Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Valproate: Difference between pages

{{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

| 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]]

| 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_US_comment = <ref name="Depakote FDA label" /><ref name="Depakote ER FDA label" />

<!-- Pharmacokinetic data -->

| 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 -->

| IUPHAR_ligand = 7009

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 39867

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| 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}}

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

<!-- 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 in fetuses 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 recipient 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" /> 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 Valporate |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018723s039lbl.pdf}}</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>

<!-- 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]] 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="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> and is available as a [[generic medication]].<ref name=AHFS2015/> In 2021, it was the 155th most commonly prescribed medication in the United States, with more than 3{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Valproate - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Valproate | access-date = 14 January 2024 | archive-date = 6 October 2021 | archive-url = https://web.archive.org/web/20211006221456/https://clincalc.com/DrugStats/Drugs/Valproate | url-status = live }}</ref>

{{TOC limit}}

==Medical uses==

[[File:Depakote 500mg ER.jpg|thumb|250px|500mg tablets of Depakote extended-release]]

It is used primarily to treat [[epilepsy]] and [[bipolar disorder]] and to prevent [[migraine headache]]s.<ref name = AMH/>

===Epilepsy===

Valproate has a broad spectrum of [[anticonvulsant]] activity, although it is primarily used as a first-line treatment for [[tonic–clonic seizures]], [[absence seizures]] and [[myoclonic seizures]] and as a second-line treatment for [[partial seizures]] and [[infantile spasms]].<ref name = AMH/><ref>{{cite journal | vauthors = Löscher W | title = Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy | journal = CNS Drugs | volume = 16 | issue = 10 | pages = 669–694 | year = 2002 | pmid = 12269861 | doi = 10.2165/00023210-200216100-00003 | s2cid = 67999301 }}</ref> It has also been successfully given [[Intravenous therapy|intravenously]] to treat [[status epilepticus]].<ref>{{cite journal | vauthors = Olsen KB, Taubøll E, Gjerstad L | title = Valproate is an effective, well-tolerated drug for treatment of status epilepticus/serial attacks in adults | journal = Acta Neurologica Scandinavica. Supplementum | volume = 187 | pages = 51–54 | year = 2007 | pmid = 17419829 | doi = 10.1111/j.1600-0404.2007.00847.x | s2cid = 11159645 }}</ref><ref>{{cite journal | vauthors = Kwan SY | title = The role of intravenous valproate in convulsive status epilepticus in the future | journal = Acta Neurologica Taiwanica | volume = 19 | issue = 2 | pages = 78–81 | date = June 2010 | pmid = 20830628 | url = http://www.ant-tnsjournal.com/Mag_Files/19-2/N201072314227_192edi.pdf | department = Editorial | access-date = 19 February 2024 | archive-date = 19 February 2024 | archive-url = https://web.archive.org/web/20240219233048/http://www.ant-tnsjournal.com/Mag_Files/19-2/N201072314227_192edi.pdf | url-status = live }}</ref>

In the US, valproic acid is an anti-epileptic drug [[indicated]] for the treatment of manic episodes associated with bipolar disorder; monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in people with multiple seizure types that include absence seizures.<ref name="Depakote FDA label" /><ref name="Depakote ER FDA label">{{cite web | title=Depakote ER- divalproex sodium tablet, extended release | website=DailyMed | date=24 February 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dc024ce-efc8-4690-7cb5-639c728fccac | access-date=19 February 2024 | archive-date=28 January 2023 | archive-url=https://web.archive.org/web/20230128143053/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dc024ce-efc8-4690-7cb5-639c728fccac | url-status=live }}</ref>

===Mental illness===

Valproate products are used to treat manic or mixed episodes of [[bipolar disorder]].<ref name=":1">{{cite web |url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/valproate-information |title=Valproate Information |publisher=U.S. [[Food and Drug Administration]] (FDA) |access-date=24 April 2015 |url-status=live |archive-url=https://web.archive.org/web/20150503091048/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm192645.htm |archive-date=3 May 2015 }}</ref><ref>{{cite journal | vauthors = Jochim J, Rifkin-Zybutz RP, Geddes J, Cipriani A | title = Valproate for acute mania | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 10 | pages = CD004052 | date = October 2019 | pmid = 31621892 | pmc = 6797024 | doi = 10.1002/14651858.CD004052.pub2 }}</ref>

A 2016 [[systematic review]] compared the efficacy of valproate as an add-on for people with [[schizophrenia]]:<ref name=Wan2016>{{cite journal | vauthors = Wang Y, Xia J, Helfer B, Li C, Leucht S | title = Valproate for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 11 | pages = CD004028 | date = November 2016 | pmid = 27884042 | pmc = 6734130 | doi = 10.1002/14651858.CD004028.pub4 | url = http://www.cochrane.org/CD004028/SCHIZ_valproate-schizophrenia | url-status = dead | access-date = 27 July 2017 | archive-url = https://web.archive.org/web/20170729002449/http://www.cochrane.org/CD004028/SCHIZ_valproate-schizophrenia | archive-date = 29 July 2017 }}</ref>

{| class="wikitable"

|-

| There is limited evidence that adding valproate to [[antipsychotic]]s may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Valproate was associated with a number of adverse events among which sedation and dizziness appeared more frequently than in the control groups.<ref name=Wan2016/>

|-

| style="padding:0;" |

{| class="wikitable collapsible collapsed" style="width:100%;"

|-

! scope="col" style="text-align: left;"| Outcome

! scope="col" style="text-align: left;"| Findings in words

! scope="col" style="text-align: left;"| Findings in numbers

! scope="col" style="text-align: left;"| Quality of evidence

|-

! colspan="4" style="text-align: left;"| Global outcome

|-

| Clinically significant response||When added to antipsychotic drugs valproate probably increases the chance of improvement. Data are based on moderate quality evidence.

|| [[Relative risk|RR]] 1.31 (1.16 to 1.47) || [[The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach|Moderate]]

|-

| Leaving the study early for any reason || Valproate in combination with antipsychotics may slightly reduce the chance of leaving the study early, but the difference between the two treatments is not clear. Data supporting this finding are based on moderate quality evidence.

|| RR 0.76 (0.47 to 1.24) || [[The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach|Moderate]]

|-

| Use of additional medication for sedation|| The combination of valproate and antipsychotic drugs may increase the chance of being given additional sedating medication, but, at present it is not possible to be confident about the difference between the two treatments and data supporting this finding are very limited.

|| RR 3.65 (0.11 to 122.31) || [[The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach|Very low]]

|-

! colspan="4" style="text-align: left;"| [[Mental health|Mental state]]

|-

| Average score ([[Positive and Negative Syndrome Scale|PANSS]] total, high = poor)|| On average, people receiving the valproate combination scored lower (better) than people treated with antipsychotics in combination with placebo or antipsychotic drugs alone. There was a clear difference between the groups, but the meaning of this in day-to-day care is unclear. || [[Mean absolute difference|MD]] 5.85 lower (7.8 lower to 3.91 lower) || [[The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach|Moderate]]

|-

! colspan="4" style="text-align: left;"| [[Adverse event]]s

|-

| Abnormal liver function (blood test changes)* || Adding valproate to antipsychotic drug treatment does not clearly cause liver problems. Data supporting this finding are based on moderate quality evidence.

|| RR 1.26 (0.72 to 2.22) || [[The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach|Moderate]]

|-

| Nausea || Adding valproate to antipsychotic drugs probably causes little or no increase to the chance of feeling sick, but the difference between the two treatments is not clear. Data supporting this finding are based on moderate quality evidence.

|| RR 1.22 (0.80 to 1.86) || [[The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach|Moderate]]

|-

! colspan="4" style="text-align: left;"| Missing outcomes and notes

|-

| || [[Quality of life]] outcomes were not reported in the included studies. <br />*Increase in alanine transaminase/gamma-glutamyl transpeptidase || ||

|-

|}

|}

===Other neurological indications===

Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the [[dopamine dysregulation syndrome]] that arise from the treatment of [[Parkinson's disease]] with [[levodopa]].<ref name="pmid25114917">{{cite journal | vauthors = Pirritano D, Plastino M, Bosco D, Gallelli L, Siniscalchi A, De Sarro G | title = Gambling disorder during dopamine replacement treatment in Parkinson's disease: a comprehensive review | journal = BioMed Research International | volume = 2014 | pages = 728038 | year = 2014 | pmid = 25114917 | pmc = 4119624 | doi = 10.1155/2014/728038 | doi-access = free }}</ref><ref name="pmid24288035">{{cite journal | vauthors = Connolly B, Fox SH | title = Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson's disease | journal = Neurotherapeutics | volume = 11 | issue = 1 | pages = 78–91 | date = January 2014 | pmid = 24288035 | pmc = 3899484 | doi = 10.1007/s13311-013-0238-x }}</ref><ref name="pmid24313567">{{cite journal | vauthors = Averbeck BB, O'Sullivan SS, Djamshidian A | title = Impulsive and compulsive behaviors in Parkinson's disease | journal = Annual Review of Clinical Psychology | volume = 10 | pages = 553–580 | year = 2014 | pmid = 24313567 | pmc = 4197852 | doi = 10.1146/annurev-clinpsy-032813-153705 }}</ref>

Valproate is also used to prevent [[Migraine|migraine headaches]].

