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Epilepsy & Behavior 8 (2006) 522–526

Long-term efficacy and safety of monotherapyand adjunctive therapy with zonisamide

William A. Tosches a,*, Jonathan Tisdell b

a Department of Neurology, University of Massachusetts, Hopedale, MA, USAb School of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

Received 27 October 2005; revised 30 January 2006; accepted 2 February 2006Available online 20 March 2006

Abstract

The long-term effects of zonisamide as monotherapy or adjunctive therapy were investigated in patients with seizure disorders. Onehundred twelve adult neurology patients treated with zonisamide were retrospectively identified through a chart review; 90 patients(n = 45 monotherapy, n = 45 adjunctive therapy) who received zonisamide for P3 months were included in the efficacy-evaluable pop-ulation, and all 112 patients were included in the safety population. The average duration of treatment was 24.3 months (range, 3–46months), and the average zonisamide dosage was 324 mg/day (range, 100–1000 mg/day). Thirty-eight of 90 patients (42%; n = 25 mono-therapy, n = 13 adjunctive therapy) were seizure-free, and an additional 26 patients (29%; n = 9 monotherapy, n = 17 adjunctive therapy)had P50% seizure frequency reduction at the last follow-up visit. Thirty of 112 patients (27%) reported mild to moderate adverse events,such as weight loss (5.4%), fatigue (4.5%), and sedation (2.7%). Zonisamide, as monotherapy or adjunctive therapy, was a safe, effective,and well-tolerated long-term treatment option in patients with various seizure types.� 2006 Elsevier Inc. All rights reserved.

Keywords: Zonisamide; Efficacy; Safety; Long-term; Monotherapy; Adjunctive therapy; Antiepileptic drugs; Seizure; Retrospective; Epilepsy

1. Introduction

Zonisamide (Zonegran�) is a structurally unique antiep-ileptic drug (AED) that is chemically classified as a sulfon-amide. It is characterized by a novel pharmacodynamicprofile and wide spectrum of antiseizure activity, andexhibits multiple mechanisms of action, such as the block-ade of voltage-sensitive sodium and T-type calcium chan-nels [1–5]. In the United States, zonisamide is indicatedfor adjunctive therapy for partial seizures, although clinicaluse as monotherapy based on the Japanese experience isoften noted. Zonisamide has been available in Japan since1989 and was approved in the United States for the adjunc-tive treatment of partial seizures in adults with epilepsy in2000. Seven clinical trials conducted in the United Statesand Europe, including three double-blind, placebo-

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doi:10.1016/j.yebeh.2006.02.001

* Corresponding author. Fax: +1 508 473 0417.E-mail address: WATMD1945@aol.com (W.A. Tosches).

controlled trials and four open-label, baseline- or histori-cal-controlled trials, established the efficacy and safety ofzonisamide as adjunctive treatment in patients with refrac-tory partial-onset seizures [3,5]. Additional evidence existsfor zonisamide as an effective adjunctive treatment forother seizure types and epilepsy syndromes, includingabsence seizures [6–8], generalized seizures [9], progressivemyoclonic epilepsy [10–13], and Lennox–Gastaut syn-drome [14].

Zonisamide has not yet received U.S. Food and DrugAdministration approval for use as monotherapy; howev-er, published literature has demonstrated that zonisamideis safe and effective for the treatment of select seizure typesas monotherapy or adjunctive therapy. Several clinicalstudies, open-label and retrospective, have investigatedthe effectiveness and tolerability of zonisamide as initialor conversion monotherapy for the treatment of partial sei-zures with or without secondary generalization [5,15,16]. Inone study, 28 patients received a mean zonisamide dosage

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of 286 mg/day (range, 100–600 mg/day) for a follow-upperiod of 0 to 28 months (mean, 14.3 months). Eighteenpatients (64.3%) were seizure-free for P6 months, includ-ing nine patients (32.1%) who maintained seizure freedomfor at least 1 year. Patients who were not seizure-free hadadditional AEDs added to their drug regimen. Twopatients discontinued zonisamide, and an additionalpatient was lost to follow-up [15]. In another study,patients with partial seizures receiving open-label zonisa-mide as monotherapy following the withdrawal of concur-rent AEDs have been shown to maintain seizure control(i.e., seizure freedom or P50% seizure frequency reduc-tion) for periods ranging from 6 to 140 weeks (10 of 208patients, 4.8%). Adverse events were mild to moderateand included somnolence, rhinitis, fatigue, and nausea. Ingeneral, the frequency of reported adverse events declinedwith long-term zonisamide use [5].

Zonisamide as monotherapy for the treatment of a vari-ety of seizures in a large, multigroup clinic has been evalu-ated in one retrospective chart review study. In that study,54 adult and pediatric patients, including 15 patients onfirst-time AED therapy, were treated with zonisamidemonotherapy (range, 100–500 mg/day) during an 18-month period. A total of 24 patients (44.4%) achieved sei-zure freedom for P6 months, including 10 patients whomaintained seizure freedom for at least 1 year. Zonisamidemonotherapy was well tolerated, and no serious adverseevents were reported [16].

