Eslicarbazepine acetate

{{short description|Anticonvulsant medication}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | image = Eslicarbazepine acetate skeletal formula.svg | image_class = skin-invert-image | width = 175 | image2 = Eslicarbazepine acetate ball-and-stick model.png | image_class2 = bg-transparent | width2 = 190

| tradename = Aptiom, Zebinix, Exalief | Drugs.com = {{drugs.com|monograph|eslicarbazepine-acetate}} | pregnancy_AU = D | pregnancy_AU_comment = <ref name="Zebinix APM summary" /> | pregnancy_category = | licence_EU = yes | routes_of_administration = By mouth | ATC_prefix = N03 | ATC_suffix = AF04 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = <ref name="Zebinix APM summary">{{cite web | title = Zebinix | date = 9 June 2021 | website = Therapeutic Goods Administration (TGA) | url = https://www.tga.gov.au/apm-summary/zebinix | access-date = 6 September 2021 }}</ref> | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title = Summary Basis of Decision (SBD) for Aptiom | date = 23 October 2014 | website = Health Canada | url = https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=RDS00484&lang=en | access-date = 29 May 2022 }}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Aptiom FDA label" /> | legal_EU = Rx-only | legal_EU_comment = <ref name="Zebinix EPAR" /> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| bioavailability = | protein_bound = ~30%<ref>{{cite book | veditors = Dinnendahl V, Fricke U | title = Arzneistoff-Profile | location = Eschborn, Germany | volume = 4 | date = 2011 | publisher = Govi Pharmazeutischer Verlag | edition = 25 | isbn = 978-3-7741-9846-3 | language = German }}</ref> | metabolism = UGT (?) | metabolites = Eslicarbazepine (active), glucuronides (inactive), etc. | elimination_half-life = 10–20 hours | excretion = ~90% renal

| CAS_number = 236395-14-5 | CAS_supplemental = | PubChem = 179344 | DrugBank = DB09119 | ChemSpiderID = 156110 | UNII = BEA68ZVB2K | KEGG = D09612 | ChEBI = 87016 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 87992

| IUPAC_name = (''S'')-10-Acetoxy-10,11-dihydro-5''H''-dibenz[b,f]azepine-5-carboxamide | C=17 | H=16 | N=2 | O=3 | smiles = CC(=O)O[C@H]1Cc2ccccc2N(C(N)=O)c2ccccc21 | StdInChI=1S/C17H16N2O3/c1-11(20)22-16-10-12-6-2-4-8-14(12)19(17(18)21)15-9-5-3-7-13(15)16/h2-9,16H,10H2,1H3,(H2,18,21)/t16-/m0/s1 | StdInChIKey = QIALRBLEEWJACW-INIZCTEOSA-N }}

'''Eslicarbazepine acetate''' ('''ESL'''), sold under the brand names '''Aptiom''' and '''Zebinix''' among others, is an anticonvulsant medication approved for use in Europe and the United States as monotherapy or as additional therapy for partial-onset seizures epilepsy.<ref name="FDA">{{cite news | title = FDA approves Aptiom to treat seizures in adults | date = 8 November 2013 | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374358.htm | publisher = US FDA | access-date = 16 December 2019 | archive-date = 11 January 2017 | archive-url = https://web.archive.org/web/20170111161034/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374358.htm | url-status = dead }}</ref><ref name="Zebinix EPAR">{{cite web | title = Zebinix EPAR | date = 17 May 2018 | website = European Medicines Agency (EMA) | url = https://www.ema.europa.eu/en/medicines/human/EPAR/zebinix | access-date = 21 January 2021 }}</ref><ref name="Aptiom FDA label">{{cite web | title = Aptiom- eslicarbazepine acetate tablet Aptiom- eslicarbazepine acetate kit | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3d0c9554-eaeb-4694-8089-00133fcadce3 | access-date = 21 January 2021 }}</ref>

