Brivaracetam

{{Short description|Medication used to treat seizures}} {{Use dmy dates|date=April 2023}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | imageL = Brivaracetam.svg | image_classL = skin-invert-image | widthL = 130 | alt = | caption = | imageR = Brivaracetam ball-and-stick model from xtal 2018.png | image_classR = bg-transparent | widthR = 110

| pronounce = {{IPAc-en|ˌ|b|r|ɪ|v|ə|ˈ|r|æ|s|ə|t|əm}} {{respell|BRIV|ə|RASS|ə-təm}} | tradename = Briviact, Nubriveo, Brivajoy | Drugs.com = {{Drugs.com|monograph|brivaracetam}} | MedlinePlus = a616027 | DailyMedID = Brivaracetam | pregnancy_AU = B3 | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth, intravenous | class = | ATC_prefix = N03 | ATC_suffix = AX23 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2016 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2016 | access-date=10 April 2023 | archive-date=10 April 2023 | archive-url=https://web.archive.org/web/20230410065503/https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2016 | url-status=live }}</ref> | legal_BR = C1 | legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}</ref> | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Health Canada New Drug Authorizations: 2016 Highlights | website=Health Canada | date=14 March 2017 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-canada-new-drug-authorizations-2016-highlights.html | access-date=7 April 2024}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Schedule V | legal_US_comment = <ref name="Briviact FDA label" /> | legal_EU = Rx-only | legal_EU_comment = | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| CAS_number_Ref = {{cascite|correct|chemspider}} | CAS_number = 357336-20-0 | CAS_supplemental = | PubChem = 9837243 | IUPHAR_ligand = | DrugBank = DB05541 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 8012964 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = U863JGG2IA | KEGG = D08879 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 133013 | ChEMBL = 607400 | ChEMBL_Ref = {{ebicite|correct|EBI}} | NIAID_ChemDB = | PDB_ligand = | synonyms =

| IUPAC_name = (2''S'')-2-[(4''R'')-2-oxo-4-propylpyrrolidin-1-yl] butanamide | C = 11 | H = 20 | N = 2 | O = 2 | SMILES = O=C(N)[C@@H](N1C(=O)C[C@@H](CCC)C1)CC | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C11H20N2O2/c1-3-5-8-6-10(14)13(7-8)9(4-2)11(12)15/h8-9H,3-7H2,1-2H3,(H2,12,15)/t8-,9+/m1/s1 | StdInChI_comment = | StdInChIKey = MSYKRHVOOPPJKU-BDAKNGLRSA-N | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | density = | density_notes = | melting_point = 72 | melting_high = 77 | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = [α]<sub>D</sub> −60° }}

'''Brivaracetam''', sold under the brand name '''Briviact''' among others, is a chemical analog of levetiracetam, a racetam derivative with anticonvulsant (antiepileptic) properties.<ref>{{cite journal | vauthors = von Rosenstiel P | title = Brivaracetam (UCB 34714) | journal = Neurotherapeutics | volume = 4 | issue = 1 | pages = 84–87 | date = January 2007 | pmid = 17199019 | pmc = 7479692 | doi = 10.1016/j.nurt.2006.11.004 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Malawska B, Kulig K | title = Brivaracetam UCB | journal = Current Opinion in Investigational Drugs | volume = 6 | issue = 7 | pages = 740–746 | date = July 2005 | pmid = 16044671 }}</ref> It has been approved since 2016. It is marketed by the pharmaceutical company UCB.<ref name=ucb>{{cite web |url=https://www.ucb.com/our-products/Products/briviact%c2%ae-epilepsy |title=Briviact Product Page |publisher=UCB |access-date=1 January 2020 |archive-date=19 September 2020 |archive-url=https://web.archive.org/web/20200919162915/https://www.ucb.com/our-products/Products/briviact%C2%AE-epilepsy |url-status=live }}</ref><ref>{{cite web |url=https://www.drugbank.ca/drugs/DB05541 |title=Brivaracetam |publisher=DrugBank |access-date=1 January 2020 |archive-date=10 January 2020 |archive-url=https://web.archive.org/web/20200110232215/https://www.drugbank.ca/drugs/DB05541 |url-status=live }}</ref> It is used to treat partial-onset seizures with or without secondary generalisation, in combination with other antiepileptic drugs.

