Zonisamide

Zonisamide is a synthetic 1,2-benzisoxazole derivative (1,2-benzisoxazole-3-methanesulfonamide). It is chemically classified as a sulfonamide with a structural similarity to serotonin. It was first introduced as an AED in Japan in 1989.

• EMEA-SmPC¹⁾: Adjunctive therapy in adult patients with focal seizures with or without secondary generalisation.
• FDA-PI²⁾: Adjunctive therapy in the treatment of focal seizures in adults with epilepsy.

• Zonisamide appears to be an effective broad-spectrum AED with extensive clinical use in Japan
• It is efficacious in focal seizures with or without GTCSs, primarily and secondarily generalised seizures including epileptic spasms of West syndrome, other epileptic encephalopathies such as Ohtahara syndrome, and probably progressive myoclonic epilepsies such as Unverricht syndrome.^{[1][2][3][4][5][6][7]}.

‘Start low and go slow’ is an important part of treatment with zonisamide^[8]. Significant adjustments are needed in co-medication with hepatic-enzyme inducers.

Adults: Start with 100 mg/day in one or two equally divided doses. After two weeks, the dose may be increased to 200 mg/day for at least two weeks. It can be increased to 300 mg/day and 400 mg/day, with the dose stable for at least two weeks to achieve steady state at each level. Evidence from controlled trials suggests that zonisamide doses of 100–600 mg/day are effective, but there is no suggestion of increasing response above 400 mg/day.

Because of the long half-life of zonisamide, up to two weeks may be required to achieve steady state levels upon reaching a stable dose or following dosage adjustment. Some experts prolong the duration of treatment at the lower doses in order to fully assess the effects of zonisamide at steady state, noting that many of the side effects of zonisamide are more frequent at doses of 300 mg per day and above. Although there is some evidence of greater response at doses above 100–200 mg/day, the increase appears small and formal dose-response studies have not been conducted.

Marked renal impairment (creatinine clearance Dosing: once or twice daily.

Children: start with 1–2 mg/kg/day for the first week and titrate in increments of 1–2 mg/kg/day every 2 weeks. Usual childhood maintenance dose is 4–8 mg/kg/day (maximum 12 mg/kg/day) in two equally divided doses.

Therapeutic drug monitoring: useful, although there is insufficient evidence to support a clear relation between the plasma concentration of zonisamide and clinical response^[9]. Zonisamide monitoring may be needed in order to adjust the dosage in co-medication with phenytoin, phenobarbital or carbamazepine.

Reference range: 15–40 mg/l (45–180 μmol/l).

see Zonisamide in the British National Formulary

Zonisamide causes many ADRs.

Frequent and/or important: sedation, somnolence, fatigue, dizziness, agitation, irritability, anorexia, weight loss, nausea, diarrhoea, dyspepsia, dry mouth, slowing of mental activity, depression, ataxia, visual hallucinations, photosensitivity, resting and postural hand tremors.

Potentially serious: some of the ADRs are similar to those of topiramate. These are:

• cognitive impairment, including word-finding difficulty; this is worse in children with plasma concentrations >140 μmol/l
• weight loss and anorexia that may become very severenephrolithiasis in 4% of patients on prolonged zonisamide therapy
• oligohidrosis and anhidrosis often accompanied by hyperthermia, especially in children and hot environments.
• Additional severe ADRs are those seen with the sulfonamides, such as rash, Stevens–Johnson syndrome, toxic epidermal necrolysis and major haematological disturbances including aplastic anaemia, which very rarely can be fatal. The incidence of rash requiring discontinuation of therapy has been approximately 2% in clinical trials.
• Depression and psychosis may be common, particularly in children. In one study, 14 of 74 patients experienced psychotic episodes within a few years of commencement of zonisamide^[10].
• Seizure exacerbation: treatment-emergent status epilepticus has been reported in 1.1% of treated patients, compared to no reported cases in placebotreated individuals^[11][12]

Considerations in women

Pregnancy: category C. Breastfeeding: the transfer rate of zonisamide through breast milk is high at about 50%. Interaction with oral hormonal contraception: none.

Main mechanisms of action The anti-epileptic mechanism of zonisamide is probably multimodal. Zonisamide blocks the sustained repetitive firing of voltage-sensitive sodium channels and reduces voltage-dependent T-type calcium current without affecting the L-type calcium current. It has mild carbonic anhydrase activity and inhibits excitatory glutamatergic transmission. It exhibits free radical-scavenging properties.

Pharmacokinetics

• Bioavailability: 100%.
• Protein binding: 40–60%.
• Metabolism and route of elimination:
  • zonisamide is metabolised in the liver and eliminated by the kidneys.
  • It is metabolised partly by CYP3A4 (reductive cleavage), and also by N-acetyl-transferases and conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymes may affect the pharmacokinetics of zonisamide.
  • It does not induce hepatic enzymes.
  • Nearly half of zonisamide is excreted unchanged in the urine.
• Elimination half-life: 60 hours, which decreases to 27–38 hours in the presence of hepatic enzyme inducers.

Interaction with other drugs

• Plasma concentrations of zonisamide are altered by drugs that either induce or inhibit CYP3A4.
• Phenytoin, phenobarbital and carbamazepine increase zonisamide plasma clearance and reduce its half-life to 27–38 hours^[13].
• Valproate also reduces its half-life to 46 hours.
• Zonisamide does not appear to affect phenytoin, but significantly increases the plasma concentration of carbamazepine epoxide when added to carbamazepine.
• Concomitant administration of carbonic anhydrase inhibitors, such as acetazolamide or topiramate, is not advised because of the increased potential for renal stone and metabolic acidosis.

Zonisamide has significant ADRs, some of which may be severe such as cognitive, psychotic episodes, anhidrosis and hyperthermia, nephrolithiasis and Stevens–Johnson syndrome. It also has many inter actions with other AEDs in polytherapy^[11].

~~AUTHORS~~