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* Vomiting (12%)
* Vomiting (12%)
* [[Weakness]] (10%)
* [[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]]
{{colend}}

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

It is worthy of mentioning that some adverse effects related to valproic acid may be dose-dependent such as pancytopenia.<ref>{{Cite journal| vauthors = Rissardo JP, Fornari Caprara AL, Freitas Silveira JO |date=30 September 2019 |title=Valproic acid-associated pancytopenia: A dose-dependent adverse effect |journal=Romanian Journal of Neurology|volume=18|issue=3|pages=150–153 |doi=10.37897/RJN.2019.3.9 |s2cid=219250201 }}</ref>

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===
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 | display-authors = 6 | 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 }}</ref> However, similar to the discussion about the adverse effect of exposure to 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|dysmorphic features]] 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 benefits 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 | display-authors = 6 | 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 }}</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 [[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 | display-authors = 6 | 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 | display-authors = 6 | 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 | display-authors = 6 | 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 | doi-broken-date = 31 December 2022 }}</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}}</ref>

===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==
==Overdose and toxicity==

Revision as of 15:00, 24 July 2023

Valproate
INN: valproic acid
Clinical data
Trade namesDepakote, Epilim, Convulex, others
Other namesValproic acid; Sodium valproate (sodium); Valproate semisodium (semisodium); 2-Propylvaleric acid
AHFS/Drugs.comMonograph
MedlinePlusa682412
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityRapid absorption
Protein binding80–90%[2]
MetabolismLiver—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Elimination half-life9–16 hours[2]
ExcretionUrine (30–50%)[2]
Identifiers
  • 2-propylpentanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.002.525 Edit this at Wikidata
Chemical and physical data
FormulaC8H16O2
Molar mass144.214 g·mol−1
3D model (JSmol)
  • O=C(O)C(CCC)CCC
  • InChI=1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10) checkY
  • Key:NIJJYAXOARWZEE-UHFFFAOYSA-N checkY
  (verify)

Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches.[3] They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.[3] They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.[3]

Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth.[3] Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended.[3] Other serious risks include pancreatitis and an increased suicide risk.[3] Valproate is known to cause serious abnormalities in fetuses if taken during pregnancy,[3][4] and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition.[3][5] 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.[6]

Valproate's precise mechanism of action is unclear.[3][7] Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases.[8][9] Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.[8]

Valproate was first made in 1881 and came into medical use in 1962.[10] It is on the World Health Organization's List of Essential Medicines[11][12] and is available as a generic medication.[3] In 2020, it was the 109th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[13][14]

Terminology

Valproic acid (VPA) is an organic weak acid. The conjugate base is valproate. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as valproate semisodium.[15]

Medical uses

500mg tablets of Depakote extended-release

It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.[16]

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.[16][17] It has also been successfully given intravenously to treat status epilepticus.[18][19]

Mental illness

Bipolar disorder

Valproate products are also used to treat manic or mixed episodes of bipolar disorder.[20][21]

Schizophrenia

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:[22]

There is limited evidence that adding valproate to antipsychotics 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.[22]

Dopamine dysregulation syndrome

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.[23][24][25]

Migraines

Valproate is also used to prevent migraine headaches.

Other

The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects.[26]

Contraindications

Contraindications include:

Adverse effects

See also: List of adverse effects of valproic acid and List of adverse effects of valproate semisodium

Most common adverse effects include:[29]

Overdose and toxicity

Therapeutic range of valproic acid
Form Lower limit Upper limit Unit
Total (including
protein bound) 		50[30] 125[30] µg/mL or mg/L
350[31] 700[31] μmol/L
Free 6[30] 22[30] µg/mL or mg/L
35[31] 70[31] μmol/L

Excessive amounts of valproic acid can result in somnolence, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death.[32] In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/L during controlled therapy, but may reach 150–1500 mg/L following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.[33] 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 (pKa of 4.9).[34]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[35][36] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.[29] Supplemental L-carnitine is indicated in patients having an acute overdose[37][38] and also prophylactically[37] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[39] than L-carnitine.

