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 ====== Zonisamide ====== ====== 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.
-Efficacy, dose and mean plasma levels were similar in multi-centre studies with Japanese and Caucasian subjects[(:cite:Wroe2009>Wroe SJ. Zonisamide. In: Shorvon S, Perucca E, Engel JJr, eds. The treatment of epilepsy (3nd edition). Oxford: Willey-Blackwell, 2009:713-20.)] [(:cite:Chadwick2002>Chadwick DW, Marson AG. Zonisamide add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2002;2:CD001416.)]. +
 ===== Authorised indications ===== ===== Authorised indications =====
  
-EMEA-SmPC: Adjunctive therapy in adult patients with focal seizures with or without secondary generalisation. +  * EMEA-SmPC[(EMEA-SmPC>European Medicines Agency-Summary of Product Characteristics)]: Adjunctive therapy in adult patients with focal seizures with or without secondary generalisation. 
-FDA-PI: Adjunctive therapy in the treatment of focal seizures in adults with epilepsy.+  * FDA-PI[(FDA-PI>U.S Food and Drug Administration-Product information)]: Adjunctive therapy in the treatment of focal seizures in adults with epilepsy.
  
 ===== Clinical applications ===== ===== Clinical applications =====
  
-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 [[content:ohtahara_syndrome|Ohtahara syndrome]], and probably progressive myoclonic epilepsies such as [[Unverricht syndrome]].[(:cite:Baulac2006>Baulac M. Introduction to zonisamide. Epilepsy Res 2006;68 Suppl 2:S3–9.)][(:cite:16542880>{{pubmed>long:16542880}})][(:cite:shinnar2009>Shinnar S, Pellock JM, Conry JA. Open-label, long-term safety study of zonisamide administered to children and adolescents with epilepsy. Eur J Paediatr Neurol 2009;13:3-9)][(:cite:arzimanoglou2006>Arzimanoglou A, Rahbani A. Zonisamide for the treatment of epilepsy. Expert Rev Neurother 2006;6:1283–92.)][(:cite:fukushima2006>Fukushima K, Seino M. A long-term follow-up of zonisamide monotherapy. Epilepsia 2006;47:1860–4)][(:cite:michael2007>Michael CT, Starr JL. Psychosis following initiation of zonisamide. Am J Psychiatry 2007;164:682.)][(:cite:sils2007>Sills G, Brodie M. Pharmacokinetics and drug interactions with zonisamide. Epilepsia 2007;48:435–41.)].+  * 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 [[content:ohtahara_syndrome|Ohtahara syndrome]], and probably progressive myoclonic epilepsies such as [[Unverricht syndrome]].[(:cite:Baulac2006>Baulac M. Introduction to zonisamide. Epilepsy Res 2006;68 Suppl 2:S3–9.)][(:cite:16542880>{{pmid>long:16542880}})][(:cite:shinnar2009>Shinnar S, Pellock JM, Conry JA. Open-label, long-term safety study of zonisamide administered to children and adolescents with epilepsy. Eur J Paediatr Neurol 2009;13:3-9)][(:cite:arzimanoglou2006>Arzimanoglou A, Rahbani A. Zonisamide for the treatment of epilepsy. Expert Rev Neurother 2006;6:1283–92.)][(:cite:fukushima2006>Fukushima K, Seino M. A long-term follow-up of zonisamide monotherapy. Epilepsia 2006;47:1860–4)][(:cite:michael2007>Michael CT, Starr JL. Psychosis following initiation of zonisamide. Am J Psychiatry 2007;164:682.)][(:cite:sils2007>Sills G, Brodie M. Pharmacokinetics and drug interactions with zonisamide. Epilepsia 2007;48:435–41.)].
  
