Adjunctive Treatment Of Partial Seizures Research Articles

A high-performance liquid chromatography-tandem mass spectrometry method for quantification of perampanel in human plasma: Effect of concomitant anti-seizure medications on perampanel concentration in patients with epilepsy

Perampanel is a first-in-class α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist and a novel anti-seizure medication. It is currently used as adjunctive treatment for partial seizures in patients over 12 years of age. With the increasing clinical application of perampanel, monitoring its concentration under certain clinical conditions is important. This study developed a rapid and sensitive high-performance liquid chromatography–tandem mass spectrometry method to quantify perampanel in human plasma. Protein precipitation with acetonitrile was performed for sample preparation. Perampanel and perampanel-d5 (internal standard) were analyzed under gradient conditions using a C18 column. The mobile phase was composed of 0.1% (v/v) formic acid in water (solvent A) and 0.1% (v/v) formic acid in acetonitrile (solvent B) at a flow rate of 0.4 mL/min. Mass detection was performed using multiple reaction monitoring in the positive ionization mode. The proposed method was validated over a range of 0.5–500 ng/mL for perampanel. The linearity (r2 value) was higher than 0.999, and the linear equation was y = 0.00116x + 0.0116. The accuracy of the low-, middle-, and high-quality control samples was between 103% and 113%, and the intra- and inter-day precisions were below 6.81%. The quality of the proposed method was evaluated in accordance with the US Food and Drug Administration Bioanalytical Method Validation Guidance for Industry. The plasma concentrations of perampanel in 25 patients were successfully determined to be 38.7–577.7 ng/mL using the validated method.

Lacosamide-Related Arrhythmias: A Systematic Analysis and Review of the Literature.

Lacosamide (LCM) is a new antiepileptic drug used as an adjunctive treatment for partial seizures with and without secondary generalization. One of the modes of action is the enhancement of slow inactivation of voltage-gated sodium channels. Experimental studies and clinical trials suggest that LCM acts upon both neurons and the heart and may increase the risk of cardiac arrhythmias. A systematic review was conducted to investigate characteristics of arrhythmias related to the use of LCM for the treatment of seizures. The search terms “lacosamide”, “arrhythmias”, “AV block”, “atrial fibrillations/flutter”, “cardiac conductions defects”, “ventricular tachycardia”, “ventricular fibrillation were used. Case reports and retrospective studies were gathered by searching Medline/PubMed, Google Scholar, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane CENTRAL (Cochrane Central Register of Controlled Trials), and Web of Science databases. Seventeen articles were selected for review. Ventricular tachycardia was the most reported LCM related arrhythmia (29.4%), followed by new-onset atrial fibrillation (17.6%), complete heart block (17.6%), Mobitz type 1 Atrio-ventricular block (11.8%), sinus pauses (11.8%), pulseless electrical activity (5.9%) and widening QRS complex (5.9%). Further research and clinical trials are needed to explore the etiopathogenesis and causative relationship between the use of LCM and arrhythmias.

Gabapentin or pregabalin induced myoclonus: A case series and literature review

Gabapentin (GBP) and pregabalin (PGB) are FDA approved for adjunctive treatment of partial seizures and for treatment of post-herpetic neuralgia. Both drugs are primarily eliminated by renal excretion. However, PGB or GBP induced myoclonus has only been reported infrequently in case reports/series. It is not discussed with patients and its sudden occurrence can lead to anxiety because of “seizure-like” nature. In addition, first-contact physicians might treat it as seizures, leading to unnecessary tests and aggressive management. Medical records of patients who had myoclonus because of PGB or GBP seen by Neurology service between Jan & May 2017 in inpatient or outpatient setting at our tertiary care setting were reviewed. We identified six patients who were on either GBP or PGB or both who developed likely subcortical myoclonus in the setting of renal insufficiency and one patient who developed myoclonus independent of renal dysfunction. Our results indicate that myoclonus is commonly seen in patients in various clinical settings with or without renal insufficiency, and is independent of the severity of the renal failure. However, this is a reversible side effect of medication and it resolves either by discontinuing the medication, removing the medication with hemodialysis or by improvement of renal dysfunction. With a high index of suspicion, aggressive testing and treatment for other possible conditions like seizures (in non-epilepsy patients) or CNS infections can be avoided. In patients with renal failure and with decreased physiological renal clearance such as the elderly, GBP or PGB dose initiation and changes should be conservative.

