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Generic Name: Zonisamide
Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Chemical Name: 1,2-Benzisoxazole-3-methanesulfonamide
Molecular Formula: C8H8N2O3S
CAS Number: 68291-97-4

Medically reviewed on October 3, 2017


Anticonvulsant; a sulfonamide.1 2 3

Uses for Zonegran

Seizure Disorders

Management (in combination with other anticonvulsants) of partial seizures in adults with epilepsy.1 2 3 8

Zonegran Dosage and Administration


  • Zonisamide therapy should not be discontinued abruptly; dosage reduction or discontinuance of the drug should be done gradually.1

  • Closely monitor for marked changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.1 14 15 16 21 (See Suicidality Risk under Cautions.)


Oral Administration

Administer orally without regard to meals.1 2 3 Patients should be encouraged to drink 6–8 glasses of water each day while receiving the drug.1

Administer initial dosage (100 mg daily) once daily; following dosage adjustment, administer once or twice daily.1 2 3

Swallow capsules whole.1



Seizure Disorders
Partial Seizures

Adults >16 years of age: Initially, 100 mg daily.1 2 3 9

After 2 weeks, dosage may be increased to 200 mg daily.1 3 Dosage can be further increased to 300 and 400 mg daily;1 2 3 9 allow ≥2 weeks between dosage changes (to achieve steady state at each dosage level).1 2 3 9 Some clinicians may prefer to administer lower dosages for longer periods (in order to fully assess safety at steady state).1

Dosages >400 mg daily may not be associated with increased therapeutic benefit.1

Adverse effects occur more frequently at dosages ≥300 mg daily.1

Prescribing Limits


Seizure Disorders
Partial Seizures

Limited experience with dosages >600 mg daily.1

Special Populations

Hepatic Impairment

Titrate dosage slowly in patients with hepatic disease.1

Renal Impairment

Titrate dosage slowly in patients with renal disease.1 2 Do not use in patients with renal failure (GFR <50 mL/minute).1

Geriatric Patients

No specific dosage recommendations for zonisamide; however, select dosage cautiously, usually starting at the lower end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant diseases or other drug therapy in this population.1

Cautions for Zonegran


  • Known hypersensitivity to zonisamide, sulfonamides, or any ingredient in the formulation.1 2



Hematologic Effects

Aplastic anemia and agranulocytosis reported rarely; causal relationship between these events and dosage or duration of therapy not established.1 2

Oligohidrosis and Hyperthermia

Oligohidrosis (a reduction in sweating) and hyperthermia reported in patients receiving zonisamide, particularly in pediatric patients.1 13 26 Closely monitor patients receiving zonisamide for evidence of decreased sweating and increased body temperature, particularly in warm or hot weather.1 13 26 Consider risk of hyperthermia when zonisamide is used concomitantly with other drugs that predispose patients to heat-related disorders.1 13 (See Pediatric Use under Cautions, Drugs Predisposing to Heat-related Disorders under Interactions, and Advice to Patients.)

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants, including zonisamide, in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).1 14 15 16 21 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.14 15 16 Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1 14 15 16

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.1 14 15 16 21 Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.15

Balance risk of suicidality with the risk of untreated illness.1 15 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.1 21 If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.1 21 (See Advice to Patients.)

Metabolic Acidosis

Zonisamide can cause metabolic acidosis, characterized by hyperchloremia and decreased serum bicarbonate concentrations.19 Often asymptomatic, but signs and symptoms of persistent metabolic acidosis may include hyperventilation, fatigue, and anorexia; more severe symptoms may include cardiac arrhythmias and stupor.19 Generally occurs early in treatment, but may occur at any time during therapy.19

Risk of developing metabolic acidosis appears greater at higher dosages of zonisamide, but it can occur with dosages ≤25 mg daily.19 Renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diets, or other drugs (e.g., acetazolamide) may predispose patients to acidosis.19 Also appears to be more frequent and severe in younger patients.19 (See Pediatric Use under Cautions.)

