Zonisamide - Drug Monograph

Introduction

Zonisamide is a second-generation sulfonamide anticonvulsant medication approved by the FDA in 2000. Originally developed in Japan, it has gained widespread use as adjunctive therapy for partial seizures in adults with epilepsy. Zonisamide's unique chemical structure and multiple mechanisms of action distinguish it from other antiepileptic drugs, offering clinicians an important therapeutic option for seizure management.

Mechanism of Action

Zonisamide exerts its antiepileptic effects through multiple mechanisms:

• Sodium channel blockade: Reduces neuronal hyperexcitability by blocking voltage-dependent sodium channels
• Calcium channel modulation: Inhibits T-type calcium channels, reducing thalamocortical transmission
• Carbonic anhydrase inhibition: Weak inhibition of carbonic anhydrase isoenzymes (primarily CA-II and CA-IV)
• GABA enhancement: Modulates GABAergic neurotransmission, though this mechanism is less pronounced than with other AEDs
• Free radical scavenging: Demonstrates antioxidant properties that may provide neuroprotective effects

Indications

• Adjunctive therapy in the treatment of partial seizures in adults with epilepsy

• Monotherapy for partial seizures (in some countries)
• Generalized seizures (tonic-clonic, myoclonic)
• Infantile spasms
• Migraine prophylaxis
• Parkinson's disease (as adjunctive therapy)
• Neuropathic pain conditions
• Bipolar disorder maintenance therapy

Dosage and Administration

• 100 mg once daily for first two weeks
• May increase to 200 mg/day after two weeks

• Effective dose range: 100-600 mg daily
• May be administered once or twice daily
• Titrate gradually by 100 mg increments at intervals of at least two weeks

• Renal impairment: Use caution; consider reduced dosing in severe impairment (CrCl <20 mL/min)
• Hepatic impairment: Use with caution; no specific dosing recommendations
• Geriatric patients: Initiate at lower doses; consider age-related renal function changes
• Pediatric patients: Limited data; not FDA-approved under age 16

• Oral administration with or without food
• Capsules should be swallowed whole
• Available in 25 mg, 50 mg, and 100 mg capsules

Pharmacokinetics

• Well absorbed orally ( bioavailability >90%)
• Food does not significantly affect absorption
• Tmax: 2-6 hours

• Volume of distribution: 1.45 L/kg
• Protein binding: 40-60%, primarily to albumin and erythrocytes
• Crosses blood-brain barrier and placenta

• Extensive hepatic metabolism via CYP3A4 and acetylation
• Primary metabolites: N-acetyl zonisamide and 2-sulfamoylacetylphenol (SMAP)
• Metabolites are pharmacologically inactive

• Elimination half-life: 63 hours (range 50-68 hours)
• Renal excretion: 62% of dose (35% as unchanged drug)
• Hemodialysis removes approximately 50% of circulating drug

Contraindications

• Hypersensitivity to zonisamide, sulfonamides, or any component of the formulation
• Patients with history of zonisamide-associated metabolic acidosis
• Severe hepatic impairment
• Concomitant use with other carbonic anhydrase inhibitors

Warnings and Precautions

• May cause hyperchloremic, non-anion gap metabolic acidosis
• Monitor serum bicarbonate levels periodically
• Risk factors: renal disease, severe respiratory disorders, ketogenic diet

• Reported in children, especially in warm weather
• Monitor for decreased sweating and increased body temperature

• Antiepileptic drugs increase risk of suicidal thoughts/behavior
• Monitor for emergence or worsening of depression

• Psychomotor slowing, difficulty concentrating, speech or language problems
• Depression, psychosis, and other psychiatric symptoms reported

• Risk of kidney stones (1-2% of patients)
• Maintain adequate hydration

• Stevens-Johnson syndrome, toxic epidermal necrolysis reported
• Discontinue at first sign of rash

• Aplastic anemia, agranulocytosis reported
• Monitor complete blood counts

• Avoid abrupt discontinuation; taper gradually

Drug Interactions

• Carbamazepine, phenytoin, phenobarbital: Decrease zonisamide levels by 25-50%

• Ketoconazole, erythromycin: May increase zonisamide levels

• Valproic acid: May cause additive CNS depression
• Alcohol: Enhanced CNS depressant effects
• Other carbonic anhydrase inhibitors: Increased risk of metabolic acidosis and renal calculi
• CNS depressants: Additive sedative effects

Adverse Effects

• Somnolence (17-28%)
• Dizziness (13-19%)
• Anorexia (13-19%)
• Headache (10-16%)
• Agitation/irritability (8-12%)
• Fatigue (8-12%)
• Cognitive impairment (6-10%)
• Weight loss (5-9%)

• Metabolic acidosis (1-5%)
• Renal calculi (1-2%)
• Oligohidrosis (<1%)
• Stevens-Johnson syndrome (<0.1%)
• Aplastic anemia (<0.1%)
• Acute pancreatitis (<0.1%)
• Rhabdomyolysis (<0.1%)

Monitoring Parameters

• Complete blood count with platelets
• Comprehensive metabolic panel (including bicarbonate)
• Renal function tests
• Pregnancy test if applicable

• Serum bicarbonate levels at baseline and periodically
• Renal function tests every 6-12 months
• Body weight regularly
• Mental status and mood assessment
• Skin examination for rash
• Signs of oligohidrosis, especially in children

• Therapeutic range: 10-40 μg/mL
• Not routinely required but useful in certain clinical situations

Patient Education

• Take medication exactly as prescribed; do not stop abruptly
• May cause drowsiness or dizziness; avoid driving until effects known
• Maintain adequate fluid intake to reduce kidney stone risk
• Report any skin rash immediately
• Watch for signs of decreased sweating or increased body temperature
• Use effective contraception; discuss pregnancy planning with provider
• Avoid alcohol and other CNS depressants
• Report mood changes, depression, or suicidal thoughts
• Regular follow-up appointments are essential
• Wear medical alert identification indicating epilepsy diagnosis

• Warm weather precautions due to possible decreased sweating
• Gradual dose titration to minimize side effects
• Importance of not crushing or chewing capsules

References

1. FDA Prescribing Information: Zonegran (zonisamide). Revised 2022. 2. Brodie MJ, Ben-Menachem E. Epilepsy: Newer Antiepileptic Drugs. Lancet. 2018;391(10115): 235-248. 3. Leppik IE. Zonisamide: Chemistry, Mechanism of Action, and Pharmacokinetics. Seizure. 2004;13 Suppl 1:S5-9. 4. Baulac M, Brodie MJ, Patten A, et al. Efficacy and Tolerability of Zonisamide Versus Controlled-Release Carbamazepine for Newly Diagnosed Partial Epilepsy: A Phase 3, Randomised, Double-Blind, Non-Inferiority Trial. Lancet Neurol. 2012;11(7):579-588. 5. Wilfong A, Schultz RJ. Zonisamide for Add-On Treatment of Refractory Partial Epilepsy. Cochrane Database Syst Rev. 2014;(7):CD001416. 6. Peters JM, Camfield CS, Camfield PR. Population-Based Study of Zonisamide for Pediatric Epilepsy. Pediatr Neurol. 2015;52(1):61-66. 7. Kato M, Kurahashi H, Hirose S, et al. Zonisamide for West Syndrome. Brain Dev. 2015;37(3):322-327. 8. Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE Treatment Guidelines: Evidence-Based Analysis of Antiepileptic Drug Efficacy and Effectiveness as Initial Monotherapy for Epileptic Seizures and Syndromes. Epilepsia. 2013;54(3):551-563.