Template:Short description Template:Use dmy dates Template:Cs1 config Template:Main other <templatestyles src="Infobox drug/styles.css"/> {{#invoke:Infobox|infobox}}Template:Template other{{#invoke:TemplatePar |check |template=Template:Infobox_drug |all= |opt= pronounce= pronounce_ref= pronounce_comment= ATC_prefix= ATC_suffix= ATC_supplemental= ATCvet= biosimilars= CAS_number_Ref= CAS_number= CAS_supplemental= ChEBI= ChEBI_Ref= ChEMBL_Ref= ChEMBL= ChemSpiderID= ChemSpiderID_Ref= chirality= class= container_only= DailyMedID= data_page= DrugBank_Ref= DrugBank= Drugs.com= duration_of_action= INN= INN_EMA= IUPAC_name= IUPHAR_ligand= KEGG_Ref= KEGG= MedlinePlus= NIAID_ChemDB= PDB_ligand= PubChemSubstance= PubChem= StdInChIKey_Ref= StdInChIKey= StdInChI_Ref= StdInChI_comment= StdInChI= UNII_Ref= UNII= DTXSID= Verifiedfields= Watchedfields= addiction_liability= alt2= altL= altR= alt= bioavailability= boiling_high= boiling_notes= boiling_point= captionLR= caption= caption2= charge= chemical_formula= chemical_formula_ref= chemical_formula_comment= class1= class2= class3= class4= class5= class6= component1= component2= component3= component4= component5= component6= density= density_notes= dependency_liability= drug_name= elimination_half-life= engvar= excretion= image2= imageL= imageR= image= image_class= image_class2= image_classL= image_classR= Jmol= legal_AU= legal_BR= legal_CA= legal_DE= legal_EU= legal_NZ= legal_UK= legal_UN= legal_US= legal_AU_comment= legal_BR_comment= legal_CA_comment= legal_DE_comment= legal_UK_comment= legal_NZ_comment= legal_US_comment= legal_UN_comment= legal_EU_comment= legal_status= licence_CA= licence_EU= licence_US= license_CA= license_EU= license_US= mab_type= melting_high= melting_notes= melting_point= metabolism= metabolites= molecular_weight= molecular_weight_round= molecular_weight_unit= molecular_weight_ref= molecular_weight_comment= onset= pregnancy_AU= pregnancy_AU_comment= pregnancy_category= protein_bound= routes_of_administration= SMILES= smiles= solubility= sol_units= source= specific_rotation= synonyms= target= tradename= type= vaccine_type= verifiedrevid= width2= widthL= widthR= width= AAN= BAN= JAN= USAN= source_tissues= target_tissues= receptors= agonists= antagonists= precursor= biosynthesis= gt_target_gene= gt_vector= gt_nucleic_acid_type= gt_editing_method= gt_delivery_method= sec_combustion= Ac=Ag=Al=Am=Ar=As=At=Au=B=Ba=Be=Bh=Bi=Bk=Br=C=Ca=Cd=Ce=Cf=Cl=Cm=Cn=Co=Cr=Cs=Cu= D=Db=Ds=Dy=Er=Es=Eu=F=Fe=Fl=Fm=Fr=Ga=Gd=Ge=H=He=Hf=Hg=Ho=Hs=I=In=Ir=K=Kr=La=Li=Lr=Lu=Lv= Mc=Md=Mg=Mn=Mo=Mt=N=Na=Nb=Nd=Ne=Nh=Ni=No=Np=O=Og=Os=P=Pa=Pb=Pd=Pm=Po=Pr=Pt=Pu=Ra=Rb=Re=Rf=Rg=Rh=Rn=Ru=S=Sb=Sc=Se=Sg=Si=Sm=Sn=Sr=Ta=Tb=Tc=Te=Th=Ti=Tl=Tm=Ts=U=V=W=Xe=Y=Yb=Zn=Zr= index_label= index2_label= index_comment= index2_comment= CAS_number2= CAS_supplemental2= ATC_prefix2= ATC_suffix2= ATC_supplemental2= PubChem2= PubChemSubstance2= IUPHAR_ligand2= DrugBank2= ChemSpiderID2= UNII2= KEGG2= ChEBI2= ChEMBL2= PDB_ligand2= NIAID_ChemDB2= SMILES2= smiles2= StdInChI2= StdInChIKey2= CAS_number2_Ref= ChEBI2_Ref= ChEMBL2_Ref= ChemSpiderID2_Ref= DrugBank2_Ref= KEGG2_Ref= StdInChI2_Ref= StdInChIKey2_Ref= UNII2_Ref= DTXSID2= QID= QID2=PLLR= pregnancy_US= pregnancy_US_comment= |cat=Pages using infobox drug with unknown parameters |format=0|errNS=0
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}}{{Infobox drug/maintenance categoriesTemplate:Yesno | drug_name = | INN = valproic acid | _drugtype =
| _has_physiological_data= | _has_gene_therapy=
| vaccine_type= | mab_type= | _number_of_combo_chemicals={{#invoke:ParameterCount |main |component1 |component2 |component3 |component4|component5|component6 }} | _vaccine_data= | _mab_data= | _mab_vaccine_data= | _mab_other_data=8162O=C(O)C(CCC)CCC1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)NIJJYAXOARWZEE-UHFFFAOYSA-NTemplate:StdinchiciteTemplate:Stdinchicite | _combo_data= | _physiological_data= | _clinical_data=Template:Drugs.coma682412Valproic acid DBy mouth, intravenousDepakote, Epilim, Convulex, othersN03 | _legal_data=S4<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>C1<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Rx-onlyPOM<ref name="Depakote FDA label" /><ref name="Depakote ER FDA label" />Rx-only
