Zonisamide

Zonisamide, sold under the brand name Zonegran among others, is a medication used to treat the symptoms of epilepsy and Parkinson's disease.[4][5] Chemically it is a sulfonamide. It serves as an anticonvulsant used primarily as an adjunctive therapy in adults with Parkinson's disease, partial-onset seizures; infantile spasm, mixed seizure types of Lennox–Gastaut syndrome, myoclonic and generalized tonic clonic seizure.[6] Despite this it is also sometimes used as a monotherapy for partial-onset seizures.[5][7]

Zonisamide
Ball-and-stick model of the zonisamide molecule
Clinical data
Trade namesZonegran, Zonisade
AHFS/Drugs.comMonograph
MedlinePlusa603008
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~100%[3]
Protein binding40%[3]
MetabolismLiver through CYP3A4[3]
Elimination half-life63 hours in plasma[3]
ExcretionKidney (62%); Faeces (3%)[3]
Identifiers
  • benzo[d]isoxazol-3-ylmethanesulfonamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.118.526
Chemical and physical data
FormulaC8H8N2O3S
Molar mass212.22 g·mol−1
3D model (JSmol)
Melting point162 °C (324 °F)
  • O=S(=O)(N)Cc2noc1ccccc12
  • InChI=1S/C8H8N2O3S/c9-14(11,12)5-7-6-3-1-2-4-8(6)13-10-7/h1-4H,5H2,(H2,9,11,12) checkY
  • Key:UBQNRHZMVUUOMG-UHFFFAOYSA-N checkY
  (verify)

In 2020, it was the 276th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[8][9]

Medical uses

Epilepsy

Zonisamide is approved in the United States,[1][10] and United Kingdom[11] for adjunctive treatment of partial seizures in adults and Japan for both adjunctive and monotherapy for partial seizures (simple, complex, secondarily generalized), generalized (tonic, tonic-clonic (grand mal), and atypical absence) and combined seizures.[12] In Australia it is marketed as both an adjunctive therapy and monotherapy for partial seizures only.[7]

Parkinson's disease

It has been approved for the treatment of the motor symptoms of Parkinson's disease (PD), as an adjunct to levodopa, in a few countries such as Japan.[4][5] In Japan, zonisamide has been used as an adjunct to levodopa treatment since 2009.[13] In addition, there is clinical evidence that zonisamide in combination with levodopa control of motor symptoms of PD but evidence for the treatment of the non motor symptoms of PD lacking.[14][15]

Adverse effects

Adverse effects by incidence:[3][16][17]

Very common (>10% incidence) adverse effects include:

  • Anorexia
  • Somnolence
  • Dizziness
  • Agitation
  • Irritability
  • Confusional state
  • Depression
  • Diplopia
  • Memory impairment
  • Decreased bicarbonate

Common (1-10% incidence) adverse effects include:

Interactions

Zonisamide and other carbonic anhydrase inhibitors such as topiramate, furosemide, and hydrochlorothiazide have been known to interfere with amobarbital, which has led to inadequate anesthetization during the Wada test.[18] Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis.[3]

Additionally, the metabolism of zonisamide is inhibited by ketoconazole, ciclosporin, miconazole, fluconazole and carbamazepine (in descending order of inhibition) due to their effects on the CYP3A4 enzyme.[19]

Zonisamide is not known to inhibit cytochrome P450 enzymes when present at therapeutic concentrations.[20]

Mechanism of action

Zonisamide is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The precise mechanism by which zonisamide exerts its antiseizure effect is unknown, although it is believed that the drug blocks sodium and T-type calcium channels, which leads to the suppression of neuronal hypersynchronization (that is, seizure-form activity).[7] It is also known to be a weak carbonic anhydrase inhibitor (similarly to the anticonvulsant topiramate). It is also known to modulate GABAergic and glutamatergic neurotransmission.[7][21][22][23][24]

Pharmacokinetics

Absorption

Variable, yet relatively rapid rate of absorption with a time to peak concentration of 2.8-3.9 hours. Bioavailability is close to 100% and food has no effect on the bioavailability of zonisamide but may affect the rate of absorption.[25][20]

Metabolism

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,[26] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.[27]

History

Zonisamide was discovered by Uno and colleagues in 1972[28] and launched by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) in 1989 as Excegran in Japan.[29] It was marketed by Élan in the United States starting in 2000 as Zonegran, before Élan transferred their interests in zonisamide to Eisai Co., Ltd. in 2004.[30] Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others)[31] and Europe (starting in Germany and the United Kingdom).[32]

Research

Tardive dyskinesia

In an open-label trial zonisamide attenuated the symptoms of tardive dyskinesia.[33]

Obesity

It has also been studied for obesity[34] with significant positive effects on body weight loss and there are three ongoing clinical trials for this indication.[35][36][37] It was to be sold, when combined with bupropion, under the brand name Empatic, until its development was discontinued.[38]

