ZONISAMIDE- zonisamide_capsule

CLINICAL PHARMACOLOGY
Mechanism of Action: In vitro 2+ In vitro in vitro 3 In vivo WARNINGS, Metabolic Acidosis max 14 Renal Impairment: DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION Effects of zonisamide on cytochrome P450 enzymes in vitro 50 Concomitant use of zonisamide, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e. , topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risks of hyperammonemia and 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 (see WARNINGS, Metabolic Acidosis Hyperammonemia and Encephalopathy PRECAUTIONS, Drug Interactions The effectiveness of zonisamide 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 U. studies, over 80% of patients were Caucasian; 100% of patients in the European study were Caucasian. Median % Reduction in All Partial Seizures and % Responders in Primary Efficacy Analyses: Intent-To-Treat Analysis *p<0. 05 compared to placebo Study Median % reduction in partial seizures % Responders Zonisamide Placebo Zonisamide Placebo Study 1: Weeks 8 to 12: n=98 n=72 n=98 n=72 Study 2: Weeks 5 to 12: n=69 n=72 n=69 n=72 Study 3: Weeks 5 to 12: n=67 n=66 n=67 n=66 Table 2. Median % Reduction in All Partial Seizures and % Responders for Dose Analyses in Study 1: Intent-To-Treat Analysis Dose Group Median % reduction in partial seizures % Responders Zonisamide Placebo Zonisamide Placebo 100 to 400 mg/day: Weeks 1 to 12: n=112 n=83 n=112 n=83 100 mg/day: Weeks 1 to 5: n=56 n=80 n=56 n=80 200 mg/day: Weeks 2 to 6: n=55 n=82 n=55 n=82 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. , a decrease in seizure rate), while a negative value indicates a worsening from baseline (i. , 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 groups compared to the placebo groups. For example, Figure 1 indicates that approximately 27% of patients treated with zonisamide experienced a 75% or greater reduction, compared to approximately 12% in the placebo groups. Figure 1 Proportion of Patients Achieving Differing Levels of Seizure Reduction in Zonisamide and Placebo Groups in Studies 2 and 3 Figure 1 Proportion of Patients Achieving Differing Levels.
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 U.S., 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 should be discontinued in patients who develop acute renal failure or a clinically significant sustained increase in the creatinine/BUN concentration. Zonisamide 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. Status Epilepticus: Information for Patients: Advise patients as follows: (See Medication Guide) Zonisamide 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 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 physicians immediately if a skin rash develops (see WARNINGS, Serious Skin Reactions Instruct patients to seek immediate medical attention if they experience blurred vision, visual disturbances, or periorbital pain (see WARNINGS, Acute Myopia and Secondary Angle Closure Glaucoma 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 (see PRECAUTIONS, Kidney Stones Patients should contact their physician immediately if a child has been taking zonisamide and is not sweating as usual with or without a fever (see WARNINGS, Oligohidrosis and Hyperthermia in Pediatric Patients Because zonisamide can cause hematological complications, patients should contact their physician immediately if they develop a fever, sore throat, oral ulcers, or easy bruising (see WARNINGS, Serious Hematologic Events Counsel patients and caregivers that AEDs, including zonisamide, may increase the risk of suicidal thoughts and behavior and advise them 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 (see WARNINGS, Suicidal Behavior and Ideation Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. Instruct patients to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status (see WARNINGS, Hyperammonemia and Encephalopathy Patients should contact their physician immediately if they develop fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations, which are possible manifestations of metabolic acidosis (see WARNINGS, 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 (see PRECAUTIONS, Use in Nursing Mothers Encourage patients 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 (see PRECAUTIONS, Pregnancy .

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 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 (see CLINICAL PHARMACOLOGY, Clinical Studies Patients with Renal or Hepatic Disease: CLINICAL PHARMACOLOGY PRECAUTIONS

