Zonisamide …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 04.01.2021
Released 05.16.2000
Expires For CME 04.01.2024

Zonisamide

Author: K K Jain MD†

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Zonisamide

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Introduction

Historical note and terminology

Zonisamide is chemically classified as a sulfonamide and is unrelated to other antiepileptic drugs. Originally developed in Japan for the treatment of epilepsy, it was later approved in 1989, and has since been licensed in many countries. It was under investigation for cerebral ischemia, but no development has been reported for this indication since 1994. Zonisamide was approved by the Food and Drug Administration in 2000 for marketing as an add-on adult focal epilepsy treatment. It is now approved in Europe as monotherapy for the treatment of partial seizures in adults affected by newly diagnosed epilepsy.

Zonisamide (chemical structure)

(Contributed by Dr. K K Jain.)

Pharmacology

Pharmacodynamics. The mechanism of the antiepileptic action of zonisamide remains unclear, but likely mechanisms include:

• Blockade of sodium channels.
• Blockade of T-type calcium channels.
• Inhibition of carbonic anhydrase.
• Free radical scavenging effect.
• Inhibiting of excitatory glutamatergic transmission.
• Modulation of glycine receptors

Zonisamide does not potentiate the synaptic activity of gamma-aminobutyric acid. In experimental animals, zonisamide suppresses the tonic-extensor components of maximal electroshock seizures and prevents the propagation of seizures from the cortex to the subcortical structures evoked by cortical freezing. Electroencephalographic studies on animal models of epilepsy show that zonisamide, like phenytoin and carbamazepine, restricts the spread or propagation of seizures and, like sodium valproate, suppresses the epileptogenic focus activity. Neuroprotective effect of zonisamide has been demonstrated in the rat model of focal ischemia induced by a transient occlusion of the left middle cerebral artery. One explanation of this neuroprotective effect is by scavenging of free radicals. Another explanation is that zonisamide is effective in reducing neuronal damage by a mechanism involving decreased ischemia-induced extracellular glutamate accumulation and interruption of excitotoxic pathways (14). As therapeutic concentrations of zonisamide positively modulate recombinant and native glycine receptors, anticonvulsant effects of zonisamide may be mediated via this action (05).

Pharmacokinetics. Pharmacokinetic profile of zonisamide in humans is as follows:

	• Following a 200 to 400 mg oral zonisamide dose, peak plasma concentrations (2 to 5 mg/mL) occur within 2 to 6 hours. The dose-serum level correlation is linear up. Almost 100% of it is absorbed. A steady state is reached in about 2 weeks.
	• Approximately 40% of zonisamide is bound to plasma proteins, primarily albumin.
	• Zonisamide has saturable binding to red blood cells (RBCs), especially to intracellular carbonic anhydrase, and is found in higher concentrations in RBCs than in plasma.
	• Zonisamide is excreted mainly in urine, and the renal clearance is increased by enzyme-inducing antiepileptic drugs. In adults, the elimination half-life of zonisamide is 50 to 62 hours.
	• Following an oral administration of 14-C-zonisamide to healthy volunteers, only zonisamide is detected in the plasma. Of the excreted dose, 35% is the parent drug, 15% the metabolite sulphamoylacetyl phenol, and 50% a glycuronide of this metabolite. Reduction of zonisamide to sulphamoylacetyl phenol is mediated by cytochrome P450 isoenzyme 3A4 (CYP3A4). Pharmacokinetics of zonisamide after oral administration is like a linear first-order elimination 2-compartment model, which may provide a reference for clinical use of zonisamide in Chinese adults (25).
	• The change in zonisamide serum concentrations in a pregnant woman suggests an increase in clearance at the end of the second trimester (23).
	• A simple and accurate liquid chromatography/mass spectrometry method for quantification of zonisamide in human plasma has been developed and validated over the concentration range of 0.5 to 50 μg/mL (18).

Routes of administration. Zonisamide is marketed as tablets for oral use. A liquid formulation for intravenous use is available. Preclinical studies of intranasal zonisamide show that drug targeting efficiency and direct transport percentage into the brain are 149.54% and 33.13%, respectively, indicating that a significant fraction of zonisamide is transported directly from the nose to the brain (09). Zonisamide has a low absolute bioavailability (54.95%) but the highest value of the ratio between the area under the curve (AUC) between brain and plasma, suggesting lower systemic adverse events and noninferior effects on central nervous system compared to intravenous and oral routes.

