Mood Stabilizer · ORAL
Brand names: Depakote
Source: U.S. FDA (openFDA) · FDA label effective April 8, 2026 · data synced September 1, 2026
WARNING: LIFE THREATENING ADVERSE REACTIONS Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1) ] . Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When divalproex sodium extended-release tablets 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. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g., Alpers Huttenlocher Syndrome). Divalproex sodium extended-release tablets are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4) ] . In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium extended-release tablets should only be used after other anticonvulsants have failed. …
This is the FDA's most serious warning. Discuss it with your prescriber.
Based on Bridgeway's clinical use. See the FDA "Uses" section below for approved indications.
1 INDICATIONS AND USAGE Divalproex sodium extended-release tablets are indicated for: • Acute treatment of manic or mixed episodes associated with bipolar disorder, with or without psychotic features ( 1.1 ) • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures ( 1.2 ) • Prophylaxis of migraine headaches ( 1.3 ) 1.1 Mania Divalproex sodium extended-release tablets are a valproate and are indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities). The efficacy of divalproex sodium extended-release tablets is based in part on studies of divalproex sodium delayed-release tablets in this indication, and was confirmed in a 3-week trial with patients meeting DSM-IV TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for acute mania [see Clinical Studies (14.1) ] . …
3 DOSAGE FORMS AND STRENGTHS Divalproex Sodium Extended-Release Tablets, USP are available containing divalproex sodium, USP equivalent to 250 mg or 500 mg of valproic acid. • The 250 mg tablets are white, film-coated, round, unscored tablets debossed with M over 177 on one side of the tablet and blank on the other side. • The 500 mg tablets are white, film-coated, oval, unscored tablets debossed with M 473 on one side of the tablet and blank on the other side. Tablets: 250 mg and 500 mg ( 3 )
5 WARNINGS AND PRECAUTIONS • Birth defects, decreased IQ, and neurodevelopmental disorders following in utero exposure: Should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant or to treat a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable ( 5.2 , 5.3 , 5.4 ) • Pancreatitis: Divalproex sodium extended-release tablets should ordinarily be discontinued ( 5.5 ) • Suicidal behavior or ideation: Antiepileptic drugs, including divalproex sodium extended-release tablets, increase the risk of suicidal thoughts or behavior ( 5.7 ) • Bleeding and other hematopoietic disorders: Monitor platelet counts and coagulation tests ( 5.8 ) • Hyperammonemia and hyperammonemic encephalopathy: Measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy ( 5.6 , 5.9 , 5.10 ) • Hypothermia: Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate ( 5.11 ) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions, serious dermatologic reactions, and angioedema: Discontinue divalproex sodium extended-release tablets unless an alternate etiology is established ( 5.12 , 5.13 , 5.14 ) 5.1 Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months of valproate therapy. …
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Hepatic Failure [see Warnings and Precautions (5.1) ] • Birth Defects [see Warnings and Precautions (5.2) ] • Decreased IQ and Neurodevelopmental Disorders following in utero exposure [see Warnings and Precautions (5.3) ] • Pancreatitis [see Warnings and Precautions (5.5) ] • Hyperammonemic Encephalopathy [see Warnings and Precautions (5.6 , 5.9 , 5.10) ] • Suicidal Behavior and Ideation [see Warnings and Precautions (5.7) ] • Bleeding and Other Hematopoietic Disorders [see Warnings and Precautions (5.8) ] • Hypothermia [see Warnings and Precautions (5.11) ] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions (5.12) ] • Serious Dermatologic Reactions [see Warnings and Precautions (5.13) ] • Angioedema [see Warnings and Precautions (5.14) ] • Somnolence in the Elderly [see Warnings and Precautions (5.16) ] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Information on pediatric adverse reactions is presented in section 8. • Most common adverse reactions (reported ≥ 15% for any indication) are abdominal pain, alopecia, asthenia, diarrhea, diplopia, dizziness, dyspepsia, headache, infection, insomnia, nausea, somnolence, thrombocytopenia, tremor, vomiting ( 6.1 , 6.2 , 6.3 ). • The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults ( 8.4 ). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of divalproex sodium extended-release tablets in the treatment of manic episodes associated with bipolar disorder. …
7 DRUG INTERACTIONS • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore, increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn ( 7.1 ) • Aspirin, carbapenem antibiotics, estrogen-containing hormonal contraceptives, methotrexate: Monitoring of valproate concentrations is recommended ( 7.1 ) • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g., diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement ( 7.2 ) • Patients stabilized on rufinamide should begin valproate therapy at a low dose, and titrate to clinically effective dose ( 7.2 ) • Dosage adjustment of amitriptyline/nortriptyline, propofol, warfarin, and zidovudine may be necessary if used concomitantly with divalproex sodium extended-release tablets ( 7.2 ) • Topiramate: Hyperammonemia and encephalopathy ( 5.10 , 7.3 ) • Cannabidiol: ALT and/or AST elevation ( 7.4 ) 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. …
FDA label text for Divalproex Sodium or a related medication mentions the following combinations. Check any two medications with our interaction tool →
About this interaction data. These interactions were identified by automatically scanning FDA prescribing-label text for medications in Bridgeway's library. This is not a complete list and is not a substitute for review by your prescriber or pharmacist, who use comprehensive clinical databases. Always share your full medication list with your care team. How we source this data →
4 CONTRAINDICATIONS Divalproex sodium extended-release tablets are contraindicated in patients: • with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1) ] . • known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions (5.1) ] . • with known hypersensitivity to divalproex sodium, sodium valproate, or valproic acid. Reactions have included multiorgan hypersensitivity, serious dermatologic reactions, and angioedema [see Warnings and Precautions (5.12 , 5.13 , 5.14) ] . • with known urea cycle disorders [see Warnings and Precautions (5.6) ] . • being treated for prophylaxis of migraine headaches: who are pregnant or in women of childbearing potential who are not using effective contraception [see Warnings and Precautions (5.2 , 5.3 , 5.4) and Use in Specific Populations (8.1) ] . …
8 USE IN SPECIFIC POPULATIONS • Pregnancy: Divalproex sodium extended-release tablets can cause congenital malformations including neural tube defects, decreased IQ, and neurodevelopmental disorders ( 5.2 , 5.3 , 8.1 ) • Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence ( 5.16 , 8.5 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including divalproex sodium extended-release tablets, during pregnancy. Encourage women who are taking divalproex sodium extended-release tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. This must be done by the patient herself. Risk Summary For use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications (4) ] . For use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see Boxed Warning and Warnings and Precautions (5.2 , 5.3) ] . …
Of 46,266 adverse-event reports mentioning Divalproex Sodium submitted to the FDA, the most frequently reported reactions are:
Source: FDA Adverse Event Reporting System (FAERS). These are voluntary, unverified reports from patients and providers worldwide — they do not mean the medication caused the reaction, and report counts reflect how widely a drug is used as much as its safety profile.
There is 1 ongoing FDA recall involving Divalproex Sodium. See full medication safety feed →
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Not medical advice. This page summarizes publicly available FDA drug labeling alongside general guidance from Bridgeway Integrated Healthcare Services. It is for educational purposes only and is not a substitute for advice from your prescriber or pharmacist. Never start, stop, or change a medication without talking to your healthcare provider. In an emergency, call 911.