Tiagabine Monotherapy in the Treatment of Partial Epilepsy

Summary: Three studies were conducted to assess tiagabine (TGB) hydrochloride monotherapy in patients with partial seizures. The first was a double-blind, placebo-controlled trial of 11 patients (seven TGB, four placebo) undergoing evaluation for epilepsy surgery. Baseline antiepileptic drug (AED) therapy was discontinued abruptly before monotherapy. Although 24-h seizure rates increased during monotherapy in both groups, patients receiving TGB experienced fewer seizures than placebo patients. Subsequent studies (an open-label, dose-ranging study; n = 31 and a double-blind, randomized comparison of 6 and 36 mg/day TGB; n = 102 and 96, respectively) involved discontinuation of baseline AEDs. In the dose-ranging study, 19 of 31 patients (61%) converted to TGB monotherapy, with a mean final dose of 38.4 mg/day (range 24–54 mg/day) in those who completed the study ( n = 12). In the low- vs. high-dosage study, median 4-week complex partial seizure rates decreased significantly in patients from both dose groups who completed the monotherapy period ( p <0.05 compared with baseline). In the intent-to-treat analysis, significantly more patients in the high-dose group experienced a reduction in seizures of at least 50% compared with the low-dose group ( p = 0.038). Overall, the types of adverse events with TGB monotherapy were similar to those observed in add-on trials. These initial trials in difficult-to-treat epilepsy patients indicate that TGB monotherapy may provide a new approach to the treatment of patients with partial seizures refractory to other AEDs.     

Preliminary Observations on Topiramate in Pediatric Epilepsies

Summary: Preliminary results of studies of topiramate (TPM) in children are now available. In a pharmacokinetic study among 18 male and female children, target daily dosages of up to 9 mg/kg/day were evaluated. TPM pharmacokinetics in children were linear. Mean TPM oral clearance (CL/F) was 44–54% higher in children [depending on concomitant antiepileptic drugs (AEDs)] compared with historical data from adults, and steady-state plasma TPM concentrations for the same mg/kg dose were 33% lower in children compared with historical adult data. In a long-term, open-label pilot study of adjunctive TPM therapy in 18 patients with Lennox-Gastaut syndrome, six of the eight patients (75%) still receiving TPM report a greater than 50% reduction in total seizures, with the best results observed in tonic-atonic, atypical absence, and generalized tonic-clonic seizures. Subsequent large double-blind, placebo-controlled trials of adjunctive TPM therapy in Lennox-Gastaut syndrome and refractory partial-onset pediatric epilepsy are ongoing, with high percentages of enrolled patients in both studies completing double-blind treatment and entering long-term TPM open extension trials. A small TPM monotherapy substitution trial in children with well controlled partial onset seizures showed that TPM monotherapeutic substitution can be achieved successfully with an acceptable amount of adverse experiences with a weekly increase of 1 mg/kg/day to a maximal dose of 3 mg/kg/day. These preliminary results suggest that TPM may be a useful new AED in pediatric patients with a variety of seizure disorders.     

International Experience with Tiagabine Add-On Therapy

Summary: Tiagabine (TGB) hydrochloride is a novel antiepileptic drug (AED) that is a potent and specific inhibitor of γ-aminobutyric acid (GABA) uptake into glial and neuronal elements. In accordance with medical and regulatory standards, the clinical development program for TGB as an AED has assessed the value of TGB in add-on treatment, focusing mainly on partial seizures, including secondarily generalized seizures. Five add-on, placebo-controlled trials and six non-comparative, open-label, long-term multicenter trials have been or are being conducted in Australia, Europe, and the U.S.A. The results of these trials, involving 2,261 patients, indicate that TGB has efficacy as add-on therapy in patients with epilepsy difficult to control with existing AEDs. Efficacy of TGB is also sustained with long-term treatment. A clear dose-response has been demonstrated, and the minimal effective dose level is 30 mg. TGB is also tolerated, and with long-term therapy no new or more severe types of adverse events develop. These studies have included a wide age range of patients, including adolescents and the elderly.     

