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IMPORTANT SAFETY INFORMATION1,3
Indications2
- Depakote ER is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features
- Depakote ER is indicated as monotherapy and adjunctive therapy in the treatment of adults and children 10 years of age and older with complex partial seizures that occur either in isolation or in association with other types of seizures
- Depakote ER is also indicated as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age and older, and adjunctively in adults and children 10 years of age and older with multiple seizure types that include absence seizures
- Depakote ER is indicated for the prophylaxis of migraine headaches in adults
Important Safety Information1,2
- Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. Patients should be monitored closely for the appearance of nonspecific symptoms that may precede hepatotoxicity. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months. Valproate should not be administered to patients with hepatic disease or significant hepatic dysfunction. Children under the age of two years are at considerably higher risk of fatal hepatotoxicity.
- Valproate can produce teratogenic effects such as neural tube defects. Accordingly, the use of Depakote in women of childbearing potential requires that the benefits of its use be weighed against the risk of injury to the fetus. This is especially important when the treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g., migraine) is contemplated. An Information sheet describing the teratogenic potential of valproate is available for patients.
- Cases of life-threatening pancreatitis have been reported with valproate, either initially or after several years of use. Some cases were described as hemorrhagic with a rapid progression from onset to death. Patients should be warned that symptoms of pancreatitis require prompt medical evaluation. If pancreatitis is diagnosed, valproate should be discontinued.
- Valproate is contraindicated in patients with known urea cycle disorders (UCDs), a group of uncommon genetic abnormalities. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with known or suspected UCDs. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate).
- Hypothermia has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia.
- Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia (with or without encephalopathy) and with hypothermia (with or without hyperammonemia) in patients who have tolerated either drug alone.
- Multi-organ hypersensitivity reactions have occurred in close temporal association to the initiation of valproate therapy. If suspected, valproate should be discontinued. Patients should be instructed to immediately report fever associated with other organ system involvement (rash, lymphadenopathy, etc).
- The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related.
- Some elderly dementia patients taking valproate in a clinical trial experienced somnolence, sometimes requiring discontinuation. In some of these patients, there was associated reduced nutritional intake, weight loss, and a trend to have a lower baseline albumin concentration, higher BUN, and lower valproate clearance.
ADVERSE EVENTS
- Most adverse events were mild to moderate in severity.
Epilepsy
- DEPAKOTE Monotherapy for Complex Partial Seizures: Adverse events occurring in >20% of patients: asthenia, nausea, diarrhea, vomiting, thrombocytopenia, tremor, somnolence, and alopecia.
- DEPAKOTE Adjunctive Therapy for Complex Partial Seizures: Most adverse events occurring in >5% of patients and significantly more often with DEPAKOTE adjunctive therapy vs placebo: nausea (48% vs 14%), asthenia (27% vs 7%), somnolence (27% vs 11%), vomiting (27% vs 7%), tremor (25% vs 6%), abdominal pain (23% vs 6%), and anorexia (12% vs 0%).
Mania Associated With Bipolar Disorder
- DEPAKOTE: Adverse event reported by significantly more patients receiving DEPAKOTE compared to placebo was vomiting [12% vs 3% (p<0.05)]. Other common adverse events vs placebo were nausea (22% vs 15%), somnolence (19% vs 12%), and dizziness (12% vs 4%).
Manic or Mixed Episodes Associated With Bipolar Disorder, With or Without Psychotic Features
- DEPAKOTE ER: Adverse events reported by >5% of DEPAKOTE ER-treated patients during placebo-controlled trials of acute mania include somnolence (26% vs 14%), dyspepsia (23% vs 11%), nausea (19% vs 13%), vomiting (13% vs 5%), diarrhea (12% vs 8%), dizziness (12% vs 7%), and abdominal pain (10% vs 5%).
Migraine Prevention
- DEPAKOTE ER: Adverse events reported by >5% of DEPAKOTE ER-treated patients during the migraine placebo-controlled trial with a greater incidence than placebo: nausea (15% vs 9%), dyspepsia (7% vs 4%), diarrhea (7% vs 3%), vomiting (7% vs 2%), abdominal pain (7% vs 5%), somnolence (7% vs 2%), and infection (15% vs 14%).
DOSE-RELATED ADVERSE EVENTS
- The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations of >110 μg/mL in females and >135 μg/mL in males.
ADDITIONAL DOSING INFORMATION1,2
- DEPAKOTE ER is an extended-release product intended for once-a-day oral administration
- DEPAKOTE ER tablets should be swallowed whole and should not be crushed or chewed
- No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made
- May be taken without regard to meals
- The starting dose in elderly patients should be reduced and dosage should be increased more slowly and with regular monitoring. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response
- As with other valproate products, doses of DEPAKOTE ER should be individualized and dose adjustment may be necessary
- If a patient requires smaller dose adjustments than those available with DEPAKOTE ER, DEPAKOTE tablets should be used instead
References
- DEPAKOTE package insert. Abbott Laboratories: Abbott Park, IL.
- DEPAKOTE ER package insert. Abbott Laboratories: Abbott Park, IL.
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