VALPROIC ACID solution

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

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Active ingredient:
VALPROIC ACID (UNII: 614OI1Z5WI) (VALPROIC ACID - UNII:614OI1Z5WI)
Available from:
Watson Laboratories, Inc.
INN (International Name):
VALPROIC ACID
Composition:
VALPROIC ACID 250 mg in 5 mL
Prescription type:
PRESCRIPTION DRUG
Authorization status:
Abbreviated New Drug Application

VALPROIC ACID- valproic acid solution

Watson Laboratories, Inc.

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VALPROIC ACID

ORAL SOLUTION, USP

Rx Only

Rev. 792:03 9/11

50383-792

VALPROIC ACID ORAL SOLUTION, USP

Rx only

BOXED WARNING:

HEPATOTOXICITY

HEPATIC FAILURE RESULTING IN FATALITIES HAS OCCURRED IN PATIENTS

RECEIVING VALPROIC ACID. EXPERIENCE HAS INDICATED THAT CHILDREN

UNDER THE AGE OF TWO YEARS ARE AT A CONSIDERABLY INCREASED RISK OF

DEVELOPING FATAL HEPATOTOXICITY, ESPECIALLY THOSE ON MULTIPLE

ANTICONVULSANTS, THOSE WITH CONGENITAL METABOLIC DISORDERS, THOSE

WITH SEVERE SEIZURE DISORDERS ACCOMPANIED BY MENTAL RETARDATION,

AND THOSE WITH ORGANIC BRAIN DISEASE. WHEN VALPROIC ACID PRODUCTS

ARE USED IN THIS PATIENT GROUP, THEY SHOULD BE USED WITH EXTREME

CAUTION AND AS A SOLE AGENT. THE BENEFITS OF THERAPY SHOULD BE

WEIGHED AGAINST THE RISKS. ABOVE THIS AGE GROUP, EXPERIENCE IN EPILEPSY

HAS INDICATED THAT THE INCIDENCE OF FATAL HEPATOTOXICITY DECREASES

CONSIDERABLY IN PROGRESSIVELY OLDER PATIENT GROUPS.

THESE INCIDENTS USUALLY HAVE OCCURRED DURING THE FIRST SIX MONTHS OF

TREATMENT. SERIOUS OR FATAL HEPATOTOXICITY MAY BE PRECEDED BY NON-

SPECIFIC SYMPTOMS SUCH AS MALAISE, WEAKNESS, LETHARGY, FACIAL EDEMA,

ANOREXIA AND VOMITING. IN PATIENTS WITH EPILEPSY, A LOSS OF SEIZURE

CONTROL MAY ALSO OCCUR. PATIENTS SHOULD BE MONITORED CLOSELY FOR

APPEARANCE OF THESE SYMPTOMS. LIVER FUNCTION TESTS SHOULD BE

PERFORMED PRIOR TO THERAPY AND AT FREQUENT INTERVALS THEREAFTER,

ESPECIALLY DURING THE FIRST SIX MONTHS.

TERATOGENICITY

VALPROATE CAN PRODUCE TERATOGENIC EFFECTS SUCH AS NEURAL TUBE

DEFECTS (E.G., SPINA BIFIDA). ACCORDINGLY, THE USE OF VALPROATE PRODUCTS

IN WOMEN OF CHILDBEARING POTENTIAL REQUIRES THAT THE BENEFITS OF ITS

USE BE WEIGHED AGAINST THE RISK OF INJURY TO THE FETUS.

THIS IS ESPECIALLY IMPORTANT WHEN THE TREATMENT OF A SPONTANEOUSLY

REVERSIBLE CONDITION NOT ORDINARILY ASSOCIATED WITH PERMANENT

INJURY OR RISK OF DEATH (E.G., MIGRAINE) IS CONTEMPLATED. SEE WARNINGS,

INFORMATION FOR PATIENTS.

A PATIENT INFORMATION LEAFLET DESCRIBING THE TERATOGENIC POTENTIAL

OF VALPROATE IS AVAILABLE FOR PATIENTS.

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.)

DESCRIPTION

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

dipropylacetic acid. Valproic acid has the following structure:

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

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

Valproic Acid Oral Solution, USP is an antiepileptic for oral administration. The oral solution contains

the equivalent of 250 mg valproic acid per 5 mL as the sodium salt.

