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Valproic acid side effects and how to avoid them

Valproic acid side effects include liver damage, weight changes, hair loss, and bradycardia
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By | Dec. 16, 2022 Medically reviewed by Josephine Bawab, Pharm.D.
Rx pill bottle and prescription pad: Valproic acid side effects

Key takeaways

  • Valproic acid is used as an anticonvulsant and mood stabilizer but can cause serious side effects like liver damage, weight changes, hair loss, and bradycardia.

  • Common side effects of valproic acid include gastrointestinal issues, mood changes, and hair thinning, with serious side effects involving organ damage and blood disorders.

  • Liver monitoring and weight management are crucial for those taking valproic acid to minimize risks.

  • Valproic acid requires careful management, including regular blood tests and avoiding certain medications and alcohol, to mitigate its side effects.

In this article:

Valproic acid is a generic prescription drug used primarily as an anticonvulsant or mood stabilizer. It is approved by the FDA to control certain types of seizures in people with epilepsy, but it is also commonly prescribed off-label to treat bipolar disorder or prevent migraine headaches. Valproate sodium is the injectable version of valproic acid. 

Most people will be given the more stable version of valproic acid, divalproex sodium, also known as the brand name Depakote. Divalproex lasts longer in the body, requires lower doses than valproic acid, has fewer severe side effects, and is FDA-approved for seizure disorders, bipolar disorder, and migraine prevention. This article focuses mainly on the side effects of valproic acid.

Common side effects of valproic acid

Common side effects of valproic acid include:

  • Nausea
  • Headache
  • Vomiting
  • Fatigue
  • Drowsiness
  • Decrease in platelets (blood clotting cells)
  • Stomach upset
  • Dizziness
  • Diarrhea
  • Stomach pain
  • Tremor
  • Hair thinning
  • Weight increase 
  • Change in appetite
  • Constipation
  • Nervousness
  • Mood swings
  • Trouble sleeping
  • Spotted bleeding under the skin 
  • Skin rash
  • Depression
  • Trouble breathing
  • Tinnitus
  • Liver dysfunction
  • Memory impairment
  • Abnormal gait
  • Double vision
  • Blurred vision
  • Rapid eye movements
  • Muscle pain
  • Sensitivity to sunlight

Serious side effects of valproic acid

The most serious side effects of valproic acid are:

  • Liver damage
  • Elevated levels of ammonia
  • Swollen pancreas
  • Low sodium
  • Blood disorders
  • Bone marrow suppression
  • Bleeding
  • Hypothermia
  • Hallucinations
  • Suicidal thoughts and behaviors
  • Parkinson’s disease symptoms (muscle rigidity, slow muscle movements, tremor)
  • Altered brain function
  • Brain shrinkage
  • Coma
  • Enlarged ovaries with ovarian cysts (polycystic ovary syndrome)
  • Withdrawal seizures
  • Severe drug or allergic reactions

Liver damage

Valproic acid can damage the liver. About 5% to 10% of people on long-term valproate treatment will experience increases in liver enzymes, usually without symptoms. However, in some people, valproic acid can cause significant liver problems, including excess ammonia (hyperammonemia), liver injury, liver failure, and, in children, a condition similar to Reye’s syndrome. People taking valproic acid should have regular blood tests to measure liver enzymes. If any symptoms of liver problems appear, immediately tell the prescriber. 

Weight changes

Weight gain is a significant problem when taking valproic acid. Approximately 57% to 58% of people taking valproic acid will gain weight during treatment. Women are more affected than men. For the most part, weight gain will become obvious in the first three months of treatment, so people taking valproic acid should regularly monitor body weight. If weight starts increasing, inform the prescriber. 

Hair loss

Hair loss is experienced by about one in nine people taking valproic acid. That being said, hair loss is a relatively common side effect of anticonvulsants with an incidence ranging from less than 1% to 6%. Usually, the hair loss caused by valproic acid is partly reversible when the drug is stopped. If one’s hair starts to thin while taking valproic acid, talk to the prescriber about other treatment options.

Bradycardia

Bradycardia occurs when there is a heart rate that is slower than normal and it is a reported side effect of valproic acid. Bradycardia and other heart rhythm problems can occur after seizures. In fact, seizure-induced bradycardia is considered one potential cause of sudden death in people with epilepsy. 

Bradycardia is a serious and potentially life-threatening medical condition. No matter what the cause, get immediate medical attention if you notice any of the symptoms of bradycardia, such as tiredness, fatigue, inability to do physical activity, dizziness, lightheadedness, fainting, confusion, or chest pain.

How soon do valproic acid side effects start?

Many of the most common side effects of valproic acid begin early in treatment. These include digestive system complaints, sleeplessness, vision changes, drowsiness, and mood issues. The most serious side effects are usually delayed side effects. However, elevated liver enzymes might happen early, and liver failure and death, though rare, could happen in the first six months of treatment. Additionally, severe and even life-threatening pancreatitis can occur right after the first few doses or months into treatment. 

