Editing Valproate (section)

{{Short description|Medication used for epilepsy, bipolar disorder and migraine}}
{{Use dmy dates|date=July 2024}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 477003327
| image = 2-propylpentanoic acid 200.svg
| image_class = skin-invert-image
| width = 250
| alt =
| image2 = Valproic acid-optimized-ball-and-stick-model.png
| width2 = 250
| alt2 =
| INN = valproic acid

<!-- Clinical data -->
| tradename = Depakote, Epilim, Convulex, [[#Formulations|others]]
| Drugs.com = {{drugs.com|monograph|valproic_acid}}
| MedlinePlus = a682412
| DailyMedID = Valproic acid
| pregnancy_AU = D
| routes_of_administration = [[Oral administration|By mouth]], [[intravenous therapy|intravenous]]
| ATC_prefix = N03
| ATC_suffix = AG01

| legal_AU = S4
| legal_BR = C1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |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=3 August 2023 |access-date=3 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| legal_CA = Rx-only
| legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=[[Health Canada]] | date=7 July 2016 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=13 July 2024}}</ref>
| legal_UK = POM
| legal_US = Rx-only
| legal_US_comment = <ref name="Depakote FDA label" /><ref name="Depakote ER FDA label" />

<!-- Pharmacokinetic data -->
| bioavailability = Rapid absorption
| protein_bound = 80–90%<ref name=MSR>{{cite web|title=Depakene, Stavzor (valproic acid) dosing, indications, interactions, adverse effects, and more|website=Medscape Reference|publisher=WebMD|access-date=13 February 2014|url=http://reference.medscape.com/drug/depakene-stavzor-valproic-acid-343024#showall|url-status=live|archive-url=https://web.archive.org/web/20140221222153/http://reference.medscape.com/drug/depakene-stavzor-valproic-acid-343024#showall|archive-date=21 February 2014}}</ref>
| metabolism = [[Liver]]—[[glucuronidation|glucuronide conjugation]] 30–50%, [[mitochondrial β-oxidation]] over 40%
| elimination_half-life = 9–16 hours<ref name = MSR/>
| excretion = Urine (30–50%)<ref name = MSR/>

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 99-66-1
| PubChem = 3121
| IUPHAR_ligand = 7009
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00313
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3009
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 614OI1Z5WI
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00399
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 39867
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 109
| NIAID_ChemDB = 057177
| synonyms = VPA; valproic acid; sodium valproate (sodium); valproate semisodium (semisodium); 2-propylvaleric acid

<!-- Chemical data -->
| IUPAC_name = 2-propylpentanoic acid
| C=8 | H=16 | O=2
| SMILES = O=C(O)C(CCC)CCC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = NIJJYAXOARWZEE-UHFFFAOYSA-N
}}
<!-- Definition and medical uses -->
'''Valproate''' ('''valproic acid''', '''VPA''', '''sodium valproate''', and '''valproate semisodium''' forms) are medications primarily used to treat [[epilepsy]] and [[bipolar disorder]] and prevent [[migraine headache]]s.<ref name=AHFS2015>{{cite web|title=Valproic Acid|url=https://www.drugs.com/monograph/valproic-acid.html|publisher=The American Society of Health-System Pharmacists|date=24 November 2020|url-status=live|archive-url=https://web.archive.org/web/20170731065623/https://www.drugs.com/monograph/valproic-acid.html|archive-date=31 July 2017}}</ref> They are useful for the prevention of seizures in those with [[absence seizure]]s, [[partial seizure]]s, and [[generalized seizure]]s.<ref name=AHFS2015/> They can be given [[intravenous]]ly or by mouth, and the tablet forms exist in both long- and short-acting formulations.<ref name=AHFS2015/>

