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Zonisamide As Artial-Onset Seizures in Epilepsy

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Zonisamide As Artial-Onset Seizures in Epilepsy pat hways Partial-onset seizures in epilepsy: zonisamide as monotherapy Evidence summary Published: 16 April 2013 nice.org.uk/guidance/esnm17 Overview The content of this evidence summary was up-to-date in April 2013. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up- to-date information. Key points from the evidence In June 2012, the approved licence for zonisamide (Zonegran; adjunctive treatment of partial seizures, with or without secondary generalisation, in adults) was extended to include monotherapy for treating partial-onset seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy. One randomised, double blind, non-inferiority trial assessed the efficacy and tolerability of zonisamide in 583 patients with newly diagnosed partial seizures. The response rates were consistently lower with zonisamide compared with carbamazepine controlled release. In the per- protocol population, 79.4% of patients taking zonisamide were seizure free for at least 26 weeks (the primary outcome) compared with 83.7% of patients taking carbamazepine, an absolute difference of 4.5% in favour of carbamazepine. Zonisamide was not shown to be non-inferior to carbamazepine because the lower confidence interval of 12.2% was outside the pre-defined absolute non-inferiority margin of 12%. However, in its assessment of zonisamide, the European Medicines Agency concluded that a lower level of efficacy was acceptable because, vo erall, the © NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 1 of conditions#notice-of-rights). 15 Partial-onset seizures in epilepsy: zonisamide as monotherapy (ESNM17) response rates were high in both study groups (around 80%); the difference in absolute and relative point estimates was less than 5%; and retention rates were similar in both groups. The incidence of adverse events that were considered to be treatment related was similar for zonisamide and carbamazepine (36% compared with 38% respectively). The most frequently reported treatment-emergent adverse events (5% or more in either group) were headache, decreased appetite, somnolence, dizziness and weight loss. The adverse events reported for each drug were consistent with their established safety profiles. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care (NICE clinical guideline 137) advises that people with newly diagnosed partial- onset seizures (also known as 'focal' seizures) should be offered monotherapy with carbamazepine or lamotrigine as first-line treatment. If carbamazepine and lamotrigine are unsuitable or not tolerated, levetiracetam, oxcarbazepine or sodium valproate is the next treatment option. If the first anti-epileptic drug tried is ineffective, an alternative from these 5 anti-epileptic drugs should be offered. Zonisamide could offer an alternative to other anti-epileptic drugs in some people because of its different mechanism of action, once-daily dosing, and adverse event and interaction profiles (unlike some other anti-epileptic drugs, zonisamide is not thought to affect the pharmacokinetics of other medicines, such as oral contraceptives, through cytochrome P450-mediated mechanisms). When making decisions about using zonisamide, localities will need to consider the available evidence suggesting similar efficacy and tolerability to carbamazepine alongside its less well established safety profile compared with other treatment options. urthermore,F the acquisition cost of zonisamide is generally, considerably higher than the other potential treatment options. Key evidence Baulac M, Brodie MJ, Patten A et al. (2012) Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. The Lancet Neurology 11: 579–88 About this evidence summary 'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically © NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 2 of conditions#notice-of-rights). 15 Partial-onset seizures in epilepsy: zonisamide as monotherapy (ESNM17) reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance. Relevance to NICE guidance programmes Zonisamide as monotherapy for treating partial-onset seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy was not considered appropriate for a NICE technology appraisal and is not currently planned into any other NICE work programme. Zonisamide as adjunctive therapy for partial-onset seizures in epilepsy was considered during the development of The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care (NICE clinical guideline 137). The Guideline Development Group found that zonisamide was one of several anti-epileptic drugs that were more costly and less effective than other cost-effective treatment alternatives. The Guideline Development Group concluded that eslicarbazepine acetate, lacosamide, pregabalin, tiagabine and zonisamide should be considered only when initial adjunctive therapy options are contraindicated, ineffective or not tolerated. See the introduction for more details. A NICE Pathway on epilepsy brings together all NICE guidance and associated products on epilepsy. Introduction Epilepsy is a common neurological condition characterised by recurring seizures. Epileptic seizures can be broadly categorised into 2 main types: partial and generalised. Partial-onset seizures (also known as 'focal' seizures) are epileptic seizures in which the neuronal discharge begins in, or is restricted to, a localised part of the brain. Generalised seizures are characterised by more diffuse neuronal discharges involving both hemispheres of the brain at the same time (see the NICE clinical guideline on epilepsy and the final scope for the NICE technology appraisal on retigabine for the adjunctive treatment of partial onset seizures in epilepsy). Epilepsy has been estimated to affect 260,000 to 416,000 people in England and Wales, 55% of whom have partial-onset seizures. It has been estimated that recurrent seizures could be controlled with anti-epileptic drugs in approximately 70% of people with active epilepsy, but only 52% of people are seizure free in clinical practice (see the final scope for the NICE technology appraisal on retigabine). © NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 3 of conditions#notice-of-rights). 15 Partial-onset seizures in epilepsy: zonisamide as monotherapy (ESNM17) The NICE clinical guideline on epilepsy advises that people with newly diagnosed partial-onset seizures should be offered monotherapy with carbamazepine or lamotrigine as first-line treatment. If carbamazepine and lamotrigine are unsuitable or not tolerated, levetiracetam, oxcarbazepine or sodium valproate is the next treatment option. If the first anti-epileptic drug tried is ineffective, an alternative from these 5 anti-epileptic drugs should be offered. According to the NICE clinical guideline on epilepsy, if first-line treatments are ineffective or not tolerated, adjunctive treatment with carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate or topiramate should be offered. If adjunctive treatment is ineffective or not tolerated, the NICE clinical guideline on epilepsy recommends that advice should be sought from a tertiary epilepsy specialist. Anti-epileptic drugs that may be considered are eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin and zonisamide. The NICE technology appraisal on retigabine for the adjunctive treatment of partial onset seizures in epilepsy (NICE technology appraisal guidance 232) recommends retigabine as an option at this point. Product overview Drug action Zonisamide is a benzisoxazole derivative that is chemically unrelated to other anti-epileptic drugs (see the summary of product characteristics). The mechanism of action of zonisamide is not fully understood. It appears to act on voltage-sensitive sodium and calcium channels, disrupting synchronised neuronal firing and reducing the spread of abnormal electrical activity in the brain and disrupting subsequent epileptic activity. Zonisamide also has a modulatory effect on gamma- aminobutyric acid (GABA)-mediated neuronal inhibition (see the European public assessment report for Zonegran). New licensed therapeutic indication In June 2012, the approved licence for zonisamide (Zonegran; adjunctive treatment of partial- onset seizures, with or without secondary generalisation, in adults) was extended to include monotherapy for treating partial-onset seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy (see the European public assessment report for Zonegran). © NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and- Page 4 of conditions#notice-of-rights). 15 Partial-onset seizures in epilepsy: zonisamide as monotherapy
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