VALPROATE SODIUM- valproate sodium injection

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

Buy It Now

Active ingredient:
VALPROATE SODIUM (UNII: 5VOM6GYJ0D) (VALPROIC ACID - UNII:614OI1Z5WI)
Available from:
West-Ward Pharmaceuticals Corp
INN (International Name):
VALPROATE SODIUM
Composition:
VALPROIC ACID 100 mg in 1 mL
Administration route:
INTRAVENOUS
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Valproate Sodium Injection, USP is indicated as an intravenous alternative in patients for whom oral administration of valproate products is temporarily not feasible in the following conditions: Valproate Sodium Injection, USP is 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. Valproate Sodium Injection, USP is also indicated for use as sole and adjunctive therapy in the treatment of patients with simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. See WARNINGS AND PRECAUTIONS (5.1) for statement regarding fatal hepatic dysfunction. Because of the ri
Product summary:
Valproate Sodium Injection, USP, equivalent to 100 mg of valproic acid per mL, is a clear, colorless solution in 5 mL single dose vials, available in trays of 10 vials (NDC 0143-9637-10). Recommended storage: Store vials at 20º to 25ºC (68º to 77ºF) with excursions between 15º and 30ºC (59º and 86ºF) [See USP Controlled Room Temperature]. No preservatives have been added. Unused portion of container should be discarded.
Authorization status:
Abbreviated New Drug Application
Authorization number:
0143-9637-01, 0143-9637-10

VALPROATE SODIUM- valproate sodium injection

West-Ward Pharmaceuticals Corp

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use VALPROATE SODIUM INJECTION, USP

safely and effectively. See full prescribing information for VALPROATE SODIUM INJECTION, USP.

VALPROATE SODIUM INJECTION, USP for intravenous injection

Initial U.S. Approval: 1996

WARNING: LIFE THREATENING ADVERSE REACTIONS

See full prescribing information for complete boxed warning

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

of two years 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)

INDICATIONS AND USAGE

Valproate Sodium Injection, USP is an anti-epileptic drug and is indicated as an intravenous alternative in patients in whom

oral administration of valproate products is temporarily not feasible in the following conditions:

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

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

DOSAGE AND ADMINISTRATION

Valproate Sodium Injection is intended for intravenous use only.

Epile psy

Complex Partial Seizures in Adults and Children 10 years of age or older: Initial dose is 10 to 15 mg/kg/day,

increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response. Maximum recommended

dose is 60 mg/kg/day (2.1).

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

mg/kg/day to achieve optimal clinical response. Maximum recommended dose is 60 mg/kg/day (2.1).

DOSAGE FORMS AND STRENGTHS

Injection: 100 mg per mL in a 5 mL single dose vial (3)

CONTRAINDICATIONS

Hepatic disease or significant hepatic dysfunction (4, 5.1)

Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) (4, 5.1)

Suspected POLG-related disorder in children under two years of age (4, 5.1)

Known hypersensitivity to the drug (4, 5.11)

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; Valproate Sodium Injection should ordinarily be discontinued (5.5)

Bleeding and other hematopoietic disorders; monitor platelet counts and coagulation tests (5.7)

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

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

therapy (5.6, 5.8, 5.9)

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

This adverse reaction can also occur in patients using concomitant topiramate (5.10)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-organ hypersensitivity reaction; discontinue

Valproate Sodium Injection (5.11)

Somnolence in the elderly can occur. Valproate Sodium Injection dosage should be increased slowly and with regular

monitoring for fluid and nutritional intake (5.13)

ADVERSE REACTIONS

Adverse reactions occurring in at least 5% of patients treated with divalproex sodium in Monotherapy or Adjunctive

Complex Partial Seizures Trials:

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, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence,

thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (6.1)

Additional adverse reactions not included above that occurred in > 0.5% of patients treated with Valproate Sodium

Inje ction:

