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Zonisamide in the management of epilepsy—Japanese experience
Epilepsy Research 68S (2006) S25–S33
Zonisamide in the management of epilepsy—Japanese experience Shunsuke Ohtahara ∗ Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho 2-5-1, Okayama, Japan Received 22 September 2005; received in revised form 4 November 2005; accepted 4 November 2005 Available online 29 November 2005
Abstract Zonisamide (Zonegran® ), a novel antiepileptic drug (AED) approved in Europe for the adjunctive treatment of refractory partial seizures in adults, has undergone extensive evaluation in pre- and post-marketing double-blind and open-label studies in Japan (where zonisamide is used widely to treat partial and generalised seizures in adults and children). These data indicate that the clinical benefit of zonisamide extends across a range of seizure types and patient ages. In an analysis based on a mixture of controlled and open studies in adults and children with partial seizures, 51–57% responded to zonisamide treatment (achieving ≥50% reduction in baseline seizure frequency). Efficacy extends across a range of generalised seizures and 22–66% of adults and children experiencing tonic–clonic, tonic, clonic, myoclonic or absence seizures responded to treatment. Even greater responder rates have been reported when zonisamide was used as monotherapy for partial seizures and generalised seizures in patients refractory to other AEDs or with newly diagnosed epilepsy. Zonisamide is also efficacious in paediatric epilepsy syndromes, including Lennox-Gastaut Syndrome, West Syndrome and Ohtahara Syndrome. Across the spectrum of epilepsy syndromes studied, zonisamide is well-tolerated with a low incidence of adverse events, which are generally mild and CNS-related. These data indicate that zonisamide represents a valuable broad-spectrum option for the treatment of epilepsy. © 2005 Elsevier B.V. All rights reserved. Keywords: Broad-spectrum; Generalised seizures; Partial seizures; Paediatric epilepsy; Zonisamide
1. Introduction The introduction of Zonegran® (zonisamide) in Europe offers a new approach to the treatment of epilepsy. Zonisamide has been shown in randomised controlled trials to provide highly effective control of partial seizures, and offers a number of additional ∗
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favourable properties including good tolerability, a long plasma half-life and limited potential for interaction with other drugs (see Baulac, this issue; Brodie, this issue). Zonisamide is currently indicated in Europe for the adjunctive therapy of refractory partial seizures in adults. Evidence from extensive clinical use of zonisamide in Japan, where it has been used widely for more than 15 years, indicates that zonisamide’s efficacy extends across a broad range of epilepsy indications in
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both adult and paediatric patients. Results from trials conducted prior to registration, post-marketing surveillance studies and independent reports in Japan indicate that zonisamide is efficacious in treating partial- and generalised-onset seizures and is beneficial in treating some epilepsy syndromes. This paper reviews these data briefly, and discusses the value of zonisamide as a treatment option for a broad range of patients with epilepsy.
2. Prescribing zonisamide in Japan Zonisamide is currently licensed in Japan as monotherapy or adjunctive therapy for a broad range of seizures in adults and children (age ≥1 year). Zonisamide is indicated for partial seizures (simple partial, complex partial and secondary generalised) and some types of generalised seizures, such as tonic–clonic, tonic and atypical absence seizures. This licence contrasts with the much more specific labels for zonisamide in the US and Europe. In the US, zonisamide is indicated as adjunctive therapy for the treatment of partial seizures in adults aged over 16 years. The European regulatory agency has recently approved zonisamide as adjunctive therapy for partial seizures with or without secondary generalisation in adults aged ≥18 years. The introduction of new generation antiepileptic drugs (AEDs) in Japan has been slow in recent years. Zonisamide is currently regarded as a first-line AED for all types of partial seizures. Zonisamide or carbamazepine are favoured over phenytoin, clobazam, valproate or phenobarbital for simple partial and complex partial seizures. Zonisamide is also considered as a first-line AED for generalised tonic–clonic seizures, and a first- or second-line drug after valproate for treating other types of generalised seizures including tonic, myoclonic and atonic or astatic seizures. Zonisamide is also used for typical and atypical absence seizures refractory to valproate and ethosuximide, and for spasms (West Syndrome) following unsuccessful intervention with high-dose Vitamin B6, adrenocorticotropic hormone (ACTH) and valproate. Overall, zonisamide represents approximately 12% of the Japanese AED market. Other agents used include carbamazepine, sodium valproate, phenytoin, clobazam, phenobarbital and ethosuximide.
3. Clinical efficacy Zonisamide has been the subject of extensive efficacy evaluation during development and marketing in Japan, and two pooled analyses of available data have been performed. One set comprises data from patients recruited to pre-registration trials during clinical development, and the second includes patients recruited to a post-marketing surveillance-prospective study (PMS-prospective study). Although many of these studies have not been published individually, proceedings and other publications have provided a considerable body of data from these studies, which are reviewed here. Overall, these datasets have indicated that zonisamide provides highly effective control of both partial seizures and generalised seizures in adults and children. 3.1. Registration studies Pooled data have been obtained for 1008 patients, including 403 children, recruited in registration studies (including Phase II and III trials, both controlled and open-label) during development (Yagi and Seino, 1992). Of this total, there were 673 cases of partial epilepsy and 286 cases of generalised epilepsy. The majority of individuals received polytherapy including zonisamide, although 55 patients received zonisamide monotherapy. Mean daily doses of zonisamide ranged from 5.9 mg/kg/day (range 1.1–17.7) in patients aged ≥16 years to 8.8 mg/kg/day (range 0.8–30.4) in young children aged 2–6 years. Infants (age ≤1 year) received a mean daily dose of 8.6 mg/kg/day (2.8–21.4) and older children and adolescents (7–15 years) received 7.1 mg/kg/day (0.7–20.2). In these pre-registration trials, 51–57% of patients with partial epilepsy responded to zonisamide treatment (≥50% reduction in baseline seizure frequency) (Yagi and Seino, 1992) (Fig. 1). Zonisamide was also efficacious in the treatment of generalised seizures; 66% of patients with idiopathic generalised epilepsy and 47% of those with symptomatic generalised epilepsy responded to zonisamide treatment. Efficacy was also attained in the treatment of LennoxGastaut Syndrome (responder rate 32%) and 2/9 (22%) patients with West Syndrome (Yagi and Seino, 1992).
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Fig. 1. Efficacy of zonisamide by seizure type in adults and children (n = 1008) in pre-registration trials (Yagi and Seino, 1992).
