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.     

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.     

Long-Term Experience with Topiramate as Adjunctive Therapy and as Monotherapy in Patients with Partial Onset Seizures: Retrospective Survey of Open-Label Treatment

Summary: Because initial studies of new antiepileptic drugs (AEDs) are add-on trials in refractory patient populations, their effectiveness as monotherapy is usually not apparent until relatively later in their development programs. The novel AED topiramate (TPM) has been found efficacious as adjunctive therapy in controlled, randomized trials in adults with partial onset seizures. We report a retrospective analysis of TPM as AED monotherapy in 214 patients from five centers who received TPM in investigational trials. Of this total, 136 (64%) were still receiving TPM at the time of the analysis, with a mean treatment duration of 2.5 years. One-third of the patients have been successfully converted to TPM monotherapy, and 62% of those converted have been seizure-free for at least 3 months. The results of this analysis suggest that TPM may prove to be a valuable new AED for both monotherapy and add-on therapy in partial onset 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.     

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.     

Tiagabine: The Safety Landscape

Summary: Tiagabine (TGB) hydrochloride is a potential new antiepileptic drug (AED) undergoing clinical development. Experience in humans amounts to 1,810 patient-years of exposure. TGB was found to be tolerated in an integrated safety analysis of five double-blind, add-on therapy trials involving approximately 1,000 patients with epilepsy with difficult-to-control seizures with existing AEDs. Discontinuation resulting from adverse events were infrequent, occurring in 15% of patients receiving TGB compared to 5% receiving placebo. The most frequently reported adverse event was dizziness, which was usually transient and did not require medical intervention. Adverse events that were statistically significantly more common with TGB than placebo were dizziness, asthenia, nervousness, tremor, diarrhea, and depression (not major depression). Adverse events were usually mild to moderate in severity and transient, and most were associated with dose titration. The incidence, type, and severity of adverse events in long-term studies were comparable with those in short-term studies. Serious adverse events were uncommon and no idiosyncratic events were reported.     

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.     

A review of the antiepileptic drug tiagabine

Tiagabine (TGB), a recently approved antiepileptic drug (AED), has a specific mechanism of action that is unique among AEDs. A potent AED with linear, predictable pharmacokineties, it inhibits gamma-aminobutyric acid (GABA) reuptake into neurons and glia. Tiagabine does not have any clinically relevant effects on hepatic metabolism or on serum concentrations of other AEDs, nor does it interact with commonly used non-AEDs. The most common side effects of TGB in controlled studies are dizziness, asthenia, somnolence, accidental injury, infection, headache, nausea, and nervousness. These events are usually mild to moderate in severity and generally do not require medical intervention. At dosages of 30-56 mg daily, TGB is an effective add-on treatment for partial seizures. Although patients who have medically refractory epilepsy can be converted to TGB monotherapy, more controlled studies are necessary to confirm the efficacy of TGB as monotherapy and to determine the effective dosage range.     

Occurrence of psychosis in patients with epilepsy randomized to tiagabine or placebo treatment

PURPOSE: Patients with drug-resistant epilepsy have a higher incidence of psychiatric problems and possibly greater intolerance to antiepileptic drugs (AEDs) than do other patients with epilepsy. Concern has been raised that gamma-aminobutyric acid (GABA)ergic drugs may be associated with treatment-emergent psychosis. Tiagabine (TGB; Gabitril), a new AED that blocks synaptic GABA uptake, was developed in trials of drug-resistant patients with epilepsy. We conducted ad hoc analyses of adverse events, drug intolerance, and treatment response to evaluate the association between TGB treatment and psychosis and whether psychiatric history might be predictive of tolerance or effectiveness of this GABAergic drug. METHODS: Data were analyzed from two multicenter, randomized, double-blind, placebo-controlled trials of add-on TGB therapy (32 or 56 mg daily) in 554 adolescents and adults with complex partial seizures (CPSs). After an 8- or 12-week baseline phase, double-blind treatment consisted of a 4-week titration period (with TGB dose gradually increased to 32 or 56 mg daily) and an 8- or 12-week fixed-dose period. Adverse events commonly associated with psychosis were evaluated. Treatment intolerance and effectiveness (> or =50% reduction in CPS rate) were compared among patients with and without psychiatric histories. RESULTS: Psychotic symptoms (hallucinations) were observed in three (0.8%) of 356 TGB-treated patients and none of 198 placebo-treated patients (p = 0.556, NS). Statistical analysis showed no interaction between psychiatric history and drug intolerance or treatment outcome. CONCLUSIONS: TGB administration appears to carry no significant increased risk of treatment-emergent psychosis. Psychiatric history was not predictive of the tolerance or effectiveness of the drug.     

