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SUN PHARMACEUTI
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62756025802

zonisamide 25 mg capsule (generic zonegran)

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Uses

Seizure Disorders

Partial Seizures

Zonisamide is used in combination with other anticonvulsants in the management of partial seizures in adults with epilepsy.

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. 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. 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. More patients receiving zonisamide experienced a reduction in seizure frequency of 50% or greater compared with baseline (i.e., responder rate) compared with placebo-treated patients. The efficacy of zonisamide reportedly is not affected by age, gender, or race.

Dosage and Administration

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. The capsules should be swallowed intact. Patients should be encouraged to drink 6-8 glasses of water each day while receiving the drug.

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

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.(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. After 2 weeks, the dosage may be increased to 200 mg daily for at least 2 weeks. 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. Results of controlled clinical trials suggest that zonisamide dosages of 100-600 mg daily are effective; however, dosages exceeding 400 mg daily may not be associated with increased therapeutic benefit. There is only limited experience with zonisamide dosages exceeding 600 mg daily. 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.

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 disease; such patients may require slower dosage titration and more frequent monitoring. Zonisamide should not be used in patients with renal failure (glomerular filtration rate [GFR] less than 50 mL/minute).

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.

Cautions

Contraindications

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

Warnings/Precautions

Warnings

Dermatologic and Sensitivity Reactions

Fatalities resulting from severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have occurred following use of zonisamide. Use of sulfonamides also rarely has caused fatalities resulting from fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias, regardless of the route of administration. Zonisamide should be discontinued immediately if signs or symptoms of hypersensitivity occur. Discontinuance of zonisamide should be considered whenever a patient receiving zonisamide develops unexplained rash; if the drug is not discontinued, the patient should be observed frequently.

Hematologic Effects

Aplastic anemia and agranulocytosis were rarely reported in patients receiving zonisamide; a causal relationship between dosage and duration of zonisamide therapy has not been established.

Oligohidrosis and Hyperthermia

Oligohidrosis (a reduction in sweating) and hyperthermia have been reported in patients receiving zonisamide, particularly in pediatric patients.(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. The risk of hyperthermia also should be considered when zonisamide is used concomitantly with other drugs that predispose patients to heat-related disorders.(See Drug Interactions: Acetazolamide and see also Drug Interactions: Other Drugs.)

Suicidality Risk

The US Food and Drug Administration (FDA) has alerted healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants, including zonisamide, compared with placebo. The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, 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%). This increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks. Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Based on the current analysis of the available data, the FDA recommends that clinicians inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy and that all patients currently receiving or beginning therapy with any anticonvulsant be closely monitored for notable changes in behavior that may indicate the emergence or worsening of suicidal thoughts or behavior or depression. Symptoms such as anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.

Clinicians who prescribe zonisamide or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness. 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. If suicidal thoughts or behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.(See Advice to Patients.)

Metabolic Acidosis

Zonisamide can cause metabolic acidosis, which is characterized by hyperchloremia and decreased serum bicarbonate concentrations in the blood. Although often asymptomatic, signs and symptoms of persistent metabolic acidosis may include hyperventilation, fatigue, and anorexia, and more severe symptoms may include cardiac arrhythmias and stupor. Zonisamide-induced metabolic acidosis generally occurs early in treatment, but may occur at any time during therapy. 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. Certain conditions or therapies, including renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diets, or other drugs (e.g., acetazolamide), may predispose patients to acidosis. In addition, zonisamide-induced metabolic acidosis appears to be more frequent and severe in younger patients.(See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Decreases in serum bicarbonate levels usually are mild to moderate (average decrease of approximately 2 mEq/L) in adults; however, some adults have experienced severe decreases (as much as 10 mEq/L below their baseline). 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 mg daily to 43% in patients treated with 300 mg daily; the incidence of persistent, abnormally low serum bicarbonate was 2% or less across all dosages studied. 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.(See Renal Effects under Warnings/Precautions: General Precautions, in Cautions.)

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

Discontinuance of Zonisamide

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.

Nervous System 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.(See Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

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

Substantial increases (8%) in mean serum creatinine and blood urea nitrogen (BUN) concentrations occurred in patients receiving zonisamide. Such increases appeared to persist over time, but were not progressive. Periodic monitoring of renal function should be considered during zonisamide therapy. The drug should be discontinued in patients who develop acute renal failure or clinically important sustained increases in serum creatinine and BUN concentrations. 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.

Sudden Unexplained Death in Epilepsy

During the premarketing development of zonisamide, 9 sudden and unexplained deaths were reported among a cohort of 991 patients with epilepsy receiving adjunctive therapy with the drug (7.7 deaths per 1000 patient-years). Although the rate of these deaths exceeds that expected to occur in a healthy (nonepileptic) population, this rate was similar to that occurring in patients with refractory epilepsy not receiving zonisamide.

