You are here: Home > Prescription(RX) Drugs > V > Valproic Acid (Ncs Healthcare Of Ky, Inc Dba Vangard Labs)

Name:Valproic Acid
Manufacturer:Ncs Healthcare Of Ky, Inc Dba Vangard Labs
Category:Prescription Marketed Drugs


Valproic Acid Capsules

VALPROIC ACID - valproic acid capsule 
NCS HealthCare of KY, Inc dba Vangard Labs

----------

Valproic Acid Capsules

Boxed Warning

BOX WARNING:

hepa totoxici ty:

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 CAPSULES, USP 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

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 Structural Formula.

Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a characteristic odor. It is slightly

soluble in water (1.3 mg/mL) and very soluble in organic solvents.

Valproic Acid Capsules, USP are antiepileptics for oral administration. Each soft gelatin capsule contains 250 mg valproic acid.

Inactive Ingredients: peanut oil, gelatin, glycerin, and titanium dioxide.

peanut oil, gelatin, glycerin, and titanium dioxide.

ClLINICAL PHARMACOLOGY

Pharmacodynamics

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

Pharmacokinetics

Absorption/Bioavailability

Equivalent oral doses of divalproex sodium products and Valproic Acid Capsules, USP 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 tablet and Valproic

Acid Capsules, USP 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

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

g/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 proteinbound

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 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 m2 and 11 L/1.73 m2, respectively. Mean

plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for

valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.

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

example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate

more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified

whenever concomitant antiepileptics are introduced or withdrawn.

Special Populations

Effect of Age:

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

children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other

enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma

protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range

of 7 to 13 hours in children greater than 2 months.

Children - Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/

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

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

compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%.

Accordingly, the initial dosage should be reduced in the elderly. (See DOSAGE AND ADMINISTRATION.)

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 m2, 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.

INFORMATION FOR PATIENTS

Information for Patients

Since Valproic Acid Capsules, USP have been associated with certain types of birth defects, female patients of child-bearing age

considering the use of Valproic Acid Capsules, USP 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

Patients, their caregivers and families should be counseled that AEDs, including Valproic

Acid Capsules, USP 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 precau tions

- Hyperammonemia) and be told to inform the prescriber if any of these symptoms occur.

- Hyperammonemia) and be told to inform the prescriber if any of these symptoms occur.

Since Valproic Acid Capsules, USP 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).

PATIENT INFORMATION LEAFLET

Important Information for Women Who Could Become Pregnant About the Use of Valproic Acid Capsules, USP.

Please read this leaflet carefully before you take this medication. This leaflet provides a summary of important information about

taking this medication to women who could become pregnant. If you have any questions or concerns, or want more information

about this medication, contact your doctor or pharmacist.

Information for Women Who Could Become Pregnant

This medication can be obtained only by prescription from your doctor. The decision to use this medication is one that you and your

doctor should make together, taking into account your individual needs and medical condition.

Before using this medication, women who can become pregnant should consider the fact that this medication has 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%.

This medication 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 this medication than some other drugs that treat

your medical condition.

Information For Women Who Are Planning to Get Pregnant

• Women taking this medication 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 this medication, you should contact your doctor immediately.

Other Important Information

• Your medication 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 your medication, contact your hospital emergency room or local poison

center immediately.

• Your medication 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 Capsules, USP to women who could become

pregnant. If you would like more information about the other potential risks and benefits of this medication, ask your doctor or

pharmacist to let you read the professional labeling and then discuss it with them. If you have any questions or concerns about

taking this medication, you should discuss them with your doctor.

CLINICAL STUDIES

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 in epilepsy 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.

Epilepsy

The efficacy of divalproex sodium tablets 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 tablets 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 Number Baseline Experimental

Treatment of Patients Incidence Incidence

divalproex sodium tablets 75 16.0 8.9*

Placebo 69 14.5 11.5

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

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

was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an

improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of

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

patients achieving any particular level of improvement was consistently higher for divalproex sodium tablets than for placebo. For

example, 45% of patients treated with divalproex sodium tablets had a ≥50% reduction in complex partial seizure rate compared

to 23% of patients treated with placebo.

-100%

-75%

-50%

-25%

25%

50%

75%

100%

0%

100 50 0

% of Patients

Divalproex

sodium

Figure 1

No Change

Improvement

% Reduction In CPS Rate

Worsening

Placebo

The second study assessed the capacity of divalproex sodium tablets 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 tablets. 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 tablet monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123

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

g/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.

Monotherapy Study

Median Incidence of CPS per 8 Weeks

Number Baseline Randomized Phase

Treatment of Patients Incidence Incidence

High dose 131 13.2 10.7*

divalproex sodium tablets

Low dose 134 14.2 13.8

divalproex sodium tablets

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

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

rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an

improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of

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

that the proportion of patients achieving any particular level of reduction was consistently higher for high dose divalproex sodium

tablets than for low dose divalproex sodium tablets. For example, when switching from carbamazepine, phenytoin, phenobarbital or

primidone monotherapy to high dose divalproex sodium tablets 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 tablets.