Migraine

Zonisamide has been studied for and used as a migraine preventative medication, when topiramate is either ineffective or cannot be continued due to side effects.[5]

Bipolar depression

It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.[39][40]

References
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  2. "Zonisade- zonisamide suspension". DailyMed. 15 July 2022. Retrieved 21 January 2023.
  3. "Zonegran Product Information" (PDF). TGA eBusiness Services. SciGen (Australia) Pty Ltd. 4 April 2013. Archived from the original on 15 October 2018. Retrieved 18 November 2013.
  4. Grover ND, Limaye RP, Gokhale DV, Patil TR (November–December 2013). "Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease". Indian Journal of Pharmacology. 45 (6): 547–55. doi:10.4103/0253-7613.121266. PMC 3847242. PMID 24347760.
  5. Brayfield, A, ed. (8 March 2016). "Zonisamide: Martindale: The Complete Drug Reference". MedicinesComplete. London, UK: Pharmaceutical Press. Archived from the original on 27 August 2021. Retrieved 19 August 2017.
  6. Souney P, Mutnick A, Shargel L (2007). Comprehensive Pharmacy Review (6th ed.). Williams & Wilkins. p. 988. ISBN 9780781765619. OCLC 869677890.
  7. Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  8. "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  9. "Zonisamide - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  10. "Drug Approval Package: Zonegran (Zonisomide) NDA #20-789". U.S. Food and Drug Administration (FDA). 24 December 1999. Archived from the original on 29 March 2021. Retrieved 20 July 2022.
  11. Eisai Ltd. (2005). "Zonegran Summary of Product Characteristics". electronic Medicines Compendium. Medicines.org.uk. Archived from the original on 8 November 2005. Retrieved 13 November 2005.
  12. Dainippon Pharmaceutical Co., Ltd. (2004). "EXCEGRAN Tablets 100 mg & EXCEGRAN Powder 20%" (PDF). Archived from the original (PDF) on 2007-09-28. Retrieved 13 March 2006.
  13. Murata M, Hasegawa K, Kanazawa I (January 2007). "Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study". Neurology. 68 (1): 45–50. doi:10.1212/01.wnl.0000250236.75053.16. PMID 17200492. S2CID 894677.
  14. Grover ND, Limaye RP, Gokhale DV, Patil TR (2013). "Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease". Indian Journal of Pharmacology. 45 (6): 547–55. doi:10.4103/0253-7613.121266. PMC 3847242. PMID 24347760.
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  27. Stiff DD, Robicheau JT, Zemaitis MA (January 1992). "Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative". Xenobiotica. 22 (1): 1–11. doi:10.3109/00498259209053097. PMID 1615700.
  28. Shah J, Kent S, Daniel MC (2002-06-15) [1972]. "Zonisamide". In René H, Levy RH, Brian SM, Perrucca E (eds.). Antiepileptic Drugs (Fifth ed.). Philadelphia: Lippincott Williams & Wilkins. p. 873. ISBN 0-7817-2321-3. Archived from the original on 2021-08-27. Retrieved 2007-11-07.
  29. Dainippon Sumitomo Pharma Co. Ltd. (2005). "Company History". Company Information. Dainippon Sumitomo Co., Ltd. Archived from the original on 13 February 2006. Retrieved 12 November 2005.
  30. Dainippon Pharmaceutical Co. Ltd. (2004). "Transfer of Rights Agreement for North America and Europe Reached on Zonegran". News Releases for Dainippon Pharmaceutical in 2004. Dainippon Sumitomo Pharma Co., Ltd. Archived from the original on 13 February 2006. Retrieved 12 November 2005.
  31. Dainippon Pharmaceutical Co. Ltd. (2005). "Dainippon Pharmaceutical and Eisai Conclude Agreement for the Development, Manufacture and Marketing of the Anti-Epileptic Agent Zonisamide in Asia". Dainippon Pharmaceutical News Releases for 2005. Dainippon Sumitomo Pharma Co., Ltd. Archived from the original on 22 February 2006. Retrieved 12 November 2005.
  32. Eisai Co. Ltd. (2005). "Eisai Announces Launch of Zonegran (zonisamide), Treatment For Epilepsy In the UK and Germany". Eisai 2005 News Releases. Eisai Co., Ltd. Archived from the original on 2005-10-28. Retrieved 12 November 2005.
  33. Iwata Y, Irie S, Uchida H, Suzuki T, Watanabe K, Iwashita S, Mimura M (April 2012). "Effects of zonisamide on tardive dyskinesia: a preliminary open-label trial". Journal of the Neurological Sciences. 315 (1–2): 137–40. doi:10.1016/j.jns.2011.12.010. PMID 22285275. S2CID 460261.
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  38. "Bupropion/zonisamide". AdisInsight. Springer. 20 May 2017. Archived from the original on 19 August 2017. Retrieved 19 August 2017.
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  • "Zonisamide". Drug Information Portal. U.S. National Library of Medicine.
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