ZONEGRAN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZONEGRAN (ZONEGRAN).
Anticonvulsant; blocks voltage-gated sodium and calcium channels, enhances GABA-mediated inhibition, and inhibits glutamate release.
| Metabolism | Primarily metabolized via hepatic glucuronidation and acetylation; CYP3A4 partially involved. |
| Excretion | Renal: approximately 62% of the dose as unchanged drug and metabolites (primarily glucuronide conjugates and N-acetylzonisamide). Fecal: approximately 16% (including metabolites). Biliary excretion is minimal. Total recovery in urine and feces accounts for ~80% of the dose. |
| Half-life | Terminal elimination half-life is approximately 63 hours (range 50-70 hours) in adults. The long half-life allows for once- or twice-daily dosing. Steady state is reached after about 2 weeks of repeated dosing. |
| Protein binding | Approximately 40-60% bound to plasma proteins, primarily albumin. Binding is not affected by drug concentration in the therapeutic range. |
| Volume of Distribution | Approximately 0.8-1.6 L/kg, indicating extensive distribution into tissues (total body water). The apparent volume of distribution is large, suggesting accumulation in tissues such as red blood cells (zonisamide concentrates in RBCs with a RBC:plasma ratio of about 8:1). |
| Bioavailability | Oral: Approximately 100% (well absorbed). The absolute bioavailability is near complete with no significant first-pass effect. Food does not affect the extent of absorption but may delay the rate. |
| Onset of Action | Oral: Clinical effect (seizure reduction) may be observed within 1-2 weeks, but full therapeutic effect may require up to 4-6 weeks due to slow titration and time to steady state. |
| Duration of Action | Duration of antiepileptic effect is approximately 24 hours with once-daily dosing, owing to the long half-life. Steady-state concentrations are maintained with regular dosing. |
| Action Class | Brain carbonic anhydrase inhibitors |
Initial: 100 mg orally once daily for 2 weeks, then may increase by 100 mg/day at 2-week intervals; usual maintenance: 200-400 mg/day divided once or twice daily; maximum: 600 mg/day.
| Dosage form | CAPSULE |
| Renal impairment | CrCl >= 50 mL/min: no adjustment; CrCl 20-49 mL/min: reduce dose by 50%; CrCl < 20 mL/min: avoid use; hemodialysis: administer 50% of usual dose after dialysis. |
| Liver impairment | Child-Pugh Class A: no adjustment; Child-Pugh Class B: use with caution, reduce dose by 50%; Child-Pugh Class C: contraindicated. |
| Pediatric use | Age >= 6 years: initial 1 mg/kg/day once daily for 2 weeks, then increase by 1 mg/kg/day at 2-week intervals; usual maintenance 2-3 mg/kg/day; maximum 6 mg/kg/day or 400 mg/day. |
| Geriatric use | Start at lower initial dose (50-100 mg/day) due to reduced renal function; titrate slowly; monitor for cognitive impairment and electrolyte disturbances. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ZONEGRAN (ZONEGRAN).
| Breastfeeding | Zonisamide is excreted in human breast milk. Milk-to-plasma ratio (M/P) is approximately 0.93. Infant serum levels can reach 1-2 mcg/mL with potential for sedation, poor feeding, and metabolic acidosis. Breastfeeding is generally not recommended due to risk of infant toxicity. |
| Teratogenic Risk | Pregnancy Category D. Zonegran (zonisamide) is associated with an increased risk of major congenital malformations, particularly neural tube defects, when used during the first trimester. Exposure in the second and third trimesters may cause fetal hydantoin syndrome, growth retardation, and developmental delay. Risk of malformations is dose-dependent and increases with polytherapy. |
■ FDA Black Box Warning
Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN); risk of oligohidrosis and hyperthermia in pediatric patients.
| Serious Effects |
Hypersensitivity to zonisamide or sulfonamides; concomitant use with other carbonic anhydrase inhibitors may increase risk of metabolic acidosis.
| Precautions | Serious skin reactions (SJS/TEN); oligohidrosis and hyperthermia in children; acute myopia and secondary angle-closure glaucoma; depression and suicidal behavior; abrupt withdrawal may precipitate seizures; renal impairment may require dose adjustment. |
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| Fetal Monitoring | Monitor zonisamide serum concentrations throughout pregnancy; target trough levels based on individual response. Perform regular fetal ultrasonography (including high-resolution anatomy scan at 18-20 weeks) to detect neural tube defects. Assess for maternal metabolic acidosis, renal function, and liver function. Monitor for signs of fetal distress and growth restriction via serial growth scans in third trimester. |
| Fertility Effects | In reproductive studies, zonisamide caused increased embryo-fetal death and skeletal anomalies. Human data on fertility are limited; however, zonisamide may impair spermatogenesis in males and cause menstrual irregularities or ovulatory dysfunction in females due to potential hormonal interactions. |