Valproate

Valproate Sodium Injection is indicated as an intravenous alternative in patients in whom oral administration of valproate products is temporarily not feasible in the following conditions: Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures, adjunctive therapy in patients with multiple seizure types that include absence seizures

Valproate sodium exists as the valproate ion in the blood. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

Valproate Sodium Injection is intended for intravenous use only. Epilepsy Complex Partial Seizures in Adults and Children 10 years of age or older: Initial dose is 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response. Maximum recommended dose is 60 mg/kg/day. Simple and Complex Absence Seizures: Initial dose is 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response.

Valproate Sodium Injection should not be administered to patients with hepatic disease or significant hepatic dysfunction. Valproate Sodium Injection is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG, e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder. Valproate Sodium Injection is contraindicated in patients with known hypersensitivity to the drug. Valproate Sodium Injection is contraindicated in patients with known urea cycle disorders.

Boxed warning (life threatening adverse reactions warning: life threatening adverse reactions): Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter. Hepatotoxicity, evaluate high risk populations and monitor serum liver tests. Birth defects, decreased IQ, and neurodevelopmental disorders following in utero exposure, should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant or to treat a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.

The following serious adverse reactions are described below and elsewhere in the labeling: Hepatic failure Birth defects Decreased IQ and Neurodevelopmental Disorders following in utero exposure Pancreatitis Hyperammonemic encephalopathy Bleeding and other hematopoietic disorders Hypothermia Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ hypersensitivity reactions Somnolence in the elderly Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The adverse reactions that can result from Valproate Sodium Injection use include all of those associated with oral forms of valproate.

Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn. Aspirin, carbapenem antibiotics, estrogen-containing hormonal contraceptives: Monitoring of valproate concentrations is recommended. Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement. Patients stabilized on rufinamide should begin valproate therapy at a low dose, and titrate to clinically effective dose.

Store vials at 20° to 25°C (68° to 77°F), excursions permitted between 15° and 30°C (59° and 86°F).