055 Effect of common concomitant antiepileptic drugs during adjunctive treatment with perampanel: post hoc analysis from the open-label extension of a phase III study in patients with idiopathic generalised epilepsy

IntroductionPerampanel is approved for adjunctive treatment of partial seizures, with or without secondarily generalised seizures, and primary generalised tonic-clonic (PGTC) seizures in epilepsy patients aged ≥12 years. Perampanel is also approved for monotherapy use for partial seizures in the US. This post hoc analysis assessed the effects of the most common concomitant Baseline antiepileptic drugs (AEDs) on discontinuation rates and treatment-emergent adverse event (TEAE) incidence during adjunctive treatment with perampanel in patients (aged ≥12 years) with idiopathic generalised epilepsy (IGE) and PGTC seizures in the open-label extension (OLEx) Phase of Study 332 (NCT02307578).MethodsPatients completing the double-blind study could receive perampanel (≤12 mg/day) during the OLEx (6 week blinded Conversion Period;≤136 weeks’ Maintenance). Here, we report results for perampanel >4–8 mg/day and >8–12 mg/day.ResultsMost common concomitant Baseline AEDs were valproic acid (n=55), lamotrigine (n=53), levetiracetam (n=37), topiramate (n=21) and zonisamide (n=12); patients may have received >1 of these Baseline AEDs. The most common reasons for discontinuing were adverse event(s) (AE), ‘other’ and patient choice. Lamotrigine: patient choice, n=6/34 (>4–8 mg/day); AE/‘other’, both n=3/19 (>8–12 mg/day). Levetiracetam: patient choice, n=5/27 (>4–8 mg/day); AE, n=2/10 (>8–12 mg/day). Topiramate: ‘other’, n=3/15 (>4–8 mg/day); AE/‘other’, both n=1/6 (>8–12 mg/day). Valproic acid: patient choice, n=6/38 (>4–8 mg/day); ‘other’, n=4/17 (>8–12 mg/day). Zonisamide: patient choice/‘other’, both n=2/10 (>4–8 mg/day); no discontinuations (>8–12 mg/day). Patient-reported TEAEs ranged from: 88.2% (lamotrigine) to 93.3% (topiramate) for perampanel >4–8 mg/day, and 70.6% (valproic acid) to 100.0% (topiramate and zonisamide) for perampanel >8–12 mg/day. The most common TEAE was dizziness.ConclusionIn this post hoc analysis, primary reasons for discontinuation and TEAE incidence differed between the most common Baseline AED subgroups and perampanel dose range, although TEAE types were similar. These data provide additional information on the safety of adjunctive perampanel in patients with IGE.Study supportEisai Inc.

Repositioning again of zonisamide for nerve regeneration.

Repositioning again of zonisamide for nerve regeneration.

Lack of effect of perampanel on QT interval duration: Results from a thorough QT analysis and pooled partial seizure Phase III clinical trials

IntroductionPerampanel is a selective, noncompetitive AMPA receptor antagonist approved as adjunctive treatment for partial seizures. To assess potential for delayed cardiac repolarization, a Phase I thorough QT study was performed, supplemented by plasma concentration–QT data modeled from 3 pooled Phase III studies. MethodsThe Phase I thorough QT study (double-blind, combined fixed-sequence, parallel-group) quantified the effect of perampanel (6mg once daily for 7 days, followed by dose escalation to a single 8-mg dose, a single 10-mg dose, then 12mg once daily for 7 days), moxifloxacin positive control (single 400-mg dose on Day 16), and placebo on QT interval duration in healthy subjects (N=261). Electrocardiograms were recorded at baseline, Day 7 (post 6mg dose), and Day 16 (post 12mg dose). Statistical comparisons were between the highest approved perampanel dose (12mg) versus placebo, a “mid-therapeutic” dose (6mg) versus placebo, and moxifloxacin versus placebo. Acknowledging that the Phase I thorough QT study could not incorporate a true “supratherapeutic” dose due to length of titration and tolerability concerns in healthy subjects, Phase III studies of perampanel included expanded electrocardiogram safety evaluations specifically intended to support concentration–QT response modeling. The lack of effect of perampanel on the QT interval is shown from pooled analysis of 3 double-blind, placebo-controlled, 19-week, Phase III studies with perampanel doses ≤12mg (N=1038, total perampanel; and N=442, placebo) in patients with partial seizures. QT measures were corrected for heart rate using Fridericia's (QTcF; the primary endpoint) and Bazett's (QTcB) formulas. ResultsIn the Phase I thorough QT study, the positive control moxifloxacin caused peak time-matched, baseline-adjusted, placebo-corrected (ΔΔ) QTcF of 12.15ms at 4h postdose, confirming a drug effect on QTc interval and study assessment sensitivity. Mean baseline-adjusted (Δ) QTcF versus nominal time curves were comparable between perampanel 12mg and placebo, with most ΔQTcF values being slightly negative. Healthy subjects receiving perampanel 6 and 12mg doses for 7 days showed no evidence of effects on cardiac repolarization. Peak ΔΔQTcF was 2.34ms at 1.5h postdose for perampanel 6mg and 3.92ms at 0.5h postdose for perampanel 12mg. At every time point, the upper 95% confidence limit of ΔΔQTcF for perampanel 6 and 12mg was <10ms. Phase III studies revealed no clinically significant difference between patients with partial seizures treated with perampanel or placebo in QTcF and QTcB values >450ms, with no dose-dependent increases or large incremental changes from baseline of >60ms. Regression analysis of individual plasma perampanel concentrations versus corresponding QTc interval values in Phase I thorough QT and Phase III studies demonstrated no relationship between perampanel concentrations and QT interval duration. ConclusionTreatment with perampanel 6mg and 12mg for 7 days did not delay cardiac repolarization in healthy volunteers. In a population analysis of 1480 patients with partial seizures treated with perampanel doses ≤12mg or placebo, no clinically significant trends in QT interval data were noted. Based on the thorough QT study and evaluations from pooled Phase III studies, there is no evidence of prolonged QT interval duration with perampanel treatment.

New antiepileptic medication linked to blue discoloration of the skin and eyes.

Ezogabine is an antiepileptic medication approved in June 2011 by the US Food and Drug Administration (FDA) as an adjunctive treatment for partial seizures. Minimal drug interactions and a novel mechanism of action made ezogabine an appealing new treatment option. However, adverse effects reported during clinical trials and following drug approval have been alarming. A Risk Evaluation Mitigation Strategy (REMS) program has been established for urinary retention. A safety alert was published in April 2013 warning ezogabine may cause retinal pigment abnormalities and/or blue-gray discoloration, most notably on or near the lips, nail beds, sclera and conjunctiva with long-term use. In October 2013, the FDA announced a formal label change to ezogabine to include a black boxed warning emphasizing the previously reported warnings of eye and skin discoloration and permanent vision changes. Given the unknown nature of the pathophysiology, consequences and potential for reversibility of these effects, GlaxoSmithKline and the FDA have published recommendations for patients currently receiving ezogabine. Further data from published case reports and long-term safety trials in the future may lend additional insight into these concerning effects.

Long-term retention rate of zonisamide in patients with epilepsy: an observational study.

Zonisamide (ZNS) is an antiepileptic drug with a broad spectrum of action mechanisms. Although ZNS is usually indicated for the adjunctive treatment of partial seizures in Western countries, it has long been used for partial and generalized seizures as monotherapy or adjunctive treatment in South Korea and Japan. The present study was to evaluate the long-term retention rate of ZNS in clinical practice. This was a retrospective, single-center, long-term observational study. A total of 148 patients (82 men, 66 women; 14-85 years) who were treated with ZNS as monotherapy or adjunctive treatment were included. Zonisamide was administrated with a starting dose of 100 mg/d, and optimal-dose adjustments were made according to individual clinical responses. Efficacy and tolerability were analyzed during a 6-year follow-up. The overall retention rate was 66.1% at 1-year and 55.1% at 6-year follow-up. Patients with monotherapy (70.8% vs 44.1%) and generalized seizures (71.6% vs 48.2%) were more likely to continue ZNS at 6-year follow-up compared with those with adjunctive therapy and partial seizures. The most common cause of discontinuation was adverse events such as somnolence, rash, and gastrointestinal problems. Our study shows the high retention rate of ZNS in the treatment of patients with epilepsy. The retention rate of ZNS was comparable with those of other antiepileptic drugs including lamotrigine, topiramate, and levetiracetam, and it can be suggested that ZNS can be considered for monotherapy and for the patients with generalized seizures.

