Introduction
Zonegran (zonisamide) is a sulfonamide-derived antiepileptic drug (AED) approved for adjunctive therapy in the treatment of partial seizures in adults with epilepsy. First approved by the FDA in 2000, it has since been used globally as an important option in seizure management.
Mechanism of Action
Zonisamide exhibits multiple mechanisms of action that contribute to its antiepileptic effects:
- Sodium channel blockade: Reduces neuronal hyperexcitability by inhibiting voltage-gated sodium channels
- Calcium channel modulation: Inhibits T-type voltage-gated calcium channels
- Weak carbonic anhydrase inhibition: May contribute to antiseizure effects
- Enhancement of GABA-mediated inhibition: Modulates neurotransmitter activity
Indications
FDA-approved indications:- Adjunctive therapy in the treatment of partial seizures in adults with epilepsy
- Migraine prophylaxis
- Bipolar disorder maintenance therapy
- Weight management (limited evidence)
- Parkinson's disease (investigational)
Dosage and Administration
Initial dosing: 100 mg once daily Titration: Increase by 100 mg/day at 2-week intervals Maintenance dose: 200-400 mg/day (divided once or twice daily) Maximum recommended dose: 600 mg/day Special populations:- Renal impairment: Use caution; consider reduced dosing
- Hepatic impairment: Use is not recommended in significant hepatic disease
- Elderly: Initiate at lower doses; monitor closely
- Pediatric: Safety and effectiveness not established under age 16
Pharmacokinetics
Absorption: Well absorbed (≈100% bioavailability); food delays absorption but does not affect extent Distribution: Volume of distribution: 1.45 L/kg; 40-50% protein binding Metabolism: Extensive hepatic metabolism via CYP3A4 with acetylation and reduction Elimination: Half-life: 63 hours; primarily renal excretion (62% of dose), with 30% as metabolites Steady-state: Achieved in approximately 13 daysContraindications
- Hypersensitivity to zonisamide, sulfonamides, or any component of the formulation
- History of sulfonamide hypersensitivity reactions
Warnings and Precautions
Boxed Warning:- Serious skin reactions including Stevens-Johnson syndrome
- Hematologic abnormalities including aplastic anemia
- Metabolic acidosis: May occur; monitor serum bicarbonate levels
- Oligohidrosis and hyperthermia: More common in pediatric patients
- Suicidal behavior and ideation: Antiepileptic drugs increase risk
- Cognitive/neuropsychiatric effects: May cause psychomotor slowing, difficulty concentrating, speech or language problems
- Renal calculi: Increased risk of kidney stones (approximately 4% incidence)
- Teratogenicity: Category C; benefits must outweigh risks in pregnancy
Drug Interactions
Significant interactions:- CYP3A4 inducers (carbamazepine, phenytoin, phenobarbital): Decrease zonisamide concentrations
- CYP3A4 inhibitors (ketoconazole, erythromycin): May increase zonisamide concentrations
- Other carbonic anhydrase inhibitors (topiramate, acetazolamide): Increased risk of renal calculi and metabolic acidosis
- Alcohol and CNS depressants: Additive sedative effects
Adverse Effects
Common (≥5%):- Somnolence (17%)
- Dizziness (13%)
- Anorexia (13%)
- Headache (10%)
- Nausea (9%)
- Agitation/irritability (9%)
- Fatigue (8%)
- Stevens-Johnson syndrome
- Aplastic anemia
- Metabolic acidosis
- Acute myopia and secondary angle-closure glaucoma
- Oligohidrosis and hyperthermia
- Suicidal behavior and ideation
- Renal calculi
Monitoring Parameters
Baseline:- Complete blood count with differential
- Serum bicarbonate levels
- Renal function tests
- Liver function tests
- Pregnancy test if applicable
- Serum bicarbonate every 3-6 months
- CBC annually or with symptoms of infection
- Monitoring for signs of depression or suicidal ideation
- Renal function annually
- Weight and nutritional status
- Signs of cognitive impairment
Patient Education
- Take medication exactly as prescribed; do not discontinue abruptly
- Be aware of potential drowsiness, dizziness, and cognitive effects
- Maintain adequate hydration to reduce kidney stone risk
- Report any skin rash, fever, sore throat, unusual bleeding or bruising immediately
- Use effective contraception; discuss pregnancy planning with healthcare provider
- Avoid alcohol and other CNS depressants
- Be aware of potential for weight loss and discuss nutritional concerns
- Report mood changes, depression, or suicidal thoughts
- Inform all healthcare providers about Zonegran use before any procedures
References
1. FDA Prescribing Information: Zonegran (zonisamide). 2021 2. Brodie MJ, et al. Epilepsy Research. 2005;62(1):49-55 3. Leppik IE, et al. Neurology. 1993;43(5 Suppl 3):S24-S30 4. Oommen KJ, et al. CNS Drugs. 2005;19(4):347-367 5. Perucca E, et al. Clinical Pharmacokinetics. 2001;40(9):641-664 6. White HS, et al. Epilepsy Research. 1997;27(1):35-43 7. Schmidt D, et al. Epilepsy Research. 1993;14(2):165-173 8. Epilepsy Foundation: Treatment Guidelines and Clinical Evidence