ゾニサミド

0.5

log Kow = 0.36 /Estimated/

0.5

0.8

Sparingly sol in chloroform, n-hexane. Sol in methanol, ethanol, ethyl acetate, and acetic acid.

In water, 0.80 mg/L, temp not specified

2.09e+00 g/L

>31.8 [ug/mL] (The mean of the results at pH 7.4)

161-163 °C

160-163 °C

161 - 163 °C

10.2

pKa = 10.2

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]；H361 (58.6%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P264, P270, P280, P301+P317, P318, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 99 reports by companies from 9 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

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.

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.

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. (L1712)

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.

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.；Likelihood score: D (possible rare cause of clinically apparent liver injury).；Mechanism of Injury；The mechanism of zonisamide hepatotoxicity is unknown but is likely to be hypersensitivity. Cases of drug hypersensitivity to zonisamide have been linked to HLA-A*02:07 in Japanese subjects.

The potential adverse reactions associated with zonisamide administration are listed below.；Common Adverse Effects；Common side effects associated with zonisamide administration include dizziness, somnolence, anorexia, ataxia, fatigue, abnormal thinking, and confusion. Zonisamide can also cause mild to moderate weight loss. Patients who are obese or who experienced weight gain associated with using other antiepileptic drugs may benefit from adding zonisamide to their regimen.；Rare Adverse Effects；Renal calculi are more common in individuals who have been taking zonisamide for at least 6 months, have a family history of nephrolithiasis, or are also taking other antiepileptic drugs. Zonisamide is not contraindicated in patients with a history of kidney stones, but care is necessary, and patients should maintain adequate hydration to maintain good urine flow.；Allergic reactions are rare but have been reported. A rash is the predominant allergic-type reaction reported. Zonisamide is chemically related to sulfonamide drugs; caution should be taken when using zonisamide in patients with prior allergic reactions to sulfa agents. Mild, relative neutropenia has been observed in some individuals.；Oligohidrosis can occur, causing decreased sweating and hyperthermia. This has been reported more in children. Children receiving zonisamide should not be exposed to extreme heat for prolonged periods.；Zonisamide, which inhibits carbonic anhydrase, can produce metabolic acidosis. Therefore, serum bicarbonate should be checked before starting treatment and regularly thereafter, especially in individuals with impaired pulmonary or renal function.；Zonisamide may alter cognition and behavior in some individuals. The true incidence of these adverse effects is unknown. Most of the reports of cognitive or behavioral problems have been in patients taking multiple antiepileptic drugs. Limited data on the teratogenic effects of zonisamide are available; use with caution.；Drug-Drug Interactions；Zonisamide is primarily metabolized through CYP3A4 and has a potential for drug interactions involving these enzyme systems. Ketoconazole, dihydroergotamine, cyclosporine A, and triazolam inhibit zonisamide metabolism by 85% to 95% compared to control. Other CYP3A4 inhibitors, including diazepam, erythromycin, lidocaine, and terfenadine, can cause a reduction in metabolism by 35% to 45%. Patients receiving CYP3A inhibitors require lower doses of zonisamide.；Drugs that can induce CYP3A4 can increase the metabolism of zonisamide. Phenytoin and carbamazepine have induced zonisamide metabolism. Other known inducers of hepatic metabolism, like phenobarbital and primidone, also can increase the metabolism of zonisamide. The dose of zonisamide may need to be increased when combined with known CYP3A inducers.；Zonisamide does not induce or inhibit hepatic enzymes and does not cause any clinically significant alteration in the pharmacokinetic disposition of other drugs.；A high concentration of CYP3A4 in the intestinal wall can metabolize drugs before they are absorbed into the systemic circulation. Some foods like grapefruit juice and lemon juice contain substances that can inhibit the activity of intestinal CYP3A4. When zonisamide is taken with foods that can inhibit the activity of intestinal CYP3A4, there is potential for increased absorption and adverse effects.

Signs and Symptoms of Overdose；Limited data are available on zonisamide overdose, and there are no cases reported thus far for monotoxicity with zonisamide. When acute or chronic zonisamide toxicity is suspected, immediate medical attention should be sought, and poison control should be contacted. The plasma concentration of zonisamide should be measured. Patients should be monitored closely and symptomatically treated. Overdose symptoms may include nausea, vomiting, somnolence, central nervous system depression, metabolic acidosis, and polyuria.；Management of Overdose；There is no specific antidote for zonisamide overdose. Supportive care, including vital sign monitoring, is essential. Due to its low protein binding, dialysis may be considered. Contact a poison control center or toxicologist for further guidance.

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.

/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 ...

Drug Induced Liver Injury Rank (DILIrank 2.0)

Zonisamide

vLess-DILI-concern

2

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

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.

N03AX15

N - Nervous system；N03 - Antiepileptics；N03A - Antiepileptics；N03AX - Other antiepileptics；N03AX15 - Zonisamide

QN - Nervous system；QN03 - Antiepileptics；QN03A - Antiepileptics；QN03AX - Other antiepileptics；QN03AX15 - Zonisamide

At concentrations between 1.0 and 7.0 μg/mL, zonisamide is approximately 40% bound to human plasma proteins. The concentration of zonisamide is 8-fold higher in red blood cells than in plasma due to its ability to bind extensively to erythrocytes. The presence of therapeutic concentrations of phenytoin, phenobarbital, or carbamazepine does not affect zonisamide protein binding.

