Divalproex Sodium: Bipolar Uses, Warnings, Side Effects, Dosage

Generic Name: divalproex sodium

Brand Names: Depakote, Depakote ER, Depakote Sprinkles

Drug Class: Anticonvulsants, Other

What is divalproex sodium, and what is it used for?

Divalproex sodium is an anticonvulsant medication used in the treatment of manic phase of bipolar disorder, and epilepsy, and in the prevention of migraine headaches.

Divalproex sodium is a stable compound of valproic acid, an organic acid, and its sodium salt form, sodium valproate. Valproate sodium gets converted in the gastrointestinal tract into valproate ion, its active form.

Divalproex sodium reduces abnormal electrical activity in the brain which causes manic episodes in bipolar disorder, or seizures in epileptic patients. The exact mechanism of divalproex is not fully clear. Divalproex sodium is believed to work by:

  • Increasing the levels of gamma-aminobutyric acid (GABA), the major inhibitory chemical messenger (neurotransmitter) in the brain
  • Enhancing and mimicking GABA’s action on nerve cells (neurons)
  • Inhibiting sodium and calcium channels in the neurons, suppressing high-frequency repetitive firing of neurons

Divalproex sodium is approved by the FDA for use in:

Off-label uses include:

  • Bipolar major depression (alternative agent)
  • Maintenance treatment of bipolar disorder
  • Intractable migraine and migraine that lasts longer than 72 hours (status migrainosus) 
  • Status epilepticus, seizures that last longer than 5 minutes

Warnings

  • Do not use divalproex sodium in patients with:
    • Hypersensitivity to valproate or any of the components of divalproex sodium
    • Urea cycle disorder, a metabolic disorder that causes accumulation of ammonia, a metabolic waste product that is neurotoxic
    • Liver disease or impaired liver function
    • Mitochondrial disorders caused by mutations in mitochondrial DNA polymerase-gamma (POLG) gene (such as Alpers-Huttenlocher syndrome, a condition with intractable epilepsy, loss of psychomotor abilities and liver disease) and children younger than 2 years with suspected POLG-related disorders
  • Do not use divalproex sodium for migraine prophylaxis in women who are pregnant or plan to become pregnant; may cause fetal harm; advise women patients on valproate therapy to use effective contraception
  • Divalproex sodium is toxic to the liver and can cause liver failure that can be fatal
    • Hepatotoxicity typically occurs in the first 6 months of treatment
    • Children younger than 2 years are at increased risk, particularly those on multiple anticonvulsants, and those with congenital metabolic disorders, POLG-related disorders, severe seizure disorders with mental retardation, or organic brain disease; use divalproex sodium with extreme caution as monotherapy
    • The liver removes ammonia from blood by converting it to urea; monitor ammonia levels and discontinue valproate in case of signs of ammonia accumulation in blood (hyperammonemia) and brain damage (encephalopathy)
  • Cases of life-threatening pancreatitis have been reported with divalproex sodium treatment in both adults and children
  • Divalproex sodium can decrease platelet levels (thrombocytopenia) and associated conditions; risk increases at trough plasma levels of 110 mcg/mL in females and 135 mcg/mL in males; monitor carefully
  • May cause porphyria, a group of disorders caused by abnormalities in the production of heme, the iron-carrying pigment in hemoglobin
  • May cause drug reaction with eosinophilia and systemic symptoms (DRESS) that can affect multiple organs
  • May produce false-positive urine ketone test and alter thyroid function tests
  • Concurrent use with topiramate may cause hyperammonemia, encephalopathy and hypothermia
  • Can cause brain tissue atrophy; assess cognitive function routinely
  • May cause central nervous system (CNS) depression and impair physical and/or mental abilities; advise patients appropriately
  • Can cause drowsiness in elderly patients; increase divalproex dosage slowly and monitor regularly
  • Do not use divalproex to prevent post-traumatic seizure in patients with acute head trauma; may increase risk for mortality




QUESTION

Another term that has been previously used for bipolar disorder is ___________________.
See Answer

What are the side effects of divalproex sodium?

