Valpros Pedia Special Precautions

General: Although there is no specific evidence on the sudden recurrence of underlying symptoms upon withdrawal of valproate treatment, there is a possibility of sudden alterations in the plasma concentrations, resulting to recurrence of symptoms. Therefore, antiepileptic drugs (AEDs), including sodium valproate, should be withdrawn gradually under the supervision of a specialist to avoid or minimize the potential for seizures or increased seizure frequency.
Hepatotoxicity: Severe liver damage, including hepatic failure, occurred in patients receiving valproate usually in the first 6 months of treatment, the period of maximum risk being 2 to 12 weeks. Some of these cases have been fatal. The frequency of adverse effects, particularly increased liver enzymes and thrombocytopenia, may increase with the dose. Non-specific symptoms (e.g., malaise, weakness, lethargy, facial edema, anorexia, somnolence, vomiting, abdominal pain, jaundice) may precede serious or fatal hepatotoxicity. Loss of seizure control leading to seizure recurrence is also observed in patients with epilepsy. These are indications for the immediate drug withdrawal. Transient increases in liver enzymes are also common, especially at the beginning of the treatment and in concurrent treatment with other anticonvulsants.
Clinical experience indicated that children under 2 years old are at considerably increased risk of developing fatal hepatotoxicity, especially those with taking multiple anticonvulsants, those with congenital metabolic disorders, severe seizure disorder associated with brain damage and/or mental retardation, with organic brain disease. Sodium valproate should be used in this population as a sole agent and with extreme caution. The benefits of the treatment should be weighed against the risks in these patients. The incidence of fatal hepatotoxicity decreases significantly with age.
Serum liver tests should be performed at baseline and at regular intervals thereafter during the first 6 months of treatment, especially at patients who are most at risk and those with history of liver disease. Physicians should not rely totally on serum biochemistry since the results of these tests may not be abnormal in all instances; the results of careful interim medical history and physical examination should also be considered. Tests reflecting protein synthesis (e.g., prothrombin time, serum fibrinogen, and albumin levels) should be performed to monitor high-risk patients. Treatment discontinuation should be considered if an abnormally low prothrombin rate, particularly in association with other biological abnormalities (e.g., significantly reduced fibrinogen and coagulation factors, increased bilirubin level and transaminases) was observed, and alternative medications should be considered to avoid precipitating convulsions. In several cases, discontinuation was followed by an uneventful recovery, but death has occurred in some patients even after drug withdrawal.
Patients or caregivers should be instructed to immediately report any signs of hepatotoxicity to a physician. Investigations such as clinical examination and biological evaluation of liver function should be undertaken immediately.
Teratogenicity: Valproate has a high teratogenic potential, and children exposed in utero are at high risk for major congenital malformations and neurodevelopmental disorders (see Use in Pregnancy & Lactation).
Use in Women of Childbearing Potential: Due to the risk of decreased IQ, neurodevelopmental disorders, and major congenital malformation to the fetus (including neural tube defects), sodium valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptoms control or are otherwise unacceptable. Women of childbearing potential should be informed regularly of the relative risks and benefits of valproate use during pregnancy. This is particularly important for women planning for pregnancy and for girls at the onset of puberty. Alternative therapeutic options should be considered in these patients.
The benefit and risk should be evaluated carefully every year, at puberty, and urgently when a woman of childbearing potential plans a pregnancy or becomes pregnant. The following should be considered in rare circumstances when valproate is the only treatment option available for women of childbearing potential: Individual circumstances are assessed and discussed with the patient to guarantee the engagement and understanding of the patient on the treatment options, including with its risks and the measures needed to mitigate the risks.
The potential for pregnancy is evaluated for all female patients.
All women of childbearing potential must be given advice by the specialist on the potential hazard of exposing the fetus to valproate in utero.
The patient should understand the necessity to undergo pregnancy testing before and during valproate therapy.
The patient should avoid being pregnant during the entire duration of valproate therapy.
The patient should understand the need for regular review of treatment by a specialist experienced in the management for epilepsy or bipolar disorders at least annually.
