Tolerability Of Zonisamide Research Articles

Results from a randomized controlled trial of zonisamide in the treatment of alcohol use disorder

There is preliminary evidence that the anticonvulsant medication Zonisamide (ZON) may be an effective, well-tolerated treatment for alcohol use disorder (AUD). However, further evaluation of its efficacy for treating patients with AUD is needed, and much remains unknown about ZON’s therapeutic mechanisms. The present study aimed to evaluate the efficacy and tolerability of ZON in a double-blind, placebo-controlled, randomized trial. Eighty-one adults (ages 21-65) diagnosed with AUD were randomly assigned to receive either ZON (at a target dose of 400 mg/d) or a pill placebo over 12 weeks, followed by a two-week taper. All participants also received a computerized alcohol reduction program, Take Control (TC). Primary drinking outcomes were average daily drinks, percentage drinking days, and percentage heavy drinking days. Further, we evaluated changes in AUD clinical severity and performance on neuropsychological measures. For both groups, drinking outcomes generally decreased, as did AUD clinical severity, though group differences were not statistically significant. Neuropsychological testing performance was similar for both groups at baseline; however, at post-treatment, participants in the ZON group demonstrated poorer working memory and lower performance on verbal fluency tests compared to the placebo group, and these differences were statistically significant with moderate-large effect sizes. One serious adverse event was reported among individuals receiving ZON. Study findings indicate that ZON combined with TC does not demonstrate superior effectiveness for reducing average daily drinks in this clinical sample with principal AUD compared to placebo and TC, and treatment with ZON may be associated with reduced neurocognitive performance over time.

Zonisamide for the Treatment of Parkinson Disease: A Current Update.

Zonisamide has been used as an add-on treatment in order to overcome the deficiencies of the general therapies currently used to resolve the motor complications and non-motor symptoms of Parkinson disease. Various trials have been designed to investigate the mechanism of action and treatment effects of zonisamide in this condition. Most clinical trials of zonisamide in Parkinson disease were from Japan. The vast majority of studies used changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) scores and daily “OFF” time as primary endpoints. Based on adequate randomized controlled trials, zonisamide is considered a safe and efficacious add-on treatment in Parkinson disease. The most convincing proof is available for a dosage of 25–50 mg, which was shown to lead to a significant reduction in the UPDRS III score and daily “OFF” time, without increasing disabling dyskinesia. Furthermore, zonisamide may play a beneficial role in improving non-motor symptoms in PD, including impulsive–compulsive disorder, rapid eye movement sleep behavior disorder, and dementia. Among the various mechanisms reported, inhibition of monoamine oxidase-B, blocking of T-type calcium channels, modulation of the levodopa–dopamine metabolism, modulation of receptor expression, and neuroprotection are the most often cited. The mechanisms underlying neuroprotection, including modulation of dopamine turnover, induction of neurotrophic factor expression, inhibition of oxidative stress and apoptosis, inhibition of neuroinflammation, modulation of synaptic transmission, and modulation of gene expression, have been most extensively studied. This review focuses on structure, pharmacokinetics, mechanisms, therapeutic effectiveness, and safety and tolerability of zonisamide in patients with Parkinson disease.

Zonisamide add-on therapy for focal epilepsy.