Decreases in serum bicarbonate levels are usually mild to moderate (average decrease of approximately 2 mEq/L) in adults; however, some adults have experienced severe decreases (as much as 10 mEq/L below their baseline).19 Chronic, untreated metabolic acidosis may increase the risk for renal calculi (kidney stones), nephrocalcinosis, and bone abnormalities (e.g., osteoporosis, osteomalacia, rickets in children) with an increased risk of fractures.19 (See Renal Calculi under Cautions.)

FDA recommends that clinicians measure serum bicarbonate levels prior to and periodically during zonisamide therapy, even in the absence of clinical symptoms, as well as if signs or symptoms of metabolic acidosis are observed.19 If metabolic acidosis develops and persists, consider reducing the zonisamide dosage or discontinuing the drug (by slowly reducing the dosage) and modifying the patient’s anticonvulsant drug regimen as appropriate.19 If the decision is made to continue patients with metabolic acidosis on zonisamide, consider alkali treatment.19

Withdrawal Seizures

Abrupt withdrawal may result in increased seizure frequency or status epilepticus; withdraw zonisamide gradually and reduce dosage slowly.1

Cognitive/Neuropsychiatric Effects

Possible somnolence or fatigue, psychiatric symptoms (e.g., depression, psychosis), and impaired psychomotor or cognitive performance (e.g., difficulties in concentrating, language, speech, and word finding).1 3 5 15 17 (See Suicidality Risk under Cautions.)

Status Epilepticus

In controlled studies, status epilepticus occurred in 1.1 or 0% of patients receiving zonisamide or placebo, respectively.1 In all (uncontrolled and controlled) clinical studies of zonisamide therapy, the incidence of status epilepticus was 1%.1

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Fatalities resulting from severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have occurred following zonisamide use.1 2 7

Fatalities resulting from fulminant hepatic necrosis, agranulocytosis, aplastic anemia, or other blood dyscrasias rarely have been caused by sulfonamides.1 2

Discontinue immediately if signs or symptoms of hypersensitivity occur.1 Consider drug discontinuance if unexplained rash occurs; if drug is not discontinued, observe patient frequently.1

General Precautions

Renal Calculi

Clinically possible or confirmed renal calculi (kidney stones), composed of calcium or urate salts, reported.1 2 3 4 8 9 12

In general, increasing fluid intake and urine output may reduce the risk of kidney stone formation, particularly in patients with predisposing risk factors; not known whether these measures reduce the risk of kidney stone formation in patients receiving zonisamide.1

Other Renal Effects

Substantial increases in Scr and BUN reported;1 such increases appeared to persist over time but were not progressive.1 Consider periodically monitoring renal function during zonisamide therapy.1

Discontinue use in patients who develop acute renal failure or clinically important, sustained increases in Scr and BUN.1

Sudden, Unexplained Deaths in Epilepsy

Higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with refractory epilepsy.1

Specific Populations


Category C.1

North American Antiepileptic Drug Pregnancy Registry at 888-233-2334 (for patients).1

FDA warns that zonisamide may cause metabolic acidosis;19 if metabolic acidosis occurs during pregnancy, may affect fetal development (i.e., decreased fetal growth, decreased fetal oxygenation, and fetal death) and the ability of the fetus to tolerate labor.19

The effect of zonisamide on labor and delivery is unknown.1

Physiologic changes during pregnancy may affect plasma zonisamide concentrations and/or therapeutic effect.1 (See Special Populations under Pharmacokinetics: Elimination.) Some clinicians recommend closely monitoring zonisamide concentrations and adjusting zonisamide dosage as necessary in pregnant women.20


Distributes into human milk.18 19 Due to potential risk in nursing infant, discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy of zonisamide not established in children <16 years of age and the drug is not approved for use in pediatric patients in the US.1 19 However, the drug has been used in some pediatric patients for the treatment of epilepsy to date and is approved for pediatric use in Japan.19 22 23 24 25 26 27

Oligohidrosis and hyperthermia, characterized by decreased sweating and abnormally high body temperatures, reported in pediatric patients (1.6–17 years of age) receiving zonisamide and sometimes have resulted in heat stroke and hospitalization.1 2 3 11 13

Closely monitor children receiving the drug for evidence of decreased sweating and increased body temperature, especially in warm or hot weather.1 13 26 Consider risk of hyperthermia when zonisamide is used concomitantly with other drugs that predispose patients to heat-related disorders.1 13 (See Oligohidrosis and Hyperthermia under Cautions, Drugs Predisposing to Heat-related Disorders under Interactions, and Advice to Patients.)

