Zonisamide as a treatment for partial epileptic seizures: a systematic review.

Adv Ther DOI 10.1007/s12325-014-0104-1

REVIEW

Zonisamide as a Treatment for Partial Epileptic Seizures: A Systematic Review Joanna H. Cox • Stefano Seri • Andrea E. Cavanna

To view enhanced content go to www.advancesintherapy.com Received: January 13, 2014 Ó Springer Healthcare 2014

ABSTRACT

of

Although the majority of people with epilepsy

benzisoxazole derivative chemically unrelated to other anticonvulsant agents. In this article,

have a good prognosis and their seizures can be

the authors present the results of a systematic

well controlled with pharmacotherapy, up to one-third of patients can develop drug-resistant

literature review summarizing the current evidence on the efficacy and tolerability of

epilepsy, especially those patients with partial seizures. This unmet need has driven

zonisamide for the treatment of partial seizures. Of particular interest within this

considerable efforts over the last few decades

updated review are the recent data on the use

aimed at developing and testing newer antiepileptic agents to improve seizure control.

of zonisamide as monotherapy, as they might open new therapeutic avenues.

the

new

generation

is

zonisamide,

a

One of the most promising antiepileptic drugs Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0104-1) contains supplementary material, which is available to authorized users. J. H. Cox A. E. Cavanna (&) Department of Neuropsychiatry, University of Birmingham, Birmingham, UK e-mail: [email protected] J. H. Cox A. E. Cavanna Birmingham and Solihul Mental Health NHS Foundation Trust, Birmingham, UK S. Seri A. E. Cavanna School of Life and Health Sciences, Aston University, Birmingham, UK A. E. Cavanna Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology and UCL, London, UK

Keywords: Efficacy;

Epilepsy;

Neurology;

Partial seizures; Tolerability; Zonisamide

TREATMENT OF PARTIAL EPILEPSY Epilepsy is a common neurological disorder with an estimated 50 million people affected worldwide [1]. In approximately 37 million of these individuals, seizures are not secondary to other neurological disorders; within the remaining

cases,

ictal

manifestations

are

caused by injuries, tumors, and other neurological conditions [1]. Epilepsy has been defined as the tendency to present recurrent

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seizures, caused by abnormal excessive or

trials of two well-tolerated AEDs have failed to

synchronous

and

result in seizure freedom [9]. As standard AEDs

manifesting with specific clinical signs and/or symptoms [2]. Epileptic seizures are divided into

are not effective in all patients, there has been renewed interest in developing novel AEDs,

two broad categories, International League

according to the Against Epilepsy

some of which have become licensed for use as ‘add-on’ therapies in previously treatment-

classification, based on the extent of the

resistant patients. Zonisamide, a sulfonamide

neurological dysfunction [3]. Generalized seizures are characterized by the involvement

AED, is one of the most promising agents of the new generation. After describing the

of both cerebral hemispheres, and can be further sub-classified according to their clinical

mechanisms of action of zonisamide, the present article reviews the existing evidence

manifestations

are

on the efficacy and safety of this medication for

characterized by limited involvement of a particular area of the brain [4]. In a

the treatment of epilepsy, with focus on partial seizures.

neuronal

[4].

activity

Partial

seizures

considerable proportion of patients, partial seizures can develop into generalized seizures (secondary

generalization).

Epilepsy

is

a

disabling and often stigmatizing chronic condition, especially in the developing world where access to treatment may be limited [5]. The mainstay of treatment for epilepsy involves antiepileptic drugs (AEDs). Other adjunctive non-pharmacological treatments have been proposed for refractory cases and these include the ketogenic diet, epilepsy surgery, and other non-resective procedures, such as deep brain stimulation and vagus nerve stimulation [6]. The first-line anticonvulsant therapy recommended by the National Institute for Health and Care Excellence for generalized seizures is sodium valproate, whereas carbamazepine or lamotrigine is recommended as elective option for newly diagnosed partial-onset epilepsy [7]. Around 50% of patients are expected to become seizure-free with the first treatment intervention; and this proportion increases with the use of polytherapy [8]. However, up

