VALPROATE

brands

Class

• Neuroscience-based Nomenclature: glutamate (Glu); yet to be determined
• Anticonvulsant, mood stabilizer, migraine prophylaxis, voltage-sensitive sodium channel modulator

VALPROATE commonly prescribed for

(Bold for FDA approved)

How VALPROATE works

• Blocks voltage-sensitive sodium channels by an unknown mechanism

• Increases brain concentrations of gammaaminobutyric acid (GABA) by an unknown mechanism

How long until VALPROATE works

• For acute mania, effects should occur within a few days depending on the formulation of the drug

• May take several weeks to months to optimize an effect on mood stabilization

• Should also reduce seizures and improve migraine within a few weeks

Notable Side Effects

• Sedation, dose-dependent tremor, dizziness, ataxia, asthenia, headache

• Abdominal pain, nausea, vomiting, diarrhea, reduced appetite, constipation, dyspepsia, weight gain

• Alopecia (unusual)

• Polycystic ovaries (controversial)

• Hyperandrogenism, hyperinsulinemia, lipid dysregulation (controversial)

• Decreased bone mineral density (controversial)

Life Threatening Side Effects

• Can cause tachycardia or bradycardia

• Rare hepatotoxicity with liver failure sometimes severe and fatal, particularly in children under 2 years old

• Rare pancreatitis, sometimes fatal

• Rare but serious skin condition known as drug reaction with eosinophilia and systemic symptoms (DRESS)

• Rare activation of suicidal ideation and behavior (suicidality)

weight gain

common

sedation

problematic

What to do about VALPROATE side effects

• Wait

• Wait

• Wait

• Take at night to reduce daytime sedation, especially with divalproex ER

• Lower the dose

• Switch to another agent

usual dosage range

• Mania: 1200–1500 mg/day

• Migraine: 500–1000 mg/day

• Epilepsy: 10–60 mg/kg per day

Dosage Forms

• Tablet (delayed-release, as divalproex sodium) 125 mg, 250 mg, 500 mg

• Tablet (extended-release, as divalproex sodium) 250 mg, 500 mg

• Tablet (extended-release, as divalproex sodium) 250 mg, 500 mg

• Capsule (delayed-release, as valproic acid) 125 mg, 250 mg, 500 mg

• Injection (as sodium valproate) 100 mg/mL (5 mL)

long term use

• Requires regular liver function tests and platelet counts

habit forming

• No

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

• 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

• 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

Breast Feeding

• Some drug is found in mother’s breast milk

• Generally considered safe to breast feed while taking valproate

• If drug is continued while breast feeding, infant should be monitored for possible adverse effects

• If infant shows signs of irritability or sedation, drug may need to be discontinued

• Bipolar disorder may recur during the postpartum period, particularly if there is a history of prior postpartum episodes of either depression or psychosis

• Relapse rates may be lower in women who receive prophylactic treatment for postpartum episodes of bipolar disorder

• Atypical antipsychotics and anticonvulsants such as valproate may be safer than lithium during the postpartum period when breast feeding