-100%

-75%

-50%

-25%

25%

50%

75%

100%

0%

100 50 0

% of Patients

High Dose

Low Dose

Figure 2

No Change

Improvement

% Reduction In CPS Rate

INDICATIONS AND USAGE

Valproic Acid Capsules, USP are indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial

seizures that occur either in isolation or in association with other types of seizures. Valproic Acid Capsules, USP are indicated for use

as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple

seizure types which include absence seizures.

Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized

epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.

CONTRAINDICATIONS

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

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 Capsules, USP to patients with a prior history of hepatic

disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure

disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience

has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity,

especially those with the aforementioned conditions. When Valproic Acid Capsules, USP 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.

T he 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 BOX

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/m2 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/

m2 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/m2 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 precau tions ).

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Valproic Acid Capsules, USP 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 19

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 placebotreated

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 increasedrisk

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 trails 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 Drug Patients Relative Risk: Risk Difference:

Patients with with Events Incidence of Additional Drug

Events Per Per 1000 Events in Patients with

1000 Patients Patients Drug Patients/ Events Per

Incidence in 1000 Patients

Placebo Patients

Epilepsy 1.0 3.4 3.5 2.4

Psychiatric 5.7 8.5 1.5 2.9

Other 1.0 1.8 1.9 0.9

Total 2.4 4.3 1.8 1.9

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

conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Valproic Acid Capsules, USP 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 tablets 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

PRECAUTIONS

Hepatic Dysfunction

See BOXED WARNING, CONTRAINDICATIONS and WARNINGS.

Pancreatitis

Pancreatitis

See BOXED WARNING and WARNINGS.

Hypothermia

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

). 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).

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).

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 Capsules, USP be monitored for platelet count

and coagulation parameters prior to planned surgery. In a clinical trial of divalproex sodium tablets 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.

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 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.

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 co-administration on the pharmacokinetics

or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are

continuously being reported.

Drugs for Which a Potentially Important Valproate Interaction has Been Observed:

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

females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease

in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in

an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with

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

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

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

carbamazepine-10, 11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.

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

absence type seizures.

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

valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and

volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination

half-life of diazepam remained unchanged upon addition of valproate.

Ethosuximide - Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg

with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of

ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and

ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.

Lamotrigine - In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26

to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered

with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported

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

concomitant valproate administration.

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

14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance

of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of

valproate.

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

concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum

barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.

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

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

Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60%

increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30%

in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.

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

phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.

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

plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.

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

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 Capsules, USP therapy is instituted in patients

taking anticoagulants.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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/m2 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.

Mutagenesis

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

not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid

exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another

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

significance of an increase in SCE frequency is not known.

Fertility

Chronic toxicity studies in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral

doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum human daily dose on a mg/m2

basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the maximum human daily dose or greater on a mg/m2 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/m2 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 Capsules, USP healthcare providers

are advised to recommend that pregnant patients taking Valproic Acid Capsules, USP 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

Pediatric Use

Experience has indicated that pediatric patients under the age of two years are at considerably increased risk of developing fatal

hepatotoxicity, especially those with the aforementioned conditions (see BOXED WARNING). When Valproic Acid Capsules, USP are

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

against the risks. Above 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/m2 basis. They were not seen at 90 mg/kg, or 40% of the

maximum human daily dose on a mg/m2 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

). 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

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 tablets

were 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 tablet-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 tablet-treated patients and

for which the incidence was greater than in a 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 tablets alone, or the combination of divalproex

sodium tablets and other antiepilepsy drugs.

Table 2

Adverse Events Reported by ≥5% of Patients Treated

with Divalproex Sodium Tablets During Placebo-Controlled

Trial of Adjunctive Therapy for Complex Partial Seizures

Divalproex sodium (%) Placebo (%)

Body System/Event (n=77) (n=70)

Body as a Whole

Headache 31 21

Asthenia 27 7

Fever 6 4

Gastrointestinal System

Nausea 48 14

Vomiting 27 7

Abdominal Pain 23 6

Diarrhea 13 6

Anorexia 12 0

Dyspepsia 8 4

Constipation 5 1

Nervous System

Somnolence 27 11

Tremor 25 6

Dizziness 25 13

Diplopia 16 9

Amblyopia/Blurred Vision 12 9

Ataxia 8 1

Nystagmus 8 1

Emotional Lability 6 4

Thinking Abnormal 6 0

Amnesia 5 1

Respiratory System

Flu Syndrome 12 9

Infection 12 6

Bronchitis 5 1

Rhinitis 5 4

Other

Alopecia 6 1

Weight Loss 6 0

Table 3 lists treatment-emergent adverse events which were reported by ≥5% of patients in the high dose divalproex sodium

