VALPROIC ACID capsule liquid filled

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

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Active ingredient:
VALPROIC ACID (UNII: 614OI1Z5WI) (VALPROIC ACID - UNII:614OI1Z5WI)
Available from:
Pliva Inc.
INN (International Name):
VALPROIC ACID
Composition:
VALPROIC ACID 250 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
Abbreviated New Drug Application

VALPROIC ACID - valproic acid capsule, liquid filled

Pliva Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Valproic Acid Capsules safely and

effectively. See full prescribing information for Valproic Acid Capsules.

Valproic Acid Capsules, USP for oral use

USP Initial U.S. Approval: 1978

WARNINGS: 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 and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and

perform serum liver testing prior to therapy and at frequent intervals thereafter (5.1)

Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ (5.2, 5.3, 5.4)

Pancreatitis, including fatal hemorrhagic cases (5.5)

RECENT MAJOR CHANGES

Warnings and Precautions, Birth Defects (5.2) 01/2015

Warnings and Precautions, Bleeding and Other Hematopeietic Disorders (5.8) 01/2015

Warnings and Precautions, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity

Reaction (5.12) 01/2015

INDICATIONS AND USAGE

Valproic Acid Capsules are an anti-epileptic drug indicated for:

Monotherapy and adjunctive therapy of complex partial seizures; sole and adjunctive therapy of simple and complex

absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1)

DOSAGE AND ADMINISTRATION

Valproic Acid Capsules are intended for oral administration. (2.1)

Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10

mg/kg/week until seizure control or limiting side effects (2.1)

Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)

DOSAGE FORMS AND STRENGTHS

Capsules: 250 mg valproic acid (3)

CONTRAINDICATIONS

Hepatic disease or significant hepatic dysfunction (4, 5.1)

Known mitochondrial disorders caused by mutations in mitochondrial DNA Polymerase γ (POLG)(4, 5.12)

Suspected POLG-related disorder in children under two years of age (4, 5.12)

Known hypersensitivity to the drug (4, 5.12)

Urea cycle disorders (4, 5.6)

WARNINGS AND PRECAUTIONS

Hepatotoxicity: Evaluate high risk populations and monitor serum liver tests (5.1)

Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy if other

medications are unacceptable; should not be administered to a woman of childbearing potential unless essential (5.2,

5.3, 5.4)

Pancreatitis: valproic acid should ordinarily be discontinued (5.5)

Suicidal Behavior or Ideation: Antiepileptic drugs, including valproic acid, increase the risk of suicidal thoughts or

behavior (5.7)

Bleeding and other hematopoietic disorders: monitor platelet counts and coagulation tests (5.8)

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

vomiting or changes in mental status (5.6, 5.9, 5.10)

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

This adverse reaction can also occur in patients using concomitant topiramate (5.11)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction: discontinue

Valproic Acid (5.12)

Somnolence in the elderly can occur. Valproic acid dosage should be increased slowly and with regular monitoring for

fluid and nutritional intake (5.14)

ADVERSE REACTIONS

Most common adverse reactions (reported >5%) are abdominal pain, alopecia, amblyopia/blurred vision, amnesia,

anorexia, asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea,

ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea,

nervousness, nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking abnormal, thrombocytopenia,

tinnitus, tremor, vomiting, weight gain, weight loss. (6.1)

The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4)

To report SUSPECTED ADVERSE REACTIONS, contact Teva USA, PHARMACOVIGILENCE at 1-866-832-8537

or Drugsafety@tevapharma.com or FDA at 1-800-FDA-1088 www.fda.gov/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 Valproic Acid Capsules (7.2)

Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)

USE IN SPECIFIC POPULATIONS

Pregnancy: Valproic acid capsules can cause congenital malformations including neural tube defects and decreased IQ

(5.2, 5.3, 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

(5.14, 8.5)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 3/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: LIFE THREATENING ADVERSE REACTIONS

1 INDICATIONS AND USAGE

1.1 Epilepsy

1.2 Important Limitations

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 Birth Defects

5.3 Decreased IQ Following in utero Exposure

5.4 Use in Women of Childbearing Potential

5.5 Pancreatitis

5.6 Urea Cycle Disorders (UCD)

5.7 Suicidal Behavior and Ideation

5.8 Bleeding and Other Hematopoietic Disorders

5.9 Hyperammonemia

5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use

5.11 Hypothermia

5.12 Drug Reaction with Eosinophilia and Systemic Symptoms(DRESS)/Multi-Organ

Hypersensitivity Reactions

5.13 Interaction with Carbapenem Antibiotics

5.14 Somnolence in the Elderly

5.15 Monitoring: Drug Plasma Concentration

5.16 Effects on Ketone and Thyroid Function Tests

5.17 Effects on HIV and CMV Viruses Replication

6 ADVERSE REACTIONS

6.1 Epilepsy

6.2 Mania

6.3 Migraine

6.4 Post-Marketing Experience

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

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 and Impairment Of Fertility

14 CLINICAL STUDIES

14.1 Epilepsy

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

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

WARNING: LIFE THREATENING ADVERSE REACTIONS

WARNING: LIFE THREATENING ADVERSE REACTIONS

Hepatotoxicity

General Population: Hepatic failure resulting in fatalities has occurred in patients receiving

valproate. 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. Serum liver tests should be performed prior to therapy and at frequent

intervals thereafter, especially during the first six months.

