Professional Information — Zonisamide

Indications and Usage

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

Dosage and Administration

Zonisamide, USP is 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 should be administered once or twice daily, using 25 mg or 100 mg capsules. Zonisamide is given orally and can be taken with or without food. Capsules should be swallowed whole.

Adults over Age 16: The prescriber should be aware that, because of the long half-life of zonisamide, up to two weeks may be required to achieve steady state levels upon reaching a stable dose or following dosage adjustment. Although the regimen described below is one that has been shown to be tolerated, the prescriber may wish to prolong the duration of treatment at the lower doses in order to fully assess the effects of zonisamide at steady state, noting that many of the side effects of zonisamide are more frequent at doses of 300 mg per day and above. Although there is some evidence of greater response at doses above 100 to 200 mg/day, the increase appears small and formal dose-response studies have not been conducted.

The initial dose of zonisamide 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 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 subsection). There is little experience with doses greater than 600 mg/day.

Patients with Renal or Hepatic Disease: Because zonisamide is metabolized in the liver and excreted by the kidneys, patients with renal or hepatic disease should be treated with caution, and might require slower titration and more frequent monitoring (see CLINICAL PHARMACOLOGY and PRECAUTIONS ).

Contraindications

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

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 and PRECAUTIONS ).

Adverse Reaction Incidence in Controlled Clinical Trials: Table 4 lists adverse reactions that occurred in at least 2% of patients treated with zonisamide 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.

Other Adverse Reactions in Clinical Trials: zonisamide has 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 who experienced an event on at least one occasion. All events are included except those already listed in the previous table or discussed in WARNINGS or PRECAUTIONS , 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.

Cardiovascular: Infrequent: Palpitation, tachycardia, vascular insufficiency, hypotension, hypertension, thrombophlebitis, syncope, bradycardia. Rare: Atrial fibrillation, heart failure, pulmonary embolus, ventricular extrasystoles.

Digestive: Frequent: Vomiting. Infrequent: Flatulence, gingivitis, gum hyperplasia, gastritis, gastroenteritis, stomatitis, cholelithiasis, glossitis, melena, rectal hemorrhage, ulcerative stomatitis, gastro-duodenal ulcer, dysphagia, gum hemorrhage. Rare: Cholangitis, hematemesis, cholecystitis, cholestatic jaundice, colitis, duodenitis, esophagitis, fecal incontinence, mouth ulceration.

Hematologic and Lymphatic: Infrequent: Leukopenia, anemia, immunodeficiency, lymphadenopathy. Rare: Thrombocytopenia, microcytic anemia, petechia.

Metabolic and Nutritional: Infrequent: Peripheral edema, weight gain, edema, thirst, dehydration. Rare: Hypoglycemia, hyponatremia, lactic dehydrogenase increased, SGOT increased, SGPT increased.

Musculoskeletal: Infrequent: Leg cramps, myalgia, myasthenia, arthralgia, arthritis.

Nervous System: Frequent: Tremor, convulsion, abnormal gait, hyperesthesia, incoordination. Infrequent: Hypertonia, twitching, abnormal dreams, vertigo, libido decreased, neuropathy, hyperkinesia, movement disorder, dysarthria, cerebrovascular accident, hypotonia, peripheral neuritis, reflexes increased. Rare: Dyskinesia, dystonia, encephalopathy, facial paralysis, hypokinesia, hyperesthesia, myoclonus, oculogyric crisis.

Behavioral Abnormalities –Non-Psychosis-Related: Infrequent: Euphoria.

Respiratory: Frequent: Pharyngitis, cough increased. Infrequent: Dyspnea. Rare: Apnea, hemoptysis.

Skin and Appendages: Frequent: Pruritus. Infrequent: Maculopapular rash, acne, alopecia, dry skin, sweating, eczema, urticaria, hirsutism, pustular rash, vesiculobullous rash.

Special Senses: Frequent: Amblyopia, tinnitus. Infrequent: Conjunctivitis, parosmia, deafness, visual field defect, glaucoma. Rare: Photophobia, iritis.

Urogenital: Infrequent: Urinary frequency, dysuria, urinary incontinence, hematuria, impotence, urinary retention, urinary urgency, amenorrhea, polyuria, nocturia. Rare: Albuminuria, enuresis, bladder pain, bladder calculus, gynecomastia, mastitis, menorrhagia.

Drug Interactions

Drug Interactions with CNS Depressants: Concomitant administration of zonisamide and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. 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.

Other Carbonic Anhydrase Inhibitors: 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 risk of kidney stone formation or the risk of hyperammonemia. 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 CLINICAL PHARMACOLOGY, Interactions of Zonisamide with Other Carbonic Anhydrase Inhibitors subsection and WARNINGS, Metabolic Acidosis subsection and Hyperammonemia and Encephalopathy subsection).

