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Wikipedia

Valproate

July 19, 2023

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.[2] They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.[2] They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.[2]

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%[1]
MetabolismLiver—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Elimination half-life9–16 hours[1]
ExcretionUrine (30–50%)[1]
Identifiers
  • 2-propylpentanoic acid
CAS Number
  • 99-66-1 Y
PubChem CID
  • 3121
IUPHAR/BPS
  • 7009
DrugBank
  • DB00313 Y
ChemSpider
  • 3009 Y
UNII
  • 614OI1Z5WI
KEGG
  • D00399 Y
ChEBI
  • CHEBI:39867 Y
ChEMBL
  • ChEMBL109 Y
NIAID ChemDB
  • 057177
CompTox Dashboard (EPA)
  • DTXSID6023733
ECHA InfoCard100.002.525
Chemical and physical data
FormulaC8H16O2
Molar mass144.214 g·mol−1
3D model (JSmol)
  • Interactive image
  • 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) Y
  • Key:NIJJYAXOARWZEE-UHFFFAOYSA-N Y
  (verify)

Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth.[2] Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended.[2] Other serious risks include pancreatitis and an increased suicide risk.[2] Valproate is known to cause serious abnormalities in fetuses if taken during pregnancy,[2][3] and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition.[2][4] 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.[5]

Valproate's precise mechanism of action is unclear.[2][6] Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases.[7][8] Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.[7]

Valproate was first made in 1881 and came into medical use in 1962.[9] It is on the World Health Organization's List of Essential Medicines[10][11] and is available as a generic medication.[2] In 2020, it was the 109th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[12][13]

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.[14]

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.[15]

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.[15][16] It has also been successfully given intravenously to treat status epilepticus.[17][18]

Mental illness

Bipolar disorder

Valproate products are also used to treat manic or mixed episodes of bipolar disorder.[19][20]

Schizophrenia

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:[21]

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.[21]

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.[22][23][24]

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.[25]

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:[28]

Serious adverse effects include:[28]

Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.[28]

It is worthy of mentioning that some adverse effects related to valproic acid may be dose-dependent such as pancytopenia.[29]

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[30][31][32] Valproic acid can also cause mydriasis, a dilation of the pupils.[33] 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.[34] Weight gain is also possible.[35]

Pregnancy

Valproate causes birth defects;[36] 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.[37][38] "Fetal valproate syndrome" (FVS) has been used to refer to the effects of valproate exposure in utero.[39] 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 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.[40] Characteristics of valproate syndrome may 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.[41] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[42]

Children of mothers taking valproate during pregnancy are at risk for lower IQs.[43][44][45] 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%.[46] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[47] The normal incidence for autism in the general population in 2018 was estimated at 1 in 44 (2.3%).[48] An updated March 2023 report estimates the number increased to 1 in 36 in 2020 (approximately 4% of boys and 1% of girls).[49] 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.[50][51][52]

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.[53][54]

Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate.[55] 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.[28] 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.[56]

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.[28]

Overdose and toxicity

Therapeutic range of valproic acid
Form Lower limit Upper limit Unit
Total (including
protein bound) 		50[57] 125[57] µg/mL or mg/L
350[58] 700[58] μmol/L
Free 6[57] 22[57] µg/mL or mg/L
35[58] 70[58] μmol/L

Excessive amounts of valproic acid can result in somnolence, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death.[59] 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.[60] 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).[61]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[62][63] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.[28] Supplemental L-carnitine is indicated in patients having an acute overdose[64][65] and also prophylactically[64] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[66] 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.[26] It may also potentiate the CNS depressant effects of alcohol.[26] 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.[26] It may also interact with:[28][26][67]

  • 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,[26] traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).[26] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[26] 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.[26]

Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism.[68] Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[69]

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.[70][71]

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.[72] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[73] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[72][73]

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.[74][75] High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.[75]

Pharmacokinetics

 
Some metabolites of valproic acid. Glucuronidation and β-oxidation are the main metabolic pathways; ω-oxidation metabolites are considered hepatotoxic.[76][77] Details see text.