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 U.S., European, or Japanese development programs. There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity:
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with zonisamide. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Zonisamide should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
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 U.S. 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 U.S., 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 U.S. 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 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.
Acute Myopia and Secondary Angle Closure Glaucoma:
Acute myopia and secondary angle closure glaucoma have been reported in patients receiving zonisamide. Elevated intraocular pressure can lead to serious sequelae, including permanent vision loss, if left untreated.
Cognitive/ Neuropsychiatric Adverse Events:
Use of zonisamide 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.
Hyperammonemia and Encephalopathy:
Hyperammonemia and encephalopathy have been reported with the postmarketing use of zonisamide. Zonisamide treatment inhibits carbonic anhydrase activity, which may cause metabolic acidosis that is associated with an increased risk for developing hyperammonemia. Hyperammonemia resulting from zonisamide can also be asymptomatic. The risks of hyperammonemia and various manifestations of encephalopathy may be increased in patients treated with zonisamide and concomitantly taking other medications that can cause hyperammonemia, including valproic acid or topiramate (see PRECAUTIONS Measure serum ammonia concentration if signs or symptoms (e.g., unexplained change in mental status, vomiting, or lethargy) of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued. Hyperammonemia from zonisamide may resolve or decrease in severity with a decrease of the daily dose.
ADVERSE REACTIONS
The most common adverse reactions with zonisamide (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 as adjunctive therapy discontinued due to an adverse reaction compared to 6% receiving placebo. Approximately 21% of the 1,336 patients with epilepsy who received zonisamide in clinical studies discontinued treatment because of an adverse reaction. The most common adverse reactions leading to 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 reactions were dose-related (see WARNINGS PRECAUTIONS Adverse Reaction Incidence in Controlled Clinical Trials: Table 4. Adverse Reactions in Placebo-Controlled, Add-On Trials (Events that occurred in at least 2% of zonisamide-treated patients and occurred more frequently in zonisamide -treated than placebo-treated patients) BODY SYSTEM/PREFERRED TERM ZONISAMIDE (n=269) % PLACEBO (n=230) % BODY AS A WHOLE Headache 10 8 Abdominal Pain 6 3 Flu Syndrome 4 3 DIGESTIVE Anorexia 13 6 Nausea 9 6 Diarrhea 5 2 Dyspepsia 3 1 Constipation 2 1 Dry Mouth 2 1 HEMATOLOGIC AND LYMPHATIC Ecchymosis 2 1 METABOLIC AND NUTRITIONAL Weight Loss 3 2 NERVOUS SYSTEM Dizziness 13 7 Ataxia 6 1 Nystagmus 4 2 Paresthesia 4 1 NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-ALTERED COGNITIVE FUNCTION Confusion 6 3 Difficulty Concentrating 6 2 Difficulty with Memory 6 2 Mental Slowing 4 2 NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-BEHAVIORAL ABNORMALITIES (NON-PSYCHOSIS- RELATED) Agitation/Irritability 9 4 Depression 6 3 Insomnia 6 3 Anxiety 3 2 Nervousness 2 1 NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-BEHAVIORAL ABNORMALITIES (PSYCHOSIS-RELATED) Schizophrenic/Schizophreniform Behavior 2 0 NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-CNS DEPRESSION Somnolence 17 7 Fatigue 8 6 Tiredness 7 5 NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-SPEECH AND LANGUAGE ABNORMALITIES Speech Abnormalities 5 2 Difficulties in Verbal Expression 2 <1 RESPIRATORY Rhinitis 2 1 SKIN AND APPENDAGES Rash 3 2 SPECIAL SENSES Diplopia 6 3 Taste Perversion 2 0 Other Adverse Reactions in Clinical Trials: WARNINGS PRECAUTIONS Events are further classified within each category and listed in order of decreasing frequency as follows: frequent infrequent rare Body as a Whole: Frequent: Infrequent: Rare: Cardiovascular: Infrequent: Rare: Digestive: Frequent: Infrequent: Rare: Hematologic and Lymphatic: Infrequent: Rare: Metabolic and Nutritional: Infrequent: Rare: Musculoskeletal: Infrequent: Nervous System: Frequent: Infrequent: Rare: Behavioral Abnormalities en dashNon-Psychosis-Related: Infrequent: Respiratory: Frequent: Infrequent Rare: Skin and Appendages: Frequent: Infrequent: Special Senses: Frequent: Infrequent: Rare: Urogenital: Infrequent: Rare: POST MARKETING EXPERIENCE The following serious adverse reactions 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, increased creatine phosphokinase, drug reaction with eosinophilia and systemic symptoms (DRESS), acute myopia and secondary angle closure glaucoma, and hyperammonemia and encephalopathy (see WARNINGS To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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

Specific Populations:
Renal Impairment: DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION Effects of zonisamide on cytochrome P450 enzymes in vitro 50
Pregnancy:
(see WARNINGS, Teratogenicity 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’s ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the non-pregnant state. (See WARNINGS, Metabolic Acidosis 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/m 2 2 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/m 2 2 There are no adequate and well-controlled studies in pregnant women. Zonisamide 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

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 risks of hyperammonemia and 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 (see WARNINGS, Metabolic Acidosis Hyperammonemia and Encephalopathy PRECAUTIONS, Drug Interactions

