Dosing and uses of Depakote (divalproex sodium)
Adult 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
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
Pediatric 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
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
Depakote (divalproex sodium) adverse (side) 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
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)
Pregnancy and 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.
Pharmacology of Depakote (divalproex sodium)
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
