Introduction
Oxcarbazepine (OXC), with the trade name Trileptal, is a kind of new anti-epileptic drug (AED). OXC is applied in the monotherapy and add-on therapy of partial epilepsy in adults and children, including simple partial seizure, complex partial seizure, and tonic-clonic seizure. OXC is the ketone group ramification of carbamzepine (CBZ), but there are many differences between OXC and CBZ [
1], such as the more complicated mechanisms and better pharmacokinetics, safety, and tolerance of OXC [
2]. Therefore, since the day OXC appeared in the market, a lot of randomized clinical trials (RCT) have been conducted to explore the efficacy and safety of OXC as monotherapy and add-on therapy for partial epilepsy [
3-
5]. In this research, we emphasized on the dose and tolerance of OXC in Chinese people. We evaluated the clinical experience with prospective and follow-up trials. The data are believed to be helpful for the clinical application of OXC.
Methods
Subjects
We recruited patients at the Epilepsy Center of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, from March 2005 to March 2006. The name, sex, age, address, family history, seizure semiology, experimental test results, and dosage and time of the therapy were all recorded in detail. The inclusion criteria were as follows: (1) newly diagnosed patients with partial epilepsy; (2) refractory patients with partial epilepsy; (3) patients that could not tolerate other first-line AEDs; (4) seizure frequency was no less than three times in the recent three months; (5) the agreement of the patients and their family had been obtained, and they promised to be followed up as requested. The exclusion criteria were: (1) rejection of the follow-up of the treatment; and (2) severe disorders of the liver, kidney, and hematologic system. Of all the patients, only one patient could not finish the therapy because of rash, which was not counted into our data.
Demography of the patients
A total of 67 patients were recruited, including 43 (64.2%) males and 24 (35.8%) females. The ratio of male to female was 1.79:1. The average age of the whole group was 16.6 years, with the range of age from 2 to 74 years. The average course of epilepsy was 2.9 years, with the range from 1 day to 20 years.
Clinical data
The clinical data of the whole group are shown in Table 1.
Methods of therapy and clinical observation
In our research, the whole group was divided into two subgroups: the monotherapy group and the add-on therapy group. The therapy protocol was carried out as follows: adult (>12 years): the initial dose of OXC was 75 to 150 mg and the dose could be increased by 75 to 150 mg per day every 5 to 7 days until the target dose, which was 10 to 15 mg per kilogram per day (300-1200 mg per day), was reached; child (<12 years): the initial dose of OXC was 8 to 10 mg per kilogram per day and was given to the patient every 8 to 12 h, and then the dose was increased by 8 to 10 mg per kilogram per day until the target dose was reached. If the patient could not tolerate other AEDs, we would treat the patient with OXC until the target dose and then reduce the dose of the former AEDs until withdrawal. Especially when we tried to use OXC instead of CBZ, we still followed this rule.
Analysis of the efficacy and safety of OXC
The baseline seizure frequency was recorded before the therapy with OXC. All the patients were followed up for 6 months. We analyzed the data of the first three months and the following three months separately. We also compared the seizure frequency after the therapy with the baseline and calculated the 50% response rate, the 75% response rate, and the percentage of seizure-free. The side effects were also recorded in the first three months and the following three months separately, so that the tolerance and safety of OXC could be evaluated.
Statistical analysis
All the data were analyzed using SPSS11.0 statistical software. Comparison of the seizure frequency in the same subgroup was performed through paired-samples t test and that between the two subgroups by χ2 test. A P < 0.05 was considered statistically significant.
Results
Efficacy of OXC for the monotherapy and add-on therapy for partial epilepsy
By paired-samples t test, seizure frequency in the whole group was decreased significantly after treatment (P = 0.002). Between the monotherapy and the add-on therapy groups, there was a significant difference in the percentage of seizure-free in the first three months (P = 0.02), and there were also significant differences in the 50% response rate (P = 0.017) and the percentage of seizure-free in the following three months (P = 0.019). No difference was found in the 50% response rate, the 75% response rate, and the percentage of seizure-free between the first three months and the following three months in the whole group and the two subsets (P>0.05; Table 2 and Fig. 1A to C).
Safety and tolerance of OXC
The incidence rate of side effects due to the therapy was 19.40% (13 of 67) in the whole group. The side effects were mainly found during the first three months. Nine cases in the monotherapy group and four in the add-on therapy group had side effects. The side effects were mild to moderate, including 2.99% of rash (2 of 67), 2.99% of descent of memory and performance record (2 of 67), 2.99% of dizziness (2 of 67), 2.99% of character alteration (2 of 67), 1.49% of impaired concentration (1 of 67), 1.49% of impairment of hematological system (1 of 67), 1.49% of appetite reduction (1 of 67), and 1.49% of symptomless hyponatremia (1 of 67). The rash in one of the two patients only appeared in the first few days of titration, then disappeared in a couple of days; the patient did not develop a fever during the appearance of the rash. We observed that all the patients with character alteration became excited or restless. The impairment of the hematological system was slight hypoleukocytosis. In add-on therapy, a symptomless hyponatremia was observed in a patient treated with OXC of 1200 mg per day. The concentration of natrium was found to return to normal when the dosage was reduced to 900 mg per day. What’s more, we found that there were three kinds of side effects in one patient. Eight patients that could not tolerate the therapy of caramazpine and topamax finished the six-month clinical trial successfully. Only one patient who got rash was excluded from the trial (Table 3).