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.[76] 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.[78][79] Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.[76]

The vast majority of valproate metabolism occurs in the liver.[80] Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6, CYP2B6, CYP2C9, and CYP3A5.[80] It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.[80] Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):[80]

  • 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.[76]

In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate.[80] The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose.[80] Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.[80] Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.[80] Only a small amount is excreted via the faeces.[76] Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.[76][79]

Chemistry

Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.[7]

History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.[81] 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.[82] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[83] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[84]

Society and culture

Valproate is available as a generic medication.[2]

Approval status

Indications  
FDA-labelled indication?[1]		  
TGA-labelled indication?[15]		  
MHRA-labelled indication?[85]		 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).[86][87][88][89]
Bipolar mania Yes Yes Yes Limited.[90]
Bipolar depression No No No Moderate.[91]
Bipolar maintenance No No No Limited.[92]
Migraine prophylaxis Yes Yes (accepted) No Limited.
Acute migraine management No No No Only negative results.[93]
Schizophrenia No No No Weak evidence.[94]
Agitation in dementia No No No Weak evidence. Not recommended for agitation in people with dementia.[95] Increased rate of adverse effects, including a risk of serious adverse effects.[95]
Fragile X syndrome Yes (orphan) No No Limited.[71]
Familial adenomatous polyposis Yes (orphan) No No Limited.
Chronic pain & fibromyalgia No No No Limited.[96]
Alcohol hallucinosis No No No One randomised double-blind placebo-controlled trial.[97]
Intractable hiccups No No No Limited, five case reports support its efficacy, however.[98]
Non-epileptic myoclonus No No No Limited, three case reports support its efficacy, however.[99]
Cluster headaches No No No Limited, two case reports support its efficacy.[100]
West syndrome No No No A prospective clinical trial supported its efficacy in treating infantile spasms.[101]
HIV infection eradication No No No Double-blind placebo-controlled trials have been negative.[102][103][104]
Myelodysplastic syndrome No No No Several clinical trials have confirmed its efficacy as a monotherapy,[105] as an adjunct to tretinoin[105] and as an adjunct to hydralazine.[106]
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.[107][108][109]
Cervical cancer No No No One clinical trial supports its use here.[110]
Malignant melanoma No No No One phase II study has seemed to discount its efficacy.[111]
Breast cancer No No No A phase II study has supported its efficacy.[112]
Impulse control disorder No No No Limited.[113][114]

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.[115][116]

Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.[117][118]

Formulations

Sodium valproate
 
 
Clinical data
Other namesvalproate sodium (USAN US)
License data
Legal status
Legal status
Identifiers
  • sodium 2-propylpentanoate
CAS Number
  • 1069-66-5  Y
PubChem CID
  • 16760703
DrugBank
  • DBSALT001257  Y
ChemSpider
  • 13428  Y
UNII
  • 5VOM6GYJ0D
KEGG
  • D00710  Y
ChEBI
  • CHEBI:9925  Y
ChEMBL
  • ChEMBL433  Y
CompTox Dashboard (EPA)
  • DTXSID6023733  
ECHA InfoCard100.002.525  
Chemical and physical data
FormulaC8H15NaO2
Molar mass166.196 g·mol−1
3D model (JSmol)
  • Interactive image
  • 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  Y
  • Key:AEQFSUDEHCCHBT-UHFFFAOYSA-M  Y
  (verify)
Valproate semisodium
   
Clinical data
Trade namesDepakote, others
Other namessemisodium valproate, divalproex sodium (USAN US)
License data
Identifiers
  • sodium 2-propylpentanoate;2-propylpentanoic acid
CAS Number
  • 76584-70-8
PubChem CID
  • 23663956
DrugBank
  • DBSALT000185
ChemSpider
  • 48337
UNII
  • 644VL95AO6
KEGG
  • D00304
ChEBI
  • CHEBI:4667
ChEMBL
  • ChEMBL2105613
CompTox Dashboard (EPA)
  • DTXSID6023733  
ECHA InfoCard100.002.525  
Chemical and physical data
FormulaC16H31NaO4
Molar mass310.410 g·mol−1
3D model (JSmol)
  • Interactive image
  • 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  Y
  • Key:MSRILKIQRXUYCT-UHFFFAOYSA-M  Y