| _other_data=2-propylpentanoic acid
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| _datapage = Valproate (data page) | _vaccine_target={{#ifeq: | vaccine | | _type_not_vaccine }} | _legal_all=S4C1Rx-onlyPOMRx-only | _ATC_prefix_supplemental=N03 | _has_EMA_link = | CAS_number=99-66-1 | PubChem=3121 | ChemSpiderID=3009 | ChEBI=39867 | ChEMBL=109 | DrugBank=DB00313 | KEGG=D00399 | _hasInChI_or_Key={{#if:1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)NIJJYAXOARWZEE-UHFFFAOYSA-N |yes}} | UNII=614OI1Z5WI | _hasJmol02 = |_hasMultipleCASnumbers = |_hasMultiplePubChemCIDs = |_hasMultipleChEBIs =
| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields= |Watchedfields=changed |verifiedrevid=477003327}} Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches.<ref name=AHFS2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.<ref name=AHFS2015/> They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.<ref name=AHFS2015/>
Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth.<ref name=AHFS2015/> Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended.<ref name=AHFS2015/> Other serious risks include pancreatitis and an increased suicide risk.<ref name=AHFS2015/> Valproate is known to cause serious abnormalities or birth defects in the unborn child if taken during pregnancy,<ref name=AHFS2015/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name=AHFS2015/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Depakote FDA label" /> Reproductive warnings have also been issued for men using the drug.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The United States Food and Drug Administration has indicated a black box warning given the frequency and severity of the side effects and teratogenicity.<ref name="Depakote FDA label" /> Additionally, there is also a black box warning due to risk of hepatotoxicity and pancreatitis.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite news</ref> Valproate has been in use in Japan for the prophylaxis of migraine since 2011.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is approved as an antimanic and antiseizure in Japan as well.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In UK, valproate is approved for bipolar mania and epilepsy, and both valproate and divalproex are approved, although divalproex sodium<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> is known as valproate semisodium.<ref name = "Fisher_2003">Template:Cite journal</ref>
Valproate's precise mechanism of action is unclear.<ref name=AHFS2015/><ref name=Owen2003>Template:Cite journal</ref> Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, inhibiting histone deacetylases, and increasing LEF1.<ref name=Gh2013>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> Valproic acid is a branched short-chain fatty acid (SCFA), a derivative of valeric acid.<ref name=Gh2013/>
Valproate was originally synthesized in 1881 and came into medical use in 1962.<ref>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> It is available as a generic medication.<ref name=AHFS2015/> In 2022, it was the 174th most commonly prescribed medication in the United States, with more than 2Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Template:TOC limit
Medical usesEdit
Valproate or valproic acid is used primarily to treat epilepsy and bipolar disorder and to prevent migraine headaches.<ref name = AMH/>
EpilepsyEdit
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.<ref name = AMH/><ref>Template:Cite journal</ref> It has also been successfully given intravenously to treat status epilepticus.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
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.<ref name="Depakote FDA label" /><ref name="Depakote ER FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Mental illnessEdit
Valproate products are used to treat manic or mixed episodes of bipolar disorder.<ref name=":1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>
A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:<ref name=Wan2016>Template:Cite journal</ref>
| 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.<ref name=Wan2016/> | ||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||
Other neurological indicationsEdit
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.<ref name="pmid25114917">Template:Cite journal</ref><ref name="pmid24288035">Template:Cite journal</ref><ref name="pmid24313567">Template:Cite journal</ref>
Valproate is not commonly used to prevent or treat migraine headaches, but it may be prescribed if other medications are not effective.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
OtherEdit
The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects.Template:Citation needed It has cardioprotective, kidney protective, antiinflammatory, and antimicrobial effects.<ref name="elsevier">Template:Cite journal</ref>
ContraindicationsEdit
Contraindications include:
- Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.<ref name = TGA>{{#invoke:citation/CS1|citation
|CitationClass=web }}</ref>
- Pregnancy 11% risk of birth defects and 30-40% risk of neuro-developmental disabilities which can be permanent<ref name=Birth_defects>{{#invoke:citation/CS1|citation
|CitationClass=web }}</ref>
- Known hypersensitivity to valproate or any of the ingredients used in the preparation<ref name = TGA/>
- Urea cycle disorders<ref name = TGA/>
- Hepatic porphyria<ref name = TGA/>
- Hepatotoxicity<ref name = TGA/>
- Mitochondrial disease<ref name = TGA/>
- Pancreatitis<ref name = TGA/>
- Porphyria<ref name=EMC>{{#invoke:citation/CS1|citation
|CitationClass=web }}</ref>
Adverse effectsEdit
Template:See also Template:Div col Most common adverse effects include:<ref name="Depakote FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
- Nausea (22%)
- Drowsiness (19%)
- Dizziness (12%)
- Vomiting (12%)
- Weakness (10%)
Serious adverse effects include:<ref name="Depakote FDA label" />
- Bleeding
- Low blood platelets
- Encephalopathy
- Suicidal behavior and thoughts
- Low body temperature
Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.<ref name="Depakote FDA label" />
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Valproic acid can also cause mydriasis, a dilation of the pupils.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref> Weight gain is also possible.<ref>Template:Cite journal</ref>
PregnancyEdit
ElderlyEdit
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.<ref name="Depakote FDA label" />
Overdose and toxicityEdit
| Form | Lower limit | Upper limit | Unit |
| Total (including protein bound) |
citation | CitationClass=web
}}</ref> || 125<ref name=mass/> || μg/mL or mg/L | |
| citation | CitationClass=web
}}</ref> || 700<ref name=molar/> || μmol/L | ||
| Free | 6<ref name=mass/> | 22<ref name=mass/> | μg/mL or mg/L |
| 35<ref name=molar/> | 70<ref name=molar/> | 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.<ref>Template:Cite journal</ref> 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).<ref>Template:Cite journal</ref>
In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.<ref>Template:Cite journal</ref><ref>R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622–1626.</ref> Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.<ref name="Depakote FDA label" /> Supplemental L-carnitine is indicated in patients having an acute overdose<ref name=pmid16277730>Template:Cite journal</ref><ref>Template:Cite journal</ref> and also prophylactically<ref name=pmid16277730/> in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly<ref>Template:Cite journal</ref> than L-carnitine.
InteractionsEdit
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.<ref name = TGA/> It may also potentiate the CNS depressant effects of alcohol.<ref name = TGA/> 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.<ref name = TGA/> It may also interact with:<ref name="Depakote FDA label" /><ref name = TGA/><ref>Template:Cite journal</ref>
- 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.