===Other===

The medication has been tested in the treatment of [[AIDS]] and [[cancer]], owing to its [[Histone deacetylase inhibitor|histone-deacetylase-inhibiting effects]]. It has cardioprotective, kidney protective, antiinflammatory, and antimicrobial effects.<ref name="elsevier">{{cite journal | vauthors = Singh D, Gupta S, Verma I, Morsy MA, Nair AB, Ahmed AF | title = Hidden pharmacological activities of valproic acid: A new insight | journal = Biomedicine & Pharmacotherapy | volume = 142 | pages = 112021 | date = October 2021 | pmid = 34463268 | doi = 10.1016/j.biopha.2021.112021 | doi-access = free }}</ref>

==Contraindications==

Contraindications include:

* Pre-existing acute or chronic liver dysfunction or family history of severe [[hepatitis|liver inflammation]] (hepatitis), particularly medicine related.<ref name = TGA>{{cite web|title=Valpro sodium valproate|website=TGA eBusiness Services|publisher=Alphapharm Pty Limited|date=16 December 2013|access-date=14 February 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04603-3|format=PDF|archive-date=27 August 2021|archive-url=https://web.archive.org/web/20210827175359/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent=&id=CP-2010-PI-04603-3|url-status=live}}</ref>

* Known [[hypersensitivity]] to valproate or any of the ingredients used in the preparation<ref name = TGA/>

* [[Urea cycle disorders]]<ref name = TGA/>

* Hepatic [[porphyria]]<ref name = TGA/>

* Hepatotoxicity<ref name = TGA/>

* [[Mitochondrial disease]]<ref name = TGA/>

* [[Pancreatitis]]<ref name = TGA/>

* [[Porphyria]]<ref name=EMC>{{cite web|title=Depakote 250mg Tablets - Summary of Product Characteristics|website=electronic Medicines Compendium|publisher=Sanofi|date=28 November 2013|access-date=18 January 2014|url=http://www.medicines.org.uk/emc/medicine/25929/SPC/Depakote+250mg+Tablets/|url-status=live|archive-url=https://web.archive.org/web/20140201115858/http://www.medicines.org.uk/emc/medicine/25929/SPC/Depakote+250mg+Tablets/|archive-date=1 February 2014}}</ref>

* [[Pregnancy]] (except when no other treatments are available for the treatment of epilepsy)

==Adverse effects==

{{See also|List of adverse effects of valproic acid|List of adverse effects of valproate semisodium}}

{{Div col|colwidth=30em}}

Most common adverse effects include:<ref name="Depakote FDA label">{{cite web|title=Depakote- divalproex sodium tablet, delayed release|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08a65cf4-7749-4ceb-6895-8f4805e2b01f |access-date=10 November 2015|url-status=live|archive-url=https://web.archive.org/web/20160305202922/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08a65cf4-7749-4ceb-6895-8f4805e2b01f|archive-date=5 March 2016}}</ref>

* Nausea (22%)

* [[Somnolence|Drowsiness]] (19%)

* Dizziness (12%)

* Vomiting (12%)

* [[Weakness]] (10%)

Serious adverse effects include:<ref name="Depakote FDA label" />

* Bleeding

* [[Thrombocytopenia|Low blood platelets]]

* [[Encephalopathy]]

* Suicidal behavior and thoughts

* [[Hypothermia|Low body temperature]]

{{div col end}}

Valproic acid has a [[black box warning]] for [[hepatotoxicity]], [[pancreatitis]], and fetal abnormalities.<ref name="Depakote FDA label" />

There is evidence that valproic acid may cause premature growth plate [[ossification]] in children and adolescents, resulting in decreased height.<ref>{{cite journal | vauthors = Wu S, Legido A, De Luca F | title = Effects of valproic acid on longitudinal bone growth | journal = Journal of Child Neurology | volume = 19 | issue = 1 | pages = 26–30 | date = January 2004 | pmid = 15032379 | doi = 10.1177/088307380401900105011 | s2cid = 19827846 }}</ref><ref>{{cite journal | vauthors = Robinson PB, Harvey W, Belal MS | title = Inhibition of cartilage growth by the anticonvulsant drugs diphenylhydantoin and sodium valproate | journal = British Journal of Experimental Pathology | volume = 69 | issue = 1 | pages = 17–22 | date = February 1988 | pmid = 3126792 | pmc = 2013195 }}</ref><ref>{{cite journal | vauthors = Guo CY, Ronen GM, Atkinson SA | title = Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy | journal = Epilepsia | volume = 42 | issue = 9 | pages = 1141–1147 | date = September 2001 | pmid = 11580761 | doi = 10.1046/j.1528-1157.2001.416800.x | s2cid = 25499280 }}</ref> Valproic acid can also cause [[mydriasis]], a dilation of the pupils.<ref>{{cite web |url=http://www.ehealthme.com/ds/depakote/mydriasis |title=Could Depakote cause Mydriasis |publisher=eHealthMe.com |date=18 November 2014 |access-date=24 April 2015 |url-status=dead |archive-url=https://web.archive.org/web/20141205082551/http://www.ehealthme.com/ds/depakote/mydriasis |archive-date=5 December 2014 }}</ref> There is evidence that shows valproic acid may increase the chance of [[polycystic ovary syndrome]] (PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder.<ref>{{cite journal | vauthors = Bilo L, Meo R | title = Polycystic ovary syndrome in women using valproate: a review | journal = Gynecological Endocrinology | volume = 24 | issue = 10 | pages = 562–570 | date = October 2008 | pmid = 19012099 | doi = 10.1080/09513590802288259 | s2cid = 36426338 }}</ref> Weight gain is also possible.<ref>{{cite journal | vauthors = Chukwu J, Delanty N, Webb D, Cavalleri GL | title = Weight change, genetics and antiepileptic drugs | journal = Expert Review of Clinical Pharmacology | volume = 7 | issue = 1 | pages = 43–51 | date = January 2014 | pmid = 24308788 | doi = 10.1586/17512433.2014.857599 | s2cid = 33444886 }}</ref>

===Pregnancy===

{{further|Fetal valproate spectrum disorder}}

{{merge from|Fetal valproate spectrum disorder|date=August 2024|section=TRUE}}

Valproate causes [[birth defect]]s;<ref>[https://www.bbc.com/news/world-europe-39657139 New evidence in France of harm from epilepsy drug valproate] {{webarchive|url=https://web.archive.org/web/20170421023357/http://www.bbc.com/news/world-europe-39657139 |date=21 April 2017 }} BBC, 2017</ref> exposure during [[pregnancy]] is associated with about three times as many major abnormalities as usual, mainly [[spina bifida]] with the risks being related to the strength of medication used and use of more than one drug.<ref name="pmid6402356">{{cite journal | vauthors = Koch S, Göpfert-Geyer I, Jäger-Roman E, Jakob S, Huth H, Hartmann A, Rating D, Helge H | title = [Anti-epileptic agents during pregnancy. A prospective study on the course of pregnancy, malformations and child development] | language = de | journal = Deutsche Medizinische Wochenschrift | volume = 108 | issue = 7 | pages = 250–257 | date = February 1983 | pmid = 6402356 | doi = 10.1055/s-2008-1069536 }}</ref><ref name="pmid10882750">{{cite journal | vauthors = Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, Dean JC | title = A clinical study of 57 children with fetal anticonvulsant syndromes | journal = Journal of Medical Genetics | volume = 37 | issue = 7 | pages = 489–497 | date = July 2000 | pmid = 10882750 | pmc = 1734633 | doi = 10.1136/jmg.37.7.489 }}</ref> "''[[Fetal Valproate Syndrome]]''" (FVS) has been used to refer to the effects of valproate exposure in utero.<ref>{{cite journal | vauthors = Ornoy A | title = Valproic acid in pregnancy: how much are we endangering the embryo and fetus? | journal = Reproductive Toxicology | volume = 28 | issue = 1 | pages = 1–10 | date = July 2009 | pmid = 19490988 | doi = 10.1016/j.reprotox.2009.02.014 | bibcode = 2009RepTx..28....1O }}</ref> However, similar to the discussion about the adverse effect of exposure to [[alcohol (drug)|alcohol]] in utero ("''[[fetal alcohol spectrum disorder]]''"), a 2019 study proposed the term "''[[Fetal valproate spectrum disorder]]''" (FVSD) because valproate exposure can lead to a wide range of possible presentations, which can be influenced by various factors (including dosage and timing of exposure). The [[dysmorphic feature]]s associated with VPA exposure can be subtle and age-dependent, making it challenging to designate individuals as having the characteristic dysmorphism or not, especially for those with limited expertise in the area. While the presence of typical facial dysmorphism is suggestive of the condition, it is not required for diagnosis. This change in terminology to FVSD would benefit individuals affected by the neurodevelopmental effects of VPA exposure without significant malformations, since they can experience impairments in their everyday functioning similar to those with classical FVS.<ref name="pmid31324220">{{cite journal | vauthors = Clayton-Smith J, Bromley R, Dean J, Journel H, Odent S, Wood A, Williams J, Cuthbert V, Hackett L, Aslam N, Malm H, James G, Westbom L, Day R, Ladusans E, Jackson A, Bruce I, Walker R, Sidhu S, Dyer C, Ashworth J, Hindley D, Diaz GA, Rawson M, Turnpenny P | title = Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability | journal = Orphanet Journal of Rare Diseases | volume = 14 | issue = 1 | pages = 180 | date = July 2019 | pmid = 31324220 | pmc = 6642533 | doi = 10.1186/s13023-019-1064-y | doi-access = free }}</ref> Characteristics of valproate syndrome may include facial features that tend to evolve with age, including a [[trigonocephaly|triangle-shaped forehead]], tall forehead with bifrontal narrowing, [[epicanthic fold]]s, medial deficiency of eyebrows, flat nasal bridge, broad [[nasal root]], anteverted nares, shallow [[philtrum]], long upper lip and thin [[vermillion border]]s, thick lower lip and small downturned mouth.<ref>{{cite journal | vauthors = Kulkarni ML, Zaheeruddin M, Shenoy N, Vani HN | title = Fetal valproate syndrome | journal = Indian Journal of Pediatrics | volume = 73 | issue = 10 | pages = 937–939 | date = October 2006 | pmid = 17090909 | doi = 10.1007/bf02859291 | s2cid = 38371596 }}</ref> While [[Intellectual disability|developmental delay]] is usually associated with altered physical characteristics ([[dysmorphic feature]]s), this is not always the case.<ref name="pmid15491979">{{cite journal | vauthors = Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J, Coyle H, Fryer A, Gorry J, Gregg J, Mawer G, Nicolaides P, Pickering L, Tunnicliffe L, Chadwick DW | title = The longer term outcome of children born to mothers with epilepsy | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 75 | issue = 11 | pages = 1575–1583 | date = November 2004 | pmid = 15491979 | pmc = 1738809 | doi = 10.1136/jnnp.2003.029132 | quote = This argues that the fetal valproate syndrome constitutes a real clinical entity that includes developmental delay and cognitive impairments, but that some children might exhibit some developmental delay without marked dysmorphism. }}</ref>

