Zonisamide Clinical Update and Literature Review

Zonisamide remains underutilized in clinical practice in the United States, despite its utility in the treatment of multiple seizure types. American Academy of Neurology and American Epilepsy Society guidelines, published in 2004, “determined [zonisamide] to be an established and effective treatment recommendation for adjunctive therapy in adults with treatment-resistant (TR) focal epilepsy.” However, they noted that additional studies were needed around the therapy’s role in pediatric patients.

In 2018, new data led to both organizations expanding the use of zonisamide in pediatric patients with TR focal epilepsy, as other second- and third-generation therapies such as clobazam, eliscarbazepine, and pregabalin, among others, did not have efficacy data for pediatric populations compared to zonisamide.

Additionally, the 2018 guidelines “provided evidence to support the use of [zonisamide] to reduce seizure frequency in both new-onset and TR focal epilepsy.” Results of a phase 3, randomized, double-blind, noninferiority trial indicated that the drug could also be useful as a monotherapy for patients with newly diagnosed focal epilepsy vs third-generation antiseizure medications.

In a recent article published in Neurology: Clinical Practice,¹ researchers collected studies from 2004 to 2002 and conducted a literature review with the goal of providing an update about the efficacy of zonisamide in the treatment of epilepsy and other central nervous system disorders.

As a benzisoxazole analog with multiple mechanisms of action, zonisamide is rapidly absorbed and has a high bioavailability; peak concentration occurs within 2 to 4 hours. The long elimination half-life of 50 to 60 hours “because of relatively lower systemic clearance suggests that [zonisamide] may be an ideal therapeutic option for once daily dosing, which may improve medication adherence.”

Zonisamide stabilizes neuronal membranes through sodium and calcium channels to reduce epileptiform activity. In both pediatric and adult patient populations, the medication has been studied in the treatment of focal, generalized tonic-clonic, absence, and childhood epilepsies as both a new-onset or refractory treatment option. In 16 articles that evaluated efficacy through the analysis of response rates and seizure free events, zonisamide was associated with “significant reductions in seizure frequency and overall improvements” in 15 of the studies.

Zonisamide has also been established as an efficacious treatment for adults with new-onset and refractory focal and generalized epilepsy. In adults, zonisamde was associated with nearly identical seizure-free rates compared with controlled release carbamazepine after 26 weeks.

Eight studies evaluated the efficacy of the drug in adult and pediatric patients with focal and generalized epilepsy. One 2013 phase 3 randomized controlled trial investigated safety, efficacy, and tolerability of zonisamide in pediatric populations; results showed that a dose of 8 mg/kg/d led to response rates higher than placebo, albeit with a slight increase in mild adverse effects. An open label extension “confirmed initial findings that [zonisamide] was well-tolerated and efficacious for up to 57 weeks.”

In absence seizures, the drug’s blockade of T-type calcium channels has been studied as a “key contributor” in the treatment of this condition. A chart review of 45 pediatric patients showed that 51.1% achieved complete freedom from absence seizures with zonisamide therapy.

Researchers have also been conducting preclinical studies to evaluate the potential uses of zonisamide outside of epilepsy. These studies have “demonstrated neuroprotective mechanisms not seen in other [antiseizure medications], including free radical scavenging activities, protection against glutamate-induced neuronal damage, and reduction in hypoxic-ischemic brain damage.”

In Parkinson disease, zonisamde can lead significantly improved motor dysfunction at a dose of 25 mg/d or 50 mg/d. Additional effects on the dopaminergic system and the inhibition of T-type calcium channels “may also lead to clinical improvements in sleep disorders, pain, and migraine.” It may also be a positive contributor to the management of comorbid disorders like diabetes and obesity, “as well as overall cardiovascular disorders,” and may be useful in treating alcohol use disorders.

Although zonisamide is generally well tolerated, there are some common adverse effects and reactions, including somnolence, anorexia, dizziness, ataxia, agitation and irritability, and difficulty with memory and concentration; these responses are generally dose and time dependent. Some more serious adverse events have been noted, including the inhibition of carbonic anhydrase activity in the brain, fatalities due to reactions to sulfonamides, and serious hematologic events, oligohydrosis, hyperthermia, acute myopia, secondary angle-closure glaucoma, suicidal behavior and ideation, and teratogenicity.

“[Zonisamide was associated with significant reductions in seizure frequent and overall improvements in most evaluated studies,” the authors wrote. “[It] is generally well-tolerated with known and manageable safety issues and multiple [mechanisms of action] contributing to antiepileptic activity.”

They continued, “[Zonisamide] is used and approved in multiple countries for the treatment of focal-onset seizures for adults and children, but has also demonstrated efficacy in LGS and absence seizures. Although there are potential concerns for bone-related [adverse events] and teratogenicity, literature findings revealed that may of these effects may be dose dependent.”

“Multiple available formulations, a once-daily dosing regimen, and a recognized safety profile allow use of this drug in patient populations in which therapeutic regimens need to be optimized for adherence, ease of use, and quality of life,” they concluded.

Reference

1. Gidal BE, Resnick T, Smith MC, Wheless JW. Zonisamide. A comprehensive, updated review for the clinician. Neurology: Clinical Practice. 2024;14:e200210. doi:10.1212/CPJ.0000000000200210