indication

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

pharmacology

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 calcium channels, which leads to the suppression of neuronal hypersynchronization (i.e. convulsions). 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).

mechanism of action

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.

toxicity

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

biotransformation

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.

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.

half life

63 hours

route of elimination

Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite.

drug interactions

Amprenavir: Amprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if amprenavir is initiated, discontinued or dose changed.

Atazanavir: Atazanavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if atazanavir is initiated, discontinued or dose changed.

Brinzolamide: As both brinzolamide and zonisamide are carbonic anhydrase inhibitors, there is an increased risk of adverse effects.The development of acid-base disorders with concurrent use of ophthalmic and oral carbonic anhydrase inhibitors has been reported. Avoid concurrent use of different carbonic anhydrase inhibitors when possible.

Clarithromycin: Clarithromcyin, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if clarithromycin is initiated, discontinued or dose changed.

Conivaptan: Conivaptan, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if conivaptan is initiated, discontinued or dose changed.

Darunavir: Darunavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if darunavir is initiated, discontinued or dose changed.

Delavirdine: Delavirdine, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if delavirdine is initiated, discontinued or dose changed.

Fosamprenavir: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if fosamprenavir is initiated, discontinued or dose changed.

Imatinib: Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if imatinib is initiated, discontinued or dose changed.

Indinavir: Indinavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if indinavir is initiated, discontinued or dose changed.

Isoniazid: Isoniazid, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if isoniazid is initiated, discontinued or dose changed.

Itraconazole: Itraconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if itraconazole is initiated, discontinued or dose changed.

Ketoconazole: Ketonconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if ketoconazole is initiated, discontinued or dose changed.

Lopinavir: Lopinavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if lopinavir is initiated, discontinued or dose changed.

Mefloquine: Mefloquine may decrease the serum concentration and therapeutic effect of zonisamide. Concomitant therapy is contraindicated in patients with history of convulsions.

Methotrimeprazine: Additive CNS depressant effects. Reduce zonisamide dose by half upon initiation of methotrimeprazine. Zonisamide dose may be adjusted once methotrimeprazine dose has been established. Monitor for increased CNS depression.

Nefazodone: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if nefazodone is initiated, discontinued or dose changed.

Nelfinavir: Nelfinavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if nelfinavir is initiated, discontinued or dose changed.

Nicardipine: Nicardipine, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if nicardipine is initiated, discontinued or dose changed.

Posaconazole: Posaconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if posaconazole is initiated, discontinued or dose changed.

Quinidine: Quinidine, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if quinidine is initiated, discontinued or dose changed.

Ritonavir: Ritonavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if ritonavir is initiated, discontinued or dose changed.

Saquinavir: Saquinavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if saquinavir is initiated, discontinued or dose changed.

Telithromycin: Telithromycin, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if telithromycin is initiated, discontinued or dose changed.

Triprolidine: The CNS depressants, Triprolidine and Zonisamide, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if voriconazole is initiated, discontinued or dose changed.