What is valproic acid

Valproic acid is a synthetic derivative of propylpentanoic acid with anticonvulsant and mood stabilizer properties used in the treatment of epilepsy and to treat bipolar disorder and migraines. Valproic acid also has potential antineoplastic and antiangiogenesis activities. Valproic acid is in a class of medications called anticonvulsants. It works by increasing the amount of a certain natural substance in the brain. In epilepsy, valproic acid appears to act by increasing the concentration of gamma-aminobutyric acid (GABA) in the brain. Valproic acid antitumor and antiangiogenesis activities may be related to the inhibition of histone deacetylases and nitric oxide synthase, which results in the inhibition of nitric oxide synthesis ¹.

Divalproex sodium, valproate sodium, and valproic acid, are all similar medications that are used by the body as valproic acid. Therefore, the term valproic acid will be used to represent all of these medications in this discussion.

Valproic acid is used alone or with other medications to treat certain types of seizures. Valproic acid is also used to treat mania (episodes of frenzied, abnormally excited mood) in people with bipolar disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Valproic acid is also used to prevent migraine headaches but not to relieve headaches that have already begun.

Valproic acid is also sometimes used to treat outbursts of aggression in children with attention deficit hyperactivity disorder (ADHD; more difficulty focusing or remaining still or quiet than other people who are the same age) ². Talk to your doctor about the possible risks of using this medication for your condition.

This medication is sometimes prescribed for other uses. Ask your doctor or pharmacist for more information.

Valproic acid medicine is only available on prescription. It comes as capsules or tablets.

Key facts

• It’s usual to take valproic acid 2 or 3 times a day. You can take it with or without food.
• If you’re pregnant, or there’s a chance you could become pregnant, valproic acid is not recommended for bipolar disorder or migraine. For epilepsy, your doctor will only prescribe valproic acid for you if there are no other suitable treatments.
• In early 2018, official guidance was published banning the use during pregnancy of valproate medicines for migraine or bipolar disorder, or for the treatment of epilepsy during pregnancy unless there is no other effective treatment available. This report can be found on the European Medicines Agency website here (https://www.ema.europa.eu/documents/press-release/new-measures-avoid-valproate-exposure-pregnancy-endorsed_en.pdf).
• You’ll usually start on a low dose. Your dose will gradually increase over a few days or weeks.
• Sodium valproate and semisodium valproate are similar to valproic acid and work in the same way. However, these medicines are used to treat different illnesses and doses will vary.
• The most common brand names of valproic acid are Depakote, Depacon, Stavzor, Valproate Sodium, Convulex. Epilim Chrono and Epilim Chronosphere contain mostly sodium valproate, with some valproic acid.

Who can and can’t take valproic acid

Valproic acid can be taken by adults and children to treat bipolar disorder or epilepsy.

It can be taken by adults (aged 18 and above) to prevent migraine.

Valproic acid isn’t suitable for some people:

• women who could become pregnant – unless they’re on Prevent, the valproate pregnancy prevention programme
• younger women or girls who are having sex (even if their periods haven’t started) – unless they’re on Prevent, the valproate pregnancy prevention programme

If you’re pregnant, do not take valproic acid to treat bipolar disorder or to prevent migraines. This is because valproic acid can seriously harm an unborn child.

For treating epilepsy during pregnancy, your doctor will only prescribe valproic acid for you if no other treatments work.

To make sure valproic acid is safe for you, tell your doctor if you:

• have ever had an allergic reaction to valproic acid or other medicines in the past
• have liver problems
• have a rare metabolic or genetic illness such as porphyria, urea cycle disorder or mitochondrial disorder
• are pregnant or trying to get pregnant.

Before taking valproic acid special precautions

• tell your doctor and pharmacist if you are allergic to valproic acid, any other medications, or any of the ingredients in the type of valproic acid that has been prescribed for you. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: acyclovir (Zovirax), anticoagulants (‘blood thinners’) such as warfarin (Coumadin), amitriptyline, aspirin, carbamazepine (Tegretol), cholestyramine (Prevalite), clonazepam (Klonopin), diazepam (Valium), doripenem (Doribax), ertapenem (Invanz), ethosuximide (Zarontin), felbamate (Felbatol), certain hormonal contraceptives (birth control pills, rings, patches, implants, injections, and intrauterine devices), imipenem and cilastatin (Primaxin), lamotrigine (Lamictal),medications for anxiety or mental illness, meropenem (Merrem), nortriptyline (Pamelor), phenobarbital, phenytoin (Dilantin), primidone (Mysoline), rifampin (Rifadin), rufinamide (Banzel), sedatives, sleeping pills, tolbutamide, topiramate (Topamax),tranquilizers,and zidovudine (Retrovir). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had episodes of confusion and loss of ability to think and understand, especially during pregnancy or childbirth; coma (loss of consciousness for a period of time); difficulty coordinating your movements; human immunodeficiency virus (HIV); or cytomegalovirus (CMV; a virus that can cause symptoms in people who have weak immune systems).
• tell your doctor if you are breast feeding.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking valproic acid.
• you should know that valproic acid may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
• remember that alcohol can add to the drowsiness caused by this medication.
• you should know that valproic acid can cause extreme drowsiness that may cause you to eat or drink less than you normally would, especially if you are elderly. Tell your doctor if you are not able to eat or drink as you normally do.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking valproic acid for the treatment of epilepsy, mental illness, or other conditions. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as valproic acid to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as one week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as valproic acid, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); talking or thinking about wanting to hurt yourself or end your life; withdrawing from friends and family; preoccupation with death and dying; giving away prized possessions; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.
• If you have diabetes and your doctor has told you to test your urine for ketones, tell the doctor that you are taking valproic acid. Valproic acid can cause false results on urine tests for ketones.
• Before having any laboratory test, tell your doctor and the laboratory personnel that you are taking valproic acid.