==Medical uses== Brivaracetam is used to treat partial-onset seizures with or without secondary generalisation, in combination with other antiepileptic drugs. Efficacy and tolerability is comparable in general and Intellectual Disability populations.<ref>{{cite journal | vauthors = Allard J, Henley W, Sellers A, O'Shaughnessy E, Thomson O, McLean B, Parrett M, Rajakulendran S, Watkins L, Maguire M, Ellawela S, Tittensor P, Sen A, Mohanraj R, Bagary M, Ram S, Brown A, Shankar R | title = Efficacy and tolerability of Brivaracetam in people with intellectual disability compared to those without intellectual disability | journal = Epilepsy & Behavior | volume = 158 | article-number = 109906 | date = September 2024 | pmid = 38936308 | doi = 10.1016/j.yebeh.2024.109906 | doi-access = free }}</ref> No data are available for its effectiveness and safety in people younger than 16 years of age.<ref name="Drugs.com">{{Drugs.com|parent|Briviact}} Drugs.com</ref><ref name="EMA" /><ref>{{cite journal | vauthors = Bresnahan R, Panebianco M, Marson AG | title = Brivaracetam add-on therapy for drug-resistant epilepsy | journal = The Cochrane Database of Systematic Reviews | volume = 2022 | issue = 3 | article-number = CD011501 | date = March 2022 | pmid = 35285519 | pmc = 8919456 | doi = 10.1002/14651858.CD011501.pub3 }}</ref>

==Adverse effects== The most common adverse effects include sleepiness, dizziness, nausea and vomiting. More rarely, coordination problems and changes in behaviour (such as severe depression, aggression, hostility, impatience, rage, suicidal ideation, etc.) can occur.<ref name="Drugs.com" /><ref name="EMA" />

No clinically relevant differences in adverse effects incidence for the starting doses were observed, except for a dose–response relationship for somnolence and fatigue.<ref name=":0">{{cite journal | vauthors = Klein P, Diaz A, Gasalla T, Whitesides J | title = A review of the pharmacology and clinical efficacy of brivaracetam | journal = Clinical Pharmacology | volume = 10 | pages = 1–22 | date = 31 December 2018 | pmid = 29403319 | pmc = 5783144 | doi = 10.2147/CPAA.S114072 | doi-access = free }}</ref>

== Interactions ==

Coadministration of brivaracetam with carbamazepine may increase exposure to carbamazepine-epoxide, the active metabolite of carbamazepine, and could theoretically lead to reduced tolerability. Coadministration of brivaracetam with phenytoin may increase phenytoin levels. Coadministration of other antiseizure drugs are unlikely to affect brivaracetam exposure. Brivaracetam provides no added therapeutic benefit when administered in conjunction with levetiracetam that acts on the same protein.<ref>{{cite journal | vauthors = Rolan P, Sargentini-Maier ML, Pigeolet E, Stockis A | title = The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men | journal = British Journal of Clinical Pharmacology | volume = 66 | issue = 1 | pages = 71–75 | date = July 2008 | pmid = 18341673 | pmc = 2485265 | doi = 10.1111/j.1365-2125.2008.03158.x | author-link1 = Paul Rolan }}</ref>

No pharmacokinetic interaction was observed between single-dose 200mg brivaracetam and 0.6g/L ethanol in healthy subjects. However, brivaracetam approximately doubled the effect of alcohol on psychomotor function, attention and memory. Alcohol use while under brivaracetam treatment is not recommended.<ref name="EMA" />

