New Medicines Committee Briefing July 2013

Zonisamide (Zonegran®)

Zonisamide (Zonegran®) is to be reviewed for use within: Primary Care 

Secondary Care 

Summary:

Zonegran® has been available in the UK since 2005 for adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, in adult patients.

Zonegran® was approved in July 2012 as monotherapy for treatment of partial seizures with or without secondary generalisation, in adults with newly diagnosed epilepsy.

Zonegran® is an orally active, benzisoxazole derivative, which contains a sulphonamide group – chemically unrelated to other antiepileptic drugs.

NICE recommends that zonisamide be considered by the tertiary specialist when adjunctive treatment is ineffective or not tolerated.

Zonegran® is accepted for restricted use within NHS Scotland as an adjunctive treatment in adult patients with partial seizures, with or without secondary generalisation.

4 published double-blind randomised controlled trials compared the efficacy of zonisamide with placebo for the adjunctive treatment of patients with partial seizures.

1 randomised, double blind trial found zonisamide to be non-inferior to controlled- release carbamazepine for monotherapy treatment of newly diagnosed partial epilepsy patients.

APPROVED ON 30/07/14 WITH AMBER 2 STATUS

Formulary application:

Oncology: Consultant submitting application: Dr Carl-Christian Moor PhD Consultant Neurologist, Clinical Lead in Epilepsy Clinical Director supporting application: Dr Simon Ellis Dr Moor has requested that Zonegran® be considered for inclusion in the North Staffordshire Joint Formulary as monotherapy and as adjunctive therapy in the treatment of partial seizures with or without secondary generalisation, in adults with newly diagnosed epilepsy. Dr Moor noted that zonisamide can be administered as once daily medication when used as adjunct therapy. Although it does not interact with contraceptive pill and has minimal interactions with other anti-epileptic drugs, he intends to use it mainly on male patients as monotherapy where he find weight an issue as zonisamide does not result in increase in weight compared to other antiepileptic drugs. As monotherapy, he said it will be around 4-5 patients per year while as an adjunctive therapy, he estimated 20-30 patients per year.

Background:

Epilepsy is a common neurological disorder characterised by recurrent seizures which are not provoked by an immediately identifiable cause. Epileptic seizures can be broadly categorised into two main classifications depending on the source of the seizure within the brain: partial and generalised. Partial or focal, onset seizures originate in and affect only a part of the brain. Generalised seizures are more widely distributed and affect both sides of the brain simultaneously. Seizures which spread from one side of the brain to the other are known as secondarily generalised seizures.1,2,3,4 In 2011 the Joint Epilepsy Council estimated there were approximately 600,000 adults in the UK with a diagnosis of epilepsy who were receiving anti-epileptic drugs (AED). The UK incidence is estimated to be around 50 cases per 100,000 of the population per year. Life expectancy is reduced by up to 10 years for people with symptomatic epilepsy, and there are around 1,000 epilepsy related deaths per year in the UK. Sudden unexpected death in epilepsy accounts for around half of all epilepsy deaths, of which around 40% are thought to be potentially avoidable.5 The UK National General Practice Study of Epilepsy found that 60% of people with epilepsy have convulsive seizures, of which two thirds have focal epilepsies and secondarily generalised seizures and the other third will have generalised tonic-clonic seizures.6 About one-third of cases have less than one seizure a year, one-third have between one and 12 seizures per year and the remainder have more than one seizure per month.7 In adults and children with epilepsy, most (70%) will enter remission (being seizure free for five years on or off treatment) but 30% develop chronic epilepsy. 8 The number of seizures in the 6 months after first presentation is an important predictive factor for both early and long-term remission of seizures.9 A wide range of AED is available to control seizures in patients with epilepsy although about one quarter to one third of patients will continue to have seizures despite receiving adequate trials of AEDs alone and 2 in combination.10 Optimal management improves health outcomes and can help to minimise other, often detrimental, impacts on social, educational and employment activity. NICE has recently published a quality standard which is meant to focus on tailoring treatment to the individual circumstances and needs of people with epilepsy so that they are offered the most suitable treatment.11 Since the development of MRI there has been an increase in the number of people identified with epilepsy who could benefit from surgery. There is also a need to ensure provision of appropriate information to people with epilepsy and their carers. Most currently available AEDs exert their main effect at pre-synaptic targets, either reducing pre- synaptic excitability and neurotransmitter release, or enhancing gamma-aminobutyric (GABA) neurotransmission.12 The mechanism involved in the generation and spread of seizures converge on a common neuronal pathway in which excitatory post-synaptic glutamate receptors play a key role. Glutamine is the primary excitatory neurotransmitter in the central nervous system and its activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is thought to be responsible for most fast excitatory synaptic transmission in the brain.13 Zonisamide is an orally active, benzisoxazole derivative, which contains a sulphonamide group. It has weak carbonic anhydrase activity in-vitro and is chemically unrelated to other AEDs.13 Zonisamide is administered once daily which may be an advantage in some patients, it also has a long half-life (63 hours) which may reduce the effect of missed doses on serum levels. The disadvantage of this long half- life is the fact that is takes 2 weeks to reach steady state therefore is not appropriate when rapid onset of action is required. There is no injectable formulation and it is unlikely to interact with other drugs including the oral contraceptive pill with no specific monitoring requirements. Zonisamide is more expensive than all the other drugs licensed for monotherapy in epilepsy, all of which are available generically.

