Introduction
Zonisamide is a sulfonamide-derived antiepileptic drug (AED) approved for adjunctive therapy in the treatment of partial seizures in adults with epilepsy. First approved in the United States in 2000, it has since been used globally as both monotherapy and adjunctive treatment in various seizure types. Zonisamide possesses multiple mechanisms of action that differentiate it from other antiepileptic medications.
Mechanism of Action
Zonisamide exhibits several anticonvulsant mechanisms:
- Voltage-gated sodium channel blockade
- T-type calcium channel modulation
- Weak carbonic anhydrase inhibition
- Modulation of GABAergic neurotransmission
- Reduction of glutamate-mediated excitatory neurotransmission
These multiple mechanisms contribute to its broad-spectrum antiepileptic activity and may explain its efficacy in various seizure types.
Indications
FDA-Approved Indications:
- Adjunctive therapy in the treatment of partial seizures in adults with epilepsy
Off-Label Uses:
- Monotherapy for partial seizures
- Generalized seizures (tonic-clonic, myoclonic, absence)
- Infantile spasms
- Lennox-Gastaut syndrome
- Migraine prophylaxis
- Parkinson's disease (investigational)
- Neuropathic pain (investigational)
- Bipolar disorder (investigational)
Dosage and Administration
Initial Dosing:
- 100 mg once daily
- May be increased to 200 mg/day after 2 weeks
- Further increases may be made at intervals of ≥2 weeks
Maintenance Dosing:
- Effective dose range: 100-600 mg/day
- Typical maintenance dose: 400-600 mg/day
- Maximum recommended dose: 600 mg/day
Special Populations:
- Renal impairment: Use with caution; consider reduced dosing
- Hepatic impairment: Use with caution; consider reduced dosing
- Geriatric patients: Initiate at lower doses; monitor closely
- Pediatric patients: Safety and effectiveness not established for children under 16 years
Administration:
- Oral administration with or without food
- Capsules should be swallowed whole
- Once or twice daily dosing
Pharmacokinetics
Absorption:
- Well absorbed orally (bioavailability >90%)
- Peak plasma concentrations reached in 2-5 hours
- Food delays absorption but does not affect bioavailability
Distribution:
- Protein binding: 40-50%
- Volume of distribution: 1.45 L/kg
- Crosses blood-brain barrier and placenta
- Distributed into breast milk
Metabolism:
- Extensive hepatic metabolism via CYP3A4
- Acetylation and reduction pathways
- Forms inactive metabolites
Elimination:
- Elimination half-life: 63 hours (allows once-daily dosing)
- Renal excretion: 62% (primarily as metabolites)
- Fecal excretion: 30%
- Hemodialysis removes approximately 50% of circulating drug
Contraindications
- Hypersensitivity to zonisamide, sulfonamides, or any component of the formulation
- History of severe allergic reactions to sulfonamide-containing drugs
Warnings and Precautions
Serious Dermatologic Reactions:
- Stevens-Johnson syndrome and toxic epidermal necrolysis reported
- Discontinue at first sign of rash unless clearly not drug-related
Oligohidrosis and Hyperthermia:
- Decreased sweating and hyperthermia, especially in pediatric patients
- Monitor body temperature, particularly in warm weather
Metabolic Acidosis:
- Hyperchloremic, non-anion gap metabolic acidosis may occur
- Measure serum bicarbonate before treatment and periodically during therapy
Suicidal Behavior and Ideation:
- Antiepileptic drugs increase risk of suicidal thoughts/behavior
- Monitor for emergence or worsening of depression/suicidal thoughts
Cognitive/Neuropsychiatric Effects:
- Psychomotor slowing, difficulty concentrating, speech/language problems
- Depression, psychosis, and other psychiatric symptoms reported
Renal Calculi:
- Risk of kidney stones (1-2% of patients)
- Maintain adequate hydration
Hematologic Effects:
- Aplastic anemia and agranulocytosis reported
- Monitor complete blood counts
Drug Interactions
Strong CYP3A4 Inducers:
- Carbamazepine, phenytoin, phenobarbital, rifampin
- May decrease zonisamide concentrations
CYP3A4 Inhibitors:
- Ketoconazole, itraconazole, clarithromycin
- May increase zonisamide concentrations
Other Antiepileptic Drugs:
- May have additive CNS depressant effects
- Potential pharmacokinetic interactions with multiple AEDs
Alcohol and CNS Depressants:
- Additive sedation and cognitive impairment
Carbon Anhydrase Inhibitors:
- Topiramate, acetazolamide
- Increased risk of metabolic acidosis and nephrolithiasis
Adverse Effects
Common (≥10%):
- Somnolence
- Dizziness
- Anorexia
- Headache
- Nausea
- Irritability
- Fatigue
Less Common (1-10%):
- Diplopia
- Cognitive impairment
- Weight loss
- Agitation
- Depression
- Insomnia
- Rash
- Constipation
Serious (<1%):
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
- Metabolic acidosis
- Oligohidrosis and hyperthermia
- Renal calculi
- Aplastic anemia
- Agranulocytosis
- Acute pancreatitis
- Suicidal ideation
Monitoring Parameters
Baseline Assessment:
- Complete blood count with differential
- Serum electrolytes including bicarbonate
- Renal function tests
- Liver function tests
- Pregnancy test if applicable
Ongoing Monitoring:
- Serum bicarbonate every 3-6 months
- Complete blood count periodically
- Renal function annually
- Body weight regularly
- Therapeutic drug monitoring (target range 10-40 μg/mL)
- Mental status and mood assessment
- Skin examination for rash
Therapeutic Drug Monitoring:
- Therapeutic range: 10-40 μg/mL
- Draw trough levels before morning dose
- Monitor more frequently with dose changes or interacting drugs
Patient Education
Administration:
- Take exactly as prescribed; do not stop abruptly
- Swallow capsules whole with water
- May take with food if stomach upset occurs
Side Effects:
- Report any skin rash immediately
- Contact healthcare provider if fever or decreased sweating occurs
- Report mood changes, depression, or suicidal thoughts
- Maintain adequate fluid intake to prevent kidney stones
Precautions:
- Avoid alcohol and other CNS depressants
- Use caution when driving or operating machinery
- Protect from excessive heat and maintain hydration
- Use effective contraception; discuss pregnancy planning with provider
Monitoring:
- Keep all scheduled appointments for laboratory monitoring
- Report any unusual symptoms or side effects promptly
- Wear medical alert identification indicating epilepsy diagnosis
References
1. FDA Prescribing Information: Zonegran (zonisamide). Revised 2022.
2. Patsalos PN, et al. Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update. Ther Drug Monit. 2018;40(5):526-548.
3. Leppik IE. Zonisamide: chemistry, mechanism of action, and pharmacokinetics. Seizure. 2004;13 Suppl 1:S5-9.
4. Baulac M, et al. Efficacy and tolerability of zonisamide in adult patients with refractory partial-onset seizures. Epilepsy Res. 2018;145:103-110.
5. Brodie MJ, et al. Zonisamide: its pharmacology, efficacy and safety in clinical trials. Acta Neurol Scand. 2012;126(186):19-28.
6. Zaccara G, et al. Adverse effects of antiepileptic drugs. Acta Neurol Scand. 2011;124(186):30-35.
7. Glauser TA, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-563.
