AHFS Class:

• Ion Channel Inhibition Agents 28:12.24

Generic Name(s):

• Zonisamide

Zonisamide, a sulfonamide, is an anticonvulsant.1,2,3

Seizure Disorders

Partial Seizures

Zonisamide is used as adjunctive therapy (i.e., in combination with other anticonvulsants) in the management of partial seizures in adults with epilepsy.1,2,3,8

Efficacy of zonisamide as adjunctive therapy was established in 3 multicenter, placebo-controlled, double-blind clinical trials in patients who had refractory partial-onset seizures with or without secondary generalization while receiving a regimen of 1 or 2 anticonvulsants and had experienced at least 4 partial seizures during each month of the baseline period.1,2,3,8 In one study, patients received either placebo or 400 mg of zonisamide daily (200-mg doses given twice daily) for 5 weeks after a 7-week titration period.1 In the other 2 studies, patients received either placebo or 400-600 mg of zonisamide daily (given in 1 or 2 daily doses; average maintenance dosages were either 530 or 430 mg daily) for about 8 weeks after a 4-week titration period.1,2,3 In these studies, patients receiving zonisamide experienced substantially greater percent reduction in partial seizure frequency from baseline compared with those receiving placebo.1 In addition, more patients receiving zonisamide had a reduction in seizure frequency of 50% or greater from baseline (i.e., responder rate) compared with placebo-treated patients.1,3,8 The efficacy of zonisamide reportedly is not affected by age, gender, or race.1

Administration

Zonisamide is administered orally once or twice daily (except the initial daily dosage of 100 mg, which is administered once daily), without regard to meals.1,2,3 The capsules should be swallowed intact.1 Patients should be encouraged to drink plenty of fluids while taking the drug to reduce the risk of kidney stones.1

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

Patients currently receiving or beginning therapy with zonisamide and/or any other anticonvulsant should be closely monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.1,14,15,21 (See Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Dosage

The initial dosage of zonisamide as adjunctive therapy for partial seizures in adults and children older than 16 years of age is 100 mg daily.1,2,3,9 After 2 weeks, the dosage may be increased to 200 mg daily for at least 2 weeks.1,3 Dosage can further be increased to 300 and 400 mg daily with at least 2 weeks between dosage changes to achieve steady state at each dosage level.1,2,3,9 Results of controlled clinical trials suggest that zonisamide dosages of 100-600 mg daily are effective;1,2,10 however, dosages exceeding 400 mg daily may not be associated with increased therapeutic benefit.1 There is only limited experience with zonisamide dosages exceeding 600 mg daily.1 The manufacturer states that although this dosage regimen has been shown to be tolerated, some clinicians may prefer to administer lower dosages of zonisamide for longer periods in order to fully assess safety of zonisamide at steady state, since adverse effects occur more frequently at dosages of 300 mg daily and higher.1

Special Populations

Since zonisamide is metabolized in the liver and excreted principally by the kidneys, the drug should be used with caution in patients with renal or hepatic impairment; such patients may require slower dosage titration and more frequent monitoring.1,2 Zonisamide should not be used in patients with renal failure (glomerular filtration rate [GFR] less than 50 mL/minute).1

Although there are no specific dosage recommendations for zonisamide in geriatric patients, dosage selection generally should be cautious, 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

Contraindications

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

Warnings/Precautions

Warnings

Dermatologic and Sensitivity Reactions

Because zonisamide is a sulfonamide, potentially fatal reactions may occur as a result of severe reactions to sulfonamides.1 Such reactions have included Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias, regardless of the route of administration.1,2,7 Zonisamide should be discontinued immediately if signs or symptoms of hypersensitivity occur.1

Rash (usually occurring early in treatment and not dose related) has been reported with zonisamide in clinical studies and has resulted in discontinuance of therapy in some patients.1 At least 49 cases of severe rash (Stevens-Johnson syndrome or toxic epidermal necrolysis) have been reported during postmarketing experience with the drug in Japan; no confirmed cases have been reported to date in the US.1 Discontinuance of zonisamide should be considered in patients who develop an unexplained rash; if the drug is continued, the patient should be observed frequently.1

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening reaction, has been reported with zonisamide.1 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1 However, signs and symptoms associated with other organ systems also may occur.1 If signs and symptoms of DRESS occur during zonisamide therapy, patients should be evaluated immediately; if an alternative cause cannot be identified, the drug should be discontinued.1

Hematologic Effects

Aplastic anemia and agranulocytosis have been reported rarely in patients receiving zonisamide; a relationship between these events and dosage or duration of zonisamide therapy has not been established.1,2

Oligohidrosis and Hyperthermia

Oligohidrosis (a reduction in sweating) and hyperthermia have been reported in patients receiving zonisamide, particularly in pediatric patients.1,13,26 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.) Patients receiving zonisamide should be monitored closely for evidence of decreased sweating and increased body temperature, particularly in warm or hot weather.1,13,26 The risk of hyperthermia also should be considered when zonisamide is used concomitantly with other drugs that predispose patients to heat-related disorders.1,13 (See Drug Interactions: Drugs Predisposing to Heat-related Disorders.)

