Zonisamide

Zonisamide
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]

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Overview

Zonisamide is an antiepileptic that is FDA approved for the {{{indicationType}}} of partial seizure. Common adverse reactions include pruritus, loss of appetite, ataxia, dizziness, somnolence, amblyopia, agitation, depression and disturbance in speech.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Partial Seizures

• Zonisamide capsules, USP are indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

• Zonisamide capsules are recommended as adjunctive therapy for the treatment of partial seizures in adults. Safety and efficacy in pediatric patients below the age of 16 have not been established. Zonisamide capsules should be administered once or twice daily, using 25 mg, 50 mg or 100 mg capsules. Zonisamide capsules are given orally and can be taken with or without food. Capsules should be swallowed whole.

• Adults over Age 16

• The prescriber should be aware that, because of the long half-life of zonisamide, up to two weeks may be required to achieve steady state levels upon reaching a stable dose or following dosage adjustment. Although the regimen described below is one that has been shown to be tolerated, the prescriber may wish to prolong the duration of treatment at the lower doses in order to fully assess the effects of zonisamide at steady state, noting that many of the side effects of zonisamide are more frequent at doses of 300 mg per day and above. Although there is some evidence of greater response at doses above 100 to 200 mg/day, the increase appears small and formal dose-response studies have not been conducted.
• The initial dose of zonisamide capsules should be 100 mg daily. After two weeks, the dose may be increased to 200 mg/day for at least two weeks. It can be increased to 300 mg/day and 400 mg/day, with the dose stable for at least two weeks to achieve steady state at each level. Evidence from controlled trials suggests that zonisamide capsules doses of 100 to 600 mg/day are effective, but there is no suggestion of increasing response above 400 mg/day. There is little experience with doses greater than 600 mg/day.

• Patients with Renal or Hepatic Disease

• Because zonisamide is metabolized in the liver and excreted by the kidneys, patients with renal or hepatic disease should be treated with caution, and might require slower titration and more frequent monitoring.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Zonisamide in adult patients.

Non–Guideline-Supported Use

Migraine, Refractory; Prophylaxis

• Oral Zonisamide, initially at a dose of 100 mg/day. Based on tolerance, dosage was increased in 100-mg increments weekly over 3 weeks to 400 mg/day.

Parkinson's disease

• 12 weeks of zonisamide 25 mg.

Partial seizure, Monotherapy for newly diagnosed or untreated epilepsy

• Oral Zonisamide 200 to 500 mg once daily.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Zonisamide in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Zonisamide in pediatric patients.

Non–Guideline-Supported Use

Migraine, Refractory; Prophylaxis

• Oral Zonisamide 5.8 mg/kg.

Contraindications

• Zonisamide capsules are contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or zonisamide.

Warnings

• Potentially Fatal Reactions to Sulfonamides

• Fatalities have occurred, although rarely, as a result of severe reactions to sulfonamides (zonisamide is a sulfonamide) including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Such reactions may occur when a sulfonamide is readministered irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur, discontinue zonisamide immediately. Specific experience with sulfonamide-type adverse reaction to zonisamide is described below.

• Serious Skin Reactions

• Consideration should be given to discontinuing zonisamide capsules in patients who develop an otherwise unexplained rash. If the drug is not discontinued, patients should be observed frequently. Seven deaths from severe rash [i.e. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)] were reported in the first 11 years of marketing in Japan. All of the patients were receiving other drugs in addition to zonisamide. In post-marketing experience from Japan, a total of 49 cases of SJS or TEN have been reported, a reporting rate of 46 per million patient-years of exposure. Although this rate is greater than background, it is probably an underestimate of the true incidence because of under-reporting. There were no confirmed cases of SJS or TEN in the US, European, or Japanese development programs.
• In the US and European randomized controlled trials, 6 of 269 (2.2%) zonisamide patients discontinued treatment because of rash compared to none on placebo. Across all trials during the US and European development, rash that led to discontinuation of zonisamide was reported in 1.4% of patients (12.0 events per 1000 patient-years of exposure). During Japanese development, serious rash or rash that led to study drug discontinuation was reported in 2.0% of patients (27.8 events per 1000 patient years). Rash usually occurred early in treatment, with 85% reported within 16 weeks in the US and European studies and 90% reported within two weeks in the Japanese studies. There was no apparent relationship of dose to the occurrence of rash.

• Serious Hematologic Events

• Two confirmed cases of aplastic anemia and one confirmed case of agranulocytosis were reported in the first 11 years of marketing in Japan, rates greater than generally accepted background rates. There were no cases of aplastic anemia and two confirmed cases of agranulocytosis in the US, European, or Japanese development programs.
• There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events.

• Oligohidrosis and Hyperthermia in Pediatric Patients

• Oligohidrosis, sometimes resulting in heat stroke and hospitalization, is seen in association with zonisamide in pediatric patients.
• During the pre-approval development program in Japan, one case of oligohidrosis was reported in 403 pediatric patients, an incidence of 1 case per 285 patient-years of exposure. While there were no cases reported in the US or European development programs, fewer than 100 pediatric patients participated in these trials.
• In the first 11 years of marketing in Japan, 38 cases were reported, an estimated reporting rate of about 1 case per 10,000 patient-years of exposure. In the first year of marketing in the US, 2 cases were reported, an estimated reporting rate of about 12 cases per 10,000 patient-years of exposure. These rates are underestimates of the true incidence because of under-reporting. There has also been one report of heat stroke in an 18-year-old patient in the US.
• Decreased sweating and an elevation in body temperature above normal characterized these cases. Many cases were reported after exposure to elevated environmental temperatures. Heat stroke, requiring hospitalization, was diagnosed in some cases. There have been no reported deaths.
• Pediatric patients appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia. Patients, especially pediatric patients, treated with zonisamide capsules should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. Caution should be used when zonisamide is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, carbonic anhydrase inhibitors and drugs with anticholinergic activity.
• The practitioner should be aware that the safety and effectiveness of zonisamide in pediatric patients have not been established, and that zonisamide is not approved for use in pediatric patients.