Common side effects of divalproex sodium include:

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug.

Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Latest Mental Health News

Trending on MedicineNet

What are the dosages of divalproex sodium?

Dosages expressed as valproic acid equivalents

Tablet, delayed-release (Depakote)

  • 125mg
  • 250mg
  • 500mg

Tablet, extended-release (Depakote ER)

  • 250mg
  • 500mg

Capsule (Depakote Sprinkles)

  • 125mg

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

Epilepsy

  • 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 is greater than 250 mg, give a divided dose

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

Pediatric:

Epilepsy

Children younger than 10 years

  • Safety and efficacy not established

Children 10 years and older

  • 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

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 (LFTs)

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

Administration

  • Depakote or Depakote Sprinkles: If the daily dose is greater than 250 mg, give a divided dose
  • Depakote ER: Administer once daily

Overdose

  • Divalproex sodium overdose may cause somnolence, heart block and deep coma that can lead to death.
  • Overdose may be treated with induced vomiting or gastric lavage to eliminate unabsorbed drug in the gastrointestinal tract, depending on the time since ingestion.
  • In severe overdose, hemodialysis or hemodialysis in tandem with external blood purification (hemoperfusion) may be used to remove drug from the blood, in addition to supportive and symptomatic care.
  • Naloxone has been reported to reverse the central nervous system depressant effects of valproate overdose. Naloxone should be used with caution in epileptic patients, because naloxone could theoretically also reverse the antiepileptic effects of valproate.

What drugs interact with divalproex sodium?

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

  • Divalproex sodium has no known severe interactions with other drugs.
  • Serious interactions of divalproex sodium include:
  • Moderate interactions of divalproex sodium include:
    • cenobamate
    • daridorexant
    • difelikefalin
    • fosphenytoin
    • lamotrigine
    • lemborexant
    • lomustine
    • mavacamten
    • midazolam intranasal
    • osilodrostat
    • ropeginterferon alfa 2b
    • ustekinumab
  • Divalproex sodium has no known mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

Subscribe to MedicineNet’s General Health Newsletter

By clicking Submit, I agree to the MedicineNet’s Terms & Conditions & Privacy Policy and understand that I may opt out of MedicineNet’s subscriptions at any time.

Pregnancy and breastfeeding

  • Divalproex sodium should be used in pregnancy only in life-threatening emergencies when no safer alternative drug is available; should not be used to prevent migraines; there is positive evidence of fetal risk from divalproex sodium use during pregnancy.
  • Divalproex sodium can cause congenital malformations including neural tube defects, craniofacial defects and cardiovascular malformations; the risk is greatest in the first trimester.
  • Maternal use of divalproex sodium can impair cognition in offspring; studies indicate that children exposed to valproate in the uterus have lower cognitive test scores than children exposed to either another antiepileptic drug or no antiepileptic in the uterus.
  • Women on valproate therapy should use effective contraception.
  • Women with epilepsy who become pregnant should not discontinue divalproex sodium abruptly, as this can precipitate major seizures and status epilepticus that can result in maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the fetus.
  • Discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient.
  • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not clear if it reduces the risk in pregnant women on valproate therapy, however, folic acid supplementation prior to conception and during pregnancy should be routinely recommended to women receiving valproate.
  • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate.
  • Pregnant women using valproate may develop clotting abnormalities or liver failure; must be monitored carefully.
  • Valproate is present in breast milk; should be used with caution in nursing mothers.
  • A pregnancy exposure registry monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs) during pregnancy; pregnant women on valproate therapy should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/

What else should I know about divalproex sodium?

  • Take divalproex sodium exactly as prescribed
  • If a dose is skipped, do not double the next dose
  • In case of overdose, immediately seek medical help or contact Poison Control Center
  • Swallow whole, do not chew or crush the tablets
  • Capsules may be opened and sprinkled on a spoonful of soft food immediately before administration
  • May impair physical and mental abilities; avoid engaging in hazardous tasks such as driving or operating heavy machinery
  • Store divalproex sodium carefully out of reach of children

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Divalproex Sodium: Bipolar Uses, Warnings, Side Effects, Dosage

Generic Name: divalproex sodium

Brand Names: Depakote, Depakote ER, Depakote Sprinkles

Drug Class: Anticonvulsants, Other

What is divalproex sodium, and what is it used for?

Divalproex sodium is an anticonvulsant medication used in the treatment of manic phase of bipolar disorder, and epilepsy, and in the prevention of migraine headaches.

Divalproex sodium is a stable compound of valproic acid, an organic acid, and its sodium salt form, sodium valproate. Valproate sodium gets converted in the gastrointestinal tract into valproate ion, its active form.

Divalproex sodium reduces abnormal electrical activity in the brain which causes manic episodes in bipolar disorder, or seizures in epileptic patients. The exact mechanism of divalproex is not fully clear. Divalproex sodium is believed to work by:

  • Increasing the levels of gamma-aminobutyric acid (GABA), the major inhibitory chemical messenger (neurotransmitter) in the brain
  • Enhancing and mimicking GABA’s action on nerve cells (neurons)
  • Inhibiting sodium and calcium channels in the neurons, suppressing high-frequency repetitive firing of neurons

Divalproex sodium is approved by the FDA for use in:

Off-label uses include:

  • Bipolar major depression (alternative agent)
  • Maintenance treatment of bipolar disorder
  • Intractable migraine and migraine that lasts longer than 72 hours (status migrainosus) 
  • Status epilepticus, seizures that last longer than 5 minutes

Warnings

  • Do not use divalproex sodium in patients with:
    • Hypersensitivity to valproate or any of the components of divalproex sodium
    • Urea cycle disorder, a metabolic disorder that causes accumulation of ammonia, a metabolic waste product that is neurotoxic
    • Liver disease or impaired liver function
    • Mitochondrial disorders caused by mutations in mitochondrial DNA polymerase-gamma (POLG) gene (such as Alpers-Huttenlocher syndrome, a condition with intractable epilepsy, loss of psychomotor abilities and liver disease) and children younger than 2 years with suspected POLG-related disorders
  • Do not use divalproex sodium for migraine prophylaxis in women who are pregnant or plan to become pregnant; may cause fetal harm; advise women patients on valproate therapy to use effective contraception
  • Divalproex sodium is toxic to the liver and can cause liver failure that can be fatal
    • Hepatotoxicity typically occurs in the first 6 months of treatment
    • Children younger than 2 years are at increased risk, particularly those on multiple anticonvulsants, and those with congenital metabolic disorders, POLG-related disorders, severe seizure disorders with mental retardation, or organic brain disease; use divalproex sodium with extreme caution as monotherapy
    • The liver removes ammonia from blood by converting it to urea; monitor ammonia levels and discontinue valproate in case of signs of ammonia accumulation in blood (hyperammonemia) and brain damage (encephalopathy)
  • Cases of life-threatening pancreatitis have been reported with divalproex sodium treatment in both adults and children
  • Divalproex sodium can decrease platelet levels (thrombocytopenia) and associated conditions; risk increases at trough plasma levels of 110 mcg/mL in females and 135 mcg/mL in males; monitor carefully
  • May cause porphyria, a group of disorders caused by abnormalities in the production of heme, the iron-carrying pigment in hemoglobin
  • May cause drug reaction with eosinophilia and systemic symptoms (DRESS) that can affect multiple organs
  • May produce false-positive urine ketone test and alter thyroid function tests
  • Concurrent use with topiramate may cause hyperammonemia, encephalopathy and hypothermia
  • Can cause brain tissue atrophy; assess cognitive function routinely
  • May cause central nervous system (CNS) depression and impair physical and/or mental abilities; advise patients appropriately
  • Can cause drowsiness in elderly patients; increase divalproex dosage slowly and monitor regularly
  • Do not use divalproex to prevent post-traumatic seizure in patients with acute head trauma; may increase risk for mortality




QUESTION

Another term that has been previously used for bipolar disorder is ___________________.
See Answer

What are the side effects of divalproex sodium?

