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In an editorial, Marson and Chadwick review some of the evidence for the effectivity and tolerability of new drug treatments for epilepsy.1 They discuss the role of randomised clinical trials for providing data that satisfy the requirements of the licensing bodies but that do not reflect day to day clinical practice. With oxcarbazepine (Trileptal®) we recently experienced another complicating factor, a change in formulation, which may influence interpretation of results of clinical trials.
Oxcarbazepine had recently been licensed in the United Kingdom and the United States but was already registered in The Netherlands in 1991. In our epilepsy centre we have had extensive clinical experience with oxcarbazepine since 1986.2 In 2001 we noticed new symptoms such as diplopia, dizziness, dysarthria, and ataxia in patients on a stable drug regimen, including oxcarbazepine. These symptoms had a fluctuating course during the day. In the autumn of 2000 the manufacturer Novartis substituted the formulation of oxcarbazepine in The Netherlands for the formulation which had been licensed in the United Kingdom and the United States. Taking into consideration this change in formulation we hypothesise that these new symptoms could be side effects of oxcarbazepine, probably caused by higher blood concentrations of the active compound in relation to this new formulation.
Oxcarbazepine is a 10-keto analogue of carbamazepine (CBZ) with similar anticonvulsant efficacy, but with a different pharmacokinetic profile and possibly a better tolerability.3 4 It is rapidly reduced to a 10-monohydroxy derivative (MHD) with an elimination half life of 1.3–3.8 hours. Oxcarbazepine acts as a prodrug of MHD, the clinically relevant metabolite of oxcarbazepine; MHD is cleared with a half life of 8.8–24.5 hours.
We evaluated steady state oxcarbaepzine and MHD serum concentrations obtained before and after change of the oxcarbaepzine formulation from four patients with presumed side effects. The mean (range) MHD concentrations increased from 27.0 (25.4−32.7) μg/ml to 38.4 (37.5−39.6) μg/ml. Routinely, we do not measure oxcarbaepzine concentrations, because they are usually very low or not detectable. As we still had all serum samples from these four patients in the freezer, analysis could be done retrospectively. The mean (range) oxcarbazepine concentrations increased from 0.7 (0.5–1.1) μg/ml to 3.2 (2.0–5.6) μg/ml. In four other patients on the new formulation and with the presumed side effects, we found that the mean (range) MHD fluctuation calculated as 100. (Cmax –Cmin)/Cmin was 55.1 (36.3—72.9)%, which is higher than the described mean fluctuation of 32.5% with the first formulation.5
Our results suggest that the new formulation of Trileptal®has a faster rate of absorption and a higher bioavailability than the old one. It is possible that the higher oxcarbazepine and MHD concentrations are due to a food effect.
It was reported that the systemic availability of the old formulation increased 17% when oxcarbazepine was administered with food, but that this effect of food was absent with the new formulation. However, it is more likely that the changes in the composition of the dosage form have influenced the rate and extent of absorption of oxcarbazepine.
The prescribers of oxcarbazepine should be aware when patients change to the new formulation that the daily dosage will probably have to be decreased in patients with high MHD concentrations. A shorter dosage interval should be considered. Monitoring in blood concentration is advised before and after the change and should not only include MHD but also the parent drug oxcarbazepine itself.
These findings support the plea of the authors for trials that better reflect the needs of the clinician and the patient. A fast clinical and pharmacological evaluation of the new formulation is necessary to avoid the reputation of oxcarbazepine as a valuable anticonvulsive drug being impaired by its unnecessary side effects.