Depakene Special Precautions

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 applied when administering divalproex sodium/valproate/valproic acid products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, those with congenital metabolic disorders including mitochondrial disorders such as carnitine deficiency, urea cycle disorders, POLG mutations (see as follows), 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 three years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When divalproex sodium/valproate/valproic acid is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy (seizure control) 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 of therapy, especially in patients at risk (refer to Interactions). 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/valproate/valproic acid 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/valproate/valproic acid. 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. Patients and guardians experiencing abdominal pain, nausea, vomiting, and/or anorexia should be warned that these could 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.
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/valproate/valproic acid 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.
Use in males of reproductive potential: A retrospective observational study suggests an increased risk of neurodevelopmental disorders (NDDs) in children born to men treated with valproate in the 3 months prior to conception, compared with the risk in those born to men treated with lamotrigine or levetiracetam (see Use in Pregnancy & Lactation).
Despite study limitations, by way of precautions, the prescriber should inform the male patients of this potential risk and consider whether valproate remains the most appropriate treatment.
The prescribers should discuss with the patient, the need for effective contraception, including for the female partner, while using valproate and for 3 months after stopping the treatment.
The study did not evaluate the risk of neurodevelopmental disorders in children born to fathers who stopped using valproate more than 3 months before conception.
The male patient should be advised: not to donate sperm during treatment and for 3 months after stopping the treatment, of the need to consult his doctor to discuss alternative treatment options, as soon as he is planning to father a child, and before discontinuing contraception, that he and his female partner should contact their doctor for counseling in case of pregnancy if he used valproate within 3 months prior to conception.
The treatment in male patient should be initiated and supervised by a specialist in the management of epilepsy, bipolar disorder, or migraine.
There is the need for regular reviews by physician to assess if valproate remains the most appropriate treatment for the patient and discuss suitable treatment alternatives with the patient. This is particularly important if the male patient is planning to conceive a child and, in this case, before discontinuing contraception.
The Marketing Authorization Holder provides educational materials to healthcare professionals. A patient guide should be provided to all men of reproductive potential using valproate.
Hyperammonemia: Hyperammonemia has been reported in association with divalproex sodium/valproate sodium/valproic acid 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/valproate sodium/valproic acid 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 Precautions).
Asymptomatic elevations of ammonia are more common and, when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproic acid therapy should be considered.
Urea Cycle Disorders (UCD) hyperammonemia: 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: 1) 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; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) 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 section Contraindications, Hyperammonemia, and Encephalopathy Associated with Concomitant Topiramate Use, Patients at risk of hypocarnitinemia as follows and Hepatotoxicity/Hepatic dysfunction as previously mentioned).
Patients at risk of hypocarnitinemia: Valproate administration may trigger occurrence or worsening of hypocarnitinemia that can result in hyperammonemia (that may lead to hyperammonemic encephalopathy). Other symptoms such as liver toxicity, hypoketotic hypoglycemia, myopathy including cardiomyopathy, rhabdomyolysis, Fanconi syndrome have been observed, mainly in patients with risk factors for hypocarnitinemia or pre-existing hypocarnitinemia. Valproate may decrease carnitine blood and tissue levels and therefore impair mitochondrial metabolism including the mitochondrial urea cycle. Patients at increased risk for symptomatic hypocarnitinemia when treated with valproate include patients with metabolic disorders including mitochondrial disorders related to carnitine (see also Warnings on Patients with known or suspected mitochondrial disease and urea cycle disorders and risk of hyperammonemia), impairment in carnitine nutritional intake, patients younger than 10 years old, concomitant use of pivalate-conjugated medicines or of other antiepileptics.
Patients should be warned to report immediately any signs of hyperammonemia such as ataxia, impaired consciousness, vomiting for further investigation. Carnitine supplementation should be considered when symptoms of hypocarnitinemia are observed.
Patients with known systemic primary carnitine deficiency and corrected for hypocarnitinemia should be treated with valproate only if the benefits of valproate treatment outweigh the risks in these patients and there is no suitable therapeutic alternative. In these patients, close monitoring for recurrence of hypocarnitinemia should be implemented.
Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when taking valproate. Carnitine supplementation should be considered in these patients (see also Interactions, Adverse Reactions and Overdosage).
Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use: 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 previously mentioned).
Hypothermia: Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with divalproex sodium/valproate/valproic acid therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate 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: There have been post marketing reports of 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 tests: 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/valproate sodium/valproic acid 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/valproate 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/valproate/valproic acid is partially eliminated in the urine as a keto-metabolite 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/valproate 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).
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.
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.
It seems prudent not to use valproate sodium in patients with acute head trauma for the prophylaxis of posttraumatic seizures until further information is available.
Multi-Organ Hypersensitivity Reactions: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multi-organ hypersensitivity reactions, has 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, hepato-renal 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 Female patients: Since divalproex sodium/valproate/valproic acid has been associated with certain types of birth defects and developmental risk, female patients of childbearing age considering the use of divalproex sodium/valproate/valproic acid should be advised of the risks associated with the use of divalproex sodium/valproate/valproic acid during pregnancy (see Precautions).
Aggravated convulsions: As with other antiepileptic drugs, some patients may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately.
Information related to excipients: This medicinal product contains 3 g of sucrose per 5 ml dose sucrose. This should be taken into account in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
May be harmful to the teeth.
This medicinal product contains Propylhydroxybenzoate E216 and Methylhydroxybenzoate E218. Those may cause allergic reactions (possibly delayed).
This medicinal product contains Sorbitol Solution E420.
Patients with rare hereditary problems of fructose intolerance should not take this medicine.
This medicinal product contains E123, amaranth. This may cause allergic reactions.
Effects on Ability to Drive and Use Machines: Since Divalproex sodium/Valproate/Valproic Acid 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 with oral valproate 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 (see Hepatotoxicity as previously mentioned). When divalproex sodium/valproate/valproic acid injection 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.
In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium/valproate/valproic acid should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with divalproex sodium/valproate/valproic acid for the development of acute liver injury with regular clinical assessments and liver function test monitoring.
The basic toxicology and pathologic manifestations of valproate sodium in neonatal (4-day old) and juvenile (14-day old) rats are similar to those seen in young adult rats. However, additional findings, including renal alterations in juvenile rats and renal alterations and retinal dysplasia in neonatal rats, have been reported. These findings occurred at 240 mg/kg/day, a dosage approximately equivalent to the human maximum recommended daily dose on a mg/m² basis. They were not seen at 90 mg/kg, or 40% of the maximum human daily dose on a mg/m² basis.
Use in the Elderly: No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.
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).