Children of mothers taking valproate during pregnancy are at risk for lower [[IQ]]s.<ref>{{cite journal | vauthors = Umur AS, Selcuki M, Bursali A, Umur N, Kara B, Vatansever HS, Duransoy YK | title = Simultaneous folate intake may prevent adverse effect of valproic acid on neurulating nervous system | journal = Child's Nervous System | volume = 28 | issue = 5 | pages = 729–737 | date = May 2012 | pmid = 22246336 | doi = 10.1007/s00381-011-1673-9 | s2cid = 20344828 }}</ref><ref>{{cite web | url = http://www.medscape.com/viewarticle/549073 | title = NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids | vauthors = Cassels C | date = 8 December 2006 | publisher = Medscape | access-date = 23 May 2007 | url-status = live | archive-url = https://web.archive.org/web/20110731160315/http://www.medscape.com/viewarticle/549073 | archive-date = 31 July 2011 }}</ref><ref>{{cite journal | vauthors = Meador KJ, Baker GA, Finnell RH, Kalayjian LA, Liporace JD, Loring DW, Mawer G, Pennell PB, Smith JC, Wolff MC | title = In utero antiepileptic drug exposure: fetal death and malformations | journal = Neurology | volume = 67 | issue = 3 | pages = 407–412 | date = August 2006 | pmid = 16894099 | pmc = 1986655 | doi = 10.1212/01.wnl.0000227919.81208.b2 }}</ref> Maternal valproate use during pregnancy increased the probability of [[autism spectrum|autism]] in the offspring compared to mothers not taking valproate from 1.5% to 4.4%.<ref>{{cite journal | vauthors = Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M | title = Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism | journal = JAMA | volume = 309 | issue = 16 | pages = 1696–1703 | date = April 2013 | pmid = 23613074 | pmc = 4511955 | doi = 10.1001/jama.2013.2270 }}</ref> A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.<ref name="pmid16108456">{{cite journal | vauthors = Rasalam AD, Hailey H, Williams JH, Moore SJ, Turnpenny PD, Lloyd DJ, Dean JC | title = Characteristics of fetal anticonvulsant syndrome associated autistic disorder | journal = Developmental Medicine and Child Neurology | volume = 47 | issue = 8 | pages = 551–555 | date = August 2005 | pmid = 16108456 | doi = 10.1017/S0012162205001076 }}</ref> The normal incidence for autism in the general population in 2018 was estimated at 1 in 44 (2.3%).<ref>Maenner MJ, Shaw KA, Bakian AV, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2018. MMWR Surveill Summ 2021;70(No. SS-11):1–16. DOI: http://dx.doi.org/10.15585/mmwr.ss7011a1</ref> An updated March 2023 report estimates the number increased to 1 in 36 in 2020 (approximately 4% of boys and 1% of girls).<ref>Maenner MJ, Warren Z, Williams AR, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020. MMWR Surveill Summ 2023;72(No. SS-2):1–14. DOI: http://dx.doi.org/10.15585/mmwr.ss7202a1</ref> A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.<ref>[https://www.nytimes.com/2009/04/16/health/research/16child.html I.Q. Harmed by Epilepsy Drug in Utero] {{webarchive|url=https://web.archive.org/web/20151229233954/http://www.nytimes.com/2009/04/16/health/research/16child.html |date=29 December 2015 }} By RONI CARYN RABIN, ''New York Times'', 15 April 2009</ref><ref>{{cite journal | vauthors = Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW | title = Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs | journal = The New England Journal of Medicine | volume = 360 | issue = 16 | pages = 1597–1605 | date = April 2009 | pmid = 19369666 | pmc = 2737185 | doi = 10.1056/NEJMoa0803531 }}</ref><ref>[https://www.drugs.com/fda/valproate-products-safety-communication-risk-impaired-cognitive-development-children-exposed-utero-12994.html Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy)] {{webarchive|url=https://web.archive.org/web/20110902085932/http://www.drugs.com/fda/valproate-products-safety-communication-risk-impaired-cognitive-development-children-exposed-utero-12994.html |date=2 September 2011 }}. FDA. June 2011</ref>

Sodium valproate has been associated with [[paroxysmal tonic upgaze]] of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.<ref>{{cite journal | vauthors = Luat AF, Asano E, Chugani HT | title = Paroxysmal tonic upgaze of childhood with co-existent absence epilepsy | journal = Epileptic Disorders | volume = 9 | issue = 3 | pages = 332–336 | date = September 2007 | pmid = 17884759 | doi = 10.1684/epd.2007.0119 }}</ref><ref>{{cite journal | vauthors = Ouvrier RA, Billson F | title = Benign paroxysmal tonic upgaze of childhood | journal = Journal of Child Neurology | volume = 3 | issue = 3 | pages = 177–180 | date = July 1988 | pmid = 3209843 | doi = 10.1177/088307388800300305 | s2cid = 38127378 }}</ref>

Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate.<ref>[http://www.lawyersandsettlements.com/lawsuit/valproate-not-to-be-used-migraine-during-pregnancy.html Valproate Not To Be Used for Migraine During Pregnancy, FDA Warns<!-- Bot generated title -->] {{webarchive|url=https://web.archive.org/web/20130709080004/http://www.lawyersandsettlements.com/lawsuit/valproate-not-to-be-used-migraine-during-pregnancy.html |date=9 July 2013 }}</ref> Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have worse outcomes for the fetus than exposure to valproate). Studies have shown that taking [[folic acid]] supplements can reduce the risk of congenital [[neural tube]] defects.<ref name="Depakote FDA label" /> The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the [[European Union]] and the [[United States]], and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.<ref>{{Cite web|url=https://www.ema.europa.eu/en/medicines/human/referrals/valproate-related-substances-0|title=New measures to avoid valproate exposure in pregnancy endorsed|date=31 May 2018|website=European Medicines Agency|access-date=16 October 2019|archive-date=16 October 2019|archive-url=https://web.archive.org/web/20191016133949/https://www.ema.europa.eu/en/medicines/human/referrals/valproate-related-substances-0|url-status=live}}</ref>

===Paternal exposure===

A 2023 retrospective study of Norway Denmark and Sweden found a significantly increased risk of neurodevelopmental disabilities in the children of fathers exposed to valproate up to 3 months prior to conception, compared to offspring paternally exposed to lamotrigine/levetiracetam.<ref name="ema">{{Cite web |title=PRAC non-interventional imposed PASS final study report assessment report |url=https://www.ema.europa.eu/en/documents/other/valproate-prac-non-interventional-imposed-pass-final-study-report-assessment-report-emea-h-n-psr-j-0043_en.pdf |website=EMA |pages=34}}</ref>{{rp |9}}

This led the [[European Medicines Agency|EMA]] to recommend "the need to consider effective contraception, while using valproate and for at least 3 months after treatment discontinuation. Male patients should not donate sperm during treatment and for at least 3 months after treatment discontinuation."<ref name="ema" />{{rp |26}}

===Elderly===

Valproate may cause increased somnolence in the elderly. In a trial of valproate in elderly patients with [[dementia]], a significantly higher portion of valproate patients had somnolence compared to placebo. In approximately one-half of such patients, there was associated reduced nutritional intake and weight loss.<ref name="Depakote FDA label" />

==Overdose and toxicity==

{| class="wikitable" align="right"

|+ Therapeutic range of valproic acid

|-

|'''Form'''

|'''Lower limit'''

|'''Upper limit'''

|'''Unit'''

|-

| rowspan=2| Total (including<br /> [[Plasma protein binding|protein bound]])

| 50<ref name=mass>{{cite web|url=http://emedicine.medscape.com/article/2090462-overview|title=Valproic Acid Level| vauthors = Suzanne B |date=11 December 2013|access-date=5 June 2015|publisher=[[Medscape]]|url-status=live|archive-url=https://web.archive.org/web/20150504030450/http://emedicine.medscape.com/article/2090462-overview|archive-date=4 May 2015}}</ref> || 125<ref name=mass/> || μg/mL or mg/L

|-

| 350<ref name=molar>{{cite web|url=https://www.cadth.ca/media/pdf/lab-tests/06_Free_Valproic_Acid_Assay_e.pdf|title=Free Valproic Acid Assay (Reference – 2013.03.006) Notice of Assessment|date=April 2014|publisher=Canadian Agency for Drugs and Technologies in Health (CADTH) with INESSS's permission|access-date=5 June 2015|url-status=dead|archive-url=https://web.archive.org/web/20160303232944/https://www.cadth.ca/media/pdf/lab-tests/06_Free_Valproic_Acid_Assay_e.pdf|archive-date=3 March 2016}}</ref> || 700<ref name=molar/> || μmol/L

|-

| rowspan=2| Free

| 6<ref name=mass/> || 22<ref name=mass/> || μg/mL or mg/L

|-

| 35<ref name=molar/> || 70<ref name=molar/> || μmol/L

|}

Excessive amounts of valproic acid can result in somnolence, [[tremor]], [[stupor]], [[respiratory depression]], [[coma]], [[metabolic acidosis]], and death. In general, serum or plasma valproic acid concentrations are in a range of 20–100&nbsp;mg/L during controlled therapy, but may reach 150–1500&nbsp;mg/L following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ [[Chromatography|gas or liquid chromatography.]]<ref>{{cite journal | vauthors = Sztajnkrycer MD | title = Valproic acid toxicity: overview and management | journal = Journal of Toxicology. Clinical Toxicology | volume = 40 | issue = 6 | pages = 789–801 | year = 2002 | pmid = 12475192 | doi = 10.1081/CLT-120014645 | s2cid = 23031095 }}</ref>

In contrast to other [[antiepileptic drugs]], at present there is little favorable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproate's weak acid property (p''K''a of 4.9).<ref>{{cite journal | vauthors = Patsalos PN, Berry DJ | title = Therapeutic drug monitoring of antiepileptic drugs by use of saliva | journal = Therapeutic Drug Monitoring | volume = 35 | issue = 1 | pages = 4–29 | date = February 2013 | pmid = 23288091 | doi = 10.1097/FTD.0b013e31827c11e7 | s2cid = 15338188 }}</ref>