 ==== Dosage and titration ==== ==== Dosage and titration ====
  
-‘Start low and go slow’ is an important part of treatment with zonisamide.2 Significant adjustments are needed in co-medication with hepatic-enzyme inducers.+‘Start low and go slow’ is an important part of treatment with zonisamide[(:cite:willmore2004>Willmore LJ, Seino M. International experiences and perspectives: zonisamide. Seizure 2004;13 Suppl 1:S1–72. 620 A Clinical Guide to Epileptic Syndromes and their Treatment)]. 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. **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.
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 **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. **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.3 Zonisamide monitoring may be needed in order to adjust the dosage in co-medication with phenytoin, phenobarbital or carbamazepine.+**Therapeutic drug monitoring:** useful, although there is insufficient evidence to support a clear relation between the plasma concentration of zonisamide and clinical response[(:cite:chadwick2002>Chadwick DW, Marson AG. Zonisamide add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2002;(2):CD001416)]. 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). **Reference range:** 15–40 mg/l (45–180 μmol/l).
 +
 +see [[https://bnfc.nice.org.uk/drug/zonisamide.html|Zonisamide in the British National Formulary]]
  
 ==== Main ADRs ==== ==== Main ADRs ====
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   * oligohidrosis and anhidrosis often accompanied by hyperthermia, especially in children and hot environments.   * 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.   * 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.9 +  * 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[(:cite:michael2007x>Michael CT, Starr JL. Psychosis following initiation of zonisamide. Am J Psychiatry 2007;164:682.)]. 
-  * 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+  * Seizure exacerbation: treatment-emergent status epilepticus has been reported in 1.1% of treated patients, compared to no reported cases in placebotreated individuals[(:cite:Willmore2009)][(:cite:2667602>{{pmid>long:2667602}})]
  
 **Considerations in women** **Considerations in women**
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 **Pharmacokinetics** **Pharmacokinetics**
-Bioavailability: 100%. +  * Bioavailability: 100%. 
-Protein binding: 40–60%. +  * 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. +  * **Metabolism and route of elimination:**  
- +    * zonisamide is metabolised in the liver and eliminated by the kidneys. 
-Elimination half-life: 60 hours, which decreases to 27–38 hours in the presence of hepatic enzyme inducers.+    * 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** **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.10 Valproate also reduces its half-life to 46 hours. +  * 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[(:cite:sills2007>Sills G, Brodie M. Pharmacokinetics and drug interactions with zonisamide. Epilepsia 2007;48:435–41.)]. 
-Zonisamide does not appear to affect phenytoin, but significantly increases the plasma concentration of carbamazepine epoxide when added to carbamazepine. +  * 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 probably ill advised because of the increased potential for renal stone and metabolic acidosis.+  * 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.
  
 ==== Main disadvantages ==== ==== Main disadvantages ====
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 ==== References ==== ==== References ====
-~~refnotes cite~~ +~~REFNOTES~~ 
-Wroe SJ. Zonisamide. In: Shorvon S, Perucca E, Engel JJr, eds. The treatment of epilepsy (3nd edition). Oxford: Willey-Blackwell, 2009:713-20. +~~AUTHORS~~ 
-Willmore LJ, Seino M. International experiences and perspectives: zonisamide. Seizure 2004;13 Suppl 1:S1–72. 620 A Clinical Guide to Epileptic Syndromes and their Treatment +{{tag>pharmacopoeia}} 
-Chadwick DW, Marson AG. Zonisamide add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2002;(2):CD001416. +~~DISCUSSION~~
-Baulac M. Introduction to zonisamide. Epilepsy Res 2006;68 Suppl 2:S3–9. +
-Tosches WA, Tisdell J. Long-term efficacy and safety of monotherapy and adjunctive therapy with zonisamide. Epilepsy Behav 2006;8:522–6. +
-Shinnar S, Pellock JM, Conry JA. Open-label, long-term safety study of zonisamide administered to children and adolescents with epilepsy. Eur J Paediatr Neurol 2009;13:3-9. +
-Arzimanoglou A, Rahbani A. Zonisamide for the treatment of epilepsy. Expert Rev Neurother 2006;6:1283–92. +
-Fukushima K, Seino M. A long-term follow-up of zonisamide monotherapy. Epilepsia 2006;47:1860–4. +
-Michael CT, Starr JL. Psychosis following initiation of zonisamide. Am J Psychiatry 2007;164:682. +
-Sills G, Brodie M. Pharmacokinetics and drug interactions with zonisamide. Epilepsia 2007;48:435–41. +
-Willmore LJ, Abelson MB, Ben-Menachem E, Pellock JM, Shields WD. Vigabatrin: 2008 update. Epilepsia 2009;50:163-173 +
-Mumford JP, Dam M. Meta-analysis of European placebo controlled studies of vigabatrin in drug resistant epilepsy. Br J Clin Pharmacol 1989;27:101S-107S.+
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