Valpros/Valpros i-IV Special Precautions

Valpros: 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 done prior to therapy and at frequent intervals thereafter, particularly during the first six months. 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 observed when administering valproate products to patients with 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.
In progressively older patient groups, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.
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. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents.
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 done in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.
Sodium valproate + valproic acid 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.
Pancreatitis: Young children are at particular risk but this risk decreases with increasing age. Severe seizures, neurological impairment or anticonvulsant polytherapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome.
Urea Cycle Disorders (UCD): Sodium valproate + valproic acid is contraindicated in patients with known UCD.
Hyperammonemic encephalopathy, sometimes fatal, has been reported after initiation of valproate therapy in patients with UCD, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase (OTC) deficiency. Prior to the 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 a 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 blood urea nitrogen (BUN), or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); and 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 UCD.
Ornithine Transcarbamylase Deficiency: The females who are heterozygous for OTC deficiency have a spectrum of clinical and biochemical findings, depending on the extent of inactivation of the X-chromosome. Females may show a range of symptoms due to hyperammonemia which, may be episodic, and therefore difficult to diagnose. The acute symptoms include headaches, vomiting, irritability, bizarre behavior, lethargy, ataxia, tremors, seizures (generalized tonic-clonic or focal) and coma. Valproate may precipitate hyperammonemia symptoms in those who have pre-existing OTC deficiency. As the symptoms may include seizures, any female with valproate-associated symptomatic hyperammonemia should be evaluated for OTC deficiency. Investigations should include measurement of plasma amino acids and the immediate cessation of valproate should result in clinical improvement.
Hyperammonemia: There has been report of hyperammonemia in association with valproate 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 should be measured. Hyperammonemia should also be considered in patients who present with hypothermia. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying UCD.
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.
Concomitant use of topiramate and valproate 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 levels of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to 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. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
Hypothermia: Hypothermia, defined as an unintentional drop in body 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 valproate after starting topiramate treatment or after increasing the daily dose of topiramate. 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.
Suicidal Behavior and Ideation: AEDs, including sodium valproate + valproic acid, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Anyone considering prescribing 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 mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior 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, their caregivers, and families 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 thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Thrombocytopenia: The frequency of adverse effects, particularly elevated liver enzymes and thrombocytopenia, may be dose-related. Because of reports of thrombocytopenia, 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. It is recommended that patients receiving sodium valproate + valproic acid be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
Weight Gain: Patients should be warned of the risk of weight gain at the initiation of therapy, and appropriate strategies should be adopted to minimize the risk.
Surgery: Prolongation of bleeding time, sometimes with thrombocytopenia, has occurred with valproate therapy. Platelet function should be monitored before surgery is undertaken in patients receiving sodium valproate + valproic acid.
Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding.
Multi-Organ Hypersensitivity Reactions: Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). 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 among drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.
Carnitine Palmitoyltransferase (CPT) Type II Deficiency: Patients with an underlying CPT type II deficiency should be warned of the greater risk of rhabdomyolysis when taking valproate.
Monitoring Drug Plasma Concentration: Periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy since valproate may interact with concurrently administered drugs which are capable of enzyme induction.
Abrupt withdrawal: The possible risk of fits after sudden cessation of sodium valproate + valproic acid should be considered. If it is the only anticonvulsant used and has to be withdrawn for more than 12 hours because of surgery, control of epilepsy may be lost.
Effect on Ability to Drive or Operate Machinery: Use of sodium valproate + valproic acid may provide seizure control such that the patient may be eligible to hold a driving license. However, patients should be warned of the risk of transient drowsiness, particularly in cases of anticonvulsant polytherapy, too high starting dose, too rapid dose escalation, or association with benzodiazepines.
Use in Children: The potential benefit of sodium valproate + valproic acid should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy. The concomitant use of salicylates should be avoided in children under 3 years old due to the risk of liver toxicity and the concomitant use of barbiturates may require dosage adjustment. Monotherapy is recommended in these children, when prescribing sodium valproate + valproic acid. Young children are at particular risk for pancreatitis; however, this risk decreases with increasing age. The safety and efficacy of sodium valproate for the treatment of manic episodes in bipolar disorder have not been evaluated in patients less than 18 years old.
Use in the Elderly: A study involving elderly patients with dementia, a significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patient with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and higher blood urea nitrogen (BUN). In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence.
Valpros i-IV: Hepatotoxicity (see Warnings): The incidents usually occurred during the first six months of therapy, the period of maximum risk being 2 to 12 weeks, and usually involved multiple anticonvulsant therapy. Monotherapy is to be preferred in this group of patients; the benefits of therapy should be weighed against the risks. Clinical symptoms are usually more helpful than laboratory investigations in the early stages of hepatic failure. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms, usually of sudden onset, such as loss of seizure control, malaise, weakness, lethargy, facial edema, anorexia, vomiting, abdominal pain, drowsiness, and jaundice. These are indications for immediate withdrawal of the medicine. Patients should be monitored closely for appearance of these symptoms and should be instructed to report any such signs to the clinician for investigation should they occur. Liver function tests should be done prior to therapy and at frequent intervals thereafter until 6 months after the controlling dose is reached, when less frequent monitoring may be appropriate. It is also advisable to monitor tests which reflect protein synthesis, e.g., prothrombin time, serum fibrinogen and albumin levels, particularly in those who seem most at risk and those with a prior history of hepatic disease. 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.