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 Valproic Acid products 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.

Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute

liver failure and resultant deaths in patients with hereditary neurometabolic syndromes

caused by DNA mutation of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.

Alpers Huttenlocher Syndrome). Valproic Acid Capsules are contraindicated in patients

known to have mitochondrial disorders caused by POLG mutations and children under two

years of age who are clinically suspected of having a mitochondrial disorder [see

Contraindications (4)]. In patients over two years of age who are clinically suspected of

having a hereditary mitochondrial disease, Valproic Acid Capsules should only be used

after other anticonvulsants have failed. This older group of patients should be closely

monitored during treatment with Valproic Acid Capsules for the development of acute liver

injury with regular clinical assessments and serum liver testing. POLG mutation screening

should be performed in accordance with current clinical practice [see Warnings and

Precautions (5.1)]

Fetal Risk

Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,

spina bifida). In addition, valproate can cause decreased IQ scores following in utero

expos ure.

Valproate should only be used to treat pregnant women with epilepsy if other medications

have failed to control their symptoms or are otherwise unacceptable. Valproate should not

be administered to a woman of childbearing potential unless the drug is essential to the

management of her medical condition. This is especially important when valproate use is

considered for a condition not usually associated with permanent injury or death (e.g.,

migraine). Women should use effective contraception while using valproate [see Warnings

and Precautions (5.2, 5.3, 5.4)].

A Medication Guide describing the risks of valproate is available for patients [see Patient

Counseling Information (17)] .

Pancreatitis

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

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

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

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

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

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

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

initiated as clinically indicated [see Warnings and Precautions (5.5)] .

1 INDICATIONS AND USAGE

1.1 Epilepsy

Valproic Acid Capsules are indicated as monotherapy and adjunctive therapy in the treatment of patients

with complex partial seizures that occur either in isolation or in association with other types of

seizures. Valproic Acid Capsules are 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 which

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.

See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.

1.2 Important Limitations

Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital

malformations, which may occur very early in pregnancy, valproate should not be administered to a

woman of childbearing potential unless the drug is essential to the management of her medical condition

[see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations (8.1) and Patient Counseling

Information (17.3)].

2 DOSAGE AND ADMINISTRATION

2.1 Epilepsy

Valproic Acid Capsules is intended for oral administration. Valproic Acid Capsules should be

swallowed whole without chewing to avoid local irritation of the mouth and throat.

Patients should be informed to take Valproic Acid Capsules every day as prescribed. If a dose is

missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is

skipped, the patient should not double the next dose.

Valproic Acid Capsules is indicated as monotherapy and adjunctive therapy in complex partial seizures

in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures.

As the Valproic Acid Capsules 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)

Valproic Acid Capsules 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 Valproic Acid 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

Valproic Acid Capsules 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 Depakote tablets, 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 concentration for most patients with absence seizures is

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

serum concentrations [see Clinical Pharmacology (12.3)] .

As the Valproic Acid dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin

may be affected [see Drug Interactions (7.2)] .

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to

prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant

hypoxia and threat to life.

The following Table is a guide for the initial daily dose of valproic acid (15 mg/kg/day):

Table 1. Initial Daily Dose

Weight

Total Daily Dose (mg)

Number of Capsules or Teaspoonfuls

of Syrup

(Kg)

(Lb)

Dose 1

Dose 2

Dose 3

10 - 24.9

22 - 54.9

25 - 39.9

55 - 87.9

40 - 59.9

88 - 131.9

60 - 74.9

132 - 164.9

1,000

75 - 89.9

165 - 197.9

1,250

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 (5.14), 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) [see Warnings and Precautions

(5.8)]. 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.

3 DOSAGE FORMS AND STRENGTHS

Valproic Acid Capsules are available as white, oblong soft gelatin capsules of 250 mg valproic acid

with imprint ‘PA2120’ for product identification.

4 CONTRAINDICATIONS

Valproic Acid Capsules should not be administered to patients with hepatic disease or significant

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

Valproic Acid contraindicated in patients known to have mitochondrial disorders caused by mutation in

mitochondrial DNA polymerase γ (POLG; e.g. Alper-Huttenlocher Syndrome) and children under two

years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions

(5.1)].

Valproic acid contraindicated in patients with known hypersensitivity to the drug [see Warnings and

Precautions (5.12)].

Valproic acid contraindicated in patients with known urea cycle disorders [see Warnings and Precautions

(5.6)].

5 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

General Information on Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving valproate. 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. Serun liver tests should be performed prior to

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

providers 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 valproate 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. See below, “Patients with Known or Suspected

Mitochondrial Disease.”

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 Valproic

Acid Capsules 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. In progressively older patient

groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases

considerably.

