Zonisamide Explained

Zonisamide, sold under the brand name Zonegran among others, is a medication used to treat the symptoms of epilepsy and Parkinson's disease.[1] [2] 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.[3] Despite this it is also sometimes used as a monotherapy for partial-onset seizures.[2]

In 2020, it was the 276th most commonly prescribed medication in the United States, with more than 1million prescriptions.[4] [5]

Medical uses

Epilepsy

Zonisamide is approved in the United States,[6] and United Kingdom[7] 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.[8] In Australia it is marketed as both an adjunctive therapy and monotherapy for partial seizures only.

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.[1] [2] In Japan, zonisamide has been used as an adjunct to levodopa treatment since 2009.[9] 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.[10] [11]

Adverse effects

Adverse effects by incidence:[12] [13] [14]

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

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

Incidence unknown

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.[16] Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis.[12]

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.[17]

Zonisamide is not known to inhibit cytochrome P450 enzymes when present at therapeutic concentrations.[18]

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). 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.[19] [20] [21] [22] [23]

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.[24]

Metabolism

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,[25] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.[26]

History

Zonisamide was discovered by Uno and colleagues in 1972[27] and launched by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) in 1989 as Excegran in Japan.[28] 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.[29] Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others)[30] and Europe (starting in Germany and the United Kingdom).[31]

Research

Tardive dyskinesia

In an open-label trial zonisamide attenuated the symptoms of tardive dyskinesia.[32]

Obesity

It has also been studied for obesity[33] with significant positive effects on body weight loss and there are three ongoing clinical trials for this indication.[34] [35] [36] It was to be sold, when combined with bupropion, under the brand name Empatic, until its development was discontinued.[37]

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.[2]

Bipolar depression

It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.[38] [39]

