Sodium valproate

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. The oral form is the only form available in the US.

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.

While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.

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, 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. Many studies have shown that Depakote may cause birth defects in humans. Sometimes, these birth defects can be very severe. 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 Depakote unless absolutely necessary. However, uncontrolled epilepsy can also be dangerous to both a pregnant woman and the fetus. You and your healthcare provider must discuss the specific benefits and risks of using Depakote during pregnancy for your particular situation. If your epilepsy is very mild (or if you have not had a seizure in several years), you may consider stopping Depakote. However, if your epilepsy is severe or difficult to control, it may be best for you to stay on Depakote. No matter what, do not stop taking Depakote suddenly (see Depakote Withdrawal). If you and your healthcare provider decide that it is best for you to continue taking Depakote during pregnancy, you will need frequent blood tests to measure your Depakote levels. Pregnancy can affect the way your body handles the drug, and it is important to keep your dose at the lowest effective level (to help protect your fetus). Your healthcare provider may suggest a higher-than-usual dose of folic acid, as this may also help protect the fetus.

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 a weak blocker of sodium ion channels; it is also a weak inhibitor of enzymes that deactivate GABA such as GABA transaminase. It may also stimulate the synthesis of GABA, but the direct mechanism is not known. Because of its many mechanisms of action, sodium valproate has efficacy in all partial and generalised seizures including absence seizures.

Formulations
Trade names are in bold, followed by the manufacturer.

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.

Australia

 * 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

New Zealand

 * 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

All the above formulations are Pharmac-subsidised.

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
 * Tablets – Epilim by Sanofi-synthelabo

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
 * Concentrations are between 150mg and 1000mg or 57,64mg/ml and 300mg/5ml

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, Depakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.

Taiwan

 * Tablets (white round tablet) – Depakine 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 Sanofi-Aventis.

India, Russia and CIS countries

 * Valprol CR by Intas Pharmaceutical (India)
 * Encorate Chrono by Sun Pharmaceutical (India)