Chest pain, euphoria, hypesthesia, injection site inflammation, injection site pain, injection site reaction, pain, sweating,

taste perversion, vasodilation (6)

Additional adverse reactions not included above that occurred in other clinical trials with divalproex sodium:

Accidental injury, back pain, increased appetite, rash (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-233-2001

or FDA at 1-800-FDA-1088 or 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, estrogen-containing hormonal contraceptives: 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)

Patients stabilized on rufinamide should begin valproate therapy at a low dose, and titrate to clinically effective dose

(7.2)

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

concomitantly with Valproate Sodium Injection (7.2)

Topiramate: Hyperammonemia and encephalopathy (5.9, 7.3)

USE IN SPECIFIC POPULATIONS

Pregnancy: Valproate Sodium Injection 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

(5.13, 8.5)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 1/2018

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

2.3 Dosing in Patients Taking Rufinamide

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

5.7 Bleeding and Other Hematopoietic Disorders

5.8 Hyperammonemia

5.9 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use

5.10 Hypothermia

5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan

Hypersensitivity Reactions

5.12 Interaction with Carbapenem Antibiotics

5.13 Somnolence in the Elderly

5.14 Post-traumatic Seizures

5.15 Monitoring: Drug Plasma Concentration

5.16 Effect on Ketone and Thyroid Function Tests

5.17 Effect on HIV and CMV Viruses Replication

6 ADVERSE REACTIONS

6.1 Epilepsy

6.2 Mania

6.3 Migraine

6.4 Postmarketing 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

Hepatotoxicity

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

valproate and its derivatives. 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 [see WARNINGS AND PRECAUTIONS (5.1)].

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 Valproate Sodium Injection 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. 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 mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.

Alpers Huttenlocher Syndrome). Valproate Sodium Injection is 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, Valproate Sodium Injection should only be used after other

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

during treatment with Valproate Sodium Injection 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) and 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

Valproate Sodium Injection, USP is indicated as an intravenous alternative in patients for whom oral

administration of valproate products is temporarily not feasible in the following conditions:

Valproate Sodium Injection, USP is 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. Valproate Sodium Injection, USP is also indicated for use as sole and adjunctive therapy in the

treatment of patients with simple and complex absence seizures, and adjunctively in patients with

multiple seizure types that include absence seizures.

Simple absence is defined as very brief clouding of the sensorium or loss of consciousness

accompanied by certain generalized epileptic discharges without other detectable clinical signs.

Complex absence is the term used when other signs are also present.

See WARNINGS AND PRECAUTIONS (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)].

2 DOSAGE AND ADMINISTRATION

2.1 Epilepsy

Valproate Sodium Injection is for intravenous use only.

Use of Valproate Sodium Injection for periods of more than 14 days has not been studied. Patients

should be switched to oral valproate products as soon as it is clinically feasible.

Valproate Sodium Injection should be administered as a 60 minute infusion (but not more than

20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and

dosage adjustments may be necessary.

In one clinical safety study, approximately 90 patients with epilepsy and with no measurable plasma

levels of valproate were given single infusions of Valproate Sodium Injection (up to 15 mg/kg and mean

dose of 1184 mg) over 5-10 minutes (1.5-3.0 mg/kg/min). Patients generally tolerated the more rapid

infusions well [see ADVERSE REACTIONS (6.1)]. This study was not designed to assess the

effectiveness of these regimens. For pharmacokinetics with rapid infusions, see CLINICAL

PHARMACOLOGY (12.3).

Initial Exposure to Valproate

The following dosage recommendations were obtained from studies utilizing oral divalproex sodium

products.

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Valproate Sodium Injection 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 Valproate Sodium

Injection 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

Valproate Sodium Injection 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 valproate, 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 Valproate Sodium Injection 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.

