|Systematic (IUPAC) name|
|Metabolism||75% by CYP enzymes|
|Excretion||20% excreted as glucuronide|
|(what is this?)|
Sodium valproate (INN) or valproate sodium (USAN) is the sodium salt of valproic acid and is an anticonvulsant used in the treatment of epilepsy, anorexia nervosa, panic attack, anxiety disorder, posttraumatic stress disorder, migraine and bipolar disorder, as well as other psychiatric conditions requiring the administration of a mood stabiliser. Sodium valproate can be used to control acute episodes of mania and acute stress reaction. Side effects can include tiredness, tremors, nausea, vomiting and sedation. The intravenous formulations are used when oral administration is not possible.
In pregnancy, valproate has the highest risk of birth defects of any of the commonly used antiepilepsy drugs. However, some epilepsy can only be controlled by valproate, and seizures also pose grave risk to mother and child.
Some of the common adverse effects include tiredness, tremor, sedation and gastrointestinal disturbances. In addition, about 10% of the users experience reversible hair loss. 
- 1 Safety in pregnancy
- 2 Safety for children
- 3 Mechanism of action
- 4 Formulations
- 5 See also
- 6 References
- 7 External links
Safety in pregnancy
The risk of birth defects with valproate is two to five times higher than other frequently used antiepileptic drugs (absolute rates of birth defects 6-11%). Children born to mothers using valproate have significantly lower IQ scores (9 points). However, some epilepsy can only be controlled by valproate, and seizures during pregnancy can have grave consequences for both mother and child. Doctors recommend women who intend to become pregnant should be switched to a different drug using combined therapy if possible, which takes several months. Women who are already pregnant and taking high doses of valproate should try to lower their doses.
All antiepileptic medications have been shown to be associated with higher risks of fetal abnormalities (mostly for spina bifida) since at least 1983, with the risks being related to the strength of medication used and use of more than one drug.
Valproate has also been recognised as sometimes causing a specific facial change ("facial phenotype") termed "fetal valproate syndrome". Sodium valproate has been associated with the rare condition paroxysmal tonic upgaze of childhood, also known as Ouvrier-Billson syndrome, from childhood or fetal exposure (this condition resolved after discontinuing valproate therapy.
A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%. The normal incidence for autism in the general population is estimated at less than one percent. Valproate may best be avoided in women with localisation epilepsy, where more effective and less risky alternatives, such as carbamazepine, are available. A 2008 study  also suggested a correlation between higher rates of autism in children whose mothers were treated for seizure disorders during pregnancy using sodium valproate (less than 1% for children who did not receive the drug in utero vs. 6.3% for children who did). However, only 632 children were followed in this study, prompting criticism that this study was too small to determine whether a definitive correlation existed between the use of sodium valproate in pregnant mothers and higher autism rates in their children, or whether other antiseizure medications used during pregnancy may cause this effect.
One multicentre trial in the UK and US compared cognitive function in 309 children born to mothers with epilepsy; it found sodium valproate use was associated with an IQ level eight points lower in children born to mothers taking sodium valproate than mothers taking other antiepileptic drugs. The authors of the study attempted to correct for confounding factors, but this was an observational study, so could not prove a causal link. Proving a causal link requires a randomised-controlled trial, which is not ethical to perform. Stronger evidence likely will not become available.
A class action lawsuit is currently underway in the United Kingdom regarding the claim that the drug used in pregnancy caused a range of problems in children, including autism, learning and social difficulties, ADHD, spinal stenosis,[specify] facial abnormalities, vision defects, dyslexia, developmental coordination disorder, and delayed speech and motor development. he U.S. Food and Drug Administration (FDA) uses a pregnancy category system to classify the possible risks to a fetus when a specific medicine is taken during pregnancy. Depakote is in pregnancy Category D when used for the treatment of epilepsy or manic episodes associated with bipolar disorder.
Pregnancy Category D is a classification given to medicines that have been shown to present a risk to the fetus in studies of pregnant women but may still offer benefits that outweigh the risks that the drug presents. A pregnancy Category D medicine may still be given to a pregnant woman if the healthcare provider believes that the benefits to the woman outweigh the possible risks to the unborn child.