Current formulary status:

The North Staffordshire Joint Formulary currently lists the following agents:

4.8 ANTIEPILEPTIC DRUGS 

4.8.1 Control of the epilepsies Restriction: Initiation and stabilisation by specialist Carbamazepine 2 See Additional Information Box Clobazam 2 Restriction: Initiation and stabilisation by specialist Clonazepam 2 Restriction: Initiation and stabilisation by specialist Ethosuximide 2 Restriction: Initiation and stabilisation by specialist Gabapentin 2 Restriction: Initiation and stabilisation by specialist Lacosamide 2 Restriction: Initiation and stabilisation by specialist  MTRAC Lamotrigine 2 Restriction: Initiation and stabilisation by specialist Levetiracetam 2 Restriction: Initiation and stabilisation by specialist  MTRAC Oxcarbazepine 2 Restriction: Initiation and stabilisation by specialist Phenobarbital 2 Restriction: Initiation and stabilisation by specialist Phenytoin 2 Restriction: Initiation and stabilisation by specialist

See Additional Information Box Primidone 2 Restriction: Initiation and stabilisation by specialist Retigabine 2 Restriction: In line with NICE Guidance only  NICE TA232 Sodium valproate 2 Restriction: Initiation and stabilisation by specialist Tiagabine 2 Restriction: Initiation and stabilisation by specialist  MTRAC Topiramate 2 Restriction: Initiation and stabilisation by specialist  MTRAC Vigabatrin 2 Restriction: Initiation and stabilisation by specialist

Additional Information July 2006: Carbamazepine: Carbamazepine suppositories are licensed for short-term treatment (maximum 7 days) only when oral therapy is temporarily not possible. Carbamazepine 125mg suppositories should be considered equivalent to 100mg tablets but plasma monitoring is recommended Phenytoin: Phenytoin 90mg in 15mL suspension may be considered approximately equivalent to capsules containing phenytoin sodium 100mg Phenytoin interacts significantly with NG feeds- please contact pharmacy for more information where necessary

Therapeutic class and mode of action:13

Zonisamide is a benzisoxazole derivative. It is an anti-epileptic medicine with weak carbonic anhydrase activity in-vitro. It is chemically unrelated to other anti-epileptic agents. The mechanism of action of zonisamide is not fully elucidated, but it appears to act on voltage-sensitive sodium and calcium channels, thereby disrupting synchronised neuronal firing, reducing the spread of seizure discharges and disrupting subsequent epileptic activity. Zonisamide also has a modulatory effect on GABA-mediated neuronal inhibition.

Licensed indication:13

Zonegran is indicated as:

monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy

adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation in adult patients.

Dosage and administration:13

Adults and adolescents Adults Dosage escalation and maintenance Zonegran may be taken as monotherapy or added to existing therapy in adults. The dose should be titrated on the basis of clinical effect. Some patients, especially those not taking CYP3A4-inducing agents, may respond to lower doses. 4

Adults - recommended dosage escalation and maintenance regimen

Treatment Regimen Titration Phase Usual Maintenance Dose

Monotherapy - Week 1 + 2 Week 3 + 4 Week 5 + 6 Newly diagnosed 300 mg per day adult patients 100 mg/day 200 mg /day 300 mg / day (once a day). (once a day) (once a day) (once a day) If a higher dose is

required: increase at two-weekly intervals in increments of 100 mg up

to a maximum of 500 mg.

Adjunctive therapy Week 1 Week 2 Week 3 to 5 - with CYP3A4- 300 to 500 mg per day 50 mg/day 100 mg /day Increase at inducing agents weekly intervals (once a day or two (in two divided (in two divided (see section 4.5) in increments of divided doses). doses) doses) 100 mg

- without CYP3A4- Week 1 + 2 Week 3 + 4 Week 5 to 10 inducing agents; or 300 to 500 mg per day with renal or hepatic 50 mg/day 100 mg / day Increase at impairment two-weekly (once a day or two (in two divided (in two divided intervals in divided doses). doses) doses) increments of up Some patients may to 100 mg respond to lower doses.