Pediatric patients may be at increased risk for zonisamide-induced metabolic acidosis; may be more severe in younger patients.19 Specific effects of zonisamide on growth and bone not studied; chronic metabolic acidosis may reduce growth rates in pediatric patients, resulting in a reduction in the maximal height achieved.19 (See Metabolic Acidosis under Cautions, Specific Drugs under Interactions, and Advice to Patients.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

Use with caution in patients with hepatic disease; slower dosage titration and more frequent monitoring may be necessary.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution in patients with renal disease; slower dosage titration and more frequent monitoring may be necessary.1

Because of insufficient experience concerning dosage and toxicity, do not use in patients with renal failure (GFR <50 mL/minute).1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Abdominal pain, anorexia, diarrhea, nausea, dyspepsia, constipation, dry mouth, taste perversion, headache, dizziness, ataxia, nystagmus, paresthesia, confusion, difficulty concentrating, impaired memory, mental slowing, speech abnormalities, difficulty in verbal expression, agitation and/or irritability, depression, insomnia, anxiety, nervousness, schizophrenic and/or schizophreniform behavior, somnolence, fatigue, tiredness, flu-like syndrome, ecchymosis, rhinitis, weight loss, rash, diplopia.1 2 3 8 9

Interactions for Zonegran

Does not appear to inhibit CYP isoenzymes in vitro;1 2 3 metabolic pathways include metabolism by CYP3A4.1

Drugs Metabolized by or Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered serum concentrations of zonisamide) with inhibitors or inducers of CYP3A4.1 2

Does not appear to interfere with metabolism of drugs metabolized by CYP isoenzymes.1 2 3


Other anticonvulsants may alter pharmacokinetics of zonisamide.1 2 (See Specific Drugs under Interactions.)

Drugs Predisposing to Heat-related Disorders

Increased risk of oligohidrosis and hyperthermia with drugs that predispose to heat-related disorders (e.g., carbonic anhydrase inhibitors, drugs with anticholinergic activity).1 13 26

Specific Drugs




Acetazolamide and other carbonic anhydrase inhibitors

Possible increased risk of developing metabolic acidosis and heat-related disorders during concurrent administration1 13 19 26


Possible decrease in plasma zonisamide concentrations;1 2 3 no change in steady-state plasma carbamazepine concentrations1 2 8

Increase in zonisamide dosage may be required2

Oral contraceptives

Pharmacokinetic interaction unlikely28


Zonisamide half-life decreased1


Possible decrease in plasma zonisamide concentrations;1 2 3 no change in steady-state plasma phenytoin concentrations1 2 8

Increase in zonisamide dosage may be required2

Valproic acid

No change in steady-state plasma concentrations of valproic acid1 2 8

Zonegran Pharmacokinetics



Rapidly and almost completely absorbed following oral administration, with nearly 100% oral bioavailability.2 3 Peak plasma concentrations attained within 2–6 hours after oral administration.1


Food delays the time to peak plasma concentration but does not affect bioavailability.1



Extensively binds to erythrocytes, resulting in an 8-fold higher concentration of zonisamide in erythrocytes than in plasma.1

Crosses the placenta;18 distributed into breast milk.18 19

Plasma Protein Binding

Approximately 40%.1



Undergoes acetylation to form N-acetyl zonisamide, subsequent reduction to form 2-sulfamoylacetyl phenol, and further glucuronide conjugation.1 3 The reduction of N-acetyl zonisamide is mediated by CYP3A4.1 2 3

Does not induce own metabolism.1

Elimination Route

Excreted principally in urine as unchanged drug and a glucuronide metabolite.1 2 3


About 63 hours.1 3

Special Populations

In patients with marked renal impairment (Clcr≤ 20 mL/minute), AUC was increased by 35%.1 Renal clearance decreases with decreasing renal function.1

In patients with hepatic impairment, pharmacokinetics not studied to date.1

Clearance of zonisamide may be increased at the end of the second trimester in pregnant women.20

Pharmacokinetics were similar in geriatric and young healthy volunteers in single-dose studies.1 (See Geriatric Patients under Dosage and Administration.)





