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Generic drug name:
divalproex
(dye VAL pro ex)
Brand name(s):
DEPAKOTE,
DEPAKOTE ER
GENERIC:
not available
FAMILIES:
Drugs for Mania, Drugs for Epilepsy
Find the drug label by
searching at DailyMed.
Generic drug name:
valproic acid
Brand name(s):
DEPAKENE
GENERIC:
available
FAMILIES:
Drugs for Mania, Drugs for Epilepsy
Find the drug label by
searching at DailyMed.
Pregnancy and Breast-feeding Warnings [top]
Pregnancy Warning
Valproic acid caused serious harm to human infants born to mothers taking this drug during pregnancy. Such infants have been born with damage to the heart, blood vessels, skull, and spinal cord. Infants have died after birth from liver failure following use of valproic acid by their mothers during pregnancy. Because of the potential for serious adverse effects to the fetus, this drug should not be used by pregnant women. In addition, valproate can cause decreased IQ scores following in utero exposure.
Breast-feeding Warning
Valproic acid is excreted in human milk. Because of the potential for serious adverse effects in nursing infants, you should not take valproic acid while nursing.
Safety Warnings For This Drug [top]
FDA BLACK-BOX WARNING
HEPATOTOXICITY (Liver Toxicity)
HEPATIC FAILURE RESULTING IN FATALITIES HAS OCCURRED IN PATIENTS RECEIVING VALPROIC ACID AND ITS DERIVATIVES. 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 DEPAKOTE 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. 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 ALSO MAY 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.
PATIENTS WITH MITOCHONDRIAL DISEASE
THERE IS AN INCREASED RISK OF VALPROIC ACID-INDUCED ACUTE LIVER FAILURE AND RESULTANT DEATHS IN PATIENTS WITH HEREDITARY NEUROMETABOLIC SYNDROMES CAUSED BY DNA MUTATIONS OF THE MITOCHONDRIAL DNA POLYMERASE Γ (POLG) GENE (E.G. ALPERS HUTTENLOCHER SYNDROME). VALPROIC ACID IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE MITOCHONDRIAL DISORDERS CAUSED BY POLG MUTATIONS AND CHILDREN UNDER TWO YEARS OF AGE WHO ARE CLINICALLY SUSPECTED OF HAVING A MITOCHONDRIAL DISORDER. IN PATIENTS OVER TWO YEARS OF AGE WHO ARE CLINICALLY SUSPECTED OF HAVING A HEREDITARY MITOCHONDRIAL DISEASE, VALPROIC ACID SHOULD ONLY BE USED AFTER OTHER ANTICONVULSANTS HAVE FAILED. THIS OLDER GROUP OF PATIENTS SHOULD BE CLOSELY MONITORED DURING TREATMENT WITH VALPROIC ACID FOR THE DEVELOPMENT OF ACUTE LIVER INJURY WITH REGULAR CLINICAL ASSESSMENTS AND SERUM LIVER TESTING. POLG MUTATION SCREENING SHOULD BE PERFORMED IN ACCORDANCE WITH CURRENT CLINICAL PRACTICE.[1][2]
TERATOGENICITY
AN INFORMATION SHEET DESCRIBING THE TERATOGENIC POTENTIAL OF VALPROIC ACID IS AVAILABLE FOR PATIENTS.
VALPROIC ACID CAN CAUSE MAJOR CONGENITAL MALFORMATIONS, PARTICULARLY NEURAL TUBE DEFECTS (FOR EXAMPLE, SPINA BIFIDA). IN ADDITION, VALPROIC ACID CAN CAUSE DECREASED IQ SCORES AND NEURODEVLOPMENTAL DISORDERS FOLLOWING IN UTERO EXPOSURE.
VALPROIC ACID IS THEREFORE CONTRAINDICATED FOR PREVENTION OF MIGRAINE HEADACHES IN PREGNANT WOMEN AND IN WOMEN OF CHILDBEARING POTENTIAL WHO ARE NOT USING EFFECTIVE CONTRACEPTION. VALPROIC ACID SHOULD NOT BE USED TO TREAT WOMEN WITH EPILEPSY OR BIPOLAR DISORDER WHO ARE PREGNANT OR WHO PLAN TO BECOME PREGNANT UNLESS OTHER MEDICATIONS HAVE FAILED TO CONTROL THEIR SYMPTOMS OR ARE OTHERWISE UNACCEPTABLE.
VALPROIC ACID SHOULD NOT BE GIVEN TO A WOMAN OF CHILDBEARING POTENTIAL UNLESS OTHER MEDICATIONS HAVE FAILED TO ADEQUATELY CONTROL SYMPTOMS OR ARE OTHERWISE UNACCEPTABLE. IN SUCH SITUATIONS, EFFECTIVE CONTRACEPTION SHOULD BE USED.
