Valproate is one of the most versatile and effective antiseizure drugs. It is widely used for myoclonic (such as in juvenile myoclonic epilepsy), atonic (as in Lennox-Gastaut syndrome), and generalized onset tonic-clonic seizures. Valproate is also effective in the treatment of generalized absence seizures and is often preferred to ethosuximide when the patient has concomitant generalized tonic-clonic seizures. Valproate is also effective in focal seizures, but it may not be as effective as carbamazepine or phenytoin. Intravenous formulations can be used to treat status epilepticus.
Valproate is well absorbed after an oral dose, with bioavailability greater than 80%. Peak blood levels are observed within 2 hours. Food may delay absorption, and the drug may have improved tolerability if it is administered after meals. Valproate is highly bound to plasma proteins, but protein binding becomes saturated as the concentration increases at the upper end of the therapeutic range, resulting in an increase in the plasma free fraction of valproate from 10% at plasma concentrations up to 75 mcg/mL to 30% at levels greater that 150 mcg/mL. Such increases lead to an apparent increase in the clearance of total valproate at high doses. The half-life varies from 9 to 18 hours; extended-release formulations are therefore preferred. Because valproate is highly protein bound, it is largely confined to blood plasma; the drug has a low volume of distribution of approximately 0.15 L/kg. Approximately 20% of the drug is excreted as a direct conjugate.
An initial daily dose of 15 mg/kg is recommended with slow titration to the therapeutic dose. Dosages of 25–30 mg/kg/d may be adequate in some patients, but others may require 60 mg/kg/d or even more. Therapeutic levels of valproate range from 50 to 100 mcg/mL, but concentrations up to 150 mcg/mL are generally tolerated and may be required.
Valproate inhibits the metabolism of several drugs, including phenobarbital and ethosuximide, leading to higher steady-state concentrations of these agents. Levels of phenobarbital may rise steeply, causing stupor or coma. Valproate displaces phenytoin from plasma proteins, causing an increase in the free fraction of phenytoin, and total phenytoin concentrations in the therapeutic range may be associated with toxicity. Although valproate does not increase levels of carbamazepine itself, levels of carbamazepine epoxide may be increased. Valproate can dramatically decrease the clearance of lamotrigine, resulting in a twoto three-fold prolongation of lamotrigine’s half-life.
The most common dose-related adverse effects of valproate are nausea, vomiting, and other gastrointestinal complaints such as abdominal pain and heartburn. The drug should be started gradually to avoid these symptoms. A fine tremor is frequently seen at higher levels. Other reversible adverse effects occurring in some patients include weight gain, increased appetite, and hair loss.
Valproate rarely causes idiosyncratic hepatic toxicity that may be severe and has been fatal. The risk is greatest for patients under 2 years of age and for those taking multiple medications. Initial aspartate aminotransferase values may not be elevated in susceptible patients, although these levels do eventually become abnormal. Most fatalities have occurred within 4 months after initiation of therapy. The other observed idiosyncratic adverse effect with valproate is thrombocytopenia, although documented cases of abnormal bleeding are lacking. Valproate can interfere with conversion of ammonia to urea. It can cause lethargy associated with increased blood ammonia concentrations. Fatal hyperammonemic encephalopathy has occurred in patients with genetic defects in urea metabolism; the drug is contraindicated in these patients.