ZONISAMIDE Zonisamide methanesulfonamide)

(1,2-benzisoxazole-3is a benzisoxazole

derivative with a sulfonamide side chain. It was first licensed for use in 1989 in Japan, and has subsequently been licensed for use in the treatment of epilepsy in South Korea, the United States of America (USA) and the European Union. It is currently approved for use in both partial and generalized seizures in patients of all ages in Japan and Korea, as an adjunctive treatment for partial seizures in adults in the USA, and as an adjunct or monotherapy for partial seizures in Europe. More recently (2013), 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 [10–13].

Mechanisms of Action

to one-third of patients with epilepsy can have seizures that prove to be refractory to treatment interventions [6]. Treatment resistance in epilepsy can be established when adequate

Zonisamide is a broad-spectrum AED with a complex mechanism of action, which is not fully understood. This medication shares

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antiepileptic properties with carbamazepine,

of absorption is slightly slower with food intake

phenytoin, and sodium valproate, which have

[14, 17, 18]. Zonisamide reversibly binds to

been described in studies involving animals and cultured neurons, as well as in clinical trials.

carbonic anhydrase in the brain, blood and, to a lesser degree, other tissues. This accounts for

Zonisamide has demonstrated an inhibitory effect on voltage-gated sodium channels,

the greater concentrations in these tissues compared with other tissues and plasma, where

preventing the repetitive firing of sodium-

protein binding is low. Zonisamide is primarily

dependent action potentials [10]. mechanism of action is shared

This with

excreted through the urinary tract, with a halflife of 63–69 h. Approximately 85% of the dose is

carbamazepine, lamotrigine, and phenytoin [11]. Furthermore, zonisamide reduces voltage-

excreted in urine within 96 h of either single or repeated doses, with the remaining 15% being

dependent

thus

excreted via the feces. The route of excretion is

inhibiting the spread of seizure discharges between cells [12]. Other proposed

not influenced by age [14, 17, 18]. The half-life is decreased with co-administration of other

mechanisms of action include potentiation of gamma aminobutyric acid inhibitory

isoenzyme-inducing AEDs, such as phenytoin, phenobarbital, and carbamazepine, but still

neurotransmission

of

remains above 24 h [17]. This long half-life

glutamatergic excitatory neurotransmission [13]. Zonisamide has also been shown to

allows once daily dosing of zonisamide, a key advantage in its clinical use.

increase extracellular concentrations dopamine and serotonin in addition

of to

Zonisamide is metabolized by the action of isoenzyme 3A4 in the liver, via the cytochrome

increasing the metabolism of acetylcholine. The exact role of these cellular mechanisms in

P450 pathway and with little first-pass or presystemic metabolism. There are two main

the prevention of seizures is still largely

metabolic steps, the first of which involves

unknown. A collateral finding is zonisamide’s modest inhibitory effect on carbonic anhydrase,

acetylation of the drug to form N-acetyl zonisamide. This is then reduced, resulting in

although to a much lesser degree than that of acetazolamide [14], and possibly topiramate

ring-opened sulfate and glucuronide conjugates, accounting for 34% of urinary

[15]. Finally, there is evidence from in vitro

radioactivity,

studies that zonisamide has neuroprotective properties [16].

accounts for 32% and does not induce its own metabolism. No active metabolites are

Pharmacokinetics and Metabolism

produced. Since this process may be affected by other AEDs if used concomitantly,

T-type

calcium

and

currents,

inhibition

while

unchanged

zonisamide

zonisamide dose adjustment may be required Zonisamide has a favorable pharmacokinetic profile,

being

rapidly

absorbed

from

when used as an adjunctive treatment [18, 19].