The majority of people with epilepsy have a good prognosis, and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop dug-resistant epilepsy, especially those with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCT) of zonisamide, used as an add-on treatment for focal epilepsy uncontrolled by one or more concomitant antiepileptic drug. This is an updated version of the Cochrane review previously published in 2018. To evaluate the efficacy and tolerability of zonisamide, when used as an add-on treatment for people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs. For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE Ovid(September 2019). In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field, to seek any ongoing or unpublished studies. Randomised controlled trials, in which add-on zonisamide was compared with placebo or another antiepileptic drug in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs. Two review authors independently selected trials for inclusion, extracted data, assessed for risk of bias using the Cochrane 'Risk of bias' tool, and assessed the certainty of the evidence, using the GRADE approach. The primary outcome was at least a 50% reduction in total seizure frequency; the secondary outcomes were (1) tolerability; and (2) adverse effects. We used an intention-to-treat approach for our primary analyses. We estimated summary risk ratios (RRs) for each outcome. We displayed a summary of the estimates of effects and certainty of the evidence for each outcome in a 'Summary of findings' table. We did not find any new studies since the last version of this review. We included eight studies (1636 participants) from previous versions of this review. The overall RR with 95% confidence interval (CI) for at least a 50% reduction in seizure frequency for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.90 (95% CI 1.63 to 2.22; 7 trials, 1371 participants; moderate-certainty evidence). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 mg to 500 mg/day) was 1.86 (95% CI 1.60 to 2.17; 7 trials, 1429 participants; moderate-certainty evidence). The number needed to treat for an additional beneficial outcome was six (95% CI 4.1 to 6.8). Two trials provided evidence of a dose-response relationship for this outcome. The RR for treatment withdrawal for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.59 (95% CI 1.18 to 2.13; 6 trials, 1099 participants; moderate-certainty evidence), and for 100 mg to 500 mg/day was 1.44 (95% CI 1.08 to 1.93; 6 trials, 1156 participants; moderate-certainty evidence). The number needed to treat for an additional harmful outcome was 15 (95% CI 9.3 to 36.7). The following adverse effects were more likely to be associated with zonisamide than with placebo: ataxia (RR 3.85, 99% CI 1.36 to 10.93; 4 trials, 734 participants; low-certainty evidence); somnolence (RR 1.52, 99% CI 1.00 to 2.31; 8 trials, 1636 participants; moderate-certainty evidence); agitation (RR 2.35, 99% CI 1.05 to 5.27; 4 trials, 598 participants; low-certainty evidence); and anorexia (RR 2.74, 99% CI 1.64 to 4.60; 6 trials, 1181 participants; low-certainty evidence). Across the eight studies, we rated risk of bias domains at low or unclear risk of bias, apart from two studies, which we rated at high risk of attrition bias. Five of the eight studies were sponsored by the drug companies that produced zonisamide. When used as an add-on treatment in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs, moderate-certainty evidence found that zonisamide was more successful than placebo at reducing the frequency of seizures by at least 50%. We were unable to identify minimum effective and maximum tolerated doses. The included trials evaluated a maximum stable-dose phase of 18 weeks, so results cannot be used to confirm longer periods of efficacy in seizure control. The results cannot be extrapolated to monotherapy, or to people with other seizure types or epilepsy syndromes.

A retrospective analysis of using zonisamide and retention in monotherapy among patients with epilepsy in routine clinical practice

Zonisamide is one of the first antiepileptic drugs of new generation with a wide spectrum of action. It is successfully used in treatment of epilepsy for 30 years. The study aims at analyzing the results of the multicenter Russian trial on the efficacy and tolerability of zonisamide and retention in monotherapy. The analysis included 92 patients with focal epilepsy, aged 18-78 years, from 20 epileptology centers in different regions of Russia. The patients were treated with zonisamide in initial and subsequent treatment. The efficacy (the reduction of seizure frequency by >50%) was achieved in 81 (91%) out of 89 patients (95% CI 83.6-95.7%). Fifty-two patients received zonisamide for more than one year. The efficacy was achieved in 50 (96.2%) (95% CI 88.2-99.2%), including 39 (79.6%) patients with remission out of 49 patients with assessment of seizure free periods (95% CI was 66.8-89% for the frequency of remissions). The adverse effects were recorded in 27 (29.3%) patients. Seven (7.6%) patients were withdrawn due to these effects. The maximal duration of observation period was 50 month. Mean time of retention in treatment was 42.4 month (95% CI 38.7-46.2 month). The total frequency of retention in treatment was 82.1% (95% CI 73.1-91%) during the whole observation period.

