DIVALPROEX SODIUM capsule

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Active ingredient:
DIVALPROEX SODIUM (UNII: 644VL95AO6) (VALPROIC ACID - UNII:614OI1Z5WI)
Available from:
McKesson Contract Packaging
INN (International Name):
DIVALPROEX SODIUM
Composition:
VALPROIC ACID 125 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
Abbreviated New Drug Application

DIVALPROEX SODIUM- divalproex sodium capsule

McKesson Contract Packaging

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Divalproex Sodium capsules (sprinkle)

(divalproex sodium USP equivalent to 125 mg of valproic acid) safely and effectively.

See full prescribing information for Divalproex Sodium apsules (sprinkle) (divalproex sodium USP equivalent

to 125 mg of valproic acid).

Initial U.S. Approval: 1989

Divalproex Sodium Capsules (Sprinkle) (divalproex sodium USP equivalent to 125 mg of valproic acid)

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 (5.8, 5.10, 5.12, 5.13, 5.14) 3/2008

Pediatric Use 8.4 3/2008

INDICATIONS AND USAGE

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)

DOSAGE AND ADMINISTRATION

Divalproex sodium capsules (sprinkle) may be swallowed whole or the contents may be sprinkled on soft food. The

drug/food mixture should be swallowed immediately (avoid chewing)

Safety of doses above 60 mg/kg/day is not established (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 (2.1)

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 (2.1)

DOSAGE FORMS AND STRENGTHS

Capsules: 125 mg (3) (4)

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 capsules (sprinkle) benefits against risk to the fetus (5.2)

Pancreatitis; Divalproex sodium capsules (sprinkle) should ordinarily be discontinued (5.3)

Suicidal behavior or ideation; Antiepileptic drugs, including divalproex sodium capsules (sprinkle) 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 (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 capsules (sprinkle) (5.10)

Somnolence in the elderly can occur. Divalproex sodium capsules (sprinkle) dosage should be increased slowly and

with regular monitoring for fluid and nutritional intake (5.12)

ADVERSE REACTIONS

Most common adverse reactions (reported >5%) are thrombocytopenia, nausea, somnolence, dizziness, vomiting,

asthenia, abdominal pain, dyspepsia, diarrhea, increased appetite, tremor, weight gain, weight loss, alopecia, headache,

fever, anorexia, constipation, diplopia, amblyopia/blurred vision, ataxia, nystagmus, emotional lability, thinking abnormal,

amnesia, flu syndrome, infection, bronchitis, rhinitis, ecchymosis, peripheral edema, insomnia, nervousness, depression,

pharyngitis, dyspnea, tinnitus (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact {enter text here} or FDA at 1-800-FDA-1088 or

www.fda.g o v/medwatch

DRUG INTERACTIONS

Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, 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 dosage adjustment are indicated whenever enzyme-

inducing or inhibiting drugs are introduced or withdrawn (7.1)

Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is 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 coated particles in capsules (7.2)

Topiramate: Hyperammonemia and encephalopathy (5.8, 7.3)

USE IN SPECIFIC POPULATIONS

Pregnancy: Divalproex sodium capsules (sprinkle) 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: 12/2011

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Epilepsy

2 DOSAGE AND ADMINISTRATION

2.1 Epilepsy

2.2 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 (UCD)

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 Effects on Ketone and Thyroid function Tests

5.15 Effects on HIV and CMV Viruses Replication

5.15 Effects on HIV and CMV Viruses Replication

6 ADVERSE REACTIONS

6.1 Epilepsy

6.2 Other Patient Population

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

8.1 Pregnancy

10 OVERDOSAGE

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 Epilepsy

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

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

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 capsules

(sprinkle) are used in this patient group, they 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 capsules (sprinkle) 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 (17.7)].

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 [seeWarnings and Precautions (5.3)].

1 INDICATIONS AND USAGE

1.1 Epilepsy

Divalproex sodium capsules (sprinkle) 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

capsules (sprinkle) are also indicated for use as sole and adjunctive therapy in the treatment of simple

and complex absence seizures, and adjunctively in patients with multiple seizure types that include

absence seizures.

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. [seeWarnings and Precautions

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

2 DOSAGE AND ADMINISTRATION

2.1 Epilepsy

Divalproex sodium capsules (sprinkle) are administered orally. As divalproex sodium 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 has not been systematically studied as initial therapy. Patients should initiate therapy

at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal

clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.

If satisfactory clinical response has not been achieved, plasma levels should be measured to determine

whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No

recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma

concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure

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

reactions.

