FDA Approves Depakote (divalproex sodium) for Manic Episodes Associated with Bipolar Disorder

Not reported in label.

Depakote (divalproex sodium) is a valproate indicated for the treatment of the manic episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood, with symptoms such as pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The efficacy was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania. The drug is also indicated as monotherapy and adjunctive therapy for complex partial seizures and simple and complex absence seizures, and for the prophylaxis of migraine headaches.

Depakote tablets are intended for oral administration, swallowed whole and not crushed or chewed. For mania, the recommended initial dose is 750 mg daily in divided doses. 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 (trough plasma concentration between 50 and 125 mcg/mL was targeted in trials). The maximum recommended dosage is 60 mg/kg/day. Patients should take it every day as prescribed; if a dose is missed, it should be taken as soon as possible unless it is almost time for the next dose, and doses should not be doubled.

The efficacy of Depakote for manic episodes was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. There is no body of evidence available from controlled trials to guide longer-term management beyond the acute manic episode. The safety and effectiveness for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Safety in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months.

Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. For prophylaxis of migraine headaches, Depakote is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception.

Depakote is indicated for the treatment of acute manic episodes associated with bipolar disorder, based on 3-week trial data in hospitalized patients. There are no efficacy data that specifically address longer-term antimanic treatment with Depakote, and its long-term usefulness for an individual patient should be continually reevaluated. While pharmacological treatment beyond an acute response is generally agreed to be desirable for maintenance and prevention of new episodes, no data support the benefits of Depakote in such longer-term treatment for mania.