The patient should understand that she needs to consult her physician as soon as she is planning pregnancy. Every effort should be made to switch the patient to a more appropriate alternative treatment before conception. If switching is not possible, the patients should be further counselled on the risks of valproate for the unborn child to support her informed decision regarding family planning.
The patient should understand that she urgently needs to consult her physician in case of pregnancy.
The patient has acknowledged that she understood the risks and necessary precautions associated with valproate therapy.
These conditions also apply to women who are not sexually active, unless the prescriber considers that there are compelling and convincing reasons to indicate that there is no risk of pregnancy.
Pregnancy must be excluded before starting valproate treatment. Treatment must not be initiated in women of childbearing potential without a negative plasma pregnancy test result, validated by a health care provider, to rule out unintended use in pregnancy.
Use in Female Children: Valproate should only be used in female children if other treatment options are ineffective or not tolerated. The prescriber must ensure the following when sodium valproate is being prescribed to female children: Parents/children understand the need to contact the specialist once their child receiving valproate treatment experiences menarche.
Parents/caregivers of female children who have experienced menarche are provided with comprehensive information on the risks of major congenital malformations and neurodevelopmental disorders, including the magnitude of these risks for children exposed to valproate in utero.
The prescribing specialist must reassess the need for continuing valproate treatment annually in patients who have experienced menarche, and alternative treatment options should be considered. Every effort should be made by the specialist to switch the female children to alternative treatment before they reach adulthood.
Pancreatitis: There have been rare reports of pancreatitis, which may be severe and life-threatening. Some of the cases were hemorrhagic and rapidly progressed from initial symptoms to death. Pancreatitis occurred shortly after initial use as well as after several years of use. Children are at increased risk for pancreatitis. However, the risk decreased with increasing age. Patients on valproate treatment are at greater risk of developing pancreatitis than the general population. There have been reports in which pancreatitis recurred following rechallenge with valproate. Potential risk factors include severe seizures, neurological impairment or anticonvulsant polytherapy. Hepatic failure with pancreatitis increases the risk of a fatal outcome.
Patients and guardians should be warned of the symptoms indicative of pancreatitis (e.g., abdominal pain, nausea, vomiting, and/or anorexia) requiring prompt medical evaluation, including measurement of serum amylase. Treatment with sodium valproate is usually discontinued upon diagnosis of pancreatitis. Alternative treatment for the underlying medical condition should be started as clinically indicated.
Multi-organ Hypersensitivity Reaction: There have been rare reports of multi-organ hypersensitivity or drug rash with eosinophilia and systemic symptoms (DRESS). These cases were in close temporal association with the initiation of sodium valproate in adults and children, with a median time to detection of 21 days (range 1 to 40). Many of these cases resulted to hospitalization and at least one death has been reported. The signs and symptoms of this disorder were diverse, but patients typically presented with fever and rash associated with other organ system involvement not noted here. Early manifestations of hypersensitivity may be present even though rash is not evident. Other associated manifestations may sometimes resemble an acute viral infection and may include, but not limited to, lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, asthenia, myocarditis, and myositis.
The patient should be evaluated immediately if multi-organ hypersensitivity reaction is suspected. Treatment with sodium valproate should be discontinued and not be resumed if an alternative etiology for the signs and symptoms cannot be established. An alternative treatment should be initiated. It should be noted that cross sensitivity among drugs associated with multi-organ hypersensitivity reaction is possible.
Use in Patients with Preexisting Conditions: Patients with known or suspected mitochondrial disease: Valproate may produce or exacerbate clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA, as well as nuclear-encoded POLG gene. Particularly, the incidence of valproate-induced acute liver failure and resultant deaths have been increased in patients with hereditary neurometabolic syndromes due to DNA mutations of the mitochondrial DNA POLG (e.g., Alpers Huttenlocher Syndrome). Most of the cases of liver failure in patients with these syndromes occurred in children and adolescents.
