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Divalproex Sodium Dosage

Medically reviewed by Drugs.com. Last updated on Mar 4, 2020.

Applies to the following strengths: 250 mg; 125 mg; 500 mg

Usual Adult Dose for:

Usual Pediatric Dose for:

Additional dosage information:

Usual Adult Dose for Epilepsy

COMPLEX PARTIAL SEIZURES:
Initial Dose: 10 to 15 mg/kg/day orally (see below for frequency)
-Increase in increments of 5 to 10 mg/kg/week to achieve optimal clinical response;
-Plasma levels should be checked if satisfactory response has not been achieved (usual accepted therapeutic range 50 to 100 mcg/mL)
Maximum dose: 60 mg/kg/day

SIMPLE AND COMPLEX ABSENCE SEIZURES:
Initial Therapy: 15 mg/kg/day orally (see below for frequency)
-Increase in increments of 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases
Maximum Recommended Dose: 60 mg/kg/day

FREQUENCY:
-Delayed-release tablets and sprinkle capsules: Doses greater than 250 mg/day should be given in divided doses
-Extended-release tablets: Should be administered once a day

CONVERSION to Monotherapy:
-Initial dose as above while concomitant antiepileptic drug (AED) is reduced by 25% every 2 weeks; AED dose reductions can begin with initiation of therapy or delayed by 1 to 2 weeks; speed and duration may be highly variable, and patients should be monitored closely during this period

CONVERSION From Delayed-Release to Extended-Release: Patients should receive an extended-release dose that is 8% to 20% higher than the total daily dose of the delayed-release

Comments:
-This drug is indicated in the treatment of complex partial seizures that occur in isolation or in association with other types of seizures; its use as initial monotherapy has not been systematically studied.
-A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect, however, a serum level between 50 and 100 mcg/mL is therapeutic for most patients; some patients may be controlled with higher or lower serum concentrations.
-Optimal clinical response is usually achieved at doses below 60 mg/kg/day; if satisfactory clinical response has not been achieved, plasma levels should be measured.
-No recommendations can be made for doses exceeding 60 mg/kg/day

Uses: As monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures; as monotherapy and adjunctive therapy for the treatment of simple and complex absence seizures; and adjunctively in patients with multiple seizure types that include absence seizures.

Usual Adult Dose for Mania

Delayed-release tablets:
Initial dose: 750 mg orally per day in divided doses
-Rapidly titrate to achieve the lowest effective dose or desired plasma concentration
Maximum dose: 60 mg/kg/day

Extended-release tablets:
Initial dose: 25 mg/kg orally once a day
-Rapidly titrate to achieve the lowest effective dose or desired plasma concentration
Maximum dose: 60 mg/kg/day

Comments:
-In clinical trials, patients receiving the delayed-release and extended-release tablets were dosed to a trough plasma concentration of 50 to 125 mcg/mL and 85 to 125 mcg/mL, respectively.
-The efficacy of this drug for long-term mania has not been demonstrated and therefore, when used for extended periods, it's use should be continually reevaluated.

Use: For the treatment of the manic episodes associated with bipolar disorder.

Usual Adult Dose for Migraine Prophylaxis

Delayed-release tablets:
Initial dose: 250 mg orally 2 times a day
Maintenance dose: Some patients may benefit from doses up to 1000 mg per day

Extended-release tablets:
Initial dose: 500 mg orally once a day for 1 week
-After 5 days, may increase to 1000 mg/day as needed
Maintenance dose: 500 to 1000 mg orally once a day

Comments:
-There is no evidence showing that this drug is useful in the acute treatment of migraine headaches.
-There is no evidence that doses over 1000 mg/day led to greater efficacy.

Use: For the prophylaxis of migraine headaches.

Usual Pediatric Dose for Epilepsy

10 years or older:
COMPLEX PARTIAL SEIZURES:
Initial Dose: 10 to 15 mg/kg/day orally (see below for frequency)
-Increase in increments of 5 to 10 mg/kg/week to achieve optimal clinical response;
-Plasma levels should be checked if satisfactory response has not been achieved (usual accepted therapeutic range 50 to 100 mcg/mL)
Maximum dose: 60 mg/kg/day

SIMPLE AND COMPLEX ABSENCE SEIZURES:
Initial Therapy: 15 mg/kg/day orally (see below for frequency)
-Increase in increments of 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases
Maximum Recommended Dose: 60 mg/kg/day

FREQUENCY:
-Delayed-release tablets and sprinkle capsules: Doses greater than 250 mg/day should be given in divided doses
-Extended-release tablets: Should be administered once a day

CONVERSION to Monotherapy:
-Initial dose as above while concomitant antiepileptic drug (AED) is reduced by 25% every 2 weeks; AED dose reductions can begin with initiation of therapy or delayed by 1 to 2 weeks; speed and duration may be highly variable, and patients should be monitored closely during this period

CONVERSION From Delayed-Release to Extended-Release: Patients should receive an extended-release dose that is 8% to 20% higher than the total daily dose of the delayed-release

Comments:
-This drug is indicated in the treatment of complex partial seizures that occur in isolation or in association with other types of seizures; its use as initial monotherapy has not been systematically studied.
-A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect, however, a serum level between 50 and 100 mcg/mL is therapeutic for most patients; some patients may be controlled with higher or lower serum concentrations.
-Optimal clinical response is usually achieved at doses below 60 mg/kg/day; if satisfactory clinical response has not been achieved, plasma levels should be measured.
-No recommendations can be made for doses exceeding 60 mg/kg/day

Uses: As monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures; as monotherapy and adjunctive therapy for the treatment of simple and complex absence seizures; and adjunctively in patients with multiple seizure types that include absence seizures.