Safety and tolerability of zonisamide in paediatric patients with epilepsy

BackgroundZonisamide has recently been approved in Europe for the adjunctive treatment of partial seizures (with or without secondary generalisation) in adolescents and children aged ≥6 years. AimTo further assess the safety of adjunctive zonisamide in paediatric epilepsy patients. MethodsA pooled analysis of data from 17 studies (including four randomised, double-blind trials) was conducted. The safety population comprised patients aged ≤16 years receiving at least one dose of study drug. Assessments included treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs and electrocardiography. ResultsThe analysis included 398 patients treated with zonisamide (<12 years, n = 191; 12–16 years, n = 207). All but seven patients received zonisamide as adjunctive therapy. Mean duration of exposure was 318.7 days (mean dose, 253.1 mg/day). Most TEAEs were of mild or moderate intensity. The most frequently reported treatment-related TEAEs were decreased appetite (15.6%), somnolence (12.1%), fatigue (9.3%), dizziness (6.0%), decreased weight (5.8%), irritability (5.8%) and headache (5.3%). Incidence of serious zonisamide-related TEAEs was low (3.5% overall). TEAEs most commonly leading to discontinuation were lethargy (1.0%) and fatigue (1.0%). TEAEs of decreased weight and decreased appetite occurred in 28 (7.0%) and 78 (19.6%) patients, respectively. Twenty-eight patients had decreased bicarbonate levels, but there were no reports of respiratory alkalosis or metabolic acidosis. No changes in vital signs of clinical concern were observed and there were no reports of clinically significant electrocardiogram abnormalities with zonisamide treatment. ConclusionZonisamide demonstrated an acceptable safety profile when used as adjunctive treatment in paediatric patients.

Zonisamide-Induced Psychosis in a Patient With Bipolar Disorder and Narcolepsy

Zonisamide is an anticonvulsant used as an adjunctive treatment for partial seizures. It has also been used off-label for treatment of mania. Abdoh et al recently reported a very interesting case of psychosis induced by zonisamide. We too observed a case of psychosis induced by zonisamide in a 34-year-old female with bipolar disorder and narcolepsy.

Perampanel for the Control of Drug-Resistant Partial-Onset Seizures in Patients 12 years and Older

Recent developments in the treatment of seizure disorders have been focused on medications with novel mechanisms of action. One such medication is perampanel, a first-in-class, noncompetitive, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist recently approved for the adjunctive treatment of partial seizures in patients 12 years of age and older when other antiepileptic medications have failed. The drug has demonstrated efficacy in several clinical trials, and appears to exert its anti-seizure activity in a dose-dependent manner. The drug has a half-life of approximately 105 hours suggesting the medication might be a logical option for individuals who have difficulty with adherence to medications that require multiple daily doses. Because of changes in serum concentration when enzyme-inducing antiepileptic drugs are employed concurrently, escalations in the initial dose of perampanel are recommended. Adverse events reported with perampanel use tend to be mild to moderate. However, psychiatric side-effects, including hostility and aggressive behavior, have been noted in some patients resulting in the inclusion of a warning on the Food and Drug Administration (FDA) approved labeling.

Myoclonus in renal failure: Two cases of gabapentin toxicity

Gabapentin, an AED approved for the adjunctive treatment of partial seizures with/without secondary generalization and for the treatment of postherpetic neuralgia, is frequently used off-label for the treatment of both psychiatric and pain disorders. Since gabapentin is cleared solely by renal excretion, dosing requires consideration of the patient's renal function. Myoclonic activity may occur as a complication of gabapentin toxicity, especially with acute kidney injury or end-stage renal disease. We report 2 cases of myoclonic activity associated with gabapentin toxicity in the setting of renal disease which resolved with discontinuation of gabapentin and treatment with hemodialysis and peritoneal dialysis. As gabapentin has multiple indications and off-label uses, an understanding of myoclonus, neurotoxicity, and renal dosing is important to clinicians in multiple specialties.