Review of Controlled Trials of Gabitril (Tiagabine): A Clinician's Viewpoint

Summary: A recent problem for doctors has been the choice of which new antiepileptic drug (AED) to select for treatment of pharmacoresistant epilepsy. This article summarizes the clinical experience to date regarding the efficacy and safety of tiagabine (TGB; Gabitril) as adjunctive therapy in patients with partial-onset seizures. In its early Phase II development, TGB was evaluated in two multicenter pilot studies. Each had an open-label enrichment phase followed by a treatment phase with randomized, double-blind, two-period, cross-over phases. Between 24 and 50% of patients experienced reductions in seizure rates of ≥50%, depending on the type of partial seizure. In Phase III, three double-blind, parallel group, placebo-controlled adjunctive studies determined the efficacy of TGB in patients with refractory partial seizures. The first was a dose-response study employing doses of TGB-HCl of 16, 32 or 56 mg/day. Significant reductions in seizure rates were found with 32 and 56 mg/day. The second and third studies evaluated the efficacy of dosing TGB twice, three times, and four times daily, all of which showed similar efficacy. TGB efficacy in partial seizures was supported in several open trials, and no tolerance to efficacy was noted in long-term continuation studies. Tolerability was documented in all trials. Most adverse events were mild or moderate and transient, occurring during dose titration. They were clearly dose-related. No relevant changes in hematologic and biochemical tests, vital signs, or body weight were attributable to TGB. TGB appears to be an effective new drug for partial seizures with an acceptable safety profile.     

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.     

Safety of tiagabine: summary of 53 trials

We reviewed the clinical safety of tiagabine HCl (TGB), a selective CNS GABA uptake inhibitor, in nearly 3100 patients from 53 separate clinical trials. TGB was found to have no clinically important effect upon hepatic metabolic processes, serum concentrations of concomitant antiepileptic drugs (AEDs), laboratory values, or important interactions with any common non-AEDs. Adverse effects were usually mild and involved the nervous system. TGB is safe and well-tolerated as add-on therapy for the treatment of partial seizures.     

Determinants of tiagabine (TGB) efficacy and safety. A Polish multicenter study of 1307 patients with focal epilepsy

Tiagabine (TGB) is a novel anti-epileptic drug providing new therapeutic possibilities to patients with focal seizures resistant to treatment. Since there is no clear algorithm for the best add-on therapy, the aim of our work was to establish factors that statistically significantly affect tiagabine efficacy and toxicity in patients with focal seizures. Data in the study were obtained from over 200 neurologists all over Poland. A group of 1307 patients aged from 3.5 to 80 years with drug-resistant focal epilepsy participated in the study. They were under observation for 16 weeks when receiving TGB as an add-on therapy. Prior to TGB treatment they had at least 1 seizure per month (mean 7.42 +/- 9.86) during the past 3 months. On the study completion 40.47% of the patients were seizure-free for at least a month. Two factors turned out to be significant for TGB efficacy: the number of drugs used since the onset of epilepsy (p = 0.005) and seizure type (p = 0.047). The best outcome was attained in patients with simple partial seizures. Co-medication with phenytoin was better than TGB + carbamazepine or TGB + valproic acid. The factor determining the presence of side effects was the rate of TGB dose increment during the first six weeks of treatment. Toxicity of TGB was not related to its target dose. Tiagabine is a safe and efficient anti-epileptic drug for children and adults with focal epilepsy. Efficacy of tiagabine treatment depends on the number of drugs administered since the epilepsy onset and on the type of seizures. A slow dose increment is crucial for safety of TGB treatment.     

Tiagabine: efficacy and safety in partial seizures – current status

Tiagabine hydrochloride (TGB) is a selective gamma-aminobutyric acid (GABA) reuptake inhibitor. TGB is effective as an add-on medication in adults and children 12 years and older in the treatment of partial seizures. Results of nonrandomized add-on trials with TGB show treatment success with seizure reduction of at least 50% in 33% to 46% of patients. In newly diagnosed patients with partial epilepsy, TGB monotherapy was as effective as carbamazepine. Comedication with TGB elevates the risk of nonconvulsive status (7.8% vs 2.7% without TGB). The most common side effects include dizziness/lightheadedness, asthenia/lack of energy and somnolence. TGB has no negative effects on cognition; it does not increase the risk of fractures or rash. TGB may interfere with color perception. TGB presents an intermediate risk for depression in patients with epilepsy (approximately 4%). Regarding the risk of overdose, 96–680 mg TGB (mean 224 mg) caused seizures or coma. TGB is an antiepileptic drug exhibiting a specific anticonvulsive mechanism of action, the efficacy of which is relatively low when used in comedication. Critical side effects, such as the induction of nonconvulsive status epilepticus, further limit its use.     