Inactive Ingredients:

FD&C Red No. 40, methylparaben, natural and artificial raspberry flavor, propylparaben, purified

water, sodium hydroxide, sorbitol, and sucrose.

CLINICAL PHARMACOLOGY

Pharmacodynamics

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

valproate exerts its antiepileptic effects have not been established. It has been suggested that its activity

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

Pharmacokinetics

Absorption/Bioavailability

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

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

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

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

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

conditions achieved in chronic use in the treatment of epilepsy.

However, it is possible that differences among the various valproate products in Tmax and Cmax could

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

greater influence on the rate of absorption of the divalproex sodium tablet (increase in Tmax from 4 to

8 hours) than on the absorption of the divalproex sodium sprinkle capsules (increase in Tmax from 3.3

to 4.8 hours).

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

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

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

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

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

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

from a practical clinical standpoint.

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

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

with epilepsy (see DOSAGE AND ADMINISTRATION). Nonetheless, any changes in dosage

administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied

by close monitoring of clinical status and valproate plasma concentrations.

Distribution

Protein Binding:

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

approximately 10% at 40 μg/mL to 18.5% at 130 μg/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 PRECAUTIONS, Drug Interactions 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 ß-oxidation is the other

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

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

unchanged in urine.

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

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

protein binding. The kinetics of unbound drug are linear.

Elimination

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

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

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

hours following oral dosing regimens of 250 to 1000 mg.

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

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

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

clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant

antiepileptics are introduced or withdrawn.

Special Populations

Effect of Age:

Ne o nate s

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.

Childre n

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.

Elde rly

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

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

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

(See DOSAGE AND ADMINISTRATION).

Effect of Gender:

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

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

Effect of Race:

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

Effect of Disease:

Liver Disease

(See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS). Liver disease impairs the

capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7

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

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

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

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

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

concentrations may appear to be normal.

Renal Disease

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

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

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

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

concentrations may be misleading.

Plasma Levels and Clinical Effect

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 μg/mL to 18.5% at 130 μg/mL. Higher than expected

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

diseases.

Epilepsy:

The therapeutic range is commonly considered to be 50 to 100 μg/mL of total valproate, although some

patients may be controlled with lower or higher plasma concentrations.

Clinical Trials

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

Epileps y

The efficacy of divalproex sodium in reducing the incidence of complex partial seizures (CPS) that

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

In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy), 144

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

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

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

antiepilepsy drug (AED), either divalproex sodium or placebo. Randomized patients were to be

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

Adjunctive Therapy Study

Median Incidence of CPS per 8 Weeks

Add-on

Treatment

Number of

Patients

Bas eline

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 divalproex

sodium than for placebo. For example, 45% of patients treated with divalproex sodium had a ≥ 50%

reduction in complex partial seizure rate compared to 23% of patients treated with placebo.

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

The second study assessed the capacity of divalproex sodium to reduce the incidence of CPS when

administered as the sole AED. The study compared the incidence of CPS among patients randomized to

either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison

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

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

phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to

divalproex sodium. Patients entering the randomized phase were then brought to their assigned target

dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks.

Less than 50% of the patients randomized, however, completed the study. In patients converted to

divalproex sodium monotherapy, the mean total valproate concentrations during monotherapy were 71

and 123 μg/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

postrandomization assessment.

Monotherapy Study

Median Incidence of CPS per 8 Weeks

Treatment

Number

of Patients

Bas eline

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

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

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

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

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

INDICATIONS AND USAGE

Valproic acid 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.

Valproic acid is indicated for use as sole and adjunctive therapy in the treatment of simple and complex

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

seizures.

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

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

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

SEE WARNINGS FOR STATEMENT REGARDING FATAL HEPATIC DYSFUNCTION.

CONTRAINDICATIONS

VALPROIC ACID SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE

OR SIGNIFICANT HEPATIC DYSFUNCTION.

Valproic acid is contraindicated in patients with known hypersensitivity to the drug.

Valproic acid is contraindicated in patients with known urea cycle disorders (see WARNINGS).