Indications

Zonisamide is indicated for the treatment of partial seizures in adults with epilepsy.

Off-label uses

West syndrome. Zonisamide has been used with some success in patients who did not respond to pyridoxine or valproic acid.

Absence epilepsy. A post-marketing study has shown that add-on zonisamide is efficient and well tolerated in juvenile patients with refractory absence epilepsy (31).

Infantile spasms. Zonisamide treatment has been shown to be beneficial in some cases of infantile spasms.

Tremor. Zonisamide reduces tremor amplitude and has been used for controlling essential tremor involving the head (29). A systematic review of randomized controlled trials concluded that there is insufficient evidence to assess the efficacy and safety of zonisamide as treatment for essential tremor (03).

Parkinson disease. Activation of dopamine synthesis and the moderate level of monoamine oxidase B inhibition are the main mechanisms of zonisamide effects on Parkinson disease. Zonisamide may be effective in reducing the duration of “off” time in patients with Parkinson disease treated with levodopa. Zonisamide has additional targets, including neuroinflammation and the voltage-gated sodium channel Nav1.6, which may contribute to its reported neuroprotective role Parkinson disease (12). In a phase 3 clinical trial on patients with Parkinson disease and Lewy body dementia, daily administration of 25 or 50 mg zonisamide significantly improved motor function compared with placebo; both doses were safe and well tolerated (21). Two phase 2 and 3 randomized trials on patients with Parkinson disease and Lewy body dementia recently reported a statistically significant improvement in motor function in those receiving zonisamide as an adjunctive treatment to levodopa (24).

Obesity. Weight loss was originally noted as an adverse effect of zonisamide but has been investigated for therapeutic use in obesity.

Migraine. Zonisamide has been used for preventive treatment of chronic migraine in patients who are refractory or intolerant to topiramate (32). In another study on refractory migraine patients, zonisamide therapy did not result in a statistically significant beneficial effect on headache or on associated symptoms.

Zonisamide is an effective prophylactic treatment for patients with chronic and episodic cluster headache disorders (17).

Idiopathic hemifacial spasm.

Brain tumor-related epilepsy. Preliminary results of an open study of zonisamide as add-on in a patient population indicate that it may represent a valid alternative to other add-on antiepileptic drugs (19).

Secondary paroxysmal dystonia (06).

Alcohol dependence. In an open-label study, zonisamide was found to be well tolerated and associated with improvement in alcohol craving (28).

Tardive dyskinesia. Results of an open-label study indicate that zonisamide may be safe and effective for the treatment of tardive dyskinesia associated with antipsychotic treatment (13).

Catatonia. Refractory periodic catatonia in a patient with schizophrenia was successfully treated with a combination of zonisamide and aripiprazole -- a partial agonist of dopamine D2 receptor (22).

Bulimia nervosa. In an open-label study, zonisamide was effective in bulimia nervosa but was associated with a high discontinuation rate (10).

Obstructive sleep apnea. In a randomized study, zonisamide was shown to reduce obstructive sleep apnea by mechanisms related to carbonic anhydrase inhibition (07).

Bipolar disorder. Zonisamide may be useful as an adjunctive therapy for the management of acute phases and weight gain in bipolar disorder (04).

Neuropathic pain. Zonisamide has shown efficacy in patients with neuropathic pain.

Special considerations

Anesthesia. No special precautions.

Pregnancy. Women of childbearing age who are given zonisamide should be advised to use effective contraception. Zonisamide was teratogenic in mice, rats, and dogs and embryolethal in monkeys when administered during the period of organogenesis. These findings suggest that the use of zonisamide during pregnancy in humans may present a significant risk to the fetus. Zonisamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Zonisamide serum concentrations may fall by more than 40% during pregnancy, which may worsen seizure control, and therapeutic drug monitoring with dose adjustments are useful measures to cope with this (26). Zonisamide concentration in breast milk is the same as that in maternal plasma, but serum levels in neonates decrease during the first month of life during nursing. Alternative drugs are preferred, but if zonisamide must be given, the infant should be monitored for drowsiness, adequate weight gain, and developmental milestones.