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.[121]

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[124]
  • Epilim Sugar Free Liquid Sanofi[124]
  • Epilim Syrup Sanofi[124]
  • Epilim Tablets Sanofi[124]
  • 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.[125]

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[126]
  • 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[127]
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[28]
  • 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. [128]

References

  1. ^ a b c d "Depakene, Stavzor (valproic acid) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. from the original on 21 February 2014. Retrieved 13 February 2014.
  2. ^ a b c d e f g h i j k "Valproic Acid". The American Society of Health-System Pharmacists. 24 November 2020. from the original on 31 July 2017.
  3. ^ "Valproate banned without the pregnancy prevention programme". GOV.UK. Retrieved 26 April 2018.
  4. ^ "Drug Safety Update - Valproate medicines (Epilim, Depakote): contraindicated in women and girls of childbearing potential unless conditions of Pregnancy Prevention Programme are met". GOV.UK - Medicines and Healthcare products Regulatory Agency. 24 April 2018.
  5. ^ Davis N (17 April 2022). "Sodium valproate: what are dangers of epilepsy drug for unborn babies?". The Observer.
  6. ^ Owens MJ, Nemeroff CB (2003). "Pharmacology of valproate". Psychopharmacology Bulletin. 37 (Suppl 2): 17–24. PMID 14624230.
  7. ^ a b c Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, et al. (April 2013). "Valproic acid pathway: pharmacokinetics and pharmacodynamics". Pharmacogenetics and Genomics. 23 (4): 236–241. doi:10.1097/FPC.0b013e32835ea0b2. PMC 3696515. PMID 23407051.
  8. ^ . DrugBank. University of Alberta. 29 July 2017. Archived from the original on 31 July 2017. Retrieved 30 July 2017.
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External links

  • "Valproic acid". Drug Information Portal. U.S. National Library of Medicine.
  • "Valproate sodium". Drug Information Portal. U.S. National Library of Medicine.
  • "Divalproex sodium". Drug Information Portal. U.S. National Library of Medicine.