Zonisamide: its pharmacology, efficacy and safety in clinical trials

Zonisamide is a benzisoxazole derivative, chemically unrelated to other antiepileptic drugs, that appears to have multiple mechanisms of action, including inhibition of Na(+) channels and reduction of T-type Ca(2+) currents. It is currently licensed in Europe and the USA for adjunctive treatment of partial seizures in adults, and in Europe as monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy. Zonisamide displays predictable, dose-dependent pharmacokinetics and has a half-life of ~60h, allowing once- or twice-daily administration. It has a low potential for interactions with other medications, including oral contraceptives. The clinical efficacy of adjunctive zonisamide therapy has been established in four pivotal, phase III, randomized, double-blind, placebo-controlled trials, which together included approximately 850 patients, aged 12-77years, with refractory partial epilepsy. In all four trials, zonisamide 300-600mg/day resulted in significant reductions in median total seizure rates vs placebo, and zonisamide was generally well tolerated; the most frequently reported adverse events being somnolence, dizziness and anorexia/weight loss. Subanalysis of the primary European trial indicated that zonisamide was effective when administered as first-line adjunctive treatment, and a long-term extension to the same trial demonstrated that the efficacy and safety/tolerability of adjunctive zonisamide was sustained for up to 36months. Once-daily monotherapy with zonisamide (200-500mg/day) has been shown to be non-inferior to, and as well tolerated as, twice-daily monotherapy with controlled-release carbamazepine (400-1200mg/day) in adults with newly diagnosed partial epilepsy. Zonisamide has also been shown to have favourable long-term retention rates, an important indication of its overall effectiveness.

Zonisamide in clinical practice

Zonisamide is currently licensed in Europe and the USA for the adjunctive treatment of partial seizures (with or without secondary generalization) in adults, based on the results of four pivotal, randomized, double-blind, placebo-controlled trials. It is also licensed in Europe as monotherapy for adults with newly diagnosed partial epilepsy, based on the results of a randomized, double-blind, non-inferiority trial. Because clinical trials are conducted under tightly controlled conditions, using rigid dosing schedules and employing strict exclusion/exclusion criteria, there is a need for 'real-world' evidence of an antiepileptic drug's effectiveness and tolerability in clinical practice, where patients are much more diverse in terms of clinical characteristics and treatment is tailored to the individual's specific needs. Several studies have demonstrated that adjunctive treatment with zonisamide is effective when administered under everyday clinical practice conditions, with a favourable safety/tolerability profile similar to that observed in clinical trials. In the Zonisamid im Alltag Der Epilepsiepatienten (ZADE) study, almost 80% of patients showed a reduction in seizure frequency of ≥50% over a median follow-up of 18weeks, and over one-third of patients became seizure free. Data from these clinical practice studies also indicate that zonisamide is effective and generally well tolerated when administered as a first-line adjunctive treatment and is associated with high retention rates and improvements in quality of life. Evidence from these clinical practice studies therefore complements data from zonisamide's clinical trial programme, providing pragmatic information on the likely benefits and risks of treatment under real-life conditions.

Comparison of Zonisamide and Carbamazepine Monotherapy in Adults with Newly Diagnosed Partial Epilepsy: Results of a Phase III, Randomized, Double-Blind, Non-Inferiority Trial (IN5-1.005)

