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Zonisamid (Excegran)

Clinical Effects:

ZONISAMIDE
  • USES: Zonisamide is a sulfonamide antiepileptic agent primarily used for treatment of partial seizure disorders. It is also used off-label as an adjunct in Parkinson’s disease. PHARMACOLOGY: Zonisamide blocks voltage-gated sodium and calcium channels. It increases dopamine effects in the brain. In addition, the agent is a reversible monoamine oxidase-B (MAO-B) inhibitor. The agent may have carbonic anhydrase inhibitor action. TOXICOLOGY: At high doses, zonisamide inhibits dopamine function, leading to CNS depression. EPIDEMIOLOGY: Both adverse effects from therapeutic use and toxicity from overdose are uncommon. Severe toxicity is rare. OVERDOSE: Very limited data is available regarding toxicity of zonisamide in overdose. MILD TO MODERATE TOXICITY: Most patients that ingest this agent in overdose experience only mild or moderate effects. The primary manifestation is CNS depression, somnolence, ataxia, and nausea and vomiting. SEVERE TOXICITY: Due to the long half-life of the agent, prolonged CNS depression and coma are possible with large overdoses. Bradycardia, hypotension, and respiratory depression have occurred following an overdose ingestion of an unknown amount of zonisamide. Multiple seizures, cardiac arrest, and wide complex tachycardia have been reported in an adult after an overdose. Based upon the pharmacologic mechanism of action causing sodium channel blockade, wide complex cardiac dysrhythmias may be possible. ADVERSE EFFECTS: The most common adverse effects associated with therapeutic administration of zonisamide include somnolence, fatigue/ataxia (6%), difficulty concentrating (2%), and nausea and vomiting (2%). Dermal hypersensitivity reactions, likely due to the sulfa moiety, have been reported in 1% to 2% of patients. Nephrolithiasis has also been reported following long-term therapy with zonisamide. Severe adverse effects are rare and include anhydrosis and subsequent hyperthermia, seizure aggravation, aplastic anemia, metabolic acidosis, and psychosis. Severe skin rashes following zonisamide therapy, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have occurred with fatalities reported.

Range of Toxicity:

ZONISAMIDE
  • TOXICITY: An adult ingested 4.8 g of zonisamide as a single agent overdose and developed recurrent tonic-clonic seizures and cardiac arrest. She was resuscitated to a perfusing wide complex tachycardia, but died from cerebral edema likely secondary to anoxic brain injury. A woman ingested 8.7 g of zonisamide and developed nausea, vomiting, diffuse chest pain, blurred vision, dizziness, mild headache, and a 5-minute seizure-like activity with tremors and altered mental status. She recovered following supportive care. THERAPEUTIC DOSES: For patients 16 years and older – 100 to 600 mg/day in 1 to 2 divided doses. This agent is not approved in children less than 16 years of age. Lower doses are recommended in patients with renal insufficiency and zonisamide is contraindicated in patients with a creatinine-clearance less than 50 mL/min.

Treatment:

ZONISAMIDE
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Supportive care remains the mainstay of care. Nausea and vomiting should be treated with antiemetics. Rashes should be treated with supportive care, discontinuation of the offending agent, and consideration of antihistamines and corticosteroids. Metabolic acidosis is generally mild and may be treated with discontinuation of the medication and isotonic fluid administration in overdose patients. Treat hypotension with IV 0.9% NaCl 10-20 mL/kg, dopamine, norepinephrine. MANAGEMENT OF SEVERE TOXICITY: Supportive care remains the mainstay of care in severe toxicity. Seizures should be treated with benzodiazepines as first line therapy followed by barbiturates or propofol if seizures persist or recur. Treat hypotension with IV 0.9% NaCl 10-20 mL/kg, dopamine, norepinephrine. QRS prolongation should be treated with boluses of sodium bicarbonate (Adults: 50 to 100 mEq, children: 1 to 2 mEq/kg). Airway protection should be employed as needed for patients with coma. In patients with fever felt to be secondary to the medication, active cooling measures should be instituted. Patients with severe metabolic acidosis may be treated with bicarbonate infusions.
  • Decontamination: PREHOSPITAL: No prehospital decontamination is indicated because of the risk of CNS depression. Prehospital care should focus on assessment of vital signs and general supportive care. HOSPITAL: Activated charcoal may be considered for patients that present early after overdose if they are awake, alert and willing to drink the charcoal. Gastric lavage is not recommended as overdose is rarely life threatening.
  • Airway management: In patients with significant CNS depression of recurrent seizures, intubation should be performed to protect the airway.
  • Antidote: None.
  • Monitoring of patient: In most facilities, therapeutic drug monitoring is not routinely available for zonisamide. The therapeutic range is 10 to 40 mg/L. Monitor CBC, renal function, and liver enzymes in symptomatic patients. Monitor fluid and serum electrolyte status in patients with significant vomiting. An ECG should be obtained to screen for signs of sodium channel blockade. A basic metabolic panel should be obtained to screen for metabolic acidosis.
  • Enhanced elimination procedure: Hemodialysis has not been studied in zonisamide toxicity. Pharmacokinetics data suggests that the agent would not be efficiently dialyzable (Vd: 1.8 L/Kg; protein binding: 50%). Whole bowel irrigation has no role in the management of zonisamide overdose.
  • Patient disposition: HOME CRITERIA: Asymptomatic patients with inadvertent ingestion of zonisamide can be observed at home. OBSERVATION CRITERIA: Symptomatic patients and those with deliberate ingestions should be sent to a healthcare facility for evaluation. Patients should be observed for 6 hours primarily monitoring signs of co-ingestant toxicity or development of significant CNS depression. ADMISSION CRITERIA: Patients with persistent or severe toxicity characterized by seizures or coma should be admitted. CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is uncertain.
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