In severe intoxication, [[hemoperfusion]] or [[hemofiltration]] can be an effective means of hastening elimination of the drug from the body.<ref>{{cite journal | vauthors = Thanacoody RH | title = Extracorporeal elimination in acute valproic acid poisoning | journal = Clinical Toxicology | volume = 47 | issue = 7 | pages = 609–616 | date = August 2009 | pmid = 19656009 | doi = 10.1080/15563650903167772 | s2cid = 13592043 }}</ref><ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622–1626.</ref> Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.<ref name="Depakote FDA label" /> Supplemental [[Carnitine|<small>L</small>-carnitine]] is indicated in patients having an acute overdose<ref name=pmid16277730>{{cite journal | vauthors = Lheureux PE, Penaloza A, Zahir S, Gris M | title = Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? | journal = Critical Care | volume = 9 | issue = 5 | pages = 431–440 | date = October 2005 | pmid = 16277730 | pmc = 1297603 | doi = 10.1186/cc3742 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mock CM, Schwetschenau KH | title = Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy | journal = American Journal of Health-System Pharmacy | volume = 69 | issue = 1 | pages = 35–39 | date = January 2012 | pmid = 22180549 | doi = 10.2146/ajhp110049 }}</ref> and also [[Preventive medicine|prophylactically]]<ref name=pmid16277730/> in high risk patients. [[Acetylcarnitine|Acetyl-<small>L</small>-carnitine]] lowers [[hyperammonemia]] less markedly<ref>{{cite journal | vauthors = Matsuoka M, Igisu H | title = Comparison of the effects of L-carnitine, D-carnitine and acetyl-L-carnitine on the neurotoxicity of ammonia | journal = Biochemical Pharmacology | volume = 46 | issue = 1 | pages = 159–164 | date = July 1993 | pmid = 8347126 | doi = 10.1016/0006-2952(93)90360-9 }}</ref> than [[Carnitine|<small>L</small>-carnitine]]. <!-- It is important for people to know the comparison between L-carnitine and Acetyl-L-carnitine for VPA induced hyperammonemia. -->

== Interactions ==

Valproate inhibits [[CYP2C9]], [[glucuronyl transferase]], and [[epoxide hydrolase]] and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves.<ref name = TGA/> It may also potentiate the CNS depressant effects of alcohol.<ref name = TGA/> It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including [[carbamazepine]], [[lamotrigine]], [[phenytoin]] and [[Phenobarbital|phenobarbitone]]) and itself.<ref name = TGA/> It may also interact with:<ref name="Depakote FDA label" /><ref name = TGA/><ref>{{cite journal | vauthors = Herzog AG, Farina EL, Blum AS | title = Serum valproate levels with oral contraceptive use | journal = Epilepsia | volume = 46 | issue = 6 | pages = 970–971 | date = June 2005 | pmid = 15946343 | doi = 10.1111/j.1528-1167.2005.00605.x | s2cid = 7696039 | doi-access = free }}</ref>

* [[Aspirin]]: may increase valproate concentrations. May also interfere with valproate's metabolism.

* [[Benzodiazepine]]s: may cause CNS depression and there are possible pharmacokinetic interactions.

* [[Carbapenem]] antibiotics: reduce valproate levels, potentially leading to seizures.

* [[Cimetidine]]: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.

* [[Erythromycin]]: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.

* [[Ethosuximide]]: valproate may increase ethosuximide concentrations and lead to toxicity.

* [[Felbamate]]: may increase plasma concentrations of valproate.

* [[Mefloquine]]: may increase valproate metabolism combined with the direct [[epileptogenic]] effects of mefloquine.

* [[Oral contraceptive pill|Oral contraceptives]]: may reduce plasma concentrations of valproate.

* [[Primidone]]: may accelerate metabolism of valproate, leading to a decline of serum levels and potential [[breakthrough seizure]].

* [[Rifampicin]]: increases the clearance of valproate, leading to decreased valproate concentrations

* [[Warfarin]]: valproate may increase free warfarin concentration and prolong bleeding time.

* [[Zidovudine]]: valproate may increase zidovudine serum concentration and lead to toxicity.

==Pharmacology==

===Pharmacodynamics===

Although the mechanism of action of valproate is not fully understood,<ref name = TGA/> traditionally, its anticonvulsant effect has been attributed to the blockade of [[voltage-gated sodium channel]]s and increased brain levels of the inhibitory synaptic neurotransmitter [[Gamma-Aminobutyric acid|gamma-aminobutyric acid]] (GABA).<ref name = TGA/> The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.<ref name = TGA/> In animals, sodium valproate raises cerebral and cerebellar levels of GABA, possibly by inhibiting GABA degradative enzymes, such as [[GABA transaminase]], [[succinate-semialdehyde dehydrogenase]] and by inhibiting the re-uptake of GABA by neuronal cells.<ref name = TGA/>

Prevention of neurotransmitter-induced hyperexcitability of nerve cells via [[KvLQT2|Kv7.2 channel]] and [[AKAP5]] may also contribute to its mechanism.<ref>{{cite journal | vauthors = Kay HY, Greene DL, Kang S, Kosenko A, Hoshi N | title = M-current preservation contributes to anticonvulsant effects of valproic acid | journal = The Journal of Clinical Investigation | volume = 125 | issue = 10 | pages = 3904–3914 | date = October 2015 | pmid = 26348896 | pmc = 4607138 | doi = 10.1172/JCI79727 }}</ref> Valproate has been shown to protect against a seizure-induced reduction in [[phosphatidylinositol (3,4,5)-trisphosphate]] (PIP3) as a potential therapeutic mechanism.<ref>{{cite journal | vauthors = Chang P, Walker MC, Williams RS | title = Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid | journal = Neurobiology of Disease | volume = 62 | pages = 296–306 | date = February 2014 | pmid = 24148856 | pmc = 3898270 | doi = 10.1016/j.nbd.2013.10.017 }}</ref>

Valproate is a [[histone deacetylase inhibitor]]. By inhibition of [[histone deacetylase]], it promotes more transcriptionally active chromatin structures, that is it exerts an epigenetic effect. This has been proven in mice: Valproic acid induced histone hyperacetylation had brain function effects on the next generation of mice through changes in sperm DNA methylation.<ref>{{cite journal | vauthors = Sakai K, Hara K, Tanemura K | title = Testicular histone hyperacetylation in mice by valproic acid administration affects the next generation by changes in sperm DNA methylation | journal = PLOS ONE | volume = 18 | issue = 3 | pages = e0282898 | date = 3 September 2023 | pmid = 36893188 | pmc = 9997898 | doi = 10.1371/journal.pone.0282898 | doi-access = free | bibcode = 2023PLoSO..1882898S }}</ref> Intermediate molecules include [[VEGF]], [[BDNF]], and [[GDNF]].<ref>{{cite journal | vauthors = Kostrouchová M, Kostrouch Z, Kostrouchová M | title = Valproic acid, a molecular lead to multiple regulatory pathways | journal = Folia Biologica | volume = 53 | issue = 2 | pages = 37–49 | year = 2007 | pmid = 17448293 | url = http://fb.cuni.cz/Data/files/folia_biologica/volume_53_2007_2/FB2007A0007.pdf | url-status = dead | access-date = 13 February 2014 | archive-url = https://web.archive.org/web/20140221230758/http://fb.cuni.cz/Data/files/folia_biologica/volume_53_2007_2/FB2007A0007.pdf | archive-date = 21 February 2014 }}</ref><ref name="Therapeutic potential of mood stabi">{{cite journal | vauthors = Chiu CT, Wang Z, Hunsberger JG, Chuang DM | title = Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder | journal = Pharmacological Reviews | volume = 65 | issue = 1 | pages = 105–142 | date = January 2013 | pmid = 23300133 | pmc = 3565922 | doi = 10.1124/pr.111.005512 | author4-link = De-Maw Chuang }}</ref>

====Endocrine actions====

Valproic acid has been found to be an [[receptor antagonist|antagonist]] of the [[androgen receptor|androgen]] and [[progesterone receptor]]s, and hence as a [[nonsteroidal]] [[antiandrogen]] and [[antiprogestogen]], at concentrations much lower than therapeutic serum levels.<ref name="pmid16165177">{{cite journal | vauthors = Death AK, McGrath KC, Handelsman DJ | title = Valproate is an anti-androgen and anti-progestin | journal = Steroids | volume = 70 | issue = 14 | pages = 946–953 | date = December 2005 | pmid = 16165177 | doi = 10.1016/j.steroids.2005.07.003 | s2cid = 25958985 | hdl = 10453/16875 | hdl-access = free }}</ref> In addition, the drug has been identified as a potent [[aromatase inhibitor]], and suppresses [[estrogen]] concentrations.<ref name="WyllieCascino2012">{{cite book|vauthors=Wyllie E, Cascino GD, Gidal BE, Goodkin HP|title=Wyllie's Treatment of Epilepsy: Principles and Practice|url=https://books.google.com/books?id=j9t6Qg0kkuUC&pg=PA288-IA37|date=17 February 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-5348-4|pages=288–|url-status=live|archive-url=https://web.archive.org/web/20140606200832/http://books.google.com/books?id=j9t6Qg0kkuUC|archive-date=6 June 2014}}</ref> These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.<ref name="pmid16165177" /><ref name="WyllieCascino2012" />

Valproic acid has been found to directly stimulate androgen biosynthesis in the [[gonad]]s via inhibition of histone deacetylases and has been associated with [[hyperandrogenism]] in women and increased [[4-androstenedione]] levels in men.<ref name="UchidaMaruyama2005">{{cite journal | vauthors = Uchida H, Maruyama T, Arase T, Ono M, Nagashima T, Masuda H, Asada H, Yoshimura Y | title = Histone acetylation in reproductive organs: Significance of histone deacetylase inhibitors in gene transcription | journal = Reproductive Medicine and Biology | volume = 4 | issue = 2 | pages = 115–122 | date = June 2005 | pmid = 29662388 | pmc = 5891791 | doi = 10.1111/j.1447-0578.2005.00101.x }}</ref><ref name="IsojärviTaubøll2005">{{cite journal | vauthors = Isojärvi JI, Taubøll E, Herzog AG | title = Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy | journal = CNS Drugs | volume = 19 | issue = 3 | pages = 207–223 | year = 2005 | pmid = 15740176 | doi = 10.2165/00023210-200519030-00003 | s2cid = 9893959 }}</ref> High rates of [[polycystic ovary syndrome]] and [[menstrual disorder]]s have also been observed in women treated with valproic acid.<ref name="IsojärviTaubøll2005" />