Elderly Caution should be exercised at initiation of treatment in elderly patients as there is limited information on the use of Zonegran in these patients. Prescribers should also take account of the safety profile of Zonegran. Renal impairment Caution must be exercised in treating patients with renal impairment, as there is limited information on use in such patients and a slower titration of Zonegran might be required. Since zonisamide and its metabolites are excreted renally, it should be discontinued in patients who develop acute renal failure or where a clinically significant sustained increase in serum creatinine is observed. In subjects with renal impairment, renal clearance of single doses of zonisamide was positively correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% in subjects with creatinine clearance < 20 ml/min. Hepatic impairment Use in patients with hepatic impairment has not been studied. Therefore use in patients with severe hepatic impairment is not recommended. Caution must be exercised in treating patients with mild to moderate hepatic impairment, and a slower titration of Zonegran may be required.

Use in patients with severe hepatic impairment is not recommended. Paediatric population The safety and efficacy of Zonegran in children and adolescents have not yet been established. Withdrawal When Zonegran treatment is to be discontinued, it should be withdrawn gradually. In clinical studies of adult patients, dose reductions of 100 mg at weekly intervals have been used with concurrent adjustment of other antiepileptic medicine doses (where necessary). Method of administration Zonegran hard capsules are for oral use and may be taken with or without food.

Presentation: 13

25 mg: Zonegran 25 mg hard capsules 50 mg: Zonegran 50 mg hard capsules

100 mg: Zonegran 100 mg hard capsules

Guidance:

NICE Guidance: NICE guidance published: Yes

NICE Clinical Guideline 137 – The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care.6 As Adjunctive therapy 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 the several anti-epileptic drugs that were mostly 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. NICE stated that children, young people and adults 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. If standard adjunctive treatment is ineffective or not tolerated, advice should be sought from a tertiary epilepsy specialist. Anti-epileptic drugs that may be considered by the tertiary epilepsy specialist are 6 eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin and zonisamide. Carefully consider the risk–benefit ratio when using vigabatrin because of the risk of an irreversible effect on visual fields. The NICE technology appraisal on retigabine for partial onset seizures in epilepsy recommends retigabine as an option for the adjunctive treatment of partial-onset seizures with or without secondary generalisation in adults aged 18 years and older with epilepsy, only when previous treatment with carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate and topiramate (standard adjunctive treatment) has not provided an adequate response, or has not been tolerated.1 NICE Evidence Summary: new medicine April 2013 ESNM17: Partial-onset seizures in epilepsy: zonisamide as monotherapy14 NICE stated that 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. It also said that localities when making decision about using zonisamide should consider the acquisition cost of zonisamide which is generally higher than other potential treatment options and its less well established safety profile. Scottish Medicines Consortium (SMC):

SMC recommended use within NHS Scotland: Yes

As Adjunctive therapy: 15 Zonegran® is accepted for restricted use within NHS Scotland as adjunctive therapy in adult patients with partial seizures, with or without secondary generalisation. It should be initiated only by physicians who have appropriate experience in the treatment of epilepsy and should be used principally in patients who have not benefited from treatment with an older anti-convulsant drug such as carbamazepine or sodium valproate, or for whom these drugs are unsuitable because of contra-indications, interaction or poor tolerance. As Monotherapy:16 Zonegran ® is not recommended for use within NHS Scotland as monotherapy for the treatment of partial seizures (with or without secondary generalization) in adults with newly diagnosed epilepsy. SMC stated that the holder of the marketing authorisation has not made a submission to SMC regarding this product in this indication. As a result they cannot recommend its use within NHS Scotland.

MTRAC MTRAC reviewed17 Yes

For the adjunctive treatment of partial epilepsy: MTRAC recommends that zonisamide is suitable for restricted prescribing under defined conditions. The recommendation was for adjunctive treatment of partial epilepsy. MTRAC stated that initiation and 7 stabilisation of treatment should be the responsibility of the specialist. It is then appropriate for GPs to prescribe zonisamide for maintenance with the guidance of a shared care agreement.

Efficacy:

1 For monotherapy for newly diagnosed partial epilepsy: Zonisamide vs carbamazepine MR for newly diagnosed partial epilepsy18 Summary: Zonisamide was non-inferior to controlled-release carbamazepine according to International League Against Epilepsy guidelines (ILAE). A phase III, multicentre, randomised, double-blind, non-inferior trial compared the efficacy and tolerability of once daily zonisamide with twice daily controlled-release carbamazepine monotherapy in adults who were newly diagnosed with partial epilepsy. The trial was conducted in 583 patients across 120 centres in Asia, Australia and Europe. It was also done according to European regulatory recommendations and ILAE guidelines with a minimum total duration of 1 year, and flexible dosing to reproduce clinical practice as closely as possible. Patients recruited had either not previously received an AED or had been treated with one AED for maximum of 2 weeks. Patients included had untreated, newly diagnosed epilepsy with at least 2 well documented, unprovoked, clinically evaluated and classified, partial seizures (with or without clear focal origin) within 12 months of the screening visit. One of seizures must have occurred within 3 months of the screening visit. 282 patients were assigned zonisamide while 301 received carbamazepine. After initiation of treatment (zonisamide 100mg/day or carbamazepine 200mg/day) and up-titration over 4 weeks to the relevant target dose (zonisamide 300mg/day or carbamazepine 600mg/day), patients entered a flexible-dosing period of 26-78 weeks (zonisamide 200-500mg/day, administered once daily or carbamazepine 400- 1200mg/day, administered twice daily. The primary endpoint was the proportion of patients who achieved seizure freedom for 26 weeks or more while receiving a stable dose of study medication. Secondary endpoints were the proportion of patients who had no seizure for at least 52 weeks, time to start of a 26 week and 52 week seizure free period, and time to withdrawal because of absence of efficacy or adverse event. The intention-to-treat (ITT) and safety populations were defined as all randomly assigned patients who received at least one dose of study medication. The per-protocol population (PPP), was all patients in the ITT, who had no major protocol violations or deviations that might affect efficacy, including less than 80% overall compliance (assessed by unused mediation), loss to follow up before end of flexible dosing; missing seizure diaries during the flexible dosing period; dosing outside of protocol requirements and failure to up-titrate after a seizure. The sample size was based on the primary efficacy endpoint. The non-inferiority margin was a relative difference of -20%, as stipulated by the ILAE, up to a maximum of an absolute difference of -12% between treatment groups for the primary endpoint, at 26 weeks. Assuming the proportion of patients who did not have a seizure in the zonisamide and carbamazepine groups was 60%, 262 patients per group provided an 80% power to test whether zonisamide was non-inferior to carbamazepine, if the

