Valproate
Clinical data | |
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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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mitochondrial β-oxidation over 40% | |
Elimination half-life | 9–16 hours[5] |
Excretion | Urine (30–50%)[5] |
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Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat
Common side effects of valproate include nausea, vomiting,
Valproate's precise mechanism of action is unclear.
Valproate was first made in 1881 and came into medical use in 1962.
Medical uses
It is used primarily to treat
Epilepsy
Valproate has a broad spectrum of
In the US, valproic acid is an anti-epileptic drug
Mental illness
Valproate products are used to treat manic or mixed episodes of bipolar disorder.[23][24]
A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:[25]
There is limited evidence that adding valproate to antipsychotics may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Valproate was associated with a number of adverse events among which sedation and dizziness appeared more frequently than in the control groups.[25] | ||||||||||||||||||||||||||||||||||||||||||||||||
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Other neurological indications
Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the
Valproate is also used to prevent migraine headaches.
Other
The medication has been tested in the treatment of
Contraindications
Contraindications include:
- Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.[30]
- Known hypersensitivity to valproate or any of the ingredients used in the preparation[30]
- Urea cycle disorders[30]
- Hepatic porphyria[30]
- Hepatotoxicity[30]
- Mitochondrial disease[30]
- Pancreatitis[30]
- Porphyria[31]
- Pregnancy (except when no other treatments are available for the treatment of epilepsy)
Adverse effects
Most common adverse effects include:[3]
- Nausea (22%)
- Drowsiness (19%)
- Dizziness (12%)
- Vomiting (12%)
- Weakness (10%)
Serious adverse effects include:[3]
- Bleeding
- Low blood platelets
- Encephalopathy
- Suicidal behavior and thoughts
- Low body temperature
Valproic acid has a
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[32][33][34] Valproic acid can also cause mydriasis, a dilation of the pupils.[35] There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder.[36] Weight gain is also possible.[37]
Pregnancy
Valproate causes
Children of mothers taking valproate during pregnancy are at risk for lower
Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.[55][56]
Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate.
Paternal exposure
A 2023 retrospective study of Norway Denmark and Sweden found a significantly increased risk of neurodevelopmental disabilities in the children of fathers exposed to valproate up to 3 months prior to conception, compared to offspring paternally exposed to lamotrigine/levetiracetam.[59]: 9 This led the EMA to recommend "the need to consider effective contraception, while using valproate and for at least 3 months after treatment discontinuation. Male patients should not donate sperm during treatment and for at least 3 months after treatment discontinuation."[59]: 26
Elderly
Valproate may cause increased somnolence in the elderly. In a trial of valproate in elderly patients with dementia, a significantly higher portion of valproate patients had somnolence compared to placebo. In approximately one-half of such patients, there was associated reduced nutritional intake and weight loss.[3]
Overdose and toxicity
Form | Lower limit | Upper limit | Unit |
Total (including protein bound) |
50[60] | 125[60] | µg/mL or mg/L |
350[61] | 700[61] | μmol/L | |
Free | 6[60] | 22[60] | µg/mL or mg/L |
35[61] | 70[61] | μmol/L |
Excessive amounts of valproic acid can result in somnolence,
In severe intoxication,
Interactions
Valproate inhibits
- Aspirin: may increase valproate concentrations. May also interfere with valproate's metabolism.
- Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
- Carbapenem antibiotics: reduce valproate levels, potentially leading to seizures.
- Cimetidine: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
- Erythromycin: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
- Ethosuximide: valproate may increase ethosuximide concentrations and lead to toxicity.
- Felbamate: may increase plasma concentrations of valproate.
- Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
- Oral contraceptives: may reduce plasma concentrations of valproate.
- breakthrough seizure.
- Rifampicin: increases the clearance of valproate, leading to decreased valproate concentrations
- Warfarin: valproate may increase free warfarin concentration and prolong bleeding time.
