Zonegran (zonisamide) Capsules

Zonegran is indicated for use as an adjunctive therapy for treatment of partial seizures (or focal seizures) in adults with epilepsy.

Zonegran, which has been available in Japan since 1989 under the trade name of Excegran, will be available on the U.S. market in May, 2000.

Epilepsy is a neurological dysfunction in which sudden and excessive bursts of electrical energy are emitted in the brain. Among the several different general categories of seizures are partial seizures, seizures resulting from electricity in local neuron populations; and generalized seizures, which occur in more general areas of the brain and often cause more serious symptoms. There are an estimated 2 million epilepsy sufferers in the U.S. alone. Approximately one third of these patients do not have sufficient control of their seizures with the anti-epileptic drugs currently available to them.

Three multicenter, placebo-controlled, double-blind studies examined the effects of the investigational drug as an adjunctive therapy in 499 patients with partial onset seizures for whom one or two antiepileptic drugs were ineffective. The primary measure of effectiveness was median percent reduction in seizure frequency.

In the first study, two dose escalation regimens were studied. Treatment with Zonegran was statistically significant for doses of 100, 200, or 400 mg/day, but not for 300 mg/day, when compared to placebo.

In the second study, varied doses of Zonegran or placebo were administered twice daily, while in the third study, they were administered once daily. In both studies, results indicated that Zonegran 400-600 mg/day was significantly more effective than placebo in weeks 5-12 of the study. No significant differences were found between once and twice daily dosing. Results also suggested that 100 and 400 mg/day were significantly effective in the first 4 weeks of the study during which only secondary comparisons were made.

Approximately 27% of patients treated with Zonegran experienced 75% or more reduction in seizure frequency, while only 12% of placebo-treated patients experienced such reduction.

Common side effects of Zonegran include but are not limited to:

• Renal calculi
• Drowsiness
• Ataxia
• Loss of appetite
• Gastrointestinal symptoms

Possible rare but serious side effects of Zonegran include but are not limited to:

• Severe rash (i.e. Stevens Johnson Syndrome [SJS] and toxic epidermal necrolysis [TEN])
• Serious hematologic events, such as aplastic anemia or agranuclocytosis
• Oligohydrosis and hyperthermia in pediatric patients

The precise mechanism(s) by which zonisamide exerts its antiseizure effect is unknown. Zonisamide demonstrated anticonvulsant activity in several experimental models. In animals, zonisamide was effective against tonic extension seizures induced by maximal electroshock but ineffective against clonic seizures induced by subcutaneous pentylenetetrazol. Zonisamide raised the threshold for generalized seizures in the kindled rat model and reduced the duration of cortical focal seizures induced by electrical stimulation of the visual cortex in cats. Furthermore, zonisamide suppressed both interictal spikes and the secondarily generalized seizures produced by cortical application of tungstic acid gel in rats or by cortical freezing in cats. The relevance of these models to human epilepsy is unknown.

Zonisamide may produce these effects through action at sodium and calcium channels. In vitro pharmacological studies suggest that zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Ca²⁺ currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization. In vitro binding studies have demonstrated that zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion which does not produce changes in chloride flux. Other in vitro studies have demonstrated that zonisamide (10-30 ug/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [³H]-GABA (rat hippocampal slices). Thus, zonisamide does not appear to potentiate the synaptic activity of GABA. In vivo microdialysis studies demonstrated that zonisamide facilitates both dopaminergic and serotonergic neurotransmission. Zonisamide also has weak carbonic anhydrase inhibiting activity, but this pharmacologic effect is not thought to be a major contributing factor in the antiseizure activity of zonisamide.
(From FDA Label)

Visit the Dainippon Pharmaceutical Co. Ltd. web site, http://www.ds-pharma.co.jp/english/, to learn more about Zonegran and about other products, research, and services provided by the company that developed this drug.

For more information about epilepsy, visit the official web site of the Epilepsy Foundation, a non-profit volunteer agency devoted to research, education, advocacy, and services in the community for people with epilepsy and their families: www.efa.org

This is what the Epilepsy Foundation says to do and not to do if you encounter a person having an epileptic seizure:

What To Do:

• Look for medical identification.
• Protect from nearby hazards.
• Loosen ties or shirt collars.
• Protect head from injury.
• Turn on side to keep airway clear unless injury exists.
• Reassure as consciousness returns.
• If a single seizure lasted less than 5 minutes, ask if hospital evaluation wanted.
• If there are multiple seizures, or if one seizure lasts longer than 5 minutes, call an ambulance.
• If person is pregnant, injured, or diabetic, call for aid at once.

What Not To Do:

• Don't put any hard implement in the mouth.
• Don't try to hold tongue. It can't be swallowed.
• Don't try to give liquids during or just after seizure,
• Don't use artificial respiration unless breathing is absent after muscle jerks subside, or unless water has been inhaled.
• Don't restrain.