Depakote (divalproex sodium) delayed-release tablets - 4 indications

Scroll down for information on each indication:

• manic episodes associated with bipolar disorder; approved 1983
• monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; approval date unavailable
• adjunctive therapy in patients with multiple seizure types that include absence seizures; approval date unavailable
• prophylaxis of migraine headaches; approval date unavailable

Depakote Sprinkle Capsules (divalproex sodium delayed release capsules) - 1 indication

• monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures; approved 1989

Depakote ER (divalproex sodium) extended-release tablets - 4 indications

Scroll down for information on each indication:

• acute treatment of manic or mixed episodes associated with bipolar disorder, with or without psychotic features; approved 2000
• monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; approval date unavailable
• adjunctive therapy in patients with multiple seizure types that include absence seizures; approval date unavailable
• prophylaxis of migraine headaches; approval date unavailable

General Information

Depakote (divalproex sodium) dissociates to the valproate ion in the gastrointestinal tract. Valproic acid exhibits its pharmacologic effects in a couple of ways, including by acting on GABA (γ aminobutyric acid) levels in the CNS, blocking voltage-gated ion channels, and also by inhibiting histone deacetylase.

Depakote Delayed-Release tablets are specifically indicated for the following conditions:

• the treatment of the manic episodes associated with bipolar disorder;
• as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures;
• the prophylaxis of migraine headaches

Depakote Sprinkle Delayed-Release capsules are specifically indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote Sprinkle Capsules are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures.

Depakote Extended-Release tablets are specifically indicated for the following conditions:

• the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features;
• as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote ER is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older with multiple seizure types that include absence seizures;
• the prophylaxis of migraine headaches

Depakote is supplied as Delayed-Release tablets, Delayed-Release capsules and Extended-Release tablets, all for oral administration. Please scroll down for specific dosing administrations for each formulation and therapeutic condition. 

Mechanism of Action

Depakote (divalproex sodium) dissociates to the valproate ion in the gastrointestinal tract. Valproic acid exhibits its pharmacologic effects in a couple of ways, including by acting on GABA (γ aminobutyric acid) levels in the CNS, blocking voltage-gated ion channels, and also by inhibiting histone deacetylase. Impaired GABAergic inhibitory activity is established pathophysiology of seizure initiation and propagation, given that controlling this pathway a potential target for antiepileptic drugs. Valproic acid may also exert antiepileptic effects by reducing the high-frequency firing of neurons by voltage-gated sodium, potassium, and calcium channel blockade. 

Side Effects

Adverse effects associated with the use of all Depakote formulations may include, but are not limited to, the following:

• abdominal pain
• accidental injury
• alopecia
• amblyopia/blurred vision
• amnesia
• anorexia
• asthenia
• ataxia
• back pain
• bronchitis
• constipation
• depression
• diarrhea
• diplopia
• dizziness
• dyspepsia
• dyspnea
• ecchymosis
• emotional lability
• fever
• flu syndrome
• headache
• increased appetite
• infection
• insomnia
• nausea
• nervousness
• nystagmus
• peripheral edema
• pharyngitis
• rash
• rhinitis
• somnolence
• thinking abnormal
• thrombocytopenia
• tinnitus
• tremor
• vomiting
• weight gain
• weight loss

The Depakote ER/DR drug label comes with the following Black Box Warning: Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter. Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ. Pancreatitis, including fatal hemorrhagic cases.

Depakote (divalproex sodium) delayed-release tablets

Indication 1 - manic episodes associated with bipolar disorder

Approved in 1983

Dosing/Administration

Depakote tablets are administered orally. 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. 

Clinical Trial Results

The FDA approval of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. 

Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Patients treated with Depakote ER showed a significant difference versus placebo on each rating scale from baseline to week 3. 

Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL.  Study 2 also included a lithium group. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint were significantly better in the Depakote treatment arm versus both placebo and lithium.

Indication 2 - monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures

Approval date unavailable

Dosing/Administration

Depakote tablets are administered orally.

• Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
• Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. . Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction.
• Adjunctive Therapy Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.

Clinical Trial Results

The FDA approval of Depakote for reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The reduction of CPS from baseline was statistically significantly greater for valproate than placebo. 

A second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. The reduction from baseline was statistically significantly greater for high dose than low dose at 8 weeks.

Indication 3 - adjunctive therapy in patients with multiple seizure types that include absence seizures

Approval date unavailable

Dosing/Administration

Depakote tablets are administered orally. The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.

Clinical Trial Results

The FDA approval of Depakote for reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The reduction of CPS from baseline was statistically significantly greater for valproate than placebo. 

A second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. The reduction from baseline was statistically significantly greater for high dose than low dose at 8 weeks.

