Valproic Acid Dosage

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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 orally or intravenously per day as an IV infusion in divided doses, increased by 5 to 10 mg/kg per week if necessary according to clinical response
Maintenance dose: 10 to 60 mg/kg per day in divided doses
Maximum dose: 60 mg/kg per day

Simple and complex absence seizures:
Initial dose: 15 mg/kg orally or intravenously per day as an IV infusion in divided doses, increased at one week intervals by 5 to 10 mg/kg/day according to seizure control and tolerability
Maximum dose: 60 mg/kg per day

Comments:
-If the total daily dose exceeds 250 mg, it should be given in 2 to 3 divided doses.
-Use of IV valproate sodium for periods longer than 14 days has not been studied; patients should be converted to oral valproate as soon as clinically feasible.
-When switching from oral to IV valproate, the total daily dose of IV valproate should be equivalent to the total daily dose of oral valproate, and administered at the same frequency as the oral product.
-Equivalence between IV and oral valproate products at steady state has only been evaluated in a 6-hourly dosing regimen. Trough plasma level monitoring may be required if IV valproate is administered 2 to 3 times a day.
-Complex partial seizures: When converting patients to valproate monotherapy, concomitant antiepileptic drug dosage can generally be reduced by approximately 25% every 2 weeks, commencing either at the start of valproate therapy or delayed by 1 to 2 weeks. Patients should be monitored closely during this period for increased seizure frequency.

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

Usual Adult Dose for Mania

Delayed-release capsules :
Initial dose: 750 mg orally per day in divided doses
Maximum dose: 60 mg/kg orally per day
Duration: Safety and efficacy beyond 3 weeks has not been established

Comments:
-The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations.
-In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration of 50 to 125 mcg/mL.
-Maximum concentrations were generally achieved within 14 days.
-Safety and efficacy for longer term use in the maintenance of the initial response and prevention of new manic episodes has not been systematically evaluated in clinical trials. Use for extended periods should be accompanied by regular review for the long-term usefulness of the drug for the individual patient.

Use: Treatment of manic episodes associated with bipolar disorder.

Usual Adult Dose for Migraine Prophylaxis

Delayed release oral capsules:
Initial dose: 250 mg orally twice a day

Comments:
-Some patients may benefit from doses up to 1000 mg per day.
-In clinical trials, there was no evidence that higher doses led to greater efficacy.

Usual Pediatric Dose for Epilepsy

10 years of age or older:
Complex partial seizures:
Initial dose: 10 to 15 mg/kg orally or intravenously per day as an IV infusion in divided doses, increased by 5 to 10 mg/kg per week if necessary according to clinical response
Maintenance dose: 10 to 60 mg/kg per day in divided doses
Maximum dose: 60 mg/kg per day

Simple and complex absence seizures:
Initial dose: 15 mg/kg orally or intravenously per day as an IV infusion in divided doses, increased at one week intervals by 5 to 10 mg/kg/day according to seizure control and tolerability
Maximum dose: 60 mg/kg per day

Comments:
-If the total daily dose exceeds 250 mg, it should be given in 2 to 3 divided doses.
-Use of IV valproate sodium for periods longer than 14 days has not been studied; patients should be converted to oral valproate as soon as clinically feasible.
-When switching from oral to IV valproate, the total daily dose of IV valproate should be equivalent to the total daily dose of oral valproate, and administered at the same frequency as the oral product.
-Equivalence between IV and oral valproate products at steady state has only been evaluated in a 6-hourly dosing regimen. Trough plasma level monitoring may be required if IV valproate is administered 2 to 3 times a day.
-Complex partial seizures: When converting patients to valproate monotherapy, concomitant antiepileptic drug dosage can generally be reduced by approximately 25% every 2 weeks, commencing either at the start of valproate therapy or delayed by 1 to 2 weeks. Patients should be monitored closely during this period for increased seizure frequency.

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

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Hepatic disease or significant hepatic dysfunction: Contraindicated

Dose Adjustments

-Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the risk of precipitating status epilepticus.
-Geriatric patients: Reduce starting dose and increase dosage more slowly
-Dose reduction should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence.
-Thrombocytopenia: The probability of thrombocytopenia increases significantly at total valproate concentrations of 110 mcg/mL (females) or 135 mcg/mL (males) or more.

Therapeutic drug monitoring:
-The relationship between plasma concentration and clinical response is not well documented.
-Epilepsy: The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.
-Mania: Patients have been dosed (in clinical trials) to clinical response with trough plasma concentrations between 50 and 125 mcg/mL
-Monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn
-Monitoring of total concentrations may be misleading in patients with liver disease since free concentrations may be substantially elevated in these patients whereas total concentrations may appear to be normal.
-Protein binding is substantially reduced in renal failure; monitoring of total concentrations may be misleading in these patients.

Precautions

BOXED WARNINGS:
HEPATOTOXICITY:
-Hepatic failure resulting in fatalities has occurred in patients taking valproate and its derivatives. This usually occurs during the first 6 months of treatment and may be preceded by nonspecific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may occur.
-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 mental retardation, and those with organic brain disease. Valproate should be used with extreme caution and only as monotherapy in this patient group. Fatal hepatotoxicity decreases considerably in older patients.
-Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months.
MITOCHONDRIAL DISEASE:
-There is an increased risk of valproate-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). Valproate 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.
-Valproate 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:
-Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida), and can cause decreased IQ scores following in utero exposure. Use is contraindicated in pregnant women treated for prophylaxis of migraine, and should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable and valproate is considered essential to the management of her medical condition.
PANCREATITIS:
-Cases of life-threatening pancreatitis have been reported in patients receiving valproate; some cases were hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported initially and after prolonged use. Abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis. If pancreatitis is diagnosed, treatment should be discontinued and alternative treatment initiated as clinically indicated.

Consult WARNINGS for additional precautions

Dialysis

Hemodialysis: Hemodialysis reduces valproate concentrations by about 20%; no adjustment recommended.
Peritoneal dialysis: Data not available

Other Comments

Administration advice:
-Oral: Delayed release capsules should be swallowed whole; administration with food may reduce gastrointestinal irritation.
-IV: Administer as an IV infusion over at least 60 minutes but not more than 20 mg/min

Reconstitution/preparation techniques: The manufacturer's product information should be consulted

IV compatibility: The manufacturer's product information should be consulted

General: The frequency of side effects may be dose-related.

Monitoring:
-General: Patients receiving doses near the maximum recommended daily dose should be monitored more closely.
-Hematologic: Platelet counts
-Hepatic: Liver function tests
-Nervous system: Seizures
-Psychiatric: Emergence or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior

Patient advice:
-Antiepileptic drugs, including valproate, may increase the risk of suicidal thoughts and behavior. 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 about self-harm. Report any behavior of concern to your healthcare provider as soon as possible.
-Valproate may cause drowsiness and dizziness; do not drive a car or operate dangerous machinery until you know how this drug affects you.

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