Patients with Known or Suspected Mitochondrial Disease

Valproic Acid Capsules are contraindicated in patients known to have mitochondrial disorders caused

by POLG mutations and children under two years of age who are clinically suspected of having a

mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and liver-

related deaths have been reported in patients with hereditary neurometabolic syndromes caused by

mutation in the gene for mitochondrial DNA polymerase γ POLG (e.g. Alpers- Huttenlocher Syndrome)

at a higher rate than those without these syndromes. Most of the reported cases of liver failure in

patients with these syndromes have been identified in children and adolescents.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms

of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory

epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor

regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or

complicated migraine with occipital aura. POLG mutation testing should be performed in accordance

with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S

mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related

disorders.

In patients over two years of age who are clinically suspected of having a hereditary mitochondrial

disease, Valproic Acid Capsules should only be used after other anticonvulsants have failed. This

older group of patients should be closely monitored during treatment with Valproic Acid Capsules for

the development of acute liver injury with regular clinical assessments and serum liver test monitoring.

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

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

drug [see Boxed Warning and Contraindications (4)].

5.2 Birth Defects

Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show

that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g.,

craniofacial defects, cardiovascular malformations hypospadias, limb malformations). The rate of

congenital malformations among babies born to mothers using valproate is about four times higher than

the rate among babies born to epileptic mothers using other anti-seizure monotherapies.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of

pregnancy decreases the risk for congenital neural tube defects in the general population.

5.3 Decreased IQ Following in utero Exposure

Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological

studies have indicated that children exposed to valproate in utero have lower cognitive test scores than

children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of

these studies is a prospective cohort study conducted in the United States and United Kingdom that

found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95%

C.I. 94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments

evaluated: lamotrigine (108 [95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]), and

phenytoin (108 [95% C.I. 104-112]). It is not known when during pregnancy cognitive effects in

valproate-exposed children occur. Because the women in this study were exposed to antiepileptic

drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period

during pregnancy could not be assessed.

Although all of the available studies have methodological limitations, the weight of the evidence

supports the conclusion that valproate exposure in utero can cause decreased IQ in children.

In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen

in humans and demonstrated neurobehavioral deficits. [see Use in Specific Populations (8.1)]

Women with epilepsy who are pregnant or who plan to become pregnant should not be treated with

valproate unless other treatments have failed to provide adequate symptom control or are otherwise

unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still

outweigh the risks.

5.4 Use in Women of Childbearing Potential

Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural

tube defects), which may occur very early in pregnancy, valproate should not be administered to a

woman of childbearing potential unless the drug is essential to the management of her medical

condition. This is especially important when valproate use is considered for a condition not usually

associated with permanent injury or death (e.g., migraine). Women should use effective contraception

while using valproate. Women who are planning a pregnancy should be counseled regarding the relative

risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be

considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)].

To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status

epilepticus with resulting maternal and fetal hypoxia and threat to life.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of

pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known

whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate

is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception

and during pregnancy should be routinely recommended for patients using valproate.

5.5 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, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical

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

5.6 Urea Cycle Disorders (UCD)

Valproic acid is contraindicated in patients with known urea cycle disorders.

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 valproate 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 (5.10)].

5.7 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Valproic Acid increase the risk of suicidal thoughts or behavior

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

be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any

unusual changes in mood or behavior.

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

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

Relative Risk 1.8, 95% 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 treatment 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 2 shows absolute and relative risk by indication for all evaluated AEDs.

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

Indication

Placebo Patients

with Events Per

1000 Patients

Drug Patients

with Events Per

1000 Patients

Relative Risk: Incidence of

Events in Drug

Patients/Incidence in

Placebo Patients

Risk Difference:

Additional Drug Patients

with Events Per 1000

Patients

Epilepsy

Psychiatric

Other

Total

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

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

epilepsy and psychiatric indications.

Anyone considering prescribing Valproic Acid Capsules 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.

5.8 Bleeding and Other Hematopoietic Disorders

Valproate is associated with dose-related thrombocytopenia. In a clinical trial of Depakote (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. Valproate use has also been

associated with decreases in other cell lines and myelodysplasia.

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

abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired von

Willebrand’s disease), measurements of complete blood counts and coagulation tests are recommended

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

Acid be monitored for blood count and coagulation parameters prior to planned surgery and during

pregnancy [see Use in Specific Populations (8.1)]. Evidence of hemorrhage, bruising, or a disorder of

hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.

5.9 Hyperammonemia

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

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

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

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

Warnings and Precautions (5.11)]. 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 (5.6, 5.10].

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.

5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use

Concomitant administration of topiramate and valproate 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 (5.11)]. In most cases, symptoms and signs abated with

discontinuation of either drug. This adverse reaction 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 valproate may

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

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

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

Precautions (5.6, 5.9)].

5.11 Hypothermia

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

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

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

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

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

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

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

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

levels.

5.12 Drug Reaction with Eosinophilia and Systemic Symptoms(DRESS)/Multi-Organ

Hypersensitivity Reactions

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan

Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-threatening.

DRESS typically, although not exclusively, presented with fever rash and/or lymphadenopathy,

associated with other organ system involvement, such as hepatitis, nephritis, hematological

abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is

often present. Because this disorder is variable in its expression, other organ system symptoms not

noted here, may be involved. It is important to note that early manifestations of hypersensitivity, such as

fever or lymphadenopathy, may be present even though rash is not evident. If such sign or symptoms are

present, the patient should be evaluated immediately. Valproate should be discontinued and not be

resumed if an alternative etiology for the sign and symptoms cannot be established.