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.[27] It may also potentiate the CNS depressant effects of alcohol.[27] 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 phenobarbitone) and itself.[27] It may also interact with:[29][27][40]

  • Aspirin: may increase valproate concentrations. May also interfere with valproate's metabolism.
  • Benzodiazepines: 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 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,[27] traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).[27] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[27] In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, 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.[27]

Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism.[41] Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[42]

It also has histone-deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.[43][44]

Endocrine actions

Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels.[45] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[46] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[45][46]

Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men.[47][48] High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.[48]

Pharmacokinetics

Some metabolites of valproic acid. Glucuronidation and β-oxidation are the main metabolic pathways; ω-oxidation metabolites are considered hepatotoxic.[49][50] Details see text.

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.[49] When in the bloodstream, 80–90% of the substance are bound to plasma proteins, 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.[51][52] Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.[49]

The vast majority of valproate metabolism occurs in the liver.[53] Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6, CYP2B6, CYP2C9, and CYP3A5.[53] It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.[53] Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):[53]

  • via glucuronidation (30–50%): valproic acid β-O-glucuronide
  • via beta oxidation (>40%): 2E-ene-valproic acid, 2Z-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid
  • via omega oxidation: 5-hydroxyvalproic acid, 2-propyl-glutaric acid
  • some others: 3E-ene-valproic acid, 3Z-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acid

All in all, over 20 metabolites are known.[49]

In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate.[53] The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose.[53] Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.[53] Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.[53] Only a small amount is excreted via the faeces.[49] Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.[49][52]

Chemistry

Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.[8]

History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.[54] 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.[55] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[56] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[57]

Society and culture

Valproate is available as a generic medication.[3]

Approval status

Indications United States
FDA-labelled indication?[2] 		Australia
TGA-labelled indication?[16] 		United Kingdom
MHRA-labelled indication?[58] 		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).[59][60][61][62]
Bipolar mania Yes Yes Yes Limited.[63]
Bipolar depression No No No Moderate.[64]
Bipolar maintenance No No No Limited.[65]
Migraine prophylaxis Yes Yes (accepted) No Limited.
Acute migraine management No No No Only negative results.[66]
Schizophrenia No No No Weak evidence.[67]
Agitation in dementia No No No Weak evidence. Not recommended for agitation in people with dementia.[68] Increased rate of adverse effects, including a risk of serious adverse effects.[68]
Fragile X syndrome Yes (orphan) No No Limited.[44]
Familial adenomatous polyposis Yes (orphan) No No Limited.
Chronic pain & fibromyalgia No No No Limited.[69]
Alcohol hallucinosis No No No One randomised double-blind placebo-controlled trial.[70]
Intractable hiccups No No No Limited, five case reports support its efficacy, however.[71]
Non-epileptic myoclonus No No No Limited, three case reports support its efficacy, however.[72]
Cluster headaches No No No Limited, two case reports support its efficacy.[73]
West syndrome No No No A prospective clinical trial supported its efficacy in treating infantile spasms.[74]
HIV infection eradication No No No Double-blind placebo-controlled trials have been negative.[75][76][77]
Myelodysplastic syndrome No No No Several clinical trials have confirmed its efficacy as a monotherapy,[78] as an adjunct to tretinoin[78] and as an adjunct to hydralazine.[79]
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.[80][81][82]
Cervical cancer No No No One clinical trial supports its use here.[83]
Malignant melanoma No No No One phase II study has seemed to discount its efficacy.[84]
Breast cancer No No No A phase II study has supported its efficacy.[85]
Impulse control disorder No No No Limited.[86][87]

Off-label uses

In 2012, pharmaceutical company 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.[88][89]

Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.[90][91]