Similarly to oxcarbazepine, ESL behaves as a prodrug to (''S'')-(+)-licarbazepine.<ref name="Rogawski_2006">{{cite journal | vauthors = Rogawski MA | title = Diverse mechanisms of antiepileptic drugs in the development pipeline | journal = Epilepsy Research | volume = 69 | issue = 3 | pages = 273–294 | date = June 2006 | pmid = 16621450 | pmc = 1562526 | doi = 10.1016/j.eplepsyres.2006.02.004 }}</ref> As such, their mechanisms of action are identical.<ref name="Rogawski_2004">{{cite journal | vauthors = Rogawski MA, Löscher W | title = The neurobiology of antiepileptic drugs | journal = Nature Reviews. Neuroscience | volume = 5 | issue = 7 | pages = 553–564 | date = July 2004 | pmid = 15208697 | doi = 10.1038/nrn1430 | s2cid = 2201038 | url = https://zenodo.org/record/1233562 }}</ref>

==Contraindications== Eslicarbazepine acetate is contraindicated in people with second- or third-degree atrioventricular block, a type of heart block, in the Austria-Codex. However heart block is not mentioned as a contraindication by the US FDA.<ref>{{cite web | title = Medication Guide, sections 4 CONTRAINDICATIONS and 5 WARNINGS AND PRECAUTION | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022416s011lbl.pdf#page=25 | archive-url = https://web.archive.org/web/20201018155137/https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022416s011lbl.pdf#page=25 | url-status = dead | archive-date = October 18, 2020 | access-date = 2025-03-11 }}</ref> It is contraindicated for people who are hypersensitive to eslicarbazepine, oxcarbazepine or carbamazepine.<ref name="Austria-Codex">{{cite book | title = Austria-Codex | location = Vienna | year = 2015 | at = Zebinix | publisher = Österreichischer Apothekerverlag | language = German }}</ref>

==Adverse effects== Adverse effects are similar to oxcarbazepine. The most common ones (more than 10% of patients) are tiredness and dizziness. Other fairly common side effects (1 to 10%) include impaired coordination, gastrointestinal disorders such as diarrhoea, nausea and vomiting, rash (1.1%), and hyponatremia (low sodium blood levels, 1.2%).<ref name="Aptiom FDA label" /><ref name="Austria-Codex" /> There may also be an increased risk of suicidal thoughts.<ref name="eMC">{{cite web | title = Zebinix 800mg tablets | publisher = Electronic Medicines Compendium (eMC) | url = https://www.medicines.org.uk/emc/medicine/22376 | access-date = 12 April 2017 }}</ref>

==Overdose== Symptoms of overdosing are similar to adverse effects of standard doses: severe hyponatraemia, somnolence, uncoordinated/unsteady gait, hemiparesis (weakness of one side of the body), along with visual and gastrointestinal disturbances. No specific antidote is available. Eslicarbazepine and metabolites can be dialyzed.<ref name="Aptiom FDA label" /><ref name="Austria-Codex" />

== Interactions ==

Like oxcarbazepine, eslicarbazepine can reduce plasma levels of drugs that are metabolized by the liver enzymes CYP3A4 (verified in studies for simvastatin and the oral contraceptive levonorgestrel/ethinylestradiol) and UDP-glucuronosyltransferase, and increase plasma levels of drugs metabolized by CYP2C19.<ref name="Aptiom FDA label" /><ref name="Austria-Codex" />

Interaction studies have been conducted with a number of common anticonvulsants. Carbamazepine reduces blood plasma concentrations of eslicarbazepine, probably because it induces glucuronidation. This drug combination also increased the risk for diplopia, impaired coordination and dizziness in a clinical study. Phenytoin also reduces eslicarbazepine plasma concentrations, which may be due to increased glucuronidation of eslicarbazepine; and concomitant administration results in an increase in phenytoin serum concentrations, which is probably due to inhibition of CYP2C19.<ref name="eMC" /> Combinations with lamotrigine, topiramate, valproic acid or levetiracetam showed no significant interactions in studies, although eslicarbazepine has been shown to cause a minor reduction in lamotrigine levels.<ref name="Austria-Codex" /><ref name="eMC" />