- Zidovudine: valproate may increase zidovudine serum concentration and lead to toxicity.
Pharmacology
Pharmacodynamics
Although the mechanism of action of valproate is not fully understood,
Valproate is a
Endocrine actions
Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels.[75] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[76] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[75][76]
Valproic acid has been found to directly stimulate androgen biosynthesis in the
Pharmacokinetics
Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.
The vast majority of valproate
- via glucuronidation (30–50%): valproic acid β-O-glucuronide
- via beta oxidation (>40%): 2E-ene-valproic acid, 2Z-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid
- via omega oxidation: 5-hydroxyvalproic acid, 2-propyl-glutaric acid
- some others: 3E-ene-valproic acid, 3Z-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acid
All in all, over 20 metabolites are known.[79]
In adult patients taking valproate alone, 30–50% of an administered dose is excreted in
Chemistry
Valproic acid is a branched
History
Valproic acid was first synthesized in 1882 by
Society and culture
Valproate is available as a
Approval status
This section needs to be updated.(February 2024) |
Indications | FDA-labelled indication?[5] |
TGA-labelled indication?[19] |
MHRA-labelled indication?[88] |
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 against |
Bipolar mania | Yes | Yes | Yes | Limited.[93][failed verification] |
Bipolar depression | No | No | No | Moderate.[94] |
Bipolar maintenance | No | No | No | Limited.[95] |
Migraine prophylaxis | Yes | Yes (accepted) | No | Limited. |
Acute migraine management | No | No | No | Only negative results.[96] |
Schizophrenia | No | No | No | Weak evidence.[97] |
Agitation in dementia | No | No | No | Weak evidence. Not recommended for agitation in people with dementia.[98] Increased rate of adverse effects, including a risk of serious adverse effects.[98] |
Fragile X syndrome | Yes (orphan) | No | No | Limited.[74] |
Familial adenomatous polyposis | Yes (orphan) | No | No | Limited. |
Chronic pain & fibromyalgia | No | No | No | Limited.[99] |
Alcohol hallucinosis | No | No | No | One randomised double-blind placebo-controlled trial.[100] |
Intractable hiccups | No | No | No | Limited, five case reports support its efficacy, however.[101] |
Non-epileptic myoclonus | No | No | No | Limited, three case reports support its efficacy, however.[102] |
Cluster headaches | No | No | No | Limited, two case reports support its efficacy.[103] |
West syndrome |
No | No | No | A prospective clinical trial supported its efficacy in treating infantile spasms.[104] |
HIV infection eradication | No | No | No | Double-blind placebo-controlled trials have been negative.[105][106][107] |
Myelodysplastic syndrome | No | No | No | Several clinical trials have confirmed its efficacy as a monotherapy,[108] as an adjunct to tretinoin[108] and as an adjunct to hydralazine.[109] |
Acute myeloid leukaemia |
No | No | No | Two clinical trials have confirmed its efficacy in this indication as both a monotherapy and as an adjunct to tretinoin.[110][111][112] |
Cervical cancer | No | No | No | One clinical trial supports its use here.[113] |
Malignant melanoma |
No | No | No | One phase II study has seemed to discount its efficacy.[114] |
Breast cancer | No | No | No | A phase II study has supported its efficacy.[115] |
Impulse control disorder |
No | No | No | Limited.[116][117] |
Off-label uses
In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.[118][119]
Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.[120][121]
Formulations
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Other names | valproate sodium (USAN US) |
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Trade names | Depakote, others | ||
Other names | semisodium valproate, divalproex sodium (USAN US) | ||
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Valproate exists in two main molecular variants: sodium valproate and valproic acid without sodium (often implied by simply valproate). A mixture between these two is termed semisodium valproate. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.[124]
Terminology
Valproate is a negative ion. The
Brand names of valproic acid
Branded products include:
- Absenor (Orion Corporation Finland)
- Convulex (G.L. Pharma GmbH Austria)
- Depakene (Abbott Laboratories in US and Canada)[126]
- Depakin (Sanofi S.R.L. Italy)[127]
- Depakine (Sanofi AventisFrance)
- Depakine (Sanofi SynthelaboRomania)
- Depalept (Sanofi AventisIsrael)
- Deprakine (Sanofi AventisFinland)
- Encorate (Sun PharmaceuticalsIndia)
- Epival (Abbott Laboratories US and Canada)
- Epilim (Sanofi SynthelaboAustralia and South Africa)
- Stavzor (Noven Pharmaceuticals Inc.)