Efficacy, tolerability, and blood concentration of zonisamide in daily clinical practice

We aimed to evaluate the efficacy, tolerability, and blood concentration of zonisamide (ZNS) used in daily clinical practice. This was a retrospective study performed at a single epilepsy center and included 149 patients with epilepsy. The efficacy and retention of ZNS for 52 weeks, percentage of patients who were seizure free for 26 weeks, and the 5-year retention rate were analyzed. The tolerability was assessed based on treatment-emergent adverse effects (AEs) and the adverse effect profile (AEP). More than 70% (105/149) of patients were on ZNS polytherapy. The mean dose of ZNS was 300 ± 170.6 mg/day, and the antiepileptic drug (AED) load was 2.0 ± 1.1 (median 1.8, range 0.2–5.3). The retention rate for 52 weeks and the percentage of patients who were seizure-free for 26 weeks were 73% and 42%, respectively. The retention rate decreased with time and reached 43% in 5 years. Younger age of onset was a significant variable affecting retention rate for 52 weeks (p = 0.044), whereas fewer concomitant AEDs were significantly associated with being seizure free for 26 weeks (p = 0.0006). AEs were reported in 24% (36/147) of patients. The number, mechanism of action, or drug load of the AEDs did not predict the development of AEs; however, blood concentration of ZNS was significantly higher in patients with AEs (p = 0.0011) than in those without AEs. ZNS is a well-tolerated and effective AED in daily clinical practice, and several clinical factors may predict the efficacy and tolerability of ZNS.

Zonisamide add-on therapy for focal epilepsy.

The majority of people with epilepsy have a good prognosis, and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCT) of zonisamide, used as an add-on treatment for focal epilepsy uncontrolled by one or more concomitant antiepileptic drug. This is an updated version of the Cochrane review previously published in 2013. To evaluate the efficacy and tolerability of zonisamide, when used as an add-on treatment for people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs. For this update, on 4 September 2017, we searched the Cochrane Epilepsy Group Specialised Register, Cochrane Register of Studies Online, MEDLINE Ovid, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform ICTRP. We searched SCOPUS on 13 February 2013, but this is no longer necessary, because RCTs and quasi-RCTs in Embase are now included in CENTRAL. In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing or unpublished studies. Randomised controlled trials, in which add-on zonisamide was compared with placebo or another antiepileptic drug in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs. Two review authors independently selected trials for inclusion, extracted data, assessed for risk of bias using the Cochrane 'Risk of bias' tool, and assessed the quality of the evidence, using the GRADE approach. The primary outcome was at least a 50% reduction in total seizure frequency; the secondary outcomes were (1) tolerability; and (2) adverse effects. We used an intention-to-treat approach for our primary analyses. We estimated summary risk ratios (RRs) for each outcome. We displayed a summary of the estimates of effects and quality of the evidence for each outcome in a 'Summary of findings' table. We included eight studies (1636 participants). The overall RR with 95% confidence interval (CI) for at least a 50% reduction in seizure frequency compared to placebo for 300 mg to 500 mg/day of zonisamide was 1.90 (95% CI 1.63 to 2.22; 7 trials, 1371 participants; moderate-quality evidence). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 mg to 500 mg/day) was 1.86 (95% CI 1.60 to 2.17; 7 trials, 1429 participants; moderate-quality evidence). The number needed to treat for an additional beneficial outcome was six (95% CI 4.1 to 6.8) for this outcome. Two trials provided evidence of a dose-response relationship for this outcome. The RR for treatment withdrawal for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.59 (95% CI 1.18 to 2.13; 6 trials, 1099 participants; moderate-quality evidence), and for 100 mg to 500 mg/day was 1.44 (95% CI 1.08 to 1.93; 6 trials, 1156 participants; moderate-quality evidence). The number needed to treat for an additional harmful outcome was 15 (95% CI 9.3 to 36.7). The CIs of the following adverse effects indicated that they were significantly associated with zonisamide: ataxia RR 3.85 (99% CI 1.36 to 10.93; 4 trials, 734 participants; low-quality evidence); somnolence RR 1.52 (99% CI 1.00 to 2.31; 8 trials, 1636 participants; moderate-quality evidence); agitation RR 2.35 (99% CI 1.05 to 5.27; 4 trials, 598 participants; low-quality evidence); and anorexia RR 2.74 (99% CI 1.64 to 4.60; 6 trials, 1181 participants; low-quality evidence).Across the eight studies, we rated risk of bias domains at low or unclear risk of bias apart from two studies which we rated at high risk of attrition bias. Five of the eight studies were sponsored by the drug companies that produced zonisamide. When used as an add-on treatment in people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs, moderate-quality evidence found that zonisamide was more successful than placebo at reducing the frequency of seizures by at least 50%. We were unable to identify minimum effective and maximum tolerated doses. The included trials evaluated a maximum stable-dose phase of 18 weeks, so results cannot be used to confirm longer periods of efficacy in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.

