Dosing considerations for rufinamide in patients with Lennox-Gastaut syndrome: Phase III trial results and real-world clinical data.

PURPOSE: Lennox-Gastaut syndrome (LGS), a rare, severe form of childhood-onset epilepsy, is difficult to control. Rufinamide is indicated for adjunctive treatment of seizures associated with LGS in adults and pediatric patients aged ≥1 year. In clinical practice, rufinamide dosing and titration may differ from the trial setting. Here, rufinamide clinical trial data are compared with real-world experience to provide insight into optimal dosing and titration strategies. METHODS: Rufinamide Phase III and open-label extension (OLE) studies were reviewed; effect of titration and dose on adverse events (AEs) and concomitant AED use were analyzed. Real-world studies of rufinamide in LGS were identified via PubMed search. Clinical data were extracted and compared. RESULTS: Results demonstrated that a rapid titration schedule (7 or 14 days) of rufinamide was tolerable for most patients and resulted in highly significant reductions in total and tonic-atonic seizures, with efficacy and tolerability sustained over 3 years. The most common AEs during the Phase III study - somnolence, vomiting, and pyrexia - occurred during the first 3 weeks of treatment, and a small subset of patients were unable to reach target dose in that time. Use of concomitant AEDs had no clinically significant effect on plasma concentrations of rufinamide. Data from real-world clinical studies are consistent with the Phase III and OLE study results. However, relative to those used in clinical trials, lower doses and slower titration schedules were commonly employed in real-world settings. CONCLUSIONS: A lower dose and slower titration schedule ("low and slow") may reduce incidence of AEs without compromising efficacy of rufinamide in LGS.

A novel design for a dose finding, safety, and drug interaction study of an antiepileptic drug (retigabine) in early clinical development.

OBJECTIVE: To obtain information on the acceptable doses of the antiepileptic drug (AED) retigabine (RTG), the maximum tolerated dose (MTD), drug interactions, safety and tolerability, and preliminary evidence of efficacy when administered as adjunctive therapy and as monotherapy. MATERIALS: Study 202 was an open-label, add-on study in patients with partial or generalized epilepsy treated with valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), or topiramate (TPM) as monotherapy. Following baseline assessments, patients entered a dose titration phase of 28 – 56 days. The initial daily RTG dose was 100 or 200 mg (2 or 3 × daily). The RTG dose was increased every 1 - 2 weeks by 50 - 200 mg to a maximum of 1,600 mg/day. Once the RTG MTD had been attained, patients entered a 14-day maintenance period. Following this, the patient's background AED dose could be reduced, with the possibility of achieving RTG monotherapy. The final dosing regimen attained was maintained for an additional 14 days. Patients who completed study 202 could choose to continue treatment with RTG (with or without other AEDs) in study 208, the long-term extension of study 202. Safety assessments included adverse event (AE) monitoring, clinical laboratory evaluations, electrocardiograms, and physical and neurologic examinations. Patients' seizure diaries to assess the frequency and type of seizures, the percentage change in seizure rate, and the responder rate (>= 50% reduction in seizure rate from baseline) were evaluated. RESULTS: 60 patients (mean age 37.2, range 16 - 64 years) were enrolled in study 202, and 47 (78%) continued treatment with RTG in the extension study (208). In study 202, the most commonly reported AEs were: dizziness (53%), asthenia (42%), somnolence (33%), nausea (27%), speech disorder (27%), and tremor (27%). In the extension study, AEs were similar and included dizziness, somnolence, diplopia, feeling "drunk", confusion, fatigue, and dysarthria. The median percent reductions in 28-day seizure rate, relative to baseline in Studies 202 and 208, were ~ 20% and 47%, respectively. RTG did not alter the pharmacokinetics of the four monotherapy AEDs investigated. CBZ and PHT increased RTG clearance by 27% and 36%, respectively, whereas TPM and VPA had no effect on RTG clearance. CONCLUSIONS: Studies 202 and 208 provided critical information on RTG safety and tolerability, and reductions in seizure rates towards the design and conduct of subsequent pivotal clinical trials. Likewise, information regarding the appropriate dosage of RTG with VPA, CBZ, PHT, or TPM was obtained, which permitted the subsequent pivotal trials to be performed appropriately. *Currently at Shire Pharmaceuticals, Behavioral Health Business Unit, Wayne, PA, USA **Currently at University of Pennsylvania, Department of Neurology, Philadelphia, PA, USA.

Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial.

