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Hepatotoxicity/Hepatic dysfunction: Conditions of occurrence: Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. These incidents usually have occurred during the first six months of treatment.
Caution should be observed when administering Divalproex sodium products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When divalproex sodium 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. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Suggestive signs: 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.
Detection: Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, physicians 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. The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug (see CONTRAINDICATIONS).
Patients with known or suspected mitochondrial disease: Valproate induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes [see CONTRAINDICATIONS].
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Divalproex sodium for the development of acute liver injury with regular clinical assessments and liver function test monitoring.
Pancreatitis: Cases of life-threatening pancreatitis have been reported in both children and adults receiving Divalproex sodium. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with Valproate. There were cases of pancreatitis without alternative etiology. Patients and guardians experiencing abdominal pain, nausea, vomiting, and/or anorexia should be warned that this could be a symptom of pancreatitis that requires 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.
Suicidal Behavior and Ideation: An increase in the risk of suicidal thoughts or behavior in patients taking antiepileptic drugs AEDs for any indication has been reported. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Divalproex sodium or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and an increase risk of suicidal thoughts and behavior. Should suicidal thoughts and behaviors emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, (and caregivers of patients), should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thought about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Interaction with Carbapenem Antibiotics: The concomitant use of INN and carbapenem agents is not recommended [see Carbapenem Antibiotics under INTERACTIONS].
Thrombocytopenia - [see General as follows].
Hyperammonemia: Hyperammonemia has been reported in association with divalproex sodium therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level measured. Hyperammonemia should also be considered in patients who present with hypothermia [see Hypothermia as follows]. If ammonia is increased, divalproex sodium therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see CONTRAINDICATIONS and as follows].
Asymptomatic elevations of ammonia are more common and, when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.
Urea Cycle Disorders (UCD): Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to initiation of valproate therapy, evaluation for UCD should be considered in the following patients: Those with a history of unexplained encephalopathy or coma, encephalopathy associated with protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; Those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, protein avoidance; Those with a family history of UCD or a family history of unexplained infant deaths (particularly males); Those with other signs or symptoms of UCD.
Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders [see CONTRAINDICATIONS and Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use as follows].
Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use: Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Hypothermia as follows]. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia.
Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons [see CONTRAINDICATIONS and Urea Cycle Disorders and Hyperammonemia as follows].
Hypothermia: Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with Divalproex sodium after starting topiramate treatment or after increasing the daily dose of topiramate [see Topiramate under INTERACTIONS and Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use and Hyperammonemia as previously mentioned]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.
Brain Atrophy: Reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use valproate products; in some cases, patients recovered with permanent sequelae [see ADVERSE REACTIONS]. The motor and cognitive functions of patients on valproate should be routinely monitored and drug should be discontinued in the presence of suspected or apparent signs of brain atrophy. Reports of cerebral atrophy with various forms of neurological problems including developmental delays and psychomotor impairment have also been reported in children who were exposed in-utero to valproate products [see USE IN PREGNANCY & LACTATION].
General: Laboratory test: Because of reports of thrombocytopenia [see Thrombocytopenia as previously mentioned], inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters (e.g., low fibrinogen), platelet counts, and coagulation tests are recommended before initiating therapy and at periodic intervals. Prior to planned surgery it is recommended that patients receiving divalproex sodium be monitored for platelet count and coagulation parameters. Evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Since Divalproex Sodium may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see INTERACTIONS]. Divalproex Sodium is partially eliminated in the urine as a ketometabolite that may lead to a false interpretation of the urine ketone test. There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown.
Recommendations: Evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Since Divalproex Sodium may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see INTERACTIONS].
Valproate stimulates the replication of HIV and CMV viruses under certain conditions. However, this is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, this should be noted when the results of routine viral load monitoring in HIV-infected patients are receiving valproate or when following clinically CMV-infected patients.
Patients with an underlying carnitine palmitoyl transferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when taking valproate. The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The therapeutic benefit that may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.
Multi-Organ Hypersensitivity Reactions: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multi-organ hypersensitivity reactions have been rarely reported in close temporal association after the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days; range 1 to 40). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported.
Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepatorenal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs not noted here may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.
INFORMATION FOR PATIENTS: Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia could be symptoms of pancreatitis and, therefore, require further medical evaluation promptly.
Patients and guardians should be informed of the signs and symptoms associated with hyperammonemic encephalopathy [see Hyperammonemia as previously mentioned] and be told to inform the prescriber if any of these symptoms occur.
Information for Female Patients: Since divalproex sodium has been associated with certain types of birth defects and developmental risk, female patients of childbearing age considering the use of Divalproex Sodium should be advised of the risks associated with the use of Divalproex Sodium during pregnancy [see Female children/Female adolescents/Women of childbearing potential/Pregnancy under WARNINGS].
Medication residue in the stool: There have been rare reports of medication residue in the stool, some of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients' clinical condition should be monitored. If clinically indicated, alternative treatment may be considered.
Effects on ability to drive and use machines: Since divalproex sodium may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.
Use in Children: Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Hepatotoxicity as previously mentioned]. When Divalproex Sodium 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. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.
The safety and effectiveness of Divalproex Sodium for the treatment of acute mania has not been studied in individuals below the age of 18 years.
The safety and effectiveness of Divalproex Sodium for the prophylaxis of migraines has not been studied in individuals below the age of 16 years.
Use in the Elderly: Patients over the age of 65 have higher percentage to accidental injury, infection, pain, somnolence, and tremor.
Somnolence in the elderly: A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see DOSAGE & ADMINISTRATION].
In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse events. Dose reductions or discontinuation of Valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see DOSAGE & ADMINISTRATION].
