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Depakote ER

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Depakote ER

Depakote ER

INDICATIONS

Mania

Depakote ER (divalproex sodium) is a valproate and is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities).

The efficacy of Depakote ER (divalproex sodium) is based in part on studies of Depakote (divalproex sodium delayed release tablets) in this indication, and was confirmed in a 3-week trial with patients meeting DSM-IV TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for acute mania [see Clinical Studies].

The effectiveness of valproate for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote ER (divalproex sodium) for extended periods should continually reevaluate the long-term risk-benefits of the drug for the individual patient.

Epilepsy

Depakote ER (divalproex sodium) is 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 ER (divalproex sodium) 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.

Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.

Migraine

Depakote ER (divalproex sodium) is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote ER (divalproex sodium) is useful in the acute treatment of migraine headaches. Because it may be a hazard to the fetus, Depakote ER (divalproex sodium) should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment [see WARNINGS AND PRECAUTIONS, Patient Counseling Information].

DOSAGE AND ADMINISTRATION

Depakote ER (divalproex sodium) is an extended-release product intended for once-a-day oral administration. Depakote ER (divalproex sodium) tablets should be swallowed whole and should not be crushed or chewed.

Mania

Depakote ER (divalproex sodium) tablets are administered orally. 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. In a placebo-controlled clinical trial of acute mania or mixed type, patients were dosed to a clinical response with a trough plasma concentration between 85 and 125 mcg/mL. The maximum recommended dosage is 60 mg/kg/day.

There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote ER (divalproex sodium) treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote ER (divalproex sodium) in such longer-term treatment (i.e., beyond 3 weeks).

Epilepsy

Depakote ER (divalproex sodium) extended release tablets are administered orally, and must be swallowed whole. As Depakote ER (divalproex sodium) dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see DRUG INTERACTIONS].

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Depakote ER (divalproex sodium) 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. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. 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. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 - 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote ER (divalproex sodium) therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

Depakote ER (divalproex sodium) 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. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see DRUG INTERACTIONS].

Simple and Complex Absence Seizures

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.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see CLINICAL PHARMACOLOGY].

As Depakote ER (divalproex sodium) dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see DRUG INTERACTIONS].

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

Migraine

Depakote ER (divalproex sodium) is indicated for prophylaxis of migraine headaches in adults.

The recommended starting dose is 500 mg once daily for 1 week, thereafter increasing to 1000 mg once daily. Although doses other than 1000 mg once daily of Depakote ER have not been evaluated in patients with migraine, the effective dose range of Depakote (divalproex sodium delayed-release tablets) in these patients is 500-1000 mg/day. As with other valproate products, doses of Depakote ER (divalproex sodium) should be individualized and dose adjustment may be necessary. If a patient requires smaller dose adjustments than that available with Depakote ER (divalproex sodium) , Depakote should be used instead.

Conversion from Depakote to Depakote ER (divalproex sodium)

In adult patients and pediatric patients 10 years of age or older with epilepsy previously receiving Depakote, Depakote ER (divalproex sodium) should be administered once-daily using a dose 8 to 20% higher than the total daily dose of Depakote (Table 1). For patients whose Depakote total daily dose cannot be directly converted to Depakote ER (divalproex sodium) , consideration may be given at the clinician's discretion to increase the patient's Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER (divalproex sodium) .

Table 1. Dose Conversion

Depakote Total Daily Dose (mg) Depakote ER (mg)
500* - 625 750
750* - 875 1000
1000*-1125 1250
1250-1375 1500
1500-1625 1750
1750 2000
1875-2000 2250
2125-2250 2500
2375 2750
2500-2750 3000
2875 3250
3000-3125 3500
* These total daily doses of Depakote cannot be directly converted to an 8 to 20% higher total daily dose of Depakote ER because the required dosing strengths of Depakote ER are not available. Consideration may be given at the clinician's discretion to increase the patient's Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.

There is insufficient data to allow a conversion factor recommendation for patients with DEPAKOTE doses above 3125 mg/day. Plasma valproate Cmin concentrations for DEPAKOTE ER (divalproex sodium) on average are equivalent to DEPAKOTE, but may vary across patients after conversion. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL) [see CLINICAL PHARMACOLOGY].

General Dosing Advice

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Starting doses in the elderly lower than 250mg can only be achieved by the use of Depakote. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see WARNINGS AND PRECAUTIONS].

Dose-Related Adverse Reactions

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see WARNINGS AND PRECAUTIONS]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

G.I. Irritation

Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.

Compliance

Patients should be informed to take Depakote ER (divalproex sodium) 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. If a dose is skipped, the patient should not double the next dose.

HOW SUPPLIED

Depakote ER (divalproex sodium) 250 mg is available as white ovaloid tablets with the corporate Abbott “A” logo , and the Abbo-Code (HF). Each Depakote ER tablet contains divalproex sodium equivalent to 250 mg of valproic acid in the following package sizes:

Dosage Forms And Strengths

Depakote ER (divalproex sodium) 250 mg is available as white ovaloid tablets with the corporate Abbott “A” logo, and the Abbo-Code (HF). Each Depakote ER tablet contains divalproex sodium equivalent to 250 mg of valproic acid.

Depakote ER (divalproex sodium) 500 mg is available as gray ovaloid tablets with the corporate Abbott “A” logo, and the Abbo-Code HC. Each Depakote ER tablet contains divalproex sodium equivalent to 500 mg of valproic acid.

Bottles of 60.......................(NDC 0074-3826-60).
Bottles of 100......................(NDC 0074-3826-13).
Bottles of 500......................(NDC 0074-3826-53).
ABBO-PAC unit dose packages of 100.............................................(NDC 0074-3826-11).

Depakote ER (divalproex sodium) 500 mg is available as gray ovaloid tablets with the corporate Abbott “A” logo, and the Abbo-Code HC. Each Depakote ER tablet contains divalproex sodium equivalent to 500 mg of valproic acid in the following packaging sizes:

Bottles of 100......................(NDC 0074-7126-13).
Bottles of 500......................(NDC 0074-7126-53).
ABBO-PAC unit dose packages of 100......................(NDC 0074-7126-11).

Recommended Storage

Store tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Depakote ER (divalproex sodium) 250 mg, Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617. Depakote ER (divalproex sodium) 500 mg, Mfd. by. Abbott Laboratories, North Chicago, IL 60064 U.S.A. or Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617. Manufactured for. Abbott Laboratories North Chicago, IL 60064 U.S.A.

Last reviewed on RxList: 11/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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