Zonisamide: Package Insert and Label Information

ZONISAMIDE- zonisamide capsule
Mylan Institutional Inc.

Zonisamide capsules, USP are an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The active ingredient is zonisamide, 1,2-benzisoxazole-3-methanesulfonamide. The molecular formula is C 8 H 8 N 2 O 3 S with a molecular weight of 212.23. Zonisamide, USP is a white or almost white crystalline powder, pK a = 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 Structural Formula

Zonisamide capsules are supplied for oral administration as capsules containing 25 mg, 50 mg or 100 mg zonisamide. Each capsule contains the labeled amount of zonisamide plus the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. The empty gelatin capsule shells contain D&C Red No. 28, FD&C Blue No. 1, gelatin and titanium dioxide. In addition, the 100 mg empty gelatin capsule contains FD&C Red No. 3.

The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.

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 Ca 2+ 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 mcg/mL 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 [ 3 H]-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).

Pharmacokinetics

Absorption

Following a 200 mg to 400 mg oral zonisamide dose, peak plasma concentrations (range: 2 mcg/mL 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 mg 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 mcg/mL 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 14 C-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 mL/min/kg 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 mL/min to 152 mL/min. Group 2 and Group 3 had creatinine clearances ranging from 14.5 mL/min to 59 mL/min and 10 mL/min to 20 mL/min, respectively. Zonisamide renal clearance decreased with decreasing renal function (3.42 mL/min, 2.50 mL/min, 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).

Hepatic Impairment

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

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 Capsules 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 capsules are not expected to affect the pharmacokinetics of other drugs via cytochrome P450-mediated mechanisms.

Potential for Zonisamide Capsules to Affect Other Drugs

Anti-Epileptic Drugs

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

Oral Contraceptives

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

CYP2D6 Substrates

Co-administration 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 IC 50 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 capsules or changing the zonisamide capsules dose in patients who are also receiving drugs which are P-gp substrates (e.g., digoxin, quinidine).

Potential for Medicinal Product to Affect Zonisamide Capsules

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 capsules are 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 capsules 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 capsules 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 capsules dosing is not necessary when co-administered with known CYP3A4 inhibitors.

Interactions of Zonisamide with Other Carbonic Anhydrase Inhibitors

Concomitant use of zonisamide capsules, 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. Therefore, if zonisamide capsules are given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis (see PRECAUTIONS: Drug Interactions).

Clinical Studies

The effectiveness of zonisamide capsules as adjunctive therapy (added to other antiepilepsy drugs) has been established in three multicenter, placebo-controlled, double blind, 3-month clinical trials (two domestic, one European) in 499 patients with refractory partial onset seizures with or without secondary generalization. Each patient had a history of at least four partial onset seizures per month in spite of receiving one or two antiepilepsy drugs at therapeutic concentrations. The 499 patients (209 women, 290 men) ranged in age from 13 to 68 years with a mean age of about 35 years. In the two U.S. studies, over 80% of patients were Caucasian; 100% of patients in the European study were Caucasian. Zonisamide capsules 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 capsules in one of two dose escalation regimens; either 1) 100 mg/day for 5 weeks, 200 mg/day for one week, 300 mg/day for one week, and then 400 mg/day for 5 weeks; or 2) 100 mg/day for one week, followed by 200 mg/day for 5 weeks, then 300 mg/day for one week, then 400 mg/day for 5 weeks. This design allowed a 100 mg vs. placebo comparison over weeks 1 mg to 5 mg, 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 to 12. The total daily dose was given as twice a day dosing. Statistically significant treatment differences favoring zonisamide capsules were seen for doses of 100 mg/day, 200 mg/day, 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 capsules for 3 months. Zonisamide capsules were introduced by administering 100 mg/day for the first week, 200 mg/day the second week, then 400 mg/day for 2 weeks, after which the dose (zonisamide capsules 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 mg/day and 430 mg/day in the second and third studies, respectively. Both studies demonstrated statistically significant differences favoring zonisamide capsules for doses of 400 mg/day 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 capsules at doses between 100 mg/day and 400 mg/day. The primary comparison in both trials was for any dose over Weeks 5 to 12.

Table 1. Median % Reduction in All Partial Seizures and % Responders in Primary Efficacy Analyses: Intent-To-Treat Analysis
*
p < 0.05 compared to placebo

Study

Median % reduction in partial seizures

% Responders

Zonisamide Capsules

Placebo

Zonisamide Capsules

Placebo

Study 1: Weeks 8 to 12:

n = 98 40.5% *

n = 72 9.0%

n = 98 41.8% *

n = 72 22.2%

Study 2: Weeks 5 to 12:

n = 69 29.6% *

n = 72 -3.2%

n = 69 29.0%

n = 72 15.0%

Study 3: Weeks 5 to 12:

n = 67 27.2% *

n = 66 -1.1%

n = 67 28.0% *

n = 66 12.0%

Table 2. Median % Reduction in All Partial Seizures and % Responders for Dose Analyses in Study 1: Intent-To-Treat Analysis
*
p < 0.05 compared to placebo
  1. Dose Group

Median % reduction in partial seizures

% Responders

Zonisamide Capsules

Placebo

Zonisamide Capsules

Placebo

100 mg/day to 400 mg/day: Weeks 1 to 12:

n = 112 32.3% *

n = 83 5.6%

n = 112 32.1% *

n = 83 9.6%

100 mg/day: Weeks 1 to 5:

n = 56 24.7% *

n = 80 8.3%

n = 56 25.0% *

n = 80 11.3%

200 mg/day: Weeks 2 to 6:

n = 55 20.4% *

n = 82 4.0%

n = 55 25.5% *

n = 82 9.8%

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 capsules groups compared to the placebo groups. For example, Figure 1 indicates that approximately 27% of patients treated with zonisamide capsules 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 Capsules and Placebo Groups in Studies 2 and 3
(click image for full-size original)

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

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