Depakote is in pregnancy Category X when used for the prevention of migraine headaches. Pregnancy Category X means that the risks of taking the medication during pregnancy clearly outweigh the benefits. Medications in this category should not be taken by women who are pregnant or planning on becoming pregnant. Women who are taking Depakote for this reason and become pregnant or plan on becoming pregnant should contact their healthcare provider before stopping the medication, as it should not be stopped abruptly.
Studies have also shown that children born to women who took valproate medications (including Depakote) during pregnancy tend to score lower on "cognitive function" tests (which are used to test intelligence, abstract reasoning, and problem solving), compared to children whose mothers took other epilepsy medications while pregnant.
Pregnant women should not take valproate unless absolutely necessary. However, uncontrolled epilepsy can also be dangerous to both a pregnant woman and the fetus. Patients and their healthcare provider must discuss the specific benefits and risks of using valproate during pregnancy for your particular situation. If the epilepsy is very mild (or if seizures have not occurred in several years), the patient may consider stopping valproate. However, if the epilepsy is severe or difficult to control, it may be best to continue medication. No matter what, patients should not stop taking valproate medications suddenly (see Depakote Withdrawal).
Patients who continue valproate therapy during pregnancy will need frequent blood testing to measure valproate levels. Pregnancy can alter the metabolism of valproate medications, and thus the lowest therapeutic dose should be used during pregnancy. Increased folic acid supplementation may be protective for the fetus (source needed).
Safety for children
Two children developed severe cognitive and behavioral deterioration suggestive of a degenerative disease while being treated with sodium valproate for idiopathic epilepsy. Magnetic resonance imaging revealed multiple areas of brain atrophy. In both patients, clinical symptoms and signs cleared in a few weeks once they ceased taking the valproate. The magnetic resonance imaging appearance improved within 3 months in 1 of the patients and normalized in both after 6 and 12 months. No metabolic changes were associated with the clinical or imaging abnormalities. Although the mechanism of this rare idiosyncratic complication of valproate therapy is unknown, we advocate discontinuing valproate therapy in all epileptic patients with neuromental deterioration or brain atrophy of unknown etiology.
Mechanism of action
Sodium valproate is effective in the treatment of partial and primary generalized seizures, including absence and myoclonic seizures. The anticonvulsant mechanism of action of sodium valproate for any of these seizure types is not known. However, valproate has several pharmacological actions that could be relevant. Sodium valproate is a weak blocker of sodium ion channels; it is also a weak inhibitor of enzymes that deactivate GABA such as GABA transaminase and Succinate Semi-aldehyde Dehydrogenase. It may also stimulate the synthesis of GABA.
Trade names are in bold, followed by the manufacturer.
- Tablets – Diplexil-R by Bial.
- 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.
- Epilim Crushable Tablets Sanofi
- Epilim Sugar Free Liquid Sanofi
- Epilim Syrup Sanofi
- Epilim Tablets Sanofi
- Sodium Valproate Sandoz Tablets Sanofi
- Valpro Tablets Alphapharm
- Valproate Winthrop Tablets Sanofi
- Valprease tablets Sigma
- Epilim crushable tablets 100mg by Sanofi-Aventis
- Epilim EC modified release tablets 200mg and 500mg by Sanofi-Aventis
- Epilim Syrup 200mg/5mL by Sanofi-Aventis
- Epilim Sugar Free Liquid 200mg/5mL by Sanofi-Aventis
- Epilim intravenous solution 100mg/mL by Sanori-Aventis
- 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.
- 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
- Syrup – Convulex by Byk Madaus
- Tablets – Epilim by Sanofi-synthelabo
- Tablets – Epilim by Sanofi-Aventis
- 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
- Concentrations are between 150mg and 1000mg or 57,64mg/ml and 300mg/5ml
- Intravenous injection – Epival or Epiject by Abbott Laboratories.
- Syrup – Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic.
- 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
In much of Europe, Depakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.
- Tablets (white round tablet) – Depakine (Chinese: 帝拔癲; pinyin: di-ba-dian) by Sanofi Winthrop Industrie (France)
Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by Sanofi-Aventis.
- Valprol CR by Intas Pharmaceutical (India)
- Encorate Chrono by Sun Pharmaceutical (India)
- Serven Chrono by Leeven APL Biotech (India)
- Gelder, M., Mayou, R., Geddes, J. (2006) Psychiatry. 3rd edition. Oxford: Oxford University Press
- Gelder, M, Mayou, R. and Geddes, J. 2005. Psychiatry. 3rd ed. New York: Oxford. pp250.
