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divalproex sodium (Rx)Brand and Other Names:Depakote, Depakote ER, more...Depakote Sprinkles

 
 
 

Dosing & Uses

AdultPediatric

Dosage Forms & 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
more...

Mania

Indicated for treatment of manic episodes associated with bipolar disorder

Depakote initial dose: 750 mg/day PO in divided doses

Depakote ER initial dose: 25 mg/kg PO 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 PO initially; may increase by 5-10 mg/kg/week to achieve optimal clinical response; not to exceed 60 mg/kg/day

Depakote: If daily dose >250 mg, give as divided dose

Migraine Prophylaxis

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

Depakote initial dose: 250 mg PO BID for 1 week

Depakote ER initial dose: 500 mg PO qDay for 1 week

May increase dose up to 1000 mg/day if needed

Dosage Modifications

Conversion to monotherapy: Decrease concomitant antiepilepsy drug dosage ~25% q2weeks

Renal impairment

  • No adjustment 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 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 drug (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

Swallow whole, do not chew or crush

Capsules may be opened and sprinkled on spoonful of soft food immediately before administration

If dose is skipped, do not double next dose

Depakote or Depakote Sprinkles: If daily dose >250 mg, give as divided dose

Depakote ER: Administer once daily

Dosage Forms & 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
more...

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 years: Safety and efficacy not established

10-15 mg/kg/day PO 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 antiepilepsy drug dosage ~25% q2weeks

Renal impairment

  • No adjustment 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 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 drug (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

Swallow whole, do not chew or crush

Capsules may be opened and sprinkled on spoonful of soft food immediately before administration

If dose is skipped, do not double next dose

Depakote or Depakote Sprinkles: If daily dose >250 mg, give as divided dose

Depakote ER: Administer once daily

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Interactions

Interaction Checker

divalproex sodium and

No Results

     
     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Nausea (48%)

            Headache (31%)

            Asthenia (27%)

            Vomiting (27%)

            Somnolence (27%)

            Tremor (25%)

            Dizziness (25%)

            Abdominal pain (23%)

            Diplopia (16%)

            Diarrhea (13%)

            Anorexia (12%)

            Amblyopia/blurred vision (12%)

            Flu syndrome (12%)

            Infection (12%)

            1-10%

            Dyspepsia (8%)

            Ataxia (8%)

            Nystagmus (8%)

            Fever (6%)

            Emotional lability (6%)

            Thinking abnormal (6%)

            Alopecia (6%)

            Weight loss (6%)

            Constipation (5%)

            Amnesia (5%)

            Bronchitis (5%)

            Rhinitis (5%)

            Frequency Not Defined

            Cerebral pseudoatrophy

            Postmarketing Reports

            Hair texture change

            Hair color change

            Photosensitivity

            Erythema multiforme

            Toxic epidermal necrolysis

            Stevens-Johnson syndrome

            Elevated testosterone level

            Hyperandrogenism

            Nail and nailbed disorders

            Weight gain

            Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology

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            Warnings

            Black Box Warnings

            Hepatotoxicity

            • 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 (eg, 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

            Teratogenicity

            • 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 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 health-care professional
            • Women should use effective contraception while taking valproate derivatives

            Pancreatitis

            • 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

            Contraindications

            Hypersensitivity

            Liver disease, significant hepatic impairment

            Urea cycle disorders

            Mitochondrial disorders caused by mutations in mitochondrial DNA polymerase-gamma (POLG; eg, Alpers-Huttenlocher Syndrome) and children <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

            Cautions

            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 <2 years, higher risk of fatal hepatotoxicity); see Black Box Warnings

            POLG mutations; see Contraindications and Black Box Warnings

            Discontinue if hyperammonemia/encephalopathy occurs; check ammonia level if emesis occurs or if the patient displays lethargy or abnormal behavior; evaluate patient for urea cycle disorder (see Contraindications) or hepatotoxicity (see Black Box Warnings);

            Pancreatitis, including fatalities reported (see Black Box 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 risk for poor cognitive outcomes and anatomical malformations, compared with 3 other common AEDs (carbamazepine, lamotrigine, phenytoin); see Black Box 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 TFTs

            Reversible cerebral and cerebellar atrophy reported; monitor motor and cognitive function routinely and assess for signs and symptoms of brain atrophy

            May cause 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 administration to post-traumatic seizure prophylaxis in patients with acute head trauma (increased mortality reported when used)

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            Pregnancy & Lactation

            Pregnancy Category: D for seizures or manic episodes associated with bipolar disorder that are unresponsive to other treatments

            Pregnancy category: X for migraine headache prevention

            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

            Known to cause neural tube defects; evidence suggests that folic acid supplementation prior to conception and during the first trimester decreases risk for congenital neural tube defects

            Lactation: Excreted in breast milk; use caution (AAP and ACOG say compatible)

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

            more...
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            Pharmacology

            Mechanism of Action

            May increase levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in brain; may enhance or mimic action of GABA at postsynaptic receptor sites; may also inhibit sodium and calcium channels

            Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide

            Absorption

            Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically, although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (eg, fasting or postprandial) and the method of administration

            These differences should be of minor clinical importance

            Peak plasma time: 4 hr (tablet); 3.3 hr (sprinkles); 4-17 hr (ER tablet)

            Food decreases rate of absorption

            Distribution

            Protein bound: Concentration dependent; free fraction increases from ~10% at 40 mcg/mL to 18.5% at 130 mcg/mL

            Protein binding reduced in the elders, chronic hepatic diseases, renal impairment, or with drug that cause displacement (aspirin)

            CSF: Approximate unbound concentration in plasma (~10% of total concentration) Vd: 11 L/1.73 m2 (total valproate); 92 L/1.73 m2 (free valproate)

            Metabolism

            Divalproex sodium dissociates to the valproate ion in the GI tract

            Valproate metabolized in liver by glucuronidation (30-50%) and mitochondrial beta-oxidation (40%) <15-20% is eliminated by other oxidative mechanisms

            Elimination

            Half-life: 9-16 hr (dose dependent)

            Total body clearance: 0.56 L/hr/1.73 m2 (total valproate); 4.6 L/hr/1.73 m2 (free valproate)

            Excretion: <3% excreted unchanged in urine

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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