JLE

Epileptic Disorders

MENU

Tolerability of tiagabine: a prospective open-label study Volume 4, issue 4, December 2002

Figures

See all figures

Introduction

Tiagabine-HCl is a new antiepileptic drug (AED) with a unique mode of anticonvulsant action. It inhibits the presynaptic re-uptake of gamma-aminobutyric acid (GABA) into neurons and glia [1]. Its anticonvulsant effect in the treatment of partial and secondarily generalised seizures has been demonstrated in several placebocontrolled studies [2]. We report the results of a large prospective openlabel study of tiagabine.

Patients and methods

Five hundred and seventy-four patients attending 298 neurological, medical and psychiatric practices or outpatient departments in Germany were enrolled. Inclusion criteria were: epilepsy with partial and/or secondarily generalised seizures resistant to anticonvulsant medication. Patients had to have at least two seizures/month. Anticonvulsant comedication was not limited. Patients with idiopathic generalised seizures were excluded. Data acquired prospectively, prior to therapy with tiagabine and after three months of treatment, included duration of epilepsy, previous treatment with AED, frequency of seizures (based on seizure charts), severity of seizures, adverse events and cognitive functions (as reported by patients and investigators, not documented by neuropsychological tests). Tiagabine was added to the pre-existing medication in a stepwise fashion (recommended starting dose of 5 mg tiagabine, followed by weekly increments of 5 mg per day). It was recommended that the final tiagabine dosage was reached within the first weeks of the study to allow determination of seizure frequency on a stable tiagabine dosage in the last four weeks of the three month observation period. The seizures were classified and categorized according to the International Classification of epileptic seizures of the International League against Epilepsy of 1981 [3].

Results

Five hundred and seventy-four patients with epilepsy with simple partial seizures, complex partial seizures and/or secondarily generalised tonic clonic seizures of cryptogenic (N = 225) or symptomatic (N = 330) aetiology took part in the study (aetiology unknown in 19 patients). The 299 men and 275 women were aged between 3 and 80 years (mean age 38.1 years). The mean duration of epilepsy was 14years (range < 1 - 67.1 years). Tiagabine was added to one (44.1%) or more (up to nine) AEDs (table II). The mean duration of follow-up after initiation of add-on therapy with tiagabine was 94.9 ± 42.7 days (range: 1-303 days). The median daily dose of tiagabine was 30 mg (mean 29.1, SD 12.0). Steady state dosage was reached in a mean of six weeks and did not differ, regardless of co-medication with hepatic enzyme-inducing or enzyme-inhibiting AEDs. Prior to add-on therapy with tiagabine, the median total seizure frequency was 4.5 seizures/4 weeks (mean 16.3; SD 58.2). During the last four weeks of the study period median total seizure frequency was 2.0 (mean 14.4; SD 64.6), 12.3% of patients remained completely free from seizures. A total seizure control was achieved for complex partial seizures or tonic clonic seizures in about 30% of patients (table III). The median number of simple partial seizures decreased from 5 seizures/4weeks (mean 17.4; SD 62.0) to 3 seizures/4 weeks (mean 13.6; SD 65.1). The median number of complex partial seizures decreased from 2.0 seizures/4weeks (mean 9.7; SD 25.1) to 1.0 seizures/4weeks (mean 22.5; SD 74.5). The median number of generalised tonic-clonic seizures decreased from 4.0 seizures/4 weeks (mean 18.3; SD 61.4) to 1.0 seizures/4weeks (mean 6.2; SD 16.9) (table III). In patients treated with a daily dose of tiagabine of more than 30 mg, the effect was similar in those receiving carbamazepine and those receiving valproate as comedication. Adverse events were reported in 78 of 574patients (13.6%). The most common disturbances were related to the central and peripheral nervous system, e.g. paresthesiae (9.1% of the patients) (table IV). Also common were psychiatric disorders (4.9%), generalised disturbances, e.g. excessive sweating or hiccups (3.0%), and disturbances of the digestive tract (1.7%). In all other classes of possible disturbances, complaints were recorded with a frequency of less than 1%. Impaired vision (blurred vision) was reported in two patients (0.3%). In the 78 reports of adverse events, a relationship to treatment with tiagabine was considered to be definite (2.3%), likely (63.8%), possible (21.3%), unlikely (1.1%) or could not be rated (5.2%). Data were not available in 6.3% of reports. Full recovery was documented after 62.6% of adverse events: 22.4% of adverse events had not fully resolved by the end of the observation period. No data on resolution were available for 13.8% of reports. In the beginning and at the end of the observation period, the physicians clinically evaluated the patients’ cognitive functions. Their impression was that cognitive functions improved in 30% of patients, remained unchanged in 55.1% of patients and worsened in 4% of patients. No data were available in 11% of patients. A relationship between dosage and effect of tiagabine on cognitive functions was not evaluated. Psychiatric disorders included psychosis (1), dysphoria (1), stupor (1), irritability (11) and confusional state (7). Two patients had depression, two anxiety. Difficulties with concentration were documented in three patients. In all but six patients (three with poor concentration, two with depression and one with stupor), adverse events ceased within days. In only one of these patients did tiagabine have to be discontinued. Tiagabine was also discontinued in three of the six patients in whom adverse events did not resolve. In two patients (0.3%), non-convulsive status epilepticus occurred during therapy with tiagabine. This is in line with findings that treatment with tiagabine is not related to an increased risk of status epilepticus [13]. Sixty-four patients (11.1%) discontinued treatment with tiagabine prematurely. Reasons for discontinuation were side effects (40 patients) and insufficient anticonvulsant effect (increase in seizure frequency in five, nonconvulsive complex partial status epilepticus in two patients) and were not recorded in 17 patients. Status epilepticus was diagnosed clinically and by electro-encephalogram. The type of status epilepticus was not different from that of isolated seizures in the patients with this adverse event. Side effects leading to discontinuation of tiagabine were dizziness (22 patients), tiredness (4), irritability (4), tremor (2) ataxia (3), poor concentration (3), stupor (1) and depression (1).