the

gastrointestinal tract and reaching peak plasma levels within 2–6 h of oral ingestion of a dose of 200–400 mg. Plasma half-life in healthy humans is 68 h, with the site and route of absorption influencing the rate, but not the extent of absorption [14, 17, 18]. For example, this rate

USE OF ZONISAMIDE FOR PARTIAL EPILEPSY The authors carried out a systematic literature review to assess the current evidence for the

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efficacy of zonisamide as both an adjunct AED and as monotherapy, in the treatment of partial seizures, in both adults and children. The authors further intended to consider the evidence surrounding safety and tolerability of zonisamide, and where it may fit into treatment regimens. The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors. All studies used in this review were identified using the PubMed and PsycInfo databases, using the search terms ‘‘zonisamide’’ AND ‘‘epilepsy’’ OR ‘‘seizures’’ and following the methodology outlined in the PRISMA statement [20]. This initially yielded 106 articles, which were manually screened. Papers were excluded if they were in a language other than English, involved molecular studies and/or animal models, or focused on generalized seizures only. Case reports, letters to the editor,

Fig. 1 Flow-chart illustrating the different stages of the systematic literature search on the use of zonisamide for the treatment of partial seizures. RCTs randomized controlled trials

commentaries, book reviews and conference abstracts were also excluded. The screening

looked specifically at a pediatric population,

process led to a total of 27 original studies,

solely adult cohort (above 18 years of age) or a mixed adolescent and adult population. The

including 7 randomized controlled trials (RCTs) and 20 open-label studies, the findings of which were discussed in this article. Furthermore, 17 review articles on zonisamide were identified,

whereas the others [21–25, 27] involved either a

seven RCTs are summarized in Table 1. Zonisamide as Adjunctive Therapy

including a number of systematic reviews. The contents of these articles were assessed to double check that no relevant references had been missed out. The full methodology used to identify relevant studies for the present review is shown in Fig. 1. The seven RCTs assessing the clinical efficacy of zonisamide in partial epilepsy identified from the literature search were carried out between 1993 and 2013. Six RCTs [21–26] assessed the use of zonisamide as an adjunct therapy for the treatment of refractory partial epilepsy, whereas one [27] investigated its use as a monotherapy in newly diagnosed epilepsy. One trial [26]

Adult Populations Five RCTs [21–25] were undertaken assessing the clinical efficacy of zonisamide as an adjunctive therapy in the treatment of refractory partial seizures in adults (aged 18 year or over). Study protocols for each trial differed slightly; however, they all involved a baseline phase, during which seizure frequency was measured, followed by a dose-titration phase and a fixed-dose maintenance phase. All relevant trials concluded that zonisamide is effective in reducing seizure frequency in adults with refractory partial seizures.

Location

Europe

USA

USA

Europe and South Africa

China

Study

Schmidt et al. [21]

Faught et al. [22]

Sackellares et al. [23]

Brodie et al. [24]

Lu et al. [25]

Double-blind placebo-controlled RCT





Study type

102 patients (aged 18–70 years) with refractory partial-onset epilepsy

351 patients (aged 12–77 years) with refractory partial-onset epilepsy)



139 adult patients with refractory partial-onset epilepsy

Participants

300 or 400 mg/day

100, 300, or 500 mg/day

400–600 mg/ day

100, 200, or 400 mg/day

7.0 mg/kg/day

Dose

Add-on

Add-on

Add-on

Add-on

Add-on

Add-on/ monotherapy

500 mg group = 81.4

Seizure freedom = not reported

Decrease in seizure frequency = not reported

400 mg Responder rate = 56.5





Decrease in seizure frequency = 51.3




78.9

300 mg group = 70.9 Seizure freedom = not reported 300 mg Responder rate = 42.2

100 mg group = 67.9


70.5

Not reported

59.2

Patients reporting adverse effects (%)




Responder rate = 26.9

Seizure freedom = 6.1


400 mg Responder rate = 42










Measure of effect (%)

