Valproate
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Trade names | Depakote, Epilim, Convulex,others |
Other names | VPA; valproic acid; sodium valproate (sodium); valproate semisodium (semisodium); 2-propylvaleric acid |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682412 |
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Routes of administration | By mouth,intravenous |
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Pharmacokineticdata | |
Bioavailability | Rapid absorption |
Protein binding | 80–90%[6] |
Metabolism | Liver—glucuronide conjugation30–50%,mitochondrial β-oxidationover 40% |
Eliminationhalf-life | 9–16 hours[6] |
Excretion | Urine (30–50%)[6] |
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CompTox Dashboard(EPA) | |
ECHA InfoCard | 100.002.525 |
Chemical and physical data | |
Formula | C8H16O2 |
Molar mass | 144.214g·mol−1 |
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Valproate(valproic acid,VPA,sodium valproate,andvalproate semisodiumforms) are medications primarily used to treatepilepsyandbipolar disorderand preventmigraine headaches.[7]They are useful for the prevention of seizures in those withabsence seizures,partial seizures,andgeneralized seizures.[7]They can be givenintravenouslyor by mouth, and the tablet forms exist in both long- and short-acting formulations.[7]
Common side effects of valproate include nausea, vomiting,somnolence,and dry mouth.[7]Serious side effects can includeliver failure,and regular monitoring ofliver function testsis therefore recommended.[7]Other serious risks includepancreatitisand an increasedsuiciderisk.[7]Valproate is known to cause serious abnormalities in fetuses if taken duringpregnancy,[7][8]and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition and the recipient is also prescribed acontraceptive.[7][9][4]TheUnited States Food and Drug Administrationhas indicated ablack box warninggiven the frequency and severity of the side effects andteratogenicity.[4]Additionally, there is also a black box warning due to risk ofhepatotoxicityand pancreatitis.[10]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.[11]
Valproate's precise mechanism of action is unclear.[7][12]Proposed mechanisms include affectingGABAlevels, blockingvoltage-gated sodium channels,inhibitinghistone deacetylases,and increasingLEF1.[13][14][15]Valproic acid is a branchedshort-chain fatty acid(SCFA), aderivativeofvaleric acid.[13]
Valproate was originally synthesized in 1881 and came into medical use in 1962.[16]It is on theWorld Health Organization's List of Essential Medicines[17][18]and is available as ageneric medication.[7]In 2021, it was the 155th most commonly prescribed medication in the United States, with more than 3million prescriptions.[19][20]
Medical uses
[edit]![](https://upload.wikimedia.org/wikipedia/commons/thumb/a/af/Depakote_500mg_ER.jpg/250px-Depakote_500mg_ER.jpg)
It is used primarily to treatepilepsyandbipolar disorderand to preventmigraine headaches.[21]
Epilepsy
[edit]Valproate has a broad spectrum ofanticonvulsantactivity, although it is primarily used as a first-line treatment fortonic–clonic seizures,absence seizuresandmyoclonic seizuresand as a second-line treatment forpartial seizuresandinfantile spasms.[21][22]It has also been successfully givenintravenouslyto treatstatus epilepticus.[23][24]
In the US, valproic acid is an anti-epileptic drugindicatedfor 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.[4][5]
Mental illness
[edit]Valproate products are used to treat manic or mixed episodes ofbipolar disorder.[25][26]
A 2016systematic reviewcompared the efficacy of valproate as an add-on for people withschizophrenia:[27]
There is limited evidence that adding valproate toantipsychoticsmay 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.[27] | ||||||||||||||||||||||||||||||||||||||||||||||||
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Other neurological indications
[edit]Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of thedopamine dysregulation syndromethat arise from the treatment ofParkinson's diseasewithlevodopa.[28][29][30]
Valproate is also used to preventmigraine headaches.