By stopping the spread of seizure discharges, zonisamide prevents the extensor component of tonic convulsion, restricts the spread of focal seizures and prevents the propagation of seizures from the cortex to subcortical structures. In animal models, zonisamide was effective against tonic extension seizures but ineffective against clonic seizures. It also increased the threshold for generalized seizures and reduced the duration of cortical focal seizures. Aside from its antiepileptic effects, zonisamide is capable of activating neuroprotective mechanisms. It inhibits nitric oxide synthase and ​​reduces ischemia-induced memory impairment and lipid peroxidation. The use of zonisamide may lead to potentially fatal reactions. Severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia have been reported in patients treated with sulfonamides such as zonisamide. Zonisamide may also lead to the development of serious hematological events, drug reaction with eosinophilia and systemic symptoms (DRESS) and multi-organ hypersensitivity, acute myopia and secondary angle closure glaucoma, as well as suicidal behaviour and ideation. Zonisamide is a carbonic anhydrase inhibitor, which may lead to metabolic acidosis in patients treated with this drug. Its therapeutic effects due to this pharmacological action are unknown.

The mechanism of action by which zonisamide controls seizures has not been fully established. However, its antiepileptic properties may be due to its effects on sodium and calcium channels. Zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents, stabilizing neuronal membranes and suppressing neuronal hypersynchronization. It affects T-type calcium currents, but has no effect on L-type calcium currents. Zonisamide suppresses synaptically-driven electrical activity by altering the synthesis, release, and degradation of neurotransmitters, such as glutamate, gamma-aminobutyric acid (GABA), dopamine, serotonin (5-hydroxytryptamine [5-HT]), and acetylcholine. Furthermore, it binds to the GABA/benzodiazepine receptor ionophore complex without producing changes in chloride flux. _In vitro_ studies have suggested that zonisamide does not affect postsynaptic GABA or glutamate responses, nor the neuronal or glial uptake of [³H]-GABA.

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.

In plasma, the elimination half-life of zonisamide is approximately 63 hours. In red blood cells, it is approximately 105 hours.

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

Zonisamide metabolites are generated mainly by principally reductive and conjugative mechanisms. Oxidation reactions play a minor role in the metabolism of zonisamide. Zonisamide is metabolized by N-acetyl-transferases to form N-acetyl zonisamide and reduced to form the open ring metabolite, 2–sulfamoylacetylphenol (SMAP). The reduction of zonisamide to SMAP is mediated by CYP3A4. Zonisamide does not induce liver enzymes or its own metabolism.

... 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.

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. Route of Elimination: Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. Half Life: 63 hours

459384H98V

ZONISAMIDE

Established Pharmacologic Class [EPC] - Anti-epileptic Agent

Physiologic Effects [PE] - Decreased Central Nervous System Disorganized Electrical Activity

Chemical Structure [CS] - Sulfonamides

Mechanisms of Action [MoA] - Carbonic Anhydrase Inhibitors

Drugs used to prevent SEIZURES or reduce their severity.

A class of drugs that act by selective inhibition of calcium influx through cellular membranes.

Between 200 and 400 mg, zonisamide follows a dose-proportional pharmacokinetic profile. At concentrations higher than 800 mg, the Cmax and AUC increase in a disproportional manner, possibly due to zonisamide binding red blood cells. In healthy volunteers given 200 to 400 mg of zonisamide orally, peak plasma concentrations (Cmax) range between 2 and 5 µg/mL and are reached within 2–6 hours (Tmax). In healthy volunteers given 100 mg of zonisamide oral suspension, the Tmax ranged from 0.5 to 5 hours. Zonisamide has a high oral bioavailability (95%). The Tmax of zonisamide was delayed by food intake (4-6 hours); however, food has no effect on its bioavailability. Steady state is achieved 14 days after a stable dose is reached.

Zonisamide is mainly excreted as the parent drug and the glucuronide of a metabolite. Urine is the main route of zonisamide excretion, and only a small portion of this drug is excreted in feces. Following multiple doses of radiolabeled zonisamide, 62% of the dose was recovered in the urine, and 3% in feces by day 10. Of the excreted dose of zonisamide, 35% was recovered unchanged, 15% as N-acetyl zonisamide, and 50% as the glucuronide of 2–sulfamoylacetylphenol (SMAP).

Following a 400 mg oral dose, zonisamide has an apparent volume of distribution (V/F) of 1.45 L/kg.

In patients not taking enzyme-inducing antiepilepsy drugs (AEDs), the plasma clearance of oral zonisamide is approximately 0.30-0.35 mL/min/kg. In patients treated with AEDs, this value increases to 0.5 mL/min/kg. Renal clearance is approximately 3.5 mL/min after a single-dose of zonisamide. In red blood cells, the clearance of an oral dose of zonisamide is 2 mL/min.

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%.

Medication: anticonvulsant

Use (kg; approx.) in Germany (2009): >250；Consumption (g per capita; approx.) in Germany (2009): 0.00305；Calculated removal (%): 22

For use as adjunctive treatment of partial seizures in adults with epilepsy.

The reaction of 3-bromomethyl-1,2-benzisoxazole with sodium sulfite in methanol/water gives sodium 1,2-benzisoxazole-3-methanesulfonate, which is converted into 1,2-benzisoxazole-3-methanesulfonyl chloride. Treatment with NH3 gives zonisamide.

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)