Valproic Acid

Valproic acid is the generic name of a widely used antiepileptic drug (AED). In the United States and Canada, valproic acid is known by the brand name Depakene. The brand name in the UK is Convulex. Brand names used in other countries include Depakine, Orfiril, Valporal, and Valprosid.

Valproic acid dissociates to the valproate ion in the gastrointestinal tract, so its effects are virtually identical to those of other forms of valproate. These include oral divalproex sodium (Depakote or Depakote ER in the United States) and sodium valproate (Epilim in the UK and Australia), as well as an injectable solution of valproate sodium (Depacon). The divalproex sodium (Depakote) products, which are slower to dissolve, are promoted as less apt to cause stomach upset.

Sometimes the savings from using generic medications instead of brand-name products are large, but with other products the price differences are rather small. Investigate before deciding whether the savings are worth any possible problems. What's important is that both the doctor and the patient should know what the pharmacy is dispensing and have control over what type of medication is used.

Patients who switch from brand-name Depakene or Depakote to generic valproic acid possibly risk having more seizures or side effects during the changeover, because of differences in absorption or metabolism. Switching from one company's generic valproic acid to another company's may have similar risks. So can switching from generic valproic acid to Depakene.

All these risks are not fully known. For some patients the effects of changing from one type to another are very small. Some use generic valproic acid successfully by always using the same company's product. Then the dosage can be adjusted to achieve the best results.

Convulex
Depakene
Depakine
Tablet
Depakine 250mg

250-mg (orange-color, soft)
Gelatin capsules marked with the word DEPAKENE

Liquid Solution

Syrup
250 mg per 5 mL(red liquid)

Orfiril
Valporal
Valprosid

Indications

Valproic acid is indicated for use as an anticonvulsant drug in people of all ages. It is used mainly as monotherapy or adjunctive therapy for simple or complex absence seizures, either alone or with other seizure types (such as for juvenile myoclonic epilepsy). It is also effective for partial seizures.

Forms

Various companies make and sell valproic acid. In the United States, it is available in two forms:

  • 250-mg capsules
  • 250 mg/5mL syrup

Dosing

See package insert.

How to take and store Valproic Acid?

Valproic acid capsules must be swallowed whole. Chewing could result in local irritation of the mouth and throat. They are best taken on a full stomach to avoid stomach upset, but they can be taken without food. Advise patients that if they take the capsule alone, they should be sure to drink a full glass of water.

The syrup can be mixed with another liquid or food for better taste, as long as it is all consumed. Instruct patients to use a standard measuring spoon or dropper for correct, consistent dosing. Both capsules and syrup should be stored at room temperature, away from heat, light, and dampness. Don't let the syrup become frozen.

Missed Doses

In general, tell patients that if they forget a dose, they should take it as soon as they remember. If it is almost time for the next dose, they should delay that dose for a few hours, instead of taking two doses very close together.

Patients who often forget doses may benefit from using a special pillbox or watch with an alarm. Switching to a once-a-day extended-release form of a valproate product (in the U.S., Depakote ER) may also help with compliance.

Mechanisms of actions of Valproic Acid

Valproate differs in structure from other antiepileptic drugs in common use. The way in which valproate works is not fully understood, but it appears to involve several mechanisms and to act on a variety of targets, probably accounting for its broad efficacy:

  • It probably blocks high-frequency, repetitive neuronal firing by blocking voltage-dependent sodium channels.
  • It may augment the action of GAD (glutamic acid decarboxylase), a GABA-synthesizing enzyme.
  • At high levels, it restricts GABA-T (GABA transaminase), an enzyme that speeds the degradation of GABA.
  • It acts against T-type calcium currents like those implicated in the spike-wave activity of absence seizures. (This action is not as apparent as with ethosuximide, however.)
Clinical Pharmacology of Valproic Acid

Generic valproic acid from different manufacturers may not be exactly equivalent pharmacologically to each other or to brand-name products. Caution is advised in changing from one product to another.

Absorption
Valproic acid is quickly absorbed when taken by mouth. The delay that occurs when it is taken with food is not important during long-term treatment, but it could have some effect when treatment is first begun. Without food, peak levels in the blood are reached in approximately 2 hours for both capsules and syrup. With food, reaching the peak level takes approximately 4 hours.