Topiramate as Adjunctive Therapy in Refractory Partial Epilepsy: Pooled Analysis of Data from Five Double-Blind, Placebo-Controlled Trials

Summary: A pooled analysis of data from five similarly designed double-blind, placebo-controlled trials of topiramate (TPM) as add-on therapy in patients with partial epilepsy was performed. The pooled analysis allowed evaluation of efficacy end points and response to treatment for a number of study subgroups not statistically evaluable in the individual study analyses due to limited sample sizes. The five trials included 534 patients, 360 who received TPM at target dosages of 200-1,000 mg daily and 174 who received placebo. In the intent-to-treat pooled analysis, TPM was significantly ( p ≤ 0.01) superior to placebo in reducing total seizures by ≥ 75% or by 100%. When seizure types were evaluated independently, TPM significantly ( p ≤ 0.001) reduced the frequency of simple partial, complex partial, and secondarily generalized seizures. TPM was significantly ( p ≤ 0.001) better than placebo regardless of gender, patient age, baseline seizure rate, and concomitant AEDs. The efficacy of TPM in partial epilepsy is consistent across efficacy end points and across strata defined by study population characteristics.     

Efficacy of Topiramate as Adjunctive Therapy in Refractory Partial Seizures: United States Trial Experience

Summary: In companion double-blind, placebo-controlled, dose-ranging trials performed in the United States, topiramate (TPM) daily target dosages of 200-1,000 mg/day were evaluated as add-on therapy in adults with refractory partial seizures with or without becoming secondarily generalized. Net reductions in median monthly seizure frequency (active drug minus placebo) with the most efficacious dosages of TPM were 35% in the low-dose trial and 40% in the high-dose trial. Substantial reductions in secondarily generalized seizures were also observed with TPM. TPM appears to be an efficacious new antiepileptic drug in the management of partial epilepsy.     

Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in adult patients with epilepsy resistant carbamazepine and valproate

Lamotrigine is a broad-spectrum antiepileptic drug which is thought to act in part via a use-dependent blockade of voltage-sensitive sodium channels to stabilise the neuronal membrane. This results in the inhibition of the excessive release of excitatory amino acids, such as glutamate, during epileptic activity. An open, multicentre, prospective trial of lamotrigine was carried out in adult patients with drug-resistant epilepsy on monotherapy with carbamazepine or valproate. The primary aim of the study was to assess add-on lamotrigine withdrawing to monotherapy. 28-week clinical trial was divided into 4 phases: (1) Dose escalation period (4 weeks), (2) Add-on period (8 weeks), (3) Standard AED withdrawal period (8 weeks), (4) Lamotrigine monotherapy (8 weeks). Thirty-three patients were previously treated with valproate, 44 with carbamazepine. Of 77 patients recruited into the study, 64 patients (83%) completed add-on therapy, 49 patients (64%) completed lamotrigine monotherapy. 44% of all patients during the add-on phase and 48% during lamotrigine monotherapy had a reduction in seizure frequency of at least 50% compared with pre-study period. 13% of all patients achieved seizure freedom during add-on therapy and 18% during monotherapy. Improvement of Visual Analogue Scale (VAS) scores was observed in 65% and 57% patients respectively. A significant proportion of patients could be successfully converted to lamotrigine monotherapy. Lamotrigine was also generally well tolerated. 23 patients (30%) had at least one adverse event (AE), but only 1/4 of all AEs might be reasonably regarded as an effect of the medication. 7 patients (9%) discontinued prematurely from the study due to adverse event. More AEs were observed in add-on therapy than in lamotrigine monotherapy. The safety profile was consistent with that seen during other clinical trials with lamotrigine. CONCLUSIONS: 1. Lamotrigine is effective AED in add-on and monotherapy (responders rate--44% and 48% respectively). 2. In most cases conversion from add-on therapy to monotherapy can be done successfully. 3. Lamotrigine is a safe and well-tolerated drug.     

Clinical Efficacy of Topiramate as Add-On Therapy in Refractory Partial Epilepsy: The European Experience

Summary: In three randomized, double-blind, placebo-controlled add-on European trials, target daily topiramate (TPM) dosages of 400, 600, and 800 mg/day (200, 300, and 400 mg bid) were evaluated in adults with refractory partial seizures with or without becoming secondarily generalized. Median reductions from baseline in monthly seizure rate were 41% with TPM 400 mg/day vs. 1% with placebo ( n = 0.065), 46% with TPM 600 mg/day compared to -12% (a 12% increase) with placebo ( p ≤ 0.005), and 36% with TPM 800 mg/day versus –18% (an 18% increase) with placebo ( p ≤ 0.001). Differences between TPM and placebo with respect to percent responders (percent of patients demonstrating a 50% or greater reduction in seizures) significantly favored TPM ( p ≤ 0.05) at all three target dosages. Significant reductions in secondarily generalized tonic-clonic seizures compared to placebo were also observed with 400 mg/day ( p = 0.002) and 800 mg/day ( p < 0.05) of TPM. TPM appears to be a promising new antiepileptic drug for use as adjunctive therapy in adults with refractory partial epilepsy.     