Table 1 Summary of the main randomized controlled trials (RCTs) on zonisamide for the treatment of partial seizures

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patients achieving at least a 50% decrease in

55.1

seizure frequency, was measured in most [21, 23–26] of the five trials. 60.0

Patients reporting adverse effects (%)

Responder rate, defined by the proportion of

The first RCT undertaken included 139 adult Caucasian patients in 9 centers across Europe




The

trial

followed by a 12-week double-blind trial period. The dose of zonisamide administered

Add-on 8 mg/kg/day (up to a maximum of 500 mg/day) Europe and India

Location

Asia, Australia, Europe

zonisamide was increased to a maximum of

Dose

period, doses were increased in order to achieve a plasma concentration of 20–30 lg/

351 patients (aged 6–17 years) with refractory partial-onset epilepsy)

was titrated from 1.5 mg/kg/day initially, to



placebo.

200–500 mg/day


or

456 patients (aged 18–75 years) with newly diagnosed partial-onset epilepsy

Responder rate = not reported

zonisamide

involved an 8- to 12-week baseline period, where seizure frequency was measured,

Double-blind non-inferiority RCT comparing zonisamide and carbamazepine

Monotherapy

add-on

Participants

Measure of effect (%)

patients were taking one to three standard AEDs, and were randomly assigned to either

3.0 mg/kg/day on day 8, and then to 6.0 mg/kg/ day on day 15. After this 4-week titration

ml. If at this point, seizure frequency had not decreased by at least 50%, the dose of 20 mg/kg/day, providing no intolerable adverse effects had occurred. This study found that the decrease in seizure frequency was significantly greater in the zonisamide group (26.9%), in comparison to placebo (a 3.9% increase). On further investigation, the decrease in simple partial seizures was 72.6% in the zonisamide group, compared to 48.1% in the placebo group. However, frequency of complex partial seizures

was

reduced

by

27.7%

in

the

zonisamide group, compared to an increase of 3.9% in the placebo group. This difference in the effect of zonisamide on simple partial seizures compared to complex partial seizures

Guerrini et al. [26]

Baulac et al. [27]

may be reflected by the low levels of simple Study

Table 1 continued

required to have a diagnosis of partial epilepsy refractory to standard AED treatment. All

Study type

Add-on/ monotherapy

[21]. For inclusion in the trial, patients were

partial seizures experienced by the cohort, both at baseline and during therapy. The authors also found a responder rate of 30.3% in the

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zonisamide group, compared to 10.9% in the

20.5% decrease, respectively. The authors of this

placebo group. It was recommended that

trial concluded that zonisamide is effective and

zonisamide may be an effective AED to be used as an adjunct therapy in the treatment of

well tolerated when used as an adjunctive therapy for treatment refractory partial-onset

refractory partial seizures [21]. A second double-blind placebo-controlled

seizures, at a minimum dose of 100 mg/day, with optimal effect at 400 mg/day [22].

RCT was undertaken in 2001 [22], involving

Another

double-blind

placebo-controlled

203 patients treated in 20 centers across the USA. This trial investigated the efficacy and

RCT was undertaken across 4 locations in the USA [23] which included 152 patients, aged

safety of zonisamide in the treatment of refractory partial-onset seizures in patients

17–67 years. All patients had a diagnosis of refractory partial epilepsy and were taking one

aged 13–68 years. To be included in the trial,

or two AEDs. The study protocol involved a

patients were required to have a diagnosis of refractory partial-onset seizures (with or