July 19, 2023
valproate, valproic, acid, sodium, valproate, valproate, semisodium, forms, medications, primarily, used, treat, epilepsy, bipolar, disorder, prevent, migraine, headaches, they, useful, prevention, seizures, those, with, absence, seizures, partial, seizures, g. 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 2 They are useful for the prevention of seizures in those with absence seizures partial seizures and generalized seizures 2 They can be given intravenously or by mouth and the tablet forms exist in both long and short acting formulations 2 ValproateINN valproic acidClinical dataTrade namesDepakote Epilim Convulex othersOther namesValproic acid Sodium valproate sodium Valproate semisodium semisodium 2 Propylvaleric acidAHFS Drugs comMonographMedlinePlusa682412License dataUS DailyMed Valproic acid US FDA Valproic 20acidPregnancycategoryAU DRoutes ofadministrationBy mouth intravenousATC codeN03AG01 WHO Legal statusLegal statusAU S4 Prescription only CA only UK POM Prescription only US onlyPharmacokinetic dataBioavailabilityRapid absorptionProtein binding80 90 1 MetabolismLiver glucuronide conjugation 30 50 mitochondrial b oxidation over 40 Elimination half life9 16 hours 1 ExcretionUrine 30 50 1 IdentifiersIUPAC name 2 propylpentanoic acidCAS Number99 66 1 YPubChem CID3121IUPHAR BPS7009DrugBankDB00313 YChemSpider3009 YUNII614OI1Z5WIKEGGD00399 YChEBICHEBI 39867 YChEMBLChEMBL109 YNIAID ChemDB057177CompTox Dashboard EPA DTXSID6023733ECHA InfoCard100 002 525Chemical and physical dataFormulaC 8H 16O 2Molar mass144 214 g mol 13D model JSmol Interactive imageSMILES O C O C CCC CCCInChI InChI 1S C8H16O2 c1 3 5 7 6 4 2 8 9 10 h7H 3 6H2 1 2H3 H 9 10 YKey NIJJYAXOARWZEE UHFFFAOYSA N Y verify Common side effects of valproate include nausea vomiting somnolence and dry mouth 2 Serious side effects can include liver failure and regular monitoring of liver function tests is therefore recommended 2 Other serious risks include pancreatitis and an increased suicide risk 2 Valproate is known to cause serious abnormalities in fetuses if taken during pregnancy 2 3 and is contra indicated for women of childbearing age unless the drug is essential to their medical condition 2 4 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 5 Valproate s precise mechanism of action is unclear 2 6 Proposed mechanisms include affecting GABA levels blocking voltage gated sodium channels and inhibiting histone deacetylases 7 8 Valproic acid is a branched short chain fatty acid SCFA made from valeric acid 7 Valproate was first made in 1881 and came into medical use in 1962 9 It is on the World Health Organization s List of Essential Medicines 10 11 and is available as a generic medication 2 In 2020 it was the 109th most commonly prescribed medication in the United States with more than 6 million prescriptions 12 13 Contents 1 Terminology 2 Medical uses 2 1 Epilepsy 2 2 Mental illness 2 2 1 Bipolar disorder 2 2 2 Schizophrenia 2 2 3 Dopamine dysregulation syndrome 2 3 Migraines 2 4 Other 3 Contraindications 4 Adverse effects 4 1 Pregnancy 4 2 Elderly 5 Overdose and toxicity 6 Interactions 7 Pharmacology 7 1 Pharmacodynamics 7 1 1 Endocrine actions 7 2 Pharmacokinetics 8 Chemistry 9 History 10 Society and culture 10 1 Approval status 10 2 Off label uses 10 3 Formulations 10 3 1 Brand names of valproic acid 10 3 2 Brand names of sodium valproate 10 3 2 1 Portugal 10 3 2 2 United States 10 3 2 3 Australia 10 3 2 4 New Zealand 10 3 2 5 UK 10 3 2 5 1 UK only 10 3 2 6 Germany Switzerland Norway Finland Sweden 10 3 2 7 South Africa 10 3 2 8 Malaysia 10 3 2 9 Romania 10 3 2 10 Canada 10 3 2 11 Japan 10 3 2 12 Europe 10 3 2 13 Taiwan 10 3 2 14 Iran 10 3 2 15 Israel 10 3 2 16 India Russia and CIS countries 10 3 3 Brand names of valproate semisodium 11 Research 12 References 13 External linksTerminology EditValproic 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 14 Medical uses Edit 500mg tablets of Depakote extended releaseIt is used primarily to treat epilepsy and bipolar disorder It is also used to prevent migraine headaches 15 Epilepsy Edit 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 15 16 It has also been successfully given intravenously to treat status epilepticus 17 18 Mental illness Edit Bipolar disorder Edit Valproate products are also used to treat manic or mixed episodes of bipolar disorder 19 20 Schizophrenia Edit A 2016 systematic review compared the efficacy of valproate as an add on for people with schizophrenia 21 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 