Valproate (Valproic acid; Depakene and Depakote)

When is valproate used?

Valproate is an effective treatment for epilepsy. The Food and Drug Administration (FDA) in the United States has approved valproate for use in people of all ages with absence seizures, either alone or with other seizure types, and in patients older than 10 years of age with partial seizures (seizures that begin in a limited area of the brain).

However, the drug is often used “off label” either alone or in combination with other seizure medicines in other types of generalized seizures, as well as in other seizure types including febrile seizures and infantile spasms.

Besides its use in epilepsy, when else is valproate used?

Often doctors find that medicines are useful for more than one purpose. It is legal to prescribe medicines for "off-label uses" even though the Food and Drug Administration (FDA) has not formally approved such use.

The only FDA-approved use of valproate is the treatment of epilepsy, but it is effective and commonly used in patients with migraine headaches, and in patients suffering from bipolar disorder.

What are the most common side effects of valproate?

Most people who take valproate tolerate it very well with few or no complaints. The most common complaints include:

  • fatigue
  • dizziness
  • upset stomach
  • vomiting
  • tremor (shaking of the hands or other parts of the body)
  • hair loss
  • weight gain
  • changes in behavior (depression in adults, irritability in children)
  • slowed thinking

If these problems do not go away within several days, or are really bothersome, call the doctor, but never stop or reduce the medicine on your own. Sometimes the doctor can help with these side effects by changing the prescription:

  • reducing the overall amount of valproate
  • changing the amount taken at certain times, such as taking a greater proportion of the drug at bedtime to reduce daytime sleepiness
  • prescribing smaller doses at more frequent intervals

Stomach upset from valproate may be less of a problem if it is taken on a full stomach. Stomach upset is more likely when another seizure medicine with similar side effects (for example, Tegretol) is also being used.

Tremor (shaking of the hands or other body parts) tends to be worse when the level of valproate in the blood is highest, a few hours after the pills are taken. Also, anxiety or caffeine may make the tremor worse.

Weight gain affects 30% to 50% of people who take valproate. It is more common in adult women but can affect anyone. The average gain for adults is 15 pounds. Exercise and a reduced-calorie diet can help patients avoid or minimize weight gain. It is uncertain whether weight gain is greater when higher doses of valproate are taken.

Hair loss occurs in 5% to 10% of people who take valproate. The hair almost always grows back after the valproate is stopped, but it often has a different texture. Adding vitamins in the diet, including Selenium, may help minimize hair loss on valproate.

People who have just started taking valproate (or who have just started taking a larger amount) should be careful during activities that might be dangerous, until they know whether they are having any side effects.

Allergic reactions

Allergic reactions such as rashes are less common with valproate than with most other seizure medicines. Even so, you should report any rash to the doctor or nurse right away, especially if treatment has just begun. It is very rare for a rash to become serious, but any rash on seizure medication should not be ignored. Often, these rashes, even if minor, require a change to a different medication.

Are there long-term side effects of valproate?

Some people who have taken valproate for many years have experienced bone loss. Taking both calcium and vitamin D may help to prevent this kind of problem. Many doctors recommend a bone density test to identify which people need treatment for bone loss.

Some women taking valproate are also found to have Polycystic Ovary Syndrome (PCOS), a syndrome mainly characterized by menstrual irregularities, excessive hair growth, weight gain, and in some circumstances, reproductive abnormalities. The relationship between valproate and PCOS is not clear, however there does seem to be an association. Depending on a woman’s gynecologic and reproductive health, valproate may or may not be a seizure medicine of choice.

Excessive weight gain on valproate can be associated with increased risk for diabetes, heart disease, high blood pressure and other disorders. Therefore, weight should be monitored very carefully on valproate, and excessive gain should be avoided.

What are the most serious side effects of valproate?

Serious reactions to valproate are very rare. However, anyone who takes this medicine should be aware of the following warning signs that might indicate the onset of a serious problem:

  • weakness, sluggishness, swelling of the face, loss of appetite, vomiting, or yellowish eyes or skin, especially in a child under 2 years of age (possible liver failure)
  • pain in the abdomen, upset stomach, vomiting, or loss of appetite (possible disease of the pancreas)
  • easy bruising, nosebleed, or other abnormal bleeding (problems with clotting)

If you notice any of these symptoms, call the doctor immediately, but do not stop or change the dose of valproate without your doctor’s instruction.

The most common serious reaction to valproate is liver failure. This disorder usually occurs within the first 6 months of treatment. The risk of liver failure is much higher in children under 2 years of age, (as high as 2 in 1000) especially if the child also takes other seizure medicine or already has another serious disorder. Doctors seldom prescribe valproate for those with the highest risk.

The risk of liver failure is much lower in children between 2 and 10, and still lower in older children and adults, perhaps 1 in 50,000. There is no evidence that long-term use of valproate causes damage to the liver.