Common side effects of divalproex sodium include:

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug.

Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Latest Mental Health News

Trending on MedicineNet

What are the dosages of divalproex sodium?

Dosages expressed as valproic acid equivalents

Tablet, delayed-release (Depakote)

  • 125mg
  • 250mg
  • 500mg

Tablet, extended-release (Depakote ER)

  • 250mg
  • 500mg

Capsule (Depakote Sprinkles)

  • 125mg

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

Epilepsy

  • 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 is greater than 250 mg, give a divided dose

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

Pediatric:

Epilepsy

Children younger than 10 years

  • Safety and efficacy not established

Children 10 years and older

  • 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

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 (LFTs)

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

Administration

  • Depakote or Depakote Sprinkles: If the daily dose is greater than 250 mg, give a divided dose
  • Depakote ER: Administer once daily

Overdose

  • Divalproex sodium overdose may cause somnolence, heart block and deep coma that can lead to death.
  • Overdose may be treated with induced vomiting or gastric lavage to eliminate unabsorbed drug in the gastrointestinal tract, depending on the time since ingestion.
  • In severe overdose, hemodialysis or hemodialysis in tandem with external blood purification (hemoperfusion) may be used to remove drug from the blood, in addition to supportive and symptomatic care.
  • Naloxone has been reported to reverse the central nervous system depressant effects of valproate overdose. Naloxone should be used with caution in epileptic patients, because naloxone could theoretically also reverse the antiepileptic effects of valproate.

What drugs interact with divalproex sodium?

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

  • Divalproex sodium has no known severe interactions with other drugs.
  • Serious interactions of divalproex sodium include:
  • Moderate interactions of divalproex sodium include:
    • cenobamate
    • daridorexant
    • difelikefalin
    • fosphenytoin
    • lamotrigine
    • lemborexant
    • lomustine
    • mavacamten
    • midazolam intranasal
    • osilodrostat
    • ropeginterferon alfa 2b
    • ustekinumab
  • Divalproex sodium has no known mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

Subscribe to MedicineNet’s General Health Newsletter

By clicking Submit, I agree to the MedicineNet’s Terms & Conditions & Privacy Policy and understand that I may opt out of MedicineNet’s subscriptions at any time.

Pregnancy and breastfeeding

  • Divalproex sodium should be used in pregnancy only in life-threatening emergencies when no safer alternative drug is available; should not be used to prevent migraines; there is positive evidence of fetal risk from divalproex sodium use during pregnancy.
  • Divalproex sodium can cause congenital malformations including neural tube defects, craniofacial defects and cardiovascular malformations; the risk is greatest in the first trimester.
  • Maternal use of divalproex sodium can impair cognition in offspring; studies indicate that children exposed to valproate in the uterus have lower cognitive test scores than children exposed to either another antiepileptic drug or no antiepileptic in the uterus.
  • Women on valproate therapy should use effective contraception.
  • Women with epilepsy who become pregnant should not discontinue divalproex sodium abruptly, as this can precipitate major seizures and status epilepticus that can result in maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the fetus.
  • Discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient.
  • Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not clear if it reduces the risk in pregnant women on valproate therapy, however, folic acid supplementation prior to conception and during pregnancy should be routinely recommended to women receiving valproate.
  • Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate.
  • Pregnant women using valproate may develop clotting abnormalities or liver failure; must be monitored carefully.
  • Valproate is present in breast milk; should be used with caution in nursing mothers.
  • A pregnancy exposure registry monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs) during pregnancy; pregnant women on valproate therapy should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/

What else should I know about divalproex sodium?

  • Take divalproex sodium exactly as prescribed
  • If a dose is skipped, do not double the next dose
  • In case of overdose, immediately seek medical help or contact Poison Control Center
  • Swallow whole, do not chew or crush the tablets
  • Capsules may be opened and sprinkled on a spoonful of soft food immediately before administration
  • May impair physical and mental abilities; avoid engaging in hazardous tasks such as driving or operating heavy machinery
  • Store divalproex sodium carefully out of reach of children

Check Also

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