Zonisade
Zonisamide · Suspension · Oral
Uses
1 INDICATIONS AND USAGE ZONISADE is indicated as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years and older. ZONISADE is indicated as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years of age and older ( 1 ).
Dosage and administration
• The recommended initial dosage of ZONISADE is 100 mg daily. The dosage may be increased by 100 mg daily every two weeks, based on clinical response and tolerability, to 400 mg daily. Patients who are tolerating ZONISADE at 400 mg daily and require further reduction of seizures may be increased up to a maximum dosage of 600 mg daily ( 2.2 ).
• ZONISADE is given orally and can be taken with or without food ( 2.2 ). 2.1 Recommended Assessments for Safety To assess for metabolic acidosis, obtain baseline serum bicarbonate prior to initiating ZONISADE, and obtain periodic serum bicarbonate during treatment [see Warnings and Precautions ( 5.8 )]. 2.2 Recommended Dosage Administer ZONISADE once or twice daily with or without food. The recommended initial dosage of ZONISADE is 100 mg daily. The dosage may be increased by 100 mg daily every two weeks, based on clinical response and tolerability, to 400 mg daily. Patients who are tolerating ZONISADE at 400 mg daily and require further reduction of seizures may be increased up to a maximum dosage of 600 mg daily. However, evidence from controlled trials shows no suggestion of increasing response above 400 mg/day [see Clinical Studies ( 14 )] . 2.3 Important Administration Information Shake well before every administration. To administer ZONISADE directly into the mouth, it is important that ZONISADE be measured with an accurate measuring device [see Overdosage ( 10 )] . A household teaspoon is not an accurate measuring device. A pharmacist will provide an appropriate device and instructions for measuring the correct dose. Administer ZONISADE orally with or without food. Discard unused portion of ZONISADE 30 days after first opening the bottle. 2.4 Discontinuation of ZONISADE When discontinuing ZONISADE, the dose should be decreased gradually. As with most antiepileptic drugs, avoid abrupt discontinuation, when possible, to minimize the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions ( 5.9 )] .
Dosage forms and strengths
Oral suspension: 100 mg/5 mL of zonisamide as a white to off-white, strawberry flavored liquid. ZONISADE: 100 mg/5 mL ( 3 ).
Contraindications
4 CONTRAINDICATIONS ZONISADE is contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or zonisamide. ZONISADE is contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or zonisamide ( 4 ).
Warnings and precautions
• Potentially Fatal Reactions to Sulfonamides: Fatalities have occurred 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 ( 5.1 ).
• Serious Skin Reactions: Discontinue ZONISADE at the first sign of rash unless clearly not drug related ( 5.2 ).
• Serious Hematologic Events: Aplastic anemia and agranulocytosis have been reported with zonisamide treatment ( 5.3 ).
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: DRESS, also known as multiorgan hypersensitivity, has occurred with zonisamide ( 5.4 ).
• Oligohidrosis and Hyperthermia in Pediatric Patients: Oligohidrosis, sometimes resulting in heat stroke and hospitalization, is seen in association with zonisamide in pediatric patients ( 5.5 ).
• Acute Myopia and Secondary Angle Closure Glaucoma: If occurs, primary treatment is discontinuation of ZONISADE ( 5.6 ).
• Suicidal Behavior and Ideation: Monitor patients for suicidal behavior or ideation ( 5.7 ).
• Metabolic Acidosis: Baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation if appropriate ( 5.8 ).
• Seizures on Withdrawal of Antiepileptic Drugs: Withdraw ZONISADE gradually ( 5.9 ).
• Teratogenicity: Based on animal data, may cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during ZONISADE treatment and for one month after discontinuation ( 5.10 , 8.1 , 8.3 ). 5.1 Potentially Fatal Reactions to Sulfonamides Fatalities have occurred 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 [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )] . 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 ZONISADE immediately. Specific experience with sulfonamide-type adverse reaction to zonisamide is described below. 5.2 Serious Skin Reactions 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 postmarketing 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 [see Clinical Studies ( 14 )] , 6 of 269 (2.2%) patients who received zonisamide discontinued treatment because of rash compared to no patients who received 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 discontinuation of zonisamide 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. Discontinue ZONISADE at the first sign of rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of ZONISADE should not be resumed and alternative therapy should be considered. 5.3 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. 5.4 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, the active ingredient in ZONISADE. 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. ZONISADE should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 5.5 Oligohidrosis and Hyperthermia in Pediatric Patients ZONISADE is not approved for use in patients below 16 years of age. 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.
Side effects
The following clinically signification adverse reactions are described elsewhere in the labeling:
• Potentially Fatal Reactions to Sulfonamides [see Warnings and Precautions ( 5.1 )]
• Serious Skin Reactions [see Warnings and Precautions ( 5.2 )]
• Serious Hematologic Events [see Warnings and Precautions ( 5.3 )]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity [see Warnings and Precautions ( 5.4 )]
• Oligohidrosis and Hyperthermia in Pediatric Patients [see Warnings and Precautions ( 5.5 )]
• Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions ( 5.6 )]
• Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.7 )]
• Metabolic Acidosis [see Warnings and Precautions ( 5.8 )]
• Seizures on Withdrawal of Antiepileptic Drugs [see Warnings and Precautions ( 5.9 )]
• Teratogenicity [see Warnings and Precautions ( 5.10 )]
• Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions ( 5.11 )]
• Hyperammonemia and Encephalopathy [see Warnings and Precautions ( 5.12 )]
• Kidney Stones [see Warnings and Precautions ( 5.13 )]
• Effect on Renal Function [see Warnings and Precautions ( 5.14 )]
• Status Epilepticus [see Warnings and Precautions ( 5.15 )] The most common adverse reactions with ZONISADE (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 ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc., at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Placebo-Controlled Trials with Zonisamide Capsules [see Clinical Studies ( 14 )] The most common adverse reactions 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 as adjunctive therapy discontinued because of 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 and Precautions ( 5 )] . Table 2 lists adverse reactions that occurred in at least 2% of patients treated with zonisamide capsules in controlled clinical trials that were numerically more common in the zonisamide group. In these studies, either zonisamide or placebo was added to the patient's current AED therapy. Table 2. Adverse Reactions that Occurred in at least 2% of Patients Treated with Zonisamide Capsules and More Frequently than in Patients who Received Placebo in Placebo-Controlled, Adjunctive Trials BODY SYSTEM/Adverse Reaction Zonisamide Capsules (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 Laboratory Tests Zonisamide increases serum chloride and alkaline phosphatase and decreases serum bicarbonate [see Warnings and Precautions ( 5.8 )] , phosphorus, calcium, and albumin. Other Adverse Reactions in Clinical Trials of Zonisamide Capsules Zonisamide capsules have been administered to 1,598 individuals during all clinical trials, only some of which were placebo-controlled. 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 [see Warnings and Precautions ( 5 )] , trivial events, those too general to be informative, and those not reasonably associated with zonisamide. Events are further classified within each category and listed in order of decreasing frequency as follows: frequent occurring in at least 1:100 patients; 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.
Drug interactions
• ZONISADE should be used with caution if used in combination with alcohol or other CNS depressants ( 7.1 ).
• Concomitant use of ZONISADE with any other carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation ( 7.2 ). 7.1 CNS Depressants Concomitant use of ZONISADE with other CNS depressants, including alcohol, may increase the risk of CNS depression, as well as other cognitive and/or neuropsychiatric adverse events [see Warnings and Precautions ( 5.11 )] . 7.2 Other Carbonic Anhydrase Inhibitors Concomitant use of ZONISADE, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor, may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation [see Warnings and Precautions ( 5.8 , 5.15 )] . Therefore, if ZONISADE is given concomitantly with another carbonic anhydrase inhibitor, monitor the patient for the appearance or worsening of metabolic acidosis [see Clinical Pharmacology ( 12.1 , 12.3 )] . 7.3 CYP3A4 Inducers If co-administration with a potent CYP3A4 inducer is necessary, the patient should be closely monitored and the dose of ZONISAMIDE and other drugs that CYP3A4 substrates may need to be adjusted [see Clinical Pharmacology ( 12.3 )] .
Use in specific populations
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs, such as ZONISADE, during pregnancy. To provide information regarding the effects of in utero exposure to ZONISADE, physicians are advised to recommend that pregnant patients taking ZONISADE enroll in the North American Antiepileptic Drug (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/. Risk Summary Based on findings from animal studies, ZONISADE may cause fetal harm when administered to a pregnant woman. Zonisamide causes metabolic acidosis in humans [see Warnings and Precautions ( 5.8 )] . There are no reports of metabolic acidosis with use of zonisamide in pregnancy; however, there are published prospective cohort studies that suggest an increased rate of small for gestational age infants in pregnancies exposed to zonisamide, which may be associated with metabolic acidosis (see Clinical Considerations and Data). The available published data from the NAAED Pregnancy Registry has not identified a drug-associated risk of major birth defects with zonisamide use in pregnancy. Although a small prospective cohort study reported an increased risk of major birth defects in zonisamide-exposed pregnancies, this study has methodologic limitations, including small sample size and inability to account for potential confounders (see Data). The available published data pertaining to the use of zonisamide during pregnancy are insufficient to evaluate for a drug-associated risk of miscarriage. In animal studies, administration of zonisamide during pregnancy produced fetal malformations in multiple species and embryofetal (monkey) or perinatal (rat) death at maternal plasma levels similar to or lower than therapeutic levels in humans [see Warnings and Precautions ( 5.10 ) and Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Dose Adjustments During Pregnancy and the Postpartum Period As with other AEDs, physiological changes during pregnancy may affect zonisamide concentrations and/or therapeutic effect. There have been reports of decreased zonisamide concentrations during pregnancy and restoration of pre-pregnancy concentrations after delivery. Dose adjustments may be necessary to maintain clinical response. Maternal Adverse Reactions 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. There are no reports of metabolic acidosis or fetal death with use of zonisamide in pregnancy [see Warnings and Precautions ( 5.8 )] . Fetal/Neonatal Adverse Reactions 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. Data Human Data A prospective cohort study from the NAAED Pregnancy Registry has not identified an increase in the rate of major birth defects (1.4%) in over 200 first trimester pregnancies exposed to zonisamide monotherapy use. Methodological limitations include small sample size and selection bias. A prospective cohort study from the United Kingdom and Ireland Epilepsy Pregnancy Registry (UKIEPR) reported an increased rate of major birth defects (13%) in 26 first trimester pregnancies exposed to zonisamide monotherapy use. Methodological limitations include small sample size and inability to account for potential confounders. Prospective cohort studies, including data from NAAED Pregnancy Registry and UKIEPR, have reported increased rates of small for gestational age infants in those exposed to zonisamide during pregnancy compared to lamotrigine-exposed pregnancies and the unexposed general population. Animal Data In mice, treatment of pregnant animals with zonisamide (0, 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. A no-effect dose for adverse effects on embryofetal development in mice was not identified. The lowest dose tested was approximately 1.5 times that in humans at the maximum recommended human dose (MRHD) of 400 mg/day on a mg/m 2 basis. In rats, an increased frequency of malformations (cardiovascular defects) and variations (persistent cords of thymic tissue, decreased skeletal ossification) was observed in the offspring of dams treated with zonisamide (0, 20, 60, or 200 mg/kg/day) throughout organogenesis at all doses. A no-effect dose for adverse effects on embryofetal development in rats was not identified. The lowest dose tested was approximately 0.5 times the MRHD on a mg/m 2 basis. Following administration of zonisamide (0, 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. Cardiovascular malformations were found in approximately 50% of all fetuses exposed to the high dose.
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs, such as ZONISADE, during pregnancy. To provide information regarding the effects of in utero exposure to ZONISADE, physicians are advised to recommend that pregnant patients taking ZONISADE enroll in the North American Antiepileptic Drug (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/. Risk Summary Based on findings from animal studies, ZONISADE may cause fetal harm when administered to a pregnant woman. Zonisamide causes metabolic acidosis in humans [see Warnings and Precautions ( 5.8 )] . There are no reports of metabolic acidosis with use of zonisamide in pregnancy; however, there are published prospective cohort studies that suggest an increased rate of small for gestational age infants in pregnancies exposed to zonisamide, which may be associated with metabolic acidosis (see Clinical Considerations and Data). The available published data from the NAAED Pregnancy Registry has not identified a drug-associated risk of major birth defects with zonisamide use in pregnancy. Although a small prospective cohort study reported an increased risk of major birth defects in zonisamide-exposed pregnancies, this study has methodologic limitations, including small sample size and inability to account for potential confounders (see Data). The available