Zonisamide

212.23

212.23

200-659-6

459384H98V

DTXSID9046023

C47790

White needles from ethyl acetate

N03AX15|N - Nervous system

2935009090

94.6

0.2

off-white solid

1.5±0.1 g/cm3

160-163 °C

457ºC

9℃

1.656

>31.8 [ug/mL]

Store at +4°C

3.3X10-6 mm Hg at 25 deg C /Estimated/

Oral-rat LD50: 1992 mg/kg; Oral-Mouse LD50; 1892 mg/kg

Flammable; burning produces toxic nitrogen oxides and sulfur oxide fumes

Odorless

Tasteless

Henry's Law constant = 4.9X10-11 atm-cu m/mole at 25 °C /Estimated/

10.2|pKa = 10.2

Hydroxyl radical reaction rate constant = 3.0X10-11 cu cm/molecule sec at 25 °C /Estimated/

UN1230 - class 3 - PG 2 - Methanol, solution

3

22-39/23/24/25-23/24/25-11

7-16-36/37-45

DE4930000

Xn,T,F

Ventilated, low temperature and dry

P210-P260-P280-P301 + P310-P311

H225-H301 + H311 + H331-H370

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl zonisamide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

moderately toxic

Symptoms of overdose include diminished breathing, loss of consciousness, low blood pressure, and slow heartbeat.

Prospective studies suggest that chronic zonisamide therapy may be accompanied by mild increases in serum alkaline phosphatase levels, but it has not been linked to significant increases in serum aminotransferase levels during treatment. Clinically apparent hepatotoxicity from zonisamide is rare, but several case reports of hepatic injury linked to zonisamide have been published. Zonisamide is typically used in combination with other anticonvulsants and its separate role in causing liver injury is often difficult to delineate. Zonisamide has been linked to a single case report of cholestatic hepatitis associated with vanishing bile duct syndrome that ultimately resolved. More commonly, zonisamide has been linked to cases of hypersensitivity (DRESS syndrome or Stevens-Johnson syndrome) with rash, fever, eosinophilia, renal failure and/or mild liver test abnormalities. In most instances, the hepatic injury was cholestatic and arose 3 to 8 weeks after starting therapy. Autoantibodies are usually not present. Interestingly, a similar cholestatic liver injury has been described in dogs receiving zonisamide.

Additive sedation effects may occur /when other CNS depression-producing medications are used with zonisamide/.|Effects of Zonegran on the pharmacokinetics of other antiepilepsy drugs (AEDs): Zonisamide had no appreciable effect on the steady state plasma concentrations of phenytoin, carbamazepine, or valproate during clinical trials. Zonisamide did not inhibit mixed-function liver oxidase enzymes (cytochrome P450), as measured in human liver microsomal preparations, in vitro.|Interaction with cimetidine: Zonisamide single dose pharmacokinetic parameters were not affected by cimetidine (300 mg four times a day for 12 days).|Concurrent administration of CYP3A4-inducing or inhibiting medications with zonisamide has altered serum concentrations and half-life values. Zonisamide serum half-life values are decreased to 27 hours in the presence of phenytoin, to 38 hours in the presence of either carbamazepine or phenobarbital, and to 46 hours when administered concomitantly with valproate.|These drugs /anticholinergics or carbonic anhydrase inhibitors/ predispose patients to heat-related disorders; caution should be used when administered concurrently with zonisamide.

LD50 Mouse oral 1892 mg/kg|LD50 Rat oral 2001 mg/kg|LD50 Mouse sc 1273 mg/kg|LD50 Rat sc 2569 mg/kg|For more Non-Human Toxicity Values (Complete) data for ZONISAMIDE (8 total), please visit the HSDB record page.

40% (at concentrations of 1.0-7.0 µg/mL)

Zonisamide is distributed into human breast milk, at a milk-to-plasma ratio of 0.93.

For use as adjunctive treatment of partial seizures in adults with epilepsy.|FDA Label|Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy;adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, in adults, adolescents, and children aged 6 years and above.|Zonegran is indicated as:monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy;adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, in adults, adolescents, and children aged six years and above.

Zonisamide is a new generation anticonvulsant that is typically used in combination with other antiepileptic medications for partial onset seizures. Zonisamide has not been associated with elevations in serum aminotransferase levels and clinically apparent drug induced liver disease has been reported with its use but is very rare.

