Valproate: History, Adverse Effects, Uses and Contraindications

It helps prevent seizures in people with absence seizures, partial seizures, and generalized seizures.

Valproate (VPA) and its valproic acid, sodium valproate, and Semisonic Valproate are used mainly to treat epilepsy and bipolar disorder and prevent migraines.

It can be administered with an intravenous injection or with pills taken orally. There are formulations of long and short action tablets.

Common side effects include nausea, vomiting, drowsiness, and dry mouth. Serious side effects may include liver problems and, therefore, regular monitoring of liver function tests is recommended.

Other serious risks include pancreatitis and an increased risk of suicide. It is known to cause severe abnormalities in the baby if taken during pregnancy. Because of this, it is generally not recommended for women of childbearing age who have migraines.

It is not clear exactly how Valproate works. The proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases. Valproic acid is a branched short-chain fatty acid (SCFA) produced from valeric acid.

Valproate was first created in 1881 and entered medical use in 1962. Valproate is included in the World Health Organization’s List of Essential Drugs, the most effective and safe medicines needed in a health system. It is available as a generic medicine.


This medicine can cause severe and sometimes fatal liver problems. This occurs more frequently within the first six months of the Valproate injection.

Call your doctor if you see dark urine, feel tired, are not hungry, have an upset stomach, are vomiting, or have yellowing of the skin or eyes.

In patients who have seizures, loss of control of attacks may occur. Ask the treating doctor to check your blood test.

Children under two years old are at a higher risk of suffering fatal liver problems. Those who take more than one anticonvulsant medication or have a metabolic disorder, a severe seizure disorder, mental retardation, or specific brain problems are at higher risk.

There is an increased risk of liver failure and death in patients with a genetic liver problem caused by a mitochondrial disorder such as Alpers-Huttenlocher syndrome.

You may need a genetic test to verify this health problem. If you have or may have mitochondrial disorders, do not take the Valproate injection before talking to your doctor.

This medicine can cause severe congenital disabilities if you take it while pregnant. It can also cause the child to have a lower IQ. Do not take Valproate to prevent migraines if you are pregnant.

If you are pregnant and are taking an injection of Valproate for seizures or bipolar disorder, talk with your doctor to see if you need to continue taking the Valproate injection.

If you can get pregnant, you should use a contraceptive method that you can trust while taking the Valproate injection. If you are taking Valproate you become pregnant, call your doctor immediately.

This medicine can cause severe and sometimes fatal pancreas problems (pancreatitis). This can happen shortly after the use and many years after service.

Signs of pancreatitis include stomach pain, upset stomach, vomiting, or lack of appetite. If you have any of these signs, immediately call your treating doctor.


Beverly S. Burton first synthesized valproic acid in 1882 as an analog of valeric acid, which is found plainly in valerian. Valproic acid is a carboxylic acid, a clear liquid at room temperature.

For many decades, its sole use was in laboratories as a “metabolically inert” solvent for organic compounds.

In 1962, French researcher Pierre Eymard accidentally discovered the anticonvulsant properties of valproic acid while using it as a vehicle for several other compounds that were being evaluated for anticonvulsant activity.

He discovered that it prevents seizures induced by pentylenetetrazole in laboratory rats.

It was approved as an antiepileptic drug in 1967 in France and has become the most commonly prescribed antiepileptic drug globally. Valproic acid has also been used to prevent migraine and bipolar disorder.

Adverse effects

List of adverse effects of valproic acid and semisodium Valproate.

The most common side effects include:

  • Nausea.
  • Drowsiness.
  • Dizziness.
  • He retched.
  • Weakness.

Serious adverse effects include:

  • Hemorrhage.
  • Low blood platelets.
  • Encephalopathy.
  • Behaviors and suicidal thoughts.
  • Low body temperature

Valproic acid has a black box warning to detect hepatotoxicity, pancreatitis, and fetal abnormalities.


