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Valproate

(Redirected from Sodium valproate)

Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches.[7] They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.[7] They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.[7]

Valproate
INN: valproic acid
Clinical data
Trade namesDepakote, Epilim, Convulex, others
Other namesVPA; valproic acid; sodium valproate (sodium); valproate semisodium (semisodium); 2-propylvaleric acid
AHFS/Drugs.comMonograph
MedlinePlusa682412
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityRapid absorption
Protein binding80–90%[6]
MetabolismLiver—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Elimination half-life9–16 hours[6]
ExcretionUrine (30–50%)[6]
Identifiers
  • 2-propylpentanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.002.525 Edit this at Wikidata
Chemical and physical data
FormulaC8H16O2
Molar mass144.214 g·mol−1
3D model (JSmol)
  • O=C(O)C(CCC)CCC
  • InChI=1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10) checkY
  • Key:NIJJYAXOARWZEE-UHFFFAOYSA-N checkY
  (verify)

Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth.[7] Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended.[7] Other serious risks include pancreatitis and an increased suicide risk.[7] Valproate is known to cause serious abnormalities or birth defects in the unborn child if taken during pregnancy,[7][8] and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition and the person is also prescribed a contraceptive.[7][9][4] Reproductive warnings have also been issued for men using the drug.[10] The United States Food and Drug Administration has indicated a black box warning given the frequency and severity of the side effects and teratogenicity.[4] Additionally, there is also a black box warning due to risk of hepatotoxicity and pancreatitis.[11] 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.[12]

Valproate's precise mechanism of action is unclear.[7][13] Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, inhibiting histone deacetylases, and increasing LEF1.[14][15][16] Valproic acid is a branched short-chain fatty acid (SCFA), a derivative of valeric acid.[14]

Valproate was originally synthesized in 1881 and came into medical use in 1962.[17] It is on the World Health Organization's List of Essential Medicines[18][19] and is available as a generic medication.[7] In 2022, it was the 174th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[20][21]

Medical uses

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500mg tablets of Depakote extended-release

Valproate or valproic acid is used primarily to treat epilepsy and bipolar disorder and to prevent migraine headaches.[22]

Epilepsy

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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.[22][23] It has also been successfully given intravenously to treat status epilepticus.[24][25]

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.[4][5]

Mental illness

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Valproate products are used to treat manic or mixed episodes of bipolar disorder.[26][27]

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:[28]

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.[28]

Other neurological indications

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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.[29][30][31]

Valproate is not commonly used to prevent or treat migraine headaches, but it may be prescribed if other medications are effective.[32]

Other

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The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects.[citation needed] It has cardioprotective, kidney protective, antiinflammatory, and antimicrobial effects.[33]

Contraindications

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Contraindications include:

Adverse effects

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See also: List of adverse effects of valproate and List of adverse effects of valproate semisodium

Most common adverse effects include:[4]

Serious adverse effects include:[4]

Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.[4]

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[37][38][39] Valproic acid can also cause mydriasis, a dilation of the pupils.[40] 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.[41] Weight gain is also possible.[42]

Pregnancy

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This section is an excerpt from Fetal valproate spectrum disorder.[edit]
 
Minor limb malformations seen after valproate exposure
Fetal valproate spectrum disorder (FVSD), previously known as fetal valproate syndrome (FVS), is a rare disease caused by prenatal exposure to valproic acid (VPA), a medication commonly used to treat epilepsy, bipolar disorder, and migraines. This exposure can lead to a range of neurodevelopmental and physical symptoms, including cognitive impairments, developmental delays, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and congenital malformations.[43][44][45]

Elderly

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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.[4]

Overdose and toxicity

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Therapeutic range of valproic acid
Form Lower limit Upper limit Unit
Total (including
protein bound) 		50[46] 125[46] μg/mL or mg/L
350[47] 700[47] μmol/L
Free 6[46] 22[46] μg/mL or mg/L
35[47] 70[47] 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 gas or liquid chromatography.[48] 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).[49]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[50][51] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.[4] Supplemental L-carnitine is indicated in patients having an acute overdose[52][53] and also prophylactically[52] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[54] than L-carnitine.

Interactions

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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.[34] It may also potentiate the CNS depressant effects of alcohol.[34] 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.[34] It may also interact with:[4][34][55]

  • 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

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Pharmacodynamics

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Although the mechanism of action of valproate is not fully understood,[34] 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).[34] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[34] 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.[34] Prevention of neurotransmitter-induced hyperexcitability of nerve cells via Kv7.2 channel and AKAP5 may also contribute to its mechanism.[56] Valproate has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[57]

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.[58] Intermediate molecules include VEGF, BDNF, and GDNF.[59][60]

Endocrine actions

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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.[61] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[62] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[61][62]

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.[63][64] High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.[64]

Pharmacokinetics

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Some metabolites of valproic acid. Glucuronidation and β-oxidation are the main metabolic pathways; ω-oxidation metabolites are considered hepatotoxic.[65][66] Details see text.

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.[65] 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.[67][68] Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.[65]

The vast majority of valproate metabolism occurs in the liver.[69] Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6, CYP2B6, CYP2C9, and CYP3A5.[69] It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.[69] Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):[69]

  • 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.[65]

In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate.[69] The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose.[69] Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.[69] Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.[69] Only a small amount is excreted via the faeces.[65] Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.[65][68]

Chemistry

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Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.[14]

History

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Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.[70] 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.[71] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[72] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[73]

Society and culture

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Valproate is available as a generic medication.[7]

Approval status

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Indications  
FDA-labelled indication?[6] 		 
TGA-labelled indication?[22] 		 
MHRA-labelled indication?[74] 		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).[75][76][77][78]
Bipolar mania Yes Yes Yes Limited.[79][failed verification]
Bipolar depression No No No Moderate.[80]
Bipolar maintenance No No No Limited.[81]
Migraine prophylaxis Yes Yes (accepted) No Limited.
Acute migraine management No No No Only negative results.[82]
Schizophrenia No No No Weak evidence.[83]
Agitation in dementia No No No Weak evidence. Not recommended for agitation in people with dementia.[84] Increased rate of adverse effects, including a risk of serious adverse effects.[84]
Fragile X syndrome Yes (orphan) No No Limited.[60]
Familial adenomatous polyposis Yes (orphan) No No Limited.
Chronic pain & fibromyalgia No No No Limited.[85]
Alcohol hallucinosis No No No One randomised double-blind placebo-controlled trial.[86]
Intractable hiccups No No No Limited, five case reports support its efficacy, however.[87]
Non-epileptic myoclonus No No No Limited, three case reports support its efficacy, however.[88]
Cluster headaches No No No Limited, two case reports support its efficacy.[89]
West syndrome No No No A prospective clinical trial supported its efficacy in treating infantile spasms.[90]
HIV infection eradication No No No Double-blind placebo-controlled trials have been negative.[91][92][93]
Myelodysplastic syndrome No No No Several clinical trials have confirmed its efficacy as a monotherapy,[94] as an adjunct to tretinoin[94] and as an adjunct to hydralazine.[95]
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.[96][97][98]
Cervical cancer No No No One clinical trial supports its use here.[99]
Malignant melanoma No No No One phase II study has seemed to discount its efficacy.[100]
Breast cancer No No No A phase II study has supported its efficacy.[101]
Impulse control disorder No No No Limited.[102][103]

Off-label uses

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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.[104][105]

Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.[106][107]

Formulations

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Sodium valproate
 
 
Clinical data
Other namesvalproate sodium (USAN US)
License data
Legal status
Legal status
Identifiers
  • sodium 2-propylpentanoate
CAS Number
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ECHA InfoCard100.002.525  
Chemical and physical data
FormulaC8H15NaO2
Molar mass166.196 g·mol−1
3D model (JSmol)
  • CCCC(CCC)C(=O)[O-].[Na ]
  • InChI=1S/C8H16O2.Na/c1-3-5-7(6-4-2)8(9)10;/h7H,3-6H2,1-2H3,(H,9,10);/q; 1/p-1  Y
  • Key:AEQFSUDEHCCHBT-UHFFFAOYSA-M  Y
  (verify)
Valproate semisodium
   
Clinical data
Trade namesDepakote, others
Other namessemisodium valproate, divalproex sodium (USAN US)
License data
Legal status
Legal status
Identifiers
  • sodium 2-propylpentanoate;2-propylpentanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
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ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.002.525  
Chemical and physical data
FormulaC16H31NaO4
Molar mass310.410 g·mol−1
3D model (JSmol)
  • CCCC(CCC)C(=O)O.CCCC(CCC)C(=O)[O-].[Na ]
  • InChI=1S/2C8H16O2.Na/c2*1-3-5-7(6-4-2)8(9)10;/h2*7H,3-6H2,1-2H3,(H,9,10);/q;; 1/p-1  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.[110]