PharmacologyEdit
PharmacodynamicsEdit
Although the mechanism of action of valproate is not fully understood,<ref name = TGA/> 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).<ref name = TGA/> The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.<ref name = TGA/> 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.<ref name = TGA/> Prevention of neurotransmitter-induced hyperexcitability of nerve cells via Kv7.2 channel and AKAP5 may also contribute to its mechanism.<ref>Template:Cite journal</ref> Valproate has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.<ref>Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref> Intermediate molecules include VEGF, BDNF, and GDNF.<ref>Template:Cite journal</ref><ref name="Therapeutic potential of mood stabi">Template:Cite journal</ref>
Endocrine actionsEdit
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.<ref name="pmid16165177">Template:Cite journal</ref> In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.<ref name="WyllieCascino2012">Template:Cite book</ref> These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.<ref name="pmid16165177" /><ref name="WyllieCascino2012" />
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.<ref name="UchidaMaruyama2005">Template:Cite journal</ref><ref name="IsojärviTaubøll2005">Template:Cite journal</ref> High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.<ref name="IsojärviTaubøll2005" />
PharmacokineticsEdit
Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.<ref name="AC" /> 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.<ref>Template:Cite book</ref><ref name="Drugs.com">Valproate Template:Drugs.com. Accessed 6 August 2021.</ref> Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.<ref name="AC" />
The vast majority of valproate metabolism occurs in the liver.<ref name="Drugbank-Valproate" /> Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6, CYP2B6, CYP2C9, and CYP3A5.<ref name="Drugbank-Valproate" /> It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.<ref name="Drugbank-Valproate" /> Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):<ref name="Drugbank-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.<ref name="AC" />
In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate.<ref name="Drugbank-Valproate" /> The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose.<ref name="Drugbank-Valproate" /> Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.<ref name="Drugbank-Valproate" /> Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.<ref name="Drugbank-Valproate">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Only a small amount is excreted via the faeces.<ref name="AC" /> Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.<ref name="AC" /><ref name="Drugs.com" />
ChemistryEdit
Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.<ref name="Gh2013" />
HistoryEdit
Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.<ref>Template:Cite journal</ref> Valproic acid has also been used for migraine prophylaxis and bipolar disorder.<ref>Template:Cite journal</ref>
Society and cultureEdit
Valproate is available as a generic medication.<ref name=AHFS2015/>
Approval statusEdit
| Indications | Template:Flagicon FDA-labelled indication?<ref name = MSR/> |
Template:Flagicon TGA-labelled indication?<ref name = AMH>Template:Cite book</ref> |
Template:Flagicon MHRA-labelled indication?<ref name = BNF>Template:Cite book</ref> |
Literature support |
|---|---|---|---|---|
| Epilepsy | Template:Yes | Template:Yes | Template: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).<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> |
| Bipolar mania | Template:Yes | Template:Yes | Template:Yes | Limited.<ref>Template:Cite journal</ref>Template:Failed verification |
| Bipolar depression | Template:No | Template:No | Template:No | Moderate.<ref>Template:Cite journal</ref> |
| Bipolar maintenance | Template:No | Template:No | Template:No | Limited.<ref>Template:Cite journal</ref> |
| Migraine prophylaxis | Template:Yes | Template:Yes (accepted) | Template:No | Limited. |
| Acute migraine management | Template:No | Template:No | Template:No | Only negative results.<ref>Template:Cite journal</ref> |
| Schizophrenia | Template:No | Template:No | Template:No | Weak evidence.<ref>Template:Cite journal</ref> |
| Agitation in dementia | Template:No | Template:No | Template:No | Weak evidence. Not recommended for agitation in people with dementia.<ref name=":2">Template:Cite journal</ref> Increased rate of adverse effects, including a risk of serious adverse effects.<ref name=":2" /> |