4-week dose-titration phase to a maintenance dose of 400–600 mg/day, dependent on

without secondary generalization), with a history of at least four seizures per month for

individual patient body mass, plasma zonisamide levels, and tolerability. Results

the previous 3 months, while taking one or two

showed a 28.9% decrease in the frequency of

AEDs. The study protocol consisted of a 4-week baseline period, where all participants took a

all partial seizures in the zonisamide group, compared to a 4.7% increase in the placebo

placebo medication, and an 8- to 12-week blinded therapy period, where patients were

group. The authors also found a greater responder rate in the zonisamide group (26.9%)

either given zonisamide or placebo. After 12 weeks, participants in the placebo group

compared to the placebo group (16.2%). In the zonisamide group, 66.2% of patients reported an

were crossed over to receive zonisamide, at a

improvement of their condition, compared to

dose of 100 mg/day, increasing by 100 mg per week to a maximum dose of 400 mg/day, which

12.3% of those in the placebo group. This finding was replicated by physicians who

was continued until week 20. The cohort receiving zonisamide was split into two

reported a general improvement in 63.6% of the zonisamide group, compared to 10.8% of

groups, one of which received 1 week of

the placebo group. The authors concluded that

100 mg/day and 5 weeks of 200 mg/day, and the other received 5 weeks of 100 mg/day and

as an adjunctive medication, zonisamide is a generally well tolerated and significantly

1 week of 200 mg/day. Both groups then went on to take 300 mg/day for 1 week, before

improves seizure control among patients with refractory partial epilepsy [23].

reaching a maintenance dose of 400 mg/day,

A larger double-blind placebo-controlled

which was continued for the remaining 12 weeks. The results of this trial showed a

RCT was undertaken in 2005 [24], assessing the efficacy of zonisamide as an adjunctive

greater percentage decrease in seizure frequency after treatment with 400 mg/day of zonisamide

therapy in patients with refractory partial seizures, who were already on one to three

(40.5%) compared to placebo (9.0%). This

AEDs. This trial included 351 patients recruited

decrease was shown to be greater at a dose of 400 mg/day, compared to lower doses of 200

from 54 centers across Europe and South Africa. Patients were aged 12–77 years, and were

and 100 mg/day, which showed a 24.7% and

randomized into four groups, receiving either

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placebo or zonisamide, at a dose of 100, 300, or

Pediatric Populations

500 mg/day. The study protocol consisted of a

The most recent double-blind placebocontrolled RCT [26] assessed the efficacy of

12-week baseline phase, a 6-week dose-titration phase, and an 18-week fixed-dose assessment phase. The authors found that at 500 mg/day, the zonisamide group experienced a 51.2% decrease in seizure frequency, compared to 16.3% in the placebo group. They also found a responder rate of 52.3%. Within the zonisamide group, a significant dose–response relationship was demonstrated. It was recommended that zonisamide may be an appropriate first-choice adjunctive therapy in patients with refractory partial-onset epilepsy [24]. Patients from this trial were followed up in an extension study [28], which suggested that with flexible dosing regimens,

long-term

safety

and

sustained

efficacy can be achieved in patients with refractory partial epilepsy. The final double-blind placebo-controlled RCT which looked into zonisamide as an adjunctive therapy involved a cohort of 104 Chinese adults with refractory partial-onset epilepsy [25]. Zonisamide was titrated to a target dose of 300–400 mg/day. The responder rate was 55.8% in the zonisamide group, compared to 36.0% in the placebo group. There was no significant difference in responder rates between those taking 300 mg/ day and those having 400 mg/day. Similar efficacy was reported in the control of simple partial seizures, complex partial seizures, and secondarily generalized seizures. The authors of this trial concluded that 300–400 mg/day of zonisamide is effective and well tolerated as an adjunct for refractory partial-onset epilepsy in adult Chinese patients. In addition to these RCTs, a number of openlabel

studies

assessing

zonisamide

as

an

adjunctive treatment in adults [29–33] reported responder rates of 40.9–79.0% and seizure freedom in 15–18%.

zonisamide as an adjunctive therapy in a pediatric population (aged 6–17 years) with refractory

partial

epilepsy.