==Pharmacology==

===Mechanism of action=== Brivaracetam is believed to act by binding to the ubiquitous synaptic vesicle glycoprotein 2A (SV2A), like levetiracetam, but with 20-fold greater affinity.<ref>{{cite journal | vauthors = Rogawski MA, Bazil CW | title = New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels | journal = Current Neurology and Neuroscience Reports | volume = 8 | issue = 4 | pages = 345–352 | date = July 2008 | pmid = 18590620 | pmc = 2587091 | doi = 10.1007/s11910-008-0053-7 }}</ref><ref name="AC">{{cite book|title=Austria-Codex| veditors = Haberfeld H |publisher= Österreichischer Apothekerverlag |location=Vienna|year=2015|language=de}}</ref> There is some evidence that racetams including levetiracetam and brivaracetam access the luminal side of recycling synaptic vesicles during vesicular endocytosis. They may reduce excitatory neurotransmitter release and enhance synaptic depression during trains of high-frequency activity, such as is believed to occur during epileptic activity.<ref>{{cite journal | vauthors = Rogawski MA | title = A New SV2A Ligand for Epilepsy | journal = Cell | volume = 167 | issue = 3 | page = 587 | date = October 2016 | pmid = 27768878 | doi = 10.1016/j.cell.2016.09.057 | doi-access = free }}</ref>

===Pharmacokinetics=== Brivaracetam exhibits linear pharmacokinetics over a wide dose range, is rapidly and completely absorbed after oral administration, has an elimination half-life of seven to eight hours, and has plasma protein binding of less than 20%. It is extensively metabolized (>90%), primarily via hydrolysis of the acetamide group, and secondarily through hydroxylation mediated by the liver enzyme CYP2C19. The three major metabolites (hydroxy, acid, and hydroxyacid) are pharmacologically inactive. Brivaracetam is eliminated as urinary metabolites, with over 95% of a radioactive test dose recovered in the urine within 72 hours, including only 8.6% as unchanged brivaracetam.<ref>{{cite journal | vauthors = Sargentini-Maier ML, Espié P, Coquette A, Stockis A | title = Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A ligand, in healthy subjects | journal = Drug Metabolism and Disposition | volume = 36 | issue = 1 | pages = 36–45 | date = January 2008 | pmid = 17908923 | doi = 10.1124/dmd.107.017129 | s2cid = 14972675 }}</ref>

Brivaracetam can be interchanged with levetiracetam as follows: 50 mg Brivaracetam by 1,000 mg levetiracetam, 100 mg of brivaracetam by 2,000 mg levetiracetam, and 200 mg of brivaracetam by 3,000 mg levetiracetam.<ref name="asadi">{{cite journal | vauthors = Asadi-Pooya AA, Patel AA, Trinka E, Mazurkiewicz-Beldzinska M, Cross JH, Welty TE | title = Recommendations for treatment strategies in people with epilepsy during times of shortage of antiseizure medications | journal = Epileptic Disorders | volume = 24 | issue = 5 | pages = 751–764 | date = October 2022 | pmid = 35894673 | doi = 10.1684/epd.2022.1468 | doi-access = free }}</ref>

=== Pharmacogenetics === As noted above, brivaracetam is primarily metabolized by hydrolysis, via amidase enzymes, to an inactive metabolite. To a lesser extent, it is also metabolized by a minor metabolic pathway via CYP2C19-dependent hydroxylation. Individuals who have no CYP2C19 enzyme activity, "CYP2C19 poor metabolizers", will have a greater exposure to standard doses of brivaracetam. Because they are less able to metabolize the drug to its inactive form for excretion, they may have an increased risk of adverse effects. The most common adverse effects of brivaracetam therapy include sedation, fatigue, dizziness, and nausea.<ref>{{cite book | title=Medical Genetics Summaries | chapter=Brivaracetam Therapy and CYP2C19 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK500036/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=National Center for Biotechnology Information (NCBI) | year=2018 | pmid=29763212 | id=Bookshelf ID: NBK500036 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ | access-date=7 February 2020 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026145821/https://www.ncbi.nlm.nih.gov/books/NBK61999/ | url-status=live }}</ref> The FDA-approved drug label for brivaracetam states that patients who are CYPC19 poor metabolizers, or are taking medicines that inhibit CYP2C19, may require a dose reduction.<ref name="Briviact FDA label">{{Cite web|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3cf2f439-0e97-443e-8e33-25ecef616f6c|title=Briviact- brivaracetam tablet, film coated Briviact- brivaracetam solution Briviact- brivaracetam injection, suspension| work = DailyMed | publisher = U.S. National Library of Medicine |access-date=25 January 2019 |date=15 May 2018 |archive-date=21 March 2021 |archive-url= https://web.archive.org/web/20210321141215/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3cf2f439-0e97-443e-8e33-25ecef616f6c |url-status=live }}</ref>

