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Valpros: 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, particularly during the first six months.
Children under two years old are at a considerably increased risk of developing fatal hepatotoxicity, particularly 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 sodium valproate + valproic acid is 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. The incidence of fatal hepatotoxicity decreases considerably in progressively older patients 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 gene (POLG; e.g., Alpers Huttenlocher Syndrome). Sodium valproate + valproic acid is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years old who are clinically suspected of having a mitochondrial disorder. In patients over two years old who are clinically suspected of having a hereditary mitochondrial disease, sodium valproate + valproic acid should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with sodium valproate + 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.
Fetal Risk: 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. Sodium valproate + valproic acid should only be used to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable. Sodium valproate + valproic acid should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is particularly 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 sodium valproate + valproic acid.
Pancreatitis: Cases of life-threatening pancreatitis have been reported in both adults and children 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, sodium valproate + valproic acid should be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.
Valpros i-IV: Hepatotoxicity: Teratogenicity: Sodium 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.
Pancreatitis: Cases of life-threatening pancreatitis have been reported in both adults and children 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.
