Oral Partial seizures with or without secondary generalisation
Adult: Monotherapy in newly diagnosed patients: Initially, 100 mg once daily, increased to 200 mg once daily after 2 weeks. Dose may be increased further at intervals of at least 2 weeks in increments of 100 mg. Usual maintenance: 300 mg once daily. Max: 500 mg daily. Adjunctive therapy: In patients taking CYP3A4-inducing agents: Initially, 50 mg daily in 2 divided doses, increased to 100 mg daily in 2 divided doses after 1 week. Subsequent doses may be increased further at weekly intervals in increments of 100 mg. Usual maintenance: 300-500 mg daily as a single or in 2 divided doses. In patients not taking CYP3A4-inducing agents: Doses must be increased at intervals of 2 weeks; some patients may respond to lower doses. Alternatively, for adjunctive therapy, initial dose of 100 mg daily may be given, then increase to 200 mg daily after 2 weeks; may increase further to 300 mg and 400 mg daily with at least 2 weeks between adjustments. Titrate doses according to clinical response. Dosage recommendations may vary among countries and individual products (refer to detailed product guideline). Child: ≥6 years Adjunctive therapy: In patients taking CYP3A4-inducing agents: Initially, 1 mg/kg once daily for 1 week, then increase at weekly intervals in increments of 1 mg/kg. Usual maintenance: 20-55 kg: 6-8 mg/kg once daily (Max: 500 mg daily); >55 kg: 300-500 mg once daily. In patients not taking CYP3A4-inducing agents: Doses must be increased at intervals of 2 weeks. Titrate doses according to clinical response. Dosage recommendations may vary among countries and individual products (refer to detailed product guideline).
Renal Impairment
Slower dosage titration may be needed; doses may be increased at intervals of 2 weeks. GFR <50 mL/min: Not recommended.
Hepatic Impairment
Mild to moderate: Slower dosage titration may be needed; doses may be increased at intervals of 2 weeks. Severe: Not recommended.
Administration
May be taken with or without food.
Contraindications
History of hypersensitivity to sulfonamides.
Special Precautions
Patient with decreased hepatic mitochondrial activity or inborn errors of metabolism; risk factors for nephrolithiasis (e.g. family history, previous stone formation, hypercalciuria), predisposition to acidosis (e.g. severe respiratory disease, status epilepticus, diarrhoea, surgery, ketogenic diet, other drugs); history of eye disorders. Avoid abrupt withdrawal. Not recommended in renal (GFR <50 mL/min) and severe hepatic impairment; in children who are underweight and have decreased appetite. Concomitant use with carbonic anhydrase inhibitors and drugs with anticholinergic activity in adults; avoid concomitant use in children. Renal and mild to moderate hepatic impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Suicidal ideation and behaviour, CNS effects (e.g. fatigue, sedation, somnolence, depression, psychosis, speech or language problems, difficulty with concentration), acute myopia, secondary angle-closure glaucoma, rash; hyperammonaemia with or without encephalopathy; hyperchloraemic, non-anion gap, metabolic acidosis (dose-dependent); elevated serum creatinine and BUN, nephrolithiasis, pancreatitis, rhabdomyolysis; decreased sweating, increased body temperature and levels of AST, ALT, gamma-glutamyltransferase (GGT) and bilirubin (particularly in children). Blood and lymphatic system disorders: Ecchymosis. Eye disorders: Diplopia, nystagmus. Gastrointestinal disorders: Nausea, dyspepsia, diarrhoea, abdominal pain, constipation, vomiting. General disorders and administration site conditions: Flu-like illness, pyrexia, peripheral oedema. Immune system disorders: Hypersensitivity. Investigations: Decreased bicarbonate levels and weight; increase blood creatine phosphokinase. Metabolism and nutrition disorders: Anorexia, decreased appetite. Nervous system disorders: Dizziness, ataxia, paraesthesia, tremor, bradyphrenia, memory impairment, attention disturbance. Psychiatric disorders: Agitation, anxiety, irritability, confusional state, mood swings, insomnia, affect lability. Skin and subcutaneous tissue disorders: Pruritus, alopecia. Potentially Fatal: Drug reaction with eosinophilia and systemic symptoms (DRESS) or multiorgan hypersensitivity reaction; heatstroke requiring hospitalisation, weight loss which may lead to deterioration of general condition (particularly in children). Rarely, serious skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme), haematologic disturbances (e.g. agranulocytosis, aplastic anaemia), fulminant hepatic necrosis.