21 Outcome Findings in words Findings in numbers Quality of evidenceGlobal outcomeClinically significant response When added to antipsychotic drugs valproate probably increases the chance of improvement Data are based on moderate quality evidence RR 1 31 1 16 to 1 47 ModerateLeaving 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 ModerateUse 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 Very lowMental stateAverage score 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 MD 5 85 lower 7 8 lower to 3 91 lower ModerateAdverse eventsAbnormal 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 ModerateNausea 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 ModerateMissing outcomes and notesQuality of life outcomes were not reported in the included studies Increase in alanine transaminase gamma glutamyl transpeptidaseDopamine dysregulation syndrome Edit 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 22 23 24 Migraines Edit Valproate is also used to prevent migraine headaches Other Edit The medication has been tested in the treatment of AIDS and cancer owing to its histone deacetylase inhibiting effects 25 Contraindications EditContraindications include Pre existing acute or chronic liver dysfunction or family history of severe liver inflammation hepatitis particularly medicine related 26 Known hypersensitivity to valproate or any of the ingredients used in the preparation 26 Urea cycle disorders 26 Hepatic porphyria 26 Hepatotoxicity 26 Mitochondrial disease 26 Pancreatitis 26 Porphyria 27 Pregnancy except when no other treatments are available for the treatment of epilepsy Adverse effects EditSee also List of adverse effects of valproic acid and List of adverse effects of valproate semisodium Most common adverse effects include 28 Nausea 22 Drowsiness 19 Dizziness 12 Vomiting 12 Weakness 10 Serious adverse effects include 28 Bleeding Low blood platelets Encephalopathy Suicidal behavior and thoughts Low body temperature Valproic acid has a black box warning for hepatotoxicity pancreatitis and fetal abnormalities 28 It is worthy of mentioning that some adverse effects related to valproic acid may be dose dependent such as pancytopenia 29 There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents resulting in decreased height 30 31 32 Valproic acid can also cause mydriasis a dilation of the pupils 33 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 34 Weight gain is also possible 35 Pregnancy Edit Valproate causes birth defects 36 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 37 38 Fetal valproate syndrome FVS has been used to refer to the effects of valproate exposure in utero 39 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 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 40 Characteristics of valproate syndrome may 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 41 While developmental delay is usually associated with altered physical characteristics dysmorphic features this is not always the case 42 Children of mothers taking valproate during pregnancy are at risk for lower IQs 43 44 45 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 46 A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8 9 47 The normal incidence for autism in the general population in 2018 was estimated at 1 in 44 2 3 48 An updated March 2023 report estimates the number increased to 1 in 36 in 2020 approximately 4 of boys and 1 of girls 49 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 50 51 52 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 53 54 Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate 55 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 28 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 56 Elderly Edit 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 28 Overdose and toxicity EditTherapeutic range of valproic acid Form Lower limit Upper limit UnitTotal including protein bound 50 57 125 57 µg mL or mg L350 58 700 58 mmol LFree 6 57 22 57 µg mL or mg L35 58 70 58 mmol LExcessive amounts of valproic acid can result in somnolence tremor stupor respiratory depression coma metabolic acidosis and death 59 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 60 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 61 In severe intoxication hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body 62 63 Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored 28 Supplemental L carnitine is indicated in patients having an acute overdose 64 65 and also prophylactically 64 in