Distribution and metabolism
Valproate is highly bound (90%) to proteins in the blood. Thus, only 10% is free or unbound and able to enter the brain. However, as the blood level rises above 80 micrograms per milliliter (mcg/mL) to 100 mcg/mL, the proportion of valproic acid that is free (and thus available to the brain) can rise markedly. Free blood and brain levels of valproic acid can range from 7% to 28% of the total levels. Since the free level is what the brain ""sees,"" at levels over approximately 90 mcg/mL, there can be a fairly dramatic increase in the brain levels. For example, a person with a total level of 75 mcg/mL may have a free blood and brain level of 7.5 mcg/mL (10%), but when the level is 130 mcg/mL, the blood and brain levels may increase to 20.8 mcg/mL (16%). This increase could be associated with improvement in seizure control and worsening of side effects in the body and brain.

More than 95% of valproate is broken down in the liver by several different metabolic pathways. Many metabolites are produced, and some of them have longer half-lives than the original drug. Some metabolites may contribute to the efficacy and side effects. The half-life ranges from 8 to 16 hours, with shorter times in children and longer times in the elderly.

The differences between peak and trough levels can be marked. In some cases the peak level is more than double the trough level. Because this medication is metabolized in the liver, Depakene should not be administered to patients with hepatic disease or significant hepatic dysfunction.

Steady state
In children, steady state is reached after about 2 days of taking a stable dose of valproic acid. It takes about 5 days for the same thing to happen in seniors. After steady state is achieved, the levels of medication in the blood can be expected to be fairly constant. The dose that a patient takes should not be increased until steady state has been reached (or some time later), so that the effects of the previous dose can be assessed."

Efficacy of Valproic Acid

Valproic acid and the other forms of valproate are highly effective antiepileptic medications. Their effectiveness in controlling seizures has been extensively studied in careful scientific trials in great numbers of patients. (There is little difference in effectiveness between the various types, so we will use the general term "valproate.")

Valproate works against almost every type of epilepsy. It was first approved to treat absence seizures. In a number of studies, valproate has completely controlled absence seizures in a high proportion of patients, and it is widely regarded as the first-choice medication for most patients with absence seizures. (Zarontin [ethosuximide] is the other drug widely used for absence seizures.) Complete control seems more likely when the absence seizures appear alone than when they are combined with another seizure type (Sato et al., 1982).

Most experts also regard valproate as the first choice for treating generalized tonic-clonic seizures. One study (Wilder et al., 1983) compared it with phenytoin in treating a group of patients with newly diagnosed generalized tonic-clonic, clonic, or tonic seizures. Of the patients treated with valproate, 82% had no seizures during the study period after the level of valproate in the blood reached a therapeutic level. The comparable figure for the patients who took phenytoin was 76%.

Photosensitivity is easily controlled by valproate. This medication also seems to be effective in controlling the seizures of juvenile myoclonic epilepsy and myoclonic seizures from other causes, such as benign myoclonic epilepsy of infancy.

Epilepsy syndromes that involve symptomatic generalized seizures, such as infantile spasms and Lennox-Gastaut syndrome, are less well controlled by valproate (or any other medication). Nevertheless, valproate is usually regarded as the first choice for treating these conditions. Some patients do experience substantial improvement and may be able to reduce their use of other seizure medicines that have more troubling side effects.

Researchers looked at whether valproate alone can be used effectively to treat partial seizures. In one large double-blind trial (Mattson et al., 1992), carbamazepine (Tegretol or Carbatrol) was more effective than valproate in controlling complex partial seizures, but valproate was shown to be a valuable alternative. Differences in the side effects need to be considered in choosing medication for each patient.

If valproic acid alone does not fully control the patient's seizures, giving it in combination with another antiepileptic drug may be more effective. Factors influencing the choice of the additional AED may include potential interactions and the mechanisms of action of the two medications. No single combination is perfect for everyone. Sometimes a series of combinations must be tried before finding what is best for the individual patient.

Valproic acid is often used as an "add-on" medication for patients who continue to have complex partial seizures while taking other seizure medicines. In one study, 144 such patients were given either valproic acid or a placebo in addition to the phenytoin (Dilantin) or carbamazepine (Tegretol) that they had been taking. The number of seizures they experienced during the 8 weeks they added either Depakene or a placebo was compared to the number they had during the preceding 8 weeks, when they were taking only Dilantin or Tegretol. The patients taking valproic acid decreased their seizure frequency from16.0 seizures before to 8.9 (7.1 fewer) seizures with add-on therapy. The patients who added a placebo decreased their seizure frequency from 14.5 to 11.5 (3.0 fewer) seizures, a significantly smaller decrease.