POLG-related disorders should be suspected in patients with a family history or with symptoms suggestive of a POLG-related disorder, such as unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delay, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. The A467T and W748S mutations are present in about two-thirds of patients with autosomal recessive POLG-related disorders. POLG mutation testing should be conducted based on current clinical practice for the diagnostic evaluation of these disorders.
Sodium valproate should be used in patients over 2 years old who are clinically suspected of having a hereditary mitochondrial disease only after other anticonvulsants have failed. This older group of patients should be closely monitored for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should also be performed based on the current clinical practice.
Treatment should be discontinued immediately if significant hepatic dysfunction (suspected or apparent) have occurred. However, the progression of hepatic dysfunction even after discontinuation has been observed in some cases.
Patients infected with HIV and CMV: In vitro studies suggest that valproate stimulates the replication of the human immunodeficiency virus (HIV) and cytomegalovirus (CMV) under certain experimental conditions. The clinical consequences and the relevance of these in vitro findings are unknown for patients receiving maximally suppressive antiretroviral therapy (see Interactions). However, peripheral blood mononuclear cells from HIV-infected subjects demonstrated that sodium valproate does not have a mitogen-like effect on inducing HIV replication. The effect of sodium valproate in HIV has not been documented in man.
This data should be considered when interpreting the results from regular monitoring of the viral load in HIV-infected patients treated with valproate or when following CMV-infected patients clinically.
Urea Cycle Disorders (UCD): Cases of hyperammonemic encephalopathy has been reported upon initiation of sodium valproate treatment in patients with UCD, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Some of the reported cases were fatal.
Prior to treatment initiation, reevaluation for UCD should be considered in the following patients: with history of unexplained encephalopathy or coma, encephalopathy associated with protein load, pregnancy or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; with cyclical vomiting, lethargy, episodic extreme irritability, ataxia, low blood urea nitrogen (BUN), and protein avoidance; with family history of UCD or of unexplained infant deaths (particularly males); and with other signs and symptoms of UCD (e.g., hyperammonemia, encephalopathy, respiratory alkalosis). Evaluation for UCD should be considered before initiating sodium valproate treatment in these patients.
Patients who develop symptoms of unexplained hyperammonemic encephalopathy during valproate therapy should be treated as appropriate. Medical evaluation should be performed for the underlying UCD. Treatment discontinuation should be considered.
Suicidal Behavior and Ideation: Patients taking AEDs for any indications, including sodium valproate, have an increased risk of suicidal ideation and behavior. This increased risk was observed as early as the first week of starting AED treatment, and persisted for the duration of treatment. In a meta-analysis of randomized placebo-controlled trials, the risk of suicidal ideation and behavior was increased in patients with epilepsy than in patients who were given one of the drugs for psychiatric and other conditions. The mechanism of this risk is unknown, and available data does not exclude the possibility of an increased risk in patients taking sodium valproate.
Epilepsy and other illnesses for which AEDs are prescribed are also associated with morbidity, mortality, and an increased risk of suicidal ideation and behavior. Physicians considering to prescribe sodium valproate or any other AED must balance the risk of suicidal ideation and behavior with the risk of the untreated illness. All patients on AED treatment for any indications should be monitored for the emergence of worsening depression, and for signs of suicidal ideation and behavior. Patients and caregivers should be advised to seek medical advice if unusual changes in mood or behavior, or signs of self-harm or suicidal ideation or behavior develop. Appropriate treatment should be considered.
Interaction with concurrent treatment: Carbapenem antibiotics: The concurrent use of sodium valproate with carbapenem antibiotics is not recommended (see Interactions).
Enzyme inducers: Since sodium valproate may interact with enzyme inducers, periodic plasma concentrations of valproate and of the concurrent medications are recommended during the early course of the therapy (see Interactions).
Somnolence in the Elderly: Studies in elderly patients demonstrated that a significantly higher number of valproate-treated patients experienced somnolence. Dehydration also occurred in these patients. About one-half of the patients with somnolence had reduced nutritional intake and weight loss; these patients also had lower baseline albumin concentration, lower valproate clearance, and a higher blood urea nitrogen. Dosage adjustments must be performed to manage these adverse effects (see Dosage & Administration).
