DIVALPROEX SODIUM - divalproex sodium tablet, film coated, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
DIVALPROEX SODIUM (UNII: 644VL95AO6) (VALPROIC ACID - UNII:614OI1Z5WI)
Available from:
Physicians Total Care, Inc.
INN (International Name):
DIVALPROEX SODIUM
Composition:
DIVALPROEX SODIUM 500 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Divalproex sodium extended-release tablets are 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 divalproex sodium extended-release tablets is based in part on studies of 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 (14.1)] . The safety
Product summary:
Divalproex sodium extended-release tablets 500 mg are white, oval, biconvex, film coated tablets printed "A511" in black ink on one side and plain on the other side. Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 500 mg of valproic acid in the following packaging sizes: Recommended Storage Store tablets at 20- 25°C (68- 77°F) [see USP Controlled Room Temperature]. Manufactured by Anchen Pharmaceuticals (Taiwan), Inc. Zhongli City, Taoyuan County 320, Taiwan Manufactured for Anchen Pharmaceuticals, Inc. Irvine, CA 92618 Revised: 07/09 Relabeling and Repackaging by: Physicians Total Care, Inc. Tulsa, OK      74146
Authorization status:
Abbreviated New Drug Application
Authorization number:
54868-6088-0, 54868-6088-1, 54868-6088-2

DIVALPROEX SODIUM - divalproex sodium tablet, film coated, extended release

Physicians Total Care, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use divalproex sodium extended-release tablets

safely and effectively. See full prescribing information for divalproex sodium extended-release tablets.

Divalproex sodium extended-release tablets for oral administration

Initial U.S. Approval: 2000

WARNING: LIFE THREATENING ADVERSE REACTIONS

See full prescribing information for complete boxed warning.

Hepatotoxicity, including fatalities, usually during first 6 months of treatment. Children under the age

of two years are at considerably higher risk of fatal hepatotoxicity. Monitor patients closely, and

perform liver function tests prior to therapy and at frequent intervals thereafter (5.1)

Teratogenicity, including neural tube defects (5.2)

Pancreatitis, including fatal hemorrhagic cases (5.3)

RECENT MAJOR CHANGES

Warnings and Precautions (5.5, 5.9, 5.11, 5.13, 5.14,

5.15

3/2008

Pediatric Use (8.4)

3/2008

INDICATIONS AND USAGE

Divalproex sodium extended-release tablets are indicated for:

Acute treatment of manic or mixed episodes associated with bipolar disorder, with or without psychotic features. (1.1)

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 (1.2)

Prophylaxis of migraine headaches (1.3)

DOSAGE AND ADMINISTRATION

Divalproex sodium extended-release tablets are intended for once-a-day oral administration. Divalproex sodium

extended-release tablets should be swallowed whole and should not be crushed or chewed.

Mania: - Initial dose is 25 mg/kg/day, increasing as rapidly as possible to achieve therapeutic response or desired

plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2)

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 (2.2). The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2).

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 (2.2).

The maximum recommended dosage is 60 mg/kg/day. (2.1, 2.2).

Migraine: The recommended starting dose is 500 mg/day for 1 week, thereafter increasing to 1000 mg/day (2.3)

DOSAGE FORMS AND STRENGTHS

Tablets: 250mg and 500mg (3)

CONTRAINDICATIONS

Hepatic disease or significant hepatic dysfunction (4, 5.1)

Known hypersensitivity to the drug (4, 5.10)

Urea cycle disorders (4, 5.4)

WARNINGS AND PRECAUTIONS

Hepatotoxicity; monitor liver function tests (5.1)

Teratogenic effects; weigh divalproex sodium extended-release tablets benefits of use during pregnancy against risk to

the fetus (5.2)

Pancreatitis; divalproex sodium extended-release tablets should ordinarily be discontinued (5.3)

Suicidal behavior ideation; Antiepileptic drugs, including divalproex sodium extended-release tablets, increase the risk

of suicidal thoughts or behavior (5.5)

Thrombocytopenia; monitor platelet counts and coagulation tests (5.6)

Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and

vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate

therapy (5.4, 5.7, 5.8)

Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia.

This adverse reaction can also occur in patients using concomitant topiramate (5.9)

Multi-organ hypersensitivity reaction; discontinue divalproex sodium extended-release tablets (5.10)

Somnolence in the elderly can occur. Divalproex sodium extended-release tablets dosage should be increased slowly

and with regular monitoring for fluid and nutritional intake (5.12)

ADVERSE REACTIONS

Most common adverse reactions (reported >5%) reported in adult studies are nausea, somnolence, dizziness,

vomiting, asthenia, abdominal pain, dyspepsia, rash, diarrhea, increased appetite, tremor, weight gain, back pain,

alopecia, headache, fever, anorexia, constipation, diplopia, ambylopia/blurred, ataxia, nystagmus, emotional lability,

thinking abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis, ecchymosis, peripheral edema, insomnia,

nervousness, depression, pharyngitis, dyspnea, tinnitus (6.1, 6.2, 6.3, 6.4).

Most common, drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in a controlled

pediatric mania study are nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash.

To report SUSPECTED ADVERSE REACTIONS, contact Anchen Pharmaceuticals at 1-888-493-0857 or FDA at

1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase

valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased

monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever

enzymeinducing or inhibiting drugs are introduced or withdrawn (7.1)

Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1)

Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide,

lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2)

Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly

with divalproex sodium extended-release tablets (7.2)

Topiramate: Hyperammonemia and encephalopathy (5.8, 7.3)

USE IN SPECIFIC POPULATIONS

Pregnancy: Divalproex sodium extended-release tablets can cause congenital malformations including neural tube

defects (5.2, 8.1)

Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4)

Geriatric: reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence

(5.12, 8.5)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 6/2011

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: LIFE THREATENING ADVERSE REACTIONS

1 INDICATIONS AND USAGE

1.1 Mania

1.2 Epilepsy

1.3 Migraine

2 DOSAGE AND ADMINISTRATION

2.1 Mania

2.2 Epilepsy

2.3 Migraine

2.4 Conversion from Divalproex Sodium Delayed-Release Tablets to Divalproex Sodium

Extended-Release Tablets

2.5 General Dosing Advice

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

5.2 Teratogenicity/Usage in Pregnancy

5.3 Pancreatitis

5.4 Urea Cycle Disorders

5.5 Suicidal Behavior and Ideation

5.6 Thrombocytopenia

5.7 Hyperammonemia

5.8 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use

5.9 Hypothermia

5.10 Multi-Organ Hypersensitivity Reactions

5.11 Interaction with Carbapenem Antibiotics

5.12 Somnolence in the Elderly

5.13 Monitoring: Drug Plasma Concentration

5.14 Effect on Ketone and Thyroid function Tests

5.15 Effect on HIV and CMV Viruses Replication

6 ADVERSE REACTIONS

6.1 Mania

6.2 Epilepsy

6.3 Migraine

6.4 Other Patient Populations

7 DRUG INTERACTIONS

7.1 Effects of Co-Administered Drugs on Valproate Clearance

7.2 Effects of Valproate on Other Drugs

7.3 Topiramate

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Effect of Disease

10 OVER DOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Mania

14.2 Epilepsy

14.3 Migraine

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Hepatotoxicity

17.2 Pancreatitis

17.3 Teratogenicity/Usage in Pregnancy

17.4 Suicidal Thinking and Behavior

17.5 Hyperammonemia

17.6 CNS depression

17.7 Multi-organ Hypersensitivity Reaction

17.8 FDA–Approved Patient Labeling

FULL PRESCRIBING INFORMATION

WARNING: LIFE THREATENING ADVERSE REACTIONS

Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its

derivatives. Children under the age of two years are at a considerably increased risk of

developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with

congenital metabolic disorders, those with severe seizure disorders accompanied by

mental retardation, and those with organic brain disease. When divalproex sodium

extended-release tablets are used in this patient group, it should be used with extreme

caution and as a sole agent. The benefits of therapy should be weighed against the risks.

The incidence of fatal hepatotoxicity decreases considerably in progressively older patient

groups .

These incidents usually have occurred during the first six months of treatment. Serious or

fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness,

lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure

control may also occur. Patients should be monitored closely for appearance of these

symptoms. Liver function tests should be performed prior to therapy and at frequent

intervals thereafter, especially during the first six months [See Warnings and Precautions

(5.1)].

Teratogenicity

Valproate can produce teratogenic effects such as neural tube defects (e.g., spina bifida).

