Zonisamide

Zonisamide is approved in the United States,{{cite web | title=Drug Approval Package: Zonegran (Zonisomide) NDA #20-789 | website=U.S. Food and Drug Administration (FDA) | date=24 December 1999 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/020789_Zonegran.cfm | access-date=20 July 2022 | archive-date=29 March 2021 | archive-url=https://web.archive.org/web/20210329072036/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/020789_Zonegran.cfm | url-status=dead }} and United Kingdom{{cite web| author=Eisai Ltd.| year=2005| title=Zonegran Summary of Product Characteristics| work=electronic Medicines Compendium| publisher=Medicines.org.uk| access-date=13 November 2005| url=http://emc.medicines.org.uk/| archive-url=https://web.archive.org/web/20051108005342/http://emc.medicines.org.uk/| archive-date=8 November 2005| url-status=dead}} 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.{{cite web | author = Dainippon Pharmaceutical Co., Ltd. | year = 2004 | url = http://www.e-search.ne.jp/~jpr/PDF/DAINIP03.PDF | title = EXCEGRAN Tablets 100 mg & EXCEGRAN Powder 20% | access-date = 13 March 2006 | archive-url = https://web.archive.org/web/20070928063802/http://www.e-search.ne.jp/~jpr/PDF/DAINIP03.PDF | archive-date = 2007-09-28 | url-status = dead }} In Australia it is marketed as both an adjunctive therapy and monotherapy for partial seizures only.

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. In Japan, zonisamide has been used as an adjunct to levodopa treatment since 2009.{{cite journal | vauthors = Murata M, Hasegawa K, Kanazawa I | title = Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study | journal = Neurology | volume = 68 | issue = 1 | pages = 45–50 | date = January 2007 | pmid = 17200492 | doi = 10.1212/01.wnl.0000250236.75053.16 | s2cid = 894677 }} 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.{{cite journal | vauthors = Grover ND, Limaye RP, Gokhale DV, Patil TR | title = Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease | journal = Indian Journal of Pharmacology | volume = 45 | issue = 6 | pages = 547–55 | date = 2013 | pmid = 24347760 | pmc = 3847242 | doi = 10.4103/0253-7613.121266 | doi-access = free }}{{cite journal | vauthors = Matsunaga S, Kishi T, Iwata N | title = Combination Therapy with Zonisamide and Antiparkinson Drugs for Parkinson's Disease: A Meta-Analysis | journal = Journal of Alzheimer's Disease | volume = 56 | issue = 4 | pages = 1229–1239 | date = 2017 | pmid = 28157097 | doi = 10.3233/JAD-161068 }}

Adverse effects by incidence:{{cite web|title=Zonegran Product Information|work=TGA eBusiness Services|publisher=SciGen (Australia) Pty Ltd|date=4 April 2013|access-date=18 November 2013|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-02002-3|format=PDF|archive-date=15 October 2018|archive-url=https://web.archive.org/web/20181015231609/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-02002-3|url-status=live}}{{cite web|title=Zonegran 25, 50, 100 mg Hard Capsules|work=electronic Medicines Compendium|date=8 October 2013|access-date=18 November 2013|url=http://www.medicines.org.uk/emc/medicine/16240/SPC/Zonegran+25%2c+50%2c+100+mg+Hard+Capsules/|publisher=Eisai Ltd|archive-date=12 January 2015|archive-url=https://web.archive.org/web/20150112051257/http://www.medicines.org.uk/emc/medicine/16240/SPC/Zonegran+25,+50,+100+mg+Hard+Capsules/|url-status=live}}{{cite web|title=zonisamide (Rx) - Zonegran|work=Medscape Reference|publisher=WebMD|access-date=18 November 2013|url=http://reference.medscape.com/drug/zonegran-zonisamide-343025|archive-date=4 December 2013|archive-url=https://web.archive.org/web/20131204211228/http://reference.medscape.com/drug/zonegran-zonisamide-343025|url-status=live}}