==Pharmacology==

===Mechanism of action=== The active component, eslicarbazepine, has the same mechanism of action as oxcarbazepine (which is a prodrug for licarbazepine, the racemate of eslicarbazepine) and most likely the closely related carbamazepine. It stabilises the inactive state of voltage-gated sodium channels, allowing for less sodium to enter neural cells, which leaves them less excitable.<ref>{{cite journal | vauthors = Almeida L, Soares-da-Silva P | title = Eslicarbazepine acetate (BIA 2-093) | journal = Neurotherapeutics| volume = 4 | issue = 1 | pages = 88–96 | date = January 2007 | pmid = 17199020 | pmc = 7479690 | doi = 10.1016/j.nurt.2006.10.005 | doi-access = free }}</ref> According to some sources, it has not been shown conclusively that this is the actual mechanism.<ref name="Aptiom FDA label" /><ref name="Austria-Codex" />

===Pharmacokinetics=== Eslicarbazepine acetate is absorbed to at least 90% from the gut, independently of food intake. It is quickly metabolised to eslicarbazepine, so that the original substance cannot be detected in the bloodstream. Peak plasma levels of eslicarbazepine are reached after 2–3 (1–4) hours, and plasma protein binding is somewhat less than 40%. Biological half-life is 10 to 20 hours, and steady-state concentrations are reached after four to five days after start of the treatment.<ref name="Aptiom FDA label" /><ref name="Austria-Codex" /> Oxcarbazepine, for comparison, is also nearly completely absorbed from the gut, and peak plasma concentrations of licarbazepine are reached after 4.5 hours on average after oxcarbazepine intake. Plasma protein binding and half-life are of course the same.<ref>{{cite book | veditors = Jasek W | title = Austria-Codex | location = Vienna | pages = 8384 | year = 2007 | publisher = Österreichischer Apothekerverlag | edition = 62nd | isbn = 978-3-85200-181-4 | language = German }}</ref>

Other metabolites of ESL are the less active (''R'')-(−)-licarbazepine (5%; the stereoisomer of eslicarbazepine), the pharmacologically active oxcarbazepine (1%), and inactive glucuronides of all of these substances. The drug is excreted mainly via the urine, of which two thirds are in the form of eslicarbazepine and one third in the form of eslicarbazepine glucuronide. The other metabolites only account for a few percent of the excreted drug.<ref name="Aptiom FDA label" /><ref name="Austria-Codex" />

===Pharmacogenomics=== Persons with certain genetic variations in human leukocyte antigens (HLAs) are under increased risk of developing skin reactions such as acute generalized exanthematous pustulosis (AGEP), but also severe ones such as Stevens–Johnson and DRESS syndrome, under treatment with carbamazepine and drugs with related chemical structures. This is true for the HLA-A*3101 allele, which occurs in 2 to 5% of Europeans and 10% of Japanese people, and the HLA-B*1502 allele, which is mainly found in people of Asian descent. Theoretically, this may also apply to ESL.<ref name="Austria-Codex" />

==Chemistry== As the name suggests, eslicarbazepine acetate is the acetate ester prodrug of eslicarbazepine. Eslicarbazepine itself is the pharmacologically more active of the two stereoisomers of licarbazepine.<ref name="Aptiom FDA label" /> More specifically, it is (''S'')-(+)-licarbazepine.

;Related drugs and active metabolites for comparison: <gallery class="center skin-invert-image"> File:Eslicarbazepine structure.svg|Eslicarbazepine, the active metabolite of ESL File:Oxcarbazepine.svg|Oxcarbazepine File:Licarbazepine structure.svg|Licarbazepine, the active metabolite of oxcarbazepine File:Carbamazepine.svg|Carbamazepine </gallery>