Clinical Studies:
The effectiveness of zonisamide 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 U. studies, over 80% of patients were Caucasian; 100% of patients in the European study were Caucasian. Median % Reduction in All Partial Seizures and % Responders in Primary Efficacy Analyses: Intent-To-Treat Analysis *p<0. 05 compared to placebo Study Median % reduction in partial seizures % Responders Zonisamide Placebo Zonisamide Placebo Study 1: Weeks 8 to 12: n=98 n=72 n=98 n=72 Study 2: Weeks 5 to 12: n=69 n=72 n=69 n=72 Study 3: Weeks 5 to 12: n=67 n=66 n=67 n=66 Table 2. Median % Reduction in All Partial Seizures and % Responders for Dose Analyses in Study 1: Intent-To-Treat Analysis Dose Group Median % reduction in partial seizures % Responders Zonisamide Placebo Zonisamide Placebo 100 to 400 mg/day: Weeks 1 to 12: n=112 n=83 n=112 n=83 100 mg/day: Weeks 1 to 5: n=56 n=80 n=56 n=80 200 mg/day: Weeks 2 to 6: n=55 n=82 n=55 n=82 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. , a decrease in seizure rate), while a negative value indicates a worsening from baseline (i. , 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 groups compared to the placebo groups. For example, Figure 1 indicates that approximately 27% of patients treated with zonisamide experienced a 75% or greater reduction, compared to approximately 12% in the placebo groups. Figure 1 Proportion of Patients Achieving Differing Levels of Seizure Reduction in Zonisamide and Placebo Groups in Studies 2 and 3 Figure 1 Proportion of Patients Achieving Differing Levels.
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. Consideration should be given to discontinuing zonisamide in patients who develop an otherwise unexplained rash. If the drug is not discontinued, patients should be observed frequently. 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 U. , European, or Japanese development programs. There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with zonisamide. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e. , fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Zonisamide should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 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 U. 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 U. , 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 U. 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 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. Acute myopia and secondary angle closure glaucoma have been reported in patients receiving zonisamide. Elevated intraocular pressure can lead to serious sequelae, including permanent vision loss, if left untreated. Antiepileptic drugs (AEDs), including zonisamide, 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. Table 3: Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients Relative Risk: Risk Difference: Epilepsy 1. 4 Psychiatric 5. 9 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. WARNINGS, Cognitive/Neuropsychiatric Adverse Events Zonisamide causes hyperchloremic, non-anion gap, metabolic acidosis (i. , decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) (see PRECAUTIONS, Laboratory Tests PRECAUTIONS, Kidney Stones PRECAUTIONS, Laboratory Tests 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 during pregnancy in humans may present a significant risk to the fetus (see PRECAUTIONS, Pregnancy Use of zonisamide 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. Hyperammonemia and encephalopathy have been reported with the postmarketing use of zonisamide. Zonisamide treatment inhibits carbonic anhydrase activity, which may cause metabolic acidosis that is associated with an increased risk for developing hyperammonemia. Hyperammonemia resulting from zonisamide can also be asymptomatic. The risks of hyperammonemia and various manifestations of encephalopathy may be increased in patients treated with zonisamide and concomitantly taking other medications that can cause hyperammonemia, including valproic acid or topiramate (see PRECAUTIONS Measure serum ammonia concentration if signs or symptoms (e. , unexplained change in mental status, vomiting, or lethargy) of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued. Hyperammonemia from zonisamide may resolve or decrease in severity with a decrease of the daily dose.
Kidney Stones:
Among 991 patients treated during the development of zonisamide, 40 patients (4.0%) with epilepsy receiving zonisamide 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 (see WARNINGS, Metabolic Acidosis WARNINGS, Metabolic Acidosis
OVERDOSAGE
Human Experience: Management: Zonisamide has a long half-life (see CLINICAL PHARMACOLOGY
MEDICATION GUIDE
Zonisamide Capsules USP ( zoe nis'' a mide What is the most important information I should know about zonisamide capsules? Zonisamide capsules may cause serious side effects, including: Serious skin rash that can cause death. Serious allergic reactions that may affect different parts of the body. Less sweating and increase in your body temperature (fever). Serious eye problems Suicidal thoughts or actions in some people. Increased level of acid in your blood (metabolic acidosis). Problems with your concentration, attention, memory, thinking, speech, or language. Blood cell changes such as reduced red and white blood cell counts. These serious side effects are described below. 1. Zonisamide capsules may cause a serious skin rash that can cause death. These serious skin reactions are more likely to happen when you begin taking zonisamide capsules within the first 4 months of treatment but may occur at later times. 