Accordingly, the use of divalproex sodium extended-release tablets in women of

childbearing potential requires that the benefits of its use be weighed against the risk of

injury to the fetus. This is especially important when the treatment of a spontaneously

reversible condition not ordinarily associated with permanent injury or risk of death (e.g.,

migraine) is contemplated. [See Warnings and Precautions (5.2)]

An information sheet describing the teratogenic potential of valproate is available for

patients [See Patient Counseling Information (17.8)].

Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults

receiving valproate. Some of the cases have been described as hemorrhagic with a rapid

progression from initial symptoms to death. Cases have been reported shortly after initial

use as well as after several years of use. Patients and guardians should be warned that

abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that

require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily

be discontinued. Alternative treatment for the underlying medical condition should be

initiated as clinically indicated [see Warnings and Precautions (5.3)].

Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

1.1 Mania

Divalproex sodium extended-release tablets are 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 divalproex sodium extended-release tablets is based in part on studies of 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 (14.1)].

The safety and effectiveness of valproate for long-term use in mania, i.e., more than 3 weeks, has not

been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use

divalproex sodium extended-release tablets for extended periods should continually reevaluate the

long-term risk-benefits of the drug for the individual patient.

1.2 Epilepsy

Divalproex sodium extended-release tablets are 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. Divalproex sodium

extended-release tablets are 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.

1.3 Migraine

Divalproex sodium extended-release tablets are indicated for prophylaxis of migraine headaches.

There is no evidence that divalproex sodium extended-release tablets are useful in the acute treatment

of migraine headaches. Because it may be a hazard to the fetus, divalproex sodium extended-release

tablets 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 (5.2), Patient Counseling Information (17.3)].

2 DOSAGE AND ADMINISTRATION

Divalproex sodium extended-release tablets are an extended-release product intended for once-a-day

oral administration. Divalproex sodium extended-release tablets should be swallowed whole and should

not be crushed or chewed.

2.1 Mania

Divalproex sodium extended-release 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 divalproex sodium extended-release tablets 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 systematically obtained data to support the benefits of divalproex sodium

extended-release tablets in such longer-term treatment (i.e., beyond 3 weeks).

2.2 Epilepsy

Divalproex sodium extended-release tablets are administered orally, and must be swallowed whole. As

divalproex sodium extended-release tablets dosage is titrated upward, concentrations of clonazepam,

diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may

be affected [see Drug Interactions (7.2)].

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Divalproex sodium extended-release tablets have 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 divalproex sodium extended-release tablets

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

Divalproex sodium extended-release tablets 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 (14.2)]. 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 (7)].

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

(12.3)].

As divalproex sodium extended-release tablets dosage is titrated upward, blood concentrations of

phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].

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.

2.3 Migraine

Divalproex sodium extended-release tablets are 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 divalproex sodium extended-release

tablets have not been evaluated in patients with migraine, the effective dose range of divalproex sodium

delayed-release tablets in these patients is 500-1000 mg/day. As with other valproate products, doses

of divalproex sodium extended-release tablets should be individualized and dose adjustment may be

necessary. If a patient requires smaller dose adjustments than that available with divalproex sodium

extended-release tablets, divalproex sodium delayed-release tablets should be used instead.

2.4 Conversion from Divalproex Sodium Delayed-Release Tablets to Divalproex Sodium

Extended-Release Tablets

In adult patients and pediatric patients 10 years of age or older with epilepsy previously receiving

divalproex sodium delayed-release tablets, divalproex sodium extended-release tablets should be

administered once-daily using a dose 8 to 20% higher than the total daily dose of divalproex sodium

delayed-release tablets (Table 1). For patients whose divalproex sodium delayed-release tablets total

daily dose cannot be directly converted to divalproex sodium extended-release tablets, consideration

may be given at the clinician's discretion to increase the patient's divalproex sodium delayed-release

tablets total daily dose to the next higher dosage before converting to the appropriate total daily dose of

divalproex sodium extended-release tablets.

Table 1. Dose Conversion

Divalproex Sodium Delayed-Release

Tablets

Total Daily Dose (mg)

Divalproex Sodium Extended-Release

Tablets

(mg)

500 -625

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

There is insufficient data to allow a conversion factor recommendation for patients with divalproex

sodium delayed-release tablet doses above 3125 mg/day. Plasma valproate Cmin concentrations for

divalproex sodium extended-release tablets on average are equivalent to divalproex sodium delayed-

release tablets, 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 (12.2)].

2.5 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 divalproex sodium delayed-release tablets. 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 (5.12)].

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

(5.6)]. 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 divalproex sodium extended-release tablets 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

These total daily doses of divalproex sodium delayed-release tablets cannot be directly

converted to an 8 to 20% higher total daily dose of divalproex sodium extended-release

tablets because the required dosing strengths of divalproex sodium extended-release

tablets are not available. Consideration may be given at the clinician's discretion to

increase the patient's divalproex sodium delayed-release tablets total daily dose to the next

higher dosage before converting to the appropriate total daily dose of divalproex sodium

extended-release tablets.

dose is skipped, the patient should not double the next dose.

3 DOSAGE FORMS AND STRENGTHS

Divalproex sodium extended-release tablets 250 mg are available as white oval, biconvex film coated

tablets printed "A510" in black ink on one side and plain on the other side. Each divalproex sodium

extended-release tablet contains divalproex sodium equivalent to 250 mg of valproic acid.

Divalproex sodium extended-release tablets 500 mg are available as white film coated tablets printed

"A511" in black ink on one side and plain on the other side. Each divalproex sodium extended-release

tablet contains divalproex sodium equivalent to 500 mg of valproic acid.

4 CONTRAINDICATIONS

Divalproex sodium extended-release tablets should not be administered to patients with hepatic

disease or significant hepatic dysfunction. [see Warnings and Precautions (5.1)].

Divalproex sodium extended-release tablets are contraindicated in patients with known

hypersensitivity to the drug. [see Warnings and Precautions (510)].

Divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle

disorders [see Warnings and Precautions (5.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. These incidents

usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be

preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and

vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be

monitored closely for appearance of these symptoms. Liver function tests should be performed prior to

therapy and at frequent intervals thereafter, especially during the first six months. However, physicians

should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but

should also consider the results of careful interim medical history and physical examination.

Caution should be observed when administering valproic acid products to patients with a prior history

of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic

disorders, those with severe seizure disorders accompanied by mental retardation, and those with

organic brain disease may be at particular risk. Experience has indicated that children under the age of

two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with

the aforementioned conditions. When divalproex sodium extended-release tablets are used in this patient

group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be

weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence

of fatal hepatotoxicity decreases considerably in progressively older patient groups.

The drug should be discontinued immediately in the presence of significant hepatic dysfunction,

suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of

drug [see Boxed Warning and Contraindications (4)]

5.2 Teratogenicity/Usage in Pregnancy

Use of divalproex sodium extended-release tablets during pregnancy can cause congenital

malformations including neural tube defects. If this drug is used during pregnancy, or if the patient

becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the

fetus. Divalproex sodium extended-release tablets should be considered for women of childbearing

potential only after the risks have been thoroughly discussed with the patient and weighed against the

potential benefits of treatment.

Data suggest that there is an increased incidence of congenital malformations associated with the use of

valproate by women with seizure disorders during pregnancy when compared to the incidence in women

with seizure disorders who do not use antiepileptic drugs during pregnancy, the incidence in women

with seizure disorders who use other antiepileptic drugs, and the background incidence for the general

population.

The data described below were gained almost exclusively from women who received valproate to treat

epilepsy. There are multiple reports in the clinical literature that indicate the use of antiepileptic drugs

during pregnancy results in an increased incidence of congenital malformations in offspring.

Antiepileptic drugs, including valproate, should be administered to women of childbearing potential

only if they are clearly shown to be essential in the management of their medical condition.

Antiepileptic drugs should not be discontinued abruptly 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. In individual cases where the severity and frequency of the seizure disorder

are such that the removal of medication does not pose a serious threat to the patient, discontinuation of

the drug may be considered prior to and during pregnancy, although it cannot be said with any

confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. [see

Boxed Warning and Use in Specific Populations (8.1)].

5.3 Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving

valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial

symptoms to death. Some cases have occurred shortly after initial use as well as after several years of

use. The rate based upon the reported cases exceeds that expected in the general population and there

have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there

were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-

years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or

anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is

diagnosed, divalproex sodium extended-release tablets should ordinarily be discontinued. Alternative

treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed

Warning]

5.4 Urea Cycle Disorders

Divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle

disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following

initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic

abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of divalproex

sodium extended-release tablets therapy, evaluation for UCD should be considered in the following

patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with

a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or

history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic

extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a

family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms

of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while

receiving valproate therapy should receive prompt treatment (including discontinuation of valproate

therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings

and Precautions (5.7)]

5.5 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including divalproex sodium extended-release tablets, increase the risk of

suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any

AED for any indication should be monitored for the emergence or worsening of depression, suicidal

thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different

AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted

Relative Risk 1.8, 95% Cl:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to

placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate

of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24%

among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal

thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in

the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about

drug effect suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week

after starting drug treatment with AEDs and persisted for the duration for treatment assessed. Because

most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or

behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of

indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary

substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative

risk by indication for all evaluated AEDs.

Table 2. Risk by indication for antiepileptic drugs in the pooled analysis

Indication

Placebo Patients

with Events Per

1000 Patients

Drug Patients

with Events Per

1000 Patients

Relative Risk:

Incidence of

Events in Drug

Patients /Incidence

in Placebo

Patients

Risk Difference:

Additional Drug

Patients with

Events Per 1000

Patients

Epilepsy

Psychiatric

Other

Total

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in

clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the

epilepsy and psychiatric indications.

Anyone considering prescribing divalproex sodium extended-release tablets or any other AED must

balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many

other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality

and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge

during treatment, the prescriber needs to consider whether the emergence of these symptoms in any

given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal

thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of

the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of

suicidal thoughts, behavior, or thoughts about self-harm. Behavior of concern should be reported

immediately to healthcare providers.

5.6 Thrombocytopenia

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be

dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients

(27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 ×

10 /L. Approximately half of these patients had treatment discontinued, with return of platelet counts to

normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the

probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥

110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the

higher doses should therefore be weighed against the possibility of a greater incidence of adverse

effects.

Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and

abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are

recommended before initiating therapy and at periodic intervals. It is recommended that patients

receiving divalproex sodium extended-release tablets be monitored for platelet count and coagulation

parameters prior to planned surgery. In a clinical trial of valproate as monotherapy in patients with

epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one

value of platelets ≤ 75 × 10 /L. Approximately half of these patients had treatment discontinued, with

return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued

treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total

valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). Evidence of

hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the

dosage or withdrawal of therapy.

5.7 Hyperammonemia

Hyperammonemia has been reported in association with valproate therapy and may be present despite

normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in

mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be

measured. Hyperammonemia should also be considered in patients who present with hypothermia [see

Warnings and Precautions (5.9)]. If ammonia is increased, valproate therapy should be discontinued.

Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should

undergo investigation for underlying urea cycle disorders [see Contraindications and Warnings and

Precautions (4, 5.4, 5.8)].

During a placebo controlled pediatric mania trial, one (1) in twenty (20) adolescents (5%) treated with

valproate developed increased plasma ammonia levels compared to no (0) patients treated with placebo.

Asymptomatic elevations of ammonia are more common and when present, require close monitoring of

plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be

considered.

5.8 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia

with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of

hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or

cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of

hyperammonemia [see Warnings and Precautions (5.8)]. In most cases, symptoms and signs abated with

discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. It is not

known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of

metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia

with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid

may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop

unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be

considered and an ammonia level should be measured. [see Contraindications (4) and Warnings and

Precautions (5.6)].

5.9 Hypothermia

Hypothermia, defined as an unintentional drop in body core temperature to < 35° C (95° F), has been

reported in association with valproate therapy both in conjunction with and in the absence of

hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with

valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug

Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop

hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy,

confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and

respiratory systems. Clinical management and assessment should include examination of blood ammonia

levels.

5.10 Multi-Organ Hypersensitivity Reactions

Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the

initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to

40 days). Although there have been a limited number of reports, many of these cases resulted in

hospitalization and at least one death has been reported. Signs and symptoms of this disorder were

diverse; however, patients typically, although not exclusively, presented with fever and rash associated

with other organ system involvement. Other associated manifestations may include lymphadenopathy,

hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia,

thrombocytopenia, neutropenia), pruritis, nephritis, oliguria, hepato-renal syndrome, arthralgia, and

asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not

noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative

treatment started. Although the existence of cross sensitivity with other drugs that produce this

syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would

indicate this to be a possibility.

5.11 Interaction with Carbapenem Antibiotics

Carbapenem antibiotics (ertapenem, imipenem, meropenem) may reduce serum valproic acid

concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid

concentrations should be monitored frequently after initiating carbapenem therapy. Alternative

antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop

significantly or seizure control deteriorates [see Drug Interactions (7.1)].

5.12 Somnolence in the Elderly

In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years),

doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion

of valproate patients had somnolence compared to placebo, and although not statistically significant,

there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also

significantly higher than with placebo. In some patients with somnolence (approximately one-half), there

was associated reduced nutritional intake and weight loss. There was a trend for the patients who

experienced these events to have a lower baseline albumin concentration, lower valproate clearance,

and a higher BUN. In elderly patients, 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 [see Dosage and Administration (2.3)].

5.13 Monitoring: Drug Plasma Concentration

Since divalproex sodium extended-release tablets may interact with concurrently administered drugs

which are capable of enzyme induction, periodic plasma concentration determinations of valproate and

concomitant drugs are recommended during the early course of therapy. [see Drug Interactions (7)].

5.14 Effect on Ketone and Thyroid function Tests

Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation

of the urine ketone test.

There have been reports of altered thyroid function tests associated with valproate. The clinical

significance of these is unknown.

5.15 Effect on HIV and CMV Viruses Replication

There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses

under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the

relevance of these in vitro findings is uncertain for patients receiving maximally suppressive

antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results

from regular monitoring of the viral load in HIV infected patients receiving valproate or when

following CMV infected patients clinically.

6 ADVERSE REACTIONS

Because clinical studies are conducted under widely varying conditions, adverse reaction rates

observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of

another drug and may not reflect the rates observed in practice.

Information on pediatric adverse reactions is presented in section 8.

6.1 Mania

The incidence of treatment-emergent events has been ascertained based on combined data from two

placebo controlled clinical trials of divalproex sodium extended-release tablets in the treatment of

manic episodes associated with bipolar disorder.

Table 3 summarizes those adverse events reactions reported for patients in these trials where the

incidence rate in the divalproex sodium extended-release tablet-treated group was greater than 5% and

greater than the placebo incidence.

Table 3. Adverse Reactions Reported by >5% of Divalproex Sodium

Extended-Release Tablet-Treated Patients During Placebo-Controlled Trial

of Acute Mania

Adverse Event

Divalproex Sodium

Extended-Releas e

Tablets

(n=338)

Placebo

(N=263)

Somnolence

26 %

14 %

Dyspepsia

23 %

11 %

Nausea

19 %

13 %

Vomiting

13 %

Diarrhea

12 %

Dizziness

12 %

Pain

11 %

10 %

Abdominal pain

10 %

Accidental injury

Asthenia

Pharyngitis

*

The following adverse reactions/event occurred at an equal or greater incidence for

The following additional adverse reactions were reported by greater than 1% but not more than 5% of

the divalproex sodium extended-release tablet -treated patients in controlled clinical trials:

Body as a Whole: Back Pain, Flu Syndrome, Infection, Infection Fungal

Cardiovascular System: Hypertension

Digestive System: Constipation, Dry Mouth, Flatulence

Hemic and Lymphatic System: Ecchymosis

Metabolic and Nutritional Disorders: Peripheral Edema

Musculoskeletal System: Myalgia

Nervous System: Abnormal Gait, Hypertonia, Tremor

Respiratory System: Rhinitis

Skin and Appendages: Pruritis, Rash

Special Senses: Conjunctivitis

Urogenital System: Urinary Tract Infection, Vaginitis

6.2 Epilepsy

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures,

divalproex sodium delayed-release tablets were generally well tolerated with most adverse reactions

rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the

divalproex sodium delayed-release tablet –treated patients (6%), compared to 1% of placebo-treated

patients.

Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of divalproex sodium

delayed-release tablet –treated patients and for which the incidence was greater than in the placebo

group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures.

Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to

determine whether the following adverse reactions can be ascribed to divalproex sodium delayed-

release tablets alone, or the combination of divalproex sodium delayed-release tablets and other

antiepilepsy drugs.

Table 4. Adverse Events Reported by >5% of Patients Treated with Valproate During

Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures

Body System/Event

Divalproex Sodium

Delayed-Release Tablets

(%)

(n=77)

Placebo (%)

(n=70)

Body as a Whole

Headache

Asthenia

Fever

Gastrointestinal System

Nausea

Vomiting

Abdominal Pain

Diarrhea

placebo than for divalproex sodium extended-release tablets: headache.