| Fragile X syndrome | Template:Yes (orphan) | Template:No | Template:No | Limited.<ref name="Therapeutic potential of mood stabi"/> |
| Familial adenomatous polyposis | Template:Yes (orphan) | Template:No | Template:No | Limited. |
| Chronic pain & fibromyalgia | Template:No | Template:No | Template:No | Limited.<ref>Template:Cite journal</ref> |
| Alcohol hallucinosis | Template:No | Template:No | Template:No | One randomised double-blind placebo-controlled trial.<ref>Template:Cite journal</ref> |
| Intractable hiccups | Template:No | Template:No | Template:No | Limited, five case reports support its efficacy, however.<ref>Template:Cite journal</ref> |
| Non-epileptic myoclonus | Template:No | Template:No | Template:No | Limited, three case reports support its efficacy, however.<ref>Template:Cite journal</ref> |
| Cluster headaches | Template:No | Template:No | Template:No | Limited, two case reports support its efficacy.<ref>Template:Cite journal</ref> |
| West syndrome | Template:No | Template:No | Template:No | A prospective clinical trial supported its efficacy in treating infantile spasms.<ref>Template:Cite journal</ref> |
| HIV infection eradication | Template:No | Template:No | Template:No | Double-blind placebo-controlled trials have been negative.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> |
| Myelodysplastic syndrome | Template:No | Template:No | Template:No | Several clinical trials have confirmed its efficacy as a monotherapy,<ref name = m2001>Template:Cite journalTemplate:Dead link</ref> as an adjunct to tretinoin<ref name = m2001/> and as an adjunct to hydralazine.<ref>Template:Cite journal</ref> |
| Acute myeloid leukaemia | Template:No | Template:No | Template:No | Two clinical trials have confirmed its efficacy in this indication as both a monotherapy and as an adjunct to tretinoin.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> |
| Cervical cancer | Template:No | Template:No | Template:No | One clinical trial supports its use here.<ref>Template:Cite journal</ref> |
| Malignant melanoma | Template:No | Template:No | Template:No | One phase II study has seemed to discount its efficacy.<ref>Template:Cite journal</ref> |
| Breast cancer | Template:No | Template:No | Template:No | A phase II study has supported its efficacy.<ref>Template:Cite journal</ref> |
| Impulse control disorder | Template:No | Template:No | Template:No | Limited.<ref name=Hicks>Template:Cite journal</ref><ref>Template:Cite journal</ref> |
Off-label usesEdit
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.<ref>Template:Cite news</ref><ref>Template:Cite news</ref>
Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
FormulationsEdit
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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.<ref>Template:Cite book</ref> In USA, Europe and many countrie the three variantes of valproate are sold: valproic acid, sodium valproate and valproate semisodium also known as divalproex sodium, the latter is believed to have fewer gastrointestinal side-effects.<ref name = "Fisher_2003" /><ref>Template:Cite journal</ref> Divalproex sodium tablets are a formulation comprising valproate sodium and valproic acid in a 1:1 molar relationship.
Magnesium valproate is also available in China.<ref name=dxy1>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=dxy2>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
TerminologyEdit
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.<ref>Template:Cite book</ref>
Brand names of valproic acidEdit
Branded products include: Template:Div col
- Absenor (Orion Corporation Finland)
- Convulex (G.L. Pharma GmbH Austria)
- Depakene (Abbott Laboratories in US and Canada)<ref name="Depakene FDA label">{{#invoke:citation/CS1|citation
|CitationClass=web }}</ref>
- Depakin (Sanofi S.R.L. Italy)<ref name="Depakin AIFA">{{#invoke:citation/CS1|citation
|CitationClass=web }}</ref>
- Depakine (Sanofi Aventis France)
- Depakine (Sanofi Synthelabo Romania)
- Depalept (Sanofi Aventis Israel)
- Deprakine (Sanofi Aventis Finland)
- Encorate (Sun Pharmaceuticals India)
- Epilim (Sanofi Synthelabo Australia and South Africa)
- Stavzor (Noven Pharmaceuticals Inc.)
- Valcote (Abbott Laboratories Argentina)
- Valpakine (Sanofi Aventis Brazil)
- Orfiril (Desitin Arzneimittel GmbH Norway)
Brand names of sodium valproateEdit
PortugalEdit
- TabletsTemplate:Snd Diplexil-R by Bial.
United StatesEdit
- Intravenous injectionTemplate:Snd Depacon by Abbott Laboratories.
- SyrupTemplate:Snd Depakene by Abbott Laboratories. (Note: Depakene capsules are valproic acid).
- Depakote tablets are a mixture of sodium valproate and valproic acid.
- TabletsTemplate:Snd Eliaxim by Bial.
