Divalproex Sodium

What Is Divalproex Sodium and How Does It Work?

Divalproex sodium is a stable coordination compound comprised of sodium valproate and valproic acid used to treat manic episodes associated with bipolar disorder, epilepsy, and migraine headaches.

  • Divalproex sodium is available under the following different brand names: Depakote, Depakote ER, and Depakote Sprinkles.

What Are Dosages of Divalproex Sodium?

Dosages of Divalproex Sodium:

Dosage Forms and Strengths

Dosages expressed as valproic acid equivalents

Tablet, delayed-release (Depakote)

  • 125mg
  • 250mg
  • 500mg

Tablet, extended-release (Depakote ER)

  • 250mg
  • 500mg

Capsule (Depakote Sprinkles)

  • 125mg
Dosage Considerations – Should be Given as Follows: Mania

Indicated for the treatment of manic episodes associated with bipolar disorder

  • Depakote initial dose: 750 mg/day orally in divided doses
  • Depakote ER initial dose: 25 mg/kg orally once daily Increase as rapidly as possible to achieve the lowest therapeutic dose that provides desired clinical effect or plasma concentration
  • Not to exceed 60 mg/kg/day
  • Complex partial seizures: Indicated as monotherapy and adjunctive therapy for complex partial seizures that occur either in isolation or in association with other types of seizures
  • Simple and complex absence seizures: Also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures


  • 10-15 mg/kg/day orally initially; may increase by 5-10 mg/kg/week to achieve optimal clinical response; not to exceed 60 mg/kg/day
  • Depakote: If a daily dose greater than 250 mg, give a divided dose


  • 10-15 mg/kg/day orally initially; may increase by 5-10 mg/kg/week to achieve optimal clinical response; not to exceed 60 mg/kg/day
  • Children under 10 years: Safety and efficacy not established
Migraine Prophylaxis

Indicated for prophylaxis of migraine headaches; there is no evidence of use for acute treatment

  • Depakote initial dose: 250 mg orally twice daily for 1 week
  • Depakote ER initial dose: 500 mg orally once/day for 1 week
  • May increase dose up to 1000 mg/day if needed
Dosage Modifications

Conversion to monotherapy: Decrease concomitant anti-epilepsy drug dosage approximately 25% every 2 weeks

Renal impairment

  • No adjustment is necessary; protein binding is reduced and may cause measurement of total valproate concentrations to be inaccurate

Hepatic impairment

  • Administer lower doses
  • Contraindicated in severe impairment
Dosing Considerations

Monitor liver function tests (LFT's)

Conversion from Depakote to Depakote ER:

  • Administered Depakote ER once daily using a dose 8-20% higher than the total daily dose of Depakote

Therapeutic range

  • Low serum albumin levels may cause an increase in unbound drugs (while total concentration may appear normal)
  • Epilepsy: 50-100 mcg/mL total valproate
  • Mania: 50-125 mcg/mL total valproate; maximum concentrations generally achieved within 14 days
  • Swallow whole, do not chew or crush
  • Capsules may be opened and sprinkled on a spoonful of soft food immediately before administration
  • If a dose is skipped, do not double the next dose

Depakote or Depakote Sprinkles:

  • If a daily dose greater than 250 mg, give a divided dose

Depakote ER:

  • Administer once daily

What Are Side Effects Associated with Using Divalproex Sodium?

Common side effects of Divalproex Sodium include:

  • Nausea
  • Headache
  • Weakness/lack of energy
  • Vomiting
  • Drowsiness
  • Tremor (shaking)
  • Dizziness
  • Abdominal pain
  • Diarrhea
  • Loss of appetite
  • Vision changes (double vision, lazy eye, blurred vision)
  • Flu syndrome
  • Infection
  • Indigestion/heartburn
  • Loss of control of bodily movements
  • Rapid, involuntary eye movements
  • Fever
  • Mood swings
  • Thinking abnormal
  • Hair loss
  • Weight loss/weight changes
  • Constipation
  • Memory problems (amnesia)
  • Bronchitis
  • Runny or stuffy nose
  • Stomach upset
  • Changes in menstrual periods
  • Enlarged breasts
  • Agitation
  • Unusual or unpleasant taste in your mouth

Other side effects of Divalproex Sodium include:

  • Worsening depression
  • Suicidal thoughts or behavior
  • Unusual changes in mood or behavior
  • Cerebral pseudoatrophy (acute or subacute cognitive decline and behavioral changes (apathy or irritability)

Postmarketing side effects of Divalproex Sodium reported include:

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

What Other Drugs Interact with Divalproex Sodium?

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

Divalproex sodium has no known severe interactions with other drugs.

  • Serious interactions of divalproex sodium include:
    • None
  • Severe interactions of Divalproex Sodium include:
  • Divalproex sodium has moderate interactions with at least 44 different drugs.
  • Divalproex sodium has mild interactions with at least 56 different drugs.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

What Are Warnings and Precautions for Divalproex Sodium?



