What is zonisamide?

What is Zonisamide?

Zonisamide is an antiepileptic drug (sulfonamide derivative) that is FDA-approved as adjunctive therapy for partial-onset seizures in adults, but is also used off-label for several other conditions including obesity, cyclic vomiting syndrome prophylaxis, and migraine prevention. 1, 2

Primary FDA-Approved Indication

• Zonisamide is approved for adjunctive treatment of partial-onset seizures in adults 1
• It is not FDA-approved for use in children under 16 years of age 1
• The drug has been used extensively in Japan since 1989 for both partial and generalized seizures, with over 2 million patient-years of international exposure 3

Mechanisms of Action

Zonisamide has multiple mechanisms of action, which explains its broad therapeutic applications: 4, 2, 3

• Sodium and calcium channel blockade - blocks voltage-gated sodium channels and reduces T-type calcium currents 4, 2
• Modulation of GABA receptors - enhances gamma-aminobutyric acid-mediated inhibition 2, 3
• These multiple mechanisms contribute to its broad-spectrum anticonvulsant activity 2

Off-Label Clinical Uses

Weight Loss and Obesity Management

• Zonisamide is used off-label by some healthcare professionals for obesity treatment, though it is not FDA-approved as an anti-obesity medication 4
• The drug is associated with weight loss as a consistent side effect 4
• In overweight/obese patients with obstructive sleep apnea, zonisamide decreased apnea-hypopnea index (AHI) and oxygen desaturation index (ODI), though it was less effective than CPAP 4
• Limited evidence exists from short-term studies; one small 16-week study showed statistically significant weight loss in patients with mean BMI of 36 kg/m², but recommendations cannot be made based on this single study 4

Cyclic Vomiting Syndrome (CVS) Prophylaxis

• Zonisamide is recommended as a prophylactic therapy option for moderate-to-severe CVS by the American Neurogastroenterology and Motility Society 4
• Starting dosage: 100 mg daily; Goal dosage: 200-400 mg daily 4
• Titrate up by 100 mg daily every 2 weeks to goal dose 4
• Common adverse effects include irritability, confusion, and depression 4
• Associated with weight loss, which may be advantageous in some patients 4

Migraine and Headache Prevention

• Zonisamide may be used as an alternative to topiramate for migraine prevention, particularly when topiramate causes excessive side effects 4
• It shares similar properties with topiramate but may have a different tolerability profile 4
• Caution is advised regarding potential side effects of depression and cognitive slowing 4

Other Potential Uses

• Clinical studies have demonstrated potential therapeutic use in neuropathic pain, bipolar disorder, eating disorders, and Parkinson's disease 5
• Effective in various seizure types including myoclonic epilepsy, Lennox-Gastaut syndrome, and infantile spasms 5

Pharmacokinetic Profile

• Half-life of approximately 60 hours, allowing once- or twice-daily administration 2
• Displays predictable, dose-dependent pharmacokinetics 2
• Low potential for drug interactions with other medications, including oral contraceptives 2
• Hepatically metabolized through cytochrome P450 pathway 3
• Does not induce its own metabolism or liver enzymes 3

Dosing for Epilepsy

• Dosages typically elevated by 100 mg/day each week during titration 6
• Minimal effective dosage: 100 mg/day; Most effective dosage: 400 mg/day for partial seizures 6
• Zonisamide 300-600 mg/day has demonstrated significant reductions in median total seizure rates versus placebo 2
• Can be administered once or twice daily due to long half-life 2

Serious Adverse Effects and Contraindications

Absolute Contraindications

• Do not use in patients with sulfonamide allergy - zonisamide is a sulfonamide derivative with risk of hypersensitivity reactions 1
• Contraindicated in pregnancy (FDA Pregnancy Category C) due to potential teratogenic risks 1
• Contraindicated in patients with kidney stones 1

Serious Adverse Effects Requiring Monitoring

• Serious skin rash that can cause death - more likely within first 4 months of treatment 1
• Decreased sweating and hyperthermia (fever) - particularly dangerous in hot weather and in children; may require hospitalization 1
• Suicidal thoughts or actions - occurs in approximately 1 in 500 patients, similar to other antiepileptic drugs 1
• Metabolic acidosis - can cause brittle/soft bones, kidney stones, and slow growth in children if untreated 1
• Kidney stones - increased risk; patients should drink plenty of fluids 1
• Cognitive problems - concentration, attention, memory, thinking, speech, or language difficulties 1
• Blood cell changes - reduced red and white blood cell counts 1

Common Adverse Effects

• Most frequently reported: somnolence, dizziness, anorexia/weight loss 2
• Irritability, confusion, depression 4
• Cognitive dysfunction, paresthesia, headache, fatigue, nausea 4

Monitoring Requirements

• Blood test to measure acid level before and during treatment (for metabolic acidosis) 1
• Monitor serum electrolytes and renal function twice annually 4
• Monitor complete blood count for blood cell changes 1
• Watch for decreased sweating and fever, especially in hot weather 1
• Monitor for mood changes, suicidal thoughts, or behavioral changes 1

Critical Safety Warnings

• Do not stop zonisamide suddenly - can cause status epilepticus (seizures that will not stop) in epilepsy patients 1
• Dose must be tapered: take one capsule every other day for at least 1 week before stopping 4
• Avoid alcohol and CNS depressants until effects are known 1
• May impair ability to drive or operate heavy machinery 1
• Increased risk of kidney stones - adequate hydration is essential 4, 1

Special Populations

• Pregnancy: May harm unborn baby; women of childbearing potential should use effective birth control 1
• Breastfeeding: Passes into breast milk; discuss risks/benefits with healthcare provider 1
• Pediatric use: Not established as safe or effective in children under 16 years for epilepsy indication 1

Clinical Efficacy Evidence

• Four pivotal phase III randomized, double-blind, placebo-controlled trials established efficacy in approximately 850 patients with refractory partial epilepsy 2
• At 400 mg/day, reduced median seizure frequency by 40.5% versus 9% with placebo (p=0.0009) 6
• Responder rate (≥50% seizure reduction): 42% of patients at 400 mg/day 6
• Long-term efficacy and safety sustained for up to 36 months 2
• Dropout rate from adverse events (10%) did not differ significantly from placebo (8.2%) 6