How long do valproic acid side effects last?

Some mild side effects, such as gastrointestinal issues, may improve as the body adjusts to the drug. Other side effects, such as liver abnormalities, blood disorders, or neurological problems, may get worse the longer the drug is taken. The drug is usually stopped in those cases. Minor side effects will usually improve after the drug has been discontinued. Liver problems, when caught in time, generally improve in a couple of days. Hair loss, weight gain, blood disorders, or some other serious side effects may take a while to reverse. 

What are the long-term side effects of valproic acid?

Valproic acid is meant to be used over the long term. Prolonged use of valproic acid makes weight gain more likely and can worsen any drug-induced hair loss. Liver problems are also worsened with long-term use, so the drug is usually discontinued at any sign of liver, pancreas, or neurological abnormalities. 

Valproic acid contraindications

Valproic acid is never prescribed to people with:

  • Liver disease: People with liver disease or significant liver dysfunction are at risk for liver failure and death when taking valproic acid.
  • Mitochondrial disease: Mitochondria are small, organ-like structures (organelles) in cells that generate the cell’s energy. People with certain types of mitochondrial diseases called POLG-related mitochondrial disorders are at risk for severe liver damage, liver failure, and death when taking valproic acid. 
  • Urea cycle disorders: People with urea cycle disorders—a set of genetic problems with the body’s enzymes—are prone to high ammonia levels, a side effect of valproic acid. High ammonia levels can cause serious and life-threatening brain problems (encephalopathy).
  • Known allergies to the drug

Pregnancy

Valproic acid is a risky medicine to take while pregnant. It has been shown to sometimes cause birth defects, such as spina bifida, neural tube defects, heart structure problems, and malformed limbs. The risk is greatest in the first trimester, but unborn babies whose mothers take valproate in the third trimester can be born with low blood sugar or potentially fatal liver failure. For this reason, valproic acid is contraindicated as a migraine medication in women who are pregnant or who are of childbearing age and not on birth control. It is only used as a seizure medication during pregnancy when no other drug will work and the benefits outweigh the risks. It is important to talk to the prescribing healthcare provider if pregnant or there are plans to get pregnant. 

Breastfeeding

Valproic acid can be taken while breastfeeding. Valproic acid is present in breast milk, but the infant’s exposure is small. So far, there is no evidence of developmental or cognitive problems, but there is at least one report of low platelet counts and anemia in a baby exposed to valproic acid. If valproic acid is used when breastfeeding, the prescriber may ask the mother to monitor the infant for signs of liver problems and unusual bleeding or bruising.

Children

Valproic acid is FDA-approved to treat complex partial seizures in children 10 years of age and older or to treat simple or complex absence seizures in children who weigh at least 22 pounds. Healthcare professionals are discouraged from using valproic acid in children younger than two years of age because of the risk of liver damage. 

Seniors

Because of declining liver function and a greater vulnerability to side effects like drowsiness, people older than 65 years of age are typically started on a low dose of valproic acid. 

Valproic acid warnings

Valproic acid has several risks, so it’s not surprising that it comes with a variety of warnings.

Black box warning

Valproic acid comes with four boxed warnings from the FDA:

  • Liver toxicity: Valproic acid can cause liver failure within six months of starting treatment. Children two years old and younger are particularly vulnerable.
  • Liver toxicity in people with mitochondrial disease: Liver failure and death are a risk when valproic acid is given to people with POLG-related mitochondrial disease. POLG screening is required before treatment can begin. 
  • Fetal risk: Valproic acid can cause serious birth defects. It should not be used in pregnant women to treat migraines. It should only be used as a last resort to treat epilepsy in pregnant women.
  • Pancreatitis: Valproic acid can cause rapidly-progressing and life-threatening pancreatitis.

Cautions

Some pre-existing medical conditions can make valproic acid riskier. These include:

  • Suspected mitochondrial disease: Valproic acid is contraindicated in people with POLG-related mitochondrial disease because of the risk of liver failure. It is prescribed cautiously in people who are suspected of having mitochondrial disease or those with a family history of POLG-related mitochondrial disease.
  • Severe kidney disease: People with severe kidney disease or kidney failure are at a higher risk of side effects when taking valproic acid.
  • History of liver disease: Because it can affect the liver, valproic acid is contraindicated in people with liver disease. It can be given to people who have had liver disease in the past, but only with extra monitoring.
  • Bleeding: Valproic acid can worsen bleeding problems.
  • Bone marrow suppression: Valproic acid can cause blood insufficiencies, such as low blood cell counts or low platelet counts, so it can worsen blood disorders due to bone marrow suppression.
  • Depression: Some people get suicidal when taking valproic acid, so it is used cautiously in people with depression or a history of depression.
  • Head injury: Because of an increased risk of death, valproic acid is avoided as a treatment for seizures due to head trauma.
  • HIV or CMV infections: Valproic acid can stimulate the growth of human immunodeficiency virus (HIV) or cytomegalovirus (CMV) infections, but it’s uncertain how this affects people taking antiviral medications.