Replacement Therapy

When switching from oral valproate products, the total daily dose of Valproate Sodium Injection should

be equivalent to the total daily dose of the oral valproate product [see CLINICAL

PHARMACOLOGY (12)], and should be administered as a 60 minute infusion (but not more than 20

mg/min) with the same frequency as the oral products, although plasma concentration monitoring and

dosage adjustments may be necessary. Patients receiving doses near the maximum recommended daily

dose of 60 mg/kg/day, particularly those not receiving enzyme-inducing drugs, should be monitored

more closely. If the total daily dose exceeds 250 mg, it should be given in a divided regimen. There is

no experience with more rapid infusions in patients receiving Valproate Sodium Injection as

replacement therapy. However, the equivalence shown between Valproate Sodium Injection and oral

valproate products (divalproex sodium) at steady state was only evaluated in an every 6 hour regimen.

Whether, when Valproate Sodium Injection is given less frequently (i.e., twice or three times a day),

trough levels fall below those that result from an oral dosage form given via the same regimen, is

unknown. For this reason, when Valproate Sodium Injection is given twice or three times a day, close

monitoring of trough plasma levels may be needed.

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 (5.13), 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 (5.7)]. The benefit of improved therapeutic effect with higher doses should be

weighed against the possibility of a greater incidence of adverse reactions.

Administration

Rapid infusion of Valproate Sodium Injection has been associated with an increase in adverse reactions.

There is limited experience with infusion times of less than 60 minutes or rates of infusion > 20 mg/min

in patients with epilepsy [see ADVERSE REACTIONS (6)].

Valproate Sodium Injection should be administered intravenously as a 60 minute infusion, as noted

above. It should be diluted with at least 50 mL of a compatible diluent. Any unused portion of the vial

contents should be discarded.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to

administration whenever solution and container permit.

Compatibility and Stability

Valproate Sodium Injection was found to be physically compatible and chemically stable in the

following parenteral solutions for at least 24 hours when stored in glass or polyvinyl chloride (PVC)

bags at controlled room temperature 15º to 30°C (59º to 86°F).

dextrose (5%) injection, USP

sodium chloride (0.9%) injection, USP

lactated ringer’s injection, USP

2.3 Dosing in Patients Taking Rufinamide

Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a

low dose, and titrate to a clinically effective dose [see Drug Interactions (7.2)].

3 DOSAGE FORMS AND STRENGTHS

Valproate Sodium Injection, equivalent to 100 mg of valproic acid per mL, is a clear, colorless solution

in 5 mL single dose vials, available in trays of 10 vials.

Recommended storage: Store vials at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room

Temperature].

No preservatives have been added. Unused portion of container should be discarded.

4 CONTRAINDICATIONS

Valproate Sodium Injection should not be administered to patients with hepatic disease or significant

hepatic dysfunction [see WARNINGS AND PRECAUTIONS (5.1)].

Valproate Sodium Injection is contraindicated in patients known to have mitochondrial disorders

caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher

Syndrome) and children under two years of age who are suspected of having a POLG-related

disorder [see WARNINGS AND PRECAUTIONS (5.1)].

Valproate Sodium Injection is contraindicated in patients with known hypersensitivity to the drug

[see WARNINGS AND PRECAUTIONS (5.11)].

Valproate Sodium Injection is 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. Serum liver tests should be performed prior to

therapy and at frequent intervals thereafter, especially during the first six months of valproate therapy.

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 Valproate

Sodium Injection 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. Use of Valproate Sodium Injection has not

been studied in children below the age of 2 years.

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

Valproate is 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 mutations 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, valproate should only be used after other anticonvulsants have failed. This older group of

patients should be closely monitored during treatment with valproate 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

Valproate Sodium Injection is contraindicated in patients with known urea cycle disorders (UCD).

Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate

therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly

ornithine transcarbamylase deficiency. Prior to the initiation of 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 (5.9)].

5.7 Bleeding and Other Hematopoietic Disorders

Valproate is associated with dose-related thrombocytopenia. In a clinical trial of divalproex sodium as

monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on

average, had at least one value of platelets ≤ 75 x 109/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 Valproate

Sodium Injection be monitored for blood counts 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.