Common side effects of Valproic Acid

Dose-related side effects
Valproic acid is one of the standard epilepsy medicines, and many people who take it (and the other forms of valproate) experience few side effects and enjoy improved control of their seizures. The most common side effects include:

  • tiredness
  • dizziness
  • nausea
  • vomiting
  • tremor
  • hair loss
  • weight gain
  • behavioral changes (depression in adults, irritability in children)

Some other side effects mentioned even less often are:

  • elevated blood ammonia levels, suggested by sleepiness, headache, confusion, or nausea
  • reduced attentiveness and response accuracy

Tiredness occurs in many individuals and is often associated with high doses and blood levels. Tiredness can include a range of effects, including slower mental processing speed and less "perkiness" and "spontaneity" in behavior. Large reductions in mental processing speed are uncommon. Effects on "motivation" and "perkiness" are very hard to measure, but they are usually mild and are not common. Patients with new prescriptions for valproic acid should be advised to be careful with driving and similar activities until they know whether their abilities are affected.

Nausea is common when therapy begins. It is often more troublesome with valproic acid than with Depakote or Depakote ER. Starting at a very low dosage or taking the medicine on a full stomach may help to reduce nausea. Vomiting is less common but occurs in susceptible individuals. Stomach upset from valproic acid is more likely when another medication with similar side effects (for example, carbamazepine or felbamate) is also being used.

Tremor is related to blood level and individual susceptibility. Usually the tremor is a fine, rapid intention tremor. Large, slow tremors can also occur, however, sometimes at rest. The tremors tend to fluctuate widely over the course of the day, probably reflecting fluctuations in valproate blood levels as well as other factors that worsen tremor, such as anxiety, caffeine, or low blood sugar. If valproic acid is critical for achieving seizure control in a particular patient but the tremor is troublesome, drugs to treat tremor (such as propranolol or primidone [Mysoline]) may be used. These may contribute to other side effects, however.

<strong>Weight gain</strong> is one of the most vexing side effects of valproic acid, affecting 30% to 50% of patients. It is more common in adult women but it also affects men and sometimes even children. Studies suggest that both increased appetite and decreased metabolism can contribute. The average gain for adults is 15 pounds. Exercise and a reduced-calorie diet can be very helpful. It remains uncertain whether weight gain is greater when higher doses of valproic acid are taken.

Hair loss occurs in 5% to 10% of patients taking valproic acid. It is uncertain whether more hair is lost when higher doses of valproic acid are taken. The hair almost always grows back after the valproic acid is stopped, but it often has a different texture. (For example, it may grow in curly instead of straight.) Taking selenium (10-20 mcg per day) and zinc (25-50 mg per day) helps some people to prevent hair loss.

Long-term use of valproate has been linked to bone loss, ankle swelling, irregular menstruation, and <link:http://www.epilepsy.com/info/women_pcos.html>polycystic ovary syndrome (PCOS).</link> Taking supplements of both calcium and vitamin D may help to prevent bone loss. Patients who have taken valproic acid or other forms of valproate for more than 5 years may be advised to have a bone density test. If the test shows significant thinning of the bones, referral to a bone metabolism specialist may be indicated.

Idiosyncratic reactions
Allergic reactions such as rashes are less common with valproic acid and other forms of valproate than with most other antiepileptic drugs. Patients should be advised to report rashes, however, especially early in the course of treatment.

Some other rare but life-threatening disorders do occur with the use of this medication. Children younger than 2 years of age and those taking other seizure medications in addition to valproic acid are at highest risk. (See Serious side effects.)

Serious Side effects of Valproic Acid

Most side effects from taking valproic acid go away with no lasting harm. But a few people have serious reactions that can even be life-threatening.