Cautions with other medicines

There are some medicines that may interfere with how valproic acid works. Valproic acid can also affect the way other medicines work.

Tell your doctor if you’re taking (or before you start taking):

• any other medicines for epilepsy such as carbamazepine
• medicines for thinning the blood such as warfarin
• aspirin for pain relief or low-dose aspirin
• cimetidine, a medicine for stomach ulcers
• medicines to treat HIV and AIDS such as ritonavir
• antibiotics such as erythromycin
• medicines for depression or other mental health problems such as venlafaxine, quetiapine or diazepam
• cholesterol-lowering medicines such as cholestyramine
• medicines to prevent malaria such as mefloquine or chloroquine

Mixing valproic acid with herbal remedies or supplements

It’s not possible to say whether complementary medicines and herbal supplements are safe to take with valproic acid.

They’re not tested in the same way as pharmacy and prescription medicines. They’re generally not tested for the effect they have on other medicines.

For safety, tell your doctor or pharmacist if you’re taking any other medicines, including herbal remedies, vitamins or supplements.

Valproic acid in pregnancy

Valproic acid is generally not recommended in pregnancy, as it can harm your unborn baby.

Sodium valproate (Epilim®) and valproic acid (Depakote®, Convulex®) medicines are approved in the US for the treatment of epilepsy and bipolar disorder, sometimes in combination with other medicines. These medicines are also sometimes used in the treatment or prevention of migraine.

In early 2018, official guidance was published banning the use during pregnancy of valproate medicines for migraine or bipolar disorder, or for the treatment of epilepsy during pregnancy unless there is no other effective treatment available. This report can be found on the European Medicines Agency website here (https://www.ema.europa.eu/documents/press-release/new-measures-avoid-valproate-exposure-pregnancy-endorsed_en.pdf).

If there’s a chance you could become pregnant while taking this medicine, your doctor will put you on Prevent, the valproate pregnancy prevention programme.

If you think you might already be pregnant, contact your doctor or nurse as soon as possible.

If you’re taking valproic acid for epilepsy and you become pregnant, do not stop taking your medicine without talking to your doctor first. This is because your symptoms or seizures may get worse.

Your doctor may continue to prescribe valproic acid, but only if there’s no other suitable treatment for your epilepsy.

Why is it not safe to take sodium valproate in pregnancy?

Sodium valproate is harmful to babies in the womb. Taking sodium valproate in pregnancy can cause a condition called Fetal Valproate Syndrome in the baby. Babies with Fetal Valproate Syndrome may have certain birth defects and lifelong alterations to learning and behavior. Some babies with Fetal Valproate Syndrome have only a few features of the condition and are very mildly affected. Others may have more serious birth defects or learning difficulties. Some babies of women who took valproic acid in pregnancy do not appear to have any features of Fetal Valproate Syndrome.

It is advisable to consider this information if you are taking sodium valproate and are pregnant or could become pregnant in the future, even if you are not currently planning on having children. If you can be treated with another drug that has been shown to be safer for an unborn baby than valproate, it is important that your doctor offers you this option. If you are not able to stop taking valproate then it is important that you are aware of the risks it poses to an unborn baby and of the importance of avoiding a pregnancy while taking valproate.

Your doctor is the best person to help you decide what is right for you and your baby.

Can taking valproic acid during my pregnancy cause birth defects?

Yes. Studies ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹² have found that women who take valproic acid have a greater chance of having a baby with a major birth defect. Birth defects are typically classified as major if they will need surgery to repair the birth defect. The chance of a birth defect seems to be greater with higher doses of valproic acid or with taking more than one seizure medication. Some of the birth defects that more likely to happen if a mom takes valproic acid in the first trimester are heart defects, cleft lip (lip develops with a split, which needs surgery to correct), or a neural tube defect (an opening in the baby’s spine or skull). The most common neural tube defect associated with valproic acid is spina bifida (opening in spine). The chance of a neural tube defect is approximately 1-2%. Taking extra folic acid before trying to get pregnant and continuing in early pregnancy might help reduce the chance of some birth defects in pregnancies exposed to valproic acid. Talk to your health care provider about how much folic acid you should take. Folic acid is found in foods and in vitamin supplements. Some babies exposed to valproic acid may also have more minor birth defects like facial differences, such as a thin upper lip.

What is the chance of valproic acid use in pregnancy causing birth defects in my baby?

A baby’s body and most internal organs are formed during the first 12 weeks of pregnancy. Taking valproic acid during this time can affect the baby’s development and increase the risk of certain birth defects.

Most studies suggest that overall, six to 10 out of every 100 babies exposed in the womb to valproic acid during the first trimester have a birth defect. This is higher than in the general population where major birth defects occur in two to three out of every 100 babies. The birth defects that have been linked to exposure to valproic acid in the womb include spina bifida, heart defects, cleft lip and palate, hypospadias (where the hole in the penis is on the underside rather than at the tip), and abnormalities of the fingers. Some valproate-exposed babies may have just one of these malformations, while others have more than one or none at all.

Each woman’s personal risk of having a baby with birth defects will depend on a number of things, including the dose of valproic acid that she is taking and her and her baby’s genetic make-up.

Will taking valproic acid during my pregnancy affect my baby’s development or behavior?

An increased chance for behavior and learning problems has been seen in babies who were exposed to valproic acid during pregnancy ¹³, ¹⁴, ¹⁵.