Conversion to Monotherapy

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10

mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at

daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels

should be measured to determine whether or not they are in the usually accepted therapeutic range (50 -

100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60

mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by

approximately 25% every 2 weeks. This reduction may be started at initiation of divalproex sodium

therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a

reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and

patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

Divalproex sodium may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage

may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal

clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has

not been achieved, plasma levels should be measured to determine whether or not they are in the usually

accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate

for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be

given in divided doses.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either

carbamazepine or phenytoin in addition to divalproex sodium, no adjustment of carbamazepine or

phenytoin dosage was needed [see Clinical studies (14)]. 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. If the total daily dose exceeds 250 mg, it should be given in divided doses.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic

effect. However, therapeutic valproate serum concentrations for most patients with absence seizures

are considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher

serum concentrations [see Clinical Pharmacology (12.2)].

As divalproex sodium dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin

may be affected [see Drug Interaction (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.

In epileptic patients previously receiving valproic acid therapy, divalproex sodium capsules (sprinkle)

should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on

divalproex sodium capsules (sprinkle), a dosing schedule of two or three times a day may be elected in

selected patients.

2.2 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. 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), Use In Specific Populations (8.5) and Clinical Pharmacology (12.3)].

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) [seeWarnings 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.

Administration of divalproex sodium capsules (sprinkle)

Divalproex sodium capsules (sprinkle) may be swallowed whole or may be administered by carefully

opening the capsule and sprinkling the entire contents on a small amount (teaspoonful) of soft food such

as applesauce or pudding. The drug/food mixture should be swallowed immediately (avoid chewing)

and not stored for future use. Each capsule is oversized to allow ease of opening.

3 DOSAGE FORMS AND STRENGTHS

Divalproex sodium capsules (sprinkle) are for oral administration. Divalproex sodium capsules

(sprinkle) contain specially coated particles of divalproex sodium equivalent to 125 mg of valproic acid

in a hard gelatin capsule.

4 CONTRAINDICATIONS

Divalproex sodium capsules (sprinkle) should not be administered to patients with hepatic disease or

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

Divalproex sodium capsules (sprinkle) are contraindicated in patients with known hypersensitivity to

the drug [see Warnings and Precautions (5.10)].

Divalproex sodium capsules (sprinkle) 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 divalproex sodium 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 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 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 andContraindications (4)].

5.2 Teratogenicity/Usage in Pregnancy

Use of divalproex sodium 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 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.

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 should ordinarily bediscontinued. Alternative treatment for the

underlying medical condition should be initiated as clinically indicated [see Boxed Warning].

5.4 Urea Cycle Disorders (UCD)

Divalproex sodium is 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 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 increase the risk of suicidal thoughts or

behavior in patients taking these drugs for any indication. Patients treated with any AED for any

indications should be monitored for the emergence or worsening of depression, suicidal thoughts for

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% CI: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 on suicide.

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

after starting drug treatments with AEDs and persisted for the duration of 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 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1. 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 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. Behaviors 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 divalproex sodium 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

x 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 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 x

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 [see Contraindications (4) and Warnings and Precaution (5.4)].

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 (4) and Warnings and

Precautions (5.4, 5.8)]. 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 (5.9)]. 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 (5.4, 5.7)].

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 cardiovacular 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 (2.4)].

5.13 Monitoring: Drug Plasma Concentration

Since divalproex sodium 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 Effects 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 [see Adverse Events (6.2)].

5.15 Effects 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

6.1 Epilepsy

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

divalproex sodium was 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-treated

patients (6%), compared to 1% of placebo-treated patients. Table 1 lists treatment-emergent adverse

reactions which were reported by ≥ 5% of divalproex sodium-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 alone, or the combination of divalproex sodium and other antiepilepsy drugs.

Table 2. Adverse reactions Reported by > 5% of Patients Treated with Divalproex Sodium

During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures

Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high

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

controlled trial of divalproex sodium 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

alone, or the combination of divalproex sodium and other antiepilepsy drugs.

Table 3. Adverse reactions Reported by > 5% of Patients in the High Dose Group in the

Controlled Trial of Divalproex Sodium Monotherapy for Complex Partial Seizures

a. 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.

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

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

Body as a Whole:

a

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.

6.2 Other Patient Population

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 delayed-release

divalproex sodium may result in reduction of gastrointestinal side effects in some patients.

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 (7.2)].

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)]. 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 (5.14)].