published data pertaining to the use of zonisamide during pregnancy are insufficient to evaluate for a drug-associated risk of miscarriage. In animal studies, administration of zonisamide during pregnancy produced fetal malformations in multiple species and embryofetal (monkey) or perinatal (rat) death at maternal plasma levels similar to or lower than therapeutic levels in humans [see Warnings and Precautions ( 5.10 ) and Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Dose Adjustments During Pregnancy and the Postpartum Period As with other AEDs, physiological changes during pregnancy may affect zonisamide concentrations and/or therapeutic effect. There have been reports of decreased zonisamide concentrations during pregnancy and restoration of pre-pregnancy concentrations after delivery. Dose adjustments may be necessary to maintain clinical response. Maternal Adverse Reactions 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. There are no reports of metabolic acidosis or fetal death with use of zonisamide in pregnancy [see Warnings and Precautions ( 5.8 )] . Fetal/Neonatal Adverse Reactions 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. Data Human Data A prospective cohort study from the NAAED Pregnancy Registry has not identified an increase in the rate of major birth defects (1.4%) in over 200 first trimester pregnancies exposed to zonisamide monotherapy use. Methodological limitations include small sample size and selection bias. A prospective cohort study from the United Kingdom and Ireland Epilepsy Pregnancy Registry (UKIEPR) reported an increased rate of major birth defects (13%) in 26 first trimester pregnancies exposed to zonisamide monotherapy use. Methodological limitations include small sample size and inability to account for potential confounders. Prospective cohort studies, including data from NAAED Pregnancy Registry and UKIEPR, have reported increased rates of small for gestational age infants in those exposed to zonisamide during pregnancy compared to lamotrigine-exposed pregnancies and the unexposed general population. Animal Data In mice, treatment of pregnant animals with zonisamide (0, 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. A no-effect dose for adverse effects on embryofetal development in mice was not identified. The lowest dose tested was approximately 1.5 times that in humans at the maximum recommended human dose (MRHD) of 400 mg/day on a mg/m 2 basis. In rats, an increased frequency of malformations (cardiovascular defects) and variations (persistent cords of thymic tissue, decreased skeletal ossification) was observed in the offspring of dams treated with zonisamide (0, 20, 60, or 200 mg/kg/day) throughout organogenesis at all doses. A no-effect dose for adverse effects on embryofetal development in rats was not identified. The lowest dose tested was approximately 0.5 times the MRHD on a mg/m 2 basis. Following administration of zonisamide (0, 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. Cardiovascular malformations were found in approximately 50% of all fetuses exposed to the high dose.
Pediatric use
8.4 Pediatric Use Safety and effectiveness of ZONISADE have been established in patients 16 years of age and older by evidence from adequate and well-controlled studies of zonisamide [see Clinical Studies ( 14 )] . Safety and effectiveness in pediatric patients below the age of 16 have not been established. Acute myopia and secondary angle closure glaucoma have been reported in pediatric patients [see Warnings and Precautions ( 5.6 )] . Cases of oligohidrosis and hyperpyrexia have been reported [see Warnings and Precautions ( 5.5 )] . Zonisamide commonly causes metabolic acidosis in pediatric patients [see Warnings and Precautions ( 5.8 )] . 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.
Geriatric use
8.5 Geriatric Use Single dose pharmacokinetic parameters are similar in elderly and young healthy volunteers [see Clinical Pharmacology ( 12.3 )] . 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.
Overdosage
10.1 Human Experience During zonisamide clinical development, three patients ingested unknown amounts of zonisamide 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 μg/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. 10.2 Management No specific antidotes for zonisamide 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 [see Clinical Pharmacology ( 12.3 )]. 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 ZONISADE overdosage.
Description
(zonisamide oral suspension) is chemically classified as a sulfonamide. The active ingredient is zonisamide, 1,2-benzisoxazole-3-methanesulfonamide. The empirical formula is C 8 H 8 N 2 O 3 S with a molecular weight of 212.23. Zonisamide is a white powder, pKa = 10.2, and is moderately soluble in water (0.80 mg/mL) and 0.1 N HCl (0.50 mg/mL). The chemical structure is: ZONISADE is an aqueous white to off-white liquid oral suspension. Each mL contains 20 mg of zonisamide. Inactive ingredients include carboxymethylcellulose sodium, citric acid monohydrate, microcrystalline cellulose, purified water, sodium benzoate, strawberry flavor, sucralose, trisodium citrate dihydrate, and xanthan gum. Chemical Structure
Mechanism of action
12.1 Mechanism of Action The precise mechanism(s) by which zonisamide exerts its anticonvulsant effects 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. Other in vitro studies have demonstrated that zonisamide (10–30 µg/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [ 3 H]-GABA (rat hippocampal slices). Thus, zonisamide does not appear to potentiate the synaptic activity of GABA. Zonisamide is a carbonic anhydrase inhibitor. The contribution of this pharmacological action to the therapeutic effects of zonisamide is unknown.
