Valproic Acid Dosage

Medically reviewed by Drugs.com. Last updated on Aug 10, 2023.

Usual Adult Dose for Epilepsy

COMPLEX PARTIAL SEIZURES:
Initial dose: 10 to 15 mg/kg/day orally; doses greater than 250 mg/day should be given in divided doses

• Increase in increments of 5 to 10 mg/kg weekly as necessary to achieve optimal response

Maximum dose: 60 mg/kg/day

Conversion to Monotherapy:
Initiate therapy as above AND reduce concomitant antiepileptic drug dose by approximately 25% every 2 weeks; reduction may start right away or be delayed by 1 to 2 weeks; speed and duration of withdrawal may be highly variable; monitor closely for increased seizure frequency

SIMPLE AND COMPLEX ABSENCE SEIZURES:
Initial dose: 15 mg/kg/day orally; doses greater than 250 mg/day should be given in divided doses

• Increase in increments of 5 to 10 mg/kg/day until seizures are controlled or side effects prevent further increases

Maximum dose: 60 mg/kg daily

Parenteral:

• IV administration may be utilized when oral administration is temporarily not feasible
• IV dosing: Equivalent to oral dose and frequency
• Administration: 60-minute IV infusion (no more than 20 mg/min)
• Drug level monitoring and dosage adjustments may be necessary
• Patients should be switched to the oral formulation as soon as clinically feasible, use of the IV formulation for periods longer than 14 days has not been studied

Comments:

• 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.
• 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.
• Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs; complex absence is the when other signs are also present.

Uses:

• As monotherapy and adjunctive therapy in the treatment of complex partial seizures that occur either in isolation or in association with other types of seizures
• As monotherapy and adjunctive therapy in the treatment of simple and complex absence seizures
• Adjunctively in multiple seizure types which include absence seizures

Usual Pediatric Dose for Epilepsy

10 years or older:
COMPLEX PARTIAL SEIZURES:
Initial dose: 10 to 15 mg/kg/day orally; doses greater than 250 mg/day should be given in divided doses

• Increase in increments of 5 to 10 mg/kg weekly as necessary to achieve optimal response

Maximum dose: 60 mg/kg/day

Conversion to Monotherapy:
Initiate therapy as above AND reduce concomitant antiepileptic drug dose by approximately 25% every 2 weeks; reduction may start right away or be delayed by 1 to 2 weeks; speed and duration of withdrawal may be highly variable; monitor closely for increased seizure frequency

SIMPLE AND COMPLEX ABSENCE SEIZURES:
Initial dose: 15 mg/kg/day orally; doses greater than 250 mg/day should be given in divided doses

• Increase in increments of 5 to 10 mg/kg/day until seizures are controlled or side effects prevent further increases

Maximum dose: 60 mg/kg/day

Parenteral:

• IV administration may be utilized when oral administration is temporarily not feasible
• IV dosing: Equivalent to oral dose and frequency
• Administration: 60-minute IV infusion (no more than 20 mg/min)
• Drug level monitoring and dosage adjustments may be necessary
• Patients should be switched to the oral formulation as soon as clinically feasible, use of the IV formulation for periods longer than 14 days has not been studied

Comments:

• A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect, however, serum levels 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 daily doses below 60 mg/kg/day; if satisfactory clinical response has not been achieved, plasma levels should be measured.

Uses:

• As monotherapy and adjunctive therapy in the treatment of complex partial seizures that occur either in isolation or in association with other types of seizures; as monotherapy and adjunctive therapy in the treatment of simple and complex absence seizures; and adjunctively in multiple seizure types which include absence seizures.
• Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs; complex absence is the when other signs are also present.

Renal Dose Adjustments

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

Liver Dose Adjustments

Hepatic disease or significant hepatic dysfunction: Contraindicated

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, although some may be controlled with lower or higher plasma concentrations
• 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 taking this drug 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, those with congenital metabolic disorders, those with severe seizure disorders accompanied by intellectual disability, or those 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. In patients over 2 years of age who are clinically suspected of having a hereditary mitochondrial disease, this drug should only be used after other anticonvulsants have failed. These patients should be closely monitored 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 product ingredients
• Hepatic disease or significant hepatic dysfunction
• Urea cycle disorders
• Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase gamma (POLG; e.g., Alpers-Huttenlocher Syndrome)
• Children under 2 years of age who are suspected of having a POLG-related disorder
• Prophylaxis of migraine headaches in pregnant women and women of childbearing potential who are not using effective contraception

Consult WARNINGS for additional precautions

Dialysis

Hemodialysis: Hemodialysis reduces valproate concentrations by about 20%

Other Comments

Administration advice:

• Take orally; swallow capsules whole or open and sprinkle contents on a small amount of soft food, consume immediately
• Oral solution: Use a calibrated measuring device to ensure accurate dosing
• IV: Administer as an IV infusion over at least 60 minutes; infusions greater than 20 mg/min are not recommended

Preparation:

• Dilute with at least 50 mL of a compatible diluent (e.g., normal saline, glucose 5% or lactated ringers); physically compatible and chemically stable for 24 hours when stored in glass or polyvinyl chloride bags at 59C to 86C (15C to 30C)

Storage: Vials should be stored at 59F to 86F (15C to 30C); vials contain no preservatives and unused portion should be discarded

General:

• This drug has not been evaluated for safety and efficacy in the prophylactic treatment of migraine headaches or in the treatment of manic episodes associated with bipolar disorder.
• This drug has not been systematically studied as initial monotherapy for complex partial seizures.

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

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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