Suicidality Risk

An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of studies using various anticonvulsants, including zonisamide, compared with placebo.1,14,15,21 The analysis of suicidality reports from 199 placebo-controlled studies involving 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1,14,15 This increased risk of suicidality was observed as early as one week after beginning therapy and continued through 24 weeks.1,14,15 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased risk of suicidality compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1,14,15

Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy; all patients currently receiving or beginning therapy with any anticonvulsant should be closely monitored for the emergence or worsening of suicidal thoughts or behavior or depression.1,14,15,21

Clinicians who prescribe zonisamide or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness.1,15 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1,21 If suicidal thoughts or behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.1,21 (See Advice to Patients.)

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate concentrations to below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in patients receiving zonisamide.1 Metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase.1 Manifestations of acute or chronic metabolic acidosis may include hyperventilation, fatigue, and anorexia, and more severe symptoms may include cardiac arrhythmias and stupor.1,19 Zonisamide-induced metabolic acidosis generally occurs early in treatment, but may occur at any time during therapy.1,19 The risk of developing metabolic acidosis appears greater at higher dosages of zonisamide, but it can occur with dosages as low as 25 mg daily.1,19 Certain conditions or therapies, including renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diets, or other drugs (e.g., acetazolamide), may predispose patients to acidosis.1,19 In addition, zonisamide-induced metabolic acidosis appears to be more frequent and severe in pediatric patients.1,19 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Decreases in serum bicarbonate concentrations usually are mild to moderate (average decrease of approximately 2-4 mEq/L) in adults; however, some adults have experienced severe decreases (as much as 10 mEq/L below their baseline).1,19 In placebo-controlled studies evaluating zonisamide monotherapy for the treatment of epilepsy† or for migraine prophylaxis† in adults, the incidence of persistent, treatment-emergent decreases in serum bicarbonate (to below 20 mEq/L) ranged from 21% in patients treated with 25 or 100 mg daily to 43% in patients treated with 300 mg daily; the incidence of persistent, abnormally low serum bicarbonate (decrease to less than 17 mEq/L and more than 5-mEq/L decrease from pretreatment value of at least 20 mEq/L) was 2% or less across all dosages studied.1,19 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.1,19 (See Renal Effects under Warnings/Precautions: General Precautions, in Cautions.)

Serum bicarbonate concentrations should be measured prior to and periodically during zonisamide therapy.1,19 Serum bicarbonate also should be measured if signs or symptoms of metabolic acidosis are observed.19 If metabolic acidosis develops and persists, consideration should be given to reducing the dosage or discontinuing zonisamide therapy (by gradually tapering the dosage) and modifying the patient's anticonvulsant drug regimen as appropriate.1,19 If the decision is made to continue zonisamide in the presence of persistent acidosis, alkali treatment should be considered.1,19

Discontinuance of Therapy

Because of the possibility of increased seizure frequency or status epilepticus if zonisamide is abruptly withdrawn in patients with epilepsy, the drug should be withdrawn gradually and dosage should be reduced slowly.1

Fetal/Neonatal Morbidity and Mortality

There is a possibility that zonisamide can cause fetal harm when administered during pregnancy.1 There are no adequate and well-controlled studies of zonisamide in pregnant women; however, the drug has produced teratogenic effects and embryolethality in several species of animals when administered during the period of organogenesis at clinically relevant dosages.1 Fetal abnormalities included cardiovascular, skeletal, and craniofacial malformations, and fetal growth retardation.1 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Cognitive/Neuropsychiatric Effects

Neuropsychiatric effects reported during zonisamide treatment are classified into 3 categories: somnolence or fatigue; psychiatric symptoms (e.g., depression, psychosis); and impaired psychomotor or cognitive performance including difficulties in concentrating, language, speech, and word finding.1,3,5,15,17 (See Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Somnolence and fatigue were frequently reported in patients receiving zonisamide, particularly at higher dosages, in clinical studies.1 Such effects generally occurred during the first month of treatment and with dosages of 300-500 mg daily.1