5.8 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 (5.10)]. 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, 5.9)].

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.

5.9 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 (5.10)]. In most cases, symptoms and signs

abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic

interaction. 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 (5.8)].

5.10 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.

5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan

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, presents with fever, rash, and/or lymphadenopathy, in

association 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 systems 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 signs or symptoms are present,

the patient should be evaluated immediately. Valproate should be discontinued and not be resumed if an

alternative etiology for the signs or symptoms cannot be established.

5.12 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)].

5.13 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)].

5.14 Post-traumatic Seizures

A study was conducted to evaluate the effect of IV valproate in the prevention of post-traumatic

seizures in patients with acute head injuries. Patients were randomly assigned to receive either IV

valproate given for one week (followed by oral valproate products for either one or six months per

random treatment assignment) or IV phenytoin given for one week (followed by placebo). In this study,

the incidence of death was found to be higher in the two groups assigned to valproate treatment

compared to the rate in those assigned to the IV phenytoin treatment group (13% vs. 8.5%, respectively).

Many of these patients were critically ill with multiple and/or severe injuries, and evaluation of the

causes of death did not suggest any specific drug-related causation. Further, in the absence of a

concurrent placebo control during the initial week of intravenous therapy, it is impossible to determine

if the mortality rate in the patients treated with valproate was greater or less than that expected in a

similar group not treated with valproate, or whether the rate seen in the IV phenytoin treated patients

was lower than would be expected. Nonetheless, until further information is available, it seems prudent

not to use Valproate Sodium Injection in patients with acute head trauma for the prophylaxis of post-

traumatic seizures.

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 Effect on Ketone and Thyroid Function Tests

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

of the urine ketone test.

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

significance of these is unknown.

5.17 Effect on HIV and CMV Viruses Replication

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

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

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

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

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

following CMV infected patients clinically.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

Hepatic failure [see Warnings and Precautions (5.1)]

Birth defects [see Warnings and Precautions (5.2)]

Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]

Pancreatitis [see Warnings and Precautions (5.5)]

Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.8, 5.9)]

Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.7)]

Hypothermia [see Warnings and Precautions (5.10)]

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

reactions [see Warnings and Precautions (5.11)]

Somnolence in the elderly [see Warnings and Precautions (5.13)]

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.

The adverse reactions that can result from Valproate Sodium Injection use include all of those

associated with oral forms of valproate. The following describes experience specifically with

Valproate Sodium Injection. Valproate Sodium Injection has been generally well tolerated in clinical

trials involving 111 healthy adult male volunteers and 352 patients with epilepsy, given at doses of 125

to 6,000 mg (total daily dose). A total of 2% of patients discontinued treatment with Valproate Sodium

Injection due to adverse reactions. The most common adverse reactions leading to discontinuation were

2 cases each of nausea/vomiting and elevated amylase. Other adverse reactions leading to

discontinuation were hallucinations, pneumonia, headache, injection site reaction, and abnormal gait.

Dizziness and injection site pain were observed more frequently at a 100 mg/min infusion rate than at

rates up to 33 mg/min. At a 200 mg/min rate, dizziness and taste perversion occurred more frequently

than at a 100 mg/min rate. The maximum rate of infusion studied was 200 mg/min.

Adverse reactions reported by at least 0.5% of all subjects/patients in clinical trials of Valproate

Sodium Injection are summarized in Table 1.