PURPOSE: To evaluate efficacy and safety of adjunctive treatment with rufinamide 1600 mg twice daily in subjects aged > or = 16 years with refractory partial seizures. METHODS: This double-blind, placebo-controlled, randomized, parallel-group, multicenter trial included an 8-week baseline phase and a 13-week double-blind phase. Treatment was initiated with rufinamide 400 mg twice daily or placebo; rufinamide was titrated to 1600 mg twice daily. Percentage change in partial seizure frequency was the primary outcome measure. Secondary outcome measures included total partial seizure frequency and the percentage of subjects experiencing a >/=50% reduction in partial seizure frequency. RESULTS: Three hundred thirteen subjects were randomized; 156 subjects received rufinamide and 157 received placebo. Rufinamide-treated subjects experienced a 20.4% median reduction in partial seizure frequency relative to baseline, while placebo-treated subjects had an increase of 1.6% (p = 0.02). Exclusion of subjects taking carbamazepine in a post hoc analysis resulted in a reduction of 29.2% versus 0.7% in the placebo group (p = 0.05), whereas the treatment difference in subjects taking carbamazepine was not significant. Of rufinamide-treated subjects, 28.2% experienced a > or = 50% decrease in partial seizure frequency versus 18.6% of placebo-treated subjects (p = 0.04). The most common adverse events associated with rufinamide treatment were dizziness, nausea, diplopia, and ataxia; they occurred primarily during the titration phase. DISCUSSION: Adjunctive therapy with rufinamide 3200 mg/day compared with matching placebo demonstrated efficacy and was generally well tolerated in adults with partial seizures. Further study of this agent in adults with partial seizures taking a range of baseline AEDs is warranted.

Optimisation and data mining techniques for the screening of epileptic patients.

Identifying abnormalities or anomalies by visual inspection on neurophysiologic signals such as ElectroEncephaloGrams (EEGs), is extremely challenging. We propose a novel Multi-Dimensional Time Series (MDTS) classification technique, called Connectivity Support Vector Machines (C-SVMs) that integrates brain connectivity network with SVMs. To alter noise in EEG data, Independent Component Analysis based on the Unbiased Quasi Newton Method was applied. C-SVM achieved 94.8% accuracy classifying subjects compared to 69.4% accuracy with standard SVMs. It suggests that C-SVM can be a rapid, yet accurate, technique for online differentiation between epileptic and normal subjects. It may solve other classification MDTS problems too.

Monotherapy clinical trial design.

Monotherapy of epilepsy is usually preferable to polytherapy for a variety of reasons. However, investigational or newer antiepileptic drugs (AEDs) are typically evaluated as add-on therapy in patients with refractory seizures. Because coadministered drugs are subject to drug interactions, add-on trials of AEDs do not necessarily address the utility of a new AED as monotherapy or its use in patients with newly diagnosed epilepsy, in whom monotherapy is usually sufficient. Monotherapy clinical trials are difficult to design because randomizing epilepsy patients to placebo or pseudoplacebo is considered unethical, and results from active-drug noninferiority designs are difficult to interpret. Active-drug superiority designs have been developed in an attempt to provide useful information about the monotherapeutic efficacy of new AEDs. The conversion to monotherapy trial design, introduced in the late 1970s, provides for initial add-on of an investigational agent to a preexisting drug in patients with uncontrolled seizures, followed by gradual discontinuation of the preexisting treatment and an eventual monotherapy phase of the investigational agent. Conversion to monotherapy trials are typically of short duration and have been criticized for failing to provide adequate time for titration to optimal dose, an inability to examine tolerance development or long-term safety, and possibly placing enrolled patients at increased risk for morbidity, but they have been used to obtain data about monotherapy efficacy sufficient for regulatory authority approval. Relevant clinical trial data are needed to guide treatment choices in patients who have failed previous monotherapy. To date, large-scale prospective trials comparing monotherapy with old and new AEDs have not shown superior efficacy of the new AEDs but have demonstrated their better tolerability and safety. It is hoped that use of appropriately designed monotherapy clinical trials will help to identify a new generation of AEDs in the future for monotherapy in epilepsy patients.

Improved quality of life in patients with partial seizures after conversion to oxcarbazepine monotherapy.

OBJECTIVE: Quality of life (QOL) was assessed in patients who switched to oxcarbazepine monotherapy because of the lack of efficacy or poor tolerability of their current antiepileptic drug (AED). METHOD: This open-label, single-arm study consisted of patients aged 12 >or= years with partial onset seizures. Oxcarbazepine (8-10mg/kg/day for children, 600 mg/day for adults) was titrated up over 4 weeks while the existing AED was tapered off. QOL was evaluated at baseline and end of study (Week 16) using the validated-in-epilepsy QOLIE-31 questionnaire. RESULTS: For all patients who completed the QOLIE-31 at baseline and completion, a statistically significant improvement was noted for both the composite and multi-item subscale QOL scores (P<0.05 vs baseline). Statistically significant mean percentage improvements of >or=10% from baseline (range=10.8-50.1%) were also noted. Significant improvements were seen in health-related QOL for patients who experienced seizure freedom or >or=50% reductions in seizure frequency with oxcarbazepine monotherapy. CONCLUSIONS: Patients with partial seizures who switched to oxcarbazepine monotherapy showed statistically significant, clinically relevant improvements in QOL.