Here's a list of symptoms that may be the start of one of these problems. Advise patients to call immediately if they notice any of these symptoms:

  • weakness, lethargy, facial edema, anorexia, vomiting, jaundice, especially in a child under 2 years of age (possible liver failure)
  • abdominal pain, nausea, vomiting, and/or loss of appetite (possible pancreatitis)
  • easy bruising, nosebleed, other abnormal bleeding (problems with clotting)

The best-known and most feared serious reaction is liver damage, which has been fatal in some patients. This damage usually occurs within the first 6 months of treatment. The risk of liver failure is much higher in children under 2 years of age, especially if they are also taking other antiepileptic drugs or if they have a congenital metabolic disorder, a severe seizure disorder with mental retardation, or other brain disease. Consult a pediatric epileptologist before prescribing valproic acid for a child who meets these criteria. The risk of liver failure is much lower in children between 2 and 10 and is very low in older children and adults, perhaps 1 in 50,000. This is similar to the frequency of liver failure when taking other medications such as phenytoin. Valproic acid can deplete the liver's stores of carnitine, and some believe that taking extra carnitine can help prevent the rare cases of liver damage. There is no clear evidence of this effect. Carnitine supplements should be considered only for those at highest risk. There is no evidence that long-term use of valproic acid will cause gradual, progressive damage to liver function.

Another rare but potentially life-threatening reaction to valproic acid is pancreatitis, which occasionally progresses to bleeding and death. This reaction may occur in both children and adults, even after several years of therapy with valproic acid. Advise patients to report promptly the symptoms listed above.

Clotting problems—thrombocytopenia or impaired platelet function—are more likely to occur when high doses of valproic acid are taken. Sometimes these problems return to normal without stopping the medication. A complete blood count, thrombocyte count, and coagulation testing should be performed before and after the initiation of treatment with valproic acid and before elective surgery.

On July 10, 2008, an advisory panel was convened by the Food and Drug Administration (FDA) to review data that the FDA had previously collected from drug studies showing an association between many of the antiepileptic drugs (AEDs) and suicidal ideation and behavior, which together are called suicidality. According to the FDA’s Alert, among the patients with epilepsy in these drug studies, 1 out of 1000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1000 people who took an AED. The FDA advisory panel voted to accept the FDA's data at its meeting on July 10.

  • Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;
  • Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
  • Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
  • Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
    • Talking or thinking about wanting to hurt yourself or end your life
    • Withdrawing from friends and family
    • Becoming depressed or having your depression get worse
    • Becoming preoccupied with death and dying
    • Giving away prized possessions

We again urge patients and families to contact their doctor before stopping an epilepsy medication because this may possibly lead to seizures and worsening of mood.

Impact of Valproic Acid on bone health

At this time there is no evidence to support that Gabapentin causes bone health problems.   However, it might. .  It is essential that if you taking this medication, that one take supplemental calcium of 1000 milligrams per day.  Talk to your doctor about bone health.  He/She may decide to check Vitamin D levels and other tests to check for the impact of this drug on your bones.

Other Uses of Valproic Acid

The only FDA-approved use of valproic acid is the treatment of epilepsy, but it also has two off-label uses:

  •     treatment of manic episodes associated with bipolar disorder
  •     prophylaxis of migraine headaches (not acute treatment)

Possible harm to the fetus should be considered before valproic acid is prescribed for women of childbearing potential. (See Pregnancy.)

Valproic Acid Contraindications

Depakene is contraindicated for patients with hepatic disease or significant hepatic dysfunction, as well as those known to be allergic to it.

Valproic Acid Interactions with other medications

Sometimes medications affect the way others are absorbed or excreted, or how effectively they work. The fact that valproic acid is often added to a regimen of other antiepileptic drugs makes the question of interactions especially important. When prescribing valproic acid, question patients or family members extensively about the use of prescription and OTC medications, herbal products, vitamins, alcohol, and other substances. Usually all necessary medications can be used, but the dosages may need to be adjusted to achieve therapeutic levels.

Effects of valproic acid on other drugs
Valproic acid inhibits certain liver enzymes and can cause the levels of Felbatol (felbamate), Lamictal (lamotrigine), Mysoline (primidone), and phenobarbital to increase markedly—in some cases, more than double. If a person taking phenobarbital is also given valproic acid, a rapid rise in phenobarbital levels can lead to extreme tiredness, slurred speech, and other signs of intoxication.

Valproic acid has more complex, variable, and less significant effects on Tegretol (carbamazepine), Zarontin (ethosuximide), Ativan (lorazepam), and Dilantin (phenytoin). Valproic acid inhibits epoxide hydrolase, thereby increasing levels of the epoxide metabolite of Tegretol. It can inhibit metabolism of Zarontin and Ativan, leading to higher levels of these medications. It also can displace Dilantin from protein binding sites and slightly increase the free Dilantin level. In each case, side effects may increase slightly.