Abuse and dependence

Drug abuse and physical dependence are not associated with valproic acid. 

Withdrawal

The sudden discontinuation of valproic acid can lead to an increase in seizures. Therefore, unless absolutely necessary to stop immediately, the drug will be discontinued using a tapering dose in people with seizure disorders. 

Overdose

Call a poison control center or get emergency medical treatment if too much valproic acid is taken. An overdose can be fatal or cause serious problems like sleepiness, low sodium, heart block, and coma. The maximum dosage depends on age, weight, and the condition being treated. However, valproic acid dosages are usually individualized, so consider the prescribed daily dose to be the maximum allowable dose and do not take more doses than prescribed.

Valproic acid interactions

Because of potentially hazardous drug interactions, certain drugs may require dose or treatment adjustments when combined with valproic acid.

Some drugs reduce the effectiveness of valproic acid. These include:

Some drugs increase the incidence and severity of valproic acid side effects. These include:

Valproic acid can worsen the side effects of other drugs, including:

Like valproic acid, the immune suppressant methotrexate can harm the liver, so the combination of these two medications is avoided or carefully monitored. Combining valproic acid with another seizure medication, topiramate, increases the risk of elevated ammonia levels and hypothermia.

Alcohol and cannabinoids (THC or CBD) should be avoided when taking valproic acid.

How to avoid valproic acid side effects

Side effects are a risk when taking valproic acid, but a few suggestions might help keep them at bay.

1. Share a complete medical history with the prescriber

To avoid problems, it is very important that the prescriber has a complete idea of medical problems or issues you might have. Make sure the prescribing healthcare provider especially knows about: 

  • Liver problems
  • Inherited mitochondrial disease
  • Inherited disorders that cause high ammonia levels in the blood
  • Depression or a history of suicide
  • HIV or CMV infection
  • Bleeding disorders
  • Kidney disease
  • Prescription drugs, over-the-counter medications, and dietary supplements being taken
  • Drinking
  • Pregnancy or pregnancy plans
  • Breastfeeding or breastfeeding plans

2. Take valproic acid as instructed

Follow the healthcare provider’s instructions when taking this medicine. Do not take larger doses than prescribed. Do not take doses more often than prescribed.

3. Keep all follow-up visits

Don’t skip or delay follow-up appointments. Spotting potentially serious side effects will require regular blood tests. Make sure to record all side effects and share that list with the prescriber during follow-up visits.

4. Avoid alcohol and any drugs that cause sleepiness

Alcohol and drugs that cause drowsiness will worsen drowsiness and other depressant side effects of valproic acid.

5. Avoid driving or other risky activities

Valproic acid can cause drowsiness and other mental impairments. Avoid driving, operating machinery, or other risky activities for a while until certain that valproic acid is not causing hazardous impairment.

How to treat side effects of valproic acid

Valproic acid has many potentially serious side effects. Here are the ones of which every person taking the medicine needs to be aware:

Liver problems

Valproic acid frequently disrupts the liver and can do damage. Regular blood tests should spot problems early, but sometimes the liver damage can evolve quickly. Get immediate medical help at any of the following signs of liver problems:

  • Upper abdominal pain
  • Dark urine
  • Fever
  • Tiredness
  • Loss of appetite
  • Yellowing of the skin or eyes (jaundice)

Swollen pancreas

Swollen pancreas (pancreatitis) is a particularly hazardous side effect of valproic acid. It can start early and progress rapidly into a fatal condition. Immediately get medical help if any of the signs of swollen pancreas are experienced, including:

  • Upper abdominal pain
  • Rapid heart rate
  • Nausea
  • Vomiting
  • Diarrhea
  • Oily stools that smell bad
  • Unexplained weight loss

Blood disorders

Low blood cell counts will require medical attention. They can’t be seen, but they can be spotted by the symptoms:

  • Unusual or prolonged bleeding
  • Frequent bruising
  • Skin discoloration, like spots or a rash
  • Nosebleeds
  • Unusual tiredness
  • Weakness
  • Pale skin

Low sodium

If sodium gets too low, symptoms will occur, such as headache, weakness, coordination problems, confusion, seizures, or coma. Get immediate medical care. 

Drug reactions

Valproic acid can cause severe drug reactions that affect the skin or even vital organs. They can be fatal if medical intervention comes too late. The drug must be stopped and immediate medical attention should be sought if any of the following symptoms are experienced:

  • Fever
  • Skin rash
  • Skin turning purple
  • Skin blisters
  • Skin peeling
  • Skin pain
  • Sores in the mouth or around the eyes
  • Burning, painful eyes
  • Swelling of the face
  • Facial redness
  • Enlarged lymph nodes
  • Signs of liver injury

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