Coagulation Abnormalities: Treatment with sodium valproate is associated with thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which can lead to bleeding or other complications, particularly in cases of decrease in factors VII, VIII, and XIII. In a clinical trial on sodium valproate monotherapy in patients with epilepsy, 27% of patients who received approximately 50 mg/kg/day on average had at least one value of platelets ≤75 x 10⁹/L. Sodium valproate was discontinued in approximately half of these patients, with the platelet counts return to normal. In the remaining patients, platelet counts normalized with continued treatment. This study demonstrated that the probability of thrombocytopenia increased significantly at total valproate concentrations of ≥110 mcg/mL in women or ≥135 mcg/mL in men. The therapeutic benefits due to higher doses should be weighed against the risk of more frequent occurrence of adverse effects.
Decreases in other cell lines and myelodysplasia have been reported with sodium valproate. Some of the manifestations of coagulation abnormalities observed were mucosal bleeding (e.g., menorrhagia, epistaxis, hematuria, melena), easy bruising, soft tissue hematoma, hemarthrosis, and intracranial hemorrhage. Because of the inhibition of the secondary phase of platelet aggregation and abnormal coagulation parameters (e.g., low fibrinogen, coagulation factor deficiencies, acquired von Willebrand's disease), measurements of complete blood counts, and coagulation tests are recommended prior to treatment and at periodic intervals thereafter. Blood counts and coagulation parameters should also be monitored prior to planned surgery, during pregnancy (see Use in Pregnancy & Lactation), and in case of spontaneous bruising or bleeding. Dose reduction or treatment discontinuation should be considered if evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation emerged during treatment. Sodium valproate should also be coadministered with caution in patients on anticoagulant therapy (see Interactions).
Post-traumatic Seizures (for IV Administration only): It is prudent to avoid the use of sodium valproate in patients with acute head trauma for the prophylaxis of post-traumatic seizures. In a randomized study, the effects of IV valproate in the prevention of post-traumatic seizures in patients with acute head injuries were evaluated. Patients were randomly assigned either to the valproate group (given with IV valproate for 1 week, followed by oral valproate taken for either 1 or 6 months per randomized treatment assignment) or IV phenytoin given for 1 week, followed by placebo. The incidence of death was higher in patients in the valproate group compared to those in the IV phenytoin group (13% versus 8.5%, respectively). Many of these patients were critically ill, with multiple and/or severe injuries. However, the evaluation of causes of death did not specify any drug-related causation. In the absence of a concurrent placebo control in the initial week of IV treatment, it is not possible to determine if the mortality rate in valproate-treated patients was greater or less than expected in a similar group not treated by valproate, or whether the rate observed in the IV phenytoin-treated patients was lower than expected.
Hyperammonemia: Cases of hyperammonemia have been reported immediately after initiation of valproate treatment, even with normal liver function tests. Patients have rarely developed encephalopathy with or without fever, without evidence of hepatic dysfunction, or abnormal valproate concentrations, shortly after introduction of valproate treatment. Clinical manifestations include vomiting, ataxia, altered levels of consciousness or mental status with or without lethargy or coma. Hyperammonemia should also be considered in patients with hypothermia.
Patients suspected of hyperammonemic encephalopathy should have their serum ammonia levels measured. In cases of increased serum ammonia levels, treatment with sodium valproate should be discontinued and appropriate interventions should be initiated. The possibility of an underlying urea cycle disorders should be investigated. Asymptomatic elevations of serum ammonia are more common and require close monitoring of serum ammonia levels. If the elevation persists, treatment discontinuation should be considered.
Concomitant administration of sodium valproate with other drugs (e.g., topiramate, acetazolamide, phenobarbital, or phenytoin) has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone (see Interactions). In most cases, symptoms and signs subsided with the discontinuation of either drug.