===Pharmacokinetics===

[[File:Valproic acid metabolism.svg|upright=1.5|thumb|250px|Some [[metabolites]] of valproic acid. [[Glucuronidation]] and [[β-oxidation]] are the main metabolic pathways; [[ω-oxidation]] metabolites are considered [[hepatotoxic]].<ref name="AC">{{cite book|title=Austria-Codex|veditors = Haberfeld H|at=Depakine chrono retard 300 mg Filmtabletten|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2021|language=German}}</ref><ref>{{cite journal | vauthors = Kumar S, Wong H, Yeung SA, Riggs KW, Abbott FS, Rurak DW | title = Disposition of valproic acid in maternal, fetal, and newborn sheep. II: metabolism and renal elimination | journal = Drug Metabolism and Disposition | volume = 28 | issue = 7 | pages = 857–864 | date = July 2000 | pmid = 10859160 }}</ref> Details see text.]]

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.<ref name="AC" /> When in the bloodstream, 80–90% of the substance are bound to [[plasma protein]]s, mainly [[albumin]]. Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patient's age, additional use of other drugs such as [[aspirin]], as well as liver and kidney impairment.<ref>{{cite book|title=Angewandte Arzneimitteltherapie | veditors = Schneemann H, Young L, Koda-Kimble MA |publisher=Springer |language=de |year=2001 |isbn=3-540-41356-1 |pages=28–29}}</ref><ref name="Drugs.com">Valproate {{Drugs.com|pro|valproate}}. Accessed 6 August 2021.</ref> Concentrations in the [[cerebrospinal fluid]] and in breast milk are 1 to 10% of blood plasma concentrations.<ref name="AC" />

The vast majority of valproate [[Drug metabolism|metabolism]] occurs in the [[liver]].<ref name="Drugbank-Valproate" /> Valproate is known to be metabolized by the [[cytochrome P450]] enzymes [[CYP2A6]], [[CYP2B6]], [[CYP2C9]], and [[CYP3A5]].<ref name="Drugbank-Valproate" /> It is also known to be metabolized by the [[UDP-glucuronosyltransferase]] enzymes [[UGT1A3]], [[UGT1A4]], [[UGT1A6]], [[UGT1A8]], [[UGT1A9]], [[UGT1A10]], [[UGT2B7]], and [[UGT2B15]].<ref name="Drugbank-Valproate" /> Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):<ref name="Drugbank-Valproate" />

* via [[glucuronidation]] (30–50%): valproic acid β-O-[[glucuronide]]

* via [[beta oxidation]] (>40%): 2''E''-ene-valproic acid, 2''Z''-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid

* via [[omega oxidation]]: 5-hydroxyvalproic acid, 2-propyl-glutaric acid

* some others: 3''E''-ene-valproic acid, 3''Z''-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acid

All in all, over 20 metabolites are known.<ref name="AC" />

In adult patients taking valproate alone, 30–50% of an administered dose is excreted in [[urine]] as the glucuronide conjugate.<ref name="Drugbank-Valproate" /> The other major pathway in the metabolism of valproate is [[mitochondria]]l beta oxidation, which typically accounts for over 40% of an administered dose.<ref name="Drugbank-Valproate" /> Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.<ref name="Drugbank-Valproate" /> Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.<ref name="Drugbank-Valproate">{{cite web | title=Valproic Acid | url=https://www.drugbank.ca/drugs/DB00313#pharmacology | work=DrugBank | publisher=University of Alberta | date=31 August 2017 | access-date=1 September 2017 | archive-date=31 July 2017 | archive-url=https://web.archive.org/web/20170731023353/https://www.drugbank.ca/drugs/DB00313#pharmacology | url-status=live }}</ref> Only a small amount is excreted via the faeces.<ref name="AC" /> [[Elimination half-life]] is 16±3 hours and can decrease to 4–9 hours when combined with [[enzyme inducer]]s.<ref name="AC" /><ref name="Drugs.com" />

==Chemistry==

Valproic acid is a branched [[short-chain fatty acid]] and the 2-''n''-[[propyl]] derivative of [[valeric acid]].<ref name="Gh2013" />

==History==

Valproic acid was first synthesized in 1882 by [[Beverly S. Burton]] as an [[analog (chemistry)|analogue]] of [[valeric acid]], found naturally in [[Valerian (herb)|valerian]].<ref>{{cite journal | vauthors = Burton BS | year = 1882 | title = On the propyl derivatives and decomposition products of ethylacetoacetate | journal = Am. Chem. J. | volume = 3 | pages = 385–395 }}</ref> Valproic acid is a [[carboxylic acid]], a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented [[pentylenetetrazol]]-induced convulsions in [[laboratory rats]].<ref>{{cite journal | vauthors = Meunier H, Carraz G, Neunier Y, Eymard P, Aimard M | title = [Pharmacodynamic properties of N-dipropylacetic acid] | language = fr | journal = Therapie | volume = 18 | pages = 435–438 | year = 1963 | pmid = 13935231 | trans-title = Pharmacodynamic properties of N-dipropylacetic acid }}</ref> It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.<ref>{{cite journal | vauthors = Perucca E | title = Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience | journal = CNS Drugs | volume = 16 | issue = 10 | pages = 695–714 | year = 2002 | pmid = 12269862 | doi = 10.2165/00023210-200216100-00004 | s2cid = 803106 }}</ref> Valproic acid has also been used for migraine [[Preventive healthcare|prophylaxis]] and bipolar disorder.<ref>{{cite journal | vauthors = Henry TR | title = The history of valproate in clinical neuroscience | journal = Psychopharmacology Bulletin | volume = 37 | issue = Suppl 2 | pages = 5–16 | year = 2003 | pmid = 14624229 }}</ref>

==Society and culture==

Valproate is available as a [[generic medication]].<ref name=AHFS2015/>

===Approval status===

{{update section|date=February 2024}}

{| class = wikitable

|-

! Indications

! {{flagicon|USA}}<br />[[Food and Drug Administration|FDA]]-labelled indication?<ref name = MSR/>

! {{flagicon|AUS}}<br />[[Therapeutic Goods Administration|TGA]]-labelled indication?<ref name = AMH>{{cite book | title = Australian Medicines Handbook | year = 2013 | publisher = The Australian Medicines Handbook Unit Trust | isbn = 978-0-9805790-9-3 | edition = 2013 | place = Adelaide | editor = Rossi, S }}</ref>

! scope="col" |{{flagicon|GBR}}<br />[[Medicines and Healthcare products Regulatory Agency|MHRA]]-labelled indication?<ref name = BNF>{{cite book | last1 = Joint Formulary Committee | title = British National Formulary (BNF) | isbn = 978-0-85711-084-8 | edition = 65 | location = London, UK | publisher = Pharmaceutical Press | year = 2013 | url-access = registration | url = https://archive.org/details/bnf65britishnati0000unse }}</ref>

! Literature support

|-

| Epilepsy || {{yes}} || {{yes}} || {{yes}} || Limited (depends on the seizure type; it can help with certain kinds of seizures: drug-resistant epilepsy, partial and absence seizures, can be used against [[glioblastoma]] and other tumors both to improve survival and treat seizures, and against [[tonic–clonic seizures]] and status epilepticus).<ref>{{cite journal | vauthors = Rimmer EM, Richens A | title = An update on sodium valproate | journal = Pharmacotherapy | volume = 5 | issue = 3 | pages = 171–184 | date = May–June 1985 | pmid = 3927267 | doi = 10.1002/j.1875-9114.1985.tb03413.x | s2cid = 7700266 }}</ref><ref>{{cite journal | vauthors = Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Capparelli EV, Adamson PC | title = Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy | journal = The New England Journal of Medicine | volume = 362 | issue = 9 | pages = 790–799 | date = March 2010 | pmid = 20200383 | pmc = 2924476 | doi = 10.1056/NEJMoa0902014 }}</ref><ref>{{cite journal|url=http://www.neurology.org/content/84/14_Supplement/P1.238|title=Co-Administration of Valproic Acid and Lamotrigine in the Treatment of Refractory Epilepsy (P1.238)|vauthors=Jiang M|date=6 April 2015|journal=Neurology|volume=84|issue=14 Supplement|pages=P1.238|doi=10.1212/WNL.84.14_supplement.P1.238|s2cid=74543829|via=www.neurology.org|access-date=4 May 2015|archive-date=27 August 2021|archive-url=https://web.archive.org/web/20210827175359/https://n.neurology.org/content/84/14_Supplement/P1.238|url-status=live|url-access=subscription}}</ref><ref>{{cite journal| vauthors = Berendsen S, Kroonen J, Seute T, Snijders T, Broekman ML, Spliet WG, Artesi M, Bours V, Robe PA |title= O9.06 * Prognostic Relevance and Oncogenic Correlates of Epilepsy in Glioblastoma Patients |date=1 September 2014|journal=Neuro-Oncology|volume=16|issue=suppl_2|pages=ii21|doi=10.1093/neuonc/nou174.77|pmc=4185847}}</ref>

|-

| Bipolar mania || {{yes}} || {{yes}} || {{yes}} || Limited.<ref>{{cite journal | vauthors = Vasudev K, Mead A, Macritchie K, Young AH | title = Valproate in acute mania: is our practice evidence based? | journal = International Journal of Health Care Quality Assurance | volume = 25 | issue = 1 | pages = 41–52 | year = 2012 | pmid = 22455007 | doi = 10.1108/09526861211192395 }}</ref>{{Failed verification|date=November 2023|reason=Cited source contains "Design/methodology/approach: Case notes from 43 (42 percent male) patients" which does not support the claim that there is limited literature support.}}

|-

| Bipolar depression || {{no}} || {{no}} || {{no}} || Moderate.<ref>{{cite journal | vauthors = Bond DJ, Lam RW, Yatham LN | title = Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis | journal = Journal of Affective Disorders | volume = 124 | issue = 3 | pages = 228–234 | date = August 2010 | pmid = 20044142 | doi = 10.1016/j.jad.2009.11.008 }}</ref>

|-

| Bipolar maintenance || {{no}} || {{no}} || {{no}} || Limited.<ref>{{cite journal | vauthors = Haddad PM, Das A, Ashfaq M, Wieck A | title = A review of valproate in psychiatric practice | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 5 | issue = 5 | pages = 539–551 | date = May 2009 | pmid = 19409030 | doi = 10.1517/17425250902911455 | s2cid = 74028228 }}</ref>

|-

| Migraine prophylaxis || {{yes}} || {{Yes}} (accepted) || {{no}} || Limited.