A very rare serious reaction to valproate is inflammation of the pancreas, or pancreatitis. Both children and adults can be affected, even after several years of taking valproate. Only extremely rarely can this be associated with bleeding or even death. Pain in the abdomen, upset stomach, vomiting, or loss of appetite should be reported to the doctor right away.

Problems with blood clotting can occur and are more likely in people who take large amounts of valproate. Sometimes the blood returns to normal without stopping the medicine. The doctor will often order blood tests before prescribing valproate, and will repeat them intermittently, especially if an abnormality is detected. Only rarely does a change in the blood count prompt discontinuation of valproate.

A complete list of all reactions to valproate can be found in the package insert for brand-name Depakene, but it is important to remember that only a tiny number of people have any of these serious problems.

Who should not take valproate?

People with liver disease should not take valproic acid, nor should anyone who has had an allergy to valproic acid or another valproate medicine in the past. Make sure the doctor knows about any liver problems, so that valproate is not prescribed.

Can valproate be taken with other medicines?
Sometimes one kind of medicine changes the way another kind of medicine works in the body. This is true not only for prescription medicines, but also for over-the-counter medicines. For instance, aspirin (ASA) may increase the side effects of valproate.

If someone who is taking valproate—especially a child—also starts to take the seizure medicine called Lamictal, the chances of a very dangerous rash will be increased. Adding Lamictal slowly reduces this danger.

Taking both valproate and another seizure medicine, Klonopin, sometimes causes absence seizures to be longer.

Any time a doctor suggests a new prescription, be sure to talk about what other medicines you are already using. If two kinds of medicine affect each other, the doctor may want to prescribe something else or change the amount to be taken.

How does valproate affect other medicines?

Valproate affects the way the body handles many other seizure medicines. Some of these are:

  • Felbatol (felbamate)
  • Lamictal (lamotrigine)
  • Mysoline (primidone)
  • phenobarbital
  • Tegretol or Carbatrol (carbamazepine)
  • Zarontin (ethosuximide)
  • Ativan (lorazepam)
  • Dilantin or Phenytek (phenytoin)

If a person taking one of these medicines starts taking valproate, the first medicine will stay in the body longer and the amount in the body will gradually rise. This may cause increased side effects like extreme tiredness and slurred speech, or any other side effect associated with that first medicine. Therefore, once a patient taking one of the above medicines starts taking valproate, the amount of the first medicine might need to be adjusted. Also, if the valproate is taken in combination with one of the medicines, stopping either of them might mean that the remaining medicine should be changed.

How do other medicines affect valproate?

Some other medicines do affect the way valproate works in the body. In particular, the following seizure medicines can reduce the amount of valproate in the body:

  • Mysoline (primidone)
  • phenobarbital
  • Tegretol or Carbatrol (carbamazepine)
  • Dilantin or Phenytek (phenytoin)

Make sure that your doctor is aware of all the medicines you are taking so that appropriate choices can be made.

If a woman takes valproate acid during pregnancy,
will it hurt the baby?

In the United States, the Food and Drug Administration (FDA) assigns each medication to a Pregnancy Category according to whether it has been proven to be harmful in pregnancy. Valproate is listed in Pregnancy Category D. This means that there is a risk to the baby, but the benefits may outweigh the risk for some women.

Birth defects are more common in the babies of women who take valproate during pregnancy than in others, particulary if taken in the first 3 months of pregnancy. That said, a large majority of women who take valproate do have healthy, normal babies (~90%). The risk of defects is higher for women who take more than one seizure medicine and women with a family history of birth defects.

If you are taking valproate and would like to become pregnant, you should discuss with your doctor reducing the dosage of valproate or even switching medications prior to conception.

All women who are capable of becoming pregnant should take at least 0.4 mg (400 mcg) of the vitamin called folic acid every day because it helps to prevent specific birth defects called Neural Tube Defects. (The most well-known of these is spina bifida, in which the spinal cord is not completely enclosed.) Women with epilepsy should take between 1 and 4 mg of folic acid daily during their reproductive years. If the doctor thinks a woman is at especially high risk, the larger dose of folic acid—4 mg (4000 mcg) per day—may be recommended, beginning before the woman becomes pregnant.

Some babies born to mothers taking antiepileptic medications have had inadequate blood clotting within the first 24 hours after birth. It is often recommended that the mother be given 10 to 20 mg of vitamin K per day during the last month of pregnancy to prevent this problem.

For those who have taken valproate during pregnancy and would like to breastfeed, the news is good. Only about 5% of valproate in the mother’s blood passes through breast milk, however even less actually enters the baby’s bloodstream. Further, how valproate affects the baby is unknown, and most babies breastfed on valproate experience no side effects. It is strongly felt by neurologists and epileptologists that the benefits of breastfeeding largely outweigh the risks of exposing the baby to antiepileptic medications, including valproate. As a matter of fact, the American Academy of Neurology and the American Epilepsy Society both recommend breastfeeding in women with epilepsy.