5.13 Interaction with Carbapenem Antibiotics

Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may

reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control.

Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy.

Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate

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

5.14 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 (2.2)] .

5.15 Monitoring: Drug Plasma Concentration

Since valproate 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)].

5.16 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.

5.17 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

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.

6.1 Epilepsy

The data described in the following section were obtained using Depakote (divalproex sodium) tablets.

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

Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in

severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%),

compared to 1% of placebo-treated patients.

Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated

patients and for which the incidence was greater than in the placebo group, in a placebo-controlled trial

of adjunctive therapy for the 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 Depakote alone, or the combination of Depakote and other antiepilepsy

drugs.

Table 3. Adverse reactions Reported by ≥5% of Patients Treated

with Depakote During Placebo-Controlled Trial of Adjunctive

Therapy for Complex Partial Seizures

Body System/Reaction

Depakote (%)

(n = 77)

Placebo (%)

(n = 70)

Body as a Whole

Headache

Asthenia

Fever

Gastrointestinal System

Nausea

Vomiting

Abdominal Pain

Diarrhea

Anorexia

Dyspepsia

Constipation

Nervous System

Somnolence

Tremor

Dizziness

Diplopia

Amblyopia/Blurred

Vision

Ataxia

Nystagmus

Emotional Lability

Thinking Abnormal

Amnesia

Respiratory System

Flu Syndrome

Infection

Bronchitis

Rhinitis

Other

Alopecia

Weight Loss

Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high

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

controlled trial of Depakote 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 Depakote alone, or the

combination of Depakote and other antiepilepsy drugs.

Table 4 Adverse Reactions Reported by ≥ 5% of Patients in the High

Dose Group in the Controlled Trial of Depakote Monotherapy for

Complex Partial Seizures

*

Body System/Reaction

High Dose (%)

(n = 131)

Low Dose (%)

(n = 134)

Body as a Whole

Asthenia

Digestive System

Nausea

Diarrhea

Vomiting

Abdominal Pain

Anorexia

Dyspepsia

Hemic/Lymphatic

Sys tem

Thrombocytopenia

Ecchymosis

Metabolic/Nutritional

Weight Gain

Peripheral Edema

Nervous System

Tremor

Somnolence

Dizziness

Insomnia

Nervousness

Amnesia

Nystagmus

Depression

Respiratory System

Infection

Pharyngitis

Dyspnea

Skin and Appendages

Alopecia

Special Senses

Amblyopia/Blurred Vision

Tinnitus

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

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

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

Cardiovascular System: Tachycardia, hypertension, palpitation.

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

abscess.

Headache was the only adverse reactions that occurred in ≥ 5% of patients in

the high dose group and at an equal or greater incidence in the low dose group.

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 Mania

Although valproic acid has not been evaluated for safety and efficacy in the treatment of manic episodes

associated with bipolar disorder, the following adverse reactions not listed above were reported by 1%

or more of patients from two placebo-controlled clinical trials of Depakote tablets.

Body as a Whole: Chills, neck pain, neck rigidity.

Cardiovascular System: Hypotension, postural hypotension, vasodilation.

Digestive System: Fecal incontinence, gastroenteritis, glossitis.

Musculoskeletal System: Arthrosis.

Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia,

vertigo.

Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.

Special Senses: Conjunctivitis, dry eyes, eye pain.

Urogenital System: Dysuria.

6.3 Migraine

Although valproic acid has not been evaluated for safety and efficacy in the treatment of prophylaxis of

migraine headaches, the following adverse reactions not listed above were reported by 1% or more of

patients from two placebo-controlled clinical trials of Depakote tablets.

Body as a Whole: Face edema.

Digestive System: Dry mouth, stomatitis.

Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.

6.4 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of valproic acid.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis, and Stevens- Johnson

syndrome.

Psychiatric: Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance

in attention, learning disorder, and behavioral deterioration.

Neurologic:: There have been several reports of acute or subacute cognitive decline and behavioral

changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate

therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully

after valproate discontinuation.

Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.

Hematologic: Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia,

anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia,

aplastic anemia, agranulocytosis, and acute intermittent porphyria.

Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid gland

swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia,

and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring

chiefly in children.

Genitourinary: Enuresis and urinary tract infection.

Special Senses: Hearing loss.

Other: Allergic reaction, anaphylaxis, developmental delay, autism and/or autism spectrum disorder,

bone pain, bradycardia, and cutaneous vasculitis.

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(such as ritonavir), 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.

Carbapenem Antibiotics

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

receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete

list) and may result in loss of seizure control. The mechanism of this interaction is 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 (5.13 )].

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

glucuronyltransferases.

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 valproate 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 valproate 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.

Olanzapine

No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with

valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy adults (n=10)

caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.

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 valproate and topiramate has been associated with hyperammonemia with

and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.6, 5.9, 5.10)].

Concomitant administration of topiramate with valproate 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 (5.9, 5.11)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].