  • Hepatic failure resulting in fatalities has occurred
  • Children younger than 2 years are at increased risk for fatal hepatotoxicity, particularly patients on multiple anticonvulsants, as well as those with congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, or organic brain disease
  • Increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA polymerase-gamma (POLG) gene (e.g., Alpers Huttenlocher Syndrome)
  • If used in children with these conditions, it should be administered with extreme caution as a sole agent
  • Hepatotoxicity usually occurs during the first 6 months of treatment and may be preceded by malaise, weakness, lethargy, facial edema, anorexia, and vomiting


  • Do not use in women of childbearing age unless the drug is essential to the management of the medical condition; all non-pregnant women of childbearing potential should use effective birth control if taking valproate products (see Contraindications and Pregnancy sections)
  • May cause neural tube defects
  • Children exposed in utero have an increased risk for lower cognitive test scores compared with those exposed in utero to other antiseizure medications
  • Alternative medications that have a lower risk for adverse birth outcomes should be considered
  • Patients should not stop taking valproate without talking to a healthcare professional
  • Women should use effective contraception while taking valproate derivatives


  • Cases of life-threatening pancreatitis have been reported in children and adults
  • Some cases have been described as hemorrhagic with a rapid progression from initial symptoms to death

This medication contains divalproex sodium. Do not take Depakote, Depakote ER, and Depakote Sprinkles if you are allergic to divalproex sodium or any ingredients contained in this drug.

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.



Liver disease, significant hepatic impairment

Urea cycle disorders

Mitochondrial disorders caused by mutations in mitochondrial DNA polymerase-gamma (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under 2 years of age who are suspected of having a POLG-related disorder

Migraine headache prevention in women who are pregnant or plan to become pregnant

Effects of Drug Abuse

  • No information available

Short-Term Effects

  • See "What Are Side Effects Associated with Using Divalproex Sodium?”

Long-Term Effects

  • See "What Are Side Effects Associated with Using Divalproex Sodium?”


  • The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations exceed 110 mcg/mL in females and 135 mcg/mL in males.
  • Hepatotoxic (age less than 2 years, higher risk of fatal hepatotoxicity); see Warnings.
  • POLG mutations; see Contraindications and Warnings.
  • Discontinue if hyperammonemia/encephalopathy occurs; check ammonia level if emesis occurs or if the patient displays lethargy or abnormal behavior; evaluate the patient for urea cycle disorder (see Contraindications) or hepatotoxicity (see Warnings).
  • Pancreatitis, including fatalities, was reported (see Warnings).
  • Hypothermia has been reported during valproate therapy with or without associated hyperammonemia; this adverse reaction can also occur in patients using concomitant topiramate.
  • In utero exposure increases the risk for poor cognitive outcomes and anatomical malformations, compared with 3 other common anti-epileptic drugs (AEDs) (carbamazepine, lamotrigine, phenytoin); see Warnings.
  • Potential for thrombocytopenia, porphyria, and multiorgan hypersensitivity reaction (also known as drug reaction with eosinophilia and systemic symptoms or DRESS).
  • May produce false-positive urine ketone test and alter thyroid function tests (TFTs).
  • Reversible cerebral and cerebellar atrophy reported; monitor motor and cognitive function routinely and assess for signs and symptoms of brain atrophy.
  • May cause central nervous system (CNS) depression and impair physical or mental abilities.
  • Somnolence in the elderly can occur; Divalproex dosage should be increased slowly and with regular monitoring for fluid and nutritional intake.
  • Not for the administration of post-traumatic seizure prophylaxis in patients with acute head trauma (increased mortality reported when used).

Pregnancy and Lactation

  • Use divalproex sodium during pregnancy or seizures or manic episodes associated with bipolar disorder that is unresponsive to other treatments only in LIFE-THREATENING emergencies when no safer drug is available. There is positive evidence of human fetal risk.
  • Do not use divalproex sodium for migraine headache prevention. The risks involved outweigh the potential benefits. Safer alternatives exist.
  • Results from epidemiologic studies concluded that children born to women who take valproate sodium or related products (valproic acid, divalproex sodium) during pregnancy have an increased risk for lower cognitive test scores, compared with children exposed to other antiseizure medications during pregnancy.
  • Divalproex sodium is known to cause neural tube defects; evidence suggests that folic acid supplementation prior to conception and during the first trimester decreases the risk for congenital neural tube defects
  • Divalproex sodium is excreted in breast milk; use caution while breastfeeding. The American Academy of Pediatrics (AAP) and the American College of Obstetricians and Gynecologists (ACOG) say divalproex sodium is compatible with nursing.
Medscape. Divalproex Sodium.
RXlist. Divalproex Sodium .

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