3.2. Post-marketing surveillance study The PMS-prospective study in Japan assessed the long-term efficacy of open-label zonisamide treatment in 1631 patients (Yamauchi and Aikawa, 2004) and safety in 1512 patients including 928 children (Ohtahara and Yamatogi, 2004; Iinuma and Haginoya, 2004), treated for between 1 and 3 years for partial epilepsy (n = 1044) or generalised epilepsy (n = 458). In contrast to the registration studies, approximately one-third of individuals (n = 424) received zonisamide only. The daily dose of zonisamide in children ranged widely, from 0.2–29 mg/kg/day, but most patients (70%) received 2–8 mg/kg/day. Adult daily doses also ranged widely (12.5–900 mg/day) with the majority of patients (77%) given zonisamide 100–400 mg/day, consistent with the recommendations in the European and US licences. Most patients in the Japanese PMSprospective study had been treated with other AEDs at the introduction of zonisamide therapy. However, 25% of patients were newly diagnosed and were prescribed zonisamide alone. Efficacy of zonisamide, assessed as a reduction in baseline seizure frequency of ≥50%, was observed over a broad range of seizure types (Fig. 2) (Yamauchi and Aikawa, 2004). Overall, 70% of patients with partial epilepsy attained at least a 50% reduction in seizure frequency. Moreover, approximately 50% of these patients became seizure free with zonisamide treatment. Excellent efficacy was also observed in patients with generalised epilepsy, particularly in the control of tonic–clonic, clonic and typical absence seizures (responder rate 68, 75 and 87.5%, respectively). These data indicate that zonisamide is highly
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Fig. 2. The efficacy of zonisamide by seizure type in 1631 adults and children receiving zonisamide for 1–3 years in a post-marketing surveillance prospective study (Yamauchi and Aikawa, 2004). The dotted line indicates median response achieved according to seizure type; n values refer to the number of patients with a particular seizure type and evaluable for efficacy at the time of the survey; values within the figure refer to the responder rate for that type of seizure (% of patients achieving ≥50% reduction in seizure frequency); an additional 30 patients had other types of seizures, of whom 43.3% were responders (data not shown).
efficacious across a broad spectrum of seizure types in adults and children. 3.2.1. Zonisamide monotherapy Comparison of responder rates determined in the PMS-prospective study indicated that zonisamide is more effective when administered as monotherapy than as polytherapy (Yamauchi and Aikawa, 2004). Overall, responder rates (patients with ≥50% reduction in seizure frequency) were 92.6% amongst patients receiving monotherapy (365/394 patients), compared to 57.8% amongst those receiving polytherapy (703/1216 patients) (P < 0.01). This pattern of superior results for monotherapy was seen both for partial seizures (responder rates 92.9% versus 61.8%) and generalised seizures (91.2% versus 48.6%). It is possible that patients with less severe epileptic disorders could have been enrolled to the monotherapy treatment group and could account for the higher responder rates among these individuals. Nevertheless these data suggest that zonisamide monotherapy may provide substantial benefit for many patients presenting in routine clinical practice. Zonisamide monotherapy was also observed to be highly efficacious in a variety of seizures in 726 patients with newly diagnosed epilepsy during a PMS drug-use investigation (Yagi, 2004) (Table 1). Responder rates in excess of 80% were obtained in
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Table 1 Efficacy of zonisamide monotherapy by seizure type in 726 patients with newly diagnosed epilepsy Seizure type Partial seizures Simple partial Complex partial Partial-onset generalised tonic–clonic Generalised seizures Tonic–clonic Tonic Absence Myoclonic Atonic
Number of patients
Responder rate (%)
128 179 149
82 80 82
257 54 34 6 1
93 93 85 83 0
Responder rate = % patients attaining ≥50% reduction in baseline seizure frequency. Data from post-marketing surveillance drug use investigation (Yagi, 2004).
patients with partial, tonic–clonic, tonic, absence or myoclonic seizures. However, it is not clear whether the patients included in this study overlap with those in the PMS study described by Yamauchi and Aikawa (2004).
4. Efficacy in paediatric patients The efficacy of zonisamide in paediatric patients with epilepsy has been studied widely in Japan. Data from the PMS-prospective study, which included 928 children receiving zonisamide as an adjunct or as monotherapy, were analysed further for 729 children with a range of seizure types, treated with zonisamide at doses ranging from 2 to over 10 mg/kg/day (most receiving 2–8 mg/kg/day) (Iinuma and Haginoya, 2004). Responder rates were 75–79% in children experiencing partial seizures (Fig. 3). Zonisamide was also efficacious in children with generalised seizures (Fig. 3), with responder rates of 37–75% observed in generalised tonic–clonic and typical absence seizures. Interestingly, although generalised tonic seizures are generally intractable in paediatric epilepsy, zonisamide resulted in ≥50% reduction in seizure frequency in 46% of treated children with generalized tonic seizures. Additional independent studies have also examined the efficacy of zonisamide as adjunctive therapy or monotherapy in paediatric patients. Four open-label trials, reviewed by Glauser and Pellock (2002), assessed
Fig. 3. The efficacy of zonisamide by seizure type in 928 children receiving zonisamide for 1–3 years in a post-marketing surveillance prospective study (Iinuma and Haginoya, 2004).
adjunctive therapy at doses of 0.7–18.6 mg/kg/day (one study, 40–600 mg/day; Kanazawa et al., 1987) in young patients with mean age 10–25 years (Kanazawa et al., 1987; Takahashi et al., 1987; Oguni et al., 1989) or an age range of 0.75–26 years (Tagawa et al., 1988). These studies showed that 22–44% of patients refractory to existing AEDs experienced ≥50% reduction in partial seizure frequency on introduction of zonisamide; pooled data indicated 34% (47/137) of patients were responders to treatment (Table 2). Data available in three of these studies (Takahashi et al., 1987; Tagawa et al., 1988; Oguni et al., 1989) indicated that up to 18% of children with refractory generalised seizures also responded to adjunctive zonisamide treatment (overall responder rate 15%; 8/54 patients). Consistent with the findings in the PMS-prospective study (see Section 3.2.1), additional open-label studies suggest high responder rates can be attained with zonisamide monotherapy for the treatment of partialor generalised-onset seizures in children. Furthermore, zonisamide monotherapy appears to be efficacious in treating seizures refractory to previous AEDs, in addition to providing benefit in newly diagnosed epilepsy. Five open-label studies evaluated zonisamide alone (1–12 mg/kg/day) in the treatment of newly diagnosed or refractory epilepsy in children aged ≤18 years (Shuto et al., 1989; Kumagai et al., 1991; Hayakawa et al., 1994; for review see Glauser and Pellock, 2002; Miura, 2004; Seki et al., 2004). The results from these
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Table 2 Summary of zonisamide studies examining efficacy in Japanese children with partial- or generalised-onset seizures Study reference
Adjunctive therapy Kanazawa et al. (1987) Takahashi et al. (1987) Tagawa et al. (1988) Oguni et al. (1989)
Patient type
Refractory Refractory Refractory Refractory
Mean age (range), years
Zonisamide dose (mg/kg/day)
Responder rate, % (n/N) Partial seizures
Generalised seizures
24.6 (5–48) 10.0 (2–18) NR (0.75–26) 13.2 (2.6–22.5)
400–600a 2–10 0.7–18.6 2–8
36 (12/33) 22 (6/27) 44 (21/48) 28 (8/29)
NA 9 (1/12) 18 (5/30) 17 (2/12)
34 (47/137)
15 (8/54)
44 (11/25) 79 (57/72) 97 (31/32)c 92 (44/48) 66 (21/32)
NA NA 50 (7/14)c 90 (18/20) 67 (10/15)
78 (164/209)
71 (35/49)
Total Monotherapy Shuto et al. (1989) Miura et al. (2004) Kumagai et al. (1991) Seki et al. (2004) Hayakawa
Refractory Newly diagnosed Mixedb Mixedb Newly diagnosed
9.4 (3–18) 8.2 (0.2–15) 8.4 (0.7–15) 8.3 (0.7–15) NR (≤15)
Total a b c
2–10 2–8 2–12 1–12 2–10
Dosage was reported in mg/day. Newly diagnosed and refractory. Some patients experienced both partial and generalised seizures; NA, not applicable; NR, not reported.