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

{{colbegin|colwidth=18em}}

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

{{colend}}

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

{{colbegin|colwidth=22em}}

• Ecchymosis
• Hypersensitivity
• Affect lability
• Anxiety
• Insomnia
• Psychotic disorder
• Bradyphrenia
• Disturbance in attention
• Nystagmus
• Paraesthesia
• Speech disorder
• Tremor
• Abdominal pain
• Constipation
• Diarrhoea
• Dyspepsia
• Nausea
• Rash
• Pruritus
• Alopecia
• Nephrolithiasis
• Fatigue
• Influenza-like illness
• Pyrexia
• Oedema peripheral
• Weight loss

{{colend}}

Incidence unknown

• Reproductive toxic effects{{cite journal | vauthors = Karaduman AB, Kilic V, Atli-Eklioglu O, Baysal M, Aydogan-Kılıc G, Ucarcan S, Ilgin S | title = Reproductive toxic effects and possible mechanisms of zonisamide in male rats | journal = Human & Experimental Toxicology | volume = 38 | issue = 12 | pages = 1384–1396 | date = December 2019 | pmid = 31476894 | doi = 10.1177/0960327119871094 | s2cid = 201804214 | bibcode = 2019HETox..38.1384K }}

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.{{cite journal | vauthors = Bookheimer S, Schrader LM, Rausch R, Sankar R, Engel J | title = Reduced anesthetization during the intracarotid amobarbital (Wada) test in patients taking carbonic anhydrase-inhibiting medications | journal = Epilepsia | volume = 46 | issue = 2 | pages = 236–43 | date = February 2005 | pmid = 15679504 | doi = 10.1111/j.0013-9580.2005.23904.x | s2cid = 20730895 | doi-access = free }} Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis.

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.{{cite journal | vauthors = Nakasa H, Nakamura H, Ono S, Tsutsui M, Kiuchi M, Ohmori S, Kitada M | title = Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data | journal = European Journal of Clinical Pharmacology | volume = 54 | issue = 2 | pages = 177–83 | date = April 1998 | pmid = 9626925 | doi = 10.1007/s002280050442 | s2cid = 6508614 | doi-access = free }}

Zonisamide is not known to inhibit cytochrome P450 enzymes when present at therapeutic concentrations.{{cite web | publisher=Electronic Medicines Compendium (eMC) | title=Zonegran 25, 50, 100 mg Hard Capsules | url=https://www.medicines.org.uk/emc/medicine/16240 | access-date=12 April 2017 | archive-date=14 February 2019 | archive-url=https://web.archive.org/web/20190214194132/https://www.medicines.org.uk/emc/medicine/16240 | url-status=live }}

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.{{cite book | veditors = Rossi S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}{{cite journal | vauthors = Leppik IE | title = Zonisamide: chemistry, mechanism of action, and pharmacokinetics | journal = Seizure | volume = 13 | issue = Suppl 1 | pages = S5–9; discussion S10 | date = December 2004 | pmid = 15511691 | doi = 10.1016/j.seizure.2004.04.016 | s2cid = 13458791 | doi-access = free }}{{cite journal | vauthors = Mimaki T, Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H | title = Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain | journal = Medical Journal of Osaka University | volume = 39 | issue = 1–4 | pages = 13–7 | date = March 1990 | pmid = 1369646 }}{{cite journal | vauthors = Mimaki T, Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H | title = [3H]zonisamide binding in rat brain | journal = Medical Journal of Osaka University | volume = 39 | issue = 1–4 | pages = 19–22 | date = March 1990 | pmid = 1369647 }}{{cite journal | vauthors = Ueda Y, Doi T, Tokumaru J, Willmore LJ | title = Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures | journal = Brain Research. Molecular Brain Research | volume = 116 | issue = 1–2 | pages = 1–6 | date = August 2003 | pmid = 12941455 | doi = 10.1016/S0169-328X(03)00183-9 }}