The Use of Zonisamide for the Treatment of Psychiatric Disorders: A Systematic Review.

Traditional pharmacotherapy has undoubtedly improved the outcome of patients with psychiatric disorders, but partial efficacy or poor tolerability persists in a number of these subjects. Among different compounds, zonisamide has been used to address unmet needs of standard pharmacotherapy. The purpose of the present article is to provide a review about the use of zonisamide for the treatment of psychiatric conditions. A research in the main database sources has been conducted to obtain an overview of the use of zonisamide in psychiatric disorders or associated conditions (obesity and smoking cessation). Most available data indicate the possible effectiveness of zonisamide for the treatment of acute phases of bipolar disorder, binge-eating disorder (BED), alcohol misuse, and obesity. A further assessment of the safety and tolerability of zonisamide is made necessary by the fact that, with the exception of BED, for all other disorders at least some data come from studies with combined pharmacological therapies. Zonisamide may have some utility, especially as an adjunctive therapy, for the management of acute phases and weight gain in bipolar disorder and for prevention of alcohol misuse. Preliminary evidence indicates zonisamide as a candidate compound for the treatment of BED and obesity. However, open-label design and small sample sizes of most available studies prevent from drawing sound conclusions about the utility of this compound in psychiatry.

Retention rate of zonisamide in intractable epilepsy.

To assess the effect and tolerability of zonisamide (ZNS) as adjunctive treatment for difficult-to-treat epilepsy in adult Scandinavian patients. 151 outpatients (mean age: 42.5 years) from 18 centres in Denmark, Sweden and Norway were recruited to the study. 81.5% had focal epilepsy, and the mean number of previously tried AEDs was 4.5. The patients were given ZNS as add-on treatment, and the ZNS dosing and the visit frequency were governed by the treating physician. The primary efficacy endpoint was the retention rate after 12-month treatment. Assessments included also responder rate, type and frequency of adverse events, healthcare resource utilization (HCRU) and quality of life (QOLIE-31). 90 patients (59.6%) completed the study. Mean daily ZNS dose was 300.8 mg. After 12 months, 81 patients were still on ZNS, that is a retention rate of 53.6%. The mean reduction of seizure frequency at 12 months was 27%. Best effect was seen in those with focal and those with secondary generalized seizures. In the QOLIE-31, there was a mean increase from baseline of 4.8 points. The tolerability was generally good. The majority of side effects were CNS-related, dizziness, fatigue, seizure aggravation, and headache being most prevalent. 21.2% had adverse events leading to withdrawal of ZNS. A retention rate of 53.6% after 1 year of treatment with ZNS is roughly in accordance with the retention rates found for lamotrigine, oxcarbazepine, levetiracetam and topiramate in drug-resistant patients.

A review of safety and efficacy of zonisamide for treatment of pediatric partial epilepsy

A review of safety and efficacy of zonisamide for treatment of pediatric partial epilepsy Maria Stella Vari, Pasquale Striano Paediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health, University of Genoa, "G Gaslini" Institute, Genova, Italy Introduction: Zonisamide is one of the most promising antiepileptic drugs that was first approved in Europe as add-on therapy in adult patients with partial seizures and recently approved as monotherapy. More recently, zonisamide has been approved for pediatric use in the UK and can now be prescribed for partial epilepsy in adolescents and children aged 6 years and above. Aim: This paper systematically reviews the current evidence on the efficacy and tolerability of zonisamide as monotherapy and adjunctive therapy for pediatric partial epilepsy. Methods: Relevant randomized clinical trials and open-label studies were identified by a structured PubMed search, supplemented by an additional hand search of reference lists and authors' files. Results: PubMed database search yielded 12 (four double-blind randomized, eight open-label) clinical trials published over the last 10 years (January 2004 to September 2014) and the pooled analysis included a total of 1,555 patients treated with zonisamide. Conclusion: Zonisamide currently represents a robust option in the treatment of children with partial epilepsy, based on its multiple mechanism of action and efficacy in different situations. Keywords: children, clinical trial, partial seizures, tolerability

