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boxed warning
WARNING: LIFE THREATENING ADVERSE REACTIONS WARNING: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. 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 ( 5.1 ) Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ ( 5.2 , 5.3 , 5.4 ) Pancreatitis, including fatal hemorrhagic cases ( 5.5 ) Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. 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. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions ( 5.1 )] . 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 divalproex sodium extended-release tablets are 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. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g., Alpers Huttenlocher Syndrome). Divalproex sodium extended-release tablets are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically susp...
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warnings and cautions
5 WARNINGS AND PRECAUTIONS 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 ( 5.2 , 5.3 , 5.4 ) Pancreatitis: Divalproex sodium extended-release tablets should ordinarily be discontinued ( 5.5 ) Suicidal behavior or ideation: Antiepileptic drugs, including divalproex sodium extended-release tablets, 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 reactions, serious dermatologic reactions, and angioedema: Discontinue divalproex sodium extended-release tablets unless an alternate etiology is established ( 5.12 , 5.13 , 5.14 ) 5.1 Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. 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. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months of valproate therapy. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be obs...
warnings and cautions table
Table 2. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9
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adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (reported > 15% for any indication) are abdominal pain, alopecia, asthenia, diarrhea, diplopia, dizziness, dyspepsia, headache, infection, insomnia, nausea, somnolence, thrombocytopenia, tremor, vomiting ( 6.1 , 6.2 , 6.3 ). 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 Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are described below and elsewhere in the labeling: Hepatic Failure [see Warnings and Precautions ( 5.1 )] Birth Defects [see Warnings and Precautions ( 5.2 )] Decreased IQ and Neurodevelopmental Disorders following in utero exposure [see Warnings and Precautions ( 5.3 )] Pancreatitis [see Warnings and Precautions ( 5.5 )] Hyperammonemic Encephalopathy [see Warnings and Precautions ( 5.6 , 5.9 , 5.10 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.7 )] Bleeding and Other Hematopoietic Disorders [see Warnings and Precautions ( 5.8 )] Hypothermia [see Warnings and Precautions ( 5.11 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions ( 5.12 )] Serious Dermatologic Reactions [see Warnings and Precautions ( 5.13 )] Angioedema [see Warnings and Precautions ( 5.14 )] Somnolence in the Elderly [see Warnings and Precautions ( 5.16 )] 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. Information on pediatric adverse reactions is presented in section 8. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of divalproex sodium extended-release tablets in the treatment of manic episodes associated with bipolar disorder. Table 3 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the divalproex sodium extended-release tablet-treated group was greater than 5% and greater than the placebo incidence. Table 3. Adverse Reactions Reported by > 5% of Di...
adverse reactions table
Table 3. Adverse Reactions Reported by > 5% of Divalproex Sodium Extended-Release Tablets-Treated Patients During Placebo-Controlled Trials of Acute Mania11The following adverse reactions/event occurred at an equal or greater incidence for placebo than for divalproex sodium extended-release tablets: headache Adverse Event Divalproex Sodium Extended-Release Tablets (n=338) % Placebo (n=263) % Somnolence 26 14 Dyspepsia 23 11 Nausea 19 13 Vomiting 13 5 Diarrhea 12 8 Dizziness 12 7 Pain 11 10 Abdominal Pain 10 5 Accidental Injury 6 5 Asthenia 6 5 Pharyngitis 6 5