• Suicidal Behavior and Ideation

• Antiepileptic drugs (AEDs), including zonisamide capsules, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
• Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
• The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
• The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
• Table 3 shows absolute and relative risk by indication for all evaluated AEDs.

This image is provided by the National Library of Medicine.

• The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
• Anyone considering prescribing zonisamide capsules or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
• Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

• Metabolic Acidosis

• Zonisamide causes hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase.
• Generally, zonisamide-induced metabolic acidosis occurs early in treatment, but it can develop at any time during treatment. Metabolic acidosis generally appears to be dose-dependent and can occur at doses as low as 25 mg daily.
• Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of zonisamide.
• Some manifestations of acute or chronic metabolic acidosis include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated, metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis. Nephrolithiasis has been observed in the clinical development program in 4 % of adults treated with zonisamide, has also been detected by renal ultrasound in 8 % of pediatric treated patients who had at least one ultrasound prospectively collected, and was reported as an adverse event in 3 % (4/133) of pediatric patients.
• Chronic, untreated metabolic acidosis may result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fracture. Of potential relevance, zonisamide treatment was associated with reductions in serum phosphorus and increases in serum alkaline phosphatase, changes that may be related to metabolic acidosis and osteomalacia.
• Chronic, untreated metabolic acidosis in pediatric patients may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of zonisamide on growth and bone-related sequelae has not been systematically investigated.
• Measurement of baseline and periodic serum bicarbonate during treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing zonisamide (using dose tapering). If the decision is made to continue patients on zonisamide in the face of persistent acidosis, alkali treatment should be considered.
• Serum bicarbonate was not measured in the adjunctive controlled trials of adults with epilepsy. However, serum bicarbonate was studied in three clinical trials for indications which have not been approved: a placebo-controlled trial for migraine prophylaxis in adults, a controlled trial for monotherapy in epilepsy in adults, and an open label trial for adjunctive treatment of epilepsy in pediatric patients (3 to 16 years). In adults, mean serum bicarbonate reductions ranged from approximately 2 mEq/L at daily doses of 100 mg to nearly 4 mEq/L at daily doses of 300 mg. In pediatric patients, mean serum bicarbonate reductions ranged from approximately 2 mEq/L at daily doses from above 100 mg up to 300 mg, to nearly 4 mEq/L at daily doses from above 400 mg up to 600 mg.
• In two controlled studies in adults, the incidence of a persistent treatment-emergent decrease in serum bicarbonate to less than 20 mEq/L (observed at 2 or more consecutive visits or the final visit) was dose-related at relatively low zonisamide doses. In the monotherapy trial of epilepsy, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 21% for daily zonisamide doses of 25 mg or 100 mg, and was 43% at a daily dose of 300 mg. In a placebo-controlled trial for prophylaxis of migraine, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 7% for placebo, 29% for 150 mg daily, and 34% for 300 mg daily. The incidence of persistent markedly abnormally low serum bicarbonate (decrease to less than 17 mEq/L and more than 5 mEq/L) from a pretreatment value of at least 20 mEq/L in these controlled trials was 2% or less.
• In the pediatric study, the incidence of persistent, treatment-emergent decreases in serum bicarbonate to levels less than 20 mEq/L was 52% at doses up to 100 mg daily, was 90% for a wide range of doses up to 600 mg daily, and generally appeared to increase with higher doses. The incidence of a persistent markedly abnormally low serum bicarbonate value was 4 % at doses up to 100 mg daily, was 18% for a wide range of doses up to 600 mg daily, and generally appeared to increase with higher doses. Some patients experienced moderately severe serum bicarbonate decrements down to a level as low as 10 mEq/L.
• The relatively high frequencies of varying severities of metabolic acidosis observed in this study of pediatric patients (compared to the frequency and severity observed in various clinical trial development programs in adults) suggest that pediatric patients may be more likely to develop metabolic acidosis than adults.

• Seizures on Withdrawal

• As with other AEDs, abrupt withdrawal of zonisamide capsules in patients with epilepsy may precipitate increased seizure frequency or status epilepticus. Dose reduction or discontinuation of zonisamide should be done gradually.

• Teratogenicity

• Women of child bearing potential 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. A variety of fetal abnormalities, including cardiovascular defects, and embryo-fetal deaths occurred at maternal plasma levels similar to or lower than therapeutic levels in humans. These findings suggest that the use of zonisamide capsules during pregnancy in humans may present a significant risk to the fetus (see PRECAUTIONS, Pregnancy subsection). Zonisamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Cognitive/ Neuropsychiatric Adverse Events

• Use of zonisamide capsules was frequently associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) psychiatric symptoms, including depression and psychosis, 2) psychomotor slowing, difficulty with concentration, and speech or language problems, in particular, word-finding difficulties, and 3) somnolence or fatigue.
• In placebo-controlled trials, 2.2% of patients discontinued zonisamide capsules or were hospitalized for depression compared to 0.4% of placebo patients. Among all epilepsy patients treated with zonisamide capsules, 1.4% were discontinued and 1.0% were hospitalized because of reported depression or suicide attempts. In placebo-controlled trials, 2.2% of patients discontinued zonisamide capsules or were hospitalized due to psychosis or psychosis-related symptoms compared to none of the placebo patients. Among all epilepsy patients treated with zonisamide capsules, 0.9% were discontinued and 1.4% were hospitalized because of reported psychosis or related symptoms.
• Psychomotor slowing and difficulty with concentration occurred in the first month of treatment and were associated with doses above 300 mg/day. Speech and language problems tended to occur after 6 to 10 weeks of treatment and at doses above 300 mg/day. Although in most cases these events were of mild to moderate severity, they at times led to withdrawal from treatment.
• Somnolence and fatigue were frequently reported CNS adverse events during clinical trials with zonisamide capsules. Although in most cases these events were of mild to moderate severity, they led to withdrawal from treatment in 0.2% of the patients enrolled in controlled trials. Somnolence and fatigue tended to occur within the first month of treatment. Somnolence and fatigue occurred most frequently at doses of 300 to 500 mg/day. Patients should be cautioned about this possibility and special care should be taken by patients if they drive, operate machinery, or perform any hazardous task.

Precautions

• General

• Somnolence is commonly reported, especially at higher doses of zonisamide capsules (see WARNINGS,Cognitive/ Neuropsychiatric Adverse Events subsection). Zonisamide is metabolized by the liver and eliminated by the kidneys; caution should therefore be exercised when administering zonisamide capsules to patients with hepatic and renal dysfunction.

• Kidney Stones

• Among 991 patients treated during the development of zonisamide capsules, 40 patients (4.0%) with epilepsy receiving zonisamide capsules developed clinically possible or confirmed kidney stones (e.g. clinical symptomatology, sonography, etc.), a rate of 34 per 1000 patient-years of exposure (40 patients with 1168 years of exposure). Of these, 12 were symptomatic, and 28 were described as possible kidney stones based on sonographic detection. In nine patients, the diagnosis was confirmed by a passage of a stone or by a definitive sonographic finding. The rate of occurrence of kidney stones was 28.7 per 1000 patient-years of exposure in the first six months, 62.6 per 1000 patient-years of exposure between 6 and 12 months, and 24.3 per 1000 patient-years of exposure after 12 months of use. There are no normative sonographic data available for either the general population or patients with epilepsy. Although the clinical significance of the sonographic findings may not be certain, the development of nephrolithiasis may be related to metabolic acidosis. The analyzed stones were composed of calcium or urate salts. In general, increasing fluid intake and urine output can help reduce the risk of stone formation, particularly in those with predisposing risk factors. It is unknown, however, whether these measures will reduce the risk of stone formation in patients treated with zonisamide capsules.
• Although not approved in pediatric patients, sonographic findings consistent with nephrolithiasis were also detected in 8 % of a subset of zonisamide treated pediatric patients who had at least one renal ultrasound prospectively performed in a clinical development program investigating open-label treatment. The incidence of kidney stone as an adverse event was 3 %.

• Effect on Renal Function

• In several clinical studies, zonisamide was associated with a statistically significant 8% mean increase from baseline of serum creatinine and blood urea nitrogen (BUN) compared to essentially no change in the placebo patients. The increase appeared to persist over time but was not progressive; this has been interpreted as an effect on glomerular filtration rate (GFR). There were no episodes of unexplained acute renal failure in clinical development in the US, Europe, or Japan. The decrease in GFR appeared within the first 4 weeks of treatment. In a 30-day study, the GFR returned to baseline within 2 to 3 weeks of drug discontinuation. There is no information about reversibility, after drug discontinuation, of the effects on GFR after long-term use. Zonisamide capsules should be discontinued in patients who develop acute renal failure or a clinically significant sustained increase in the creatinine/BUN concentration. Zonisamide capsules should not be used in patients with renal failure (estimated GFR <50 mL/min) as there has been insufficient experience concerning drug dosing and toxicity.

• Sudden Unexplained Death in Epilepsy

• During the development of zonisamide capsules, nine sudden unexplained deaths occurred among 991 patients with epilepsy receiving zonisamide capsules for whom accurate exposure data are available. This represents an incidence of 7.7 deaths per 1000 patient years. Although this rate exceeds that expected in a healthy population, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with refractory epilepsy not receiving zonisamide capsules (ranging from 0.5 per 1000 patient-years for the general population of patients with epilepsy, to 2 to 5 per 1000 patient-years for patients with refractory epilepsy; higher incidences range from 9 to 15 per 1000 patient-years among surgical candidates and surgical failures). Some of the deaths could represent seizure-related deaths in which the seizure was not observed.

• Status Epilepticus

• Estimates of the incidence of treatment emergent status epilepticus in zonisamide capsule-treated patients are difficult because a standard definition was not employed. Nonetheless, in controlled trials, 1.1% of patients treated with zonisamide capsules had an event labeled as status epilepticus compared to none of the patients treated with placebo. Among patients treated with zonisamide capsules across all epilepsy studies (controlled and uncontrolled), 1.0% of patients had an event reported as status epilepticus.

Adverse Reactions

Clinical Trials Experience

• The most commonly observed adverse events related to treatment with zonisamide capsules (an incidence at least 4% greater than placebo) in controlled clinical trials and shown in descending order of frequency were somnolence, anorexia, dizziness, ataxia, agitation/irritability, and difficulty with memory and/or concentration.