Amelioration of erectile dysfunction following a switch from carbamazepine to oxcarbazepine: recent clinical experience.

Oxcarbazepine is an antiepileptic drug (AED) indicated for use as monotherapy and add-on therapy in adults and children 4 years of age and older. Despite being structurally related to carbamazepine, oxcarbazepine differs substantially in its pharmacokinetic and safety profile; oxcarbazepine has a much lower risk of pharmacokinetic drug-drug interactions than carbamazepine. Carbamazepine has also been shown to induce the hepatic synthesis of sex hormone-binding globulin, thus reducing free serum testosterone levels and possibly causing erectile dysfunction (ED) in some men; these effects have not been observed with oxcarbazepine. This paper provides a discussion of recent clinical experience with men who presented in private clinical practice with complaints of ED while being treated with carbamazepine for seizure disorders. The four illustrative case studies presented in this report suggest that switching AED treatment from carbamazepine to oxcarbazepine in men with epilepsy can reduce the ED side effects observed with carbamazepine.

Efficacy and tolerability of the new antiepileptic drugs, I: Treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.

PURPOSE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane Library for relevant articles from 1987 until September 2002, with selected manual searches up to 2003. RESULTS: Evidence exists, either from comparative or dose-controlled trials, that GBP, LTG, TPM, and OXC have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. Evidence also shows that LTG is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes for which more evidence is necessary.

Efficacy and tolerability of the new antiepileptic drugs, II: Treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.

PURPOSE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) [gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS)] in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane Library for relevant articles from 1987 to March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. GBP can be effective for the treatment of mixed seizure disorders, and GBP, LTG, OXC, and TPM for the treatment of refractory partial seizures in children. Limited evidence suggests that LTG and TPM also are effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox-Gastaut syndrome. CONCLUSIONS: The choice of AED depends on seizure and/or syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes for which more evidence is necessary.

Caffeinated beverages and decreased seizure control.

Seizure control is often affected by seizure threshold lowering behaviours. In this case report, the authors address excessive caffeine ingestion from tea with increased seizure frequency. When decaffeinated beverages were substituted for the tea, seizure frequency returned to baseline. Similar findings occurred when the patient was re-challenged. The authors recommend avoidance of excessive caffeine in patients with epilepsy.

Sustained efficacy and long-term safety of oxcarbazepine: one-year open-label extension of a study in refractory partial epilepsy.

PURPOSE: To evaluate the long-term efficacy, tolerability, and safety of oxcarbazepine (OXC) in medically refractory partial epilepsy. METHODS: This study is the open-label extension phase that followed a multicenter, randomized, double-blind, dose-response clinical study of OXC monotherapy in patients with medically refractory partial epilepsy. We analyzed the efficacy, tolerability, and safety of OXC during the first 48 weeks of open-label therapy. To evaluate efficacy, we compared the change in seizure frequency throughout the 48 weeks of treatment with OXC with the baseline seizure frequency that preceded the double-blind phase of the core study by an intent-to-treat and completer analysis. Safety and tolerability were evaluated by using an intent-to-treat analysis. RESULTS: Of the 87 patients enrolled in the double-blind study, 76 patients participated in the open-label extension phase. Fifty-five (72%) patients completed 48 weeks of open-label treatment on a median OXC dose of 2,400 mg/day. Based on an intent-to-treat analysis, the median reduction in seizure frequency was 47%(p = 0.0054); the 50 and 75% responder rates were 46.1 and 25.0%, respectively, with 6.6% of patients remaining seizure free. The completer analysis yielded comparable efficacy results. OXC was well tolerated, with 13% of patients exiting because of adverse events. The six most common adverse events, irrespective of their causal relation to OXC, were dizziness, headache, fatigue, diplopia, nausea, and rash. For the most part, these adverse events tended to be transient. CONCLUSIONS: The efficacy of OXC is sustained with good safety and tolerability profiles during long-term treatment of patients with medically refractory partial epilepsy.

Effects of oxcarbazepine on sodium concentration and water handling.