Table 1. Adverse Reactions

Reported During Studies of

Valproate Sodium Injection

Body System/Reaction

N = 463

Body as a Whole

Chest Pain

1.7%

Headache

4.3%

Injection Site Inflammation

0.6%

Injection Site Pain

2.6%

Injection Site Reaction

2.4%

Pain (unspecified)

1.3%

Cardiovascular

Vasodilation

0.9%

Dermatologic

Sweating

0.9%

Digestive System

Abdominal Pain

1.1%

Diarrhea

0.9%

Nausea

3.2%

Vomiting

1.3%

Nervous System

Dizziness

5.2%

Euphoria

0.9%

Hypesthesia

0.6%

Nervousness

0.9%

Paresthesia

0.9%

Somnolence

1.7%

Tremor

0.6%

Respiratory

Pharyngitis

0.6%

Special Senses

Taste Perversion

1.9%

In a separate clinical safety trial, 112 patients with epilepsy were given infusions of Valproate Sodium

Injection (up to 15 mg/kg) over 5 to 10 minutes (1.5 - 3.0 mg/kg/min). The common adverse reactions (>

2%) were somnolence (10.7%), dizziness (7.1%), paresthesia (7.1%), asthenia (7.1%), nausea (6.3%),

and headache (2.7%). While the incidence of these adverse reactions was generally higher than in Table

1 (experience encompassing the standard, much slower infusion rates), e.g., somnolence (1.7%),

dizziness (5.2%), paresthesia (0.9%), asthenia (0%), nausea (3.2%), and headache (4.3%), a direct

comparison between the incidence of adverse reactions in the 2 cohorts cannot be made because of

differences in patient populations and study designs.

Ammonia levels have not been systematically studied after IV valproate, so that an estimate of the

incidence of hyperammonemia after IV Valproate Sodium Injection cannot be provided.

Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of Valproate

Sodium Injection.

6.1 Epilepsy

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

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

divalproex sodium was generally well tolerated with most adverse reactions rated as mild to moderate

in severity. Intolerance was the primary reason for discontinuation in the divalproex sodium-treated

patients (6%), compared to 1% of placebo-treated patients.

Table 2 lists treatment-emergent adverse reactions which were reported by ≥ 5% of divalproex sodium-

treated patients and for which the incidence was greater than in the placebo group, in the placebo-

controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also

treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the

following adverse reactions can be ascribed to divalproex sodium alone, or the combination of

divalproex sodium and other antiepilepsy drugs.

Table 2. Adverse Reactions Reported by ≥ 5% of Patients

Treated with Divalproex Sodium During Placebo-Controlled Trial

of Adjunctive Therapy for Complex Partial Seizures

Body System/Reaction

Divalproex Sodium (%)

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

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

controlled trial of divalproex sodium monotherapy treatment of complex partial seizures. Since patients

were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in

many cases, to determine whether the following adverse reactions can be ascribed to divalproex sodium

alone, or the combination of valproate and other antiepilepsy drugs.

Table 3. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the

Controlled Trial of Valproate 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 System

Thrombocytopenia

Ecchymosis

Metabolic/Nutritional

Weight Gain

Peripheral Edema

Nervous System

Tremor

Somnolence

Dizziness

Insomnia

Nervousness

Amnesia

Nystagmus

Depression

*

Respiratory System

Infection

Pharyngitis

Dyspnea

Skin and Appendages

Alopecia

Special Senses

Amblyopia/Blurred Vision

Tinnitus

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

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

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

Cardiovascular System: Tachycardia, hypertension, palpitation.

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

abscess.

Hemic and Lymphatic System: Petechia.

Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.

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

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

dreams, personality disorder.

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

Skin and Appendages: Rash, pruritus, dry skin.

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

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

6.2 Mania

Although Valproate Sodium Injection 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 divalproex sodium

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.

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

or greater incidence in the low dose group.

Urogenital: Dysuria.

6.3 Migraine

Although Valproate Sodium Injection has not been evaluated for safety and efficacy in the prophylactic

treatment 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 divalproex sodium tablets.

Body as a Whole: Face edema.

Digestive System: Dry mouth, stomatitis.

Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.

6.4 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Valproate Sodium

Injection. 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: Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic

epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.

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

in attention, learning disorder, and behavioral deterioration.

Neurologic: Paradoxical convulsion, parkinsonism

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.

There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia

levels, elevated valproate levels, or neuroimaging changes. The encephalopathy reversed partially or

fully after valproate discontinuation.

