Other Warnings/Precautions

✽ Be alert to the following symptoms of hepatotoxicity that require immediate attention: malaise, weakness, lethargy, facial edema, anorexia, vomiting, yellowing of the skin and eyes

✽ Be alert to the following symptoms of pancreatitis that require immediate attention: abdominal pain, nausea, vomiting, anorexia

✽ Teratogenic effects in developing fetuses such as neural tube defects may occur with valproate use

✽ Somnolence may be more common in the elderly and may be associated with dehydration, reduced nutritional intake, and weight loss, requiring slower dosage increases, lower doses, and monitoring of fluid and nutritional intake

• Use in patients with thrombocytopenia is not recommended; patients should report easy bruising or bleeding

• Evaluate for urea cycle disorders, as hyperammonemic encephalopathy, sometimes fatal, has been associated with valproate administration in these uncommon disorders; urea cycle disorders, such as ormithine transcarbamylase deficiency, are associated with unexplained encephalopathy, mental retardation, elevated plasma ammonia, cyclical vomiting, and lethargy

• Warn patients and their caregivers about the possibility of activation of suicidal ideation and advise them to report such side effects immediately

Do Not Use

• If patient has pancreatitis

• If patient has serious liver disease

• If patient has urea cycle disorder

• If there is a proven allergy to valproic acid, valproate, or divalproex

VALPROATE: SPECIAL POPULATIONS

Renal Impairment

• No dose adjustment necessary

Hepatic Impairment

• Contraindicated

Cardiac Impairment

• No dose adjustment necessary

Elderly

• Reduce starting dose and titrate slowly; dosing is generally lower than in healthy adults

✽ Sedation in the elderly may be more common and associated with dehydration, reduced nutritional intake, and weight loss

• Monitor fluid and nutritional intake

• 1 in 3 elderly patients in long-term care who receive valproate may ultimately develop thrombocytopenia

Children and Adolescents

✽ Not generally recommended for use in children under age 10 for bipolar disorder except by experts and when other options have been considered

• Children under age 2 have significantly increased risk of hepatotoxicity, as they have a markedly decreased ability to eliminate valproate compared to older children and adults

• Use requires close medical supervision

Pregnancy

• Risk Category D [positive evidence of risk to human fetus; potential benefits may still justify its use during pregnancy]

✽ Use during first trimester may raise risk of neural tube defects (e.g., spina bifida) or other congenital anomalies

• Cases of developmental delay in the absence of teratogenicity associated with fetal exposure have been identified

• Increased risk of lower cognitive test scores in children whose mothers took valproate during pregnancy

• Use in women of childbearing potential requires weighing potential benefits to the mother against the risks to the fetus

✽ If drug is continued, monitor clotting parameters and perform tests to detect birth defects

✽ If drug is continued, start on folate 1 mg/day early in pregnancy to reduce risk of neural tube defects

✽ If drug is continued, consider vitamin K during the last 6 weeks of pregnancy to reduce risks of bleeding

• Antiepileptic Drug Pregnancy Registry: (888) 233–2334

• Taper drug if discontinuing

• Seizures, even mild seizures, may cause harm to the embryo/fetus

✽ For bipolar patients, valproate should generally be discontinued before anticipated pregnancies

• Recurrent bipolar illness during pregnancy can be quite disruptive

✽ For bipolar patients, given the risk of relapse in the postpartum period, mood stabilizer treatment such as valproate should generally be restarted immediately after delivery if patient is unmedicated during pregnancy

✽ Atypical antipsychotics may be preferable to lithium or anticonvulsants such as valproate if treatment of bipolar disorder is required during pregnancy

• Bipolar symptoms may recur or worsen during pregnancy and some form of treatment may be necessary