Xonimide ODT

Nobody knows exactly how zonisamide controls seizures. It showed anticonvulsant activity in several experimental models. In animals, it worked against tonic extension seizures induced by maximal electroshock, but it didn't work against clonic seizures induced by subcutaneous pentylenetetrazol. Zonisamide raised the threshold for generalized seizures in the kindled rat model, and it shortened cortical focal seizures induced by electrical stimulation of the visual cortex in cats. It also 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. How far these models apply to human epilepsy is unknown.

Zonisamide may produce these effects through action at sodium and calcium channels. In vitro pharmacological studies suggest that it blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Ca2+ currents). This stabilizes neuronal membranes and suppresses neuronal hypersynchronization. In vitro binding studies have shown that zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion, and this does not change chloride flux. Other in vitro studies have shown that zonisamide (10 to 30 μg/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons). Neuronal or glial uptake of [3H]-GABA (rat hippocampal slices) was not affected either. So zonisamide does not appear to potentiate the synaptic activity of GABA. In vivo microdialysis studies showed that it facilitates both dopaminergic and serotonergic neurotransmission.

Zonisamide is a carbonic anhydrase inhibitor. What this action contributes to its therapeutic effects is unknown. But because it inhibits carbonic anhydrase, zonisamide may cause metabolic acidosis

Zonisamide may cause serious harm to the unborn baby, based on both clinical and nonclinical data. It was teratogenic in several animal species.

In humans, zonisamide causes metabolic acidosis. Its effect in pregnancy hasn't been studied. Still, metabolic acidosis in pregnancy from other causes may be linked to slower fetal growth, lower fetal oxygenation and fetal death, and it may affect how well the fetus tolerates labor. Pregnant patients should be monitored for metabolic acidosis and treated as they would be when not pregnant.

Zonisamide passes to the fetus, and transient metabolic acidosis may occur after birth. So newborns of mothers treated with zonisamide should be monitored for metabolic acidosis. Transient metabolic acidosis has been reported in neonates born to mothers who were treated during pregnancy with a different carbonic anhydrase inhibitor.

Renal or hepatic disease

Zonisamide is broken down in the liver and passed out by the kidneys. So people with kidney or liver disease should be treated with caution. They may need the dose raised more slowly and be monitored more often.

Pediatric use

The safety and effectiveness of Zonisamide in children under age 16 have not been established. Cases of oligohidrosis and hyperpyrexia have been reported. Metabolic acidosis is common in children who take the medicine. If it goes untreated for a long time, it may cause nephrolithiasis and/or nephrocalcinosis, and osteoporosis and/or osteomalacia (which can lead to rickets). It may also slow growth, and slower growth may in the end lower the maximum height a child reaches. The effect on growth and bone-related problems has not been studied systematically.

Geriatric use

Single-dose pharmacokinetic parameters are similar in elderly and young healthy volunteers. Clinical studies did not include enough people aged 65 and over to show whether they respond differently from younger people. Other reported clinical experience has not found any difference in response between elderly and younger patients. In general, the dose for an elderly patient should be chosen with care, usually starting at the low end of the dosing range. This is because decreased liver, kidney or heart function, other diseases and other drug therapy are more frequent in older people.

Experience with Zonisamide at daily doses over 800 mg/day is limited. During clinical development, three patients took unknown amounts of Zonisamide in suicide attempts, and all three were admitted to hospital with CNS symptoms. One of them became comatose and developed bradycardia, hypotension and respiratory depression. His Zonisamide plasma level was 100.1 μg/mL, measured 31 hours after ingestion. The level fell with a half-life of 57 hours, and the patient was alert again five days later.

Management

There is no specific antidote for Zonisamide overdosage. If an overdose is suspected to have happened recently, vomiting should be induced or gastric lavage done, with the usual precautions to protect the airway. General supportive care is indicated, which includes frequent monitoring of vital signs and close observation.

Zonisamide has a long half-life. Its protein binding is low (40%), so renal dialysis may be effective, though nobody has formally studied how well dialysis works as a treatment for overdose. A poison control center should be contacted for advice on managing Zonisamide overdosage.