Valproic acid (VPA) is a weak organic acid. The conjugate base is Valproate. The acid’s sodium salt is sodium valproate, and a coordinating complex of the two is known as divalproex sodium.


Valproate exists in two main molecular variants: Valproate sodium and valproic acid without sodium (often simply involved by Valproate). A mixture between these two is called Semisonic Valproate.

It is not clear if there is any difference in efficacy between these variants, except that approximately 10% more Valproate sodium is needed than valproic acid without sodium to compensate for sodium itself.

Valproic acid brands

Branded products include:

  • Absenor (Orion Corporation Finland).
  • Convulex (G.L. Pharma GmbH Austria).
  • Depakene (Abbott Laboratories en EE. UU. y Canadá).
  • Depakine (Sanofi Aventis Francia).
  • Depakine (Sanofi Synthelabo Rumania).
  • Depalept (Sanofi Aventis Israel).
  • Deprakine (Sanofi Aventis Finland).
  • Epival (Abbott Laboratories EE. UU. y Canadá).
  • Epilim (Sanofi Synthelabo Australia y Sudáfrica).
  • Stavzor (Noven Pharmaceuticals Inc.).
  • Valcote (Laboratorios Abbott Argentina).
  • Valpakine (Sanofi Aventis Brasil).

It has been found that valproic acid directly stimulates the androgen biosynthesis in the gonads through the inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased levels of 4-androstenedione in men.

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

Medical uses

It is mainly used to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.


Valproate has a broad spectrum of anticonvulsant activity. However, it is used primarily as a first-line treatment for tonic-clonic seizures, absence crises, and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms.

It was also successfully administered intravenously to treat status epilepticus.

Mental diseases:

Bipolar disorder:

Valproate products are also used to treat manic or mixed episodes of bipolar disorder.


A 2016 systematic review compared the efficacy of Valproate as a supplement for people with schizophrenia.

There is limited evidence that the increase in antipsychotics with Valproate can be effective for the general response and specific symptoms, especially in terms of excitation and aggression.

The evidence was based entirely on open randomized controlled trials. Valproate was associated with a series of adverse events, among which sedation and dizziness appeared significantly more frequently than in the control groups.

Dopamine dysregulation syndrome:

Based on five case reports, valproic acid may effectively control the symptoms of the dopamine dysregulation syndrome that arise from the treatment of Parkinson’s disease with levodopa.


Valproate is also used to prevent migraines. Because this medication can be potentially harmful to the fetus, Valproate should be considered for women of childbearing age only after discussing the risks.


The drug has been tested to treat AIDS and cancer due to its inhibitory effects of histone deacetylase.

What should I tell my doctor before taking a Valproate injection?

If you are allergic to the Valproate injection or any part of the Valproate injection.

Suppose you are allergic to any medication or a drug like this, food, or other substances. Tell your treating doctor about allergies and other signs such as a rash, wheezing, hives, difficulty breathing, itching, swelling of the face, lips, tongue, throat, cough, or any other symptom/sign.

If you have any of these health problems, such as liver disease or a urea cycle disorder.

This is not a list of all medications, drugs, or health problems interacting with Valproate.

Tell your doctor and pharmacist about all your medications (prescription drugs, natural products, vitamins) and health problems.

Do not start, stop or change the dose of any medication without first checking with your treating doctor. You should verify that it is safe to take Valproate with all your drugs and health problems.

While taking Valproate, what should I know or do before?

Tell your doctors, nurses, pharmacists, and dentists that you take Valproate. This includes all of your health care providers.

Avoid driving and doing other tasks or actions that call you to stay alert or have a clear view until you see how Valproate injection affects you.

Have a blood test as told by the doctor.

Talk to your doctor before drinking alcohol or using other medications and natural products that decrease your actions.

This medication may alter specific or several laboratory tests. Tell all your health care providers and laboratory workers that you take the Valproate injection.

It can bleed more easily. Be careful and avoid injuries. Use a soft toothbrush and electric razor.

There have been elevated ammonia levels in the blood with Valproate injection. This can lead to specific brain problems. In some people, this has been deadly.

Some people have had specific brain problems without high ammonia levels in their blood. Sometimes, these brain problems have returned to normal after stopping the Valproate injection. However, sometimes they have not returned to normal.

A terrible reaction, and sometimes fatal, has happened with the injection of Valproate. This reaction has fever, rash, or inflammation of the glands with problems in the body’s organs such as the liver, kidney, blood, heart, muscles, and joints or lungs.

Patients who take the Valproate injection may be at higher risk for suicidal thoughts or actions. The risk may be higher in people who have had these thoughts or actions.

Call the doctor immediately if the signs of a bad mood ( depression ), nervousness, restlessness, lousy mood, panic attacks, or changes in the air or the actions are new or worse. Call your treating doctor immediately if you have thoughts, tendencies, or suicidal actions.

Valproate can affect the number of other medications or drugs in your body. If you are taking other drugs, talk to your doctor. You may need to have a blood test more closely while taking the Valproate injection with your other medications.

Some other medicines can affect the amount of Valproate injection in your body. Talk to your doctor or pharmacist to see if any of your other medications may interact with Valproate injection.

If you are 65 or older, use the Valproate injection carefully. You could have more side effects.

Use with care in children; talk to the doctor first.

This medicine can harm an unborn baby if you take it while pregnant. If you are pregnant, if you suspect that you may be pregnant, or if you become pregnant while taking Valproate, call your treating doctor immediately.

Tell your doctor if you are breastfeeding. You will have to clear up any doubts about any risk to your baby.

What are some side effects of calling my doctor right away?

Although it may be strange, some people can develop symptoms or severe side effects, sometimes even fatal, by taking some medication.

Inform your attending physician or seek medical attention immediately if you experience any of the following signs or symptoms, as they may be related to one of these severe side effects:

Signs of an allergic reaction such as rash, hives, tightness in the chest or throat, itching, red and swollen skin, blistered or scaling with or without fever, unusual hoarseness, wheezing, difficulty breathing, swallowing, or talking; swelling of the mouth, face, lips, tongue or throat.

Signs of infection include fever, chills, severe sore throat, pain in the ears or sinuses, cough, more sputum or changes in sputum color, painful urination, sores in the mouth, or wounds that do not heal.

Signs of high ammonia levels include a heartbeat that does not feel normal, breathing that is not normal, confusion, pale skin, slow heartbeat, seizures, sweating, vomiting, or spasms. As well:

  • Chest pain.
  • Swelling/swelling in the arms and legs.
  • Change in view
  • Memory or loss problems
  • Feeling very tired or weak
  • Change in balance
  • Problems walking
  • Any bruising or unexplained bleeding.
  • Purple spots or redness of the skin.
  • You can not pass urine or change the amount of urine you give.
  • Swollen gland
  • Muscle pain or weakness
  • Joint pain or swelling
  • Instability.
  • The seizures are worse or are not the same after starting the Valproate injection.
  • Changes in behavior or the way of acting.
  • He can not control eye movements.
  • Sound in the ears
  • Feeling very sleepy

Side effects of Valproate injection:

Valproate can cause secondary shunts. However, many people have no side effects or only have minor side effects.

Contact your attending physician or seek hospital help if any of these symptoms or side effects or any other secondary consequence bothers you or does not go away:

  • Pain or discomfort in the head.
  • Stomach upset or vomiting
  • Dizziness.
  • Feeling sleepy
  • Hard stools (constipation).
  • Loose stools (diarrhea).
  • Bellyache.
  • Not being able to sleep / insomnia.
  • Feeling more or less hungry
  • Weight gain or loss
  • Hair loss.
  • Feeling tired or weak
  • He feels nervous and excitable.

These are not all symptoms because of the side effects that may occur. Contact your treating doctor if you have questions about symptoms due to side effects. Call your treating doctor for medical information about side effects.