Notes and References

  1. Grover ND, Limaye RP, Gokhale DV, Patil TR . Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease . Indian Journal of Pharmacology . 45 . 6 . 547–55 . November–December 2013 . 24347760 . 3847242 . 10.4103/0253-7613.121266 . free .
  2. Web site: Zonisamide: Martindale: The Complete Drug Reference. Pharmaceutical Press. MedicinesComplete. 8 March 2016. 19 August 2017. Brayfield A . London, UK. 27 August 2021. https://web.archive.org/web/20210827200334/https://about.medicinescomplete.com/wp-content/uploads/2021/05/AMC-homepage-aboutMCsectionimage-May2021-896x364px.png. live.
  3. Book: Comprehensive Pharmacy Review. 2007. Williams & Wilkins. 9780781765619. 988. 6th. Souney P, Mutnick A, Shargel L . 869677890.
  4. Web site: The Top 300 of 2020 . ClinCalc . 7 October 2022.
  5. Web site: Zonisamide - Drug Usage Statistics . ClinCalc . 7 October 2022.
  6. Web site: Drug Approval Package: Zonegran (Zonisomide) NDA #20-789 . U.S. Food and Drug Administration (FDA) . 24 December 1999 . 20 July 2022 . 29 March 2021 . https://web.archive.org/web/20210329072036/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/020789_Zonegran.cfm . live .
  7. Web site: Eisai Ltd.. 2005. Zonegran Summary of Product Characteristics. electronic Medicines Compendium. Medicines.org.uk. 13 November 2005. https://web.archive.org/web/20051108005342/http://emc.medicines.org.uk/. 8 November 2005. dead.
  8. Web site: Dainippon Pharmaceutical Co., Ltd. . 2004 . EXCEGRAN Tablets 100 mg & EXCEGRAN Powder 20% . 13 March 2006 . https://web.archive.org/web/20070928063802/http://www.e-search.ne.jp/~jpr/PDF/DAINIP03.PDF . 2007-09-28 . dead .
  9. Murata M, Hasegawa K, Kanazawa I . Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study . Neurology . 68 . 1 . 45–50 . January 2007 . 17200492 . 10.1212/01.wnl.0000250236.75053.16 . 894677 .
  10. Grover ND, Limaye RP, Gokhale DV, Patil TR . Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease . Indian Journal of Pharmacology . 45 . 6 . 547–55 . 2013 . 24347760 . 3847242 . 10.4103/0253-7613.121266 . free .
  11. Matsunaga S, Kishi T, Iwata N . Combination Therapy with Zonisamide and Antiparkinson Drugs for Parkinson's Disease: A Meta-Analysis . Journal of Alzheimer's Disease . 56 . 4 . 1229–1239 . 2017 . 28157097 . 10.3233/JAD-161068 .
  12. Web site: Zonegran Product Information. TGA eBusiness Services. SciGen (Australia) Pty Ltd. 4 April 2013. 18 November 2013. PDF. 15 October 2018. https://web.archive.org/web/20181015231609/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-02002-3. live.
  13. Web site: Zonegran 25, 50, 100 mg Hard Capsules. electronic Medicines Compendium. 8 October 2013. 18 November 2013. Eisai Ltd. 12 January 2015. https://web.archive.org/web/20150112051257/http://www.medicines.org.uk/emc/medicine/16240/SPC/Zonegran+25,+50,+100+mg+Hard+Capsules/. live.
  14. Web site: zonisamide (Rx) - Zonegran. Medscape Reference. WebMD. 18 November 2013. 4 December 2013. https://web.archive.org/web/20131204211228/http://reference.medscape.com/drug/zonegran-zonisamide-343025. live.
  15. Karaduman AB, Kilic V, Atli-Eklioglu O, Baysal M, Aydogan-Kılıc G, Ucarcan S, Ilgin S . Reproductive toxic effects and possible mechanisms of zonisamide in male rats . Human & Experimental Toxicology . 38 . 12 . 1384–1396 . December 2019 . 31476894 . 10.1177/0960327119871094 . 201804214 . 2019HETox..38.1384K .
  16. Bookheimer S, Schrader LM, Rausch R, Sankar R, Engel J . Reduced anesthetization during the intracarotid amobarbital (Wada) test in patients taking carbonic anhydrase-inhibiting medications . Epilepsia . 46 . 2 . 236–43 . February 2005 . 15679504 . 10.1111/j.0013-9580.2005.23904.x . 20730895 . free .
  17. Nakasa H, Nakamura H, Ono S, Tsutsui M, Kiuchi M, Ohmori S, Kitada M . Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data . European Journal of Clinical Pharmacology . 54 . 2 . 177–83 . April 1998 . 9626925 . 10.1007/s002280050442 . 6508614 . free .
  18. Web site: Electronic Medicines Compendium (eMC) . Zonegran 25, 50, 100 mg Hard Capsules . 12 April 2017 . 14 February 2019 . https://web.archive.org/web/20190214194132/https://www.medicines.org.uk/emc/medicine/16240 . live .
  19. Book: Rossi S . 978-0-9805790-9-3 . Australian Medicines Handbook . Adelaide . The Australian Medicines Handbook Unit Trust . 2013 . 2013 .
  20. Leppik IE . Zonisamide: chemistry, mechanism of action, and pharmacokinetics . Seizure . 13 . Suppl 1 . S5–9; discussion S10 . December 2004 . 15511691 . 10.1016/j.seizure.2004.04.016 . 13458791 . free .