Drug Abuse and Dependence

The abuse and dependence potential of zonisamide 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.

Overdosage

Human Experience: Experience with zonisamide daily doses over 800 mg/day is limited. 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 mcg/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.

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 section). 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 zonisamide overdosage.

Description

Zonisamide, USP is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The active ingredient is zonisamide USP, 1,2-benzisoxazole-3-methanesulfonamide. The empirical formula is C₈H₈N₂O₃S with a molecular weight of 212.23. Zonisamide USP 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 is supplied for oral administration as capsules containing 25, 50 and 100 mg of zonisamide.

Each capsule contains the labeled amount of zonisamide plus the following inactive ingredients: microcrystalline cellulose, hydrogenated vegetable oil, gelatin and colorants. Components of gelatin capsules,titanium dioxide, gelatin and Imprint ink dye (Black SW- 9008/SW-9009). In addition, 100 mg capsule conatins:  FDA/E172 red iron oxide and 50 mg capsule contains: FD&C Blue No#2. 

Clinical Pharmacology

Mechanism of Action: The precise mechanism(s) by which zonisamide exerts its antiseizure effect is unknown. Zonisamide demonstrated anticonvulsant activity in several experimental models. In animals, zonisamide was effective against tonic extension seizures induced by maximal electroshock but ineffective against clonic seizures induced by subcutaneous pentylenetetrazol. Zonisamide raised the threshold for generalized seizures in the kindled rat model and reduced the duration of cortical focal seizures induced by electrical stimulation of the visual cortex in cats. Furthermore, zonisamide suppressed both interictal spikes and the secondarily generalized seizures produced by cortical application of tungstic acid gel in rats or by cortical freezing in cats. The relevance of these models to human epilepsy 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 and suppressing neuronal hypersynchronization. In vitro binding studies have demonstrated that zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion which does not produce changes in chloride flux. Other in vitro studies have demonstrated that zonisamide (10 to 30 mcg/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [³H]-GABA (rat hippocampal slices). Thus, zonisamide does not appear to potentiate the synaptic activity of GABA. In vivo microdialysis studies demonstrated that zonisamide facilitates both dopaminergic and serotonergic neurotransmission.

Zonisamide is a carbonic anhydrase inhibitor. The contribution of this pharmacological action to the therapeutic effects of zonisamide is unknown. However, as a carbonic anhydrase inhibitor, zonisamide may cause metabolic acidosis (see WARNINGS, Metabolic Acidosis subsection).

Pharmacokinetics:

Absorption

Following a 200 to 400 mg oral zonisamide dose, peak plasma concentrations (range: 2 to 5 mcg/mL) in normal volunteers occur within 2 to 6 hours. In the presence of food, the time to maximum concentration is delayed; occurring at 4 to 6 hours, but food has no effect on the bioavailability of zonisamide. Zonisamide absorption is dose-proportional in the range of 200 to 400 mg. C_max and AUC, however, increase disproportionately at 800 mg, possibly due to saturable binding of zonisamide to red blood cells. Once a stable dose is reached, steady state is achieved within 14 days.

Distribution

The apparent volume of distribution (V/F) of zonisamide is about 1.45 L/kg following a 400 mg oral dose. Zonisamide, at concentrations of 1.0 to 7.0 mcg/mL, is approximately 40% bound to human plasma proteins. Zonisamide extensively binds to erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells than in plasma. Protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital or carbamazepine.

Metabolism and Elimination

Following oral administration of ¹⁴C-zonisamide to healthy volunteers, only zonisamide was detected in plasma. Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. Following multiple dosing, 62% of the radiolabeled dose was recovered in the urine, with 3% in the feces by day 10. Zonisamide undergoes acetylation by N-acetyl-transferases to form N-acetyl zonisamide and reduction to form the open ring metabolite, 2–sulfamoylacetyl phenol (SMAP). Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of SMAP. Reduction of zonisamide to SMAP is mediated by cytochrome P450 isozyme 3A4 (CYP3A4).

Zonisamide does not induce its own metabolism. The plasma clearance of oral zonisamide is approximately 0.30 to 0.35 mL/min/kg in patients not receiving enzyme-inducing antiepilepsy drugs (AEDs). The clearance of zonisamide is increased to 0.5 mL/min/kg in patients concurrently on enzyme-inducing AEDs.

After a single-dose administration, renal clearance of zonisamide is approximately 3.5 mL/min. The clearance of an oral dose of zonisamide from red blood cells is 2 mL/min. The elimination half-life of zonisamide in plasma is approximately 63 hours. The elimination half-life of zonisamide in red blood cells is approximately 105 hours.