Transient dystonias in three patients treated with tiagabine

PURPOSE: Tiagabine (TGB) is a new antiepileptic drug (AED) with gamma-aminobutyric acid (GABA)ergic mechanism of action. GABAergic compounds may influence the extrapyramidal system, probably via modulation of dopaminergic nigrostriatal neurons. A well-known side effect of TGB is probably dose-related extrapyramidal tremor. To our knowledge, acute dystonias associated with TGB treatment have yet to be described. METHODS: Three patients with transient acute dystonic reactions while taking TGB as add-on therapy with carbamazepine (CBZ) are presented. The focal limb dystonia in one case, an oromandibular dystonia in second, and writer's cramp in third one were observed. RESULTS: In all cases dystonic movements resolved spontaneously without discontinuation of TGB therapy and without any concomitant treatment. CONCLUSIONS: Tiagabine may cause various mild extrapyramidal side effects. All three cases reported were diagnosed with transient possibly drug-related dystonia after increase in TGB dose. It remain unclear whether dystonic movements are specific for patients treated with TGB/CBZ bitherapy.     

Tiagabine: Efficacy and Safety in Adjunctive Treatment of Partial Seizures

PURPOSE: To assess the efficacy and safety of tiagabine (TGB), a new antiepileptic drug (AED), as add-on therapy in patients with refractory partial seizures. METHODS: This response-dependent study used an open-label screening phase (in which patients were titrated to their optimal TGB dose, < or =64 mg/day) followed by a double-blind, placebo-controlled, crossover phase. Initial eligibility criteria included (a) seizures inadequately controlled by existing AEDs, and (b) six or more partial seizures during an 8-week baseline period. Patients showing benefit from TGB (> or =25% reduction in total seizure rate relative to baseline) were eligible for randomization into the double-blind phase, which comprised two 7-week assessment periods separated by a 3-week crossover period. RESULTS: Forty-four (50%) of the 88 enrolled patients entered the double-blind phase of the study during which there were significant reductions compared with placebo in all partial (p < 0.01), complex partial (p < 0.001), and secondarily generalized tonic-clonic seizure rates (p < 0.05). Thirty-three percent of patients experienced a reduction of > or =50% in the all partial seizure rate. Eight (22%) patients receiving TGB during the double-blind phase reported adverse events, of which dizziness and incoordination were the most frequent. Three patients withdrew from treatment during the double-blind phase because of adverse events; two during treatment with TGB and one during treatment with placebo. TGB did not affect plasma concentrations of other coadministered AEDs. CONCLUSIONS: TGB was significantly better than placebo in terms of seizure rate reduction and was generally well-tolerated in patients with difficult to control seizures.     

Women with Epilepsy: Must Contraception and Pregnan Add to the Burden of Epilepsy?

Summary: In addition to seizure control, women with epilepsy face particular complications associated with menstruation, fertility, contraception, pregnancy, and breastfeeding. With traditional long-term antiepileptic drug (AED) therapy there is a risk of menstrual irregularities, contraceptive failure, and adverse pregnancy outcome. Many women intentionally discontinue AED therapy during pregnancy because of concerns about the risk of fetal malformation and effects on fetal growth and development. However, trauma resulting from seizures is the leading cause of maternal and fetal death in women with epilepsy. In addition, mothers are concerned about the presence of AEDs in breast milk and therefore tend to choose bottle feeding. Clearly, a balance must be achieved between seizure control for the mother and exposure of the fetus or infant to AEDs. Tiagabine (TGB) is a new AED which acts by inhibiting uptake of the neurotransmitter γ-aminobutyric acid into glial cells. Animal studies show that TGB has no toxic effects either on reproductive function or on the developing fetus, although there is still insufficient evidence to permit conclusions from human studies. TGB does not induce hepatic metabolism, and a study in healthy volunteers indicates no interaction with oral contraceptives. It is hoped that the availability of new AEDs such as TGB, with the promise of a better safety profile and a lower propensity for drug interactions, will alleviate the burden for women with epilepsy.     