- I.Q. Harmed by Epilepsy Drug in Utero By RONI CARYN RABIN, New York Times, April 15, 2009
- Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs, Kimford J. Meador et al. for the NEAD Study Group, N Engl J Med 360:1597 April 16, 2009
- Which drug for the pregnant woman with epilepsy? Torbjorn Tomson, N Engl J Med 360:1597 April 16, 2009
- Koch S, Göpfert-Geyer I, Jäger-Roman E et al. (February 1983). "[Anti-epileptic agents during pregnancy. A prospective study on the course of pregnancy, malformations and child development]". Dtsch. Med. Wochenschr. (in German) 108 (7): 250–7. doi:10.1055/s-2008-1069536. PMID 6402356.
- Moore SJ, Turnpenny P, Quinn A et al. (July 2000). "A clinical study of 57 children with fetal anticonvulsant syndromes". J. Med. Genet. 37 (7): 489–97. doi:10.1136/jmg.37.7.489. PMC 1734633. PMID 10882750.
- DiLiberti JH, Farndon PA, Dennis NR, Curry CJ (November 1984). "The fetal valproate syndrome". Am. J. Med. Genet. 19 (3): 473–81. doi:10.1002/ajmg.1320190308. PMID 6439041.
- Epileptic Disord. 2007 Sep; 9(3):332-6
- J Child Neurol. 1988 Jul;3(3):177-80
- Adab N, Kini U, Vinten J et al. (November 2004). "The longer term outcome of children born to mothers with epilepsy". J. Neurol. Neurosurg. Psychiatr. 75 (11): 1575–83. doi:10.1136/jnnp.2003.029132. PMC 1738809. PMID 15491979.
This argues that the fetal valproate syndrome constitutes a real clinical entity that includes developmental delay and cognitive impairments, but that some children might exhibit some developmental delay without marked dysmorphism.
- Rasalam AD, Hailey H, Williams JH et al. (August 2005). "Characteristics of fetal anticonvulsant syndrome associated autistic disorder". Dev Med Child Neurol 47 (8): 551–5. doi:10.1017/S0012162205001076. PMID 16108456.
- Autism Society of America: About Autism
- Bromley L, Mawer G, Clayton-Smith J, Baker GA et al. (December 2008). "Autism spectrum disorders following in utero exposure to antiepileptic drugs". Neurology 71 (23): 1923–4. doi:10.1212/01.wnl.0000339399.64213.1a. PMID 19047565.
- Meador KJ, Baker GA, Browning N et al. (2009). "Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs". N Engl J Med 360 (16): 1597–1605. doi:10.1056/NEJMoa0803531. PMC 2737185. PMID 19369666.
- Tomson T (2009). "Which drug for the pregnant woman with epilepsy?". N Engl J Med 360 (16): 1667–1669. doi:10.1056/NEJMe0901550. PMID 19369673.
- Families Sue Europe’s Largest Drug Company Over Anti-Convulsant Drug as Deadline Is Given By High Court
- "Legal action over Epilim". Epilepsy Action. 24 April 2007. Retrieved 15 April 2009.
- Brimelow A (1 October 2004). "Women sue over epilepsy drug risk". BBC News. Retrieved 15 April 2009.
- "Reversible dementia and apparent brain atrophy during valproate therapy" Annals of Neurology Volume 38, Issue 4, pages 687–691, October 1995. http://onlinelibrary.wiley.com/
- Rogawski MA (1990). "Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds". Pharmacol Rev 42 (3): 223–286. PMID 2217531.
- Rogawski MA, Löscher W (2004). "The neurobiology of antiepileptic drugs". Nat Rev Neurosci 5 (3): 553–564. doi:10.1038/nrn1430. PMID 15208697.
- "Sodium valproate -- Pharmaceutical Schedule". Pharmaceutical Management Agency. Retrieved 22 June 2014.
- Chemical Land21: Sodium Valproate
- RXList.com: Depacon (Sodium Valproate)
- British National Formulary Edition 58
- Med Broadcast.com: Epival
- Drugs.com: Depaken Syrup