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 (5.7 and 5.8)], 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 [see

Warnings and Precautions (5.9)].

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Hepatic failure (5.1)

Teratogenicity (5.2)

Pancreatitis (5.3)

Hyperammonemic encephalopathy (5.4, 5.7)

Somnolence in the elderly (5.12)

Thrombocytopenia (5.6)

Multi-organ hypersensitivity reactions (5.10)

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.

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. Caution should be observed if valproate and aspirin are to be co-administered.

the presence of aspirin. 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 antiobiotics (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 co-administered 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 (4) and Warnings and Precautions (5.4, 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 (5.7, 5.9)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category D.

Use of divalproex sodium 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 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 [see Warnings and Precautions

(5.2)].

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 (MRHD) on a mg/m basis 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 capsules

(sprinkle), healthcare providers are advised to recommend that pregnant patients taking divalproex

sodium capsules (sprinkle) enroll in the North Americam 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 at 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

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 divalproex sodium 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.

Younger children, especially those receiving enzyme inducing drugs, will require larger maintenance

doses to attain targeted total and unbound valproic acid concentrations. Pediatric patients (i.e., between 3

months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults.

Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

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.

Divalproex sodium has not been established to be safe and effective for the treatment of partial seizures

in children under the age of 10 years.

Pediatric Clinical Trials

Divalproex sodium was studied in seven pediatric clinical trials.

Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of

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

divalproex sodium) and migraine (304 patients aged 12 to 17 years, 231 of whom were on divalproex

sodium). Efficacy was not established for either the treatment of migraine or the treatment of mania.

The remaining five trials were long term safety studies. Two six-month pediatric studies were

conducted to evaluate the long-term safety of divalproex sodium for 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 for the indication of migraine (353 patients aged 12 to 17 years). One

twelve-month study was conducted to evaluate the safety of divalproex sodium in the indication of

partial seizures (169 patients aged 3 to 10 years).

The safety and tolerability of divalproex sodium in pediatric patients were shown to be comparable to

those in adults [see Adverse Reactions (6)].

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 (2.2)]. 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), andWarnings And Precautions (5) and Clinical

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

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category D.

Use of divalproex sodium 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 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 [see Warnings and Precautions

(5.2)].

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

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

recommended daily human dose (MRHD) on a mg/m basis 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

Women who become pregnant while using valproic acid should be encouraged to enroll in the AED

(antiepileptic drug) Pregnancy Registry at 1-888-233-2334.

10 OVERDOSAGE

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 to off white powder, very soluble in chloroform, freely soluble

in methanol and ethyl ether, soluble in acetone, practically insoluble in acetonitrile.

Divalproex sodium capsules (sprinkle) are for oral administration. Divalproex sodium capsules

(sprinkle) contain specially coated particles of divalproex sodium equivalent to 125 mg of valproic acid

in a hard gelatin capsule.

Inactive Ingredients

Divalproex sodium capsule (sprinkle): black iron oxide, D&C Red 28, ethyl cellulose, FD&C Blue 1,

gelatin, hypromellose, magnesium stearate, sugar sphere, titanium dioxide, and triethyl citrate NF.

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. One

contributing 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 50 to 100 mcg/mL of total valproate,

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

12.3 Pharmacokinetics

Absorption/Bioavailability

Equivalent oral doses of divalproex sodium products and valproic acid capsules deliver equivalent

quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the

formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and

the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the

capsule is taken intact), these differences should be of minor clinical importance under the steady state

conditions achieved in chronic use in the treatment of epilepsy.

However, it is possible that differences among the various valproate products in T

and C

could

be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a

greater influence on the rate of absorption of the tablet (increase in T

from 4 to 8 hours) than on the

absorption of the coated particles in capsules (increase in T

from 3.3 to 4.8 hours).

While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with

dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely

to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as

studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic

bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in

the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential

from a practical clinical standpoint.

Co-administration of oral valproate products with food and substitution among the various divalproex

sodium and valproic acid formulations should cause no clinical problems in the management of patients

with epilepsy.

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) [seeDrug Interactions (7) for more

detailedinformation 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 areintroduced or withdrawn.

Special Populations

Effect of Age

Children

Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on

weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic

parameters that approximate those of 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.

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 freeconcentrations may be substantially elevated in patients with hepatic disease

whereas total concentrations may appear to be normal [seeBoxed 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

biologicalsignificance 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 amg/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.

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Epilepsy

The efficacy of divalproex sodium 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 or placebo. Randomized patients were to be

followed for a total of 16 weeks. The following Table presents the findings.