WARNINGS

Hepatotoxicity

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

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

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

facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also

occur. Patients should be monitored closely for appearance of these symptoms. Liver function

tests should be performed prior to therapy and at frequent intervals thereafter, especially during

the first six months. However, 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 valproic acid to patients with a prior history of

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

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

with organic brain disease may be at particular risk. Experience has indicated that children under

the age of two years are at considerably increased risk of developing fatal hepatotoxicity,

especially those with the aforementioned conditions. When valproic acid products are used in this

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

therapy should be weighed against the risks. Above this age group, experience has indicated that

the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

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

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

discontinuation of drug.

Usage in Pregnancy

VALPROATE CAN PRODUCE TERATOGENIC EFFECTS. DATA SUGGEST THAT THERE IS

AN INCREASED INCIDENCE OF CONGENITAL MALFORMATIONS ASSOCIATED WITH THE

USE OF VALPROATE BY WOMEN WITH SEIZURE DISORDERS DURING PREGNANCY WHEN

COMPARED TO THE INCIDENCE IN WOMEN WITH SEIZURE DISORDERS WHO DO NOT

USE ANTIEPILEPTIC DRUGS DURING PREGNANCY, THE INCIDENCE IN WOMEN WITH

SEIZURE DISORDERS WHO USE OTHER ANTIEPILEPTIC DRUGS, AND THE BACKGROUND

INCIDENCE FOR THE GENERAL POPULATION. THEREFORE, VALPROATE SHOULD BE

CONSIDERED FOR WOMEN OF CHILDBEARING POTENTIAL ONLY AFTER THE RISKS

HAVE BEEN THOROUGHLY DISCUSSED WITH THE PATIENT AND WEIGHED AGAINST

THE POTENTIAL BENEFITS OF TREATMENT.

THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE THAT INDICATE THE

USE OF ANTIEPILEPTIC DRUGS DURING PREGNANCY RESULTS IN AN INCREASED

INCIDENCE OF CONGENITAL MALFORMATIONS IN OFFSPRING. ANTIEPILEPTIC DRUGS,

INCLUDING VALPROATE, SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING

POTENTIAL ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSENTIAL IN THE

MANAGEMENT OF THEIR MEDICAL CONDITION.

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

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

hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder

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

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

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

Human Data

Congenital Malformations

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

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

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

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

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

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

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

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

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

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

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

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

or bipolar disorder).

THE STRONGEST ASSOCIATION OF MATERNAL VALPROATE USAGE WITH CONGENITAL

MALFORMATIONS IS WITH NEURAL TUBE DEFECTS (AS DISCUSSED UNDER THE NEXT

SUBHEADING). HOWEVER, OTHER CONGENITAL ANOMALIES (E.G. CRANIOFACIAL

DEFECTS, CARDIOVASCULAR MALFORMATIONS AND ANOMALIES INVOLVING

VARIOUS BODY SYSTEMS), COMPATIBLE AND INCOMPATIBLE WITH LIFE, HAVE BEEN

REPORTED. SUFFICIENT DATA TO DETERMINE THE INCIDENCE OF THESE CONGENITAL

ANOMALIES IS NOT AVAILABLE.

Neural Tube Defects

THE INCIDENCE OF NEURAL TUBE DEFECTS IN THE FETUS IS INCREASED IN MOTHERS

RECEIVING VALPROATE DURING THE FIRST TRIMESTER OF PREGNANCY. THE CENTERS

FOR DISEASE CONTROL (CDC) HAS ESTIMATED THE RISK OF VALPROIC ACID EXPOSED

WOMEN HAVING CHILDREN WITH SPINA BIFIDA TO BE APPROXIMATELY 1 TO 2%. THE

AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS (ACOG) ESTIMATES

THE GENERAL POPULATION RISK FOR CONGENITAL NEURAL TUBE DEFECTS AS 0.14%

TO 0.2%.

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

part of routine prenatal care in pregnant women receiving valproate.

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

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

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

specifically is reduced by folic acid supplementation is unknown. DIETARY FOLIC ACID

SUPPLEMENTATION BOTH PRIOR TO AND DURING PREGNANCY SHOULD BE

ROUTINELY RECOMMENDED TO PATIENTS CONTEMPLATING PREGNANCY.