• In controlled clinical trials, 12% of patients receiving zonisamide capsules as adjunctive therapy discontinued due to an adverse event compared to 6% receiving placebo. Approximately 21% of the 1,336 patients with epilepsy who received zonisamide capsules in clinical studies discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were somnolence, fatigue and/or ataxia (6%), anorexia (3%), difficulty concentrating (2%), difficulty with memory, mental slowing, nausea/vomiting (2%), and weight loss (1%). Many of these adverse events were dose-related.

Adverse Event Incidence in Controlled Clinical Trials

• Table 4 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with zonisamide capsules in controlled clinical trials that were numerically more common in the zonisamide capsules group. In these studies, either zonisamide capsules or placebo was added to the patient’s current AED therapy. Adverse events were usually mild or moderate in intensity.

• The prescriber should be aware that these figures, obtained when zonisamide capsules were added to concurrent AED therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis by which to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

This image is provided by the National Library of Medicine.

Other Adverse Events Observed During Clinical Trials

• Zonisamide capsules have been administered to 1,598 individuals during all clinical trials, only some of which were placebo-controlled. During these trials, all events were recorded by the investigators using their own terms. To provide a useful estimate of the proportion of individuals having adverse events, similar events have been grouped into a smaller number of standardized categories using a modified COSTART dictionary. The frequencies represent the proportion of the 1,598 individuals exposed to zonisamide capsules who experienced an event on at least one occasion. All events are included except those already listed in the previous table or discussed in WARNINGS or PRECAUTIONS, trivial events, those too general to be informative, and those not reasonably associated with zonisamide capsules.

• Events are further classified within each category and listed in order of decreasing frequency as follows: frequent occurring in at least 1:100 patient; infrequent occurring in 1:100 to 1:1000 patients; rare occurring in fewer than 1:1000 patients.

Body as a Whole

Frequent: Accidental injury, asthenia. Infrequent: Chest pain, flank pain, malaise, allergic reaction, face edema, neck rigidity. Rare: Lupus erythematosus.

Cardiovascular

Infrequent: Palpitation, tachycardia, vascular insufficiency, hypotension, hypertension, thrombophlebitis, syncope, bradycardia. Rare: Atrial fibrillation, heart failure, pulmonary embolus, ventricular extrasystoles.

Digestive

Frequent: Vomiting. Infrequent: Flatulence, gingivitis, gum hyperplasia, gastritis, gastroenteritis, stomatitis, cholelithiasis, glossitis, melena, rectal hemorrhage, ulcerative stomatitis, gastro-duodenal ulcer, dysphagia, gum hemorrhage. Rare: Cholangitis, hematemesis, cholecystitis, cholestatic jaundice, colitis, duodenitis, esophagitis, fecal incontinence, mouth ulceration.

Hematologic and Lymphatic

Infrequent: Leukopenia, anemia, immunodeficiency, lymphadenopathy. Rare: Thrombocytopenia, microcytic anemia, petechia.

Metabolic and Nutritional

Infrequent: Peripheral edema, weight gain, edema, thirst, dehydration. Rare: Hypoglycemia, hyponatremia, lactic dehydrogenase increased, SGOT increased, SGPT increased.

Musculoskeletal

Infrequent: Leg cramps, myalgia, myasthenia, arthralgia, arthritis.

Nervous System

Frequent: Tremor, convulsion, abnormal gait, hyperesthesia, incoordination. Infrequent: Hypertonia, twitching, abnormal dreams, vertigo, libido decreased, neuropathy, hyperkinesia, movement disorder, dysarthria, cerebrovascular accident, hypotonia, peripheral neuritis, reflexes increased. Rare: Dyskinesia, dystonia, encephalopathy, facial paralysis, hypokinesia, hyperesthesia, myoclonus, oculogyric crisis.

Behavioral Abnormalities –Non-Psychosis-Related

Infrequent: Euphoria.

Respiratory

Frequent: Pharyngitis, cough increased. Infrequent: Dyspnea. Rare: Apnea, hemoptysis.

Skin and Appendages

Frequent: Pruritus. Infrequent: Maculopapular rash, acne, alopecia, dry skin, sweating, eczema, urticaria, hirsutism, pustular rash, vesiculobullous rash.

Special Senses

Frequent: Amblyopia, tinnitus. Infrequent: Conjunctivitis, parosmia, deafness, visual field defect, glaucoma. Rare: Photophobia, iritis.

Urogenital

Infrequent: Urinary frequency, dysuria, urinary incontinence, hematuria, impotence, urinary retention, urinary urgency, amenorrhea, polyuria, nocturia. Rare: Albuminuria, enuresis, bladder pain, bladder calculus, gynecomastia, mastitis, menorrhagia.

Postmarketing Experience

• The following serious adverse events have been reported since approval and use of zonisamide worldwide.These reactions are reported voluntarily from a population of uncertain size;therefore,it is not possible to estimate their frequency or establish a causal relationship to drug exposure.

• Acute pancreatitis, rhabdomyolysis,creatine phosphokinase increased.

Drug Interactions

• Effects of zonisamide capsules on the pharmacokinetics of other antiepilepsy drugs (AEDs)

• Zonisamide had no appreciable effect on the steady state plasma concentrations of phenytoin, carbamazepine, or valproate during clinical trials. Zonisamide did not inhibit mixed-function liver oxidase enzymes (cytochrome P450), as measured in human liver microsomal preparations, in vitro. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes.

