Divalproex Sodium-ER

Depakote is the brand name used in the United States for divalproex sodium, a compound of sodium valproate and valproic acid. Divalproex sodium 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 sodium valproate (Epilim in the UK and Australia) and valproic acid (Depakene in the U.S. and Canada, Convulex in the UK), as well as an injectable solution of valproate sodium (Depacon).

Extended-release Depakote ER, formulated to allow once-daily dosing, became available in the United States in 2000. It is not available in Canada, the UK, or Australia. Depakote ER was first used to prevent migraines but in 2002 the FDA approved it for the treatment of several kinds of seizures. Even before its approval for epilepsy, however, many neurologists were prescribing it for epilepsy patients because its sustained-release properties help to maintain steadier levels of medication in the blood.

Depakote ER
Depakote ER 250mg

White ovaloid tablets with Abbott logo and "HF".

Depakote ER 500mg

Gray ovaloid tablets with Abbott logo and "HC".


Depakote ER 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.


Depakote ER is marketed in the United States by http://www.depakote.com   Abbott Labortories. The name or appearance may differ in other places. These descriptions apply to U.S. versions:


Please see package insert.

How to take and store Divalproex Sodium-ER?

Depakote ER tablets should be swallowed whole, not chewed or crushed. They can be taken either with food or without food.

Depakote ER tablets should be stored at room temperature (77°F, 25°C) and protected from heat and moisture.

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 instead of taking two doses close together. Since Depakote ER is generally taken once every 24 hours, they should allow an interval of about 12 hours before taking the second dose, and then resume a 24-hour schedule the next day.

Patients who often forget doses may benefit from using a special pillbox or watch with an alarm.

Mechanisms of actions of Divalproex Sodium-ER

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 Divalproex Sodium-ER


Depakote ER tablets use a polymer matrix technology to release medication over an extended period. After the outside film coating dissolves in the stomach, the outer layer of the matrix begins to absorb fluid, forming a gel layer that releases the drug slowly. Peak levels of valproate in the blood are reached in 7 to 14 hours. At equal doses, the bioavailability of Depakote ER is about 89% that of regular Depakote. To achieve equivalent bioavailability, the once-daily dose of Depakote ER needs to be 8% to 20% higher than the total multiple daily doses of Depakote.

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 with the use of Depakote ER are 10% to 20% less than the fluctuations with regular Depakote, which can be marked.

Because this medication is metabolized in the liver, Depakote ER 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 Depakote ER. 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 Divalproex Sodium-ER

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 valproate alone does not fully control the patient's seizures, a combination of valproate and another seizure medicine may be more effective. Factors influencing the choice of the additional medication 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.

Valproate 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 valproate or a placebo in addition to the phenytoin or carbamazepine that they had been taking. The number of seizures they experienced during the 8 weeks they added either valproate or a placebo was compared to the number they had during the preceding 8 weeks, when they were taking only phenytoin or carbamazepine. The patients taking valproate 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 Divalproex Sodium-ER

Dose-related side effects

Valproate is one of the standard epilepsy medicines, and many people who take Depakote ER (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 Depakote ER should be advised to be careful with driving and similar activities until they know whether their abilities are affected.

Nausea sometimes occurs when Depakote ER therapy begins, but it is less frequent than with regular Depakote and is much less likely than with Depakene. Starting at a very low dosage or taking the medicine on a full stomach may help to reduce nausea. Vomiting is even less common. Stomach upset from Depakote 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. Because blood levels fluctuate less with Depakote ER, tremor may be reduced. If valproate 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.

Weight gain  is one of the most vexing side effects of Depakote ER, 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 Depakote ER are taken.

Hair loss occurs in 5% to 10% of patients taking Depakote ER. It is uncertain whether more hair is lost when higher doses are taken. The hair almost always grows back after the medication 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 polycystic ovary syndrome (PCOS). Taking supplements of both calcium and vitamin D may help to prevent bone loss. Patients who have taken Depekote ER 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 Depakote ER 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 valproate. Children younger than 2 years of age (who are unlikely to use Depakote ER) and those also taking other seizure medications are at highest risk. (See Serious side effects.)

Serious Side effects of Divalproex Sodium-ER

Most side effects from taking Depakote ER 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. These children are not candidates for the use of Depakote ER. Consult a pediatric epileptologist before prescribing other forms of valproate 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. There is no evidence that long-term use of Depakote ER will cause gradual, progressive damage to liver function.

Another rare but potentially life-threatening reaction to Depakote ER 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 Depakote ER or other types of valproate. 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 Depakote ER 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 Depakote ER 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 Divalproex Sodium-ER on bone health

At this time there is no evidence to support this medication 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 Divalproex Sodium-ER

Besides the treatment of seizures, Depakote ER is also FDA-approved for the prophylaxis of migraine headaches (not acute treatment). (This was the initial indication for Depakote ER.)

Depakote ER is also FDA-approved for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features.