PO: Z (Associated with increased risk of infant born small for gestational age. Use only when benefits outweigh risks. If used, monitor drug levels and adjust dose accordingly.)
Patient Counseling Information
This drug may cause drowsiness, sedation, and difficulty with concentration; if affected, do not drive or operate machinery. Ensure adequate hydration or fluid intake, particularly in children. Avoid exposure to excessive temperatures and strenuous physical activity. Women of childbearing potential must use proven birth control methods during therapy and for 1 month after stopping the treatment.
Monitoring Parameters
Monitor serum bicarbonate levels before initiation and periodically during treatment; metabolic profile (particularly BUN and serum creatinine); ammonia levels (if signs or symptoms of encephalopathy occur); pancreatic lipase and amylase levels (in patients who develop pancreatitis); serum creatine phosphokinase and aldolase levels (in those who experience severe muscle pain or weakness with or without fever). Assess for signs and symptoms of emergence or worsening of suicidal thoughts or behaviour, depression and/or unusual changes in behaviour; decreased sweating and increased body temperature specifically during hot or warm weather (particularly in children).
Overdosage
Symptoms: Somnolence, nystagmus, myoclonus, nausea, gastritis, bradycardia, reduced renal function, hypotension, coma, and respiratory depression. Management: Supportive treatment. May induce emesis or perform gastric lavage with usual precautions to protect the airway. Closely observe the patient and frequently monitor vital signs.
Drug Interactions
May increase the risk of metabolic acidosis, hyperammonaemia, and kidney stone formation with other carbonic anhydrase inhibitors (e.g. topiramate, acetazolamide). Risk of heat-related disorders may be increased with carbonic anhydrase inhibitors and drugs with anticholinergic activity (e.g. haloperidol, diphenhydramine, clomipramine, oxybutynin), especially in children. May decrease exposure and serum concentration with CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital, rifampicin). May cause additive CNS effects (e.g. fatigue, somnolence) with other CNS depressants.
Food Interaction
May enhance the CNS depressant effects of alcohol. Time to peak plasma concentrations may be delayed with food.
Action
Description: Mechanism of Action: Zonisamide is a benzisoxazole derivative anticonvulsant agent that contains a sulfonamide group. The exact mechanism of action is not fully elucidated; however, it is suggested that it acts on the voltage-sensitive Na and Ca channels, thus disrupting synchronised neuronal firing, decreasing the spread of seizure discharges, and suppressing subsequent epileptic activity. It does not affect GABA activity. It is found to be a weak carbonic anhydrase inhibitor. Pharmacokinetics: Absorption: Rapidly and almost completely absorbed from the gastrointestinal tract. Food may delay the time to peak plasma concentrations. Bioavailability: Approx 100% (not affected by food). Time to peak plasma concentration: Within 2-6 hours. Distribution: Widely distributed into body tissues; highly concentrated in erythrocytes. Crosses the placenta and enters breast milk. Volume of distribution: 1.45 L/kg. Plasma protein binding: 40-50%. Metabolism: Metabolised in the liver via N-acetylation into N-acetylzonisamide and via reduction by CYP3A4 isoenzyme to form 2-sulfamoylacetylphenol (SMAP); SMAP further undergoes conjugation with glucuronide. Excretion: Mainly via urine (62%; 65% as metabolites, 35% as unchanged drug); faeces (3%). Plasma elimination half-life: Approx 63 hours (range: 50-68 hours).
Chemical Structure
Zonisamide Source: National Center for Biotechnology Information. PubChem Database. Zonisamide, CID=5734, https://pubchem.ncbi.nlm.nih.gov/compound/Zonisamide (accessed on Jan. 24, 2020)
Storage
Store between 15-30°C. Protect from light and moisture.
N03AX15 - zonisamide ; Belongs to the class of other antiepileptics.
References
Anon. Zonisamide. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 07/05/2021.Anon. Zonisamide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 07/05/2021.Buckingham R (ed). Zonisamide. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 07/05/2021.Desizon 20 mg/mL Oral Suspension (Desitin Arzneimittel GmbH). MHRA. https://products.mhra.gov.uk. Accessed 07/05/2021.Joint Formulary Committee. Zonisamide. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 07/05/2021.Zonegran 100 mg Tablets (Eisai [Malaysia] Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 07/05/2021.Zonegran 50 mg Hard Capsules (Eisai Europe Limited). MHRA. https://products.mhra.gov.uk. Accessed 07/05/2021.Zonegran Capsule (Concordia Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 07/05/2021.
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