What is the chance that taking valproic acid in pregnancy will affect my child’s learning and behavior?

A baby’s brain continues to develop right up until the end of pregnancy. It is therefore possible that taking certain medicines at any stage of pregnancy could have a lasting effect on a child’s learning or behavior.

A large number of studies have shown that children who were exposed to valproic acid in the womb are more likely to have problems with co-ordination, movement, learning and behavior compared to children not exposed to valproic acid. Studies have also shown that children exposed to valproate in the womb have a higher chance of having autism spectrum disorder (ASD) and possibly attention deficit hyperactivity disorder (ADHD). These effects on learning and behavior have been observed in children both with and without birth defects or other features of fetal valproate syndrome.

It is difficult to work out the overall chance of a child’s learning or behavior being affected by exposure to valproic acid in the womb from the scientific studies that have investigated this. This is because these studies used different tests and have assessed slightly different aspects of learning and behavior. It is therefore often not possible to directly compare their results. Three studies have shown that between two and six out of every 10 children exposed to valproic acid in the womb require extra help at school, but because of the way that these studies were carried out, we cannot say for sure that these figures are accurate, and more research into this subject is required.

Is there a safe dose of valproate that won’t cause fetal valproate syndrome in the baby?

There is no known safe dose of valproate. However, it is clear that as the dose of valproate a woman takes increases, so does the likelihood of her baby having fetal valproate syndrome. For example, in one study eight out of 100 women who took 500mg valproic acid a day had a baby with a birth defect, whereas 62 out of 100 women who took 3000mg a day had a baby with a birth defect. This shows that although high doses present the highest risk, lower doses of valproic acid may still cause fetal valproate syndrome in some pregnancies.

There is much less information on how the dose of valproate taken in pregnancy relates to a child having learning or behavioral difficulties after birth. The few studies that are available suggest that learning and behavioral problems are more common than would be expected in the general population with doses above 800-1,000mg per day during pregnancy, but further research is required to confirm this.

Is slow release valproate or taking multiple smaller doses of valproic acid in a 24-hour period okay during pregnancy?

No. There is no evidence that slow release valproic acid or taking multiple smaller doses of valproic acid is less likely to result in Fetal Valproate Syndrome. ALL medicines that contain valproate should be avoided in pregnancy unless the mother has epilepsy that cannot be controlled with any other medicine.

Do not alter the dose of any medicine you are taking without first speaking to your doctor. Making changes to your medicine yourself may be more harmful to both you and your baby than continuing to take that medicine as prescribed.

Should I stop taking valproic acid during my pregnancy?

You should never stop taking any medication without first discussing it with your healthcare provider. The possible benefits of taking valproic acid to treat your specific illness must be weighed against the possible risks to the pregnancy.

What should I do if I have become pregnant while taking valproic acid?

If you are taking valproic acid, let your doctor know as soon as you realize that you are pregnant. Do not stop taking your medicine without seeking advice from your doctor first. Stopping valproic acid suddenly may be harmful to both you and your baby. If appropriate, your doctor will explain how to stop valproic acid as safely as possible. You may be advised to start a different medication to replace valproic acid.

In some women with epilepsy continued treatment with valproic acid during pregnancy may be considered necessary. This decision should be made under the care of a specialist neurologist. Women who need to continue taking valproic acid during pregnancy should be made fully aware of the risks of taking valproic acid during pregnancy.

I am taking valproic acid, but I would like to stop taking it before becoming pregnant. How long will valproic acid stay in my body?

Each person’s ability to break down the medication can be different. Liver disease can affect the amount of time it takes for your body to clear this medication. On average, it takes 2-3 days after your last dose for valproic acid to leave your body.

Women with epilepsy or bipolar disorder who are planning a pregnancy or could become pregnant should discuss their treatment options with their healthcare provider before becoming pregnant.

What could happen to my baby if I stopped taking my valproic acid and then had a seizure during my pregnancy?

Pregnant women should not change seizure medications (anticonvulsants) during pregnancy without the advice of a healthcare provider. Having a seizure while pregnant may be harmful to the baby ¹⁶, ¹⁷.

Complications for your baby depend on many things, such as the type of seizure, how long the seizure lasts, and the number of seizures that happen. Epileptic seizures might cause periods of time when the baby is not getting enough oxygen. Not having enough oxygen could lead to problems with development. These seizures could also be life-threatening for both mother and baby. A seizure could cause a mother to fall or have an accident that could injure herself or her baby.

What could happen to my baby if I stopped taking my valproic acid and then had a relapse of bipolar disorder during my pregnancy?

Pregnant women with bipolar disorder should not stop or change their medications during pregnancy without the advice of a healthcare provider. Women with bipolar disorder who stop taking medication during their pregnancy may be at an increased risk for episodes of depression or mania that could be harmful to both the mother and the baby. Recurrence of depression or mania is very stressful for the mother and her family. During mania or depressive episodes, the pregnant woman may have more trouble taking care of herself and keeping herself safe.

I have been taking valproic acid for the last few years and I just found out I am pregnant. What tests are available to see if my baby has spina bifida or other birth defects?

Prenatal screening for neural tube defects is available in pregnancy. A blood test can be done to measure the amount of a substance called alpha fetoprotein (AFP) in the mother’s blood. We know that babies with spina bifida have higher levels of alpha fetoprotein (AFP). If the alpha fetoprotein (AFP) is higher than usual in the blood test, more testing may be offered to you to assess if the baby has birth defects.

An ultrasound that looks at the baby’s spine can also be used to screen for spina bifida. Ultrasounds can also screen for other structural birth defects like a heart defect or cleft lip. All of these prenatal testing options can be discussed with your healthcare provider. There are no tests available during a pregnancy that can tell if there has been any effect on behavior or ability to learn.

Will taking high dose folic acid protect my baby against the harmful effects of valproic acid?

Valproic acid can cause low folic acid levels. Folic acid is necessary for a baby’s growth and development in the womb. Women who have low folic acid levels in early pregnancy are much more likely to have a baby with a birth defect of the spine. It is therefore recommended in the US that all women taking valproic acid also take high dose folic acid (5mg/day) instead of the standard dose of 400ucg whilst trying to conceive and during the first trimester of pregnancy. High dose folic acid has to be prescribed by a doctor.

There is not yet any scientific evidence to show that taking folic acid supplements at either high or standard doses can protect against the birth defects that are caused by valproic acid. However, until more scientific information is available, high dose folic acid is advised.

What should I do if I am taking valproic acid and could become pregnant in the future?

If you have not yet gone through the menopause request an appointment with your doctor to review whether you can stop taking valproic acid. The new guidance states that valproic acid medicines must not be used in any woman or girl able to have children unless a pregnancy prevention programme is in place. The programme is designed to ensure that patients are made fully aware of the risks, the need to avoid becoming pregnant, the need for pregnancy tests, and are using appropriate contraception.

Is it true that women who have had a child with fetal valproate syndrome are more likely to have another child with fetal valproate syndrome?

Two small studies have both suggested that unborn babies who are exposed in the womb to valproic acid have a higher chance of being born with fetal valproate syndrome if they already have a brother or sister with fetal valproate syndrome. The studies showed up to six out of every 10 pregnant women who had a previous child with fetal valproate syndrome had another baby with fetal valproate syndrome in their next pregnancy. In contrast, fewer than two out of every 10 pregnant women whose previous child had not had fetal valproate syndrome (even though they took valproic acid in pregnancy) then had a baby with fetal valproate syndrome. This suggests that certain genes carried by the mother and/or her children may influence how valproic acid affects an unborn baby. It is hoped that future research will help to develop a way of identifying women and girls who are at high risk of having a baby with fetal valproate syndrome before they start a family.

Is taking valproic acid with other epilepsy treatments more harmful to the baby than taking it on its own?

Valproic acid is sometimes taken in combination with other medicines to treat epilepsy. Most studies have not found that women taking valproic acid in combination with other antiepileptics were at higher risk of having a baby with a birth defect than women who took only valproic acid. If you are taking more than one medicine to control epilepsy you should discuss any concerns that you may have with your doctor.

Can taking valproic acid in pregnancy cause miscarriage?

One small study has shown that women who took daily valproic acid doses of 750mg or more were about three times more likely to have a miscarriage than women not receiving epilepsy treatments during pregnancy. Because these results are from just one study, more research is required to confirm these findings.

Can taking valproic acid in pregnancy cause stillbirth, or preterm birth?

A single small study found no links between valproic acid use in pregnancy and stillbirth or preterm birth. However, many more women taking valproic acid in pregnancy need to be studied to confirm these findings.

Can taking valproic acid in pregnancy cause my baby to be small at birth (low birth weight)?

No increased risk of the baby being smaller than expected for the stage of pregnancy was identified in one study of 410 babies born to women who took valproic acid in pregnancy. Another small study of 120 babies exposed to valproic acid in the womb showed that these babies were slightly lighter on average at birth (although their birth weights were still in the normal range) than babies not exposed to valproic acid. More research is required to confirm that taking valproic acid in pregnancy does not increase the risk of low birth weight in the baby.

Can taking valproic acid in pregnancy cause withdrawal symptoms in the baby at birth (‘neonatal withdrawal’)?

Withdrawal symptoms are thought to occur when a newborn baby’s body has to adapt to no longer getting certain types of medicines through the placenta.

Valproic acid works in a similar way to other medicines that are known to cause neonatal withdrawal. There are reports of babies who were exposed to valproic acid in the womb suffering from withdrawal symptoms at birth. Close monitoring of your baby for a few days after birth may be therefore advised if you have taken valproic acid regularly in the weeks before delivery. Monitoring of your baby may be particularly important if you have taken valproic acid in combination with other antiepileptic medicines or medicines that act on the brain.

Will my baby need extra monitoring?

Most women will be offered a scan at around 20 weeks of pregnancy to look for birth defects as part of their routine antenatal care. Women who have taken valproic acid during the first trimester should be offered more detailed anomaly scans from as early as around 12 weeks of pregnancy. It is, however, harder to see birth defects at this stage of pregnancy, which is why the main scan for birth defects is generally offered at around 20 weeks of pregnancy. It is important to understand that scans are not able to pick up all birth defects and cannot predict whether a baby will have problems with learning and behavior. In general, women with epilepsy may be more closely monitored during pregnancy to ensure that they remain well throughout and that their baby is growing and developing as expected.

If you have taken valproic acid around the time of delivery your baby may require extra monitoring after birth because of the risk of neonatal withdrawal.

What should I do if I am concerned that my child has fetal valproate syndrome?

There is no simple test to diagnose fetal valproate syndrome. If you took valproic acid during pregnancy and are concerned that it may have caused problems in your child it is best to speak to your doctor. They will arrange for your child to be referred to a pediatrician who will assess your child’s development and health, and will, if necessary, rule out other illnesses that may cause problems with development, some of which can be treated.

Spelling errors (mutations) in a person’s genetic code (DNA) can also cause similar problems to those seen in children with fetal valproate syndrome. It is likely that your doctor or pediatrician will therefore also suggest that your child is reviewed by a clinical geneticist, a type of doctor who specializes in assessing children for genetic conditions as well conditions caused by medicines such as valproic acid.

