Valproic Acid

Valproic Acid (VPA, Depakene, Depakote) is effective in treating simple and complex absence seizures, generalized tonic-clonic seizures, and partial seizures. It is also used to treat manic episodes associated with bipolar disorder and as a prophylactic drug for migraine headache. In the U.S., the most popular pharmaceutical formulation is sodium valproate enteric-coated tablets in doses of 125, 250 and 500 mg. Therapeutic doses range from 200 to 2500 mg daily. Patients generally do not develop tolerance to its anticonvulsant effects. Rapid and complete absorption takes place after oral ingestion, although some delay may occur if taken with a meal. Peak levels are reached 1 to 4 hours after a single dose of the sodium salt or delayed 4 to 8 hours after ingestion of enteric-coated tablets. The circulating half-life is 9 to 18 hours in adults and 7 to 13 hours in children. More than 90% of valproic acid is bound to albumin. Protein saturation occurs at valproic acid levels around 50 ug/mL. The minimum effective serum concentration for optimal seizure control is approximately 50 ug/mL and seizure control tends to improve as concentration increases over the range of 50 to 100 ug/mL. Clearance occurs through the kidneys. Serum concentrations can fluctuate significantly from day to day due to valproic acid’s rapid absorption and relatively short half-life.

A precise correlation between valproic acid concentration and seizure control does not exist. The literature frequently cites therapeutic trough levels as 40 to 100 ug/mL. The United States Pharmacopoeial Convention has stated that the therapeutic range is 50 to 150 ug/mL. Refractory patients often require trough levels above 100 ug/mL for seizure control. Treatment of the mania phase of bipolar disorder requires trough levels between 50 and 125 ug/mL. Migraine prophylaxis uses a therapeutic range of 70 to 120 ug/mL.Serum levels >150 ug/mL are considered critical values.

Careful clinical monitoring should be performed during the first 6 months of therapy with valproic acid. Idiosyncratic reactions include hair loss and hepatic failure. Hepatic failure is more common in children than adults and usually occurs in the first 90 days of therapy. It is usually associated with serum concentrations exceeding 110 ug/mL. Other toxicities include acute hemorrhagic pancreatitis and thrombocytopenia. Thrombocytopenia is generally dose related and occurs at trough levels greater than 110 ug/mL in females and 135 ug/mL in males.

The most common side effects (15 - 30% of patients) are gastrointestinal: anorexia, nausea, and vomiting are usually transient. CNS side effects include sedation, ataxia, and tremor. Valproic acid increases the plasma concentration of phenobarbital and primidone, and has a variable effect on phenytoin levels.

The expanded use of valproic acid has resulted in increased availability and a subsequent increase in the incidence of overdose ingestion. All reported cases of overdose have occurred in patients known to be taking the drug. Initial serum concentrations may be misleading in assessment of the severity of overdose because peak serum values may be delayed for as long as 17 hours after ingestion of massive doses. Therefore, a second valproic acid serum level should be measured 4 to 6 hours after admission to ensure that peak absorption has occurred. The vast majority of patients with overdose ingestions have serum levels <450 ug/mL and exhibit minimal toxicity such as nausea, vomiting, mild ataxia and lethargy. Patients with serum concentrations >850 ug/mL have a higher risk of life-threatening intoxication with coma, respiratory depression, metabolic acidosis or hypotension.

Steady state levels are reached one to four days after therapy is initiated. Specimens for therapeutic drug monitoring should not be drawn until a steady state has been reached.Trough specimens should be drawn immediately preceding the next dose. Specimen requirement is one plain red top tube of blood. SST tubes are not acceptable.

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