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 add-on for drug-resistant partial epilepsy

The majority of people with epilepsy have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding zonisamide, when used as an add-on treatment for drug-resistant partial epilepsy. To evaluate the efficacy and tolerability of zonisamide when used as an add-on treatment for people with drug-resistant partial epilepsy. We searched the Cochrane Epilepsy Group Specialized Register (12 February 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 1) (January 2013), MEDLINE (Ovid, 1946 to 12 February 2013), SCOPUS (13 February 2013), ClinicalTrials.gov (12 February 2013) and the WHO International Clinical Trials Registry Platform ICTRP (13 February 2013). In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing/unpublished studies. Randomised, placebo-controlled, add-on trials of zonisamide in people with drug-resistant partial epilepsy. Two review authors independently selected trials for inclusion and extracted data. Outcomes were: (1) 50% or greater reduction in total seizure frequency; (2) treatment withdrawal; (3) adverse effects. Primary analyses were intention-to-treat. We estimated summary risk ratios (RRs) for each outcome. All studies were assessed for risk of bias using the Cochrane risk of bias tool and the quality of evidence was assessed using the GRADE approach and presented in a summary of findings table. Five trials (949 participants) were included. The overall RR with 95% confidence interval (CI) for 50% reduction in seizure frequency compared to placebo for 300 to 500 mg/day of zonisamide was 2.00 (95% CI 1.58 to 2.54). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 to 500 mg per day) was 1.92 (95% CI 1.52 to 2.42). The number needed to treat (NNT) was 6 for this outcome. Two trials provide evidence of a dose response relationship for this outcome. The RR for treatment withdrawal for 300 to 500 mg/day of zonisamide compared to placebo was 1.64 (95% CI 1.20 to 2.25) and for 100 to 500 mg per day was 1.47 (95% CI 1.07 to 2.01). NNT for this outcome was 21. The CIs of the following adverse effects indicate that they are significantly associated with zonisamide: ataxia 3.77 (99% CI 1.28 to 11.11); somnolence 1.83 (99% CI 1.08 to 3.11); agitation 2.35 (99% CI 1.05 to 5.27) and anorexia 2.71 (99% CI 1.29 to 5.69). Across the 5 studies, risk of bias domains were rated as low is bias or unclear. None of the evidence for outcomes was downgraded for quality. Zonisamide has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. In this review minimum effective and maximum tolerated doses cannot be identified. The trials reviewed were of a maximum stable-dose phase of 18 weeks in duration and results cannot be used to confirm longer periods of effectiveness in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.

Zonisamide regulates basal ganglia transmission via astroglial kynurenine pathway

To clarify the anti-parkinsonian mechanisms of action of zonisamide (ZNS), we determined the effects of ZNS on tripartite synaptic transmission associated with kynurenine (KYN) pathway (KP) in cultured astrocytes, and transmission in both direct and indirect pathways of basal ganglia using microdialysis. Interactions between cytokines [interferon-γ (IFNγ) and tumor-necrosis factor-α (TNFα)] and ZNS on astroglial releases of KP metabolites, KYN, kynurenic-acid (KYNA), xanthurenic-acid (XTRA), cinnabarinic-acid (CNBA) and quinolinic-acid (QUNA), were determined by extreme liquid-chromatography with mass-spectrometry. Interaction among metabotropic glutamate-receptor (mGluR), KP metabolites and ZNS on striato-nigral, striato-pallidal GABAergic and subthalamo-nigral glutamatergic transmission was examined by microdialysis with extreme liquid-chromatography fluorescence resonance-energy transfer detection. Acute and chronic ZNS administration increased astroglial release of KYN, KYNA, XTRA and CNBA, but not QUNA. Chronic IFNγ administration increased the release of KYN, KYNA, CNBA and QUNA, but had minimal inhibitory effect on XTRA release. Chronic TNFα administration increased CNBA and QUNA, but not KYN, KYNA or XTRA. ZNS inhibited IFNγ-induced elevation of KYN, KYNA and QUNA, but enhanced IFNγ-induced that of CNBA. TNFα-induced rises in CNBA and QUNA were inhibited by ZNS. ZNS inhibited striato-nigral GABAergic, striato-pallidal GABAergic and subthalamo-nigral glutamatergic transmission via activation of groups II and III mGluRs. ZNS enhanced astroglial release of endogenous agonists of group II mGluR, XTRA and group III mGluR, CNBA. Activated endogenous mGluR agonists inhibited transmission in direct and indirect pathways of basal ganglia. These mechanisms contribute to effectiveness and well tolerability of ZNS as an adjunct treatment for Parkinson's disease during l-DOPA monotherapy.This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’.

