ZONISADE

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 ).

2 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 )] .

5 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 co…

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 ).

7 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 )] .

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…

6 ADVERSE REACTIONS 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 FU…