high risk patients Acetyl L carnitine lowers hyperammonemia less markedly 66 than L carnitine Interactions EditValproate 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 26 It may also potentiate the CNS depressant effects of alcohol 26 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 26 It may also interact with 28 26 67 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 EditPharmacodynamics Edit Although the mechanism of action of valproate is not fully understood 26 traditionally its anticonvulsant effect has been attributed to the blockade of voltage gated sodium channels and increased brain levels of gamma aminobutyric acid GABA 26 The GABAergic effect is also believed to contribute towards the anti manic properties of valproate 26 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 26 Prevention of neurotransmitter induced hyperexcitability of nerve cells via Kv7 2 channel and AKAP5 may also contribute to its mechanism 68 Also it has been shown to protect against a seizure induced reduction in phosphatidylinositol 3 4 5 trisphosphate PIP3 as a potential therapeutic mechanism 69 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 70 71 Endocrine actions Edit 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 72 In addition the drug has been identified as a potent aromatase inhibitor and suppresses estrogen concentrations 73 These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment 72 73 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 74 75 High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid 75 Pharmacokinetics Edit Some metabolites of valproic acid Glucuronidation and b oxidation are the main metabolic pathways w oxidation metabolites are considered hepatotoxic 76 77 Details see text Taken by mouth valproate is rapidly and virtually completely absorbed from the gut 76 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 78 79 Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10 of blood plasma concentrations 76 The vast majority of valproate metabolism occurs in the liver 80 Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6 CYP2B6 CYP2C9 and CYP3A5 80 It is also known to be metabolized by the UDP glucuronosyltransferase enzymes UGT1A3 UGT1A4 UGT1A6 UGT1A8 UGT1A9 UGT1A10 UGT2B7 and UGT2B15 80 Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include see image 80 via glucuronidation 30 50 valproic acid b O glucuronide via beta oxidation gt 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 acidAll in all over 20 metabolites are known 76 In adult patients taking valproate alone 30 50 of an administered dose is excreted in urine as the glucuronide conjugate 80 The other major pathway in the metabolism of valproate is mitochondrial beta oxidation which typically accounts for over 40 of an administered dose 80 Typically less than 20 of an administered dose is eliminated by other oxidative mechanisms 80 Less than 3 of an administered dose of valproate is excreted unchanged i e as valproate in urine 80 Only a small amount is excreted via the faeces 76 Elimination half life is 16 3 hours and can decrease to 4 9 hours when combined with enzyme inducers 76 79 Chemistry EditValproic acid is a branched short chain fatty acid and the 2 n propyl derivative of valeric acid 7 History EditValproic acid was first synthesized in 1882 by Beverly S Burton as an analogue of valeric acid found naturally in valerian 81 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 82 It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide 83 Valproic acid has also been used for migraine prophylaxis and bipolar disorder 84 Society and culture EditValproate is available as a generic medication 2 Approval status Edit Indications FDA labelled indication 1 TGA labelled indication 15 MHRA labelled indication 85 Literature supportEpilepsy 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 86 87 88 89 Bipolar mania Yes Yes Yes Limited 90 Bipolar depression No No No Moderate 91 Bipolar maintenance No No No Limited 92 Migraine prophylaxis Yes Yes accepted No Limited Acute migraine management No No No Only negative results 93 Schizophrenia No No No Weak evidence 94 Agitation in dementia No No No Weak evidence Not recommended for agitation in people with dementia 95 Increased rate of adverse effects including a risk of serious adverse effects 95 Fragile X syndrome Yes orphan No No Limited 71 Familial adenomatous polyposis Yes orphan No No Limited Chronic pain amp fibromyalgia No No No Limited 96 Alcohol hallucinosis No No No One randomised double