Discussion

This prospective, open-label study examines the clinical tolerability and efficacy of tiagabine as an add-on treatment for partial epilepsy. During add-on therapy with tiagabine, the median total seizure frequency decreased from 4.5 to 2.0 seizures/4 weeks. 12.3% of patients were completely free from seizures during the last four weeks of the documentation period. Of course this is a short evaluation period and does not mean that seizures will not recur during further treatment. This is a limitation of this study, which was not intended to provide information on the long-term efficacy of tiagabine. Our results are in line with the findings of randomized controlled efficacy studies of tiagabine [2, 4] and are comparable to the anticonvulsant effect of topiramate and lamotrigine [5, 6]. The median daily dosage of tiagabine was 30 mg. This has been shown to be an effective dosage in other treatment trials, although an increase of tiagabine above 50 mg may improve the anticonvulsant effect [7-9]. In this study, the daily tiagabine dosage exceeded 50 mg in only 5.7% of patients. The tolerability of tiagabine was good. As in other studies, most adverse effects were related to the central nervous system [10]. Visual field defects, found in patients treated with vigabatrin [11] were not reported in this study or in a long-term observation of patients receiving tiagabine by Kälviäinen et al. [12]. However, visual field examination was not performed by computerised perimetric testing. Physicians only recorded patients’ complaints, these did not include visual field defects. Tiagabine proved to be a well tolerated and effective anticonvulsant drug in the treatment of partial epilepsy.

CONCLUSION

Statement on conflict of interest

This work was supported by Sanofi-Synthelabo, Germany. An independent biometrical institute (Winicker Norimed) analysed seizure frequency and adverse events. The results of the study were reported to the German Federal Institute for the Safety of Medicines as postmarketing safety documentation.

Received February 28, 2002 Accepted August 26, 2002