Is it safe to breastfeed while taking valproic acid?

Yes ¹⁸. Valproic acid is passed into breast milk, but at low levels and seems to be compatible with breastfeeding ¹⁹. As the amount is so small it’s unlikely to harm your baby, unless your baby was born premature or has kidney problems. There is concern that breastfed infants whose mothers are taking valproic acid are at risk for liver toxicity, so the infants should be monitored for any changes or problems. Be sure to discuss all your breastfeeding questions with your healthcare provider.

Talk to your doctor about the benefits and risks of taking valproic acid while breastfeeding. They may still recommend valproic acid if it’s the only medicine that works for you.

I have been taking valproic acid for many years. Can this make it harder for me to get pregnant?

This is possible ²⁰. Studies have found that women with seizure disorders and women with bipolar disorder might have menstrual problems and difficulty getting pregnant.

What if the father of the baby takes valproic acid?

Valproic acid may have effects on sperm shape and movement that could make it harder to get pregnant ²⁰. In general, medications that the father takes do not increase risk to a pregnancy.

Valproic acid mechanism of action

Valproic acid is an anticonvulsant (or anti-epileptic) medicine. The mechanisms of valproic acid therapeutic actions are not well understood. Valproic acid may act by increasing the amount of a chemical called gamma-aminobutyric acid (GABA) levels in the brain or by altering the properties of voltage dependent sodium channels ¹. GABA blocks transmission across nerves in the brain and has a calming effect.

It’s not really clear how valproic acid or sodium valproate prevent migraine. These medicines may limit how your nerves transmit pain signals in the brain.

For treating epilepsy, valproic acid prevents epileptic fits by reducing excessive electrical activity in your brain.

When will I feel better?

It takes a few weeks for valproic acid to work properly. You may still have symptoms during this time.

How long will I take valproic acid for?

Once your illness is under control, you’ll usually need to keep taking valproic acid for many years.

Is it safe to take valproic acid for a long time?

Many people can take valproic acid safely for many months or years.

However there are potential side effects that can happen over a long time. Long-term treatment with valproic acid can cause osteoporosis and osteopenia (increasing your risk of breaking a bone).

Your doctor can arrange for tests to check the strength of your bones. Regular exercise and a good diet can also help to keep your bones strong.

Can I get addicted to valproic acid?

Valproic acid is not known to be addictive.

What will happen when I come off valproic acid?

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.

If you’re taking valproic acid for epilepsy, it’s possible that you’ll get seizures again once you stop taking it. You can prevent these withdrawal seizures by reducing your dose of valproic acid gradually.

Are there similar medicines to valproic acid?

Sodium valproate and semisodium valproate are very similar to valproic acid. They work in the same way but these medicines are sometimes given at different doses for different conditions.

If you decide to try sodium valproate or semisodium valproate instead, your doctor will explain how to come off valproic acid safely.

How does valproic acid compare with other medicines for epilepsy?

There are many different medicines for treating epilepsy (anti-epileptic medicines). It’s not possible to say that one works better than the other. It varies from person to person and depends on the type of seizures and how often you have them.

Before prescribing a medicine, your doctor will also take into account your age and gender, the medicines you’re already taking and any other health problems you may have.

It’s usual to try to treat epilepsy using a single medicine. If this medicine isn’t working well, or you’re getting side effects, your doctor will generally try you on a different one.

If a single medicine isn’t preventing your seizures, then your doctor may recommend taking 2 or more anti-epileptic medicines at the same time.

If valproic acid is giving you side effects, or you’re worried it isn’t suitable for you, ask your doctor or specialist to recommend a different medicine.

Other anti-epileptic medicines include:

• Carbamazepine
• Clobazam
• Ethosuximide
• Gabapentin
• Lamotrigine
• Levetiracetam
• Phenytoin
• Pregabalin
• Topiramate

How does valproic acid compare with other medicines for treating bipolar disorder?

If you have bipolar disorder, there are several types of medicine to prevent mood swings and treat mania. It’s not possible to say that one works better than another and it varies from person to person.

Lithium is commonly used for bipolar disorder, as well as anti-epileptic medicines like valproic acid and antipsychotic medicines like olanzapine. You can take valproic acid instead of lithium, or together with lithium, depending on what your doctor recommends.

Your doctor or specialist will find the medicines that work best for you. It depends on your mood swings, how often they happen, how severe they are and how well you cope with a medicine.

How does valproic acid compare with other medicines for migraine?

For many people topiramate, propranolol and amitriptyline work better than valproic acid at preventing migraines. These medicines are likely to cause fewer side effects – so your doctor or specialist will usually prescribe one of these first.

Valproic acid isn’t used as often for preventing migraine. However your doctor may recommend it if these other medicines are causing side effects or aren’t working for you.

Your doctor may also prescribe valproic acid if you have a health problem that means you can’t take other migraine medicines.

Will recreational drugs affect valproic acid?

Valproic acid can affect recreational drugs like cannabis and heroin.

If you use recreational drugs alongside valproic acid, you may be more likely to have side effects like panic attacks, anxiety and memory loss.

Can I drink alcohol with valproic acid?

Drinking alcohol while taking valproic acid may make you feel sleepy or tired. For this reason it’s best to stop drinking alcohol during the first few days, until you see how the medicine affects you.

If you do drink, try not to have more than the recommended guidelines of up to 14 units of alcohol a week. A standard glass of wine (175ml) is 2 units. A pint of lager or beer is usually 2 to 3 units of alcohol.