Other Adverse Pregnancy Effects

PATIENTS TAKING VALPROATE MAY DEVELOP CLOTTING ABNORMALITIES (SEE

PRECAUTIONS - GENERAL and WARNINGS). A PATIENT WHO HAD LOW FIBRINOGEN

WHEN TAKING MULTIPLE ANTICONVULSANTS INCLUDING VALPROATE GAVE BIRTH

TO AN INFANT WITH AFIBRINOGENEMIA WHO SUBSEQUENTLY DIED OF HEMORRHAGE.

IF VALPROATE IS USED IN PREGNANCY, THE CLOTTING PARAMETERS SHOULD BE

MONITORED CAREFULLY.

PATIENTS TAKING VALPROATE MAY DEVELOP HEPATIC FAILURE (SEE WARNINGS -

HEPATOTOXICITY and BOXED WARNING). FATAL HEPATIC FAILURES, IN A NEWBORN

AND IN AN INFANT, HAVE BEEN REPORTED FOLLOWING THE MATERNAL USE OF

VALPROATE DURING PREGNANCY.

There have been reports of developmental delay, autism and/or autism spectrum disorder in the

offspring of women exposed to valproate during pregnancy.

Animal Data

Animal studies have demonstrated valproate-induced teratogenicity. Increased frequencies of

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

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

the most common structural abnormalities produced in experimental animals, but neural tube closure

defects have been seen in mice exposed to maternal plasma valproate concentrations exceeding 230

μg/mL (2.3 times the upper limit of the human therapeutic range) during susceptible periods of

embryonic development. Administration of an oral dose of 200 mg/kg/day or greater (50% of the

maximum human daily dose or greater on a mg/m basis) to pregnant rats during organogenesis produced

malformations (skeletal, cardiac, and urogenital) and growth retardation in the offspring. These doses

resulted in peak maternal plasma valproate levels of approximately 340 μg/mL or greater (3.4 times the

upper limit of the human therapeutic range or greater). Behavioral deficits have been reported in the

offspring of rats given a dose of 200 mg/kg/day throughout most of pregnancy. An oral dose of 350

mg/kg/day (approximately 2 times the maximum human daily dose on a mg/m basis) produced skeletal

and visceral malformations in rabbits exposed during organogenesis. Skeletal malformations, growth

retardation, and death were observed in rhesus monkeys following administration of an oral dose of 200

mg/kg/day (equal to the maximum human daily dose on a mg/m basis) during organogenesis. This dose

resulted in peak maternal plasma valproate levels of approximately 280 μg/mL (2.8 times the upper limit

of the human therapeutic range).

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).

Urea Cycle Disorders (UCD)

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

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

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

ornithine transcarbamylase deficiency. Prior to the initiation of valproate therapy, evaluation for UCD

should be considered in the following patients: 1) those with a history of unexplained encephalopathy

or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum

encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2)

those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein

avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths

(particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of

unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt

treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle

disorders (see CONTRAINDICATIONS and PRECAUTIONS).

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including valproic acid, increase the risk of suicidal thoughts or behavior

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

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

unusual changes in mood or behavior.

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

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

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

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

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

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

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

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

drug effect on suicide.

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

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

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

behavior beyond 24 weeks could not be assessed.

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

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

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

substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative

risk by indication for all evaluated AEDs.

Table 1

Risk by indication for antiepileptic drugs in the pooled analysis

Indication

Placebo Patients

with Events Per

1000 Patients

Drug Patients

with Events Per

1000 Patients

Relative Risk:

Incidence of Events in

Drug Patients/Incidence

in Placebo Patients

Risk Difference:Additional

Drug Patients with Events

Per 1000 Patients

Epilepsy

Psychiatric

Other

Total

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

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

epilepsy and psychiatric indications.

Anyone considering prescribing valproic acid or any other AED must balance the risk of suicidal

thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which

AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of

suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the

prescriber needs to consider whether the emergence of these symptoms in any given patient may be

related to the illness being treated.

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

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

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

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

immediately to healthcare providers.

Interaction with Carbapenem Antibiotics

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

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

concentrations should be monitored frequently after initiating carbapenem therapy. Alternative

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

significantly or seizure control deteriorates (see PRECAUTIONS - Drug Interactions).

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 events. 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).

