Clinical data
Trade names Convulex, Depakote, Epilim, Stavzor, Vilapro
AHFS/ Monograph
MedlinePlus a682412
License data
  • AU: D
  • US: X (Contraindicated) - for control of conditions other than severe epilepsy not amenable to other drugs
Routes of
By mouth, intravenous
ATC code N03AG01 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability Rapid absorption
Protein binding 80–90%[1]
Metabolism Hepaticglucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Biological half-life 9–16 hours[1]
Excretion Urine (30-50%)[1]
Synonyms 2-Propylvaleric acid
CAS Number 99-66-1 YesY
PubChem (CID) 3121
DrugBank DB00313 YesY
ChemSpider 3009 YesY
KEGG D00399 YesY
ChEBI CHEBI:39867 YesY
NIAID ChemDB 057177
ECHA InfoCard 100.002.525
Chemical and physical data
Formula C8H16O2
Molar mass 144.211 g/mol
3D model (Jmol) Interactive image

Valproate (VPA), and its valproic acid, sodium valproate, and divalproex sodium forms, are medications primarily used to treat epilepsy and bipolar disorder and to prevent migraine headaches.[2] It is useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. It can be given intravenously or by mouth. Long and short acting formulations exist.[2]

Common side effects include nausea, vomiting, sleepiness, and a dry mouth. Serious side effects can include liver problems and regular monitoring of liver function tests is therefore recommended. Other serious risks include pancreatitis and an increased suicide risk. It is known to cause serious abnormalities in the baby if taken during pregnancy. Because of this it is not typically recommended in women of childbearing age who have migraines. It is unclear how valproate works.[2]

Valproate was first made in 1881 and came into medical use in 1962.[3] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[4] It is available as a generic medication.[2] The wholesale cost in the developing world is between 0.14 and 0.52 USD per day.[5] In the United States it costs about 0.90 USD per day. It is marketed under the brand name Depakote among others.[2]


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 divalproex sodium.

Medical uses

It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.[6]


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.[6][7] It has also been successfully given intravenously to treat status epilepticus.[8][9]

Psychiatric disorders

Valproate products are also used to treat manic or mixed episodes of bipolar disorder.[10]

Off-label uses include impulse control disorders, suggested by recent evidence of efficacy in controlling this adverse effect of Parkinson's disease medical therapy.[11]


Valproate is also used to prevent migraine headaches. Because this medication can be potentially harmful to the fetus, valproate should be considered for women of childbearing potential only after the risks have been discussed.[12]


The medication has been tested in the treatment of AIDS and cancer, owing to its histone deacetylase-inhibiting effects.[13]

Adverse effects

Most common adverse effects include:[12]

Serious adverse effects include:[12]

Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.[12]

Other possible side effects

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[14][15][16][17] Valproic acid can also cause mydriasis, a dilation of the pupils.[18] 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.[19]


Valproate causes birth defects; 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.[20][21] More rarely, with several other defects, possibly including a "valproate syndrome".[22] Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.[23] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[24]

Children of mothers taking valproate during pregnancy are at risk for lower IQs.[25][26][27] Maternal valproate use during pregnancy has been associated with a significantly higher probability of autism in the offspring.[28] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[29] The normal incidence for autism in the general population is estimated at less than one percent.[30] 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.[31][32][33]

Sodium valproate has been associated with the rare condition paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.[34][35]

Women who intend to become pregnant should switch to a different medication if possible, or decrease their dose of valproate.[36] 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 even worse consequences.) Studies have shown that taking folic acid can reduce the risk of congenital neural tube defects.[12]


Valproate in elderly people with dementia caused increased sleepiness. More people stopped the medication for this reason. Additional side effects of weight loss and decreased food intake was also associated in one half of people who become sleepy.[12]


Contraindications include:[37]


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.[37] It may also potentiate the CNS depressant effects of alcohol.[37] 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.[37] It may also interact with:[12][37][39]

Overdose and toxicity

Therapeutic range of valproic acid
Form Lower limit Upper limit Unit
Total (including
protein bound)
50[40] 125[40] µg/mL or mg/l
350[41] 700[41] μmol/L
Free 6[40] 22[40] µg/mL or mg/l
35[41] 70[41] μmol/L

Excessive amounts of valproic acid can result in sleepiness, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. 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.[42] 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).[43]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[44][45] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.[12] Supplemental L-carnitine is indicated in patients having an acute overdose[46][47] and also prophylactically[46] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[48] than L-carnitine.

Mechanism of action

Although the mechanism of action of valproate is not fully understood,[37] it has recently been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[49] In addition, its anticonvulsant effect has been attributed to the blockade of voltage-dependent sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).[37] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[37] 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.[37]

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.[50][51]

Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a non-steroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels.[52] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[53] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[52][53]


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


It is available as a generic medication.[2] The wholesale cost in the developing world is between 0.14 and 0.52 USD per day.[5] In the European Union, end-user costs are less than 0.60 EUR for an average daily dose in Germany.[58] In the United States it costs about 0.90 USD per day.[2]

Approval status

Indications United States
FDA-labelled indication?[1]
TGA-labelled indication?[6]
United Kingdom
MHRA-labelled indication?[59]
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).[60][61][62][63]
Bipolar mania Yes Yes Yes Limited.[64]
Bipolar depression No No No Moderate.[65]
Bipolar maintenance No No No Limited.[66]
Migraine prophylaxis Yes Yes (accepted) No Limited.
Acute migraine management No No No Only negative results.[67]
Schizophrenia No No No Weak and mostly negative evidence.[68]
Agitation in dementia No No No Weak and mostly negative evidence.[69]
Fragile X syndrome Yes (orphan) No No Limited.[70]
Familial adenomatous polyposis Yes (orphan) No No Limited.
Chronic pain & fibromyalgia No No No Limited.[71]
Alcohol hallucinosis No No No One randomised double-blind placebo-controlled trial.[72]
Intractable hiccups No No No Limited, five case reports support its efficacy, however.[73]
Non-epileptic myoclonus No No No Limited, three case reports support its efficacy, however.[74]
Cluster headaches No No No Limited, two case reports support its efficacy.[75]
West syndrome No No No A prospective clinical trial supported its efficacy in treating infantile spasms.[76]
HIV infection eradication No No No Double-blind placebo-controlled trials have been negative.[77][78][79]
Myelodysplastic syndrome No No No Several clinical trials have confirmed its efficacy as a monotherapy,[80] as an adjunct to tretinoin[80] and as an adjunct to hydralazine.[81]
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.[82][83][84]
Cervical cancer No No No One clinical trial supports its use here.[85]
Malignant melanoma No No No One phase II study has seemed to discount its efficacy.[86]
Breast cancer No No No A phase II study has supported its efficacy.[87]
Impulse control disorder No No No Limited.[11][88]


Sodium valproate
CAS Number 1069-66-5 YesY
ChemSpider 13428 YesY
KEGG D00710 YesY
ECHA InfoCard 100.002.525
Chemical and physical data
Formula C8H15NaO2
Molar mass 166.20 g·mol−1
3D model (Jmol) Interactive image

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 of sodium vaproate is needed than valproic acid without sodium to compensate for the sodium itself.[89]

Brand names of valproic acid

Branded products include:

Brand names of sodium valproate

United States
New Zealand

All the above formulations are Pharmac-subsidised.[90]

UK only
Germany, Switzerland, Norway, Finland, Sweden
South Africa

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


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

Brand names of valproate semisodium


As of 2016 it is also registered for 45 phase II clinical trials (some completed) for various cancers.[91]


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