Warning: Life-Threatening Adverse Reactions
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.
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 (divalproex sodium) tablets, for oral use, Depakote ER (divalproex sodium) extended-release tablets, for oral use, or Depakote Sprinkle Capsules (divalproex sodium delayed release capsules), for oral use, 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. 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). Depakote, Depakote ER, and Depakote Sprinkle Capsules are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and in 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, Depakote, Depakote ER, or Depakote Sprinkle Capsules should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote, Depakote ER, or Depakote Sprinkle Capsules 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.
Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure.
Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable.
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.
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.
Most common adverse reactions (reported ≥5%) reported in adult studies are abdominal pain, abnormal thinking, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss, accidental injury, back pain, increased appetite, rash.
Keep Depakote and all other medications where children cannot reach them.
Life-threatening adverse reactions have been reported with Depakote:
Total Daily Dose (mg)
Total Daily Dose (mg)
These total daily doses of Depakote cannot be directly converted to an 8% to 20% higher total daily dose of Depakote ER because the required dosing strengths of Depakote ER are not available. Consideration may be given at the clinician’s discretion to increase the patient’s total daily doses of Depakote to the next higher dosage before converting to the appropriate total daily dose of Depakote ER.References: