ZONISADE ZONISAMIDE 100 mg/5mL Suspension — NDC 52652-8001-1 (Billing 52652-8001-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics As a carbonic anhydrase inhibitor, ZONISADE may cause metabolic acidosis and may also increase the risks of hyperammonemia and kidney stone formation [see Warnings and Precautions ( 5.8 , 5.13 , 5.15 ) and Drug Interactions ( 7.2 )].

12.3Pharmacokinetics Absorption Following a 100 mg ZONISADE dose in normal volunteers, the time to maximum plasma concentrations (T max ) occurred within 0.5–5 hours. Zonisamide pharmacokinetics are dose-proportional in the range of 200 to 400 mg. Once a stable dose is reached, steady state is achieved within 14 days.

Effect of Food When ZONISADE is administered with food, the zonisamide T max is delayed, occurring at 3.5–7.5 hours, but food has no effect on the bioavailability of zonisamide. Distribution The apparent volume of distribution (V/F) of zonisamide is about

1.45L/kg following a 400 mg oral dose. Zonisamide, at concentrations of 1.0–7.0 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. Elimination The plasma clearance of oral zonisamide is approximately 0.30–0.35 mL/min/kg in patients not receiving enzyme-inducing antiepileptic drugs (AEDs). The clearance of zonisamide is increased to 0.5 mL/min/kg in patients concurrently on enzyme-inducing AEDs (see Potential for Other Drugs to Affect ZONISADE) .

After a single-dose administration, renal clearance of zonisamide is approximately 3.5 mL/min. Metabolism Zonisamide is metabolized by N-acetyl-transferases to form N-acetyl zonisamide and by CYP3A4 to form 2–sulfamoylacetylphenol (SMAP). Excretion 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. 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.

Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of SMAP. Specific Populations Patients with 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 70–152 mL/min.

Group 2 and Group 3 had creatinine clearances ranging from 14.5–59 mL/min and 10–20 mL/min, respectively. Zonisamide renal clearance decreased with decreasing renal function (3.42, 2.50, and 2.23 mL/min, respectively). Marked renal impairment (creatinine clearance < 20 mL/min) was associated with an increase in zonisamide AUC of 35% [see Use in Specific Populations ( 8.6 )] .

Patients with Hepatic Impairment The pharmacokinetics of zonisamide in patients with impaired liver function have not been studied . Age The ph… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics Absorption Following a 100 mg ZONISADE dose in normal volunteers, the time to maximum plasma concentrations (T max ) occurred within 0.5–5 hours. Zonisamide pharmacokinetics are dose-proportional in the range of 200 to 400 mg. Once a stable dose is reached, steady state is achieved within 14 days.

Effect of Food When ZONISADE is administered with food, the zonisamide T max is delayed, occurring at 3.5–7.5 hours, but food has no effect on the bioavailability of zonisamide. Distribution The apparent volume of distribution (V/F) of zonisamide is about

1.45L/kg following a 400 mg oral dose. Zonisamide, at concentrations of 1.0–7.0 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. Elimination The plasma clearance of oral zonisamide is approximately 0.30–0.35 mL/min/kg in patients not receiving enzyme-inducing antiepileptic drugs (AEDs). The clearance of zonisamide is increased to 0.5 mL/min/kg in patients concurrently on enzyme-inducing AEDs (see Potential for Other Drugs to Affect ZONISADE) .

After a single-dose administration, renal clearance of zonisamide is approximately 3.5 mL/min. Metabolism Zonisamide is metabolized by N-acetyl-transferases to form N-acetyl zonisamide and by CYP3A4 to form 2–sulfamoylacetylphenol (SMAP). Excretion 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. 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.

Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of SMAP. Specific Populations Patients with 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 70–152 mL/min.

Group 2 and Group 3 had creatinine clearances ranging from 14.5–59 mL/min and 10–20 mL/min, respectively. Zonisamide renal clearance decreased with decreasing renal function (3.42, 2.50, and 2.23 mL/min, respectively). Marked renal impairment (creatinine clearance < 20 mL/min) was associated with an increase in zonisamide AUC of 35% [see Use in Specific Populations ( 8.6 )] .