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

Hematologic: Relative lymphocytosis, macrocytosis, leucopenia, anemia including macrocytic with or

without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis,

and acute intermittent porphyria.

Endocrine: Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated

testosterone level, 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.

Metabolism and nutrition: Weight gain.

Reproductive: Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male

infertility, and abnormal spermatozoa morphology.

Genitourinary: Enuresis and urinary tract infection.

Special Senses: Hearing loss.

Other: Allergic reaction, anaphylaxis, developmental delay, 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 (5.12)].

Estrogen-Containing Hormonal Contraceptives

Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result

in decreased concentration of valproate and potentially increased seizure frequency. Prescribers should

monitor serum valproate concentrations and clinical response when adding or discontinuing estrogen

containing products.

Felbamate

A study involving the co-administration of 1,200 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 2,400 mg/day increased the

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

dosage may be necessary when felbamate therapy is initiated.

Rifampin

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

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

Valproate dosage adjustment may be necessary when it is co-administered with rifampin.

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

Antacids

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

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

of valproate.

Chlorpromazine

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

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

valproate.

Haloperidol

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

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

Cimetidine and Ranitidine

Cimetidine and ranitidine do not affect the clearance of valproate.

7.2 Effects of Valproate on Other Drugs

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

glucuronosyltransferases.

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

co administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed

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

Drugs for which a potentially important valproate interaction has been observed

Amitriptyline/Nortriptyline

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

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

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

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

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

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

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

presence of valproate.

Carbamazepine/carbamazepine-10,11-Epoxide

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

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

Clonazepam

The concomitant use of 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 (1,500 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 1,600 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.

Propofol

The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce

the dose of propofol when co-administering with valproate. Monitor patients closely for signs of

increased sedation or cardiorespiratory depression.

Rufinamide

Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate.

Rufinamide concentrations were increased by <16% to 70%, dependent on concentration of valproate

(with the larger increases being seen in pediatric patients at high doses or concentrations of valproate).

Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a

low dose, and titrate to a clinically effective dose [see Dosage and Administration (2.3)]. Similarly,

patients on valproate should begin at a rufinamide dose lower than 10 mg/kg per day (pediatric patients)

or 400 mg per day (adults).

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 (5.8, 5.9)]. 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 (5.8, 5.10)].

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 Valproate Sodium Injection, physicians

should encourage pregnant patients taking Valproate Sodium Injection to enroll in the North American

Antiepileptic Drug (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 IQ 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).

Valproate 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

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

complications in the neonate including death [see Warnings and Precautions (5.7)]. 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 other antiepileptic drugs taken in

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 with oral valproate 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]. The safety of Valproate Sodium Injection has

not been studied in individuals below the age of 2 years. If a decision is made to use Valproate Sodium

Injection in this age 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 valproate concentrations.

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

No unique safety concerns were identified in the 35 patients age 2 to 17 years who received Valproate

Sodium Injection in clinical trials.

One twelve-month study was conducted to evaluate the safety of divalproex sodium sprinkle capsules in

the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of

divalproex sodium in pediatric patients were shown to be comparable to those in adults [see ADVERSE

REACTIONS (6)].

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 (5.13)]. 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)].

No unique safety concerns were identified in the 21 patients > 65 years of age receiving Valproate

Sodium Injection in clinical trials.

10 OVERDOSAGE

Overdosage with valproate may result in somnolence, heart block, deep coma and hypernatremia.

Fatalities have been reported; however patients have recovered from valproate serum concentrations 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. 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

Valproate sodium is the sodium salt of valproic acid designated as sodium 2-propylpentanoate.

Valproate sodium has the following structure:

Valproate sodium has a molecular weight of 166.2. It occurs as an essentially white and odorless,

crystalline, deliquescent powder.

