Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in March 2014. See summaries of product characteristics (SPCs), British national formulary (BNF), BNF for children (BNFc) or the MHRA or NICE websites for up-to-date information.

Summary

In a double-blind, randomised controlled trial (RCT) in 207 children and young people aged 6–17 years with partial seizures, zonisamide (as adjunctive treatment) statistically significantly increased the number of participants achieving at least a 50% reduction in seizure frequency from baseline compared with placebo. Although the general safety profile for zonisamide in children and young people is similar to that in adults, certain adverse events raise concerns because they may have greater implications in children than in adults.

Effectiveness

  • In a double-blind RCT (n=207) in patients receiving a stable regimen of 1 or 2 antiepileptic drugs for at least 1 month, zonisamide compared with placebo statistically significantly:

    • increased the number of participants achieving at least a 50% reduction in seizure frequency from baseline (responder rate: 50% with zonisamide compared with 31% with placebo; p=0.0044)

    • reduced 28-day seizure frequency from baseline (50% reduction in zonisamide group compared with 24.5% reduction in the placebo group; median difference between the groups: 25.2%; 95% CI 12.2% to 38.7%, p<0.0001).

Safety

  • General safety profile for zonisamide in children and young people is similar to that in adults. However, some adverse events may have greater implications in children than in adults; for example, weight loss, changes in bicarbonate levels, and decreased sweating and elevated body temperature that can lead to heat stroke.

Patient factors

  • Zonisamide is only available in capsule formulation, and capsules have to be swallowed whole. This may mean it is unsuitable for children and young people with swallowing difficulties.

  • Administration in children and young people is once daily, which may be preferable to some.

  • Treatment-emergent adverse events that occurred more frequently in the zonisamide group than in the placebo group included decreased appetite (6.5% compared with 4.0%), weight loss (4.7% compared with 3.0%), somnolence (4.7% compared with 2.0%), vomiting (3.7% compared with 2.0%), and diarrhoea (3.7% compared with 1.0%).

Resource implications

  • Zonisamide (Zonegran, Eisai Limited) capsules cost:

    • £8.82 for 14×25 mg capsules

    • £47.04 for 56×50 mg capsules

    • £62.72 for 56×100 mg capsules.

  • Cost per year for a maintenance dose for a child or young person aged 6 years and over weighing between 20 and 55 kg is estimated to be between £638.75 and £1941.80 depending on the dose and child's weight

  • Cost per year for a maintenance dose for a child or young person aged 6 years or over, weighing more than 55 kg, is £1226.40 to £2044.00.

Key points

In October 2013, the approved licence for zonisamide (Zonegran, Eisai Limited; adjunctive treatment of partial seizures, with or without secondary generalisation, in adults) was extended to include 'adolescents' and children aged 6 years and over (see the European public assessment report (EPAR) for Zonegran).

NICE published an evidence summary on zonisamide monotherapy for treating partial-onset seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy in April 2013 (ESNM17).

This evidence summary is based on a phase III double-blind RCT that assessed the efficacy and safety of adjunctive zonisamide therapy in 207 children and young people with partial epilepsy (Guerrini et al. 2013). This trial was the main efficacy study assessed by the European Medicines Agency when a licence extension application was submitted for zonisamide (see the EPAR for Zonegran). An open-label extension study (Guerrini et al. 2014) assessing the longer term (45–57 weeks) efficacy and safety of adjunctive zonisamide therapy in children and young people with partial epilepsy has been published and is discussed in the safety section.

In Guerrini et al. (2013), zonisamide statistically significantly increased the number of participants who experienced a 50% or greater reduction in seizure frequency from baseline compared with placebo (responder rate: 50% with zonisamide compared with 31% with placebo; p=0.0044). Zonisamide also resulted in a greater reduction in 28-day seizure frequency from baseline during the maintenance period compared with placebo (50% reduction in the zonisamide group compared with 24.5% in the placebo group, median between group difference: 25.2%, 95% confidence interval [CI] 12.2% to 38.7%, p<0.0001).

The incidence of treatment-emergent adverse events was similar in the zonisamide and placebo groups (55.1% compared with 50.0% respectively). However, the incidence of treatment-related, treatment-emergent adverse events was higher in the zonisamide group than the placebo group (33.6% compared with 24.0% respectively). Treatment-emergent adverse events that were reported more frequently in the zonisamide group than in the placebo group included decreased appetite (6.5% compared with 4.0%), weight loss (4.7% compared with 3.0%), somnolence (4.7% compared with 2.0%), vomiting (3.7% compared with 2.0%), and diarrhoea (3.7% compared with 1.0%). Four participants in the zonisamide group and 2 in the placebo group experienced serious treatment-emergent adverse events, including 1 participant in the zonisamide group who died. The death was considered to be possibly treatment-related: the young person experienced weight loss and diarrhoea which weakened his general condition to such an extent he was unable to take his anti-epileptic medications, triggering a fatal episode of status epilepticus.

The primary outcome in Guerrini et al. (2013) was assessed using the last observation carried forward (LOCF) approach to take account of missing data. This approach can affect the robustness of trial results; however, in Guerrini et al. (2013) sensitivity analyses showed similar results for responder rates (the primary outcome), which provides reassurance about the reliability of the results. The trial was undertaken in 41 centres in Europe and India meaning some centres would have enrolled fewer than 10 children and young people. It is possible that this may have affected how rigorously and consistently trial outcomes were assessed.

In the EPAR, the Committee for Medicinal Products for Human Use concluded that although the general safety profile for zonisamide in children is similar to that in adults, there are several important issues that raise concerns such as weight loss, dehydration and decrease in bicarbonate levels, because they may have greater implications in children than in adults. The product information has been updated to include warnings about adverse events that may more relevant to children.

The NICE clinical guideline The Epilepsies: the diagnosis and clinical management of the epilepsies in adults and children in primary and secondary care (NICE clinical guideline 137) advises that monotherapy with carbamazepine or lamotrigine should be offered as first-line treatment to children, young people and adults with newly diagnosed partial (focal) seizures. If carbamazepine and lamotrigine are unsuitable or not tolerated, the person should be offered monotherapy with levetiracetam, oxcarbazepine or sodium valproate (bearing in mind the teratogenic risks of sodium valproate). If the first anti-epileptic drug tried is ineffective, an alternative from these 5 anti-epileptic drugs should be offered. If standard first-line treatments are ineffective or not tolerated, the person should be offered adjunctive treatment with carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate or topiramate.

If adjunctive treatment is ineffective or not tolerated, the guideline recommends that decisions about treatment options should be made after advice from a tertiary epilepsy specialist. Anti-epileptic drugs that may be considered include eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin and zonisamide.

Prescribers should be aware that not all the drugs mentioned above currently have a UK marketing authorisation for use for the particular indication or population mentioned (for example, depending on the age of the person). In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using drugs outside their authorised indications.

Local decision makers will need to consider the place of zonisamide alongside other available adjunctive treatments for partial seizures. It is unclear how zonisamide compares with other drugs used at this stage in the care pathway; however the European Medicines Agency states that the efficacy of zonisamide appears similar to other anti-epileptic drugs already indicated for adjunctive use in children. The nature of potential adverse effects, cost, and individual patient/parent/carer preference will all influence the decision to use a particular adjunctive anti-epileptic drug in each person.

Key evidence

Guerrini R, Rosati A, Segieth J et al. (2013) A randomized phase III trial of adjunctive zonisamide in pedatric patients with partial epilepsy. Epilepsia 54: 1473–80

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 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.