• Effects of other drugs on zonisamide capsules pharmacokinetics

• Drugs that induce liver enzymes increase the metabolism and clearance of zonisamide and decrease its half-life. The half-life of zonisamide following a 400 mg dose in patients concurrently on enzyme-inducing AEDs such as phenytoin, carbamazepine, or phenobarbital was between 27 to 38 hours; the half-life of zonisamide in patients concurrently on the non-enzyme inducing AED, valproate, was 46 hours. Concurrent medication with drugs that either induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide.

• Interaction with cimetidine

• Zonisamide single dose pharmacokinetic parameters were not affected by cimetidine (300 mg four times a day for 12 days).

• Drug Interactions with CNS Depressants

• Concomitant administration of zonisamide and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of zonisamide to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, zonisamide should be used with caution if used in combination with alcohol or other CNS depressants.

• Other Carbonic Anhydrase Inhibitors

• Concomitant use of zonisamide, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if zonisamide is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category C

• Zonisamide may cause serious adverse fetal effects, based on clinical and nonclinical data. Zonisamide was teratogenic in multiple animal species.

• Zonisamide treatment causes metabolic acidosis in humans. The effect of zonisamide-­induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) may be associated with decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the non-pregnant state.

• Newborns of mothers treated with zonisamide should be monitored for metabolic acidosis because of transfer of zonisamide to the fetus and possible occurrence of transient metabolic acidosis following birth. Transient metabolic acidosis has been reported in neonates born to mothers treated during pregnancy with a different carbonic anhydrase inhibitor.

• Zonisamide was teratogenic in mice, rats, and dogs and embryolethal in monkeys when administered during the period of organogenesis. Fetal abnormalities or embryo-fetal deaths occurred in these species at zonisamide dosage and maternal plasma levels similar to or lower than therapeutic levels in humans, indicating that use of this drug in pregnancy entails a significant risk to the fetus. A variety of external, visceral, and skeletal malformations was produced in animals by prenatal exposure to zonisamide. Cardiovascular defects were prominent in both rats and dogs.

• Following administration of zonisamide (10, 30, or 60 mg/kg/day) to pregnant dogs during organogenesis, increased incidences of fetal cardiovascular malformations (ventricular septal defects, cardiomegaly, various valvular and arterial anomalies) were found at doses of 30 mg/kg/day or greater. The low effect dose for malformations produced peak maternal plasma zonisamide levels (25 mcg/mL) about 0.5 times the highest plasma levels measured in patients receiving the maximum recommended human dose (MRHD) of 400 mg/day. In dogs, cardiovascular malformations were found in approximately 50% of all fetuses exposed to the high dose, which was associated with maternal plasma levels (44 mcg/mL) approximately equal to the highest levels measured in humans receiving the MRHD. Incidences of skeletal malformations were also increased at the high dose, and fetal growth retardation and increased frequencies of skeletal variations were seen at all doses in this study. The low dose produced maternal plasma levels (12 mcg/mL) about 0.25 times the highest human levels.

• In cynomolgus monkeys, administration of zonisamide (10 or 20 mg/kg/day) to pregnant animals during organogenesis resulted in embryo-fetal deaths at both doses. The possibility that these deaths were due to malformations cannot be ruled out. The lowest embryolethal dose in monkeys was associated with peak maternal plasma zonisamide levels (5 mcg/mL) approximately 0.1 times the highest levels measured in patients at the MRHD.

• In a mouse embryo-fetal development study, treatment of pregnant animals with zonisamide (125, 250, or 500 mg/kg/day) during the period of organogenesis resulted in increased incidences of fetal malformations (skeletal and/or craniofacial defects) at all doses tested. The low dose in this study is approximately 1.5 times the MRHD on a mg/m2 basis. In rats, increased frequencies of malformations (cardiovascular defects) and variations (persistent cords of thymic tissue, decreased skeletal ossification) were observed among the offspring of dams treated with zonisamide (20, 60, or 200 mg/kg/day) throughout organogenesis at all doses. The low effect dose is approximately 0.5 times the MRHD on a mg/m2 basis.

• Perinatal death was increased among the offspring of rats treated with zonisamide (10, 30, or 60 mg/kg/day) from the latter part of gestation up to weaning at the high dose, or approximately 1.4 times the MRHD on a mg/m2 basis. The no effect level of 30 mg/kg/day is approximately 0.7 times the MRHD on a mg/m2 basis.

• There are no adequate and well-controlled studies in pregnant women. Zonisamide capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• To provide information regarding the effects of in utero exposure to zonisamide capsules, physicians are advised to recommend that pregnant patients taking zonisamide capsules enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zonisamide in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Zonisamide during labor and delivery.

Nursing Mothers

• Zonisamide is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from zonisamide, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.

Pediatric Use

• The safety and effectiveness of zonisamide capsules in children under age 16 have not been established. Cases of oligohidrosis and hyperpyrexia have been reported. Zonisamide commonly causes metabolic acidosis in pediatric patients. Chronic untreated metabolic acidosis in pediatric patients may cause nephrolithiasis and/or nephrocalcinosis, osteoporosis and/or osteomalacia (potentially resulting in rickets), and may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of zonisamide on growth and bone-related sequelae has not been systematically investigated.

Geriatic Use

• Single dose pharmacokinetic parameters are similar in elderly and young healthy volunteers. Clinical studies of zonisamide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Gender

There is no FDA guidance on the use of Zonisamide with respect to specific gender populations.