Anorexia

Dyspepsia

Constipation

Nervous System

Somnolence

Tremor

Dizziness

Diplopia

Amblyopia/Blurred Vision

Ataxia

Nystagmus

Emotional Lability

Thinking Abnormal

Amnesia

Respiratory System

Flu Syndrome

Infection

Bronchitis

Rhinitis

Other

Alopecia

Weight Loss

Table 5 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high

dose valproate group, and for which the incidence was greater than in the low dose group, in a

controlled trial of divalproex sodium delayed-release tablets monotherapy treatment of complex partial

seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the

trial, it is not possible, in many cases, to determine whether the following adverse reactions can be

ascribed to divalproex sodium delayed-release tablets alone, or the combination of valproate and other

antiepilepsy drugs.

Table 5. Adverse Events Reported by >5% of Patients in the High Dose Group in the

Controlled Trial of Valproate Monotherapy for Complex Partial Seizures

Body System/Event

High Dose (%)

(N=131)

Low Dose (%)

(N=134)

Body as a Whole

Asthenia

Digestive System

Nausea

Diarrhea

Vomiting

Abdominal Pain

Anorexia

Dyspepsia

Hemic/Lymphatic System

Thrombocytopenia

Ecchymosis

Metabolic/Nutritional

*

Weight Gain

Peripheral Edema

Nervous System

Tremor

Somnolence

Dizziness

Insomnia

Nervousness

Amnesia

Nystagmus

Depression

Respiratory System

Infection

Pharyngitis

Dyspnea

Skin and Appendages

Alopecia

Special Senses

Amblyopia/Blurred Vision

Tinnitus

The following additional adverse reactions were reported by greater than 1% but less than 5% of the

358 patients treated with valproate in the controlled trials of complex partial seizures:

Body as a Whole: Back pain, chest pain, malaise.

Cardiovascular System: Tachycardia, hypertension, palpitation.

Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal

abscess.

Hemic and Lymphatic System: Petechia.

Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.

Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.

Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal

dreams, personality disorder.

Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.

Skin and Appendages: Rash, pruritus, dry skin.

Special Senses: Taste perversion, abnormal vision, deafness, otitis media.

Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.

6.3 Migraine

Based on two placebo-controlled clinical trials and their long term extension, valproate was generally

well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients

exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is

compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the

adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate -treated

Headache was the only adverse event that occurred in ≥ 5% of patients in the high dose group and at

an equal or greater incidence in the low dose group.

patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence

(1%), elevated SGOT and/or SGPT (1%), and depression (1%).

Table 6 includes those adverse reactions reported for patients in the placebo-controlled trial where the

incidence rate in the divalproex sodium extended-release tablet -treated group was greater than 5% and

was greater than that for placebo patients.

Table 6. Adverse Reactions Reported by >5% of Divalproex Sodium Extended-Release

Tablet-Treated Patients During the Migraine Placebo-Controlled Trial with a Greater

Incidence than Patients Taking Placebo

Body System

Event

Divalproex Sodium

Extended-Releas e

Tablets

(N=122)

Placebo

(N=115)

Gastrointestinal System

Nausea

15 %

Dyspepsia

Diarrhea

Vomiting

Abdominal Pain

Nervous System

Somnolence

Other

Infection

15 %

14 %

The following additional adverse reactions were reported by greater than 1% but not more than 5% of

divalproex sodium extended-release tablet -treated patients and with a greater incidence than placebo in

the placebo-controlled clinical trial for migraine prophylaxis:

Body as a Whole

Accidental injury, viral infection.

Digestive System

Increased appetite, tooth disorder.

Metabolic and Nutritional Disorders

Edema, weight gain.

Nervous System

Abnormal gait, dizziness, hypertonia, insomnia, nervousness, tremor, vertigo.

Respiratory System

Pharyngitis, rhinitis.

Skin and Appendages

Rash.

Special Senses

T innitus.

*

The following adverse events occurred in greater than 5% of divalproex sodium extended-release

tablet -treated patients and at a greater incidence for placebo than for divalproex sodium extended-

release tablets: asthenia and flu syndrome.

Table 7 includes those adverse reactions reported for patients in the placebo-controlled trials where

the incidence rate in the valproate-treated group was greater than 5% and was greater than that for

placebo patients.

Table 7. Adverse Reaction Reported by >5% of Divalproex Sodium Extended-Release

Tablet-Treated Patients During Migraine Placebo-Controlled Trials with a Greater

Incidence than Patients Taking Placebo

Body System

Event

Divalproex Sodium Delayed-

Release Tablets

(N=202)

Placebo

(N=81)

Gastrointestinal System

Nausea

31 %

10 %

Dyspepsia

13 %

Diarrhea

12 %

Vomiting

11 %

Abdominal Pain

Increased Appetite

Nervous System

Asthenia

20 %

Somnolence

17 %

Dizziness

12 %

Tremor

Other

Weight Gain

Back Pain

Alopecia

The following additional adverse reactions were reported by greater than 1% but not more than 5% of

the 202 valproate-treated patients in the controlled clinical trials:

Body as a Whole: Chest pain.

Cardiovascular System: Vasodilatation.

Digestive System: Constipation, dry mouth, flatulence, and stomatitis.

Hemic and Lymphatic System: Ecchymosis.

Metabolic and Nutritional Disorders: Peripheral edema.

Musculoskeletal System: Leg cramps.

Nervous System: Abnormal dreams, confusion, paresthesia, speech disorder, and thinking abnormalities.

Respiratory System: Dyspnea, and sinusitis.

Skin and Appendages: Pruritus.

Urogenital System: Metrorrhagia.

6.4 Other Patient Populations

Mania

*

The following adverse events occurred in greater than 5% of divalproex sodium delayded-release

tablet -treated patients and at a greater incidence for placebo than for divalproex sodium delayded-

release tablets: flu syndrome and pharyngitis.

The following adverse reactions not listed previously were reported by greater than 1% of divalproex

sodium immediate-release tablet-treated patients and with a greater incidence than placebo in placebo-

controlled trials of manic episodes associated with bipolar disorder:

Body as a Whole: Chills, chills and fever, drug level increased, neck rigidity

Cardiovascular System: Arrhythmia, hypotension, postural hypotension.

Digestive System: Dysphagia, fecal incontinence, gastroenteritis, glossitis, gum hemorrhage, mouth

ulceration.

Hemic and Lymphatic System: Anemia, bleeding time increased, leucopenia.

Metabolic and Nutritional Disorders: Hypoproteinemia

Musculoskeletal System: Arthrosis.

Nervous System: Agitation, catatonic reaction, dysarthria, hallucinations, hypokinesia, psychosis,

reflexes increased, sleep disorder, tardive dyskinesia.

Respiratory System: Hiccup

Skin and Appendages: Discoid lupus erythematosis, erythema nodosum, furunculosis, macularpapular

rash, seborrhea, sweating, vesiculobullous rash.

Special Senses: Conjunctivitis, dry eyes, eye disorder, eye pain, photophobia, taste perversion.

Urogenital System: Cystitis, menstrual disorder.

Epilepsy

Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials,

spontaneous reports, and other sources are listed below by body system.

Gastrointestinal

The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and

indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea,

abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and

increased appetite with weight gain have also been reported. The administration of In some patients,

many of whom have functional or anatomic (including ileostomy or colostomy) gastrointestinal

disorders with shortened GI transit times, there have been postmarketing reports of divalproex sodium

extended-release tablets in stool.

CNS Effects

Sedative effects have occurred in patients receiving valproate alone but occur most often in patients

receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication.

Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots

before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism

have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving

valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without

fever has developed shortly after the introduction of valproate monotherapy without evidence of

hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been

described following drug withdrawal, there have been fatalities in patients with hyperammonemic

encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and

Precautions (5.4)].

Several reports have noted reversible cerebral atrophy and dementia in association with valproate

therapy.

Dermatologic

Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-

Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case

in a 6 month old infant taking valproate and several other concomitant medications. An additional case of

toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking

several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin

reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug

Interactions (7)].

Psychiatric

Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral

deterioration.

Musculoskeletal

Weakness.

Hematologic

Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in

altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see

Warnings and Precautions (5.6) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis,

hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate

deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute

intermittent porphyria.

Hepatic

Minor elevations of transaminases (eg, SGOT and SGPT) and LDH are frequent and appear to be dose-

related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes

in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings

and Precautions (5.1)].

Endocrine

Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling.

Abnormal thyroid function tests [see Warnings and Precautions (5.13)].

There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship

has not been established.

Pancreatic: Acute pancreatitis including fatalities [see Warnings and Precautions (5.3)].

Metabolic: Hyperammonemia [see Warnings and Precautions (5.6), hyponatremia, and inappropriate ADH

secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children.

Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.

Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent

nonketotic hyperglycinemia.