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.{{cite web|url=https://www.drugbank.ca/drugs/DB00909|title=Zonisamide|website=www.drugbank.ca|access-date=2019-01-31|archive-date=2019-01-31|archive-url=https://web.archive.org/web/20190131093517/https://www.drugbank.ca/drugs/DB00909|url-status=live}}

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,{{cite journal | vauthors = Ohmori S, Nakasa H, Asanome K, Kurose Y, Ishii I, Hosokawa M, Kitada M | title = Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1380 | issue = 3 | pages = 297–304 | date = May 1998 | pmid = 9555064 | doi = 10.1016/s0304-4165(97)00156-6 }} to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.{{cite journal | vauthors = Stiff DD, Robicheau JT, Zemaitis MA | title = Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative | journal = Xenobiotica | volume = 22 | issue = 1 | pages = 1–11 | date = January 1992 | pmid = 1615700 | doi = 10.3109/00498259209053097 }}

Zonisamide was discovered by Uno and colleagues in 1972{{cite book |vauthors=Shah J, Kent S, Daniel MC |veditors=René H, Levy RH, Brian SM, Perrucca E |title=Antiepileptic Drugs |orig-year=1972 |access-date=2007-11-07 |edition=Fifth |date=2002-06-15 |publisher=Lippincott Williams & Wilkins |location=Philadelphia |isbn=0-7817-2321-3 |chapter=Zonisamide |chapter-url=https://books.google.com/books?id=HAOY0qG-vAYC&q=zonisamide+synthesized&pg=PA873 |page=873 |archive-date=2021-08-27 |archive-url=https://web.archive.org/web/20210827200322/https://books.google.com/books?id=HAOY0qG-vAYC&q=zonisamide+synthesized&pg=PA873 |url-status=live }} and launched by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) in 1989 as Excegran in Japan.{{cite web |author=Dainippon Sumitomo Pharma Co. Ltd. |year=2005 |title=Company History |work=Company Information |publisher=Dainippon Sumitomo Co., Ltd. |url=http://www.ds-pharma.co.jp/english/profile/history.html |access-date=12 November 2005 |archive-url=https://web.archive.org/web/20060213055236/http://www.ds-pharma.co.jp/english/profile/history.html |archive-date=13 February 2006 |url-status=dead }} 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.{{cite web |author=Dainippon Pharmaceutical Co. Ltd. |year=2004 |url=http://www.ds-pharma.co.jp/english/news/dainippon_2004.html |title=Transfer of Rights Agreement for North America and Europe Reached on Zonegran |work=News Releases for Dainippon Pharmaceutical in 2004 |publisher=Dainippon Sumitomo Pharma Co., Ltd |access-date=12 November 2005 |archive-url=https://web.archive.org/web/20060213055615/http://www.ds-pharma.co.jp/english/news/dainippon_2004.html |archive-date=13 February 2006 |url-status=dead }} Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others){{cite web |author=Dainippon Pharmaceutical Co. Ltd. |year=2005 |title=Dainippon Pharmaceutical and Eisai Conclude Agreement for the Development, Manufacture and Marketing of the Anti-Epileptic Agent Zonisamide in Asia |work=Dainippon Pharmaceutical News Releases for 2005 |publisher=Dainippon Sumitomo Pharma Co., Ltd. |url=http://www.ds-pharma.co.jp/english/news/dainippon_2005/no_002.html |access-date=12 November 2005 |archive-url=https://web.archive.org/web/20060222095009/http://www.ds-pharma.co.jp/english/news/dainippon_2005/no_002.html |archive-date=22 February 2006 |url-status=dead }} and Europe (starting in Germany and the United Kingdom).{{cite web | author=Eisai Co. Ltd. | year=2005 | title=Eisai Announces Launch of Zonegran (zonisamide), Treatment For Epilepsy In the UK and Germany | work=Eisai 2005 News Releases | publisher=Eisai Co., Ltd. | url=http://www.eisai.co.jp/enews/index.html | access-date=12 November 2005 | archive-url=https://web.archive.org/web/20051028020742/http://www.eisai.co.jp/enews/index.html | archive-date=2005-10-28 | url-status=dead }}