Renal Dose Adjustments

Use caution; no adjustment recommended, but higher than expected free fractions may be expected

Liver Dose Adjustments

Contraindicated in patients with hepatic disease or with significant hepatic dysfunction

Dose Adjustments

Elderly Patients:
-Starting doses should be reduced and doses should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions; ultimate therapeutic dose should be achieved based on tolerability and clinical response

Concomitant use of rufinamide:
-For patients stabilized on rufinamide prior to initiating valproate, begin valproate at a low dose, and titrate to a clinically effective dose

Therapeutic drug monitoring:
-Epilepsy: Therapeutic range: 50 to 100 mcg/mL; some may be controlled with lower or higher plasma concentrations
-Mania: Trough plasma concentration: 50 to 125 mcg/mL (delayed-release tablets); 85 to 125 mcg/mL (extended-release tablets)
-Monitoring for total concentrations may be misleading in patients with higher free concentrations; higher than expected free fractions occur in the elderly, in patients with hyperlipidemia, and in patients with hepatic, and renal diseases
-Monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn
-Thrombocytopenia: The probability of thrombocytopenia increases significantly at total valproate concentrations of 110 mcg/mL (females) or 135 mcg/mL (males) or more

Drug Withdrawal/Discontinuation:
-Abrupt discontinuation should be avoided, especially in patients for whom this drug is prescribed to prevent major seizures because of the strong possibility of precipitating status epilepticus

Precautions

US BOXED WARNINGS: LIFE-THREATENING ADVERSE REACTIONS:
HEPATOTOXICITY:
-General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first 6 months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months
-Children: Children younger than 2 years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, or with congenital metabolic disorders, or with severe seizure disorders accompanied by intellectual disability, or with organic brain disease. If this drug is used, use with extreme caution and only as monotherapy. The benefits of therapy should be weighed against the risk; the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
-Patients with Mitochondrial Disease: There is an increased risk of drug-induced acute liver failure and resultant death in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase gamma (POLG) gene (e.g., Alpers Huttenlocher Syndrome). This drug is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under 2 years of age who are clinically suspected of having a mitochondrial disorder. This drug should only be used in patients over 2 years of age who are clinically suspected of having a hereditary mitochondrial disease after other anticonvulsants have failed. These patients should be closely monitored during treatment for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice.
FETAL RISK:
-This drug can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). It can also cause decreased IQ scores following in utero exposure.
-Therefore, this drug is contraindicated for prophylaxis of migraine headache in pregnant women and in women of childbearing potential who are not using effective contraception. The drug should not be used to treat women with epilepsy or bipolar disorder who are pregnant or plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.
-This drug should not be administered to women of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. In such situations, effective contraception should be used. A medication guide describing the risks of valproate is available for patients.
PANCREATITIS: Cases of life-threatening pancreatitis have been reported in children and adults receiving this drug; some cases were hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initiating therapy as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

CONTRAINDICATIONS:
-Hypersensitivity to the active component or any of the ingredients
-Hepatic disease or significant hepatic dysfunction
-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
-Urea cycle disorders
-Prophylaxis of migraine headaches in pregnant women
-Prophylaxis of migraine headaches in women of child-bearing potential not using effective contraception

Safety and efficacy have not been established in patients younger than 10 years for epilepsy or younger than 18 years for any other indication.

Consult WARNINGS section for additional precautions.

Dialysis

Hemodialysis reduces serum valproate concentrations by approximately 20%; however, no specific dose adjustment guidelines have been suggested

Other Comments

Administration advice:
Take orally; If a patient experiences gastrointestinal irritation, take with food; may start at lower dose and slowly increase dose when possible
-Delayed-release tablets: Swallow whole; do not crush or chew
-Delayed-release sprinkle capsules: Swallow whole or open and sprinkle contents on small amount of soft food; consume immediately without chewing
-Extended-release tablets: Swallow whole; do not crush or chew

Missed doses: If a dose is missed, take as soon as possible, unless it is almost time for the next dose. If a dose is skipped, do not double next dose

General:
-Due to fetal risks of decreased IQ, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, this drug should not be used to treat women of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable; for prophylaxis of migraine headaches, this drug is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception.

Monitoring:
-Hematologic: Monitor blood counts and coagulation parameters for patients undergoing surgery, during pregnancy, and as clinically indicated
-Hepatic: Perform clinical assessments regularly for signs of hepatotoxicity; liver function tests should be obtained prior to therapy and at frequent intervals thereafter, especially during the first 6 months
-Nervous system: Monitor for increased seizure frequency, especially with changes to concomitant medications
-Psychiatric: Monitor for the emergence or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior
-Metabolic: Monitor ammonia levels as clinically indicated
-Elderly: Monitor fluid and nutritional intake, monitor for dehydration and somnolence

Patient advice:
-Patients should be instructed to read the US FDA-approved patient labeling (Medication Guide).
-Patients should be instructed to report signs or symptoms of hepatic injury, pancreatitis, or hyperammonemia promptly; patients with a fever associated with other organ system involvement such as a rash or lymphadenopathy should report this to their healthcare provider immediately.
-Patients should understand that antiepileptic drugs, including this drug, may increase the risk of suicidal thoughts and behavior; patients/caregivers should be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm and should be instructed to report these behaviors promptly.
-Women of childbearing potential should be instructed to discuss pregnancy planning with their healthcare provider and immediately notify their healthcare provide if they suspect they are pregnant; effective contraception should be used while taking this drug.
-Patients should understand that this drug may cause drowsiness and dizziness and they should be instructed not to drive or operate dangerous machinery until they know how this drug affects them.

Further information

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