Indication 4 - prophylaxis of migraine headaches

Approval date unavailable

Dosing/Administration

Depakote tablets are administered orally.  The recommended starting dose is 250 mg twice daily. 

Clinical Trial Results

The FDA approval of Depakote for was based on the results of two multicenter, randomized, double-blind, placebo-controlled clinical trials. Both studies employed identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase.

In the first study, a total of 107 patients were randomized 2:1: Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group. These rates were significantly different.

In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results. Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group.

Depakote Sprinkle Capsules (divalproex sodium delayed release capsules) 

Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures

Approved in 1989

Dosing/Administration

Depakote Sprinkle Capsules are administered orally. Depakote Sprinkle Capsules may be swallowed whole or the contents may be sprinkled on soft food. The drug/food mixture should be swallowed immediately (avoid chewing).  Safety of doses above 60 mg/kg/day is not established.

•  Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy
• Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects

Clinical Trial Results

The FDA approval of Depakote Sprinkle Delayed-Released capsules was based on the Depakote Delayed-Release tablets clinical trials in patients with seizures. Please see above for clinical trial information.

Depakote ER (divalproex sodium) extended-release tablets

Indication 1- acute treatment of manic or mixed episodes associated with bipolar disorder, with or without psychotic features

Approved in 2000

Dosing/Administration

Depakote ER is an extended-release product intended for once-a-day oral administration. Depakote ER tablets should be swallowed whole and should not be crushed or chewed. The recommended initial dose is 25 mg/kg/day given once daily. 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. 

Clinical Trial Results

The effectiveness of Depakote ER for the treatment of acute mania is based in part on studies establishing the effectiveness of Depakote (divalproex sodium delayed release tablets) for this indication. Depakote ER’s effectiveness was confirmed in one randomized, double-blind, placebo-controlled, parallel group, 3-week, multicenter study. The study was designed to evaluate the safety and efficacy of Depakote ER in the treatment of bipolar I disorder, manic or mixed type, in adults. Adult male and female patients who had a current DSM-IV TR primary diagnosis of bipolar I disorder, manic or mixed type, and who were hospitalized for acute mania, were enrolled into this study. Depakote ER was initiated at a dose of 25 mg/kg/day given once daily, increased by 500 mg/day on Day 3, then adjusted to achieve plasma valproate concentrations in the range of 85-125 mcg/mL. Depakote ER was significantly more effective than placebo in reduction of the MRS total score.

Indication 2 - monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures

Approval date unavailable

Dosing/Administration

Depakote ER is an extended-release product intended for once-a-day oral administration. 

• Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy. The maximum recommended dosage is 60 mg/kg/day. 
• Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects. The maximum recommended dosage is 60 mg/kg/day

Clinical Trial Results

The FDA approval of Depakote Extended-Release Capsules was based on the Depakote Delayed-Release tablets clinical trials in patients with seizures. Please see above for clinical trial information.

Indication 3 - adjunctive therapy in patients with multiple seizure types that include absence seizures

Approval date unavailable

Dosing/Administration

Depakote ER is an extended-release product intended for once-a-day oral administration. 

• Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy. The maximum recommended dosage is 60 mg/kg/day. 
• Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects. The maximum recommended dosage is 60 mg/kg/day

Clinical Trial Results

The FDA approval of Depakote Extended-Release Capsules was based on the Depakote Delayed-Release tablets clinical trials in patients with seizures. Please see above for clinical trial information.

Indication 4 - prophylaxis of migraine headaches

Approval date unavailable

Dosing/Administration

Depakote ER is an extended-release product intended for once-a-day oral administration. The recommended starting dose is 500 mg/day for 1 week, thereafter increasing to 1,000 mg/day.

Clinical Trial Results

The results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial demonstrated the effectiveness of Depakote ER in the prophylactic treatment of migraine headache. This trial recruited patients with a history of migraine headaches with or without aura occurring on average twice or more a month for the preceding three months. Patients with cluster or chronic daily headaches were excluded. Patients who experienced ≥ 2 migraine headaches in the 4-week baseline period were randomized in a 1:1 ratio to Depakote ER or placebo and treated for 12 weeks. Patients initiated treatment on 500 mg once daily for one week, and were then increased to 1,000 mg once daily with an option to permanently decrease the dose back to 500 mg once daily during the second week of treatment if intolerance occurred. Ninety-eight of 114 Depakote ER-treated patients (86%) and 100 of 110 placebo-treated patients (91%) treated at least two weeks maintained the 1,000 mg once daily dose for the duration of their treatment periods. Treatment outcome was assessed on the basis of reduction in 4-week migraine headache rate in the treatment period compared to the baseline period. The mean reduction in 4-week migraine headache rate was 1.2 from a baseline mean of 4.4 in the Depakote ER group, versus 0.6 from a baseline mean of 4.2 in the placebo group. The treatment difference was statistically significant.