How supplied
16.1 How Supplied ZONISADE (zonisamide oral suspension) is a white to off-white, strawberry flavored liquid containing 100 mg/5 mL zonisamide. It is supplied in a 150 mL amber colored PET bottle with a child resistant cap. NDC Number: 52652-8001-1 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F), excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Discard unused portion of ZONISADE 30 days after first opening of the bottle. 16.1 How Supplied ZONISADE (zonisamide oral suspension) is a white to off-white, strawberry flavored liquid containing 100 mg/5 mL zonisamide. It is supplied in a 150 mL amber colored PET bottle with a child resistant cap. NDC Number: 52652-8001-1
Storage
16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F), excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Discard unused portion of ZONISADE 30 days after first opening of the bottle.
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Administration Inform patients that a pharmacist will provide an appropriate device and instructions for measuring the correct dose and that a household teaspoon is not an accurate measuring device. Instruct patients to shake ZONISADE well and discard any unused portion after 30 days of opening the bottle [see Dosage and Administration ( 2.2 )] . Drowsiness ZONISADE 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 ZONISADE 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, ZONISADE should be used with caution if used in combination with alcohol or other CNS depressants. Serious Skin Reactions Patients should contact their physicians immediately if a skin rash develops [see Warnings and Precautions ( 5.2 )] . Acute Myopia and Secondary Angle Closure Glaucoma Instruct patients to seek immediate medical attention if they experience blurred vision, visual disturbances, or periorbital pain [see Warnings and Precautions ( 5.6 )] . Kidney Stones 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 Warnings and Precautions ( 5.15 )] . Oligohidrosis and Hyperthermia in Pediatric Patients Patients should contact their physician immediately if a child has been taking ZONISADE and is not sweating as usual with or without a fever [see Warnings and Precautions ( 5.5 )]. Serious Hematologic Events 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 and Precautions ( 5.3 )]. Suicidal Behavior and Ideation Counsel patients and caregivers that AEDs, including ZONISADE, 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 and Precautions ( 5.7 )]. Hyperammonemia and Encephalopathy 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 and Precautions ( 5.13 )]. Metabolic Acidosis Patients should contact their physician immediately if they develop fast breathing, fatigue/tiredness, loss of appetite, or irregular heartbeat or palpitations, which are possible manifestations of metabolic acidosis [see Warnings and Precautions ( 5.8 )]. Pregnancy Advise pregnant women and females of reproductive potential of the risk to a fetus. Advise pregnant women to inform their healthcare provider of a known or suspected pregnancy. Advise women who are exposed to ZONISADE during pregnancy that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to ZONISADE during pregnancy. Encourage patients to report their pregnancy to North American Antiepileptic Drug (NAAED) Pregnancy Registry at 1-888-233-2334 or http://www.aedpregnancyregistry.org/ [see Use in Specific Populations ( 8.1 )]. Lactation Advise breastfeeding women using ZONISADE to monitor infants for increased sleepiness, decreased appetite, and elevated temperature and to seek medical attention if they notice these signs [see Use in Specific Populations ( 8.2 )]. Manufactured for: Azurity Pharmaceuticals, Inc. Woburn, MA 01801 Made in United Kingdom Patent: https://azurity.com/patents This product’s labeling may have been updated. For current Full Prescribing Information, please visit www.zonisade.com PN: 51097-65628-00630 REV#: 02 MAY2025
Label text from the FDA structured product label by Azurity Pharmaceuticals, Inc. (revised Sep 8, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Zonisamide in 1 product
Zonisade NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 52652-8001 | Zonisamide 100 mg/5mL Suspension | Azurity Pharmaceuticals, Inc. | NDA |
Frequently asked questions
What is Zonisade used for?
1 INDICATIONS AND USAGE ZONISADE is indicated as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years and older. ZONISADE is indicated as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years of age and older ( 1 ).
What are the side effects of Zonisade?
The following clinically signification adverse reactions are described elsewhere in the labeling: • Potentially Fatal Reactions to Sulfonamides [see Warnings and Precautions ( 5.1 )] • Serious Skin Reactions [see Warnings and Precautions ( 5.2 )] • Serious Hematologic Events [see Warnings and Precautions ( 5.3 )] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ… See the full label for the complete list.
Who makes Zonisade?
Zonisade is listed by 1 labeler in the FDA NDC directory, including Azurity Pharmaceuticals, Inc..