|-

| Acute migraine management || {{no}} || {{no}} || {{no}} || Only negative results.<ref>{{cite journal | vauthors = Frazee LA, Foraker KC | title = Use of intravenous valproic acid for acute migraine | journal = The Annals of Pharmacotherapy | volume = 42 | issue = 3 | pages = 403–407 | date = March 2008 | pmid = 18303140 | doi = 10.1345/aph.1K531 | s2cid = 207263036 }}</ref>

|-

| Schizophrenia || {{no}} || {{no}} || {{no}} || Weak evidence.<ref>{{cite journal | vauthors = Wang Y, Xia J, Helfer B, Li C, Leucht S | title = Valproate for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 11 | pages = CD004028 | date = November 2016 | pmid = 27884042 | pmc = 6734130 | doi = 10.1002/14651858.CD004028.pub4 }}</ref>

|-

| Agitation in dementia || {{no}} || {{no}} || {{no}} || Weak evidence. Not recommended for agitation in people with dementia.<ref name=":2">{{cite journal | vauthors = Baillon SF, Narayana U, Luxenberg JS, Clifton AV | title = Valproate preparations for agitation in dementia | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 10 | pages = CD003945 | date = October 2018 | pmid = 30293233 | pmc = 6516950 | doi = 10.1002/14651858.CD003945.pub4 }}</ref> Increased rate of adverse effects, including a risk of serious adverse effects.<ref name=":2" />

|-

| [[Fragile X syndrome]] || {{yes}} (orphan) || {{no}} || {{no}} || Limited.<ref name="Therapeutic potential of mood stabi"/>

|-

| [[Familial adenomatous polyposis]] || {{yes}} (orphan) || {{no}} || {{no}} || Limited.

|-

| Chronic pain & fibromyalgia || {{no}} || {{no}} || {{no}} || Limited.<ref>{{cite journal | vauthors = Gill D, Derry S, Wiffen PJ, Moore RA | title = Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2011 | issue = 10 | pages = CD009183 | date = October 2011 | pmid = 21975791 | pmc = 6540387 | doi = 10.1002/14651858.CD009183.pub2 }}</ref>

|-

| Alcohol hallucinosis || {{no}} || {{no}} || {{no}} || One randomised double-blind placebo-controlled trial.<ref>{{cite journal | vauthors = Aliyev ZN, Aliyev NA | title = Valproate treatment of acute alcohol hallucinosis: a double-blind, placebo-controlled study | journal = Alcohol and Alcoholism | volume = 43 | issue = 4 | pages = 456–459 | date = July–August 2008 | pmid = 18495806 | doi = 10.1093/alcalc/agn043 | doi-access = free }}</ref>

|-

| Intractable hiccups || {{no}} || {{no}} || {{no}} || Limited, five case reports support its efficacy, however.<ref>{{cite journal | vauthors = Jacobson PL, Messenheimer JA, Farmer TW | title = Treatment of intractable hiccups with valproic acid | journal = Neurology | volume = 31 | issue = 11 | pages = 1458–1460 | date = November 1981 | pmid = 6796902 | doi = 10.1212/WNL.31.11.1458 | s2cid = 1578958 }}</ref>

|-

| Non-epileptic myoclonus || {{no}} || {{no}} || {{no}} || Limited, three case reports support its efficacy, however.<ref>{{cite journal | vauthors = Sotaniemi K | title = Valproic acid in the treatment of nonepileptic myoclonus | journal = Archives of Neurology | volume = 39 | issue = 7 | pages = 448–449 | date = July 1982 | pmid = 6808975 | doi = 10.1001/archneur.1982.00510190066025 }}</ref>

|-

| Cluster headaches || {{no}} || {{no}} || {{no}} || Limited, two case reports support its efficacy.<ref>{{cite journal | vauthors = Wheeler SD | title = Significance of migrainous features in cluster headache: divalproex responsiveness | journal = Headache | volume = 38 | issue = 7 | pages = 547–551 | date = July–August 1998 | pmid = 15613172 | doi = 10.1046/j.1526-4610.1998.3807547.x | s2cid = 27948702 | doi-access = free }}</ref>

|-

| [[West syndrome]] || {{no}} || {{no}} || {{no}} || A prospective clinical trial supported its efficacy in treating infantile spasms.<ref>{{cite journal | vauthors = Siemes H, Spohr HL, Michael T, Nau H | title = Therapy of infantile spasms with valproate: results of a prospective study | journal = Epilepsia | volume = 29 | issue = 5 | pages = 553–560 | date = September–October 1988 | pmid = 2842127 | doi = 10.1111/j.1528-1157.1988.tb03760.x | s2cid = 23789333 }}</ref>

|-

| HIV infection eradication || {{no}} || {{no}} || {{no}} || Double-blind placebo-controlled trials have been negative.<ref>{{cite journal | vauthors = Smith SM | title = Valproic acid and HIV-1 latency: beyond the sound bite | journal = Retrovirology | volume = 2 | issue = 1 | pages = 56 | date = September 2005 | pmid = 16168066 | pmc = 1242254 | doi = 10.1186/1742-4690-2-56 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Routy JP, Tremblay CL, Angel JB, Trottier B, Rouleau D, Baril JG, Harris M, Trottier S, Singer J, Chomont N, Sékaly RP, Boulassel MR | title = Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study | journal = HIV Medicine | volume = 13 | issue = 5 | pages = 291–296 | date = May 2012 | pmid = 22276680 | doi = 10.1111/j.1468-1293.2011.00975.x | s2cid = 27571864 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Archin NM, Cheema M, Parker D, Wiegand A, Bosch RJ, Coffin JM, Eron J, Cohen M, Margolis DM | title = Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection | journal = PLOS ONE | volume = 5 | issue = 2 | pages = e9390 | date = February 2010 | pmid = 20186346 | pmc = 2826423 | doi = 10.1371/journal.pone.0009390 | doi-access = free | bibcode = 2010PLoSO...5.9390A }}</ref>

|-

| [[Myelodysplastic syndrome]] || {{no}} || {{no}} || {{no}} || Several clinical trials have confirmed its efficacy as a monotherapy,<ref name = m2001>{{cite journal | vauthors = Hardy JR, Rees EA, Gwilliam B, Ling J, Broadley K, A'Hern R | title = A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain | journal = Journal of Pain and Symptom Management | volume = 21 | issue = 3 | pages = 204–209 | date = March 2001 | pmid = 11239739 | doi = 10.1016/S0885-3924(00)00266-9 | doi-access = free }}{{Dead link|date=October 2019 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> as an adjunct to [[tretinoin]]<ref name = m2001/> and as an adjunct to hydralazine.<ref>{{cite journal | vauthors = Candelaria M, Herrera A, Labardini J, González-Fierro A, Trejo-Becerril C, Taja-Chayeb L, Pérez-Cárdenas E, de la Cruz-Hernández E, Arias-Bofill D, Vidal S, Cervera E, Dueñas-Gonzalez A | title = Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial | journal = Annals of Hematology | volume = 90 | issue = 4 | pages = 379–387 | date = April 2011 | pmid = 20922525 | doi = 10.1007/s00277-010-1090-2 | s2cid = 13437134 }}</ref>

|-

| [[Acute myeloid leukaemia]] || {{no}} || {{no}} || {{no}} || Two clinical trials have confirmed its efficacy in this indication as both a monotherapy and as an adjunct to [[tretinoin]].<ref>{{cite journal | vauthors = Bug G, Ritter M, Wassmann B, Schoch C, Heinzel T, Schwarz K, Romanski A, Kramer OH, Kampfmann M, Hoelzer D, Neubauer A, Ruthardt M, Ottmann OG | title = Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia | journal = Cancer | volume = 104 | issue = 12 | pages = 2717–2725 | date = December 2005 | pmid = 16294345 | doi = 10.1002/cncr.21589 | s2cid = 1802132 }}</ref><ref>{{cite journal | vauthors = Kuendgen A, Schmid M, Schlenk R, Knipp S, Hildebrandt B, Steidl C, Germing U, Haas R, Dohner H, Gattermann N | title = The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia | journal = Cancer | volume = 106 | issue = 1 | pages = 112–119 | date = January 2006 | pmid = 16323176 | doi = 10.1002/cncr.21552 | s2cid = 43747497 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Fredly H, Gjertsen BT, Bruserud O | title = Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents | journal = Clinical Epigenetics | volume = 5 | issue = 1 | pages = 12 | date = July 2013 | pmid = 23898968 | pmc = 3733883 | doi = 10.1186/1868-7083-5-12 | doi-access = free }}</ref>

|-

| [[Cervical cancer]] || {{no}} || {{no}} || {{no}} || One clinical trial supports its use here.<ref>{{cite journal | vauthors = Coronel J, Cetina L, Pacheco I, Trejo-Becerril C, González-Fierro A, de la Cruz-Hernandez E, Perez-Cardenas E, Taja-Chayeb L, Arias-Bofill D, Candelaria M, Vidal S, Dueñas-González A | title = A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results | journal = Medical Oncology | volume = 28 | issue = Suppl 1 | pages = S540–S546 | date = December 2011 | pmid = 20931299 | doi = 10.1007/s12032-010-9700-3 | s2cid = 207372333 }}</ref>