Other
[edit]The medication has been tested in the treatment ofAIDSandcancer,owing to itshistone-deacetylase-inhibiting effects.It has cardioprotective, kidney protective, antiinflammatory, and antimicrobial effects.[31]
Contraindications
[edit]Contraindications include:
- Pre-existing acute or chronic liver dysfunction or family history of severeliver inflammation(hepatitis), particularly medicine related.[32]
- Knownhypersensitivityto valproate or any of the ingredients used in the preparation[32]
- Urea cycle disorders[32]
- Hepaticporphyria[32]
- Hepatotoxicity[32]
- Mitochondrial disease[32]
- Pancreatitis[32]
- Porphyria[33]
- Pregnancy(except when no other treatments are available for the treatment of epilepsy)
Adverse effects
[edit]Most common adverse effects include:[4]
- Nausea (22%)
- Drowsiness(19%)
- Dizziness (12%)
- Vomiting (12%)
- Weakness(10%)
Serious adverse effects include:[4]
- Bleeding
- Low blood platelets
- Encephalopathy
- Suicidal behavior and thoughts
- Low body temperature
Valproic acid has ablack box warningforhepatotoxicity,pancreatitis,and fetal abnormalities.[4]
There is evidence that valproic acid may cause premature growth plateossificationin children and adolescents, resulting in decreased height.[34][35][36]Valproic acid can also causemydriasis,a dilation of the pupils.[37]There is evidence that shows valproic acid may increase the chance ofpolycystic 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.[38]Weight gain is also possible.[39]
Pregnancy
[edit]![]() | It has been suggested thatFetal valproate spectrum disorderbemergedinto this section. (Discuss)Proposed since August 2024. |
Valproate causesbirth defects;[40]exposure duringpregnancyis associated with about three times as many major abnormalities as usual, mainlyspina bifidawith the risks being related to the strength of medication used and use of more than one drug.[41][42]"Fetal Valproate Syndrome"(FVS) has been used to refer to the effects of valproate exposure in utero.[43]However, similar to the discussion about the adverse effect of exposure toalcoholin 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). Thedysmorphic featuresassociated with VPA exposure can be subtle and age-dependent, making it challenging to designate individuals as having the characteristic dysmorphism or not, especially for those with limited expertise in the area. While the presence of typical facial dysmorphism is suggestive of the condition, it is not required for diagnosis. This change in terminology to FVSD would benefit individuals affected by the neurodevelopmental effects of VPA exposure without significant malformations, since they can experience impairments in their everyday functioning similar to those with classical FVS.[44]Characteristics of valproate syndrome may include facial features that tend to evolve with age, including atriangle-shaped forehead,tall forehead with bifrontal narrowing,epicanthic folds,medial deficiency of eyebrows, flat nasal bridge, broadnasal root,anteverted nares, shallowphiltrum,long upper lip and thinvermillion borders,thick lower lip and small downturned mouth.[45]Whiledevelopmental delayis usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[46]
Children of mothers taking valproate during pregnancy are at risk for lowerIQs.[47][48][49]Maternal valproate use during pregnancy increased the probability ofautismin the offspring compared to mothers not taking valproate from 1.5% to 4.4%.[50]A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[51]The normal incidence for autism in the general population in 2018 was estimated at 1 in 44 (2.3%).[52]An updated March 2023 report estimates the number increased to 1 in 36 in 2020 (approximately 4% of boys and 1% of girls).[53]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.[54][55][56]
Sodium valproate has been associated withparoxysmal tonic upgazeof childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.[57][58]
Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate.[59]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 takingfolic acidsupplements can reduce the risk of congenitalneural tubedefects.[4]The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in theEuropean Unionand theUnited States,and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.[60]
Paternal exposure
[edit]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.[61]: 9 This led theEMAto 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."[61]: 26
Elderly
[edit]Valproate may cause increased somnolence in the elderly. In a trial of valproate in elderly patients withdementia,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.[4]
Overdose and toxicity
[edit]Form | Lower limit | Upper limit | Unit |
Total (including protein bound) |
50[62] | 125[62] | μg/mL or mg/L |
350[63] | 700[63] | μmol/L | |
Free | 6[62] | 22[62] | μg/mL or mg/L |
35[63] | 70[63] | μmol/L |
Excessive amounts of valproic acid can result in somnolence,tremor,stupor,respiratory depression,coma,metabolic acidosis,and death. In general, serum or plasma valproic acid concentrations are in a range of 20–100 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 employgas or liquid chromatography.[64] In contrast to otherantiepileptic 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).[65]
In severe intoxication,hemoperfusionorhemofiltrationcan be an effective means of hastening elimination of the drug from the body.[66][67]Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.[4]SupplementalL-carnitineis indicated in patients having an acute overdose[68][69]and alsoprophylactically[68]in high risk patients.Acetyl-L-carnitinelowershyperammonemialess markedly[70]thanL-carnitine.