Formulations

Sodium valproate
Clinical data
Other namesvalproate sodium (USAN US)
License data
Legal status
Legal status
Identifiers
  • sodium 2-propylpentanoate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.002.525 Edit this at Wikidata
Chemical and physical data
FormulaC8H15NaO2
Molar mass166.196 g·mol−1
3D model (JSmol)
  • CCCC(CCC)C(=O)[O-].[Na+]
  • InChI=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 checkY
  • Key:AEQFSUDEHCCHBT-UHFFFAOYSA-M checkY
  (verify)
Valproate semisodium
Clinical data
Trade namesDepakote, others
Other namessemisodium valproate, divalproex sodium (USAN US)
License data
Legal status
Legal status
Identifiers
  • sodium 2-propylpentanoate;2-propylpentanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.002.525 Edit this at Wikidata
Chemical and physical data
FormulaC16H31NaO4
Molar mass310.410 g·mol−1
3D model (JSmol)
  • CCCC(CCC)C(=O)O.CCCC(CCC)C(=O)[O-].[Na+]
  • InChI=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 checkY
  • Key:MSRILKIQRXUYCT-UHFFFAOYSA-M checkY

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.[94]

Brand names of valproic acid

Branded products include:

Brand names of sodium valproate

Portugal
  • Tablets – Diplexil-R by Bial.
United States
  • Intravenous injection – Depacon by Abbott Laboratories.
  • Syrup – Depakene by Abbott Laboratories. (Note Depakene capsules are valproic acid).
  • Depakote tablets are a mixture of sodium valproate and valproic acid.
  • Tablets – Eliaxim by Bial.
Australia
  • Epilim Crushable Tablets Sanofi[97]
  • Epilim Sugar Free Liquid Sanofi[97]
  • Epilim Syrup Sanofi[97]
  • Epilim Tablets Sanofi[97]
  • 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 Pharmac-subsidised.[98]

UK
  • Depakote Tablets (as in USA)
  • Tablets – Orlept by Wockhardt and Epilim by Sanofi
  • Oral solution – Orlept Sugar Free by Wockhardt and Epilim by Sanofi
  • Syrup – Epilim by Sanofi-Aventis
  • Intravenous injection – Epilim Intravenous by Sanofi
  • Extended release tablets – Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.
  • Enteric-coated tablets – Epilim EC200 by Sanofi is a 200-mg sodium valproate enteric-coated tablet.
UK only
  • Capsules – Episenta prolonged release by Beacon
  • Sachets – Episenta prolonged release by Beacon
  • Intravenous solution for injection – Episenta solution for injection by Beacon
Germany, Switzerland, Norway, Finland, Sweden
  • Tablets – Orfiril by Desitin Pharmaceuticals
  • Intravenous injection – Orfiril IV by Desitin Pharmaceuticals
South Africa
  • Syrup – Convulex by Byk Madaus[99]
  • Tablets – Epilim by Sanofi-synthelabo
Malaysia
  • Tablets – Epilim (200 ENTERIC COATED) by Sanofi-Aventis
  • Controlled release tablets – Epilim Chrono (500 CONTROLLED RELEASE) by Sanofi-Aventis[100]
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
Japan
  • Tablets – Depakene by Kyowa Hakko Kirin
  • Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa
  • Syrup – Depakene by Kyowa Hakko Kogyo
Europe

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

Taiwan
Iran
  • Tablets – Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo
  • Slow release tablets – Depakine Chrono by 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 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)

Brand names of valproate semisodium

  • Brazil – Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil
  • Canada – Epival by Abbott Laboratories
  • Mexico – Epival and Epival ER (extended release) by Abbott Laboratories
  • United Kingdom – Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics
  • United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics[29]
  • India – 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 – Ergenyl Chrono by Sanofi-Aventis and generics
  • Chile – Valcote and Valcote ER by Abbott Laboratories
  • France and other European countries — Depakote
  • Peru – Divalprax by AC Farma Laboratories
  • China – 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. [101]

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