Valproate Sodium Injection, USP is available in 5 mL single dose vials for intravenous injection. Each

mL contains valproate sodium equivalent to 100 mg valproic acid, edetate disodium 0.40 mg, and water

for injection to volume. The pH is adjusted to 7.6 with sodium hydroxide and/ or hydrochloric acid.

The solution is clear and colorless.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Valproate sodium exists as the valproate ion in the blood. The mechanisms by which valproate exerts its

therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related

to increased brain concentrations of gamma-aminobutyric acid (GABA).

12.2 Pharmacodynamics

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

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

the clearance of the drug. Thus, monitoring of total serum valproate 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 in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate,

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

Equivalent doses of Valproate Sodium Injection and divalproex sodium yield equivalent plasma levels

of the valproate ion [see CLINICAL PHARMACOLOGY (12.3)].

12.3 Pharmacokinetics

Bioavailability

Equivalent doses of intravenous (IV) valproate and oral valproate products are expected to result in

equivalent C

, and total systemic exposure to the valproate ion when the IV valproate is

administered as a 60 minute infusion. However, the rate of valproate ion absorption may vary with the

formulation used. These differences should be of minor clinical importance under the steady state

conditions achieved in chronic use in the treatment of epilepsy.

Administration of divalproex sodium tablets and IV valproate (given as a one hour infusion), 250 mg

every 6 hours for 4 days to 18 healthy male volunteers resulted in equivalent AUC, C

steady state, as well as after the first dose. The T

after IV Valproate Sodium Injection occurs at the

end of the one hour infusion, while the T

after oral dosing with divalproex sodium occurs at

approximately 4 hours. Because the kinetics of unbound valproate are linear, bioequivalence between

Valproate Sodium Injection and divalproex sodium up to the maximum recommended dose of

60 mg/kg/day can be assumed. The AUC and C

resulting from administration of IV valproate 500 mg

as a single one hour infusion and a single 500 mg dose of valproic acid syrup to 17 healthy male

volunteers were also equivalent.

Patients maintained on valproic acid doses of 750 mg to 4250 mg daily (given in divided doses every 6

hours) as oral divalproex sodium alone (n = 24) or with another stabilized antiepileptic drug

[carbamazepine (n = 15), phenytoin (n = 11), or phenobarbital (n = 1)], showed comparable plasma levels

for valproic acid when switching from oral divalproex sodium to IV valproate (1 hour infusion).

Eleven healthy volunteers were given single infusions of 1000 mg IV valproate over 5, 10, 30, and 60

minutes in a 4-period crossover study. Total valproate concentrations were measured; unbound

concentrations were not measured. After the 5 minute infusions (mean rate of 2.8 mg/ kg/ min), mean

was 145 ± 32 mcg/mL, while after the 60 minute infusions, mean C

was 115 ± 8 mcg/ mL.

Ninety to 120 minutes after infusion initiation, total valproate concentrations were similar for all 4 rates

of infusion. Because protein binding is nonlinear at higher total valproate concentrations, the

corresponding increase in unbound C

at faster infusion rates will be greater.

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 terminal half-life for valproate monotherapy after an intravenous infusion

of 1,000 mg was 16 ± 3.0 hours.

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 years). 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:

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

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

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

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

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

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

whereas total concentrations may appear to be normal [see BOXED WARNING,

CONTRAINDICATIONS (4), and WARNINGS AND PRECAUTIONS (5.1)].

Renal Disease:

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

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

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

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

concentrations may be misleading.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, 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.

Impairment of 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 parameters and fertility in humans is unknown.

14 CLINICAL STUDIES

The studies described in the following section were conducted with oral divalproex sodium tablets.

14.1 Epilepsy

The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in

isolation or in association with other seizure types was established in two controlled trials.

In one, 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 divalproex sodium or placebo. Randomized patients were to be

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

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

Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence

Divalproex sodium

16.0

Placebo

14.5

11.5

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

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

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

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

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

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

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

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

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

The second study assessed the capacity of valproate to reduce the incidence of CPS when administered

as the sole AED. The study compared the incidence of CPS among patients randomized to either a high

or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this

study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long

period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital,

or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients

entering the randomized phase were then brought to their assigned target dose, gradually tapered off

their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients

randomized, however, completed the study. In patients converted to divalproex sodium monotherapy, the

mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and

high dose groups, respectively.