Thrombocytopenia

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia (see

PRECAUTIONS) may be dose-related. In a clinical trial of divalproex sodium as monotherapy in

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

least one value of platelets ≤ 75 x 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 μg/mL (females) or ≥ 135 μg/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.

PRECAUTIONS

Hepatic Dysfunction

See BOXED WARNING, CONTRAINDICATIONS, and WARNINGS.

Pancreatitis

See BOXED WARNING and WARNINGS.

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 - Topiramate). 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.

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

PRECAUTIONS - Hypothermia). If ammonia is increased, valproate therapy should be discontinued.

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

undergo investigation for underlying urea cycle disorders (see CONTRAINDICATIONS and

WARNINGS - Urea Cycle Disorders (UCD) and PRECAUTIONS - Hyperammonemia and

Encephalopathy Associated with Concomitant Topiramate Use).

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.

Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use

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

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

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

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

hyperammonemia (see PRECAUTIONS - Hypothermia). In most cases, symptoms and signs abated

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

not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of

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

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

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

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

considered and an ammonia level should be measured. (see CONTRAINDICATIONS and

WARNINGS - Urea Cycle Disorders and PRECAUTIONS - Hyperammonemia).

General

Because of reports of thrombocytopenia (see WARNINGS), inhibition of the secondary phase of

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

coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended

that patients receiving valproic acid be monitored for platelet count and coagulation parameters prior to

planned surgery. 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 µg/mL (females) or ≥ 135 µg/mL (males). Evidence of hemorrhage, bruising, or

a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of

therapy.

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 PRECAUTIONS - Drug Interactions).

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.

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.

Multi-organ Hypersensitivity Reaction

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

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

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

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

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

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

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

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

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

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

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

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

indicate this to be a possibility.

Information for Patients

Since valproic acid has been associated with certain types of birth defects, female patients of

childbearing age considering the use of valproic acid should be advised of the risk and of alternative

therapeutic options and to read the Patient Information Leaflet, which appears as the last section of the

labeling. This is especially important when the treatment of a spontaneously reversible condition

not ordinarily associated with permanent injury or risk of death (e.g., migraine) is considered.

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy

Registry if they become pregnant. This registry is collecting information about the safety of

antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334

(see PRECAUTIONS - Pregnancy).

Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be

symptoms of pancreatitis and, therefore, require further medical evaluation promptly.

Suicidal Thinking and Behavior

Patients, their caregivers, and families should be counseled that AEDs, including valproic acid, may

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

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

emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be

reported immediately to the healthcare providers (see WARNINGS).

Patients should be informed of the signs and symptoms associated with hyperammonemic

encephalopathy (see PRECAUTIONS - Hyperammonemia) and be told to inform the prescriber if

any of these symptoms occur.

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

CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as

driving an automobile or operating dangerous machinery, until it is known that they do not become

drowsy from the drug.

Patients should be instructed that a fever associated with other organ system involvement (rash,

lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately (see

PRECAUTIONS - Multi-organ Hypersensitivity Reaction).

Drug Interactions

Effects of Co-Administered Drugs on Valproate Clearance

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

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

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

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

polytherapy with antiepilepsy drugs.

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

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

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

oxidation.

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

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

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

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

new interactions are continuously being reported.

Drugs for Which a Potentially Important Interaction Has Been Observed:

Aspirin

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

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

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

valproate alone. The ß-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.

Felbamate

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

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

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

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

be necessary when felbamate therapy is initiated.

Carbapenem Antibiotics

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

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

control. The mechanism of this interaction 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).

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.

Effects of Valproate on Other Drugs

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

glucuronyltransferases.

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

coadministration 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 coadministration of valproate and CBZ to epileptic patients.

Clonazepam

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

history of absence type seizures.

Diazepam

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

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

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

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

remained unchanged upon addition of valproate.

Ethosuximide

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

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

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

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

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

Lamotrigine

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

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

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

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

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

concomitant valproate administration.

Phenobarbital

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

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

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

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

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

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

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

possible, and the barbiturate dosage decreased, if appropriate.

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

Phenytoin

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

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

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

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

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

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

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

clinical situation.

Tolbutamide

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

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

displacement is unknown.