Race

There is no FDA guidance on the use of Zonisamide with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Zonisamide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Zonisamide in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Zonisamide in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Zonisamide in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

Monitoring

There is limited information regarding Monitoring of Zonisamide in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Zonisamide in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Experience with zonisamide capsules daily doses over 800 mg/day is limited. During zonisamide capsules clinical development, three patients ingested unknown amounts of zonisamide capsules as suicide attempts, and all three were hospitalized with CNS symptoms. One patient became comatose and developed bradycardia, hypotension, and respiratory depression; the zonisamide plasma level was 100.1 mcg/mL measured 31 hours post-ingestion. Zonisamide plasma levels fell with a half-life of 57 hours, and the patient became alert five days later.

Management

• No specific antidotes for zonisamide capsules overdosage are available. Following a suspected recent overdose, emesis should be induced or gastric lavage performed with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation.

• Zonisamide has a long half-life. Due to the low protein binding of zonisamide (40%), renal dialysis may be effective. The effectiveness of renal dialysis as a treatment of overdose has not been formally studied. A poison control center should be contacted for information on the management of zonisamide capsules overdosage.

Chronic Overdose

There is limited information regarding Chronic Overdose of Zonisamide in the drug label.

Pharmacology

Zonisamide
Systematic (IUPAC) name
benzo[d]isoxazol-3-ylmethanesulfonamide
Identifiers
CAS number	68291-97-4
ATC code	N03AX15
PubChem	5734
DrugBank	DB00909
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	212.227 g/mol
SMILES	eMolecules & PubChem
Physical data
Melt. point	162 °C (324 °F)
Pharmacokinetic data
Bioavailability	~100%
Protein binding	40%
Metabolism	Hepatic through CYP3A4
Half life	63 hours in plasma
Excretion	Renal (62%); Faeces (3%)
Therapeutic considerations
Pregnancy cat.	D(AU) C(US)
Legal status	Prescription Only (S4)(AU) ?(CA) POM(UK) [[Prescription drug|Template:Unicode-only]](US)
Routes	Oral

Mechanism of Action

• The precise mechanism(s) by which zonisamide exerts its antiseizure effect is unknown. Zonisamide demonstrated anticonvulsant activity in several experimental models. In animals, zonisamide was effective against tonic extension seizures induced by maximal electroshock but ineffective against clonic seizures induced by subcutaneous pentylenetetrazol. Zonisamide raised the threshold for generalized seizures in the kindled rat model and reduced the duration of cortical focal seizures induced by electrical stimulation of the visual cortex in cats. Furthermore, zonisamide suppressed both interictal spikes and the secondarily generalized seizures produced by cortical application of tungstic acid gel in rats or by cortical freezing in cats. The relevance of these models to human epilepsy is unknown.

• Zonisamide may produce these effects through action at sodium and calcium channels. In vitro pharmacological studies suggest that zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Ca2+ currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization. In vitro binding studies have demonstrated that zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion which does not produce changes in chloride flux. Other in vitro studies have demonstrated that zonisamide (10 to 30 mcg/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [3H]-GABA (rat hippocampal slices). Thus, zonisamide does not appear to potentiate the synaptic activity of GABA. In vivo microdialysis studies demonstrated that zonisamide facilitates both dopaminergic and serotonergic neurotransmission.

• Zonisamide is a carbonic anhydrase inhibitor. The contribution of this pharmacological action to the therapeutic effects of zonisamide is unknown. However, as a carbonic anhydrase inhibitor, zonisamide may cause metabolic acidosis (see WARNINGS, Metabolic Acidosis subsection).

Structure

• Zonisamide capsules, USP are an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The active ingredient is zonisamide, 1,2- benzisoxazole-3-methanesulfonamide. The molecular formula is C8H8N2O3S with a molecular weight of 212.23. Zonisamide is a white powder, pKa = 10.2, and is soluble in methanol, ethanol, ethyl acetate and acetic acid, sparingly soluble in water, chloroform and n-hexane.

• The chemical structure is:

This image is provided by the National Library of Medicine.

• Each capsule, for oral administration, contains 25 mg, 50 mg or 100 mg of zonisamide. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, microcrystalline cellulose, stearic acid and talc.

• The 25 mg capsule shell contains gelatin and titanium dioxide. The 50 mg capsule shell contains black iron oxide, gelatin and titanium dioxide. The 100 mg capsule shell contains D&C yellow #10, FD&C red #40, gelatin and titanium dioxide.

• The 25 mg and 50 mg capsule imprinting ink contains strong ammonia solution, black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol and shellac.

• The 100 mg capsule imprinting ink contains D&C yellow #10 Aluminum Lake, FD&C blue #1 Aluminum Lake, FD&C blue #2 Aluminum Lake, FD&C red #40 Aluminum Lake, n-butyl alcohol, pharmaceutical glaze, propylene glycol and synthetic black iron oxide.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Zonisamide in the drug label.

Pharmacokinetics

• Following a 200 to 400 mg oral zonisamide dose, peak plasma concentrations (range: 2 to 5 mcg/mL) in normal volunteers occur within 2 to 6 hours. In the presence of food, the time to maximum concentration is delayed, occurring at 4 to 6 hours, but food has no effect on the bioavailability of zonisamide. Zonisamide extensively binds to erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells (RBC) than in plasma. The pharmacokinetics of zonisamide are dose proportional in the range of 200 to 400 mg, but the Cmax and AUC increase disproportionately at 800 mg, perhaps due to saturable binding of zonisamide to RBC. Once a stable dose is reached, steady state is achieved within 14 days. The elimination half-life of zonisamide in plasma is about 63 hours. The elimination half-life of zonisamide in RBC is approximately 105 hours.