Pregnancy Registry

To collect information on the effects of in utero exposure to valproic acid, physicians should

encourage pregnant patients taking valproic acid to enroll in the NAAED Pregnancy Registry. This can

be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information

on the registry can be found at the website http://www.aedpregnancyregistry.org/.

Fetal Risk Summary

All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or

other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any

indication increases the risk of congenital malformations, particularly neural tube defects, but also

malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations,

hypospadias, limb malformations). The risk of major structural abnormalities is greatest during the first

trimester; however, other serious developmental effects can occur with valproate use throughout

pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used

valproate during pregnancy has been shown to be about four times higher than the rate among babies

born to epileptic mothers who used other anti-seizure monotherapies[see Warnings and Precautions

(5.3)].

Several published epidemiological studies have indicated that children exposed to valproate in utero

have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to

no antiepileptic drugs in utero[see Warnings and Precautions (5.3)].

An observational study has suggested that exposure to valproate products during pregnancy may

increase the risk of autism spectrum disorders. In this study, children born to mothers who had used

valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7-4.9) of

developing autism spectrum disorders compared to children born to mothers not exposed to valproate

products during pregnancy. The absolute risks for autism spectrum disorders were 4.4% (95% CI:

2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI:1.5%-1.6%) in children not exposed to

valproate products. Because the study was observational in nature, conclusions regarding a causal

association between in utero valproate exposure and an increased risk of autism spectrum disorder

cannot be considered definitive.

In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to

those seen in humans and demonstrated neurobehavioral deficits.

Clinical Considerations

Neural tube defects are the congenital malformation most strongly associated with maternal

valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated

as 1 - 2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07%

(6 to 7 in 10,000 births).

Valproate can cause decreased IQ scores in children whose mothers were treated with valproate

during pregnancy.

Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may

occur very early in pregnancy:

Valproate should not be administered to a woman of childbearing potential unless the drug is

essential to the management of her medical condition. This is especially important when valproate

use is considered for a condition not usually associated with permanent injury or death (e.g.,

migraine).

Valproic Acid should not be used to treat women with epilepsy who are pregnant or who plan to

become pregnant unless other treatments have failed to provide adequate symptom control or are

otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy

may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential,

carefully consider both the potential risks and benefits of treatment and provide appropriate

counseling.

To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this

can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even

minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation

of the drug may be considered prior to and during pregnancy in individual cases if the seizure

disorder severity and frequency do not pose a serious threat to the patient.

Available prenatal diagnostic testing to detect neural tube and other defects should be offered to

pregnant women using valproate.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester

of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not

known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving

valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to

conception and during pregnancy should be routinely recommended for patients using valproate.

Pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia,

hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic

complications in the neonate including death [see Warnings and Precautions (5.8)] . If valproate is

used in pregnancy, the clotting parameters should be monitored carefully in the mother. If abnormal

in the mother, then these parameters should also be monitored in the neonate.

Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and

Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also

been reported following maternal use of valproate during pregnancy.

Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy

Data

Human

There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the

risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s

National Birth Defects Prevention Network, the risk of spina bifida in the general population is about

0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be

approximately 1 to 2%.

The NAAED Pregnancy Registry has reported a major malformation rate of 9-11% in the offspring of

women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. These data

show up to a five-fold increased risk for any major malformation following valproate exposure in utero

compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. The

compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. The

major congenital malformations included cases of neural tube defects, cardiovascular malformations,

craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g.,

clubfoot, polydactyly), and malformations of varying severity involving other body systems.

Published epidemiological studies have indicated that children exposed to valproate in utero have lower

IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs

in utero. The largest of these studies is a prospective cohort study conducted in the United States and

United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores

at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug

monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]), carbamazepine (105 [95% C.I.

102-108]) and phenytoin (108 [95% C.I. 104-112]). It is not known when during pregnancy cognitive

effects in valproate-exposed children occur. Because the women in this study were exposed to

antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular

time period during pregnancy could not be assessed.

Although all of the available studies have methodological limitations, the weight of the evidence

supports a causal association between valproate exposure in utero and subsequent adverse effects on

cognitive development.

There are published case reports of fatal hepatic failure in offspring of women who used valproate

during pregnancy.

Animal

In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal

structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following

treatment of pregnant animals with valproate during organogenesis at clinically relevant doses

(calculated on a body surface area basis). Valproate induced malformations of multiple organ systems,

including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal

neural tube defects have been reported following valproate administration during critical periods of

organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral

abnormalities (including cognitive, locomotor, and social interaction deficits) and brain

histopathological changes have also been reported in mice and rat offspring exposed prenatally to

clinically relevant doses of valproate.

8.3 Nursing Mothers

Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a

nursing woman.

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]. When valproic acid is used in this patient group, it should be used with extreme

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

of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases

considerably in progressively older patient groups.

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.

Pediatric Clinical Trials

Depakote was studied in seven pediatric clinical trials.

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

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

Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER).

Efficacy was not established for either the treatment of migraine or the treatment of mania. The most

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

controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia,

gastritis and rash.

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

conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients

aged 10 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote

Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). In these seven

trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those

in adults [see Adverse Reactions (6)] .