Coagulation tests should be carefully checked if patients taking anticoagulants such as Coumadin (warfarin) begin taking valproic acid.

Effects of other drugs on valproic acid
Enzyme-inducing antiepileptic drugs, including carbamazepine, phenytoin, phenobarbital, and primidone, will markedly increase the metabolism (and thus the clearance) of Depakote.

Moderate or rapid introduction of Lamictal in a patient taking valproic acid, especially a child, can significantly increase the chances of a potentially life-threatening rash (Stevens-Johnson syndrome).

If valproic acid and Klonopin (clonazepam) are given together to a patient with a history of absence seizures, prolonged absence seizures (absence status) may occur.

Aspirin (acetylsalicylic acid, ASA) can increase some metabolites of valproic acid that may contribute to side effects.

Patients taking valproic acid along with testosterone-type androgens should be regularly checked for liver problems.

AED Interaction Sheets:
Seizure drugs are often affected by drug-drug interactions. Print these informative sheets for practical help.

 

 

Valproic Acid effects on Children

As a broad-spectrum antiepileptic drug, valproic acid can be effective against many types of seizures common in children. It has been used for many years to treat children with absence seizures, for which it is just as effective as Zarontin (ethosuximide). These two drugs can be used in combination. Valproic acid also is the first-choice drug for myoclonic seizures in adolescents, including those with juvenile myoclonic epilepsy. It can be effective against generalized tonic-clonic seizures in children, and is a first choice for Lennox-Gastaut syndrome. It is sometimes used to treat infantile spasms (West syndrome). It also controls photosensitivity.

The risk of liver failure is much higher in children under 2 or 3 years of age who take any form of valproate, especially if they are also taking other antiepileptic drugs or if they have a congenital metabolic disorder, a severe seizure disorder with mental retardation, or other brain disease. Consult a pediatric epileptologist before prescribing valproic acid for a child who meets these criteria. The risk of liver failure is much lower in children between 2 and 10 and is very low in older children and adults, perhaps 1 in 50,000. Liver damage usually occurs within the first 6 months of treatment. Diagnosis usually depends on recognition of clinical features, which include vomiting, anorexia, lethargy, and perhaps loss of seizure control, jaundice, or edema. Some doctors recommend carnitine supplements (100 mg/kg/day) for infants and young children who take valproic acid, especially if they have other risk factors for liver damage.

Elevated testosterone levels have been reported in many peripubertal girls taking valproate. Clinical consequences were not evident, but a connection to the later development of polycystic ovary syndrome is possible. Weight gain in these girls may be related to these changes.

Occasionally behavioral changes such as irritability are reported in children who take valproic acid, though it is usually well tolerated.

The initial dose may be 5-10 mg/kg per day, in one to three doses. Steady state is reached after about 2 days of taking a stable dose of valproic acid. The half-life is shorter for children than for adults, so children may require higher doses than adults, commonly 15-60 mg/kg per day. The higher doses are usually needed by children taking combination therapy. Interactions between medications may be so pronounced in children that some never reach the usual therapeutic level of valproate, even with very high doses.

Blood levels fluctuate considerably over the course of a day and are not clearly related to clinical results, so single measurements have limited value for most patients.

The syrup form of valproic acid offers a way of administering valproate to small children who cannot swallow tablets. The time to peak level with the syrup is shorter than for Depakote sprinkle capsules. The overall bioavailability is the same.

Valproic Acid and Pregnancy

The U.S. Food and Drug Administration (FDA) lists valproic acid in Pregnancy Category D. This indicates that there is clear evidence of risk to the human fetus, but the benefits may outweigh the risk for pregnant women who have a serious condition that cannot be treated effectively with a safer drug.

The babies of women taking valproic acid have a greater than usual number of minor craniofacial abnormalities, organ malformations, limb deficiencies, or developmental delay. The risk of defects is higher for women who take more than one AED and for women with a family history of birth defects. Moreover the NEAD study showed that children born to women who took Valproic acid, had lower IQ scores than children born to women with epilepsy who tool other seizure medications.

