Valproate ( valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches.[ They can be given or by mouth, and the tablet forms exist in both long- and short-acting formulations.][
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Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth.[ Serious side effects can include Hepatotoxicity, and regular monitoring of liver function tests is therefore recommended.][ Other serious risks include pancreatitis and an increased suicide risk.][ Valproate is known to cause serious abnormalities or birth defects in the unborn child if taken during pregnancy,]
Valproate's precise mechanism of action is unclear.[
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Valproate was originally synthesized in 1881 and came into medical use in 1962.[ In 2022, it was the 174th most commonly prescribed medication in the United States, with more than 2million prescriptions.]
Medical uses
Valproate or valproic acid is used primarily to treat epilepsy and bipolar disorder and to prevent migraine headaches.[
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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.
In the US, valproic acid is also prescribed as an anti-epileptic drug indicated for the treatment of manic episodes associated with bipolar disorder; monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in people with multiple seizure types that include absence seizures.
Mental illness
Valproate products are used to treat manic or mixed episodes of bipolar disorder.
A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:
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There is limited evidence that adding valproate to 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. |
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| When added to antipsychotic drugs valproate probably increases the chance of improvement. Data are based on moderate quality evidence.
| Moderate
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| 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.
| Moderate
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| 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.
| Very low
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| Moderate |
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| Adding valproate to antipsychotic drug treatment does not clearly cause liver problems. Data supporting this finding are based on moderate quality evidence.
| Moderate
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| 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.
| Moderate
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Other neurological indications
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.
Valproate is not commonly used to prevent or treat Migraine, but it may be prescribed if other medications are not effective.
Other
The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects. It has cardioprotective, kidney protective, antiinflammatory, and antimicrobial effects.
Contraindications
Contraindications include:
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Pre-existing acute or chronic liver dysfunction or family history of severe hepatitis (hepatitis), particularly medicine related.
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Pregnancy 11% risk of birth defects and 30-40% risk of neuro-developmental disabilities which can be permanent
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Known hypersensitivity to valproate or any of the ingredients used in the preparation
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Urea cycle disorders
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Hepatic porphyria
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Hepatotoxicity
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Mitochondrial disease
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Pancreatitis
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Porphyria
Adverse effects
Most common adverse effects include:
Serious adverse effects include:
Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.
Pregnancy
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.
Overdose and toxicity
| + Therapeutic range of valproic acid |
| Form | Lower limit | Upper limit | Unit |
Total (including
protein bound) | μg/mL or mg/L |
| μmol/L |
| Free | μg/mL or mg/L |
| 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 employ Chromatography
In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622–1626.] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.[ in high risk patients. Acetylcarnitine lowers hyperammonemia less markedly]
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.[ It may also potentiate the CNS depressant effects of alcohol.][ 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 Phenobarbital) and itself.][ It may also interact with:]
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Aspirin: may increase valproate concentrations. May also interfere with valproate's metabolism.
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: may cause CNS depression and there are possible pharmacokinetic interactions.
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Carbapenem antibiotics: reduce valproate levels, potentially leading to seizures.
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Cimetidine: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
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Erythromycin: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
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Ethosuximide: valproate may increase ethosuximide concentrations and lead to toxicity.
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Felbamate: may increase plasma concentrations of valproate.
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Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
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Oral contraceptives: may reduce plasma concentrations of valproate.
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Primidone: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure.
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Rifampicin: increases the clearance of valproate, leading to decreased valproate concentrations.
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Warfarin: valproate may increase free warfarin concentration and prolong bleeding time.
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Zidovudine: valproate may increase zidovudine serum concentration and lead to toxicity.
Pharmacology
Pharmacodynamics
Although the mechanism of action of valproate is not fully understood,[ traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of the inhibitory synaptic neurotransmitter gamma-aminobutyric acid (GABA).][ The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.][ In animals, sodium valproate raises cerebral and cerebellar levels of 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.][
Prevention of neurotransmitter-induced hyperexcitability of nerve cells via Kv7.2 channel and AKAP5 may also contribute to its mechanism.]
Valproate is a histone deacetylase inhibitor. By inhibition of histone 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.
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.
Valproic acid has been found to directly stimulate androgen biosynthesis in the via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men.
Pharmacokinetics
Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.[Valproate . Accessed 6 August 2021.] Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.
The vast majority of valproate Drug metabolism occurs in the liver.
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via glucuronidation (30–50%): valproic acid β-O-glucuronide
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via beta oxidation (>40%): 2 E-ene-valproic acid, 2 Z-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid
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via omega oxidation: 5-hydroxyvalproic acid, 2-propyl-glutaric acid
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some others: 3 E-ene-valproic acid, 3 Z-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acid
All in all, over 20 metabolites are known.
In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate.
Chemistry
Valproic acid is a branched short-chain fatty acid and the 2- n-propyl derivative of valeric acid.
History
Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.