==Chemical and physical properties== class=skin-invert-image|thumb|left|upright=0.5|Levetiracetam, for comparison Brivaracetam is the 4''R''-propyl analogue of the anticonvulsant levetiracetam. {{clear left}}

==History== Positive preliminary results from stage III trials were recorded in 2008,<ref>{{cite journal | vauthors = Rogawski MA | title = Brivaracetam: a rational drug discovery success story | journal = British Journal of Pharmacology | volume = 154 | issue = 8 | pages = 1555–1557 | date = August 2008 | pmid = 18552880 | pmc = 2518467 | doi = 10.1038/bjp.2008.221 }}</ref> along with evidence that it is around ten times more potent for the prevention of certain types of seizure in mouse models than its analogue levetiracetam.<ref>{{cite journal | vauthors = Matagne A, Margineanu DG, Kenda B, Michel P, Klitgaard H | title = Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A | journal = British Journal of Pharmacology | volume = 154 | issue = 8 | pages = 1662–1671 | date = August 2008 | pmid = 18500360 | pmc = 2518465 | doi = 10.1038/bjp.2008.198 }}</ref>

On 14 January 2016, the European Commission,<ref name="EMA">{{cite web|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003898/human_med_001945.jsp&mid=WC0b01ac058001d124|title=Briviact|publisher=European Medicines Agency|access-date=30 May 2016|archive-date=10 June 2016|archive-url=https://web.archive.org/web/20160610025506/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F003898%2Fhuman_med_001945.jsp&mid=WC0b01ac058001d124|url-status=live}}</ref> and on 18 February 2016, the U.S. Food and Drug Administration (FDA)<ref>{{cite news |date=19 February 2016 |title=FDA approves Briviact to treat partial onset seizures |publisher=U.S. Food and Drug Administration (FDA) |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm486827.htm |access-date=20 May 2023 |archive-url=https://web.archive.org/web/20190423091022/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm486827.htm |archive-date=23 April 2019}}</ref> approved brivaracetam under the trade name ''Briviact''. The Drug Enforcement Administration (DEA) issued an interim final rule{{clarify|date=May 2016|reason=What is "interim final"? Seems contradictory.}} placing brivaracetam into schedule V of the Controlled Substances Act (CSA) effective 9 March 2017.<ref>{{cite journal | author = Drug Enforcement Administration Department of Justice | title = Schedules of Controlled Substances: Placement of Brivaracetam Into Schedule V. Interim final rule, with request for comments | journal = Federal Register | volume = 81 | issue = 92 | pages = 29487–29492 | date = May 2016 | pmid = 27192732 }}</ref> {{as of|2016|5}}, brivaracetam is not approved in some other countries. It was approved in Australia in August 2016.<ref>{{cite web|url=https://www.tga.gov.au/sites/default/files/auspar-brivaracetam-170307.pdf|title=Australian Public Assessment Report for brivaracetam|publisher=Therapeutic Goods Administration|year=2017|access-date=13 June 2020|archive-date=14 August 2021|archive-url=https://web.archive.org/web/20210814083416/https://www.tga.gov.au/sites/default/files/auspar-brivaracetam-170307.pdf|url-status=live}}</ref>