8 lower limit of the 95% CI of the treatment difference is above -12% for the ITT population. Assuming a 10% drop-out rate, 582 patients were required. 161 patients (57%) in the zonisamide group and 192 patients (64%) in the carbamazepine group completed the study. A large number of patients dropped out of study. More patients discontinued treatment with zonisamide compared with carbamazepine (43% compared with 36% respectively). The main reasons for discontinuation were adverse events, withdrawal of consent, lack of efficacy, and loss to follow up. Few patients withdrew between 26 and 52 weeks because of absence of efficacy or an adverse event, and the groups did not differ significantly. In the PPP, 177 of 223 (79·4%) patients in the zonisamide group were seizure free for 26 weeks compared to 195 of 233 (83·7%) patients in the carbamazepine group, absolute treatment difference of - 4.5% (95% CI: -12.2 - 3.1). In the ITT population, 195 of 281 (69·4%) patients were seizure free for 26 weeks in the zonisamide group compared to 224 of 300 (74·7%) in the carbamazepine group with absolute treatment difference -6.1% (95% CI: –13·6 to 1·4). The proportion of participants in the PPP who did not have seizures for 52 weeks was 146 of 216 (67·6%) in the zonisamide group versus 171 of 229 (74·7%) in the carbamazepine group, absolute treatment difference -7.9% (95% CI: −17·2 to 1·5). The PPP who did not have a seizure for 52 weeks was 157 of 281 (55·9%) in the zonisamide group versus 187 of 300 (62·3%) in the carbamazepine group and the absolute treatment difference between groups was −7·7% (95% CI: −16·1 to 0·7). The number of patients who were seizure free at 52 weeks in the PPP was matched by the ITT population. The median time to seizure freedom at 26 weeks was 204 days for both groups and the median time to seizure freedom 52 weeks was 381 days for both groups. The results for ITT population were similar. The overall incidence of treatment-emergent adverse events was similar for zonisamide (170 [60%]) versus carbamazepine (185 [62%]), as was the incidence of treatment-related treatment-emergent adverse events (102 [36%] vs 115 [38%]. The most frequently reported treatment-emergent adverse events (≥5% patients in either group) were headache, decreased appetite, somnolence, dizziness, and weight loss. Decreased appetite and weight loss were more frequently reported in the zonisamide group than in the carbamazepine group. Dizziness was more frequently reported in the carbamazepine group than in the zonisamide group. Most treatment-emergent adverse events were of mild or moderate severity. Patients with serious treatment-emergent adverse events were 15 in the zonisamide group and 17 in carbamazepine group while serious treatment-related treatment-emergent adverse events were 3 and 7 respectively. In the Baulac trial, the dose of zonisamide allowed was up to the maximum for monotherapy (500mg/day). However, the maximum carbamazepine dose allowed was 1200mg/day which is only around half of the licensed maximum dose (2g/day). Although this maximum dose of carbamazepine is rarely tolerated, it could be argued that this dosing disparity gave zonisamide an unfair advantage over carbamazepine, as it allowed zonisamide to have a potentially greater effect than the carbamazepine i.e. the trial did not give carbamazepine the same chance to be effective as zonisamide. Increasing the carbamazepine dose to the licensed maximum would have been difficult to achieve within the time frame of the clinical trial. No therapeutic drug monitoring (TDM) was carried out; therefore the carbamazepine doses could have been sub-therapeutic, however, in practice TDM is rarely performed with carbamazepine. Zonisamide monotherapy demonstrated non-inferiority to carbamazepine 9 monotherapy which was, after all, the purpose of the trial, which was designed purely as a means of obtaining the monotherapy license. Despite any potential advantage zonisamide had in terms of dosage, the carbamazepine group was still associated with a numerically higher proportion of patients who were seizure free at both time points. 2 For adjunctive therapy for diagnosed partial epilepsy: 4 published double-blind randomised controlled trials compared the efficacy of zonisamide with placebo for the adjunctive treatment of patients with partial seizures.19,20,21,22 Only one of these studies used a treatment duration considered long enough by the European Medicines Agency for the assessment of efficacy of zonisamide for licensing for this indication. This was a phase III study (study 302) that assessed the efficacy of fixed doses of zonisamide (100mg, 300mg 500mg/day) versus placebo over 18 weeks following a 6 week titration period in 351 patients. The primary objective was to evaluate the efficacy and safety of 500mg/day zonisamide compared with placebo when used in combination with existing AEDs in patients with refractory partial seizures. The secondary objectives included evaluation of the safety and efficacy of zonisamide 100mg/day and 300mg/day and assessment of a dose-response relation with zonisamide. The two primary end-points were: 1 The median percentage change from baseline in the frequency of complex partial seizures without secondary generalisation was normalised to a 28 day period and analysed using an analysis of variance (ANOVA) model rank-transformed data with the main effects of treatment and study centre. 2 The percentage of responders, where response was defined as >50% reduction in the frequency of complex seizures from baseline, was compared between the zonisamide 500mg/day and placebo using the Cochran-Mantel-Haenszel test with treatment centre as the stratification variable. For the primary efficacy population, zonisamide 500mg/day reduced the median frequency of complex seizures by 51.2% compared to 16.3% in placebo group (p<0.0001) and was associated with a significantly higher proportion of complex seizure responders (52.3% vs. 21.3%, p<0.001). There was also a significant reduction in the median frequency of all partial seizures without secondary generalisation in 500mg/day zonisamide compared to placebo (50.6% vs. 19.4%, p<0.0001) and of all seizures (51.3% vs. 18.1%, p<0.0001). Zonisamide 300mg/day was also associated with significant reduction in the median frequency of all partial (46.4% vs. 19.4%, p=0.0007) and all seizures (41.8% vs. 18.1%, p=0.0005) compared to placebo but not complex seizures (p=0.316). SMC15 noted that the patients in the zonisamide 300mg/day group were younger than those in the other groups, had a shorter median time since epilepsy diagnosis, a substantially lower historic complex partial seizure frequency and a higher simple partial seizure frequency compared with other groups. Zonisamide is licenced for partial seizures with or without generalisation but the primary endpoint in the main trial was complex seizure without generalisation. Zonisamide has not been compared yet in trials with competitor products for this indication therefore evidence is restricted to placebo-controlled trials.

Safety and adverse effects: 13

Contraindications: Hypersensitivity to the active substance, to any of the excipients or to sulphonamides. Adverse effects: Very common (≥1/10): Dizziness and somnolence; common (1/100 to <1/10): aggression, anger, anxiety, confusional state, ataxia, dysarthria, balance disorder, irritability, diplopia, vision blurred, vertigo, nausea, back pain, gait disturbance, fatigue, weight increased ,decrease and increased appetite. Overdose: There is limited clinical experience with perampanel overdose in humans. In a report of an intentional overdose that could have resulted in a dose up to 264 mg, the patient experienced events of altered mental status, agitation and aggressive behaviour and recovered without sequelae. There is no available specific antidote to the effects of perampanel. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. In view of its long half-life, the effects caused by perampanel could be prolonged. Because of low renal clearance special interventions such as forced diuresis, dialysis or haemoperfusion are unlikely to be of value. Unexplained Rash

Serious rashes occur in association with Zonegran therapy, including cases of Stevens-Johnson syndrome.