Juvenile Animal Toxicology

In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal

dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats

treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these

findings was less than the maximum recommended human dose on a mg/m basis.

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 (5.14)]. 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)].

10 OVERDOSAGE

Overdosage 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 overdosage. Because

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

caution in patients with epilepsy.

11 DESCRIPTION

Valproic acid is a carboxylic acid designated as 2-propylpentanoic acid. It is also known as

dipropylacetic acid. Valproic acid has the following structure:

Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a

characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents.

Valproic Acid Capsules are antiepileptics for oral administration. Each soft gelatin capsule contains

250 mg valproic acid.

Inactive Ingredients

Corn oil, FD&C Blue No. 1, gelatin, glycerin, purified water and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which

valproate exerts its antiepileptic 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 cannot provide a reliable index of

the bioactive valproate species.

For example, because the plasma protein binding of valproate is concentration dependent, the free

fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than

expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and

renal diseases.

Epilepsy

The therapeutic range 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 Depakote (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 Depakote tablet (increase in T

from 4 to 8 hours)

than on the absorption of the Depakote sprinkle 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 are inconsequential from a practical clinical

standpoint.

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

formulations should cause no clinical problems in the management of patients with epilepsy [see

Dosage and Administration (2.1)]. Nonetheless, any changes in dosage administration, or the addition or

discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical

status and valproate plasma concentrations.

Distribution

Protein Binding

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

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

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

presence of other drugs (e.g., aspirin).

Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine,

warfarin, and tolbutamide).(See Drug Interactions (7.2) for more detailed information on the

pharmacokinetic interactions of valproate with other drugs).

CNS Distribution

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

(about 10% of total concentration).

Metabolism

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

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

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

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

unchanged in urine.

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

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

protein binding. The kinetics of unbound drug are linear.

Elimination

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

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

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

hours following oral dosing regimens of 250 to 1000 mg.

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

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

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

clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant

antiepileptics are introduced or withdrawn.

Special Populations

Effect of Age

Neonates

Children within the first two months of life have a markedly decreased ability to eliminate valproate

compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in

development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as

well as increased volume of distribution (in part due to decreased plasma protein binding). For example,

in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of

7 to 13 hours in children greater than 2 months.

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 [see

Dosage and Administration (2.2)] .

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

[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease impairs

the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50%

in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy

subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is

also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold

increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free

concentrations may be substantially elevated in patients with hepatic disease whereas total

concentrations may appear to be normal.

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 and Impairment Of Fertility

Carcinogenesis

Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the

maximum recommended human dose on a mg/m basis) for two years. The primary findings were an

increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and

a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance

of these findings for humans is unknown.

Mutagenesis

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

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

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

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

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

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

Fertility

Chronic toxicity studies of valproate 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 recommended human dose (MRHD) on a mg/m basis) and 150

mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m basis). Fertility

studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day

(approximately equal to the MRHD on a mg/m basis) for 60 days. The effect of valproate on testicular

development and on sperm production and fertility in humans is unknown.

14 CLINICAL STUDIES

The studies described in the following section were conducted using Depakote (divalproex sodium)

tablets.

14.1 Epilepsy

The efficacy of Depakote 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, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144

patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of

monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma

concentrations within the "therapeutic range" were randomized to receive, in addition to their original

antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a

total of 16 weeks. The following Table presents the findings.

Table 5:Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks

Add-on Treatment

Number of Patients

Baseline Incidence

Experimental Incidence

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

Depakote

16.0

8.9*

Placebo

14.5

11.5

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

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

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

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

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

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

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

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

The second study assessed the capacity of Depakote 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 Depakote. 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 Depakote 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 6:Monotherapy Study Median Incidence of CPS per 8 Weeks

Treatment

Number of Patients

Baseline Incidence

Randomized Phase Incidence

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

level.

High dose Depakote

13.2

10.7*

Low dose Depakote

14.2

13.8

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

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

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

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

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

shows that the proportion of patients achieving any particular level of reduction was consistently higher

for high dose Depakote than for low dose Depakote. For example, when switching from carbamazepine,

phenytoin, phenobarbital or primidone monotherapy to high dose Depakote monotherapy, 63% of

patients experienced no change or a reduction in complex partial seizure rates compared to 54% of

patients receiving low dose Depakote.

15 REFERENCES

1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes

at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12

(3):244-252.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each white, oblong soft-gelatin capsule is imprinted PA2120, contains 250 mg valproic acid in bottles

of 100's (NDC # 50111-852-01).

The softgels should be protected from moisture and humidity and stored between 59 to 77°F (15 to

25°C) as per the container label. Dispense in a tight, light-resistant container as defined in the USP/NF.

Maalox

is a registered trademark of Novartis Consumer Health Canada Inc.

T itralac

is a registered trademark of 3M.

Depakote

is a registered trademark of Abbott Laboratories.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Hepatotoxicity

Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or

jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly

[see Warnings and Precautions (5.1)] .

Pancreatitis

Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of

pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions

(5.5)] .