Specific Populations:

Renal Impairment: Single 300 mg zonisamide doses were administered to three groups of volunteers. Group 1 was a healthy group with a creatinine clearance ranging from 70 to 152 mL/min. Group 2 and Group 3 had creatinine clearances ranging from 14.5 to 59 mL/min and 10 to 20 mL/min, respectively. Zonisamide renal clearance decreased with decreasing renal function (3.42, 2.50, 2.23 mL/min, respectively). Marked renal impairment (creatinine clearance <20 mL/min) was associated with an increase in zonisamide AUC of 35% (see DOSAGE AND ADMINISTRATION section).

Hepatic Impairment: The pharmacokinetics of zonisamide in patients with impaired liver function have not been studied (see DOSAGE AND ADMINISTRATION section).

Age: The pharmacokinetics of a 300 mg single dose of zonisamide was similar in young (mean age 28 years) and elderly subjects (mean age 69 years).

Gender and Race: Information on the effect of gender and race on the pharmacokinetics of zonisamide is not available.

Effects of Zonisamide on cytochrome P450 enzymes

In vitro studies using human liver microsomes show insignificant (<25%) inhibition of cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4, 2B6 or 2C8 at zonisamide levels approximately two-fold or greater than clinically relevant unbound serum concentrations. Therefore, Zonisamide is not expected to affect the pharmacokinetics of other drugs via cytochrome P450-mediated mechanisms.

Potential for Zonisamide to affect other drugs

Anti-epileptic drugs

In epileptic patients, steady state dosing with Zonisamide resulted in no clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.

Oral contraceptives

In healthy subjects, steady state dosing with Zonisamide did not affect serum concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.

CYP2D6 substrates

Coadministration of multiple dosing of zonisamide up to 400 mg/day with single 50 mg doses of desipramine did not significantly affect the pharmacokinetic parameters of desipramine, a probe drug for CYP2D6 activity.

P-gp substrate

An in vitro study showed that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC₅₀ of 267 μmol/L. There is a theoretical potential for zonisamide to affect the pharmacokinetics of drugs which are P-gp substrates.
Caution is advised when starting or stopping Zonisamide or changing the Zonisamide dose in patients who are also receiving drugs which are P-gp substrates (e.g., digoxin, quinidine).

Potential for Medicinal Products to Affect Zonisamide

Concomitant medications that can induce or inhibit CYP3A4 or N-acetyl-transferases may affect the pharmacokinetics of zonisamide. Drugs which inhibit or induce glucuronide conjugation are not expected to influence the pharmacokinetics of zonisamide.

The absence of a clinically significant pharmacokinetic interaction between zonisamide and lamotrigine indicates a low potential for zonisamide to interact with substances which are metabolized by UDP-GT.

CYP3A4 Induction: Drugs that induce liver enzymes increase the metabolism and clearance of zonisamide and decrease its half-life. The half-life of zonisamide following a 400 mg dose in patients concurrently on enzyme-inducing AEDs such as phenytoin, carbamazepine, or phenobarbital was between 27 to 38 hours, the half-life of zonisamide in patients concurrently on the non-enzyme inducing AED, valproate, was 46 hours.

These effects are unlikely to be of clinical significance when Zonisamide is added to existing therapy; however, changes in zonisamide concentrations may occur if concomitant CYP3A4 inducing anti-epileptic or other drugs are withdrawn, dose adjusted or introduced, an adjustment of the Zonisamide dose may be required. If co-administration with a potent CYP3A4 inducer (e.g., rifampicin) is necessary, the patient should be closely monitored and the dose of Zonisamide and other drugs that are CYP3A4 substrate may need to be adjusted.

CYP3A4 Inhibition: Steady-state dosing of either ketoconazole (400 mg/day) or cimetidine (1200 mg/day) had no clinically relevant effects on the single dose pharmacokinetics of zonisamide given to healthy subjects. Therefore, modification of Zonisamide dosing is not necessary when co-administered with known CYP3A4 inhibitors.

Interactions of Zonisamide with Other Carbonic Anhydrase Inhibitors: 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 subsection and Hyperammonemia and Encephalopathy subsection and PRECAUTIONS, Drug Interactions subsection).

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 US studies, over 80% of patients were Caucasian; 100% of patients in the European study were Caucasian. Zonisamide or placebo was added to the existing therapy. The primary measure of effectiveness was median percent reduction from baseline in partial seizure frequency. The secondary measure was proportion of patients achieving a 50% or greater seizure reduction from baseline (responders). The results described below are for all partial seizures in the intent-to-treat populations.

In the first study (n = 203), all patients had a 1-month baseline observation period, then received placebo or zonisamide in one of two dose escalation regimens; either 1) 100 mg/day for five weeks, 200 mg/day for one week, 300 mg/day for one week, and then 400 mg/day for five weeks; or 2) 100 mg/day for one week, followed by 200 mg/day for five weeks, then 300 mg/day for one week, then 400 mg/day for five weeks. This design allowed a 100 mg vs. placebo comparison over weeks 1 to 5, and a 200 mg vs. placebo comparison over weeks 2 to 6; the primary comparison was 400 mg (both escalation groups combined) vs. placebo over weeks 8 to12. The total daily dose was given as twice a day dosing. Statistically significant treatment differences favoring zonisamide were seen for doses of 100, 200, and 400 mg/day.