Discussion
In this research, we conducted a clinical follow-up and case-control trial prospectively to study the efficacy and safety of OXC. To evaluate the long-term efficacy and the duration of the side effects, we designed a trial to contrast all the clinical data between the first three months and the following three months. This is the first systematic clinical trial about OXC in China. We hope our data will provide some clinical experiences for the application of OXC as a kind of new AED for epilepsy patients in China and other countries.
Efficacy of OXC: seizure reduction and persistence of the efficacy
Although there are many similarities between OXC and CBZ, OXC, a kind of new AED, seems to have better tolerance, safety, and efficacy. OXC is recommended by the International League Against Epilepsy (ILAE) and the American Academy of Neurology (AAN), mainly to be used as monotherapy and add-on therapy for partial epilepsy of adults and children [
6-
9]. OXC showed good efficacy in monotherapy for partial epilepsy, especially in treating the patients with short course of disease who had never had AEDs [
10]. In our research, the medium induction of seizure frequency reached 75.93% to 78.53%, and the percentage of seizure-free at the end of the sixth month reached 56.86% to 60.78%. There were significant differences between the pre-therapy and the post-therapy (
P = 0.002). As for the add-on therapy for partial epilepsy, our data indicated that there were some differences in efficacy compared with the monotherapy group. In the first 3 months of our trial, there was no difference in the 50% response rate and the 75% response rate between the two groups, whereas statistical difference was found in the percentage of seizure-free between the two groups (
P < 0.05). In the following 3 months, statistical differences in the 50% response rate and the seizure-free rate were both observed between the two groups (
P < 0.05). We suppose that this was partially because of the higher proportion of patients with refractory and drug-resistant epilepsy in the add-on therapy group. Our results are consistent with those of Pauletto [
11,
12]. Therefore, this research indicates that OXC would have good efficacy for treating partial seizures in the near future.
We should also answer whether the efficacy of OXC can persist. We compared the seizures between the first 3 months and the following 3 months, and found no statistical difference in the 50% response rate, the 75% response rate, and the proportion of seizure-free in the two subgroups and the whole group (
P>0.05). These data were also consistent with that of Ahmad [
12]. They carried out a 48-week clinical trial to evaluate the short-term and long-term efficacy and safety of OXC as one of the AEDs for monotherapy and add-on therapy. They collected 76 patients with partial epilepsy, and the results also indicated that, comparing the first 24 weeks and the last 24 weeks, there was no significant difference in the medium induction of seizure frequency, and the 50% and the 75% response rates [
12]. Therefore, we presume that OXC can keep its efficacy from the very beginning to a long period of time, unless there are some factors that would induce seizures, such as sleeping disorder, alcohol abuse, and other diseases. Even if both the mechanism and the efficacy of OXC and CBZ are similar, our trial indicates that the direct “overnight” switch from CBZ to OXC can exaggerate the seizures. From this it is believed that there should be a titration period for OXC till the target dose, and the reduction of CBZ should not be earlier than that. This rule was also recommended by Schmidt [
13,
14], especially when the dose of CBZ was beyond 1000 mg.
Safety of OXC: common side effects and their duration
As a kind of new AED, OXC is superior to others for its safety. The most common side effects of OXC in other researches include nausea (17%), headache (14%), mitigate (7%), dizziness (31%), and symptomless hyponatremia (35%) [
15-
17]. Our data have some conflict with these because of the small sample size. In our group with 67 patients, only 13 of them encountered side effects of mild to moderate degree. Most of the side effects disappeared or were tolerated by the patients as the therapy progressed. One patient, however, was excluded because of rash. One patient was found to have symptomless hyponatremia when the dose of OXC was pretty high, and the concentration of natrium returned to normal after the dose of OXC was reduced. The results of Novatis indicated that the symptomless hyponatremia would occur in the first two months after therapy [
18], which was also supported by our data. We asked all the patients to check the concentration of natrium on the 30th, 90th, and 180th day after therapy. The results indicated that there were no obvious changes among them. And the hyponatremia was detected on the 30th day. Generally speaking, symptomless hyponatremia was more common in gerontal patients [
13]. In our research, this side effect happened in 25 patients with hepatitis C virus infection when the treatment dose reached 1200 mg per day. The reduction of dose could make the concentration of natrium return to normal level. All these indicated that the symptomless hyponatremia was related to the dose of OXC. Most of the researches supposed that there were no severe side effects on hematological system, or liver and kidney impairment [
19]. But till now there are no data on the impact of OXC on the blood-clotting function of children and adolescents in large sample trials. In our research, one child developed hypolekocytosis. We also found another remarkable phenomenon, which was the high incidence rate of recognition disorder. This kind of disorder is usually characterized by character alteration, and impaired concentration and memory. Although there was no obvious impairment of recognition function caused by OXC according to other researches [
20], we still think recognition disorder can probably appear during the period of titration. For this reason, the period of titration should be long enough [
21,
22]. In conclusion, the side effects of OXC are dose-dependent and patients will get good tolerance with low dose. We also tried OXC in patients that cannot tolerate the therapy of CBZ and Topiramate (TPM) to find a better tolerance.
OXC has superior characteristics in clinical and pharmacology compared with traditional AEDs such as CBZ. It is the first-line and first choice to treat partial seizures especially refractory ones [
23]. However, evidence from multi-center RCTs with large samples is still lacking. The shortcoming of this research is also the small number of patients. We will try to collect cases and details as much as possible in the future to complete this trial. We hope that with the accumulation of clinical and pharmacological data, OXC will be further proven to be a kind of promising new AED for partial seizures.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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