General Precautions

Renal Effects

Clinically possible or confirmed renal calculi (kidney stones), composed of calcium or urate salts, were reported in 4% of patients with epilepsy receiving zonisamide.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; however, whether these measures reduce the risk of kidney stone formation in patients receiving zonisamide is not known.1

Substantial increases (8%) in mean serum creatinine and blood urea nitrogen (BUN) concentrations occurred in patients receiving zonisamide.1 Such increases appeared to persist over time, but were not progressive.1 Periodic monitoring of renal function should be considered during zonisamide therapy.1 The drug should be discontinued in patients who develop acute renal failure or clinically important sustained increases in serum creatinine and BUN concentrations.1 In addition, zonisamide should not be used in patients with renal failure (glomerular filtration rate [GFR] less than 50 mL/minute) since there has been insufficient experience concerning drug dosing and toxicity in such patients.1

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, the incidence of status epilepticus in patients receiving the drug was 1%.1

Specific Populations

Pregnancy

Zonisamide may cause fetal harm; the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1 Women of childbearing potential should be advised to use effective contraception during zonisamide therapy.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Women who are pregnant while receiving zonisamide should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry; patients can enroll by calling 888-233-2334.1 Information on the registry also can be found on the website [Web].1

Zonisamide therapy can cause metabolic acidosis.1 (See Metabolic Acidosis under Warnings/Precautions: Warnings, in Cautions.) The effect of zonisamide-induced metabolic acidosis has not been specifically studied during pregnancy; however, metabolic acidosis from other causes during pregnancy can result in decreased fetal growth, decreased fetal oxygenation, and fetal death, and also may affect the ability of the fetus to tolerate labor.1 Therefore, pregnant women receiving zonisamide should be monitored and treated for metabolic acidosis in the same manner as nonpregnant patients.1 In addition, neonates born to women treated with zonisamide should be monitored for metabolic acidosis because of possible drug transfer to the fetus and possible occurrence of transient metabolic acidosis following birth.1

Some clinicians recommend closely monitoring plasma zonisamide concentrations and adjusting zonisamide dosage as necessary in pregnant women.20

Lactation

Zonisamide is distributed into milk.1,18,19 Because of the potential for serious adverse reactions to zonisamide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy of zonisamide in children younger than 16 years of age have not been established.1,19,26 However, the drug has been used for the treatment of epilepsy in some pediatric patients†; studies conducted with pediatric patients indicate that the frequency of some adverse effects (e.g., metabolic acidosis, oligohidrosis and hyperthermia) may be increased compared with adults.1,19,22,23,24,25,26,27

Oligohidrosis and hyperthermia, characterized by decreased sweating and abnormally high body temperatures, have been reported in pediatric patients (1.6-17 years of age) receiving zonisamide and have sometimes resulted in heat stroke and hospitalization.1,2,3,11,13,26,27 (See Oligohidrosis and Hyperthermia under Warnings/Precautions: Warnings, in Cautions.) As of December 31, 2001, there were 40 reported cases of oligohidrosis and hyperthermia in patients receiving zonisamide, including 38 in the first 11 years of marketing in Japan (approximately one case per 10,000 patient-years of exposure) and 2 in the first year of marketing in the US (approximately 12 cases per 10,000 patient-years of exposure).1,13 However, it generally is recognized that postmarketing data are subject to underreporting.1,13 In many of the reported cases, oligohidrosis and hyperthermia occurred after exposure to elevated environmental temperatures; in some cases, heat stroke requiring hospitalization resulted.1,13,26 There have been no reported deaths associated with these adverse effects thus far.1,13

If zonisamide is used in pediatric patients (not an FDA-labeled population), they should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather or when other drugs that predispose patients to heat-related disorders (e.g., carbonic anhydrase inhibitors) are used concomitantly.1,13,26 (See Drug Interactions: Drugs Predisposing to Heat-related Disorders.)

Pediatric patients may be at increased risk for zonisamide-induced metabolic acidosis and the condition may be more severe in younger patients.1,19 In an open-label trial evaluating adjunctive zonisamide therapy in pediatric patients 3-16 years of age with partial epilepsy, the incidence of a persistent decrease in serum bicarbonate to levels less than 20 mEq/L was up to 90% and generally increased with higher dosages.1,19 The incidence of persistent and abnormally low serum bicarbonate values (less than 17 mEq/L and more than 5 mEq/L decrease from pretreatment value of at least 20 mEq/L) was as high as 18% and appeared to increase with higher dosages.1,19 Although the specific effects of zonisamide on growth and bone have not been studied, chronic metabolic acidosis in pediatric patients can reduce growth rates, resulting in a reduction in the maximal height achieved.1,19 (See Metabolic Acidosis under Warnings/Precautions: Warnings, in Cautions and see also Advice to Patients.)