blind placebo controlled trial 97 Intractable hiccups No No No Limited five case reports support its efficacy however 98 Non epileptic myoclonus No No No Limited three case reports support its efficacy however 99 Cluster headaches No No No Limited two case reports support its efficacy 100 West syndrome No No No A prospective clinical trial supported its efficacy in treating infantile spasms 101 HIV infection eradication No No No Double blind placebo controlled trials have been negative 102 103 104 Myelodysplastic syndrome No No No Several clinical trials have confirmed its efficacy as a monotherapy 105 as an adjunct to tretinoin 105 and as an adjunct to hydralazine 106 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 107 108 109 Cervical cancer No No No One clinical trial supports its use here 110 Malignant melanoma No No No One phase II study has seemed to discount its efficacy 111 Breast cancer No No No A phase II study has supported its efficacy 112 Impulse control disorder No No No Limited 113 114 Off label uses Edit 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 115 116 Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language 117 118 Formulations Edit Sodium valproate Clinical dataOther namesvalproate sodium USAN US License dataUS DailyMed Valproate sodiumLegal statusLegal statusUS only 119 120 IdentifiersIUPAC name sodium 2 propylpentanoateCAS Number1069 66 5 YPubChem CID16760703DrugBankDBSALT001257 YChemSpider13428 YUNII5VOM6GYJ0DKEGGD00710 YChEBICHEBI 9925 YChEMBLChEMBL433 YCompTox Dashboard EPA DTXSID6023733 ECHA InfoCard100 002 525 Chemical and physical dataFormulaC 8H 15Na O 2Molar mass166 196 g mol 13D model JSmol Interactive imageSMILES CCCC CCC C O O Na InChI 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 YKey AEQFSUDEHCCHBT UHFFFAOYSA M Y verify Valproate semisodium Clinical dataTrade namesDepakote othersOther namessemisodium valproate divalproex sodium USAN US License dataUS DailyMed Divalproex sodiumIdentifiersIUPAC name sodium 2 propylpentanoate 2 propylpentanoic acidCAS Number76584 70 8PubChem CID23663956DrugBankDBSALT000185ChemSpider48337UNII644VL95AO6KEGGD00304ChEBICHEBI 4667ChEMBLChEMBL2105613CompTox Dashboard EPA DTXSID6023733 ECHA InfoCard100 002 525 Chemical and physical dataFormulaC 16H 31Na O 4Molar mass310 410 g mol 13D model JSmol Interactive imageSMILES CCCC CCC C O O CCCC CCC C O O Na InChI 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 YKey MSRILKIQRXUYCT UHFFFAOYSA M YValproate 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 121 Brand names of valproic acid Edit Branded products include Absenor Orion Corporation Finland Convulex G L Pharma GmbH Austria Depakene Abbott Laboratories in US and Canada 122 Depakin Sanofi S R L Italy 123 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 Inc Valcote Abbott Laboratories Argentina Valpakine Sanofi Aventis Brazil Orfiril Desitin Arzneimittel GmbH Norway Brand names of sodium valproate Edit Portugal Edit Tablets Diplexil R by Bial United States Edit 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 Edit Epilim Crushable Tablets Sanofi 124 Epilim Sugar Free Liquid Sanofi 124 Epilim Syrup Sanofi 124 Epilim Tablets Sanofi 124 Sodium Valproate Sandoz Tablets Sanofi Valpro Tablets Alphapharm Valproate Winthrop Tablets Sanofi Valprease tablets SigmaNew Zealand Edit Epilim by Sanofi AventisAll the above formulations are Pharmac subsidised 125 UK Edit 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 Edit Capsules Episenta prolonged release by Beacon Sachets Episenta prolonged release by Beacon Intravenous solution for injection Episenta solution for injection by BeaconGermany Switzerland Norway Finland Sweden Edit Tablets Orfiril by Desitin Pharmaceuticals Intravenous injection Orfiril IV by Desitin PharmaceuticalsSouth Africa Edit Syrup Convulex by Byk Madaus 126 Tablets Epilim by Sanofi synthelaboMalaysia Edit Tablets Epilim 200 ENTERIC COATED by Sanofi Aventis Controlled release tablets Epilim Chrono 500 CONTROLLED RELEASE by Sanofi Aventis 127 Romania Edit 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 tabletsCanada Edit Intravenous injection Epival or Epiject by Abbott Laboratories Syrup Depakene by Abbott Laboratories its generic formulations include Apo Valproic and ratio Valproic Japan Edit 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 KogyoEurope Edit In much of Europe Depakine and Depakine Chrono tablets are equivalent to Epilim and Epilim Chrono above Taiwan Edit Tablets white round tablet Depakine Chinese 帝拔癲 pinyin di