Zonisamide

Zonisamide (Zonegran®, Excegran®) is a new-generation, broad-spectrum antiepileptic drug (AED) currently approved as adjunctive therapy for the treatment of medically refractory partial seizures in adults in the US and as adjunctive therapy or monotherapy in the control of partial and generalised seizures in adults and children in Japan and Korea.

Either as adjunctive therapy or monotherapy, zonisamide effectively reduces the frequency of partial seizures, with or without secondary generalisation to tonic-clonic seizures, in adults and children with epilepsy. The drug is generally well tolerated and, additionally, has a favourable pharmacokinetic profile permitting once- or twice-daily administration. Direct head-to-head comparisons with other AEDs would be beneficial in fully defining the place of zonisamide in therapy. In the meantime, adjunctive therapy or monotherapy with zonisamide is a convenient, useful option for the management of partial seizures, including those refractory to other AEDs.

Zonisamide demonstrates anticonvulsant activity in animal models of epilepsy, as well as in patients with various types of epilepsy. The drug appears to block the spread of seizure discharges and to suppress the epileptic focus, although the precise mechanism(s) of antiseizure activity are unknown.

Peak plasma zonisamide concentrations are attained 2–5 hours after administration of single oral doses of 200–800mg in healthy volunteers in Japan and the US. The drug has a bioavailability of ≈100%; food affects the rate, but not extent, of absorption. Steady-state concentrations are achieved within 14 days. Linear pharmacokinetics have been observed in adults and children with epilepsy in Japan, but not in adult volunteers or patients with epilepsy in the US.

Zonisamide is metabolised in the liver and excreted primarily by the kidneys. It has a long plasma terminal elimination half-life: 50–68 hours after single oral 200–800mg doses in healthy volunteers in the US and Japan. The pharmacokinetics of the drug are unaffected by advanced age, although the plasma clearance of the drug appears to be moderately higher in children than in adults in Japan. Zonisamide should not be used in patients with renal failure (estimated glomerular filtration rate <50 mL/min [<3.0 L/h]). Zonisamide has no hepatic enzyme-inducing effects; while it is sensitive to induction by enzyme-inducing AEDs (e.g. carbamazepine and phenytoin), these drug interactions seem to be of minor clinical significance.

In four short-term (≤24 weeks), placebo-controlled trials conducted in the US or Europe (n = 138–351), once- or twice-daily administration of zonisamide at dosages of ≥300 mg/day was mostly effective in the treatment of patients with medically refractory partial seizures, with or without secondary generalisation to tonic-clonic seizures, based on significantly greater reductions in median seizure frequency for all partial seizures, for complex partial seizures only and for all seizure types. The corresponding responder rates (i.e. patients achieving a ≥50% reduction from baseline in seizure frequency) in zonisamide ≥400 mg/day recipients were generally significantly greater than with placebo. When assessed in two of the above-mentioned trials, twice-daily administration of zonisamide 100 or 200 mg/day was mostly effective in one study, whereas 100 mg/day was not effective in the other.

Longer term, the antiepileptic efficacy of zonisamide was maintained in patients who continued therapy for up to 2 years, with no evidence of tachyphylaxis or pharmacological tolerance.

The efficacy of zonisamide at mean dosages of 5.9–8.8 mg/kg/day was demonstrated in a total of 1008 adults or children in Japan with various types of epilepsy mainly refractory to treatment who were recruited to a series of predominantly noncomparative clinical trials. In the only active comparator-controlled study performed to date, zonisamide (mean dosage 330 mg/day) was judged to be as effective as carbamazepine (mean dosage 600 mg/day) in Japanese patients with predominantly partial epilepsies.

Pooled analyses of open-label studies specifically in young adults and/or children showed zonisamide to be effective as adjunctive therapy for refractory partial seizures (dosage of 2.0–18.6 mg/kg/day) and as monotherapy for newly diagnosed or refractory partial seizures (dosage of 1–12 mg/kg/day).

Zonisamide was generally well tolerated as adjunctive therapy in patients (n = 499) with refractory partial seizures enrolled in placebo-controlled trials conducted in the US and Europe, and as adjunctive therapy or monotherapy in adults or children in Japan (n = 1008) with various types of epilepsy recruited in predominantly noncomparative clinical trials. The most frequently occurring adverse events common to these studies were somnolence, anorexia, ataxia, gastrointestinal discomfort/abdominal pain, mental slowing, weight loss and skin rash/itch.

Adverse events usually occurred early during treatment (within 4 weeks), were generally of mild-to-moderate intensity, and decreased with time in the US and European studies. Patient tolerability of zonisamide was optimised during slow titration from low initial dosages to therapeutic dosages over 4–8 weeks.

The tolerability profile of zonisamide in a Japanese study was generally similar to that of carbamazepine, although anorexia occurred more frequently with zonisamide, and ataxia was noted more frequently with carbamazepine.

Patients mainly in the US and Europe appear to be at increased risk of developing kidney stones (incidence equivalent to 18 cases per 1000 patient-years of exposure), while paediatric patients, in particular, appear to be at increased risk of zonisamide-associated oligohidrosis/hyperthermia (estimated reporting rate ≈1–2 cases per 10 000 patient-years of exposure).