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content:zonisamide [2020/02/13 15:07]
icna [Main ADRs]
content:zonisamide [2020/02/23 22:55] (current)
icna [Zonisamide]
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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 serotoninIt was first introduced as an AED in Japan in 1989.
-Efficacydose and mean plasma levels were similar in multi-centre studies with Japanese and Caucasian subjects[(:cite:Wroe2009>Wroe SJ. Zonisamide. In: Shorvon SPerucca E, Engel JJr, eds. The treatment of epilepsy (3nd edition). Oxford: Willey-Blackwell, 2009:713-20.)] [(:cite:Chadwick2002>Chadwick DW, Marson AGZonisamide add-on for drug-resistant partial epilepsyCochrane 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 JapanIt 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>{{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.)].
  
 ==== Dosage and titration ==== ==== Dosage and titration ====
  
-‘Start low and go slow’ is an important part of treatment with zonisamide.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.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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 **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 MPharmacokinetics 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. +
-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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