Topiramate

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

with and without encephalopathy (see CONTRAINDICATIONS and WARNINGS - Urea Cycle

Disorders and PRECAUTIONS - Hyperammonemia and - Hyperammonemia and Encephalopathy

Associated with Concomitant Topiramate Use). Concomitant administration of topiramate with

valproic acid has also been associated with hypothermia in patients who have tolerated either drug

alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia

has been reported (see PRECAUTIONS - Hypothermia and Hyperammonemia).

Warfarin

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

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

is instituted in patients taking anticoagulants.

Zidovudine

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

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

was unaffected.

Drugs for Which Either No Interaction or a Likely Clinically Unimportant Interaction Has Been

Observed:

Acetaminophen

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

concurrently administered to three epileptic patients.

Clozapine

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

clozapine.

Lithium

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

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

Lorazepam

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

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

Oral Contraceptive Steroids

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

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenes is

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

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

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

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

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

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

Mutagenes is

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

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

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

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

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

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

Fertility:

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

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

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

(approximately 1.4 times the maximum human daily dose or greater on a mg/m basis). Segment I fertility

studies in rats have shown oral doses up to 350 mg/kg/day (approximately equal to the maximum human

daily dose on a mg/m basis) for 60 days to have no effect on fertility. THE EFFECT OF

VALPROATE ON TESTICULAR DEVELOPMENT AND ON SPERM PRODUCTION AND

FERTILITY IN HUMANS IS UNKNOWN.

Pregnancy:

Pregnancy Category D: See WARNINGS.

To provide information regarding the effects of in utero exposure to valproic acid, healthcare

providers are advised to recommend that pregnant patients taking valproic acid enroll in the NAAED

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

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

http://www.aedpregnancyregistry.org/.

Nursing Mothers:

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

serum concentrations. It is not known what effect this would have on a nursing infant. Consideration

should be given to discontinuing nursing when valproic acid is administered to a nursing woman.

Pediatric Use

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

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

(see BOXED WARNING). When valproic acid is used in this patient group, it should be used with

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

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

decreases considerably in progressively older patient groups.

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

doses to attain targeted total and unbound valproic acid concentrations.

The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid

concentrations. Interpretation of valproic acid concentrations in children should include consideration

of factors that affect hepatic metabolism and protein binding.

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

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

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

been reported. These findings occurred at 240 mg/kg/day, a dosage approximately equivalent to the

human maximum recommended daily dose on a mg/m basis. They were not seen at 90 mg/kg, or 40% of

the maximum human daily dose on a mg/m basis.

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 - Somnolence in the Elderly). 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).

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Hi-Tech Pharmacal Co., Inc. at 1-800-262-

9010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Epileps y

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 events 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 events which were reported by ≥ 5% of divalproex sodium-

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

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

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

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

sodium and other antiepilepsy drugs.

Table 2

Adverse Events Reported by 5% of Patients Treated

with Divalproex Sodium During Placebo-Controlled Trial of

Adjunctive Therapy for Complex Partial Seizures

Body System/Even

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 events which were reported by ≥ 5% of patients in the high

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

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

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

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

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

Table 3

Adverse Events Reported by 5% of Patients in the High Dose

Group in the Controlled Trial of Divalproex Sodium Monotherapy for

Complex Partial Seizures

Body System/Event

High Dose (%)

(n = 131)

Low Dose (%)

(n = 134)

Body as a Whole

Asthenia

Digestive System

Nausea

Diarrhea

Vomiting

Abdominal Pain

Anorexia

Dyspepsia

Hemic/Lymphatic System

Thrombocytopenia

Ecchymosis

Metabolic/Nutritional

Weight Gain

Peripheral Edema

Nervous System

Tremor

Somnolence

Dizziness

Insomnia

Nervousness

Amnesia

Nystagmus

Depression

Respiratory System

Infection

Pharyngitis

Dyspnea

Skin and Appendages

Alopecia

Special Senses

Amblyopia/Blurred Vision

Tinnitus

The following additional adverse events were reported by greater than 1% but less than 5% of the 358

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

Body as a Whole:

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.

Other Patient Populations

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

or greater incidence in the low dose group.

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

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

Gastrointestinal:

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

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

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

increased appetite with weight gain have also been reported. The administration of delayed-release

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

CNS Effects:

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

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

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

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

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

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

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

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

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

encephalopathy, particularly in patients with underlying urea cycle disorders (see WARNINGS - Urea

Cycle Disorders and PRECAUTIONS).