|-

| [[Malignant melanoma]] || {{no}} || {{no}} || {{no}} || One phase II study has seemed to discount its efficacy.<ref>{{cite journal | vauthors = Rocca A, Minucci S, Tosti G, Croci D, Contegno F, Ballarini M, Nolè F, Munzone E, Salmaggi A, Goldhirsch A, Pelicci PG, Testori A | title = A phase I-II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma | journal = British Journal of Cancer | volume = 100 | issue = 1 | pages = 28–36 | date = January 2009 | pmid = 19127265 | pmc = 2634690 | doi = 10.1038/sj.bjc.6604817 }}</ref>

|-

| [[Breast cancer]] || {{no}} || {{no}} || {{no}} || A phase II study has supported its efficacy.<ref>{{cite journal | vauthors = Munster P, Marchion D, Bicaku E, Lacevic M, Kim J, Centeno B, Daud A, Neuger A, Minton S, Sullivan D | title = Clinical and biological effects of valproic acid as a histone deacetylase inhibitor on tumor and surrogate tissues: phase I/II trial of valproic acid and epirubicin/FEC | journal = Clinical Cancer Research | volume = 15 | issue = 7 | pages = 2488–2496 | date = April 2009 | pmid = 19318486 | doi = 10.1158/1078-0432.CCR-08-1930 | s2cid = 3230087 }}</ref>

|-

| [[Impulse control disorder]] || {{no}} || {{no}} || {{no}} || Limited.<ref name=Hicks>{{cite journal | vauthors = Hicks CW, Pandya MM, Itin I, Fernandez HH | title = Valproate for the treatment of medication-induced impulse-control disorders in three patients with Parkinson's disease | journal = Parkinsonism & Related Disorders | volume = 17 | issue = 5 | pages = 379–381 | date = June 2011 | pmid = 21459656 | doi = 10.1016/j.parkreldis.2011.03.003 }}</ref><ref>{{cite journal | vauthors = Sriram A, Ward HE, Hassan A, Iyer S, Foote KD, Rodriguez RL, McFarland NR, Okun MS | title = Valproate as a treatment for dopamine dysregulation syndrome (DDS) in Parkinson's disease | journal = Journal of Neurology | volume = 260 | issue = 2 | pages = 521–527 | date = February 2013 | pmid = 23007193 | doi = 10.1007/s00415-012-6669-1 | s2cid = 21544457 }}</ref>

|}

===Off-label uses===

In 2012, pharmaceutical company [[Abbott Laboratories|Abbott]] paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.<ref>{{cite news|url=https://www.washingtonpost.com/national/health-science/abbott-laboratories-agrees-to-16-billion-settlement-over-marketing-of-depakote/2012/05/07/gIQAh5098T_story.html|newspaper=Washington Post|access-date=27 June 2018|title=Abbott Laboratories to pay $1.6 billion over illegal marketing of Depakote|date=7 May 2012|vauthors=Aizenman NC|archive-date=28 June 2018|archive-url=https://web.archive.org/web/20180628100610/https://www.washingtonpost.com/national/health-science/abbott-laboratories-agrees-to-16-billion-settlement-over-marketing-of-depakote/2012/05/07/gIQAh5098T_story.html|url-status=live}}</ref><ref>{{cite news|url=https://www.nytimes.com/2012/05/08/business/abbott-to-pay-1-6-billion-over-illegal-marketing.html|website=New York Times|access-date=27 June 2018|date=8 May 2012|title=Abbott settles marketing lawsuit|vauthors=Schmidt M, Thomas K|archive-date=28 June 2018|archive-url=https://web.archive.org/web/20180628075612/https://www.nytimes.com/2012/05/08/business/abbott-to-pay-1-6-billion-over-illegal-marketing.html|url-status=live}}</ref>

Some studies have suggested that valproate may reopen the [[critical period]] for learning [[absolute pitch]] and possibly other skills such as language.<ref>{{cite journal | vauthors = Gervain J, Vines BW, Chen LM, Seo RJ, Hensch TK, Werker JF, Young AH | title = Valproate reopens critical-period learning of absolute pitch | journal = Frontiers in Systems Neuroscience | volume = 7 | pages = 102 | date = 2013 | pmid = 24348349 | pmc = 3848041 | doi = 10.3389/fnsys.2013.00102 | doi-access = free }}</ref><ref>{{cite web |vauthors=Thomson H |title=Learning drugs reawaken grown-up brain's inner child |url=https://www.newscientist.com/article/dn24831-learning-drugs-reawaken-grown-up-brains-inner-child/ |website=New Scientist |publisher=New Scientist Ltd. |access-date=8 May 2021 |archive-date=8 May 2021 |archive-url=https://web.archive.org/web/20210508154258/https://www.newscientist.com/article/dn24831-learning-drugs-reawaken-grown-up-brains-inner-child/ |url-status=live }}</ref>

===Formulations===

{{Infobox drug

| drug_name = Sodium valproate

| verifiedrevid = 464404696

| image = Sodium-valproate-2D-skeletal.png

| width = 250

| alt =

| image2 = Valproato Sódico.png

| alt2 =

| USAN = valproate sodium

<!-- Clinical data -->

| tradename =

| DailyMedID = Valproate sodium

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 1069-66-5

| PubChem = 16760703

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DBSALT001257

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 13428

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 5VOM6GYJ0D

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D00710

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 9925

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 433

| legal_US = Rx-only

| legal_US_comment = <ref>{{cite web | title=Valproate sodium injection | website=DailyMed | date=1 January 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bcf57b31-4811-4104-82b3-46fb91a53ee0 | access-date=7 October 2022 | archive-date=8 October 2022 | archive-url=https://web.archive.org/web/20221008050729/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bcf57b31-4811-4104-82b3-46fb91a53ee0 | url-status=live }}</ref><ref>{{cite web | title=Valproate sodium injection, solution | website=DailyMed | date=29 April 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c572ece7-03d3-4c2a-aeb5-61f2023b28ea | access-date=7 October 2022 | archive-date=9 October 2022 | archive-url=https://web.archive.org/web/20221009184059/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c572ece7-03d3-4c2a-aeb5-61f2023b28ea | url-status=live }}</ref><ref name="Depakote FDA label" /><ref name="Depakote ER FDA label" />

<!-- Chemical and physical data -->

| IUPAC_name = sodium 2-propylpentanoate

| C=8 | H=15 | Na=1 | O=2

| SMILES = CCCC(CCC)C(=O)[O-].[Na+]

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C8H16O2.Na/c1-3-5-7(6-4-2)8(9)10;/h7H,3-6H2,1-2H3,(H,9,10);/q;+1/p-1

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = AEQFSUDEHCCHBT-UHFFFAOYSA-M

}}

{{Infobox drug

| drug_name = Valproate semisodium

| imageL = Sodium valproate.svg

| widthL = 250

| altL =

| imageR = 2-propylpentanoic acid 200.svg

| widthR = 250

| altR =

| captionLR =

| USAN = divalproex sodium

<!-- Clinical data -->

| tradename = Depakote, others

| DailyMedID = Divalproex sodium

| legal_US = Rx-only

| legal_US_comment = <ref name="Depakote FDA label" /><ref name="Depakote ER FDA label" />

<!-- Identifiers -->

| CAS_number = 76584-70-8

| PubChem = 23663956

| DrugBank = DBSALT000185

| ChemSpiderID = 48337

| UNII = 644VL95AO6

| KEGG = D00304

| ChEBI = 4667

| ChEMBL = 2105613

| synonyms = semisodium valproate

<!-- Chemical and physical data -->

| IUPAC_name = sodium 2-propylpentanoate;2-propylpentanoic acid

| C=16 | H=31 | Na=1 | O=4

| SMILES = CCCC(CCC)C(=O)O.CCCC(CCC)C(=O)[O-].[Na+]

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/2C8H16O2.Na/c2*1-3-5-7(6-4-2)8(9)10;/h2*7H,3-6H2,1-2H3,(H,9,10);/q;;+1/p-1

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = MSRILKIQRXUYCT-UHFFFAOYSA-M

}}

Valproate exists in two main molecular variants: ''sodium valproate'' and ''valproic acid without sodium'' (often implied by simply ''valproate''). A mixture between these two is termed ''semisodium valproate''. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass of ''sodium valproate'' is needed than ''valproic acid without sodium'' to compensate for the sodium itself.<ref>{{cite book |title=The Maudsley Prescribing Guidelines |edition=Tenth |vauthors=Taylor D, Paton C, Kapur S |publisher=CRC Press |year=2009 |isbn=978-0-203-09283-5 |url=https://books.google.com/books?id=pbvLBQAAQBAJ&pg=PA124 |page=124 |access-date=17 September 2017 |archive-date=14 January 2023 |archive-url=https://web.archive.org/web/20230114092530/https://books.google.com/books?id=pbvLBQAAQBAJ&pg=PA124 |url-status=live }}</ref>

===Terminology===

Valproate is a negative ion. The [[conjugate base|conjugate acid]] of valproate is valproic acid (VPA). Valproic acid is fully ionized into valproate at the physiologic pH of the human body, and valproate is the active form of the drug. Sodium valproate is the sodium [[salt (chemistry)|salt]] of valproic acid. Divalproex sodium is a [[coordination complex]] composed of equal parts of valproic acid and sodium valproate.<ref>{{Cite book|url=https://www.medicinescomplete.com/mc/martindale/current/ms-10447-z.htm|title=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|veditors=Brayfield A|location=London|access-date=3 March 2018|archive-date=27 August 2021|archive-url=https://web.archive.org/web/20210827175406/https://about.medicinescomplete.com/wp-content/themes/mc-marketing/assets/images/favicons-tiles/favicon.ico|url-status=live}}</ref>

====Brand names of valproic acid====

<!-- Please do not add sodium valproate-based products to this list. That drug has its own list below -->

Branded products include:

{{Div col|colwidth=30em}}

* Absenor ([[Orion Corporation (pharmaceutical company)|Orion Corporation]] Finland)