• The apparent volume of distribution (V/F) of zonisamide is about 1.45 L/kg following a 400 mg oral dose. Zonisamide, at concentrations of 1.0 to 7.0 mcg/mL, is approximately 40% bound to human plasma proteins. Protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital or carbamazepine.

• Metabolism and Excretion

• Following oral administration of 14C-zonisamide to healthy volunteers, only zonisamide was detected in plasma. Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. Following multiple dosing, 62% of the 14C dose was recovered in the urine, with 3% in the feces by day 10. Zonisamide undergoes acetylation to form N-acetyl zonisamide and reduction to form the open ring metabolite, 2–sulfamoylacetyl phenol (SMAP). Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of SMAP. Reduction of zonisamide to SMAP is mediated by cytochrome P450 isozyme 3A4 (CYP3A4). Zonisamide does not induce its own metabolism. Plasma clearance of zonisamide is approximately 0.30 to 0.35 mL/min/kg in patients not receiving enzyme-inducing antiepilepsy drugs (AEDs). The clearance of zonisamide is increased to 0.5 mL/min/kg in patients concurrently on enzyme-inducing AEDs.
• Renal clearance is about 3.5 mL/min. The clearance of an oral dose of zonisamide from RBC is 2 mL/min.

• Special Populations

• Renal Insufficiency

• Single 300 mg zonisamide doses were administered to three groups of volunteers. Group 1 was a healthy group with a creatinine clearance ranging from 70 to 152 mL/min. Group 2 and Group 3 had creatinine clearances ranging from 14.5 to 59 mL/min and 10 to 20 mL/min, respectively. Zonisamide renal clearance decreased with decreasing renal function (3.42, 2.50, 2.23 mL/min, respectively). Marked renal impairment (creatinine clearance < 20 mL/min) was associated with an increase in zonisamide AUC of 35%.

• Hepatic Disease

• The pharmacokinetics of zonisamide in patients with impaired liver function have not been studied.

• Age

• The pharmacokinetics of a 300 mg single dose of zonisamide was similar in young (mean age 28 years) and elderly subjects (mean age 69 years).

• Gender and Race

• Information on the effect of gender and race on the pharmacokinetics of zonisamide is not available.

• Interactions of Zonisamide with Other Antiepilepsy Drugs (AEDs)

• Concurrent medication with drugs that either induce or inhibit CYP3A4 may alter serum concentrations of zonisamide. Concomitant administration of phenytoin and carbamazepine increases zonisamide plasma clearance from 0.30 to 0.35 mL/min/kg to 0.35 to 0.5 mL/min/kg. The half-life of zonisamide is decreased to 27 hours by phenytoin, to 38 hours by phenobarbital and carbamazepine, and to 46 hours by valproate. Plasma protein binding of phenytoin and carbamazepine was not affected by zonisamide administration.

• Interactions of Zonisamide with Other Carbonic Anhydrase Inhibitors

• Concomitant use of zonisamide, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if zonisamide is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis.

Nonclinical Toxicology

• No evidence of carcinogenicity was found in mice or rats following dietary administration of zonisamide for two years at doses of up to 80 mg/kg/day. In mice, this dose is approximately equivalent to the maximum recommended human dose (MRHD) of 400 mg/day on a mg/m2 basis. In rats, this dose is 1 to 2 times the MRHD on a mg/m2 basis.

• Zonisamide was mutagenic in an in vitro chromosomal aberration assay in CHL cells. Zonisamide was not mutagenic or clastogenic in other in vitro assays (Ames, mouse lymphoma tk assay, chromosomal aberration in human lymphocytes) or in the in vivo rat bone marrow cytogenetics assay.

• Rats treated with zonisamide (20, 60, or 200 mg/kg) before mating and during the initial gestation phase showed signs of reproductive toxicity (decreased corpora lutea, implantations, and live fetuses) at all doses. The low dose in this study is approximately 0.5 times the maximum recommended human dose (MRHD) on a mg/m2 basis.

Clinical Studies

• The effectiveness of zonisamide capsules as adjunctive therapy (added to other antiepilepsy drugs) has been established in three multicenter, placebo-controlled, double blind, 3-month clinical trials (two domestic, one European) in 499 patients with refractory partial onset seizures with or without secondary generalization. Each patient had a history of at least four partial onset seizures per month in spite of receiving one or two antiepilepsy drugs at therapeutic concentrations. The 499 patients (209 women, 290 men) ranged in age from 13 to 68 years with a mean age of about 35 years. In the two US studies, over 80% of patients were Caucasian; 100% of patients in the European study were Caucasian. Zonisamide capsules or placebo was added to the existing therapy. The primary measure of effectiveness was median percent reduction from baseline in partial seizure frequency. The secondary measure was proportion of patients achieving a 50% or greater seizure reduction from baseline (responders). The results described below are for all partial seizures in the intent-to-treat populations.

• In the first study (n = 203), all patients had a 1-month baseline observation period, then received placebo or zonisamide capsules in one of two dose escalation regimens; either 1) 100 mg/day for five weeks, 200 mg/day for one week, 300 mg/day for one week, and then 400 mg/day for five weeks; or 2) 100 mg/day for one week, followed by 200 mg/day for five weeks, then 300 mg/day for one week, then 400 mg/day for five weeks. This design allowed a 100 mg vs. placebo comparison over weeks 1 to 5, and a 200 mg vs. placebo comparison over weeks 2 to 6; the primary comparison was 400 mg (both escalation groups combined) vs. placebo over weeks 8 to 12. The total daily dose was given as twice a day dosing. Statistically significant treatment differences favoring zonisamide capsules were seen for doses of 100, 200, and 400 mg/day.

