Valproate/Divalproex

Warning

Hepatotoxicity

• Potentially fatal hepatic failure can occur.

• Usually occurs during the initial 6 months of therapy.

• Children <2 years of age are at considerably increased risk of developing fatal hepatotoxicity, especially those receiving multiple anticonvulsants and those with congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, or organic brain disease. Use with extreme caution in this age group and only as single-agent therapy; carefully weigh benefits versus risks. Incidence of fatal hepatotoxicity appears to decrease progressively with increasing age.

• Serious or fatal hepatotoxicity may be preceded by nonspecific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting.

• In epileptic patients, loss of seizure control also may precede development of hepatotoxicity.

• Monitor patients closely for development of any such changes.

• Perform liver function tests prior to and at frequent intervals during therapy, especially during the first 6 months. (See Hepatotoxicity under Cautions.)

• Increased risk of acute liver failure (sometimes resulting in death) in patients with hereditary mitochondrial disorders caused by mutations in the polymerase gamma (POLG) gene (e.g., Alpers-Huttenlocher syndrome); contraindicated in patients known to have such disorders and in children <2 years of age in whom there is a clinical suspicion of a mitochondrial disorder. In children >2 years of age with suspected hereditary mitochondrial disease, use only if other anticonvulsant therapies have failed; closely monitor such patients with regular clinical assessments and liver function tests. Perform POLG mutation screening according to current clinical practice.

Fetal Risk

• Risk of major congenital malformations, particularly neural tube defects (NTDs).

• Risk of decreased IQ scores following in utero exposure.

• Contraindicated in pregnant women for migraine prophylaxis. In pregnant women with epilepsy or bipolar disorder, use only if other therapies fail or are otherwise unacceptable.

• Do not use in women of childbearing potential unless the drug is essential to their medical condition. This is particularly important when contemplating treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g., migraine headaches). (See Pregnancy under Cautions.)

• A medication guide describing the risks of valproic acid is available for patients. (See Advice to Patients.)

Pancreatitis

• Life-threatening pancreatitis has occurred both in children and adults.

• Some cases described as hemorrhagic with rapid progression from initial symptoms to death.

• Can occur shortly after initial use as well as after several years of use.

• Warn patients and caregivers that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation.

• Usually discontinue the drug and initiate alternative therapy