studies are summarised in Table 2. Responder rate for partial seizures in these five studies ranged from 44 to 97%, with 78% (164/209) children overall attaining ≥50% reduction in partial seizure frequency with zonisamide monotherapy. Data from three of these studies demonstrated that zonisamide monotherapy was also highly efficacious in treating generalised-onset seizures. Responder rates of 50–90% were reported among children receiving zonisamide monotherapy for refractory or newly diagnosed generalised seizures (Kumagai et al., 1991; Hayakawa et al., 1994; Seki et al., 2004), with pooled analysis indicating 71% (35/49) of children attained ≥50% reduction in the frequency of generalised seizures (Glauser and Pellock, 2002). 4.1. Specific epilepsy syndromes Observations made in a pooled analysis of open-label and controlled trials conducted prior to registration in Japan (see Section 3.1) indicated that zonisamide is efficacious in the treatment of specific types of malignant paediatric epilepsy syndrome, including Lennox-Gastaut Syndrome and West Syndrome (Yagi and Seino, 1992). Independent studies have confirmed excellent efficacy of zonisamide in the treatment of these syndromes and of Ohtahara Syndrome in Japanese children.
4.1.1. Lennox-Gastaut Syndrome In a pooled analysis of data from registration studies in Japan, 32% of individuals with Lennox-Gastaut Syndrome (42/132) responded to zonisamide treatment with a reduction of ≥50% in total seizure frequency (Yagi and Seino, 1992). Comparable efficacy in treating the severe, often refractory seizures of this syndrome has been reported in three independent studies in Japan evaluating a total of 77 children with LennoxGastaut Syndrome. Responder rates in these three studies were 26, 50 and 54% following zonisamide treatment (Sakamoto et al., 1986; Yamatogi and Ohtahara, 1991; Iinuma and Haginoya, 2004); pooled analysis of these studies indicated that 35% (27/77) of patients attain at least a 50% reduction in seizure frequency following zonisamide treatment. A more detailed analysis of the study conducted at the author’s centre has indicated that zonisamide is a highly efficacious treatment for some children with Lennox-Gastaut Syndrome (Yamatogi and Ohtahara, 1991). Among the 10/20 children who were responders to zonisamide treatment, seizures were markedly improved in two cases (10% of study population). In addition, complete cessation of seizures after introduction of zonisamide was achieved in three patients (15% of study population). An increase in seizure frequency was observed in only one case in this study. These
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data suggest that the broad efficacy of zonisamide can provide considerable benefit in controlling the multiple seizure types occurring in this severe form of epilepsy. 4.1.2. West Syndrome Efficacy of zonisamide in the treatment of West Syndrome has been demonstrated in pre-registration studies (Yagi and Seino, 1992) and six independent studies in Japan. Case reports on three infants with hypsarrhythmia and/or tonic spasms showed zonisamide treatment resulted in cessation of spasms and disappearance of hypsarrhythmia in each child (Kishi et al., 2000). Three other studies (n = 9–27) have described a similar response to zonisamide in 33–38% of treated infants (Hikima et al., 1993; Yanagihara et al., 1995; Yanai et al., 1999). In addition, zonisamide monotherapy has been demonstrated to be effective in 20–25% of infants evaluated in two further studies involving 54 and 16 children (Kawawaki et al., 1999; Suzuki, 2001). A total of 122 cases have been evaluated in these six studies, of which 35 children (29%) responded to zonisamide with cessation of spasms and disappearance of hypsarrhythmia. Furthermore, no serious adverse events occurred with the use of zonisamide in these infants, which contrasts with the side effects associated with ACTH treatment. In one study, the short- and long-term efficacy of zonisamide in West Syndrome was examined in detail (Suzuki, 2001). In the evaluation of short-term efficacy, 54 infants (mean age of seizure onset 6.9 months) who were intractable to high-dose Vitamin B6 were treated with zonisamide monotherapy. (Other than zonisamide, Vitamin B6 is the most commonly used agent for treating infantile spasms in Japan, in the absence of other AEDs indicated for this condition.) Zonisamide was started at doses of 3–4 mg/kg/day and titrated upward every fourth day until seizures stopped or maximal dose (10–13 mg/kg/day) was reached. Overall, 20.3% (11/54) infants experienced a response to therapy defined as cessation of spasms and disappearance of hypsarrhythmia. Cryptogenic patients showed a better response than symptomatic patients; 4 (28.5%) of 14 patients with cryptogenic West Syndrome responded compared with 7 (17.5%) of 40 symptomatic patients. Spasms ceased for most responders within 2 weeks of commencing treatment, and with a mean zonisamide dose of 7.2 mg/kg/day (range 4–12 mg/kg/day).
The 11 infants responding to zonisamide in the short-term study continued to receive zonisamide (at the dose taken at cessation of spasms) for 24–79 months and seizure recurrence and long-term psychomotor development were monitored. Throughout this period, seven (64%; four cryptogenic and three symptomatic cases) of the 11 patients remained seizure free with zonisamide monotherapy. Of the remaining patients (all symptomatic), three experienced relapses of spasms within 4–10 weeks and one patient developed complex partial seizures 4 years after the initial suppression of seizures. Sustained seizure freedom was associated with a more favourable long-term developmental prognosis. Five (four cryptogenic, one symptomatic) of the seven patients remaining seizure free had a developmental quotient (DQ) >70. However, of the four cases relapsing, DQ was 30–70 in the child developing complex partial seizures and was <30 in the three cases suffering seizure relapses. Although requiring confirmation in further studies, these data suggest zonisamide can provide long-term seizure-freedom and improved developmental outcome for infants with West Syndrome. 4.1.3. Ohtahara Syndrome Ohtahara Syndrome (early infantile epileptic encephalopathy with suppression-bursts) is the most intractable type of malignant paediatric epilepsy syndrome. Diagnosis is made from age of seizure onset, the different seizure types experienced and the suppression burst pattern on ECG. Babies experience multiple seizure types and the efficacy of high-dose Vitamin B6, ACTH and other AEDs is limited. Four case reports have indicated that zonisamide is effective in suppressing the seizures of Ohtahara Syndrome (Ohno et al., 2000; Yamatogi and Ohtahara, 2002). At the author’s centre, Ohtahara Syndrome has been treated with zonisamide in three cases, and complete seizure suppression has been observed (Yamatogi and Ohtahara, 2002). For example, a newborn child experienced frequent tonic spasms and complex partial seizures from age 9 days, with suppression-bursts noted in waking and sleeping EEG records. Commencing zonisamide treatment (20 mg/day) from age 26 days resulted in disappearance of seizures at age 1 month 22 days. An EEG record obtained 1 week later indicated disappearance of the suppression-burst pattern.
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At age 7 months, this child remained seizure free although considerable psychomotor retardation, with social smile but incomplete head control, was observed. Similar dose-dependent efficacy of zonisamide has been reported for the control of partial seizures and tonic spasms in a separate case study of an infant with Ohtahara Syndrome (Ohno et al., 2000). These encouraging results from case studies suggest that further trials of zonisamide in the control of this highly intractable syndrome are merited.