Anticonvulsants

Anticonvulsant|Zonisamide is indicated for adjunctive therapy use in the treatment of partial seizures in adults with epilepsy. /Included in US product labeling/

Zonisamide (ZNS)-induced behavior disorders are reported in a 1-year-old girl and a 3-year-old boy. Both patients, who had no previous developmental or mental problems, displayed secondarily generalized motor seizures. Serum concentrations of ZNS were not high, 8.8 and 12.3 micrograms/ml (effective range 10-30 micrograms/ml) respectively. Although many cases of ZNS-related psychotic reactions and/or behavior disorders have been reported, all affected patients had complex partial seizures (CPS) and had received combination therapy with phenytoin (PHT). Thus, whether the disorders were induced only by ZNS, by an interaction between ZNS and PHT, or by CPS could not be determined. In the children reported, however, ZNS clearly induced behavior disorders at plasma ZNS levels within or even below the therapeutic range.|Oligohidrosis and Hyperthermia in Pediatric Patients: Oligohidrosis, sometimes resulting in heat stroke and hospitalization, is seen in association with zonisamide in pediatric patients. ... Decreased sweating and an elevation in body temperature above normal characterized these cases. Many cases were reported after exposure to elevated environmental temperatures. Heat stroke, requiring hospitalization, was diagnosed in some cases. There have been no reported deaths. Pediatric patients appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia. Patients, especially pediatric patients, treated with Zonegran should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. Caution should be used when zonisamide is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, carbonic anhydrase inhibitors and drugs with anticholinergic activity.|Fatalities resulting from severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have occurred following use of zonisamide. Use of sulfonamides also rarely has caused fatalities resulting from fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias, regardless of the route of administration. Zonisamide should be discontinued immediately if signs or symptoms of hypersensitivity occur. Discontinuance of zonisamide should be considered whenever a patient receiving zonisamide develops unexplained rash; if the drug is not discontinued, the patient should be observed frequently.|During the premarketing development of zonisamide, 9 sudden and unexplained deaths were reported among a cohort of 991 patients with epilepsy receiving adjunctive therapy with the drug (7.7 deaths per 1000 patient-years). Although the rate of these deaths exceeds that expected to occur in a healthy (nonepileptic) population, this rate was similar to that occurring in patients with refractory epilepsy not receiving zonisamide.|For more Drug Warnings (Complete) data for ZONISAMIDE (22 total), please visit the HSDB record page.

Zonisamide is a sulfonamide and therefore unrelated to other seizure medications. The mechanism is not know but it may block sodium and calcium channels. Blocking of these channels may prevent neuronal hypersynchronization. Sonisamide has also been found to potentiate dopaminergic and serotonergic neurotransmission but does not appear to potentiate syanptic activity by GABA (gamma amino butyric acid).

A class of drugs that act by selective inhibition of calcium influx through cellular membranes. (See all compounds classified as Calcium Channel Blockers.)|Drugs used to prevent SEIZURES or reduce their severity. (See all compounds classified as Anticonvulsants.)

The absorption is rapid with a time to peak concentration of 2.8-3.9 hours. Food has not effect on bioavailability.|Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite.|1.45 L/kg|0.30 - 0.35 mL/min/kg [patients not receiving enzyme-inducing antiepilepsy drugs (AEDs)]|Elimination: Renal: 62%, Fecal: 3%. Plasma clearance of zonisamide is approximately 0.30 to 0.35 mL/min/kg in patients not receiving concomitant therapy with enzyme-inducing anticonvulsants. Zonisamide clearance is increased to 0.5 mL/min/kg in patients concurrently receiving enzyme-inducing anticonvulsant medications.|In patients with creatinine clearance <20 mL/min, the area under the concentration-time curve (AUC) for zonisamide is increased by 35%.|Zonisamide is distributed to breast milk, cerebrospinal fluid, and erythrocytes. Concentration in erythrocytes is approximately 8 times higher than in plasma and the milk-to-plasma ratio is 0.93. The concentration of zonisamide in cerebrospinal fluid is approximately 76% of the concentration found in plasma.|Following a 200-400 mg oral zonisamide dose, peak plasma concentrations (range: 2-5 ug/mL) in normal volunteers occur within 2-6 hours. In the presence of food, the time to maximum concentration is delayed, occurring at 4-6 hours, but food has no effect on the bioavailability of zonisamide. Zonisamide extensively binds to erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells (RBC) than in plasma. The pharmacokinetics of zonisamide are dose proportional in the range of 200-400 mg, but the Cmax and AUC increase disproportionately at 800 mg, perhaps due to saturable binding of zonisamide to RBC. Once a stable dose is reached, steady state is achieved within 14 days. ...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 1.0-7.0 ug/mL, is approximately 40% bound to human plasma proteins. Protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital or carbamazepine.|Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. ... Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of 2-sulfamoylacetyl phenol (SMAP)

Primarily hepatic through cytochrome P450 isoenzyme 3A4 (CYP3A4). Undergoes acetylation and reduction, forming N-acetyl zonisamide, and the open-ring metabolite 2–sulfamoylacetyl phenol, respectively.|... Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. ... Zonisamide undergoes acetylation 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.|Zonisamide undergoes acetylation to form N-acetyl zonisamide and reduction to form the open ring metabolite, 2-sulfamoylacetyl phenol (SMAP). ... Reduction of zonisamide to SMAP is mediated by cytochrome P450 isozyme 3A4 (CYP3A4). Zonisamide does not induce its own metabolism.