Pediatric. Use of zonisamide is safe in children less than 16 years of age, and the adverse event profile is like that of adults in studies in the United States and Europe.

An extension study of a phase 3 trial showed that approximately one-third of children treated with zonisamide had 5% or greater weight loss, but it was not associated with any effects on growth and development (15).

Geriatric. Single-dose pharmacokinetic parameters are similar in healthy volunteers of all ages. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of the decreased.

However, data from uncontrolled studies suggest that zonisamide is effective and well tolerated when administered as monotherapy or adjunctive antiepileptic treatment in the elderly (27).

References

01: Baulac M, Brodie MJ, Patten A, Segieth J, Giorgi L. Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol 2012;11(7):579-88. PMID 22683226
02: Brigo F, Lattanzi S, Igwe SC, Behzadifar M, Bragazzi NL. Zonisamide add-on therapy for focal epilepsy. Cochrane Database Syst Rev 2018;10:CD001416.** PMID 30335200
03: Bruno E, Nicoletti A, Filippini G, Quattrocchi G, Colosimo C, Zappia M. Zonisamide for essential tremor. Cochrane Database Syst Rev 2017;8:CD009684.** PMID 28836659
04: Buoli M, Grassi S, Ciappolino V, Serati M, Altamura AC. The use of zonisamide for the treatment of psychiatric disorders: a systematic review. Clin Neuropharmacol 2017;40(2):85-92. PMID 28195838
05: Devenish SO, Winters BL, Anderson LL, et al. The anticonvulsant zonisamide positively modulates recombinant and native glycine receptors at clinically relevant concentrations. Neuropharmacology 2021;182:108371.** PMID 33122032
06: Egel RT, Hoganson GE, Katerji MA, Borenstein MJ. Zonisamide ameliorates symptoms of secondary paroxysmal dystonia. Pediatr Neurol 2010;43(3):205-8. PMID 20691944
07: Eskandari D, Zou D, Karimi M, Stenlöf K, Grote L, Hedner J. Zonisamide reduces obstructive sleep apnoea: a randomised placebo-controlled study. Eur Respir J 2014;44(1):140-9. PMID 24627538
08: Eun SH, Kim HD, Eun BL, et al. Comparative trial of low- and high-dose zonisamide as monotherapy for childhood epilepsy. Seizure 2011;20(7):558-63. PMID 21543239
09: Gonçalves J, Alves G, Carona A, et al. Pre-clinical assessment of the nose-to-brain delivery of zonisamide after intranasal administration. Pharm Res 2020;37(4):74. PMID 32215749
10: Guerdjikova AI, Blom TJ, Martens BE, Keck PE Jr, McElroy SL. Zonisamide in the treatment of bulimia nervosa: an open-label, pilot, prospective study. Int J Eat Disord 2013;46(7):747-50. PMID 23893331
11: Holder JL Jr, Wilfong AA. Zonisamide in the treatment of epilepsy. Expert Opin Pharmacother 2011;12(16):2573-81. PMID 21967409
12: Hossain MM, Weig B, Reuhl K, Gearing M, Wu LJ, Richardson JR. The anti-parkinsonian drug zonisamide reduces neuroinflammation: role of microglial Nav 1.6. Exp Neurol 2018;308:111-19.** PMID 30017881
13: Iwata Y, Irie S, Uchida H, et al. Effects of zonisamide on tardive dyskinesia: a preliminary open-label trial. J Neurol Sci 2012;315(1-2):137-40. PMID 22285275
14: Jain KK. A handbook of neuroprotection, 2nd edition. New York: Humana/Springer, 2019.
15: Lagae L, Meshram C, Giorgi L, Patten A. Effects of adjunctive zonisamide treatment on weight and body mass index in children with partial epilepsy. Acta Neurol Scand 2015;131(5):341-6. PMID 26559828
16: Lee YJ, Kang HC, Seo JH, Lee JS, Kim HD. Efficacy and tolerability of adjunctive therapy with zonisamide in childhood intractable epilepsy. Brain Dev 2010;32(3):208-12. PMID 19304420
17: Limmer AL, Holland LC, Loftus BD. Zonisamide for cluster headache prophylaxis: a case series. Headache 2019;59(6):924-9. PMID 31038740
18: Matar KM. A simple and accurate liquid chromatography-tandem mass spectrometry method for quantification of zonisamide in plasma and its application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2014;961:103-9. PMID 24874192
19: Maschio M, Dinapoli L, Saveriano F, et al. Efficacy and tolerability of zonisamide as add-on in brain tumor-related epilepsy: preliminary report. Acta Neurol Scand 2009;120(3):210-2. PMID 19719809
20: Miro J, Jaraba S, Juvany R, Santurino M, Cobo S, Falip M. Could adult European pharmacoresistant epilepsy patients be treated with higher doses of zonisamide? Clin Neuropharmacol 2016;39(3):121-4. PMID 26818046
21: Murata M, Odawara T, Hasegawa K, et al. Effect of zonisamide on parkinsonism in patients with dementia with Lewy bodies: a phase 3 randomized clinical trial. Neurology 2019;S1353-8020(19):30524-3.** PMID 31982288
22: Nakagawa M, Yamamura S, Motomura E, Shiroyama T, Tanii H, Okada M. Combination therapy of zonisamide with aripiprazole on ECT- and benzodiazepine-resistant periodic catatonia. J Neuropsychiatry Clin Neurosci 2012;24(3):E9. PMID 23037658
23: Oles KS, Bell WL. Zonisamide concentrations during pregnancy. Ann Pharmacother 2008;42(7):1139-41. PMID 18577760
24: Panza F, Lozupone M, Watling M, Imbimbo BP. Pharmacological management of dementia with Lewy bodies with a focus on zonisamide for treating parkinsonism. Expert Opin Pharmacother 2021;22(3):325-37.** PMID 33021110 PMID: 33021110
25: Qiu X, Dai Q, Sun F, et al. Population pharmacokinetics of zonisamide after oral administration in healthy Chinese volunteers. Int J Clin Pharmacol Ther 2016;54(5):362-8. PMID 27007995
26: Reimers A, Helde G, Becser Andersen N, et al. Zonisamide serum concentrations during pregnancy. Epilepsy Res 2018;144:25-9. PMID 29751353
27: Romigi A, Femia EA, Fattore C, Vitrani G, Di Gennaro G, Franco V. Zonisamide in the management of epilepsy in the elderly. Clin Interv Aging 2015;10:931-7. PMID 26089654
28: Rubio G, López-Muñoz F, Ferre F, et al. Effects of zonisamide in the treatment of alcohol dependence. Clin Neuropharmacol 2010;33(5):250-3. PMID 20811276
29: Song IU, Kim JS, Lee SB, et al. Effects of zonisamide on isolated head tremor. Eur J Neurol 2008;15(11):1212-5. PMID 18754763
30: Suzuki Y, Imai K, Toribe Y, et al. Long-term response to zonisamide in patients with West syndrome. Neurology 2002;58:1556-9. PMID 12034801
31: Velizarova R, Crespel A, Genton P, Serafini A, Gelisse P. Zonisamide for refractory juvenile absence epilepsy. Epilepsy Res 2014;108(7):1263-6. PMID 24907183
32: Villani V, Ciuffoli A, Prosperini L, Sette G. Zonisamide for migraine prophylaxis in topiramate-intolerant patients: an observational study. Headache 2011;51(2):287-91. PMID 21284610
33: Vivar KL, Mancl K, Seminario-Vidal L. Stevens-Johnson syndrome/toxic epidermal necrolysis associated with zonisamide. Clin Case Rep 2017;6(2):258-61. PMID 29445458

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Zonisamide

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Zonisamide …

Zonisamide

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Idiopathic hemifacial spasm.

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Drug-induced myasthenic syndromes

Epilepsy with auditory features

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Zonisamide

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Idiopathic hemifacial spasm.

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Drug-induced myasthenic syndromes

Epilepsy with auditory features

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

This is an article preview.
Start a Free Account
to access the full version.