5. Safety and tolerability Extensive clinical experience with zonisamide has provided a well-defined safety profile. In the PMSprospective study, a low incidence of adverse events (31.5%) was reported by patients receiving zonisamide for up to 3 years (Ohtahara and Yamatogi, 2004). In common with other AEDs, central nervous system (CNS)-related adverse events were reported most commonly (19.4% of cases), followed by gastrointestinal (8.7%), neurological (5.8%) and general condition events (5.3%). The CNS-related events reported most frequently were sleepiness (16.3% of cases), decreased spontaneity (7.7%) and irritability (2.3%). Other adverse events, including sleep disturbance, depression and amnesia, were reported by fewer than 1% of patients. The incidence of adverse events was considerably lower in paediatric patients (26%) compared with adults (40%), following either adjunctive zonisamide (polytherapy) or monotherapy. In both the paediatric and adult population, the incidence of adverse events was also lower in patients receiving zonisamide monotherapy compared with polytherapy. Overall, these data indicate that zonisamide was well-tolerated in all patient populations evaluated during PMS. 5.1. Specific adverse events Kidney stones are a rare adverse event reported following administration of zonisamide, occurring in 0.2% of 1008 patients evaluated in registration trials and in only 0.06% of patients included in PMS pooled data in Japan. This incidence is lower than reported in pooled data from US and European studies (1.4–4.0%; Eisai Ltd., data on file); the reason for this difference is
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unclear, but may reflect genetic and dietary differences between eastern and western populations. In addition, the majority of cases in the US and European trials were asymptomatic and identified only on sonographic evidence from screening incorporated into the study designs. Oligohidrosis has been reported rarely in Japanese studies (incidence 0.1–0.9% in pooled data from registration studies and PMS-prospective study) and appears to be confined to young children and infants, especially, based on personal experience, severely handicapped children. The incidence of oligohidrosis may therefore be higher in some paediatric populations. It also appears to be particularly associated with hot climates, and patients should be monitored accordingly. Adverse events affecting the CNS are common to all AEDs and have potential to influence schooling and social lives of treated patients. Sleepiness, sleep disturbance, depression and amnesia have been reported by a small number of zonisamide-treated patients, and continued monitoring for these events and any influence on the individual’s daily functioning, may be useful for some patients. 5.2. Teratogenicity At present, information regarding the use of zonisamide during pregnancy is limited. Experience with zonisamide during the pre- and post-marketing period in Japan includes 25 cases of birth and pregnancy in women participating in registration studies or the PMSprospective study (Dainippon, data on file). Among six women receiving zonisamide monotherapy during pregnancy, there were no reports of foetal malformation. The remaining 19 female patients received polytherapy including zonisamide, and there were two cases of malformation. Malformation of the cerebrum and cerebellum with a skull defect occurred in one foetus from a woman treated with phenytoin and zonisamide, and the other case reported was atrial septal defect in a child born to a woman treated with phenytoin, carbamazepine and zonisamide. A further report (June 2001; Dainippon, data on file) describes the birth of a baby with ventricular septal defect to a woman receiving zonisamide monotherapy during pregnancy. As available information is limited, current guidelines recommend that administration of zonisamide to pregnant women, or women suspected of being pregnant,
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should occur only if the therapeutic benefits are considered to outweigh any possible risk to the foetus.
6. Conclusions Extensive use of zonisamide in Japan, as reported in post-marketing surveys and a number of diverse openlabel and controlled trials, has indicated it to be a potent AED with a broad-spectrum of efficacy in the control of partial and generalised epilepsies in adults and children. In addition to providing benefit as adjunctive therapy, zonisamide monotherapy has been shown to be efficacious for a wide range of seizure types in patients refractory to other AEDs and in newly diagnosed individuals. Moreover, zonisamide appears to be a useful treatment option for paediatric epilepsy syndromes that are commonly intractable to other interventions, including Lennox-Gastaut Syndrome, West Syndrome and Ohtahara Syndrome. Zonisamide is well-tolerated with a low incidence of mild-moderate adverse events reported, particularly in paediatric cases and in patients receiving zonisamide monotherapy, based both on the author’s experience and findings reported as pooled data from open-label and controlled trials. In the author’s opinion, clinical experience in Japan indicates that zonisamide is a valuable approach to the treatment of epilepsy in a broad range of patients.
References Glauser, T.A., Pellock, J.M., 2002. Zonisamide in paediatric epilepsy: review of the Japanese experience. J. Child. Neurol. 17, 87–96. Hayakawa, T., Nejihashi, Y., Kishi, T., Kajiyama, M., 1994. Serum zonisamide concentration in fresh cases of childhood epilepsy following zonisamide monotherapy. J. Jpn. Epilepsy Soc. 12, 249–254 (in Japanese). Hikima, A., Shimizu, N., Takizawa, N., 1993. Treatment of West syndrome with zonisamide: 13 case reports. No To Hattatsu 25 (Suppl.), 132 (in Japanese). Iinuma, K., Haginoya, K., 2004. Clinical efficacy of zonisamide in childhood epilepsy after long-term treatment: a postmarketing, multi-institutional survey. Seizure 13 (Suppl. 1), 34–39 (discussion 40). Kanazawa, K., Segoku, A., Kawai, I., 1987. A clinical trial of zonisamide, a new antiepileptic drug, on adults and children with refractory epilepsy. J. Clin. Therapeut. Med. 3, 1181–1186 (in Japanese).