Safety and tolerability of zonisamide in elderly patients with epilepsy

To assess the safety/tolerability of zonisamide in elderly patients. A pooled analysis of clinical study data from elderly (≥65years) patients receiving add-on/monotherapy zonisamide for partial seizures was compared with pooled adult (18-65years) study data. Assessments included treatment-emergent adverse events (TEAEs), clinical laboratory parameters and weight change. Data were analyzed from 95 elderly and 1389 adult patients. Incidence of total TEAEs was similar (elderly, 78/95 [82%] vs adult, 1165/1389 [84%]); but lower in elderly versus adult patients for treatment-related TEAEs (53/95 [56%] vs 1010/1389 [73%]), severe TEAEs (11/95 [12%] vs 289/1389 [21%]), serious TEAEs (12/95 [13%] vs 230/1389 [17%]) and TEAEs leading to withdrawal (17/95 [18%] vs 312/1389 [23%]). Most TEAEs were of mild-to-moderate intensity. TEAEs reported more frequently by elderly versus adult patients included fatigue (11/95 [12%] vs 135/1389 [10%]), nasopharyngitis (8/95 [8%] vs 100/1389 [7%]), constipation (7/95 [7%] vs 67/1389 [5%]) and pruritus (6/95 [6%] vs 29/1389 [2%]). The only serious TEAEs reported by ≥2% of elderly patients were 'convulsions' (4/95 [4%] vs 49/1389 [4%]). Three elderly patients died; one death was considered treatment-related. TEAEs leading to discontinuation of ≥2% of elderly patients were dizziness (4/95 [4%]), headache (2/95 [2%]), somnolence (2/95 [2%]) and confusional state (2/95 [2%]). For elderly patients, there were minimal changes in clinical laboratory parameters, no reports of respiratory alkalosis or metabolic acidosis and no significant weight changes. Zonisamide demonstrated a favourable safety/tolerability profile in elderly patients. No new or unexpected safety findings were identified.

Zonisamide efficacy as adjunctive therapy in children with refractory epilepsy.

Approximately one third of epileptic children do not achieve complete seizure improvement. Zonisamide is a new antiepileptic drug which is effective as adjunctive therapy in treatment of intractable partial seizures. The purpose of the current study was to evaluate the effectiveness, safety, and tolerability of Zonisamide in epileptic children. From November 2011 until October 2012, 68 children who referred to Children's Medical Center and Mofid Children Hospital due to refractory epilepsy (failure of seizure control with the use of two or more anticonvulsant drugs) entered the study. The patients were treated with Zonisamide by dose of 2- 12 mg/kg daily in addition to the previous medication. We followed the children every three to four-weeks intervals based on daily frequency, severity and duration of seizures. During the follow-up equal and more than fifty percent reduction in seizure frequency or severity known as response to the drug. In this study 68 patients were examined that 61 children reached the last stage.35 (57.4%) were male and 26 (42.6%) patients were female. After first and six months of Zonisamide administration daily seizure frequency decreased to 2.95±3.54 and 3.73±3.5 respectively. There was significant difference between seizure frequency in first and six month after Zonisamide toward initial attacks. After six months ZNS therapy a little side effects were created in 10 patients (16.4%) including stuttering(4.9%), decreased appetite (4.9%), hallucination (1.6%), dizziness(1.6%), blurred vision(1.6%) and suspiring(1.6%) as all of them eliminated later dosage reduction. This study confirms the short term efficacy and safety of Zonisamide in children with refractory epilepsies.