In Canada it was approved on 9 March 2016 under the trade name ''Brivlera''.<ref>{{cite news | author = UCB Canada Inc. | date = 29 July 2020 | publisher = Cision Canada | url = https://www.newswire.ca/news-releases/health-canada-approves-brivlera-r-brivaracetam-to-treat-partial-onset-seizures-in-pediatric-epilepsy-patients-868605074.html | title = Health Canada Approves BRIVLERA® (brivaracetam) to treat partial-onset seizures in pediatric epilepsy patients | access-date = 16 October 2021 | archive-date = 19 October 2021 | archive-url = https://web.archive.org/web/20211019105818/https://www.newswire.ca/news-releases/health-canada-approves-brivlera-r-brivaracetam-to-treat-partial-onset-seizures-in-pediatric-epilepsy-patients-868605074.html | url-status = live }}</ref>

== Society and culture ==

As of 2022, the US Food and Drug Administration approved a generic drug version of brivaracetam, but as of 2023 it was not yet available as a generic medication.<ref>{{cite web | title=2022 First Generic Drug Approvals | website=U.S. Food and Drug Administration (FDA) | date=3 March 2023 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals | archive-url=https://web.archive.org/web/20230630003602/https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals | archive-date=30 June 2023 | access-date=30 June 2023}}</ref><ref>{{cite web | title=Competitive Generic Therapy Approvals | website=U.S. Food and Drug Administration (FDA) | date=29 June 2023 | url=https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | access-date=29 June 2023 | archive-date=29 June 2023 | archive-url=https://web.archive.org/web/20230629233651/https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | url-status=live }}</ref>

In Argentina, brivaracetam has been sold under the brand Brivaxon from Raffo Laboratories and Briviact from Biopas Argentina.<ref>{{cite web |title=Brivaxon |url=https://www.raffo.com.ar/producto/brivaxon/ |website=Laboratorios Raffo |access-date=12 April 2024}}</ref><ref>{{cite web |title=Biopas Portal para Médicos |url=https://biopasmed.com.co/ipp-ar/briviact/ |website=Biopas Colombia |access-date=12 April 2024}}</ref>

In Germany, UCB was unable to demonstrate an additional benefit in 2016,<ref>{{Cite web |title=Nutzenbewertungsverfahren zum Wirkstoff Brivaracetam (Fokale Anfälle bei Epilepsie, ≥ 16 Jahre) - Gemeinsamer Bundesausschuss |url=https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/218/#beschluesse |access-date=2024-06-16 |website=www.g-ba.de}}</ref> 2018<ref>{{Cite web |date=2018-11-02 |title=[A18-48] Brivaracetam (Epilepsie) - Nutzenbewertung gemäß § 35a SGB V |url=https://www.iqwig.de/projekte/a18-48.html |access-date=2024-06-16 |website=Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) |language=de-DE}}</ref> and 2022<ref>{{Cite web |date=2022-05-18 |title=Brivaracetam (Epilepsie bei Kindern von ≥ 2 bis < 4 Jahren) – Nutzenbewertung gemäß § 35a SGB V |url=https://www.iqwig.de/download/a22-32_brivaracetam_nutzenbewertung-35a-sgb-v_v1-0.pdf |access-date=2024-06-16}}</ref> by adding brivaracetam. In Germany, newly approved drugs with new active ingredients have to be evaluated by the Federal Joint Committee (Germany)(Gemeinsamer Bundesausschuss) if the pharmaceutical manufacturer wishes to achieve a higher selling price than just the fixed amount. Only if there is an additional benefit, the pharmaceutical manufacturer can negotiate a price with the top association of statutory health insurance companies.

== References == {{reflist}}

== Further reading == {{refbegin}} * {{cite book | vauthors=Dean L | chapter=Brivaracetam Therapy and CYP2C19 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK500036/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | title=Medical Genetics Summaries | publisher=National Center for Biotechnology Information (NCBI) | year=2018 | pmid=29763212 | id=Bookshelf ID: NBK500036 | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }} {{refend}}

Category:Anticonvulsants Category:Carboxamides Category:Propyl compounds Category:Racetams Category:Synaptic vesicle glycoprotein ligands