BOXED WARNING
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakote ER is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions ].
Teratogenicity
Valproate can produce teratogenic effects such as neural tube defects (e.g., spina bifida). Accordingly, the use of Depakote ER 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 [see Warnings and Precautions ].
An information sheet describing the teratogenic potential of valproate is available for patients [see Patient Counseling Information ].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions ].
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DEPAKOTE ER SUMMARY
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide.
DEPAKOTE ER is indicated for prophylaxis of migraine headaches in adults. There is no evidence that DEPAKOTE ER is useful in the acute treatment of migraine headaches. Because valproic acid may be a hazard to the fetus, DEPAKOTE ER should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment (see WARNINGS
— Usage In Pregnancy, PRECAUTIONS
— Information for Patients).
DEPAKOTE ER is indicated as monotherapy and adjunctive therapy in the treatment of adults and children 10 years of age or older with complex partial seizures that occur either in isolation or in association with other types of seizures. DEPAKOTE ER is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.
SEE WARNINGS FOR STATEMENT REGARDING FATAL HEPATIC DYSFUNCTION.
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NEWS HIGHLIGHTS
Published Studies Related to Depakote ER (Divalproex)
Olanzapine-Divalproex combination versus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-blind, placebo-controlled study. [2009.09.22]
CONCLUSION: Adjunctive olanzapine yielded greater and earlier reduction of manic and depressive symptoms in mixed-episode patients with inadequate response to at least 2 weeks of divalproex. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00402324. (c) Copyright 2009 Physicians Postgraduate Press, Inc.
A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents. [2009.05]
CONCLUSIONS: The results of the study do not provide support for the use of divalproex ER in the treatment of youths with bipolar I disorder, mixed or manic state. Further controlled trials are required to confirm or refute the findings from this study.
Divalproex ER combined with olanzapine or risperidone for treatment of acute exacerbations of schizophrenia. [2009.04]
The objective of this study was to evaluate the efficacy and safety of divalproex sodium extended release (divalproex ER) vs placebo in combination with olanzapine or risperidone for the treatment of acute exacerbations of schizophrenia. In this 12-week, randomized, double-blind, parallel-group, multi-center trial, a total of 402 patients were randomized and treated; 103 received olanzapine/placebo, 99 received olanzapine/divalproex ER, 101 received risperidone/placebo, and 99 received risperidone/divalproex ER...
A preliminary controlled trial of divalproex in posttraumatic stress disorder. [2009.04]
BACKGROUND: Case reports and open trials have reported beneficial effects of divalproex in the treatment of posttraumatic stress disorder (PTSD). The objective of this study was to conduct a placebo-controlled study of the efficacy and tolerability of divalproex in chronic PTSD patients... CONCLUSIONS: Divalproex was not superior to placebo in this study. This could be due to lack of efficacy of divalproex in this population, inadequate sample size to detect differences, or other factors. Further study of divalproex is needed to better clarify the role of this agent in PTSD.
Comparative efficacy and safety of oxcarbazepine versus divalproex sodium in the treatment of acute mania: a pilot study. [2009.04]
CONCLUSION: Oxcarbazepine demonstrated comparable efficacy to divalproex sodium in the management of acute mania. Also the overall adverse event profile was found to be superior for oxcarbazepine.
Clinical Trials Related to Depakote ER (Divalproex)
Pediatric Switch Study for Children and Adolescent Patients With Epilepsy [Completed]
To assess the tolerability of switching from Depakote Sprinkle Capsules or Depakote tablets
to Depakote ER tablets in the pediatric population.
Valproate in Late Life Schizophrenia [Completed]
The purpose of this research study is to analyze the effectiveness and tolerability of a
medication, valproate ( Depakote and Depakote ER), in individuals age 50 years and older who
have schizophrenia.
A Comparison Study of the Efficacy and Tolerability of Depakote ER and Depakote DR [Completed]
To compare the time to response, response rates, remission rates, and side effects in Bipolar
Disorder inpatients treated with Depakote ER or Depakote DR for acute mania or mixed mania.
An Open Label, Double Blind Study Using Consecutive Intravenous Depacon With Oral Depakote ER for the Treatment of Cluster Headaches. [Completed]
The purpose of this study is to collect and evaluate information on the use of Depakote
Extended Release (ER) and Depacon Intravenous (IV) in patients with cluster headaches.
Patients who are currently in a cluster cycle will be treated with 2 consecutive days of IV
Depacon followed by oral Depakote ER. Patients will receive a total of 1,000mg of Depacon
and 1,000mg of Depakote ER each day. Patients may have a 3rd day of IV Depacon followed by
oral Depakote ER if the primary investigator believes it to be beneficial. The patient is
then sent home on oral Depakote ER. The dose of Depakote ER can range from 500mg to 2,000mg
this dose is to be determined by the primary investigator. The patient will continue the
oral Depakote ER until the end of their cluster cycle or for a maximum of 6 weeks, which ever
comes first.
Depakote Monotherapy, Olanzapine Monotherapy, and Combination Therapy of Depakote Plus Olanzapine in Stable Subjects During the Maintenance Phase of Bipolar Illness [Terminated]
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Page last updated: 2009-10-20
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