Kawawaki, H., Tomiwa, K., Shiraishi, K., Murata, R., 1999. Efficacy of zonisamide in West syndrome. No To Hattatsu 31, 263–267 (in Japanese). Kishi, T., Nejihashi, Y., Kajiyama, M., Ueda, K., 2000. Successful zonisamide treatment for infants with hypsarrhythmia. Pediatr. Neurol. 23, 274–277. Kumagai, N., Seki, T., Yamawaki, H., Suzuki, N., Kimiya, S., Yamada, T., Hara, M., Hashimoto, R., Takuma, Y., Hirai, K., 1991. Monotherapy for childhood epilepsies with zonisamide. Jpn. J. Psychiatry Neurol. 45, 357–359. Miura, H., 2004. Zonisamide monotherapy with once-daily dosing in children with cryptogenic localization-related epilepsies: clinical effects and pharmacokinetic studies. Seizure 13 (Suppl. 1), 17–23 (discussion 24–25). Oguni, H., Hayakawa, T., Fukuyama, Y., 1989. Clinical trial of zonisamide, a new antiepileptic drug, in cases of refractory childhood epilepsy. J. Jpn. Epilepsy Soc. 7, 43–50 (in Japanese). Ohno, M., Shimotsuji, Y., Abe, J., Shimada, M., Tamiya, H., 2000. Zonisamide treatment of early infantile epileptic encephalopathy. Pediatr. Neurol. 23, 341–344. Ohtahara, S., Yamatogi, Y., 2004. Safety of zonisamide therapy: prospective follow-up survey. Seizure 13 (Suppl. 1), 50–55 (discussion 56). Sakamoto, K., Kurokawa, S., Tomita, S., Chen, A., Kitamoto, I., Ueda, H., Hanai, T., Narazaki, O., Maeda, Y., 1986. Therapeutic effects of zonisamide (AD-810) on infantile epilepsy. Med. Consult New Remedies 23, 2571–2581. Seki, T., Kumagai, N., Maezawa, M., 2004. Effects of zonisamide monotherapy in children with epilepsy. Seizure 13 (Suppl. 1), 26–32 (discussion 33). Shuto, H., Sugimoto, T., Yasuhara, A., Hatanaka, T., Woo, M., Murakami, K., Araki, A., Kobayashi, Y., 1989. Efficacy of zonisamide in children with refractory partial seizures. Curr. Ther. Res. 45, 1031–1036. Suzuki, Y., 2001. Zonisamide in West syndrome. Brain Dev. 23, 658–661. Tagawa, T., Mimaki, T., Shuto, H., Sugimoto, T., Matsuoka, O., Murata, R., Issiki, G., Kobayashi, Y., Yabuuchi, H., 1988. Treatment of childhood epilepsies with zonisamide (AD-810), efficacy and blood concentration. J. Pediatr. Pract. 51, 539–543 (in Japanese). Takahashi, I., Yamamoto, N., Furune, S., Aso, K., Takaesu, E., Negoro, T., Watanabe, K., Matsumoto, A., Takeuchi, T., Hakamada, S., Hayakawa, F., Maehara, M., 1987. Efficacy of zonisamide for intractable epilepsy in childhood. J. Jpn. Epilepsy Soc. 5, 100–105 (in Japanese). Yagi, K., 2004. Overview of Japanese experience-controlled and uncontrolled trials. Seizure 13 (Suppl. 1), 11–15 (discussion 16). Yagi, K., Seino, M., 1992. Methodological requirements for clinical trials in refractory epilepsies - our experience with zonisamide. Prog. Neuropsychopharmacol. Biol. Psychiatry 16, 79–85. Yamatogi, Y., Ohtahara, S., 1991. Current topics on treatment. In: Ohtahara, S., Roger, J. (Eds.), New Trends in Pediatric Epileptology. Okayama University Medical School, pp. 136– 148.
S. Ohtahara / Epilepsy Research 68S (2006) S25–S33 Yamatogi, Y., Ohtahara, S., 2002. Early-infantile epileptic encephalopathy with suppression-bursts, Ohtahara syndrome; its overview referring to our 16 cases. Brain Dev. 24, 13–23. Yamauchi, T., Aikawa, H., 2004. Efficacy of zonisamide: our experience. Seizure 13 (Suppl. 1), 41–48 (discussion 49).
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Yanagihara, K., Imai, K., Otani, K., Futagi, Y., 1995. The effect of zonisamide in West syndrome. No To Hattatsu 27, 500–502 (in Japanese). Yanai, S., Hanai, T., Narazaki, O., 1999. Treatment of infantile spasms with zonisamide. Brain Dev. 21, 157–161.
Zonisamide in the management of epilepsy—Japanese experience Shunsuke Ohtahara ∗ Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho 2-5-1, Okayama, Japan Received 22 September 2005; received in revised form 4 November 2005; accepted 4 November 2005 Available online 29 November 2005
Abstract Zonisamide (Zonegran® ), a novel antiepileptic drug (AED) approved in Europe for the adjunctive treatment of refractory partial seizures in adults, has undergone extensive evaluation in pre- and post-marketing double-blind and open-label studies in Japan (where zonisamide is used widely to treat partial and generalised seizures in adults and children). These data indicate that the clinical benefit of zonisamide extends across a range of seizure types and patient ages. In an analysis based on a mixture of controlled and open studies in adults and children with partial seizures, 51–57% responded to zonisamide treatment (achieving ≥50% reduction in baseline seizure frequency). Efficacy extends across a range of generalised seizures and 22–66% of adults and children experiencing tonic–clonic, tonic, clonic, myoclonic or absence seizures responded to treatment. Even greater responder rates have been reported when zonisamide was used as monotherapy for partial seizures and generalised seizures in patients refractory to other AEDs or with newly diagnosed epilepsy. Zonisamide is also efficacious in paediatric epilepsy syndromes, including Lennox-Gastaut Syndrome, West Syndrome and Ohtahara Syndrome. Across the spectrum of epilepsy syndromes studied, zonisamide is well-tolerated with a low incidence of adverse events, which are generally mild and CNS-related. These data indicate that zonisamide represents a valuable broad-spectrum option for the treatment of epilepsy. © 2005 Elsevier B.V. All rights reserved. Keywords: Broad-spectrum; Generalised seizures; Partial seizures; Paediatric epilepsy; Zonisamide
1. Introduction The introduction of Zonegran® (zonisamide) in Europe offers a new approach to the treatment of epilepsy. Zonisamide has been shown in randomised controlled trials to provide highly effective control of partial seizures, and offers a number of additional ∗
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favourable properties including good tolerability, a long plasma half-life and limited potential for interaction with other drugs (see Baulac, this issue; Brodie, this issue). Zonisamide is currently indicated in Europe for the adjunctive therapy of refractory partial seizures in adults. Evidence from extensive clinical use of zonisamide in Japan, where it has been used widely for more than 15 years, indicates that zonisamide’s efficacy extends across a broad range of epilepsy indications in
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both adult and paediatric patients. Results from trials conducted prior to registration, post-marketing surveillance studies and independent reports in Japan indicate that zonisamide is efficacious in treating partial- and generalised-onset seizures and is beneficial in treating some epilepsy syndromes. This paper reviews these data briefly, and discusses the value of zonisamide as a treatment option for a broad range of patients with epilepsy.
2. Prescribing zonisamide in Japan Zonisamide is currently licensed in Japan as monotherapy or adjunctive therapy for a broad range of seizures in adults and children (age ≥1 year). Zonisamide is indicated for partial seizures (simple partial, complex partial and secondary generalised) and some types of generalised seizures, such as tonic–clonic, tonic and atypical absence seizures. This licence contrasts with the much more specific labels for zonisamide in the US and Europe. In the US, zonisamide is indicated as adjunctive therapy for the treatment of partial seizures in adults aged over 16 years. The European regulatory agency has recently approved zonisamide as adjunctive therapy for partial seizures with or without secondary generalisation in adults aged ≥18 years. The introduction of new generation antiepileptic drugs (AEDs) in Japan has been slow in recent years. Zonisamide is currently regarded as a first-line AED for all types of partial seizures. Zonisamide or carbamazepine are favoured over phenytoin, clobazam, valproate or phenobarbital for simple partial and complex partial seizures. Zonisamide is also considered as a first-line AED for generalised tonic–clonic seizures, and a first- or second-line drug after valproate for treating other types of generalised seizures including tonic, myoclonic and atonic or astatic seizures. Zonisamide is also used for typical and atypical absence seizures refractory to valproate and ethosuximide, and for spasms (West Syndrome) following unsuccessful intervention with high-dose Vitamin B6, adrenocorticotropic hormone (ACTH) and valproate. Overall, zonisamide represents approximately 12% of the Japanese AED market. Other agents used include carbamazepine, sodium valproate, phenytoin, clobazam, phenobarbital and ethosuximide.