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

therapy.

Dermatologic:

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

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

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

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

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

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

PRECAUTIONS - Drug Interactions).

Psychiatric:

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

deterioration.

Musculoskeletal:

Weakness.

Hematologic:

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

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

PRECAUTIONS - General and Drug Interactions). Relative lymphocytosis, macrocytosis,

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

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

intermittent porphyria.

Hepatic:

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

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

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

WARNINGS).

Endocrine:

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

Abnormal thyroid function tests (see PRECAUTIONS).

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

has not been established.

Pancreatic:

Acute pancreatitis, including fatalities (see WARNINGS).

Metabolic:

Hyperammonemia (see PRECAUTIONS), hyponatremia, and inappropriate ADH secretion.

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

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

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

nonketotic hyperglycemia.

Genitourinary:

Enuresis and urinary tract infection.

Special Senses:

Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect

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

Other:

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

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

Mania

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

associated with bipolar disorder, the following adverse events 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.

Urogenital System:

Dysuria.

Migraine

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

migraine headaches, the following adverse events 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.

OVERDOSAGE

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

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

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

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

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

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

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

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

caution in patients with epilepsy.

DOSAGE AND ADMINISTRATION

Valproic acid is administered orally. Valproic acid is indicated as monotherapy and adjunctive therapy

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

complex absence seizures. As the valproic acid dosage is titrated upward, concentrations of

phenobarbital, carbamazepine, and/or phenytoin may be affected (see PRECAUTIONS - Drug

Interactions ).

Complex Partial Seizures:

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy):

Valproic acid has not been systematically studied as initial therapy. Patients should initiate therapy at 10

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

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

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

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

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

The probability of thrombocytopenia increases significantly at total trough valproate plasma

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

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

reactions.

Conversion to Monotherapy:

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

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

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

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

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

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

approximately 25% every 2 weeks. This reduction may be started at initiation of valproic acid therapy,

or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The

speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be

monitored closely during this period for increased seizure frequency.

Adjunctive Therapy:

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

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

response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been

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

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

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

in divided doses.

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

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

phenytoin dosage was needed (see CLINICAL STUDIES). However, since valproate may interact with

these or other concurrently administered AEDs as well as other drugs (see Drug Interactions),

periodic plasma concentration determinations of concomitant AEDs are recommended during the early

course of therapy (see PRECAUTIONS - Drug Interactions).

Simple and Complex Absence Seizures:

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day

until seizures are controlled or side effects preclude further increases. The maximum recommended

dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.

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

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

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

serum concentrations (see CLINICAL PHARMACOLOGY).

As the valproic acid dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin

may be affected (see PRECAUTIONS).

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

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

hypoxia and threat to life.

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

Weight

(Kg) (Lb)

Total

Daily

Dose (mg)

Number of Teaspoonfuls

of Oral Solution

Dose 1

Dose 2

Dose 3

10 - 24.9

22 - 54.9

25 - 39.9

55 - 87.9

40 - 59.9

88 - 131.9

60 - 74.9

132 - 164.9 1,000

75 - 89.9

165 - 197.9 1,250

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 events. Dose reductions or discontinuation of valproate should be considered in patients with

decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose

should be achieved on the basis of both tolerability and clinical response (see WARNINGS).

Dose-Related Adverse Events

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

dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate

concentrations of ≥ 110 μg/mL (females) or ≥ 135 μg/mL (males) (see PRECAUTIONS). The benefit

of improved therapeutic effect with higher doses should be weighed against the possibility of a greater

incidence of adverse reactions.

G.I. Irritation

Patients who experience G.I. irritation may benefit from administration of the drug with food or by

slowly building up the dose from an initial low level.

HOW SUPPLIED

Valproic Acid Oral Solution, USP is available as a raspberry flavored, reddish clear oral solution

containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of 16 ounces, in

5 mL unit dose and in 10 mL unit dose.

Store at controlled room temperature 15°-30°C (59°-86°F).

Manufactured by:

HI-TECH PHARMACAL CO., INC.