<!-- Side effects and mechanism -->
Common side effects of valproate include nausea, vomiting, [[somnolence]], and dry mouth.<ref name=AHFS2015/> Serious side effects can include [[Hepatotoxicity|liver failure]], and regular monitoring of [[liver function test]]s is therefore recommended.<ref name=AHFS2015/> Other serious risks include [[pancreatitis]] and an increased [[suicide]] risk.<ref name=AHFS2015/> Valproate is known to cause serious abnormalities or birth defects in the unborn child if taken during [[pregnancy]],<ref name=AHFS2015/><ref>{{cite web|title=Valproate banned without the pregnancy prevention programme|url=https://www.gov.uk/government/news/valproate-banned-without-the-pregnancy-prevention-programme|website=GOV.UK|access-date=26 April 2018|archive-date=24 April 2018|archive-url=https://web.archive.org/web/20180424123455/https://www.gov.uk/government/news/valproate-banned-without-the-pregnancy-prevention-programme|url-status=live}}</ref> and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition and the person is also prescribed a [[contraceptive]].<ref name=AHFS2015/><ref>{{Cite web |title=Drug Safety Update - Valproate medicines (Epilim, Depakote): contraindicated in women and girls of childbearing potential unless conditions of Pregnancy Prevention Programme are met |author= |work=GOV.UK - Medicines and Healthcare products Regulatory Agency |date=24 April 2018 |url=https://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-contraindicated-in-women-and-girls-of-childbearing-potential-unless-conditions-of-pregnancy-prevention-programme-are-met |access-date=17 April 2022 |archive-date=7 January 2023 |archive-url=https://web.archive.org/web/20230107044324/https://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-contraindicated-in-women-and-girls-of-childbearing-potential-unless-conditions-of-pregnancy-prevention-programme-are-met |url-status=live }}</ref><ref name="Depakote FDA label" /> Reproductive warnings have also been issued for men using the drug.<ref>{{cite web |title=Men on sodium valproate told to use contraception |url=https://www.bbc.com/news/articles/czjy8zne34xo |website=BBC News |publisher=BBC |access-date=5 September 2024}}</ref> The [[United States Food and Drug Administration]] has indicated a [[black box warning]] given the frequency and severity of the side effects and [[teratogen]]icity.<ref name="Depakote FDA label" /> Additionally, there is also a black box warning due to risk of  [[hepatotoxicity]] and pancreatitis.<ref>{{Cite web |title=FDA Information on Valproate |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018723s039lbl.pdf|archive-url=https://web.archive.org/web/20111005054657/http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018723s039lbl.pdf|url-status=dead|archive-date=5 October 2011}}</ref> As of 2022 the drug was still prescribed in the UK to potentially pregnant women, but use declined by 51% from 2018–19 to 2020–21.<ref>{{Cite news |title=Sodium valproate: what are dangers of epilepsy drug for unborn babies? |vauthors=Davis N |newspaper=The Observer |date=17 April 2022 |url=https://www.theguardian.com/society/2022/apr/17/sodium-valproate-what-are-dangers-of-epilepsy-drug-for-unborn-babies |access-date=17 April 2022 |archive-date=28 July 2022 |archive-url=https://web.archive.org/web/20220728154028/https://www.theguardian.com/society/2022/apr/17/sodium-valproate-what-are-dangers-of-epilepsy-drug-for-unborn-babies |url-status=live }}</ref> Valproate has been in use in Japan for the prophylaxis of migraine since 2011.<ref>{{Cite web |title=Appendix-II |url=https://www.neurology-jp.org/guidelinem/ch/appendix-II.html |access-date=2025-03-05 |website=www.neurology-jp.org}}</ref> It is approved as an antimanic and antiseizure in Japan as well.<ref>{{Cite web |title=Kusuri-no-Shiori(Drug Information Sheet) |url=https://www.rad-ar.or.jp/siori/english/search/result?n=36129 |access-date=2025-03-05 |website=www.rad-ar.or.jp |language=en}}</ref> In UK, valproate is approved for bipolar mania and epilepsy, and both valproate and divalproex are approved, although divalproex sodium<ref>{{Cite web |title=Depakote® (divalproex sodium): bipolar mania & epilepsy |url=https://www.depakote.com/prescribing-information |access-date=2025-03-05 |website=www.depakote.com}}</ref> is known as valproate semisodium.<ref name = "Fisher_2003">{{Cite journal | vauthors = Fisher C, Broderick W |date= December 2003 |title=Sodium valproate or valproate semisodium: is there a difference in the treatment of bipolar disorder? |url=https://www.cambridge.org/core/journals/psychiatric-bulletin/article/sodium-valproate-or-valproate-semisodium-is-there-a-difference-in-the-treatment-of-bipolar-disorder/1D4A40731B4B819FB049D5667653397C |journal=Psychiatric Bulletin |language=en |volume=27 |issue=12 |pages=446–448 |doi=10.1192/pb.27.12.446 |issn=0955-6036}}</ref>