Genitourinary: Enuresis and urinary tract infection.

Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a cause

and effect relationship has not been established. Ear pain has also been reported.

Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough

increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.

7 DRUG INTERACTIONS

7.1 Effects of Co-Administered Drugs on Valproate Clearance

Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of

glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,

carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients

on monotherapy will generally have longer half-lives and higher concentrations than patients receiving

polytherapy with antiepilepsy drugs.

In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be

expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated

oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-

oxidation.

Because of these changes in valproate clearance, monitoring of valproate and concomitant drug

concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.

The following list provides information about the potential for an influence of several commonly

prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since

new interactions are continuously being reported.

Drugs for which a potentially important interaction has been observed

Aspirin

A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to

pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of

valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to

valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-

keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in

the presence of aspirin. Whether or not the interaction observed in this study applies to adults is

unknown, but caution should be observed if valproate and aspirin are to be co-administered.

Carbapenem antibiotics

A clinically significant reduction in serum valproic acid concentration has been reported in patients

receiving carbapenem antibiotics (ertapenem, imipenem, meropenem) and may result in loss of seizure

control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations

should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or

anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or

seizure control deteriorates [see Warnings and Precautions (5.11)].

Felbamate

A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with

epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115

mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean

valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage

may be necessary when felbamate therapy is initiated.

Rifampin

A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of

daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate.

Valproate dosage adjustment may be necessary when it is coadministered with rifampin.

Drugs for which either no interaction or a likely clinically unimportant interaction has been observed

Antacids

A study involving the co-administration of valproate 500 mg with commonly administered antacids

(Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption

of valproate.

Chlorpromazine

A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients

already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of

valproate.

Haloperidol

A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already

receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.

Cimetidine and Ranitidine

Cimetidine and ranitidine do not affect the clearance of valproate.

7.2 Effects of Valproate on Other Drugs

Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and

glucuronosyltransferases.

The following list provides information about the potential for an influence of valproate co-

administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed

medications. The list is not exhaustive, since new interactions are continuously being reported.

Drugs for which a potentially important valproate interaction has been observed

Amitriptyline/Nortriptyline

Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5

females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of

amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of

concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been

received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity.

Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with

amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the

presence of valproate.

Carbamazepine/carbamazepine-10,11-Epoxide

Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide

(CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.

Clonazepam

The concomitant use of valproic acid and clonazepam may induce absence status in patients with a

history of absence type seizures.

Diazepam

Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-

administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in

healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced

by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam

remained unchanged upon addition of valproate.

Ethosuximide

Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of

500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by a 25%

increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared

to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other

anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.

Lamotrigine

In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased

from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine

should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-

Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and

valproate administration. See lamotrigine package insert for details on lamotrigine dosing with

concomitant valproate administration.

Phenobarbital

Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg

BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and

a 30% decrease in plasma clearance of Phenobarbital (60 mg single-dose). The fraction of

phenobarbital dose excreted unchanged increased by 50% in presence of valproate.

There is evidence for severe CNS depression, with or without significant elevations of barbiturate or

valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be

closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if

possible, and the barbiturate dosage decreased, if appropriate.

Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.

Phenytoin

Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism.

Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was

associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent

volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and

apparent volume of distribution of free phenytoin were reduced by 25%.

In patients with epilepsy, there have been reports of breakthrough seizures occurring with the

combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the

clinical situation.

Tolbutamide

From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when

added to plasma samples taken from patients treated with valproate. The clinical relevance of this

displacement is unknown.

Warfarin

In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic

relevance of this is unknown; however, coagulation tests should be monitored if valproic acid therapy

is instituted in patients taking anticoagulants.

Zidovudine

In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was

decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine

was unaffected.

Drugs for which either no interaction or a likely clinically unimportant interaction has been observed

Acetaminophen

Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was

concurrently administered to three epileptic patients.

Clozapine

In psychotic patients (n=11), no interaction was observed when valproate was co-administered with

clozapine.

Lithium

Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male

volunteers (n=16) had no effect on the steady-state kinetics of lithium.

Lorazepam

Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male

volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.

Oral Contraceptive Steroids

Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on

valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.

7.3 Topiramate

Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia

with and without encephalopathy [see Contraindications and Warnings and Precautions (4, 5.7, 5.8)].

Concomitant administration of topiramate with valproic acid has also been associated with

hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood

ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings

and Precautions (5.6, 5.8)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category D.

Use of divalproex sodium extended-release tablets during pregnancy can cause congenital

malformations including neural tube defects. If this drug is used during pregnancy, or if the patient

becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the

fetus. Divalproex sodium extended-release tablets should be considered for women of childbearing

potential only after the risks have been thoroughly discussed with the patient and weighed against the

potential benefits of treatment.

Human Data

Congenital Malformations

The North American Antiepileptic Drug Pregnancy Registry reported 16 cases of congenital

malformations among the offspring of 149 women with epilepsy who were exposed to valproic acid

monotherapy during the first trimester of pregnancy at doses of approximately 1,000 mg per day, for a

prevalence rate of 10.7% (95% CI 6.3%-16.9%). Three of the 149 offspring (2%) had neural tube

defects and 6 of the 149 (4%) had less severe malformations. Among epileptic women who were

exposed to other antiepileptic drug monotherapies during pregnancy (1,048 patients) the malformation

rate was 2.9% (95% CI 2.0% to 4.1%). There was a 4-fold increase in congenital malformations among

infants with valproic acid-exposed mothers compared with those treated with other antiepileptic

monotherapies as a group (Odds Ratio 4.0; 95% CI 2.1 to 7.4). This increased risk does not reflect a

comparison versus any specific antiepileptic drug, but the risk versus the heterogeneous group of all

other antiepileptic drug monotherapies combined. The increased teratogenic risk from valproic acid in

women with epilepsy is expected to be reflected in an increased risk in other indications (e.g., migraine

or bipolar disorder).

The strongest association of maternal valproate usage with congenital malformations is with neural tube

defects (as discussed under the next subheading). However, other congenital anomalies (e.g.

craniofacial defects, cardiovascular malformations and anomalies involving various body systems),

compatible and incompatible with life, have been reported. Sufficient data to determine the incidence of

these congenital anomalies are not available.

Neural Tube Defects

The incidence of neural tube defects in the fetus is increased in mothers receiving valproate during the

first trimester of pregnancy. The Centers for Disease Control (CDC) has estimated the risk of valproic

acid exposed women having children with spina bifida to be approximately 1 to 2%. The American

College of Obstetricians and Gynecologists (ACOG) estimates the general population risk for

congenital neural tube defects as 0.14% to 0.2%.

Tests to detect neural tube and other defects using currently accepted procedures should be considered

a part of routine prenatal care in pregnant women receiving valproate.

Evidence suggests that pregnant women who receive folic acid supplementation may be at decreased

risk for congenital neural tube defects in their offspring compared to pregnant women not receiving

folic acid. Whether the risk of neural tube defects in the offspring of women receiving valproate

specifically is reduced by folic acid supplementation is unknown. Dietary folic acid supplementation

both prior to and during pregnancy should be routinely recommended to patients contemplating

pregnancy.

Other Adverse Pregnancy Effects

Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.6)]. A

patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an

infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy,

the clotting parameters should be monitored carefully.

Patients taking valproate may develop hepatic failure [see Warnings and Precautions (5.1)]. Fatal hepatic

failures, in a newborn and in an infant, have been reported following the maternal use of valproate

during pregnancy.

Animal Data

Reproduction studies have demonstrated valproate-induced teratogenicity. Increased incidences of

malformations, as well as intrauterine growth retardation and death, have been observed in mice, rats,

rabbits, and monkeys following prenatal exposure to valproate. Malformations of the skeletal system are

the most common structural abnormalities produced in experimental animals; however, neural tube

closure defects were observed in mice exposed during organogenesis to maternal plasma valproate

concentrations 2.3 times the upper limit of the human therapeutic range.

In pregnant rats, oral administration during organogenesis of a dose ≥0.5 times the maximum

recommended daily human dose on a mg/m basis (MRHD) produced malformations (e.g. skeletal,

cardiac, and urogenital) and growth retardation in the offspring. These doses resulted in peak maternal

plasma valproate levels of ≥3.4 times the upper limit of the human therapeutic range. Behavioral

deficits have been reported in the offspring of rats given 0.5 times the MRHD on a mg/m basis

throughout most of pregnancy.

Valproate produced skeletal and visceral malformations in the offspring of pregnant rabbits given an

oral dose approximately 2 times the MRHD on a mg/m basis during organogenesis. Skeletal

malformations, growth retardation, and death were observed in rhesus monkeys following an oral dose

equal to the MRHD on a mg/m basis during organogenesis. This dose resulted in peak maternal plasma

valproate levels 2.8 times the upper limit of the human therapeutic range.

