ZONEGRAN

What it is

Zonegran is a hard capsule formulation containing zonisamide, available in strengths of 25 mg, 50 mg and 100 mg. Zonisamide is a benzisoxazole derivative and an antiepileptic medicine with weak carbonic anhydrase inhibiting activity in vitro.

Approved indications —

Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy who are intolerant to other agents or where other agents are contraindicated. — Adjunctive therapy in the treatment of adult patients with partial seizures, with or without secondary generalisation.

Dosing overview

Zonegran may be taken as monotherapy or added to existing therapy in adults, with doses titrated on the basis of clinical effect. For monotherapy in newly diagnosed adult patients, the recommended escalation involves 100 mg per day in weeks 1–2, 200 mg per day in weeks 3–4, and 300 mg per day in weeks 5–6, with a maximum maintenance dose of 300 mg per day (once daily), and if higher doses are required, increases at two-weekly intervals in increments of 100 mg up to a maximum of 500 mg. Some patients, especially those not taking CYP3A4-inducing agents, may respond to lower doses. In elderly patients, caution should be exercised at initiation of treatment as there is limited information on the use of Zonegran in these patients. The safety and efficacy in children and adolescents under 18 years have not been established, and use in these patients is not recommended.

Key safety warnings

Antiepileptic drugs, including Zonegran, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication, and patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and any unusual changes in mood or behaviour. In clinical trials with a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among AED-treated patients was 0.43%, compared to 0.24% among placebo-treated patients. Potentially fatal reactions to sulphonamides (zonisamide is a sulphonamide) including Stevens–Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anaemia and other blood dyscrasias have occurred rarely; such reactions may occur when a sulphonamide is readministered irrespective of the route of administration, and if signs of hypersensitivity or other serious reactions occur, Zonegran must be discontinued immediately. Hyperammonaemia and encephalopathy have been reported with postmarketing use of zonisamide; zonisamide treatment inhibits carbonic anhydrase activity, which may cause metabolic acidosis that is associated with an increased risk for developing hyperammonaemia. Zonegran can cause a hyperchloraemic, non-anion gap, metabolic acidosis (decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis), which is often asymptomatic. Serum bicarbonate should be measured pre-treatment (baseline), on commencement of maintenance dosing, when dosage is increased and when strong CYP3A4 inhibitors are newly co-prescribed with Zonegran and at a minimum 6 monthly from the adoption of a maintenance regimen. A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in adult and paediatric patients receiving zonisamide, with symptoms including acute onset of decreased visual acuity and/or ocular pain. Kidney stones have occurred in patients treated with zonisamide, and Zonegran should be used with caution in patients who have risk factors for nephrolithiasis, including prior stone formation, a family history of nephrolithiasis and hypercalcuria. Zonegran may cause weight loss, and a dietary supplement or increased food intake may be considered if the patient is losing weight or is underweight; if substantial undesirable weight loss occurs, discontinuation of Zonegran should be considered.

Contraindications

Zonegran is contraindicated in patients with hypersensitivity to zonisamide, to sulphonamides or any of the excipients.

PBS listing

Zonegran is listed on the PBS in three strengths: 25 mg capsules (ex-manufacturer price A$10.41), 50 mg capsules (A$17.36) and 100 mg capsules (A$28.93), each with 2 PBS items, under streamlined restrictions.

Regulatory history

Zonegran was first registered on the ARTG on 31 July 2007 in three capsule strengths (25 mg, 50 mg and 100 mg) under licence category RE. On 4 April 2013, the TGA approved Zonegran as monotherapy for the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy who are intolerant to other agents or where other agents are contraindicated.