2. Zonisamide capsules can cause other types of allergic reactions or serious problems that may affect different parts of the body such as your liver, kidneys, heart, or blood cells. You may or may not have a rash with these types of reactions. These reactions can be very serious and can cause death. Call your health care provider right away if you have: fever severe muscle pain rash swollen lymph glands swelling of your face unusual bruising or bleeding weakness, fatigue yellowing of your skin or the white part of your eyes 3. Zonisamide capsules may cause you to sweat less and to increase your body temperature (fever). You may need to be hospitalized for this. You should watch for decreased sweating and fever, especially when it is hot and especially in children taking zonisamide capsules. Call your health care provider right away if you have: high fever, recurring fever, or long lasting fever less sweat than normal 4. Zonisamide capsules may cause eye problems. Serious eye problems include: sudden decrease in vision with or without eye pain and redness a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma) These eye problems can lead to permanent loss of vision if not treated. Call your healthcare provider right away if you have any new eye symptoms, including any eye pain or redness or any new problems with your vision. 5. Like other antiepileptic drugs, zonisamide capsules may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempt to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Do not stop zonisamide capsules without first talking to a healthcare provider. Stopping zonisamide capsules suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus). 6. Zonisamide capsules can increase the level of acid in your blood (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones and can slow the rate of growth in children. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will: feel tired not feel hungry (loss of appetite) feel changes in heartbeat have trouble thinking clearly Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with zonisamide capsules. 7. Zonisamide capsules may cause problems with your concentration, attention, memory, thinking, speech, or language. 8. Zonisamide capsules can cause blood cell changes such as reduced red and white blood cell counts. Call your healthcare provider if you develop fever, sore throat, sores in your mouth, or unusual bruising. Zonisamide capsules can have other serious side effects. For more information ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you. Be sure to read the section titled “What are the possible side effects of zonisamide capsules?” What are zonisamide capsules? Zonisamide capsules is a prescription medicine that is used with other medicines to treat partial seizures in adults. It is not known if zonisamide capsules is safe or effective in children under 16 years of age. Do not take zonisamide capsules: Do not take zonisamide capsules if you are allergic to medicines that contain sulfa. Before taking zonisamide capsules, tell your healthcare provider about all your medical conditions, including if you: have or have had depression, mood problems or suicidal thoughts or behavior have kidney problems have liver problems have a history of metabolic acidosis (too much acid in your blood) have weak, brittle bones or soft bones (osteomalacia, osteopenia or osteoporosis) have a growth problem are on a diet high in fat called a ketogenic diet have diarrhea have high blood levels of ammonia Tell your healthcare provider if you: are pregnant or plan to become pregnant. Zonisamide capsules may harm your unborn baby. Women who can become pregnant should use effective birth control. Tell your healthcare provider right away if you become pregnant while taking zonisamide capsules. You and your healthcare provider should decide if you should take zonisamide capsules while you are pregnant. If you become pregnant while taking zonisamide capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. are breastfeeding or plan to breastfeed. Zonisamide can pass into your breast milk. It is not known if zonisamide in your breast milk can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take zonisamide capsules. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins or herbal supplements. How should I take zonisamide capsules? Take zonisamide capsules exactly as prescribed. Your healthcare prescriber may change your dose. Your healthcare provider will tell you how much zonisamide to take. Take zonisamide capsules with or without food. Swallow the capsules whole. If you take too much zonisamide, call your local Poison Control Center or go to the nearest emergency room right away. Do not stop taking zonisamide capsules without talking to your healthcare provider. Stopping zonisamide capsules suddenly can cause serious problems, including seizures that will not stop (status epilepticus). What should I avoid while taking zonisamide capsules? Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking zonisamide capsules until you talk to your health care provider. Zonisamide capsules taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse. Do not drive, operate heavy machinery, or do other dangerous activities until you know how zonisamide capsules affects you. Zonisamide capsules can slow your thinking and motor skills. What are the possible side effects of zonisamide capsules? Zonisamide capsules can cause serious side effects. See “What is the most important information I should know about zonisamide capsules?” Other serious side effects include: kidney stones: problems with mood or thinking hig h blood ammonia levels. The most common side effects of zonisamide capsules include: drowsiness loss of appetite dizziness problems with concentration or memory trouble with walking and coordination agitation or irritability Side effects can happen at any time, but are more likely to happen during the first several weeks after starting zonisamide capsules. These are not all of the possible side effects of zonisamide capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store zonisamide capsules? Store zonisamide capsules at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] Keep zonisamide capsules dry and away from light Keep zonisamide capsules and all medicines out of the reach of children. General Information about the safe and effective use of zonisamide capsules. What are the ingredients in zonisamide capsules? Active ingredient: Inactive ingredients in zonisamide capsules: This Medication Guide has been approved by the U.S. Food and Drug Administration Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

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