/day orally in 3 divided doses, although some patients may be well controlled on twice-daily regimens. This dosage may be increased as clinically indicated. When substituting oxcarbazepine for carbamazepine, gradual replacement of each 200mg carbamazepine with 300mg oxcarbazepine is suggested, followed by dosage titration as clinically indicated.
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