PANCREATITIS (Inflammation of the Pancreas)
CASES OF LIFE-THREATENING PANCREATITIS HAVE BEEN REPORTED IN BOTH CHILDREN AND ADULTS RECEIVING VALPROIC ACID. 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, VALPROIC ACID SHOULD ORDINARILY BE DISCONTINUED. ALTERNATIVE TREATMENT FOR THE UNDERLYING MEDICAL CONDITION SHOULD BE INITIATED AS CLINICALLY INDICATED.
Facts About This Drug [top]
Divalproex (DEPAKOTE, DEPAKOTE ER) is essentially two molecules of valproic acid hooked together. The Food and Drug Administration (FDA) approved divalproex to treat certain types of epilepsy, to prevent migraine headaches and to manage manic episodes associated with bipolar disorder.[3] Valproic acid, however, is approved only for epilepsy.[4]
The product labels for divalproex and valproic acid are required by the FDA to have a black-box warning about liver toxicity, birth defects and...
Divalproex (DEPAKOTE, DEPAKOTE ER) is essentially two molecules of valproic acid hooked together. The Food and Drug Administration (FDA) approved divalproex to treat certain types of epilepsy, to prevent migraine headaches and to manage manic episodes associated with bipolar disorder.[3] Valproic acid, however, is approved only for epilepsy.[4]
The product labels for divalproex and valproic acid are required by the FDA to have a black-box warning about liver toxicity, birth defects and inflammation of the pancreas. A black-box warning is the strongest type of warning that the FDA can require. It appears at the beginning of this drug profile in the “Safety Warnings For These Drugs” section.
Valproic acid and divalproex are two of a limited number of drugs for which the FDA requires that a Medication Guide be dispensed when the prescription is filled. An FDA advisory committee has unanimously recommended that all prescription drugs be accompanied by such Medication Guides, but at present, less than 5% of drugs are. The other 95% of drugs are accompanied by unregulated, often dangerously incomplete information leaflets that are not approved by the FDA.
Adverse effects
Birth defects
Valproic acid is associated with an increased risk of neural tube defects (NTDs) among babies exposed to the drug during early pregnancy. There have been an increasing number of reports suggesting that valproic acid may cause malformations other than NTDs.
In April 2006, an article was published in which the authors found 11 studies that reported cases of women with an increased risk of having babies with malformations when exposed to valproic acid during early pregnancy. This risk was dose-dependent.[5]
An article published in Prescrire International in 2009 stated that children who were exposed to valproic acid during pregnancy have a higher risk of birth defects, including malformations, cardiac disorders and developmental disorders. The article also stated that several studies show that valproic acid is more teratogenic (causes birth defects) than other antiepileptic drugs.[6] (See “Regulatory actions surrounding divalproex and valproic acid: 2009” below.)
On May 6, 2013, the FDA released an important safety communication warning pregnant women and women of childbearing age not to use divalproex or valproic acid for the treatment of migraines under any circumstances. The communication stated that they should resort to using the drugs for bipolar disorder and epilepsy only if there are no other acceptable treatment options available to them.
A 2013 study, called Neurodevelopmental Effects of Antiepileptic Drugs (NEAD), that was published in Lancet Neurology found that children of mothers exposed to the drugs during pregnancy had IQ scores by age 6 that were eight to 11 points lower than those of children exposed to other anti-epileptic drugs.
The NEAD study results prompted the FDA to reclassify divalproex or valproic acid from pregnancy Category D (drugs whose possible benefits might outweigh the potential risks) to pregnancy Category X (drugs whose risks clearly outweigh any potential benefits) for the treatment of migraines.[7] Although these drugs remained in Category D for the treatment of bipolar disorder and epilepsy, the FDA’s communication specified that they should be used for these conditions only if there is no other acceptable treatment option available.[8]
In November 2014, the European Medicines Agency, a regulatory agency similar to the FDA, advised doctors in the European Union not to prescribe medicines like divalproex or valproic acid to pregnant women, to women who can become pregnant or to girls. If valproic acid is the only option for the treatment of epilepsy or bipolar disorder for these patients, patients must be informed of the risk and carefully monitored.[9]
Pregnant women using divalproex or valproic acid or other antiepileptic drugs should enroll in the North American AED (antiepileptic drug) Pregnancy Registry (1-888-233-2334).