Amityville, NY 11701

Rev. 792:03 9/11

MG #9485

PATIENT INFORMATION LEAFLET

PATIENT INFORMATION LEAFLET

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

Oral Solution, USP

Please read this leaflet carefully before you take valproic acid oral solution, USP. This leaflet

provides a summary of important information about taking valproic acid oral solution, USP to women

who could become pregnant. If you have any questions or concerns, or want more information about

valproic acid oral solution, USP, contact your doctor or pharmacist.

Information for Women Who Could Become Pregnant

Valproic acid oral solution, USP can be obtained only by prescription from your doctor. The decision

to use valproic acid oral solution, USP is one that you and your doctor should make together, taking into

account your individual needs and medical condition.

Before using valproic acid oral solution, USP, women who can become pregnant should consider

the fact that these medications have been associated with birth defects, in particular, with spina

bifida and other defects related to failure of the spinal canal to close normally. Approximately 1 to

2% of children born to women with epilepsy taking divalproex sodium in the first 12 weeks of

pregnancy had these defects (based on data from the Centers for Disease Control, a U.S. agency

based in Atlanta). The incidence in the general population is 0.1 to 0.2%.

Valproic acid oral solution, USP has also been associated with other birth defects such as defects of

the heart, the bones, and other parts of the body. Information suggests that birth defects may be more

likely to occur with these medications than some other drugs that treat your medical condition.

Information for Women Who Are Planning to Get Pregnant

Women taking valproic acid oral solution, USP who are planning to get pregnant should discuss the

treatment options with their doctor.

Information for Women Who Become Pregnant

If you become pregnant while taking valproic acid oral solution, USP you should contact your

doctor immediately.

Other Important Information

Valproic acid oral solution, USP should be taken exactly as prescribed by your doctor to get the

most benefit from your medication and reduce the risk of side effects.

If you have taken more than the prescribed dose of valproic acid oral solution, USP, contact your

hospital emergency room or local poison center immediately.

Valproic acid oral solution, USP was prescribed for your particular condition. Do not use it for

another condition or give the drug to others.

Facts About Birth Defects

It is important to know that birth defects may occur even in children of individuals not taking any

medications or without any additional risk factors.

This summary provides important information about the use of valproic acid oral solution, USP to

women who could become pregnant. If you would like more information about the other potential risks

and benefits of valproic acid oral solution, USP, ask your doctor or pharmacist to let you read the

professional labeling and then discuss it with them. If you have any questions or concerns about taking

valproic acid oral solution, USP, you should discuss them with your doctor.

Call your doctor for medical advice about side effects. You may report side effects to Hi-Tech

Pharmacal Co., Inc. at 1-800-262-9010 or FDA at 1-800-FDA-1088.

Manufactured by:

Hi-Tech Pharmacal Co., Inc.

Amityville, NY 11701

Rev. 792:03 9/11

PRINCIPAL DISPLAY PANEL

NDC 0591-0426-16

Valproic

Acid Oral

Solution

USP

250 mg/5 mL

Watson Rx only 16 fl oz (473 mL)

VALPROIC ACID

valproic acid solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 59 1-0 426

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

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

VALPROIC ACID

250 mg in 5 mL

Inactive Ingredients

Watson Laboratories, Inc.

Ingredient Name

Stre ng th

FD&C RED NO . 4 0 (UNII: WZB9 127XOA)

METHYLPARABEN (UNII: A2I8 C7HI9 T)

PRO PYLPARABEN (UNII: Z8 IX2SC1OH)

WATER (UNII: 0 59 QF0 KO0 R)

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

SO RBITO L (UNII: 50 6 T6 0 A25R)

SUCRO SE (UNII: C151H8 M554)

Product Characteristics

Color

RED (reddish clear)

S core

S hap e

S iz e

Flavor

RASPBERRY (natural and artificial raspberry flavo r)

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 59 1-0 426 -16

473 mL in 1 BOTTLE, PLASTIC

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 740 6 0

0 1/13/19 9 5

Labeler -

Watson Laboratories, Inc. (966714656)

Registrant -

Hi-T ech Pharmacal Co., Inc. (101196749)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Hi-Tech Pharmacal Co ., Inc.

10 119 6 749

MANUFACTURE(0 59 1-0 426 )

Revised: 6/2012

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