Table 4: Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks

*Reduction from baseline statistically significantly greater for divalproex sodium than placebo at p ≤

0.05 level.

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 divalproex

sodium than for placebo. For example, 45% of patients treated with divalproex sodium 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 divalproex sodium 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

divalproex sodium. 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 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 5: Monotherapy Study Median Incidence of CPS per 8 Weeks

*Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05

level.

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 divalproex sodium than for low dose divalproex sodium. For example, when switching

from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose divalproex

sodium monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure

rates compared to 54% of patients receiving low dose divalproex sodium.

Figure 2

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

Divalproex sodium capsules (sprinkle), 125 mg (divalproex sodium USP equivalent to 125 mg of

valproic acid) are white to off-white, coated particles filled in ‘size 1’ hard gelatin capsules of light

blue transparent cap imprinted ‘ ↑THIS END UP↑ ’ and white opaque body imprinted ‘RDY 532’ on the

body using black ink and are supplied in bottles of 30’s, 100’s, and 500's and unit dose package of 100

(10 x 10).

Bottles of 30 NDC 55111-532-30

Bottles of 100 NDC 55111-532-01

Bottles of 500 NDC 55111-532-05

Unit dose package of 100 (10 x 10) NDC 55111-532-78

Recommended storage

Store at 20°-25°C (68°-77°F); [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

DIVALPROEX SODIUM CAPSULES (SPRINKLE)

Divalproex sodium capsules (sprinkle) may be swallowed whole or the capsule contents may be

sprinkled onto soft food such as applesauce or pudding.

Serving Suggestions

Divalproex sodium capsules (sprinkle) provide the medicine that your doctor has prescribed. The

sprinkles are flavorless. Soft foods such as applesauce or pudding are best to use for mixing and taking

divalproex sodium capsules (sprinkle).

TO ADMINISTER WITH FOOD:

Make sure this medicine is taken exactly as your doctor prescribed it. If you have any questions, please

contact your doctor or pharmacist. Keep all of your doctor's appointments as scheduled. Make sure that

divalproex sodium capsules (sprinkle) and all other medicines are kept out of the reach of children.

Note

You may see the specially coated particles in divalproex sodium capsules (sprinkle) in stool. Ask your

doctor or pharmacist about possible side effects with divalproex sodium capsules (sprinkle).

R Only

Manufactured by:

Dr. Reddy’s Laboratories Limited

Bachepalli – 502 325 INDIA

Revised: 0310

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, (17.6) which appears as the last section of the labeling [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,

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 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. Behaviors of

concern should be reported immediately to 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 (e.g., 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)].

PATIENT INFORMATION SHEET

17.8 FDA-Approved Patient Labeling

Important Information for Women Who Could Become Pregnant About the Use of Divalproex

Sodium Capsules (Sprinkle).

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 take 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 capsules (sprinkle), and valproic acid 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.

Package Label Principal Display Panel

NDC 76237-155-30

Divalproex Sodium Capsules (Sprinkle) 125 mg Valproic Acid Activity

Each capsule contains: Divalproex Sodium USP equivalent to valproic acid 125 mg

WARNING: Keep out of reach of children

Store at 20° to 25°C (68° to 77°F); [See USP controlled room temperature]

Dispense in a tight, light-resistant container

DIVALPROEX SODIUM

divalproex sodium capsule

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:76 237-155(NDC:55111-532)

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)

VALPROIC ACID

125 mg

Inactive Ingredients

Ingredient Name

Stre ng th

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

D&C RED NO . 2 8 (UNII: 76 7IP0 Y5NH)

ETHYLCELLULO SES (UNII: 7Z8 S9 VYZ4B)

FD&C BLUE NO . 1 (UNII: H3R47K3TBD)

GELATIN (UNII: 2G8 6 QN327L)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

McKesson Contract Packaging

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

SUCRO SE (UNII: C151H8 M554)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

STARCH, CO RN (UNII: O8 232NY3SJ)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

CAPSULE

S iz e

19 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:76 237-155-30

6 in 1 BOX, UNIT-DOSE

1

5 in 1 BLISTER PACK

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 9 79

12/14/20 11

Labeler -

McKesson Contract Packaging (968953377)

Registrant -

McKesson Packaging Services a business unit of McKesson Corporation (140529962)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

McKesso n Packaging Services a business unit o f McKesso n Co rpo ratio n

140 529 9 6 2

REPACK(76 237-155)

Revised: 12/2011

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