Zonisamide

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.

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