  21. Mimaki T, Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H . Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain . Medical Journal of Osaka University . 39 . 1–4 . 13–7 . March 1990 . 1369646 .
  22. Mimaki T, Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H . [3H]zonisamide binding in rat brain . Medical Journal of Osaka University . 39 . 1–4 . 19–22 . March 1990 . 1369647 .
  23. Ueda Y, Doi T, Tokumaru J, Willmore LJ . Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures . Brain Research. Molecular Brain Research . 116 . 1–2 . 1–6 . August 2003 . 12941455 . 10.1016/S0169-328X(03)00183-9 .
  24. Web site: Zonisamide. www.drugbank.ca. 2019-01-31. 2019-01-31. https://web.archive.org/web/20190131093517/https://www.drugbank.ca/drugs/DB00909. live.
  25. Ohmori S, Nakasa H, Asanome K, Kurose Y, Ishii I, Hosokawa M, Kitada M . Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells . Biochimica et Biophysica Acta (BBA) - General Subjects . 1380 . 3 . 297–304 . May 1998 . 9555064 . 10.1016/s0304-4165(97)00156-6 .
  26. Stiff DD, Robicheau JT, Zemaitis MA . Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative . Xenobiotica . 22 . 1 . 1–11 . January 1992 . 1615700 . 10.3109/00498259209053097 .
  27. Book: Shah J, Kent S, Daniel MC . René H, Levy RH, Brian SM, Perrucca E . Antiepileptic Drugs . 1972 . 2007-11-07 . Fifth . 2002-06-15 . Lippincott Williams & Wilkins . Philadelphia . 0-7817-2321-3 . Zonisamide . https://books.google.com/books?id=HAOY0qG-vAYC&q=zonisamide+synthesized&pg=PA873 . 873 . 2021-08-27 . https://web.archive.org/web/20210827200322/https://books.google.com/books?id=HAOY0qG-vAYC&q=zonisamide+synthesized&pg=PA873 . live .
  28. Web site: Dainippon Sumitomo Pharma Co. Ltd. . 2005 . Company History . Company Information . Dainippon Sumitomo Co., Ltd. . 12 November 2005 . https://web.archive.org/web/20060213055236/http://www.ds-pharma.co.jp/english/profile/history.html . 13 February 2006 . dead .
  29. Web site: 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 . 12 November 2005 . https://web.archive.org/web/20060213055615/http://www.ds-pharma.co.jp/english/news/dainippon_2004.html . 13 February 2006 . dead .
  30. Web site: 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. . 12 November 2005 . https://web.archive.org/web/20060222095009/http://www.ds-pharma.co.jp/english/news/dainippon_2005/no_002.html . 22 February 2006 . dead .
  31. Web site: 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. . 12 November 2005 . https://web.archive.org/web/20051028020742/http://www.eisai.co.jp/enews/index.html . 2005-10-28 . dead .
  32. Iwata Y, Irie S, Uchida H, Suzuki T, Watanabe K, Iwashita S, Mimura M . Effects of zonisamide on tardive dyskinesia: a preliminary open-label trial . Journal of the Neurological Sciences . 315 . 1–2 . 137–40 . April 2012 . 22285275 . 10.1016/j.jns.2011.12.010 . 460261 .
  33. Gadde KM, Franciscy DM, Wagner HR, Krishnan KR . Zonisamide for weight loss in obese adults: a randomized controlled trial . JAMA . 289 . 14 . 1820–5 . April 2003 . 12684361 . 10.1001/jama.289.14.1820 .
  34. Web site: University of Cincinnati . 2005 . Zonegran in the Treatment of Binge Eating Disorder Associated With Obesity . ClinicalTrials.gov . 2006-05-04 . 2006-10-13 . https://web.archive.org/web/20061013165457/http://clinicaltrials.gov/show/NCT00221442 . live .
  35. Web site: Tuscaloosa Research . Education Advancement Corporation . 2005 . Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial . ClinicalTrials.gov . 2006-05-04 . 2007-05-04 . https://web.archive.org/web/20070504062857/http://clinicaltrials.gov/show/NCT00203450 . live .
  36. Web site: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) . 2006 . Zonisamide for Weight Reduction in Obese Adults . ClinicalTrials.gov . 2006-05-04 . 2006-10-11 . https://web.archive.org/web/20061011172240/http://clinicaltrials.gov/show/NCT00275834 . live .
  37. Web site: Bupropion/zonisamide. AdisInsight. Springer. 20 May 2017. 19 August 2017. 19 August 2017. https://web.archive.org/web/20170819105130/http://adisinsight.springer.com/drugs/800024638. live.
  38. Web site: Zonegran. 2006-11-29. 2004. Loftus BD . 2008-10-23. https://web.archive.org/web/20081023172014/http://www.bellaireneurology.com/seizure/epil_trt_zonegran.html. live.
  39. Hasegawa H . Utilization of zonisamide in patients with chronic pain or epilepsy refractory to other treatments: a retrospective, open label, uncontrolled study in a VA hospital . Current Medical Research and Opinion . 20 . 5 . 577–80 . May 2004 . 15140322 . 10.1185/030079904125003313 . 43580909 .

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