Consideration must be given to discontinuing Zonegran in patients who develop an otherwise unexplained rash. All patients who develop a rash while taking Zonegran must be closely supervised, with additional levels of caution applied to those patients receiving concomitant antiepileptic agents that may independently induce skin rashes. Withdrawal seizures In accordance with current clinical practice, discontinuation of Zonegran in patients with epilepsy must be accomplished by gradual dose reduction, to reduce the possibility of seizures on withdrawal. There are insufficient data for the withdrawal of concomitant anti-epileptic medicines once seizure control with Zonegran has been achieved in the add-on situation, in order to reach monotherapy with Zonegran. Therefore withdrawal of concomitant anti-epileptic medicinal products must be undertaken with caution. Sulphonamide reactions Zonegran is a benzisoxazole derivative, which contains a sulphonamide group. Serious immune based adverse reactions that are associated with medicinal products containing a sulphonamide group include rash, allergic reaction and major haematological disturbances including aplastic anaemia, which very rarely can be fatal. Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and leucocytosis have been reported. There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events. 11

Suicide ideation and behaviour Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Zonegran. Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge. Kidney stones Kidney stones have occurred in patients treated with zonisamide. Zonegran should be used with caution in patients who have risk factors for nephrolithiasis, including prior stone formation, a family history of nephrolithiasis and hypercalcuria. Such patients may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. In addition, patients taking other medications associated with nephrolithiasis may be at increased risk. Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly in those with predisposing risk factors. Metabolic acidosis Hyperchloraemic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with Zonegran treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of Zonegran in placebo- controlled clinical trials and in the post-marketing period. Generally, zonisamide-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. The amounts by which bicarbonate is decreased are usually small – moderate (average decrease of approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients can experience more severe decreases. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or medicinal products) may be additive to the bicarbonate lowering effects of zonisamide. The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in patients taking zonisamide who have underlying conditions which might increase the risk of acidosis, in patients who are at an increased risk of adverse consequences of metabolic acidosis and in patients with symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing Zonegran (by gradual discontinuation or reduction of a therapeutic dose) as osteopenia may develop. If the decision is made to continue patients on Zonegran in the face of persistent acidosis, alkali treatment should be considered. Zonegran should be used with caution in patients being treated concomitantly with carbonic anhydrase inhibitors such as topiramate, as there are insufficient data to rule out a pharmacodynamic interaction.

Heat stroke Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric patients. Heat stroke requiring hospital treatment was diagnosed in some cases. Most reports occurred during periods of warm weather. Patients or their carers must be warned to take care to maintain hydration and avoid exposure to excessive temperatures. Caution should be used when Zonegran is prescribed with other medicinal products that predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity. Pancreatitis In patients taking Zonegran who develop the clinical signs and symptoms of pancreatitis, it is recommended that pancreatic lipase and amylase levels are monitored. If pancreatitis is evident, in the absence of another obvious cause, it is recommended that discontinuation of Zonegran be considered and appropriate treatment initiated. Rhabdomyolysis In patients taking Zonegran, in whom severe muscle pain and/or weakness develop either in the presence or absence of a fever, it is recommended that markers of muscle damage be assessed, including serum creatine phosphokinase and aldolase levels. If elevated, in the absence of another obvious cause such as trauma or grand mal seizures, it is recommended that Zonegran discontinuation be considered and appropriate treatment initiated. Women of child-bearing potential must use adequate contraception during treatment with Zonegran and for one month after discontinuation. Physicians treating patients with Zonegran should try to ensure that appropriate contraception is used, and should use clinical judgement when assessing whether oral contraceptives (OCs), or the doses of the OC components, are adequate based on the individual patient's clinical situation. Body-weight There is limited data from clinical studies in patients with a body weight of less than 40 kg. Therefore these patients should be treated with caution. Zonegran may cause weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight or is underweight whilst on this medication. If substantial undesirable weight loss occurs, discontinuation of Zonegran should be considered Refer to the Summary of Product Characteristics for a full list of adverse effects.

Drug Interactions:13

Effect of Zonegran on cytochrome P450 enzymes In vitro studies using human liver microsomes show no or little (<25%) inhibition of cytochrome P450 isozymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 at zonisamide levels approximately two-fold or greater than clinically relevant unbound serum concentrations. Therefore Zonegran is not expected to

13 affect the pharmacokinetics of other medicinal products via cytochrome P450-mediated mechanisms, as demonstrated for carbamazepine, phenytoin, ethinylestradiol and desipramine in vivo. Potential for Zonegran to affect other medicinal products Anti-epileptic medicinal products In epileptic patients, steady-state dosing with Zonegran resulted in no clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate. Oral contraceptives In clinical studies in healthy subjects, steady-state dosing with Zonegran did not affect serum concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive. Carbonic anhydrase inhibitors Zonegran should be used with caution in patients treated concomitantly with carbonic anhydrase inhibitors such as topiramate, as there are insufficient data to rule out a possible pharmacodynamic interaction. P-gp substrate

