Valproic acid

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# Black Box Warning

# Overview
Valproic acid is a anticonvulsant drug that is FDA approved for the {{{indicationType}}} of absence seizure, Simple and complex, complex partial epileptic seizur, manic, bipolar I disorder, migraine; Prophylaxis. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include peripheral edema,alopecia, rash, increased appetite, weight increased, abdominal pain, constipation, diarrhea, indigestion, loss of appetite, nausea, vomiting, ecchymosis, sthenia, backache, amnesia, ataxia, dizziness, headache, insomnia, somnolence, tremor, amblyopia, blurred vision, diplopia, nystagmus, tinnitus, depression, disturbance in thinking, feeling nervous, mood swings, bronchitis, dyspnea, pharyngitis, respiratory tract infection, rhinitis, fever, influenza.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Absence seizure, simple and complex
- Initial 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg
- Maintenance increase dosage 5 to 10 mg/kg/day PO at 1-week intervals give in 2 to 3 divided doses if total daily dose exceeds 250 mg max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
- Complex partial epileptic seizure
- Initial 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal respons max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
- Conversion to monotherapy, 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
- Adjunct may be added to the regimen at an initial dosage of 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less.
- Manic bipolar I disorder
- Initial, delayed-release 750 mg PO daily, in divided doses; may increase dose to achieve desired clinical response max 60 mg/kg/day or less
- Migraine Prophylaxis
- Delayed-release 250 mg PO twice daily, max dose 1000 mg/day

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Valproic acid in adult patients.

### NonGuideline-Supported Use
- Alcohol hallucinosis
- Bipolar disorder
- Myelodysplastic syndrome
- Myoclonic seizure
There is limited information about Off-Label NonGuideline-Supported Use of Valproic acid in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- Risk of fatal hepatotoxicity in patients under the age of 2 years
- Absence seizure, Simple and complexfor 2.5 to 13 years
- 10 mg/kg/day for 2 weeks, 15 mg/kg/day for weeks 3 and 4, 20 mg/kg/day for weeks 5 and 6, 30 mg/kg/day for weeks 7 and 8, 40 mg/kg/day for weeks 9 and 10, 50 mg/kg/day for weeks 11 and 12, 60 mg/kg/day for weeks 13 through 16; max dose 60 mg/kg/day or 3000 mg/day, whichever lower, mean dose, 34.9 mg/kg/day
- For 10 years or older, initial, 15 mg/kg/day PO give in 2 to 3 divided doses if dose exceeds 250 mg, maintenance 5 to 10 mg/kg/day PO 1-week intervals until seizures are controlled or side effects preclude further increases in 2 to 3 divided doses if total daily dose exceeds 250 mg max 60 mg/kg/day or less with a therapeutic serum range of 50 to 100 mcg/mL
- Complex partial epileptic seizure 10 years or older
- Monotherapy, initial 10 to 15 mg/kg/day PO give in 2 to 3 divided doses if total daily dose exceeds 250 mg, may increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less
- conversion to monotherapy, 10 to 15 mg/kg/day ORALLY (give in 2 to 3 divided doses if total daily dose exceeds 250 mg), may increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day or less
- Adjunct, may be added to the regimen at an initial dosage of 10 to 15 mg/kg/day PO in 2 to 3 divided doses if total daily dose exceeds 250 mg, may increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Valproic acid in pediatric patients.

### NonGuideline-Supported Use
There is limited information about Off-Label NonGuideline-Supported Use of Valproic acid in pediatric patients.

# Contraindications
There is limited information regarding Valproic acid Contraindications in the drug label.

# Warnings
There is limited information regarding Valproic acid Warnings' in the drug label.

# Adverse Reactions

## Clinical Trials Experience
Gastrointestinal
CNS Effects
Dermatologic
Psychiatric
Musculoskeletal
Hematologic
Hepatic
Endocrine
Pancreatic
Metabolic
Genitourinary
Special Senses
Miscellaneous

## Postmarketing Experience
There is limited information regarding Valproic acid Postmarketing Experience in the drug label.

# Drug Interactions
Effects of Co-Administered Drugs on Valproate Clearance
- Aspirin
- Carbapenem Antibiotics
- Felbamate
- Rifampin
- Antacids
- Chlorpromazine
- Haloperidol
- Cimetidine and Ranitidine
Effects of Valproate on Other Drugs
- Amitriptyline/Nortriptyline
- Carbamazepine/carbamazepine-10,11-Epoxide
- Clonazepam
- Diazepam
- Ethosuximide
- Lamotrigine
- Phenobarbital
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.
- Phenytoin
- Tolbutamide
- Warfarin
- Zidovudine
- Acetaminophen
- Clozapine
- Lithium
- Lorazepam
- Olanzapine
- Oral Contraceptive Steroids
- Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.
Topiramate

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): D
- Pregnancy Registry
- Fetal Risk Summary
- Clinical Considerations
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valproic acid in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Valproic acid during labor and delivery.

### Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate 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 . When Depakene is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.
- Pediatric Clinical Trials
- Juvenile Animal Toxicology

### Geriatic 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. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence .

### 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).

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

### Renal Impairment
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.

### Hepatic Impairment
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, Patients with Known or Suspected Mitochondrial Disease.
Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakene 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. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.
Note - Warnings and Precautions
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.

### Females of Reproductive Potential and Males
Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients .
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate.

### Immunocompromised Patients
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.

### Epilepsy
The efficacy of divalproex sodium in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium or placebo. Randomized patients were to be followed for a total of 16 weeks. The following table presents the findings.
Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on TreatmentNumber of PatientsBaseline IncidenceExperimental Incidence- Reduction from baseline statistically significantly greater for divalproex sodium than placebo at p0.05 level.Divalproex sodium7516.08.9*Placebo6914.511.5Figure 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 a50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.

# Administration and Monitoring

### Administration
There is limited information regarding Valproic acid Administration in the drug label.

### Monitoring
There is limited information regarding Valproic acid Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Valproic acid and IV administrations.

# Overdosage
There is limited information regarding Valproic acid overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology
There is limited information regarding Valproic acid Pharmacology in the drug label.

## Mechanism of Action
There is limited information regarding Valproic acid Mechanism of Action in the drug label.

## Structure

## Pharmacodynamics
There is limited information regarding Valproic acid Pharmacodynamics in the drug label.

## Pharmacokinetics
There is limited information regarding Valproic acid Pharmacokinetics in the drug label.

## Nonclinical Toxicology
There is limited information regarding Valproic acid Nonclinical Toxicology in the drug label.

# Clinical Studies
There is limited information regarding Valproic acid Clinical Studies in the drug label.

# How Supplied
There is limited information regarding Valproic acid How Supplied in the drug label.

## Storage
There is limited information regarding Valproic acid Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly.
Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly.
Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death. Advise patients to read the Medication Guide, which appears as the last section of the labeling.
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.
Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers.
Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told to inform the prescriber if any of these symptoms occur
CNS Depression
Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.
Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately.

# Precautions with Alcohol
Alcohol-Valproic acid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
There is limited information regarding Valproic acid Brand Names in the drug label.

# Look-Alike Drug Names
There is limited information regarding Valproic acid Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price