Aggravation of partial seizures by antiepileptic drugs: is there evidence from clinical trials?

OBJECTIVES: To assess clinical trials for evidence that antiepileptic drugs (AED) aggravate partial seizures. To determine if the methodology used to examine drug efficacy can also be used to examine seizure aggravation. BACKGROUND: It is widely accepted that AED aggravate epilepsy in some patients. However, there is little published objective or quantitative evidence. Most reports concern generalized epilepsies. METHODS: Pharmaceutical companies responsible for the development of five of the new AED were asked to provide data concerning seizure increases during randomized placebo-controlled, add-on clinical trials in patients with uncontrolled partial seizures. Seizure frequency in individual patients taking drug or placebo was compared with the baseline pretreatment seizure frequency. The counterpart of the 50% reduction used in efficacy analyses is a 100% increase, because both represent a twofold change. A dose-response relationship was also explored. RESULTS: More than 40% of subjects in clinical trials of tiagabine (TGB), topiramate (TPM), and levetiracetam (LEV) experienced an increase in seizures while taking a placebo. Seizure increases were no more likely to occur when taking any of the three drugs than taking placebo. A doubling or more of seizure frequency was less likely to occur with TPM or LEV than with placebo but more likely with TGB. However, for TGB, this did not reach significance. There was some evidence for a dose-response effect with TGB but a negative effect with TPM (aggravation less likely with increasing dose). Data on gabapentin and lamotrigine were not provided. CONCLUSIONS: Many patients with partial seizures experience an increase in seizures when a new AED is added to their therapy. However, it occurs no more frequently when taking drug than placebo. It probably represents the spontaneous fluctuation of seizure frequency. When a patient who has started a new AED deteriorates, this is not necessarily a drug effect.     

Clinical experience with topiramate dosing and serum levels in patients with epilepsy.

OBJECTIVE: To investigate the relevance of serum topiramate (TPM) levels (SL) monitoring in the clinical management of epileptic patients. METHODS: Twenty-seven patients with different epileptic syndromes on TPM therapy were studied. TPM was used as add-on in 26 patients, only in one as monotherapy de novo; one case changed from TPM as add-on to TPM monotherapy. The mean follow-up time was 11 months. TPM SL were measured by fluorescence polarization immunoassay. RESULTS: We analyzed the TPM SL in 43 samples from 27 patients. Mean TPM dose was 3.9mg/kg, mean TPM SL 13.43mumol/l. The mean level to dose ratio (LDR) was 3.63mumol/l/mg/kg. Four patients became seizure-free, all with TPM dosages lower than the mean. Eleven patients had at least 50% seizure reduction. The comedication with enzyme-inducing AED significantly reduced TPM SL and LDR. On the other hand, the influence of valproic acid (VPA) on TPM LDR was not univocal. Indeed, patients younger than 15 years showed SL values lower than the adults did, although not significant. CONCLUSION: We could not detect a direct relationship between high TPM SL and efficacy neither between high TPM SL and tolerability. However, the data we collected seem to favour the hypothesis that high TPM dosage and SL might be associated to a greater probability to reduce seizure severity.     

An Overview of the Efficacy and Tolerability of New Antiepileptic Drugs

Summary: To evaluate the efficacy and tolerability of recently developed antiepileptic drugs (AEDs), a systematic review of placebo-controlled, randomized controlled trials (RCTs) of the AEDs as add-on therapy in refractory partial epilepsy was conducted. Two or more RCTs meeting our inclusion criteria were found for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS). The outcome selected for estimation of efficacy was the proportion of patients experiencing a ≥50% reduction in seizure frequency from baseline. Tolerability was estimated on the basis of rates of patient withdrawal from study for any reason. Efficacy and tolerability odds ratios (ORs) and 95% confidence intervals (95% CIs) for each measure were generated for each trial included in the analysis, and overall efficacy and tolerability ORs were calculated for each AED across all trials and drug dosages evaluated. Because 95% CIs for both efficacy and tolerability overlapped for the six drugs, conclusive evidence of between-drug differences in effectiveness or safety were not obtained from the analysis. However, the data suggest that the drug with the highest OR for efficacy (TPM) may be approximately twice as effective as the AED with the lowest OR for efficacy (GBP), and that the treatment that appears to most frequently cause withdrawal (ZNS) may be about four times more likely to do so that the AED with the lowest withdrawal rate (LTG). RCTs comparing newer AEDs with the older standard drugs and with each other are needed to further evaluate their relative utility.     

Felbamate: Successful Development of a New Compound for the Treatment of Epilepsy

Summary: Felbamate (FBM) is an effective and safe novel antiepileptic drug (AED) for add-on treatment in adults with refractory partial seizures as shown in three pivotal controlled trials. In addition, FBM is effective and safe in monotherapy in adults with refractory partial seizures. FBM is also effective and safe as add-on therapy for children and adults with refractory Lennox-Gastaut syndrome. The effective daily dosage is ˜30–45 mg/kg divided into three or four doses with resulting plasma concentrations of 50–80 mg/L. The safety profile of FBM is limited to mild gastrointestinal complaints, insomnia, and nonspecific CNS symptoms. Six pivotal controlled trials, with both classic and innovative design, showed that FBM is a useful AED.     

Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation.

PURPOSE: the choices available for patients whose partial seizures are poorly controlled include seven new antiepileptic drugs (AEDs) or vagal nerve stimulation (VNS) as add-on therapy. Comparisons are needed to help physicians and patients select among the options for treatment. METHODS: we compared efficacy and adverse events of new treatments from controlled clinical trials of patients with uncontrolled partial seizures. Response rates (> or =50% decrease in partial seizures) at doses recommended in product labeling for adjunct therapy were tabulated for overall success (placebo response rate subtracted from AED response rate). Adverse events listed in product labeling were tabulated as complaint rates (placebo events subtracted from AED events). VNS trials used low dose stimulation as a pseudo-placebo. RESULTS: overall success rates fell into two general groups with ranges of 12-20% for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), zonisamide and 27-29% for levetiracetam, oxcarbazepine, and topiramate (TPM). Summary Complaint Scores also fell into two general groups with ranges of -27 to -82 for GBP, levetiracetam, TGB, zonisamide and -113 to -205 for LTG, oxcarbazepine and TPM. VNS scores were in the lower or higher success and summary complaint categories depending on whether scores from the pseudo-placebo group were subtracted from the high dose group. CONCLUSIONS: these data allow comparisons among AEDs and VNS using similar data from standard types of clinical trials.     

Long-term efficacy and tolerability of topiramate as add-on therapy in refractory partial epilepsy: An observational study

Purpose:   To evaluate the long-term efficacy and tolerability of topiramate (TPM) as add-on therapy in patients with refractory partial epilepsy.
Methods:   This is a retrospective, single-center, long-term observational study. Patients fulfilling the criteria of medical intractability proposed by Berg et al. were entered into the study if they were newly prescribed TPM as add-on therapy between January 2000 and June 2002. The usual starting dosage of TPM was 50 mg/day and optimal-dose adjustments were made according to individual clinical responses. Efficacy and tolerability were analyzed every year during 5-year follow-up in the "intention-to-treat (ITT) population." Retention rate was estimated by Kaplan-Meyer analysis.
Results:   A total of 125 patients were included in the study and 107 patients (85.6%) were followed for 5 years. Retention rate was 87.2% at 1 year and 64% at 5 years. At the end of 5 years, the median seizure frequency reduction rate was 69.0% and responder rate was 43.2% in the ITT population. Cumulative seizure-free rate (SFR) was 30.4% and the terminal 1-year SFR was 12.8% in the ITT population (20.0% in completers) at 5-year follow-up. Adverse events (AEs) occurred in 39.2% of patients, including significant AEs leading to antiepileptic drug (AED) withdrawal in 14.4%. The most common AEs were anorexia (16.0%), weight loss (10.4%), and gastrointestinal symptoms (8.8%). Concomitant AEDs were reduced in 25.0% of the completers.
Discussion:   Low-dose and slow-dose escalation of TPM in add-on therapy for patients with refractory partial epilepsy is effective and well tolerated in long-term, individualized clinical practice.     

Monotherapy trials: prerequisite data.

