Zonisamide Capsules
25 mg, 50 mg and 100 mg
Rx only

Zonisamide capsules are antiseizure drugs chemically classified as a sulfonamide and unrelated to other antiseizure agents. The active ingredient is zonisamide, 1,2-benzisoxazole-3-methanesulfonamide. The empirical formula is C₈H₈N₂O₃S 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:

Zonisamide capsules are supplied for oral administration as capsules containing 25 mg, 50 mg or 100 mg zonisamide. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, FD&C Yellow #6, gelatin, hydrogenated vegetable oil, microcrystalline cellulose and titanium dioxide. FD&C Yellow #10 and FD&C Blue #1 are present in the 25 mg and 50 mg strengths only.

INDICATIONS AND USAGE
Zonisamide capsules are indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

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

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

Pregnancy Category C (see WARNINGS, Teratogenicity subsection): 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 µg/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 µg/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 µg/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 µg/mL) approximately 0.1 times the highest levels measured in patients at the MRHD.

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

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

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

ADVERSE REACTIONS
The most commonly observed adverse events associated with the use of zonisamide capsules in controlled clinical trials that were not seen at an equivalent frequency among placebo-treated patients were somnolence, anorexia, dizziness, headache, nausea, and agitation/irritability.

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

DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of zonisamide capsules has not been evaluated in human studies (see WARNINGS, Cognitive/Neuropsychiatric Adverse Events subsection). In a series of animal studies, zonisamide did not demonstrate abuse liability and dependence potential. Monkeys did not self-administer zonisamide in a standard reinforcing paradigm. Rats exposed to zonisamide did not exhibit signs of physical dependence of the CNS-depressant type. Rats did not generalize the effects of diazepam to zonisamide in a standard discrimination paradigm after training, suggesting that zonisamide does not have abuse potential of the benzodiazepine-CNS depressant type.

DOSAGE AND ADMINISTRATION
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.

Zonisamide capsules 25 mg are dark green, opaque, hard gelatin capsules imprint with cor over 177 body and cap. They are supplied as follows:

           Bottles of 100                    (NDC 64720-177-10)
           Bottles of 1000                  (NDC 64720-177-11)

Zonisamide capsules 50 mg are dark green cap with white body, opaque, hard gelatin capsules imprint with cor over 178 body and cap. They are supplied as follows:

           Bottles of 100                    (NDC 64720-178-10)
           Bottles of 1000                  (NDC 64720-178-11)

Zonisamide capsules 100 mg are orange cap with white body, opaque, hard gelatin capsules imprint with cor over 179 body and cap. They are supplied as follows:

           Bottles of 100                    (NDC 64720-179-10)
           Bottles of 500                    (NDC 64720-179-50)
             Bottles of 1000                (NDC 64720-179-11)

Store at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled Room Temperature].

Dispense in a light-resistant, tight container as defined in the USP.

Keep this and all drugs out of the reach of children

ANIMAL TOXICOLOGY
In dogs treated with zonisamide (10, 30, or 75 mg/kg/day) for 1 year, dark brown discoloration of the liver and concentric lamellar bodies in the cytoplasm of hepatocytes were observed in association with clinical chemistry changes indicative of liver damage (elevated alkaline phosphatase, gamma glutamyl transferase, and alanine amino transferase; decreased albumin) and altered drug metabolism at the highest dose, which is approximately 6 times the maximum recommended human dose (MRHD) of 400 mg/day on a mg/m2 basis. Gross liver changes not clearly accompanied by biochemical evidence of hepatotoxicity were noted at 30 mg/kg/day, or approximately 2.4 times the MRHD on mg/m² basis. The no effect dose of 10 mg/kg/day is slightly less than the MRHD on mg/m² basis. The significance of these findings for humans is not known.

Manufactured and Distributed by:
Corepharma, LLC.
Middlesex, NJ 08846

MF # 452
Rev. January 2007

(bar code)
177-452

PATIENT INFORMATION LEAFLET

What is the most important information I should know about zonisamide capsules?

Some people taking zonisamide (zoe NIS ay mide) capsules can get serious reactions. If you get any of the following symptoms, call your doctor right away:

• Rash (may be a sign of a dangerous condition)
• Fever, sore throat, sores in your mouth, or bruising easily (may be signs of a blood problem)
• Sudden back pain, abdominal (stomach area) pain, pain when urinating, bloody or dark urine (may be signs of a kidney stone)
• Decreased sweating or a rise in body temperature (especially in patients under 17 years old)
• Depression
• Thoughts that are unusual for you
• Speech or language problems

Zonisamide capsules can cause drowsiness and coordination problems. Do not drive or operate dangerous machinery until you know how zonisamide capsules affect you.