Specific Populations

Pregnancy

Category C.

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

FDA warns that zonisamide may cause metabolic acidosis. Although the effects of zonisamide-induced metabolic acidosis on the fetus have not been established, metabolic acidosis during pregnancy (due to other causes) may affect fetal development (i.e., decreased fetal growth, decreased fetal oxygenation, and fetal death) and the ability of the fetus to tolerate labor.

The effect of zonisamide on labor and delivery is unknown.

Physiologic changes during pregnancy may affect plasma zonisamide concentrations and/or therapeutic effect. Some clinicians recommend closely monitoring plasma zonisamide concentrations and adjusting zonisamide dosage as necessary in pregnant women.

Lactation

Zonisamide is distributed into milk. 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.

Pediatric Use

Safety and efficacy of zonisamide in children younger than 16 years of age have not been established, and the drug is not approved for use in pediatric patients in the US. However, the drug has been used for the treatment of epilepsy in some pediatric patients to date and is approved for pediatric use in Japan.

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. As of December 31, 2001, there have been 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). However, it generally is recognized that postmarketing data are subject to underreporting. In many of the reported cases, oligohidrosis and hyperthermia occurred after exposure to elevated environmental temperatures; in some cases, heat stroke requiring hospitalization resulted. There have been no reported deaths associated with these adverse effects thus far.

Because children appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia, children receiving the drug should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. In addition, the risk of hyperthermia should be considered when zonisamide is used concomitantly with other drugs that predispose patients to heat-related disorders.(See Drug Interactions: Acetazolamide and see also Drug Interactions: Other Drugs.)

Pediatric patients may be at increased risk for zonisamide-induced metabolic acidosis and the condition may be more severe in younger patients. In one large, uncontrolled clinical 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. 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. 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.(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. Other reported clinical experience has not identified differences in responses between geriatric and younger patients. Pharmacokinetics were similar in geriatric and young healthy volunteers in single-dose studies.(See Dosage and Administration: Special Populations.)

Renal or Hepatic Impairment

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

Because zonisamide is metabolized in the liver and excreted principally by the kidneys, patients with renal or hepatic disease should be treated with caution and may require slower dosage titration and more frequent monitoring.(See Dosage and Administration: Special Populations.)

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 diplopia were reported in 2% or more patients in clinical studies in which zonisamide was administered in conjunction with other anticonvulsants.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of cytochrome P-450 (CYP) 3A4 isoenzyme: potential pharmacokinetic interaction (altered serum concentrations of zonisamide).

Zonisamide does not appear to interfere with the metabolism of drugs that are metabolized by cytochrome P-450 isoenzymes.

Anticonvulsants

It appears that zonisamide does not affect steady-state plasma concentrations of phenytoin, carbamazepine, or valproic acid. However, other anticonvulsants may alter pharmacokinetics of zonisamide. In patients receiving zonisamide concomitantly with phenytoin or carbamazepine, plasma clearance of zonisamide is increased, which may result in reduced plasma concentrations of zonisamide and might require increasing the dosage of zonisamide. In addition, phenytoin, phenobarbital, and carbamazepine decrease the plasma half-life of zonisamide.

Acetazolamide

Concurrent administration of zonisamide and acetazolamide may increase the risk of metabolic acidosis.(See Metabolic Acidosis under Warnings/Precautions: Warnings, in Cautions.) Concurrent administration of these drugs also may predispose patients to heat-related disorders.(See Oligohidrosis and Hyperthermia under Warnings/Precautions: Warnings, in Cautions.)

Cimetidine

Single-dose pharmacokinetics of zonisamide were not affected by multiple-dose cimetidine administration.

Oral Contraceptives

Pharmacokinetic interaction unlikely.

Other Drugs

Drugs that predispose patients to heat-related disorders (e.g., carbonic anhydrase inhibitors, drugs with anticholinergic activity): potential pharmacologic interaction (increased risk of oligohidrosis and hyperthermia).(See Oligohidrosis and Hyperthermia under Warnings/Precautions: Warnings, in Cautions and see also Drug Interactions: Acetazolamide.)

Pharmacokinetics

Absorption

Bioavailability

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

Food

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

Distribution

Extent

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

Zonisamide crosses the placenta and is distributed into breast milk.

Plasma Protein Binding

Approximately 40%.

Elimination

Metabolism

Undergoes acetylation to form N-acetyl zonisamide, subsequent reduction to form 2-sulfamoylacetyl phenol, and further glucuronide conjugation. The reduction of N-acetyl zonisamide is mediated by cytochrome P450 (CYP) 3A4.

Does not induce own metabolism.

Elimination Route

Excreted principally in urine as unchanged drug and a glucuronide of a metabolite.

Half-life

About 63 hours.

Special Populations

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

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

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

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