Is it possible for an antiepileptic drug (AED) to be effective as add-on therapy in refractory epilepsy but ineffective as monotherapy for the same seizure type(s)? If the answer is 'no', why not award a new AED a monotherapy licence once it has been shown to be effective as adjunctive treatment in placebo controlled, dose-ranging studies in patients with difficult-to-control epilepsy? The recent comparative study between carbamazepine and remacemide, however, suggests that subtle pharmacokinetic/pharmacodynamic interactions between established and new AEDs can indicate efficacy in add-on studies that does not necessarily transfer to monotherapy. There is some evidence that an AED whose primary mechanism of action does not involve blockade of voltage-dependent sodium channels may do less well than carbamazepine in terms of efficacy end-points in a double-blind, head-to-head comparison. These observations lead to the conclusion that monotherapy trials are, indeed, required. They should be undertaken after proof of efficacy has been obtained using a single short presurgical AED withdrawal study backed up by a substantive dose-ranging phase III efficacy trial. There is no reason to recommend earlier assessment since the clinical need for new AEDs is in refractory epilepsy. The subsequent monotherapy trial programme should contain elements utilising comparative and withdrawal designs. Sponsors should be able to seek a licence for their drug either as a first choice treatment in newly diagnosed epilepsy or as substitution monotherapy once treatment with at least one other AED has failed.     

Tiagabine in the Management of Epilepsy

Summary: Tiagabine (TGB) is a new antiepileptic drug (AED) that uniquely reduces the uptake of the inhibitory neurotransmitter -γ-aminobutyric acid into presynaptic neuronal and glial cells. It is metabolized in the liver with an elimination half-life of approximately 7 to 9 h. Although TGB does not induce or inhibit hepatic metabolic processes, it does provide a target for other enzyme-inducing AEDs. TGB has proved effective as add-on treatment for partial seizures, with or without becoming secondarily generalized, as demonstrated in five placebo-controlled trials and six long-term open studies. Preliminary results with TGB in children with refractory epilepsy and as monotherapy are promising. Few patients withdrew from these trials because of adverse events. The most common side effects with TGB involved the central nervous system, i.e., dizziness, asthenia, somnolence, nervousness, headache, and tremor. Most adverse events occurred during dosage titration, were often transient, and were usually of mild to moderate severity. The recommended maintenance dose for TGB, when combined with enzyme-inducing drugs as add-on therapy, is 30 to 50 mg/day. Trials are under way in patients with primarily generalized seizures and in newly diagnosed epilepsy. TGB is a well-tolerated and effective novel AED that will find an enduring place in the management of epilepsy.     

Topiramate in refractory epilepsy: a prospective observational study

PURPOSE: This prospective observational study explored the efficacy and tolerability of topiramate (TPM) in patients with refractory epilepsy attending a single outpatient clinic. METHODS: One hundred seventy patients (82 men, 88 women, aged 18-75 years) with refractory localization-related (n = 134) or idiopathic generalized epilepsy (n = 36) were started on adjunctive TPM using a standard titration schedule. TPM was introduced after a 3-month prospective baseline, and doses were adjusted according to clinical response. End points were seizure freedom for 6 months, > or =50% seizure reduction for 6 months compared with baseline at the highest tolerated TPM dose (responder), or discontinuation of TPM because of side effects, lack of efficacy, or both. RESULTS: Thirty-nine (23%) patients were seizure-free, and 80 (47%) more patients had a useful therapeutic response. Thirteen seizure-free patients and 16 responders took 100 mg of TPM daily or less. TPM was discontinued in 51 (30%) patients. The most common side effects resulting in withdrawal were fatigue, weight loss, irritability, paresthesia, depression, and headache. Concomitant antiepileptic drugs (AEDs) were stopped in 30 patients. Twelve were established on TPM monotherapy, eight of whom remained seizure-free. Final TPM doses and concentrations varied widely among the three outcome groups. CONCLUSIONS: TPM was efficacious as add-on and monotherapy in patients with refractory partial and generalized seizures in everyday clinical use. A good response was obtained in many patients with TPM doses substantially lower than those studied in regulatory clinical trials. The wide variation in dose-response and dose-toxicity relationships may reflect different neurobiologies causing refractory epilepsy and differential efficacy of AED combinations.     

