Zonisamide

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Zonegran (Sci Gen)
25 mg, 50 mg and 100 mg capsules
Approved indication: partial seizures
Australian Medicines Handbook section 16.1.3

Many adults with refractory epilepsy have partial seizures which may or may not become generalised. When monotherapy fails, it can be difficult to decide which adjunctive treatment will help the patient. Zonisamide adds to the list of drugs such as gabapentin, lamotrigine, tiagabine and topiramate, which can be used as add-on therapy. While it is a new drug in Australia, zonisamide has been available for many years in Japan.

Zonisamide is a sulfonamide, but its mechanism of action in epilepsy is uncertain. It may stabilise neuronal membranes by blocking sodium and calcium channels. Zonisamide is also a weak inhibitor of carbonic anhydrase.

The capsules are well absorbed and food does not affect bioavailability. Zonisamide has a long half-life so it takes up to 14 days for its concentration to reach a steady state. The dose should therefore not be increased at intervals of less than one week. Treatment begins with twice-daily doses, but patients can switch to once daily after the dose has been titrated to an effective level. Most of the dose is excreted in the urine as unchanged drug and metabolites, so clearance falls with declining renal function. Doses may therefore need to be titrated more slowly in patients with renal or hepatic impairment. The metabolism of zonisamide includes cytochrome P450 3A4 so there is a potential for interactions with other drugs acting on this enzyme system. Clearance is increased by phenytoin, sodium valproate and carbamazepine. Zonisamide may possibly interact with carbonic anhydrase inhibitors such as topiramate.

A study in the USA compared zonisamide with placebo in 203 patients with refractory partial seizures. Different regimens were used to titrate the dose, but all patients randomised to take zonisamide were on 400 mg daily from the eighth week of the study. Patients continued their usual antiepileptic drugs.

In the month before randomisation the median frequency of partial seizures was 13 in the placebo group and 11–13 in the zonisamide groups. During weeks 8–12 of the study, the median frequency of all seizures was reduced by 9% in the placebo group and by 40.5% in the zonisamide group.¹

Another American study randomised 152 patients to add zonisamide or a placebo to their usual treatment for 12 weeks. The dose of zonisamide was titrated over four weeks to 400–600 mg daily. The baseline median frequency of seizures was approximately nine per month, but there was a 25.5% reduction after patients took zonisamide. In the placebo group there was a 6.6% increase in seizure frequency.²

In a European study 347 patients added a placebo or one of three doses of zonisamide to their usual therapy. The fixed-dose phase of the trial lasted for 18 weeks. During this phase, seizure frequency reduced by 17.4% in the placebo group and by 38.5% in patients taking zonisamide 300 mg daily. The efficacy of zonisamide 100 mg was not statistically different from placebo. While the median reduction in seizure frequency with zonisamide 500 mg was 46.1%, the response probably does not greatly increase above a daily dose of 400 mg.³

Frequent adverse effects with zonisamide include somnolence, dizziness and anorexia. Some patients lost weight during the trials.^1,3 Adverse neurological events include ataxia, nystagmus, agitation and altered cognitive function. Driving skills may be impaired.

Zonisamide can cause rashes, including Stevens-Johnson syndrome. The product information states that it is contraindicated if the patient has an allergy to sulfonamides.

Prescribers may need to consider monitoring renal function as zonisamide has been associated with increases in urea and creatinine concentrations. Patients should be advised to maintain their hydration in warmer weather as oligohydrosis and hyperthermia have been reported (mainly in children). Early development of the drug in the USA was halted because 3.5% of patients developed kidney stones.¹

Zonisamide is teratogenic in animals and is not approved for use in children.

Although zonisamide reduces seizure frequency more than placebo, few patients will become free of seizures. Depending on the dose, a greater than 50% reduction in the frequency of all seizures is achieved by 30–53% of patients.

manufacturer provided the clinical evaluation

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Notes on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).