Birth Defects and Decreased IQ

Inform pregnant women and women of childbearing potential that use of valproate during pregnancy

increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to

use effective contraception while using valproate. When appropriate, counsel these patients about

alternative therapeutic options. This is particularly important when valproate use is considered for a

condition not usually associated with permanent injury or death. Advise patients to read the Medication

Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.2, 5.3, 5.4) and

Use in Specific Populations (8.1)].

Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact

their doctor immediately if they think they are preganant.

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if

they become pregnant. This registry is collecting information about the safety of antiepileptic drugs

during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific

Populations (8.1)].

Suicidal Thinking and Behavior

Counsel patients, their caregivers, and families that AEDs, including Valproic Acid, may increase the

risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence

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

of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to

report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions

(5.7)].

Hyperammonemia

Inform patientsof 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 (5.9, 5.10)].

CNS Depression

Since valproate products may produce CNS depression, especially when combined with another CNS

depressant (e.g., alcohol), advise patients 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.

Multi-Organ Hypersensitivity Reactions

Instruct patients 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 (5.12)].

Valproic Acid Capsules

Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.

For TEVA PHARMACEUTICALS USA, Sellersville, PA 18960

MEDICATION GUIDE

Valproic Acid Capsules

Read this Medication Guide before you start taking Valproic Acid Capsules and each time you get a

refill. There may be new information. This information does not take the place of talking to your

healthcare provider about your medical condition or treatment.

What is the most important information I should know about Valproic Acid Capsules?

Do not stop taking Valproic Acid Capsules without first talking to your healthcare provider.

Stopping valproic acid suddenly can cause serious problems.

Valproic Acid Capsules can cause serious side effects, including:

1. Serious liver damage that can cause death, especially in children younger than 2 years old.

The risk of getting this serious liver damage is more likely to happen within the first 6 months of

treatment.

Call your healthcare provider right away if you get any of the following symptoms:

nausea or vomiting that does not go away

loss of appetite

pain on the right side of your stomach (abdomen)

dark urine

swelling of your face

yellowing of your skin or the whites of your eyes

In some cases, liver damage may continue despite stopping the drug.

2. Valproic Acid Capsules may harm your unborn baby.

If you take Valproic Acid Capsules during pregnancy for any medical condition, your baby is at risk

for serious birth defects. The most common birth defects with Valproic Acid affect the brain and

spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of

every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin

in the first month, even before you know you are pregnant. Other birth defects can happen.

Birth defects may occur even in children born to women who are not taking any medicines and do not

have other risk factors.

Taking folic acid supplements before getting pregnant and during early pregnancy can lower the

chance of having a baby with a neural tube defect.

If you take Valproic Acid Capsules during pregnancy for any medical condition, your child is at risk

for having a lower IQ.

There may be other medicines to treat your condition that have a lower chance of causing birth

defects and decreased IQ in your child.

Women who are pregnant must not take Valproic Acid Capsules to prevent migraine headaches.

All women of child-bearing age should talk to their healthcare provider about using other

possible treatments instead of Valproic Acid Capsules. If the decision is made to use Valproic

Acid Capsules, you should use effective birth control (contraception) unless you are planning

to become pregnant.

Tell your healthcare provider right away if you become pregnant while taking Valproic Acid

Capsules. You and your healthcare provider should decide if you will continue to take Valproic

Acid Capsules while you are pregnant.

Pregnancy Registry: If you become pregnant while taking Valproic Acid Capsules, talk to your

healthcare provider about registering with the North American Antiepileptic Drug Pregnancy

Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is

to collect information about the safety of antiepileptic drugs during pregnancy.

3. Inflammation of your pancreas that can cause death.

Call your healthcare provider right away if you have any of these symptoms:

severe stomach pain that you may also feel in your back

nausea or vomiting that does not go away

4. Like other antiepileptic drugs, Valproic Acid Capsules may cause suicidal thoughts or actions

in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are

new, worse, or worry you:

new, worse, or worry you:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.

Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop Valproic Acid Capsules without first talking to a healthcare provider. Stopping

Valproic Acid Capsules suddenly can cause serious problems. Stopping a seizure medicine suddenly in

a patient who has epilepsy can cause seizures that do not stop (status epilepticus).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts

or actions, your healthcare provider may check for other causes.

What are Valproic Acid Capsules?

Valproic Acid Capsules are prescription medicines used:

to treat manic episodes associated with bipolar disorder

alone or with other medicines, to treat:

complex partial seizures in adults and children 10 years of age and older

simple and complex absence seizures, with or without other seizure types

to prevent migraine headaches

Who should not take Valproic Acid Capsules?

Do not take Valproic Acid Capsules if you:

have liver problem

have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-

Huttenlocher syndrome)

are allergic to Depakote, valproic acid, sodium valproate, or any of the ingredients in Valproic Acid

Capsules. See the end of this leaflet for a complete list of ingredients in Valproic Acid Capsules.

have a genetic problem called urea cycle disorder

are pregnant for the prevention of migraine headaches

What should I tell my healthcare provider before taking Valproic Acid Capsules?

