Valproate

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Valproate semisodium
)

Valproate
INN: valproic acid
Clinical data
Trade namesDepakote, Epilim, Convulex, others
Other namesVPA; valproic 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
mitochondrial β-oxidation over 40%
Elimination half-life9–16 hours[5]
ExcretionUrine (30–50%)[5]
Identifiers
  • 2-propylpentanoic acid
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 (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat

intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.[6]

Common side effects of valproate include nausea, vomiting,

teratogenicity.[3] 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.[9]

Valproate's precise mechanism of action is unclear.

GABA levels, blocking voltage-gated sodium channels, inhibiting histone deacetylases, and increasing LEF1.[11][12][13] Valproic acid is a branched short-chain fatty acid (SCFA), a derivative of valeric acid.[11]

Valproate was first made in 1881 and came into medical use in 1962.

generic medication.[6] In 2021, it was the 155th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[17][18]

Medical uses

500mg tablets of Depakote extended-release

It is used primarily to treat

migraine headaches.[19]

Epilepsy

Valproate has a broad spectrum of

infantile spasms.[19][20] It has also been successfully given intravenously to treat status epilepticus.[21][22]

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.[3][4]

Mental illness

Valproate products are used to treat manic or mixed episodes of bipolar disorder.[23][24]

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:[25]

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.[25]

Other neurological indications

Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the

levodopa.[26][27][28]

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. It has cardioprotective, kidney protective, antiinflammatory, and antimicrobial effects.[29]

Contraindications

Contraindications include:

Adverse effects

Most common adverse effects include:[3]

Serious adverse effects include:[3]

Valproic acid has a

black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.[3]

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[32][33][34] Valproic acid can also cause mydriasis, a dilation of the pupils.[35] 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.[36] Weight gain is also possible.[37]

Pregnancy

Valproate causes

vermillion borders, thick lower lip and small downturned mouth.[43] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[44]

Children of mothers taking valproate during pregnancy are at risk for lower

IQs.[45][46][47] Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%.[48] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[49] The normal incidence for autism in the general population in 2018 was estimated at 1 in 44 (2.3%).[50] An updated March 2023 report estimates the number increased to 1 in 36 in 2020 (approximately 4% of boys and 1% of girls).[51] 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.[52][53][54]

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.[55][56]

Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate.

folic acid supplements can reduce the risk of congenital neural tube defects.[3] 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.[58]

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.[59]: 9  This led the 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."[59]: 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.[3]

Overdose and toxicity

Therapeutic range of valproic acid
Form Lower limit Upper limit Unit
Total (including
protein bound)
50[60] 125[60] µg/mL or mg/L
350[61] 700[61] μmol/L
Free 6[60] 22[60] µg/mL or mg/L
35[61] 70[61] μmol/L

Excessive amounts of valproic acid can result in somnolence,

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.[62]
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).[63]

In severe intoxication,

prophylactically[66] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[68] than L-carnitine
.

Interactions

Valproate inhibits

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.[30] It may also potentiate the CNS depressant effects of alcohol.[30] 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.[30] It may also interact with:[3][30][69]

  • 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.
  • 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,

GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.[30]
Prevention of neurotransmitter-induced hyperexcitability of nerve cells via Kv7.2 channel and AKAP5 may also contribute to its mechanism.[70] Valproate has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[71]

Valproate is a

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.[75] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[76] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[75][76]

Valproic acid has been found to directly stimulate androgen biosynthesis in the

4-androstenedione levels in men.[77][78] High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.[78]

Pharmacokinetics

Details see text.

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.

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.[81][82] Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.[79]

The vast majority of valproate

UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.[83] Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):[83]

  • 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.[79]

In adult patients taking valproate alone, 30–50% of an administered dose is excreted in

Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.[79][82]

Chemistry

Valproic acid is a branched

propyl derivative of valeric acid.[11]

History

Valproic acid was first synthesized in 1882 by

laboratory rats.[85] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[86] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[87]

Society and culture

Valproate is available as a

Approval status

Indications United States
FDA-labelled indication?[5]
Australia
TGA-labelled indication?[19]
United Kingdom
MHRA-labelled indication?[88]
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
tonic–clonic seizures and status epilepticus).[89][90][91][92]
Bipolar mania Yes Yes Yes Limited.[93][failed verification]
Bipolar depression No No No Moderate.[94]
Bipolar maintenance No No No Limited.[95]
Migraine prophylaxis Yes Yes (accepted) No Limited.
Acute migraine management No No No Only negative results.[96]
Schizophrenia No No No Weak evidence.[97]
Agitation in dementia No No No Weak evidence. Not recommended for agitation in people with dementia.[98] Increased rate of adverse effects, including a risk of serious adverse effects.[98]
Fragile X syndrome Yes (orphan) No No Limited.[74]
Familial adenomatous polyposis Yes (orphan) No No Limited.
Chronic pain & fibromyalgia No No No Limited.[99]
Alcohol hallucinosis No No No One randomised double-blind placebo-controlled trial.[100]
Intractable hiccups No No No Limited, five case reports support its efficacy, however.[101]
Non-epileptic myoclonus No No No Limited, three case reports support its efficacy, however.[102]
Cluster headaches No No No Limited, two case reports support its efficacy.[103]
West syndrome
No No No A prospective clinical trial supported its efficacy in treating infantile spasms.[104]
HIV infection eradication No No No Double-blind placebo-controlled trials have been negative.[105][106][107]
Myelodysplastic syndrome No No No Several clinical trials have confirmed its efficacy as a monotherapy,[108] as an adjunct to tretinoin[108] and as an adjunct to hydralazine.[109]
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.[110][111][112]
Cervical cancer No No No One clinical trial supports its use here.[113]
Malignant melanoma
No No No One phase II study has seemed to discount its efficacy.[114]
Breast cancer No No No A phase II study has supported its efficacy.[115]
Impulse control disorder
No No No Limited.[116][117]

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.[118][119]

Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.[120][121]

Formulations

Sodium valproate
Clinical data
Other namesvalproate sodium (USAN US)
License data
Legal status
Legal status
Identifiers
  • sodium 2-propylpentanoate
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
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.[124]

Terminology

Valproate is a negative ion. The

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 of valproic acid. Divalproex sodium is a coordination complex composed of equal parts of valproic acid and sodium valproate.[125]

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[128]
  • Epilim Sugar Free Liquid Sanofi[128]
  • Epilim Syrup Sanofi[128]
  • Epilim Tablets Sanofi[128]
  • 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.[129]

UK
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[130]
  • 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[131]
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
  • Tablets (white round tablet) – Depakine (
    Sanofi Winthrop Industrie
    (France)
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)
Uruguay
  • Tablets – DI DPA by Megalabs

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[3]
  • 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.[132]

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