Oxcarbazepine, a keto-analogue of carbamazepine, was recently approved in the United States for the treatment of seizures of partial onset. Some patients treated with oxcarbazepine showed the development of hyponatremia, which in most instances was asymptomatic. Understanding the mechanisms by which oxcarbazepine can lead to a reduction of serum sodium levels could have therapeutic implications for the few patients in whom symptomatic hyponatremia develops. In this study, we evaluated sodium and water handling in patients with epilepsy and in healthy subjects titrated over 3 weeks to a maximum daily oxcarbazepine dose of 2,400mg. All subjects were evaluated in a hospital setting after an overnight fast and after an acute water-load test performed before oxcarbazepine exposure and after maintenance on the medication for 3 weeks. Before oxcarbazepine exposure, the percentage of water load excreted was normal as both groups excreted more than 80% of the administered water load. After the intake of oxcarbazepine, the water load resulted in a reduction of the serum sodium and free water clearance without a concomitant increase in the arginine vasopressin serum levels. Most subjects in both groups failed to excrete 80% or more of the water load, suggesting that the effect of oxcarbazepine is physiological. We found that, after the water load, serum sodium and free water clearance were diminished in both groups without a concomitant increase in the arginine vasopressin serum levels. These findings indicate that oxcarbazepine-induced hyponatremia is not attributable to the syndrome of inappropriate secretion of antidiuretic hormone. Possible mechanisms include a direct effect of oxcarbazepine on the renal collecting tubules or an enhancement of their responsiveness to circulating antidiuretic hormone.

Tiagabine in the Management of Postencephalitic Epilepsy and Impulse Control Disorder.

Rationale. Anticonvulsants are used as primary or adjunctive agents in the treatment of psychiatric disorders. gamma-Aminobutyric acid (GABA) ergic modulation has been shown to be important in impulsive aggression. We investigated the treatment of impulse control disorders with aggressive features in two patients with post-encephalitic epilepsy using the anticonvulsant tiagabine, a novel GABA reuptake inhibitor.Methods. The cases of two patients who were previously treated with other anticonvulsants, had uncontrolled behaviors with intractable seizures and were placed on adjunctive tiagabine with control of both psychiatric and neurologic symptoms, were analyzed.Results. In case 1, 12 mg adjunctive tiagabine daily resulted in behavioral improvement that further improved with increased titration; however, when tiagabine was discontinued, abrupt behavioral decompensation occurred. In case 2, adjunctive tiagabine resulted in both seizure control and marked diminution of disinhibited behaviors with aggressive outbursts; however, when tiagabine was titrated from 20 mg daily to 24 mg daily increased irritability was noted that resolved with tiagabine reduction to 20 mg daily.Conclusion. In two cases, adjunctive tiagabine was effective in the management of both epilepsy and severe impulse control disorder. Optimal dosing to maximize anticonvulsant and psychotropic effects needs to be established. Further studies using tiagabine in the treatment of impulse control disorders are indicated.

Oxcarbazepine for Treatment of Partial Epilepsy: A Review and Recommendations for Clinical Use.

Recent trials and extensive postmarketing use confirm the efficacy and safety of oxcarbazepine (OXC) as a first-line treatment for adults and children with simple partial seizures, complex partial seizures, and partial seizures evolving to secondarily generalized seizures. OXC undergoes reductive metabolism at its keto moiety to form 10-hydroxy-10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (MHD), which is glucuronidated and excreted in the urine, with minimal involvement of the hepatic cytochrome P450-dependent enzymes. OXC has some drug interactions, and does not require titration, allowing for better tolerability. Titration for monotherapy and adjunctive therapy of OXC could begin at 150 mg/day and be increased by 150 mg every 2-3 days until the target dose of 900-1200 mg/day is reached. If necessary, one can go faster and start with up to 600 mg/day and titrate with weekly increments up to 600 mg/day if necessary for seizure control. Conversion to monotherapy can be done overnight or gradually. For gradual conversion, use the recommended titration of OXC and withdraw the baseline antiepileptic drugs gradually by 25%, starting at Day 14 or earlier in case of baseline tolerability issues. Consider reducing the dose of the primary antiepileptic drug during adjunctive therapy in case of adverse events or increase the dose of OXC in case of incomplete seizure control. In children OXC should be started at 8-10 mg/kg/day in two or three divided doses. If clinically indicated the dose can then be increased by 10 mg/kg/day in weekly intervals with final doses up to 30-46 mg/kg/day. Dose adjustment may be necessary in very young children (age 2-5 years) and in patients with renal dysfunction, based on renal clearance. However no adjustment of OXC dose is needed in patients with mild to moderate hepatic dysfunction. OXC has a number of advantages which include rapid titration, no need for safety monitoring (except for uncommon and mostly asymptomatic hyponatremia), a low potential for drug-drug interactions (except for those possibly impairing the effectiveness of oral contraceptives and increasing the serum concentration of phenytoin), a rash rate of less than 5%, similar efficacy and similar or better tolerability and safety compared with first-generation antiepileptic drugs. OXC is a valuable alternative to current treatment options.