3. Clinical efficacy Zonisamide has been the subject of extensive efficacy evaluation during development and marketing in Japan, and two pooled analyses of available data have been performed. One set comprises data from patients recruited to pre-registration trials during clinical development, and the second includes patients recruited to a post-marketing surveillance-prospective study (PMS-prospective study). Although many of these studies have not been published individually, proceedings and other publications have provided a considerable body of data from these studies, which are reviewed here. Overall, these datasets have indicated that zonisamide provides highly effective control of both partial seizures and generalised seizures in adults and children. 3.1. Registration studies Pooled data have been obtained for 1008 patients, including 403 children, recruited in registration studies (including Phase II and III trials, both controlled and open-label) during development (Yagi and Seino, 1992). Of this total, there were 673 cases of partial epilepsy and 286 cases of generalised epilepsy. The majority of individuals received polytherapy including zonisamide, although 55 patients received zonisamide monotherapy. Mean daily doses of zonisamide ranged from 5.9 mg/kg/day (range 1.1–17.7) in patients aged ≥16 years to 8.8 mg/kg/day (range 0.8–30.4) in young children aged 2–6 years. Infants (age ≤1 year) received a mean daily dose of 8.6 mg/kg/day (2.8–21.4) and older children and adolescents (7–15 years) received 7.1 mg/kg/day (0.7–20.2). In these pre-registration trials, 51–57% of patients with partial epilepsy responded to zonisamide treatment (≥50% reduction in baseline seizure frequency) (Yagi and Seino, 1992) (Fig. 1). Zonisamide was also efficacious in the treatment of generalised seizures; 66% of patients with idiopathic generalised epilepsy and 47% of those with symptomatic generalised epilepsy responded to zonisamide treatment. Efficacy was also attained in the treatment of LennoxGastaut Syndrome (responder rate 32%) and 2/9 (22%) patients with West Syndrome (Yagi and Seino, 1992).
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Fig. 1. Efficacy of zonisamide by seizure type in adults and children (n = 1008) in pre-registration trials (Yagi and Seino, 1992).
3.2. Post-marketing surveillance study The PMS-prospective study in Japan assessed the long-term efficacy of open-label zonisamide treatment in 1631 patients (Yamauchi and Aikawa, 2004) and safety in 1512 patients including 928 children (Ohtahara and Yamatogi, 2004; Iinuma and Haginoya, 2004), treated for between 1 and 3 years for partial epilepsy (n = 1044) or generalised epilepsy (n = 458). In contrast to the registration studies, approximately one-third of individuals (n = 424) received zonisamide only. The daily dose of zonisamide in children ranged widely, from 0.2–29 mg/kg/day, but most patients (70%) received 2–8 mg/kg/day. Adult daily doses also ranged widely (12.5–900 mg/day) with the majority of patients (77%) given zonisamide 100–400 mg/day, consistent with the recommendations in the European and US licences. Most patients in the Japanese PMSprospective study had been treated with other AEDs at the introduction of zonisamide therapy. However, 25% of patients were newly diagnosed and were prescribed zonisamide alone. Efficacy of zonisamide, assessed as a reduction in baseline seizure frequency of ≥50%, was observed over a broad range of seizure types (Fig. 2) (Yamauchi and Aikawa, 2004). Overall, 70% of patients with partial epilepsy attained at least a 50% reduction in seizure frequency. Moreover, approximately 50% of these patients became seizure free with zonisamide treatment. Excellent efficacy was also observed in patients with generalised epilepsy, particularly in the control of tonic–clonic, clonic and typical absence seizures (responder rate 68, 75 and 87.5%, respectively). These data indicate that zonisamide is highly
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Fig. 2. The efficacy of zonisamide by seizure type in 1631 adults and children receiving zonisamide for 1–3 years in a post-marketing surveillance prospective study (Yamauchi and Aikawa, 2004). The dotted line indicates median response achieved according to seizure type; n values refer to the number of patients with a particular seizure type and evaluable for efficacy at the time of the survey; values within the figure refer to the responder rate for that type of seizure (% of patients achieving ≥50% reduction in seizure frequency); an additional 30 patients had other types of seizures, of whom 43.3% were responders (data not shown).
efficacious across a broad spectrum of seizure types in adults and children. 3.2.1. Zonisamide monotherapy Comparison of responder rates determined in the PMS-prospective study indicated that zonisamide is more effective when administered as monotherapy than as polytherapy (Yamauchi and Aikawa, 2004). Overall, responder rates (patients with ≥50% reduction in seizure frequency) were 92.6% amongst patients receiving monotherapy (365/394 patients), compared to 57.8% amongst those receiving polytherapy (703/1216 patients) (P < 0.01). This pattern of superior results for monotherapy was seen both for partial seizures (responder rates 92.9% versus 61.8%) and generalised seizures (91.2% versus 48.6%). It is possible that patients with less severe epileptic disorders could have been enrolled to the monotherapy treatment group and could account for the higher responder rates among these individuals. Nevertheless these data suggest that zonisamide monotherapy may provide substantial benefit for many patients presenting in routine clinical practice. Zonisamide monotherapy was also observed to be highly efficacious in a variety of seizures in 726 patients with newly diagnosed epilepsy during a PMS drug-use investigation (Yagi, 2004) (Table 1). Responder rates in excess of 80% were obtained in
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Table 1 Efficacy of zonisamide monotherapy by seizure type in 726 patients with newly diagnosed epilepsy Seizure type Partial seizures Simple partial Complex partial Partial-onset generalised tonic–clonic Generalised seizures Tonic–clonic Tonic Absence Myoclonic Atonic
Number of patients
Responder rate (%)
128 179 149
82 80 82
257 54 34 6 1
93 93 85 83 0
Responder rate = % patients attaining ≥50% reduction in baseline seizure frequency. Data from post-marketing surveillance drug use investigation (Yagi, 2004).
patients with partial, tonic–clonic, tonic, absence or myoclonic seizures. However, it is not clear whether the patients included in this study overlap with those in the PMS study described by Yamauchi and Aikawa (2004).
4. Efficacy in paediatric patients The efficacy of zonisamide in paediatric patients with epilepsy has been studied widely in Japan. Data from the PMS-prospective study, which included 928 children receiving zonisamide as an adjunct or as monotherapy, were analysed further for 729 children with a range of seizure types, treated with zonisamide at doses ranging from 2 to over 10 mg/kg/day (most receiving 2–8 mg/kg/day) (Iinuma and Haginoya, 2004). Responder rates were 75–79% in children experiencing partial seizures (Fig. 3). Zonisamide was also efficacious in children with generalised seizures (Fig. 3), with responder rates of 37–75% observed in generalised tonic–clonic and typical absence seizures. Interestingly, although generalised tonic seizures are generally intractable in paediatric epilepsy, zonisamide resulted in ≥50% reduction in seizure frequency in 46% of treated children with generalized tonic seizures. Additional independent studies have also examined the efficacy of zonisamide as adjunctive therapy or monotherapy in paediatric patients. Four open-label trials, reviewed by Glauser and Pellock (2002), assessed
Fig. 3. The efficacy of zonisamide by seizure type in 928 children receiving zonisamide for 1–3 years in a post-marketing surveillance prospective study (Iinuma and Haginoya, 2004).