Hypothermia: Hypothermia, or the unintentional drop in the core body temperature to <35°C (95°F), has been reported during sodium valproate therapy either with or without hyperammonemia. This adverse reaction also occurred in patients concurrently taking sodium valproate and topiramate (see Interactions). Hypothermia may be manifested by a variety of clinical abnormalities, including cardiovascular and respiratory systems. Clinical management should include the examination and correction of blood ammonia levels. Treatment discontinuation should be considered in patients who develop hypothermia.
Brain Atrophy: Cases of reversible and irreversible cerebral and cerebellar atrophy accompanied by neurological symptoms and cognitive decline have been reported in postmarketing experience in children, adults, and the elderly. The development of cerebral atrophy and associated signs and symptoms have been temporally associated with valproate therapy. In some cases, symptoms have disappeared upon treatment discontinuation; however, patients recovered with permanent sequelae. The motor and cognitive functions should be routinely monitored during valproate therapy, and the drug should be discontinued if signs of brain atrophy are suspected.
Rhabdomyolysis: Rhabdomyolysis independent of neuroleptic malignant syndrome, have been reported in patients treated with sodium valproate. Cases have included renal failure and fatalities.
Sodium valproate should be prescribed with caution in patients with predisposing risk factors for rhabdomyolysis, including those with prior history of muscular disorders (e.g., carnitine palmitoyltransferase type II deficiency), uncontrolled hypothyroidism, hepatic or renal impairment, and those concurrently taking medications associated with rhabdomyolysis (see Interactions).
Careful monitoring for signs and symptoms of rhabdomyolysis (e.g., muscle pain, tenderness, weakness, malaise, fever, and tea-colored urine) should be performed in patients on valproate therapy. Blood creatine phosphokinase (CPK) levels should be assessed in patients experiencing these symptoms. Treatment should be discontinued if CPK levels are significantly elevated, or if signs and symptoms indicative of rhabdomyolysis occurred.
Thyroid Gland Abnormalities: Increased serum thyroid stimulating hormone or decreased serum thyroxine levels were observed in children on valproate treatment. Hypothyroidism and hyperthyroidism were also reported in adults and children receiving valproate monotherapy.
Effects on Ability to Drive and Use Machines: Patients should be warned that sodium valproate may produce CNS depression and may affect the ability to drive or operate machines, especially in cases of concomitant use with other CNS depressants or anticonvulsants, administration of a high starting dose, or rapid dose escalation.
Use in Children: Children less than 2 years old are at significantly increased risk of developing fatal hepatotoxicity, especially those with risk factors (see Precautions). Sodium valproate should only be used in children with extreme caution as monotherapy. The benefits of the treatment should be carefully weighed against the risks.
It was observed in children with epilepsy older than 2 years old that the incidence of fatal hepatotoxicity significantly decreased with increasing age. In addition, valproate should only be used children in this age group who are clinically suspected of having a hereditary mitochondrial disease after other anticonvulsants have failed.
Younger children receiving valproate with other enzyme-inducing drugs will require larger maintenance dose to achieve the targeted total and unbound valproate concentrations (see Dosage & Administration).
The variability in free fraction limits the clinical usefulness of monitoring the total serum valproate concentrations. Factors that affect the hepatic metabolism and protein binding should be considered in the interpretation of valproate concentrations in children.
Use in the Elderly: Dosage in the elderly should be adjusted carefully since the pharmacokinetics of sodium valproate are altered in this population. Dosage should be determined by seizure control. In a case review, higher percentage of patients older than 65 years old have reported accidental injury, infection, pain, somnolence or tremor, compared to younger patients. Discontinuation of treatment was occasionally associated with somnolence or tremor. It is not clear if these events indicate additional risks of drug therapy, or if these events resulted from preexisting conditions or concurrent medications used in the elderly.
Studies in elderly patients demonstrated that a significantly higher number of valproate-treated patients experienced somnolence (see Precautions).
The efficacy and safety of sodium valproate has not been evaluated in elderly patients with epilepsy. Since elderly patients have more frequent hepatic and renal dysfunctions, dose selection should be performed with caution.