An in vitro study shows that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC50 of 267 µmol/l and there is the theoretical potential for zonisamide to affect the pharmacokinetics of substances which are P-gp substrates. Caution is advised when starting or stopping zonisamide treatment or changing the zonisamide dose in patients who are also receiving medicinal products which are P-gp substrates (e.g. digoxin, quinidine). Potential medicinal product interactions affecting Zonegran In clinical studies co-administration of lamotrigine had no apparent effect on zonisamide pharmacokinetics. The combination of Zonegran with other medicinal products that may lead to urolithiasis may enhance the risk of developing kidney stones; therefore the concomitant administration of such medicinal products should be avoided. Zonisamide is metabolised partly by CYP3A4 (reductive cleavage), and also by N-acetyl-transferases and conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymes may affect the pharmacokinetics of zonisamide: - Enzyme induction: Exposure to zonisamide is lower in epileptic patients receiving CYP3A4-inducing agents such as phenytoin, carbamazepine, and phenobarbitone. These effects are unlikely to be of clinical significance when Zonegran is added to existing therapy; however, changes in zonisamide concentrations may occur if concomitant CYP3A4-inducing anti-epileptic or other medicinal products are withdrawn, dose adjusted or introduced, and an adjustment of the Zonegran dose may be required. Rifampicin is a potent CYP3A4 inducer. If co-administration is necessary, the patient should be closely monitored and the dose of Zonegran and other CYP3A4 substrates adjusted as needed. - CYP3A4 inhibition: Based upon clinical data, known specific and non-specific CYP3A4 inhibitors appear to have no clinically relevant effect on zonisamide pharmacokinetic exposure parameters. Steady-state dosing of either ketoconazole (400 mg/day) or cimetidine (1200 mg/day) had no clinically relevant effects on the single-dose pharmacokinetics of zonisamide given to healthy subjects. Therefore,

14 modification of Zonegran dosing should not be necessary when co-administered with known CYP3A4 inhibitors. Women of childbearing potential Women of childbearing potential must use adequate contraception during treatment with Zonegran, and for one month after discontinuation. Pregnancy There are no adequate data from the use of Zonegran in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Zonegran must not be used during pregnancy unless clearly necessary, in the opinion of the physician, and only if the potential benefit is considered to justify the risk to the foetus. The need for anti-epileptic treatment should be reviewed in patients planning to become pregnant. If Zonegran is prescribed, careful monitoring is recommended. Specialist advice should be given to women who are likely to become pregnant in order to consider the optimal treatment during pregnancy. Women of childbearing potential should be given specialist advice regarding possible effects of Zonegran on the foetus and the risk should be discussed with the patient in relation to the benefits before starting treatment. The risk of birth defect is increased by factor 2 to 3 in the offspring of mothers treated with an antiepileptic medicinal product. The most frequently reported are cleft lip, cardiovascular malformations and neural tube defect. Multiple antiepileptic medicinal product therapy may be associated with a higher risk of congenital malformations than monotherapy. No sudden discontinuation of anti-epileptic therapy should be undertaken as this may lead to breakthrough seizures which could have serious consequences for both mother and child. Breast-feeding Zonisamide is excreted in human milk; the concentration in breast milk is similar to maternal plasma. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zonegran therapy. Due to the long retention time of zonisamide in the body, breast-feeding must not be resumed until one month after Zonegran therapy is completed.

Cost analysis:

Product Pack size Cost per OP (ex. VAT)23

Primary Care (Exc. VAT) Secondary Care (Inc. VAT)

Zonegran ® 25mg x 14 capsules £8.82 £10.58

50mg x 56 capsules £47.04 £56.45

100mg x 56 capsules £62.72 £75.26

Expenditure in Primary and Secondary Care for a 12-month period: (January-December 2012): Product UHNS Stoke-on-Trent CCG North Staffordshire CCG Zonisamide £2,522.46 £44,315.85 £20,041.56 Perampanel £0 £64.52 £0 Gabapentin £8,596.37 £159,826.00 £84,729.44 Levetiracetam £51,945.36 £314,359.36 £220,544.60 Pregabalin £54,099.46 £799,829.78 £573,427.77 Locasamide £2,223.01 £31,700.62 £16,020.62 Topiramate £766.79 £56,354.18 £57,866.90 Eslicarbazepine £1,866.36 £39,013.84 £13,926.90 Vigabatrin £235.02 £1,154.32 £1,023.17 Tagabine £10.12 £161.66 £0

Costs of treatment alternatives Preparation Usual adult maintenance dose* Estimated cost per 28 day (ex VAT)** Carbamazepine 800 - 1200mg daily in 2 divided doses £5.02 to £7.53*