Parkinsonism
In January 2006, there were 10 case reports of patients who developed reversible parkinsonism with or without cognitive impairment during treatment with valproic acid for epilepsy.[10]
In 2023, Pediatric Nephrology published an article showing that valproic acid was associated with kidney damage.[11]
Treatment for Alzheimer’s disease
A September 2011 article published in the scientific journal Neurology examined the use of divalproex on brain volume in patients with mild-to-moderate Alzheimer’s disease. According to the article, the data reviewed showed that patients treated with divalproex experienced an accelerated brain volume loss over one year. The authors of the article stated: “We cannot advocate additional divalproex or VPA [valproic acid] treatment trials in dementia given the risks and potentially detrimental findings presented here.”[12]
Regulatory actions surrounding divalproex and valproic acid
2008: The FDA issued a warning that there have been reports of suicidality (suicidal behavior or thoughts) associated with the use of antiepileptic drugs, including valproic acid. According to the study cited by the FDA, patients receiving these drugs had twice the risk of suicidal behavior or thoughts as patients receiving a placebo. This increased risk was observed as early as one week after starting the drug.[13] (Read more in the November 2008 Worst Pills, Best Pills News.)
In December, the FDA issued another advisory that stated that it had completed its analysis of suicidality reports from placebo-controlled clinical trials of drugs used to treat epilepsy, psychiatric disorders and other conditions. Based on the outcome of this review, the FDA required all manufacturers of drugs in this class to include a warning on their labels and to develop a Medication Guide to be provided to patients prescribed these drugs to inform them of the risks of suicidal thoughts or actions.[14]
2009: The FDA issued an advisory in 2009 on the increased risk of NTD and other major birth defects in babies exposed to valproic acid and related products (valproic acid and divalproex sodium) during pregnancy. Other major birth defects associated with these drugs include craniofacial defects and cardiovascular malformations.[15]
2011: The FDA issued an update concerning the use of phenytoin (DILANTIN, PHENYTEK) and the occurrence of a condition known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). DRESS is also known as multi-organ hypersensitivity and in some cases can be life-threatening. The FDA update stated that DRESS had been reported in patients taking antiepileptic drugs, including gabapentin.
In June, the FDA issued information from a study showing that children tend to score lower on cognitive tests (IQ and other tests) when their mothers took valproic acid and divalproex sodium during pregnancy than children whose mothers took other antiseizure medications during pregnancy.[16]
2013: The FDA released an important safety communication warning pregnant women and women of childbearing age not to use valproic acid drugs for the treatment of migraines under any circumstances (see above section titled “Birth Defects”).
In 2013, the Medicines and Healthcare products Regulatory Agency (a government agency in the U.K. similar to the FDA) issued drug safety advice on the risk of neurodevelopmental delay in children whose mothers took valproic acid drugs during pregnancy.[17]
2017: The labeling for valproic acid was revised to warn that using hormonal contraceptives containing estrogen with valproic acid may cause an increase in the rate of seizures.[18]
Before You Use This Drug [top]
Do not use if you have or have had:
Tell your doctor if you have or have had:
Tell your doctor about any other drugs you take, including aspirin, herbs, vitamins, and other nonprescription products.
When You Use This Drug [top]
How to Use This Drug [top]
Interactions with Other Drugs [top]
The following drugs, biologics (e.g., vaccines, therapeutic antibodies), or foods are listed in Evaluations of Drug Interactions 2003 as causing “highly clinically significant” or “clinically significant” interactions when used together with any of the drugs in this section. In some sections with multiple drugs, the interaction may have been reported for one but not all drugs in this section, but we include the interaction because the drugs in this section are similar to one another. We have also included potentially serious interactions listed in the drug’s FDA-approved professional package insert or in published medical journal articles. There may be other drugs, especially those in the families of drugs listed below, that also will react with this drug to cause severe adverse effects. Make sure to tell your doctor and pharmacist the drugs you are taking and tell them if you are taking any of these interacting drugs:
amitriptyline, aspirin, carbamazepine, COUMADIN, diazepam, DILANTIN, ECOTRIN, EES, ELAVIL, ERYTHROCIN, erythromycin, ethosuximide, felbamate, FELBATOL, GABITRIL, GENUINE BAYER ASPIRIN, LAMICTAL, lamotrigene, LUMINAL, MYSOLINE, nortriptyline, ORINASE, oxcarbazepine, PAMELOR, phenobarbital, phenytoin, primidone, RETROVIR, RIFADIN, rifampin, RIMACTANE, SOLFOTON, TEGRETOL, tiagabine, tolbutamide, TRILEPTAL, VALIUM, warfarin, ZARONTIN, zidovudine (AZT).
Adverse Effects [top]
Call your doctor immediately if you experience:
Call your doctor if these symptoms continue:
Withdrawal: When drug is to be discontinued dosage should be reduced gradually
Overdose: For the management of overdose or unintentional ingestion contact a Poison Control Center.
Periodic Tests[top]
Ask your doctor which of these tests should be done periodically while you are taking this drug:
last reviewed June 30, 2024
Worst Pills, Best Pills is a project of Public Citizen's Health Research Group Group. As an independent, nonprofit organization, we take no corporate or government contributions and accept no advertising. Copyright © 2024 Public Citizen's Health Research Group. All rights reserved.
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