Will valproic acid affect my fertility?

Valproic acid can reduce fertility in both men and women. Once you stop taking this medicine, your fertility will return.

In men valproic acid has been reported to cause infertility. However, this is rare.

In women it can change your menstrual cycle, causing delayed or missed periods. Valproic acid has also been reported to cause polycystic ovary syndrome (PCOS), though this happens rarely.

Talk to your doctor if you’re concerned about how valproic acid may affect your fertility.

• Valproic acid is no longer recommended for girls or women who may become pregnant. If you’re taking valproic acid and want to start a family, it’s important to talk your doctor as soon as possible. This is because valproic acid can harm your unborn child.

Will valproic acid affect my contraception?

Valproic acid doesn’t affect any type of contraception, including the combined pill and emergency contraception.

Women and girls who could become pregnant while taking sodium valproate must use contraception. Your doctor will put you on Prevent, the valproate pregnancy prevention programme.

Speak to a pharmacist or your doctor if you have any questions about this programme.

Can I drive or ride a bike while taking valproic acid?

You may feel sleepy, tired or dizzy when you first start taking valproic acid. This may also happen if your dose has increased. If you’re affected, do not drive or ride a bike until you feel more alert.

If you have epilepsy, you’re not allowed to drive until you’ve had no seizures for 1 year (or only have seizures while you’re asleep).

If you change your epilepsy medicine, you are not allowed to drive for the first 6 months of treatment.

Can valproic acid be used to treat dementia?

You may have read some stories in the news linking valproic acid to treatment for dementia.

It was hoped that valproic acid could prevent aggressive behavior and agitation in people with different types of dementia, including Alzheimer’s disease.

However, the medicine has been tested in a number of trials and overall the results show it’s unlikely to improve these symptoms.

Valproic acid uses

Valproic acid is used to treat certain types of seizures (epilepsy). Valproic acid is an anticonvulsant that works in the brain tissue to stop seizures.

Valproic acid is also used to treat the manic phase of bipolar disorder (manic-depressive illness), and helps prevent migraine headaches.

Valproic acid dosage

Valproic acid comes as a capsule, an extended-release (long-acting) tablet, a delayed-release ( releases the medication in the intestine to prevent damage to the stomach) tablet, a sprinkle capsule (capsule that contains small beads of medication that can be sprinkled on food), and a syrup (liquid) to take by mouth. The syrup, capsules, delayed-release tablets, and sprinkle capsules are usually taken two or more times daily. The extended-release tablets are usually taken once a day. Take valproic acid at around the same time(s) every day. Take valproic acid with food to help prevent the medication from upsetting your stomach. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take valproic acid exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Valproic acid is available in the following dosage forms:

• Capsule, Delayed Release
• Syrup
• Capsule, Liquid Filled
• Tablet, Extended Release
• Tablet, Enteric Coated
• Tablet, Delayed Release

Swallow the regular capsules, delayed-release capsule, and extended-release tablets whole; do not split, chew, or crush them.

You can swallow the sprinkle capsules whole, or you can open the capsules and sprinkle the beads they contain on a teaspoonful of soft food, such as applesauce or pudding. Swallow the mixture of food and medication beads right after you prepare it. Be careful not to chew the beads. Do not store unused mixtures of food and medication.

Do not mix the syrup into any carbonated drink.

Divalproex sodium, valproate sodium, and valproic acid products are absorbed by the body in different ways and cannot be substituted for one another. If you need to switch from one product to another, your doctor may need to adjust your dose. Each time you receive your medication, check to be sure that you have received the product that was prescribed for you. Ask your pharmacist if you are not sure that you received the right medication.

Your doctor may start you on a low dose of valproic acid and gradually increase your dose.

Valproic acid may help to control your condition but will not cure it. Continue to take valproic acid even if you feel well. Do not stop taking valproic acid without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood or if you find out that you are pregnant. 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.

Valproic acid is a prescription medicine. It’s important to take it as advised by your doctor.

• For treating bipolar disorder in adults: the usual dose is 750mg to 2,000mg a day, split into 2 or 3 doses.
• For treating bipolar disorder in children: the doctor will work out the right dose for your child.
• For preventing migraine in adults: daily doses vary from a single dose of 400mg to 1,500mg split into 2 doses.
• For treating epilepsy in adults and older children (aged 12 years and over): the usual dose is 600mg to 2,000mg a day, split into 2 to 4 doses.
• For treating epilepsy in younger children (weighing more than 20kg): doses vary. The doctor will use your child’s weight to work out the right amount of medicine to give them.

If you need to take your medicine a few times a day, the amount you take each time depends on your total daily dose. You’ll take a number of equal doses that add up to your daily total. Ask your doctor or a pharmacist if you’re unsure how much to take each time.

If you’re taking valproic acid and also have kidney problems, your doctor may prescribe a lower dose.

To prevent the chance of side effects, your doctor will start you off on a low dose of valproic acid. They will increase it gradually over a few days or weeks.

Once you find a dose that suits you, it will usually stay the same – unless your condition changes, or your doctor starts you on a new medicine that may interfere with valproic acid.

How and when take valproic acid

Valproic acid comes as “gastro resistant” tablets and capsules. These release the valproic acid into your body as soon as they pass through your stomach.

Swallow the tablets or capsules whole with a drink of water or juice. Do not chew them.

You can take valproic acid with or without food, but it’s best to do the same each time.

• Gastro resistant tablets – you’ll usually take these 2 to 3 times a day.
• Gastro resistant capsules – you’ll usually take these 2 to 4 times a day.