Registry

To provide information regarding the effects of in utero exposure to divalproex sodium extended-

release tablets, healthcare providers are advised to recommend that pregnant patients taking divalproex

sodium extended-release tablets enroll in the North American Antiepileptic Drug (NAAED) Pregnancy

Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by

patients themselves. Information on the registry can also be found the website

http://www.aedpregnancyregistry.org/.

8.3 Nursing Mothers

Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1-10% of

serum concentrations. Because of the potential for adverse reactions in a nursing infant, a decision

between the physician and the patient should be made on whether to discontinue nursing or consider an

alternative drug treatment for the mother, as appropriate.

8.4 Pediatric Use

Divalproex sodium delayed-release tablets were studied in seven pediatric clinical trials. Two of the

pediatric studies were placebo-controlled to evaluate the efficacy divalproex sodium delayed-release

tablets for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on divalproex

sodium extended-release tablets) and of migraine (304 patients aged 12 to 17 years, 231 of whom were

on divalproex sodium extended-release tablets).

Mania

A single 4-week outpatient, double-blind, placebo controlled study of 150 patients aged 10 – 17 years

of age with pediatric bipolar disorder was conducted to evaluate the efficacy of divalproex sodium

extended-release tablets in the treatment of pediatric bipolar disorder. Initial daily doses of 15mg/kg

(max. 750mg/day) and flexible dosing was used to achieve a clinical response and/or a target serum

valproate level of 80 – 125 mcg/ml with a maximum allowable dose set at 35mg/kg. Patients on stimulant

medications at screening were allowed to continue and maintain current stimulant doses during the trial

provided that doses were clinically stable. The trial efficacy endpoint was change from baseline on the

YMRS scale at final visit.

Results from the trial revealed that the mean maximum daily dose of 1457 mg (27.1 mg/kg) with a mean

final serum valproate concentration of 80mcg/ml was attained in this clinical trial.

Efficacy was not established in this study.

Migraine Prophylaxis

A single, double-blind, placebo-controlled, parallel-group, four equal armed (placebo, 250 mg, 500 mg

and 1,000 mg) trial was performed to evaluate the efficacy of divalproex sodium extended-release

tablets in adolescent patients with migraine (304 patients, ages 12-17 years old). The study consisted of

a 4 week baseline period followed by a 12 week experimental period (including an initial 2 week

titration phase).

The primary endpoint was the reduction from baseline in the 4 week migraine headache rate. Placebo

was compared to each dose.

Efficacy was not established in this migraine study.

Epilepsy

Divalproex sodium extended-release tablets have not been proven to be safe and effective for epilepsy

in children less than 10 years of age.

Pediatric Safety

Two six-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium

extended-release tablets in the indication of mania (292 patients aged 10 to 17 years).

Two twelve-month pediatric studies were conducted to evaluate the long-term safety of divalproex

sodium extended-release tablets in the indication of migraine (353 patients aged 12 to 17 years). One

twelve-month study was conducted to evaluate the safety of divalproex sodium delayed-release

sprinkles capsules in the indication of partial seizures (169 patients aged 3 to 10 years).

Safety Studies-Mania

Safety Study-Controlled Mania Trial

The incidence of treatment-emergent events for the pediatric population was based on the data from the

single placebo-controlled clinical trial of divalproex sodium extended-release tablets in the treatment

of manic or mixed episodes associated with bipolar disorder.

Table 8 includes those adverse reactions reported for pediatric patients in the placebo-controlled mania

trial where the incidence rate in the valproate-treated group was >5% and was at least twice the rate than

that for placebo patients.

Table 8:Common, Drug-Related Adverse Reactions reported by >5% of

Divalproex Sodium Extended-Release Tablets Treated Patients during

Placebo Controlled Trials for Pediatric Acute Mania

Adverse Reaction-preferred

term

Divalproex Sodium

Extended-Releas e

Tablets

(N=76)

Placebo

(N=74)

Nausea

Upper abdominal Pain

Somnolence

Increased Ammonia

Gastritis

Rash

In addition, patients taking Divalproex Sodium Extended-Release Tablets had a statistically significant

1.5 lbs mean increase in weight and 0.4 unit BMI mean increase from baseline values over placebo

treated patients.

Safety Study-Open Label Mania Safety Data

In the two long-term (six month) safety studies in pediatric patients (n=292) between the ages of 10 and

17 years old, no clinically meaningful differences in the adverse reaction profile were observed when

compared to adults.

The safety and tolerability of Divalproex Sodium Extended-Release Tablets in pediatric patients were

shown to be comparable to those in adults [see Adverse Reactions (6.1, 6.2, 6.3)]

Safety Study-Epilepsy (open label)

Safety and tolerability in this study was found comparable to that observed in adult epilepsy studies.

Safety Studies-Migraine (controlled and open label)

Safety and tolerability in this study was found comparable to that observed in adult migraine studies.

Prior Safety Experience

Experience has indicated that pediatric patients under the age of two years are at a considerably

increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions

[see Boxed Warning, Warning and Precautions (5.1)]. When valproic acid is used in this patient group, it

should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed

against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of

fatal hepatotoxicity decreases considerably in progressively older patient groups.The variability in

free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations.

Interpretation of valproic acid concentrations in children should include consideration of factors that

affect hepatic metabolism and protein binding.

The safety and effectiveness of valproic acid for the treatment of acute mania has not been established

in individuals below the age of 18 years.

The safety and effectiveness of valproic acid for the prophylaxis of migraines has not been studied in

individuals below the age of 12 years.

Nonclinical Developmental Toxicology

The basic toxicology and pathologic manifestations of valproate sodium in neonatal (4-day old) and

juvenile (14-day old) rats are similar to those seen in young adult rats. However, additional findings,

including renal alterations in juvenile rats and renal alterations and retinal dysplasia in neonatal rats, have

been reported. These findings occurred at a dose approximately equal to the maximum recommended

daily human dose (MRHD). They were not seen at a dose 0.4 times the MRHD.

8.5 Geriatric Use

No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania

associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater

than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury,

infection, pain, somnolence, and tremor.

Discontinuation of valproate was occasionally associated with the latter two events. It is not clear

whether these events indicate additional risk or whether they result from preexisting medical illness and

concomitant medication use among these patients.

A study of elderly patients with dementia revealed drug related somnolence and discontinuation for

somnolence [see Warnings and Precautions (5.12)]. The starting dose should be reduced in these

patients, and dosage reductions or discontinuation should be considered in patients with excessive

somnolence [see Dosage and Administration (2.3)].

There is insufficient information available to discern the safety and effectiveness of valproic acid for

the prophylaxis of migraines in patients over 65.

The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be

reduced compared to younger adults (age range: 22 to 26) [see Clinical Pharmacology (12.3)].

8.6 Effect of Disease

Liver Disease

(see Boxed Warning, Contraindications(4), and Warnings And Precautions (5) and Clinical Pharmacology

(12.3)]. Liver disease impairs the capacity to eliminate valproate.

10 OVER DOSAGE

Over dosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been

reported; however patients have recovered from valproate levels as high as 2120 mcg/mL.

In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem

hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric

lavage or emesis will vary with the time since ingestion. General supportive measures should be

applied with particular attention to the maintenance of adequate urinary output.

Naloxone has been reported to reverse the CNS depressant effects of valproate over dosage. Because

naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with

caution in patients with epilepsy.

11 DESCRIPTION

Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic

acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5

equivalent of sodium hydroxide.

Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the

following structure:

Divalproex sodium occurs as a white powder with a characteristic odor.

Divalproex sodium extended-release tablets 250 and 500 mg are for oral administration. Divalproex

sodium extended-release tablets contain divalproex sodium in a once-a-day extended-release

formulation equivalent to 250 and 500 mg of valproic acid.

Inactive Ingredients

Divalproex sodium extended-release tablets 250 and 500 mg: ethylcellulose, hydroxyethyl cellulose,

hypromellose, magnesium stearate, polyethylene glycol, povidone, silicon dioxide, talc, titanium

dioxide, and iron oxide black.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by

which valproate exerts its therapeutic effects have not been established. It has been suggested that its

activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

12.2 Pharmacodynamics

The relationship between plasma concentration and clinical response is not well documented.