<!-- Pharmacology and chemistry -->
Valproate's precise mechanism of action is unclear.<ref name=AHFS2015/><ref name=Owen2003>{{cite journal | vauthors = Owens MJ, Nemeroff CB | title = Pharmacology of valproate | journal = Psychopharmacology Bulletin | volume = 37 | issue = Suppl 2 | pages = 17–24 | year = 2003 | pmid = 14624230 }}</ref> Proposed mechanisms include affecting [[GABA]] levels, blocking [[voltage-gated sodium channel]]s, inhibiting [[histone deacetylase]]s, and increasing [[Lymphoid enhancer-binding factor 1|LEF1]].<ref name=Gh2013>{{cite journal | vauthors = Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, Altman RB, Klein TE | title = Valproic acid pathway: pharmacokinetics and pharmacodynamics | journal = Pharmacogenetics and Genomics | volume = 23 | issue = 4 | pages = 236–241 | date = April 2013 | pmid = 23407051 | pmc = 3696515 | doi = 10.1097/FPC.0b013e32835ea0b2 }}</ref><ref>{{cite web|title=Valproic acid|url=https://www.drugbank.ca/drugs/DB00313|website=DrugBank|publisher=University of Alberta|access-date=30 July 2017|date=29 July 2017|url-status=dead|archive-url=https://web.archive.org/web/20170731023353/https://www.drugbank.ca/drugs/DB00313|archive-date=31 July 2017}}</ref><ref>{{cite journal | vauthors = Santos R, Linker SB, Stern S, Mendes AP, Shokhirev MN, Erikson G, Randolph-Moore L, Racha V, Kim Y, Kelsoe JR, Bang AG, Alda M, Marchetto MC, Gage FH | title = Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients | journal = Molecular Psychiatry | volume = 26 | issue = 6 | pages = 2440–2456 | date = June 2021 | pmid = 33398088 | pmc = 9129103 | doi = 10.1038/s41380-020-00981-3 }}</ref> Valproic acid is a branched [[short-chain fatty acid]] (SCFA), a [[derivative (chemistry)|derivative]] of [[valeric acid]].<ref name=Gh2013/>

<!-- History, society, and culture -->
Valproate was originally synthesized in 1881 and came into medical use in 1962.<ref>{{cite book |vauthors=Scott DF |title=The history of epileptic therapy : an account of how medication was developed |date=1993 |publisher=Parthenon Publ. Group |location=Carnforth u.a. |isbn=978-1-85070-391-4 |page=131 |edition=1st |url=https://books.google.com/books?id=8DlOOps7D4oC&pg=PA131 |access-date=17 September 2017 |archive-date=14 January 2023 |archive-url=https://web.archive.org/web/20230114092529/https://books.google.com/books?id=8DlOOps7D4oC&pg=PA131 |url-status=live }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/> In 2022, it was the 174th most commonly prescribed medication in the United States, with more than 2{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Valproate Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Valproate | access-date = 30 August 2024 }}</ref>
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