Zonisamide for Weight Reduction in Obese Adults

Obese individuals who have failed to achieve adequate weight loss with lifestyle changes have limited nonsurgical therapeutic options. We evaluated the efficacy and tolerability of zonisamide, an antiepileptic drug, for enhancing weight loss in obese patients receiving diet and lifestyle guidance. This was a 1-year, randomized, double-blind, placebo-controlled trial conducted from January 9, 2006, through September 20, 2011, at Duke University Medical Center. A total of 225 obese (mean [SD] body mass index, 37.6 [4.9]) participants included 134 women (59.6%) and 91 men (40.4%) without diabetes mellitus. (Body mass index is calculated as weight in kilograms divided by height in meters squared.) Interventions were daily dosing with placebo (n = 74), 200 mg of zonisamide (n = 76), or 400 mg of zonisamide (n = 75), in addition to diet and lifestyle counseling by a dietitian for 1 year. Primary outcome was change in body weight at 1 year. Of the 225 randomized patients, 218 (96.9%) provided 1-year follow-up assessments. Change in body weight was -4.0 kg (95% CI, -5.8 to -2.3 kg; least squares mean, -3.7%) for placebo, -4.4 kg (-6.1 to -2.6 kg; -3.9%; P = .79 vs placebo) for 200 mg of zonisamide, and -7.3 kg (-9.0 to -5.6 kg; -6.8%; P = .009 vs placebo) for 400 mg of zonisamide. In the categorical analysis, 23 (31.1%) assigned to placebo, 26 (34.2%; P = .72) assigned to 200 mg of zonisamide, and 41 (54.7%; P = .007) assigned to 400 mg of zonisamide achieved 5% or greater weight loss; for 10% or greater weight loss, the corresponding numbers were 6 (8.1%), 17 (22.4%; P = .02), and 24 (32.0%; P < .001). Gastrointestinal, nervous system, and psychiatric adverse events occurred at a higher incidence with zonisamide than with placebo. Zonisamide at the daily dose of 400 mg moderately enhanced weight loss achieved with diet and lifestyle counseling but had a high incidence of adverse events. clinicaltrials.gov Identifier: NCT00275834

Zonisamide in Parkinson&amp;rsquo;s Disease: An Evidence-Based Review of its Impact on Clinical Outcomes

Zonisamide is a benzoisoxazole derivate with a multimodal mechanism of action that is widely available as antieplieptic drug. Serpendipitously discovered to exert beneficial effects on motor symptoms of Parkinson's disease (PD), zonisamide has been approved exclusively in Japan for the adjunctive treatment of Parkinsonian symptoms after the positive results of three controlled clinical trials. The current review gives a resume of the main findings of clinical trials and casuistic reports of the effects of zonisamide in PD with special emphasis on possible mechanisms of action and adverse effects. Summarized, at that time, the use of zonisamide in PD is still investigational; further studies are warranted to confirm the preliminary promising findings and to better define effects, indications and tolerability of zonisamide in PD.

Zonisamide produces weight loss in psychotropic drug-treated psychiatric outpatients

This study examined the long-term effectiveness and tolerability of zonisamide for weight control in psychiatric outpatients using various psychotropic medications. We conducted a systematic chart review of 82 psychiatric outpatients with unwanted weight gain after the introduction of psychotropic drugs between January 2008 and September 2009 at Korea University Ansan Hospital. The primary outcome measure was the effect of zonisamide on body mass index (BMI). Additional outcome measures included safety and tolerability as assessed by the clinical global impression-severity of illness scale (CGI-S) and discontinuation rate. The mean final dose of zonisamide was 124.6±53.4 mg/day and ranged from 50mg/day to 300 mg/day. The mean BMI reduction was 0.8±1.7 kg/m(2) and ranged from -2.9 kg/m(2) to 4.7 kg/m(2) (p<0.001). We also observed a significant reduction in CGI-S scores from the baseline (3.8±0.9) to the endpoint (3.3±0.8; p<0.001). Twelve patients (14.6%) discontinued their zonisamide treatment due to its side effects. Patients treated with zonisamide showed significant weight loss. Furthermore, its treatment was generally safe and well tolerated with few negative effects on patients' overall psychiatric symptoms. Additional research is required to confirm these results and to investigate whether patients have rebound weight gains after discontinuing zonisamide.