Raised liver enzymes are not uncommon during treatment with valproate, particularly if used in conjunction with other anticoagulants, and are usually transient or respond to dosage reduction. Patients with such biochemical abnormalities should be reassessed clinically and tests of liver function should be monitored more frequently. An abnormally low prothrombin rate, particularly in association with other relevant abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of treatment and the substitution of alternative medicines to avoid precipitating convulsions. Uneventful recovery has been recorded in several cases where therapy with valproate has ceased, but death has occurred in some patients in spite of the medicine being withdrawn.
Sodium valproate 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.
Pancreatitis (see Warnings): Severe pancreatitis, which may result in fatalities, has been very rarely reported. Some cases have occurred shortly after initial use while others have occurred after several years of use. There have also been cases in which pancreatitis recurred after rechallenge with sodium valproate.
Young children are at particular risk but this risk decreases with increasing age. Severe seizures, neurological impairment or anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome.
Urea Cycle Disorders (UCD): The use of valproate in patients with known UCD (a group of uncommon genetic abnormalities) is contraindicated. Hyperammonemic encephalopathy, which is sometimes fatal, has been reported after initiation of valproate in patients with UCD particularly ornithine transcarbamylase deficiency.
Metabolic investigations should be done prior to treatment. Evaluation for UCD should be considered in the following patients: 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; Signs and symptoms of UCD [e.g., cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low blood urea nitrogen (BUN), protein avoidance]; Family history of UCD or a family history of unexplained infant deaths (particularly males); 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 UCD.
Hyperammonemia: Hyperammonemia, which may be present in the absence of abnormal liver function tests, can occur in patients during valproate therapy.
Likewise, concomitant use of valproate with topiramate has been shown to produce hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. This adverse event is not due to 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 increased risk for hyperammonemia with or without encephalopathy.
Hyperammonemia may occasionally present clinically, with or without lethargy or coma, as vomiting, ataxia and increasing clouding of consciousness. Should these symptoms occur, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for the treatment of hyperammonemia should be initiated.
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including sodium valproate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence of worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Anyone considering prescribing sodium valproate or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior 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, their caregivers and families 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 thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Post-traumatic Seizure: Sodium valproate injection should not be used in patients with acute head trauma for the prophylaxis of post-traumatic seizures.
Hypothermia: Hypothermia, an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with sodium valproate therapy both in conjunction with and in the absence of hyperammonemia. Hypothermia may be manifested by a variety of clinical abnormalities such as lethargy, confusion, coma, and significant alterations in other major organ systems (i.e., cardiovascular and respiratory). Consideration should be given to discontinuing valproate therapy in patients who develop hypothermia. Examination of blood ammonia levels should be included in the clinical management and assessment of patient.
Weight Gain: Patients should be warned of the risk of weight gain at the initiation of therapy, and appropriate strategies should be adopted to minimize the risk.
Multi-organ Hypersensitivity Reaction: Although there have been rare reports of multi-organ hypersensitivity reactions associated with valproate therapy in adult and pediatric patients (median time to detection 21 days; range 1 to 40 days), many of these cases resulted in hospitalization and even death. Patients typically presented with fever and rash associated with other organ system involvement. If this reaction is suspected, sodium valproate should be discontinued and an alternative treatment should be started.
Serious Skin Reactions: Serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with concomitant lamotrigine and sodium valproate use.
Thrombocytopenia: The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of 110 mcg/mL or greater (females) or 135 mcg/mL or greater (males). Blood tests (e.g., blood cell count, including platelet count, bleeding time and coagulation tests) are recommended before initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding. Evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of sodium valproate dose or withdrawal of therapy.
Lupus erythematosus: Although immune disorders have been noted only exceptionally during the use of sodium valproate, the potential benefit of sodium valproate should be weighed against its potential risk in patients with systemic lupus erythematosus.
Effects on Ability to Drive and/or Operate Machines: Since valproate may produce central nervous system (CNS) depression, particularly when combined with another CNS depressant such as alcohol, patients should be warned that sodium valproate may impair ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery or driving a motor vehicle).
HIV and CMV viruses Replication: In vitro studies showed that valproate stimulates the replication of the human immunodeficiency virus (HIV) and cytomegalovirus (CMV) viruses under certain experimental conditions. The clinical consequence, if any, is not known. However, these data should be considered when interpreting the results from regular monitoring of the viral load in HIV-infected patients taking sodium valproate or when following CMV-infected patients clinically.
Abrupt Withdrawal: The possible risk of convulsions after sudden cessation of sodium valproate injection should be considered. If it is the only anticonvulsant used and has to be withdrawn for more than 12 hours because of surgery, control of epilepsy may be lost.
Use in Children: The safety of intravenous sodium valproate has not been studied in children below 2 years old. If a decision is made to use sodium valproate injection in this age group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks.
The safety and efficacy of sodium valproate for the treatment of manic episodes in bipolar disorder have not been evaluated in patients below 18 years old.
Use in the Elderly: A case review study showed that a higher percentage of patients above 65 years old reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with somnolence and tremor. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant drug use among these patients.
A study in elderly patients with dementia showed 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.
No unique safety concerns were identified in patients >65 years old receiving intravenous sodium valproate.