Onecontributing factor is the nonlinear, concentration dependent protein binding of valproate which

affects the clearance of the drug. Thus, monitoring of total serum valproate may not provide a reliable

index of the bioactive valproate species as protein binding may be affected by age and disease state

(e.g. hepatic or renal insufficiency, hyperlipidemia)

Epilepsy

The therapeutic range in epilepsy is commonly considered to be 85 to 100 mcg/mL of total valproate,

although some patients may be controlled with lower or higher plasma concentrations.

Mania

In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough

plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration (2.1)].

12.3 Pharmacokinetics

Absorption/Bioavailability

The absolute bioavailability of divalproex sodium extended-release tablets administered as a single

dose after a meal was approximately 90% relative to intravenous infusion.

When given in equal total daily doses, the bioavailability of divalproex sodium extended-release tablets

is less than that of divalproex sodium delayed-release tablets. In five multiple-dose studies in healthy

subjects (N=82) and in subjects with epilepsy (N=86), when administered under fasting and nonfasting

conditions, divalproex sodium extended-release tablets given once daily produced an average

bioavailability of 89% relative to an equal total daily dose of divalproex sodium delayed-release

tablets given BID, TID, or QID. The median time to maximum plasma valproate concentrations (C

after divalproex sodium extended-release tablets administration ranged from 4 to 17 hours. After

multiple once-daily dosing of divalproex sodium extended-release tablets, the peak-to-trough

fluctuation in plasma valproate concentrations was 10-20% lower than that of regular divalproex sodium

delayed-release tablets given BID, TID, or QID.

Conversion from Divalproex Sodium Delayed-Release Tablets to Divalproex Sodium Extended-

Release Tablets

When divalproex sodium extended-release tablets are given in doses 8 to 20% higher than the total

daily dose of divalproex sodium delayed-release tablets, the two formulations are bioequivalent. In two

randomized, crossover studies, multiple daily doses of divalproex sodium delayed-release tablets were

compared to 8 to 20% higher oncedaily doses of divalproex sodium extended-release tablets. In these

two studies, divalproex sodium extended-release tablets and divalproex sodium delayed-release tablets

regimens were equivalent with respect to area under the curve (AUC; a measure of the extent of

bioavailability). Additionally, valproate C

was lower, and C

was either higher or not different,

for divalproex sodium extended-release tablets relative to divalproex sodium delayed-release tablets

regimens (see Table 9).

Table 9. Bioavailability of Divalproex Sodium Extended-Release Tablets Relative to Divalproex

Sodium Delayed-Release Tablets When Divalproex Sodium Extended-Release Tablets Dose is 8

to 20% Higher

Study Population

Regimens

Relative Bioavailability

Divalproex Sodium Extended-Release Tablets

vs. Divalproex Sodium Delayed-Release Tablets

AUC

C

C

Healthy Volunteers

(N=35)

1000 & 1500 mg divalproex sodium extended-

release tablets vs. 875 & 1250 mg divalproex

sodium delayed-release tablets

1.059

0.882

1.173

Patients with

epilepsy on

concomitant

enzyme-inducing

antiepilepsy drugs

(N=64)

1000 to 5000 mg divalproex sodium extended-

release tablets vs. 875 to 4250 mg divalproex

sodium delayed-release tablets

1.008

0.899

1.022

24

max

min

Concomitant antiepilepsy drugs (topiramate, phenobarbital, carbamazepine, phenytoin, and lamotrigine

were evaluated) that induce the cytochrome P450 isozyme system did not significantly alter valproate

bioavailability when converting between divalproex sodium delayed-release tablets and divalproex

sodium extended-release tablets.

Distribution

Protein Binding

The plasma protein binding of valproate is concentration dependent and the free fraction increases from

approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in

the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the

presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs

(e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [See Drug Interactions (7)] for more detailed

information on the pharmacokinetic interactions of valproate with other drugs].

CNS Distribution

Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma

(about 10% of total concentration).

Metabolism

Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an

administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other

major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of

the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted

unchanged in urine.

The relationship between dose and total valproate concentration is nonlinear; concentration does not

increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma

protein binding. The kinetics of unbound drug are linear.

Elimination

Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m and 11

L/1.73 m , respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6

L/hr/1.73 m and 92 L/1.73 m . Mean terminal half-life for valproate monotherapy ranged from 9 to 16

hours following oral dosing regimens of 250 to 1000 mg.

The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing

enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine,

phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate

clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant

antiepileptics are introduced or withdrawn.

Special Populations

Effect of Age

Pediatric

The valproate pharmacokinetic profile following administration of divalproex sodium extended-release

tablets was characterized in a multiple-dose, nonfasting, open label, multi-center study in children and

adolescents. Divalproex sodium extended-release tablets once daily doses ranged from 250-1750 mg.

Once daily administration of divalproex sodium extended-release tablets in pediatric patients (10-17

years) produced plasma VPA concentration-time profiles similar to those that have been observed in

adults.

Elderly

The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be

reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the

free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see

Dosage and Administration (2.3)].

Effect of Sex

There are no differences in the body surface area adjusted unbound clearance between males and

females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m , respectively).

Effect of Race

The effects of race on the kinetics of valproate have not been studied.

Effect of Disease

Liver Disease

Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate

was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,

compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18

hours. Liver disease is also associated with decreased albumin concentrations and larger unbound

fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be

misleading since free concentrations may be substantially elevated in patients with hepatic disease

whereas total concentrations may appear to be normal [See Boxed Warning, Contraindications (4),

Warnings and Precautions (5.1)].

Renal Disease

A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal

failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate

concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with

renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total

concentrations may be misleading.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Valproic acid was administered orally to Sprague Dawley rats and ICR (HA/ICR) mice at doses of 80

and 170 mg/kg/day (approximately 10 to 50% of the maximum human daily dose on a mg/m basis) for

two years. A variety of neoplasms were observed in both species. The primary findings were a

statistically significant increase in the incidence of subcutaneous fibrosarcomas in high dose male rats

receiving valproic acid and a statistically significant dose-related trend for benign pulmonary adenomas

in male mice receiving valproic acid. The significance of these findings for humans is unknown.

Mutagenesis

Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal

effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in

rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of

epileptic children taking valproate, but this association was not observed in another study conducted in

adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The

biological significance of an increase in SCE frequency is not known.

Fertility

Chronic toxicity studies in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and

testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or

greater than the maximum human daily dose (MHD) on a mg/m basis) and 150 mg/kg/day or greater in

dogs (approximately 1.4 times the MHD or greater on a mg/m basis). Fertility studies in rats have

shown doses up to 350 mg/kg/day (approximately equal to the MHD on a mg/m basis) for 60 days to

have no effect on fertility. The effect of valproate on testicular development and on sperm production

and fertility in humans is unknown.

14 CLINICAL STUDIES

14.1 Mania

The effectiveness of divalproex sodium extended-release tablets for the treatment of acute mania is

based in part on studies establishing the effectiveness of divalproex sodium delayed release tablets for

this indication. Divalproex sodium extended-release tablet'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 divalproex sodium extended-release tablets 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. Divalproex sodium extended-release tablets

were 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. Mean daily

divalproex sodium extended-release tablet doses for observed cases were 2362 mg (range: 500-4000),

2874 mg (range: 1500-4500), 2993 mg (range: 1500-4500), 3181 mg (range: 1500-5000), and 3353 mg

(range: 1500-5500) at Days 1, 5, 10, 15, and 21, respectively. Mean valproate concentrations were 96.5

mcg/mL, 102.1 mcg/mL, 98.5 mcg/mL, 89.5 mcg/mL at Days 5, 10, 15 and 21, respectively. Patients

were assessed on the Mania Rating Scale (MRS; score ranges from 0-52).

Divalproex sodium extended-release tablets were significantly more effective than placebo in reduction

of the MRS total score.

14.2 Epilepsy

The efficacy of valproate in 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, multiclinic, 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 divalproex sodium delayed-release tablets or placebo. Randomized

patients were to be followed for a total of 16 weeks. The following Table presents the findings.

Table 10: Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks

Add-on Treatment

Number of Patients

Baseline Incidence

Experimental Incidence

Divalproex Sodium

Delayed-Release Tablets

16.0

Placebo

14.5

11.5

Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in

complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy

study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency),

while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an

effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion

of patients achieving any particular level of improvement was consistently higher for valproate than for

Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level.

placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial

seizure rate compared to 23% of patients treated with placebo.

Figure 1

The 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. Less than 50% of the patients

randomized, however, completed the study. In patients converted to divalproex sodium delayed-release

tablets monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123

mcg/mL in the low dose and high dose groups, respectively.

The following Table presents the findings for all patients randomized who had at least one post-

randomization assessment.