• In the second (n = 152) and third (n = 138) studies, patients had a 2 to 3 month baseline, then were randomly assigned to placebo or zonisamide capsules for three months. Zonisamide capsules were introduced by administering 100 mg/day for the first week, 200 mg/day the second week, then 400 mg/day for two weeks, after which the dose (zonisamide capsules or placebo) could be adjusted as necessary to a maximum dose of 20 mg/kg/day or a maximum plasma level of 40 mcg/mL. In the second study, the total daily dose was given as twice a day dosing; in the third study, it was given as a single daily dose. The average final maintenance doses received in the studies were 530 and 430 mg/day in the second and third studies, respectively. Both studies demonstrated statistically significant differences favoring zonisamide capsules for doses of 400 to 600 mg/day, and there was no apparent difference between once daily and twice daily dosing (in different studies). Analysis of the data (first 4 weeks) during titration demonstrated statistically significant differences favoring zonisamide capsules at doses between 100 and 400 mg/day. The primary comparison in both trials was for any dose over Weeks 5 to 12.

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

• Figure 1 presents the proportion of patients (X-axis) whose percentage reduction from baseline in the all partial seizure rate was at least as great as that indicated on the Y-axis in the second and third placebo-controlled trials. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure rate), while a negative value indicates a worsening from baseline (i.e., an increase in seizure rate). Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure rate was consistently higher for the zonisamide capsules groups compared to the placebo groups. For example, Figure 1 indicates that approximately 27% of patients treated with zonisamide capsules experienced a 75% or greater reduction, compared to approximately 12% in the placebo groups.

This image is provided by the National Library of Medicine.

• No differences in efficacy based on age, sex or race, as measured by a change in seizure frequency from baseline, were detected.

How Supplied

• Zonisamide capsules, USP 25 mg are available for oral administration as hard gelatin capsules with a white opaque body and a white opaque cap. “APO 25” is imprinted on each capsule in black ink. They are supplied as follows:

• Bottles of 30 (NDC 60505-2545-3)
• Bottles of 60 (NDC 60505-2545-6)
• Bottles of 90 (NDC 60505-2545-9)
• Bottles of 100 (NDC 60505-2545-1)
• Bottles of 500 (NDC 60505-2545-5)
• Bottles of 1000 (NDC 60505-2545-8)

• Zonisamide capsules, USP 50 mg are available for oral administration as hard gelatin capsules with a white opaque body and a grey opaque cap. “APO 50” is imprinted on each capsule in black ink. They are supplied as follows:

• Bottles of 30 (NDC 60505-2546-3)
• Bottles of 60 (NDC 60505-2546-6)
• Bottles of 90 (NDC 60505-2546-9)
• Bottles of 100 (NDC 60505-2546-1)
• Bottles of 500 (NDC 60505-2546-5)
• Bottles of 1000 (NDC 60505-2546-8)

• Zonisamide capsules, USP 100 mg are available for oral administration as hard gelatin capsules with a white opaque body and a red opaque cap. “APO 100” is imprinted on each capsule in black ink. They are supplied as follows:

• Bottles of 30 (NDC 60505-2547-3)
• Bottles of 60 (NDC 60505-2547-6)
• Bottles of 90 (NDC 60505-2547-9)
• Bottles of 100 (NDC 60505-2547-1)
• Bottles of 500 (NDC 60505-2547-5)
• Bottles of 1000 (NDC 60505-2547-8)

• Storage

• Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
• Store in a dry place. Protect from light.
• Store in a tight, light-resistant container.

Storage

There is limited information regarding Zonisamide Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

• Patients should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking zonisamide capsules. Patients should be instructed to take zonisamide capsules only as prescribed.

• Patients should be advised as follows:

• Zonisamide capsules may produce drowsiness, especially at higher doses. Patients should be advised not to drive a car or operate other complex machinery until they have gained experience on zonisamide capsules sufficient to determine whether it affects their performance. Because of the potential of zonisamide to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, zonisamide should be used with caution if used in combination with alcohol or other CNS depressants.
• Patients should contact their physician immediately if a skin rash develops or seizures worsen.
• Patients should contact their physician immediately if they develop signs or symptoms, such as sudden back pain, abdominal pain, and/or blood in the urine, that could indicate a kidney stone. Increasing fluid intake and urine output may reduce the risk of stone formation, particularly in those with predisposing risk factors for stones.
• Patients should contact their physician immediately if a child has been taking zonisamide capsules and is not sweating as usual with or without a fever.
• Because zonisamide can cause hematological complications, patients should contact their physician immediately if they develop a fever, sore throat, oral ulcers, or easy bruising.
• Suicidal Thinking and Behavior - Patients, their caregivers, and families should be counseled that AEDs, including zonisamide capsules, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
• Patients should contact their physician immediately if they develop fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations (possible manifestations of metabolic acidosis).
• As with other AEDs, patients should contact their physician if they intend to become pregnant or are pregnant during zonisamide therapy. Patients should notify their physician if they intend to breast-feed or are breast-feeding an infant.
• Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.

This image is provided by the National Library of Medicine.

Precautions with Alcohol

• Alcohol-Zonisamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ZONISAMIDE ®

Look-Alike Drug Names

• Zonegran® — SINEquan®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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