If you’re taking valproic acid twice a day, try to leave a gap of 10 to 12 hours between doses. For example you could take your first dose in the morning (between 7am and 8am) and a second dose in the evening (between 7pm and 8pm).

If you take your medicine 3 to 4 times a day, try to space your doses evenly through the day. If you need to take 3 doses, for example, you could take your medicine first thing in the morning, early afternoon and bedtime.

Adult Dose for Epilepsy

Uses: Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures

Complex partial seizures:

• Initial dose: 10 to 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response
• Maintenance dose: 10 to 60 mg/kg daily
• Maximum dose: 60 mg/kg daily

Simple and complex absence seizures:

• Initial dose: 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response
• Maintenance dose: 10 to 60 mg/kg daily
• Maximum dose: 60 mg/kg daily

Comments:

• If the total daily dose exceeds 250 mg, it should be given in divided doses.
• When converting to monotherapy, concomitant antiepilepsy drug (antiepilepsy drug) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of this drug, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant antiepilepsy drug can be highly variable.
• Optimal clinical response is usually achieved at daily doses below 60 mg/kg/day; if satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). There is no recommendation regarding the safety of this drug at doses above 60 mg/kg/day.
• If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.
• Antiepilepsy drugs should not be abruptly discontinued because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

Comments:

• The IV formulation should be administered as a 60-minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary.
• Use of the IV formulation for periods longer than 14 days has not been studied.
• Patients on the IV formulation should be switched to the oral formulation as soon as it is clinically feasible.

Pediatric Dose for Epilepsy

10 years or older:

Uses: Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures

• Complex partial seizures:
  • Initial dose: 10 to 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response
  • Maintenance dose: 10 to 60 mg/kg daily
  • Maximum dose: 60 mg/kg daily
• Simple and complex absence seizures:
  • Initial dose: 15 mg/kg orally or IV daily; increase by 5 to 10 mg/kg per week if necessary according to clinical response
  • Maintenance dose: 10 to 60 mg/kg daily
  • Maximum dose: 60 mg/kg daily

Comments:

• If the total daily dose exceeds 250 mg, it should be given in divided doses.
• When converting to monotherapy, concomitant antiepilepsy drug (antiepilepsy drug) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of this drug, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant antiepilepsy drug can be highly variable.
• Optimal clinical response is usually achieved at daily doses below 60 mg/kg/day; if satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). There is no recommendation regarding the safety of this drug at doses above 60 mg/kg/day.
• If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.
• Antiepilepsy drugs should not be abruptly discontinued because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

Comments:

• The IV formulation should be administered as a 60-minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary.
• Use of the IV formulation for periods longer than 14 days has not been studied.
• Patients on the IV formulation should be switched to the oral formulation as soon as it is clinically feasible.

Renal Dose Adjustments

• No adjustment recommended.

Liver Dose Adjustments

• Hepatic disease or significant hepatic dysfunction: Contraindicated

Therapeutic drug monitoring

• The relationship between plasma concentration and clinical response is not well documented.
• Epilepsy: The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.
• Mania: Patients have been dosed (in clinical trials) to clinical response with trough plasma concentrations between 50 and 125 mcg/mL
• Monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn
• Monitoring of total concentrations may be misleading in patients with liver disease since free concentrations may be substantially elevated in these patients whereas total concentrations may appear to be normal.
• Protein binding is substantially reduced in renal failure; monitoring of total concentrations may be misleading in these patients.

What if I forget to take valproic acid?

If you forget a dose take it as soon as you remember, unless it’s less than 2 hours to your next dose. In this case, skip the missed dose and take your next one at the usual time.

Never take 2 doses at the same time. Never take an extra dose to make up for a forgotten one.

If you have epilepsy, it’s important to take this medicine regularly. Missing doses can trigger a seizure.

If you forget doses often, it may help to set an alarm to remind you. You could also ask your pharmacist for advice on other ways to help you remember to take your medicine.

What if I take too much valproic acid?

Taking too much valproic acid by accident can lead to symptoms such as:

• feeling or being sick (nausea or vomiting)
• headaches, or feeling dizzy
• muscle weakness
• breathing problems
• feeling confused, or changes to your normal behavior
• passing out

Call your doctor or go to emergency department straight away if you take too much valproic acid and feel unwell

If you need to go to hospital, take the valproic acid packet or the leaflet inside it, plus any remaining medicine, with you.

Valproic acid side effects

Like all medicines, valproic acid can cause side effects, although not everyone gets them.

Valproic acid common side effects

These common side effects may happen in more than 1 in 100 people. They’re usually mild and go away by themselves.

Keep taking the medicine but talk to your doctor if these side effects bother you or don’t go away:

• stomach pain, feeling or being sick (nausea or vomiting)
• diarrhea
• dry or sore mouth, or swollen gums
• shakes (tremors) in a part of your body, or unusual eye movements
• feeling tired or sleepy
• headache
• weight gain
• thinning hair, or changes to the color or texture of your hair
• irregular or delayed periods

If you are taking the sprinkle capsules, you may notice the medication beads in your stool. This is normal and does not mean that you did not get the full dose of medication.

Valproic acid serious side effects

It’s unusual to have serious side effects after taking valproic acid. Tell a doctor straight away if you have:

• thoughts of harming or killing yourself – a small number of people taking valproic acid have had suicidal thoughts
• yellowing of your skin or whites of your eyes – these may be warning signs of liver problems
• long-lasting and severe nausea, vomiting or stomach pain – these may be warning signs of an inflamed pancreas
• unusual bruises or bleeding – these may be warning signs of a blood disorder

Serious allergic reaction

In rare cases, valproic acid may cause a serious allergic reaction (anaphylaxis).