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

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 tablets alone, or the combination of divalproex sodium tablets 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 Tablets Monotherapy for Complex Partial Seizures1

H igh Dose (%) Low Dose (%)

Body System/Event (n=131) (n=134)

Body as a Whole

Asthenia 21 10

Digestive System

Nausea 34 26

Diarrhea 23 19

Vomiting 23 15

Abdominal Pain 12 9

Anorexia 11 4

Dyspepsia 11 10

Hemic/Lymphatic System

Thrombocytopenia 24 1

Ecchymosis 5 4

Metabolic/Nutritional

Weight Gain 9 4

Peripheral Edema 8 3

Nervous System

Tremor 57 19

Somnolence 30 18

Dizziness 18 13

Insomnia 15 9

Nervousness 11 7

Amnesia 7 4

Nystagmus 7 1

Depression 5 4

Respiratory System

Infection 20 13

Pharyngitis 8 2

Dyspnea 5 1

Skin and Appendages

Alopecia 24 13

Special Senses

Amblyopia/Blurred Vision 8 4

Tinnitus 7 1

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

in the low dose group.

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

divalproex sodium tablets 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

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).

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).

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

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 hyperglycinemia.

Genitourinary: Enuresis and urinary tract infection.

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

not been established. Ear pain has also been reported.

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

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

Mania

Although Valproic Acid Capsules, USP have 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 Capsules, USP have 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

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

DOSAGE AND ADMINISTRATION

THE CAPSULES SHOULD BE SWALLOWED WITHOUT CHEWING TO AVOID LOCAL IRRITATION OF THE MOUTH AND THROAT.

Valproic Acid Capsules, USP are administered orally. Valproic Acid Capsules, USP are indicated as monotherapy and

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

complex absence seizures. As the Valproic Acid Capsules, USP 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 Capsules, USP have not been systematically studied as initial therapy. Patients should

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

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

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

100 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 -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 Capsules, USP therapy, or delayed by 1 to 2 weeks if there is a

concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be

highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy: Valproic Acid Capsules, USP 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

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

), 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 Capsules, USP 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 Capsules, USP (15 mg/kg/day):

Weight Number of Capsules

Total Daily

(Kg) (Lb) Dose (mg) Dose 1 Dose 2 Dose 3

10-24.9 22-54.9 250 0 0 1

25-39.9 55-87.9 500 1 0 1

40-59.9 88-131.9 750 1 1 1

60-74.9 132-164.9 1,000 1 1 2

75-89.9 165-197.9 1,250 2 1 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 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 Capsules, USP 250 mg: Each off-white colored soft gelatin capsule, imprinted with VALPROIC 250, contains Valproic

Acid, USP packaged in blisterpacks of 30 Capsules and 31 Capsules. Store at 20-25oC (68-77oF). Excursions permitted to 15-30oC (59-86oF). [See USP

Controlled Room Temperature.]

Dispense in a tight, light-resistant container.

REFERENCES

Manufactured by:

Catalent Pharma Solutions

2725 Scherer Drive

St. Petersburg, FL 33716-1016

PRINCIPAL DISPLAY PANEL

Principal Display Panel- Valproic Acid Caps 250mgValproic Acid Caps.

USP 250mg


VALPROIC ACID 
valproic acid capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0615-1325(NDC:0832-1008)
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
VALPROIC ACID (VALPROIC ACID) VALPROIC ACID 250 mg
Product Characteristics
Color WHITE (Off White) Score no score
Shape CAPSULE (Oblong) Size 18mm
Flavor Imprint Code
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0615-1325-31 31 CAPSULE (31 CAPSULE) in 1 BLISTER PACK None
2 NDC:0615-1325-39 30 CAPSULE (30 CAPSULE) in 1 BLISTER PACK None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA073229 10/29/1991

Labeler - NCS HealthCare of KY, Inc dba Vangard Labs (050052943)
Establishment
Name Address ID/FEI Operations
NCS HealthCare of KY, Inc dba Vangard Labs 050052943 RELABEL, REPACK

Revised: 08/2010 NCS HealthCare of KY, Inc dba Vangard Labs



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


Copyright © 2017 Drugsdb.eu by Dionisios Fentas || Terms of Use

Loading

Prescription Marketed Drugs Alphabetically
A| B| C| D| E| F| G| H| I| J| K| L| M| N| O| P| Q| R| S| T| U| V| W| X| Y| Z| 0-9

Categories:
Prescription(RX) Drugs
Over-the-counter (OTC) Drugs
Homeopathic Drugs
Animal Drugs
Feedback