Geriatric Use

Clinical studies of zonisamide did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adults.1 Other reported clinical experience has not identified differences in responses between geriatric and younger patients.1 Pharmacokinetics were similar in geriatric and young healthy volunteers in single-dose studies.1 (See Dosage and Administration: Special Populations.)

Hepatic Impairment

Because zonisamide is metabolized in the liver, the drug should be used with caution in patients with hepatic impairment.1 (See Dosage and Administration: Special Populations.)

Renal Impairment

Because zonisamide is eliminated principally by the kidneys, the drug should be used with caution in patients with renal impairment.1 (See Dosage and Administration: Special Populations.)

Zonisamide should not be used in patients with renal failure (glomerular filtration rate [GFR] less than 50 mL/minute).1

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, and diplopia1,2,3,8,9,17 were reported in 2% or more patients in clinical studies in which zonisamide was administered in conjunction with other anticonvulsants.1

Drugs Metabolized by or Affecting Hepatic Microsomal Enzymes

Zonisamide is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1 Concomitant use of drugs that inhibit or induce CYP3A4 may alter the pharmacokinetics of zonisamide.1 The interaction with CYP3A4 inhibitors is not expected to be clinically important based on studies with known CYP3A4 inhibitors (e.g., ketoconazole, cimetidine). 2 Dosage adjustment of zonisamide is not necessary when administered concomitantly with CYP3A4 inhibitors.1 Clinically important changes in zonisamide concentrations can occur when concomitant CYP3A4-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, rifampin) are introduced or withdrawn from therapy, or dosage is adjusted.1 Patients receiving such concomitant therapy should be closely monitored, and dosage of zonisamide adjusted as necessary.1

Zonisamide is not expected to alter the pharmacokinetics of drugs metabolized by CYP isoenzymes.1 In vitro studies indicate that the drug does not substantially inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4, 2B6, or 2C8.1 Concomitant administration of zonisamide and desipramine (a probe substrate for CYP2D6) did not substantially alter the pharmacokinetics of desipramine.1

Drugs Affected by P-Glycoprotein

In vitro studies indicate that zonisamide is a weak inhibitor of P-glycoprotein (P-gp) and may potentially affect the pharmacokinetics of P-gp substrates (e.g., digoxin, quinidine).1

Drugs Affected by Uridine Diphosphate-glucuronosyltransferases

Zonisamide is not expected to interact with drugs that are metabolized by uridine diphosphate-glucuronosyltransferases (UGT) enzymes.1

Drugs Predisposing to Heat-related Disorders

Increased risk of oligohidrosis and hyperthermia is possible with concomitant use of zonisamide and drugs that predispose patients to heat-related disorders (e.g., carbonic anhydrase inhibitors, drugs with anticholinergic activity); caution is advised when topiramate is used in combination with such drugs.1 (See Oligohidrosis and Hyperthermia under Warnings/Precautions: Warnings, in Cautions.)

Anticonvulsants

Zonisamide does not appear to affect steady-state plasma concentrations of phenytoin, carbamazepine, lamotrigine, or valproic acid.1,2,8 However, other anticonvulsants may alter pharmacokinetics of zonisamide.1,2 In patients receiving zonisamide concomitantly with CYP3A4-inducing anticonvulsants (phenytoin, carbamazepine, or phenobarbital), plasma clearance of zonisamide is increased and half-life is decreased,1,2,3 which may result in reduced plasma concentrations of zonisamide; dosage increase of zonisamide may be required.1,2 (See Drug Interactions: Drugs Metabolized by or Affecting Hepatic Microsomal Enzymes.)1

Carbonic Anhydrase Inhibitors

Zonisamide is a carbonic anhydrase inhibitor; concomitant use of other carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, topiramate) may increase the risk of metabolic acidosis and also may increase the risk of kidney stone formation.1,19 (See Metabolic Acidosis under Warnings/Precautions: Warnings, in Cautions.) If zonisamide is used concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the onset or worsening of metabolic acidosis.1,13,26 (See Oligohidrosis and Hyperthermia under Warnings/Precautions: Warnings, in Cautions.)

Cimetidine

In healthy individuals, cimetidine (a known CYP3A4 inhibitor) did not have a clinically important effect on the single-dose pharmacokinetics of zonisamide.1,21

CNS Depressants

Additive CNS effects (e.g., somnolence, fatigue) are possible if zonisamide is used concomitantly with alcohol or other CNS depressants.1 (See Advice to Patients.)