Objective: To compare efficacy and safety of once-daily zonisamide (ZNS) and twice-daily controlled-release carbamazepine (CBZ) monotherapy in adults with newly diagnosed partial epilepsy. Background ZNS is a benzisoxazole derivative, chemically unrelated to other antiepileptic drugs (AEDs), which displays multiple mechanisms of action. It is currently licensed (USA, Europe) for adjunctive treatment of partial seizures in adults. Design/Methods: Phase III, international, randomized, double-blind, non-inferiority trial, in which 583 untreated adults (18–75 years) with newly diagnosed partial epilepsy received ZNS or CBZ monotherapy. Following initiation (ZNS 100 mg/day; CBZ 200 mg/day) and up-titration (to 300 and 600 mg/day, respectively), patients entered a 26–78-week flexible-dosing period (200–500 and 400–1200 mg/day, respectively, according to response/tolerability). Once seizure-free for 26 weeks, patients entered a 26-week maintenance phase. Primary endpoint was proportion of patients achieving seizure freedom for ≥26 weeks. Safety/tolerability evaluation included assessment of treatment-emergent adverse events (TEAEs). Results: Overall, 161/282 (57.1%) patients randomized to ZNS and 192/301 (63.8%) patients randomized to CBZ completed the trial. 26-week seizure freedom rates were 79.4% (177/223) for ZNS vs. 83.7% (195/233) for CBZ (Per Protocol Population). Adjusted absolute treatment difference was -4.5% (95% confidence interval [CI]: -12.2, 3.1). The lower CI limit narrowly exceeded the protocol-specified -12% margin, but the lower CI limit of relative difference (-14.7%) was within the ILAE-recommended margin (-20%). In most patients seizure freedom was achieved at the lowest target dose level (ZNS 300 mg, 87.0%; CBZ 600 mg, 88.7%). Incidence of TEAEs was similar for ZNS (60.5%) vs. CBZ (61.7%), as was incidence of serious TEAEs (5.3% vs. 5.7%) and TEAEs leading to withdrawal (11.0% vs. 11.7%). Conclusions: In a trial using flexible dosing to reproduce clinical practice, both ZNS and CBZ demonstrated high seizure-freedom rates and were well-tolerated in newly diagnosed partial epilepsy patients. Supported by: Eisai. Disclosure: Dr. Baulac has received personal compensation for activities with Eisai Inc., USB Pharma, Pfizer Inc, Medtronics and Novartis as a speaker and/or participant on an advisory board. Dr. Brodie has received personal compensation for activities with Pfizer Inc, UCB Pharma, Eisai Inc., GlaxoSmithKline, Inc., Sanofi-Aventis Pharmaceuticals, Inc., and Lundbeck Research USA, Inc. Dr. Brodie has received research support from Eisai Inc. Dr. Segieth has received personal compensation for activities with Eisai Ltd as an employee. Dr. Giorgi has received personal compensation for activities with Eisai Ltd as an employee.

Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial

Efficacious and safe monotherapy options are needed for adult patients with newly diagnosed epilepsy. As an adjunctive treatment for partial seizures, pregabalin compares favourably with lamotrigine and is an effective, approved treatment. We studied the efficacy and safety of pregabalin as monotherapy, using a design that complied with European regulatory requirements and International League Against Epilepsy guidelines. This phase 3, double-blind, randomised, non-inferiority study compared the efficacy and tolerability of pregabalin and lamotrigine monotherapy in patients with newly diagnosed partial seizures at 105 centres, mostly in Europe and Asia. Randomisation to treatment groups (1:1 ratio) was by a computer-generated pseudorandom code (random permuted blocks), with patients sequentially assigned numbers by telephone. Investigators, site staff, and patients were masked to the assigned treatment. After randomisation, patients were titrated to either 75 mg oral pregabalin or 50 mg oral lamotrigine twice daily during a 4-week dose-escalation phase, followed by a 52-week efficacy assessment phase during which the daily dose could be increased as needed to a maximum of 600 mg and 500 mg, respectively. The primary efficacy endpoint was the proportion of patients who remained seizure-free for 6 or more continuous months during the efficacy assessment phase; analysis included all patients who were randomly assigned to treatment groups and received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT00280059. 660 patients were randomly assigned to treatment groups (330 pregabalin, 330 lamotrigine), of whom 622 entered the efficacy assessment phase (314 pregabalin, 308 lamotrigine). Fewer patients in the pregabalin group than in the lamotrigine group became seizure-free for 6 or more continuous months (162 [52%] vs 209 [68%]; difference in proportion, -0·16, 95% CI -0·24 to -0·09). The overall incidence of adverse events was similar between the groups and consistent with that in previous studies; dizziness (55 [17%] vs 45 [14%] patients), somnolence (29 [9%] vs 14 [4%]), fatigue (27 [8%] vs 19 [6%]), and weight increase (21 [6%] vs 7 [2%]) were numerically more common in the pregabalin group than in the lamotrigine group. Pregabalin has similar tolerability but seems to have inferior efficacy to lamotrigine for the treatment of newly diagnosed partial seizures in adults. Inferior efficacy of pregabalin might have been attributable to limitations in the study design, as treatment doses might have not been optimised adequately or early enough. Pfizer Inc.