In the second (n = 152) and third (n = 138) studies, patients had a 2 to 3 month baseline, then were randomly assigned to placebo or zonisamide for three months. zonisamide was introduced by administering 100 mg/day for the first week, 200 mg/day the second week, then 400 mg/day for two weeks, after which the dose (zonisamide or placebo) could be adjusted as necessary to a maximum dose of 20 mg/kg/day or a maximum plasma level of 40 mcg/mL. In the second study, the total daily dose was given as twice a day dosing; in the third study, it was given as a single daily dose. The average final maintenance doses received in the studies were 530 and 430 mg/day in the second and third studies, respectively. Both studies demonstrated statistically significant differences favoring zonisamide for doses of 400 to 600 mg/day, and there was no apparent difference between once daily and twice daily dosing (in different studies). Analysis of the data (first 4 weeks) during titration demonstrated statistically significant differences favoring zonisamide at doses between 100 and 400 mg/day. The primary comparison in both trials was for any dose over Weeks 5 to 12.

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.e., a decrease in seizure rate), while a negative value indicates a worsening from baseline (i.e., 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

No differences in efficacy based on age, sex or race, as measured by a change in seizure frequency from baseline, were detected.

Clinical Studies

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 US studies, over 80% of patients were Caucasian; 100% of patients in the European study were Caucasian. Zonisamide or placebo was added to the existing therapy. The primary measure of effectiveness was median percent reduction from baseline in partial seizure frequency. The secondary measure was proportion of patients achieving a 50% or greater seizure reduction from baseline (responders). The results described below are for all partial seizures in the intent-to-treat populations.

In the first study (n = 203), all patients had a 1-month baseline observation period, then received placebo or zonisamide in one of two dose escalation regimens; either 1) 100 mg/day for five weeks, 200 mg/day for one week, 300 mg/day for one week, and then 400 mg/day for five weeks; or 2) 100 mg/day for one week, followed by 200 mg/day for five weeks, then 300 mg/day for one week, then 400 mg/day for five weeks. This design allowed a 100 mg vs. placebo comparison over weeks 1 to 5, and a 200 mg vs. placebo comparison over weeks 2 to 6; the primary comparison was 400 mg (both escalation groups combined) vs. placebo over weeks 8 to12. The total daily dose was given as twice a day dosing. Statistically significant treatment differences favoring zonisamide were seen for doses of 100, 200, and 400 mg/day.

In the second (n = 152) and third (n = 138) studies, patients had a 2 to 3 month baseline, then were randomly assigned to placebo or zonisamide for three months. zonisamide was introduced by administering 100 mg/day for the first week, 200 mg/day the second week, then 400 mg/day for two weeks, after which the dose (zonisamide or placebo) could be adjusted as necessary to a maximum dose of 20 mg/kg/day or a maximum plasma level of 40 mcg/mL. In the second study, the total daily dose was given as twice a day dosing; in the third study, it was given as a single daily dose. The average final maintenance doses received in the studies were 530 and 430 mg/day in the second and third studies, respectively. Both studies demonstrated statistically significant differences favoring zonisamide for doses of 400 to 600 mg/day, and there was no apparent difference between once daily and twice daily dosing (in different studies). Analysis of the data (first 4 weeks) during titration demonstrated statistically significant differences favoring zonisamide at doses between 100 and 400 mg/day. The primary comparison in both trials was for any dose over Weeks 5 to 12.

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.e., a decrease in seizure rate), while a negative value indicates a worsening from baseline (i.e., 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

No differences in efficacy based on age, sex or race, as measured by a change in seizure frequency from baseline, were detected.

How Supplied / Storage and Handling

Zonisamide, USP is available as 25mg, 50mg and 100 mg wth  two-piece hard gelatin capsules. The capsules imprinted with codes are printed in black ink. Zonisamide, USP is available in bottles with strengths and capsule description as follows:

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature], in a dry place and protected from light.

Revised: 03/21

Patient Counseling Information

Information for Patients: Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking zonisamide. Instruct patients to take zonisamide only as prescribed.

Advise patients as follows: (See Medication Guide)

1. 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.
2. Patients should contact their physicians immediately if a skin rash develops (see WARNINGS, Serious Skin Reactions subsection).
3. 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 subsection).
4. 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 subsection).
5. 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 subsection).
6. 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 subsection).
7. 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 subsection).
8. 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 subsection).
9. 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 subsection).
10. 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 subsection).
11. 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 subsection).