Terminology

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Valproate is a negative ion. The conjugate acid of valproate is valproic acid (VPA). Valproic acid is fully ionized into valproate at the physiologic pH of the human body, and valproate is the active form of the drug. Sodium valproate is the sodium salt of valproic acid. Divalproex sodium is a coordination complex composed of equal parts of valproic acid and sodium valproate.[111]

Brand names of valproic acid

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Branded products include:

Brand names of sodium valproate

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Portugal
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  • Tablets – Diplexil-R by Bial.
United States
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  • 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
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  • Epilim Crushable Tablets Sanofi[114]
  • Epilim Sugar Free Liquid Sanofi[114]
  • Epilim Syrup Sanofi[114]
  • Epilim Tablets Sanofi[114]
  • Sodium Valproate Sandoz Tablets Sanofi
  • Valpro Tablets Alphapharm
  • Valproate Winthrop Tablets Sanofi
  • Valprease tablets Sigma
New Zealand
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  • Epilim by Sanofi-Aventis

All the above formulations are Pharmac-subsidised.[115]

UK
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  • 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
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  • 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
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  • Tablets – Orfiril by Desitin Pharmaceuticals
  • Intravenous injection – Orfiril IV by Desitin Pharmaceuticals
South Africa
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  • Syrup – Convulex by Byk Madaus[116]
  • Tablets – Epilim by Sanofi-synthelabo
Malaysia
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  • Tablets – Epilim (200 ENTERIC COATED) by Sanofi-Aventis
  • Controlled release tablets – Epilim Chrono (500 CONTROLLED RELEASE) by Sanofi-Aventis[117]
Romania
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  • 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
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Japan
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  • 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
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In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.

Taiwan
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Iran
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  • 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
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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
  • Valprol CR by Intas Pharmaceutical (India)
  • Encorate Chrono by Sun Pharmaceutical (India)
  • 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
  • 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[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

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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.[118]

References

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  1. ^ a b c "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 3 August 2023.
  3. ^ "Product monograph brand safety updates". Health Canada. 7 July 2016. Retrieved 13 July 2024.
  4. ^ a b c d e f g h i j k l m "Depakote- divalproex sodium tablet, delayed release". Archived from the original on 5 March 2016. Retrieved 10 November 2015.
  5. ^ a b c d "Depakote ER- divalproex sodium tablet, extended release". DailyMed. 24 February 2023. Archived from the original on 28 January 2023. Retrieved 19 February 2024.
  6. ^ 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. Retrieved 13 February 2014.
  7. ^ a b c d e f g h i j k "Valproic Acid". The American Society of Health-System Pharmacists. 24 November 2020. Archived from the original on 31 July 2017.
  8. ^ "Valproate banned without the pregnancy prevention programme". GOV.UK. Archived from the original on 24 April 2018. Retrieved 26 April 2018.
  9. ^ "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. Archived from the original on 7 January 2023. Retrieved 17 April 2022.
  10. ^ "Men on sodium valproate told to use contraception". BBC News. BBC. Retrieved 5 September 2024.
  11. ^ "FDA Information on Valporate" (PDF).
  12. ^ Davis N (17 April 2022). "Sodium valproate: what are dangers of epilepsy drug for unborn babies?". The Observer. Archived from the original on 28 July 2022. Retrieved 17 April 2022.
  13. ^ Owens MJ, Nemeroff CB (2003). "Pharmacology of valproate". Psychopharmacology Bulletin. 37 (Suppl 2): 17–24. PMID 14624230.
  14. ^ 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.
  15. ^ "Valproic acid". DrugBank. University of Alberta. 29 July 2017. Archived from the original on 31 July 2017. Retrieved 30 July 2017.
  16. ^ Santos R, Linker SB, Stern S, Mendes AP, Shokhirev MN, Erikson G, et al. (June 2021). "Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients". Molecular Psychiatry. 26 (6): 2440–2456. doi:10.1038/s41380-020-00981-3. PMC 9129103. PMID 33398088.
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