adjunctive therapy at doses of 0.7–18.6 mg/kg/day (one study, 40–600 mg/day; Kanazawa et al., 1987) in young patients with mean age 10–25 years (Kanazawa et al., 1987; Takahashi et al., 1987; Oguni et al., 1989) or an age range of 0.75–26 years (Tagawa et al., 1988). These studies showed that 22–44% of patients refractory to existing AEDs experienced ≥50% reduction in partial seizure frequency on introduction of zonisamide; pooled data indicated 34% (47/137) of patients were responders to treatment (Table 2). Data available in three of these studies (Takahashi et al., 1987; Tagawa et al., 1988; Oguni et al., 1989) indicated that up to 18% of children with refractory generalised seizures also responded to adjunctive zonisamide treatment (overall responder rate 15%; 8/54 patients). Consistent with the findings in the PMS-prospective study (see Section 3.2.1), additional open-label studies suggest high responder rates can be attained with zonisamide monotherapy for the treatment of partialor generalised-onset seizures in children. Furthermore, zonisamide monotherapy appears to be efficacious in treating seizures refractory to previous AEDs, in addition to providing benefit in newly diagnosed epilepsy. Five open-label studies evaluated zonisamide alone (1–12 mg/kg/day) in the treatment of newly diagnosed or refractory epilepsy in children aged ≤18 years (Shuto et al., 1989; Kumagai et al., 1991; Hayakawa et al., 1994; for review see Glauser and Pellock, 2002; Miura, 2004; Seki et al., 2004). The results from these
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Table 2 Summary of zonisamide studies examining efficacy in Japanese children with partial- or generalised-onset seizures Study reference
Adjunctive therapy Kanazawa et al. (1987) Takahashi et al. (1987) Tagawa et al. (1988) Oguni et al. (1989)
Patient type
Refractory Refractory Refractory Refractory
Mean age (range), years
Zonisamide dose (mg/kg/day)
Responder rate, % (n/N) Partial seizures
Generalised seizures
24.6 (5–48) 10.0 (2–18) NR (0.75–26) 13.2 (2.6–22.5)
400–600a 2–10 0.7–18.6 2–8
36 (12/33) 22 (6/27) 44 (21/48) 28 (8/29)
NA 9 (1/12) 18 (5/30) 17 (2/12)
34 (47/137)
15 (8/54)
44 (11/25) 79 (57/72) 97 (31/32)c 92 (44/48) 66 (21/32)
NA NA 50 (7/14)c 90 (18/20) 67 (10/15)
78 (164/209)
71 (35/49)
Total Monotherapy Shuto et al. (1989) Miura et al. (2004) Kumagai et al. (1991) Seki et al. (2004) Hayakawa
Refractory Newly diagnosed Mixedb Mixedb Newly diagnosed
9.4 (3–18) 8.2 (0.2–15) 8.4 (0.7–15) 8.3 (0.7–15) NR (≤15)
Total a b c
2–10 2–8 2–12 1–12 2–10
Dosage was reported in mg/day. Newly diagnosed and refractory. Some patients experienced both partial and generalised seizures; NA, not applicable; NR, not reported.
studies are summarised in Table 2. Responder rate for partial seizures in these five studies ranged from 44 to 97%, with 78% (164/209) children overall attaining ≥50% reduction in partial seizure frequency with zonisamide monotherapy. Data from three of these studies demonstrated that zonisamide monotherapy was also highly efficacious in treating generalised-onset seizures. Responder rates of 50–90% were reported among children receiving zonisamide monotherapy for refractory or newly diagnosed generalised seizures (Kumagai et al., 1991; Hayakawa et al., 1994; Seki et al., 2004), with pooled analysis indicating 71% (35/49) of children attained ≥50% reduction in the frequency of generalised seizures (Glauser and Pellock, 2002). 4.1. Specific epilepsy syndromes Observations made in a pooled analysis of open-label and controlled trials conducted prior to registration in Japan (see Section 3.1) indicated that zonisamide is efficacious in the treatment of specific types of malignant paediatric epilepsy syndrome, including Lennox-Gastaut Syndrome and West Syndrome (Yagi and Seino, 1992). Independent studies have confirmed excellent efficacy of zonisamide in the treatment of these syndromes and of Ohtahara Syndrome in Japanese children.
4.1.1. Lennox-Gastaut Syndrome In a pooled analysis of data from registration studies in Japan, 32% of individuals with Lennox-Gastaut Syndrome (42/132) responded to zonisamide treatment with a reduction of ≥50% in total seizure frequency (Yagi and Seino, 1992). Comparable efficacy in treating the severe, often refractory seizures of this syndrome has been reported in three independent studies in Japan evaluating a total of 77 children with LennoxGastaut Syndrome. Responder rates in these three studies were 26, 50 and 54% following zonisamide treatment (Sakamoto et al., 1986; Yamatogi and Ohtahara, 1991; Iinuma and Haginoya, 2004); pooled analysis of these studies indicated that 35% (27/77) of patients attain at least a 50% reduction in seizure frequency following zonisamide treatment. A more detailed analysis of the study conducted at the author’s centre has indicated that zonisamide is a highly efficacious treatment for some children with Lennox-Gastaut Syndrome (Yamatogi and Ohtahara, 1991). Among the 10/20 children who were responders to zonisamide treatment, seizures were markedly improved in two cases (10% of study population). In addition, complete cessation of seizures after introduction of zonisamide was achieved in three patients (15% of study population). An increase in seizure frequency was observed in only one case in this study. These
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data suggest that the broad efficacy of zonisamide can provide considerable benefit in controlling the multiple seizure types occurring in this severe form of epilepsy. 4.1.2. West Syndrome Efficacy of zonisamide in the treatment of West Syndrome has been demonstrated in pre-registration studies (Yagi and Seino, 1992) and six independent studies in Japan. Case reports on three infants with hypsarrhythmia and/or tonic spasms showed zonisamide treatment resulted in cessation of spasms and disappearance of hypsarrhythmia in each child (Kishi et al., 2000). Three other studies (n = 9–27) have described a similar response to zonisamide in 33–38% of treated infants (Hikima et al., 1993; Yanagihara et al., 1995; Yanai et al., 1999). In addition, zonisamide monotherapy has been demonstrated to be effective in 20–25% of infants evaluated in two further studies involving 54 and 16 children (Kawawaki et al., 1999; Suzuki, 2001). A total of 122 cases have been evaluated in these six studies, of which 35 children (29%) responded to zonisamide with cessation of spasms and disappearance of hypsarrhythmia. Furthermore, no serious adverse events occurred with the use of zonisamide in these infants, which contrasts with the side effects associated with ACTH treatment. In one study, the short- and long-term efficacy of zonisamide in West Syndrome was examined in detail (Suzuki, 2001). In the evaluation of short-term efficacy, 54 infants (mean age of seizure onset 6.9 months) who were intractable to high-dose Vitamin B6 were treated with zonisamide monotherapy. (Other than zonisamide, Vitamin B6 is the most commonly used agent for treating infantile spasms in Japan, in the absence of other AEDs indicated for this condition.) Zonisamide was started at doses of 3–4 mg/kg/day and titrated upward every fourth day until seizures stopped or maximal dose (10–13 mg/kg/day) was reached. Overall, 20.3% (11/54) infants experienced a response to therapy defined as cessation of spasms and disappearance of hypsarrhythmia. Cryptogenic patients showed a better response than symptomatic patients; 4 (28.5%) of 14 patients with cryptogenic West Syndrome responded compared with 7 (17.5%) of 40 symptomatic patients. Spasms ceased for most responders within 2 weeks of commencing treatment, and with a mean zonisamide dose of 7.2 mg/kg/day (range 4–12 mg/kg/day).