- Valcote (Abbott Laboratories Argentina)
- Valpakine (Sanofi AventisBrazil)
- Orfiril (Desitin Arzneimittel GmbH Norway)
Brand names of sodium valproate
Portugal
- Tablets – Diplexil-R by Bial.
United States
- Intravenous injection – Depacon by Abbott Laboratories.
- Syrup – Depakene by Abbott Laboratories. (Note: Depakene capsules are valproic acid).
- Depakote tablets are a mixture of sodium valproate and valproic acid.
- Tablets – Eliaxim by Bial.
Australia
- Epilim Crushable Tablets Sanofi[128]
- Epilim Sugar Free Liquid Sanofi[128]
- Epilim Syrup Sanofi[128]
- Epilim Tablets Sanofi[128]
- Sodium Valproate Sandoz Tablets Sanofi
- Valpro Tablets Alphapharm
- Valproate Winthrop Tablets Sanofi
- Valprease tablets Sigma
New Zealand
- Epilim by Sanofi-Aventis
All the above formulations are
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[130]
- Tablets – Epilim by Sanofi-synthelabo
Malaysia
- Tablets – Epilim (200 ENTERIC COATED) by Sanofi-Aventis
- Controlled release tablets – Epilim Chrono (500 CONTROLLED RELEASE) by Sanofi-Aventis[131]
Romania
- Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH
- Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets
Canada
- Intravenous injection – Epival or Epiject by Abbott Laboratories.
- Syrup – Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic.
Japan
- Tablets – Depakene by Kyowa Hakko Kirin
- Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa
- Syrup – Depakene by Kyowa Hakko Kogyo
Europe
In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.
Taiwan
- Tablets (white round tablet) – Depakine (Sanofi Winthrop Industrie(France)
Iran
- Tablets – Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo
- Slow release tablets – Depakine Chrono by Sanofi Winthrop Industrie(France)
Israel
Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by
India, Russia and CIS countries
- Valparin Chrono by Sanofi India
- Valprol CR by Intas Pharmaceutical (India)
- Encorate Chrono by Sun Pharmaceutical (India)
- Serven Chrono by Leeven APL Biotech (India)
Uruguay
- Tablets – DI DPA by Megalabs
Brand names of valproate semisodium
- Brazil – Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil
- Canada – Epival by Abbott Laboratories
- Mexico – Epival and Epival ER (extended release) by Abbott Laboratories
- United Kingdom – Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventisand generics
- United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics[3]
- India – Valance and Valance OD by Abbott Healthcare Pvt Ltd, Divalid ER by Linux laboratories Pvt Ltd, Valex ER by Sigmund Promedica, Dicorate by Sun Pharma
- Germany – Ergenyl Chrono by Sanofi-Aventis and generics
- Chile – Valcote and Valcote ER by Abbott Laboratories
- France and other European countries – Depakote
- Peru – Divalprax by AC Farma Laboratories
- China – Diprate OD
Research
A 2023 systematic review of the literature identified only one study in which valproate was evaluated in the treatment of seizures in infants aged 1 to 36 months. In a randomized control trial, valproate alone was found to show poorer outcomes for infants than valproate plus levetiracetam in terms of reduction of seizures, freedom from seizures, daily living ability, quality of life, and cognitive abilities.[132]
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