800 - 1200 mg daily in 2 or 3 divided Carbamazepine MR £10.24 to £15.44* doses

100 - 200 mg OD or in 2 divided Lamotrigine £1.54 to £3.08* doses

1000 - 2000 mg daily in 2 divided Levetiracetam £5.52 to £11.53* doses

600 - 2400 mg daily in 2 divided Oxcarbazepine £24.83 to £99.34* doses

1000 - 2000 mg daily in 2 divided Sodium valproate £5.24 to £10.47* doses

Sodium valproate 1000 - 2000 mg once daily or in 2 £16.30 to £32.60* MR divided doses

Zonisamide 300 – 500 mg daily £94.08 to £156.80*

*Doses taken from the relevant SPCs. The doses do not represent the full range that can be used; they are for general comparison and do not imply therapeutic equivalence. *Costs for solid dose forms taken from Drug Tariff March 2013 *Costs taken from MIMS March 2013.

References

1 NICE. Retigabine for the adjunctive treatment of partial onset seizures in epilepsy. Understanding NICE guidance – a summary for patients and carers. July 2011. www.nice.org.uk/nicemedia. 2Treiman DM. Management of refractory complex partial seizures: current state of the art. Neuropsychiatric Disease and Treatment 2010;6:297- 308. 3 Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurology 2011; 10:446-56. 4 Rugg-Gunn FJ, Sander JW. Management of chronic epilepsy. British Medical Journal 2012; 345:e4576. 5 Joint Epilepsy Council of the UK and Ireland. Epilepsy prevalence, incidence and other statistics. December 2011. ww.jointepilepsycouncil.org.uk. 6 NICE. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. Clinical Guideline 137. January 2012. http://guidance.nice.org.uk/CG137 7 Brown S, Betts T, Crawford P et al. Epilepsy needs revisited: a revised epilepsy needs document for the UK. Seizure. 1998; 7(6):435-446. 8 Cockerell OC, Johnson AL, Sander JW et al. Remission of epilepsy: results from the National General Practice Study of Epilepsy. Lancet. 1995; 346(8968):140-144. 9 MacDonald BK, Johnson AL, Goodridge DM et al. Factors predicting prognosis of epilepsy after presentation with seizures. Ann Neurol. 2000; 48(6):833-841 10 Plosker G.L. Perampanel as adjunctive therapy in patients with partial-onset seizures. CNS Drugs 2012:26: 1085-1096. 11 NICE. Quality Standards for epilepsies in adults. Quality Standard 26. February 2013. http://publications.nice.org.uk/quality-standard-for-the- epilepsies-in-adults-qs26/about-this-quality-standard. 12 Rogawski M, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004; 5: 553-564. 13 Zonisamide (Zonegran®) tablet - Summary of Product Characteristics. via http://www.medicines.org.uk 14 National Institute for health and Care Excellence (NICE) Evidence summary: new medicine ESNM17: Partial-onset seizures in epilepsy: zonisamide as monotherapy. April 2013. http://www.nice.org.uk/mpc/evidencesummariesnewmedicines/ESNM17. 15 Scottish Medicines Consortium (SMC). Zonisamide (Zonegran®) 25mg, 50mg, 100mg Hard Capsules SMC No.216; November 2005. Accessed via: www.scottishmedicines.org.uk. 16 Scottish Medicines Consortium (SMC). Zonisamide (Zonegran®) 25mg, 50mg, 100mg Hard Capsules SMC No.817; September 2012. Accessed via http:// www.scottishmedicines.org.uk 17 Midlands Therapeutics Review and Advisory Committee (MTRAC) Verdict & Summary Zonisamide (Zonegran®) For the adjunctive treatment of partial epilepsy. March 2007. http://www.keele.ac.uk/pharmacy/mtrac 18 Baulac M, Brodie M, Patten A et al. 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 2012; 11: 579–88. 19 Sackellares J, Ramsay R., Wilder B et al. Randomised, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures. Epilepsia 2004; 45:610-617. 20 Brodie MJ, Duncan R, Vespignani H et al. Dose-dependent safety and efficacy of zonisamide: A randomised, double-blinded, placebo- controlled study in patients with refactory partial seizures Epilepsia 2005; 46:31-41. 21 Schmidt D, Jacob R, Loiseau P et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res. 1993; 15 (1): 67-73 (Study 912-EU) 22 Faught E, Ayala R, Montouris GG et al. Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology 2001; 57 (10): 1774-1779 (Study 922) 23 British National Formulary (BNF) 65, March 2013. Accessed via: www.bnf.org

Produced by Sr. Maria Chidiamara Njoku Primary Care/Secondary Care Interface Pharmacist University Hospital of North Staffordshire Telephone: 01782 674541 e-mail: [email protected] Produced for use within the NHS. Not to be reproduced for commercial purposes.