Clobazam in the Treatment of Epilepsy: A Review of the Literature

Summary: The literature was reviewed to define the role of clobazam (CLB) in the treatment of epilepsy. CLB is an effective antiepileptic drug (AED) in most varieties of seizures and epilepsies for both short-term and long-term treatment. Tolerability of CLB is satisfactory, better than for conventional benzodiazepines. CLB has no significant interaction with other drugs. Tolerance may develop, but this aspect may have been overemphasized: a long-term benefit figure of 28% can be expected without tolerance. When CLB maintains efficacy, patients continue to benefit for years without drug dependence or unwanted side effects. CLB appears to be a useful treatment for epilepsy as intermittent or short-term add-on therapy; but it should also be tried as long-term therapy in some situations, especially as add-on therapy for patients with refractory epilepsy, as add-on or monotherapy for patients with anxiety, or in some women in association with oral contraceptives.     

New statistical method for analyzing time to first seizure: example using data comparing carbamazepine and valproate monotherapy

INTRODUCTION: Time to first seizure is a common outcome in antiepileptic drug (AED) studies. Previous studies have typically failed to find statistically significant differences between carbamazepine (CBZ) and valproate (VPS). We re-analyzed a meta-analysis comparing CBZ and VPS monotherapy with new powerful statistical methods that incorporate baseline seizure rate information. Methods: Individual patient data were available on 1,265 patients from a meta-analysis of five trials. The outcome measure was time to first seizure after randomization, adjusted for background variables and baseline seizure rate. RESULTS: We found strong evidence of an interaction between treatment and epilepsy type, and between treatment and age. For generalized onset seizures, VPS was statistically significantly better than CBZ: VPS delayed the first seizure after treatment 58%, 52%, 44%, and 36% longer than CBZ for individuals aged 10, 20, 30, or 40, respectively. For partial onset seizures in individuals older than 30, CBZ was significantly better then VPS; CBZ delayed the time to first seizure by 9%, 25%, 44%, and 66% longer than VPS for individuals aged 20, 30, 40, or 50, respectively. CONCLUSION: The results show clear age-varying differences between the effectiveness of CBZ and VPS for generalized onset and partial onset seizures, which have not been identified in previous studies using standard statistical methods. In future trials of AED monotherapy or add-on where time to first or Nth seizure is an outcome, methodology that can incorporate baseline seizure rate information would allow more powerful comparisons between treatments or between treatment and placebo.     

Clinical Development Outlook of Oxcarbazepine

Summary: Oxcarbazepine (OCBZ) has been accepted for registration as a first-line antiepileptic drug (AED) in several countries. However, because of changing regulations, further studies confirming statistically significant proof of efficacy are necessary in accordance with new standards. Therefore, Ciba has initiated a worldwide clinical development program to achieve registration. Four different types of design to demonstrate statistically significant proof of efficacy in partial seizures will be initiated. These studies are a "classical" poly-therapy add-on study, a monotherapy substitution trial, a high-dose/low-dose active-control monotherapy study, and a study in presurgical patients.
Anticonvulsants     

Prognostic factors affecting long-term retention of topiramate in patients with chronic epilepsy

PURPOSE: To determine the long-term retention rate of topiramate (TPM) therapy in patients with chronic epilepsy and to identify the relevant prognostic factors that influence retention. METHODS: All patients with chronic epilepsy (n = 393) prescribed TPM between October 1, 1995, and December 31, 1998, at a tertiary referral centre for epilepsy were analysed. The retention rate for TPM was calculated by using Kaplan-Meier survival analysis, and the prognostic factors influencing retention were analysed by using Cox regression. RESULTS: Of patients prescribed TPM, 30% continued taking the drug beyond 3 years. Discontinuation was mainly due to adverse events and lack of efficacy. Use of more than one new concurrent antiepileptic drug (AED) and lower maximal daily doses were more likely to result in treatment discontinuation due to adverse events. Older age at onset of epilepsy, a history of having previously taken more than one new AED [lamotrigine (LTG), gabapentin (GBP), or vigabatrin (VGB)], and lower maximal daily doses were more likely to lead to discontinuation due to lack of efficacy. CONCLUSIONS: A third of patients with chronic epilepsy started on TPM therapy will continue on treatment for >3 years. Absence of learning disabilities, late age at onset of seizures, previous use of more than one new AED, two or more concurrent AED use, and low maximal daily doses of TPM are more likely to result in discontinuation of medication. These factors should be taken into account when considering the use of TPM for the treatment of chronic epilepsy.