See a doctor straight away if:

• you get a skin rash that may include itchy, red, swollen, blistered or peeling skin
• you’re wheezing
• you get tightness in the chest or throat
• you have trouble breathing or talking
• your mouth, face, lips, tongue or throat start swelling

These are warning signs of a serious allergic reaction. A serious allergic reaction is an emergency.

These are not all the side effects of valproic acid. For a full list, see the leaflet inside your medicine packet.

In case of valproic acid overdose

Symptoms of overdose may include the following:

• sleepiness
• irregular heartbeat
• coma (loss of consciousness for a period of time)

In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can’t be awakened, immediately call your local emergency services number.

How to cope with side effects

What to do about:

• Stomach pain, feeling or being sick (nausea or vomiting) – take valproic acid with or after a meal or snack. It may also help if you don’t eat rich or spicy food.
• Diarrhea – have small but frequent sips of water. Speak to a pharmacist if you have signs of dehydration, such as peeing less than usual or having dark, strong-smelling pee. Do not take any other medicines to treat diarrhoea without speaking to a pharmacist or doctor.
• Dry or sore mouth, or swollen gums – for a dry mouth try sugar-free gum or sweets, or sipping cold drinks. If this doesn’t help, or you have mouth ulcers, talk to your pharmacist or doctor. If you’re bothered by swollen gums or this symptom doesn’t go away, talk to your doctor or dentist.
• Shakes (tremors) in a part of your body, or unusual eye movements – talk to your doctor if this is bothering you. These symptoms can be a sign that the dose is too high for you. It may help to change your dose or take your medicine at a different time of day.
• Feeling tired or sleepy – as your body gets used to valproic acid, these side effects should wear off. If these symptoms don’t get better within a week or two, your doctor may either reduce your dose or increase it more slowly. If that doesn’t work you may need to switch to a different medicine.
• Headache – make sure you rest and drink plenty of fluids. Do not drink too much alcohol. Ask your pharmacist to recommend a painkiller. Talk to your doctor if your headaches last longer than a week or are severe.
• Weight gain – if you find you’re putting on weight after taking valproic acid, try to have a healthy balanced diet. Regular exercise will also help you keep your weight stable. Your doctor will usually monitor your weight while you’re taking this medicine. Speak to them if you have any concerns.
• Thinning hair, or changes to the color or texture of your hair – if these symptoms bother you, ask your doctor whether it’s possible to lower your dose. Your hair may regrow after either reducing your dose or switching to a different medicine.
• Irregular or delayed periods – if you usually have regular periods, tell your doctor straight away if your period is late. As well as being a side effect of valproic acid, it’s a sign that you could be pregnant – and valproic acid can be harmful for an unborn baby. Changes to your periods can also be a symptom of polycystic ovary syndrome (PCOS), a rare side effect of valproic acid. Your doctor will be able to do some tests to check whether you have PCOS.

1. Valproic acid. https://pubchem.ncbi.nlm.nih.gov/compound/valproic_acid[↩][↩]
2. Valproic Acid. https://medlineplus.gov/druginfo/meds/a682412.html[↩]
3. Weston J, et al. 2016. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev. 11:Cd010224.[↩]
4. Veroniki AA, et al. 2017. Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC medicine. 15(1):95.[↩]
5. Vajda FJ, et al. 2013. Dose dependence of fetal malformations associated with valproate. Neurology;81(11):999-1003.[↩]
6. Smith, J et al. 2009. Sodium valproate and the fetus: a case study and review of the literature. Neonatal Netw 28: 363-7.[↩]
7. Ornoy A. 2009. Valproic acid in pregnancy: how much are we endangering the embryo and fetus? ReprodToxicol 28: 1-10.[↩]
8. Mawhinney E, et al. 2012. Valproate and the risk for congenital malformations: Is formulation and dosage regime important? Seizure;21(3):215-218.[↩]
9. Jentink J, et al. 2010. Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations. N Engl J Med 362:2185-93.[↩]
10. Harden CL, et al. 2009. Management issues for women with epilepsy – Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 50: 1237-46.[↩]
11. Tomson T, et al. 2015. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia. 56(7):1006-19.[↩]
12. Einarson A et al. 2009. Use and safety of antipsychotic drugs during pregnancy. J Psychiatr Pract 15: 183-92.[↩]
13. Shallcross R, et al. 2014. In utero exposure to levetiracetam vs valproate: development and language at 3 years of age. Neurology;82(3):213-21.[↩]
14. Meador KJ, et al. 2012. Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years. Neurology; 78(16):1207-14.[↩]
15. Deshmukh U, et al. 2016. Behavioral outcomes in children exposed prenatally to lamotrigine, valproate, or carbamazepine. Neurotoxicol Teratol. 54:5-14.[↩]
16. Sveberg L, et al. 2015. The impact of seizures on pregnancy and delivery. Seizure. 28:35-8.[↩]
17. Abe K, et al. 2014. Impact of planning of pregnancy in women with epilepsy on seizure control during pregnancy and on maternal and neonatal outcomes. Seizure. 23(2):112-6.[↩]
18. Aydin B, et al. 2015. Olanzapine and quetiapine use during breastfeeding: excretion into breast milk and safe breastfeeding strategy. J Clin Psychopharmacol; 35(2):206-8.[↩]
19. Meador KJ, et al. 2014. Breastfeeding in children of women taking antiepileptic drugs: Cognitive outcomes at age 6 years. JAMA Pediatr. 168:729-36.[↩]
20. Valproic Acid. https://mothertobaby.org/fact-sheets/valproic-acid-pregnancy/[↩][↩]