Interactions
[edit]Valproate inhibitsCYP2C9,glucuronyl transferase,andepoxide hydrolaseand is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves.[32]It may also potentiate the CNS depressant effects of alcohol.[32]It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (includingcarbamazepine,lamotrigine,phenytoinandphenobarbitone) and itself.[32]It may also interact with:[4][32][71]
- Aspirin:may increase valproate concentrations. May also interfere with valproate's metabolism.
- Benzodiazepines:may cause CNS depression and there are possible pharmacokinetic interactions.
- Carbapenemantibiotics: 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 directepileptogeniceffects of mefloquine.
- Oral contraceptives:may reduce plasma concentrations of valproate.
- Primidone:may accelerate metabolism of valproate, leading to a decline of serum levels and potentialbreakthrough 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
[edit]Pharmacodynamics
[edit]Although the mechanism of action of valproate is not fully understood,[32]traditionally, its anticonvulsant effect has been attributed to the blockade ofvoltage-gated sodium channelsand increased brain levels of the inhibitory synaptic neurotransmittergamma-aminobutyric acid(GABA).[32]The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[32]In animals, sodium valproate raises cerebral and cerebellar levels of GABA, possibly by inhibiting GABA degradative enzymes, such asGABA transaminase,succinate-semialdehyde dehydrogenaseand by inhibiting the re-uptake of GABA by neuronal cells.[32] Prevention of neurotransmitter-induced hyperexcitability of nerve cells viaKv7.2 channelandAKAP5may also contribute to its mechanism.[72]Valproate has been shown to protect against a seizure-induced reduction inphosphatidylinositol (3,4,5)-trisphosphate(PIP3) as a potential therapeutic mechanism.[73]
Valproate is ahistone deacetylase inhibitor.By inhibition ofhistone deacetylase,it promotes more transcriptionally active chromatin structures, that is it exerts an epigenetic effect. This has been proven in mice: Valproic acid induced histone hyperacetylation had brain function effects on the next generation of mice through changes in sperm DNA methylation.[74]Intermediate molecules includeVEGF,BDNF,andGDNF.[75][76]
Endocrine actions
[edit]Valproic acid has been found to be anantagonistof theandrogenandprogesterone receptors,and hence as anonsteroidalantiandrogenandantiprogestogen,at concentrations much lower than therapeutic serum levels.[77]In addition, the drug has been identified as a potentaromatase inhibitor,and suppressesestrogenconcentrations.[78]These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[77][78]
Valproic acid has been found to directly stimulate androgen biosynthesis in thegonadsvia inhibition of histone deacetylases and has been associated withhyperandrogenismin women and increased4-androstenedionelevels in men.[79][80]High rates ofpolycystic ovary syndromeandmenstrual disordershave also been observed in women treated with valproic acid.[80]
Pharmacokinetics
[edit]![](https://upload.wikimedia.org/wikipedia/commons/thumb/6/6d/Valproic_acid_metabolism.svg/250px-Valproic_acid_metabolism.svg.png)
Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.[81]When in the bloodstream, 80–90% of the substance are bound toplasma proteins,mainlyalbumin.Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patient's age, additional use of other drugs such asaspirin,as well as liver and kidney impairment.[83][84]Concentrations in thecerebrospinal fluidand in breast milk are 1 to 10% of blood plasma concentrations.[81]
The vast majority of valproatemetabolismoccurs in theliver.[85]Valproate is known to be metabolized by thecytochrome P450enzymesCYP2A6,CYP2B6,CYP2C9,andCYP3A5.[85]It is also known to be metabolized by theUDP-glucuronosyltransferaseenzymesUGT1A3,UGT1A4,UGT1A6,UGT1A8,UGT1A9,UGT1A10,UGT2B7,andUGT2B15.[85]Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):[85]
- viaglucuronidation(30–50%): valproic acid β-O-glucuronide
- viabeta oxidation(>40%): 2E-ene-valproic acid, 2Z-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid
- viaomega 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.[81]