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

Divalproex Sodium-ER Contraindications

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

Divalproex Sodium-ER Interactions with other medications

Sometimes medications affect the way others are absorbed or excreted, or how effectively they work. The fact that Depakote ER is often added to a regimen of other antiepileptic drugs makes the question of interactions especially important. When prescribing Depakote ER, 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 Depakote ER (extended-release divalproex sodium) on other drugs

Depakote ER 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 Depakote ER, a rapid rise in phenobarbital levels can lead to extreme tiredness, slurred speech, and other signs of intoxication.

Depakote ER has more complex, variable, and less significant effects on Tegretol (carbamazepine), Zarontin (ethosuximide), Ativan (lorazepam), and Dilantin (phenytoin). Depakote ER 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 Depakote ER.

Effects of other drugs on Depakote ER (extended-release divalproex sodium)

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

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

If Depakote ER 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 Depakote ER that may contribute to side effects.

Patients taking Depakote ER 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.

Interaction sheet for valproate

Divalproex Sodium-ER effects on Children

As a broad-spectrum antiepileptic drug, Depakote ER can be effective against many types of seizures common in children. Other forms of valproate have 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. Valproate 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. Valproate is sometimes used to treat infantile spasms (West syndrome), but Depakote ER's tablet form makes it unsuitable for this purpose. 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. These children are not candidates for the use of Depakote ER. Consult a pediatric epileptologist before prescribing other forms of valproate 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, perhaps 1 in 50,000.

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 valproate, though it is usually well tolerated.

The initial dose of valproate for children may be 5-10 mg/kg per day. Since Depakote ER tablets are available only in 250-mg and 500-mg doses, smaller children (even if they can swallow the tablet) may need to begin by using another form of valproate and switch to Depakote ER when they reach a higher dosage. (To achieve bioequivalence, the dose of Depakote ER will need to be 8% to 20% higher than the total daily dose of regular Depakote.)

Steady state is reached after about 2 days. 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.

Children's blood levels of valproate 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. Depakote ER should help to reduce these fluctuations.

Divalproex Sodium-ER and Pregnancy

The U.S. Food and Drug Administration (FDA) lists Depakote ER and other forms of valproate 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 valproate 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.

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:

  • avoiding high peak blood levels by using Depakote ER instead of other forms of valproate
  • reducing the daily dose of valproate
  • using a different medication

About 20% to 35% of women have seizures more often during pregnancy because of changes in hormones or changes in how valproate 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 Depakote ER 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 of valproate.

Divalproex Sodium-ER 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. The smallest dose of Depakote ER, 250 mg, may be too high as an initial dose for some seniors, who will have to begin by taking regular Depakote and converting to Depakote ER later.

Reduced elimination extends the half-life of valproate for elderly patients, so that many need to take regular Depakote only once a day. They may still benefit from the more even blood levels produced by Depakote ER.

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 valproate and is sometimes mistaken for a parkinsonian tremor. The less extreme blood level fluctuations with Depakote ER may reduce this problem. Nevertheless, 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.

Divalproex Sodium-ER Dosing and titration

Most doctors start patients on 5 to 12.5 mg/kg (250-750 mg) of Depakote ER per day, in one dose. The dosage then can be 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. Taking more than 4,000 mg per day is seldom recommended.

Patients who have been taking regular Depakote or Depakene will need to take 8% to 20% more Depakote ER to achieve the same effect. A conversion table appears in the package insert for Depakote ER.

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.


Algorithm for dosing valproate
Algorithm for adding lamotrigine to valproate
Algorithm for adding valproate to lamotrigine

Divalproex Sodium-ER 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:

Dutta S, Zhang Y, Selness DS, Lee LL, Williams LA, Sommerville KW. Comparison of the bioavailability of unequal doses of divalproex sodium extended-release formulation relative to the delayed-release formulation in healthy volunteers. Epilepsy Res. 2002 Mar;49(1):1-10. PMID: 11948003.

Giving doses of Depakote ER that were 14-20% higher than doses of regular Depakote produced an equivalent level of medication in the blood with reduced fluctuations.

Freitag FG, Collins SD, Carlson HA, Goldstein J, Saper J, Silberstein S, Mathew N, Winner PK, Deaton R, Sommerville K; Depakote ER Migraine Study Group. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 2002 Jun 11;58(11):1652-9. PMID: 12058094.

The rate of migraine headaches was reduced in patients who took Depakote ER, without excessive adverse effects.

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.

Depakote and Tegretol (carbamazepine) are equally effective for treating secondarily generalized tonic-clonic seizures in adults. Although other studies show that Depakote is effective for newly diagnosed partial seizures, in this study Tegretol 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.

Depakote was slightly more effective than Dilantin 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.

Depakote and Zarontin were equally effective against both newly diagnosed and refractory absence seizures.

Divalproex Sodium-ER 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 Depakote capsules is found at:


The U.S. package insert for Depakote-ER tablets 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."

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