In an open-label trial zonisamide attenuated the symptoms of tardive dyskinesia.{{cite journal | vauthors = Iwata Y, Irie S, Uchida H, Suzuki T, Watanabe K, Iwashita S, Mimura M | title = Effects of zonisamide on tardive dyskinesia: a preliminary open-label trial | journal = Journal of the Neurological Sciences | volume = 315 | issue = 1–2 | pages = 137–40 | date = April 2012 | pmid = 22285275 | doi = 10.1016/j.jns.2011.12.010 | s2cid = 460261 }}

It has also been studied for obesity{{cite journal | vauthors = Gadde KM, Franciscy DM, Wagner HR, Krishnan KR | title = Zonisamide for weight loss in obese adults: a randomized controlled trial | journal = JAMA | volume = 289 | issue = 14 | pages = 1820–5 | date = April 2003 | pmid = 12684361 | doi = 10.1001/jama.289.14.1820 | doi-access = }} with significant positive effects on body weight loss and there are three ongoing clinical trials for this indication.{{cite web | author = University of Cincinnati | year = 2005 | title = Zonegran in the Treatment of Binge Eating Disorder Associated With Obesity | work = ClinicalTrials.gov | url = http://clinicaltrials.gov/show/NCT00221442 | access-date = 2006-05-04 | archive-date = 2006-10-13 | archive-url = https://web.archive.org/web/20061013165457/http://clinicaltrials.gov/show/NCT00221442 | url-status = live }}{{cite web | author1 = Tuscaloosa Research | author2 = Education Advancement Corporation | year = 2005 | title = Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial | work = ClinicalTrials.gov | url = http://clinicaltrials.gov/show/NCT00203450 | access-date = 2006-05-04 | archive-date = 2007-05-04 | archive-url = https://web.archive.org/web/20070504062857/http://clinicaltrials.gov/show/NCT00203450 | url-status = live }}{{cite web | author = National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | year = 2006 | title = Zonisamide for Weight Reduction in Obese Adults | work = ClinicalTrials.gov | url = http://clinicaltrials.gov/show/NCT00275834 | access-date = 2006-05-04 | archive-date = 2006-10-11 | archive-url = https://web.archive.org/web/20061011172240/http://clinicaltrials.gov/show/NCT00275834 | url-status = live }} It was to be sold, when combined with bupropion, under the brand name Empatic, until its development was discontinued.{{cite web|title=Bupropion/zonisamide|website=AdisInsight|publisher=Springer|date=20 May 2017|access-date=19 August 2017|url=http://adisinsight.springer.com/drugs/800024638|archive-date=19 August 2017|archive-url=https://web.archive.org/web/20170819105130/http://adisinsight.springer.com/drugs/800024638|url-status=live}}

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.

It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.{{Cite web|url=http://www.bellaireneurology.com/seizure/epil_trt_zonegran.html|title=Zonegran|access-date=2006-11-29|year=2004| vauthors = Loftus BD |archive-date=2008-10-23|archive-url=https://web.archive.org/web/20081023172014/http://www.bellaireneurology.com/seizure/epil_trt_zonegran.html|url-status=live}}{{cite journal | vauthors = Hasegawa H | title = Utilization of zonisamide in patients with chronic pain or epilepsy refractory to other treatments: a retrospective, open label, uncontrolled study in a VA hospital | journal = Current Medical Research and Opinion | volume = 20 | issue = 5 | pages = 577–80 | date = May 2004 | pmid = 15140322 | doi = 10.1185/030079904125003313 | s2cid = 43580909 }}

{{Reflist}}

{{Anticonvulsants}}

{{Channelergics}}

{{Portal bar | Medicine}}

Category:Anticonvulsants

Category:Benzisoxazoles

Category:Calcium channel blockers

Category:Carbonic anhydrase inhibitors

Category:Sodium channel blockers

Category:Sulfonamides