Spina bifida and other neural tube defects are estimated to affect at least 1-2% of infants whose mothers took valproate during the first trimester. This figure may be higher than for some other antiepileptic drugs. Advise women who are capable of becoming pregnant to take at least 400 mcg (0.4 mg) of folic acid (folate) daily to help prevent neural tube defects. Women at high risk, such as those with a history of a neural tube defect in a previous pregnancy, should take 4000 mcg (4 mg) daily, beginning before they become pregnant. The effectiveness of prophylactic folic acid use in preventing defects related to valproate has not been proven, however, so diagnostic ultrasonography at the 18th to 20th week is recommended, especially if pregnancy termination is an option.

Higher doses and peak blood levels of valproate appear to be associated with some defects, so preventive measures may include:

  • use of a different medication
  • lower dosage of valproic acid
  • prescribing smaller doses taken more often (or extended-release Depakote ER) to avoid high peak blood levels

About 20% to 35% of women have seizures more often during pregnancy because of changes in hormones or changes in how valproic acid is handled by the body. Check the blood levels of valproate regularly during pregnancy so that the dosage can be adjusted as needed.

Breast-feeding by mothers taking valproic acid should be safe for healthy, full-term newborns, although a small amount (3-5%) of the medication will appear in the milk. The dose received is estimated to be less than 6% of the initial pediatric dose.

Valproic Acid effects on Seniors

Older people metabolize valproate more slowly than younger adults and they are often more susceptible to side effects. Lower initial doses and caution in titration are required. A total daily dose of 5-10 mg/kg per day is appropriate for many elderly patients.

Reduced elimination extends the half-life of valproate for elderly patients, so that many need to take valproic acid only once a day.

Side effects such as sleepiness, depression, or weight gain may exacerbate pre-existing problems of seniors, and their greater risk of injury from falls or other accidents makes this an area of concern. Tremor is a common side effect of valproic acid and is sometimes mistaken for a parkinsonian tremor. Other antiepileptic drugs may be preferable for patients with Parkinson's disease.

Interactions with other medications are less common with valproate than with some other antiepileptic drugs but still may be a concern. Changes in dosages of both medications are often required.

Valproic Acid Dosing and titration

Most doctors start patients on 5 to 12.5 mg/kg (250-750 mg) of valproic acid per day. The dosage is then usually increased each week by 5 to 10 mg/kg until seizures stop or the patient experiences too many side effects. Most patients take a total of 750 to 3,000 mg each day, divided into two or three doses. Taking more than 4,000 mg per day is seldom recommended.

Children may require higher doses and seniors usually need less.A therapeutic blood level of valproate is generally considered to be 50-100 mcg/mL (lower for seniors), but adjustments should depend on clinical response.

Valproic Acid Package insert

In the United States, companies that manufacture medicines are required to publish certain kinds of information about each product. This document is commonly known as a “package insert” because it is usually included with each package of the medicine.

You can also read these documents (also called "prescribing information") online. The U.S. package insert for Depakene (valproic acid) is found at:

Some of the information may differ in other countries.

To learn how to read and understand a package insert, see  "How to read a package insert."

Valproic Acid References for Professionals

Abstracts of articles relevant to this topic are available through PubMed, a service of the National Library of Medicine:

Here are links to some articles relevant to this subject:

Mattson RH, Cramer JA, et al. A comparison of valproate with carbamazepine for the treatment of partial seizures and secondarily generalized tonic-clonic seizures in adults. New England Journal of Medicine, 327:765-771, 1992. PMID: 1298221.

Valproic acid and carbamazepine are equally effective for treating secondarily generalized tonic-clonic seizures in adults. Although other studies show that valproate is effective for newly diagnosed partial seizures, in this study carbamazepine provided better control of complex partial seizures. The side effects of these two medications are different.

Wilder BJ, Ramsay RE, Murphy JV, Karas BJ, Marquardt K, Hammond EJ. Comparison of valproic acid and phenytoin in newly diagnosed tonic-clonic seizures. Neurology 1983 Nov;33(11):1474-6. PMID: 6415511.

Valproic acid was slightly more effective than phenytoin in controlling generalized tonic-clonic seizures.

Sato S, White BG, Penry JK, et al. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology 1982 Feb;32(2):157-63. PMID: 6798490.

Valproic acid and ethosuximide were equally effective against both newly diagnosed and refractory absence seizures.

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