Depakote

[Divalproex]

Epilepsy

DEPAKOTE ER is indicated as monotherapy and adjunctive therapy for complex partial seizures, and for simple and complex absence seizures in adult patients and pediatric patients 10 years of age or older. As the DEPAKOTE ER dosage is titrated upward, concentrations of phenobarbital, carbamazepine, and/ or phenytoin may be affected (see PRECAUTIONS --Drug Interactions).

Complex Partial Seizures for adult patients and children 10 years of age or older

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Monotherapy (Initial Therapy) :

DEPAKOTE ER 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 µg/ 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 µg/ mL in females and 135 µg/ 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 µg/ 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 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 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 µg/ 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 DEPAKOTE, 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 (see Drug Interactions ), periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy (see PRECAUTIONS --Drug Interactions ).

Simple and Complex Absence Seizures for adult patients and children 10 years of age or older

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 concentrations for most patients with absence seizures is considered to range from 50 to 100 µg/ mL. Some patients may be
controlled with lower or higher serum concentrations (see CLINICAL PHARMACOLOGY ).

As the DEPAKOTE ER dosage is titrated upward, blood concentrations of phenobarbital and/ or phenytoin may be affected (see PRECAUTIONS ).

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.

Conversion from DEPAKOTE to DEPAKOTE ER

In adult patients and pediatric patients 10 years of age or older with epilepsy previously receiving DEPAKOTE, DEPAKOTE ER should be administered once-daily using a dose 8 to 20% higher than the total daily dose of DEPAKOTE (Table 5). For patients whose DEPAKOTE total daily dose can not be directly converted to DEPAKOTE ER, 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.
Table 5 Dose Conversion
DEPAKOTE DEPAKOTE ER
Total Daily Dose (mg) (mg) 500* -625

750* -875 750 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 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 µg/ mL) (see Pharmacokinetics-Absorption/
Bioavailability).

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 250 mg 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 events. 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).

Dose-Related Adverse Events -

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 µg/ mL (females) or > 135 µg/ mL (males) (see 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 initiating therapy with a lower dose of DEPAKOTE.

Compliance -

Patients should be informed to take DEPAKOTE ER 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 250 mg is available as white ovaloid tablets with the corporate 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:

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 500 mg is available as gray ovaloid tablets with the corporate 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].

New Manufactured by:

DOSAGE AND 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.

Migraine

DEPAKOTE ER 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 should be individualized and dose adjustment may be necessary. If a patient requires smaller dose adjustments than that available with DEPAKOTE ER, DEPAKOTE should be used instead.
Epilepsy DEPAKOTE ER is indicated as monotherapy and adjunctive therapy for complex partial seizures, and for simple and complex absence seizures in adult patients and pediatric patients 10 years of age or older. As the DEPAKOTE ER dosage is titrated upward, concentrations of phenobarbital, carbamazepine, and/ or phenytoin may be affected (see PRECAUTIONS --Drug Interactions).

Complex Partial Seizures for adult patients and children 10 years of age or older

Monotherapy (Initial Therapy) : DEPAKOTE ER 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 µg/ 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 µg/ mL in females and 135 µg/ 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 µg/ 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 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 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 µg/ 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 DEPAKOTE, 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
(see Drug Interactions ), periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy (see PRECAUTIONS --Drug Interactions ).

Simple and Complex Absence Seizures for adult patients and children 10 years of age or older

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 concentrations for most patients with absence seizures is considered to range from 50 to 100 µg/ mL. Some patients may be
controlled with lower or higher serum concentrations (see CLINICAL PHARMACOLOGY ).

As the DEPAKOTE ER dosage is titrated upward, blood concentrations of phenobarbital and/ or phenytoin may be affected (see PRECAUTIONS ).

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.
Conversion from DEPAKOTE to DEPAKOTE ER: In adult patients and pediatric patients 10 years of age or older with epilepsy previously receiving DEPAKOTE, DEPAKOTE ER should be administered once-daily using a dose 8 to 20% higher than the total daily dose of DEPAKOTE (Table 5). For patients whose DEPAKOTE total daily dose can not be directly converted to DEPAKOTE ER, 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.
Table 5 Dose Conversion
DEPAKOTE DEPAKOTE ER
Total Daily Dose (mg) (mg) 500* -625

750* -875 750 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 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 µg/ mL) (see Pharmacokinetics-Absorption/
Bioavailability).
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 250 mg 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 events. 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). Dose-Related Adverse Events -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 µg/ mL (females) or > 135 µg/ mL (males) (see 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 initiating therapy with a lower dose of DEPAKOTE. Compliance -Patients should be informed to take DEPAKOTE ER 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 250 mg is available as white ovaloid tablets with the corporate 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:

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 500 mg is available as gray ovaloid tablets with the corporate 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].

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