The

authors

recruited 207 patients who were taking one or two AEDs for their partial-onset epilepsy, with or without secondary generalization, from centers in Europe and India. Dose adjustments were made during a titration phase, to a target dose of 8 mg/kg/day (maximum 500 mg/day). Responder rate was assessed during the 12-week maintenance phase, and 50% of the zonisamide group had achieved at least a 50% reduction in partial seizure frequency, compared to 31% in the placebo group. The median decrease in seizure frequency from baseline was 50% for zonisamide, compared to 24.5% for placebo, a difference that reached significance. This trial showed a significantly higher placebo response rate compared to other trials, which may limit the reliability of its results [26]. Two further studies involved mixed cohorts of both children and young adults [34, 35]. Coppola et al. [35] reported seizure freedom in 10.9% of their sample, and a responder rate in 37.8%, at a mean dose of 5.7 mg/kg/day as an add-on therapy in refractory partial epilepsy. Kluger et al. [34] assessed the use of zonisamide in 18 patients with severe partial epilepsy syndromes. Responder rates were 50.0% at 8 weeks and 38.9% at 18 months. Another study looking at the use of zonisamide as an adjunctive therapy in pediatric populations [36] reported a median decrease in partial seizure frequency of 1.3 per week per individual, which approached significance (P = 0.056). Neither responder rate nor percentage decrease in seizure frequency was measured in this study [36]. Furthermore, a retrospective case-notes review of pediatric patients treated with

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a

low

a much lower rate of seizure freedom (29.8%),

however,

the

although 77.1% of patients demonstrated at

incidence of adverse effects was lower than other studies. Finally, two studies undertaken in

least a 50% decrease in seizure frequency. Two additional open-label studies [45, 46]

patients with intractable epilepsy [38, 39] reported responder rates of 40.0% and 40.5%,

assessed the efficacy of zonisamide in children with epilepsy, but did not report separate results

respectively.

for patients on monotherapy or polytherapy.

Zonisamide as Monotherapy

The authors concluded that zonisamide is beneficial in managing seizures in children

Adult Populations

with epilepsy. Combined evidence identified from RCTs

adjunctive

zonisamide

responder

rate

of

[37]

23.5%;

found

A double-blind, parallel-group non-inferiority trial was undertaken across 120 centers in Asia,

and open-label trials suggests that zonisamide

Australasia, and Europe [27] to assess the

can be useful as either adjunctive therapy in refractory partial epilepsy or as monotherapy in

efficacy of zonisamide monotherapy in newly diagnosed partial epilepsy, compared to

newly diagnosed partial epilepsy [13]. Results appear consistent for both adult and pediatric

carbamazepine. Data from 456 patients aged 18–75 years were analyzed, and no significant

populations. Variations in reported seizure

difference in terms of absolute treatment was

freedom or responder rates may reflect the variation in sample sizes, severity of the

found between zonisamide and carbamazepine. Seizure freedom was reported in 79.4% of

epilepsy, and non-blinding in open-label trials. There also appears to be a significant dose–

patients in the zonisamide group, compared to 83.7% of the carbamazepine group. Rates of

response relationship, with optimum efficacy occurring at around 6–8 mg/kg/day [47, 48].

adverse events were similar for both groups. The authors recommended zonisamide as a

Safety and Tolerability

potential monotherapy for patients with newly diagnosed partial epilepsy [27]. A retrospective chart review of adult patients

The majority of the reviewed trials also assessed the prevalence of treatment-emergent adverse

taking zonisamide as monotherapy [40] found it to be effective in managing a broad spectrum of

events, alongside efficacy for partial seizures. Zonisamide appears to be a relatively well-

seizure types, with the exception of complex

tolerated medication: the presence of side

partial seizures.

effects in the RCTs ranged from 55.1% [26] to 81.4% [24], however, the vast majority of these

Pediatric Populations Three open-label studies [41–43] assessed the

were mild. The most frequently reported side effects include dizziness, headache,

use of zonisamide as monotherapy in children.