Dry place at 25°C (may be exposed to 15–30°C); protect from light.1


  • Exact mechanism of action is not known; anticonvulsant activity may be associated with the drug’s sodium- and calcium-channel blocking activities.1 2 3 9

  • May potentiate dopaminergic and serotonergic neurotransmission1 2 3 but does not appear to potentiate the synaptic activity of GABA.1

  • Exhibits weak inhibition of carbonic anhydrase activity;1 2 3 not thought to contribute substantially to anticonvulsant activity.1

Advice to Patients

  • Importance of providing copy of written patient information (medication guide) each time zonisamide is dispensed.1 21

  • Risk of serious skin rash that can cause death; these skin reactions are more likely to happen within the first 4 months of starting therapy, but may occur later.1 Importance of immediately contacting clinician if skin rash occurs.1

  • Importance of patients being aware that zonisamide can prevent sweating, which makes it harder for the body to cool down when it gets very hot; this is more likely to occur in warmer weather, in children, and during physical exercise.1 13 26 Importance of avoiding exposure to heat, maintaining adequate hydration, and informing clinicians immediately if fever or increased body temperature and/or decreased sweating occurs, particularly in children or in hot weather.1 13 26

  • Risk of blood cell abnormalities such as reduced RBC and WBC counts.1 Importance of contacting clinician if fever, sore throat, sores in the mouth, or unusual bruising occurs.1

  • Risk of suicidality (anticonvulsants, including zonisamide, may increase risk of suicidal thoughts or actions in about 1 in 500 people).1 15 21 Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1 15

  • Importance of patients being aware that zonisamide may cause metabolic acidosis.19 Importance of patients being aware that blood tests to measure serum bicarbonate levels may be performed.19 Symptoms of metabolic acidosis include breathing fast (hyperventilation), fatigue, and loss of appetite; more severe symptoms include an irregular heart beat or unconsciousness.19

  • May cause drowsiness, especially at higher dosages.1 Avoid driving or operating machinery while taking zonisamide until experience with the drug’s effects has been established.1

  • Risk of kidney stones.1 Importance of informing patients that increasing fluid intake (i.e., by drinking 6–8 glasses of water a day) and urine output may reduce the risk of stone formation, particularly in those with predisposing factors.1 Importance of immediately reporting symptoms of kidney stones (e.g., sudden back pain, abdominal pain, and/or blood in urine) to clinician.1

  • Importance of immediately reporting worsening of seizures and severe muscle pain and/or weakness to clinician.1

  • Importance of women informing clinicians if they are or plan to become pregnant.1 19 Importance of informing women who are or plan to become pregnant that zonisamide may cause metabolic acidosis, which may negatively affect fetal development during pregnancy.19 Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).1

  • Importance of informing nursing women and those who plan to breast-feed that zonisamide can appear in the breast milk, and that the effects of this exposure on the infant are unknown.19 Importance of women informing clinicians if they plan to breast-feed.1 19

  • Importance of swallowing zonisamide capsules whole and not biting into or breaking into the capsules; zonisamide may be taken with or without food.1

  • Importance of informing patients not to stop taking zonisamide without talking to their clinician since stopping the drug suddenly can cause serious problems, including seizures.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription drugs, OTC drugs, and special diets (e.g., ketogenic diet), as well as any concomitant illnesses (e.g., liver disease, kidney disease, severe lung disorders, diarrhea, surgery, depression, bipolar disorder) or family history of suicidality or bipolar disorder.1 13 19

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)


Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name



Dosage Forms


Brand Names




25 mg*



Zonisamide Capsules

50 mg*

Zonisamide Capsules

100 mg*



Zonisamide Capsules

AHFS DI Essentials. © Copyright 2018, Selected Revisions October 3, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.


