Depakote ER is an anti-epileptic drug indicated for:

• Acute treatment of manic or mixed episodes associated with bipolar disorder, with or without psychotic features (1.1)
• 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 (1.2)
• Prophylaxis of migraine headaches (1.3)

• Depakote ER is intended for once-a-day oral administration. Depakote ER should be swallowed whole and should not be crushed or chewed (2.1, 2.2).
• Mania: Initial dose is 25 mg/kg/day, increasing as rapidly as possible to achieve therapeutic response or desired plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Migraine: The recommended starting dose is 500 mg/day for 1 week, thereafter increasing to 1000 mg/day (2.3).

Tablets: 250 mg and 500 mg (3)
CONTRAINDICATIONS

• Hepatotoxicity; eva luate high risk populations and monitor serum liver tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakote ER should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakote ER, increase the risk of suicidal thoughts or behavior (5.7)
• Bleeding and other hematopoietic disorders; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.11)
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction; discontinue Depakote ER (5.12)
• Somnolence in the elderly can occur. Depakote ER dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14)

• Most common adverse reactions (reported >5%) reported in adult studies are nausea, somnolence, dizziness, vomiting, asthenia, abdominal pain, dyspepsia, rash, diarrhea, increased appetite, tremor, weight gain, back pain, alopecia, headache, fever, anorexia, constipation, diplopia, amblyopia/blurred, ataxia, nystagmus, emotional lability, thinking abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis, ecchymosis, peripheral edema, insomnia, nervousness, depression, pharyngitis, dyspnea, tinnitus (6.1, 6.2, 6.3, 6.4).
• The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4).
   

To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, 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 dose adjustment is indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1)
• 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 (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with Depakote ER (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)

• Pregnancy: Depakote ER can cause congenital malformations including neural tube defects and decreased IQ. (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence (5.14, 8.5)