somnolence, nausea/vomiting, anorexia, and

Seizure freedom was reported in 63–83% of patients, and no significant differences in

fatigue. In addition, both psychiatric and cognitive adverse effects have been reported,

seizure freedom rates were found between lowor high-dose zonisamide. A further open-label

with prevalence figures that are in line with other new generation AEDs [49–54]. Rates of

trial [44] undertaken in a mixed pediatric and young adult population (aged 1–22 years) found

serious side effects ranged from 3.7% [23] to 11.9% [22], and withdrawal rates due to side

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effects ranged from 0.9% [23] to 27.1% [24].

results for zonisamide as monotherapy in

Differences across trials may reflect a number of

newly

issues including recall bias, responder bias, and misattribution of a symptom to the medication.

thereby prompting further RCTs. Taken together with other studies showing good

Adverse effect rates of up to 68% were reported in placebo groups [24]. Serious side effects are

results in terms of both efficacy and tolerability in generalized epilepsy syndromes

rare; as a weak carbonic anhydrase inhibitor,

[63–65], the reviewed studies show promising

the risk of renal calculi has warranted investigation; however, the overall incidence is

results which might potentially open new treatment avenues for patients with epilepsy.

reported to be 1% or less [18]. Other serious, though rare, side effects include oligohydrosis

The evidence in support of the use of zonisamide in pediatric populations,

and hyperthermia in children and severe skin

particularly as monotherapy, is still limited,

reactions [55]. The tolerability of zonisamide has been shown to improve with slow dose

indicating the need for further trials. Future studies should also include large-scale

titration [56, 57], a practice now widely implemented. There is a paucity of evidence

controlled trials focusing on the use of this medication either as a monotherapy for newly

surrounding

with

diagnosed partial epilepsy, or as an adjunct to

zonisamide, however, a preclinical study suggested teratogenic potential, prompting

traditional AEDs for the treatment of refractory partial epilepsy, with particular attention on

contraindication in pregnancy [57]. The administration of zonisamide

special populations (e.g., post-lesional epilepsy, elderly patients, learning disability, and

teratogenicity

associated

in

combination with other AEDs (phenytoin, valproate, lamotrigine) has shown no clinically

diagnosed

partial-onset

epilepsy,

neuropsychiatric settings).

significant effects on their pharmacokinetic profiles, indicating that it is safe to use zonisamide in combination with other AEDs,

ACKNOWLEDGMENTS

and no dose adjustment is required [58–60]. Unlike other AEDs, zonisamide has shown no

No funding or sponsorship was received for this study or publication of this article. All named

effect on the pharmacokinetic profile of oral

authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the

contraceptives [61].

integrity of the work as a whole, and have given final approval for the version to be published.

CONCLUSIONS Conflict of interest. Andrea E. Cavanna has Based on the reviewed evidence, zonisamide appears to be a well-tolerated and effective AED either as monotherapy or as add-on in the treatment of partial epileptic seizures. The majority of trials evaluated zonisamide as an adjunctive therapy [62], and the only monotherapy RCT compared it to carbamazepine. This trial showed promising

received Board Membership fees and research grants from Eisai Pharmaceuticals and lectureship grants from Eisai Pharmaceuticals and Janssen-Cilag. Stefano Seri has received unrestricted educational grants from Eisai Pharmaceuticals, UCB Pharma, and Beacon Pharmaceuticals Limited. Joanna H. Cox has no conflict of interest.

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Compliance

with ethics guidelines. The

analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.

12. Kito M, Maehara M, Watanabe K. Mechanisms of T-type calcium channel blockade by zonisamide. Seizure. 1996;5:115–9. 13. Mula M. Profile of once-daily zonisamide as monotherapy for treatment of partial seizures in adults. Drug Des Dev Ther. 2013;7:397–402. 14. Masuda Y, Ishizaki M, Shimizu M. Zonisamide: pharmacology and clinical efficacy in epilepsy. CNS Drug Rev. 1998;4:341–60.

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