In adult patients taking valproate alone, 30–50% of an administered dose is excreted inurineas the glucuronide conjugate.[85]The other major pathway in the metabolism of valproate ismitochondrialbeta oxidation, which typically accounts for over 40% of an administered dose.[85]Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.[85]Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.[85]Only a small amount is excreted via the faeces.[81]Elimination half-lifeis 16±3 hours and can decrease to 4–9 hours when combined withenzyme inducers.[81][84]
Chemistry
[edit]Valproic acid is a branchedshort-chain fatty acidand the 2-n-propylderivative ofvaleric acid.[13]
History
[edit]Valproic acid was first synthesized in 1882 byBeverly S. Burtonas ananalogueofvaleric acid,found naturally invalerian.[86]Valproic acid is acarboxylic 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 preventedpentylenetetrazol-induced convulsions inlaboratory rats.[87]It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[88]Valproic acid has also been used for migraineprophylaxisand bipolar disorder.[89]
Society and culture
[edit]Valproate is available as ageneric medication.[7]
Approval status
[edit]![]() | This section needs to beupdated.(February 2024) |
Indications | ![]() FDA-labelled indication?[6] |
![]() TGA-labelled indication?[21] |
![]() MHRA-labelled indication?[90] |
Literature support |
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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 againstglioblastomaand other tumors both to improve survival and treat seizures, and againsttonic–clonic seizuresand status epilepticus).[91][92][93][94] |
Bipolar mania | Yes | Yes | Yes | Limited.[95][failed verification] |
Bipolar depression | No | No | No | Moderate.[96] |
Bipolar maintenance | No | No | No | Limited.[97] |
Migraine prophylaxis | Yes | Yes (accepted) | No | Limited. |
Acute migraine management | No | No | No | Only negative results.[98] |
Schizophrenia | No | No | No | Weak evidence.[99] |
Agitation in dementia | No | No | No | Weak evidence. Not recommended for agitation in people with dementia.[100]Increased rate of adverse effects, including a risk of serious adverse effects.[100] |
Fragile X syndrome | Yes (orphan) | No | No | Limited.[76] |
Familial adenomatous polyposis | Yes (orphan) | No | No | Limited. |
Chronic pain & fibromyalgia | No | No | No | Limited.[101] |
Alcohol hallucinosis | No | No | No | One randomised double-blind placebo-controlled trial.[102] |
Intractable hiccups | No | No | No | Limited, five case reports support its efficacy, however.[103] |
Non-epileptic myoclonus | No | No | No | Limited, three case reports support its efficacy, however.[104] |
Cluster headaches | No | No | No | Limited, two case reports support its efficacy.[105] |
West syndrome | No | No | No | A prospective clinical trial supported its efficacy in treating infantile spasms.[106] |
HIV infection eradication | No | No | No | Double-blind placebo-controlled trials have been negative.[107][108][109] |
Myelodysplastic syndrome | No | No | No | Several clinical trials have confirmed its efficacy as a monotherapy,[110]as an adjunct totretinoin[110]and as an adjunct to hydralazine.[111] |
Acute myeloid leukaemia | No | No | No | Two clinical trials have confirmed its efficacy in this indication as both a monotherapy and as an adjunct totretinoin.[112][113][114] |
Cervical cancer | No | No | No | One clinical trial supports its use here.[115] |
Malignant melanoma | No | No | No | One phase II study has seemed to discount its efficacy.[116] |
Breast cancer | No | No | No | A phase II study has supported its efficacy.[117] |
Impulse control disorder | No | No | No | Limited.[118][119] |
Off-label uses
[edit]In 2012, pharmaceutical companyAbbottpaid $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.[120][121]
Some studies have suggested that valproate may reopen thecritical periodfor learningabsolute pitchand possibly other skills such as language.[122][123]
Formulations
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Other names | valproate sodium (USANUS) |
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ECHA InfoCard | 100.002.525 |
Chemical and physical data | |
Formula | C8H15NaO2 |