Tiagabine (Gabitril) Experience in Children

Summary: Tiagabine (TGB) is indicated as adjunctive therapy for partial seizures in adults and children aged 12 years and older. Double-blind, placebo-controlled studies of TGB treatment are under way in younger children with various forms of epilepsy. The results of pediatric pharmacokinetic trials indicate patterns similar to those seen in adults. An open-label study was conducted in the United States in 31 children with refractory complex partial seizures, with doses escalated every 2 weeks by 0.25 mg/kg up to a maximal daily dose of 1 mg/kg. Twenty-nine patients were treated with TGB for >1 year; 26 completed the study, of whom 18 were receiving monotherapy at study completion. A European dose-escalation study evaluated TGB (0.25–1.5 mg/kg/day) as add-on therapy in 52 children aged 2–15 years. TGB appeared to be more effective in localization-related epilepsy syndromes, with 17 of 23 patients with localization-related epilepsy having a 33% median reduction of seizure rate compared with baseline in the fourth month of treatment, and six patients having ≥50% seizure rate reduction. In this study, myoclonic seizures and spasms showed a poor response as opposed to encouraging findings reported by other groups with these seizure types. The adverse effect profile of TGB in children with epilepsy is similar to that in adults. In the U.S. study, most common adverse events were related to the central nervous system (CNS) and decreased over time. In the European study, mostly mild to moderate adverse events, including asthenia (19%), nervousness (19%), dizziness (17%), and somnolence (17%), were reported by 83% of TGB-treated children (39% of children reported adverse events during the single-blind placebo period). In summary, preliminary pediatric data with TGB suggest particular efficacy against epilepsy characterized by partial seizures or other syndromes, and further investigation is warranted.     

Levetiracetam in the treatment of childhood epilepsy

Epilepsy is a common pediatric neurologic disorder that is difficult to manage in a substantial portion of children. Levetiracetam (LEV) is a novel antiepileptic drug (AED) that has recently been approved as add-on treatment for various seizure types in epilepsy populations that include children: for refractory partial seizures in epilepsy patients ≥4 years old, for myoclonic seizures in juvenile myoclonic epilepsy patients ≥12 years old, and for primary generalized tonic-clonic seizures in idiopathic generalized epilepsy patients (≥6 years old with FDA approval; ≥12 years old with EMEA approval). A review of published pediatric studies indicates that the efficacy of LEV is best established for partial seizures; however, results from recent double-blind and open-label trials indicate that adjunctive LEV also controls generalized seizures – particularly myoclonic and generalized tonic-clonic – in children and adolescents with primary generalized epilepsy. LEV was well-tolerated in pediatric studies. The most common adverse events (AEs) reported were sedation related. Behavioral AEs were among the most commonly reported events in some trials; conversely, improvements in behavior and cognition were also frequently reported. LEV appears to be a safe and effective AED with unique characteristics that benefit the treatment of children with epilepsy.     

Outcome of short-term antiepileptic treatment in patients with solitary cerebral cysticercus granuloma

OBJECTIVES: The duration of antiepileptic drug (AED) therapy in cases of solitary cerebral cysticercus granuloma (SCCG) presents a major dilemma and the efficacy of short-term (6 months) vs long-term (2 years) AED therapy has been studied. MATERIALS AND METHODS: Prospective randomized study of short-term vs long-term AED treatment with SCCG has been undertaken. A total of 206 subjects with new onset seizures with SCCG were randomized into two groups: group A (98 patients) were treated for 6 months and group B (108 patients) were treated for 2 years with AED therapy. The patients were evaluated periodically during and at least 18 months after the tapering of drugs. RESULTS: Partial seizures with or without secondary generalization has been found to be the commonest manifestation occurring in 80.6% of patients with SCCG. In group A 66.3% and in group B 57.4% patients showed complete resolution of computerized tomographic lesion and rest had punctated residual calcification. Statistically, no significant difference in the recurrence of seizures was found in two groups with disappearance of lesion but the difference between calcified residua and complete resolution subset was significant. In patients having residual calcification, 42.2% in group A and 21.7% in group B had recurrence of seizures and the difference was statistically significant (Z = 1.97, P < 0.05). CONCLUSIONS: The study revealed that SCCG with epilepsy is a benign self-limiting disease. A longer duration of therapy is not warranted in patients having total resolution of lesion. Calcified lesion was found to be the most common cause of recurrence of seizures. Higher recurrence rate was observed in short-term therapy in patients having calcified lesions and may require long-term AED treatment.