Table 11: Monotherapy Study Median Incidence of CPS per 8 Weeks

Treatment

Number of Patients

Baseline Incidence

Randomized Phase

Incidence

High dose Valproate

13.2

10.7

Low dose Valproate

14.2

13.8

Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in

complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy

study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency),

while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a

more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure

shows that the proportion of patients achieving any particular level of reduction was consistently higher

for high dose valproate than for low dose valproate. For example, when switching from carbamazepine,

phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of

patients experienced no change or a reduction in complex partial seizure rates compared to 54% of

Reduction from baseline statistically significantly greater for high dose than low dose at p ≤0.05 level.

patients receiving low dose valproate.

Figure 2

Information on pediatric studies are presented in section 8.

14.3 Migraine

The results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial

demonstrated the effectiveness of divalproex sodium extended-release tablets 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. Women of childbearing potential were allowed

in the trial if they were deemed to be practicing an effective method of contraception.

Patients who experienced ≥ 2 migraine headaches in the 4-week baseline period were randomized in a

1:1 ratio to divalproex sodium extended-release tablets or placebo and treated for 12 weeks. Patients

initiated treatment on 500 mg once daily for one week, and were then increased to 1000 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 divalproex sodium extended-release tablet-

treated patients (86%) and 100 of 110 placebo-treated patients (91%) treated at least two weeks

maintained the 1000 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.

Patients (50 male, 187 female) ranging in age from 16 to 69 were treated with divalproex sodium

extended-release tablets (N=122) or placebo (N=115). Four patients were below the age of 18 and 3

were above the age of 65. Two hundred and two patients (101 in each treatment group) completed the

treatment period. The mean reduction in 4-week migraine headache rate was 1.2 from a baseline mean of

4.4 in the divalproex sodium extended-release tablets group, versus 0.6 from a baseline mean of 4.2 in

the placebo group. The treatment difference was statistically significant (see Figure 3).

Figure 3. Mean Reduction In 4-Week Migraine Headache Rates

16 HOW SUPPLIED/STORAGE AND HANDLING

Divalproex sodium extended-release tablets 500 mg are white, oval, biconvex, film coated tablets

printed "A511" in black ink on one side and plain on the other side. Each divalproex sodium extended-

release tablet contains divalproex sodium equivalent to 500 mg of valproic acid in the following

packaging sizes:

Bottles of 10

NDC 54868-6088-0

Bottles of 30

NDC 54868-6088-2

Bottles of 60

NDC 54868-6088-1

Recommended Storage

Store tablets at 20- 25°C (68- 77°F) [see USP Controlled Room Temperature].

Manufactured by

Anchen Pharmaceuticals (Taiwan), Inc.

Zhongli City, Taoyuan County 320, Taiwan

Manufactured for

Anchen Pharmaceuticals, Inc.

Irvine, CA 92618

Revised: 07/09

Relabeling and Repackaging by:

Physicians Total Care, Inc.

Tulsa, OK 74146

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (17.8)

17.1 Hepatotoxicity

Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea,

asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical

evaluation promptly.

17.2 Pancreatitis

Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be

symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and

Precautions (5.3)].

17.3 Teratogenicity/Usage in Pregnancy

Use of valproate during pregnancy increases the risk for neural tube defects and other malformations.

Female patients of childbearing age, who require therapy for epilepsy, bipolar disorder, or migraines,

should be advised of the risks of valproate use during pregnancy and appropriate therapeutic options.

This is particularly important when the treatment of a spontaneously reversible condition not ordinarily

associated with permanent injury or risk of death (e.g. migraine) is considered. Patients should read the

Patient Information Leaflet, which appears as the last section of the labeling [see Use in Specific

Populations (8.1)].

Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant.

This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To

enroll, patients can call the toll free number 1-888-233-2334 [see Use in specific Populations (8.1)].

17.4 Suicidal Thinking and Behavior

Patients, their caregivers, and families should be counseled that AEDs, including divalproex sodium

extended-release tablets, may increase the risk of suicidal thoughts and behavior and should be advised

of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes

in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to the healthcare providers [see Warnings and

Precautions (5.5)].

17.5 Hyperammonemia

Patients should be informed of the signs and symptoms associated with hyperammonemic

encephalopathy and be told to inform the prescriber if any of these symptoms occur [see Warnings and

Precautions (5.7, 5.8)].

17.6 CNS depression

Since valproate products may produce CNS depression, especially when combined with another CNS

depressant (eg, alcohol), patients should be advised not to engage in hazardous activities, such as

driving an automobile or operating dangerous machinery, until it is known that they do not become

drowsy from the drug.

17.7 Multi-organ Hypersensitivity Reaction

Patients should be instructed that a fever associated with other organ system involvement (rash,

lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see

Warnings and Precautions (5.10)].

17.8 FDA–Approved Patient Labeling

Important Information for Women Who Could Become Pregnant About the Use of Divalproex

Sodium Extended-Release Tablets.

Please read this leaflet carefully before you take any of this medication. This leaflet provides a

summary of important information about taking this medication to women who could become pregnant. If

you have any questions or concerns, or want more information about this medication, contact your

doctor or pharmacist.

Information For Women Who Could Become Pregnant

You can only obtain this medication by prescription from your doctor. The decision to use this medicine

should be made by you and your doctor based on your health needs and medical condition.

Before starting this medicine, you should know that using this medicine during pregnancy causes an

increased chance of birth defects in your baby. These birth defects may include spina bifida and other

defects where the spinal canal does not close normally. These defects usually occur in 1 to 2 out of

every 1000 babies born in the United States. Studies show that for babies born to epileptic women who

took valproate in the first 12 weeks of pregnancy, these defects occur in 1 to 2 out of every 100 babies.

Use of valproate during pregnancy also increases the chance of other birth defects such as of the heart,

bones, and other parts of the body. Studies suggest that other medicines used to treat your condition may

be less likely to cause these defects.

Information For Women Who Are Planning to Get Pregnant

Women using valproate who plan to get pregnant should discuss their treatment options with their

doctor.

Information For Women Who Become Pregnant

If you become pregnant while taking valproate, you should contact your doctor immediately.

Other Important Information

You should take your medicine exactly as prescribed by your doctor to get the most benefit from

your medicine and reduce the risk of side effects.

If you have taken more than the prescribed dose, contact your hospital emergency room or local

poison center immediately.

Your medicine was prescribed for your particular condition. Do not use it for another condition or

give the drug to others.

Facts About Birth Defects

It is important to know that birth defects may occur even in children born to women who are not taking

any medicines and do not have other risk factors.

This summary provides important information about the use of divalproex sodium extended-release

tablets to women who could become pregnant. If you would like more information, ask your doctor or

pharmacist to let you read the professional labeling and then discuss it with them. If you have any

questions or concerns about taking this medication, you should discuss them with your doctor. To

report SUSPECTED ADVERSE REACTIONS, contact Anchen Pharmaceuticals, Inc. at 1-888-

493-0857 or 1-800-FDA-1088 or www.fda.gov/medwatch.

Divalproex Sodium Extended-Release Tablets 250 mg and 500 mg

Manufactured by

Anchen Pharmaceuticals (Taiwan), Inc.

Zhongli City, Taoyuan County 320, Taiwan

Manufactured for

Anchen Pharmaceuticals, Inc.

Irvine, CA 92618

Revised: 07/09

PRINCIPAL DISPLAY PANEL - 500 mg Tablet Bottle

Divalproex Sodium

Extended-Releas e

Tablets

500 mg

Valproic Acid Activity

Rx only

DIVALPROEX SODIUM

divalproex sodium tablet, film coated, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:548 6 8 -6 0 8 8 (NDC:249 79 -511)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

DIVALPRO EX SO DIUM (UNII: 6 44VL9 5AO6 ) (VALPROIC ACID - UNII:6 14OI1Z5WI)

DIVALPROEX SODIUM

50 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ETHYLCELLULO SES (UNII: 7Z8 S9 VYZ4B)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

PO VIDO NE (UNII: FZ9 8 9 GH9 4E)

PO LYETHYLENE GLYCO L (UNII: 3WJQ0 SDW1A)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

Physicians Total Care, Inc.

Product Characteristics

Color

white

S core

no sco re

S hap e

OVAL

S iz e

19 mm

Flavor

Imprint Code

A511

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:548 6 8 -6 0 8 8 -0

10 in 1 BOTTLE

2

NDC:548 6 8 -6 0 8 8 -1

6 0 in 1 BOTTLE

3

NDC:548 6 8 -6 0 8 8 -2

30 in 1 BOTTLE, PLASTIC

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 445

11/20 /20 0 9

Labeler -

Physicians T otal Care, Inc. (194123980)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Physicians To tal Care, Inc.

19 41239 8 0

relabel, repack

Revised: 7/2009

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