Before you take Valproic Acid Capsules, tell your healthcare provider if you:

have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher

syndrome)

drink alcohol

are pregnant or breastfeeding. Valproic acid can pass into breast milk. Talk to your healthcare

provider about the best way to feed your baby if you take Valproic Acid Capsules.

have or have had depression, mood problems, or suicidal thoughts or behavior

have any other medical conditions

Tell your healthcare provider about all the medicines you take, including prescription and

nonprescription medicines, vitamins, herbal supplements and medicines that you take for a short period

of time.

Taking Valproic Acid Capsules with certain other medicines can cause side effects or affect how well

they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and

pharmacist each time you get a new medicine.

How should I take Valproic Acid Capsules?

Take Valproic Acid Capsules exactly as your healthcare provider tells you. Your healthcare

provider will tell you how many Valproic Acid Capsules to take and when to take it.

Your healthcare provider may change your dose.

Do not change your dose of valproic acid without talking to your healthcare provider.

Do not stop taking Valproic Acid Capsules without first talking to your healthcare provider.

Stopping valproic acid suddenly can cause serious problems.

Swallow Valproic Acid Capsules whole. Do not crush or chew Valproic Acid Capsules. Tell your

healthcare provider if you can not swallow Valproic Acid Capsules whole. You may need a

different medicine.

If you take too much Valproic Acid Capsules, call your healthcare provider or local Poison Control

Center right away.

What should I avoid while taking Valproic Acid Capsules?

Valproic Acid Capsules can cause drowsiness and dizziness. Do not drink alcohol or take other

medicines that make you sleepy or dizzy while taking Valproic Acid Capsules, until you talk with

your doctor. Taking Valproic Acid Capsules with alcohol or drugs that cause sleepiness or

dizziness may make your sleepiness or dizziness worse.

Do not drive a car or operate dangerous machinery until you know how Valproic Acid Capsules

affect you. Valproic acid can slow your thinking and motor skills.

What are the possible side effects of Valproic Acid Capsules?

See "What is the most important information I should know about Valproic Acid Capsules?"

Valproic Acid Capsules may cause other serious side effects including:

Bleeding Problems: red or purple spots on your skin, bruising pain and swelling into your joints

due to bleeding or bleeding from your mouth or nose.

High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.

Low body temperature (hypothermia ): drop in your body temperature to less than 95°F, feeling

tired, confusion, coma.

Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin blistering

and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue,

or throat, trouble swallowing or breathing.

Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink

less than you normally would. Tell your doctor if you are not able to eat or drink as you normally

do. Your doctor may start you at a lower dose of valproic acid.

Call your healthcare provider right away, if you have any of the symptoms listed above.

The common side effects of Valproic Acid Capsules include:

nausea

headache

sleepiness

vomiting

weakness

tremor

dizziness

stomach pain

blurry vision

double vision

diarrhea

increased appetite

weight gain

hair loss

loss of appetite

problems with walking or coordination

These are not all of the possible side effects of Valproic Acid Capsules. For more information, ask

your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that

bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-

800-FDA-1088.

How should I store Valproic Acid Capsules?

Store Valproic Acid Capsules at 59°F to 77°F (15°C to 25°C).

Keep Valproic Acid Capsules and all medicines out of the reach of children.

General information about the safe and effective use of Valproic Acid Capsules

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use Valproic Acid Capsules for a condition for which it was not prescribed. Do not give Valproic

Acid Capsules to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Valproic Acid Capsules. If

you would like more information, talk with your healthcare provider. You can ask your pharmacist or

healthcare provider for information about Valproic Acid Capsules that is written for health

professionals.

For more information, call 1-800-222-0190.

What are the ingredients in Valproic Acid Capsules?

Active ingredient: valproic acid

Inactive ingredients: Corn oil, FD&C Blue No. 1, gelatin, glycerin, purified water and titanium

dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured By

Banner Pharmacaps, Inc.,

High Point, NC 27265

Manufactured For

TEVA PHARMACEUTICALS USA,

Sellersville, PA 18960

Printed in U.S.A

Rev. 02/2015

NDC 50111-852-01

VALPROIC ACID

Capsules, USP

250 mg

Dispense the accompanying Medication Guide to each Patient.

Rx only

100 SOFT GELATIN CAPSULES

VALPROIC ACID

valproic acid capsule, liquid filled

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:50 111-8 52(NDC:10 8 8 8 -2120 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

VALPRO IC ACID (UNII: 6 14OI1Z5WI) (VALPROIC ACID - UNII:6 14OI1Z5WI)

VALPROIC ACID

250 mg

Pliva Inc.

Inactive Ingredients

Ingredient Name

Stre ng th

CO RN O IL (UNII: 8 470 G57WFM)

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

GELATIN (UNII: 2G8 6 QN327L)

GLYCERIN (UNII: PDC6 A3C0 OX)

WATER (UNII: 0 59 QF0 KO0 R)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

OVAL (Oblo ng)

S iz e

19 mm

Flavor

Imprint Code

PA2120

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 111-8 52-0 1

10 0 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 7348 4

10 /31/19 9 3

Labeler -

Pliva Inc. (001627975)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Banner Pharmacaps Inc.

9 4549 450 8

MANUFACTURE(50 111-8 52)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Katwijk Chemie

40 6 0 37531

API MANUFACTURE(50 111-8 52)

Revised: 3/2015

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