Flexible dosing of adjunctive zonisamide in the treatment of adult partial-onset seizures: a non-comparative, open-label study (ZEUS)

To assess the efficacy and tolerability of zonisamide in a study allowing flexible dosing in a more diverse and less refractory population than assessed in randomized controlled trials. This 19-week, non-comparative study of adjunctive zonisamide included 281 adults who had at least four partial-onset seizures within 8 weeks on one or two antiepileptic drugs. Alterations to zonisamide doses were allowed after titration, except during two fixed-dose periods (weeks 10-13 and 16-19). At the end of the second fixed-dose period (median dose 300 mg/day), the median reduction in monthly seizure frequency was 33.3-41.1%; > or =50% responder rate was 40.9-44.2%; and seizure freedom rate was 15.0-15.9%, depending on the analysis used. The most common adverse events were fatigue (16.7%) and somnolence (15.3%). Zonisamide demonstrated efficacy in a setting more reflective of clinical practice and was generally well tolerated.

Effectiveness and tolerability of zonisamide in children with epilepsy: A retrospective review

Purpose To evaluate the effectiveness and tolerability of zonisamide in children with epilepsy. Method Retrospective case note review of young people (less than 19 years) with epilepsy from three UK tertiary centres who received treatment with zonisamide and were followed up for a minimum of 12 months. Results Fifty-seven children were included, aged 1.5–18.5 (median, 12) years. Thirty-three (57.9%) patients had generalised epilepsy, 21 (36.8%) focal epilepsy, and three (5.3%) a mixed, generalised and focal, epilepsy. Fifty-six of the 57 patients had been refractory to at least three previous antiepileptic drugs. The maintenance dose of zonisamide was [range (median)] 0.7–14 (5) mg/kg/day. The median duration of treatment for all patients was 12 (range 0.25–35) months. After 2 months of treatment, 51 patients remained on zonisamide, 18 (35.3%) of whom demonstrated a ≥50% reduction in seizure frequency. At the end of the follow-up period, there was a loss of effect for some patients. Thirteen (25.5%) of the 51 patients continued to demonstrate a ≥50% reduction in seizure frequency whilst two who had become seizure-free started having seizures again. Six (11.8%) had <50% reduction, twenty-four (47%) had no change, and eight (15.7%) had increasing seizures. Twenty-five (43.9%) patients reported unwanted effects although this contributed to the withdrawal of zonisamide in only ten (17.6%) patients. Conclusions Zonisamide appeared to be a reasonably effective and generally well-tolerated antiepileptic drug in a heterogeneous group of 57 children with poorly controlled epilepsy and provides another treatment option for children with refractory seizures.

Efficacy and tolerability of zonisamide as add-on in brain tumor-related epilepsy: preliminary report

Zonisamide (ZNS) is an antiepileptic drug (AED) with broad spectrum action that demonstrated a good efficacy in controlling seizures as add-on in adult and pediatric epilepsy. To date there have been no studies on ZNS in patients with brain tumor-related epilepsy (BTRE). To evaluate efficacy and tolerability of ZNS as add-on in BTRE. We followed six patients suffering from BTRE who had already been treated with other AEDs and who had had not experienced adequate seizure control. Three patients underwent chemotherapy while being treated with ZNS. Mean duration of follow-up was 8 months. Mean seizure number in the last month prior to the introduction of ZNS had been 27.7/month. ZNS mean dosage was of 283.3 mg/day. At last follow-up, the mean seizure number was reduced to 8.8/month. Responder rate was 83.3%.Two patients discontinued the drug because of side effects. There were no other reported side effects. Preliminary data on the use of ZNS in add-on in patients with BTRE indicate that this drug may represent a valid alternative as add-on in this particular patient population. However, larger samples are necessary to draw definitive conclusions.