ba dian by Sanofi Winthrop Industrie France Iran Edit 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 Edit 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 Edit 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 Edit 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 28 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 ODResearch EditA 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 128 References Edit a b c d Depakene Stavzor valproic acid dosing indications interactions adverse effects and more Medscape Reference WebMD Archived from the original on 21 February 2014 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al April 2011 Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome Preliminary results of a phase II trial Annals of Hematology 90 4 379 387 doi 10 1007 s00277 010 1090 2 PMID 20922525 S2CID 13437134 Bug G Ritter M Wassmann B Schoch C Heinzel T Schwarz K et al December 2005 Clinical trial of valproic acid and all trans retinoic acid in patients with poor risk acute myeloid leukemia Cancer 104 12 2717 2725 doi 10 1002 cncr 21589 PMID 16294345 S2CID 1802132 Kuendgen A Schmid M Schlenk R Knipp S Hildebrandt B Steidl C et al January 2006 The histone deacetylase HDAC inhibitor valproic acid as monotherapy or in combination with all trans retinoic acid in patients with acute myeloid leukemia Cancer 106 1 112 119 doi 10 1002 cncr 21552 PMID 16323176 S2CID 43747497 Fredly H Gjertsen BT Bruserud O July 2013 Histone deacetylase inhibition in the treatment of acute myeloid leukemia the effects of valproic acid on leukemic cells and the clinical and experimental 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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 Clinical Cancer Research 15 7 2488 2496 doi 10 1158 1078 0432 CCR 08 1930 PMID 19318486 S2CID 3230087 Hicks CW Pandya MM Itin I Fernandez HH June 2011 Valproate for the treatment of medication induced impulse control disorders in three patients with Parkinson s disease Parkinsonism amp Related Disorders 17 5 379 381 doi 10 1016 j parkreldis 2011 03 003 PMID 21459656 Sriram A Ward HE Hassan A Iyer S Foote KD Rodriguez RL et al February 2013 Valproate as a treatment for dopamine dysregulation syndrome DDS in Parkinson s disease Journal of Neurology 260 2 521 527 doi 10 1007 s00415 012 6669 1 PMID 23007193 S2CID 21544457 Aizenman NC 7 May 2012 Abbott Laboratories to pay 1 6 billion over illegal marketing of Depakote Washington Post Retrieved 27 June 2018 Schmidt M Thomas K 8 May 2012 Abbott settles marketing lawsuit New York Times Retrieved 27 June 2018 Gervain J Vines BW Chen LM Seo RJ Hensch TK Werker JF Young AH 2013 Valproate reopens critical period learning of absolute pitch Frontiers in Systems Neuroscience 7 102 doi 10 3389 fnsys 2013 00102 PMC 3848041 PMID 24348349 Thomson H Learning drugs reawaken grown up brain s inner child New Scientist New Scientist Ltd Retrieved 8 May 2021 Valproate sodium injection DailyMed 1 January 2021 Retrieved 7 October 2022 Valproate sodium injection solution DailyMed 29 April 2021 Retrieved 7 October 2022 Taylor D Paton C Kapur S 2009 The Maudsley Prescribing Guidelines Tenth ed CRC Press p 124 ISBN 9780203092835 Depakene valproic acid capsule liquid filled DailyMed 19 September 2019 Retrieved 14 April 2020 Depakin Banca Dati Farmaci dell AIFA Depakin The AIFA Medicines Database farmaci agenziafarmaco gov it in Italian Italian Medicines Agency 6 June 2023 Archived from the original on 6 June 2023 Retrieved 6 June 2023 a b c d Australian product information epilim sodium valproate crushable tablets enteric coated tablets syrup liquid PDF TGA eBS 15 April 2020 Retrieved 15 April 2020 Sodium valproate Pharmaceutical Schedule Pharmaceutical Management Agency Archived from the original on 4 March 2016 Retrieved 22 June 2014 South African Electronic Package Inserts Convulex Archived from the original on 12 August 2010 Retrieved 2 January 2006 Malaysian Package Inserts Epilim Retrieved 5 June 2023 Management of Infantile Epilepsies effectivehealthcare ahrq gov doi 10 23970 ahrqepccer252 Retrieved 12 July 2023 External links Edit Valproic acid Drug Information Portal U S National Library of Medicine Valproate sodium Drug Information Portal U S National Library of Medicine Divalproex sodium Drug Information Portal U S National Library of Medicine Portal Medicine Retrieved from https en wikipedia org w index php title Valproate amp oldid 1165380713, wikipedia, wiki, book, books, library,

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