1. Elan Pharma International Ltd, (manufacturer) and Eisai Inc. (distributor). Zonegran (zonisamide) capsules prescribing information. Woodcliff Lake, NJ; 2009 Apr.

2. Anon. Zonisamide (Zonegran) for epilepsy. Med Lett Drugs Ther. 2000; 42:94-5.

3. Schachter SC. The next wave of anticonvulsants: focus on levetiracetam, oxcarbazepine and zonisamide. Drugs. 2000; 14:229-49.

4. Leppik IE, Willmore LJ, Homan RW et al. Efficacy and safety of zonisamide: results of a multicenter study. Epilepsy Res. 1993; 14:165-73.

5. Berent S, Sackellares JC, Giordani B et al. Zonisamide (CI-912) and cognition: results from preliminary study. Epilepsia. 1987; 28:61-7.

6. Sackellares JC, Donofrio PD, Wagner JG et al. Pilot study of zonisamide (1,2-benzisoxazole-3-methanesulfonamide) in patients with refractory partial seizures. Epilepsia. 1985; 26:206-11.

7. Wilensky AJ, Friel PN, Ojemann LM Et al. Zonisamide in epilepsy: a pilot study. Epilepsia. 1985; 26:212-20.

8. Schmidt D, Jacob R, Loiseau P et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res. 1993 May; 15:67-73.

9. Oommen KJ, Mathews S. Zonisamide: a new antiepileptic drug. Clin Neuropharmacol. 1999; 22:192-200.

10. Leppik IE. Zonisamide. Epilepsia. 1999; 40(Suppl 5):S23-9.

11. Okumura A, Hayakawa F, Kuno K et al. Oligohidrosis caused by zonisamide. No To Hattatsu. 1996; 28:44-7.

12. Kubota M, Nishi-Nagase M, Sakakihara Y et al. Zonisamide-induced urinary lithiasis in patients with intractable epilepsy. Brain Dev. 2000; 22:230-3.

13. O’Brien C. Dear doctor letter regarding oligohidrosis and hyperthermia in pediatric patients. San Diego, CA: Elan Pharmaceuticals; 2002. From the FDA website.

14. Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

15. Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

16. Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website.

17. Kalinin VV. Suicidality and antiepileptic drugs: is there a link?. Drug Saf. 2007; 30:123-42.

18. Kawada K, Itoh S, Kusaka T et al. Pharmacokinetics of zonisamide in perinatal period. Brain Dev. 2002; 24:95-7.

19. Food and Drug Administration. FDA Alert: Information for healthcare professionals: zonisamide (marketed as Zonegran, and generics). Rockville, MD; 2009 Feb 23. From the FDA website.

20. Oles KS, Bell WL. Zonisamide concentrations during pregnancy. Ann Pharmacother. 2008; 42:1139-41.

21. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website.

22. Lee YJ, Kang HC, Seo JH et al. Efficacy and tolerability of adjunctive therapy with zonisamide in childhood intractable epilepsy. Brain Dev. 2009; Mar 20:[epub ahead of print].

23. Coppola G, Grosso S, Verrotti A et al. Zonisamide in children and young adults with refractory epilepsy: an open label, multicenter Italian study. Epilepsy Res. 2009; 83:112-6.

24. Santos CC, Brotherton T. Use of zonisamide in pediatric patients. Pediatr Neurol. 2005; 33:12-4.

25. Wilfong AA. Zonisamide monotherapy for epilepsy in children and young adults. Pediatr Neurol. 2005; 32:77-80.

26. Low PA, James S, Peschel T et al. Zonisamide and associated oligohidrosis and hyperthermia. Epilepsy Res. 2004; 62:27-34.

27. Shinnar S, Pellock JM, Conry JA. Open-label, long-term safety study of zonisamide administered to children and adolescents with epilepsy. Eur J Paediatr Neurol. 2009; 13:3-9.

28. Griffith SG, Dai Y. Effect of zonisamide on the pharmacokinetics and pharmacodynamics of a combination ethinyl estradiol-norethindrone oral contraceptive in healthy women. Clin Ther.. 2004; 26:2056-65.