The following table presents the findings for all patients randomized who had at least one

post randomization assessment.

Table 5. Monotherapy Study Median Incidence of CPS per 8 Weeks

Treatment

Number of Patients

Baseline

Incidence

Randomized

Phase Incidence

High dose divalproex sodium

13.2

10.7

Low dose divalproex sodium

14.2

13.8

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

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

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

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

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

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

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

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

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

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

patients receiving low dose valproate.

Information on pediatric studies is presented in section 8.

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

Valproate Sodium Injection, USP, equivalent to 100 mg of valproic acid per mL, is a clear, colorless

solution in 5 mL single dose vials, available in trays of 10 vials (NDC 0143-9637-10).

Recommended storage: Store vials at 20º to 25ºC (68º to 77ºF) with excursions between 15º and 30ºC

(59º and 86ºF) [See USP Controlled Room Temperature].

No preservatives have been added. Unused portion of container should be discarded.

17 PATIENT COUNSELING INFORMATION

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 [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 pregnant.

Hyperammonemia

Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and to

notify the prescriber if any of these symptoms occur [see WARNINGS AND PRECAUTIONS (5.8,

5.9)].

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.

Multiorgan 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 (5.11)].

Rx Only

Manufactured by: HIKMA FARMACÊUTICA (PORTUGAL), S.A.

Estrada do Rio da Mó, 8, 8A e 8B - Fervença - 2705-906 Terrugem SNT, PORTUGAL

Distributed by: WEST-WARD PHARMACEUTICALS CORP.

Eatontown, NJ 07724 USA

Novaplus is a registered trademark of Vizient, Inc.

Revised: January 2018

PIN321-NOV/4

PRINCIPAL DISPLAY PANEL

NDC 0143-9637-01

VALPROATE

Sodium Injection, USP

FOR IV INFUSION ONLY

500 mg/5 mL

(100 mg/mL)

5 mL Single Dose Vial

Rx ONLY

NDC 0143-9637-10

VALPROATE

Sodium Injection, USP

FOR IV INFUSION ONLY

500 mg/5 mL

(100 mg/mL)

10 x 5 mL Single Dose Vials

Rx ONLY

SERIALIZATION IMAGE

West-Ward Pharmaceuticals Corp

VALPROATE SODIUM

valproate sodium injection

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 143-9 6 37

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

VALPRO ATE SO DIUM (UNII: 5VOM6 GYJ0 D) (VALPROIC ACID - UNII:6 14OI1Z5WI)

VALPROIC ACID

10 0 mg in 1 mL

Inactive Ingredients

Ingredient Name

Stre ng th

EDETATE DISO DIUM (UNII: 7FLD9 1C8 6 K)

0 .40 mg in 1 mL

WATER (UNII: 0 59 QF0 KO0 R)

SO DIUM HYDRO XIDE (UNII: 55X0 4QC32I)

HYDRO CHLO RIC ACID (UNII: QTT1758 2CB)

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:0 143-9 6 37-

10 in 1 TRAY

0 4/15/20 13

1

NDC:0 143-9 6 37-

5 mL in 1 VIAL, SINGLE-DOSE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 523

0 4/15/20 13

Labeler -

West-Ward Pharmaceuticals Corp (001230762)

Registrant -

West-ward Pharmaceuticals Corp (001230762)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

HIKMA FARMACEUTICA

(PORTUGAL), S.A

4527429 43

ANALYSIS(0 143-9 6 37) , LABEL(0 143-9 6 37) , MANUFACTURE(0 143-

9 6 37) , PACK(0 143-9 6 37)

Revised: 12/2018

Similar products

Search alerts related to this product

Share this information