An open-label, add-on study of pregabalin in patients with partial seizures: A multicenter trial in Greece

Introduction Pregabalin efficacy and safety as an adjunctive treatment for partial seizures was evaluated using an open-label, flexible-dose. Study design In 98 adults with refractory partial epilepsy taking 1–3 anti-epileptic drugs with ≥2 seizures during an 8-week baseline period. Methods Pregabalin was increased to ≤600 mg/day during a 9-week dose optimization period with dosage maintained for 12 additional weeks. Primary endpoint was the percentage change in partial seizure frequency between the 8-week baseline and 12-week observation period. Results Pregabalin treatment was associated with a significant reduction in partial seizure frequency: median percent change in partial seizure frequency from baseline to 12 weeks was −33% and −22% in patients with a baseline seizure frequency of ≤3 and >3 per 28 days, respectively. The 50% and 75% responder rates were 41.94% (95% CI: 31.91–51.96) and 30.11% (95% CI: 20.78–39.43), respectively. Nineteen percent of subjects were seizure-free throughout the last 12 weeks. Pregabalin administration resulted in a significant reduction in anxiety (mean reduction in Hospital Anxiety and Depression Scale scores of 1.68 units, 95% CI: −2.60 to −0.76). Most patients were much improved or very much improved on Patient Global Impression of Change (53.8%) and Clinical Global Impression of Change (53.8%). The most frequently self-reported adverse events (AEs) were mild or moderate somnolence (20.4%) and dizziness (5.1%) with a low AE discontinuation rate (5.1%). Conclusions The efficacy and side-effect profile of pregabalin were similar to previous pregabalin double-blind, controlled studies. Additionally, pregabalin, as an add-on treatment for partial epilepsy, exhibits significant anti-anxiety properties.

Ezogabine for the Adjunctive Treatment of Partial Onset Seizures in Adults with Epilepsy

Partial seizures are frequently resistant to pharmacologic treatment. There are a plethora of medications currently approved for use in partial epilepsy. However, despite the large number of medications available, seizure control often remains elusive. A new medication with a unique mechanism of action has recently been approved for the adjunctive treatment of partial seizures in adults. Ezogabine (retigabine) exerts its actions at the level of voltage-gated potassium channels. In clinical trials it has demonstrated efficacy similar to that of other agents approved for resistant partial epilepsy. Adverse events tend to be central nervous system related. However, significant urinary retention has been noted in some persons exposed to the drug. A Risk Evaluation and Mitigation Strategy is being implemented to minimize urinary adverse events. Ezogabine represents an important addition to the partial epilepsy medication arsenal.

Update on rufinamide in childhood epilepsy

Rufinamide is an orally active, structurally novel compound (1-[(2,6-difluorophenil1) methyl1]-1 hydro 1,2,3-triazole-4 carboxamide), which is structurally distinct from other anticonvulsant drugs. It was granted orphan drug status for the adjunctive treatment of Lennox-Gastaut syndrome (LGS) in the United States in 2004, and released for use in Europe in 2007. In January 2009, rufinamide was approved by the United States Food and Drug Administration for treatment of LGS in children 4 years of age and older. It is also approved for adjunctive treatment for partial seizures in adults and adolescents. Rufinamide’s efficacy mainly against atonic/tonic seizures in patients with LGS seems nowadays indubitable and has been confirmed both in randomized controlled trial and in open label extension studies. More recently, rufinamide was evaluated for the adjunctive treatment of childhood-onset epileptic encephalopathies and epileptic syndromes other than LGS, including epileptic spasms, multifocal epileptic encephalopathy with spasm/tonic seizures, myoclonic-astatic epilepsy, Dravet syndrome and malignant migrating partial seizures in infancy. This review updates the existing literature data on the efficacy and safety/tolerability of rufinamide in childhood-onset epilepsy syndromes.

Betting After the Race Is Run

After gabapentin received FDA approval in 1993 for adjunctive treatment of partial seizures, the drug was widely used off-label for other