Patients with Hepatic Impairment The pharmacokinetics of zonisamide in patients with impaired liver function have not been studied . Age The pharmacokinetics of a 300 mg single dose of zonisamide were similar in young (mean age 28 years) and elderly subjects (mean age 69 years). Drug Interaction Studies In-Vitro Studies 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, ZONISADE is not expected to affect the pharmacokinetics of other drugs via cytochrome P450-mediated mechanisms. Transporters An in-vitro study showed that zonisamide is a weak inhibitor of P-gp (MDR1). In-Vivo Studies Potential for Zonisamide to Affect Other Drugs Antiepileptic 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 Coadministration of multiple dosing of zonisa… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics As a carbonic anhydrase inhibitor, ZONISADE may cause metabolic acidosis and may also increase the risks of hyperammonemia and kidney stone formation [see Warnings and Precautions ( 5.8 , 5.13 , 5.15 ) and Drug Interactions ( 7.2 )].

14 CLINICAL STUDIES The efficacy of ZONISADE is based upon a bioavailability study comparing ZONISADE oral suspension to zonisamide capsules in healthy subjects. The clinical studies information described below pertains to the zonisamide capsule formulation. The effectiveness of zonisamide as adjunctive therapy 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) had 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 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 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 1–5, and a 200 mg vs. placebo comparison over weeks 2–6; the primary comparison was 400 mg (both escalation groups combined) vs. placebo over weeks 8–12.

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 2–3 month baseline, then were randomly assigned to placebo or zonisamide capsules 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 could be adjusted as necessary to a maximum dose of 20 mg/kg/day or a maximum plasma level of 40 µg/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 400–600 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 5–12.

Table 3. Median % Reduction in All Partial-Onset Seizures and % Responders in Primary Efficacy Analyses: Intent-To-Treat Analysis Study Median % Reduction in Partial-Onset Seizures % Responders Zonisamide Capsules Placebo Zonisamide Capsules Placebo Study 1: n=98 n=72 n=98 n=72 Weeks 8-12: 40.5% p<0.05 compared to placebo 9.0% 41.8% 22.2% Study 2: n=69 n=72 n=69 n=72 Weeks 5-12: 29.6% -3.2% 29.0% 15.0% Study 3: n=67 n=66 n=67 n=66 Weeks 5-12: 27.2% -1.1% 28.0% 12.0% Table 4. Median % Reduction in All Partial-Onset Seizures and % Responders for Dose Analyses in Study 1: Intent-To-Treat Analysis Dose Group Median % Reduction in Partial-Onset Seizures % Responders Zonisamide Capsules Placebo Zonisamide Capsules Placebo 100-400 mg/day: n=112 n=83 n=112 n=83 Weeks… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenicity, Mutagenesis, Impairment of Fertility Carcinogenicity No evidence of carcinogenicity was found in mice or rats following dietary administration of zonisamide for two years at doses of up to 80 mg/kg/day. In mice, this dose is approximately equivalent to the maximum recommended human dose (MRHD) of 400 mg/day on a mg/m2 basis. In rats, this dose is 1–2 times the MRHD on a mg/m2 basis.

Mutagenesis Zonisamide was mutagenic in an in vitro chromosomal aberration assay in CHL cells. Zonisamide was not mutagenic or clastogenic in other in vitro assays (Ames, mouse lymphoma tk assay, chromosomal aberration in human lymphocytes) or in the in vivo rat bone marrow cytogenetics assay. Impairment of Fertility Rats treated with zonisamide (20, 60, or 200 mg/kg) before mating and during the initial gestation phase showed signs of reproductive toxicity (decreased corpora lutea, implantations, and live fetuses) at all doses.

The low dose in this study is approximately 0.5 times the maximum recommended human dose (MRHD) on a mg/m 2 basis.