63 hours|Elimination /half-life/ in plasma: 63 hours; Elimination /half-life/ in erythrocytes: 105 hours.

Zonisamide binds to sodium channels and voltage sensitive calcium channels, which suppresses neuronal depolarization and hypersynchronization. Zonisamide also inhibits carbonic anhydrase to a weaker extent, but such an effect is not thought to contribute substantially to the drug's anticonvulsant activity.|The exact method by which zonisamide exerts its anticonvulsant effect is unknown. Some in vitro studies suggest a blockade of sodium channels, with consequent stabilization of neuronal membranes and suppression of neuronal hypersynchronization, whereas other in vitro studies have shown zonisamide to suppress synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses. It appears then, that zonisamide dose not potentiate the synaptic activity of GABA. Zonisamide also serves as a weak inhibitor of carbonic anhydrase.|Epileptiform discharges and behavioral seizures may be the consequences of excess excitation associated with the neurotransmitter glutamate, or from inadequate inhibitory effects associated with gamma-aminobutyric acid (GABA). Synaptic effects of these neurotransmitters are terminated by the action of transporter proteins that remove amino acids from the synaptic cleft. Excitation initiated by the synaptic release of glutamate is attenuated by the action of glial transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), and the neuronal transporter excitatory amino-acid carrier-1 (EAAC-1). GABA is removed from synaptic regions by the action of the transporters proteins GABA transporter-1 (GAT-1) and GABA transporter-3 (GAT-3). Albino rats with chronic, spontaneous recurrent seizures induced by the amygdalar injection of eCl3 were treated for 14 days with zonisamide (ZNS) (40 mg/kg, ip). Control animals underwent saline injection into the same amygdalar regions. Treatment control for both groups of intracerebrally injected animals was ip injection of equal volumes of saline. Western blotting was used to measure the quantity of glutamate and GABA transporters in hippocampus and frontal cortex. ZNS caused increase in the quantity of EAAC-1 protein in hippocampus and cortex and down regulation of the GABA transporter GAT-1. These changes occurred in both experimental and ZNS treated control animals. These data show that the molecular effect of ZNS, with up-regulation of EAAC-1 and decreased production of GABA transporters, should result in increased tissue and synaptic concentrations of GABA.

Treatment of overdose: Emesis should be induced or gastric lavage applied, employing appropriate airway protection techniques. To enhance elimination: Renal dialysis may not be effective, due to the low protein binding profile (40%) of zonisamide. There are no specific treatments or antidotes for zonisamide toxicity. Treatment is generally symptomatic and supportive. Monitoring of electrocardiographic rhythm, blood pressure, and respiratory function. Supportive care: Maintaining respiratory and cardiac function. Usual and customary measures of managing circulatory collapse. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

/HUMAN EXPOSURE STUDIES/ During the premarketing development of zonisamide, 9 sudden and unexplained deaths were reported among a cohort of 991 patients with epilepsy receiving adjunctive therapy with the drug (7.7 deaths per 1000 patient-years). Although the rate of these deaths exceeds that expected to occur in a healthy (nonepileptic) population, this rate was similar to that occurring in patients with refractory epilepsy not receiving zonisamide.|/HUMAN EXPOSURE STUDIES/ Experience with ZONEGRAN daily doses over 800 mg/day is limited. During ZONEGRAN clinical development, three patients ingested unknown amounts of ZONEGRAN 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 ug/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.|/SIGNS AND SYMPTOMS/ Fatalities resulting from severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have occurred following use of zonisamide. Use of sulfonamides also rarely has caused fatalities resulting from fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias, regardless of the route of administration. Zonisamide should be discontinued immediately if signs or symptoms of hypersensitivity occur. Discontinuance of zonisamide should be considered whenever a patient receiving zonisamide develops unexplained rash; if the drug is not discontinued, the patient should be observed frequently.|/SIGNS AND SYMPTOMS/ Aplastic anemia and agranulocytosis were rarely reported in patients receiving zonisamide ...

3 Sulfamoylmethyl 1,2 benzisoxazole

Elan Pharmaceuticals, Inc. San Diego, CA 92121 /Zonegran/|Zonegran is supplied for oral administration as capsules containing 100 mg zonisamide.

Preparation: H. Uno et al., JP Kokai 78 77057; eidem, US 4172896 (1978, 1979 both to Dainippon)|Information available in 2004 indicated that Zonisamide was used in the manufacture of pharmaceutical preparations in the following countries: Japan, USA (1,2)

HPLC determination in serum.

Human drugs -> Zonisamide Mylan -> EMA Drug Category|Antiepileptics -> Human pharmacotherapeutic group|Human drugs -> Zonegran -> EMA Drug Category|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients