Valproic Acid

Valproic Acid Uses, Dosage, Side Effects, Food Interaction and all others data.

Valproic Acid, or valproate, is an fatty acid derivative and anticonvulsant originally synthesized in 1881 by Beverly S. Burton. It enjoyed use as a popular organic solvent in industry and pharmaceutical manufacturing for nearly a century. In 1963, a serendipitous discovery was made by George Carraz during his investigations into the anticonvulsant effects of khelline when he found that all of his samples, dissolved in valproic acid, exerted a similar degree of anticonvulsive activity. It first received approval on February 28, 1978 from the FDA under the trade name Depakene.

Since then, it has been investigated for neuroprotective, anti-manic, and anti-migraine effects. It is currently a compound of interest in the field of oncology for its anti-proliferative effects and is the subject of many clinical trials in a variety of cancer types.

Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches. It also improves symptom control in bipolar mania. Although the exact mechanisms responsible are unknown, it is thought that valproate produces increased cortical inhibition to contribute to control of neural synchrony. It is also thought that valproate exerts a neuroprotective effect preventing damage and neural degeneration in epilepsy, migraines, and bipolar disorder.

Trade Name Valproic Acid
Generic Valproic acid
Valproic acid Other Names acide valproïque, ácido valproico, acidum valproicum, Dipropylacetic acid, Valproate, Valproic acid, Valproinsäure
Weight 100mg/ml, 250mg, 250mg/5ml
Type Intravenous Solution, Oral Capsule, Oral Liquid, Syrup
Formula C8H16O2
Weight Average: 144.2114
Monoisotopic: 144.115029756
Protein binding

Protein binding is linear at low concentrations with a free fraction of approximately 10% at 40 mcg/mL but becomes non-linear at higher concentrations with a free fraction of 18.5% at 135 mcg/mL. This may be due to binding at separate high and low-affinity sites on albumin proteins. Binding is expected to decrease in the elderly and patients with hepatic dysfunction.

Groups Approved, Investigational
Therapeutic Class
Manufacturer Indofarma, Etercon, Dexa Medica, Mersifarma Tirmaku Mercusana
Available Country United States, Indonesia
Last Updated: September 19, 2023 at 7:00 am
Valproic Acid
Valproic Acid


Valproic Acid is an anticonvulsant used to control complex partial seizures and both simple and complex absence seizures.

Indicated for:

1) Use as monotherapy or adjunctive therapy in the management of complex partial seizures and simple or complex absence seizures.

2) Adjunctive therapy in the management of multiple seizure types that include absence seizures.

3) Prophylaxis of migraine headaches.

4) Acute management of mania associated with bipolar disorder.

Off-label uses include:

1) Maintenance therapy for bipolar disorder.

2) Treatment for acute bipolar depression.

3) Emergency treatment of status epilepticus.

Valproic Acid is also used to associated treatment for these conditions: Acute Depressive Episode, Bipolar Disorder (BD), Complex Partial Seizures, Migraine, Seizure, Absence, Seizure, multiple types, Acute Manic episode

How Valproic Acid works

The exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action.

Valproate is known to inhibit succinic semialdehyde dehydrogenase. This inhibition results in an increase in succinic semialdehyde which acts as an inhibitor of GABA transaminase ultimately reducing GABA metabolism and increasing GABAergic neurotransmission. As GABA is an inhibitory neurotransmitter, this increase results in increased inhibitory activity. A possible secondary contributor to cortical inhibition is a direct suppression of voltage gated sodium channel activity and indirect suppression through effects on GABA.

It has also been suggested that valproate impacts the extracellular signal-related kinase pathway (ERK). These effects appear to be dependent on mitogen-activated protein kinase (MEK) and result in the phosphorylation of ERK1/2. This activation increases expression of several downstream targets including ELK-1 with subsequent increases in c-fos, growth cone-associated protein-43 which contributes to neural plasticity, B-cell lymphoma/leukaemia-2 which is an anti-apoptotic protein, and brain-derived neurotrophic factor (BDNF) which is also involved in neural plasticity and growth. Increased neurogenesis and neurite growth due to valproate are attributed to the effects of this pathway. An additional downstream effect of increased BDNF expression appears to be an increase in GABAA receptors which contribute further to increased GABAergic activity.

Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase. This results in reduced de novo synthesis of inositol monophosphatase and subsequent inositol depletion. It is unknown how this contributed to valproate's effects on bipolar disorder but [lithium] is known to exert a similar inositol-depleting effect. Valproate exposure also appears to produce down-regulation of protein kinase C proteins (PKC)-α and -ε which are potentially related to bipolar disorder as PKC is unregulated in the frontal cortex of bipolar patients. This is further supported by a similar reduction in PKC with lithium. The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis. Myristoylated alanine-rich C kinase substrate, a PKC substrate, is also downregulated by valproate and may contribute to changes in synaptic remodeling through effects on the cytoskeleton.

Valproate also appears to impact fatty acid metabolism. Less incorporation of fatty acid substrates in sterols and glycerolipids is thought to impact membrane fluidity and result in increased action potential threshold potentially contributing to valproate's antiepileptic action. Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase. Inhibition of this enzyme decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins. It is thought that this may be a mechanism behind valproate's efficacy in migraine prophylaxis as migraines are routinely treated with non-steroidal anti-inflammatory drugs which also inhibit prostaglandin production.

Finally, valproate acts as a direct histone deactylase (HDAC) inhibitor. Hyperacetylation of lysine residues on histones promoted DNA relaxation and allows for increased gene transcription. The scope of valproate's genomic effects is wide with 461 genes being up or down-regulated. The relation of these genomic effects to therapeutic value is not fully characterized however H3 and H4 hyperacetylation correlates with improvement of symptoms in bipolar patients. Histone hyperacetylation at the BDNF gene, increasing BDNF expression, post-seizure is known to occur and is thought to be a neuroprotective mechanism which valproate may strengthen or prolong. H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosphate dehydrogenase, a pro-apoptotic enzyme, contributing further to valproate's neuroprotective effects.


LD50 Values

Oral, mouse: 1098 mg/kg

Oral, rat: 670 mg/kg


Symptoms of overdose include somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported, however patients have recovered from valproate serum concentrations as high as 2120 mcg/mL. The unbound fraction may be removed by hemodialysis. Naloxone has been demonstrated to reverse the CNS depressant effects of overdose but may also reverse the anti-epileptic effects.

Reproductive Toxicity

Valproate use in pregnancy is known to increase the risk of neural tube defects and other structural abnormalities. The risk of spina bifida increases from 0.06-0.07% in the normal population to 1-2% in valproate users. The North American Antiepileptic Drug (NAAED) Pregnancy Registry reports a major malformation rate of 9-11%, 5 times the baseline rate. These malformations include neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems. Other antiepileptic drugs, lamotrigine, carbemazepine, and phenytoin, have been found to reduce IQ in children exposed in utero. Valproate was also studied however the results did not achieve statistical significance (97 IQ (CI: 94-101)). Observational studies report an absolute risk increase of 2.9% (relative risk 2.9 times baseline) of autism spectrum disorder in children exposed to valproate in utero. There have been case reports of fatal hepatic failure in children of mothers who used valproate during pregnancy.

There have been reports of male infertility when taking valproate.


Valproate is excreted in human milk. Data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk.

Other Toxicity Considerations

Use in pediatrics under 2 years of age increases the risk of fatal hepatotoxicity.

Food Interaction

  • Avoid alcohol.
  • Avoid milk and dairy products.
  • Take with food.

Volume of Distribution

11 L/1.73m2.

Elimination Route

The intravenous and oral forms of valproic acid are expected to produce the same AUC, Cmax, and Cmin at steady-state. The oral delayed-release tablet formulation has a Tmax of 4 hours. Differences in absorption rate are expected from other formulations but are not considered to be clinically important in the context of chronic therapy beyond impacting frequency of dosing. Differences in absorption may create earlier Tmax or higher Cmax values on initiation of therapy and may be affected differently by meals. The extended release tablet formulation had Tmax increase from 4 hours to 8 hours when taken with food. In comparison, the sprinkle capsule formulation had Tmax increase from 3.3 hours to 4.8 hours. Bioavailability is reported to be approximately 90% with all oral formulations with enteric-coated forms possibly reaching 100%.

Half Life

13-19 hours.

The half-life in neonates ranges from 10-67 hours while the half-life in pediatric patients under 2 months of age ranges from 7-13 hours.


0.56 L/hr/m2

Pediatric patients between 3 months and 10 years of age have 50% higher clearances by weight. Pediatric patients 10 years of age or older approximate adult values.

Elimination Route

Most drug is eliminated through hepatic metabolism, about 30-50%. The other major contributing pathway is mitochondrial β-oxidation, about 40%. Other oxidative pathways make up an additional 15-20%. Less than 3% is excreted unchanged in the urine.

Innovators Monograph

You find simplified version here Valproic Acid


What is Valproic Acid used for?

Valproic Acid is used to treat certain types of seizures (epilepsy). This Valproic Acid is an anticonvulsant that works in the brain tissue to stop seizures. Valproic Acid used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures

How safe is Valproic Acid?

Valproic Acid may cause serious or life-threatening damage to the pancreas. This may occur at any time during your treatment.

How does Valproic Acid work?

Valproic Acid works by restoring the balance of certain natural substances (neurotransmitters) in the brain.

What are the common side effects of Valproic Acid?

Common side effects of Valproic Acid are include:

  • drowsiness
  • dizziness
  • headache
  • diarrhea
  • constipation
  • changes in appetite
  • weight changes
  • back pain
  • agitation
  • mood swings
  • abnormal thinking
  • uncontrollable shaking of a part of the body
  • problems with walking or coordination
  • uncontrollable movements of the eyes
  • blurred or double vision
  • ringing in the ears
  • hair loss

Is Valproic Acid safe during pregnancy?

There is not a known increased chance for miscarriage with the use of Valproic Acid during pregnancy. The maternal condition that the woman is taking the medication for may have a small increased chance for miscarriage.

Is Valproic Acid safe during breastfeeding?

No definite adverse reactions to Valproic Acid in breastfed infants have been reported. Theoretically, breastfed infants are at risk for Valproic Acid -induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage during maternal therapy.

Can I drink alcohol with Valproic Acid?

Alcohol can increase the nervous system side effects of Valproic Acid such as dizziness, drowsiness, and difficulty concentrating. Some people may also experience impairment in thinking and judgment. You should avoid or limit the use of alcohol while being treated with Valproic Acid.

Can I drive after talking Valproic Acid?

Valproic Acid may cause some people to become dizzy, lightheaded, drowsy, or less alert than they are normally. Do not drive or do anything else that could be dangerous until you know how this medicine affects you.

How long does Valproic Acid take to work?

When used as a mood stabilizer to control a manic episode, Valproic Acid needs to be taken for 1 to 2 weeks before you notice an improvement in your symptoms. You may notice an improvement earlier if Valproic Acid is combined with other medications.

How long does Valproic Acid stay in my system?

In healthy adults, it takes 2-3 days, on average, for most of the valproic acid to be gone from the body.

How many time can I take Valproic Acid daily?

Valproic Acid are usually taken two or more times daily.

How often should I take Valproic Acid?

You'll usually take valproic acid 2 or 3 times a day. You'll usually start on a low dose. Your dose will gradually increase over a few days or weeks.

Can I take Valproic Acid on an empty stomach?

You can take Valproic Acid with or without food.

Who should not take Valproic Acid?

You should not use Valproic Acid if you are allergic to it, or if you have: liver disease; a urea cycle disorder; or a genetic mitochondrial (MYE-toe-KON-dree-al) disorder such as Alpers' disease or Alpers Huttenlocher syndrome, especially in a child younger than 2 years old.

What happen If I suddenly stop taking Valproic Acid?

If you suddenly stop taking Valproic Acid, you may experience a severe, long-lasting and possibly life-threatening seizure. Your doctor will probably decrease your dose gradually.

Can I stop taking Valproic Acid suddenly?

Do not stop taking Valproic Acid suddenly, unless your doctor tells you to. You're unlikely to get any extra symptoms when you stop taking this medicine. However if you're taking it for bipolar disorder or to prevent migraine, your condition could get worse for a short time after you stop taking the medicine.

What happens if I miss a dose?

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

What happen if I overdose on Valproic Acid?

Taking too much Valproic Acid can lead to symptoms such as: feeling or being sick (nausea or vomiting) headaches, or feeling dizzy. muscle weakness.

Can Valproic Acid cause irregular heartbeat?

We conclude that patients with severe Valproic Acid intoxication may benefit from secondary detoxication. In addition to generally known symptoms Valproic Acid intoxication may also be associated with cardiac arrhythmias.

Can Valproic Acid affect my kidneys?

However, there is growing evidence that Valproic Acid cause renal tubular injury in children, and there are increasing reports of Valproic Acid-induced Fanconi's syndrome where the renal tubules lose their ability to reabsorb electrolytes, urea, glucose and protein.

Can Valproic Acid affects my liver?

Valproic Acid may cause serious or life-threatening damage to the liver that is most likely to occur within the first 6 months of therapy.
*** Taking medicines without doctor's advice can cause long-term problems.