Only a limited number of studies, primarily retrospec-tive, have provided information concerning the drug’s useas monotherapy in adult patients with seizure types otherthan partial seizures. Andriola et al. conducted a retrospec-tive database analysis for four zonisamide-treated patientswith absence epilepsy; the analysis yielded one patient whowas seizure-free for 6 months while on monotherapy [6].

Information is limited regarding the long-term use ofzonisamide, as well as the use of zonisamide as monothera-py for a wide variety of seizure and epilepsy-related disor-ders. This study investigated the long-term effects ofzonisamide as an initial monotherapy, as well as an adjunc-tive therapy, for the treatment of multiple seizure andepilepsy types.

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Fig. 1. Efficacy of zonisamide monotherapy and adjunctive therapy.Percentage reduction in seizure frequency from baseline to the end of thetreatment period for patients on monotherapy (n = 45) and adjunctivetherapy (n = 45) with zonisamide.

2. Methods

A retrospective chart review of neurology clinic patients was conductedto identify outcomes for patients treated with zonisamide for a minimumof 3 months. Male and female patients were started on zonisamide mono-therapy for treatment of new-onset seizures, or zonisamide was employedas an additional AED, due to its favorable safety profile and limited drug–drug interactions. Some patients had been referred to the neurology clinicby other physicians and were already receiving older AEDs. Patients witha known hypersensitivity to sulfonamides were excluded from this study.Efficacy of zonisamide was determined by seizure frequency reductionrecorded at the end of treatment, defined as: seizure freedom, P50%reduction, <50% reduction, no effect, or unknown effect. Patients who dis-continued treatment with zonisamide before 3 months or whose seizureresponse data were unavailable were not included in the efficacy analyses.Frequency and types of adverse events were recorded to assess the safety

of zonisamide. Positive effects of zonisamide were also examined. At fol-low-up clinic visits, seizure frequency and reduction, as well as side effects,were recorded by the physician and/or patient.

3. Results

3.1. Demographic and treatment data

One hundred twelve charts were identified; 90 charts (50for male patients, 40 for female patients) contained data onseizure response to zonisamide treatment for P3 monthsand were included in the efficacy analysis. All 112 chartswere included in the safety analysis. Sixty-one femalesand 51 males (age range, 14–97; mean, 54) received a meanzonisamide dosage of 324 mg/day (range, 100–1000 mg/day) for 3 to 46 months (mean, 24.3 months). Equal num-bers of patients used zonisamide as monotherapy (n = 45)and adjunctive therapy (n = 45). A total of 18 patientsreceived zonisamide as first-drug monotherapy. Of thepatients who used zonisamide adjunctively, 34 patientsused one additional AED, 8 patients used two additionalAEDs, and 3 patients used three additional AEDs. Themost common adjunctive AEDs were carbamazepine, val-proic acid, phenytoin, and clonazepam.

3.2. Efficacy profile

The results of adjunctive and monotherapy zonisamidetreatment ranged from seizure freedom to no effect(Fig. 1). Of the adjunctive and monotherapy patientscombined, 38 of 90 patients (42%) became seizure-free,and an additional 26 patients (29%) experienced aP50% reduction in seizure frequency. Zonisamide useresulted in no change in seizure frequency for 9 of the90 monotherapy and adjunctive therapy patients (10%)and an unknown effect for 6 of 90 patients (7%) who

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Fig. 2. Zonisamide monotherapy: response by seizure type. *No additional classification of seizure type was available.

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Fig. 3. Zonisamide adjunctive therapy: response by seizure type. *No additional classification of seizure type was available.

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were lost to follow-up. Of the 45 patients on monothera-py, 25 (56%) were seizure-free, and an additional 9patients (20%) had a P50% reduction in seizure frequen-cy. The most common seizure type for patients on mono-therapy was partial seizures secondarily generalized(n = 15). Fig. 2 illustrates response by seizure type forzonisamide monotherapy.

Adjunctive zonisamide resulted in seizure freedom for13 of 45 patients (29%); an additional 17 patients (38%)experienced P50% seizure frequency reduction. The most

common seizure type for patients on zonisamide adjunctivetherapy was partial seizures secondarily generalized(n = 30). Fig. 3 shows response by seizure type for zonisa-mide as adjunctive therapy.

3.3. Safety profile

Thirty of 112 patients (27%) reported mild to moderateadverse events (Table 1); the most frequently reportedadverse events were weight loss (5.4%), fatigue (4.5%),

Table 2Reasons for discontinuing use of zonisamide (N = 112)

Reason n (%)

Adverse events 13 (11.6)Gastrointestinal distress 2 (1.8)Rash/pruritus 2 (1.8)Weight loss 2 (1.8)Light-headedness 2 (1.8)Hyperactivity 1 (0.9)Fatigue 1 (0.9)Auras 1 (0.9)Cognitive dysfunction 1 (0.9)Malaise 1 (0.9)

Unknown reason 8 (7.1)Ineffective seizure control 1 (0.9)

Table 1Adverse events with zonisamide (N = 112)

Adverse event n (%)