Other possible side effects:

There is evidence that valproic acid can cause premature ossification of growth plates in children and adolescents, decreasing height. Valproic acid can also cause mydriasis and dilation of the pupils.

Evidence shows that valproic acid may increase the chances of polycystic ovarian syndrome (PCOS) in women with epilepsy or bipolar disorder.

Studies have shown that this risk of polycystic ovary syndrome is higher in women with epilepsy compared to people with bipolar disorder.

The pregnancy

Valproate causes congenital disabilities; exposure during pregnancy is associated with about three times more critical abnormalities than usual, mainly spina bifida. The risks are related to the intensity of the medication used and the use of more than one medicine.

More rarely, with several other defects, possibly including a ” Valproate syndrome. “

The characteristics of this Valproato syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, high front with bifrontal narrowing, epicranial folds, and medial eyebrow deficiency.

Also, flat nasal bridge, broad nasal root, anteverted nostrils, long upper edge and thin borders of vermilion, thick lower lip, and smallmouth down.

The children of mothers who take Valproate during pregnancy run the risk of lower IQ. The use of maternal Valproate during pregnancy has been associated with a significantly greater likelihood of autism in the offspring.

A 2005 study found that the rates of autism among children exposed to Valproate sodium before birth in the study cohort were 8.9%. The average incidence of autism in the general population is estimated at less than one percent.

A 2009 study found that 3-year-old children of pregnant women taking Valproate had an IQ nine points lower than a well-balanced control group. However, more research is needed on older children and adults.

Sodium valproate has been associated with the rare paroxysmal involvement of childhood, also known as Ouvrier-Billson syndrome, since childhood or fetal exposure. This condition resolved after stopping treatment with Valproate.

Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of Valproate.

Women who become pregnant while taking Valproate should be advised that it causes congenital disabilities and cognitive impairment in the newborn.

Especially in high doses (although Valproate is sometimes the only medication that can control seizures, and seizures during pregnancy can have worse consequences).

Studies have shown that taking folic acid can reduce the risk of congenital neural tube defects.

Elderly people

Valproate in older adults with dementia caused an increase in sleepiness. More people stopped the medication for this reason. Additional side effects of weight loss and decreased food intake were also associated with half of the sleepy people.


Contraindications include:

  • Pre-existing acute or chronic hepatic dysfunction or family history of severe hepatic inflammation (hepatitis), particularly related to medications.
  • Known hypersensitivity to Valproate or any of the ingredients used in the preparation.
  • Disorders of the urea cycle.
  • Hepatic porphyria.
  • Hepatotoxicidad.
  • Mitochondrial disease
  • Pancreatitis.
  • Porphyria.


Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase. Therefore, it is highly protein-bound and can interact with drugs that are substrates of any of these enzymes or that have a high protein content.

It can also potentiate the depressant effects on the central nervous system of alcohol. It should not be administered together with other antiepileptic drugs because of the possibility of reduced elimination of other antiepileptic drugs (including carbamazepinelamotrigine, phenytoin, and phenobarbitone) and of itself. You can also interact with:

Aspirin: can increase the concentrations of Valproate. It can also interfere with the metabolism of Valproate.

Benzodiazepines: can cause central nervous system depression, and there are possible pharmacokinetic interactions.

Antibiotics carbapenem: reduces the levels of Valproate, which can lead to seizures.

Cimetidine: inhibits the metabolism of Valproate in the liver, which increases the concentrations of Valproate.

Erythromycin: inhibits the metabolism of Valproate in the liver, which increases the concentrations of Valproate.

Ethosuximide: can increase the concentrations of ethosuximide and lead to toxicity.

Felbamate: may increase plasma concentrations of Valproate.

Mefloquine: can increase the metabolism of Valproate combined with the direct epileptogenic effects of mefloquine.

Oral contraceptives: can reduce the plasma concentrations of Valproate.