Society and culture
Valproate is available as a generic medication.[
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Approval status
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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). |
Limited. |
Moderate. |
Limited. |
| Limited. |
Only negative results. |
Weak evidence. |
Weak evidence. Not recommended for agitation in people with dementia. |
Limited. |
| Limited. |
Limited. |
One randomised double-blind placebo-controlled trial. |
Limited, five case reports support its efficacy, however. |
Limited, three case reports support its efficacy, however. |
Limited, two case reports support its efficacy. |
A prospective clinical trial supported its efficacy in treating infantile spasms. |
Double-blind placebo-controlled trials have been negative. |
Several clinical trials have confirmed its efficacy as a monotherapy,[ and as an adjunct to hydralazine.] |
Two clinical trials have confirmed its efficacy in this indication as both a monotherapy and as an adjunct to tretinoin. |
One clinical trial supports its use here. |
One phase II study has seemed to discount its efficacy. |
A phase II study has supported its efficacy. |
Limited. |
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.
Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.
Formulations
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.
Magnesium valproate is also available in China.
Terminology
Valproate is a negative ion. The conjugate base of valproate is valproic acid (VPA). Valproic acid is fully ionized into valproate at the physiologic pH of the human body, and valproate is the active form of the drug. Sodium valproate is the sodium salt of valproic acid. Divalproex sodium is a coordination complex composed of equal parts of valproic acid and sodium valproate.
Brand names of valproic acid
Branded products include:
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Absenor (Orion Corporation Finland)
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Convulex (G.L. Pharma GmbH Austria)
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Depakene (Abbott Laboratories in US and Canada)
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Depakin (Sanofi Italy)
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Depakine (Sanofi Aventis France)
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Depakine (Sanofi Synthelabo Romania)
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Depalept (Sanofi Aventis Israel)
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Deprakine (Sanofi Aventis Finland)
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Encorate (Sun Pharmaceuticals India)
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Epilim (Sanofi Synthelabo Australia and South Africa)
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Stavzor (Noven Pharmaceuticals Inc.)
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Valcote (Abbott Laboratories Argentina)
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Valpakine (Sanofi Aventis Brazil)
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Orfiril (Desitin Arzneimittel GmbH Norway)
Brand names of sodium valproate
Portugal
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Tablets Diplexil-R by Bial.
United States
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Intravenous injection Depacon by Abbott Laboratories.
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Syrup Depakene by Abbott Laboratories. (Note: Depakene capsules are valproic acid).
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Depakote tablets are a mixture of sodium valproate and valproic acid.
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Tablets Eliaxim by Bial.
Australia
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Epilim Crushable Tablets Sanofi
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Epilim Sugar Free Liquid Sanofi
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Epilim Syrup Sanofi
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Epilim Tablets Sanofi
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Sodium Valproate Sandoz Tablets Sanofi
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Valpro Tablets Alphapharm
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Valproate Winthrop Tablets Sanofi
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Valprease tablets Sigma
New Zealand
All the above formulations are Pharmac-subsidised.
UK
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Depakote Tablets (as in USA)
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Tablets Orlept by Wockhardt and Epilim by Sanofi
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Oral solution Orlept Sugar Free by Wockhardt and Epilim by Sanofi
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Syrup Epilim by Sanofi-Aventis
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Intravenous injection Epilim Intravenous by Sanofi
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Extended release tablets Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.
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Enteric-coated tablets Epilim EC200 by Sanofi is a 200 mg sodium valproate Enteric coating tablet.
UK only
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Capsules Episenta prolonged release by Beacon
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Sachets Episenta prolonged release by Beacon
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Intravenous solution for injection Episenta solution for injection by Beacon
Germany, Switzerland, Norway, Finland, Sweden
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Tablets Orfiril by Desitin Pharmaceuticals
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Intravenous injection Orfiril IV by Desitin Pharmaceuticals
South Africa
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Syrup Convulex by Byk Madaus
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Tablets Epilim by Sanofi-synthelabo
Malaysia
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Tablets Epilim ( 200 ENTERIC COATED) by Sanofi-Aventis
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Controlled release tablets Epilim Chrono ( 500 CONTROLLED RELEASE) by Sanofi-Aventis
Romania
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Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH
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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
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Intravenous injection Epival or Epiject by Abbott Laboratories.
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Syrup Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic.
Japan
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Tablets Depakene by Kyowa Hakko Kirin
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Extended release tablets Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa
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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
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Tablets (white round tablet) Depakine (p=di-ba-dian) by Sanofi-Aventis (France)
Iran
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Tablets Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo
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Slow release tablets Depakine Chrono by Sanofi-Aventis (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
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Valparin Chrono by Sanofi India
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Valprol CR by Intas Pharmaceutical (India)
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Encorate Chrono by Sun Pharmaceutical (India)
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Serven Chrono by Leeven APL Biotech (India)
Uruguay
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Tablets DI DPA by Megalabs
Brand names of valproate semisodium
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Brazil Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil
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Canada Epival by Abbott Laboratories
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Mexico Epival and Epival ER (extended release) by Abbott Laboratories
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United Kingdom Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics
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United States Depakote and Depakote ER (extended release) by Abbott Laboratories and generics
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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
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Germany Ergenyl Chrono by Sanofi-Aventis and generics
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Chile Valcote and Valcote ER by Abbott Laboratories
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France and other European countries Depakote
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Peru Divalprax by AC Farma Laboratories
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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.