==History== Eslicarbazepine acetate was developed by the Portuguese pharmaceutical company Bial. In early 2009, Bial sold the marketing rights in Europe to the Japanese company Eisai.<ref>{{cite news | title = Eisai and Bial Announce Partnership Agreement for the European Commercialisation of the Novel Once Daily Anti-Epileptic Zebinix | date = 19 February 2009 | url = http://www.prnewswire.co.uk/news-releases/eisai-and-bial-announce-partnership-agreement-for-the-european-commercialisation-of-the-novel-once-daily-anti-epileptic-zebinixr-153037325.html | publisher = PR Newswire }}</ref> The drug was approved in the European Union in April 2009 under the trade names ''Zebinix'' and ''Exalief'', but was marketed only under the first name.<ref>{{cite web | title = Summary of Product Characteristics for Zebinix | pages = 14 | url = http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000988/WC500047225.pdf | publisher = European Medicines Agency | access-date = 2016-05-22 | archive-date = 2018-09-20 | archive-url = https://web.archive.org/web/20180920114125/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000988/WC500047225.pdf | url-status = dead }}</ref><ref>{{cite web | title = Exalief (eslicarbazepine acetate): Expiry of the marketing authorisation in the European Union | date = 30 July 2012 | url = http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2012/08/WC500130787.pdf | publisher = European Medicines Agency | access-date = 22 May 2016 | archive-date = 20 September 2018 | archive-url = https://web.archive.org/web/20180920114129/http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2012/08/WC500130787.pdf | url-status = dead }}</ref> In the US it is marketed by Sunovion (formerly Sepracor) and was approved in November 2013.<ref name="FDA" />

In May 2025, the medication's primary US patents expired, and generic versions of the medication became available as a generic drug.<ref>{{Cite web | title = Generic Aptiom Availability | url = https://www.drugs.com/availability/generic-aptiom.html | access-date = 2025-08-16 | website = Drugs.com | language = en }}</ref> This lowered the all-discounted retail cost from thousands of dollars to as little as $67.25 for the consumer - even more significant as alternative studied treatments such as trigeminal neuralgia are excluded from most US insurance coverage, due to Bial/Sunovion not submitting approval for additional treatments to the FDA.<ref>{{Cite web | title = Eslicarbazepine Prices, Coupons & Savings Tips - GoodRx | url = https://www.goodrx.com/eslicarbazepine | archive-url = https://web.archive.org/web/20250619070442/https://www.goodrx.com/eslicarbazepine | archive-date = 2025-06-19 | access-date = 2025-08-16 | website = www.goodrx.com | language = en | url-status = live }}</ref>

==Research== Studies for the use of ESL as an anticonvulsant for children are under way {{as of|2016|lc=on}}.<ref>{{ClinicalTrialsGov|NCT00988156|Eslicarbazepine Acetate (BIA 2 093) as Therapy for Refractory Partial Seizures in Children}}</ref>

Like oxcarbazepine, ESL has potential uses for the treatment of trigeminal neuralgia<ref>{{cite journal | vauthors = Sanchez-Larsen A, Sopelana D, Diaz-Maroto I, Perona-Moratalla AB, Gracia-Gil J, García-Muñozguren S, Palazón-García E, Segura T | title = Assessment of efficacy and safety of eslicarbazepine acetate for the treatment of trigeminal neuralgia | journal = European Journal of Pain | volume = 22 | issue = 6 | pages = 1080–1087 | date = July 2018 | pmid = 29369456 | doi = 10.1002/ejp.1192 }}</ref> and bipolar disorder. A 2015 assessment showed no statistical difference to placebo for the latter disorder.<ref>{{cite journal | vauthors = Grunze H, Kotlik E, Costa R, Nunes T, Falcão A, Almeida L, Soares-da-Silva P | title = Assessment of the efficacy and safety of eslicarbazepine acetate in acute mania and prevention of recurrence: experience from multicentre, double-blind, randomised phase II clinical studies in patients with bipolar disorder I | journal = Journal of Affective Disorders | volume = 174 | pages = 70–82 | date = March 2015 | pmid = 25484179 | doi = 10.1016/j.jad.2014.11.013 }}</ref>

== References == {{Reflist}}

== External links == * {{cite web | title = Eslicarbazepine acetate | url = https://druginfo.nlm.nih.gov/drugportal/name/Eslicarbazepine%20acetate | archive-url = https://web.archive.org/web/20211031190142/https://druginfo.nlm.nih.gov/drugportal/name/Eslicarbazepine%20acetate | url-status = dead | archive-date = October 31, 2021 | publisher = U.S. National Library of Medicine | work = Drug Information Portal }}

{{DEFAULTSORT:Eslicarbazepine Acetate}} Category:Acetate esters Category:Anticonvulsants Category:CYP3A4 inducers Category:Dibenzazepines Category:Enantiopure drugs Category:Portuguese inventions Category:Ureas