* Convulex ([[G.L. Pharma GmbH]] Austria)

* Depakene ([[Abbott Laboratories]] in US and Canada)<ref name="Depakene FDA label">{{cite web | title=Depakene- valproic acid capsule, liquid filled | website=DailyMed | date=19 September 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a0288919-75bf-4752-975f-40579572c0f7 | access-date=14 April 2020 | archive-date=11 July 2020 | archive-url=https://web.archive.org/web/20200711130306/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a0288919-75bf-4752-975f-40579572c0f7 | url-status=live }}</ref>

* Depakin ([[Sanofi|Sanofi S.R.L.]] Italy)<ref name="Depakin AIFA">{{Cite web |url=https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/farmaco?farmaco=022483 |title=Depakin - Banca Dati Farmaci dell'AIFA |date=6 June 2023 |access-date=6 June 2023 |website=farmaci.agenziafarmaco.gov.it |archive-url=https://web.archive.org/web/20230606001333/https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/farmaco?farmaco=022483 |archive-date=6 June 2023 |url-status=live |publisher=[[Italian Medicines Agency]] |language=it |trans-title=Depakin - The AIFA Medicines Database}}</ref>

* Depakine ([[Sanofi Aventis]] France)

* Depakine ([[Sanofi Synthelabo]] Romania)

* Depalept ([[Sanofi Aventis]] Israel)

* Deprakine ([[Sanofi Aventis]] Finland)

* Encorate ([[Sun Pharmaceuticals]] India)

* Epival ([[Abbott Laboratories]] US and Canada)

* Epilim ([[Sanofi Synthelabo]] Australia and South Africa)

* Stavzor ([[Noven Pharmaceuticals|Noven Pharmaceuticals Inc.]])

* Valcote ([[Abbott Laboratories]] Argentina)

* Valpakine ([[Sanofi Aventis]] Brazil)

* Orfiril (Desitin Arzneimittel GmbH Norway)

{{div col end}}

====Brand names of sodium valproate====

=====Portugal=====

* Tablets{{snd}} Diplexil-R by [[Bial]].

=====United States=====

* Intravenous injection{{snd}} Depacon by Abbott Laboratories.

* Syrup{{snd}} Depakene by Abbott Laboratories. (Note: Depakene ''capsules'' are valproic acid).

* Depakote tablets are a mixture of sodium valproate and valproic acid.

* Tablets{{snd}} Eliaxim by Bial.

=====Australia=====

* Epilim Crushable Tablets Sanofi<ref name="Epilim TGA PI">{{cite web | title=Australian product information epilim (sodium valproate) crushable tablets, enteric-coated tablets, syrup, liquid | website=TGA eBS | date=15 April 2020 | url=http://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05620-3 | format=PDF | access-date=15 April 2020 | archive-date=15 March 2020 | archive-url=https://web.archive.org/web/20200315112531/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05620-3 | url-status=live }}</ref>

* Epilim Sugar Free Liquid Sanofi<ref name="Epilim TGA PI" />

* Epilim Syrup Sanofi<ref name="Epilim TGA PI" />

* Epilim Tablets Sanofi<ref name="Epilim TGA PI" />

* Sodium Valproate Sandoz Tablets Sanofi

* Valpro Tablets Alphapharm

* Valproate Winthrop Tablets Sanofi

* Valprease tablets Sigma

=====New Zealand=====

* Epilim by Sanofi-Aventis

All the above formulations are [[Pharmaceutical Management Agency|Pharmac]]-subsidised.<ref>{{cite web |url= http://www.pharmac.govt.nz/Schedule?osq=Sodium%20valproate |title= Sodium valproate -- Pharmaceutical Schedule |publisher= Pharmaceutical Management Agency |access-date= 22 June 2014 |url-status= dead |archive-url= https://web.archive.org/web/20160304081454/http://www.pharmac.govt.nz/Schedule?osq=Sodium%20valproate |archive-date= 4 March 2016 }}</ref>

=====UK=====

* Depakote Tablets (as in USA)

* Tablets{{snd}} Orlept by Wockhardt and Epilim by Sanofi

* Oral solution{{snd}} Orlept Sugar Free by Wockhardt and Epilim by Sanofi

* Syrup{{snd}} Epilim by Sanofi-Aventis

* Intravenous injection{{snd}} Epilim Intravenous by Sanofi

* Extended release tablets{{snd}} Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.

* Enteric-coated tablets{{snd}} Epilim EC200 by Sanofi is a 200&nbsp;mg sodium valproate [[Enteric coating|enteric-coated]] tablet.

======UK only======

* Capsules{{snd}} Episenta prolonged release by Beacon

* Sachets{{snd}} Episenta prolonged release by Beacon

* Intravenous solution for injection{{snd}} Episenta solution for injection by Beacon

=====Germany, Switzerland, Norway, Finland, Sweden=====

* Tablets{{snd}} Orfiril by Desitin Pharmaceuticals

* Intravenous injection{{snd}} Orfiril IV by Desitin Pharmaceuticals

=====South Africa=====

* Syrup{{snd}} Convulex by Byk Madaus<ref>{{Cite web |url=http://home.intekom.com/pharm/byk/convulex.html |title=South African Electronic Package Inserts: Convulex |access-date=2 January 2006 |archive-date=12 August 2010 |archive-url=https://web.archive.org/web/20100812052527/http://home.intekom.com/pharm/byk/convulex.html |url-status=dead }}</ref>

* Tablets{{snd}} Epilim by Sanofi-synthelabo

=====Malaysia=====

* Tablets{{snd}} Epilim (''200 ENTERIC COATED'') by Sanofi-Aventis

* Controlled release tablets{{snd}} Epilim Chrono (''500 CONTROLLED RELEASE'') by Sanofi-Aventis<ref name="Sanofi in Malaysia Products - Epilim & Epilim Chrono">{{cite web |title=Malaysian Package Inserts: Epilim |url=https://www.sanofi.com.my/en/products/epilim |access-date=5 June 2023 |archive-date=5 June 2023 |archive-url=https://web.archive.org/web/20230605142828/https://www.sanofi.com.my/en/products/epilim |url-status=live }}</ref>

=====Romania=====

* Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH

* Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets

=====Canada=====

* Intravenous injection{{snd}} Epival or Epiject by [[Abbott Laboratories]].

* Syrup{{snd}} Depakene by [[Abbott Laboratories]] its generic formulations include [https://web.archive.org/web/20070928082043/http://www.apotex.ca/Products/EN/Detail.asp?MaterialNumber=000000000000042290 Apo-Valproic] and [https://web.archive.org/web/20080115210712/http://www.ratiopharm.ca/e/Products/productSearch.asp?Cap=V ratio-Valproic].

=====Japan=====

* Tablets{{snd}} Depakene by [[Kyowa Hakko Kirin]]

* Extended release tablets{{snd}} Depakene-R by Kyowa Hakko Kogyo and Selenica-R by [[Kowa Co.|Kowa]]

* Syrup{{snd}} Depakene by Kyowa Hakko Kogyo

=====Europe=====

In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.

=====Taiwan=====

* Tablets (white round tablet){{snd}} Depakine ({{zh-cp|c=帝拔癲|p=di-ba-dian}}) by [[Sanofi-Aventis|Sanofi Winthrop Industrie]] (France)

=====Iran=====

* Tablets{{snd}} Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo

* Slow release tablets{{snd}} Depakine Chrono by [[Sanofi-Aventis|Sanofi Winthrop Industrie]] (France)

=====Israel=====

Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by [[Sanofi-Aventis]].

===== India, Russia and [[Commonwealth of Independent States|CIS]] countries =====

* Valparin Chrono by Sanofi India

* Valprol CR by Intas Pharmaceutical (India)

* Encorate Chrono by Sun Pharmaceutical (India)

* Serven Chrono by Leeven APL Biotech (India)

=====Uruguay=====

* Tablets{{snd}} DI DPA by Megalabs

====Brand names of valproate semisodium====

* Brazil{{snd}} Depakote by [[Abbott Laboratories]] and Torval CR by Torrent do Brasil

* Canada{{snd}} Epival by Abbott Laboratories

* Mexico{{snd}} Epival and Epival ER (extended release) by Abbott Laboratories

* United Kingdom{{snd}} Depakote (for psychiatric conditions) and Epilim (for epilepsy) by [[Sanofi-Aventis]] and generics

* United States{{snd}} Depakote and Depakote ER (extended release) by Abbott Laboratories and generics<ref name="Depakote FDA label" />

* India{{snd}} Valance and Valance OD by Abbott Healthcare Pvt Ltd, Divalid ER by Linux laboratories Pvt Ltd, Valex ER by Sigmund Promedica, Dicorate by Sun Pharma

* Germany{{snd}} Ergenyl Chrono by Sanofi-Aventis and generics

* Chile{{snd}} Valcote and Valcote ER by Abbott Laboratories

* France and other European countries{{snd}} Depakote

* Peru{{snd}} Divalprax by AC Farma Laboratories

* China{{snd}} Diprate OD

== Research ==

A 2023 systematic review of the literature identified only one study in which valproate was evaluated in the treatment of seizures in infants aged 1 to 36 months. In a randomized control trial, valproate alone was found to show poorer outcomes for infants than valproate plus levetiracetam in terms of reduction of seizures, freedom from seizures, daily living ability, quality of life, and cognitive abilities.<ref>{{Cite report |vauthors=Treadwell JR, Wu M, Tsou AY |date=October 2022 |title=Management of Infantile Epilepsies |url=https://effectivehealthcare.ahrq.gov/products/management-infantile-epilepsy/research |access-date=12 July 2023 |website=effectivehealthcare.ahrq.gov |language=en |doi=10.23970/ahrqepccer252 |pmid=36383706 |location=Rockville (MD) |publisher=Agency for Healthcare Research and Quality (US) |id=Report No.: 22(23)-EHC004 Report No.: 2021-SR-01 |archive-date=5 July 2023 |archive-url=https://web.archive.org/web/20230705073433/https://effectivehealthcare.ahrq.gov/products/management-infantile-epilepsy/research |url-status=live |url-access=subscription }}</ref>

== References ==

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