Uses of Xonimide: - Epilepsy/Seizures Adjunct in partial seizures, Monotherapy for partial seizures with or without secondary generalisation Hypersensitivity to zonisamide or sulfonamides

Adjunct anti-epileptic drugs

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 voltagedependent, 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 μg/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 is a carbonic anhydrase inhibitor. The contribution of this pharmacological action to the therapeutic effects of zonisamide is unknown. However, as a carbonic anhydrase inhibitor, zonisamide may cause metabolic acidosis

How to use Zonisamide: Take this medicine in the dose and duration as advised by your doctor. Swallow it as a whole. Do not chew, crush or break it. Zonisamide may be taken with or without food, but it is better to take it at a fixed time. Administration: May be taken with or without food. Adult Dose: Oral Adjunct in partial seizures Adult: Initially, 50 mg daily in 2 divided doses, increase to 100 mg daily after 1 wk. Thereafter, may further increase dose at wkly intervals in increments of up to 100 mg. Usual maintenance dose: 300-500 mg daily, some patients may respond to lower doses. Monotherapy for partial seizures with or without secondary generalisation Adult: In patients w/ newly diagnosed epilepsy: Initially, 100 mg once daily, increase to 200 mg once daily after 2 wk. May further increase by increments of 100 mg at intervals of at least 2 wk. Usual maintenance dose: 300 mg once daily, up to 500 mg daily. Hepatic impairment: Mild to moderate: Slower dosage titration may be needed. Severe: Not recommended. Child Dose: Oral Adjunct in partial seizures Child: >6 yr Initially, 1 mg/kg once daily for 1 wk, may increase by increments of 1 mg/kg at wkly interval. Usual maintenance dose: 20-55 kg: 6-8 mg/kg once daily; >55 kg: 300-500 mg once daily, some may respond to lower dose. Renal Dose: Renal impairment: GFR ?50 mL/min: Slower dosage titration may be needed. GFR <50 mL/min: Not recommended.

Reduced plasma concentration w/ phenytoin, phenobarbital, carbamazepine. Increased risk of metabolic acidosis w/ carbonic anhydrase inhibitors (e.g. acetazolamide).

Hypersensitivity to zonisamide or sulfonamides

Common - Dizziness - Loss of appetite - Memory impairment - Drowsiness - Impaired concentration - Altered walking - Impaired coordination - Anger >10% Somnolence (17%) Anorexia (13%) Dizziness (13%) 1-10% Headache (10%) Nausea (9%) Agitation (9%) Abdominal pain (6%) Ataxia (6%) Confusion (6%) Depression (6%) Diplopia (6%) Insomnia (6%) Diarrhea (5%) Speech disorder (5%) Flu-like symptoms (4%) Kidney stones (4%) Nystagmus (4%) Paresthesia (4%) Dysgeusia (3%) Weight loss (3%) Anxiety (3%) Rash (3%) Constipation (2%) Rhinitis (2%) Xerostomia (2%)

Zonisamide may cause serious adverse fetal effects, based on clinical and nonclinical data. Zonisamide was teratogenic in multiple animal species.Zonisamide treatment causes metabolic acidosis in humans. The effect of zonisamide-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) may be associated with decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus's ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the non-pregnant state. Newborns of mothers treated with zonisamide should be monitored for metabolic acidosis because of transfer of zonisamide to the fetus and possible occurrence of transient metabolic acidosis following birth. Transient metabolic acidosis has been reported in neonates born to mothers treated during pregnancy with a different carbonic anhydrase inhibitor.

Precaution: Patient at risk of nephrolithiasis. Avoid abrupt withdrawal. Renal or hepatic impairment. Childn. Pregnancy and lactation. Patient Counselling Increase fluid intake (i.e. 6-8 glasses of water/day) to reduce risk of renal stone. This drug may cause drowsiness or difficulty w/ concentration, if affected, do not drive or operate machinery. Increase in suicidal ideation may occur with use. Monitoring Parameters Monitor metabolic profile specifically BUN, serum creatinine; serum bicarbonate, body temp, suicidality, decreased sweating. Lactation: Unknown; avoid during breastfeeding

Human Experience: Experience with Zonisamide daily doses over 800 mg/day is limited. During Zonisamide clinical development, three patients ingested unknown amounts of Zonisamide as suicide attempts, and all three were hospitalized with CNS symptoms. One patient became comatose and developed bradycardia, hypotension, and respiratory depression; the zonisamide plasma level was 100.1 μg/mL measured 31 hours post-ingestion. Zonisamide plasma levels fell with a half-life of 57 hours, and the patient became alert five days later.Management: No specific antidotes for Zonisamide overdosage are available. Following a suspected recent overdose, emesis should be induced or gastriclavage performed with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation.Zonisamide has a long half-life. Due to the low protein binding of zonisamide (40%), renal dialysis may be effective. The effectiveness of renal dialysis as a treatment of overdose has not been formally studied. A poison control center should be contacted for information on the management of Zonisamide overdosage.

Zonisamide is a benzisoxazole derivative anticonvulsant containing sulfonamide. It may act on voltage sensitive Na and Ca channels, thereby affecting neuronal firing, hence reducing the spread of seizure discharges. It may modulate GABA-mediated neuronal inhibition.