Molar mass | 166.196g·mol−1 |
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Trade names | Depakote, others | ||
Other names | semisodium valproate, divalproex sodium (USANUS) | ||
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ECHA InfoCard | 100.002.525 | ||
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Formula | C16H31NaO4 | ||
Molar mass | 310.410g·mol−1 | ||
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Valproate exists in two main molecular variants:sodium valproateandvalproic acid without sodium(often implied by simplyvalproate). A mixture between these two is termedsemisodium valproate.It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass ofsodium valproateis needed thanvalproic acid without sodiumto compensate for the sodium itself.[126]
Terminology
[edit]Valproate is a negative ion. Theconjugate acidof 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 sodiumsaltof valproic acid. Divalproex sodium is acoordination complexcomposed of equal parts of valproic acid and sodium valproate.[127]
Brand names of valproic acid
[edit]Branded products include:
- Absenor (Orion CorporationFinland)
- Convulex (G.L. Pharma GmbHAustria)
- Depakene (Abbott Laboratoriesin US and Canada)[128]
- Depakin (Sanofi S.R.L.Italy)[129]
- Depakine (Sanofi AventisFrance)
- Depakine (Sanofi SynthelaboRomania)
- Depalept (Sanofi AventisIsrael)
- Deprakine (Sanofi AventisFinland)
- Encorate (Sun PharmaceuticalsIndia)
- Epival (Abbott LaboratoriesUS and Canada)
- Epilim (Sanofi SynthelaboAustralia and South Africa)
- Stavzor (Noven Pharmaceuticals Inc.)
- Valcote (Abbott LaboratoriesArgentina)
- Valpakine (Sanofi AventisBrazil)
- Orfiril (Desitin Arzneimittel GmbH Norway)
Brand names of sodium valproate
[edit]Portugal
[edit]- Tablets – Diplexil-R byBial.
United States
[edit]- Intravenous injection – Depacon by Abbott Laboratories.
- Syrup – Depakene by Abbott Laboratories. (Note: Depakenecapsulesare valproic acid).
- Depakote tablets are a mixture of sodium valproate and valproic acid.
- Tablets – Eliaxim by Bial.
Australia
[edit]- Epilim Crushable Tablets Sanofi[130]
- Epilim Sugar Free Liquid Sanofi[130]
- Epilim Syrup Sanofi[130]
- Epilim Tablets Sanofi[130]
- Sodium Valproate Sandoz Tablets Sanofi
- Valpro Tablets Alphapharm
- Valproate Winthrop Tablets Sanofi
- Valprease tablets Sigma
New Zealand
[edit]- Epilim by Sanofi-Aventis
All the above formulations arePharmac-subsidised.[131]
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 valproateenteric-coatedtablet.
UK only
[edit]- 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
[edit]- Tablets – Orfiril by Desitin Pharmaceuticals
- Intravenous injection – Orfiril IV by Desitin Pharmaceuticals
South Africa
[edit]- Syrup – Convulex by Byk Madaus[132]
- Tablets – Epilim by Sanofi-synthelabo
Malaysia
[edit]- Tablets – Epilim (200 ENTERIC COATED) by Sanofi-Aventis
- Controlled release tablets – Epilim Chrono (500 CONTROLLED RELEASE) by Sanofi-Aventis[133]
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 tablets
Canada
[edit]- Intravenous injection – Epival or Epiject byAbbott Laboratories.
- Syrup – Depakene byAbbott Laboratoriesits generic formulations includeApo-Valproicandratio-Valproic.
Japan
[edit]- Tablets – Depakene byKyowa Hakko Kirin
- Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R byKowa
- Syrup – Depakene by Kyowa Hakko Kogyo
Europe
[edit]In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.
Taiwan
[edit]- Tablets (white round tablet) – Depakine (Chinese:Đế bạt điên;pinyin:di-ba-dian) bySanofi 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 bySanofi Winthrop Industrie(France)
Israel
[edit]Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed bySanofi-Aventis.
- 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
[edit]- Tablets – DI DPA by Megalabs
Brand names of valproate semisodium
[edit]- Brazil – Depakote byAbbott Laboratoriesand 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) bySanofi-Aventisand generics
- United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics[4]
- 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
[edit]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.[134]
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