Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and as a mood stabilizer in the treatment of bipolar disorder.[4] They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.[4] They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.[4]
Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth.[4] Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended.[4] Other serious risks include pancreatitis and an increased suicide risk.[4]
Valproate is known to cause serious abnormalities or birth defects in the fetus if taken during pregnancy,[4][5] 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.[4][6] Reproductive warnings have also been issued for men using the drug.[7]
Valproate is restricted in the United Kingdom for both women and men under age 55 due to teratogenicity in pregnant women and fertility problems in men. It is also restricted in the European Union.[8][9] The United States Food and Drug Administration has indicated a black box warning given the frequency and severity of the side effects and teratogenicity. Additionally, there is also a black box warning due to risk of hepatotoxicity and pancreatitis.[10]
Valproate has been in use in Japan for the prophylaxis of migraine since 2011.[11] It is approved as an antimanic and antiseizure in Japan as well.[12] In UK, valproate is approved for bipolar mania and epilepsy, and both valproate and divalproex are approved, although divalproex sodium[13] is known as valproate semisodium.[14]
Valproate's precise mechanism of action is unclear.[4][15] Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, inhibiting histone deacetylases, and increasing LEF1.[16][17][18] Valproic acid is a branched short-chain fatty acid (SCFA), a derivative of valeric acid.[16]
Valproate was originally synthesized in 1881 and came into medical use in 1962.[19] It is on the World Health Organization's List of Essential Medicines.[20] It is available as a generic medication.[4] In 2023, it was the 160th most commonly prescribed medication in the United States, with more than 3million prescriptions.[21][22]
Medical uses
Valproate or valproic acid is used primarily to treat epilepsy and bipolar disorder.
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.[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.
Contraindications
Contraindications include:
- Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.[35]
- Pregnancy 11% risk of birth defects and 30-40% risk of neuro-developmental disabilities which can be permanent[36]
- Known hypersensitivity to valproate or any of the ingredients used in the preparation[35]
- Urea cycle disorders[35]
- Hepatic porphyria[35]
Adverse effects
Most common adverse effects include:[38]
Serious adverse effects include:[38]
Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.[38]
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[39][40][41]
Overdose and toxicity
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.[51] 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).[52]
In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[53][54]
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.[35] It may also potentiate the CNS depressant effects of alcohol.[35] 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.[35] It may also interact with:[38][35][58]
Pharmacology
Pharmacodynamics
Although the mechanism of action of valproate is not fully understood,[35] 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).[35] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[35] 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.[35] Prevention of neurotransmitter-induced hyperexcitability of nerve cells via Kv7.2 channel and AKAP5 may also contribute to its mechanism.[59]
Chemistry
Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.[16]
History
Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.[73] 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.[74] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[75] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[76]
Society and culture
Valproate is available as a generic medication.[4]
Restrictions
In 2024, for those under age 55, additional restrictions for valproate prescription have been imposed in the United Kingdom.[77] Patients under 55 can still receive valproate, but need to obtain the permission of two specialists. The restrictions are, in women, due to the potential for birth defects in children born of women of childbearing age. In men, the restrictions are due to the potential for reversible male infertility, testicular problems, and the risks of neurodevelopmental conditions in children born to men taking valproate in the 3 months before conception.[78][79] Similar restrictions have been imposed in the European Union for both women and men.
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.[131]
References
- Anvisa. RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial Diário Oficial da União, 31 March 2023, retrieved 3 August 2023^
- Product monograph brand safety updates Health Canada, 7 July 2016, retrieved 13 July 2024^
- Depakene, Stavzor (valproic acid) dosing, indications, interactions, adverse effects, and more