Weight loss/loss of appetite 6 (5.4)Fatigue 5 (4.5)Sedation 3 (2.7)Gastrointestinal distress 3 (2.7)Dizziness 2 (1.8)Headaches 2 (1.8)Cognitive dysfunction 2 (1.8)Rash/pruritus 2 (1.8)Blurred vision 2 (1.8)Malaise 1 (0.9)Auras 1 (0.9)Hyperactivity 1 (0.9)

Table 3Positive effects of zonisamide (n = 90)

Positive effect n (%)

Mood improvement 6 (6.7)Elevated alertness 4 (4.4)Migraine headache aid 3 (3.3)Parkinson tremor aid 1 (1.1)Calmer and less pain 1 (1.1)Restless legs aid 1 (1.1)Decreased hallucinations 1 (1.1)Postherpetic neuralgia aid 1 (1.1)

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and sedation (2.7%). A total of 22 patients (20%; 11 males,11 females) discontinued zonisamide therapy (Table 2),with 17 (15%) completing P3 months of zonisamide treat-ment; among these 17 patients, the incidence of adverseevents was more frequent in the adjunctive therapy group(n = 12) compared with the monotherapy group (n = 5).Thirteen patients (12%) discontinued treatment due toadverse events, with gastrointestinal distress, rash/pruritus,weight loss, and light-headedness (n = 2 each) being themost common events. Eight patients (7%) discontinuedtreatment for unknown reasons, and an additional patient(1%) terminated treatment due to ineffective seizurecontrol.

Eighteen of 90 patients (20%) included in the efficacyanalysis reported positive neurological effects (Table 3).The most frequently reported positive effects were moodimprovement (6.7%), elevated alertness (4.4%), andmigraine headache aid (3.3%).

4. Discussion

This chart review study supports previous findings onthe efficacy and safety of zonisamide as long-term mono-therapy and adjunctive treatment for an extensive rangeof seizure and epilepsy types. With an average zonisamidetreatment duration of approximately 2 years, more than70% of patients experienced seizure control (i.e., seizurefreedom or P50% seizure frequency reduction) for partialseizures with or without secondary generalization, general-ized seizures, or generalized tonic–clonic, tonic, or atonicseizures. This result exceeded the effect observed in a previ-ous long-term clinical study, where 28.1 to 55% of zonisa-mide-treated patients with partial seizures reported seizurecontrol [5].

In the cohort of patients using zonisamide as mono-therapy, more than 75% of patients experienced seizurecontrol (56% achieving seizure freedom; 20% experiencingP50% seizure frequency reduction). Zonisamide as mono-therapy appeared to be most effective against complex par-tial seizures in the current study and was also an effectivetreatment for generalized seizures and partial seizures sec-ondarily generalized. In contrast, the greatest effect whenusing zonisamide as adjunctive therapy was observed inpatients with partial seizures secondarily generalized.

Zonisamide was well tolerated and associated with onlymild to moderate adverse events; no serious adverseevents were reported. Thirteen patients (12%) discontin-ued treatment with zonisamide because of adverse eventssuch as gastrointestinal distress and rash/pruritus (1.8%each); however, published literature suggests that adverseevents reported in the first few weeks of zonisamide treat-ment regress over time [17]. In fact, the majority of dis-continuations due to adverse events in this studyoccurred before 3 months of treatment were completed(n = 8), suggesting that adverse events that may lead todiscontinuation are most likely to occur within the first3 months of treatment. The positive psychotropic effectsalso observed in this study indicated that zonisamidetreatment may lead to improved medication complianceand quality of life.

Zonisamide as monotherapy offered several advantagesto patients with epilepsy. Zonisamide monotherapy pro-vided effective seizure control and limited the occurrenceof adverse events to those observed for single-drug thera-py versus the more complex profiles associated with multi-ple AED use. Previous studies have identified a lower riskof toxicity and a reduction in the number of adverseevents when a single AED is prescribed [18–20]. Anticon-vulsant polytherapy increases the likelihood of drug–druginteractions and increases the potential for long-term

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endocrine effects such as bone loss, inhibition of lipidmetabolism, and alteration of sex hormones [21]. In addi-tion, the cost of monotherapy is frequently lower than thecost of multiple AEDs, and patient compliance has beenshown to improve with monotherapy [20,22]. The longhalf-life of zonisamide (>60 hours) when used as mono-therapy also makes once-daily dosing possible, anotherimportant factor in patient medication compliance [23,24].In general, zonisamide monotherapy was effective and safefor the treatment of seizures and epilepsy disorders.

In this study, zonisamide, when used as monotherapy orconcomitant therapy, proved effective as an anticonvulsantand was well tolerated over time. Adverse events tended tooccur early in zonisamide treatment and no serious adverseevents were noted. Moreover, the positive side effects ofzonisamide treatment may provide additional benefits inpatients with epilepsy diagnosed with concomitant neuro-logical or psychiatric disorders.

Acknowledgments

The authors acknowledge Natalie Boone and WendellValdecantos of MedLogix Communications, LLC, fortheir editorial assistance.

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