AustraliaEdit
- Epilim Crushable Tablets Sanofi<ref name="Epilim TGA PI">{{#invoke:citation/CS1|citation
|CitationClass=web }}</ref>
- Epilim Sugar Free Liquid Sanofi<ref name="Epilim TGA PI" />
- Epilim Syrup Sanofi<ref name="Epilim TGA PI" />
- Epilim Tablets Sanofi<ref name="Epilim TGA PI" />
- Sodium Valproate Sandoz Tablets Sanofi
- Valpro Tablets Alphapharm
- Valproate Winthrop Tablets Sanofi
- Valprease tablets Sigma
New ZealandEdit
- Epilim by Sanofi-Aventis
All the above formulations are Pharmac-subsidised.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
UKEdit
- Depakote Tablets (as in USA)
- TabletsTemplate:Snd Orlept by Wockhardt and Epilim by Sanofi
- Oral solutionTemplate:Snd Orlept Sugar Free by Wockhardt and Epilim by Sanofi
- SyrupTemplate:Snd Epilim by Sanofi-Aventis
- Intravenous injectionTemplate:Snd Epilim Intravenous by Sanofi
- Extended release tabletsTemplate:Snd Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.
- Enteric-coated tabletsTemplate:Snd Epilim EC200 by Sanofi is a 200 mg sodium valproate enteric-coated tablet.
UK onlyEdit
- CapsulesTemplate:Snd Episenta prolonged release by Beacon
- SachetsTemplate:Snd Episenta prolonged release by Beacon
- Intravenous solution for injectionTemplate:Snd Episenta solution for injection by Beacon
Germany, Switzerland, Norway, Finland, SwedenEdit
- TabletsTemplate:Snd Orfiril by Desitin Pharmaceuticals
- Intravenous injectionTemplate:Snd Orfiril IV by Desitin Pharmaceuticals
South AfricaEdit
- SyrupTemplate:Snd Convulex by Byk Madaus<ref>{{#invoke:citation/CS1|citation
|CitationClass=web }}</ref>
- TabletsTemplate:Snd Epilim by Sanofi-synthelabo
MalaysiaEdit
- TabletsTemplate:Snd Epilim (200 ENTERIC COATED) by Sanofi-Aventis
- Controlled release tabletsTemplate:Snd Epilim Chrono (500 CONTROLLED RELEASE) by Sanofi-Aventis<ref name="Sanofi in Malaysia Products - Epilim & Epilim Chrono">{{#invoke:citation/CS1|citation
|CitationClass=web }}</ref>
RomaniaEdit
- 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
CanadaEdit
- Intravenous injectionTemplate:Snd Epival or Epiject by Abbott Laboratories.
- SyrupTemplate:Snd Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic.
JapanEdit
- TabletsTemplate:Snd Depakene by Kyowa Hakko Kirin
- Extended release tabletsTemplate:Snd Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa
- SyrupTemplate:Snd Depakene by Kyowa Hakko Kogyo
EuropeEdit
In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.
TaiwanEdit
- Tablets (white round tablet)Template:Snd Depakine (Template:Lang-zh) by Sanofi Winthrop Industrie (France)
IranEdit
- TabletsTemplate:Snd Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo
- Slow release tabletsTemplate:Snd Depakine Chrono by Sanofi Winthrop Industrie (France)
IsraelEdit
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 countriesEdit
- Valparin Chrono by Sanofi India
- Valprol CR by Intas Pharmaceutical (India)
- Encorate Chrono by Sun Pharmaceutical (India)
- Serven Chrono by Leeven APL Biotech (India)
UruguayEdit
- TabletsTemplate:Snd DI DPA by Megalabs
Brand names of valproate semisodiumEdit
- BrazilTemplate:Snd Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil
- CanadaTemplate:Snd Epival by Abbott Laboratories
- MexicoTemplate:Snd Epival and Epival ER (extended release) by Abbott Laboratories
- United KingdomTemplate:Snd Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics
- United StatesTemplate:Snd Depakote and Depakote ER (extended release) by Abbott Laboratories and generics<ref name="Depakote FDA label" />
- IndiaTemplate:Snd 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
- GermanyTemplate:Snd Ergenyl Chrono by Sanofi-Aventis and generics
- ChileTemplate:Snd Valcote and Valcote ER by Abbott Laboratories
- France and other European countriesTemplate:Snd Depakote
- PeruTemplate:Snd Divalprax by AC Farma Laboratories
- ChinaTemplate:Snd Diprate OD
ResearchEdit
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.<ref>Template:Cite report</ref>
ReferencesEdit
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