The 11 infants responding to zonisamide in the short-term study continued to receive zonisamide (at the dose taken at cessation of spasms) for 24–79 months and seizure recurrence and long-term psychomotor development were monitored. Throughout this period, seven (64%; four cryptogenic and three symptomatic cases) of the 11 patients remained seizure free with zonisamide monotherapy. Of the remaining patients (all symptomatic), three experienced relapses of spasms within 4–10 weeks and one patient developed complex partial seizures 4 years after the initial suppression of seizures. Sustained seizure freedom was associated with a more favourable long-term developmental prognosis. Five (four cryptogenic, one symptomatic) of the seven patients remaining seizure free had a developmental quotient (DQ) >70. However, of the four cases relapsing, DQ was 30–70 in the child developing complex partial seizures and was <30 in the three cases suffering seizure relapses. Although requiring confirmation in further studies, these data suggest zonisamide can provide long-term seizure-freedom and improved developmental outcome for infants with West Syndrome. 4.1.3. Ohtahara Syndrome Ohtahara Syndrome (early infantile epileptic encephalopathy with suppression-bursts) is the most intractable type of malignant paediatric epilepsy syndrome. Diagnosis is made from age of seizure onset, the different seizure types experienced and the suppression burst pattern on ECG. Babies experience multiple seizure types and the efficacy of high-dose Vitamin B6, ACTH and other AEDs is limited. Four case reports have indicated that zonisamide is effective in suppressing the seizures of Ohtahara Syndrome (Ohno et al., 2000; Yamatogi and Ohtahara, 2002). At the author’s centre, Ohtahara Syndrome has been treated with zonisamide in three cases, and complete seizure suppression has been observed (Yamatogi and Ohtahara, 2002). For example, a newborn child experienced frequent tonic spasms and complex partial seizures from age 9 days, with suppression-bursts noted in waking and sleeping EEG records. Commencing zonisamide treatment (20 mg/day) from age 26 days resulted in disappearance of seizures at age 1 month 22 days. An EEG record obtained 1 week later indicated disappearance of the suppression-burst pattern.
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At age 7 months, this child remained seizure free although considerable psychomotor retardation, with social smile but incomplete head control, was observed. Similar dose-dependent efficacy of zonisamide has been reported for the control of partial seizures and tonic spasms in a separate case study of an infant with Ohtahara Syndrome (Ohno et al., 2000). These encouraging results from case studies suggest that further trials of zonisamide in the control of this highly intractable syndrome are merited.
5. Safety and tolerability Extensive clinical experience with zonisamide has provided a well-defined safety profile. In the PMSprospective study, a low incidence of adverse events (31.5%) was reported by patients receiving zonisamide for up to 3 years (Ohtahara and Yamatogi, 2004). In common with other AEDs, central nervous system (CNS)-related adverse events were reported most commonly (19.4% of cases), followed by gastrointestinal (8.7%), neurological (5.8%) and general condition events (5.3%). The CNS-related events reported most frequently were sleepiness (16.3% of cases), decreased spontaneity (7.7%) and irritability (2.3%). Other adverse events, including sleep disturbance, depression and amnesia, were reported by fewer than 1% of patients. The incidence of adverse events was considerably lower in paediatric patients (26%) compared with adults (40%), following either adjunctive zonisamide (polytherapy) or monotherapy. In both the paediatric and adult population, the incidence of adverse events was also lower in patients receiving zonisamide monotherapy compared with polytherapy. Overall, these data indicate that zonisamide was well-tolerated in all patient populations evaluated during PMS. 5.1. Specific adverse events Kidney stones are a rare adverse event reported following administration of zonisamide, occurring in 0.2% of 1008 patients evaluated in registration trials and in only 0.06% of patients included in PMS pooled data in Japan. This incidence is lower than reported in pooled data from US and European studies (1.4–4.0%; Eisai Ltd., data on file); the reason for this difference is
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unclear, but may reflect genetic and dietary differences between eastern and western populations. In addition, the majority of cases in the US and European trials were asymptomatic and identified only on sonographic evidence from screening incorporated into the study designs. Oligohidrosis has been reported rarely in Japanese studies (incidence 0.1–0.9% in pooled data from registration studies and PMS-prospective study) and appears to be confined to young children and infants, especially, based on personal experience, severely handicapped children. The incidence of oligohidrosis may therefore be higher in some paediatric populations. It also appears to be particularly associated with hot climates, and patients should be monitored accordingly. Adverse events affecting the CNS are common to all AEDs and have potential to influence schooling and social lives of treated patients. Sleepiness, sleep disturbance, depression and amnesia have been reported by a small number of zonisamide-treated patients, and continued monitoring for these events and any influence on the individual’s daily functioning, may be useful for some patients. 5.2. Teratogenicity At present, information regarding the use of zonisamide during pregnancy is limited. Experience with zonisamide during the pre- and post-marketing period in Japan includes 25 cases of birth and pregnancy in women participating in registration studies or the PMSprospective study (Dainippon, data on file). Among six women receiving zonisamide monotherapy during pregnancy, there were no reports of foetal malformation. The remaining 19 female patients received polytherapy including zonisamide, and there were two cases of malformation. Malformation of the cerebrum and cerebellum with a skull defect occurred in one foetus from a woman treated with phenytoin and zonisamide, and the other case reported was atrial septal defect in a child born to a woman treated with phenytoin, carbamazepine and zonisamide. A further report (June 2001; Dainippon, data on file) describes the birth of a baby with ventricular septal defect to a woman receiving zonisamide monotherapy during pregnancy. As available information is limited, current guidelines recommend that administration of zonisamide to pregnant women, or women suspected of being pregnant,
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should occur only if the therapeutic benefits are considered to outweigh any possible risk to the foetus.
6. Conclusions Extensive use of zonisamide in Japan, as reported in post-marketing surveys and a number of diverse openlabel and controlled trials, has indicated it to be a potent AED with a broad-spectrum of efficacy in the control of partial and generalised epilepsies in adults and children. In addition to providing benefit as adjunctive therapy, zonisamide monotherapy has been shown to be efficacious for a wide range of seizure types in patients refractory to other AEDs and in newly diagnosed individuals. Moreover, zonisamide appears to be a useful treatment option for paediatric epilepsy syndromes that are commonly intractable to other interventions, including Lennox-Gastaut Syndrome, West Syndrome and Ohtahara Syndrome. Zonisamide is well-tolerated with a low incidence of mild-moderate adverse events reported, particularly in paediatric cases and in patients receiving zonisamide monotherapy, based both on the author’s experience and findings reported as pooled data from open-label and controlled trials. In the author’s opinion, clinical experience in Japan indicates that zonisamide is a valuable approach to the treatment of epilepsy in a broad range of patients.
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