Primidone: can accelerate the metabolism of Valproate, which leads to a decrease in serum levels and a potential epileptic seizure.

Rifampin: increases the clearance of Valproate, which leads to a decrease in Valproate concentrations

Warfarin: can increase the concentration of warfarin and prolong the bleeding time.

Zidovudine: can increase the serum concentration of zidovudine and lead to toxicity.

Overdose and toxicity

Excessive amounts of valproic acid can cause drowsiness, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death.

In general, serum or plasma valproic acid concentrations are in a range of 20-100mg / l during controlled therapy but may reach 150-1500mg / l after acute intoxication.

Serum level control is often carried out using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.

Unlike other antiepileptic drugs, there is currently little favorable evidence for monitoring therapeutic salivary medicines. Salivary valproic acid levels correlate poorly with serum levels, in part due to the weak acid property of Valproate (pKa of 4.9).

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of accelerating the elimination of medication from the body.

Supportive therapy should be given to all patients who experience an overdose, and urine production should be monitored.

Supplemental L-carnitine is indicated in patients with an acute overdose and prophylactically in high-risk patients. Acetyl-L-carnitine reduces hyperammonaemia less markedly than L-carnitine.



Although the mechanism of action of Valproate is not entirely known, traditionally, its anticonvulsant effect has been attributed to the blocking of voltage-gated sodium channels and the increase of gamma-aminobutyric acid (GABA) levels in the brain.

It is also believed that the GABAergic effect contributes to the antimanic properties of Valproate.

In animals, sodium valproate increases brain and cerebellar levels of the inhibitory synaptic neurotransmitter, gamma-aminobutyric acid, possibly by inhibiting gamma-aminobutyric acid-degrading enzymes such as gamma-aminobutyric acid transaminase.

The prevention of neurotransmitter-induced hyperexcitability of nerve cells through the Kv7.2 and AKAP5 channels may also contribute to its mechanism.

In addition, it has been shown to protect against seizure-induced reduction in phosphatidylinositol (3,4,5) -trisphosphate (PIP3) as a potential therapeutic mechanism.

It also possesses inhibitory histone deacetylase results by promoting more transcriptionally active chromatin structures, probably presenting the epigenetic mechanism for regulating many of the neuroprotective effects attributed to valproic acid.

Intermediate molecules that mediate these effects include:

  • Vascular endothelial growth factors.
  • Neurotrophic factors are derived from the brain.
  • Neurotrophic factors are derived from the glial cell line.

Endocrine actions

It has been found that valproic acid is an antagonist of the androgen and progesterone receptors and, therefore, as a non-steroidal anti-androgen antiprogesterone, in concentrations much lower than the therapeutic serum levels.

In addition, the drug has been identified as a potent aromatase inhibitor and suppresses estrogen levels. These actions are probably involved in the reproductive endocrine alterations observed with the treatment with valproic acid.

If your symptoms or health problems do not improve or if they get worse, call your doctor.

Do not consume pre-written medication for another person, and also, very importantly, do not share your medicines with other people.

Have a list of all your medications (prescription drugs, natural products, vitamins, OTC medications). Give this list to your treating doctor.

Talk to your doctor before starting any new medicine, including prescription or over-the-counter medications, natural products, or vitamins.

Keep Valproate tablets or injections in a sheltered place. Keep all medications (pills and injections of Valproate or others) out of the reach of infants and animals.

Boat Valproate is not used or expired. Do not flush the toilet or pour it down a drain unless instructed. Ask your pharmacist if you know the best way to dispose of the medication. There may be medication restitution events where you live.

Some medications manage to have another catalog of information for the patient. Check with your pharmaceutical provider. If you have any questions about the injections or the Valproate tablets, talk to your treating doctor, nurse, pharmacist, or other healthcare professionals.

If you think you have had an overdose, take steps to describe or show what was taken, how much, and when it happened, call emergency or your poison control center and get medical attention immediately.