Ketoconazole

In healthy individuals, ketoconazole (a known CYP3A4 inhibitor) did not have a clinically important effect on the single-dose pharmacokinetics of zonisamide.1

Oral Contraceptives

Pharmacokinetic interaction is unlikely.28 In healthy individuals, concomitant use of zonisamide and an oral contraceptive containing ethinyl estradiol and norethisterone did not alter concentrations of either component of the contraceptive.1

Pharmacokinetics

Absorption

Bioavailability

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

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

Distribution

Extent

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

Zonisamide crosses the placenta18 and is distributed into breast milk.18,19

Plasma Protein Binding

Approximately 40%.1

Elimination

Metabolism

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 cytochrome P450 (CYP) 3A4.1,2,3

Does not induce own metabolism.1

Elimination Route

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

Half-life

About 63 hours.1,3

Special Populations

In patients with marked renal impairment (creatinine clearance of 20 mL/minute or less), systemic exposure of zonisamide was increased by 35%.1 Renal clearance decreases with decreasing renal function.1

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

Limited data suggest that clearance of zonisamide may be increased at the end of the second trimester in pregnant women.20

Description

Zonisamide, a sulfonamide, is an anticonvulsant agent that is structurally and chemically unrelated to other currently available anticonvulsants.1,2,3,6 The exact mechanism of action of the drug is not known; however, the anticonvulsant activity of zonisamide may be associated with the drug's sodium- and calcium-channel blocking activities.1,2,3,9 The drug may potentiate dopaminergic and serotonergic neurotransmission1,2,3 but does not appear to potentiate the synaptic activity of γ-aminobutyric acid (GABA).1 Although zonisamide exhibits weak carbonic anhydrase inhibiting activity,1,2,3 such an effect is not thought to contribute substantially to the anticonvulsant activity of the drug.1

In animal models, zonisamide protects against electroshock-induced tonic extension seizures, increases generalized seizure threshold, and reduces duration of cortical focal seizures induced by electrical current, but offers no protection against clonic seizures induced by pentylenetetrazol.1,3,10 In addition, zonisamide reduces EEG interictal spike activity and secondarily generalized seizures induced by chemoconvulsants.1,3 The relevance of these findings to humans is not known.1

Zonisamide is rapidly and almost completely absorbed following oral administration as capsules and oral bioavailability of the drug is nearly 100%.3 Steady-state plasma concentrations of zonisamide are not reached for up to 2 weeks because of the drug's long half-life (about 63 hours).1,3 Zonisamide 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 cytochrome P-450 (CYP) isoenzyme 3A4.1,2,3 Zonisamide is excreted principally in urine as unchanged drug and a glucuronide metabolite.1,2,3

Advice to Patients

Importance of instructing patients to read the patient information (medication guide) prior to initiating zonisamide therapy.1,21

Importance of patients taking zonisamide exactly as prescribed.1

Risk of serious skin rash that can cause death; these skin reactions are more likely to happen within the first 4 months of 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 red and white blood cell counts.1 Importance of contacting clinician if fever, sore throat, sores in the mouth, or unusual bruising occurs.1

Importance of patients, family members, and caregivers being aware that anticonvulsants, including zonisamide, may increase the risk of having suicidal thoughts or actions in a very small number of people (about 1 in 500).1,15,21 Advise patients, family members, and caregivers to pay close attention to any day-to-day changes in mood, behavior, and actions; these changes can happen very quickly.1,15 They should also be aware of common warning signs that may signal suicide risk (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 Advise patients, family members, and caregivers to contact the responsible clinician immediately if these or any new and worrisome behaviors occur.1,15

Importance of advising patients that zonisamide may cause metabolic acidosis and that blood tests to measure serum bicarbonate concentrations may be performed.1,19 Patients should contact their clinician immediately if they develop symptoms of metabolic acidosis such as fast breathing (hyperventilation), fatigue, and loss of appetite; more severe symptoms may include an irregular heart beat, palpitations, or unconsciousness.1,19

Potential for drowsiness, especially at higher dosages.1 Importance of advising patients to avoid driving or operating complex machinery while taking zonisamide until experience with the drug's effects has been established.1 Because of the potential for additive CNS effects, patients should be advised to use caution when consuming alcohol or taking concomitant CNS depressants.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 or plan to breast-feed.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 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 (including acetazolamide), 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 advising patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Esai. Zonegran^® (zonisamide) capsules prescribing information. Woodcliff Lake, NJ; 2017 Feb.

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. [PubMed 8453952]

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