Zonisamide

Epilepsy

Zonisamide is approved in the United States, United Kingdom, and Australia for adjunctive treatment of partial seizures in adults and in Japan for both adjunctive and monotherapy for partial seizures (simple, complex, secondarily generalized), generalized (tonic, tonic-clonic (grand mal), and atypical absence) and combined seizures. For epilepsy, most studies have used oral zonisamide in daily doses ranging from 200 to 600 milligrams/day, divided in 2 daily doses, adjusted to maintain serum levels of 15 to 40 micrograms/milliliter

Tardive dyskinesia

In an open-label trial zonisamide attenuated the symptoms of tardive dyskinesia.

Obesity

It has also been studied for obesity with significant positive effects on body weight and there are three ongoing clinical trials for this indication. It is to be sold, when combined with bupropion, under the brand name Empatic.

Migraine

Zonisamide has been studied for and used as a migraine preventative medication, and has also been shown to be effective in some cases of neuropathic pain.

Bipolar depression

It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.

Adverse effects

Adverse effects by incidence:

Very common (>10% incidence) adverse effects include:

Common (1-10% incidence) adverse effects include:

Interactions

Zonisamide and other carbonic anhydrase inhibitors such as topiramate, furosemide, and hydrochlorothiazide have been known to interfere with amobarbital, which has led to inadequate anesthetization during the Wada test. Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis.

Additionally, the metabolism of zonisamide is inhibited by ketoconazole, ciclosporin, miconazole, fluconazole and carbamazepine (in descending order of inhibition) due to their effects on the CYP3A4 enzyme.

Mechanism of action

Zonisamide is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The precise mechanism by which zonisamide exerts its antiseizure effect is unknown, although it is believed that the drug blocks sodium and T-type calcium channels, which leads to the suppression of neuronal hypersynchronization (that is, seizure-form activity). It is also known to be a weak carbonic anhydrase inhibitor (similarly to the anticonvulsant, acetazolamide). It is also known to modulate GABAergic and glutamatergic neurotransmission.

Absorption

Variable, yet relatively rapid rate of absorption with a time to peak concentration of 2.8-3.9 hours. Food has no effect on the bioavailability of zonisamide

Metabolism

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5, to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.

History

Zonisamide was discovered by Uno and colleagues in 1972 and launched by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) in 1989 as Excegran in Japan. It was marketed by Élan in the United States starting in 2000 as Zonegran, before Élan transferred their interests in zonisamide to Eisai Co., Ltd. in 2004. Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others) and Europe (starting in Germany and the United Kingdom).